Managing adverse effects of immunotherapy.

PubMed

Gerson, James N; Ramamurthy, Chethan; Borghaei, Hossein

2018-05-01

Remarkable efficacy has been achieved in a variety of cancer types by targeting immune checkpoints. The cytotoxic T-lymphocyte-associated antigen 4 inhibitor ipilimumab, the programmed death 1 inhibitors nivolumab and pembrolizumab, and the programmed death ligand 1 inhibitors atezolizumab, avelumab, and durvalumab are the agents currently approved by the US Food and Drug Administration for the treatment of certain advanced malignancies. These agents mark a departure from both standard cytotoxic chemotherapy and targeted therapy. However, they are associated with a unique set of immune-related adverse events (irAEs), which can manifest as a wide range of autoimmune phenomena. The irAEs can affect any system in the body and in rare cases are life-threatening. It is critical for the practicing medical oncologist to recognize and promptly treat any irAEs that may develop.

Targeting the Immune System’s Natural Response to Cell Death to Improve Therapeutic Response in Breast Cancers

DTIC Science & Technology

2015-07-01

epithelial cells (MECs) are cleared from the mammary gland through efferocytosis, a process by which macrophages and other phagocytes recognize, bind to...chronic inflammatory lung disease. Chest. 2006;129(6):1673–1682. 48. deCathelineau AM, Henson PM. The final step in programmed cell death: phagocytes ...carry apoptotic cells to the grave. Essays Biochem. 2003;39:105–117. 49. Erwig LP, Henson PM. Clearance of apop- totic cells by phagocytes . Cell Death

Economic Appraisal of Ontario's Universal Influenza Immunization Program: A Cost-Utility Analysis

PubMed Central

Sander, Beate; Kwong, Jeffrey C.; Bauch, Chris T.; Maetzel, Andreas; McGeer, Allison; Raboud, Janet M.; Krahn, Murray

2010-01-01

Background In July 2000, the province of Ontario, Canada, initiated a universal influenza immunization program (UIIP) to provide free seasonal influenza vaccines for the entire population. This is the first large-scale program of its kind worldwide. The objective of this study was to conduct an economic appraisal of Ontario's UIIP compared to a targeted influenza immunization program (TIIP). Methods and Findings A cost-utility analysis using Ontario health administrative data was performed. The study was informed by a companion ecological study comparing physician visits, emergency department visits, hospitalizations, and deaths between 1997 and 2004 in Ontario and nine other Canadian provinces offering targeted immunization programs. The relative change estimates from pre-2000 to post-2000 as observed in other provinces were applied to pre-UIIP Ontario event rates to calculate the expected number of events had Ontario continued to offer targeted immunization. Main outcome measures were quality-adjusted life years (QALYs), costs in 2006 Canadian dollars, and incremental cost-utility ratios (incremental cost per QALY gained). Program and other costs were drawn from Ontario sources. Utility weights were obtained from the literature. The incremental cost of the program per QALY gained was calculated from the health care payer perspective. Ontario's UIIP costs approximately twice as much as a targeted program but reduces influenza cases by 61% and mortality by 28%, saving an estimated 1,134 QALYs per season overall. Reducing influenza cases decreases health care services cost by 52%. Most cost savings can be attributed to hospitalizations avoided. The incremental cost-effectiveness ratio is Can$10,797/QALY gained. Results are most sensitive to immunization cost and number of deaths averted. Conclusions Universal immunization against seasonal influenza was estimated to be an economically attractive intervention. Please see later in the article for the Editors' Summary PMID:20386727

Symptoms of internalizing and externalizing problems: modeling recovery curves after the death of a parent.

PubMed

Schmiege, Sarah J; Khoo, Siek Toon; Sandler, Irwin N; Ayers, Tim S; Wolchik, Sharlene A

2006-12-01

The death of a parent is a major family disruption that can place children at risk for later depression and other mental health problems. Theoretically based randomized controlled trial for parentally bereaved children. Two-hundred and forty-four children and adolescents and their caregivers from 156 families were randomly assigned to the Family Bereavement Program (FBP) intervention condition (90 families; 135 children) or to a control condition (66 families; 109 children). Data collection occurred from 1996 to 1998. Children and caregivers in the intervention condition met separately for 12 two-hour weekly sessions. Skills targeted by the program for children included positive coping, stress appraisals, control beliefs, and self-esteem. The caregiver program targeted caregiver mental health, life stressors, and improved discipline in the home. Both child and caregiver programs focused on improved quality of the caregiver-child relationship. Child and caregiver reports of internalizing and externalizing symptoms. Longitudinal growth curve modeling was performed to model symptoms over time from the point of parental death. The rate of recovery for girls in the program condition was significantly different from that of girls in the control condition across all outcomes. Boys in both conditions showed reduced symptoms over time. The methodology offers a conceptually unique way of assessing recovery in terms of reduced mental health problems over time after an event and has contributed to further understanding of FBP intervention effects. The intervention program facilitated recovery among girls, who did not show reduction in behavior problems without the program, while boys demonstrated decreased symptoms even without intervention.

[Parental death in childhood: the state of theoretical knowledge and clinical challenges in the future].

PubMed

Mentec, Margaux; Flahault, Cécile

2015-03-01

Although children's psychological adaptation to parental cancer is a wide field for psycho-oncological research, few empirical studies target children bereavement specifically following parental cancer. In this paper, our purpose is to make a state of art about literature concerning parental death. Literature dealing with grief concerns psychopathological consequences of parental loss and most recently post-traumatic growth. Although references about support programs have emerged, few of these programs have been scientifically evaluated. This review underlines that more studies are needed with prospective quantitative and qualitative studies, in order to describe more precisely children bereavement process and long term effects of bereavement. Psychological support for other family members and evaluation of support programs seem to be critical to improve children adaptation to parental death. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Combining chemotherapy with PD-1 blockade in NSCLC.

PubMed

Mathew, Matthen; Enzler, Thomas; Shu, Catherine A; Rizvi, Naiyer A

2018-06-01

Antitumor immunity relies on the ability of the immune system to recognize tumor cells as foreign and eliminate them. An effective immune response in this setting is due to surveillance of tumor-specific antigens that induce an adaptive immune response resulting in T-cell mediated cytotoxicity. Immune checkpoint inhibitors, specifically those targeting the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis, have demonstrated promising activity in non-small cell lung cancer (NSCLC). However, there remains a crucial need for better treatment strategies for the majority of patients with advanced NSCLC, particularly in the frontline setting. Chemotherapy can increase antigenicity via immunogenic cell death (ICD) of tumor cells as well as also reduce "off target" immunosuppression in the tumor microenvironment (TME). Combining chemotherapy with PD-1 blockade harnesses the potential synergy between these agents and has led to encouraging results in the up-front treatment of NSCLC. In this review, we summarize the preclinical rationale behind these combinations and review recent trial data demonstrating their efficacy. Copyright © 2018. Published by Elsevier Inc.

From surveillance to action: early gains from the National Violent Death Reporting System.

PubMed

Campbell, R; Weis, M A; Millet, L; Powell, V; Hull-Jilly, D; Hackman, H

2006-12-01

Drawing from the experiences of individual state programs that currently participate in the National Violent Death Reporting System (NVDRS), this article reviews some of the practical benefits that may accrue from the introduction of violent death surveillance systems. As a state-based surveillance system that uses multiple data sources and relies upon multiple stakeholders, the NVDRS program has fostered an array of initiatives within and among individual state programs. State-based initiatives highlighted in this article were selected on the basis of a purposive sampling strategy intended to illustrate key aspects of program development. The NVDRS state programs are in Alaska, California, Colorado, Georgia, Kentucky, Maryland, Massachusetts, New Jersey, New Mexico, North Carolina, Oklahoma, Oregon, Rhode Island, South Carolina, Utah, Virginia, and Wisconsin. The NVDRS has helped to build alliances and collaborative efforts between key stakeholders, facilitated the recognition of violent death as a public health problem through outreach and media attention, acted as a catalyst for new projects, enhanced surveillance of special populations and utility for evaluation, and identified key circumstances that will target interventions in state prevention planning. The NVDRS has implemented data collection efforts and is beginning to produce and analyze findings. In the process of implementing the data collection system and publicizing findings, state NVDRS programs are realizing other gains that strengthen their surveillance efforts. The use of data for prevention purposes will be the ultimate indicator of program success.

RNA Structure Design Improves Activity and Specificity of trans-Splicing-Triggered Cell Death in a Suicide Gene Therapy Approach.

PubMed

Poddar, Sushmita; Loh, Pei She; Ooi, Zi Hao; Osman, Farhana; Eul, Joachim; Patzel, Volker

2018-06-01

Spliceosome-mediated RNA trans-splicing enables correction or labeling of pre-mRNA, but therapeutic applications are hampered by issues related to the activity and target specificity of trans-splicing RNA (tsRNA). We employed computational RNA structure design to improve both on-target activity and specificity of tsRNA in a herpes simplex virus thymidine kinase/ganciclovir suicide gene therapy approach targeting alpha fetoprotein (AFP), a marker of hepatocellular carcinoma (HCC) or human papillomavirus type 16 (HPV-16) pre-mRNA. While unstructured, mismatched target binding domains significantly improved 3' exon replacement (3'ER), 5' exon replacement (5'ER) correlated with the thermodynamic stability of the tsRNA 3' end. Alternative on-target trans-splicing was found to be a prevalent event. The specificity of trans-splicing with the intended target splice site was improved 10-fold by designing tsRNA that harbors secondary target binding domains shielding alternative on-target and blinding off-target splicing events. Such rationally designed suicide RNAs efficiently triggered death of HPV-16-transduced or hepatoblastoma-derived human tissue culture cells without evidence for off-target cell killing. Highest cell death activities were observed with novel dual-targeting tsRNAs programmed for trans-splicing toward AFP and a second HCC pre-mRNA biomarker. Our observations suggest trans-splicing represents a promising approach to suicide gene therapy. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

The DNA Inflammasome in Human Myeloid Cells Is Initiated by a STING-Cell Death Program Upstream of NLRP3

PubMed Central

Gaidt, Moritz M.; Ebert, Thomas S.; Chauhan, Dhruv; Ramshorn, Katharina; Pinci, Francesca; Zuber, Sarah; O’Duill, Fionan; Schmid-Burgk, Jonathan L.; Hoss, Florian; Buhmann, Raymund; Wittmann, Georg; Latz, Eicke; Subklewe, Marion; Hornung, Veit

2018-01-01

Summary Detection of cytosolic DNA constitutes a central event in the context of numerous infectious and sterile inflammatory conditions. Recent studies have uncovered a bipartite mode of cytosolic DNA recognition, in which the cGAS-STING axis triggers antiviral immunity, whereas AIM2 triggers inflammasome activation. Here, we show that AIM2 is dispensable for DNA-mediated inflammasome activation in human myeloid cells. Instead, detection of cytosolic DNA by the cGAS-STING axis induces a cell death program initiating potassium efflux upstream of NLRP3. Forward genetics identified regulators of lysosomal trafficking to modulate this cell death program, and subsequent studies revealed that activated STING traffics to the lysosome, where it triggers membrane permeabilization and thus lysosomal cell death (LCD). Importantly, the cGAS-STING-NLRP3 pathway constitutes the default inflammasome response during viral and bacterial infections in human myeloid cells. We conclude that targeting the cGAS-STING-LCD-NLRP3 pathway will ameliorate pathology in inflammatory conditions that are associated with cytosolic DNA sensing. PMID:29033128

Comprehensive Evaluation of Programmed Death-Ligand 1 Expression in Primary and Metastatic Prostate Cancer.

PubMed

Haffner, Michael C; Guner, Gunes; Taheri, Diana; Netto, George J; Palsgrove, Doreen N; Zheng, Qizhi; Guedes, Liana Benevides; Kim, Kunhwa; Tsai, Harrison; Esopi, David M; Lotan, Tamara L; Sharma, Rajni; Meeker, Alan K; Chinnaiyan, Arul M; Nelson, William G; Yegnasubramanian, Srinivasan; Luo, Jun; Mehra, Rohit; Antonarakis, Emmanuel S; Drake, Charles G; De Marzo, Angelo M

2018-06-01

Antibodies targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-L1) interaction have shown clinical activity in multiple cancer types. PD-L1 protein expression is a clinically validated predictive biomarker of response for such therapies. Prior studies evaluating the expression of PD-L1 in primary prostate cancers have reported highly variable rates of PD-L1 positivity. In addition, limited data exist on PD-L1 expression in metastatic castrate-resistant prostate cancer (mCRPC). Here, we determined PD-L1 protein expression by immunohistochemistry using a validated PD-L1-specific antibody (SP263) in a large and representative cohort of primary prostate cancers and prostate cancer metastases. The study included 539 primary prostate cancers comprising 508 acinar adenocarcinomas, 24 prostatic duct adenocarcinomas, 7 small-cell carcinomas, and a total of 57 cases of mCRPC. PD-L1 positivity was low in primary acinar adenocarcinoma, with only 7.7% of cases showing detectable PD-L1 staining. Increased levels of PD-L1 expression were noted in 42.9% of small-cell carcinomas. In mCRPC, 31.6% of cases showed PD-L1-specific immunoreactivity. In conclusion, in this comprehensive evaluation of PD-L1 expression in prostate cancer, PD-L1 expression is rare in primary prostate cancers, but increased rates of PD-L1 positivity were observed in mCRPC. These results will be important for the future clinical development of programmed cell death protein 1/PD-L1-targeting therapies in prostate cancer. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Pools of programmed death-ligand within the oral cavity tumor microenvironment: Variable alteration by targeted therapies.

PubMed

Shah, Sujay; Caruso, Andria; Cash, Harrison; Waes, Carter Van; Allen, Clint T

2016-08-01

Enhanced understanding of programmed death-ligand (PD-L) expression in oral cancer is important for establishing rational combinations of emerging immune checkpoint and molecular targeted therapies. We assessed PD-L and interferon (IFN) expression in immunogenic murine oral cancer-1 (MOC1) and poorly immunogenic MOC2 cell models after treatment with mammalian target of rapamycin (mTOR) and MEK1/2 small molecule inhibitors in vitro and in vivo. PD-L1 but not PD-L2 is expressed on MOC1 and 2 cells and is type I and II IFN-dependent. PD-L1 is differentially expressed on cancer and endothelial cells and infiltrating myeloid-derived suppressor cells, macrophages, and regulatory T cells (Tregs) in highly and poorly immunogenic tumors. PD-L1 expression is variably altered after treatment with inhibitors in vivo, with an imperfect relationship to alterations in IFN levels in the tumor microenvironment. PD-L1 expressed on cancer and infiltrating immune cells is variably altered by targeted therapies and may, in part, reflect changes in tumor IFN. © 2016 Wiley Periodicals, Inc. Head Neck 38:1176-1186, 2016. © 2016 Wiley Periodicals, Inc.

Necroptosis: an emerging type of cell death in liver diseases.

PubMed

Saeed, Waqar Khalid; Jun, Dae Won

2014-09-21

Cell death has been extensively evaluated for decades and it is well recognized that pharmacological interventions directed to inhibit cell death can prevent significant cell loss and can thus improve an organ's physiological function. For long, only apoptosis was considered as a sole form of programmed cell death. Recently necroptosis, a RIP1/RIP3-dependent programmed cell death, has been identified as an apoptotic backup cell death mechanism with necrotic morphology. The evidences of necroptosis and protective effects achieved by blocking necroptosis have been extensively reported in recent past. However, only a few studies reported the evidence of necroptosis and protective effects achieved by inhibiting necroptosis in liver related disease conditions. Although the number of necroptosis initiators is increasing; however, interestingly, it is still unclear that what actually triggers necroptosis in different liver diseases or if there is always a different necroptosis initiator in each specific disease condition followed by specific downstream signaling molecules. Understanding the precise mechanism of necroptosis as well as counteracting other cell death pathways in liver diseases could provide a useful insight towards achieving extensive therapeutic significance. By targeting necroptosis and/or other parallel death pathways, a significant cell loss and thus a decrement in an organ's physiological function can be prevented.

Collecting Sexual Orientation and Gender Identity Data in Suicide and Other Violent Deaths: A Step Towards Identifying and Addressing LGBT Mortality Disparities

PubMed Central

Lane, Andrew

2015-01-01

Abstract Sexual orientation and gender identity (SO/GI) are not systematically recorded at time of death, limiting identification of mortality disparities in lesbian, gay, bisexual, and transgender (LGBT) people. LGBT populations are thought to have elevated risk of suicide based on high rates of reported lifetime suicide attempts. Lack of data on suicide deaths, however, hinders understanding of the prevalence and patterns of suicide among LGBT populations and development of targeted interventions and prevention programs. This report describes recent efforts to address this knowledge gap by systematically collecting SO/GI information in the investigation of suicide and other violent deaths. PMID:26790023

Collecting Sexual Orientation and Gender Identity Data in Suicide and Other Violent Deaths: A Step Towards Identifying and Addressing LGBT Mortality Disparities.

PubMed

Haas, Ann P; Lane, Andrew

2015-03-01

Sexual orientation and gender identity (SO/GI) are not systematically recorded at time of death, limiting identification of mortality disparities in lesbian, gay, bisexual, and transgender (LGBT) people. LGBT populations are thought to have elevated risk of suicide based on high rates of reported lifetime suicide attempts. Lack of data on suicide deaths, however, hinders understanding of the prevalence and patterns of suicide among LGBT populations and development of targeted interventions and prevention programs. This report describes recent efforts to address this knowledge gap by systematically collecting SO/GI information in the investigation of suicide and other violent deaths.

76 FR 71048 - Assistance to Firefighters Grant Program

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-16

... the highest-scoring applications for awards. Applications that involve interoperable communications... categories: (1) Activities designed to reach high- risk target groups and mitigate incidences of death and... communications project is consistent with the Statewide Communications Interoperability Plan (SCIP). If the State...

METACASPASE9 modulates autophagy to confine cell death to the target cells during Arabidopsis vascular xylem differentiation

PubMed Central

Escamez, Sacha; André, Domenique; Zhang, Bo; Bollhöner, Benjamin; Pesquet, Edouard; Tuominen, Hannele

2016-01-01

ABSTRACT We uncovered that the level of autophagy in plant cells undergoing programmed cell death determines the fate of the surrounding cells. Our approach consisted of using Arabidopsis thaliana cell cultures capable of differentiating into two different cell types: vascular tracheary elements (TEs) that undergo programmed cell death (PCD) and protoplast autolysis, and parenchymatic non-TEs that remain alive. The TE cell type displayed higher levels of autophagy when expression of the TE-specific METACASPASE9 (MC9) was reduced using RNAi (MC9-RNAi). Misregulation of autophagy in the MC9-RNAi TEs coincided with ectopic death of the non-TEs, implying the existence of an autophagy-dependent intercellular signalling from within the TEs towards the non-TEs. Viability of the non-TEs was restored when AUTOPHAGY2 (ATG2) was downregulated specifically in MC9-RNAi TEs, demonstrating the importance of autophagy in the spatial confinement of cell death. Our results suggest that other eukaryotic cells undergoing PCD might also need to tightly regulate their level of autophagy to avoid detrimental consequences for the surrounding cells. PMID:26740571

Combined blockade of vascular endothelial growth factor and programmed death 1 pathways in advanced kidney cancer.

PubMed

Einstein, David J; McDermott, David F

2017-06-01

Targeted and immune-based therapies have improved outcomes in advanced kidney cancer, yet novel strategies are needed to extend the duration of these benefits and expand them to more patients. Combined inhibition of vascular endothelial growth factor (VEGF) and the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathways with therapeutic agents already in clinical use may offer such a strategy. Here, we describe the development and clinical evaluation of VEGF inhibitors and, separately, PD-1/PD-L1 inhibitors. We present preclinical evidence of interaction between these pathways and the rationale for combined blockade. Beyond well-known effects on pathologic angiogenesis, VEGF blockade also may decrease immune tolerance and enhance PD-1/PD-L1 blockade. We conclude with the results of several early trials of combined VEGF and PD-1/PD-L1 blockade, which demonstrate encouraging antitumor activity, and we pose questions for future study.

Statins and Voriconazole Induce Programmed Cell Death in Acanthamoeba castellanii

PubMed Central

López-Arencibia, Atteneri; Sifaoui, Ines; Reyes-Batlle, María; Valladares, Basilio; Martínez-Carretero, Enrique; Piñero, José E.; Maciver, Sutherland K.; Lorenzo-Morales, Jacob

2015-01-01

Members of the genus Acanthamoeba are facultative pathogens of humans, causing a sight-threatening keratitis and a life-threatening encephalitis. In order to treat those infections properly, it is necessary to target the treatment not only to the trophozoite but also to the cyst. Furthermore, it may be advantageous to avoid parasite killing by necrosis, which may induce local inflammation. We must also avoid toxicity of host tissue. Many drugs which target eukaryotes are known to induce programmed cell death (PCD), but this process is poorly characterized in Acanthamoeba. Here, we study the processes of programmed cell death in Acanthamoeba, induced by several drugs, such as statins and voriconazole. We tested atorvastatin, fluvastatin, simvastatin, and voriconazole at the 50% inhibitory concentrations (IC50s) and IC90s that we have previously established. In order to evaluate this phenomenon, we investigated the DNA fragmentation, one of the main characteristics of PCD, with quantitative and qualitative techniques. Also, the changes related to phosphatidylserine exposure on the external cell membrane and cell permeability were studied. Finally, because caspases are key to PCD pathways, caspase activity was evaluated in Acanthamoeba. All the drugs assayed in this study induced PCD in Acanthamoeba. To the best of our knowledge, this is the first study where PCD induced by drugs is described quantitatively and qualitatively in Acanthamoeba. PMID:25733513

Calcein+/PI- as an early apoptotic feature in Leishmania.

PubMed

Basmaciyan, Louise; Azas, Nadine; Casanova, Magali

2017-01-01

Although leishmaniases are responsible for high morbidity and mortality all over the world, no really satisfying treatment exists. Furthermore, the corresponding parasite Leishmania undergoes a very characteristic form of programmed cell death. Indeed, different stimuli can induce morphological and biochemical apoptotic-like features. However, the key proteins involved in mammal apoptosis, such as caspases and death receptors, are not encoded in the genome of this parasite. Currently, little is known about Leishmania apoptosis, notably owing to the lack of specific tools for programmed cell death analysis in these parasites. Furthermore, there is a need for a better understanding of Leishmania programmed cell death in order (i) to better understand the role of apoptosis in unicellular organisms, (ii) to better understand apoptosis in general through the study of an ancestral eukaryote, and (iii) to identify new therapeutic targets against leishmaniases. To advance understanding of apoptosis in Leishmania, in this study we developed a new tool based on the quantification of calcein and propidium iodide by flow cytometry. This double labeling can be employed to distinguish early apoptosis, late apoptosis and necrosis in Leishmania live cells with a very simple and rapid assay. This paper should, therefore, be of interest for people working on Leishmania and related parasites.

Programed death-1/programed death-ligand 1 expression in lymph nodes of HIV infected patients: results of a pilot safety study in rhesus macaques using anti–programed death-ligand 1 (Avelumab)

PubMed Central

Gill, Amanda L.; Green, Samantha A.; Abdullah, Shahed; Le Saout, Cecile; Pittaluga, Stefania; Chen, Hui; Turnier, Refika; Lifson, Jeffrey; Godin, Steven; Qin, Jing; Sneller, Michael C.; Cuillerot, Jean-Marie; Sabzevari, Helen; Lane, H. Clifford; Catalfamo, Marta

2016-01-01

Objective: The programed death-1 (PD1)/programed death-ligand 1 (PD-L1) pathway plays a critical role in balancing immunity and host immunopathology. During chronic HIV/SIV infection, there is persistent immune activation accompanied by accumulation of virus-specific cells with terminally differentiated phenotypes and expression of regulatory receptors such as PD1. These observations led us to hypothesize that the PD1/PD-L1 pathway contributes to the functional dysregulation and ineffective viral control, and its blockade may be a potential immunotherapeutic target. Methods: Lymph node biopsies from HIV-infected patients (n = 23) were studied for expression of PD1 and PD-L1. In addition, we assessed the safety and biological activity of a human anti-PD-L1 antibody (Avelumab) in chronically SIV-infected rhesus macaques. Results: PD-L1 expression was observed in cells with myloid/macrophage morphology in HIV-infected lymph nodes. Administration of anti-PD-L1 was well tolerated, and no changes in body weights, hematologic, or chemistry parameters were observed during the study. Blockade of PD-L1 led to a trend of transient viral control after discontinuation of treatment. Conclusion: Administration of anti-PD-L1 in chronic SIV-infected rhesus macaques was well tolerated. Overall, these data warrant further investigation to assess the efficacy of anti-PD-L1 treatment on viral control in chronic SIV infection as a prelude to such therapy in humans. PMID:27490642

Programed death-1/programed death-ligand 1 expression in lymph nodes of HIV infected patients: results of a pilot safety study in rhesus macaques using anti-programed death-ligand 1 (Avelumab).

PubMed

Gill, Amanda L; Green, Samantha A; Abdullah, Shahed; Le Saout, Cecile; Pittaluga, Stefania; Chen, Hui; Turnier, Refika; Lifson, Jeffrey; Godin, Steven; Qin, Jing; Sneller, Michael C; Cuillerot, Jean-Marie; Sabzevari, Helen; Lane, H Clifford; Catalfamo, Marta

2016-10-23

The programed death-1 (PD1)/programed death-ligand 1 (PD-L1) pathway plays a critical role in balancing immunity and host immunopathology. During chronic HIV/SIV infection, there is persistent immune activation accompanied by accumulation of virus-specific cells with terminally differentiated phenotypes and expression of regulatory receptors such as PD1. These observations led us to hypothesize that the PD1/PD-L1 pathway contributes to the functional dysregulation and ineffective viral control, and its blockade may be a potential immunotherapeutic target. Lymph node biopsies from HIV-infected patients (n = 23) were studied for expression of PD1 and PD-L1. In addition, we assessed the safety and biological activity of a human anti-PD-L1 antibody (Avelumab) in chronically SIV-infected rhesus macaques. PD-L1 expression was observed in cells with myloid/macrophage morphology in HIV-infected lymph nodes. Administration of anti-PD-L1 was well tolerated, and no changes in body weights, hematologic, or chemistry parameters were observed during the study. Blockade of PD-L1 led to a trend of transient viral control after discontinuation of treatment. Administration of anti-PD-L1 in chronic SIV-infected rhesus macaques was well tolerated. Overall, these data warrant further investigation to assess the efficacy of anti-PD-L1 treatment on viral control in chronic SIV infection as a prelude to such therapy in humans.

PD-1-PD-L1 immune-checkpoint blockade in malignant lymphomas.

PubMed

Wang, Yi; Wu, Ling; Tian, Chen; Zhang, Yizhuo

2018-02-01

Tumor cells can evade immune surveillance through overexpressing the ligands of checkpoint receptors on tumor cells or adjacent cells, leading T cells to anergy or exhaustion. Growing evidence of the interaction between tumor cells and microenvironment promoted the emergence of immune-checkpoint blockade. By targeting programmed cell death-1 (PD-1) pathway, cytotoxic activity of T cell is enhanced significantly and tumor cell lysis is induced subsequently. Currently, various antibodies against PD-1 and programmed death-ligand 1 (PD-L1) are under clinical studies in lymphomas. In this review, we outline the rationale for investigation of PD-1-PD-L1 immune-checkpoint blockade in lymphomas and discuss their prospect of applications in clinical treatment.

Screening Program Reduced Melanoma Mortality at the Lawrence Livermore National Laboratory, 1984-1996

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schneider, MD, J S; II, PhD, D; MD, PhD, M

Worldwide incidence of cutaneous malignant melanoma has increased substantially, and no screening program has yet demonstrated reduction in mortality. We evaluated the education, self examination and targeted screening campaign at the Lawrence Livermore National Laboratory (LLNL) from its beginning in July 1984 through 1996. The thickness and crude incidence of melanoma from the years before the campaign were compared to those obtained during the 13 years of screening. Melanoma mortality during the 13-year period was based on a National Death Index search. Expected yearly deaths from melanoma among LLNL employees were calculated by using California mortality data matched by age,more » sex, and race/ethnicity and adjusted to exclude deaths from melanoma diagnosed before the program began or before employment at LLNL. After the program began, crude incidence of melanoma thicker than 0.75 mm decreased from 18 to 4 cases per 100,000 person-years (p = 0.02), while melanoma less than 0.75mm remained stable and in situ melanoma increased substantially. No eligible melanoma deaths occurred among LLNL employees during the screening period compared with a calculated 3.39 expected deaths (p = 0.034). Education, self examination and selective screening for melanoma at LLNL significantly decreased incidence of melanoma thicker than 0.75 mm and reduced the melanoma-related mortality rate to zero. This significant decrease in mortality rate persisted for at least 3 yr after employees retired or otherwise left the laboratory.« less

Kennedy Space Center Coronary Heart Disease Risk Screening Program

NASA Technical Reports Server (NTRS)

Tipton, David A.; Scarpa, Philip J.

1999-01-01

Coronary heart disease (CHD) is the number one cause of death in the U.S. It is a likely cause of death and disability in the lives of employees at Kennedy Space Center (KSC) as well. The KSC Biomedical Office used a multifactorial formula developed by the Framingham Heart Study to calculate CHD risk probabilities for individuals in a segment of the KSC population who require medical evaluation for job certification. Those individuals assessed to have a high risk probability will be targeted for intervention.

Hartford's gun buy-back program: are we on target?

PubMed

Marinelli, Laura W; Thaker, Shefali; Borrup, Kevin; Shapiro, David S; Bentley, George C; Saleheen, Hassan; Lapidus, Garry; Campbell, Brendan T

2013-09-01

Gunbuy-backprograms have been proposed as away to remove unwanted firearms from circulation, but remain controversial because their ability to prevent firearm injuries remains unproven. The purpose of this study is to describe the demographics of individuals participating in Connecticut's gun buy-backprogram in the context of annual gun sales and the epidemiology of firearm violence in the state. Over four years the buy-back program collected 464 firearms, including 232 handguns. In contrast, 91,602 firearms were sold in Connecticut during 2009 alone. The incidence of gun-related deaths was unchanged in the two years following the inception of the buy-back program. Suicide was associated with older age (mean = 51 +/- 18years) and Caucasian race (n = 539, 90%). Homicide was associated with younger age (mean = 30 +/- 12 years) and minority race (n = 425, 81%). A gun buy-back program alone is not likely to produce a measurable decrease in firearm injuries and deaths.

Targeting the upstream transcriptional activator of PD-L1 as an alternative strategy in melanoma therapy.

PubMed

Zhu, Bo; Tang, Liming; Chen, Shuyang; Yin, Chengqian; Peng, Shiguang; Li, Xin; Liu, Tongzheng; Liu, Wei; Han, Changpeng; Stawski, Lukasz; Xu, Zhi-Xiang; Zhou, Guangbiao; Chen, Xiang; Gao, Xiumei; Goding, Colin R; Xu, Nan; Cui, Rutao; Cao, Peng

2018-05-22

Programmed cell death ligand 1 (PD-L1) interacts with programmed cell death protein-1 (PD-1) as an immune checkpoint. Reactivating the immune response by inhibiting PD-L1 using therapeutic antibodies provides substantial clinical benefits in many, though not all, melanoma patients. However, transcriptional suppression of PD-L1 expression as an alternative therapeutic anti-melanoma strategy has not been exploited. Here we provide biochemical evidence demonstrating that ultraviolet radiation (UVR) induction of PD-L1 in skin is directly controlled by nuclear factor E2-related transcription factor 2 (NRF2). Depletion of NRF2 significantly induces tumor infiltration by both CD8 + and CD4 + T cells to suppress melanoma progression, and combining NRF2 inhibition with anti-PD-1 treatment enhanced its anti-tumor function. Our studies identify a critical and targetable PD-L1 upstream regulator and provide an alternative strategy to inhibit the PD-1/PD-L1 signaling in melanoma treatment.

Immune checkpoint inhibitors in lung cancer: current status and future directions.

PubMed

Fan, Yun; Mao, Weimin

2017-04-01

Recently, the immune checkpoint inhibitors that target programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) have made a breakthrough in treating advanced non-small cell lung cancer (NSCLC) with the efficacy of approximately 20%; among which, nivolumab has acquired treatment indications in lung squamous cell carcinoma. The inhibitors targeting cytotoxic T lymphocyte associated antigen 4 (CTLA-4) are also undergoing clinical trials. Researches on immune checkpoint inhibitors have been rapidly implemented in a variety of different types of lung cancer, such as small cell lung cancer (SCLC) and locally advanced NSCLC, and these inhibitors began to be applied in combination with some established treatments, including chemotherapy, targeting therapy and radiotherapy. Undoubtedly, the immune checkpoint inhibitors have become a hot spot in the research and treatment of lung cancer. However, many problems wait to be solved, such as searching for ideal biomarkers, constituting the best criteria for curative effect evaluation, exploring different combination treatment models, and clearly understanding the mechanisms of primary or secondary drug resistance. Along with these problems to be successfully solved, the immune checkpoint inhibitors will have more broad applications in lung cancer therapy.

Comparison of Analysis and Quantification of Cell Death in vivo and in vitro

DTIC Science & Technology

1985-05-01

mammalian somatic cells appear to have a finite life span that is genetically programmed ( Hayflick , 1977). Following the consummation of this program... limited situations it is possible to evaluate the proliferation kinetics of cell populations in tis- sues by autoradiographically detecting radiolabeled...are, therefore, virtually limited to the analysis of toxicity of directly active chemicals. Primary cultures of target cells retain the ability to

Unintentional asphyxia, SIDS, and medically explained deaths: a descriptive study of outcomes of child death review (CDR) investigations following sudden unexpected death in infancy.

PubMed

Garstang, Joanna; Ellis, Catherine; Griffiths, Frances; Sidebotham, Peter

2016-12-01

A comprehensive child death review (CDR) program was introduced in England and Wales in 2008, but as yet data have only been analyzed at a local level, limiting the learning from deaths. The aim of this study is to describe the profile of causes and risk factors for sudden unexpected death in infancy (SUDI) as determined by the new CDR program. This was a descriptive outcome study using data from child death overview panel Form C for SUDI cases dying during 2010-2012 in the West Midlands region of England. The main outcome measures were: cause of death, risk factors and potential preventability of death, and determination of deaths probably due to unintentional asphyxia. Data were obtained for 65/70 (93 %) SUDI cases. 20/65 (31 %) deaths were initially categorized as due to medical causes; 21/65 (32 %) as SIDS; and 24/65 (37 %) as undetermined. Reanalysis suggested that 2/21 SIDS and 7/24 undetermined deaths were probably due to unintentional asphyxia, with 6 of these involving co-sleeping and excessive parental alcohol consumption. Deaths classified as "undetermined" had significantly higher total family and environmental risk factor scores (mean 2.6, 95 % CI 2.0-3.3) compared to those classified as SIDS (mean 1.6, 95 % CI 1.2-1.9), or medical causes for death (mean 1.1, 95 % CI 0.8-1.3). 9/20 (47 %) of medical deaths, 19/21 (90 %) SIDS, and 23/24 (96 %) undetermined deaths were considered to be potentially preventable. There were inadequacies in medical provision identified in 5/20 (25 %) of medically explained deaths. The CDR program results in detailed information about risk factors for SUDI cases but failed to recognize deaths probably due to unintentional asphyxia. The misclassification of probable unintentional asphyxial deaths and SIDS as "undetermined deaths" is likely to limit learning from these deaths and inhibit prevention strategies. Many SUDI occurred in families with mental illness, substance misuse and chaotic lifestyles and most in unsafe sleep environments. This knowledge could be used to better target safe sleep advice for vulnerable families and prevent SUDI in the future.

CaMKII determines mitochondrial stress responses in heart

PubMed Central

Joiner, Mei-ling A.; Koval, Olha M.; Jingdong, Li; He, B. Julie; Allamargot, Chantal; Gao, Zhan; Luczak, Elizabeth D.; Hall, Duane D.; Fink, Brian D.; Chen, Biyi; Yang, Jinying; Moore, Steven A.; Scholz, Thomas D.; Strack, Stefan; Mohler, Peter J.; Sivitz, William I.; Song, Long-Sheng; Anderson, Mark E.

2012-01-01

Myocardial cell death is initiated by excessive mitochondrial Ca2+ entry, causing Ca2+ overload, mitochondrial permeability transition pore (mPTP) opening and dissipation of the mitochondrial inner membrane potential (ΔΨm)1,2. However, the signaling pathways that control mitochondrial Ca2+ entry through the inner membrane mitochondrial Ca2+ uniporter (MCU)3–5 are not known. The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is activated in ischemia reperfusion (I/R), myocardial infarction (MI) and neurohumoral injury, common causes of myocardial death and heart failure, suggesting CaMKII could couple disease stress to mitochondrial injury. Here we show that CaMKII promotes mPTP opening and myocardial death by increasing MCU current (IMCU). Mitochondrial-targeted CaMKII inhibitory protein or cyclosporin A (CsA), an mPTP antagonist with clinical efficacy in I/R injury6, equivalently prevent mPTP opening, ΔΨm deterioration and diminish mitochondrial disruption and programmed cell death in response to I/R injury. Mice with myocardial and mitochondrial-targeted CaMKII inhibition are resistant to I/R injury, MI and neurohumoral injury, suggesting pathological actions of CaMKII are substantially mediated by increasing IMCU. Our findings identify CaMKII activity as a central mechanism for mitochondrial Ca2+ entry and suggest mitochondrial-targeted CaMKII inhibition could prevent or reduce myocardial death and heart failure dysfunction in response to common experimental forms of pathophysiological stress. PMID:23051746

Broad targeting of resistance to apoptosis in cancer

PubMed Central

Mohammad, Ramzi M.; Muqbil, Irfana; Lowe, Leroy; Yedjou, Clement; Hsu, Hsue-Yin; Lin, Liang-Tzung; Siegelin, Markus David; Fimognari, Carmela; Kumar, Nagi B.; Dou, Q. Ping; Yang, Huanjie; Samadi, Abbas K.; Russo, Gian Luigi; Spagnuolo, Carmela; Ray, Swapan K.; Chakrabarti, Mrinmay; Morre, James D.; Coley, Helen M.; Honoki, Kanya; Fujii, Hiromasa; Georgakilas, Alexandros G.; Amedei, Amedeo; Niccolai, Elena; Amin, Amr; Ashraf, S. Salman; Helferich, William G.; Yang, Xujuan; Boosani, Chandra S.; Guha, Gunjan; Bhakta, Dipita; Ciriolo, Maria Rosa; Aquilano, Katia; Chen, Sophie; Mohammed, Sulma I.; Keith, W. Nicol; Bilsland, Alan; Halicka, Dorota; Nowsheen, Somaira; Azmi, Asfar S.

2015-01-01

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer. PMID:25936818

Spinosad induces programmed cell death involves mitochondrial dysfunction and cytochrome C release in Spodoptera frugiperda Sf9 cells.

PubMed

Yang, Mingjun; Wang, Bo; Gao, Jufang; Zhang, Yang; Xu, Wenping; Tao, Liming

2017-02-01

Spinosad, a reduced-risk insecticide, acts on the nicotinic acetylcholine receptors and the gamma-aminobutyric acid receptor in the nervous system of target insects. However, its mechanism of action in non-neural insect cells is unclear. This study aimed to evaluate mitochondrial functional changes associated with spinosad in Spodoptera frugiperda (Sf9) insect cells. Our results indicate that in Sf9 cells, spinosad induces programmed cell death and mitochondrial dysfunction through enhanced reactive oxygen species production, mitochondrial permeability transition pore (mPTP) opening, and mitochondrial membrane potential collapse, eventually leading to cytochrome C release and apoptosis. The cytochrome C release induced by spinosad treatment was partly inhibited by the mPTP inhibitors cyclosporin A and bongkrekic acid. Subsequently, we found that spinosad downregulated Bcl-2 expression and upregulated p53 and Bax expressions, activated caspase-9 and caspase-3, and triggered PARP cleavage in Sf9 cells. These findings suggested that spinosad-induced programmed cell death was modulated by mitochondrial dysfunction and cytochrome C release. Copyright © 2016 Elsevier Ltd. All rights reserved.

Reductions in Sepsis Mortality and Costs After Design and Implementation of a Nurse-Based Early Recognition and Response Program

PubMed Central

Jones, Stephen L.; Ashton, Carol M.; Kiehne, Lisa; Gigliotti, Elizabeth; Bell-Gordon, Charyl; Disbot, Maureen; Masud, Faisal; Shirkey, Beverly A.; Wray, Nelda P.

2016-01-01

Background Sepsis is a leading cause of death, but evidence suggests that early recognition and prompt intervention can save lives. In 2005 Houston Methodist Hospital prioritized sepsis detection and management in its ICU. In late 2007, because of marginal effects on sepsis death rates, the focus shifted to designing a program that would be readily used by nurses and ensure early recognition of patients showing signs suspicious for sepsis, as well as the institution of prompt, evidence-based interventions to diagnose and treat it. Methods The intervention had four components: organizational commitment and data-based leadership; development and integration of an early sepsis screening tool into the electronic health record; creation of screening and response protocols; and education and training of nurses. Twice-daily screening of patients on targeted units was conducted by bedside nurses; nurse practitioners initiated definitive treatment as indicated. Evaluation focused on extent of implementation, trends in inpatient mortality, and, for Medicare beneficiaries, a before-after (2008–2011) comparison of outcomes and costs. A federal grant in 2012 enabled expansion of the program. Results By year 3 (2011) 33% of inpatients were screened (56,190 screens in 9,718 unique patients), up from 10% in year 1 (2009). Inpatient sepsis-associated death rates decreased from 29.7% in the preimplementation period (2006–2008) to 21.1% after implementation (2009–2014). Death rates and hospital costs for Medicare beneficiaries decreased from preimplementation levels without a compensatory increase in discharges to postacute care. Conclusion This program has been associated with lower inpatient death rates and costs. Further testing of the robustness and exportability of the program is under way. PMID:26484679

Correctional Recreation on Death Row: Should Pardon Be Granted?

ERIC Educational Resources Information Center

Williams, D. J.; Walker, Gordon J.; Strean, William B.

2005-01-01

Because of significant recent budget cuts across the U.S., various correctional services have been targeted for possible elimination (Polson, 2002). Correctional recreation (CR) often appears to be viewed by policy makers, correctional administrators and staff as an offender privilege or perhaps even a luxury, and such programs frequently struggle…

Remodelling of lace plant leaves: antioxidants and ROS are key regulators of programmed cell death.

PubMed

Dauphinee, Adrian N; Fletcher, Jacob I; Denbigh, Georgia L; Lacroix, Christian R; Gunawardena, Arunika H L A N

2017-07-01

Antioxidants and reactive oxygen species are integral for programmed cell death signaling during perforation formation in the lace plant ( Aponogeton madagascariensis ). The lace plant is an excellent model system for studying developmentally regulated programmed cell death (PCD). During early lace plant leaf development, PCD systematically deletes cells resulting in a perforated leaf morphology that is unique in planta. A distinct feature in young lace plant leaves is an abundance of anthocyanins, which have antioxidant properties. The first sign of PCD induction is the loss of anthocyanin pigmentation in cells that are targeted for destruction, which results in a visible gradient of cell death. The cellular dynamics and time course of lace plant PCD are well documented; however, the signals involved in the pathway remain elusive. This study investigates the roles of antioxidants and ROS in developmental PCD signaling during lace plant perforation formation. The involvement of antioxidants and ROS in the pathway was determined using a variety of techniques including pharmacological whole plant experimentation, long-term live cell imaging, the 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid anti-radical activity assay, and western blot analysis. Results indicate that antioxidants and ROS are key regulators of PCD during the remodelling of lace plant leaves.

Necroptosis Signaling Pathways in Stroke: from Mechanisms to Therapies.

PubMed

Jun-Long, Huang; Yi, Li; Bao-Lian, Zhao; Jia-Si, Li; Ning, Zhang; Zhou-Heng, Ye; Xue-Jun, Sun; Wen-Wu, Liu

2018-04-16

It has been confirmed that apoptosis, autophagy and necrosis are the three major modes of cell death. For a long time, necrosis is regarded as a deranged or accidental cell demise. In recent years, there is evidence showing that necrotic cell death can be a well regulated and orchestrated event, which is also known as programmed cell death or "necroptosis". Necroptosis can be triggered by a variety of external stimuli and regulated by a caspase-independent pathway. It plays a key role in the pathogenesis of some diseases including neurological diseases. In the past two decades, a variety of studies have revealed that the necroptosis related pathway is activated in stroke, and plays a crucial role in the pathogenesis of stroke. Moreover, necroptosis may serve as a potential target in the therapy of stroke because genetic or pharmacological inhibition of necroptosis has been shown to be neuroprotective in stroke in vitro and in vivo. In this review, we briefly summarize recent advance in necroptosis, introduce the mechanism and strategies targeting necroptosis in stroke, and finally propose some issues in the treatment of stroke by targeting necroptosis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Novel Mechanisms of Target Cell Death and Survival and of Therapeutic Action of IVIg in Pemphigus

PubMed Central

Arredondo, Juan; Chernyavsky, Alexander I.; Karaouni, Ali; Grando, Sergei A.

2005-01-01

Pemphigus vulgaris (PV) is a potentially lethal mucocutaneous blistering disease characterized by cell-cell detachment within the stratified epithelium (acantholysis) caused by IgG autoantibodies. Intravenous immunoglobulin (IVIg) therapy effectively treats PV, but the mechanism is not fully understood. To further understand acantholysis and the efficacy of IVIg, we measured effects of IgG fractions from PV patients on keratinocyte death processes. Using IgGs from representative PV patients who improved with IVIg, we identified apoptotic and oncotic signaling pathways in in vitro and in vivo PV models. We identified two groups of PV patients, each producing autoantibodies activating predominantly either apoptotic or oncotic cell death pathway. Experimental treatments with caspase 3 or calpain inhibitors demonstrated that PV IgGs induced acantholysis through both pathways. Upstream, the apoptotic signaling involved activation of caspases 8 and 3 and up-regulation of Fas ligand mRNA, whereas calpain-mediated cell death depended on elevated intracellular free Ca2+. IVIg reduced PV IgG-mediated acantholysis and cell death and up-regulated the caspase inhibitor FLIP and the calpain inhibitor calpastatin. These results indicate that in different PV patients, IgG-induced acantholysis proceeds predominantly via distinct, yet complementary, pathways of programmed cell death differentially mediated by apoptosis and oncosis effectors, with IVIg protecting target cells by up-regulating endogenous caspase and calpain inhibitors. PMID:16314468

Programmed activation of cancer cell apoptosis: A tumor-targeted phototherapeutic topoisomerase I inhibitor

NASA Astrophysics Data System (ADS)

Shin, Weon Sup; Han, Jiyou; Kumar, Rajesh; Lee, Gyung Gyu; Sessler, Jonathan L.; Kim, Jong-Hoon; Kim, Jong Seung

2016-07-01

We report here a tumor-targeting masked phototherapeutic agent 1 (PT-1). This system contains SN-38—a prodrug of the topoisomerase I inhibitor irinotecan. Topoisomerase I is a vital enzyme that controls DNA topology during replication, transcription, and recombination. An elevated level of topoisomerase I is found in many carcinomas, making it an attractive target for the development of effective anticancer drugs. In addition, PT-1 contains both a photo-triggered moiety (nitrovanillin) and a cancer targeting unit (biotin). Upon light activation in cancer cells, PT-1 interferes with DNA re-ligation, diminishes the expression of topoisomerase I, and enhances the expression of inter alia mitochondrial apoptotic genes, death receptors, and caspase enzymes, inducing DNA damage and eventually leading to apoptosis. In vitro and in vivo studies showed significant inhibition of cancer growth and the hybrid system PT-1 thus shows promise as a programmed photo-therapeutic (“phototheranostic”).

Apoptosis-Like Death in Bacteria Induced by HAMLET, a Human Milk Lipid-Protein Complex

PubMed Central

Hakansson, Anders P.; Roche-Hakansson, Hazeline; Mossberg, Ann-Kristin; Svanborg, Catharina

2011-01-01

Background Apoptosis is the primary means for eliminating unwanted cells in multicellular organisms in order to preserve tissue homeostasis and function. It is characterized by distinct changes in the morphology of the dying cell that are orchestrated by a series of discrete biochemical events. Although there is evidence of primitive forms of programmed cell death also in prokaryotes, no information is available to suggest that prokaryotic death displays mechanistic similarities to the highly regulated programmed death of eukaryotic cells. In this study we compared the characteristics of tumor and bacterial cell death induced by HAMLET, a human milk complex of alpha-lactalbumin and oleic acid. Methodology/Principal Findings We show that HAMLET-treated bacteria undergo cell death with mechanistic and morphologic similarities to apoptotic death of tumor cells. In Jurkat cells and Streptococcus pneumoniae death was accompanied by apoptosis-like morphology such as cell shrinkage, DNA condensation, and DNA degradation into high molecular weight fragments of similar sizes, detected by field inverse gel electrophoresis. HAMLET was internalized into tumor cells and associated with mitochondria, causing a rapid depolarization of the mitochondrial membrane and bound to and induced depolarization of the pneumococcal membrane with similar kinetic and magnitude as in mitochondria. Membrane depolarization in both systems required calcium transport, and both tumor cells and bacteria were found to require serine protease activity (but not caspase activity) to execute cell death. Conclusions/Significance Our results suggest that many of the morphological changes and biochemical responses associated with apoptosis are present in prokaryotes. Identifying the mechanisms of bacterial cell death has the potential to reveal novel targets for future antimicrobial therapy and to further our understanding of core activation mechanisms of cell death in eukaryote cells. PMID:21423701

Apoptosis-like death in bacteria induced by HAMLET, a human milk lipid-protein complex.

PubMed

Hakansson, Anders P; Roche-Hakansson, Hazeline; Mossberg, Ann-Kristin; Svanborg, Catharina

2011-03-10

Apoptosis is the primary means for eliminating unwanted cells in multicellular organisms in order to preserve tissue homeostasis and function. It is characterized by distinct changes in the morphology of the dying cell that are orchestrated by a series of discrete biochemical events. Although there is evidence of primitive forms of programmed cell death also in prokaryotes, no information is available to suggest that prokaryotic death displays mechanistic similarities to the highly regulated programmed death of eukaryotic cells. In this study we compared the characteristics of tumor and bacterial cell death induced by HAMLET, a human milk complex of alpha-lactalbumin and oleic acid. We show that HAMLET-treated bacteria undergo cell death with mechanistic and morphologic similarities to apoptotic death of tumor cells. In Jurkat cells and Streptococcus pneumoniae death was accompanied by apoptosis-like morphology such as cell shrinkage, DNA condensation, and DNA degradation into high molecular weight fragments of similar sizes, detected by field inverse gel electrophoresis. HAMLET was internalized into tumor cells and associated with mitochondria, causing a rapid depolarization of the mitochondrial membrane and bound to and induced depolarization of the pneumococcal membrane with similar kinetic and magnitude as in mitochondria. Membrane depolarization in both systems required calcium transport, and both tumor cells and bacteria were found to require serine protease activity (but not caspase activity) to execute cell death. Our results suggest that many of the morphological changes and biochemical responses associated with apoptosis are present in prokaryotes. Identifying the mechanisms of bacterial cell death has the potential to reveal novel targets for future antimicrobial therapy and to further our understanding of core activation mechanisms of cell death in eukaryote cells.

Smoke Alarm Giveaway and Installation Programs

PubMed Central

Liu, Ying; Mack, Karin A.; Diekman, Shane T.

2015-01-01

Background The burden of residential fire injury and death is substantial. Targeted smoke alarm giveaway and installation programs are popular interventions used to reduce residential fire mortality and morbidity. Purpose To evaluate the cost effectiveness and cost benefit of implementing a giveaway or installation program in a small hypothetic community with a high risk of fire death and injury through a decision-analysis model. Methods Model inputs included program costs; program effectiveness (life-years and quality-adjusted life-years saved); and monetized program benefits (medical cost, productivity, property loss and quality-of-life losses averted) and were identified through structured reviews of existing literature (done in 2011) and supplemented by expert opinion. Future costs and effectiveness were discounted at a rate of 3% per year. All costs were expressed in 2011 U.S. dollars. Results Cost-effectiveness analysis (CEA) resulted in anaverage cost-effectiveness ratio (ACER) of $51,404 per quality-adjusted life-years (QALYs) saved and $45,630 per QALY for the giveaway and installation programs, respectively. Cost–benefit analysis (CBA) showed that both programs were associated with a positive net benefit with a benefit–cost ratio of 2.1 and 2.3, respectively. Smoke alarm functional rate, baseline prevalence of functional alarms, and baseline home fire death rate were among the most influential factors for the CEA and CBA results. Conclusions Both giveaway and installation programs have an average cost-effectiveness ratio similar to or lower than the median cost-effectiveness ratio reported for other interventionsto reduce fatal injuries in homes. Although more effort is required, installation programs result in lower cost per outcome achieved compared with giveaways. PMID:22992356

Medicaid-based child restraint system disbursement and education and the vaccines for children program: comparative cost-effectiveness.

PubMed

Goldstein, Jesse A; Winston, Flaura K; Kallan, Michael J; Branas, Charles C; Schwartz, J Sanford

2008-01-01

Low-income children are disproportionately at risk for preventable motor-vehicle injury. Many of these children are covered by Medicaid programs placing substantial economic burden on states. Child restraint systems (CRSs) have demonstrated efficacy in preventing death and injury among children in crashes but remain underutilized because of poor access and education. The objective of this study was to evaluate the cost-effectiveness of Medicaid-based reimbursement for CRS disbursement and education for low-income children and compare it with vaccinations covered under the Vaccines For Children (VFC) program. A cost-effectiveness analysis was performed of Medicaid reimbursement for CRS disbursement/education for low-income children based on data from public and private databases. Primary outcomes measured include cost per life-year saved, death, serious injury, and minor injury averted, as well as medical, parental work loss, and future productivity loss costs averted. Cost-effectiveness calculations were compared with published cost-effectiveness data for vaccinations covered under the VFC program. The adoption of a CRS disbursement/education program could prevent up to 2 deaths, 12 serious injuries, and 51 minor injuries per 100,000 low-income children annually. When fully implemented, the program could save Medicaid over $1 million per 100,000 children in direct medical costs while costing $13 per child per year after all 8 years of benefit. From the perspective of Medicaid, the program would cost $17,000 per life-year saved, $60,000 per serious injury prevented, and $560,000 per death averted. The program would be cost saving from a societal perspective. These data are similar to published vaccination cost-effectiveness data. Implementation of a Medicaid-funded CRS disbursement/education program was comparable in cost-effectiveness with federal vaccination programs targeted toward similar populations and represents an important potential strategy for addressing injury disparities among low-income children.

The in vitro cleavage of the hAtg proteins by cell death proteases.

PubMed

Norman, Joanna M; Cohen, Gerald M; Bampton, Edward T W

2010-11-01

It is becoming increasingly clear that there is crosstalk between the apoptotic and autophagic pathways, with autophagy helping to contribute to cell death by providing energy to allow the energy-requiring programmed cell death process to complete, as well as degrading cellular material in its own right. Recent evidence has suggested that Atg proteins can themselves be targets of caspases, providing potential regulation of autophagy as well as uncovering novel functions for fragments derived from Atg proteins. However, to date there has not been a detailed examination of which Atg proteins may be the targets of which death proteases. We show that the majority of human Atg (hAtg) proteins can be cleaved by calpain 1, which is activated in some apoptotic paradigms, as well as other forms of death. We also show that hAtg3 is cleaved by caspases-3, -6 and -8, hAtg6 (Beclin 1) is cleaved by caspase-3 and -6, while hAtg9, hAtg7 and the hAtg4 homologues can be cleaved by caspase-3. Cleavage of Beclin 1 was also seen in apoptosis of HeLa cells induced by staurosporine and TRAIL, along with cleavage of Atg3 and Atg4C. There were subtle effects of caspase inhibition on GFP-LC3 lipidation but more marked effects on the formation of GFP-LC3 puncta (a marker of autophagosome formation) and p62 degradation, indicating that caspase cleavage of autophagy-related proteins can affect the autophagic process. Notably we show that p62 is a target for caspase-6 and -8 cleavage.

Immune Checkpoint Inhibition in Hepatocellular Carcinoma: Basics and Ongoing Clinical Trials.

PubMed

Kudo, Masatoshi

2017-01-01

Clinical trials of antibodies targeting the immune checkpoint inhibitors programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) for the treatment of advanced hepatocellular carcinoma (HCC) are ongoing. Expansion cohorts of a phase I/II trial of the anti-PD-1 antibody nivolumab in advanced HCC showed favorable results. Two phase III studies are currently ongoing: a comparison of nivolumab and sorafenib in the first-line setting for advanced HCC, and a comparison of the anti-PD-1 antibody pembrolizumab and a placebo in the second-line setting for patients with advanced HCC who progressed on sorafenib therapy. The combination of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies is being evaluated in other phase I/II trials, and the results suggest that an anti-PD-1 antibody combined with locoregional therapy or other molecular targeted agents is an effective treatment strategy for HCC. Immune checkpoint inhibitors may therefore open new doors to the treatment of HCC. © 2017 S. Karger AG, Basel.

The contribution of the programmed cell death machinery in innate immune cells to lupus nephritis.

PubMed

Tsai, FuNien; Perlman, Harris; Cuda, Carla M

2017-12-01

Systemic lupus erythematosus (SLE) is a chronic multi-factorial autoimmune disease initiated by genetic and environmental factors, which in combination trigger disease onset in susceptible individuals. Damage to the kidney as a consequence of lupus nephritis (LN) is one of the most prevalent and severe outcomes, as LN affects up to 60% of SLE patients and accounts for much of SLE-associated morbidity and mortality. As remarkable strides have been made in unlocking new inflammatory mechanisms associated with signaling molecules of programmed cell death pathways, this review explores the available evidence implicating the action of these pathways specifically within dendritic cells and macrophages in the control of kidney disease. Although advancements into the underlying mechanisms responsible for inducing cell death inflammatory pathways have been made, there still exist areas of unmet need. By understanding the molecular mechanisms by which dendritic cells and macrophages contribute to LN pathogenesis, we can improve their viability as potential therapeutic targets to promote remission. Copyright © 2016 Elsevier Inc. All rights reserved.

Apoptosis: a guide for the perplexed.

PubMed

Sloviter, Robert S

2002-01-01

The term 'apoptosis' describes an active process of cellular deconstruction originally contrasted morphologically with necrosis. The mistaken equivalence of the terms apoptosis and 'programmed cell death' has caused confusion and implied that apoptosis is an identifiable therapeutic target rather than a name of a type of cell death. The roots of confusion are suggested to lie not in superficial disagreements about the morphology and biochemistry of cell death, but in the lamentable disconnection of modern science from its philosophical foundations (i.e. Socratic definition, nominalism versus realism, and William of Ockham's advocacy of Aristotelian metaphysics over Plato's Theory of Forms). Renewed awareness of these issues might be the key to understanding that apoptosis is a created concept, not a real entity, and that the use of terms that defy definition has become an obstacle to clear thinking about preventable cell death.

Programmatic Impact of 5 Years of Mortality Surveillance of New York City Homeless Populations

PubMed Central

Marder, Dova; Begier, Elizabeth; Gutkovich, Alexander; Mos, Robert; Griffin, Angela; Zimmerman, Regina; Madsen, Ann

2013-01-01

A homeless mortality surveillance system identifies emerging trends in the health of the homeless population and provides this information to key stakeholders in a timely and ongoing manner to effect evidence-based, programmatic change. We describe the first 5 years of the New York City homeless mortality surveillance system and, for the first time in peer-reviewed literature, illustrate the impact of key elements of sustained surveillance (i.e., timely dissemination of aggregate mortality data and real-time sharing of information on individual homeless decedents) on the programs of New York City’s Department of Homeless Services. These key elements had a positive impact on the department’s programs that target sleep-related infant deaths and hypothermia, drug overdose, and alcohol-related deaths among homeless persons. PMID:24148068

Programmed Cell Death and Caspase Functions During Neural Development.

PubMed

Yamaguchi, Yoshifumi; Miura, Masayuki

2015-01-01

Programmed cell death (PCD) is a fundamental component of nervous system development. PCD serves as the mechanism for quantitative matching of the number of projecting neurons and their target cells through direct competition for neurotrophic factors in the vertebrate peripheral nervous system. In addition, PCD plays roles in regulating neural cell numbers, canceling developmental errors or noise, and tissue remodeling processes. These findings are mainly derived from genetic studies that prevent cells from dying by apoptosis, which is a major form of PCD and is executed by activation of evolutionarily conserved cysteine protease caspases. Recent studies suggest that caspase activation can be coordinated in time and space at multiple levels, which might underlie nonapoptotic roles of caspases in neural development in addition to apoptotic roles. © 2015 Elsevier Inc. All rights reserved.

The Significance of the PD-L1 Expression in Non-Small-Cell Lung Cancer: Trenchant Double Swords as Predictive and Prognostic Markers.

PubMed

Takada, Kazuki; Toyokawa, Gouji; Shoji, Fumihiro; Okamoto, Tatsuro; Maehara, Yoshihiko

2018-03-01

Lung cancer is the leading cause of death due to cancer worldwide. Surgery, chemotherapy, and radiotherapy have been the standard treatment for lung cancer, and targeted molecular therapy has greatly improved the clinical course of patients with non-small-cell lung cancer (NSCLC) harboring driver mutations, such as in epidermal growth factor receptor and anaplastic lymphoma kinase genes. Despite advances in such therapies, the prognosis of patients with NSCLC without driver oncogene mutations remains poor. Immunotherapy targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) has recently been shown to improve the survival in advanced NSCLC. The PD-L1 expression on the surface of tumor cells has emerged as a potential biomarker for predicting responses to immunotherapy and prognosis after surgery in NSCLC. However, the utility of PD-L1 expression as a predictive and prognostic biomarker remains controversial because of the existence of various PD-L1 antibodies, scoring systems, and positivity cutoffs. In this review, we summarize the data from representative clinical trials of PD-1/PD-L1 immune checkpoint inhibitors in NSCLC and previous reports on the association between PD-L1 expression and clinical outcomes in patients with NSCLC. Furthermore, we discuss the future perspectives of immunotherapy and immune checkpoint factors. Copyright © 2017 Elsevier Inc. All rights reserved.

Powerful inner/outer controlled multi-target magnetic nanoparticle drug carrier prepared by liquid photo-immobilization

NASA Astrophysics Data System (ADS)

Guan, Yan-Qing; Zheng, Zhe; Huang, Zheng; Li, Zhibin; Niu, Shuiqin; Liu, Jun-Ming

2014-05-01

Nanomagnetic materials offer exciting avenues for advancing cancer therapies. Most researches have focused on efficient delivery of drugs in the body by incorporating various drug molecules onto the surface of nanomagnetic particles. The challenge is how to synthesize low toxic nanocarriers with multi-target drug loading. The cancer cell death mechanisms associated with those nanocarriers remain unclear either. Following the cell biology mechanisms, we develop a liquid photo-immobilization approach to attach doxorubicin, folic acid, tumor necrosis factor-α, and interferon-γ onto the oleic acid molecules coated Fe3O4 magnetic nanoparticles to prepare a kind of novel inner/outer controlled multi-target magnetic nanoparticle drug carrier. In this work, this approach is demonstrated by a variety of structural and biomedical characterizations, addressing the anti-cancer effects in vivo and in vitro on the HeLa, and it is highly efficient and powerful in treating cancer cells in a valuable programmed cell death mechanism for overcoming drug resistance.

Advances of Molecular Targeted Therapy in Gastric Cancer.

PubMed

Cetin, Bulent; Gumusay, Ozge; Cengiz, Mustafa; Ozet, Ahmet

2016-06-01

Gastric cancer is the second most common cause of cancer-related death in the world, and its prognosis remains poor with a median overall survival of 12 months for advanced disease. Advances in the understanding of molecular genetics have led to the development of directed molecular targeted therapy in gastric cancer, leading to improve patient outcomes and quality of life. In the treatment of human epidermal growth factor receptor 2 (HER2)-positive gastric cancer, the addition of trastuzumab significantly improves survival in the first-line setting of therapy. Ramucirumab, an antibody directed against vascular endothelial growth factor receptor 2, significantly improved progression-free and overall survival and has been approved for second-line treatment of gastric cancer. Anti-mesenchymal-epithelial transition (c-MET), mammalian target of rapamycin inhibitors, and polo-like kinase 1 inhibitors are under investigation as a novel therapeutic option for the treatment of gastric cancer. The novel therapies target the key immune checkpoint interaction between a T cell co-inhibitory receptor called programmed death 1 (PD-1) and one of its immunosuppressive ligands, PD-L1. This article reviews molecular targeted therapies in gastric cancer, in light of recent advances.

Will the European Union reach the United Nations Millennium declaration target of a 50% reduction of tuberculosis mortality between 1990 and 2015?

PubMed

van der Werf, Marieke J; Bonfigli, Sandro; Hruba, Frantiska

2017-07-06

The Millennium Development Goals (MDG) provide targets for 2015. MDG 6 includes a target to reduce the tuberculosis (TB) death rate by 50% compared with 1990. We aimed to assess whether this target was reached by the European Union (EU) and European Economic Area countries. We used Eurostat causes of death data to assess whether the target was reached in the EU. We calculated the reduction in reported and adjusted death rates and the annual average percentage decline based on the available data. Between 1999 and 2014, the TB death rate decreased by 50%, the adjusted death rate by 56% and the annual average percentage decline was 5.43% (95% confidence interval 4.94-6.74) for the EU. Twenty of 26 countries reporting >5 TB deaths in the first reporting year reached the target of 50% reduction in adjusted death rate. The EU reached the MDG target of a 50% reduction of the TB death rate and also the annual average percentage decline was larger than the 2.73% needed to reach the target. The World Health Organization 'End TB Strategy' requires a further reduction of the number of TB deaths of 35% by 2020 compared to 2015, which will challenge TB prevention and care services in the EU.

Photoreceptor cell death and rescue in retinal detachment and degenerations

PubMed Central

Murakami, Yusuke; Notomi, Shoji; Hisatomi, Toshio; Nakazawa, Toru; Ishibashi, Tatsuro; Miller, Joan W.; Vavvas, Demetrios G.

2013-01-01

Photoreceptor cell death is the ultimate cause of vision loss in various retinal disorders, including retinal detachment (RD). Photoreceptor cell death has been thought to occur mainly through apoptosis, which is the most characterized form of programmed cell death. The caspase family of cysteine proteases plays a central role for inducing apoptosis, and in experimental models of RD, dying photoreceptor cells exhibit caspase activation; however, there is a paradox that caspase inhibition alone does not provide a sufficient protection against photoreceptor cell loss, suggesting that other mechanisms of cell death are involved. Recent accumulating evidence demonstrates that non-apoptotic forms of cell death, such as autophagy and necrosis, are also regulated by specific molecular machinery, such as those mediated by autophagy-related proteins and receptor-interacting protein kinases, respectively. Here we summarize the current knowledge of cell death signaling and its roles in photoreceptor cell death after RD and other retinal degenerative diseases. A body of studies indicate that not only apoptotic but also autophagic and necrotic signaling are involved in photoreceptor cell death, and that combined targeting of these pathways may be an effective neuroprotective strategy for retinal diseases associated with photoreceptor cell loss. PMID:23994436

Necroptosis in neurodegenerative diseases: a potential therapeutic target

PubMed Central

Zhang, Shuo; Tang, Mi-bo; Luo, Hai-yang; Shi, Chang-he; Xu, Yu-ming

2017-01-01

Neurodegenerative diseases are a group of chronic progressive disorders characterized by neuronal loss. Necroptosis, a recently discovered form of programmed cell death, is a cell death mechanism that has necrosis-like morphological characteristics. Necroptosis activation relies on the receptor-interacting protein (RIP) homology interaction motif (RHIM). A variety of RHIM-containing proteins transduce necroptotic signals from the cell trigger to the cell death mediators RIP3 and mixed lineage kinase domain-like protein (MLKL). RIP1 plays a particularly important and complex role in necroptotic cell death regulation ranging from cell death activation to inhibition, and these functions are often cell type and context dependent. Increasing evidence suggests that necroptosis plays an important role in the pathogenesis of neurodegenerative diseases. Moreover, small molecules such as necrostatin-1 are thought inhibit necroptotic signaling pathway. Understanding the precise mechanisms underlying necroptosis and its interactions with other cell death pathways in neurodegenerative diseases could provide significant therapeutic insights. The present review is aimed at summarizing the molecular mechanisms of necroptosis and highlighting the emerging evidence on necroptosis as a major driver of neuron cell death in neurodegenerative diseases. PMID:28661482

Suicide Interventions Targeted toward At-Risk Youth

ERIC Educational Resources Information Center

Langhinrichsen-Rohling, Jennifer; Lamis, Dorian A.; McCullars, Adrianne

2012-01-01

Suicide is currently the third leading cause of death among youth; it has been named a public health concern. A number of programs have been developed to prevent suicide; many of these involve intervening with youth who are known to be at-risk because of their depression, expressed suicide ideation, or previous suicide attempts. This paper serves…

Smoke alarm giveaway and installation programs: an economic evaluation.

PubMed

Liu, Ying; Mack, Karin A; Diekman, Shane T

2012-10-01

The burden of residential fire injury and death is substantial. Targeted smoke alarm giveaway and installation programs are popular interventions used to reduce residential fire mortality and morbidity. To evaluate the cost effectiveness and cost benefit of implementing a giveaway or installation program in a small hypothetic community with a high risk of fire death and injury through a decision-analysis model. Model inputs included program costs; program effectiveness (life-years and quality-adjusted life-years saved); and monetized program benefits (medical cost, productivity, property loss and quality-of-life losses averted) and were identified through structured reviews of existing literature (done in 2011) and supplemented by expert opinion. Future costs and effectiveness were discounted at a rate of 3% per year. All costs were expressed in 2011 U.S. dollars. Cost-effectiveness analysis (CEA) resulted in an average cost-effectiveness ratio (ACER) of $51,404 per quality-adjusted life-years (QALYs) saved and $45,630 per QALY for the giveaway and installation programs, respectively. Cost-benefit analysis (CBA) showed that both programs were associated with a positive net benefit with a benefit-cost ratio of 2.1 and 2.3, respectively. Smoke alarm functional rate, baseline prevalence of functional alarms, and baseline home fire death rate were among the most influential factors for the CEA and CBA results. Both giveaway and installation programs have an average cost-effectiveness ratio similar to or lower than the median cost-effectiveness ratio reported for other interventions to reduce fatal injuries in homes. Although more effort is required, installation programs result in lower cost per outcome achieved compared with giveaways. Published by Elsevier Inc.

Modeling activity and target-dependent developmental cell death of mouse retinal ganglion cells ex vivo.

PubMed

Voyatzis, Sylvie; Muzerelle, Aude; Gaspar, Patricia; Nicol, Xavier

2012-01-01

Programmed cell death is widespread during the development of the central nervous system and serves multiple purposes including the establishment of neural connections. In the mouse retina a substantial reduction of retinal ganglion cells (RGCs) occurs during the first postnatal week, coinciding with the formation of retinotopic maps in the superior colliculus (SC). We previously established a retino-collicular culture preparation which recapitulates the progressive topographic ordering of RGC projections during early post-natal life. Here, we questioned whether this model could also be suitable to examine the mechanisms underlying developmental cell death of RGCs. Brn3a was used as a marker of the RGCs. A developmental decline in the number of Brn3a-immunolabelled neurons was found in the retinal explant with a timing that paralleled that observed in vivo. In contrast, the density of photoreceptors or of starburst amacrine cells increased, mimicking the evolution of these cell populations in vivo. Blockade of neural activity with tetrodotoxin increased the number of surviving Brn3a-labelled neurons in the retinal explant, as did the increase in target availability when one retinal explant was confronted with 2 or 4 collicular slices. Thus, this ex vivo model reproduces the developmental reduction of RGCs and recapitulates its regulation by neural activity and target availability. It therefore offers a simple way to analyze developmental cell death in this classic system. Using this model, we show that ephrin-A signaling does not participate to the regulation of the Brn3a population size in the retina, indicating that eprhin-A-mediated elimination of exuberant projections does not involve developmental cell death.

Screening for Cryptococcal Antigenaemia in Patients Accessing an Antiretroviral Treatment Program in South Africa

PubMed Central

Jarvis, Joseph N; Lawn, Stephen D; Vogt, Monica; Bangani, Nonzwakazi; Wood, Robin; Harrison, Thomas S

2009-01-01

Background Cryptococcal meningitis is a leading cause of death in AIDS patients and contributes substantially to the high early mortality in antiretroviral treatment (ART) programs in low-resource settings. Screening for cryptococcal antigen (CRAG) in patients enrolling in ART programs may identify those at risk of cryptococcal meningitis and permit targeted use of pre-emptive therapy. Methods In this retrospective study, CRAG was measured in stored plasma samples obtained from patients as they enrolled in a well characterised ART cohort in South Africa. The predictive value of screening for CRAG prior to ART for development of microbiologically confirmed cryptococcal meningitis or death during the first year of follow-up was determined. Results Of 707 participants with a baseline median CD4 count of 97 (IQR 46-157) cells/μL, 46 (7%) had a positive CRAG. Antigenaemia was 100% sensitive for predicting development of cryptococcal meningitis during the first year of ART and in multivariate analysis was an independent predictor of mortality (AHR 3.2, 95%CI 1.5-6.6). Most (92%) cases of cryptococcal meningitis developed in patients with a CD4 count ≤100 cells/μL. In this sub-set of patients, a CRAG titre ≥1 in 8 was 100% sensitive and 96% specific for predicting incident cryptococcal meningitis during the first year of ART in those with no previous history of the disease. Conclusions CRAG screening prior to commencing ART in patients with a CD4 count ≤100 cells/μL is highly effective at identifying those at risk of cryptococcal meningitis and death and might permit implementation of a targeted pre-emptive treatment strategy. PMID:19222372

Necroptosis in cardiovascular disease - a new therapeutic target.

PubMed

Gupta, Kartik; Phan, Noel; Wang, Qiwei; Liu, Bo

2018-05-01

Contrary to the apoptosis-necrosis binary view of cell death, recent experimental evidence demonstrates that several forms of necrosis, represented by necroptosis, are regulated or programmed in nature. Multiple death stimuli known to be associated with cardiovascular disease are capable of causing either apoptosis or necroptosis. Whether a cell dies from apoptosis or necroptosis has distinct consequences on inflammation. It is known that apoptosis, a non-lytic form of death mediated by the caspase family of proteases, does not generally evoke an immune response. Necroptosis, on the other hand, is a lytic form of cell death. Due to the rapid loss of plasma membrane integrity, cells dying from necroptosis release proinflammatory intracellular contents and subsequently cause inflammation. Our review delineates various genetic and biochemical evidence that demonstrates a compelling role of necroptosis in the pathogenesis and/or progression of cardiovascular disease including myocardial infarction, atherosclerosis, and aortic aneurysm. Through recent studies of necroptosis in cardiovascular diseases, we attempt to discuss the role of necroptosis in vascular inflammation as well as the potential of necroptosis inhibitors in future clinical management of cardiovascular events. Inhibiting necroptosis in the vasculature has an overall protective role and necroptosis may represent a new therapeutic target to prevent the development and progression of cardiovascular diseases. Copyright © 2018 Elsevier Ltd. All rights reserved.

Impact of a Six-Year Project to Enhance the Awareness of Community-Based Palliative Care on the Place of Death.

PubMed

Murakami, Nozomu; Tanabe, Kouichi; Morita, Tatsuya; Fujikawa, Yasunaga; Koseki, Shiro; Kajiura, Shinya; Nakajima, Kazunori; Hayashi, Ryuji

2018-05-03

To examine the clinical outcomes of a project to enhance the awareness of community-based palliative care (awareness-enhancing project), focusing on home death and care rates in communities. A single-center study on community-based intervention was conducted. The awareness-enhancing project, consisting of three intervention approaches (outreach, palliative care education for community-based medical professionals, and information-sharing tool use), was executed, and changes in the home death rate in the community were examined. The home death rate markedly exceeded the national mean from 2010. In 2012-2013, it was as high as 19.9%, greater than the previous 5.9% (p = 0.001). Through multivariate analysis, the participation of home care physicians and visiting nurses in a palliative care education program, and patients' Palliative Prognostic Index values were identified as factors significantly influencing the home death rate. The three intervention approaches time dependently increased the home death rate as a clinical outcome in the community, although they targeted limited areas. These approaches may aid in increasing the number of individuals who die in their homes.

Love is a battlefield: programmed cell death during fertilization.

PubMed

Heydlauff, Juliane; Groß-Hardt, Rita

2014-03-01

Plant development and growth is sustained by the constant generation of tremendous amounts of cells, which become integrated into various types of tissues and organs. What is all too often overlooked is that this thriving life also requires the targeted degeneration of selected cells, which undergo cell death according to genetically encoded programmes or environmental stimuli. The side-by-side existence of generation and demise is particularly evident in the haploid phase of the flowering plants cycle. Here, the lifespan of terminally differentiated accessory cells contrasts with that of germ cells, which by definition live on to form the next generation. In fact, with research in recent years it is becoming increasingly clear that the gametophytes of flowering plants constitute an attractive and powerful system for investigating the molecular mechanisms underlying selective cell death.

Targeting programmed cell death ligand 1 by CRISPR/Cas9 in osteosarcoma cells

PubMed Central

Liao, Yunfei; Chen, Lulu; Feng, Yong; Shen, Jacson; Gao, Yan; Cote, Gregory; Choy, Edwin; Harmon, David; Mankin, Henry; Hornicek, Francis; Duan, Zhenfeng

2017-01-01

Programmed cell death ligand 1 (PD-L1) is a transmembrane protein that is expressed on tumor cells that suppresses the T cell-mediated immune response. Therapies targeting the PD-L1 pathway promote anti-tumor immunity and have shown promising results in some types of cancers. However, the functional and therapeutic roles of PD-L1 in osteosarcoma remain largely unknown. In this study, we found that PD-L1 protein was expressed in osteosarcoma cell lines and tissue microarray of patient tumors. Tissue microarray immunohistochemistry analysis showed that the overall and five-year survival rates of patients with high levels of PD-L1 expression were significantly shorter than patients with low levels. High levels of PD-L1 expression were also associated with metastasis in osteosarcoma patients. Furthermore, we applied the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system to target PD-L1 gene at the DNA level in osteosarcoma cell lines. We found that the expression of PD-L1 could be efficiently disrupted by CRISPR/Cas9 system and PD-L1 knockdown increased drug sensitivities for doxorubicin and paclitaxel. These results suggest that PD-L1 is an independent prognostic factor in osteosarcoma and that PD-L1 knockout by CRISPR/Cas9 may be a therapeutic approach for the treatment of osteosarcoma. PMID:28415820

Targeting programmed cell death ligand 1 by CRISPR/Cas9 in osteosarcoma cells.

PubMed

Liao, Yunfei; Chen, Lulu; Feng, Yong; Shen, Jacson; Gao, Yan; Cote, Gregory; Choy, Edwin; Harmon, David; Mankin, Henry; Hornicek, Francis; Duan, Zhenfeng

2017-05-02

Programmed cell death ligand 1 (PD-L1) is a transmembrane protein that is expressed on tumor cells that suppresses the T cell-mediated immune response. Therapies targeting the PD-L1 pathway promote anti-tumor immunity and have shown promising results in some types of cancers. However, the functional and therapeutic roles of PD-L1 in osteosarcoma remain largely unknown. In this study, we found that PD-L1 protein was expressed in osteosarcoma cell lines and tissue microarray of patient tumors. Tissue microarray immunohistochemistry analysis showed that the overall and five-year survival rates of patients with high levels of PD-L1 expression were significantly shorter than patients with low levels. High levels of PD-L1 expression were also associated with metastasis in osteosarcoma patients. Furthermore, we applied the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system to target PD-L1 gene at the DNA level in osteosarcoma cell lines. We found that the expression of PD-L1 could be efficiently disrupted by CRISPR/Cas9 system and PD-L1 knockdown increased drug sensitivities for doxorubicin and paclitaxel. These results suggest that PD-L1 is an independent prognostic factor in osteosarcoma and that PD-L1 knockout by CRISPR/Cas9 may be a therapeutic approach for the treatment of osteosarcoma.

Past, Current, and Future Developments of Therapeutic Agents for Treatment of Chronic Hepatitis B Virus Infection.

PubMed

Pei, Yameng; Wang, Chunting; Yan, S Frank; Liu, Gang

2017-08-10

For decades, treatment of hepatitis B virus (HBV) infection has been relying on interferon (IFN)-based therapies and nucleoside/nucleotide analogues (NAs) that selectively target the viral polymerase reverse transcriptase (RT) domain and thereby disrupt HBV viral DNA synthesis. We have summarized here the key steps in the HBV viral life cycle, which could potentially be targeted by novel anti-HBV therapeutics. A wide range of next-generation direct antiviral agents (DAAs) with distinct mechanisms of actions are discussed, including entry inhibitors, transcription inhibitors, nucleoside/nucleotide analogues, inhibitors of viral ribonuclease H (RNase H), modulators of viral capsid assembly, inhibitors of HBV surface antigen (HBsAg) secretion, RNA interference (RNAi) gene silencers, antisense oligonucleotides (ASOs), and natural products. Compounds that exert their antiviral activities mainly through host factors and immunomodulation, such as host targeting agents (HTAs), programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors, and Toll-like receptor (TLR) agonists, are also discussed. In this Perspective, we hope to provide an overview, albeit by no means being comprehensive, for the recent development of novel therapeutic agents for the treatment of chronic HBV infection, which not only are able to sustainably suppress viral DNA but also aim to achieve functional cure warranted by HBsAg loss and ultimately lead to virus eradication and cure of hepatitis B.

Chemotherapeutic agents for the treatment of metastatic breast cancer: An update.

PubMed

Abotaleb, Mariam; Kubatka, Peter; Caprnda, Martin; Varghese, Elizabeth; Zolakova, Barbora; Zubor, Pavol; Opatrilova, Radka; Kruzliak, Peter; Stefanicka, Patrik; Büsselberg, Dietrich

2018-05-01

Breast cancer is the second greatest cause of death among women worldwide; it comprises a group of heterogeneous diseases that evolves due to uncontrolled cellular growth and differentiation and the loss of normal programmed cell death. There are different molecular sub-types of breast cancer; therefore, various options are selected for treatment of different forms of metastatic breast cancer. However, the use of chemotherapeutic drugs is usually accompanied by deleterious side effects and the development of drug resistance when applied for a longer period. This review offers a classification of these chemotherapeutic agents according to their modes of action and therefore improves the understanding of molecular targets that are affected during treatment. Overall, it will allow the clinician to identify more specific targets to increase the effectiveness of a drug and to reduce general toxicity, resistance and other side effects. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Interrogating the relevance of mitochondrial apoptosis for vertebrate development and postnatal tissue homeostasis

PubMed Central

Kaufmann, Thomas; Villunger, Andreas

2016-01-01

“Programmed cell death or ‘apoptosis’ is critical for organogenesis during embryonic development and tissue homeostasis in the adult. Its deregulation can contribute to a broad range of human pathologies, including neurodegeneration, cancer, or autoimmunity…” These or similar phrases have become generic opening statements in many reviews and textbooks describing the physiological relevance of apoptotic cell death. However, while the role in disease has been documented beyond doubt, facilitating innovative drug discovery, we wonder whether the former is really true. What goes wrong in vertebrate development or in adult tissue when the main route to apoptotic cell death, controlled by the BCL2 family, is impaired? Such scenarios have been mimicked by deletion of one or more prodeath genes within the BCL2 family, and gene targeting studies in mice exploring the consequences have been manifold. Many of these studies were geared toward understanding the role of BCL2 family proteins and mitochondrial apoptosis in disease, whereas fewer focused in detail on their role during normal development or tissue homeostasis, perhaps also due to an irritating lack of phenotype. Looking at these studies, the relevance of classical programmed cell death by apoptosis for development appears rather limited. Together, these many studies suggest either highly selective and context-dependent contributions of mitochondrial apoptosis or significant redundancy with alternative cell death mechanisms, as summarized and discussed here. PMID:27798841

FDA approved Immunosuppressants Targeting Staphylococcal Superantigens: Mechanisms and Insights

DTIC Science & Technology

2016-12-02

cells , resulting in polyclonal T- cell activation [4-6]. Staphylococcal superantigens hyperactivate cells of the innate immune system and adaptive T... innate host defense responses, antiviral genes, apoptotic programs, immunoproteasomes, and has many immunomodulatory functions. The cell death...1692. 104. Mendis C, Das R, Hammamieh R, Royaee A, Yang D, Peel S, et al. Transcriptional response signature of human lymphoid cells to

Sexual Behavior Among Young Carers in the Context of a Kenyan Empowerment Program Combining Cash-Transfer, Psychosocial Support, and Entrepreneurship.

PubMed

Goodman, Michael L; Selwyn, Beatrice J; Morgan, Robert O; Lloyd, Linda E; Mwongera, Moses; Gitari, Stanley; Keiser, Philip H

2016-01-01

This study examined associations between sexual initiation, unprotected sex, and having multiple sex partners in the past year with participation in a three-year empowerment program targeting orphan and vulnerable children (OVC). The Kenya-based program combines community-conditioned cash transfer, psychosocial empowerment, health education, and microenterprise development. Program participants (n = 1,060) were interviewed in a cross-sectional design. Analyses used gender-stratified hierarchical logit models to assess program participation and other potential predictors. Significant predictors of increased female sexual activity included less program exposure, higher age, younger age at most recent parental death, fewer years of schooling, higher food consumption, higher psychological resilience, and lower general self-efficacy. Significant predictors of increased male sexual activity included more program exposure, higher age, better food consumption, not having a living father, and literacy. Findings support a nuanced view of current cash transfer programs, where female sexual activity may be reduced through improved financial status but male sexual activity may increase. Targeting of OVC sexual risk behaviors would likely benefit from being tailored according to associations found in this study. Data suggest involving fathers in sexual education, targeting women who lost a parent at a younger age, and providing social support for female OVC may decrease risk of human immunodeficiency virus (HIV) transmission.

An Innovative Model for Naloxone Use Within an OTP Setting: A Prospective Cohort Study

PubMed Central

Katzman, Joanna G.; Takeda, Mikiko Y.; Bhatt, Snehal R.; Moya Balasch, Monica; Greenberg, Nina; Yonas, Howard

2018-01-01

Objectives: Unintentional opioid overdose deaths are a public health crisis, and naloxone is the most effective harm reduction tool to curb many of these deaths. There is growing evidence that take-home naloxone can prevent opioid overdose in targeted populations. The goal of this study is to measure the opioid overdose reversal rate with take-home naloxone among participants with a diagnosis of opioid use disorder (OUD) in an opioid treatment program (OTP) setting. Methods: Patients enrolled in an outpatient OTP program were eligible for this prospective cohort study between April 4, 2016 and July 4, 2016. Two hundred forty-four study participants received overdose education, instruction on how to use naloxone, and were provided with 2 doses of a take-home naloxone auto-injector kit. They were subsequently followed for 3 months. Results: Thirty-one study participants reported overdose reversals using naloxone auto-injector kits on 38 community members. All overdose reversals were heroin-related. Eighty-seven per cent of the community members reversed with naloxone were friends or relatives of the study participants. Conclusions: This study validates that naloxone is not commonly used on the index study participant, but is often used on a secondary target among people who inject drugs. The large number of overdose reversals reported in this prospective study suggests that this novel model for naloxone use may be replicated at other OTP settings to reduce opioid overdose deaths. PMID:29227321

Factors associated with treatment failure, dropout, and death in a cohort of tuberculosis patients in Recife, Pernambuco State, Brazil.

PubMed

de Albuquerque, Maria de Fátima Pessoa Militão; Ximenes, Ricardo Arraes de Alencar; Lucena-Silva, Norma; de Souza, Wayner Vieira; Dantas, Andréa Tavares; Dantas, Odimariles Maria Souza; Rodrigues, Laura Cunha

2007-07-01

A cohort of cases initiating tuberculosis treatment from May 2001 to July 2003 was followed in Recife, Pernambuco State, Brazil, to investigate biological, clinical, social, lifestyle, and healthcare access factors associated with three negative tuberculosis treatment outcomes (treatment failure, dropout, and death) separately and as a group. Treatment failure was associated with treatment delay, illiteracy, and alcohol consumption. Factors associated with dropout were age, prior TB treatment, and illiteracy. Death was associated with age, treatment delay, HIV co-infection, and head of family's income. Main factors associated with negative treatment outcomes as a whole were age, HIV co-infection, illiteracy, alcoholism, and prior TB treatment. We suggest the following strategies to increase cure rates: further training of the Family Health Program personnel in TB control, awareness-raising on the need to tailor their activities to special care for cases (e.g., literacy training); targeting use of directly observed therapy for higher risk groups; establishment of a flexible referral scheme to handle technical and psychosocial problems, including alcoholism; and increased collaboration with the HIV/AIDS program.

Recent updates of precision therapy for gastric cancer: Towards optimal tailored management.

PubMed

Joo, Moon Kyung; Park, Jong-Jae; Chun, Hoon Jai

2016-05-21

Signaling pathways of gastric carcinogenesis and gastric cancer progression are being avidly studied to seek optimal treatment of gastric cancer. Among them, hepatocyte growth factor (HGF)/c-MET, phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathways have been widely investigated. Their aberrant expression or mutation has been significantly associated with advanced stage or poor prognosis of gastric cancer. Recently, aberrations of immune checkpoints including programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) have been suggested as an important step in the formation of a microenvironment favorable for gastric cancer. Accomplishments in basic research have led to the development of novel agents targeting these signaling pathways. However, phase III studies of selective anti-HGF/c-MET antibodies and mTOR inhibitor failed to show significant benefits in terms of overall survival and progression-free survival. Few agents directly targeting STAT3 have been developed. However, this target is still critical issue in terms of chemoresistance, and SH2-containing protein tyrosine phosphatase 1 might be a significant link to effectively inhibit STAT3 activity. Inhibition of PD-1/PD-L1 showed durable efficacy in phase I studies, and phase III evaluation is warranted. Therapeutic strategy to concurrently inhibit multiple tyrosine kinases is a reasonable option, however, lapatinib needs to be further evaluated to identify good responders. Regorafenib has shown promising effectiveness in prolonging progression-free survival in a phase II study. In this topic highlight, we review the biologic roles and outcomes of clinical studies targeting these signaling pathways.

The role of necroptosis in pulmonary diseases.

PubMed

Mizumura, Kenji; Maruoka, Shuichiro; Gon, Yasuhiro; Choi, Augustine M K; Hashimoto, Shu

2016-11-01

By regulating the cell number and eliminating harmful cells, programmed cell death plays a critical role in development, homeostasis, and disease. While apoptosis is a recognized form of programmed cell death, necrosis was considered a type of uncontrolled cell death induced by extreme physical or chemical stress. However, recent studies have revealed the existence of a genetically programmed and regulated form of necrosis, termed necroptosis. Necroptosis is defined as necrotic cell death that is dependent on receptor-interacting protein kinase 3 (RIPK3). RIPK3, receptor-interacting protein kinase 1 (RIPK1), and a mixed-lineage kinase domain-like protein (MLKL) form a multiprotein complex called a necrosome. Although necroptosis generally provides a cell-autonomous host defense, on the other hand, cell rupture caused by necroptosis induces inflammation through the release of damage-associated molecular patterns, such as mitochondrial DNA, HMGB1, and IL-1. Previously, necroptosis was considered an alternative to apoptosis, but it is becoming increasingly clear that necroptosis itself is relevant to clinical disease, independent of apoptosis. According to some recent studies, autophagy, a cellular process for organelle and protein turnover, regulates necroptosis. This review outlines the principal components of necroptosis and provides an overview of the emerging importance of necroptosis in the pathogenesis of pulmonary disease, including chronic obstructive pulmonary disease, lung cancer, infection, and sepsis. We also discuss the molecular relationship between necroptosis and autophagy. Strategies targeting necroptosis may yield novel therapies for pulmonary diseases. Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Repurposing anticancer drugs for targeting necroptosis.

PubMed

Fulda, Simone

2018-04-25

Necroptosis represents a form of programmed cell death that can be engaged by various upstream signals, for example by ligation of death receptors, by viral sensors or by pattern recognition receptors. It depends on several key signaling proteins, including the kinases Receptor-Interacting Protein (RIP)1 and RIP3 and the pseudokinase mixed-lineage kinase domain-like protein (MLKL). Necroptosis has been implicated in a number of physiological and pathophysiological conditions and is disturbed in many human diseases. Thus, targeted interference with necroptosis signaling may offer new opportunities for the treatment of human diseases. Besides structure-based drug design, in recent years drug repositioning has emerged as a promising alternative to develop drug-like compounds. There is accumulating evidence showing that multi-targeting kinase inhibitors, for example Dabrafenib, Vemurafenib, Sorafenib, Pazopanib and Ponatinib, used for the treatment of cancer also display anti-necroptotic activity. This review summarizes recent evidence indicating that some anticancer kinase inhibitors also negatively affect necroptosis signaling. This implies that some cancer therapeutics may be repurposed for other pathologies, e.g. ischemic or inflammatory diseases.

Concanavalin A: A potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis for cancer therapeutics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Wen-wen; Yu, Jia-ying; Xu, Huai-long

2011-10-22

Highlights: {yields} ConA induces cancer cell death targeting apoptosis and autophagy. {yields} ConA inhibits cancer cell angiogenesis. {yields} ConA is utilized in pre-clinical and clinical trials. -- Abstract: Concanavalin A (ConA), a Ca{sup 2+}/Mn{sup 2+}-dependent and mannose/glucose-binding legume lectin, has drawn a rising attention for its remarkable anti-proliferative and anti-tumor activities to a variety of cancer cells. ConA induces programmed cell death via mitochondria-mediated, P73-Foxo1a-Bim apoptosis and BNIP3-mediated mitochondrial autophagy. Through IKK-NF-{kappa}B-COX-2, SHP-2-MEK-1-ERK, and SHP-2-Ras-ERK anti-angiogenic pathways, ConA would inhibit cancer cell survival. In addition, ConA stimulates cell immunity and generates an immune memory, resisting to the same genotypic tumor.more » These biological findings shed light on new perspectives of ConA as a potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis in pre-clinical or clinical trials for cancer therapeutics.« less

Programmed Cell Death Ligand 1 Expression in Primary Central Nervous System Lymphomas: A Clinicopathological Study.

PubMed

Hayano, Azusa; Komohara, Yoshihiro; Takashima, Yasuo; Takeya, Hiroto; Homma, Jumpei; Fukai, Junya; Iwadate, Yasuo; Kajiwara, Koji; Ishizawa, Shin; Hondoh, Hiroaki; Yamanaka, Ryuya

2017-10-01

Programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) have been shown to predict response to PD-L1/PD-1-targeted therapy. We analyzed PD-L1 expression in primary central nervous system lymphomas (PCNSLs). PD-L1 protein and mRNA expression were evaluated in 64 PCNSL tissue samples. IFN-γ, IL-10, CD4, and CD8 mRNA expression was also evaluated. PD-L1 protein was detected in tumor cells in 2 (4.1%) cases and in tumor microenvironments in 25 (52%) cases. PD-L1 mRNA positively correlated with IFN-γ (p=0.0024) and CD4 (p=0.0005) mRNA expression. IFN-γ mRNA positively correlated with CD8 mRNA expression (p=0.0001). Furthermore, tumor cell PD-L1 expression correlated positively with overall survival (p=0.0177), whereas microenvironmental PD-L1 expression exhibited an insignificant negative trend with overall survival (p=0.188). PD-L1 was expressed on both tumor and/or tumor-infiltrating immune cells in PCNSL. The biological roles of this marker warrant further investigation. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

A novel Meloidogyne enterolobii effector MeTCTP promotes parasitism by suppressing programmed cell death in host plants.

PubMed

Zhuo, Kan; Chen, Jiansong; Lin, Borong; Wang, Jing; Sun, Fengxia; Hu, Lili; Liao, Jinling

2017-01-01

Meloidogyne enterolobii is one of the most important plant-parasitic nematodes that can overcome the Mi-1 resistance gene and damage many economically important crops. Translationally controlled tumour protein (TCTP) is a multifunctional protein that exists in various eukaryotes and plays an important role in parasitism. In this study, a novel M. enterolobii TCTP effector, named MeTCTP, was identified and functionally characterized. MeTCTP was specifically expressed within the dorsal gland and was up-regulated during M. enterolobii parasitism. Transient expression of MeTCTP in protoplasts from tomato roots showed that MeTCTP was localized in the cytoplasm of the host cells. Transgenic Arabidopsis thaliana plants overexpressing MeTCTP were more susceptible to M. enterolobii infection than wild-type plants in a dose-dependent manner. By contrast, in planta RNA interference (RNAi) targeting MeTCTP suppressed the expression of MeTCTP in infecting nematodes and attenuated their parasitism. Furthermore, MeTCTP could suppress programmed cell death triggered by the pro-apoptotic protein BAX. These results demonstrate that MeTCTP is a novel plant-parasitic nematode effector that promotes parasitism, probably by suppressing programmed cell death in host plants. © 2016 BSPP and John Wiley & Sons Ltd.

The role of necroptosis in the treatment of diseases.

PubMed

Cho, Young Sik

2018-04-11

Necroptosis is an emerging form of programmed cell death occurring via active and well-regulated necrosis, distinct from apoptosis morphologically, and biochemically. Necroptosis is mainly unmasked when apoptosis is compromised in response to cell stress. Unlike apoptotic cells, which are cleared by macrophages or neighboring cells, necrotic cells release danger signals, triggering inflammation, and exacerbating tissue damage. Evidence increasingly suggests that programmed necrosis is not only associated with pathophysiology of disease, but also induces innate immune response to viral infection. Therefore, necroptotic cell death plays both physiological and pathological roles. Physiologically, necroptosis induce an innate immune response as well as premature assembly of viral particles in cells infected with virus that abrogates host apoptotic machinery. On the other hand, necroptosis per se is detrimental, causing various diseases such as sepsis, neurodegenerative diseases and ischemic reperfusion injury. This review discusses the signaling pathways leading to necroptosis, associated necroptotic proteins with target-specific inhibitors and diseases involved. Several studies currently focus on protective approaches to inhibit necroptotic cell death. In cancer biology, however, anticancer drug resistance severely hampers the efficacy of chemotherapy based on apoptosis. Pharmacological switch of cell death finds therapeutic application in drug-resistant cancers. Therefore, the possible clinical role of necroptosis in cancer control will be discussed in brief.

Mechanisms of immune evasion and current status of checkpoint inhibitors in non-small cell lung cancer.

PubMed

Qin, Angel; Coffey, David G; Warren, Edus H; Ramnath, Nithya

2016-09-01

In the past several years, immunotherapy has emerged as a viable treatment option for patients with advanced non-small cell lung cancer (NSCLC) without actionable driver mutations that have progressed on standard chemotherapy. We are also beginning to understand the methods of immune evasion employed by NSCLC which likely contribute to the 20% response rate to immunotherapy. It is also yet unclear what tumor or patient factors predict response to immunotherapy. The objectives of this review are (1) review the immunogenicity of NSCLC (2) describe the mechanisms of immune evasion (3) summarize efforts to target the anti-program death-1 (PD-1) and anti-program death-ligand 1(PD-L1) pathway (4) outline determinants of response to PD-1/PD-L1 therapy and (5) discuss potential future areas for research. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Development of Halo Nevi in a Lung Cancer Patient: A Novel Immune-Related Cutaneous Event from Atezolizumab.

PubMed

Birnbaum, Mathew R; Ma, Michelle W; Casey, Michael A; Amin, Bijal D; Jacobson, Mark; Cheng, Haiying; McLellan, Beth N

2017-10-01

Immunotherapy-induced vitiligo is an immune-related adverse event (irAE) observed in metastatic melanoma patients treated with immune checkpoint inhibitors that target the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1) pathways. To date, the development of leukoderma, poliosis, and halo nevi during immunotherapy has largely been reported in metastatic melanoma patients. We report a case of immunotherapy-induced leukoderma presenting as halo nevi in a patient with non-small cell lung cancer (NSCLC) treated with atezolizumab, a programmed cell death ligand (PD-L1) antibody. Immunotherapy-induced vitiligo in metastatic melanoma patients may be associated with improved survival, but it remains to be determined whether its occurrence in non-melanoma cancers has the same prognostic significance.

J Drugs Dermatol. 2017;16(10):1047-1049.

On Programmed Cell Death in Plasmodium falciparum: Status Quo

PubMed Central

Engelbrecht, Dewaldt; Durand, Pierre Marcel; Coetzer, Thérèsa Louise

2012-01-01

Conflicting arguments and results exist regarding the occurrence and phenotype of programmed cell death (PCD) in the malaria parasite Plasmodium falciparum. Inconsistencies relate mainly to the number and type of PCD markers assessed and the different methodologies used in the studies. In this paper, we provide a comprehensive overview of the current state of knowledge and empirical evidence for PCD in the intraerythrocytic stages of P. falciparum. We consider possible reasons for discrepancies in the data and offer suggestions towards more standardised investigation methods in this field. Furthermore, we present genomic evidence for PCD machinery in P. falciparum. We discuss the potential adaptive or nonadaptive role of PCD in the parasite life cycle and its possible exploitation in the development of novel drug targets. Lastly, we pose pertinent unanswered questions concerning the PCD phenomenon in P. falciparum to provide future direction. PMID:22287973

Recent developments in small molecule therapies for renal cell carcinoma.

PubMed

Song, Minsoo

2017-12-15

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults and is known to be the 10th most common type of cancer in the world. Most of the currently available RCC drugs are tyrosine kinase inhibitors (TKIs). However, combination therapies of TKIs and immune checkpoint inhibitors such as programmed cell death protein 1 (PD-1) and programmed cell death protein 1 ligand 1 (PD-L1) inhibitors are the focus of most of the final stage clinical trials. Meanwhile, other small molecule therapies for RCC that target indoleamine-2,3-dioxygenase (IDO1), glutaminase, C-X-C chemokine receptor 4 (CXCR4), and transglutaminase 2 (TG2) are emerging as the next generation of therapeutics. In this review, these three major streams for the development of small molecule drugs for RCC are described. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Semaphorin 3A is a retrograde cell death signal in developing sympathetic neurons

PubMed Central

Wehner, Amanda B.; Abdesselem, Houari; Dickendesher, Travis L.; Imai, Fumiyasu; Yoshida, Yutaka; Giger, Roman J.; Pierchala, Brian A.

2016-01-01

ABSTRACT During development of the peripheral nervous system, excess neurons are generated, most of which will be lost by programmed cell death due to a limited supply of neurotrophic factors from their targets. Other environmental factors, such as ‘competition factors' produced by neurons themselves, and axon guidance molecules have also been implicated in developmental cell death. Semaphorin 3A (Sema3A), in addition to its function as a chemorepulsive guidance cue, can also induce death of sensory neurons in vitro. The extent to which Sema3A regulates developmental cell death in vivo, however, is debated. We show that in compartmentalized cultures of rat sympathetic neurons, a Sema3A-initiated apoptosis signal is retrogradely transported from axon terminals to cell bodies to induce cell death. Sema3A-mediated apoptosis utilizes the extrinsic pathway and requires both neuropilin 1 and plexin A3. Sema3A is not retrogradely transported in older, survival factor-independent sympathetic neurons, and is much less effective at inducing apoptosis in these neurons. Importantly, deletion of either neuropilin 1 or plexin A3 significantly reduces developmental cell death in the superior cervical ganglia. Taken together, a Sema3A-initiated apoptotic signaling complex regulates the apoptosis of sympathetic neurons during the period of naturally occurring cell death. PMID:27143756

Highlights of Fire in the United States: Deaths, Injuries, Dollar Loss, and Incidents at the National, State, and Local Levels.

ERIC Educational Resources Information Center

National Fire Prevention and Control Administration (DOC), Washington, DC. National Fire Data Center.

This report provides fire departments, federal and state governments, and others active in the fire protection field with information which can be used to improve the efficacy and targeting of fire prevention programs. As a byproduct, it illustrates ways that state and local governments might analyze their own fire problems. The report describes…

Estimating the burden of lung cancer and the efficiency of home radon mitigation systems in some Canadian provinces.

PubMed

Al-Arydah, Mo'tassem

2018-06-01

Lung cancer (LC) is the leading cause of death of cancer in Canada in both men and women, and indoor radon is the second leading cause of LC after tobacco smoking. The Population Attributable Risk (PAR) is used to assess radon exposure risk. In this work we estimate the burden of LC in some Canadian provinces. We use the PAR to identify the radon levels responsible for most LC cases. Finally, we use the PAR function of the two variables, radon action and target levels, to search for a possible optimal mitigation program. The LC burden for Ontario, Alberta, Manitoba, Quebec and British Columbia was estimated using provincial radon and mortality data. Then the PAR and LC cases for these provinces were estimated over the period 2006-2009 at different given indoor radon exposure levels. Finally, the PAR function when radon action levels and radon target levels are variables was analyzed. The highest burden of LC in 2006-2009 was in Ontario and Quebec. During the period 2006-2009, 6% of houses in Ontario, 9% of houses in Alberta, 19% of houses in Manitoba, 7% of houses in Quebec, and 5% of houses in British Columbia had radon levels higher than 200 Bq/m 3 and were responsible about 913, 211, 260, 972, and 258 lives, respectively. Radon mitigation programs could have prevented these LC cases. The BEIR VI assumption for the United States (US) population, 95% of LC deaths in men and 90% of LC deaths in women are Ever-Smokers (ES), can be applied to the Canadian population. The PAR is a linear function in the target radon value with an estimated slope of 0.0001 for Ontario, Alberta, Quebec and British Columbia, and 0.0004 for Manitoba. The PAR is almost a square root function in the radon action level. The PAR is sensitive to changes in the radon mitigation program and as such, any improvement is a worthwhile investment. Copyright © 2018 Elsevier B.V. All rights reserved.

Mortality audit of the Finnish cervical cancer screening program.

PubMed

Lönnberg, Stefan; Nieminen, Pekka; Luostarinen, Tapio; Anttila, Ahti

2013-05-01

Incidence-based evaluations of cervical cancer screening programs have suggested age-specific impacts and there is uncertainty regarding the effectiveness of screening outside the ages of 30-60 years. We audited the screening histories of cervical cancer deaths and conducted a case-control evaluation of the effectiveness of organized screening in different ages with mortality as outcome. We included all 506 cervical cancer deaths in Finland in 2000-2009 due to cancers diagnosed in 1990 or later, and 3,036 controls matched by age at diagnosis to the cases. Squamous cell carcinoma constituted 59% of the cases, adenocarcinomas 29%, and the remaining 12% were other specified and unspecified cervical malignancies. Most deaths (54%) were due to cancers diagnosed more than 5 years after last screening invitation, 24% were diagnosed among nonattenders and only 14% of deaths occurred among women who had attended invitational screening. The risk reduction associated with attending a single program screen at an age below 40 was nonsignificant (OR 0.70; 95% CI 0.33-1.48), while clear risk reductions were observed after screening at the age of 40-54 (OR 0.33; CI 0.20-0.56) and 55-69 (OR 0.29; CI 0.16-0.54). This study also provides some indication of a long-lasting additional effect of screening at the age of 65. Possible avenues for improving the effectiveness of the Finnish screening program include efforts to increase attendance and an extension of the target ages to include 65-to 69-year-old women. The potential benefit of increasing the sensitivity of the screening test or shortening the screening interval is smaller. Copyright © 2012 UICC.

NGO-promoted women's credit program, immunization coverage, and child mortality in rural Bangladesh.

PubMed

Amin, R; Li, Y

1997-01-01

A growing number of non-governmental organizations (NGOs) are adopting the collateral-free credit programs by anchoring them with their social development programs aimed at improved program effectiveness and sustainability. Drawing upon a sample of 3,564 targeted poor households covered by five small NGOs in rural Bangladesh, this study finds that the NGO credit-members as well as those who reside in the NGO program area are higher adopters of child immunization than those in the non-program area. Similarly, the study found that infant and child mortality is lower among the NGO credit members than among the non-members and that under five-year deaths of children progressively decline with the increase in the doses of vaccines. Implications of these findings are discussed in the study.

Increases in Drug and Opioid-Involved Overdose Deaths - United States, 2010-2015.

PubMed

Rudd, Rose A; Seth, Puja; David, Felicita; Scholl, Lawrence

2016-12-30

The U.S. opioid epidemic is continuing, and drug overdose deaths nearly tripled during 1999-2014. Among 47,055 drug overdose deaths that occurred in 2014 in the United States, 28,647 (60.9%) involved an opioid (1). Illicit opioids are contributing to the increase in opioid overdose deaths (2,3). In an effort to target prevention strategies to address the rapidly changing epidemic, CDC examined overall drug overdose death rates during 2010-2015 and opioid overdose death rates during 2014-2015 by subcategories (natural/semisynthetic opioids, methadone, heroin, and synthetic opioids other than methadone).* Rates were stratified by demographics, region, and by 28 states with high quality reporting on death certificates of specific drugs involved in overdose deaths. During 2015, drug overdoses accounted for 52,404 U.S. deaths, including 33,091 (63.1%) that involved an opioid. There has been progress in preventing methadone deaths, and death rates declined by 9.1%. However, rates of deaths involving other opioids, specifically heroin and synthetic opioids other than methadone (likely driven primarily by illicitly manufactured fentanyl) (2,3), increased sharply overall and across many states. A multifaceted, collaborative public health and law enforcement approach is urgently needed. Response efforts include implementing the CDC Guideline for Prescribing Opioids for Chronic Pain (4), improving access to and use of prescription drug monitoring programs, enhancing naloxone distribution and other harm reduction approaches, increasing opioid use disorder treatment capacity, improving linkage into treatment, and supporting law enforcement strategies to reduce the illicit opioid supply.

Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection

NASA Astrophysics Data System (ADS)

Doitsh, Gilad; Galloway, Nicole L. K.; Geng, Xin; Yang, Zhiyuan; Monroe, Kathryn M.; Zepeda, Orlando; Hunt, Peter W.; Hatano, Hiroyu; Sowinski, Stefanie; Muñoz-Arias, Isa; Greene, Warner C.

2014-01-01

The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood although apoptosis has been proposed as a key mechanism. We now show that caspase-3-mediated apoptosis accounts for the death of only a small fraction of CD4 T cells corresponding to those that are both activated and productively infected. The remaining over 95% of quiescent lymphoid CD4 T cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis corresponds to an intensely inflammatory form of programmed cell death in which cytoplasmic contents and pro-inflammatory cytokines, including IL-1β, are released. This death pathway thus links the two signature events in HIV infection--CD4 T-cell depletion and chronic inflammation--and creates a pathogenic vicious cycle in which dying CD4 T cells release inflammatory signals that attract more cells to die. This cycle can be broken by caspase 1 inhibitors shown to be safe in humans, raising the possibility of a new class of `anti-AIDS' therapeutics targeting the host rather than the virus.

In vivo inhibition of the mitochondrial H+-ATP synthase in neurons promotes metabolic preconditioning.

PubMed

Formentini, Laura; Pereira, Marta P; Sánchez-Cenizo, Laura; Santacatterina, Fulvio; Lucas, José J; Navarro, Carmen; Martínez-Serrano, Alberto; Cuezva, José M

2014-04-01

A key transducer in energy conservation and signaling cell death is the mitochondrial H(+)-ATP synthase. The expression of the ATPase inhibitory factor 1 (IF1) is a strategy used by cancer cells to inhibit the activity of the H(+)-ATP synthase to generate a ROS signal that switches on cellular programs of survival. We have generated a mouse model expressing a mutant of human IF1 in brain neurons to assess the role of the H(+)-ATP synthase in cell death in vivo. The expression of hIF1 inhibits the activity of oxidative phosphorylation and mediates the shift of neurons to an enhanced aerobic glycolysis. Metabolic reprogramming induces brain preconditioning affording protection against quinolinic acid-induced excitotoxicity. Mechanistically, preconditioning involves the activation of the Akt/p70S6K and PARP repair pathways and Bcl-xL protection from cell death. Overall, our findings provide the first in vivo evidence highlighting the H(+)-ATP synthase as a target to prevent neuronal cell death.

Biomarkers for immunotherapy in bladder cancer: a moving target.

PubMed

Aggen, David H; Drake, Charles G

2017-11-21

Treatment options for metastatic urothelial carcinoma (mUC) remained relative unchanged over the last 30 years with combination chemotherapy as the mainstay of treatment. Within the last year the landscape for mUC has seismically shifted following the approval of five therapies targeting the programmed cell death protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis. Notably, the anti-PD-1 antibody pembrolizumab demonstrated improved OS relative to chemotherapy in a randomized phase III study for second line treatment of mUC; this level 1 evidence led to approval from the U.S. Food and Drug Administration (FDA). The PD-1 antibody nivolumab also demonstrated an overall survival benefit, in this case in comparison to historical controls. Similarly, antibodies targeting PD-L1 including atezolizumab, durvalumab, and avelumab have now received accelerated approval from the FDA as second line treatments for mUC, with durable response lasting more than 1 year in some patients. Some of these agents are approved in the first line setting as well - based on single-arm phase II studies atezolizumab and pembrolizumab received accelerated approval for first-line treatment of cisplatin ineligible patients. Despite these multiple approvals, the development of clinically useful biomarkers to determine the optimal treatment for patients remains somewhat elusive. In this review, we examine key clinical trial results with anti-PD1/PD-L1 antibodies and discuss progress towards developing novel biomarkers beyond PD-L1 expression.

Immune checkpoint therapy in liver cancer.

PubMed

Xu, Feng; Jin, Tianqiang; Zhu, Yuwen; Dai, Chaoliu

2018-05-29

Immune checkpoints include stimulatory and inhibitory checkpoint molecules. In recent years, inhibitory checkpoints, including cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death ligand 1 (PD-L1), have been identified to suppress anti-tumor immune responses in solid tumors. Novel drugs targeting immune checkpoints have succeeded in cancer treatment. Specific PD-1 blockades were approved for treatment of melanoma in 2014 and for treatment of non-small-cell lung cancer in 2015 in the United States, European Union, and Japan. Preclinical and clinical studies show immune checkpoint therapy provides survival benefit for greater numbers of patients with liver cancer, including hepatocellular carcinoma and cholangiocarcinoma, two main primary liver cancers. The combination of anti-PD-1/PD-L1 with anti-CTLA-4 antibodies is being evaluated in phase 1, 2 or 3 trials, and the results suggest that an anti-PD-1 antibody combined with locoregional therapy or other molecular targeted agents is an effective treatment strategy for HCC. In addition, studies on activating co-stimulatory receptors to enhance anti-tumor immune responses have increased our understanding regarding this immunotherapy in liver cancer. Epigenetic modulations of checkpoints for improving the tumor microenvironment also expand our knowledge of potential therapeutic targets in improving the tumor microenvironment and restoring immune recognition and immunogenicity. In this review, we summarize current knowledge and recent developments in immune checkpoint-based therapies for the treatment of hepatocellular carcinoma and cholangiocarcinoma and attempt to clarify the mechanisms underlying its effects.

Interrogating the relevance of mitochondrial apoptosis for vertebrate development and postnatal tissue homeostasis.

PubMed

Tuzlak, Selma; Kaufmann, Thomas; Villunger, Andreas

2016-10-01

"Programmed cell death or 'apoptosis' is critical for organogenesis during embryonic development and tissue homeostasis in the adult. Its deregulation can contribute to a broad range of human pathologies, including neurodegeneration, cancer, or autoimmunity…" These or similar phrases have become generic opening statements in many reviews and textbooks describing the physiological relevance of apoptotic cell death. However, while the role in disease has been documented beyond doubt, facilitating innovative drug discovery, we wonder whether the former is really true. What goes wrong in vertebrate development or in adult tissue when the main route to apoptotic cell death, controlled by the BCL2 family, is impaired? Such scenarios have been mimicked by deletion of one or more prodeath genes within the BCL2 family, and gene targeting studies in mice exploring the consequences have been manifold. Many of these studies were geared toward understanding the role of BCL2 family proteins and mitochondrial apoptosis in disease, whereas fewer focused in detail on their role during normal development or tissue homeostasis, perhaps also due to an irritating lack of phenotype. Looking at these studies, the relevance of classical programmed cell death by apoptosis for development appears rather limited. Together, these many studies suggest either highly selective and context-dependent contributions of mitochondrial apoptosis or significant redundancy with alternative cell death mechanisms, as summarized and discussed here. © 2016 Tuzlak et al.; Published by Cold Spring Harbor Laboratory Press.

The suppression of apoptosis by α-herpesvirus

PubMed Central

You, Yu; Cheng, An-Chun; Wang, Ming-Shu; Jia, Ren-Yong; Sun, Kun-Feng; Yang, Qiao; Wu, Ying; Zhu, Dekang; Chen, Shun; Liu, Ma-Feng; Zhao, Xin-Xin; Chen, Xiao-Yue

2017-01-01

Apoptosis, an important innate immune mechanism that eliminates pathogen-infected cells, is primarily triggered by two signalling pathways: the death receptor pathway and the mitochondria-mediated pathway. However, many viruses have evolved various strategies to suppress apoptosis by encoding anti-apoptotic factors or regulating apoptotic signalling pathways, which promote viral propagation and evasion of the host defence. During its life cycle, α-herpesvirus utilizes an elegant multifarious anti-apoptotic strategy to suppress programmed cell death. This progress article primarily focuses on the current understanding of the apoptosis-inhibition mechanisms of α-herpesvirus anti-apoptotic genes and their expression products and discusses future directions, including how the anti-apoptotic function of herpesvirus could be targeted therapeutically. PMID:28406478

[The relationship between necroptosis and blinding eye diseases].

PubMed

Xie, L L; Jiang, B

2018-03-11

As a programmed cell death manner which is distinguished from apoptosis and autophagy, necroptosis is a newly discovered pathway of regulated necrosis that requires the protein receptor interacting protein kinases 1 and 3 and mixed lineage kinase domain-like protein. Necroptosis is mediated by death receptors, toll-like receptors and probably other mediators. Emerging evidences have delineated that necroptosis plays an important role in the occurrence and development of various blinding eye diseases. In this review, the related mechanism of necroptosis, the relationship between necroptosis and multiple blinding eye diseases, such as age-related macular degeneration, retinitis pigmentosa and glaucoma, and the potential therapeutic targets of necroptosis are discussed. (Chin J Ophthalmol, 2018, 54: 234-240) .

CHECKPOINT INHIBITOR IMMUNE THERAPY: Systemic Indications and Ophthalmic Side Effects.

PubMed

Dalvin, Lauren A; Shields, Carol L; Orloff, Marlana; Sato, Takami; Shields, Jerry A

2018-06-01

To review immune checkpoint inhibitor indications and ophthalmic side effects. A literature review was performed using a PubMed search for publications between 1990 and 2017. Immune checkpoint inhibitors are designed to treat system malignancies by targeting one of three ligands, leading to T-cell activation for attack against malignant cells. These ligands (and targeted drug) include cytotoxic T-lymphocyte antigen-4 (CTLA-4, ipilimumab), programmed death protein 1 (PD-1, pembrolizumab, nivolumab), and programmed death ligand-1 (PD-L1, atezolizumab, avelumab, durvalumab). These medications upregulate the immune system and cause autoimmune-like side effects. Ophthalmic side effects most frequently manifest as uveitis (1%) and dry eye (1-24%). Other side effects include myasthenia gravis (n = 19 reports), inflammatory orbitopathy (n = 11), keratitis (n = 3), cranial nerve palsy (n = 3), optic neuropathy (n = 2), serous retinal detachment (n = 2), extraocular muscle myopathy (n = 1), atypical chorioretinal lesions (n = 1), immune retinopathy (n = 1), and neuroretinitis (n = 1). Most inflammatory side effects are managed with topical or periocular corticosteroids, but advanced cases require systemic corticosteroids and cessation of checkpoint inhibitor therapy. Checkpoint inhibitors enhance the immune system by releasing inhibition on T cells, with risk of autoimmune-like side effects. Ophthalmologists should include immune-related adverse events in their differential when examining cancer patients with new ocular symptoms.

Immune checkpoint inhibitors for nonsmall cell lung cancer treatment.

PubMed

Chen, Yuh-Min

2017-01-01

Immune checkpoint inhibition with blocking antibodies that target cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the programmed cell death protein 1 (PD-1) pathway [PD-1/programmed death-ligand 1 (PD-L1)] have demonstrated promise in a variety of malignancies. While ipilimumab has been approved as a CTLA-4 blocking antibody by the US Food and Drug Administration for the treatment of advanced melanoma, it is still not approved for lung cancer treatment. In contrast, nivolumab and pembrolizumab, both PD-1 blocking antibodies, have been approved for second-line treatment of nonsmall cell lung cancer in 2015 because of their high potency and long-lasting effects in some patient subgroups. Other PD-1 and PD-L1 monoclonal antibodies are also in active development phase. Treatment with such immune checkpoint inhibitors is associated with a unique pattern of immune-related adverse events or side effects. Combination approaches involving CTLA-4 and PD-1/PD-L1 blockade or checkpoint inhibitors with chemotherapy or radiotherapy are being investigated to determine whether they may enhance the efficacy of treatment. Despite many challenges ahead, immunotherapy with checkpoint inhibitors has already become a new and important treatment modality for lung cancer in the last decade following the discovery of targeted therapy. Copyright © 2016. Published by Elsevier Taiwan LLC.

Expression and clinicopathological significance of microRNA-21 and programmed cell death 4 in malignant melanoma.

PubMed

Jiao, Jian; Fan, Yu; Zhang, Yan

2015-10-01

To measure levels of microRNA (miR)-21 and its target gene, programmed cell death 4 (PDCD4), in samples of human cutaneous malignant melanoma and normal non-malignant control skin. Relative levels of miR-21 and PDCD4 mRNA were measured using a quantitative real-time reverse transcription-polymerase chain reaction. Correlations between the levels of the two molecules and the clinicopathological characteristics of malignant melanoma were analysed. A total of 67 cases of human cutaneous malignant melanoma were analysed and compared with 67 samples of normal nonmalignant control skin. Compared with normal skin samples, the relative level of miR-21 was significantly higher and the relative level of PDCD4 mRNA was significantly lower in the melanoma specimens. A significant negative correlation between PDCD4 mRNA and miR-21 was demonstrated in malignant melanoma (r = -0.602). Elevated miR-21 and reduced PDCD4 mRNA levels were both significantly correlated with increased tumour size, a higher Clark classification level and the presence of lymph node metastases in malignant melanoma. These findings suggest that miR-21 and PDCD4 might be potential biomarkers for malignant melanoma and might provide treatment targets in the future. © The Author(s) 2015.

Clinical Implementation of Novel Targeted Therapeutics in Advanced Breast Cancer.

PubMed

Chamberlin, Mary D; Bernhardt, Erica B; Miller, Todd W

2016-11-01

The majority of advanced breast cancers have genetic alterations that are potentially targetable with drugs. Through initiatives such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), data can be mined to provide context for next-generation sequencing (NGS) results in the landscape of advanced breast cancer. Therapies for targets other than estrogen receptor alpha (ER) and HER2, such as cyclin-dependent kinases CDK4 and CDK6, were recently approved based on efficacy in patient subpopulations, but no predictive biomarkers have been found, leaving clinicians to continue a trial-and-error approach with each patient. Next-generation sequencing identifies potentially actionable alterations in genes thought to be drivers in the cancerous process including phosphatidylinositol 3-kinase (PI3K), AKT, fibroblast growth factor receptors (FGFRs), and mutant HER2. Epigenetically directed and immunologic therapies have also shown promise for the treatment of breast cancer via histone deacetylases (HDAC) 1 and 3, programmed T cell death 1 (PD-1), and programmed T cell death ligand 1 (PD-L1). Identifying biomarkers to predict primary resistance in breast cancer will ultimately affect clinical decisions regarding adjuvant therapy in the first-line setting. However, the bulk of medical decision-making is currently made in the secondary resistance setting. Herein, we review the clinical potential of PI3K, AKT, FGFRs, mutant HER2, HDAC1/3, PD-1, and PD-L1 as therapeutic targets in breast cancer, focusing on the rationale for therapeutic development and the status of clinical testing. J. Cell. Biochem. 117: 2454-2463, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Influence of antiretroviral therapy on programmed death-1 (CD279) expression on T cells in lymph nodes of human immunodeficiency virus-infected individuals.

PubMed

Ehrhard, Simone; Wernli, Marion; Dürmüller, Ursula; Battegay, Manuel; Gudat, Fred; Erb, Peter

2009-10-01

Human immunodeficiency virus infection leads to T-cell exhaustion and involution of lymphoid tissue. Recently, the programmed death-1 pathway was found to be crucial for virus-specific T-cell exhaustion during human immunodeficiency virus infection. Programmed death-1 expression was elevated on human immunodeficiency virus-specific peripheral blood CD8+ and CD4+ T cells and correlated with disease severity. During human immunodeficiency infection, lymphoid tissue acts as a major viral reservoir and is an important site for viral replication, but it is also essential for regulatory processes important for immune recovery. We compared programmed death-1 expression in 2 consecutive inguinal lymph nodes of 14 patients, excised before antiretroviral therapy (antiretroviral therapy as of 1997-1999) and 16 to 20 months under antiretroviral therapy. In analogy to lymph nodes of human immunodeficiency virus-negative individuals, in all treated patients, the germinal center area decreased, whereas the number of germinal centers did not significantly change. Programmed death-1 expression was mostly found in germinal centers. The absolute extent of programmed death 1 expression per section was not significantly altered after antiretroviral therapy resulting in a significant-relative increase of programmed death 1 per shrunken germinal center. In colocalization studies, CD45R0+ cells that include helper/inducer T cells strongly expressed programmed death-1 before and during therapy, whereas CD8+ T cells, fewer in numbers, showed a weak expression for programmed death-1. Thus, although antiretroviral therapy seems to reduce the number of programmed death-1-positive CD8+ T lymphocytes within germinal centers, it does not down-regulate programmed death-1 expression on the helper/inducer T-cell subset that may remain exhausted and therefore unable to trigger immune recovery.

Prior irradiation results in elevated programmed cell death protein 1 (PD-1) in T cells.

PubMed

Li, Deguan; Chen, Renxiang; Wang, Yi-Wen; Fornace, Albert J; Li, Heng-Hong

2018-05-01

In this study we addressed the question whether radiation-induced adverse effects on T cell activation are associated with alterations of T cell checkpoint receptors. Expression levels of checkpoint receptors on T cell subpopulations were analyzed at multiple post-radiation time points ranging from one to four weeks in mice receiving a single fraction of 1 or 4 Gy of γ-ray. T cell activation associated metabolic changes were assessed. Our results showed that prior irradiation resulted in significant elevated expression of programmed cell death protein 1 (PD-1) in both CD4+ and CD8+ populations, at all three post-radiation time points. T cells with elevated PD-1 mostly were either central memory or naïve cells. In addition, the feedback induction of PD-1 expression in activated T cells declined after radiation. Taken together, the elevated PD-1 level observed at weeks after radiation exposure is connected to T cell dysfunction. Recent preclinical and clinical studies have showed that a combination of radiotherapy and T cell checkpoint blockade immunotherapy including targeting the programmed death-ligand 1 (PD-L1)/PD-1 axis may potentiate the antitumor response. Understanding the dynamic changes in PD-1 levels in T cells after radiation should help in the development of a more effective therapeutic strategy.

Dandelion root extract affects colorectal cancer proliferation and survival through the activation of multiple death signalling pathways

PubMed Central

Ovadje, Pamela; Ammar, Saleem; Guerrero, Jose-Antonio; Arnason, John Thor; Pandey, Siyaram

2016-01-01

Dandelion extracts have been studied extensively in recent years for its anti-depressant and anti-inflammatory activity. Recent work from our lab, with in-vitro systems, shows the anti-cancer potential of an aqueous dandelion root extract (DRE) in several cancer cell models, with no toxicity to non-cancer cells. In this study, we examined the cancer cell-killing effectiveness of an aqueous DRE in colon cancer cell models. Aqueous DRE induced programmed cell death (PCD) selectively in > 95% of colon cancer cells, irrespective of their p53 status, by 48 hours of treatment. The anti-cancer efficacy of this extract was confirmed in in-vivo studies, as the oral administration of DRE retarded the growth of human colon xenograft models by more than 90%. We found the activation of multiple death pathways in cancer cells by DRE treatment, as revealed by gene expression analyses showing the expression of genes implicated in programmed cell death. Phytochemical analyses of the extract showed complex multi-component composition of the DRE, including some known bioactive phytochemicals such as α-amyrin, β-amyrin, lupeol and taraxasterol. This suggested that this natural extract could engage and effectively target multiple vulnerabilities of cancer cells. Therefore, DRE could be a non-toxic and effective anti-cancer alternative, instrumental for reducing the occurrence of cancer cells drug-resistance. PMID:27564258

The serine protease inhibitor TLCK attenuates intrinsic death pathways in neurons upstream of mitochondrial demise.

PubMed

Reuther, C; Ganjam, G K; Dolga, A M; Culmsee, C

2014-11-01

It is well-established that activation of proteases, such as caspases, calpains and cathepsins are essential components in signaling pathways of programmed cell death (PCD). Although these proteases have also been linked to mechanisms of neuronal cell death, they are dispensable in paradigms of intrinsic death pathways, e.g. induced by oxidative stress. However, emerging evidence implicated a particular role for serine proteases in mechanisms of PCD in neurons. Here, we investigated the role of trypsin-like serine proteases in a model of glutamate toxicity in HT-22 cells. In these cells glutamate induces oxytosis, a form of caspase-independent cell death that involves activation of the pro-apoptotic protein BH3 interacting-domain death agonist (Bid), leading to mitochondrial demise and ensuing cell death. In this model system, the trypsin-like serine protease inhibitor Nα-tosyl-l-lysine chloromethyl ketone hydrochloride (TLCK) inhibited mitochondrial damage and cell death. Mitochondrial morphology alterations, the impairment of the mitochondrial membrane potential and ATP depletion were prevented and, moreover, lipid peroxidation induced by glutamate was completely abolished. Strikingly, truncated Bid-induced cell death was not affected by TLCK, suggesting a detrimental activity of serine proteases upstream of Bid activation and mitochondrial demise. In summary, this study demonstrates the protective effect of serine protease inhibition by TLCK against oxytosis-induced mitochondrial damage and cell death. These findings indicate that TLCK-sensitive serine proteases play a crucial role in cell death mechanisms upstream of mitochondrial demise and thus, may serve as therapeutic targets in diseases, where oxidative stress and intrinsic pathways of PCD mediate neuronal cell death.

Apoptosis and Molecular Targeting Therapy in Cancer

PubMed Central

Hassan, Mohamed; Watari, Hidemichi; AbuAlmaaty, Ali; Ohba, Yusuke; Sakuragi, Noriaki

2014-01-01

Apoptosis is the programmed cell death which maintains the healthy survival/death balance in metazoan cells. Defect in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals contribute into safeguarding the genomic integrity while defective apoptosis may promote carcinogenesis. The apoptotic signals are complicated and they are regulated at several levels. The signals of carcinogenesis modulate the central control points of the apoptotic pathways, including inhibitor of apoptosis (IAP) proteins and FLICE-inhibitory protein (c-FLIP). The tumor cells may use some of several molecular mechanisms to suppress apoptosis and acquire resistance to apoptotic agents, for example, by the expression of antiapoptotic proteins such as Bcl-2 or by the downregulation or mutation of proapoptotic proteins such as BAX. In this review, we provide the main regulatory molecules that govern the main basic mechanisms, extrinsic and intrinsic, of apoptosis in normal cells. We discuss how carcinogenesis could be developed via defective apoptotic pathways or their convergence. We listed some molecules which could be targeted to stimulate apoptosis in different cancers. Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction. PMID:25013758

Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth

NASA Astrophysics Data System (ADS)

Kim, Sung Eun; Zhang, Li; Ma, Kai; Riegman, Michelle; Chen, Feng; Ingold, Irina; Conrad, Marcus; Turker, Melik Ziya; Gao, Minghui; Jiang, Xuejun; Monette, Sebastien; Pauliah, Mohan; Gonen, Mithat; Zanzonico, Pat; Quinn, Thomas; Wiesner, Ulrich; Bradbury, Michelle S.; Overholtzer, Michael

2016-11-01

The design of cancer-targeting particles with precisely tuned physicochemical properties may enhance the delivery of therapeutics and access to pharmacological targets. However, a molecular-level understanding of the interactions driving the fate of nanomedicine in biological systems remains elusive. Here, we show that ultrasmall (<10 nm in diameter) poly(ethylene glycol)-coated silica nanoparticles, functionalized with melanoma-targeting peptides, can induce a form of programmed cell death known as ferroptosis in starved cancer cells and cancer-bearing mice. Tumour xenografts in mice intravenously injected with nanoparticles using a high-dose multiple injection scheme exhibit reduced growth or regression, in a manner that is reversed by the pharmacological inhibitor of ferroptosis, liproxstatin-1. These data demonstrate that ferroptosis can be targeted by ultrasmall silica nanoparticles and may have therapeutic potential.

Live imaging of muscle histolysis in Drosophila metamorphosis.

PubMed

Kuleesha, Yadav; Puah, Wee Choo; Wasser, Martin

2016-05-04

The contribution of programmed cell death (PCD) to muscle wasting disorders remains a matter of debate. Drosophila melanogaster metamorphosis offers the opportunity to study muscle cell death in the context of development. Using live cell imaging of the abdomen, two groups of larval muscles can be observed, doomed muscles that undergo histolysis and persistent muscles that are remodelled and survive into adulthood. To identify and characterize genes that control the decision between survival and cell death of muscles, we developed a method comprising in vivo imaging, targeted gene perturbation and time-lapse image analysis. Our approach enabled us to study the cytological and temporal aspects of abnormal cell death phenotypes. In a previous genetic screen for genes controlling muscle size and cell death in metamorphosis, we identified gene perturbations that induced cell death of persistent or inhibit histolysis of doomed larval muscles. RNA interference (RNAi) of the genes encoding the helicase Rm62 and the lysosomal Cathepsin-L homolog Cysteine proteinase 1 (Cp1) caused premature cell death of persistent muscle in early and mid-pupation, respectively. Silencing of the transcriptional co-repressor Atrophin inhibited histolysis of doomed muscles. Overexpression of dominant-negative Target of Rapamycin (TOR) delayed the histolysis of a subset of doomed and induced ablation of all persistent muscles. RNAi of AMPKα, which encodes a subunit of the AMPK protein complex that senses AMP and promotes ATP formation, led to loss of attachment and a spherical morphology. None of the perturbations affected the survival of newly formed adult muscles, suggesting that the method is useful to find genes that are crucial for the survival of metabolically challenged muscles, like those undergoing atrophy. The ablation of persistent muscles did not affect eclosion of adult flies. Live imaging is a versatile approach to uncover gene functions that are required for the survival of muscle undergoing remodelling, yet are dispensable for other adult muscles. Our approach promises to identify molecular mechanisms that can explain the resilience of muscles to PCD.

Programming stress-induced altruistic death in engineered bacteria

PubMed Central

Tanouchi, Yu; Pai, Anand; Buchler, Nicolas E; You, Lingchong

2012-01-01

Programmed death is often associated with a bacterial stress response. This behavior appears paradoxical, as it offers no benefit to the individual. This paradox can be explained if the death is ‘altruistic': the killing of some cells can benefit the survivors through release of ‘public goods'. However, the conditions where bacterial programmed death becomes advantageous have not been unambiguously demonstrated experimentally. Here, we determined such conditions by engineering tunable, stress-induced altruistic death in the bacterium Escherichia coli. Using a mathematical model, we predicted the existence of an optimal programmed death rate that maximizes population growth under stress. We further predicted that altruistic death could generate the ‘Eagle effect', a counter-intuitive phenomenon where bacteria appear to grow better when treated with higher antibiotic concentrations. In support of these modeling insights, we experimentally demonstrated both the optimality in programmed death rate and the Eagle effect using our engineered system. Our findings fill a critical conceptual gap in the analysis of the evolution of bacterial programmed death, and have implications for a design of antibiotic treatment. PMID:23169002

Substance Abuse Prevention.

PubMed

LeNoue, Sean R; Riggs, Paula D

2016-04-01

Substance use disorders account for approximately 6% of deaths worldwide and cost about $700 billion in the United States. Approximately 80% of drug users begin using during adolescence, underscoring the public health importance of effective substance prevention programs for youth and families. Prevention science designates 3 intervention categories: (1) universal prevention, targeting all individuals in the population, (2) selective interventions, targeting high-risk groups, and (3) indicated prevention interventions for youth with risk-taking behaviors. School-based and non-school-based interventions are reviewed, as well as the limitations of existing research, gaps in access and availability, and directions for future research and development. Copyright © 2016 Elsevier Inc. All rights reserved.

Cell Death and Cancer Therapy: Don't Forget to Kill the Cancer Cell!

PubMed

Letai, Anthony

2015-11-15

In our current age of targeted therapies, there is understandably considerable attention paid to the specific molecular targets of pharmaceutical intervention. For a targeted drug to work, it must bind to a target selectively and impair its function. Monitoring biomarkers of the impaired target function can provide vital in vivo pharmacodynamic information. Moreover, genetic changes to the target are often the source of resistance to targeted agents. However, for the treatment of cancer, it is necessary that the therapy not only provide efficient binding and inhibition of the target, but also that this intervention reliably kills the cancer cell. In this CCR Focus section, four articles make the connection between therapies that target T-cell activation, autophagy, IAP proteins, and BCL-2 and the commitment of cancer cells to cell death. Before addressing those exciting classes of targeted therapies, however, an overview is provided to discuss cell death induced by what is arguably still the most successful set of drugs in the history of medical oncology, conventional chemotherapy. See all articles in this CCR Focus section, "Cell Death and Cancer Therapy." ©2015 American Association for Cancer Research.

Association between non-fatal opioid overdose and encounters with healthcare and criminal justice systems: Identifying opportunities for intervention.

PubMed

Wagner, Karla D; Liu, Lin; Davidson, Peter J; Cuevas-Mota, Jazmine; Armenta, Richard F; Garfein, Richard S

2015-08-01

Accidental overdose, driven largely by opioids, is a leading cause of death among people who inject drugs (PWIDs). We conducted secondary analysis of data from a cohort of PWIDs to identify venues where high-risk PWID could be targeted by overdose education/naloxone distribution (OEND) programs. 573 PWIDs completed a quantitative survey between June, 2012 and January, 2014, which was analyzed using multivariable logistic regression. The dependent variable was a dichotomous indicator of experiencing a heroin/opioid-related overdose in the past six months. Independent variables included: demographics, drug use behavior, and encounters with two venues - the health care and criminal justice systems - that could serve as potential venues for OEND programs. Almost half (41.5%) reported ever experiencing a heroin/opioid overdose, and 45 (7.9%) reported experiencing at least one heroin/opioid overdose in the past six months. In the final multivariable model, receiving care in a hospital in the past six months (Adjusted Odds Ratio [AdjOR] 4.08, 95% Confidence Interval [C.I.] 2.07, 8.04, p<0.001) and being arrested for drug possession in the past six months (AdjOR 5.17, 95% C.I. 2.37, 11.24, p<0.001) were associated with experiencing an opioid overdose in the past six months. Identifying venues outside of those that traditionally target services to PWIDs (i.e., syringe exchange programs) will be critical to implementing OEND interventions at a scale sufficient to address the growing epidemic of heroin/opioid related deaths. Clinical settings, such as hospitals, and drug-related encounters with law enforcement officers are promising venues for the expansion of OEND programs. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Programmed cell death in trypanosomatids and other unicellular organisms.

PubMed

Debrabant, Alain; Lee, Nancy; Bertholet, Sylvie; Duncan, Robert; Nakhasi, Hira L

2003-03-01

In multicellular organisms, cellular growth and development can be controlled by programmed cell death (PCD), which is defined by a sequence of regulated events. However, PCD is thought to have evolved not only to regulate growth and development in multicellular organisms but also to have a functional role in the biology of unicellular organisms. In protozoan parasites and in other unicellular organisms, features of PCD similar to those in multicellular organisms have been reported, suggesting some commonality in the PCD pathway between unicellular and multicellular organisms. However, more extensive studies are needed to fully characterise the PCD pathway and to define the factors that control PCD in the unicellular organisms. The understanding of the PCD pathway in unicellular organisms could delineate the evolutionary origin of this pathway. Further characterisation of the PCD pathway in the unicellular parasites could provide information regarding their pathogenesis, which could be exploited to target new drugs to limit their growth and treat the disease they cause.

A case of fulminant Type 1 diabetes following anti-PD1 immunotherapy in a genetically susceptible patient.

PubMed

Araújo, Manuel; Ligeiro, Dário; Costa, Luís; Marques, Filipa; Trindade, Helder; Correia, José Manuel; Fonseca, Candida

2017-06-01

Programmed cell death-1 protein (PD-1) is an immune checkpoint that has gained popularity in the treatment of several advanced cancers. Inhibiting this checkpoint is known to enhance immune response, but is also known to diminish immune tolerance and to increase autoimmune toxicity. We discuss a case of rapid onset fulminant Type 1 diabetes induced by treatment with anti-programmed cell death-1 monoclonal antibody, nivolumab, in a patient with late-stage non-small-cell lung adenocarcinoma. The patient had no history of previous diabetes but did reveal a high-risk genotype for Type 1 diabetes development (DR3-DQ2; DR4-DQ8). This finding supports that acute Type 1 diabetes can be an important adverse effect of immunotherapies targeting T-cell activation regulation. Because of the severity of this adverse effect, physicians should be aware of it, and studies directed to the detection of new biomarkers for early risk stratification (e.g., HLA) should be sought.

Supportive care in the era of immunotherapies for advanced non-small-cell lung cancer.

PubMed

Awada, Gil; Klastersky, Jean

2018-03-01

The therapeutic armamentarium for advanced non-small-cell lung cancer has evolved considerably over the past years. Immune checkpoint inhibitors targeting programmed cell death-1 such as pembrolizumab and nivolumab or programmed cell death ligand 1 such as atezolizumab, durvalumab and avelumab have shown favorable efficacy results in this patient population in the first-line and second-line setting. These immunotherapies are associated with a distinct toxicity profile based on autoimmune organ toxicity which is a new challenge for supportive care during treatment with these drugs. The differential diagnosis of events occurring during immune checkpoint inhibitor treatment is broad: they can be due to immune-related or nonimmune-related adverse events, atypical tumor responses (pseudoprogression or hyperprogression) or events related to comorbidities or other treatments. The management of these patients includes a thorough baseline clinical, biological and radiologic evaluation, patient education, correct follow-up and management by a multidisciplinary team with a central role for the medical oncologist. Immune-related toxicities should be managed according to available guidelines.

Found in translation: how preclinical research is guiding the clinical development of the BCL-2-selective inhibitor venetoclax

PubMed Central

Leverson, Joel D.; Sampath, Deepak; Souers, Andrew J.; Rosenberg, Saul H.; Fairbrother, Wayne J.; Amiot, Martine; Konopleva, Marina; Letai, Anthony

2017-01-01

Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high priority goal for cancer therapy. After decades of effort, drug discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL-2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL-2 biology, were essential to the development of BH3 mimetics such as the BCL-2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL-2 biology and facilitated the clinical development of venetoclax. PMID:29146569

Crimes of gender.

PubMed

Heise, L

1990-01-01

Everyday, thousands of women are targets of violation that range from simple cases of sexual harassment to extreme cases of dowry deaths. This article describes different forms of violence against women. Wife beating has been prevalent in all societies regardless of race, culture, and socioeconomic status. In India, incidents like bride burning and dowry death are common because laws against these crimes have never been enforced. In Chile, the constitution grants the husband marital authority over his wife, resulting to wife beating due to unequal power balance. Due to the prevalence of these violations, shelters, legal reforms, and various groups and agencies to combat violence against women all over the world have initiated programs. Coalitions have also been organized to promote awareness and denounce male violence.

Struck-by-lightning deaths in the United States.

PubMed

Adekoya, Nelson; Nolte, Kurt B

2005-05-01

The objective of the research reported here was to examine the epidemiologic characteristics of struck-by-lightning deaths. Using data from both the National Centers for Health Statistics (NCHS) multiple-cause-of-death tapes and the Census of Fatal Occupational Injuries (CFOI), which is maintained by the Bureau of Labor Statistics, the authors calculated numbers and annualized rates of lightning-related deaths for the United States. They used resident estimates from population microdata files maintained by the Census Bureau as the denominators. Work-related fatality rates were calculated with denominators derived from the Current Population Survey of employment data. Four illustrative investigative case reports of lightning-related deaths were contributed by the New Mexico Office of the Medical Investigator. It was found that a total of 374 struck-by-lightning deaths had occurred during 1995-2000 (an average annualized rate of 0.23 deaths per million persons). The majority of deaths (286 deaths, 75 percent) were from the South and the Midwest. The numbers of lightning deaths were highest in Florida (49 deaths) and Texas (32 deaths). A total of 129 work-related lightning deaths occurred during 1995-2002 (an average annual rate of 0.12 deaths per million workers). Agriculture and construction industries recorded the most fatalities at 44 and 39 deaths, respectively. Fatal occupational injuries resulting from being struck by lightning were highest in Florida (21 deaths) and Texas (11 deaths). In the two national surveillance systems examined, incidence rates were higher for males and people 20-44 years of age. In conclusion, three of every four struck-by-lightning deaths were from the South and the Midwest, and during 1995-2002, one of every four struck-by-lightning deaths was work-related. Although prevention programs could target the entire nation, interventions might be most effective if directed to regions with the majority of fatalities because they have the majority of lightning strikes per year.

Axotomy-induced target disconnection promotes an additional death mechanism involved in motoneuron degeneration in ALS transgenic mice

PubMed Central

Haulcomb, Melissa M.; Mesnard, Nichole A.; Batka, Richard J.; Alexander, Thomas D.; Sanders, Virginia M.; Jones, Kathryn J.

2014-01-01

The target disconnection theory of amyotrophic lateral sclerosis (ALS) pathogenesis suggests disease onset is initiated by a peripheral pathological event resulting in neuromuscular junction loss and motoneuron (MN) degeneration. Pre-symptomatic mSOD1G93A mouse facial MN (FMN) are more susceptible to axotomy-induced cell death than wild-type (WT) FMN, which suggests additional CNS pathology. We have previously determined that the mSOD1 molecular response to facial nerve axotomy is phenotypically regenerative and indistinguishable from WT, whereas the surrounding microenvironment shows significant dysregulation in the mSOD1 facial nucleus. To elucidate the mechanisms underlying the enhanced mSOD1 FMN loss after axotomy, we superimposed the facial nerve axotomy model on pre-symptomatic mSOD1 mice and investigated gene expression for death receptor pathways after target disconnection by axotomy vs. disease progression. We determined that the TNFR1 death receptor pathway is involved in axotomy-induced FMN death in WT, and partially responsible for the mSOD1 FMN death. In contrast, an inherent mSOD1 CNS pathology resulted in a suppressed glial reaction and an upregulation in the Fas death pathway after target disconnection. We propose that the dysregulated mSOD1 glia fail to provide support to injured MN, leading to Fas-induced FMN death. Finally, we demonstrated that during disease progression, the mSOD1 facial nucleus displays target disconnection-induced gene expression changes that mirror those induced by axotomy. This validates the use of axotomy as an investigative tool in understanding the role of peripheral target disconnection in the pathogenesis of ALS. PMID:24424947

Phase I dose-finding study of monotherapy with atezolizumab, an engineered immunoglobulin monoclonal antibody targeting PD-L1, in Japanese patients with advanced solid tumors.

PubMed

Mizugaki, Hidenori; Yamamoto, Noboru; Murakami, Haruyasu; Kenmotsu, Hirotsugu; Fujiwara, Yutaka; Ishida, Yoshimasa; Kawakami, Tomohisa; Takahashi, Toshiaki

2016-10-01

Background Atezolizumab is an engineered immunoglobulin monoclonal antibody that targets the programmed death-1/programmed death-ligand 1 pathway. Methods In this phase I dose-finding study, we assessed the safety, feasibility, pharmacokinetics (PK), and exploratory anti-tumor activity of atezolizumab monotherapy up to 20 mg/kg in Japanese patients with advanced solid tumors who had failed standard therapy or for whom there is no standard therapy. Results Six patients were enrolled and received intravenous atezolizumab every 3 weeks (q3w) at doses of 10 or 20 mg/kg. Tumor types were non-small cell lung cancer (n = 3), melanoma (n = 1), pancreatic cancer (n = 1), and thymic cancer (n = 1). No dose-limiting toxicities were observed. All adverse events (AEs) were grade 1 or 2 in severity. No discontinuations or deaths due to AEs were observed. As of the data cutoff, no partial responses were observed; however, stable disease was observed in all six patients. The maximum mean serum atezolizumab concentration was 220 μg/mL (SD ± 21.9), with 10-mg/kg dosing and 536 μg/mL (SD ± 49.4) with 20-mg/kg dosing. Three patients were still on treatment, and three of the six had achieved a progression-free survival of >12 months. Conclusions Atezolizumab was well tolerated in Japanese patients at doses up to 20 mg/kg q3w. The safety profile and Cycle 1 serum atezolizumab concentrations were similar to those previously observed in non-Japanese patients. These data support the participation of Japanese patients in ongoing pivotal global studies of atezolizumab.

Lack of the programmed death-1 receptor renders host susceptible to enteric microbial infection through impairing the production of the mucosal natural killer cell effector molecules.

PubMed

Solaymani-Mohammadi, Shahram; Lakhdari, Omar; Minev, Ivelina; Shenouda, Steve; Frey, Blake F; Billeskov, Rolf; Singer, Steven M; Berzofsky, Jay A; Eckmann, Lars; Kagnoff, Martin F

2016-03-01

The programmed death-1 receptor is expressed on a wide range of immune effector cells, including T cells, natural killer T cells, dendritic cells, macrophages, and natural killer cells. In malignancies and chronic viral infections, increased expression of programmed death-1 by T cells is generally associated with a poor prognosis. However, its role in early host microbial defense at the intestinal mucosa is not well understood. We report that programmed death-1 expression is increased on conventional natural killer cells but not on CD4(+), CD8(+) or natural killer T cells, or CD11b(+) or CD11c(+) macrophages or dendritic cells after infection with the mouse pathogen Citrobacter rodentium. Mice genetically deficient in programmed death-1 or treated with anti-programmed death-1 antibody were more susceptible to acute enteric and systemic infection with Citrobacter rodentium. Wild-type but not programmed death-1-deficient mice infected with Citrobacter rodentium showed significantly increased expression of the conventional mucosal NK cell effector molecules granzyme B and perforin. In contrast, natural killer cells from programmed death-1-deficient mice had impaired expression of those mediators. Consistent with programmed death-1 being important for intracellular expression of natural killer cell effector molecules, mice depleted of natural killer cells and perforin-deficient mice manifested increased susceptibility to acute enteric infection with Citrobacter rodentium. Our findings suggest that increased programmed death-1 signaling pathway expression by conventional natural killer cells promotes host protection at the intestinal mucosa during acute infection with a bacterial gut pathogen by enhancing the expression and production of important effectors of natural killer cell function. © Society for Leukocyte Biology.

Pyroptosis drives CD4 T-cell depletion in HIV-1 infection

PubMed Central

Doitsh, Gilad; Galloway, Nicole LK; Geng, Xin; Yang, Zhiyuan; Monroe, Kathryn M.; Zepeda, Orlando; Hunt, Peter W.; Hatano, Hiroyu; Sowinski, Stefanie; Muñoz-Arias, Isa; Greene, Warner C.

2014-01-01

The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood. Apoptosis has been proposed as the key mechanism for CD4 T-cell loss. We now show that caspase-3-mediated apoptosis accounts for the death of only a small fraction of productively infected cells. The remaining >95% of quiescent lymphoid CD4 T-cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis corresponds to an intensely inflammatory form of programmed cell death where cytoplasmic contents and pro-inflammatory cytokines including IL-1β, are released. This death pathway thus links the two signature events in HIV infection––CD4 T-cell depletion and chronic inflammation––and creates a vicious pathogenic cycle where dying CD4 T-cells release inflammatory signals that attract more cells to die. This cycle can be broken by caspase-1 inhibitors shown to be safe in humans, raising the possibility of a new class of “anti-AIDS” therapeutics targeting the host rather than the virus. PMID:24356306

Epidermal Cell Death in Rice Is Regulated by Ethylene, Gibberellin, and Abscisic Acid

PubMed Central

Steffens, Bianka; Sauter, Margret

2005-01-01

Programmed cell death (PCD) of epidermal cells that cover adventitious root primordia in deepwater rice (Oryza sativa) is induced by submergence. Early suicide of epidermal cells may prevent injury to the growing root that emerges under flooding conditions. Induction of PCD is dependent on ethylene signaling and is further promoted by gibberellin (GA). Ethylene and GA act in a synergistic manner, indicating converging signaling pathways. Treatment of plants with GA alone did not promote PCD. Treatment with the GA biosynthesis inhibitor paclobutrazol resulted in increased PCD in response to ethylene and GA presumably due to an increased sensitivity of epidermal cells to GA. Abscisic acid (ABA) was shown to efficiently delay ethylene-induced as well as GA-promoted cell death. The results point to ethylene signaling as a target of ABA inhibition of PCD. Accumulation of ethylene and GA and a decreased ABA level in the rice internode thus favor induction of epidermal cell death and ensure that PCD is initiated as an early response that precedes adventitious root growth. PMID:16169967

Virus inhibition of RIP3-dependent necrosis.

PubMed

Upton, Jason W; Kaiser, William J; Mocarski, Edward S

2010-04-22

Viral infection activates cytokine expression and triggers cell death, the modulation of which is important for successful pathogenesis. Necroptosis is a form of programmed necrosis dependent on two related RIP homotypic interaction motif (RHIM)-containing signaling adaptors, receptor-interacting protein kinases (RIP) 1 and 3. We find that murine cytomegalovirus infection induces RIP3-dependent necrosis. Whereas RIP3 kinase activity and RHIM-dependent interactions control virus-associated necrosis, virus-induced death proceeds independently of RIP1 and is therefore distinct from TNFalpha-dependent necroptosis. Viral M45-encoded inhibitor of RIP activation (vIRA) targets RIP3 during infection and disrupts RIP3-RIP1 interactions characteristic of TNFalpha-induced necroptosis, thereby suppressing both death pathways. Importantly, attenuation of vIRA mutant virus in wild-type mice is normalized in RIP3-deficient mice. Thus, vIRA function validates necrosis as central to host defense against viral infections and highlights the benefit of multiple virus-encoded cell-death suppressors that inhibit not only apoptotic, but also necrotic mechanisms of virus clearance. Copyright 2010 Elsevier Inc. All rights reserved.

A Single-Amino-Acid Substitution in Obg Activates a New Programmed Cell Death Pathway in Escherichia coli.

PubMed

Dewachter, Liselot; Verstraeten, Natalie; Monteyne, Daniel; Kint, Cyrielle Ines; Versées, Wim; Pérez-Morga, David; Michiels, Jan; Fauvart, Maarten

2015-12-22

Programmed cell death (PCD) is an important hallmark of multicellular organisms. Cells self-destruct through a regulated series of events for the benefit of the organism as a whole. The existence of PCD in bacteria has long been controversial due to the widely held belief that only multicellular organisms would profit from this kind of altruistic behavior at the cellular level. However, over the past decade, compelling experimental evidence has established the existence of such pathways in bacteria. Here, we report that expression of a mutant isoform of the essential GTPase ObgE causes rapid loss of viability in Escherichia coli. The physiological changes that occur upon expression of this mutant protein--including loss of membrane potential, chromosome condensation and fragmentation, exposure of phosphatidylserine on the cell surface, and membrane blebbing--point to a PCD mechanism. Importantly, key regulators and executioners of known bacterial PCD pathways were shown not to influence this cell death program. Collectively, our results suggest that the cell death pathway described in this work constitutes a new mode of bacterial PCD. Programmed cell death (PCD) is a well-known phenomenon in higher eukaryotes. In these organisms, PCD is essential for embryonic development--for example, the disappearance of the interdigital web--and also functions in tissue homeostasis and elimination of pathogen-invaded cells. The existence of PCD mechanisms in unicellular organisms like bacteria, on the other hand, has only recently begun to be recognized. We here demonstrate the existence of a bacterial PCD pathway that induces characteristics that are strikingly reminiscent of eukaryotic apoptosis, such as fragmentation of DNA, exposure of phosphatidylserine on the cell surface, and membrane blebbing. Our results can provide more insight into the mechanism and evolution of PCD pathways in higher eukaryotes. More importantly, especially in the light of the looming antibiotic crisis, they may point to a bacterial Achilles' heel and can inspire innovative ways of combating bacterial infections, directed at the targeted activation of PCD pathways. Copyright © 2015 Dewachter et al.

Injury Deaths among People with Epilepsy in Rural Bangladesh

PubMed Central

Mateen, Farrah J.; Shinohara, Russell T.; Alam, Nurul; Black, Robert E.; Streatfield, Peter K.

2012-01-01

Background Accidental death in people with epilepsy (PWE) has been described in high income settings where the relative risk of death is known to be higher than in the standard population. Population-based studies of injury deaths among PWE in developing countries are uncommon. Methods A population-based verbal autopsy study in Matlab, Bangladesh, performed at a health and demographic surveillance system site (mean population 223,886 in 142 villages), was used to assess the possible causes of all deaths. All cases of accidental injury (2005–2008) were evaluated and compared between people with and without a diagnosis of epilepsy. Results There were 12 accidental deaths among PWE (8 female, age range 12–58 years old) out of a total of 316 deaths due to accidental injuries (3.8% of all injury deaths). Causes of mortality were drowning (n=10) and burns (n=2). The proportion of deaths due to drowning among PWE was significantly higher than that of the standard population (83% (10/12) vs. 7% (21/304), relative risk 12.6 (95% CI, 7.7–20.7, p<0.0001)). Mortality due to injury in PWE occurred at a younger age compared to people without epilepsy (mean difference 20.7 years (95% CI 6.7, 34.3), p<0.004). Conclusions There is a high proportion of accidental deaths due to drowning in PWE in Bangladesh compared to the standard population. Given the risk of seasonal flooding and low level of formal education, programs targeting water safety for PWE at all ages should be emphasized, appropriate for level of ability. PMID:22341966

Technical aids for the flexible use of the Leksell stereotactic system.

PubMed

Salcman, M; Bellis, E H; Sewchand, W; Amin, P

1989-06-01

As part of a multimodality therapy program for intracranial tumours, 105 stereotactic and implant procedures have been carried out utilizing the CT-compatible Leksell stereotactic system. In the iridium implant series, 86 catheters have been implanted for an average of 3.6 targets per patient. There have been no deaths or missed targets and only two incidential haemorrhages detected. In order to facilitate the reliability, safety and speed of multiple catheter insertion, several techniques have been developed including: (a) a standardized single-length catheter and flange system; (b) a ceramic catheter for microwave hyperthermia; (c) a mnemonic card for ease of calculation; (d) a radiation shield for nursing; (e) a stereotactic drill and surgical approaches to far lateral and posterior fossa targets. Principles for the use of these technical aids are discussed.

Renal Cell Carcinoma Programmed Death-ligand 1, a New Direct Target of Hypoxia-inducible Factor-2 Alpha, is Regulated by von Hippel-Lindau Gene Mutation Status.

PubMed

Messai, Yosra; Gad, Sophie; Noman, Muhammad Zaeem; Le Teuff, Gwenael; Couve, Sophie; Janji, Bassam; Kammerer, Solenne Florence; Rioux-Leclerc, Nathalie; Hasmim, Meriem; Ferlicot, Sophie; Baud, Véronique; Mejean, Arnaud; Mole, David Robert; Richard, Stéphane; Eggermont, Alexander M M; Albiges, Laurence; Mami-Chouaib, Fathia; Escudier, Bernard; Chouaib, Salem

2016-10-01

Clear cell renal cell carcinomas (ccRCC) frequently display a loss of function of the von Hippel-Lindau (VHL) gene. To elucidate the putative relationship between VHL mutation status and immune checkpoint ligand programmed death-ligand 1 (PD-L1) expression. A series of 32 renal tumors composed of 11 VHL tumor-associated and 21 sporadic RCCs were used to evaluate PD-L1 expression levels after sequencing of the three exons and exon-intron junctions of the VHL gene. The 786-O, A498, and RCC4 cell lines were used to investigate the mechanisms of PD-L1 regulation. Fisher's exact test was used for VHL mutation and Kruskal-Wallis test for PD-L1 expression. If no covariate accounted for the association of VHL and PD-L1, then a Kruskal-Wallis test was used; otherwise Cochran-Mantel-Haenzsel test was used. We also used the Fligner-Policello test to compare two medians when the distributions had different dispersions. We demonstrated that tumors from ccRCC patients with VHL biallelic inactivation (ie, loss of function) display a significant increase in PD-L1 expression compared with ccRCC tumors carrying one VHL wild-type allele. Using the inducible VHL 786-O-derived cell lines with varying hypoxia-inducible factor-2 alpha (HIF-2α) stabilization levels, we showed that PD-L1 expression levels positively correlate with VHL mutation and HIF-2α expression. Targeting HIF-2α decreased PD-L1, while HIF-2α overexpression increased PD-L1 mRNA and protein levels in ccRCC cells. Interestingly, chromatin immunoprecipitation and luciferase assays revealed a direct binding of HIF-2α to a transcriptionally active hypoxia-response element in the human PD-L1 proximal promoter in 786-O cells. Our work provides the first evidence that VHL mutations positively correlate with PD-L1 expression in ccRCC and may influence the response to ccRCC anti-PD-L1/PD-1 immunotherapy. We investigated the relationship between von Hippel-Lindau mutations and programmed death-ligand 1 expression. We demonstrated that von Hippel-Lindau mutation status significantly correlated with programmed death-ligand 1 expression in clear cell renal cell carcinomas. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

A Needs Assessment of Brain Death Education in Pediatric Critical Care Medicine Fellowships.

PubMed

Ausmus, Andrew M; Simpson, Pippa M; Zhang, Liyun; Petersen, Tara L

2018-04-12

To assess the current training in brain death examination provided during pediatric critical care medicine fellowship. Internet-based survey. United States pediatric critical care medicine fellowship programs. Sixty-four pediatric critical care medicine fellowship program directors and 230 current pediatric critical care medicine fellows/recent graduates were invited to participate. Participants were asked demographic questions related to their fellowship programs, training currently provided at their fellowship programs, previous experience with brain death examinations (fellows/graduates), and perceptions regarding the adequacy of current training. Twenty-nine program directors (45%) and 91 current fellows/graduates (40%) responded. Third-year fellows reported having performed a median of five examinations (interquartile range, 3-6). On a five-point Likert scale, 93% of program directors responded they "agree" or "strongly agree" that their fellows receive enough instruction on performing brain death examinations compared with 67% of fellows and graduates (p = 0.007). The responses were similar when asked about opportunity to practice brain death examinations (90% vs 54%; p < 0.001). In a regression tree analysis, number of brain death examinations performed was the strongest predictor of trainee satisfaction. Both fellows and program directors preferred bedside demonstration or simulation as educational modalities to add to the fellowship curriculum. Pediatric critical care medicine fellows overall perform relatively few brain death examinations during their training. Pediatric critical care medicine fellows and program directors disagree in their perceptions of the current training in brain death examination, with fellows perceiving a need for increased training. Both program directors and fellows prefer additional training using bedside demonstration or simulation. Since clinical exposure to brain death examinations is variable, adding simulated brain death examinations to the pediatric critical care medicine fellowship curriculum could help standardize the experience.

Atezolizumab: First Global Approval.

PubMed

Markham, Anthony

2016-08-01

Atezolizumab (Tecentriq™)-a monoclonal antibody targeting programmed death ligand 1 (PD-L1 or CD274 antigen)-is being developed by Genentech as treatment for a variety of haematological malignancies and solid tumours. It been approved in the US as a second-line therapy for urothelial carcinoma and is awaiting approval as a second-line therapy for non-small cell lung cancer. This article summarizes the milestones in the development of atezolizumab leading to this first approval for urothelial carcinoma.

Dendritic Cells and Programmed Death-1 Blockade: A Joint Venture to Combat Cancer.

PubMed

Versteven, Maarten; Van den Bergh, Johan M J; Marcq, Elly; Smits, Evelien L J; Van Tendeloo, Viggo F I; Hobo, Willemijn; Lion, Eva

2018-01-01

Two decades of clinical cancer research with dendritic cell (DC)-based vaccination have proved that this type of personalized medicine is safe and has the capacity to improve survival, but monotherapy is unlikely to cure the cancer. Designed to empower the patient's antitumor immunity, huge research efforts are set to improve the efficacy of next-generation DC vaccines and to find synergistic combinations with existing cancer therapies. Immune checkpoint approaches, aiming to breach immune suppression and evasion to reinforce antitumor immunity, have been a revelation in the immunotherapy field. Early success of therapeutic antibodies blocking the programmed death-1 (PD-1) pathway has sparked the development of novel inhibitors and combination therapies. Hence, merging immunoregulatory tumor-specific DC strategies with PD-1-targeted approaches is a promising path to explore. In this review, we focus on the role of PD-1-signaling in DC-mediated antitumor immunity. In the quest of exploiting the full potential of DC therapy, different strategies to leverage DC immunopotency by impeding PD-1-mediated immune regulation are discussed, including the most advanced research on targeted therapeutic antibodies, lessons learned from chemotherapy-induced immune activation, and more recent developments with soluble molecules and gene-silencing techniques. An overview of DC/PD-1 immunotherapy combinations that are currently under preclinical and clinical investigation substantiates the clinical potential of such combination strategies.

Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer.

PubMed

Mason, Jacqueline M; Wei, Xin; Fletcher, Graham C; Kiarash, Reza; Brokx, Richard; Hodgson, Richard; Beletskaya, Irina; Bray, Mark R; Mak, Tak W

2017-03-21

Loss of cell-cycle control is a hallmark of human cancer. Cell-cycle checkpoints are essential for maintaining genome integrity and balanced growth and division. They are specifically deregulated in cancer cells and contain regulators that represent potential therapeutic targets. Monopolar spindle 1 (Mps1; also known as TTK protein kinase) is a core component of the spindle assembly checkpoint (SAC), a genome-surveillance mechanism that is important for cell survival, and has emerged as a candidate target for anticancer therapy. Here, we report the cellular and antitumor effects of CFI-402257, a potent (Mps1 K i = 0.09 ± 0.02 nM; cellular Mps1 EC 50 = 6.5 ± 0.5 nM), highly selective, and orally active small-molecule inhibitor of Mps1 that was identified through a drug-discovery program. Human cancer cells treated with CFI-402257 exhibit effects consistent with Mps1 kinase inhibition, specifically SAC inactivation, leading to chromosome missegregation, aneuploidy, and ultimately cell death. Oral administration of CFI-402257 in monotherapy or in combination with an anti-programmed cell death 1 (PD-1) antibody in mouse models of human cancer results in inhibition of tumor growth at doses that are well-tolerated. Our findings provide a rationale for the clinical evaluation of CFI-402257 in patients with solid tumors.

Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer

PubMed Central

Mason, Jacqueline M.; Wei, Xin; Fletcher, Graham C.; Kiarash, Reza; Brokx, Richard; Hodgson, Richard; Beletskaya, Irina; Bray, Mark R.; Mak, Tak W.

2017-01-01

Loss of cell-cycle control is a hallmark of human cancer. Cell-cycle checkpoints are essential for maintaining genome integrity and balanced growth and division. They are specifically deregulated in cancer cells and contain regulators that represent potential therapeutic targets. Monopolar spindle 1 (Mps1; also known as TTK protein kinase) is a core component of the spindle assembly checkpoint (SAC), a genome-surveillance mechanism that is important for cell survival, and has emerged as a candidate target for anticancer therapy. Here, we report the cellular and antitumor effects of CFI-402257, a potent (Mps1 Ki = 0.09 ± 0.02 nM; cellular Mps1 EC50 = 6.5 ± 0.5 nM), highly selective, and orally active small-molecule inhibitor of Mps1 that was identified through a drug-discovery program. Human cancer cells treated with CFI-402257 exhibit effects consistent with Mps1 kinase inhibition, specifically SAC inactivation, leading to chromosome missegregation, aneuploidy, and ultimately cell death. Oral administration of CFI-402257 in monotherapy or in combination with an anti-programmed cell death 1 (PD-1) antibody in mouse models of human cancer results in inhibition of tumor growth at doses that are well-tolerated. Our findings provide a rationale for the clinical evaluation of CFI-402257 in patients with solid tumors. PMID:28270606

Molecular classification of gastric adenocarcinoma: translating new insights from the cancer genome atlas research network.

PubMed

Sunakawa, Yu; Lenz, Heinz-Josef

2015-04-01

Gastric cancer is a heterogenous cancer, which may be classified into several distinct subtypes based on pathology and epidemiology, each with different initiating pathological processes and each possibly having different tumor biology. A classification of gastric cancer should be important to select patients who can benefit from the targeted therapies or to precisely predict prognosis. The Cancer Genome Atlas (TCGA) study collaborated with previous reports regarding subtyping gastric cancer but also proposed a refined classification based on molecular characteristics. The addition of the new molecular classification strategy to a current classical subtyping may be a promising option, particularly stratification by Epstein-Barr virus (EBV) and microsatellite instability (MSI) statuses. According to TCGA study, EBV gastric cancer patients may benefit the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibodies or phosphoinositide 3-kinase (PI3K) inhibitors which are now being developed. The discoveries of predictive biomarkers should improve patient care and individualized medicine in the management since the targeted therapies may have the potential to change the landscape of gastric cancer treatment, moreover leading to both better understanding of the heterogeneity and better outcomes. Patient enrichment by predictive biomarkers for new treatment strategies will be critical to improve clinical outcomes. Additionally, liquid biopsies will be able to enable us to monitor in real-time molecular escape mechanism, resulting in better treatment strategies.

Dendritic Cells and Programmed Death-1 Blockade: A Joint Venture to Combat Cancer

PubMed Central

Versteven, Maarten; Van den Bergh, Johan M. J.; Marcq, Elly; Smits, Evelien L. J.; Van Tendeloo, Viggo F. I.; Hobo, Willemijn; Lion, Eva

2018-01-01

Two decades of clinical cancer research with dendritic cell (DC)-based vaccination have proved that this type of personalized medicine is safe and has the capacity to improve survival, but monotherapy is unlikely to cure the cancer. Designed to empower the patient’s antitumor immunity, huge research efforts are set to improve the efficacy of next-generation DC vaccines and to find synergistic combinations with existing cancer therapies. Immune checkpoint approaches, aiming to breach immune suppression and evasion to reinforce antitumor immunity, have been a revelation in the immunotherapy field. Early success of therapeutic antibodies blocking the programmed death-1 (PD-1) pathway has sparked the development of novel inhibitors and combination therapies. Hence, merging immunoregulatory tumor-specific DC strategies with PD-1-targeted approaches is a promising path to explore. In this review, we focus on the role of PD-1-signaling in DC-mediated antitumor immunity. In the quest of exploiting the full potential of DC therapy, different strategies to leverage DC immunopotency by impeding PD-1-mediated immune regulation are discussed, including the most advanced research on targeted therapeutic antibodies, lessons learned from chemotherapy-induced immune activation, and more recent developments with soluble molecules and gene-silencing techniques. An overview of DC/PD-1 immunotherapy combinations that are currently under preclinical and clinical investigation substantiates the clinical potential of such combination strategies. PMID:29599770

Use of programmed cell death protein ligand 1 assay to predict the outcomes of non-small cell lung cancer patients treated with immune checkpoint inhibitors

PubMed Central

Tibaldi, Carmelo; Lunghi, Alice; Baldini, Editta

2017-01-01

The recent discovery of immune checkpoints inhibitors, especially anti-programmed cell death protein 1 (PD-1) and anti-programmed cell death protein ligand 1 (PD-L1) monoclonal antibodies, has opened new scenarios in the management of non-small cell lung cancer (NSCLC) and this new class of drugs has achieved a rapid development in the treatment of this disease. However, considering the costs of these drugs and the fact that only a subset of patients experience long-term disease control, the identification of predictive biomarkers for the selection of candidates suitable for treatment has become a priority. The research focused mainly on the expression of the PD-L1 receptor on both tumor cells and/or immune infiltrates determined by immunohistochemistry (IHC). However, different checkpoint inhibitors were tested, different IHC assays were used, different targets were considered (tumor cells, immune infiltrates or both) and different expression thresholds were employed in clinical trials. In some trials the assay was used prospectively to select the patients, while in other trials it was evaluated retrospectively. Some confusion emerges, which makes it difficult to easily compare the literature data and to translate them in practice management. This mini-review shows the possibilities and pitfalls of the PD-L1 expression to predict the activity and efficacy of anti PD1/PD-L1 monoclonal antibodies in the treatment of NSCLC. PMID:28848698

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax.

PubMed

Leverson, Joel D; Sampath, Deepak; Souers, Andrew J; Rosenberg, Saul H; Fairbrother, Wayne J; Amiot, Martine; Konopleva, Marina; Letai, Anthony

2017-12-01

Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high-priority goal for cancer therapy. After decades of effort, drug-discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL2 biology, were essential to the development of BH3 mimetics such as the BCL2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL2 biology and facilitated the clinical development of venetoclax. Significance: Basic research into the pathways governing programmed cell death have paved the way for the discovery of apoptosis-inducing agents such as venetoclax, a BCL2-selective inhibitor that was recently approved by the FDA and the European Medicines Agency. Preclinical studies aimed at identifying BCL2-dependent tumor types have translated well into the clinic thus far and will likely continue to inform the clinical development of venetoclax and other BCL2 family inhibitors. Cancer Discov; 7(12); 1376-93. ©2017 AACR. ©2017 American Association for Cancer Research.

A new chemotherapy agent-free theranostic system composed of graphene oxide nano-complex and aptamers for treatment of cancer cells.

PubMed

Bahreyni, Amirhossein; Yazdian-Robati, Rezvan; Hashemitabar, Shirin; Ramezani, Mohammad; Ramezani, Pouria; Abnous, Khalil; Taghdisi, Seyed Mohammad

2017-06-30

The common cancer treatment strategies like chemotherapy and radiotherapy are nonspecific and can trigger severe side effects by damaging normal cells. So, targeted cancer therapies, such as apoptosis induction, have attracted great attention in recent years. In this project, two nano-complexes, MUC1 aptamer-NAS-24 aptamer-Graphene oxide (GO) and MUC1 aptamer-Cytochrome C aptamer-GO, were designed to induce cell programmed death in MDA-MB-231 and MCF-7 cells (breast cancer cell lines) and to verify the level of apoptosis in both cell lines. MUC1 aptamer was a molecular recognition probe that led the internalization of two nano-complexes into MDA-MB-231 and MCF-7 cells (MUC1 positive cells) but not into HepG2 cell (liver cancer cell line, MUC1 negative cells). The apoptosis induction relied on binding of NAS-24 aptamer to its target, vimentin, in MDA-MB-231 and MCF-7 (target cells) with different levels of vimentin content. The function of first nano-complex was confirmed by binding of FAM-labeled cytochrome C aptamer to its target (cytochrome C) which was released from mitochondria, based on the function of the first nano-complex. Fluorometric analysis and gel retardation assay proved the formation of nano-complexes. The results of flow cytometry and fluorescence microscopy indicated efficient apoptosis induction just in target cells (MDA-MB-231 and MCF-7 cells) but not in non-target cells (HepG2 cell). The results of MTT assay also confirmed cell death process. Overall, our results proved excellent targeted apoptosis in breast cancer cells by designed nano-complexes which can be applied as an efficient cancer therapy method. Copyright © 2017 Elsevier B.V. All rights reserved.

Autophagy Therapeutic Potential of Garlic in Human Cancer Therapy

PubMed Central

Chu, Yung-Lin; Raghu, Rajasekaran; Lu, Kuan-Hung; Liu, Chun-Ting; Lin, Shu-Hsi; Lai, Yi-Syuan; Cheng, Wei-Cheng; Lin, Shih-Hang; Sheen, Lee-Yan

2013-01-01

Cancer is one of the deadliest diseases against humans. To tackle this menace, humans have developed several high-technology therapies, such as chemotherapy, tomotherapy, targeted therapy, and antibody therapy. However, all these therapies have their own adverse side effects. Therefore, recent years have seen increased attention being given to the natural food for complementary therapy, which have less side effects. Garlic (Dà Suàn; Allium sativum), is one of most powerful food used in many of the civilizations for both culinary and medicinal purpose. In general, these foods induce cancer cell death by apoptosis, autophagy, or necrosis. Studies have discussed how natural food factors regulate cell survival or death by autophagy in cancer cells. From many literature reviews, garlic could not only induce apoptosis but also autophagy in cancer cells. Autophagy, which is called type-II programmed cell death, provides new strategy in cancer therapy. In conclusion, we wish that garlic could be the pioneer food of complementary therapy in clinical cancer treatment and increase the life quality of cancer patients. PMID:24716172

Autophagy therapeutic potential of garlic in human cancer therapy.

PubMed

Chu, Yung-Lin; Raghu, Rajasekaran; Lu, Kuan-Hung; Liu, Chun-Ting; Lin, Shu-Hsi; Lai, Yi-Syuan; Cheng, Wei-Cheng; Lin, Shih-Hang; Sheen, Lee-Yan

2013-07-01

Cancer is one of the deadliest diseases against humans. To tackle this menace, humans have developed several high-technology therapies, such as chemotherapy, tomotherapy, targeted therapy, and antibody therapy. However, all these therapies have their own adverse side effects. Therefore, recent years have seen increased attention being given to the natural food for complementary therapy, which have less side effects. Garlic (Dà Suàn; Allium sativum), is one of most powerful food used in many of the civilizations for both culinary and medicinal purpose. In general, these foods induce cancer cell death by apoptosis, autophagy, or necrosis. Studies have discussed how natural food factors regulate cell survival or death by autophagy in cancer cells. From many literature reviews, garlic could not only induce apoptosis but also autophagy in cancer cells. Autophagy, which is called type-II programmed cell death, provides new strategy in cancer therapy. In conclusion, we wish that garlic could be the pioneer food of complementary therapy in clinical cancer treatment and increase the life quality of cancer patients.

Granzyme B Disrupts Central Metabolism and Protein Synthesis in Bacteria to Promote an Immune Cell Death Program.

PubMed

Dotiwala, Farokh; Sen Santara, Sumit; Binker-Cosen, Andres Ariel; Li, Bo; Chandrasekaran, Sriram; Lieberman, Judy

2017-11-16

Human cytotoxic lymphocytes kill intracellular microbes. The cytotoxic granule granzyme proteases released by cytotoxic lymphocytes trigger oxidative bacterial death by disrupting electron transport, generating superoxide anion and inactivating bacterial oxidative defenses. However, they also cause non-oxidative cell death because anaerobic bacteria are also killed. Here, we use differential proteomics to identify granzyme B substrates in three unrelated bacteria: Escherichia coli, Listeria monocytogenes, and Mycobacteria tuberculosis. Granzyme B cleaves a highly conserved set of proteins in all three bacteria, which function in vital biosynthetic and metabolic pathways that are critical for bacterial survival under diverse environmental conditions. Key proteins required for protein synthesis, folding, and degradation are also substrates, including multiple aminoacyl tRNA synthetases, ribosomal proteins, protein chaperones, and the Clp system. Because killer cells use a multipronged strategy to target vital pathways, bacteria may not easily become resistant to killer cell attack. Copyright © 2017 Elsevier Inc. All rights reserved.

Theranostic Gold Nanoantennas for Simultaneous Multiplexed Raman Imaging of Immunomarkers and Photothermal Therapy.

PubMed

Webb, Joseph A; Ou, Yu-Chuan; Faley, Shannon; Paul, Eden P; Hittinger, Joseph P; Cutright, Camden C; Lin, Eugene C; Bellan, Leon M; Bardhan, Rizia

2017-07-31

In this study, we demonstrate the theranostic capability of actively targeted, site-specific multibranched gold nanoantennas (MGNs) in triple-negative breast cancer (TNBC) cells in vitro. By utilizing multiplexed surface-enhanced Raman scattering (SERS) imaging, enabled by the narrow peak widths of Raman signatures, we simultaneously targeted immune checkpoint receptor programmed death ligand 1 (PDL1) and the epidermal growth factor receptor (EGFR) overexpressed in TNBC cells. A 1:1 mixture of MGNs functionalized with anti-PDL1 antibodies and Raman tag 5,5-dithio-bis-(2-nitrobenzoic acid) (DTNB) and MGNs functionalized with anti-EGFR antibodies and Raman tag para -mercaptobenzoic acid ( p MBA) were incubated with the cells. SERS imaging revealed a cellular traffic map of MGN localization by surface binding and receptor-mediated endocytosis, enabling targeted diagnosis of both biomarkers. Furthermore, cells incubated with anti-EGFR- p MBA-MGNs and illuminated with an 808 nm laser for 15 min at 4.7 W/cm 2 exhibited photothermal cell death only within the laser spot (indicated by live/dead cell fluorescence assay). Therefore, this study not only provides an optical imaging platform that can track immunomarkers with spatiotemporal control but also demonstrates an externally controlled light-triggered therapeutic approach enabling receptor-specific treatment with biocompatible theranostic nanoprobes.

Theranostic Gold Nanoantennas for Simultaneous Multiplexed Raman Imaging of Immunomarkers and Photothermal Therapy

PubMed Central

2017-01-01

In this study, we demonstrate the theranostic capability of actively targeted, site-specific multibranched gold nanoantennas (MGNs) in triple-negative breast cancer (TNBC) cells in vitro. By utilizing multiplexed surface-enhanced Raman scattering (SERS) imaging, enabled by the narrow peak widths of Raman signatures, we simultaneously targeted immune checkpoint receptor programmed death ligand 1 (PDL1) and the epidermal growth factor receptor (EGFR) overexpressed in TNBC cells. A 1:1 mixture of MGNs functionalized with anti-PDL1 antibodies and Raman tag 5,5-dithio-bis-(2-nitrobenzoic acid) (DTNB) and MGNs functionalized with anti-EGFR antibodies and Raman tag para-mercaptobenzoic acid (pMBA) were incubated with the cells. SERS imaging revealed a cellular traffic map of MGN localization by surface binding and receptor-mediated endocytosis, enabling targeted diagnosis of both biomarkers. Furthermore, cells incubated with anti-EGFR–pMBA–MGNs and illuminated with an 808 nm laser for 15 min at 4.7 W/cm2 exhibited photothermal cell death only within the laser spot (indicated by live/dead cell fluorescence assay). Therefore, this study not only provides an optical imaging platform that can track immunomarkers with spatiotemporal control but also demonstrates an externally controlled light-triggered therapeutic approach enabling receptor-specific treatment with biocompatible theranostic nanoprobes. PMID:28782050

Necroptosis inhibitors as therapeutic targets in inflammation mediated disorders - a review of the current literature and patents.

PubMed

Kopalli, Spandana Rajendra; Kang, Tae-Bong; Koppula, Sushruta

2016-11-01

Recent studies have shown substantial interplay between the apoptosis and necroptosis pathways. Necroptosis, a form of programmed cell death, has been found to stimulate the immune system contributing to the pathophysiology of several inflammation-mediated disorders. Determining the contribution of necroptotic signaling pathways to inflammation may lead to the development of selective and specific molecular target implicated necroptosis inhibitors. Areas covered: This review summarizes the recently published and patented necroptosis inhibitors as therapeutic targets in inflammation-mediated disorders. The role of several necroptosis inhibitors, focusing on specific signaling molecules, was discussed with particular attention to inflammation-mediated disorders. Data was obtained from Espacenet®, WIPO®, USPTO® patent websites, and other relevant sources (2006-2016). Expert opinion: Necroptosis inhibitors hold promise for treatment of inflammation-mediated clinical conditions in which necroptotic cell death plays a major role. Although necroptosis inhibitors reviewed in this survey showed inhibitory effects against several inflammation-mediated disorders, only a few have passed to the stage of clinical testing and need extensive research for therapeutic practice. Revisiting the existing drugs and developing novel necroptosis inhibiting agents as well as understanding their mechanism are essential. A detailed study of necroptosis function in animal models of inflammation may provide us an alternative strategy for the development of drug-like necroptosis inhibitors.

ZBP1/DAI ubiquitination and sensing of influenza vRNPs activate programmed cell death

PubMed Central

Kuriakose, Teneema; Malireddi, R.K. Subbarao; Mishra, Ashutosh

2017-01-01

Innate sensing of influenza virus infection induces activation of programmed cell death pathways. We have recently identified Z-DNA–binding protein 1 (ZBP1) as an innate sensor of influenza A virus (IAV). ZBP1-mediated IAV sensing is critical for triggering programmed cell death in the infected lungs. Surprisingly, little is known about the mechanisms regulating ZBP1 activation to induce programmed cell death. Here, we report that the sensing of IAV RNA by retinoic acid inducible gene I (RIG-I) initiates ZBP1-mediated cell death via the RIG-I–MAVS–IFN-β signaling axis. IAV infection induces ubiquitination of ZBP1, suggesting potential regulation of ZBP1 function through posttranslational modifications. We further demonstrate that ZBP1 senses viral ribonucleoprotein (vRNP) complexes of IAV to trigger cell death. These findings collectively indicate that ZBP1 activation requires RIG-I signaling, ubiquitination, and vRNP sensing to trigger activation of programmed cell death pathways during IAV infection. The mechanism of ZBP1 activation described here may have broader implications in the context of virus-induced cell death. PMID:28634194

Population-based screening program for reducing oral cancer mortality in 2,334,299 Taiwanese cigarette smokers and/or betel quid chewers.

PubMed

Chuang, Shu-Lin; Su, William Wang-Yu; Chen, Sam Li-Sheng; Yen, Amy Ming-Fang; Wang, Cheng-Ping; Fann, Jean Ching-Yuan; Chiu, Sherry Yueh-Hsia; Lee, Yi-Chia; Chiu, Han-Mo; Chang, Dun-Cheng; Jou, Yann-Yuh; Wu, Chien-Yuan; Chen, Hsiu-Hsi; Chen, Mu-Kuan; Chiou, Shu-Ti

2017-05-01

To reduce oral cancer mortality, an organized, population-based screening program for the early detection of oral premalignancy and oral cancer was designed for high-risk individuals with habits of betel quid chewing, cigarette smoking, or both. The objective of this report was to evaluate the long-term effectiveness of this program in reducing the incidence of advanced disease and deaths from oral cancer. A nationwide, population-based screening program for oral cancer has been conducted in Taiwan since 2004. Residents aged ≥ 18 years with oral habits of cigarette smoking and/or betel quid chewing were invited. The standardized mortality ratio method was used to compare the observed numbers of advanced oral cancers and deaths from oral cancer among screening attendees with the expected numbers derived from mortality among nonattendees. An intention-to-treat analysis of the relative rate of reductions in advanced-stage oral cancers and oral cancer mortality also was conducted. The overall screening rate was 55.1%. The relative risk of death from oral cancer was 0.53 (95% confidence interval [CI], 0.51-0.56) as a result of screening compared with the expected risk of oral cancer deaths in the absence of screening. The corresponding relative risk was 0.74 (95% CI, 0.72-0.77) after adjusting for self-selection bias. The relative risk of advanced oral cancer for the screened group versus the nonscreened group was 0.62 (95% CI, 0.59-0.64), which increased to 0.79 (95% CI, 0.76-0.82) after adjustment for self-selection bias. An organized, population-based oral cancer screening program targeting more than 2 million Taiwanese cigarette smokers and/or betel quid chewers demonstrated the effectiveness of reducing stage III or IV oral cancers and oral cancer mortality. These evidence-based findings corroborate and support the screening strategy of oral visual inspection for the prevention of oral cancer among high-risk individuals in areas with a high incidence of oral cancer. Cancer 2017;123:1597-1609. © 2017 American Cancer Society. © 2017 American Cancer Society.

Balancing the benefits and detriments among women targeted by the Norwegian Breast Cancer Screening Program.

PubMed

Hofvind, Solveig; Román, Marta; Sebuødegård, Sofie; Falk, Ragnhild S

2016-12-01

To compute a ratio between the estimated numbers of lives saved from breast cancer death and the number of women diagnosed with a breast cancer that never would have been diagnosed during the woman's lifetime had she not attended screening (epidemiologic over-diagnosis) in the Norwegian Breast Cancer Screening Program. The Norwegian Breast Cancer Screening Program invites women aged 50-69 to biennial mammographic screening. Results from published studies using individual level data from the programme for estimating breast cancer mortality and epidemiologic over-diagnosis comprised the basis for the ratio. The mortality reduction varied from 36.8% to 43% among screened women, while estimates on epidemiologic over-diagnosis ranged from 7% to 19.6%. We computed the average estimates for both values. The benefit-detriment ratio, number of lives saved, and number of women over-diagnosed were computed for different scenarios of reduction in breast cancer mortality and epidemiologic over-diagnosis. For every 10,000 biennially screened women, followed until age 79, we estimated that 53-61 (average 57) women were saved from breast cancer death, and 45-126 (average 82) were over-diagnosed. The benefit-detriment ratio using average estimates was 1:1.4, indicating that the programme saved about one life per 1-2 women with epidemiologic over-diagnosis. The benefit-detriment ratio estimates of the Norwegian Breast Cancer Screening Program, expressed as lives saved from breast cancer death and epidemiologic over-diagnosis, should be interpreted with care due to substantial uncertainties in the estimates, and the differences in the scale of values of the events compared. © The Author(s) 2016.

What a Shock: No Apoptosis without Heat Shock Protein 90α | Center for Cancer Research

Cancer.gov

Apoptosis, also known as programmed cell death, consists of a series of reactions designed to systematically chop up a cell and its contents. The process is used to eliminate specific cells during development or to remove old or damaged cells without harming any surrounding cells. Since cancer cells can develop mechanisms to avoid apoptosis, researchers may be able to identify new targets to combat cancer by better understanding the details of the apoptotic process.

Targeting B7x and B7 H3 as New Immunotherapies for Prostate Cancer

DTIC Science & Technology

2015-09-01

andMelnick, A. M. (2013) EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 23...symptoms, signs, or laboratoryLigands from the B7 family bind to receptors of the CD28 family, which regulate early T cell activation in lymphoid organs...was first identified in lymphoid cells lines induced to undergo programmed cell death [17]. Later reports noted that PD-1 is expressed on acti- vated

High performance nanobio photocatalyst for targeted brain cancer therapy.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rozhkova, E.; Ulasov, I.; Dimitrijevic, N. M.

We report pronounced and specific antiglioblastoma cell phototoxicity of 5 nm TiO{sub 2} particles covalently tethered to an antibody via a dihydroxybenzene bivalent linker. The linker application enables absorption of a visible part of the solar spectrum by the nanobio hybrid. The phototoxicity is mediated by reactive oxygen species (ROS) that initiate programmed death of the cancer cell. Synchrotron X-ray fluorescence microscopy (XFM) was applied for direct visualization of the nanobioconjugate distribution through a single brain cancer cell at the submicrometer scale.

Phenotypic Changes in Transgenic Tobacco Plants Overexpressing Vacuole-Targeted Thermotoga maritima BglB Related to Elevated Levels of Liberated Hormones.

PubMed

Nguyen, Quynh Anh; Lee, Dae-Seok; Jung, Jakyun; Bae, Hyeun-Jong

2015-01-01

The hyperthermostable β-glucosidase BglB of Thermotoga maritima was modified by adding a short C-terminal tetrapeptide (AFVY, which transports phaseolin to the vacuole, to its C-terminal sequence). The modified β-glucosidase BglB was transformed into tobacco (Nicotiana tabacum L.) plants. We observed a range of significant phenotypic changes in the transgenic plants compared to the wild-type (WT) plants. The transgenic plants had faster stem growth, earlier flowering, enhanced root systems development, an increased biomass biosynthesis rate, and higher salt stress tolerance in young plants compared to WT. In addition, programed cell death was enhanced in mature plants. Furthermore, the C-terminal AFVY tetrapeptide efficiently sorted T. maritima BglB into the vacuole, which was maintained in an active form and could perform its glycoside hydrolysis function on hormone conjugates, leading to elevated hormone [abscisic acid (ABA), indole 3-acetic acid (IAA), and cytokinin] levels that likely contributed to the phenotypic changes in the transgenic plants. The elevation of cytokinin led to upregulation of the transcription factor WUSCHELL, a homeodomain factor that regulates the development, division, and reproduction of stem cells in the shoot apical meristems. Elevation of IAA led to enhanced root development, and the elevation of ABA contributed to enhanced tolerance to salt stress and programed cell death. These results suggest that overexpressing vacuole-targeted T. maritima BglB may have several advantages for molecular farming technology to improve multiple targets, including enhanced production of the β-glucosidase BglB, increased biomass, and shortened developmental stages, that could play pivotal roles in bioenergy and biofuel production.

Differentiation of a Highly Tumorigenic Basal Cell Compartment in Urothelial Carcinoma

PubMed Central

He, Xiaobing; Marchionni, Luigi; Hansel, Donna E.; Yu, Wayne; Sood, Akshay; Yang, Jie; Parmigiani, Giovanni; Matsui, William; Berman, David M.

2011-01-01

Highly tumorigenic cancer cell (HTC) populations have been identified for a variety of solid tumors and assigned stem cell properties. Strategies for identifying HTCs in solid tumors have been primarily empirical rather than rational, particularly in epithelial tumors, which are responsible for 80% of cancer deaths. We report evidence for a spatially restricted bladder epithelial (urothelial) differentiation program in primary urothelial cancers (UCs) and in UC xenografts. We identified a highly tumorigenic UC cell compartment that resembles benign urothelial stem cells (basal cells), co-expresses the 67-kDa laminin receptor and the basal cell-specific cytokeratin CK17, and lacks the carcinoembryonic antigen family member CEACAM6 (CD66c). This multipotent compartment resides at the tumor-stroma interface, is easily identified on histologic sections, and possesses most, if not all, of the engraftable tumor-forming ability in the parental xenograft. We analyzed differential expression of genes and pathways in basal-like cells versus more differentiated cells. Among these, we found significant enrichment of pathways comprising “hallmarks” of cancer, and pharmacologically targetable signaling pathways, including Janus kinase-signal transducer and activator of transcription, Notch, focal adhesion, mammalian target of rapamycin, epidermal growth factor receptor (erythroblastic leukemia viral oncogene homolog [ErbB]), and wingless-type MMTV integration site family (Wnt). The basal/HTC gene expression signature was essentially invisible within the context of nontumorigenic cell gene expression and overlapped significantly with genes driving progression and death in primary human UC. The spatially restricted epithelial differentiation program described here represents a conceptual advance in understanding cellular heterogeneity of carcinomas and identifies basal-like HTCs as attractive targets for cancer therapy. PMID:19544456

PD-1 blocks lytic granule polarization with concomitant impairment of integrin outside-in signaling in the natural killer cell immunological synapse.

PubMed

Huang, Yu; Chen, Zhiying; Jang, Joon Hee; Baig, Mirza S; Bertolet, Grant; Schroeder, Casey; Huang, Shengjian; Hu, Qian; Zhao, Yong; Lewis, Dorothy E; Qin, Lidong; Zhu, Michael Xi; Liu, Dongfang

2018-04-18

The inhibitory receptor programmed cell death protein 1 (PD-1) is upregulated on a variety of immune cells, including natural killer (NK) cells, during chronic viral infection and tumorigenesis. Blockade of PD-1 or its ligands produces durable clinical responses with tolerable side effects in patients with a broad spectrum of cancers. However, the underlying molecular mechanisms of how PD-1 regulates NK cell function remain poorly characterized. We sought to determine the effect of PD-1 signaling on NK cells. PD-1 was overexpressed in CD16-KHYG-1 (a human NK cell line with both antibody-dependent cellular cytotoxicity through CD16 and natural cytotoxicity through NKG2D) cells and stimulated by exposing the cells to NK-sensitive target cells expressing programmed death ligand 1 (PD-L1). PD-1 engagement by PD-L1 specifically blocked NK cell-mediated cytotoxicity without interfering with the conjugation between NK cells and target cells. Further examination showed that PD-1 signaling blocked lytic granule polarization in NK cells, which was accompanied by failure of integrin-linked kinase, a key molecule in the integrin outside-in signaling pathway, to accumulate in the immunological synapse after NK-target cell conjugation. Our results suggest that NK cell cytotoxicity is inhibited by PD-1 engagement, which blocks lytic granule polarization to the NK cell immunological synapse with concomitant impairment of integrin outside-in signaling. This study provides novel mechanistic insights into how PD-1 inhibition disrupts NK cell function. Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

PD-L1 Is a Therapeutic Target of the Bromodomain Inhibitor JQ1 and, Combined with HLA Class I, a Promising Prognostic Biomarker in Neuroblastoma.

PubMed

Melaiu, Ombretta; Mina, Marco; Chierici, Marco; Boldrini, Renata; Jurman, Giuseppe; Romania, Paolo; D'Alicandro, Valerio; Benedetti, Maria C; Castellano, Aurora; Liu, Tao; Furlanello, Cesare; Locatelli, Franco; Fruci, Doriana

2017-08-01

Purpose: This study sought to evaluate the expression of programmed cell death-ligand-1 (PD-L1) and HLA class I on neuroblastoma cells and programmed cell death-1 (PD-1) and lymphocyte activation gene 3 (LAG3) on tumor-infiltrating lymphocytes to better define patient risk stratification and understand whether this tumor may benefit from therapies targeting immune checkpoint molecules. Experimental Design: In situ IHC staining for PD-L1, HLA class I, PD-1, and LAG3 was assessed in 77 neuroblastoma specimens, previously characterized for tumor-infiltrating T-cell density and correlated with clinical outcome. Surface expression of PD-L1 was evaluated by flow cytometry and IHC in neuroblastoma cell lines and tumors genetically and/or pharmacologically inhibited for MYC and MYCN. A dataset of 477 human primary neuroblastomas from GEO and ArrayExpress databases was explored for PD-L1, MYC, and MYCN correlation. Results: Multivariate Cox regression analysis demonstrated that the combination of PD-L1 and HLA class I tumor cell density is a prognostic biomarker for predicting overall survival in neuroblastoma patients ( P = 0.0448). MYC and MYCN control the expression of PD-L1 in neuroblastoma cells both in vitro and in vivo Consistently, abundance of PD-L1 transcript correlates with MYC expression in primary neuroblastoma. Conclusions: The combination of PD-L1 and HLA class I represents a novel prognostic biomarker for neuroblastoma. Pharmacologic inhibition of MYCN and MYC may be exploited to target PD-L1 and restore an efficient antitumor immunity in high-risk neuroblastoma. Clin Cancer Res; 23(15); 4462-72. ©2017 AACR . ©2017 American Association for Cancer Research.

Merkel Cell Carcinoma Therapeutic Update.

PubMed

Cassler, Nicole M; Merrill, Dean; Bichakjian, Christopher K; Brownell, Isaac

2016-07-01

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Early-stage disease can be cured with surgical resection and radiotherapy (RT). Sentinel lymph node biopsy (SLNB) is an important staging tool, as a microscopic MCC is frequently identified. Adjuvant RT to the primary excision site and regional lymph node bed may improve locoregional control. However, newer studies confirm that patients with biopsy-negative sentinel lymph nodes may not benefit from regional RT. Advanced MCC currently lacks a highly effective treatment as responses to chemotherapy are not durable. Recent work suggests that immunotherapy targeting the programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint holds great promise in treating advanced MCC and may provide durable responses in a portion of patients. At the same time, high-throughput sequencing studies have demonstrated significant differences in the mutational profiles of tumors with and without the Merkel cell polyomavirus (MCV). An important secondary endpoint in the ongoing immunotherapy trials for MCC will be determining if there is a response difference between the virus-positive MCC tumors that typically lack a large mutational burden and the virus-negative tumors that have a large number of somatic mutations and predicted tumor neoantigens. Interestingly, sequencing studies have failed to identify a highly recurrent activated driver pathway in the majority of MCC tumors. This may explain why targeted therapies can demonstrate exceptional responses in case reports but fail when treating all comers with MCC. Ultimately, a precision medicine approach may be more appropriate for treating MCC, where identified driver mutations are used to direct targeted therapies. At a minimum, stratifying patients in future clinical trials based on tumor viral status should be considered as virus-negative tumors are more likely to harbor activating driver mutations.

The Role of Programmed Cell Death Ligand-1 (PD-L1/CD274) in the Development of Graft versus Host Disease

PubMed Central

Al-Chaqmaqchi, Heevy; Sadeghi, Behnam; Abedi-Valugerdi, Manuchehr; Al-Hashmi, Sulaiman; Fares, Mona; Kuiper, Raoul; Lundahl, Joachim

2013-01-01

Programmed cell death ligand-1 (PD-L1/CD274) is an immunomodulatory molecule involved in cancer and complications of bone marrow transplantation, such as graft rejection and graft-versus-host disease. The present study was designed to assess the dynamic expression of this molecule after hematopoietic stem cell transplantation in relation to acute graft-versus-host disease. Female BALB/c mice were conditioned with busulfan and cyclophosphamide and transplanted with either syngeneic or allogeneic (male C57BL/6 mice) bone marrow and splenic cells. The expression of PD-L1 was evaluated at different time points employing qPCR, western blot and immunohistochemistry. Allogeneic- but not syngeneic-transplanted animals exhibited a marked up-regulation of PD-L1 expression in the muscle and kidney, but not the liver, at days 5 and 7 post transplantation. In mice transplanted with allogeneic bone marrow cells, the enhanced expression of PD-L1 was associated with high serum levels of IFNγ and TNFα at corresponding intervals. Our findings demonstrate that PD-L1 is differently induced and expressed after allogeneic transplantation than it is after syngeneic transplantation, and that it is in favor of target rather than non-target organs at the early stages of acute graft-versus-host disease. This is the first study to correlate the dynamics of PD-L1 at the gene-, protein- and activity levels with the early development of acute graft-versus-host disease. Our results suggest that the higher expression of PD-L1 in the muscle and kidney (non-target tissues) plays a protective role in skeletal muscle during acute graft-versus-host disease. PMID:23593203

Phenotypic Changes in Transgenic Tobacco Plants Overexpressing Vacuole-Targeted Thermotoga maritima BglB Related to Elevated Levels of Liberated Hormones

PubMed Central

Nguyen, Quynh Anh; Lee, Dae-Seok; Jung, Jakyun; Bae, Hyeun-Jong

2015-01-01

The hyperthermostable β-glucosidase BglB of Thermotoga maritima was modified by adding a short C-terminal tetrapeptide (AFVY, which transports phaseolin to the vacuole, to its C-terminal sequence). The modified β-glucosidase BglB was transformed into tobacco (Nicotiana tabacum L.) plants. We observed a range of significant phenotypic changes in the transgenic plants compared to the wild-type (WT) plants. The transgenic plants had faster stem growth, earlier flowering, enhanced root systems development, an increased biomass biosynthesis rate, and higher salt stress tolerance in young plants compared to WT. In addition, programed cell death was enhanced in mature plants. Furthermore, the C-terminal AFVY tetrapeptide efficiently sorted T. maritima BglB into the vacuole, which was maintained in an active form and could perform its glycoside hydrolysis function on hormone conjugates, leading to elevated hormone [abscisic acid (ABA), indole 3-acetic acid (IAA), and cytokinin] levels that likely contributed to the phenotypic changes in the transgenic plants. The elevation of cytokinin led to upregulation of the transcription factor WUSCHELL, a homeodomain factor that regulates the development, division, and reproduction of stem cells in the shoot apical meristems. Elevation of IAA led to enhanced root development, and the elevation of ABA contributed to enhanced tolerance to salt stress and programed cell death. These results suggest that overexpressing vacuole-targeted T. maritima BglB may have several advantages for molecular farming technology to improve multiple targets, including enhanced production of the β-glucosidase BglB, increased biomass, and shortened developmental stages, that could play pivotal roles in bioenergy and biofuel production. PMID:26618153

N-Desmethyldauricine Induces Autophagic Cell Death in Apoptosis-Defective Cells via Ca2+ Mobilization.

PubMed

Law, Betty Y K; Mok, Simon W F; Chen, Juan; Michelangeli, Francesco; Jiang, Zhi-Hong; Han, Yu; Qu, Yuan Q; Qiu, Alena C L; Xu, Su-Wei; Xue, Wei-Wei; Yao, Xiao-Jun; Gao, Jia Y; Javed, Masood-Ul-Hassan; Coghi, Paolo; Liu, Liang; Wong, Vincent K W

2017-01-01

Resistance of cancer cells to chemotherapy remains a significant problem in oncology. Mechanisms regulating programmed cell death, including apoptosis, autophagy or necrosis, in the treatment of cancers have been extensively investigated over the last few decades. Autophagy is now emerging as an important pathway in regulating cell death or survival in cancer therapy. Recent studies demonstrated variety of natural small-molecules could induce autophagic cell death in apoptosis-resistant cancer cells, therefore, discovery of novel autophagic enhancers from natural products could be a promising strategy for treatment of chemotherapy-resistant cancer. By computational virtual docking analysis, biochemical assays, and advanced live-cell imaging techniques, we have identified N -desmethyldauricine (LP-4), isolated from rhizoma of Menispermum dauricum DC as a novel inducer of autophagy. LP-4 was shown to induce autophagy via the Ulk-1-PERK and Ca 2+ /Calmodulin-dependent protein kinase kinase β (CaMKKβ)-AMPK-mTOR signaling cascades, via mobilizing calcium release through inhibition of SERCA, and importantly, lead to autophagic cell death in a panel of cancer cells, apoptosis-defective and apoptosis-resistant cells. Taken together, this study provides detailed insights into the cytotoxic mechanism of a novel autophagic compound that targeting the apoptosis resistant cancer cells, and new implication on drug discovery from natural products for drug resistant cancer therapy.

Multiple Modes of Cell Death Discovered in a Prokaryotic (Cyanobacterial) Endosymbiont

PubMed Central

Zheng, Weiwen; Rasmussen, Ulla; Zheng, Siping; Bao, Xiaodong; Chen, Bin; Gao, Yuan; Guan, Xiong; Larsson, John; Bergman, Birgitta

2013-01-01

Programmed cell death (PCD) is a genetically-based cell death mechanism with vital roles in eukaryotes. Although there is limited consensus on similar death mode programs in prokaryotes, emerging evidence suggest that PCD events are operative. Here we present cell death events in a cyanobacterium living endophytically in the fern Azolla microphylla, suggestive of PCD. This symbiosis is characterized by some unique traits such as a synchronized development, a vertical transfer of the cyanobacterium between plant generations, and a highly eroding cyanobacterial genome. A combination of methods was used to identify cell death modes in the cyanobacterium. Light- and electron microscopy analyses showed that the proportion of cells undergoing cell death peaked at 53.6% (average 20%) of the total cell population, depending on the cell type and host developmental stage. Biochemical markers used for early and late programmed cell death events related to apoptosis (Annexin V-EGFP and TUNEL staining assays), together with visualization of cytoskeleton alterations (FITC-phalloidin staining), showed that all cyanobacterial cell categories were affected by cell death. Transmission electron microscopy revealed four modes of cell death: apoptotic-like, autophagic-like, necrotic-like and autolytic-like. Abiotic stresses further enhanced cell death in a dose and time dependent manner. The data also suggest that dynamic changes in the peptidoglycan cell wall layer and in the cytoskeleton distribution patterns may act as markers for the various cell death modes. The presence of a metacaspase homolog (domain p20) further suggests that the death modes are genetically programmed. It is therefore concluded that multiple, likely genetically programmed, cell death modes exist in cyanobacteria, a finding that may be connected with the evolution of cell death in the plant kingdom. PMID:23822984

Programmed Cell Death During Caenorhabditis elegans Development

PubMed Central

Conradt, Barbara; Wu, Yi-Chun; Xue, Ding

2016-01-01

Programmed cell death is an integral component of Caenorhabditis elegans development. Genetic and reverse genetic studies in C. elegans have led to the identification of many genes and conserved cell death pathways that are important for the specification of which cells should live or die, the activation of the suicide program, and the dismantling and removal of dying cells. Molecular, cell biological, and biochemical studies have revealed the underlying mechanisms that control these three phases of programmed cell death. In particular, the interplay of transcriptional regulatory cascades and networks involving multiple transcriptional regulators is crucial in activating the expression of the key death-inducing gene egl-1 and, in some cases, the ced-3 gene in cells destined to die. A protein interaction cascade involving EGL-1, CED-9, CED-4, and CED-3 results in the activation of the key cell death protease CED-3, which is tightly controlled by multiple positive and negative regulators. The activation of the CED-3 caspase then initiates the cell disassembly process by cleaving and activating or inactivating crucial CED-3 substrates; leading to activation of multiple cell death execution events, including nuclear DNA fragmentation, mitochondrial elimination, phosphatidylserine externalization, inactivation of survival signals, and clearance of apoptotic cells. Further studies of programmed cell death in C. elegans will continue to advance our understanding of how programmed cell death is regulated, activated, and executed in general. PMID:27516615

7 CFR 82.17 - Death, incompetency, or disappearance.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 3 2010-01-01 2010-01-01 false Death, incompetency, or disappearance. 82.17 Section... DOMESTIC CONSUMPTION PROGRAMS CLINGSTONE PEACH DIVERSION PROGRAM § 82.17 Death, incompetency, or disappearance. In the case of death, incompetency, disappearance, or dissolution of a clingstone peach grower...

7 CFR 82.17 - Death, incompetency, or disappearance.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 3 2014-01-01 2014-01-01 false Death, incompetency, or disappearance. 82.17 Section... DOMESTIC CONSUMPTION PROGRAMS CLINGSTONE PEACH DIVERSION PROGRAM § 82.17 Death, incompetency, or disappearance. In the case of death, incompetency, disappearance, or dissolution of a clingstone peach grower...

7 CFR 82.17 - Death, incompetency, or disappearance.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 3 2013-01-01 2013-01-01 false Death, incompetency, or disappearance. 82.17 Section... DOMESTIC CONSUMPTION PROGRAMS CLINGSTONE PEACH DIVERSION PROGRAM § 82.17 Death, incompetency, or disappearance. In the case of death, incompetency, disappearance, or dissolution of a clingstone peach grower...

7 CFR 82.17 - Death, incompetency, or disappearance.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 3 2011-01-01 2011-01-01 false Death, incompetency, or disappearance. 82.17 Section... DOMESTIC CONSUMPTION PROGRAMS CLINGSTONE PEACH DIVERSION PROGRAM § 82.17 Death, incompetency, or disappearance. In the case of death, incompetency, disappearance, or dissolution of a clingstone peach grower...

7 CFR 82.17 - Death, incompetency, or disappearance.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 3 2012-01-01 2012-01-01 false Death, incompetency, or disappearance. 82.17 Section... DOMESTIC CONSUMPTION PROGRAMS CLINGSTONE PEACH DIVERSION PROGRAM § 82.17 Death, incompetency, or disappearance. In the case of death, incompetency, disappearance, or dissolution of a clingstone peach grower...

Mitochondrial fission proteins regulate programmed cell death in yeast.

PubMed

Fannjiang, Yihru; Cheng, Wen-Chih; Lee, Sarah J; Qi, Bing; Pevsner, Jonathan; McCaffery, J Michael; Hill, R Blake; Basañez, Gorka; Hardwick, J Marie

2004-11-15

The possibility that single-cell organisms undergo programmed cell death has been questioned in part because they lack several key components of the mammalian cell death machinery. However, yeast encode a homolog of human Drp1, a mitochondrial fission protein that was shown previously to promote mammalian cell death and the excessive mitochondrial fragmentation characteristic of apoptotic mammalian cells. In support of a primordial origin of programmed cell death involving mitochondria, we found that the Saccharomyces cerevisiae homolog of human Drp1, Dnm1, promotes mitochondrial fragmentation/degradation and cell death following treatment with several death stimuli. Two Dnm1-interacting factors also regulate yeast cell death. The WD40 repeat protein Mdv1/Net2 promotes cell death, consistent with its role in mitochondrial fission. In contrast to its fission function in healthy cells, Fis1 unexpectedly inhibits Dnm1-mediated mitochondrial fission and cysteine protease-dependent cell death in yeast. Furthermore, the ability of yeast Fis1 to inhibit mitochondrial fission and cell death can be functionally replaced by human Bcl-2 and Bcl-xL. Together, these findings indicate that yeast and mammalian cells have a conserved programmed death pathway regulated by a common molecular component, Drp1/Dnm1, that is inhibited by a Bcl-2-like function.

Opiate users' knowledge about overdose prevention and naloxone in New York City: a focus group study

PubMed Central

Worthington, Nancy; Markham Piper, Tinka; Galea, Sandro; Rosenthal, David

2006-01-01

Background Drug-induced and drug-related deaths have been increasing for the past decade throughout the US. In NYC, drug overdose accounts for nearly 900 deaths per year, a figure that exceeds the number of deaths each year from homicide. Naloxone, a highly effective opiate antagonist, has for decades been used by doctors and paramedics during emergency resuscitation after an opiate overdose. Following the lead of programs in Europe and the US who have successfully distributed take-home naloxone, the Overdose Prevention and Reversal Program at the Lower East Side Harm Reduction Center (LESHRC) has started providing a similar resource for opiate users in NYC. Participants in the program receive a prescription for two doses of naloxone, with refills as needed, and comprehensive training to reduce overdose risk, administer naloxone, perform rescue breathing, and call 911. As of September 2005, 204 participants have received naloxone and been trained, and 40 have revived an overdosing friend or family member. While naloxone accessibility stands as a proven life-saving measure, some opiates users at LESHRC have expressed only minimal interest in naloxone use, due to past experiences and common misconceptions. Methods In order to improve the naloxone distribution program two focus groups were conducted in December 2004 with 13 opiate users at LESHRC to examine knowledge about overdose and overdose prevention. The focus groups assessed participants' (i) experiences with overdose response, specifically naloxone (ii) understanding and perceptions of naloxone, (iii) comfort level with naloxone administration and (iv) feedback about increasing the visibility and desirability of the naloxone distribution program. Results Analyses suggest that there is both support for and resistance to take-home naloxone, marked by enthusiasm for its potential role in reviving an overdosing individual, numerous misconceptions and negative views of its impact and use. Conclusion Focus group results will be used to increase participation in the program and reshape perceptions about naloxone among opiate users, also targeting those already prescribed naloxone to increase their comfort using it. Since NYC is advancing toward a citywide naloxone distribution program, the LESHRC program will play an important role in establishing protocol for effective and wide-reaching naloxone availability. PMID:16822302

7 CFR 81.17 - Death, incompetency, or disappearance.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 3 2010-01-01 2010-01-01 false Death, incompetency, or disappearance. 81.17 Section... DOMESTIC CONSUMPTION PROGRAMS PRUNE/DRIED PLUM DIVERSION PROGRAM § 81.17 Death, incompetency, or disappearance. In the case of death, incompetency, disappearance, or dissolution of a prune/plum producer that...

7 CFR 81.17 - Death, incompetency, or disappearance.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 3 2013-01-01 2013-01-01 false Death, incompetency, or disappearance. 81.17 Section... DOMESTIC CONSUMPTION PROGRAMS PRUNE/DRIED PLUM DIVERSION PROGRAM § 81.17 Death, incompetency, or disappearance. In the case of death, incompetency, disappearance, or dissolution of a prune/plum producer that...

7 CFR 81.17 - Death, incompetency, or disappearance.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 3 2014-01-01 2014-01-01 false Death, incompetency, or disappearance. 81.17 Section... DOMESTIC CONSUMPTION PROGRAMS PRUNE/DRIED PLUM DIVERSION PROGRAM § 81.17 Death, incompetency, or disappearance. In the case of death, incompetency, disappearance, or dissolution of a prune/plum producer that...

7 CFR 81.17 - Death, incompetency, or disappearance.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 3 2012-01-01 2012-01-01 false Death, incompetency, or disappearance. 81.17 Section... DOMESTIC CONSUMPTION PROGRAMS PRUNE/DRIED PLUM DIVERSION PROGRAM § 81.17 Death, incompetency, or disappearance. In the case of death, incompetency, disappearance, or dissolution of a prune/plum producer that...

7 CFR 81.17 - Death, incompetency, or disappearance.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 3 2011-01-01 2011-01-01 false Death, incompetency, or disappearance. 81.17 Section... DOMESTIC CONSUMPTION PROGRAMS PRUNE/DRIED PLUM DIVERSION PROGRAM § 81.17 Death, incompetency, or disappearance. In the case of death, incompetency, disappearance, or dissolution of a prune/plum producer that...

The Influence of Programmed Cell Death in Myeloid Cells on Host Resilience to Infection with Legionella pneumophila or Streptococcus pyogenes

PubMed Central

Gamradt, Pia; Xu, Yun; Gratz, Nina; Duncan, Kellyanne; Kobzik, Lester; Högler, Sandra; Decker, Thomas

2016-01-01

Pathogen clearance and host resilience/tolerance to infection are both important factors in surviving an infection. Cells of the myeloid lineage play important roles in both of these processes. Neutrophils, monocytes, macrophages, and dendritic cells all have important roles in initiation of the immune response and clearance of bacterial pathogens. If these cells are not properly regulated they can result in excessive inflammation and immunopathology leading to decreased host resilience. Programmed cell death (PCD) is one possible mechanism that myeloid cells may use to prevent excessive inflammation. Myeloid cell subsets play roles in tissue repair, immune response resolution, and maintenance of homeostasis, so excessive PCD may also influence host resilience in this way. In addition, myeloid cell death is one mechanism used to control pathogen replication and dissemination. Many of these functions for PCD have been well defined in vitro, but the role in vivo is less well understood. We created a mouse that constitutively expresses the pro-survival B-cell lymphoma (bcl)-2 protein in myeloid cells (CD68(bcl2tg), thus decreasing PCD specifically in myeloid cells. Using this mouse model we explored the impact that decreased cell death of these cells has on infection with two different bacterial pathogens, Legionella pneumophila and Streptococcus pyogenes. Both of these pathogens target multiple cell death pathways in myeloid cells, and the expression of bcl2 resulted in decreased PCD after infection. We examined both pathogen clearance and host resilience and found that myeloid cell death was crucial for host resilience. Surprisingly, the decreased myeloid PCD had minimal impact on pathogen clearance. These data indicate that the most important role of PCD during infection with these bacteria is to minimize inflammation and increase host resilience, not to aid in the clearance or prevent the spread of the pathogen. PMID:27973535

Programmed death-ligand 1 is upregulated in intrahepatic lymphoepithelioma-like cholangiocarcinoma.

PubMed

Wang, Lei; Dong, Hui; Ni, Shujuan; Huang, Dan; Tan, Cong; Chang, Bin; Sheng, Weiqi

2016-10-25

Intrahepatic lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare variant of cholangiocarcinoma. Here, we report the largest single series of LELCC cases yet studied (n = 13). We retrospectively analyzed the clinical data of the 13 patients and measured the expression of programmed death-ligand 1 (PD-L1) in tumors using immunohistochemical staining. We also analyzed 15 cases of conventional intrahepatic cholangiocarcinoma (IHCC) for comparison. We found that eight patients with LELCC were infected with Epstein-Barr Virus (EBV), and EBV infection correlated with poor prognosis in LELCC. Four patients among the five (80.0%) without EBV had a history of chronic viral hepatitis B. None of the 15 cases of conventional cholangiocarcinoma were positive for EBV. PD-L1 was expressed in both the tumor cells and tumor-infiltrating immune cells in LELCC patients at higher levels than in IHCC patients (P < 0.05). These observations suggest that EBV infection may promote the development of LELCC, and that PD-L1 may be a potential therapeutic target for treatment of EBV-associated LELCC.

Nma111p, the pro-apoptotic HtrA-like nuclear serine protease in Saccharomyces cerevisiae: a short survey.

PubMed

Fahrenkrog, Birthe

2011-10-01

The baker's yeast, Saccharomyces cerevisiae, is also capable of undergoing programmed cell death or apoptosis, for example in response to viral infection as well as during chronological and replicative aging. Intrinsically, programmed cell death in yeast can be induced by, for example, H2O2, acetic acid or the mating-type pheromone. A number of evolutionarily conserved apoptosis-regulatory proteins have been identified in yeast, one of which is the HtrA (high-temperature requirement A)-like serine protease Nma111p (Nma is nuclear mediator of apoptosis). Nma111p is a nuclear serine protease of the HtrA family, which targets Bir1p, the only known inhibitor-of-apoptosis protein in yeast. Nma111p mediates apoptosis in a serine-protease-dependent manner and exhibits its activity exclusively in the nucleus. How the activity of Nma111p is regulated has remained largely elusive, but some evidence points to a control by phosphorylation. Current knowledge of Nma111p's function in apoptosis will be discussed in the present review.

Amoebicidal Activity of Caffeine and Maslinic Acid by the Induction of Programmed Cell Death in Acanthamoeba

PubMed Central

Martín-Navarro, Carmen M.; López-Arencibia, Atteneri; Sifaoui, Ines; Reyes-Batlle, María; Fouque, Emilie; Osuna, Antonio; Valladares, Basilio; Piñero, José E.; Héchard, Yann; Maciver, Sutherland K.

2017-01-01

ABSTRACT Free-living amoebae of the genus Acanthamoeba are the causal agents of a sight-threatening ulceration of the cornea called Acanthamoeba keratitis, as well as the rare but usually fatal disease granulomatous amoebic encephalitis. Although there are many therapeutic options for the treatment of Acanthamoeba infections, they are generally lengthy and/or have limited efficacy. For the best clinical outcome, treatments should target both the trophozoite and the cyst stages, as cysts are known to confer resistance to treatment. In this study, we document the activities of caffeine and maslinic acid against both the trophozoite and the cyst stages of three clinical strains of Acanthamoeba. These drugs were chosen because they are reported to inhibit glycogen phosphorylase, which is required for encystation. Maslinic acid is also reported to be an inhibitor of extracellular proteases, which may be relevant since the protease activities of Acanthamoeba species are correlated with their pathogenicity. We also provide evidence for the first time that both drugs exert their anti-amoebal effects through programmed cell death. PMID:28320723

A bacterial cysteine protease effector protein interferes with photosynthesis to suppress plant innate immune responses.

PubMed

Rodríguez-Herva, José J; González-Melendi, Pablo; Cuartas-Lanza, Raquel; Antúnez-Lamas, María; Río-Alvarez, Isabel; Li, Ziduo; López-Torrejón, Gema; Díaz, Isabel; Del Pozo, Juan C; Chakravarthy, Suma; Collmer, Alan; Rodríguez-Palenzuela, Pablo; López-Solanilla, Emilia

2012-05-01

The bacterial pathogen Pseudomonas syringae pv tomato DC3000 suppresses plant innate immunity with effector proteins injected by a type III secretion system (T3SS). The cysteine protease effector HopN1, which reduces the ability of DC3000 to elicit programmed cell death in non-host tobacco, was found to also suppress the production of defence-associated reactive oxygen species (ROS) and callose when delivered by Pseudomonas fluorescens heterologously expressing a P. syringae T3SS. Purified His(6) -tagged HopN1 was used to identify tomato PsbQ, a member of the oxygen evolving complex of photosystem II (PSII), as an interacting protein. HopN1 localized to chloroplasts and both degraded PsbQ and inhibited PSII activity in chloroplast preparations, whereas a HopN1(D299A) non-catalytic mutant lost these abilities. Gene silencing of NtPsbQ in tobacco compromised ROS production and programmed cell death by DC3000. Our data reveal PsbQ as a contributor to plant immunity responses and a target for pathogen suppression. © 2012 Blackwell Publishing Ltd.

Meeting the Healthy People 2020 Objectives to Reduce Cancer Mortality.

PubMed

Weir, Hannah K; Thompson, Trevor D; Soman, Ashwini; Møller, Bjorn; Leadbetter, Steven; White, Mary C

2015-07-02

Healthy People 2020 (HP2020) calls for a 10% to 15% reduction in death rates from 2007 to 2020 for selected cancers. Trends in death rates can be used to predict progress toward meeting HP2020 targets. We used mortality data from 1975 through 2009 and population estimates and projections to predict deaths for all cancers and the top 23 cancers among men and women by race. We apportioned changes in deaths from population risk and population growth and aging. From 1975 to 2009, the number of cancer deaths increased among white and black Americans primarily because of an aging white population and a growing black population. Overall, age-standardized cancer death rates (risk) declined in all groups. From 2007 to 2020, rates are predicted to continue to decrease while counts of deaths are predicted to increase among men (15%) and stabilize among women (increase <10%). Declining death rates are predicted to meet HP2020 targets for cancers of the female breast, lung and bronchus, cervix and uterus, colon and rectum, oral cavity and pharynx, and prostate, but not for melanoma. Cancer deaths among women overall are predicted to increase by less than 10%, because of, in part, declines in breast, cervical, and colorectal cancer deaths among white women. Increased efforts to promote cancer prevention and improve survival are needed to counter the impact of a growing and aging population on the cancer burden and to meet melanoma target death rates.

Meeting the Healthy People 2020 Objectives to Reduce Cancer Mortality

PubMed Central

Thompson, Trevor D.; Soman, Ashwini; Møller, Bjorn; Leadbetter, Steven; White, Mary C.

2015-01-01

Introduction Healthy People 2020 (HP2020) calls for a 10% to 15% reduction in death rates from 2007 to 2020 for selected cancers. Trends in death rates can be used to predict progress toward meeting HP2020 targets. Methods We used mortality data from 1975 through 2009 and population estimates and projections to predict deaths for all cancers and the top 23 cancers among men and women by race. We apportioned changes in deaths from population risk and population growth and aging. Results From 1975 to 2009, the number of cancer deaths increased among white and black Americans primarily because of an aging white population and a growing black population. Overall, age-standardized cancer death rates (risk) declined in all groups. From 2007 to 2020, rates are predicted to continue to decrease while counts of deaths are predicted to increase among men (15%) and stabilize among women (increase <10%). Declining death rates are predicted to meet HP2020 targets for cancers of the female breast, lung and bronchus, cervix and uterus, colon and rectum, oral cavity and pharynx, and prostate, but not for melanoma. Conclusion Cancer deaths among women overall are predicted to increase by less than 10%, because of, in part, declines in breast, cervical, and colorectal cancer deaths among white women. Increased efforts to promote cancer prevention and improve survival are needed to counter the impact of a growing and aging population on the cancer burden and to meet melanoma target death rates. PMID:26133647

Programmed death ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density differences between paired primary and brain metastatic lesions in non-small cell lung cancer.

PubMed

Zhou, Jie; Gong, Zhihua; Jia, Qingzhu; Wu, Yan; Yang, Zhen-Zhou; Zhu, Bo

2018-04-15

Immunotherapy targeting the programmed cell death-1/programmed death ligand 1(PD-L1) pathway has shown promising antitumor activity in brain metastases (BMs) of non-small cell lung cancer (NSCLC) patients with an acceptable safety profile; however, the response rates often differ between primary lesions and intracranial lesions. Studies are necessary to identify detailed characterizations of the response biomarkers. In this study, we aimed to compare the differences of PD-L1 expression and CD8 + tumor-infiltrating lymphocyte (TIL) density, two major response biomarkers of PD-1/PD-L1 blockade, between paired primary and brain metastatic lesions in advanced NSCLC. We observed that among primary lesions or BMs, only a small number of patients harbored common PD-L1 expression on both tumor cells and tumor-infiltrating immune cells. Additionally, we found that the numbers of CD8 + TILs were significantly fewer in BMs than in primary lung cancers. Low stromal CD8 + TIL numbers in BMs were associated with significantly shorter overall survival compared to high stromal CD8 + TIL counts. Notably, we demonstrated a discrepancy in PD-L1 expression and CD8 + TIL density between primary lung cancers and their corresponding BMs. Such heterogeneities are significantly associated with the time at which BMs occurred. Our study emphasizes the spatial and temporal heterogeneity of biomarkers for anti-PD-1/PD-L1 therapy, which should be concerned in clinical practice. Copyright © 2018 Elsevier Inc. All rights reserved.

The Emerging Role of PD-1/PD-L1-Targeting Immunotherapy in the Treatment of Metastatic Urothelial Carcinoma.

PubMed

Gwynn, Morgan E; DeRemer, David L

2018-01-01

To summarize and evaluate immunotherapy agents targeting programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) recently approved for the treatment of metastatic urothelial carcinomas (UC). A literature review was performed using PubMed (2012 to June 2017), the American Society of Clinical Oncology abstract databases (2012 to June 2017 Annual Meetings/symposia), and the America Association for Cancer Research symposia (2012 to June 2017). A search using clinicaltrials.gov was conducted to identify studies for atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab. English language phase I to III studies assessing PD-1 and PD-L1 in UC were incorporated. Atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab have demonstrated clinical efficacy with tolerable toxicities in patients with metastatic UC with disease progression following platinum-based chemotherapy. Anti-PD-1/PD-L1 therapies may provide overall survival advantage; these are currently being evaluated in ongoing phase 3 studies. Greater objective response rates seem to be observed in PD-L1-positive patients versus PD-L1-negative patients, but methodologies in this assessment differ among clinical trials. The identification of biomarkers that provide greater insight into patients who positively respond to PD-1/PD-L1 therapies are needed. Treatment options for metastatic UC have expanded to include PD-1/PD-L1 therapies. These agents should be strongly considered as second-line therapy over single-agent chemotherapy for patients who fail or progress after platinum-based treatment.

Many si/shRNAs can kill cancer cells by targeting multiple survival genes through an off-target mechanism

PubMed Central

van Dongen, Stijn; Haluck-Kangas, Ashley; Sarshad, Aishe A; Bartom, Elizabeth T; Kim, Kwang-Youn A; Scholtens, Denise M; Hafner, Markus; Zhao, Jonathan C; Murmann, Andrea E

2017-01-01

Over 80% of multiple-tested siRNAs and shRNAs targeting CD95 or CD95 ligand (CD95L) induce a form of cell death characterized by simultaneous activation of multiple cell death pathways preferentially killing transformed and cancer stem cells. We now show these si/shRNAs kill cancer cells through canonical RNAi by targeting the 3’UTR of critical survival genes in a unique form of off-target effect we call DISE (death induced by survival gene elimination). Drosha and Dicer-deficient cells, devoid of most miRNAs, are hypersensitive to DISE, suggesting cellular miRNAs protect cells from this form of cell death. By testing 4666 shRNAs derived from the CD95 and CD95L mRNA sequences and an unrelated control gene, Venus, we have identified many toxic sequences - most of them located in the open reading frame of CD95L. We propose that specific toxic RNAi-active sequences present in the genome can kill cancer cells. PMID:29063830

A Personalized Risk Stratification Platform for Population Lifetime Healthcare.

PubMed

Daowd, Ali; Abidi, Samina Raza; Abusharekh, Ashraf; Abidi, Syed Sibte Raza

2018-01-01

Chronic diseases are the leading cause of death worldwide. It is well understood that if modifiable risk factors are targeted, most chronic diseases can be prevented. Lifetime health is an emerging health paradigm that aims to assist individuals to achieve desired health targets, and avoid harmful lifecycle choices to mitigate the risk of chronic diseases. Early risk identification is central to lifetime health. In this paper, we present a digital health-based platform (PRISM) that leverages artificial intelligence, data visualization and mobile health technologies to empower citizens to self-assess, self-monitor and self-manage their overall risk of major chronic diseases and pursue personalized chronic disease prevention programs. PRISM offers risk assessment tools for 5 chronic conditions, 2 psychiatric disorders and 8 different cancers.

Upregulated miR-29b promotes neuronal cell death by inhibiting Bcl2L2 after ischemic brain injury.

PubMed

Shi, Guodong; Liu, Yang; Liu, Tielong; Yan, Wangjun; Liu, Xiaowei; Wang, Yuan; Shi, Jiangang; Jia, Lianshun

2012-01-01

It is increasingly clear that microRNAs (miRNAs) play an important role in controlling cell survival. However, the functional significance of miRNAs in ischemic brain injury remains poorly understood. In the present study, we assayed the expression levels of miR-29b after ischemic brain injury, and defined the target genes and biological functions of miR-29b. We found that the miR-29b levels were significantly increased in rat brain after transient middle cerebral artery occlusion and neurons after oxygen-glucose deprivation. Moreover, ectopic expression of miR-29b promoted neuronal cell death, whereas its repression decreased cell death. Furthermore, we verified that miR-29b directly targeted and inhibited Bcl2L2 gene expression, and then increased neuronal cell death. Importantly, Bcl2L2 overexpression rescued neuronal cell death induced by miR-29b. These results suggest an important role of miR-29b in regulating neuronal cell death, thus offering a new target for the development of therapeutic agents against ischemic brain injury.

Programmed cell death

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

The purpose of this conference to provide a multidisciplinary forum for exchange of state-of-the-art information on the role programmed cell death plays in normal development and homeostasis of many organisms. This volume contains abstracts of papers in the following areas: invertebrate development; immunology/neurology; bcl-2 family; biochemistry; programmed cell death in viruses; oncogenesis; vertebrate development; and diseases.

Analysis of the Death Gratuity Program: History, Current Issues and Future Implications

DTIC Science & Technology

2005-12-01

addition to the death gratuity, there are also a number of other benefits available to families and beneficiaries upon the death of a servicemember...An entire chapter is dedicated to covering these other benefits . Finally, this project analyzes an alternative method of funding the death gratuity...program and presents the advantages and drawbacks of such an alternative. 15. NUMBER OF PAGES 59 14. SUBJECT TERMS Death gratuity

TRAIL-induced programmed necrosis as a novel approach to eliminate tumor cells

PubMed Central

2014-01-01

Background The cytokine TRAIL represents one of the most promising candidates for the apoptotic elimination of tumor cells, either alone or in combination therapies. However, its efficacy is often limited by intrinsic or acquired resistance of tumor cells to apoptosis. Programmed necrosis is an alternative, molecularly distinct mode of programmed cell death that is elicited by TRAIL under conditions when the classical apoptosis machinery fails or is actively inhibited. The potential of TRAIL-induced programmed necrosis in tumor therapy is, however, almost completely uncharacterized. We therefore investigated its impact on a panel of tumor cell lines of wide-ranging origin. Methods Cell death/viability was measured by flow cytometry/determination of intracellular ATP levels/crystal violet staining. Cell surface expression of TRAIL receptors was detected by flow cytometry, expression of proteins by Western blot. Ceramide levels were quantified by high-performance thin layer chromatography and densitometric analysis, clonogenic survival of cells was determined by crystal violet staining or by soft agarose cloning. Results TRAIL-induced programmed necrosis killed eight out of 14 tumor cell lines. Clonogenic survival was reduced in all sensitive and even one resistant cell lines tested. TRAIL synergized with chemotherapeutics in killing tumor cell lines by programmed necrosis, enhancing their effect in eight out of 10 tested tumor cell lines and in 41 out of 80 chemotherapeutic/TRAIL combinations. Susceptibility/resistance of the investigated tumor cell lines to programmed necrosis seems to primarily depend on expression of the pro-necrotic kinase RIPK3 rather than the related kinase RIPK1 or cell surface expression of TRAIL receptors. Furthermore, interference with production of the lipid ceramide protected all tested tumor cell lines. Conclusions Our study provides evidence that TRAIL-induced programmed necrosis represents a feasible approach for the elimination of tumor cells, and that this treatment may represent a promising new option for the future development of combination therapies. Our data also suggest that RIPK3 expression may serve as a potential predictive marker for the sensitivity of tumor cells to programmed necrosis and extend the previously established role of ceramide as a key mediator of death receptor-induced programmed necrosis (and thus as a potential target for future therapies) also to the tumor cell lines examined here. PMID:24507727

The effects of a short-term death training program on nursing home nursing staff.

PubMed

Mullins, L C; Merriam, S

1984-01-01

This study examines the effects on nursing home nurses of a two-day training program concerned with nurses and their response to the dying patient. Utilizing the Solomon four-group design, the study investigates whether exposure to information on death and dying (a) results in the acquisition of greater knowledge about death and dying, (b) is accompanied by a more positive attitude toward the elderly, and (c) is accompanied by a change in anxiety about death. Based on t tests and one-way analyses of covariance, the results point up the mixed nature of short-term training programs. It was found that there was a significant increase in the nurses' knowledge about death and dying, there was no change in their attitudes toward the elderly, and there was a significant increase among the nurses in the death anxiety experienced. This is not to suggest that training programs of this sort should not be conducted with nursing home staff. On the one hand such programs provide information useful for job performance. On the other hand they create some sensitization to death, which at the very least could give nurses greater insights into the concerns of the patients and perhaps stimulate empathetic responses.

Infrared Space Observatory (ISO) Key Project: the Birth and Death of Planets

NASA Technical Reports Server (NTRS)

Stencel, Robert E.; Creech-Eakman, Michelle; Fajardo-Acosta, Sergio; Backman, Dana

1999-01-01

This program was designed to continue to analyze observations of stars thought to be forming protoplanets, using the European Space Agency's Infrared Space Observatory, ISO, as one of NASA Key Projects with ISO. A particular class of Infrared Astronomy Satellite (IRAS) discovered stars, known after the prototype, Vega, are principal targets for these observations aimed at examining the evidence for processes involved in forming, or failing to form, planetary systems around other stars. In addition, this program continued to provide partial support for related science in the WIRE, SOFIA and Space Infrared Telescope Facility (SIRTF) projects, plus approved ISO supplementary time observations under programs MCREE1 29 and VEGADMAP. Their goals include time dependent changes in SWS spectra of Long Period Variable stars and PHOT P32 mapping experiments of recognized protoplanetary disk candidate stars.

The diphenylether herbicide lactofen induces cell death and expression of defense-related genes in soybean.

PubMed

Graham, Madge Y

2005-12-01

Lactofen belongs to the diphenylether class of herbicides, which targets protoporphyrinogen oxidase, which in turn causes singlet oxygen generation. In tolerant plants like soybean (Glycine max), the chemical nonetheless causes necrotic patches called "bronzing" in contact areas. Here it is shown that such bronzing is accompanied by cell death, which was quantified from digital microscopic images using Assess Software. Cellular autofluorescence accompanied cell death, and a homolog of the cell death marker gene, Hsr203j, was induced by lactofen in treated soybean tissues. Thus, this form of chemically induced cell death shares some hallmarks of certain types of programmed cell death. In addition to the cell death phenotype, lactofen caused enhanced expressions of chalcone synthase and chalcone reductase genes, mainly in the exposed and immediately adjacent (proximal) cells. Furthermore, isoflavone synthase genes, which are wound inducible in soybean, were up-regulated by lactofen in both proximal and distal cell zones in minimally wounded cotyledons and further enhanced in wounded tissues. Moreover, if the wall glucan elicitor from Phytophthora sojae was present during lactofen treatment, the induction of isoflavone synthase was even more rapid. These results are consistent with the fact that lactofen triggers massive isoflavone accumulations and activates the capacity for glyceollin elicitation competency. In addition, lactofen induces late expression of a selective set of pathogenesis-related (PR) protein genes, including PR-1a, PR-5, and PR-10, mainly in treated proximal tissues. These various results are discussed in the context of singlet oxygen-induced responses and lactofen's potential as a disease resistance-inducing agent.

Viewing death on television increases the appeal of advertised products.

PubMed

Dar-Nimrod, Ilan

2012-01-01

References to death abound in many television programs accessible to most people. Terror Management Theory postulates that existential anxiety, which death reminders activate, may reinforce materialistic tendencies. The current article explores the effect of a death reminder in television shows on the desirability of advertised products. Consistent with Terror Management Theory's predictions, in two studies participants show greater desire for products, which were advertised immediately following clips from programs that featured a death scene, compared with programs that did not. Cognitive accessibility of death predicted the appeal difference while changes in affect or interest in the show did not. The findings are discussed in light on affective and existential theories which make opposite predictions. Implications and future directions are considered.

Viewing Death on Television Increases the Appeal of Advertised Products

PubMed Central

DAR-NIMROD, ILAN

2012-01-01

References to death abound in many television programs accessible to most people. Terror Management Theory (TMT) postulates that existential anxiety, which death reminders activate, may reinforce materialistic tendencies. The current paper explores the effect of a death reminder in television shows on the desirability of advertised products. Consistent with TMT's predictions, in two studies participants show greater desire for products, which were advertised immediately following clips from programs that featured a death scene, compared with programs that did not. Cognitive accessibility of death predicted the appeal difference while changes in affect or interest in the show did not. The findings are discussed in light on affective and existential theories which make opposite predictions. Implications and future directions are considered. PMID:22468421

Kokua Mau: a statewide effort to improve end-of-life care.

PubMed

Braun, Kathryn L; Zir, Ana; Crocker, Joanna; Seely, Marilyn R

2005-04-01

Many Americans die in pain, without hospice, and without regard to advance directives, suggesting a need to improve end-of-life (EOL) awareness and services. This paper describes Kokua Mau, a community-state partnership to improve EOL in Hawaii funded by The Robert Wood Johnson Foundation (RWJF). Coalition activities were guided by innovation-diffusion theory, targeting "innovators" and "change agents" within communities and organizations willing to learn about and facilitate improvements to EOL care. Evaluation of a community-wide intervention to improve EOL care. Honolulu, Hawaii. We tracked dissemination of campaign messages by counting numbers of coalition members (including innovators and change agents to carry on the work), individuals reached through awareness and educational offerings, and new EOL projects initiated during and after the initial 3-year RWJF funding. To measure change, we counted the number of legislative policies that were modified by the coalition as well as indicators of hospice utilization, advance directive (AD) completion, support for physician-assisted death, and place of death. In the first 3 years of the project: coalition membership grew to 350 members; EOL care curricula were developed and offered to various target audiences; 17,000 individuals attended educational events; policy changes were facilitated; decreases were seen in proportions of residents supporting physician-assisted suicide; and increases were seen in advance directive completion rates and hospice utilization. Most importantly, after the grant period, coalition members went on to develop and implement new programs to improve care to the dying. Although it will take several years to effect comprehensive and sustained changes in the way death is perceived and the dying process is facilitated, findings suggest that programs based on innovation-diffusion theory can increase EOL awareness and help develop the change agents and role models needed to affect community-wide change over the long term.

Impact of specific postoperative complications on the outcomes of emergency general surgery patients.

PubMed

McCoy, Christopher Cameron; Englum, Brian R; Keenan, Jeffrey E; Vaslef, Steven N; Shapiro, Mark L; Scarborough, John E

2015-05-01

The relative contribution of specific postoperative complications on mortality after emergency operations has not been previously described. Identifying specific contributors to postoperative mortality following acute care surgery will allow for significant improvement in the care of these patients. Patients from the 2005 to 2011 American College of Surgeons' National Surgical Quality Improvement Program database who underwent emergency operation by a general surgeon for one of seven diagnoses (gallbladder disease, gastroduodenal ulcer disease, intestinal ischemia, intestinal obstruction, intestinal perforation, diverticulitis, and abdominal wall hernia) were analyzed. Postoperative complications (pneumonia, myocardial infarction, incisional surgical site infection, organ/space surgical site infection, thromboembolic process, urinary tract infection, stroke, or major bleeding) were chosen based on surgical outcome measures monitored by national quality improvement initiatives and regulatory bodies. Regression techniques were used to determine the independent association between these complications and 30-day mortality, after adjustment for an array of patient- and procedure-related variables. Emergency operations accounted for 14.6% of the approximately 1.2 million general surgery procedures that are included in American College of Surgeons' National Surgical Quality Improvement Program but for 53.5% of the 19,094 postoperative deaths. A total of 43,429 emergency general surgery patients were analyzed. Incisional surgical site infection had the highest incidence (6.7%). The second most common complication was pneumonia (5.7%). Stroke, major bleeding, myocardial infarction, and pneumonia exhibited the strongest associations with postoperative death. Given its disproportionate contribution to surgical mortality, emergency surgery represents an ideal focus for quality improvement. Of the potential postoperative targets for quality improvement, pneumonia, myocardial infarction, stroke, and major bleeding have the strongest associations with subsequent mortality. Since pneumonia is both relatively common after emergency surgery and strongly associated with postoperative death, it should receive priority as a target for surgical quality improvement initiatives. Prognostic and epidemiologic study, level III.

IκB kinaseα/β control biliary homeostasis and hepatocarcinogenesis in mice by phosphorylating the cell-death mediator receptor-interacting protein kinase 1.

PubMed

Koppe, Christiane; Verheugd, Patricia; Gautheron, Jérémie; Reisinger, Florian; Kreggenwinkel, Karina; Roderburg, Christoph; Quagliata, Luca; Terracciano, Luigi; Gassler, Nikolaus; Tolba, René H; Boege, Yannick; Weber, Achim; Karin, Michael; Luedde, Mark; Neumann, Ulf P; Weiskirchen, Ralf; Tacke, Frank; Vucur, Mihael; Trautwein, Christian; Lüscher, Bernhard; Preisinger, Christian; Heikenwalder, Mathias; Luedde, Tom

2016-10-01

The IκB-Kinase (IKK) complex-consisting of the catalytic subunits, IKKα and IKKβ, as well as the regulatory subunit, NEMO-mediates activation of the nuclear factor κB (NF-κB) pathway, but previous studies suggested the existence of NF-κB-independent functions of IKK subunits with potential impact on liver physiology and disease. Programmed cell death is a crucial factor in the progression of liver diseases, and receptor-interacting kinases (RIPKs) exerts strategic control over multiple pathways involved in regulating novel programmed cell-death pathways and inflammation. We hypothesized that RIPKs might be unrecognized targets of the catalytic IKK-complex subunits, thereby regulating hepatocarcinogenesis and cholestasis. In this present study, mice with specific genetic inhibition of catalytic IKK activity in liver parenchymal cells (LPCs; IKKα/β(LPC-KO) ) were intercrossed with RIPK1(LPC-KO) or RIPK3(-/-) mice to examine whether RIPK1 or RIPK3 might be downstream targets of IKKs. Moreover, we performed in vivo phospho-proteome analyses and in vitro kinase assays, mass spectrometry, and mutagenesis experiments. These analyses revealed that IKKα and IKKβ-in addition to their known function in NF-κB activation-directly phosphorylate RIPK1 at distinct regions of the protein, thereby regulating cell viability. Loss of this IKKα/β-dependent RIPK1 phosphorylation in LPCs inhibits compensatory proliferation of hepatocytes and intrahepatic biliary cells, thus impeding HCC development, but promoting biliary cell paucity and lethal cholestasis. IKK-complex subunits transmit a previously unrecognized signal through RIPK1, which is fundamental for the long-term consequences of chronic hepatic inflammation and might have potential implications for future pharmacological strategies against cholestatic liver disease and cancer. (Hepatology 2016;64:1217-1231). © 2016 by the American Association for the Study of Liver Diseases.

A Traumatic Death Support Group Program: Applying an Integrated Conceptual Framework

ERIC Educational Resources Information Center

Walijarvi, Corrine M.; Weiss, Ann H.; Weinman, Maxine L.

2012-01-01

This article describes an 8-week, curriculum-based traumatic death support group program that is offered at Bo's Place, a grief and bereavement center in Houston, Texas. The program was implemented in 2006 in an effort to help family members who had experienced a death in the family by suicide, murder, accident, or sudden medical problem. The…

Stress Management in Cyst-Forming Free-Living Protists: Programmed Cell Death and/or Encystment

PubMed Central

Khan, Naveed Ahmed; Iqbal, Junaid

2015-01-01

In the face of harsh conditions and given a choice, a cell may (i) undergo programmed cell death, (ii) transform into a cancer cell, or (iii) enclose itself into a cyst form. In metazoans, the available evidence suggests that cellular machinery exists only to execute or avoid programmed cell death, while the ability to form a cyst was either lost or never developed. For cyst-forming free-living protists, here we pose the question whether the ability to encyst was gained at the expense of the programmed cell death or both functions coexist to counter unfavorable environmental conditions with mutually exclusive phenotypes. PMID:25648302

Global mortality associated with rotavirus disease among children in 2004.

PubMed

Parashar, Umesh D; Burton, Anthony; Lanata, Claudio; Boschi-Pinto, Cynthia; Shibuya, Kenji; Steele, Duncan; Birmingham, Maureen; Glass, Roger I

2009-11-01

As new rotavirus vaccines are being introduced in immunization programs, global and national estimates of disease burden, especially rotavirus-associated mortality, are needed to assess the potential health benefits of vaccination and to monitor vaccine impact. We identified 76 studies that were initiated after 1990, lasted at least 1 full year, and examined rotavirus among >100 children hospitalized with diarrhea. The studies were assigned to 5 groups (A-E) with use of World Health Organization classification of countries by child mortality and geography. For each group, the mean rotavirus detection rate was multiplied by diarrhea-related mortality figures from 2004 for countries in that group to yield estimates of rotavirus-associated mortality. Overall, rotavirus accounted for 527,000 deaths (95% confidence interval, 475,000-580,000 deaths) annually or 29% of all deaths due to diarrhea among children <5 years of age. Twenty-three percent of deaths due to rotavirus disease occurred in India, and 6 countries (India, Nigeria, Congo, Ethiopia, China, and Pakistan) accounted for more than one-half of deaths due to rotavirus disease. The high mortality associated with rotavirus disease underscores the need for targeted interventions, such as vaccines. To realize the full life-saving potential of vaccines, it will be vital to ensure that they reach children in countries with high mortality. These baseline figures will allow future assessment of vaccine impact on rotavirus-associated mortality.

Emergency department utilization and subsequent prescription drug overdose death

PubMed Central

Brady, Joanne E.; DiMaggio, Charles J.; Keyes, Katherine M.; Doyle, John J.; Richardson, Lynne D.; Li, Guohua

2015-01-01

Purpose Prescription drug overdose (PDO) deaths are a critical public health problem in the United States. This study aims to assess the association between emergency department (ED) utilization patterns in a cohort of ED patients and the risk of subsequent unintentional PDO mortality. Methods Using data from the New York Statewide Planning and Research Cooperative System for 2006–2010, a nested case-control design was used to examine the relationship between ED utilization patterns in New York State residents of age 18–64 years and subsequent PDO death. Results The study sample consisted of 2732 case patients who died of PDO and 2732 control ED patients who were selected through incidence density sampling. With adjustment for demographic characteristics, and diagnoses of pain, substance abuse, and psychiatric disorders, the estimated odds ratios of PDO death relative to one ED visit or less in the previous year were 4.90 (95% confidence interval [CI]: 4.50–5.34) for those with two ED visits, 16.61 (95% CI: 14.72–18.75) for those with three ED visits, and 48.24 (95% CI: 43.23–53.83) for those with four ED visits or more. Conclusions Frequency of ED visits is strongly associated with the risk of subsequent PDO death. Intervention programs targeting frequent ED users are warranted to reduce PDO mortality. PMID:25935710

Trends in traffic fatalities in Mexico: examining progress on the decade of action for road safety 2011-2020.

PubMed

Cervantes-Trejo, Arturo; Leenen, Iwin; Fabila-Carrasco, John Stewart; Rojas-Vargas, Roy

2016-11-01

We explore demographic, temporal and geographic patterns of 256,588 road traffic fatalities from 1998 to 2013 in Mexico, in context of UN´s decade of action for road safety 2010-2020 (DARS). Combined traffic mortality data and population counts were analyzed using mixed-effects logistic regression, distinguishing sex-age groups, vulnerable and protected road users, and municipal size. Rapid growth from 1998 to 2008 in traffic mortality rates has been reversed since 2009. Most deaths averted are among young male protected road users (reduction of 0.95 fatalities per 100,000 per year in males 12-49). In spite of a steady decrease over the full study period, mortality rates remain high in vulnerable road users over 50, with a high mortality rate of 26 per 100,000 males over 75 years in 2013. Progress on the reduction of deaths advances in Mexico, in line with DARS targets. National road safety efforts require strengthening. Initiatives should target vulnerable road users, specifically adults >50 years in urban areas. Strengthening of drink driving programs aimed at young drivers/occupants is promising.

[Role of vaccination in chronic disease prevention and control].

PubMed

Wang, Zhuoqun; Huang, Shue; Zhao, Yanfang; Zhao, Wenhua; Liang, Xiaofeng

2015-08-01

Chronic non-communicable disease is a major public health problem affecting the health of residents in china. Evidence shows that, in addition to four major risk factors, i.e. unreasonable dietary, lack of physical activity, smoking and drinking, epidemic and severe outcome of chronic disease is associated with many infectious diseases. Increasingly cancers have been shown to have an infectious etiology. There is also a significantly increased risk of infectious disease such as influenza, pneumonia and other infectious disease in people with pre-existing chronic non-communicable diseases like diabetes, heart disease, and lung diseases. And more than that, there is a high risk of susceptibility to death and severe outcomes among them. Epidemiological studies has confirmed, that through targeted vaccine inoculation, liver cancer, cervical cancer can be effectively prevented, while influenza or pneumonia vaccine are related to reduced risk of hospitalization or death and hospitalization expenses regarding with a variety of chronic diseases. World Health Organization and several other professional organizations have put forward recommendations on vaccine inoculation of chronic disease patients. Programs targeting infectious factors are also an important aspect of chronic diseases prevention and control, therefore, related researches need to be strengthened in the future.

Targeting B7x and B7-H3 as New Immunotherapies for Prostate Cancer

DTIC Science & Technology

2016-09-01

lymphoid cells lines induced to undergo programmed cell death [17]. Later reports noted that PD-1 is expressed on acti- vated T and B cells , dendritic...is PD-L1 (B7-H1) with wide expression at the mRNA level in lymphoid and nonlymphoid tissues [37]. It is a cell surface protein that is expressed...of PD-1 [38]. The PD-1/PD-L1 interac- tion induce T- cell tolerance in lymphoid tissue before their exit to the periphery, and blockade of this

Cullin 5: A Destabilizing Force for Some Oncogenes | Center for Cancer Research

Cancer.gov

Cancer can result when cellular processes such as proliferation and cell death go haywire. Among the many mechanisms in place to regulate these critical processes are molecular chaperones, which help proteins attain their proper functional shape and also regulate protein degradation through the cell’s recycling program, called the ubiquitin/proteasome system. One molecular chaperone, heat shock protein 90 (Hsp90), is of particular interest to cancer researchers because many of its target proteins—sometimes called client proteins—have been implicated in the maintenance and progression of a number of cancers.

Predator Bounties in Western Canada Cause Animal Suffering and Compromise Wildlife Conservation Efforts

PubMed Central

Proulx, Gilbert; Rodtka, Dwight

2015-01-01

Although predation bounty programs (rewards offered for capturing or killing an animal) ended more than 40 years ago in Canada, they were reintroduced in Alberta in 2007 by hunting, trapping, and farming organizations, municipalities and counties, and in 2009 in Saskatchewan, by municipal and provincial governments and the Saskatchewan Cattlemen’s Association. Bounty hunters use inhumane and non-selective killing methods such as shooting animals in non-vital regions, and killing neck snares and strychnine poisoning, which cause suffering and delayed deaths. They are unselective, and kill many non-target species, some of them at risk. Predator bounty programs have been found to be ineffective by wildlife professionals, and they use killing methods that cause needless suffering and jeopardize wildlife conservation programs. Our analysis therefore indicates that government agencies should not permit the implementation of bounty programs. Accordingly, they must develop conservation programs that will minimize wildlife-human conflicts, prevent the unnecessary and inhumane killing of animals, and ensure the persistence of all wildlife species. PMID:26479482

Predator Bounties in Western Canada Cause Animal Suffering and CompromiseWildlife Conservation Efforts.

PubMed

Proulx, Gilbert; Rodtka, Dwight

2015-10-19

Although predation bounty programs (rewards offered for capturing or killing an animal) ended more than 40 years ago in Canada, they were reintroduced in Alberta in 2007 by hunting, trapping, and farming organizations, municipalities and counties, and in 2009 in Saskatchewan, by municipal and provincial governments and the Saskatchewan Cattlemen's Association. Bounty hunters use inhumane and non-selective killing methods such as shooting animals in non-vital regions, and killing neck snares and strychnine poisoning, which cause suffering and delayed deaths. They are unselective, and kill many non-target species, some of them at risk. Predator bounty programs have been found to be ineffective by wildlife professionals, and they use killing methods that cause needless suffering and jeopardize wildlife conservation programs. Our analysis therefore indicates that government agencies should not permit the implementation of bounty programs. Accordingly, they must develop conservation programs that will minimize wildlife-human conflicts, prevent the unnecessary and inhumane killing of animals, and ensure the persistence of all wildlife species.

76 FR 63906 - Henry Gordy International, Inc., Provisional Acceptance of a Settlement Agreement and Order

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-14

...'' (``Target Set''). Each Target Set consisted of the following: A toy gun; soft, pliable, plastic toy darts... report of a death involving a Target Set on or about May 1, 2006, after an 8-year-old boy choked on a dart and died on March 9, 2006. 8. In response to the death reported on or about May 1, 2006, Henry...

IKKβ and NFκB transcription govern lymphoma cell survival through AKT-induced plasma membrane trafficking of GLUT1

PubMed Central

Sommermann, Thomas; O’Neill, Kathleen; Plas, David R.; Cahir-McFarland, Ellen

2011-01-01

All cancer cells require increased nutrient uptake to support proliferation. Here we investigated the signals that govern glucose uptake in B-cell lymphomas and determined that the protein kinase IKKβ induced GLUT1 membrane trafficking in both viral and spontaneous B-cell lymphomas. IKKβ induced AKT activity, while IKKβ-driven NFκB transcription was required for GLUT1 surface localization downstream of AKT. Activated NFκB promoted AKT-mediated phosphorylation of the GLUT1 regulator, AKT Substrate 160kD (AS160), but was not required for AKT phosphorylation of the mammalian target of rapamycin (mTOR) regulator Tuberous Sclerosis 2 (TSC2). In Epstein Barr virus (EBV) transformed B-cells, NFκB inhibition repressed glucose uptake and induced caspase-independent cell death associated with autophagy. After NFκB inhibition, an alternate carbon source ameliorated both autophagy and cell death, whereas autophagy inhibitors specifically accelerated cell death. Taken together, the results suggest that NFκB signaling establishes a metabolic program supporting proliferation and apoptosis resistance by driving glucose import. PMID:21987722

A Bereavement Support Program for Survivors of Cancer Deaths: A Description and Evaluation.

ERIC Educational Resources Information Center

Souter, Susan J.; Moore, Timothy E.

1990-01-01

Describes bereavement support program for survivors of cancer deaths developed by Riverdale Hospital in Toronto, Ontario. Presents detailed program evaluation which asked bereaved survivors who were program participants for one year to evaluate program aspects and facilitation of their grief by volunteers. Recommendations for expansion and…

Impact of the national targeted Hepatitis A immunisation program in Australia: 2000-2014.

PubMed

Thompson, Craig; Dey, Aditi; Fearnley, Emily; Polkinghorne, Benjamin; Beard, Frank

2017-01-03

In November 2005, hepatitis A vaccine was funded under the Australian National Immunisation Program for Aboriginal and Torres Strait Islander (Indigenous) children aged 12-24months in the targeted jurisdictions of Queensland, South Australia, Western Australia and the Northern Territory. We reviewed the epidemiology of hepatitis A from 2000 to 2014 using data from the Australian National Notifiable Diseases Surveillance System, the National Hospital Morbidity Database, and Australian Bureau of Statistics causes-of-death data. The impact of the national hepatitis A immunisation program was assessed by comparison of pre-vaccine (2000-2005) and post-vaccine time periods (2006-2014), by age group, Indigenous status and jurisdiction using incidence rate ratios (IRR) per 100,000 population and 95% confidence intervals (CI). The national pre-vaccine notification rate in Indigenous people was four times higher than the non-Indigenous rate, and declined from 8.41 per 100,000 (95% CI 5.03-11.79) pre-vaccine to 0.85 per 100,000 (95% CI 0.00-1.99) post-vaccine, becoming similar to the non-Indigenous rate. Notification and hospitalisation rates in Indigenous children aged <5years from targeted jurisdictions declined in the post-vaccine period when compared to the pre-vaccine period (notifications: IRR=0.07; 95% CI 0.04-0.13; hospitalisations: IRR=0.04; 95% CI 0.01-0.16). As did notification rates in Indigenous people aged 5-19 (IRR=0.08; 95% CI 0.05-0.13) and 20-49years (IRR=0.06; 95% CI 0.02-0.15) in targeted jurisdictions. For non-Indigenous people from targeted jurisdictions, notification rates decreased significantly in children aged <5years (IRR 0.47; 95% CI 0.31-0.71), and significantly more overall (IRR=0.43; 95% CI 0.39-0.47) compared to non-Indigenous people from non-targeted jurisdictions (IRR=0.60; 95% CI 0.56-0.64). The national hepatitis A immunisation program has had a significant impact in the targeted population with relatively modest vaccine coverage, with evidence suggestive of substantial herd protection effects. Copyright © 2016 Elsevier Ltd. All rights reserved.

Repeated Exposure of Epithelial Cells to Apoptotic Cells Induces the Specific Selection of an Adaptive Phenotype: Implications for Tumorigenesis.

PubMed

Feng, Lanfei; Vujicic, Snezana; Dietrich, Michael E; Litbarg, Natalia; Setty, Suman; Antoni, Angelika; Rauch, Joyce; Levine, Jerrold S

2018-05-16

The consequences of apoptosis extend beyond mere death of the cell. We have shown that receptor-mediated recognition of apoptotic target cells by viable kidney proximal tubular epithelial cells (PTECs) inhibits PTEC proliferation, growth, and survival. Here we tested the hypothesis that continual exposure to apoptotic targets can induce a phenotypic change in responding PTECs, as in other instances of natural selection. In particular, we demonstrate that repeated exposure to apoptotic targets leads to emergence of a PTEC line (denoted BU.MPT SEL ) resistant to apoptotic target-induced death. Resistance is exquisitely specific. Not only are BU.MPT SEL responders fully resistant to apoptotic target-induced death (~85% survival versus <10% survival of non-selected cells), but do so while retaining sensitivity to all other target-induced responses, including inhibition of proliferation and growth. Moreover, the resistance of BU.MPT SEL responders is specific to target-induced apoptosis, as apoptosis in response to other suicidal stimuli occurs normally. Comparison of the signaling events induced by apoptotic target exposure in selected versus non-selected responders indicated that the acquired resistance of BU.MPT SEL cells lies in a regulatory step affecting the generation of the pro-apoptotic protein, truncated BH3 interacting-domain death agonist (tBID), most likely at the level of BID cleavage by caspase-8. This specific adaptation has especial relevance for cancer, in which the prominence and persistence of cell death entail magnification of the post-mortem effects of apoptotic cells. Just as cancer cells acquire specific resistance to chemotherapeutic agents, we propose that cancer cells may also adapt to their ongoing exposure to apoptotic targets. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death.

PubMed

Clark, Amy L; Kanekura, Kohsuke; Lavagnino, Zeno; Spears, Larry D; Abreu, Damien; Mahadevan, Jana; Yagi, Takuya; Semenkovich, Clay F; Piston, David W; Urano, Fumihiko

2017-07-17

Pro-inflammatory cytokines are important mediators of islet inflammation, leading to beta cell death in type 1 diabetes. Although alterations in both endoplasmic reticulum (ER) and cytosolic free calcium levels are known to play a role in cytokine-mediated beta cell death, there are currently no treatments targeting cellular calcium homeostasis to combat type 1 diabetes. Here we show that modulation of cellular calcium homeostasis can mitigate cytokine- and ER stress-mediated beta cell death. The calcium modulating compounds, dantrolene and sitagliptin, both prevent cytokine and ER stress-induced activation of the pro-apoptotic calcium-dependent enzyme, calpain, and partly suppress beta cell death in INS1E cells and human primary islets. These agents are also able to restore cytokine-mediated suppression of functional ER calcium release. In addition, sitagliptin preserves function of the ER calcium pump, sarco-endoplasmic reticulum Ca 2+ -ATPase (SERCA), and decreases levels of the pro-apoptotic protein thioredoxin-interacting protein (TXNIP). Supporting the role of TXNIP in cytokine-mediated cell death, knock down of TXNIP in INS1-E cells prevents cytokine-mediated beta cell death. Our findings demonstrate that modulation of dynamic cellular calcium homeostasis and TXNIP suppression present viable pharmacologic targets to prevent cytokine-mediated beta cell loss in diabetes.

Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment.

PubMed

Yoshida, Go J

2017-03-09

The 2016 Nobel Prize in Physiology or Medicine was awarded to the researcher that discovered autophagy, which is an evolutionally conserved catabolic process which degrades cytoplasmic constituents and organelles in the lysosome. Autophagy plays a crucial role in both normal tissue homeostasis and tumor development and is necessary for cancer cells to adapt efficiently to an unfavorable tumor microenvironment characterized by hypo-nutrient conditions. This protein degradation process leads to amino acid recycling, which provides sufficient amino acid substrates for cellular survival and proliferation. Autophagy is constitutively activated in cancer cells due to the deregulation of PI3K/Akt/mTOR signaling pathway, which enables them to adapt to hypo-nutrient microenvironment and exhibit the robust proliferation at the pre-metastatic niche. That is why just the activation of autophagy with mTOR inhibitor often fails in vain. In contrast, disturbance of autophagy-lysosome flux leads to endoplasmic reticulum (ER) stress and an unfolded protein response (UPR), which finally leads to increased apoptotic cell death in the tumor tissue. Accumulating evidence suggests that autophagy has a close relationship with programmed cell death, while uncontrolled autophagy itself often induces autophagic cell death in tumor cells. Autophagic cell death was originally defined as cell death accompanied by large-scale autophagic vacuolization of the cytoplasm. However, autophagy is a "double-edged sword" for cancer cells as it can either promote or suppress the survival and proliferation in the tumor microenvironment. Furthermore, several studies of drug re-positioning suggest that "conventional" agents used to treat diseases other than cancer can have antitumor therapeutic effects by activating/suppressing autophagy. Because of ever increasing failure rates and high cost associated with anticancer drug development, this therapeutic development strategy has attracted increasing attention because the safety profiles of these medicines are well known. Antimalarial agents such as artemisinin and disease-modifying antirheumatic drug (DMARD) are the typical examples of drug re-positioning which affect the autophagy regulation for the therapeutic use. This review article focuses on recent advances in some of the novel therapeutic strategies that target autophagy with a view to treating/preventing malignant neoplasms.

76 FR 59109 - Agency Information Collection Activities: Proposed Collection; Comment Request-Supplemental...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-23

... Nutrition Assistance Program Prisoner and Death Match Requirements AGENCY: Food and Nutrition Service (FNS.... SUPPLEMENTARY INFORMATION: Title: Supplemental Nutrition Assistance Program Prisoner and Death Match... verification and death matching procedures as mandated by legislation and previously implemented through agency...

Honokiol induces autophagic cell death in malignant glioma through reactive oxygen species-mediated regulation of the p53/PI3K/Akt/mTOR signaling pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Chien-Ju

Honokiol, an active constituent extracted from the bark of Magnolia officinalis, possesses anticancer effects. Apoptosis is classified as type I programmed cell death, while autophagy is type II programmed cell death. We previously proved that honokiol induces cell cycle arrest and apoptosis of U87 MG glioma cells. Subsequently in this study, we evaluated the effect of honokiol on autophagy of glioma cells and examined the molecular mechanisms. Administration of honokiol to mice with an intracranial glioma increased expressions of cleaved caspase 3 and light chain 3 (LC3)-II. Exposure of U87 MG cells to honokiol also induced autophagy in concentration- andmore » time-dependent manners. Results from the addition of 3-methyladenine, an autophagy inhibitor, and rapamycin, an autophagy inducer confirmed that honokiol-induced autophagy contributed to cell death. Honokiol decreased protein levels of PI3K, phosphorylated (p)-Akt, and p-mammalian target of rapamycin (mTOR) in vitro and in vivo. Pretreatment with a p53 inhibitor or transfection with p53 small interfering (si)RNA suppressed honokiol-induced autophagy by reversing downregulation of p-Akt and p-mTOR expressions. In addition, honokiol caused generation of reactive oxygen species (ROS), which was suppressed by the antioxidant, vitamin C. Vitamin C also inhibited honokiol-induced autophagic and apoptotic cell death. Concurrently, honokiol-induced alterations in levels of p-p53, p53, p-Akt, and p-mTOR were attenuated following vitamin C administration. Taken together, our data indicated that honokiol induced ROS-mediated autophagic cell death through regulating the p53/PI3K/Akt/mTOR signaling pathway. - Highlights: • Exposure of mice with intracranial gliomas to honokiol induces cell apoptosis and autophagy. • Honokiol triggers autophagy of human glioma cells via the PISK/AKT/mTOR signaling pathway. • P53 induces autophagy via regulating the AKT/mTOR pathway in honokiol-treated glioma cells. • ROS participates in honokiol-induced cell death through the p53-mediated signaling pathway. • Honokiol induces ROS-mediated autophagic cell death via the p53/PI3K/Akt/mTOR mechanism.« less

Tales of cannibalism, suicide, and murder: Programmed cell death in C. elegans.

PubMed

Kinchen, Jason M; Hengartner, Michael O

2005-01-01

"Life is pleasant. Death is peaceful. It's the transition that's troublesome," said Isaac Asimov. Indeed, much scientific work over the last hundred years centered around attempts either to stave off or to induce the onset of death, at both the organismal and the cellular levels. In this quest, the nematode C. elegans has proven an invaluable tool, first, in the articulation of the genetic pathway by which programmed cell death proceeds, and also as a continuing source of inspiration. It is our purpose in this Chapter to familiarize the reader with the topic of programmed cell death in C. elegans and its relevance to current research in the fields of apoptosis and cell corpse clearance.

Programmed death receptor-1/programmed death receptor ligand-1 blockade after transient lymphodepletion to treat myeloma.

PubMed

Kearl, Tyce J; Jing, Weiqing; Gershan, Jill A; Johnson, Bryon D

2013-06-01

Early phase clinical trials targeting the programmed death receptor-1/ligand-1 (PD-1/PD-L1) pathway to overcome tumor-mediated immunosuppression have reported promising results for a variety of cancers. This pathway appears to play an important role in the failure of immune reactivity to malignant plasma cells in multiple myeloma patients, as the tumor cells express relatively high levels of PD-L1, and T cells show increased PD-1 expression. In the current study, we demonstrate that PD-1/PD-L1 blockade with a PD-L1-specific Ab elicits rejection of a murine myeloma when combined with lymphodepleting irradiation. This particular combined approach by itself has not previously been shown to be efficacious in other tumor models. The antitumor effect of lymphodepletion/anti-PD-L1 therapy was most robust when tumor Ag-experienced T cells were present either through cell transfer or survival after nonmyeloablative irradiation. In vivo depletion of CD4 or CD8 T cells completely eliminated antitumor efficacy of the lymphodepletion/anti-PD-L1 therapy, indicating that both T cell subsets are necessary for tumor rejection. Elimination of myeloma by T cells occurs relatively quickly as tumor cells in the bone marrow were nearly nondetectable by 5 d after the first anti-PD-L1 treatment, suggesting that antimyeloma reactivity is primarily mediated by preactivated T cells, rather than newly generated myeloma-reactive T cells. Anti-PD-L1 plus lymphodepletion failed to improve survival in two solid tumor models, but demonstrated significant efficacy in two hematologic malignancy models. In summary, our results support the clinical testing of lymphodepletion and PD-1/PD-L1 blockade as a novel approach for improving the survival of patients with multiple myeloma.

Early impact of a national multi-faceted road safety intervention program in Mexico: results of a time-series analysis.

PubMed

Chandran, Aruna; Pérez-Núñez, Ricardo; Bachani, Abdulgafoor M; Híjar, Martha; Salinas-Rodríguez, Aarón; Hyder, Adnan A

2014-01-01

In January 2008, a national multifaceted road safety intervention program (IMESEVI) funded by the Bloomberg Philanthropies was launched in Mexico. Two years later in 2010, IMESEVI was refocused as part of a 10-country international consortium demonstration project (IMESEVI/RS10). We evaluate the initial effects of each phase of the road safety intervention project on numbers of RT crashes, injuries and deaths in Mexico and in the two main target cities of Guadalajara-Zapopan and León. An interrupted time series analysis using autoregressive integrated moving average (ARIMA) modeling was performed using monthly data of rates of RT crashes and injuries (police data), as well as deaths (mortality system data) from 1999-2011 with dummy variables representing each intervention phase. In the period following the first intervention phase at the country level and in the city of León, the rate of RT crashes decreased significantly (p<0.05). Notably, following the second intervention phase although there was no reduction at the country level, there has been a decrease in the RT crash rate in both Guadalajara-Zapopan (p = 0.029) and in León (p = 0.029). There were no significant differences in the RT injury or death rates following either intervention phase in either city. These initial results suggest that a multi-faceted road safety intervention program appears to be effective in reducing road crashes in a middle-income country setting. Further analysis is needed to differentiate the effects of various interventions, and to determine what other economic and political factors might have affected this change.

Prognostic impact of programmed cell death 1 ligand 1 expression in human leukocyte antigen class I-positive hepatocellular carcinoma after curative hepatectomy.

PubMed

Umemoto, Yuichiroh; Okano, Shinji; Matsumoto, Yoshihiro; Nakagawara, Hidekazu; Matono, Rumi; Yoshiya, Shohei; Yamashita, Yo-Ichi; Yoshizumi, Tomoharu; Ikegami, Toru; Soejima, Yuji; Harada, Mamoru; Aishima, Shinichi; Oda, Yoshinao; Shirabe, Ken; Maehara, Yoshihiko

2015-01-01

Hepatocellular carcinoma (HCC) is one of the most common solid tumors worldwide. Surgery is potentially curative, but high recurrence rates worsen patient prognosis. The interaction between the proteins programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) is an important immune checkpoint. The significance of PD-L1 expression and human leukocyte antigen class I (HLA class I), recognized by CD8 T cells, in the prognosis of patients with HCC remains to be determined. We assessed the levels of PD-L1 and HLA class I expression on HCC samples from 80 patients who had undergone hepatectomy at our institution, and evaluated the correlations between PD-L1 and HLA class I expression and patient prognosis. High HLA class I expression was correlated with significantly better recurrence-free survival (RFS), but not overall survival (OS). Multivariate analysis showed that high HLA class I expression was an independent predictor of improved RFS. Low expression of PD-L1 on HCC tended to predict better OS, but the difference was not statistically significant. PD-L1 expression on HCC correlated with the number of CD163-positive macrophages and HLA class I expression with CD3-positive cell infiltration. Univariable and multivariable analyses showed that combined PD-L1 low/HLA class I high expression on HCCs was prognostic for improved OS and RFS. PD-L1 status may be a good predictor of prognosis in HCC patients with high HLA class I expression. Novel therapies targeting the PD-L1/PD-1 pathway may improve the prognosis of patients with HCC.

Early Impact of a National Multi-Faceted Road Safety Intervention Program in Mexico: Results of a Time-Series Analysis

PubMed Central

Chandran, Aruna; Pérez-Núñez, Ricardo; Bachani, Abdulgafoor M.; Híjar, Martha; Salinas-Rodríguez, Aarón; Hyder, Adnan A.

2014-01-01

Background In January 2008, a national multifaceted road safety intervention program (IMESEVI) funded by the Bloomberg Philanthropies was launched in Mexico. Two years later in 2010, IMESEVI was refocused as part of a 10-country international consortium demonstration project (IMESEVI/RS10). We evaluate the initial effects of each phase of the road safety intervention project on numbers of RT crashes, injuries and deaths in Mexico and in the two main target cities of Guadalajara-Zapopan and León. Methods An interrupted time series analysis using autoregressive integrated moving average (ARIMA) modeling was performed using monthly data of rates of RT crashes and injuries (police data), as well as deaths (mortality system data) from 1999–2011 with dummy variables representing each intervention phase. Results In the period following the first intervention phase at the country level and in the city of León, the rate of RT crashes decreased significantly (p<0.05). Notably, following the second intervention phase although there was no reduction at the country level, there has been a decrease in the RT crash rate in both Guadalajara-Zapopan (p = 0.029) and in León (p = 0.029). There were no significant differences in the RT injury or death rates following either intervention phase in either city. Conclusion These initial results suggest that a multi-faceted road safety intervention program appears to be effective in reducing road crashes in a middle-income country setting. Further analysis is needed to differentiate the effects of various interventions, and to determine what other economic and political factors might have affected this change. PMID:24498114

New Chimeric Antigen Receptor Design for Solid Tumors

PubMed Central

Wang, Yuedi; Luo, Feifei; Yang, Jiao; Zhao, Chujun; Chu, Yiwei

2017-01-01

In recent years, chimeric antigen receptor (CAR) T-cell therapy has become popular in immunotherapy, particularly after its tremendous success in the treatment of lineage-restricted hematologic cancers. However, the application of CAR T-cell therapy for solid tumors has not reached its full potential because of the lack of specific tumor antigens and inhibitory factors in suppressive tumor microenvironment (TME) (e.g., programmed death ligand-1, myeloid-derived suppressor cells, and transforming growth factor-β). In this review, we include some limitations in CAR design, such as tumor heterogeneity, indefinite spatial distance between CAR T-cell and its target cell, and suppressive TME. We also summarize some new approaches to overcome these hurdles, including targeting neoantigens and/or multiple antigens at once and depleting some inhibitory factors. PMID:29312360

Gibberellin control of stamen development: a fertile field.

PubMed

Plackett, Andrew R G; Thomas, Stephen G; Wilson, Zoe A; Hedden, Peter

2011-10-01

Stamen development is governed by a conserved genetic pathway, within which the role of hormones has been the subject of considerable recent research. Our understanding of the involvement of gibberellin (GA) signalling in this developmental process is further advanced than for the other phytohormones, and here we review recent experimental results in rice (Oryza sativa) and Arabidopsis (Arabidopsis thaliana) that have provided insight into the timing and mechanisms of GA regulation of stamen development, identifying the tapetum and developing pollen as major targets. GA signalling governs both tapetum secretory functions and entry into programmed cell death via the GAMYB class of transcription factor, the targets of which integrate with the established genetic framework for the regulation of tapetum function at multiple hierarchical levels. Copyright © 2011 Elsevier Ltd. All rights reserved.

Dignity, death, and dilemmas: a study of Washington hospices and physician-assisted death.

PubMed

Campbell, Courtney S; Black, Margaret A

2014-01-01

The legalization of physician-assisted death in states such as Washington and Oregon has presented defining ethical issues for hospice programs because up to 90% of terminally ill patients who use the state-regulated procedure to end their lives are enrolled in hospice care. The authors recently partnered with the Washington State Hospice and Palliative Care Organization to examine the policies developed by individual hospice programs on program and staff participation in the Washington Death with Dignity Act. This article sets a national and local context for the discussion of hospice involvement in physician-assisted death, summarizes the content of hospice policies in Washington State, and presents an analysis of these findings. The study reveals meaningful differences among hospice programs about the integrity and identity of hospice and hospice care, leading to different policies, values, understandings of the medical procedure, and caregiving practices. In particular, the authors found differences 1) in the language used by hospices to refer to the Washington statute that reflect differences among national organizations, 2) the values that hospice programs draw on to support their policies, 3) dilemmas created by requests by patients for hospice staff to be present at a patient's death, and 4) five primary levels of noninvolvement and participation by hospice programs in requests from patients for physician-assisted death. This analysis concludes with a framework of questions for developing a comprehensive hospice policy on involvement in physician-assisted death and to assist national, state, local, and personal reflection. Copyright © 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Health hazards among working children in Texas.

PubMed

Cooper, S P; Rothstein, M A

1995-05-01

This report represents the first attempt to assemble existing data from a variety of sources regarding children less than 18 years of age in the work force in Texas. These data include the frequency of detected violations of child labor laws, reports of injuries to the Texas Workers' Compensation Commission, and work-related deaths as ascertained from death certificates. More than 1,000 minors were detected as being illegally employed in Texas each year since 1986 and nearly 1,100 work-related injuries in children 18 years of age and younger were reported to the Texas Workers' Compensation Commission in 1991. A review of Texas death certificates from 1980 to 1990 revealed 125 work-related fatalities among children. The leading cause of death was motor vehicle injuries, followed by injuries from machinery (usually agricultural machinery). The magnitude and severity of occupational illnesses in working children are unknown. Because of physiologic differences in size, metabolism, and absorption, children may be especially susceptible to work-related injury and illness. Health and safety data on working children in Texas, as in most other places, are fragmented and incomplete. These data are needed to identify children at high risk of injuries and illnesses, to target prevention programs, and to identify areas for additional legislation. More rigorous enforcement of current legislation is also needed.

Racial and Ethnic Differences in Homicides of Adult Women and the Role of Intimate Partner Violence - United States, 2003-2014.

PubMed

Petrosky, Emiko; Blair, Janet M; Betz, Carter J; Fowler, Katherine A; Jack, Shane P D; Lyons, Bridget H

2017-07-21

Homicide is one of the leading causes of death for women aged ≤44 years.* In 2015, homicide caused the death of 3,519 girls and women in the United States. Rates of female homicide vary by race/ethnicity (1), and nearly half of victims are killed by a current or former male intimate partner (2). To inform homicide and intimate partner violence (IPV) prevention efforts, CDC analyzed homicide data from the National Violent Death Reporting System (NVDRS) among 10,018 women aged ≥18 years in 18 states during 2003-2014. The frequency of homicide by race/ethnicity and precipitating circumstances of homicides associated with and without IPV were examined. Non-Hispanic black and American Indian/Alaska Native women experienced the highest rates of homicide (4.4 and 4.3 per 100,000 population, respectively). Over half of all homicides (55.3%) were IPV-related; 11.2% of victims of IPV-related homicide experienced some form of violence in the month preceding their deaths, and argument and jealousy were common precipitating circumstances. Targeted IPV prevention programs for populations at disproportionate risk and enhanced access to intervention services for persons experiencing IPV are needed to reduce homicides among women.

Induction of cell death by tospoviral protein NSs and the motif critical for cell death does not control RNA silencing suppression activity.

PubMed

Singh, Ajeet; Permar, Vipin; Jain, R K; Goswami, Suneha; Kumar, Ranjeet Ranjan; Canto, Tomas; Palukaitis, Peter; Praveen, Shelly

2017-08-01

Groundnut bud necrosis virus induces necrotic symptoms in different hosts. Previous studies showed reactive oxygen species-mediated programmed cell death (PCD) resulted in necrotic symptoms. Transgenic expression of viral protein NSs mimics viral symptoms. Here, we showed a role for NSs in influencing oxidative burst in the cell, by analyzing H 2 O 2 accumulation, activities of antioxidant enzymes and expression levels of vacuolar processing enzymes, H 2 O 2 -responsive microRNA 319a.2 plus its possible target metacaspase-8. The role of NSs in PCD, was shown using two NSs mutants: one in the Trp/GH3 motif (a homologue of pro-apototic domain) (NSs S189R ) and the other in a non-Trp/GH3 motif (NSs L172R ). Tobacco rattle virus (TRV) expressing NSs S189R enhanced the PCD response, but not TRV-NSs L172R , while RNA silencing suppression activity was lost in TRV-NSs L172R , but not in TRV-NSs S189R . Therefore, we propose dual roles of NSs in RNA silencing suppression and induction of cell death, controlled by different motifs. Copyright © 2017 Elsevier Inc. All rights reserved.

Molecular Imaging of Apoptosis: From Micro to Macro

PubMed Central

Zeng, Wenbin; Wang, Xiaobo; Xu, Pengfei; Liu, Gang; Eden, Henry S.; Chen, Xiaoyuan

2015-01-01

Apoptosis, or programmed cell death, is involved in numerous human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer, and is often confused with other types of cell death. Therefore strategies that enable visualized detection of apoptosis would be of enormous benefit in the clinic for diagnosis, patient management, and development of new therapies. In recent years, improved understanding of the apoptotic machinery and progress in imaging modalities have provided opportunities for researchers to formulate microscopic and macroscopic imaging strategies based on well-defined molecular markers and/or physiological features. Correspondingly, a large collection of apoptosis imaging probes and approaches have been documented in preclinical and clinical studies. In this review, we mainly discuss microscopic imaging assays and macroscopic imaging probes, ranging in complexity from simple attachments of reporter moieties to proteins that interact with apoptotic biomarkers, to rationally designed probes that target biochemical changes. Their clinical translation will also be our focus. PMID:25825597

The Road to Dog Rabies Control and Elimination—What Keeps Us from Moving Faster?

PubMed Central

Fahrion, Anna S.; Taylor, Louise H.; Torres, Gregorio; Müller, Thomas; Dürr, Salome; Knopf, Lea; de Balogh, Katinka; Nel, Louis H.; Gordoncillo, Mary Joy; Abela-Ridder, Bernadette

2017-01-01

Rabies, a vaccine preventable neglected tropical disease, still claims an estimated 35,000–60,000 human lives annually. The international community, with more than 100 endemic countries, has set a global target of 0 human deaths from dog-transmitted rabies by 2030. While it has been proven in several countries and regions that elimination of rabies as a public health problem is feasible and tools are available, rabies deaths globally have not yet been prevented effectively. While there has been extensive rabies research, specific areas of implementation for control and elimination have not been sufficiently addressed. This article highlights some of the commonest perceived barriers for countries to implementing rabies control and elimination programs and discusses possible solutions for sociopolitical, organizational, technical, and resource-linked requirements, following the pillars of the global framework for the elimination of dog-mediated human rabies adopted at the global rabies meeting in December 2015. PMID:28555183

Cytochrome c/cardiolipin relations in mitochondria: a kiss of death

PubMed Central

Kagan, Valerian E.; Bayir, Hülya A.; Belikova, Natalia A.; Kapralov, Olexandr; Tyurina, Yulia Y.; Tyurin, Vladimir A.; Jiang, Jianfei; Stoyanovsky, Detcho A.; Wipf, Peter; Kochanek, Patrick M.; Greenberger, Joel S.; Pitt, Bruce; Shvedova, Anna A.; Borisenko, Grigory

2009-01-01

Recently, phospholipid peroxidation products gained a reputation as key regulatory molecules and participants in oxidative signaling pathways. During apoptosis, a mitochondria-specific phospholipid, cardiolipin (CL), interacts with cytochrome c (cyt c) to form a peroxidase complex that catalyzes CL oxidation; this process plays a pivotal role in the mitochondrial stage of the execution of the cell death program. This review is focused on redox mechanisms and essential structural features of cyt c's conversion into a CL-specific peroxidase that represent an interesting and maybe still unique example of a functionally significant ligand change in hemoproteins. Furthermore, specific characteristics of CL in mitochondria – its asymmetric trans-membrane distribution and mechanisms of collapse, regulation of its synthesis, remodeling and fatty acid composition – are given significant consideration. Finally, new concepts in drug discovery based on the design of mitochondria-targeted inhibitors of cyt c/CL peroxidase and CL peroxidation with anti-apoptotic effects are presented. PMID:19285551

Hemoglobins, programmed cell death and somatic embryogenesis.

PubMed

Hill, Robert D; Huang, Shuanglong; Stasolla, Claudio

2013-10-01

Programmed cell death (PCD) is a universal process in all multicellular organisms. It is a critical component in a diverse number of processes ranging from growth and differentiation to response to stress. Somatic embryogenesis is one such process where PCD is significantly involved. Nitric oxide is increasingly being recognized as playing a significant role in regulating PCD in both mammalian and plant systems. Plant hemoglobins scavenge NO, and evidence is accumulating that events that modify NO levels in plants also affect hemoglobin expression. Here, we review the process of PCD, describing the involvement of NO and plant hemoglobins in the process. NO is an effector of cell death in both plants and vertebrates, triggering the cascade of events leading to targeted cell death that is a part of an organism's response to stress or to tissue differentiation and development. Expression of specific hemoglobins can alter this response in plants by scavenging the NO, thus, interrupting the death process. Somatic embryogenesis is used as a model system to demonstrate how cell-specific expression of different classes of hemoglobins can alter the embryogenic process, affecting hormone synthesis, cell metabolite levels and genes associated with PCD and embryogenic competence. We propose that plant hemoglobins influence somatic embryogenesis and PCD through cell-specific expression of a distinct plant hemoglobin. It is based on the premise that both embryogenic competence and PCD are strongly influenced by cellular NO levels. Increases in cellular NO levels result in elevated Zn(2+) and reactive-oxygen species associated with PCD, but they also result in decreased expression of MYC2, a transcription factor that is a negative effector of indoleacetic acid synthesis, a hormone that positively influences embryogenic competence. Cell-specific hemoglobin expression reduces NO levels as a result of NO scavenging, resulting in cell survival. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Development of targeted therapy and immunotherapy for treatment of small cell lung cancer.

PubMed

Saito, Motonobu; Shiraishi, Kouya; Goto, Akiteru; Suzuki, Hiroyuki; Kohno, Takashi; Kono, Koji

2018-05-14

Targeted therapy against druggable genetic aberrations has shown a significantly positive response rate and longer survival in various cancers, including lung cancer. In lung adenocarcinoma (LADC), specific thyroxin kinase inhibitors against EGFR mutations and ALK fusions are used as a standard treatment regimen and show significant positive efficacy. On the other hand, targeted therapy against driver gene aberrations has not been adapted yet in small cell lung cancer (SCLC). This is because driver genes and druggable aberrations are rarely identified by next generation sequencing in SCLC. Recent advances in the understanding of molecular biology have revealed several candidate therapeutic targets. To date, poly [ADP-ribose] polymerase (PARP), enhancer of zeste homologue 2 (EZH2) or delta-like canonical Notch ligand 3 (DLL3) are considered to be druggable targets in SCLC. In addition, another candidate of personalized therapy for SCLC is immune blockade therapy of programmed death-1 (PD-1) and its ligand, PD-L1. PD-1/PD-L1 blockade therapy is not a standard therapy for SCLC, so many clinical trials have been performed to investigate its efficacy. Herein, we review gene aberrations exploring the utility of targeted therapy and discuss blockade of immune checkpoints therapy in SCLC.

Determinants of mortality and nondeath losses from an antiretroviral treatment service in South Africa: implications for program evaluation.

PubMed

Lawn, Stephen D; Myer, Landon; Harling, Guy; Orrell, Catherine; Bekker, Linda-Gail; Wood, Robin

2006-09-15

The scale-up of antiretroviral treatment (ART) services in resource-limited settings requires a programmatic model to deliver care to large numbers of people. Understanding the determinants of key outcome measures--including death and nondeath losses--would assist in program evaluation and development. Between September 2002 and August 2005, all in-program (pretreatment and on-treatment) deaths and nondeath losses were prospectively ascertained among treatment-naive adults (n=1235) who were enrolled in a community-based ART program in South Africa. At study censorship, 927 patients had initiated ART after a median of 34 days after enrollment in the program. One hundred twenty-one (9.8%) patients died. Mortality rates were 33.3 (95% CI, 25.5-43.0), 19.1 (95% CI, 14.4-25.2), and 2.9 (95% CI, 1.8-4.8) deaths/100 person-years in the pretreatment interval, during the first 4 months of ART (early deaths), and after 4 months of ART (late deaths), respectively. Pretreatment and early treatment deaths together accounted for 87% of deaths, and were independently associated with advanced immunodeficiency at enrollment. Late deaths were comparatively few and were only associated with the response to ART at 4 months. Nondeath program losses (loss to follow-up, 2.3%; transfer-out, 1.9%; relocation, 0.7%) were not associated with immune status and were evenly distributed during the study period. Loss to follow-up and late mortality rates were low, reflecting good cohort retention and treatment response. However, the extremely high pretreatment and early mortality rates indicate that patients are enrolling in ART programs with far too advanced immunodeficiency. Causes of late access to the ART program, such as delays in health care access, health system delays, or inappropriate treatment criteria, need to be addressed.

Place of Residence Moderates the Risk of Infant Death in Kenya: Evidence from the Most Recent Census 2009.

PubMed

Gruebner, Oliver; Lautenbach, Sven; Khan, M M H; Kipruto, Samuel; Epprecht, Michael; Galea, Sandro

2015-01-01

Substantial progress has been made in reducing childhood mortality worldwide from 1990-2015 (Millennium Development Goal, target 4). Achieving target goals on this however remains a challenge in Sub-Saharan Africa. Kenya's infant mortality rates are higher than the global average and are more pronounced in urban areas as compared to rural areas. Only limited knowledge exists about the differences in individual level risk factors for infant death among rural, non-slum urban, and slum areas in Kenya. Therefore, this paper aims at 1) assess individual and socio-ecological risk factors for infant death in Kenya, and at 2) identify whether living in rural, non-slum urban, or slum areas moderated individual or socio-ecological risk factors for infant death in Kenya. We used a cross-sectional study design based on the most recent Kenya Population and Housing Census of 2009 and extracted the records of all females who had their last child born in 12 months preceding the survey (N = 1,120,960). Multivariable regression analyses were used to identify risk factors that accounted for the risk of dying before the age of one at the individual level in Kenya. Place of residence (rural, non-slum urban, slum) was used as an interaction term to account for moderating effects in individual and socio-ecological risk factors. Individual characteristics of mothers and children (older age, less previously born children that died, better education, girl infants) and household contexts (better structural quality of housing, improved water and sanitation, married household head) were associated with lower risk for infant death in Kenya. Living in non-slum urban areas was associated with significantly lower infant death as compared to living in rural or slum areas, when all predictors were held at their reference levels. Moreover, place of residence was significantly moderating individual level predictors: As compared to rural areas, living in urban areas was a protective factor for mothers who had previous born children who died, and who were better educated. However, living in urban areas also reduced the health promoting effects of better structural quality of housing (i.e. poor or good versus non-durable). Furthermore, durable housing quality in urban areas turned out to be a risk factor for infant death as compared to rural areas. Living in slum areas was also a protective factor for mothers with previous child death, however it also reduced the promoting effects of older ages in mothers. While urbanization and slum development continues in Kenya, public health interventions should invest in healthy environments that ideally would include improvements to access to safe water and sanitation, better structural quality of housing, and to access to education, health care, and family planning services, especially in urban slums and rural areas. In non-slum urban areas however, health education programs that target healthy diets and promote physical exercise may be an important adjunct to these structural interventions.

Propolis Augments Apoptosis Induced by Butyrate via Targeting Cell Survival Pathways

PubMed Central

Drago, Eric; Bordonaro, Michael; Lee, Seon; Atamna, Wafa; Lazarova, Darina L.

2013-01-01

Diet is one of the major lifestyle factors affecting incidence of colorectal cancer (CC), and despite accumulating evidence that numerous diet-derived compounds modulate CC incidence, definitive dietary recommendations are not available. We propose a strategy that could facilitate the design of dietary supplements with CC-preventive properties. Thus, nutrient combinations that are a source of apoptosis-inducers and inhibitors of compensatory cell proliferation pathways (e.g., AKT signaling) may produce high levels of programmed death in CC cells. Here we report the combined effect of butyrate, an apoptosis inducer that is produced through fermentation of fiber in the colon, and propolis, a honeybee product, on CC cells. We established that propolis increases the apoptosis of CC cells exposed to butyrate through suppression of cell survival pathways such as the AKT signaling. The programmed death of CC cells by combined exposure to butyrate and propolis is further augmented by inhibition of the JNK signaling pathway. Analyses on the contribution of the downstream targets of JNK signaling, c-JUN and JAK/STAT, to the apoptosis of butyrate/propolis-treated CC cells ascertained that JAK/STAT signaling has an anti-apoptotic role; whereas, the role of cJUN might be dependent upon regulatory cell factors. Thus, our studies ascertained that propolis augments apoptosis of butyrate-sensitive CC cells and re-sensitizes butyrate-resistant CC cells to apoptosis by suppressing AKT signaling and downregulating the JAK/STAT pathway. Future in vivo studies should evaluate the CC-preventive potential of a dietary supplement that produces high levels of colonic butyrate, propolis, and diet-derived JAK/STAT inhibitors. PMID:24023824

Pan-Cancer Analysis Links PARK2 to BCL-XL-Dependent Control of Apoptosis.

PubMed

Gong, Yongxing; Schumacher, Steven E; Wu, Wei H; Tang, Fanying; Beroukhim, Rameen; Chan, Timothy A

2017-02-01

Mutation of the PARK2 gene can promote both Parkinson's Disease and cancer, yet the underlying mechanisms of how PARK2 controls cellular physiology is incompletely understood. Here, we show that the PARK2 tumor suppressor controls the apoptotic regulator BCL-XL and modulates programmed cell death. Analysis of approximately 10,000 tumor genomes uncovers a striking pattern of mutual exclusivity between PARK2 genetic loss and amplification of BCL2L1, implicating these genes in a common pathway. PARK2 directly binds to and ubiquitinates BCL-XL. Inactivation of PARK2 leads to aberrant accumulation of BCL-XL both in vitro and in vivo, and cancer-specific mutations in PARK2 abrogate the ability of the ubiquitin E3 ligase to target BCL-XL for degradation. Furthermore, PARK2 modulates mitochondrial depolarization and apoptosis in a BCL-XL-dependent manner. Thus, like genes at the nodal points of growth arrest pathways such as p53, the PARK2 tumor suppressor is able to exert its antiproliferative effects by regulating both cell cycle progression and programmed cell death. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

[PD-L1 expression: An emerging biomarker in non-small cell lung cancer].

PubMed

Adam, Julien; Planchard, David; Marabelle, Aurélien; Soria, Jean-Charles; Scoazec, Jean-Yves; Lantuéjoul, Sylvie

2016-01-01

Therapies targeting immune checkpoints, in particular programmed death 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1), are major new strategies for the treatment of several malignancies including mestatatic non-small cell lung cancer (NSCLC). The identification of predictive biomarkers of response is required, considering efficacy, cost and potential adverse events. Expression of PD-L1 by immunohistochemistry has been associated with higher response rate and overall survival in several clinical trials evaluating anti-PD-1 and anti-PD-L1 monoclonal antibodies. Thus, PD-L1 immunohistochemical companion assays could be required for treatment with some of these therapies in NSCLC. However, heterogeneity in methodologies of PD-L1 assays in terms of primary antibodies and scoring algorithms, and tumor heterogenity for PD-L1 expression are important issues to be considered. More studies are required to compare the different assays, ensure their harmonization and standardization and identify the optimal conditions for testing. PD-L1 expression is likely an imperfect predictive biomarker for patient selection and association with other markers of the tumor immune microenvironment will be probably necessary in the future. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Anti–PD-1/PD-L1 therapy of human cancer: past, present, and future

PubMed Central

Chen, Lieping; Han, Xue

2015-01-01

Major progress has been made toward our understanding of the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway (referred to as the PD pathway). mAbs are already being used to block the PD pathway to treat human cancers (anti-PD therapy), especially advanced solid tumors. This therapy is based on principles that were discovered through basic research more than a decade ago, but the great potential of this pathway to treat a broad spectrum of advanced human cancers is just now becoming apparent. In this Review, we will briefly review the history and development of anti-PD therapy, from the original benchwork to the most up-to-date clinical results. We will then focus the discussion on three basic principles that define this unique therapeutic approach and highlight how anti-PD therapy is distinct from other immunotherapeutic approaches, namely tumor site immune modulation, targeting tumor-induced immune defects, and repairing ongoing (rather than generating de novo) tumor immunity. We believe that these fundamental principles set the standard for future immunotherapies and will guide our efforts to develop more efficacious and less toxic immune therapeutics to treat human cancers. PMID:26325035

MTOR-driven quasi-programmed aging as a disposable soma theory: blind watchmaker vs. intelligent designer.

PubMed

Blagosklonny, Mikhail V

2013-06-15

If life were created by intelligent design, we would indeed age from accumulation of molecular damage. Repair is costly and limited by energetic resources, and we would allocate resources rationally. But, albeit elegant, this design is fictional. Instead, nature blindly selects for short-term benefits of robust developmental growth. "Quasi-programmed" by the blind watchmaker, aging is a wasteful and aimless continuation of developmental growth, driven by nutrient-sensing, growth-promoting signaling pathways such as MTOR (mechanistic target of rapamycin). A continuous post-developmental activity of such gerogenic pathways leads to hyperfunctions (aging), loss of homeostasis, age-related diseases, non-random organ damage and death. This model is consistent with a view that (1) soma is disposable, (2) aging and menopause are not programmed and (3) accumulation of random molecular damage is not a cause of aging as we know it.

Hepatitis B vaccination for injection drug users--Pierce County, Washington, 2000.

PubMed

2001-05-18

Hepatitis B vaccination has been recommended for injection drug users (IDUs) since 1982, but vaccination coverage of IDUs remains low (1), and outbreaks of hepatitis B among IDUs continue to occur. An outbreak of hepatitis B primarily among IDUs in Pierce County, Washington, detected in April 2000, included 60 cases and resulted in three deaths among IDUs co-infected with hepatitis delta virus. A program to administer hepatitis B vaccine to IDUs was implemented to control the outbreak, and the number of cases identified decreased from 13 per month in May to two cases since November. This report describes a vaccination program during which IDUs accepted hepatitis B vaccination provided free of charge in community-based settings and illustrates how effective hepatitis B vaccination programs targeted at IDUs can be implemented through collaborations between departments of health and corrections and community organizations.

REDUCE CHILD MORTALITY AS A MILLENNIUM DEVELOPMENI GOAL IN ROMANIA.

PubMed

Duma, Olga-Odetta; Roşu, Solange Tamara; Petrariu, F D; Manole, M; Constantin, Brânduşa

2016-01-01

To assess the efforts made in Romania towards achieving the Goal 4 from MDGs--Reduce Child Mortality. A descriptive study about the deaths among Romanian children under five, between 2002 and 2015, from the perspective of the MDGs. To help track progress toward this commitment, following specific targets and indicators were developed: Target 1-Halve the mortality rate in children aged 1-4 years between 2002-2015; Target 2--Reduce infant mortality by 40% between 2002 and 2015; Target 3--Eliminate measles by 2007. The comparison allows establish the status (achieved or not) for each target. From 2002, the under-five mortality rate recorded a continuous descendent trend till now (20.8 to 10.3 under five deaths per 1000 inhabitants in 2013). The infant mortality rates declined from 17.3 to 8.5 deaths per 1,000 live births (2002-2013). Eliminating measles by 2007--was achieved one year later, because of the measles epidemic in 2005 and 2006. High vaccination rates have been maintained, with the proportion of children 1 year old vaccinated against measles reaching and being maintained at between 94-98%. Substantial progress has been made in Romania, in achieving the Millennium Development Goal no. 4. All the three targets were achieved. However, infant mortality still remains above the average of European Union (4 infant deaths per 1,000 live-births).

Cell death proteomics database: consolidating proteomics data on cell death.

PubMed

Arntzen, Magnus Ø; Bull, Vibeke H; Thiede, Bernd

2013-05-03

Programmed cell death is a ubiquitous process of utmost importance for the development and maintenance of multicellular organisms. More than 10 different types of programmed cell death forms have been discovered. Several proteomics analyses have been performed to gain insight in proteins involved in the different forms of programmed cell death. To consolidate these studies, we have developed the cell death proteomics (CDP) database, which comprehends data from apoptosis, autophagy, cytotoxic granule-mediated cell death, excitotoxicity, mitotic catastrophe, paraptosis, pyroptosis, and Wallerian degeneration. The CDP database is available as a web-based database to compare protein identifications and quantitative information across different experimental setups. The proteomics data of 73 publications were integrated and unified with protein annotations from UniProt-KB and gene ontology (GO). Currently, more than 6,500 records of more than 3,700 proteins are included in the CDP. Comparing apoptosis and autophagy using overrepresentation analysis of GO terms, the majority of enriched processes were found in both, but also some clear differences were perceived. Furthermore, the analysis revealed differences and similarities of the proteome between autophagosomal and overall autophagy. The CDP database represents a useful tool to consolidate data from proteome analyses of programmed cell death and is available at http://celldeathproteomics.uio.no.

VX-induced cell death involves activation of caspase-3 in cultured rat cortical neurons.

PubMed

Tenn, Catherine C; Wang, Yushan

2007-05-01

Exposure of cell cultures to organophosphorous compounds such as VX can result in cell death. However, it is not clear whether VX-induced cell death is necrotic or involves programmed cell death mechanisms. Activation of caspases, a family of cysteine proteases, is often involved in cell death, and in particular, caspase-3 activation appears to be a key event in programmed cell death processes including apoptosis. In this study, we investigated VX-induced neuronal cell death, as well as the underlying mechanism in terms of its effect on caspase-3 activity. Primary cortical neuronal cultures were prepared from gestational days 17 to 19 Sprague Dawley rat fetuses. At maturation, the cells were treated with varying concentrations of VX and cell death was evaluated by lactate dehydrogenase (LDH) release. VX induced an increase in LDH release in a concentration-dependent manner. Morphological VX-induced cell death was also characterized by using nuclear staining with propidium iodide and Hoechst 33342. VX induced a concentration- and time-dependent increase in caspase-3 activation. Caspase-3 activation was also confirmed by the proteolytic cleavage of poly(ADP-ribose)polymerase (PARP), an endogenous caspase-3 substrate. These data suggested that in rat cortical neurons, VX-induced cell death via a programmed cell death pathway that involves changes in caspase-3 protease.

Classification of human natural killer cells based on migration behavior and cytotoxic response.

PubMed

Vanherberghen, Bruno; Olofsson, Per E; Forslund, Elin; Sternberg-Simon, Michal; Khorshidi, Mohammad Ali; Pacouret, Simon; Guldevall, Karolin; Enqvist, Monika; Malmberg, Karl-Johan; Mehr, Ramit; Önfelt, Björn

2013-02-21

Despite intense scrutiny of the molecular interactions between natural killer (NK) and target cells, few studies have been devoted to dissection of the basic functional heterogeneity in individual NK cell behavior. Using a microchip-based, time-lapse imaging approach allowing the entire contact history of each NK cell to be recorded, in the present study, we were able to quantify how the cytotoxic response varied between individual NK cells. Strikingly, approximately half of the NK cells did not kill any target cells at all, whereas a minority of NK cells was responsible for a majority of the target cell deaths. These dynamic cytotoxicity data allowed categorization of NK cells into 5 distinct classes. A small but particularly active subclass of NK cells killed several target cells in a consecutive fashion. These "serial killers" delivered their lytic hits faster and induced faster target cell death than other NK cells. Fast, necrotic target cell death was correlated with the amount of perforin released by the NK cells. Our data are consistent with a model in which a small fraction of NK cells drives tumor elimination and inflammation.

Avoiding 40% of the premature deaths in each country, 2010-30: review of national mortality trends to help quantify the UN sustainable development goal for health.

PubMed

Norheim, Ole F; Jha, Prabhat; Admasu, Kesetebirhan; Godal, Tore; Hum, Ryan J; Kruk, Margaret E; Gómez-Dantés, Octavio; Mathers, Colin D; Pan, Hongchao; Sepúlveda, Jaime; Suraweera, Wilson; Verguet, Stéphane; Woldemariam, Addis T; Yamey, Gavin; Jamison, Dean T; Peto, Richard

2015-01-17

The UN will formulate ambitious Sustainable Development Goals for 2030, including one for health. Feasible goals with some quantifiable, measurable targets can influence governments. We propose, as a quatitative health target, "Avoid in each country 40% of premature deaths (under-70 deaths that would be seen in the 2030 population at 2010 death rates), and improve health care at all ages". Targeting overall mortality and improved health care ignores no modifiable cause of death, nor any cause of disability that is treatable (or also causes many deaths). 40% fewer premature deaths would be important in all countries, but implies very different priorities in different populations. Reinforcing this target for overall mortality in each country are four global subtargets for 2030: avoid two-thirds of child and maternal deaths; two-thirds of tuberculosis, HIV, and malaria deaths; a third of premature deaths from non-communicable diseases (NCDs); and a third of those from other causes (other communicable diseases, undernutrition, and injuries). These challenging subtargets would halve under-50 deaths, avoid a third of the (mainly NCD) deaths at ages 50-69 years, and so avoid 40% of under-70 deaths. To help assess feasibility, we review mortality rates and trends in the 25 most populous countries, in four country income groupings, and worldwide. UN sources yielded overall 1970-2010 mortality trends. WHO sources yielded cause-specific 2000-10 trends, standardised to country-specific 2030 populations; decreases per decade of 42% or 18% would yield 20-year reductions of two-thirds or a third. Throughout the world, except in countries where the effects of HIV or political disturbances predominated, mortality decreased substantially from 1970-2010, particularly in childhood. From 2000-10, under-70 age-standardised mortality rates decreased 19% (with the low-income and lower-middle-income countries having the greatest absolute gains). The proportional decreases per decade (2000-10) were: 34% at ages 0-4 years; 17% at ages 5-49 years; 15% at ages 50-69 years; 30% for communicable, perinatal, maternal, or nutritional causes; 14% for NCDs; and 13% for injuries (accident, suicide, or homicide). Moderate acceleration of the 2000-10 proportional decreases in mortality could be feasible, achieving the targeted 2030 disease-specific reductions of two-thirds or a third. If achieved, these reductions avoid about 10 million of the 20 million deaths at ages 0-49 years that would be seen in 2030 at 2010 death rates, and about 17 million of the 41 million such deaths at ages 0-69 years. Such changes could be achievable by 2030, or soon afterwards, at least in areas free of war, other major effects of political disruption, or a major new epidemic. UK Medical Research Council, Norwegian Agency for Development Cooperation, Centre for Global Health Research, and Bill & Melinda Gates Foundation. Copyright © 2015 Norheim et al. Open Access article distributed under the terms of CC BY-NC-SA. Published by Elsevier Ltd. All rights reserved.

Folic acid-functionalized polyethylenimine superparamagnetic iron oxide nanoparticles as theranostic agents for magnetic resonance imaging and PD-L1 siRNA delivery for gastric cancer

PubMed Central

Luo, Xin; Peng, Xia; Hou, Jingying; Wu, Shuyun; Shen, Jun; Wang, Lingyun

2017-01-01

Programmed death ligand-1 (PD-L1), which is highly expressed in gastric cancers, interacts with programmed death-1 (PD-1) on T cells and is involved in T-cell immune resistance. To increase the therapeutic safety and accuracy of PD-1/PD-L1 blockade, RNA interference through targeted gene delivery was performed in our study. We developed folic acid (FA)- and disulfide (SS)–polyethylene glycol (PEG)-conjugated polyethylenimine (PEI) complexed with superparamagnetic iron oxide Fe3O4 nanoparticles (SPIONs) as a siRNA-delivery system for PD-L1 knockdown. The characterization, binding ability, cytotoxicity, transfection efficiency, and cellular internalization of the polyplex were determined. At nitrogen:phosphate (N:P) ratios of 10 or above, the FA-PEG-SS-PEI-SPIONs bound to PD-L1 siRNA to form a polyplex with a diameter of approximately 120 nm. Cell-viability assays showed that the polyplex had minimal cytotoxicity at low N:P ratios. The FA-conjugated polyplex showed higher transfection efficiency and cellular internalization in the folate receptor-overexpressing gastric cancer cell line SGC-7901 than a non-FA-conjugated polyplex. Subsequently, we adopted the targeted FA-PEG-SS-PEI-SPION/siRNA polyplexes at an N:P ratio of 10 for function studies. Cellular magnetic resonance imaging (MRI) showed that the polyplex could also act as a T2-weighted contrast agent for cancer MRI. Furthermore, one of four PD-L1 siRNAs exhibited effective PD-L1 knockdown in PD-L1-overexpressing SGC-7901. To determine the effects of the functionalized polyplex on T-cell function, we established a coculture model of activated T cells and SGC-7901 cells and demonstrated changes in secreted cytokines. Our findings highlight the potential of this class of multifunctional theranostic nanoparticles for effective targeted PD-L1-knockdown therapy and MRI diagnosis in gastric cancers. PMID:28794626

Folic acid-functionalized polyethylenimine superparamagnetic iron oxide nanoparticles as theranostic agents for magnetic resonance imaging and PD-L1 siRNA delivery for gastric cancer.

PubMed

Luo, Xin; Peng, Xia; Hou, Jingying; Wu, Shuyun; Shen, Jun; Wang, Lingyun

2017-01-01

Programmed death ligand-1 (PD-L1), which is highly expressed in gastric cancers, interacts with programmed death-1 (PD-1) on T cells and is involved in T-cell immune resistance. To increase the therapeutic safety and accuracy of PD-1/PD-L1 blockade, RNA interference through targeted gene delivery was performed in our study. We developed folic acid (FA)- and disulfide (SS)-polyethylene glycol (PEG)-conjugated polyethylenimine (PEI) complexed with superparamagnetic iron oxide Fe 3 O 4 nanoparticles (SPIONs) as a siRNA-delivery system for PD-L1 knockdown. The characterization, binding ability, cytotoxicity, transfection efficiency, and cellular internalization of the polyplex were determined. At nitrogen:phosphate (N:P) ratios of 10 or above, the FA-PEG-SS-PEI-SPIONs bound to PD-L1 siRNA to form a polyplex with a diameter of approximately 120 nm. Cell-viability assays showed that the polyplex had minimal cytotoxicity at low N:P ratios. The FA-conjugated polyplex showed higher transfection efficiency and cellular internalization in the folate receptor-overexpressing gastric cancer cell line SGC-7901 than a non-FA-conjugated polyplex. Subsequently, we adopted the targeted FA-PEG-SS-PEI-SPION/siRNA polyplexes at an N:P ratio of 10 for function studies. Cellular magnetic resonance imaging (MRI) showed that the polyplex could also act as a T 2 -weighted contrast agent for cancer MRI. Furthermore, one of four PD-L1 siRNAs exhibited effective PD-L1 knockdown in PD-L1-overexpressing SGC-7901. To determine the effects of the functionalized polyplex on T-cell function, we established a coculture model of activated T cells and SGC-7901 cells and demonstrated changes in secreted cytokines. Our findings highlight the potential of this class of multifunctional theranostic nanoparticles for effective targeted PD-L1-knockdown therapy and MRI diagnosis in gastric cancers.

Current Challenges in Cancer Treatment.

PubMed

Zugazagoitia, Jon; Guedes, Cristiano; Ponce, Santiago; Ferrer, Irene; Molina-Pinelo, Sonia; Paz-Ares, Luis

2016-07-01

In this review, we highlight the current concepts and discuss some of the current challenges and future prospects in cancer therapy. We frequently use the example of lung cancer. We conducted a nonsystematic PubMed search, selecting the most comprehensive and relevant research articles, clinical trials, translational papers, and review articles on precision oncology and immuno-oncology. Papers were prioritized and selected based on their originality and potential clinical applicability. Two major revolutions have changed cancer treatment paradigms in the past few years: targeting actionable alterations in oncogene-driven cancers and immuno-oncology. Important challenges are still ongoing in both fields of cancer therapy. On the one hand, druggable genomic alterations are diverse and represent only small subsets of patients in certain tumor types, which limits testing their clinical impact in biomarker-driven clinical trials. Next-generation sequencing technologies are increasingly being implemented for molecular prescreening in clinical research, but issues regarding clinical interpretation of large genomic data make their wide clinical use difficult. Further, dealing with tumor heterogeneity and acquired resistance is probably the main limitation for the success of precision oncology. On the other hand, long-term survival benefits with immune checkpoint inhibitors (anti-programmed death cell protein-1/programmed death cell ligand-1[PD-1/L1] and anti-cytotoxic T lymphocyte antigen-4 monoclonal antibodies) are restricted to a minority of patients, and no predictive markers are yet robustly validated that could help us recognize these subsets and optimize treatment delivery and selection. To achieve long-term survival benefits, drug combinations targeting several molecular alterations or cancer hallmarks might be needed. This will probably be one of the most challenging but promising precision cancer treatment strategies in the future. Targeting single molecular abnormalities or cancer pathways has achieved good clinical responses that have modestly affected survival in some cancers. However, this approach to cancer treatment is still reductionist, and many challenges need to be met to improve treatment outcomes with our patients. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Xenon Protects Against Septic Acute Kidney Injury via miR-21 Target Signaling Pathway.

PubMed

Jia, Ping; Teng, Jie; Zou, Jianzhou; Fang, Yi; Wu, Xie; Liang, Mingyu; Ding, Xiaoqiang

2015-07-01

Septic acute kidney injury is one of the most common and life-threatening complications in critically ill patients, and there is no approved effective treatment. We have shown xenon provides renoprotection against ischemia-reperfusion injury and nephrotoxicity in rodents via inhibiting apoptosis. Here, we studied the effects of xenon preconditioning on septic acute kidney injury and its mechanism. Experimental animal investigation. University research laboratory. Experiments were performed with male C57BL/6 mice, 10 weeks of age, weighing 20-25 g. We induced septic acute kidney injury by a single intraperitoneal injection of Escherichia coli lipopolysaccharide at a dose of 20 mg/kg. Mice were exposed for 2 hours to either 70% xenon or 70% nitrogen, 24 hours before the onset of septic acute kidney injury. In vivo knockdown of miR-21 was performed using locked nucleic acid-modified anti-miR, the role of miR-21 in renal protection conferred by the xenon preconditioning was examined, and miR-21 signaling pathways were analyzed. Xenon preconditioning provided morphologic and functional renoprotection, characterized by attenuation of renal tubular damage, apoptosis, and a reduction in inflammation. Furthermore, xenon treatment significantly upregulated the expression of miR-21 in kidney, suppressed proinflammatory factor programmed cell death protein 4 expression and nuclear factor-κB activity, and increased interleukin-10 production. Meanwhile, xenon preconditioning also suppressed the expression of proapoptotic protein phosphatase and tensin homolog deleted on chromosome 10, activating protein kinase B signaling pathway, subsequently increasing the expression of antiapoptotic B-cell lymphoma-2, and inhibiting caspase-3 activity. Knockdown of miR-21 upregulated its target effectors programmed cell death protein 4 and phosphatase and tensin homolog deleted on chromosome 10 expression, resulted in an increase in apoptosis, and exacerbated lipopolysaccharide-induced acute kidney injury. Our findings demonstrated that xenon preconditioning protected against lipopolysaccharide-induced acute kidney injury via activation of miR-21 target signaling pathways.

Changes in Relatives' Perspectives on Quality of Death, Quality of Care, Pain Relief, and Caregiving Burden Before and After a Region-Based Palliative Care Intervention.

PubMed

Maeda, Isseki; Miyashita, Mitsunori; Yamagishi, Akemi; Kinoshita, Hiroya; Shirahige, Yutaka; Izumi, Noriko; Yamaguchi, Takuhiro; Igarashi, Miyuki; Kato, Masashi; Morita, Tatsuya

2016-11-01

A region-based palliative care intervention (Outreach Palliative Care Trial of Integrated Regional Model Study) increased home death, access to specialist palliative care, quality of care, and quality of death and dying. The objective of this study was to examine changes in palliative care outcomes in different care settings (hospitals, palliative care units, and home) and obtain insights into how to improve region-level palliative care. The intervention program was implemented from April 2008 to March 2011. Two bereavement surveys were conducted before and after intervention involving 4228 family caregivers of deceased cancer patients. Family-perceived quality of care (range 1-6), quality of death and dying (1-7), pain relief (1-7), and caregiver burden (1-7) were measured. Response rates were 69% (preintervention) and 66% (postintervention), respectively. Family-perceived quality of care (adjusted mean 4.89, 95% CI 4.54-5.23) and quality of death and dying (4.96, 4.72-5.20) at home were the highest and sustained throughout the study. Palliative care units were at the intermediate level between home and hospitals. In hospitals, both quality of care and quality of death and dying were low at baseline but significantly improved after intervention (quality of care: 4.24, 4.13-4.34 to 4.43, 4.31-4.54, P = 0.002; quality of death and dying: 4.22, 4.09-4.36 to 4.36, 4.22-4.50, P = 0.012). Caregiver burden did not significantly increase after intervention, regardless of place of death. The dual strategies of transition of place of death to home and improving quality of care in hospitals should be recognized as important targets for improving region-level palliative care. Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

78 FR 54920 - Agency Information Collection Activities; Proposed Collection; Revision of a Currently Approved...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-06

... Activities; Proposed Collection; Revision of a Currently Approved Collection; Comment Requested: Deaths in... facility level, which will better inform the Deaths in Custody Reporting Program (DCRP) and other BJS...) The title of the Form/Collection: Deaths in Custody Reporting Program. (3) The agency form number, if...

7 CFR 1463.113 - Issuance of payments in event of death.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 10 2014-01-01 2014-01-01 false Issuance of payments in event of death. 1463.113 Section 1463.113 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT... PROGRAM Tobacco Transition Payment Program § 1463.113 Issuance of payments in event of death. If a quota...

7 CFR 1463.113 - Issuance of payments in event of death.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 10 2012-01-01 2012-01-01 false Issuance of payments in event of death. 1463.113 Section 1463.113 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT... PROGRAM Tobacco Transition Payment Program § 1463.113 Issuance of payments in event of death. If a quota...

7 CFR 1463.113 - Issuance of payments in event of death.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 10 2013-01-01 2013-01-01 false Issuance of payments in event of death. 1463.113 Section 1463.113 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT... PROGRAM Tobacco Transition Payment Program § 1463.113 Issuance of payments in event of death. If a quota...

7 CFR 1463.113 - Issuance of payments in event of death.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 10 2011-01-01 2011-01-01 false Issuance of payments in event of death. 1463.113 Section 1463.113 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT... PROGRAM Tobacco Transition Payment Program § 1463.113 Issuance of payments in event of death. If a quota...

The need for a culturally-tailored gatekeeper training intervention program in preventing suicide among Indigenous peoples: a systematic review.

PubMed

Nasir, Bushra Farah; Hides, Leanne; Kisely, Steve; Ranmuthugala, Geetha; Nicholson, Geoffrey C; Black, Emma; Gill, Neeraj; Kondalsamy-Chennakesavan, Srinivas; Toombs, Maree

2016-10-21

Suicide is a leading cause of death among Indigenous youth worldwide. The aim of this literature review was to determine the cultural appropriateness and identify evidence for the effectiveness of current gatekeeper suicide prevention training programs within the international Indigenous community. Using a systematic strategy, relevant databases and targeted resources were searched using the following terms: 'suicide', 'gatekeeper', 'training', 'suicide prevention training', 'suicide intervention training' and 'Indigenous'. Other internationally relevant descriptors for the keyword "Indigenous" (e.g. "Maori", "First Nations", "Native American", "Inuit", "Metis" and "Aboriginal") were also used. Six articles, comprising five studies, met criteria for inclusion; two Australian, two from USA and one Canadian. While pre and post follow up studies reported positive outcomes, this was not confirmed in the single randomised controlled trial identified. However, the randomised controlled trial may have been underpowered and contained participants who were at higher risk of suicide pre-training. Uncontrolled evidence suggests that gatekeeper training may be a promising suicide intervention in Indigenous communities but needs to be culturally tailored to the target population. Further RCT evidence is required.

Implementing a Death with Dignity program at a comprehensive cancer center.

PubMed

Loggers, Elizabeth Trice; Starks, Helene; Shannon-Dudley, Moreen; Back, Anthony L; Appelbaum, Frederick R; Stewart, F Marc

2013-04-11

The majority of Death with Dignity participants in Washington State and Oregon have received a diagnosis of terminal cancer. As more states consider legislation regarding physician-assisted death, the experience of a comprehensive cancer center may be informative. We describe the implementation of a Death with Dignity program at Seattle Cancer Care Alliance, the site of care for the Fred Hutchinson-University of Washington Cancer Consortium, a comprehensive cancer center in Seattle that serves the Pacific Northwest. Institution-level data were compared with publicly available statewide data from Oregon and Washington. A total of 114 patients inquired about our Death with Dignity program between March 5, 2009, and December 31, 2011. Of these, 44 (38.6%) did not pursue the program, and 30 (26.3%) initiated the process but either elected not to continue or died before completion. Of the 40 participants who, after counseling and upon request, received a prescription for a lethal dose of secobarbital (35.1% of the 114 patients who inquired about the program), all died, 24 after medication ingestion (60% of those obtaining prescriptions). The participants at our center accounted for 15.7% of all participants in the Death with Dignity program in Washington (255 persons) and were typically white, male, and well educated. The most common reasons for participation were loss of autonomy (97.2%), inability to engage in enjoyable activities (88.9%), and loss of dignity (75.0%). Eleven participants lived for more than 6 months after prescription receipt. Qualitatively, patients and families were grateful to receive the lethal prescription, whether it was used or not. Overall, our Death with Dignity program has been well accepted by patients and clinicians.

UV-Induced cell death in plants.

PubMed

Nawkar, Ganesh M; Maibam, Punyakishore; Park, Jung Hoon; Sahi, Vaidurya Pratap; Lee, Sang Yeol; Kang, Chang Ho

2013-01-14

Plants are photosynthetic organisms that depend on sunlight for energy. Plants respond to light through different photoreceptors and show photomorphogenic development. Apart from Photosynthetically Active Radiation (PAR; 400-700 nm), plants are exposed to UV light, which is comprised of UV-C (below 280 nm), UV-B (280-320 nm) and UV-A (320-390 nm). The atmospheric ozone layer protects UV-C radiation from reaching earth while the UVR8 protein acts as a receptor for UV-B radiation. Low levels of UV-B exposure initiate signaling through UVR8 and induce secondary metabolite genes involved in protection against UV while higher dosages are very detrimental to plants. It has also been reported that genes involved in MAPK cascade help the plant in providing tolerance against UV radiation. The important targets of UV radiation in plant cells are DNA, lipids and proteins and also vital processes such as photosynthesis. Recent studies showed that, in response to UV radiation, mitochondria and chloroplasts produce a reactive oxygen species (ROS). Arabidopsis metacaspase-8 (AtMC8) is induced in response to oxidative stress caused by ROS, which acts downstream of the radical induced cell death (AtRCD1) gene making plants vulnerable to cell death. The studies on salicylic and jasmonic acid signaling mutants revealed that SA and JA regulate the ROS level and antagonize ROS mediated cell death. Recently, molecular studies have revealed genes involved in response to UV exposure, with respect to programmed cell death (PCD).

UV-Induced Cell Death in Plants

PubMed Central

Nawkar, Ganesh M.; Maibam, Punyakishore; Park, Jung Hoon; Sahi, Vaidurya Pratap; Lee, Sang Yeol; Kang, Chang Ho

2013-01-01

Plants are photosynthetic organisms that depend on sunlight for energy. Plants respond to light through different photoreceptors and show photomorphogenic development. Apart from Photosynthetically Active Radiation (PAR; 400–700 nm), plants are exposed to UV light, which is comprised of UV-C (below 280 nm), UV-B (280–320 nm) and UV-A (320–390 nm). The atmospheric ozone layer protects UV-C radiation from reaching earth while the UVR8 protein acts as a receptor for UV-B radiation. Low levels of UV-B exposure initiate signaling through UVR8 and induce secondary metabolite genes involved in protection against UV while higher dosages are very detrimental to plants. It has also been reported that genes involved in MAPK cascade help the plant in providing tolerance against UV radiation. The important targets of UV radiation in plant cells are DNA, lipids and proteins and also vital processes such as photosynthesis. Recent studies showed that, in response to UV radiation, mitochondria and chloroplasts produce a reactive oxygen species (ROS). Arabidopsis metacaspase-8 (AtMC8) is induced in response to oxidative stress caused by ROS, which acts downstream of the radical induced cell death (AtRCD1) gene making plants vulnerable to cell death. The studies on salicylic and jasmonic acid signaling mutants revealed that SA and JA regulate the ROS level and antagonize ROS mediated cell death. Recently, molecular studies have revealed genes involved in response to UV exposure, with respect to programmed cell death (PCD). PMID:23344059

Programmed cell death as a defence against infection

PubMed Central

Jorgensen, Ine; Rayamajhi, Manira; Miao, Edward A.

2017-01-01

Eukaryotic cells can die from physical trauma, resulting in necrosis. Alternately, they can die via programmed cell death upon stimulation of specific signalling pathways. Here we discuss the utility of four cell death pathways in innate immune defence against bacterial and viral infection: apoptosis, necroptosis, pyroptosis and NETosis. We describe the interactions that interweave different programmed cell death pathways, which create complex signalling networks that cross-guard each other in the evolutionary arms race with pathogens. Finally, we describe how the resulting cell corpses — apoptotic bodies, pore-induced intracellular traps (PITs) and neutrophil extracellular traps (NETs) — promote clearance of infection. PMID:28138137

Differential Expression of Programmed Cell Death on the Follicular Development in Normal and Miniature Pig Ovary

PubMed Central

Kim, Sang Hwan; Min, Kwan Sik; Kim, Nam Hyung; Yoon, Jong Taek

2012-01-01

Follicles are important in oocyte maturation. Successful estrous cycle requires remodeling of follicular cells, and proper execution of programmed cell death is crucial for normal follicular development. The objectives of the present study were to understand programmed cell death during follicle development, to analyze the differential follicle development patterns, and to assess the patterns of apoptosis and autophagy expression during follicle development in normal and miniature pigs. Through the analysis of differential patterns of programmed cell death during follicular development in porcine, MAP1LC3A, B and other autophagy-associated genes (ATG5, mTOR, Beclin-1) were found to increase in normal pigs, while it decreased in miniature pigs. However, for the apoptosis-associated genes, progression of genes during follicular development increased in miniature pigs, while it decreased in normal pigs. Thus, results show that normal and miniature pigs showed distinct patterns of follicular remodeling manifesting that programmed cell death largely depends on the types of pathway during follicular development (Type II or autophagy for normal pigs and Type I or apoptosis for miniature pigs). PMID:23056260

Novel Immunologic Approaches to Melanoma Treatment.

PubMed

Escandell, I; Martín, J M; Jordá, E

2017-10-01

Approaches to treating melanoma have changed radically since the introduction of immunotherapy, and survival figures are now higher than possible with earlier therapies. The immunomodulators currently available mainly block CTLA-4 (cytotoxicT lymphocyte-associated molecule-4) and PD-1 (programed cell death protein 1) translocated to the cell surface, where they inhibit the antitumor immune response. Treatments blocking these molecules are being more widely used. Research now seeks new molecular targets, the best combinations of available drugs, and biomarkers that can identify ideal candidates for each one. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Fundamental Use of Surgical Energy (FUSE): An Essential Educational Program for Operating Room Safety

PubMed Central

Jones, Stephanie B; Munro, Malcolm G; Feldman, Liane S; Robinson, Thomas N; Brunt, L Michael; Schwaitzberg, Steven D; Jones, Daniel B; Fuchshuber, Pascal R

2017-01-01

Operating room (OR) safety has become a major concern in patient safety since the 1990s. Improvement of team communication and behavior is a popular target for safety programming at the institutional level. Despite these efforts, essential safety gaps remain in the OR and procedure rooms. A prime example is the use of energy-based devices in ORs and procedural areas. The lack of fundamental understanding of energy device function, design, and application contributes to avoidable injury and harm at a rate of approximately 1 to 2 per 1000 patients in the US. Hundreds of OR fires occur each year in the US, some causing severe injury and even death. Most of these fires are associated with the use of energy-based surgical devices. In response to this safety issue, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) developed the Fundamental Use of Surgical Energy (FUSE) program. This program includes a standardized curriculum targeted to surgeons, other physicians, and allied health care professionals and a psychometrically designed and validated certification test. A successful FUSE certification documents acquisition of the basic knowledge needed to safely use energy-based devices in the OR. By design FUSE fills a void in the curriculum and competency assessment for surgeons and other procedural specialists in the use of energy-based devices in patients. PMID:28241913

Cell Death in C. elegans Development.

PubMed

Malin, Jennifer Zuckerman; Shaham, Shai

2015-01-01

Cell death is a common and important feature of animal development, and cell death defects underlie many human disease states. The nematode Caenorhabditis elegans has proven fertile ground for uncovering molecular and cellular processes controlling programmed cell death. A core pathway consisting of the conserved proteins EGL-1/BH3-only, CED-9/BCL2, CED-4/APAF1, and CED-3/caspase promotes most cell death in the nematode, and a conserved set of proteins ensures the engulfment and degradation of dying cells. Multiple regulatory pathways control cell death onset in C. elegans, and many reveal similarities with tumor formation pathways in mammals, supporting the idea that cell death plays key roles in malignant progression. Nonetheless, a number of observations suggest that our understanding of developmental cell death in C. elegans is incomplete. The interaction between dying and engulfing cells seems to be more complex than originally appreciated, and it appears that key aspects of cell death initiation are not fully understood. It has also become apparent that the conserved apoptotic pathway is dispensable for the demise of the C. elegans linker cell, leading to the discovery of a previously unexplored gene program promoting cell death. Here, we review studies that formed the foundation of cell death research in C. elegans and describe new observations that expand, and in some cases remodel, this edifice. We raise the possibility that, in some cells, more than one death program may be needed to ensure cell death fidelity. © 2015 Elsevier Inc. All rights reserved.

DPL-1 DP, LIN-35 Rb and EFL-1 E2F act with the MCD-1 zinc-finger protein to promote programmed cell death in Caenorhabditis elegans.

PubMed

Reddien, Peter W; Andersen, Erik C; Huang, Michael C; Horvitz, H Robert

2007-04-01

The genes egl-1, ced-9, ced-4, and ced-3 play major roles in programmed cell death in Caenorhabditis elegans. To identify genes that have more subtle activities, we sought mutations that confer strong cell-death defects in a genetically sensitized mutant background. Specifically, we screened for mutations that enhance the cell-death defects caused by a partial loss-of-function allele of the ced-3 caspase gene. We identified mutations in two genes not previously known to affect cell death, dpl-1 and mcd-1 (modifier of cell death). dpl-1 encodes the C. elegans homolog of DP, the human E2F-heterodimerization partner. By testing genes known to interact with dpl-1, we identified roles in cell death for four additional genes: efl-1 E2F, lin-35 Rb, lin-37 Mip40, and lin-52 dLin52. mcd-1 encodes a novel protein that contains one zinc finger and that is synthetically required with lin-35 Rb for animal viability. dpl-1 and mcd-1 act with efl-1 E2F and lin-35 Rb to promote programmed cell death and do so by regulating the killing process rather than by affecting the decision between survival and death. We propose that the DPL-1 DP, MCD-1 zinc finger, EFL-1 E2F, LIN-35 Rb, LIN-37 Mip40, and LIN-52 dLin52 proteins act together in transcriptional regulation to promote programmed cell death.

Forkhead Transcription Factors: Formulating a FOXO Target for Cognitive Loss.

PubMed

Maiese, Kenneth

2017-01-01

With almost 47 million individuals worldwide suffering from some aspect of dementia, it is clear that cognitive loss impacts a significant proportion of the global population. Unfortunately, definitive treatments to resolve or prevent the onset of cognitive loss are limited. In most cases such care is currently non-existent prompting the need for novel treatment strategies. Mammalian forkhead transcription factors of the O class (FoxO) are one such avenue of investigation that offer an exciting potential to bring new treatments forward for disorders that involve cognitive loss. Here we examine the background, structure, expression, and function of FoxO transcription factors and their role in cognitive loss, programmed cell death in the nervous system with apoptosis and autophagy, and areas to target FoxOs for dementia and specific disorders such as Alzheimer's disease. FoxO proteins work in concert with a number of other cell survival pathways that involve growth factors, such as erythropoietin and neurotrophins, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), Wnt1 inducible signaling pathway protein 1 (WISP1), Wnt signaling, and cancer-related pathways. FoxO transcription factors oversee proinflammatory pathways, affect nervous system amyloid (Aβ) production and toxicity, lead to mitochondrial dysfunction, foster neuronal apoptotic cell death, and accelerate the progression of degenerative disease. However, under some scenarios such as those involving autophagy, FoxOs also can offer protection in the nervous system and reduce toxic intracellular protein accumulations and potentially limit Aβ toxicity. Given the ability of FoxOs to not only promote apoptotic cell death in the nervous system, but also through the induction of autophagy offer protection against degenerative disease that can lead to dementia, a fine balance in the activity of FoxOs may be required to target cognitive loss in individuals. Future work should yield exciting new prospects for FoxO proteins as new targets to treat the onset and progression of cognitive loss and dementia. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Signaling pathways that regulate life and cell death: evolution of apoptosis in the context of self-defense.

PubMed

Muñoz-Pinedo, Cristina

2012-01-01

Programmed Cell Death is essential for the life cycle of many organisms. Cell death in multicellular organisms can occur as a consequence of massive damage (necrosis) or in a controlled form, through engagement of diverse biochemical programs. The best well known form of programmed cell death is apoptosis. Apoptosis occurs in animals as a consequence of a variety of stimuli including stress and social signals and it plays essential roles in morphogenesis and immune defense. The machinery of apoptosis is well conserved among animals and it is composed of caspases (the proteases which execute cell death), adapter proteins (caspase activators), Bcl-2 family proteins and Inhibitor of Apoptosis Proteins (IAPs). We will describe in this chapter the main apoptotic pathways in animals: the extrinsic (death receptor-mediated), the intrinsic/mitochondrial and the Granzyme B pathway. Other forms of non-apoptotic Programmed Cell Death which occur in animals will also be discussed. We will summarize the current knowledge about apoptotic-like and other forms of cell death in other organisms such as plants and protists.Additionally, we will discuss the hypothesis that apoptosis originated as part of a host defense mechanism. We will explore the similarities between the protein complexes which mediate apoptosis (apoptosomes) and complexes involved in immunity: inflammasomes. Additional functions of apoptotic proteins related to immune function will be summarized, in an effort to explore the evolutionary origins of cell death.

Heat-shock protein 27 (HSP27, HSPB1) is synthetic lethal to cells with oncogenic activation of MET, EGFR and BRAF.

PubMed

Konda, John D; Olivero, Martina; Musiani, Daniele; Lamba, Simona; Di Renzo, Maria F

2017-06-01

The small heat-shock protein of 27 kDa (HSP27) is highly expressed in many cancers and is associated with aggressive tumour behaviour, metastasis, poor prognosis and resistance to chemotherapy. We aimed at assessing the role of HSP27 in modulating responses to target therapies. We selected several oncogene-addicted cancer cell lines, which undergo either cell cycle blockade or cell death in response to agents that target the specific oncogene. Surprisingly, HSP27 suppression alone resulted in the apoptotic death of MET-addicted EBC-1 lung cancer cells, epidermal growth factor receptor (EGFR)-addicted colorectal carcinoma (CRC) DiFi cells and BRAF-addicted CRC COLO205 and OXCO-1 and melanoma COLO741 cells, all of which also undergo death when treated with the specific targeted agent. In other cell lines, such as MET-addicted gastric carcinoma MKN45 and EGFR-addicted CRC SW48 lines, where oncogene inhibition only blocked proliferation, HSP27 knockdown made targeted agents switch from cytostatic to cytotoxic activity. Mechanistically, the more the cells were susceptible to HSP27 suppression, the more they were primed for death, as demonstrated by increased levels of mitochondrial outer membrane permeabilization. Priming for death was accompanied by the increase in pro-apoptotic proteins of the BCL2 family and of active caspase-3 and lamin B. Together, these data suggest that oncogene-addicted cells require HSP27 for survival and that HSP27 might interfere with the effectiveness of targeted agents. © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Subfamily-Specific Fluorescent Probes for Cysteine Proteases Display Dynamic Protease Activities during Seed Germination.

PubMed

Lu, Haibin; Chandrasekar, Balakumaran; Oeljeklaus, Julian; Misas-Villamil, Johana C; Wang, Zheming; Shindo, Takayuki; Bogyo, Matthew; Kaiser, Markus; van der Hoorn, Renier A L

2015-08-01

Cysteine proteases are an important class of enzymes implicated in both developmental and defense-related programmed cell death and other biological processes in plants. Because there are dozens of cysteine proteases that are posttranslationally regulated by processing, environmental conditions, and inhibitors, new methodologies are required to study these pivotal enzymes individually. Here, we introduce fluorescence activity-based probes that specifically target three distinct cysteine protease subfamilies: aleurain-like proteases, cathepsin B-like proteases, and vacuolar processing enzymes. We applied protease activity profiling with these new probes on Arabidopsis (Arabidopsis thaliana) protease knockout lines and agroinfiltrated leaves to identify the probe targets and on other plant species to demonstrate their broad applicability. These probes revealed that most commercially available protease inhibitors target unexpected proteases in plants. When applied on germinating seeds, these probes reveal dynamic activities of aleurain-like proteases, cathepsin B-like proteases, and vacuolar processing enzymes, coinciding with the remobilization of seed storage proteins. © 2015 American Society of Plant Biologists. All Rights Reserved.

Current and future management of Ph/BCR-ABL positive ALL.

PubMed

Maino, Elena; Sancetta, Rosaria; Viero, Piera; Imbergamo, Silvia; Scattolin, Anna Maria; Vespignani, Michele; Bassan, Renato

2014-06-01

Following the introduction of targeted therapy with tyrosine kinase inhibitors (TKI) at the beginning of the past decade, the outcome of patients with Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) has dramatically improved. Presently, the use of refined programs with first/second generation TKI's and chemotherapy together with allogeneic stem cell transplantation allow up to 50% of all patients to be cured. Further progress is expected with the new TKI ponatinib, overcoming resistance caused by T315I point mutation, other targeted therapies, autologous transplantation in molecularly negative patients, therapeutic monoclonal antibodies like inotuzumab ozogamicin and blinatumomab, and chimeric antigen receptor-modified T cells. Ph+ ALL could become curable in the near future even without allogeneic stem cell transplantation, minimizing the risk of therapy-related death and improving greatly the quality of patients' life.

Cell Death Pathways in Mutant Rhodopsin Rat Models Identifies Genotype-Specific Targets Controlling Retinal Degeneration.

PubMed

Viringipurampeer, Ishaq A; Gregory-Evans, Cheryl Y; Metcalfe, Andrew L; Bashar, Emran; Moritz, Orson L; Gregory-Evans, Kevin

2018-06-18

Retinitis pigmentosa (RP) is a group of inherited neurological disorders characterized by rod photoreceptor cell death, followed by secondary cone cell death leading to progressive blindness. Currently, there are no viable treatment options for RP. Due to incomplete knowledge of the molecular signaling pathways associated with RP pathogenesis, designing therapeutic strategies remains a challenge. In particular, preventing secondary cone photoreceptor cell loss is a key goal in designing potential therapies. In this study, we identified the main drivers of rod cell death and secondary cone loss in the transgenic S334ter rhodopsin rat model, tested the efficacy of specific cell death inhibitors on retinal function, and compared the effect of combining drugs to target multiple pathways in the S334ter and P23H rhodopsin rat models. The primary driver of early rod cell death in the S334ter model was a caspase-dependent process, whereas cone cell death occurred though RIP3-dependent necroptosis. In comparison, rod cell death in the P23H model was via necroptotic signaling, whereas cone cell loss occurred through inflammasome activation. Combination therapy of four drugs worked better than the individual drugs in the P23H model but not in the S334ter model. These differences imply that treatment modalities need to be tailored for each genotype. Taken together, our data demonstrate that rationally designed genotype-specific drug combinations will be an important requisite to effectively target primary rod cell loss and more importantly secondary cone survival.

The Death Penalty in the United States. Public Talk Series.

ERIC Educational Resources Information Center

Pasquerella, Lynn

This program guide provides the information a study circle will need to discuss the death penalty. It offers a balanced, nonpartisan presentation of a spectrum of views. The four positions and the supporting material are designed for use in a single-session program of approximately 2 hours. The four positions are as follows: (1) the death penalty…

The anticancer immune response of anti-PD-1/PD-L1 and the genetic determinants of response to anti-PD-1/PD-L1 antibodies in cancer patients

PubMed Central

Han, Weidong; Wang, Xian; Fang, Yong; Li, Da; Pan, Hongming; Zhang, Li

2015-01-01

The programmed death-1 (PD-1), a coinhibitory receptor expressed on activated T cells and B cells, is demonstrated to induce an immune-mediated response and play a critical role in tumor initiation and development. The cancer patients harboring PD-1 or PD ligand 1 (PD-L1) protein expression have often a poor prognosis and clinical outcome. Currently, targeting PD-1 pathway as a potential new anticancer strategy is attracting more and more attention in cancer treatment. Several monoclonal antibodies against PD-1 or PD-L1 have been reported to enhance anticancer immune responses and induce tumor cell death. Nonetheless, the precise molecular mechanisms by which PD-1 affects various cancers remain elusive. Moreover, this therapy is not effective for all the cancer patients and only a fraction of patients respond to the antibodies targeting PD-1 or PD-L1, indicating these antibodies may only works in a subset of certain cancers. Thus, understanding the novel function of PD-1 and genetic determinants of response to anti-PD-1 therapy will allow us to develop a more effective and individualized immunotherapeutic strategy for cancer. PMID:26305724

An orally effective dihydropyrimidone (DHPM) analogue induces apoptosis-like cell death in clinical isolates of Leishmania donovani overexpressing pteridine reductase 1.

PubMed

Singh, Neeloo; Kaur, Jaspreet; Kumar, Pranav; Gupta, Swati; Singh, Nasib; Ghosal, Angana; Dutta, Avijit; Kumar, Ashutosh; Tripathi, Ramapati; Siddiqi, Mohammad Imran; Mandal, Chitra; Dube, Anuradha

2009-10-01

The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis. The enzyme pteridine reductase 1 (PTR1) of L. donovani acts as a metabolic bypass for drugs targeting dihydrofolate reductase (DHFR); therefore, for successful antifolate chemotherapy to be developed against Leishmania, it must target both enzyme activities. Leishmania cells overexpressing PTR1 tagged at the N-terminal with green fluorescent protein were established to screen for proprietary dihydropyrimidone (DHPM) derivatives of DHFR specificity synthesised in our laboratory. A cell-permeable molecule with impressive antileishmanial in vitro and in vivo oral activity was identified. Structure activity relationship based on homology model drawn on our recombinant enzyme established the highly selective inhibition of the enzyme by this analogue. It was seen that the leishmanicidal effect of this analogue is triggered by programmed cell death mediated by the loss of plasma membrane integrity as detected by binding of annexin V and propidium iodide (PI), loss of mitochondrial membrane potential culminating in cell cycle arrest at the sub-G0/G1 phase and oligonucleosomal DNA fragmentation. Hence, this DHPM analogue [(4-fluoro-phenyl)-6-methyl-2-thioxo-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylic acid ethyl ester] is a potent antileishmanial agent that merits further pharmacological investigation.

Necroptosis: a potential, promising target and switch in acute pancreatitis.

PubMed

Wang, Gang; Qu, Feng-Zhi; Li, Le; Lv, Jia-Chen; Sun, Bei

2016-02-01

Pancreatic acinar cell death is the major pathophysiological change in early acute pancreatitis (AP), and the death modalities are important factors determining its progression and prognosis. During AP, acinar cells undergo two major modes of death, including necrosis and apoptosis. Acinar necrosis can lead to intensely local and systemic inflammatory responses, which both induce and aggravate the lesion. Necrosis has long been considered an unregulated, and passive cell death process. Since the effective interventions of necrosis are difficult to perform, its relevant studies have not received adequate attention. Necroptosis is a newly discovered cell death modality characterized by both necrosis and apoptosis, i.e., it is actively regulated by special genes, while has the typical morphological features of necrosis. Currently, necroptosis is gradually becoming an important topic in the fields of inflammatory diseases. The preliminary results from necroptosis in AP have confirmed the existence of acinar cell necroptosis, which may be a potential target for effectively regulating inflammatory injuries and improving its outcomes; however, the functional changes and mechanisms of necroptosis still require further investigation. This article reviewed the progress of necroptosis in AP to provide a reference for deeply understanding the pathogenic mechanisms of AP and identifying new therapeutic targets.

SCRG1, a potential marker of autophagy in transmissible spongiform encephalopathies.

PubMed

Dron, Michel; Bailly, Yannick; Beringue, Vincent; Haeberlé, Anne-Marie; Griffond, Bernadette; Risold, Pierre-Yves; Tovey, Michael G; Laude, Hubert; Dandoy-Dron, Françoise

2006-01-01

The Scrg1 gene was initially discovered as one of the genes upregulated in transmissible spongiform encephalopathies (TSE). Scrg1 encodes a highly conserved, cysteine-rich protein expressed principally in the central nervous system. The protein is targeted to the Golgi apparatus and large dense-core vesicles/secretory granules in neurons. We have recently shown that the Scrg1 protein is widely induced in neurons of scrapie-infected mice, suggesting that Scrg1 is involved in the host response to stress and/or the death of neurons. At the ultrastructural level, Scrg1 is associated with dictyosomes of the Golgi apparatus and autophagic vacuoles of degenerative neurons. It is well known that apoptosis plays a major role in the events leading to neuronal cell death in TSE. However, autophagy was identified in experimentally induced scrapie a long time ago and was recently reevaluated as a possible cell death program in prion diseases. The consistent association of Scrg1 with autophagic structures typical of scrapie is in agreement with the recruitment of Golgi-specific proteins in this degradation process and we suggest that Scrg1 might be used as a specific probe to identify neuronal autophagy in TSE.

A novel mitochondrial matrix serine/threonine protein phosphatase regulates the mitochondria permeability transition pore and is essential for cellular survival and development

PubMed Central

Lu, Gang; Ren, Shuxun; Korge, Paavo; Choi, Jayoung; Dong, Yuan; Weiss, James; Koehler, Carla; Chen, Jau-nian; Wang, Yibin

2007-01-01

Mitochondria play a central role in the regulation of programmed cell death signaling. Here, we report the finding of a mitochondrial matrix-targeted protein phosphatase 2C family member (PP2Cm) that regulates mitochondrial membrane permeability transition pore (MPTP) opening and is essential for cell survival, embryonic development, and cardiac function. PP2Cm is highly conserved among vertebrates, with the highest expression levels detected in the heart and brain. Small hairpin RNA (shRNA)-mediated knockdown of PP2Cm resulted in cell death associated with loss of mitochondrial membrane potential in cultured cardiac mycoytes and an induction of hepatocyte apoptosis in vivo. PP2Cm-deficient mitochondria showed elevated susceptibility to calcium-induced MPTP opening, whereas mitochondrial oxidative phosphorylation activities were not affected. Finally, inactivation of PP2Cm in developing zebrafish embryos caused abnormal cardiac and neural development as well as heart failure associated with induced apoptosis. These data suggest that PP2Cm is a novel mitochondrial protein phosphatase that has a critical function in cell death and survival, and may play a role in regulating the MPTP opening. PMID:17374715

Substrate Specificity and Possible Heterologous Targets of Phytaspase, a Plant Cell Death Protease*

PubMed Central

Galiullina, Raisa A.; Kasperkiewicz, Paulina; Chichkova, Nina V.; Szalek, Aleksandra; Serebryakova, Marina V.; Poreba, Marcin; Drag, Marcin; Vartapetian, Andrey B.

2015-01-01

Plants lack aspartate-specific cell death proteases homologous to animal caspases. Instead, a subtilisin-like serine-dependent plant protease named phytaspase shown to be involved in the accomplishment of programmed death of plant cells is able to hydrolyze a number of peptide-based caspase substrates. Here, we determined the substrate specificity of rice (Oryza sativa) phytaspase by using the positional scanning substrate combinatorial library approach. Phytaspase was shown to display an absolute specificity of hydrolysis after an aspartic acid residue. The preceding amino acid residues, however, significantly influence the efficiency of hydrolysis. Efficient phytaspase substrates demonstrated a remarkable preference for an aromatic amino acid residue in the P3 position. The deduced optimum phytaspase recognition motif has the sequence IWLD and is strikingly hydrophobic. The established pattern was confirmed through synthesis and kinetic analysis of cleavage of a set of optimized peptide substrates. An amino acid motif similar to the phytaspase cleavage site is shared by the human gastrointestinal peptide hormones gastrin and cholecystokinin. In agreement with the established enzyme specificity, phytaspase was shown to hydrolyze gastrin-1 and cholecystokinin at the predicted sites in vitro, thus destroying the active moieties of the hormones. PMID:26283788

Bridging the Technology Readiness "Valley of Death" Utilizing Nanosats

NASA Technical Reports Server (NTRS)

Bauer, Robert A.; Millar, Pamela S.; Norton, Charles D.

2015-01-01

Incorporating new technology is a hallmark of space missions. Missions demand ever-improving tools and techniques to allow them to meet the mission science requirements. In Earth Science, these technologies are normally expressed in new instrument capabilities that can enable new measurement concepts, extended capabilities of existing measurement techniques, or totally new detection capabilities, and also, information systems technologies that can enhance data analysis or enable new data analyses to advance modeling and prediction capabilities. Incorporating new technologies has never been easy. There is a large development step beyond demonstration in a laboratory or on an airborne platform to the eventual space environment that is sometimes referred to as the "technology valley of death." Studies have shown that non-validated technology is a primary cause of NASA and DoD mission delays and cost overruns. With the demise of the New Millennium Program within NASA, opportunities for demonstrating technologies in space have been rare. Many technologies are suitable for a flight project after only ground testing. However, some require validation in a relevant or a space flight environment, which cannot be fully tested on the ground or in airborne systems. NASA's Earth Science Technology Program has initiated a nimble program to provide a fairly rapid turn-around of space validated technologies, and thereby reducing future mission risk in incorporating new technologies. The program, called In-Space Validation of Earth Science Technology (InVEST), now has five tasks in development. Each are 3U CubeSats and they are targeted for launch opportunities in the 2016 time period. Prior to formalizing an InVEST program, the technology program office was asked to demonstrate how the program would work and what sort of technologies could benefit from space validation. Three projects were developed and launched, and have demonstrated the technologies that they set out to validate. This paper will provide a brief status of the pre-InVEST CubeSats, and discuss the development and status of the InVEST program. Figure

Influenza-related mortality trends in Japanese and American seniors: evidence for the indirect mortality benefits of vaccinating schoolchildren.

PubMed

Charu, Vivek; Viboud, Cécile; Simonsen, Lone; Sturm-Ramirez, Katharine; Shinjoh, Masayoshi; Chowell, Gerardo; Miller, Mark; Sugaya, Norio

2011-01-01

The historical Japanese influenza vaccination program targeted at schoolchildren provides a unique opportunity to evaluate the indirect benefits of vaccinating high-transmitter groups to mitigate disease burden among seniors. Here we characterize the indirect mortality benefits of vaccinating schoolchildren based on data from Japan and the US. We compared age-specific influenza-related excess mortality rates in Japanese seniors aged ≥65 years during the schoolchildren vaccination program (1978-1994) and after the program was discontinued (1995-2006). Indirect vaccine benefits were adjusted for demographic changes, socioeconomics and dominant influenza subtype; US mortality data were used as a control. We estimate that the schoolchildren vaccination program conferred a 36% adjusted mortality reduction among Japanese seniors (95%CI: 17-51%), corresponding to ∼1,000 senior deaths averted by vaccination annually (95%CI: 400-1,800). In contrast, influenza-related mortality did not change among US seniors, despite increasing vaccine coverage in this population. The Japanese schoolchildren vaccination program was associated with substantial indirect mortality benefits in seniors.

Regulatory role of calpain in neuronal death

PubMed Central

Cheng, Si-ying; Wang, Shu-chao; Lei, Ming; Wang, Zhen; Xiong, Kun

2018-01-01

Calpains are a group of calcium-dependent proteases that are over activated by increased intracellular calcium levels under pathological conditions. A wide range of substrates that regulate necrotic, apoptotic and autophagic pathways are affected by calpain. Calpain plays a very important role in neuronal death and various neurological disorders. This review introduces recent research progress related to the regulatory mechanisms of calpain in neuronal death. Various neuronal programmed death pathways including apoptosis, autophagy and regulated necrosis can be divided into receptor interacting protein-dependent necroptosis, mitochondrial permeability transition-dependent necrosis, pyroptosis and poly (ADP-ribose) polymerase 1-mediated parthanatos. Calpains cleave series of key substrates that may lead to cell death or participate in cell death. Regarding the investigation of calpain-mediated programed cell death, it is necessary to identify specific inhibitors that inhibit calpain mediated neuronal death and nervous system diseases. PMID:29623944

Practical Considerations in Donation After Circulatory Determination of Death in Switzerland.

PubMed

Dalle Ave, Anne L; Shaw, David M; Elger, Bernice

2017-09-01

Faced with similar issues of organ scarcity to its neighbors, Switzerland has developed donation after circulatory determination of death (DCDD) as a way to expand the organ pool since 1985. Here, we analyze the history, practical considerations, and ethical issues relating to the Swiss donation after circulatory death programs. In Switzerland, determination of death for DCDD requires a stand-off period of 10 minutes. This time between cardiac arrest and the declaration of death is mandated in the guidelines of the Swiss Academy of Medical Sciences. As in other DCDD programs, safeguards are put to avoid physicians denying lifesaving treatment to savable patients because of being influenced by receivers' interest. An additional recommendation could be made: Recipients should be transparently informed of the worse graft outcomes with DCDD programs and given the possibility to refuse such organs.

Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib.

PubMed

Burger, Jan A; Li, Kelvin W; Keating, Michael J; Sivina, Mariela; Amer, Ahmed M; Garg, Naveen; Ferrajoli, Alessandra; Huang, Xuelin; Kantarjian, Hagop; Wierda, William G; O'Brien, Susan; Hellerstein, Marc K; Turner, Scott M; Emson, Claire L; Chen, Shih-Shih; Yan, Xiao-Jie; Wodarz, Dominik; Chiorazzi, Nicholas

2017-01-26

BACKGROUND. Ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL) that inhibits Bruton's tyrosine kinase (BTK), a kinase involved in B cell receptor signaling. METHODS. We used stable isotopic labeling with deuterated water ( 2 H 2 O) to measure directly the effects of ibrutinib on leukemia cell proliferation and death in 30 patients with CLL. RESULTS. The measured average CLL cell proliferation ("birth") rate before ibrutinib therapy was 0.39% of the clone per day (range 0.17%-1.04%); this decreased to 0.05% per day (range 0%-0.36%) with treatment. Death rates of blood CLL cells increased from 0.18% per day (average, range 0%-0.7%) prior to treatment to 1.5% per day (range 0%-3.0%) during ibrutinib therapy, and they were even higher in tissue compartments. CONCLUSIONS. This study provides the first direct in vivo measurements to our knowledge of ibrutinib's antileukemia actions, demonstrating profound and immediate inhibition of CLL cell proliferation and promotion of high rates of CLL cell death. TRIAL REGISTRATION. This trial was registered at clinicaltrials.gov (NCT01752426). FUNDING. This study was supported by a Cancer Center Support Grant (National Cancer Institute grant P30 CA016672), an NIH grant (CA081554) from the National Cancer Institute, MD Anderson's Moon Shots Program in CLL, and Pharmacyclics, an AbbVie company.

OsNAC2 positively affects salt-induced cell death and binds to the OsAP37 and OsCOX11 promoters.

PubMed

Mao, Chanjuan; Ding, Jialin; Zhang, Bin; Xi, Dandan; Ming, Feng

2018-05-01

Plant development and adaptation to environmental stresses are intimately associated with programmed cell death (PCD). Although some of the mechanisms regulating PCD [e.g., accumulation of reactive oxygen species (ROS)] are common among responses to different abiotic stresses, the pathways mediating salt-induced PCD remain largely uncharacterized. Here we report that overexpression of OsNAC2, which encodes a plant-specific transcription factor, promotes salt-induced cell death accompanied by the loss of plasma membrane integrity, nuclear DNA fragmentation, and changes to caspase-like activity. In OsNAC2-knockdown lines, cell death was markedly decreased in response to severe salt stress. Additionally, OsNAC2 expression was enhanced in rice seedlings exposed to a high NaCl concentration. Moreover, the results of quantitative real-time PCR, chromatin immunoprecipitation, dual-luciferase, and yeast one-hybrid assays indicated that OsNAC2 targeted genes that encoded an ROS scavenger (OsCOX11) and a caspase-like protease (OsAP37). Furthermore, K + -efflux channels (OsGORK and OsSKOR) were clearly activated by OsNAC2. Overall, our results suggested that OsNAC2 accelerates NaCl-induced PCD and provide new insights into the mechanisms that affect ROS accumulation, plant caspase-like activity, and K + efflux. © 2018 The Authors The Plant Journal © 2018 John Wiley & Sons Ltd.

An Integrative Suicide Prevention Program for Visitor Charcoal Burning Suicide and Suicide Pact

ERIC Educational Resources Information Center

Wong, Paul W. C.; Liu, Patricia M. Y.; Chan, Wincy S. C.; Law, Y. W.; Law, Steven C. K.; Fu, King-Wa; Li, Hana S. H.; Tso, M. K.; Beautrais, Annette L.; Yip, Paul S. F.

2009-01-01

An integrative suicide prevention program was implemented to tackle an outbreak of visitor charcoal burning suicides in Cheung Chau, an island in Hong Kong, in 2002. This study evaluated the effectiveness of the program. The numbers of visitor suicides reduced from 37 deaths in the 51 months prior to program implementation to 6 deaths in the 42…

[Deaths and life expectancy losses attributable to diet high in sodium in China].

PubMed

Liu, S W; Cai, Y; Zeng, X Y; Yin, P; Qi, J L; Liu, Y N; Liu, J M; Zhao, Z P; Zhang, M; Wang, L M; Wang, L J; Xue, M; Zhou, M G

2017-08-10

Objective: To quantitatively estimate the deaths and life expectancy losses attributable to diet high in sodium in China, and examine the gains and shifts under different control scenarios of sodium consumption. Methods: Based on data from the cause-of-death through the National Mortality Surveillance System, and 24 hours urinary sodium values from Global Burden of Disease study on Chinese's estimates, population attributable fractions with the framework of comparative risk assessment were used to analyze the deaths and life expectancy losses due to diet high in sodium. The same methods were followed to examine the gains and shifts under different control scenarios of sodium consumption. Results: In 2013, 1 430 (940 for men and 490 for women) thousand deaths were attributable to diet high in sodium, accounting for 15.6% (17.4% for men and 13.0% for women) of all-cause deaths in China, which causing 2.17 (2.49 for men and 1.71 for women) years of life expectancy loss. Diet with high sodium in 2013 caused 1 200, 50 and 180 thousand deaths from cardiovascular disease, chronic kidney disease and stomach cancer respectively, accounting for 31.5%, 30.8% and 64.8% of those specific causes. Comparing to the baseline in 2013, if the targets of 10% decrease of sodium consumption by 2020 and 15% by 2030 for Chinese chronic disease prevention and treatment planning, and 30% decrease by 2030 for WHO non-communicable disease monitoring framework are achieved, 220, 340 and 730 thousand deaths will be averted, which may gain 0.30, 0.45 and 0.95 years of life expectancy, respectively. Conclusions: As one of the leading risk factors, diet high in sodium had caused heavy burden of disease from cardiovascular disease, chronic kidney disease and stomach cancer on Chinese residents. Intervention programs on sodium-reduction are urgently needed in China and related cost-effectiveness is highly expected.

A Novel Recombinant Anti-CD22 Immunokinase Delivers Proapoptotic Activity of Death-Associated Protein Kinase (DAPK) and Mediates Cytotoxicity in Neoplastic B Cells.

PubMed

Lilienthal, Nils; Lohmann, Gregor; Crispatzu, Giuliano; Vasyutina, Elena; Zittrich, Stefan; Mayer, Petra; Herling, Carmen Diana; Tur, Mehmet Kemal; Hallek, Michael; Pfitzer, Gabriele; Barth, Stefan; Herling, Marco

2016-05-01

The serine/threonine death-associated protein kinases (DAPK) provide pro-death signals in response to (oncogenic) cellular stresses. Lost DAPK expression due to (epi)genetic silencing is found in a broad spectrum of cancers. Within B-cell lymphomas, deficiency of the prototypic family member DAPK1 represents a predisposing or early tumorigenic lesion and high-frequency promoter methylation marks more aggressive diseases. On the basis of protein studies and meta-analyzed gene expression profiling data, we show here that within the low-level context of B-lymphocytic DAPK, particularly CLL cells have lost DAPK1 expression. To target this potential vulnerability, we conceptualized B-cell-specific cytotoxic reconstitution of the DAPK1 tumor suppressor in the format of an immunokinase. After rounds of selections for its most potent cytolytic moiety and optimal ligand part, a DK1KD-SGIII fusion protein containing a constitutive DAPK1 mutant, DK1KD, linked to the scFv SGIII against the B-cell-exclusive endocytic glyco-receptor CD22 was created. Its high purity and large-scale recombinant production provided a stable, selectively binding, and efficiently internalizing construct with preserved robust catalytic activity. DK1KD-SGIII specifically and efficiently killed CD22-positive cells of lymphoma lines and primary CLL samples, sparing healthy donor- or CLL patient-derived non-B cells. The mode of cell death was predominantly PARP-mediated and caspase-dependent conventional apoptosis as well as triggering of an autophagic program. The notoriously high apoptotic threshold of CLL could be overcome by DK1KD-SGIII in vitro also in cases with poor prognostic features, such as therapy resistance. The manufacturing feasibility of the novel CD22-targeting DAPK immunokinase and its selective antileukemic efficiency encourage intensified studies towards specific clinical application. Mol Cancer Ther; 15(5); 971-84. ©2016 AACR. ©2016 American Association for Cancer Research.

Predictors of Place of Death of Individuals in a Home-Based Primary and Palliative Care Program.

PubMed

Prioleau, Phoebe G; Soones, Tacara N; Ornstein, Katherine; Zhang, Meng; Smith, Cardinale B; Wajnberg, Ania

2016-11-01

To investigate factors associated with place of death of individuals in the Mount Sinai Visiting Doctors Program (MSVD). A retrospective chart review was performed of all MSVD participants who died in 2012 to assess predictors of place of death in the last month of life. MSVD, a home-based primary and palliative care program in New York. MSVD participants who were discharged from the program because of death between January 2012 and December 2012 and died at home, in inpatient hospice, or in the hospital (N = 183). Electronic medical records were reviewed to collect information on demographic characteristics, physician visits, and end-of-life conversations. Of 183 participants, 103 (56%) died at home, approximately twice the national average; 28 (15%) died in inpatient hospice; and 52 (28%) died in the hospital. Bivariate analyses showed that participants who were white, aged 90 and older, non-Medicaid, or had a recorded preference for place of death were more likely to die outside the hospital. Diagnoses and living situation were not significantly associated with place of death. Multivariate logistic regression analysis showed no statistical association between place of death and home visits in the last month of life (odds ratio = 1.21, 95% confidence interval = 0.52-2.77). Home-based primary and palliative care results in a high likelihood of nonhospital death, although certain demographic characteristics are strong predictors of death in the hospital. For MSVD participants, home visits in the last month of life were not associated with death outside the hospital. © 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.

Survey of New York City Resident Physicians on Cause-of-Death Reporting, 2010

PubMed Central

Wexelman, Barbara A.; Eden, Edward

2013-01-01

Introduction Death certificates contain critical information for epidemiology, public health research, disease surveillance, and community health programs. In most teaching hospitals, resident physicians complete death certificates. The objective of this study was to examine the experiences and opinions of physician residents in New York City on the accuracy of the cause-of-death reporting system. Methods In May and June 2010, we conducted an anonymous, Internet-based, 32-question survey of all internal medicine, emergency medicine, and general surgery residency programs (n = 70) in New York City. We analyzed data by type of residency and by resident experience in reporting deaths. We defined high-volume respondents as those who completed 11 or more death certificates in the last 3 years. Results A total of 521 residents from 38 residency programs participated (program response rate, 54%). We identified 178 (34%) high-volume respondents. Only 33.3% of all respondents and 22.7% of high-volume residents believed that cause-of-death reporting is accurate. Of all respondents, 48.6% had knowingly reported an inaccurate cause of death; 58.4% of high-volume residents had done so. Of respondents who indicated they reported an inaccurate cause, 76.8% said the system would not accept the correct cause, 40.5% said admitting office personnel instructed them to “put something else,” and 30.7% said the medical examiner instructed them to do so; 64.6% cited cardiovascular disease as the most frequent diagnosis inaccurately reported. Conclusion Most resident physicians believed the current cause-of-death reporting system is inaccurate, often knowingly documenting incorrect causes. The system should be improved to allow reporting of more causes, and residents should receive better training on completing death certificates. PMID:23660118

An empirical assessment of the Healthy Early Childhood Program in Rio Grande do Sul State, Brazil.

PubMed

Ribeiro, Felipe Garcia; Braun, Gisele; Carraro, André; Teixeira, Gibran da Silva; Gigante, Denise Petrucci

2018-01-01

We investigate the effect of a family-based primary health care program (Healthly Early Childhood Program) on infant mortality in the state of Rio Grande do Sul, Brazil. We estimate infant mortality's counterfactual trajectories using the differences-in-differences approach, combined with the use of longitudinal data for all municipalities in the state of Rio Grande do Sul. Our main result is that the program reduced the number of deaths caused by external causes. The length of exposure to the program seems to potentiate the effects. For the number of deaths by general causes, there is no evidence of impact. Our findings are consistent with the nature of the program that aims to improve adults care with children. The Healthly Early Childhood Program is effective in reducing the number of avoidable deaths in infants.

Die another way – non-apoptotic mechanisms of cell death

PubMed Central

Tait, Stephen W. G.; Ichim, Gabriel; Green, Douglas R.

2014-01-01

ABSTRACT Regulated, programmed cell death is crucial for all multicellular organisms. Cell death is essential in many processes, including tissue sculpting during embryogenesis, development of the immune system and destruction of damaged cells. The best-studied form of programmed cell death is apoptosis, a process that requires activation of caspase proteases. Recently it has been appreciated that various non-apoptotic forms of cell death also exist, such as necroptosis and pyroptosis. These non-apoptotic cell death modalities can be either triggered independently of apoptosis or are engaged should apoptosis fail to execute. In this Commentary, we discuss several regulated non-apoptotic forms of cell death including necroptosis, autophagic cell death, pyroptosis and caspase-independent cell death. We outline what we know about their mechanism, potential roles in vivo and define outstanding questions. Finally, we review data arguing that the means by which a cell dies actually matters, focusing our discussion on inflammatory aspects of cell death. PMID:24833670

A Comprehensive Approach to Motorcycle-Related Head Injury Prevention: Experiences from the Field in Vietnam, Cambodia, and Uganda.

PubMed

Craft, Greig; Van Bui, Truong; Sidik, Mirjam; Moore, Danielle; Ederer, David J; Parker, Erin M; Ballesteros, Michael F; Sleet, David A

2017-11-30

Motorcyclists account for 23% of global road traffic deaths and over half of fatalities in countries where motorcycles are the dominant means of transport. Wearing a helmet can reduce the risk of head injury by as much as 69% and death by 42%; however, both child and adult helmet use are low in many countries where motorcycles are a primary mode of transportation. In response to the need to increase helmet use by all drivers and their passengers, the Global Helmet Vaccine Initiative (GHVI) was established to increase helmet use in three countries where a substantial portion of road users are motorcyclists and where helmet use is low. The GHVI approach includes five strategies to increase helmet use: targeted programs, helmet access, public awareness, institutional policies, and monitoring and evaluation. The application of GHVI to Vietnam, Cambodia, and Uganda resulted in four key lessons learned. First, motorcyclists are more likely to wear helmets when helmet use is mandated and enforced. Second, programs targeted to at-risk motorcyclists, such as child passengers, combined with improved awareness among the broader population, can result in greater public support needed to encourage action by decision-makers. Third, for broad population-level change, using multiple strategies in tandem can be more effective than using a single strategy alone. Lastly, the successful expansion of GHVI into Cambodia and Uganda has been hindered by the lack of helmet accessibility and affordability, a core component contributing to its success in Vietnam. This paper will review the development of the GHVI five-pillar approach in Vietnam, subsequent efforts to implement the model in Cambodia and Uganda, and lessons learned from these applications to protect motorcycle drivers and their adult and child passengers from injury.

Tackling Cancer Resistance by Immunotherapy: Updated Clinical Impact and Safety of PD-1/PD-L1 Inhibitors.

PubMed

Abdin, Shifaa M; Zaher, Dana M; Arafa, El-Shaimaa A; Omar, Hany A

2018-01-25

Cancer therapy has been constantly evolving with the hope of finding the most effective agents with the least toxic effects to eradicate tumors. Cancer immunotherapy is currently among the most promising options, fulfilling this hope in a wide range of tumors. Immunotherapy aims to activate immunity to fight cancer in a very specific and targeted manner; however, some abnormal immune reactions known as immune-related adverse events (IRAEs) might occur. Therefore, many researchers are aiming to define the most proper protocols for managing these complications without interfering with the anticancer effect. One of these targeted approaches is the inhibition of the interaction between the checkpoint protein, programmed death-receptor 1 (PD-1), and its ligand, programmed death-ligand 1 (PD-L1), via a class of antibodies known as PD-1/PD-L1 inhibitors. These antibodies achieved prodigious success in a wide range of malignancies, including those where optimal treatment is not yet fully identified. In this review, we have critically explored and discussed the outcome of the latest PD-1 and PD-L1 inhibitor studies in different malignancies compared to standard chemotherapeutic alternatives with a special focus on the clinical efficacy and safety. The approval of the clinical applications of nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab in the last few years clearly highlights the hopeful future of PD-1/PD-L1 inhibitors for cancer patients. These promising results of PD-1/PD-L1 inhibitors have encouraged many ongoing preclinical and clinical trials to explore the extent of antitumor activity, clinical efficacy and safety as well as to extend their applications.

Tackling Cancer Resistance by Immunotherapy: Updated Clinical Impact and Safety of PD-1/PD-L1 Inhibitors

PubMed Central

Abdin, Shifaa M.

2018-01-01

Cancer therapy has been constantly evolving with the hope of finding the most effective agents with the least toxic effects to eradicate tumors. Cancer immunotherapy is currently among the most promising options, fulfilling this hope in a wide range of tumors. Immunotherapy aims to activate immunity to fight cancer in a very specific and targeted manner; however, some abnormal immune reactions known as immune-related adverse events (IRAEs) might occur. Therefore, many researchers are aiming to define the most proper protocols for managing these complications without interfering with the anticancer effect. One of these targeted approaches is the inhibition of the interaction between the checkpoint protein, programmed death-receptor 1 (PD-1), and its ligand, programmed death-ligand 1 (PD-L1), via a class of antibodies known as PD-1/PD-L1 inhibitors. These antibodies achieved prodigious success in a wide range of malignancies, including those where optimal treatment is not yet fully identified. In this review, we have critically explored and discussed the outcome of the latest PD-1 and PD-L1 inhibitor studies in different malignancies compared to standard chemotherapeutic alternatives with a special focus on the clinical efficacy and safety. The approval of the clinical applications of nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab in the last few years clearly highlights the hopeful future of PD-1/PD-L1 inhibitors for cancer patients. These promising results of PD-1/PD-L1 inhibitors have encouraged many ongoing preclinical and clinical trials to explore the extent of antitumor activity, clinical efficacy and safety as well as to extend their applications. PMID:29370105

Specific expression of PD-L1 in RELA-fusion supratentorial ependymoma: Implications for PD-1-targeted therapy.

PubMed

Witt, Davis A; Donson, Andrew M; Amani, Vladimir; Moreira, Daniel C; Sanford, Bridget; Hoffman, Lindsey M; Handler, Michael H; Levy, Jean M Mulcahy; Jones, Kenneth L; Nellan, Anandani; Foreman, Nicholas K; Griesinger, Andrea M

2018-05-01

A desperate need for novel therapies in pediatric ependymoma (EPN) exists, as chemotherapy remains ineffective and radiotherapy often fails. EPN have significant infiltration of immune cells, which correlates with outcome. Immune checkpoint inhibitors provide an avenue for new treatments. This study characterizes tumor-infiltrating immune cells in EPN and aims at predicting candidates for clinical trials using checkpoint inhibitors targeting PD-L1/PD-1 (programmed death ligand 1/programmed death 1). The transcriptomic profiles of the primary study cohort of EPN and other pediatric brain tumors were interrogated to identify PD-L1 expression levels. Transcriptomic findings were validated using the western blotting, immunohistochemistry and flow cytometry. We evaluated PD-L1 mRNA expression across four intracranial subtypes of EPN in two independent cohorts and found supratentorial RELA fusion (ST-RELA) tumors to have significantly higher levels. There was a correlation between high gene expression and protein PD-L1 levels in ST-RELA tumors by both the western blot and immunohistochemisty. The investigation of EPN cell populations revealed PD-L1 was expressed on both tumor and myeloid cells in ST-RELA. Other subtypes had little PD-L1 in either tumor or myeloid cell compartments. Lastly, we measured PD-1 levels on tumor-infiltrating T cells and found ST-RELA tumors express PD-1 in both CD4 and CD8 T cells. A functional T-cell exhaustion assay found ST-RELA T cells to be exhausted and unable to secrete IFNγ on stimulation. These findings in ST-RELA suggest tumor evasion and immunsuppression due to PD-L1/PD-1-mediated T-cell exhaustion. Trials of checkpoint inhibitors in EPN should be enriched for ST-RELA tumors. © 2018 Wiley Periodicals, Inc.

Histopathological Effects of the Yen-Tc Toxin Complex from Yersinia entomophaga MH96 (Enterobacteriaceae) on the Costelytra zealandica (Coleoptera: Scarabaeidae) Larval Midgut

PubMed Central

Hares, Michelle C.; Jones, Sandra A.; Harper, Lincoln A.; Vernon, James R.; Harland, Duane P.; Jackson, Trevor A.; Hurst, Mark R. H.

2012-01-01

Yersinia entomophaga MH96, which was originally isolated from the New Zealand grass grub, Costelytra zealandica, produces an orally active proteinaceous toxin complex (Yen-Tc), and this toxin is responsible for mortality in a range of insect species, mainly within the Coleoptera and Lepidoptera. The genes encoding Yen-Tc are members of the toxin complex (Tc) family, with orthologs identified in several other bacterial species. As the mechanism of Yen-Tc activity remains unknown, a histopathological examination of C. zealandica larvae was undertaken in conjunction with cultured cells to identify the effects of Yen-Tc and to distinguish the contributions that its individual subunit components make upon intoxication. A progressive series of events that led to the deterioration of the midgut epithelium was observed. Additionally, experiments using a cell culture assay system were carried out to determine the cellular effects of intoxication on cells after topical application and the transient expression of Yen-Tc and its individual components. While observations were broadly consistent with those previously reported for other Tc family members, some differences were noted. In particular, the distinct stepwise disintegration of the midgut shared features associated with both apoptosis and necrotic programmed cell death pathways. Second, we observed, for the first time, a contribution of toxicity from two chitinases associated with the Yen-Tc complex. Our findings were suggestive of the activities encoded within the subunit components of Yen-Tc targeting different sites along putative programmed cell death pathways. Given the observed broad host range for Yen-Tc, these targeted loci are likely to be widely shared among insects. PMID:22544254

Chronic Respiratory Diseases in the Regions of Northern Russia: Epidemiological Distinctions in the Results of a National Population Study.

PubMed

Gambaryan, Marine H; Shalnova, Svetlana A; Deev, Alexander D; Drapkina, Oxana M

2017-07-26

The aim of the study is to investigate the epidemiological situation regarding chronic respiratory diseases in populations that inhabit different climatic-geographical regions of Russia, and to develop targeted programs for prevention of these diseases. (1) a comparative analysis of the standardized mortality data in Russia and other selected regions of the Russian North using the European standard for respiratory diseases, in a population aged 25-64; and (2) data from a randomized cross-sectional epidemiological study, with subjects from three different climatic-geographical regions of Russia. (1) the respiratory disease-related mortality rates in the majority of Russian Northern regions were much higher compared to the national average. Although death rates from chronic lower respiratory diseases were higher among the Northern regions and in the whole of Russia relative to the countries of European Union (EU), the cause of death in the populations of the Northern regions tend to be lower respiratory infections and pneumonia; and (2) despite the absence of any significant differences in the prevalence of smoking, the prevalence of chronic respiratory diseases (COPD) is significantly higher in Far North Yakutsk compared to the other two regions in this study-Chelyabinsk and Vologda. The status of hyperborean had the highest chance of a significant contribution to COPD and cardiorespiratory pathology among all other risk factors. The results revealed a need for effective targeted strategies for primary and secondary prevention of chronic respiratory diseases for the populations of the Northern regions of Russia. The revealed regional distinctions regarding the prevalence of, and mortality from, chronic respiratory diseases should be taken into consideration when designing integrated programs for chronic non-communicable disease prevention in these regions.

Poliomyelitis and its elimination in Cuba: an historical overview.

PubMed

Beldarraín, Enrique

2013-04-01

Polio was first detected in Cuba in the late 19th century among residents of the US community on the Isla de Pinos (Isle of Pines, now Isle of Youth), apparently introduced through migration from the USA. The first outbreak was reported in 1906 on the Isle, with the first epidemic reported in the former province of Las Villas in 1909. The epidemics subsequently intensified, by 1934 becoming periodic every four to five years, and accompanied by high morbidity, mortality and crippling sequelae, primarily among children. To review and analyze the history of polio and its control in Cuba, from the disease's first appearance in 1898 until WHO/PAHO certification of elimination in 1994. The historiological method was used; archival documents, medical records, and available polio morbidity and mortality statistics from the Ministry of Public Health's National Statistics Division before 1959 and from 1959 through 2000 were reviewed. Crude morbidity and mortality rates were calculated using population estimates at mid-period. Reports and scientific publications describing polio vaccination campaigns and their results were also reviewed, and key informants were interviewed. After initial introduction of polio in Cuba, five major epidemics occurred between 1932 and 1958: in 1934 (434 cases, 82 deaths); 1942 (494 cases, 58 deaths); 1946 (239 cases, 33 deaths), 1952 (492 cases, 15 deaths) and 1955 (267 cases, 8 deaths). Between 1957 and 1961 the disease's endemicity reached epidemic levels, with the last outbreak occurring in 1961, with 342 cases, 30% of them in children aged >4 years. In 1962, Cuba launched a nationwide polio vaccination campaign, the first of annual campaigns thereafter carried out in the framework of a coherent national program aimed at polio elimination. Using the Sabin oral vaccine and targeting the entire pediatric population in a single time period, five million doses were administered in the first campaign, reaching 87.5% of the target population aged 1 month through 14 years, constituting 109.4% of planned coverage. Since that year, no deaths from polio have been recorded (there were ten cases between 1963 and 1989) and WHO/PAHO certified polio elimination in Cuba in 1994. Cuba controlled polio with effective vaccination strategies and appropriate epidemiological measures, in the context of social, financial and political support. KEYWORDS History, poliomyelitis, epidemiology, disease control, vaccination, Sabin vaccine, Cuba.

Trends in AIDS Deaths, New Infections and ART Coverage in the Top 30 Countries with the Highest AIDS Mortality Burden; 1990–2013

PubMed Central

Granich, Reuben; Gupta, Somya; Hersh, Bradley; Williams, Brian; Montaner, Julio; Young, Benjamin; Zuniga, José M.

2015-01-01

Background Antiretroviral therapy (ART) prevents human immunodeficiency virus (HIV) disease progression, mortality and transmission. We assess the impact of expanded HIV treatment for the prevention of Acquired Immunodeficiency Syndrome (AIDS)-related deaths and simulate four treatment scenarios for Nigeria and South Africa. Methods For 1990–2013, we used the Joint United Nations Programme on HIV/AIDS (UNAIDS) database to examine trends in AIDS deaths, HIV incidence and prevalence, ART coverage, annual AIDS death rate, AIDS death-to-treatment and HIV infections to treatment ratios for the top 30 countries with the highest AIDS mortality burden and compare them with data from high-income countries. We projected the 1990–2020 AIDS deaths for Nigeria and South Africa using four treatment scenarios: 1) no ART; 2) maintaining current ART coverage; 3) 90% ART coverage based on 2013 World Health Organization (WHO) ART guidelines by 2020; and 4) reaching the United Nations 90-90-90 Target by 2020. Findings In 2013, there were 1.3 million (1.1 million–1.6 million) AIDS deaths in the top 30 countries representing 87% of global AIDS deaths. Eight countries accounted for 58% of the global AIDS deaths; Nigeria and South Africa accounted for 27% of global AIDS deaths. The highest death rates per 1000 people living with HIV were in Central African Republic (91), South Sudan (82), Côte d’Ivoire (75), Cameroon (72) and Chad (71), nearly 8–10 times higher than the high-income countries. ART access in 2013 has averted as estimated 1,051,354 and 422,448 deaths in South Africa and Nigeria, respectively. Increasing ART coverage in these two countries to meet the proposed UN 90-90-90 Target by 2020 could avert 2.2 and 1.2 million deaths, respectively. Interpretation Over the past decade the expansion of access to ART averted millions of deaths. Reaching the proposed UN 90-90-90 Target by 2020 will prevent additional morbidity, mortality and HIV transmission. Despite progress, high-burden countries will need to accelerate access to ART treatment to avert millions of premature AIDS deaths and new HIV infections. PMID:26147987

Effect of Gamma Knife Radiosurgery and Programmed Cell Death 1 Receptor Antagonists on Metastatic Melanoma

PubMed Central

Hubbard, Molly; Nordmann, Tyler; Sperduto, Paul W; Clark, H. Brent; Hunt, Matthew A

2017-01-01

Learning objectives To evaluate radiation-induced changes in patients with brain metastasis secondary to malignant melanoma who received treatment with Gamma Knife radiosurgery (GKRS) and programmed cell death 1 (PD-1) receptor antagonists. Introduction  Stereotactic radiosurgery and chemotherapeutics are used together for treatment of metastatic melanoma and have been linked to delayed radiation-induced vasculitic leukoencephalopathy (DRIVL). There have been reports of more intense interactions with new immunotherapeutics targeting PD-1 receptors, but their interactions have not been well described and may result in an accelerated response to GKRS. Here we present data on subjects treated with this combination from a single institution. Methods Records from patients who underwent treatment for metastatic melanoma to the brain with GKRS from 2011 to 2016 were reviewed. Demographics, date of brain metastasis diagnosis, cause of death when applicable, immunotherapeutics, and imaging findings were recorded. The timing of radiation therapy and medications were also documented.  Results A total of 79 subjects were treated with GKRS, and 66 underwent treatment with both GKRS and immunotherapy. Regarding the 30 patients treated with anti-PD-1 immunotherapy, 21 patients received pembrolizumab, seven patients received nivolumab, and two patients received pembrolizumab and nivolumab. Serial imaging was available for interpretation in 25 patients, with 13 subjects who received GKRS and anti-PD-1 immunotherapy less than six weeks of each other. While four subjects had indeterminate/mixed findings on subsequent magnetic resonance imaging (MRI), nine subjects were noted to have progression. Two of these patients showed progression but subsequent imaging revealed a decrease in progression or improvement on MRI to previously targeted lesions by GKRS. None of the 13 subjects had surgery following their combined therapies. Conclusions This data suggests that there is need for further investigation of the role for concurrent treatment with PD-1 inhibitors and GKRS to enhance the treatment of metastatic melanoma. We present data on 13 patients who appear to have some radiologic benefit to this treatment combination, two of whom had radiographic pseudoprogression. PMID:29468099

Using the Lives Saved Tool to aid country planning in meeting mortality targets: a case study from Mali.

PubMed

Keita, Youssouf; Sangho, Hamadoun; Roberton, Timothy; Vignola, Emilia; Traoré, Mariam; Munos, Melinda

2017-11-07

Mali is one of four countries implementing a National Evaluation Platform (NEP) to build local capacity to answer evaluation questions for maternal, newborn, child health and nutrition (MNCH&N). In 2014-15, NEP-Mali addressed questions about the potential impact of Mali's MNCH&N plans and strategies, and identified priority interventions to achieve targeted mortality reductions. The NEP-Mali team modeled the potential impact of three intervention packages in the Lives Saved Tool (LiST) from 2014 to 2023. One projection included the interventions and targets from Mali's ten-year health strategy (PDDSS) for 2014-2023, and two others modeled intervention packages that included scale up of antenatal, intrapartum, and curative interventions, as well as reductions in stunting and wasting. We modeled the change in maternal, newborn and under-five mortality rates under these three projections, as well as the number of lives saved, overall and by intervention. If Mali were to achieve the MNCH&N coverage targets from its health strategy, under-5 mortality would be reduced from 121 per 1000 live births to 93 per 1000, far from the target of 69 deaths per 1000. Projections 1 and 2 produced estimated mortality reductions from 121 deaths per 1000 to 70 and 68 deaths per 1000, respectively. With respect to neonatal mortality, the mortality rate would be reduced from 39 to 32 deaths per 1000 live births under the current health strategy, and to 25 per 1000 under projections 1 and 2. This study revealed that achieving the coverage targets for the MNCH&N interventions in the 2014-23 PDDSS would likely not allow Mali to achieve its mortality targets. The NEP-Mali team was able to identify two packages of MNCH&N interventions (and targets) that achieved under-5 and neonatal mortality rates at, or very near, the PDDSS targets. The Malian Ministry of Health and Public Hygiene is using these results to revise its plans and strategies.

Mortality investigation of workers in an electromagnetic pulse test program.

PubMed

Muhm, J M

1992-03-01

A standardized mortality ratio study of 304 male employees of an electromagnetic pulse (EMP) test program was conducted. Outcomes were ascertained by two methods: the World Health Organization's underlying cause of death algorithm; and the National Center for Health Statistics' algorithm to identify multiple listed causes of death. In the 3362 person-years of follow-up, there was one underlying cause of death due to leukemia compared with with 0.2 expected (standard mortality ratio [SMR] = 437, 95% confidence interval [CI] = 11-2433), and two multiple listed causes of death due to leukemia compared with 0.3 expected (SMR = 775, 95% CI = 94-2801). Although the study suggested an association between death due to leukemia and employment in the EMP test program, firm conclusions could not be drawn because of limitations of the study. The findings warrant further investigation in an independent cohort.

Strategies to reduce driving under the influence of alcohol.

PubMed

DeJong, W; Hingson, R

1998-01-01

The purpose of this review is to update research on the prevention of alcohol-related traffic deaths since the 1988 Surgeon General's Workshop on Drunk Driving. Four primary areas of research are reviewed here: (a) general deterrence policies, (b) alcohol control policies, (c) mass communications campaigns, including advertising restrictions, and (d) community traffic safety programs. Modern efforts to combat drunk driving in the United States began with specific deterrence strategies to punish convicted drunk drivers, and then evolved to include general deterrence strategies that were targeted to the population as a whole. Efforts next expanded to include the alcohol side of the problem, with measures installed to decrease underage drinking and excessive alcohol consumption. In the next several years, greater efforts are needed on all these fronts. Also needed, however, are programs that integrate drunk driving prevention with other traffic safety initiatives.

Natural products as promising drug candidates for the treatment of Alzheimer's disease: molecular mechanism aspect.

PubMed

Ansari, Niloufar; Khodagholi, Fariba

2013-07-01

Alzheimer's disease (AD) is the most common neurodegenerative disorder to date, with no curative or preventive therapy. Histopathological hallmarks of AD include deposition of β-amyloid plaques and formation of neurofibrillary tangles. Extent studies on pathology of the disease have made important discoveries regarding mechanism of disease and potential therapeutic targets. Many cellular changes including oxidative stress, disruption of Ca2+ homeostasis, inflammation, metabolic disturbances, and accumulation of unfolded/misfolded proteins can lead to programmed cell death in AD. Despite intensive research, only five approved drugs are available for the management of AD. Hence, there is a need to look at alternative therapies. Use of natural products and culinary herbs in medicine has gained popularity in recent years. Several natural substances with neuroprotective effects have been widely studied. Most of these compounds have remarkable antioxidant properties and act mainly by scavenging free radical species. Some of them increase cell survival and improve cognition by directly affecting amyloidogenesis and programmed cell death pathways. Further studies on these natural products and their mechanism of action, parallel with the use of novel pharmaceutical drug design and delivery techniques, enable us to offer an addition to conventional medicine. This review discussed some natural products with potential neuroprotective properties against Aβ with respect to their mechanism of action.

Expected Paradigm Shift in Brain Metastases Therapy-Immune Checkpoint Inhibitors.

PubMed

Jindal, Vishal; Gupta, Sorab

2018-01-30

Brain metastasis (BM) is one of the dreadful complications of malignancies. The prognosis after BM is extremely poor and life expectancy is meager. Currently, our treatment modalities are limited to radiotherapy and surgical resection, which also has poor outcomes and leads to various neurological deficits and affects the quality of life of patients. New treatment modality, i.e., immune checkpoint inhibitors, has brought revolution in management of melanoma, renal cancer, and non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors basically enhance the immune response of the body to fight against cancers. Immune response in the brain is highly regulated; therefore, it is challenging to use immune-modulator drugs in BM. The microenvironment of BM is rich in cytotoxic T lymphocytes and which is the target of immune checkpoint inhibitors. Few studies have shown some hope regarding use of immune checkpoint inhibitors in management of BM. It works through inhibiting immune check point gates, i.e., CTLA-4 (cytotoxic T-lymphocyte-associated protein) and PD-1/PD-L1 (programmed cell death protein-1/program death ligand-1). This article explains the basic mechanism of immune check point inhibitors, rationale behind their usage in BM, and some of the clinical studies which have shown the efficacy of immune check point inhibitors in BM.

PD-1/PD-L1 Pathway Mediates the Alleviation of Pulmonary Fibrosis by Human Mesenchymal Stem Cells in Humanized Mice.

PubMed

Ni, Ke; Liu, Ming; Zheng, Jian; Wen, Liyan; Chen, Qingyun; Xiang, Zheng; Lam, Kowk-Tai; Liu, Yinping; Chan, Godfrey Chi-Fung; Lau, Yu-Lung; Tu, Wenwei

2018-06-01

Pulmonary fibrosis is a chronic progressive lung disease with few treatments. Human mesenchymal stem cells (MSCs) have been shown to be beneficial in pulmonary fibrosis because they have immunomodulatory capacity. However, there is no reliable model to test the therapeutic effect of human MSCs in vivo. To mimic pulmonary fibrosis in humans, we established a novel bleomycin-induced pulmonary fibrosis model in humanized mice. With this model, the benefit of human MSCs in pulmonary fibrosis and the underlying mechanisms were investigated. In addition, the relevant parameters in patients with pulmonary fibrosis were examined. We demonstrate that human CD8 + T cells were critical for the induction of pulmonary fibrosis in humanized mice. Human MSCs could alleviate pulmonary fibrosis and improve lung function by suppressing bleomycin-induced human T-cell infiltration and proinflammatory cytokine production in the lungs of humanized mice. Importantly, alleviation of pulmonary fibrosis by human MSCs was mediated by the PD-1/programmed death-ligand 1 pathway. Moreover, abnormal PD-1 expression was found in circulating T cells and lung tissues of patients with pulmonary fibrosis. Our study supports the potential benefit of targeting the PD-1/programmed death-ligand 1 pathway in the treatment of pulmonary fibrosis.

Acquired immunodeficiency syndrome in older African Americans.

PubMed Central

Funnyé, Allen S.; Akhtar, Abbasi J.; Biamby, Gisele

2002-01-01

The purpose of this study was to determine if older African Americans are disproportionately affected by acquired immunodeficiency syndrome (AIDS), and to review the clinical impact of AIDS and the importance of prevention and treatment efforts. A review of the literature and statistics was obtained using Medline and the AIDS Public Information Data Set offered by the Centers for Disease Control and Prevention. Twenty-seven percent of the U.S. population is above the age of 50, and the number of AIDS cases in this group is growing, with African Americans accounting for the highest proportion of cases and deaths. Testing for HIV may be delayed and symptoms attributed to other illnesses. Though 5% of new cases occur in those over 50, prevention programs, testing, and the perception of risk by providers may be insufficient. There are few research studies on HIV treatment in older patients and no specific guidelines for antiretroviral treatments available. Although death rates for AIDS has been declining, adults over 50 still have the highest mortality rate. Co-morbid conditions, such as heart disease and hypertension, may require taking multiple drugs, which may complicate treatment. Increasing heterosexual transmission rates and a lack of information on HIV reinforces the need for specific prevention programs targeted toward older African Americans. PMID:11991333

Pulmonary Sarcoidosis Activation following Neoadjuvant Pembrolizumab plus Chemotherapy Combination Therapy in a Patient with Non-Small Cell Lung Cancer: A Case Report.

PubMed

Fakhri, Ghina; Akel, Reem; Salem, Ziad; Tawil, Ayman; Tfayli, Arafat

2017-01-01

Pembrolizumab is a humanized monoclonal antibody which serves to enhance the antitumor immune response by targeting programmed cell death 1 receptor. The use of pembrolizumab plus carboplatin/pemetrexed combination therapy results in improvement in overall survival and progression-free survival rates for non-small cell lung cancer (NSCLC) patients as compared to chemotherapy alone. However, numerous immune-mediated toxicities of pembrolizumab have been reported. We report the case of a 74-year-old male patient diagnosed with stage IIIA programmed death-ligand 1-positive non-small cell lung adenocarcinoma treated with 4 cycles of carboplatin/pemetrexed plus pembrolizumab combination therapy followed by 2 cycles of pembrolizumab treatment. Follow-up PET-CT scanning showed a very good response at the level of the tumor but new-onset activity in bilateral hilar and mediastinal lymph nodes. Biopsy of these lymph nodes revealed a benign pathology with noncaseating granulomas consistent with immune-mediated sarcoidosis. The pathogenesis of immunotherapy-induced sarcoidosis is not yet known but has been reported in different cancers and using different checkpoint inhibitors. To our knowledge, this case is the first in the literature displaying pulmonary sarcoidosis in a patient with NSCLC 4 months after having initiated chemotherapy plus pembrolizumab combination therapy.

Pulmonary Sarcoidosis Activation following Neoadjuvant Pembrolizumab plus Chemotherapy Combination Therapy in a Patient with Non-Small Cell Lung Cancer: A Case Report

PubMed Central

Fakhri, Ghina; Akel, Reem; Salem, Ziad; Tawil, Ayman; Tfayli, Arafat

2017-01-01

Background Pembrolizumab is a humanized monoclonal antibody which serves to enhance the antitumor immune response by targeting programmed cell death 1 receptor. The use of pembrolizumab plus carboplatin/pemetrexed combination therapy results in improvement in overall survival and progression-free survival rates for non-small cell lung cancer (NSCLC) patients as compared to chemotherapy alone. However, numerous immune-mediated toxicities of pembrolizumab have been reported. Case Presentation We report the case of a 74-year-old male patient diagnosed with stage IIIA programmed death-ligand 1-positive non-small cell lung adenocarcinoma treated with 4 cycles of carboplatin/pemetrexed plus pembrolizumab combination therapy followed by 2 cycles of pembrolizumab treatment. Follow-up PET-CT scanning showed a very good response at the level of the tumor but new-onset activity in bilateral hilar and mediastinal lymph nodes. Biopsy of these lymph nodes revealed a benign pathology with noncaseating granulomas consistent with immune-mediated sarcoidosis. Conclusion The pathogenesis of immunotherapy-induced sarcoidosis is not yet known but has been reported in different cancers and using different checkpoint inhibitors. To our knowledge, this case is the first in the literature displaying pulmonary sarcoidosis in a patient with NSCLC 4 months after having initiated chemotherapy plus pembrolizumab combination therapy. PMID:29515398

Advances in cancer immunology and cancer immunotherapy.

PubMed

Voena, Claudia; Chiarle, Roberto

2016-02-01

After decades of setbacks, cancer immunology is living its Golden Age. Recent advances in cancer immunology have provided new therapeutic approaches to treat cancer. The objective clinical response observed in patients treated with antibodies that block the immune checkpoints, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell-death protein 1 (PD-1)/programmed cell-death 1 ligand 1 (PD-L1) pathways, has led to their FDA approval for the treatment of melanoma in 2011 and in 2014, respectively. The anti-PD-1 antibody nivolumab has received the FDA-approval in March 2015 for squamous lung cancer treatment. In addition, antibodies targeting PD-1 or PD-L1 have demonstrated their efficacy and safety in additional tumors, including non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), bladder cancer, and Hodgkin's lymphoma. Almost at the same time, the field of adoptive cell transfer has exploded. The chimeric antigen receptor (CAR) T technology has provided strong evidence of efficacy in the treatment of B cell malignancies, and different T cell based treatments are currently under investigation for different types of tumors. In this review we will discuss the latest advances in cancer immunology and immunotherapy as well as new treatments now under development in the clinic and potential strategies that have shown promising results in preclinical models.

Host–virus dynamics and subcellular controls of cell fate in a natural coccolithophore population

PubMed Central

Vardi, Assaf; Haramaty, Liti; Van Mooy, Benjamin A. S.; Fredricks, Helen F.; Kimmance, Susan A.; Larsen, Aud; Bidle, Kay D.

2012-01-01

Marine viruses are major evolutionary and biogeochemical drivers in marine microbial foodwebs. However, an in-depth understanding of the cellular mechanisms and the signal transduction pathways mediating host–virus interactions during natural bloom dynamics has remained elusive. We used field-based mesocosms to examine the “arms race” between natural populations of the coccolithophore Emiliania huxleyi and its double-stranded DNA-containing coccolithoviruses (EhVs). Specifically, we examined the dynamics of EhV infection and its regulation of cell fate over the course of bloom development and demise using a diverse suite of molecular tools and in situ fluorescent staining to target different levels of subcellular resolution. We demonstrate the concomitant induction of reactive oxygen species, caspase-specific activity, metacaspase expression, and programmed cell death in response to the accumulation of virus-derived glycosphingolipids upon infection of natural E. huxleyi populations. These subcellular responses to viral infection simultaneously resulted in the enhanced production of transparent exopolymer particles, which can facilitate aggregation and stimulate carbon flux. Our results not only corroborate the critical role for glycosphingolipids and programmed cell death in regulating E. huxleyi–EhV interactions, but also elucidate promising molecular biomarkers and lipid-based proxies for phytoplankton host–virus interactions in natural systems. PMID:23134731

Ending of preventable deaths from pneumonia and diarrhoea: an achievable goal.

PubMed

Chopra, Mickey; Mason, Elizabeth; Borrazzo, John; Campbell, Harry; Rudan, Igor; Liu, Li; Black, Robert E; Bhutta, Zulfiqar A

2013-04-27

Global under-5 mortality has fallen rapidly from 12 million deaths in 1990, to 6·9 million in 2011; however, this number still falls short of the target of a two-thirds reduction or a maximum of 4 million deaths by 2015. Acceleration of reductions in deaths due to pneumonia and diarrhoea, which together account for about 2 million child deaths every year, is essential if the target is to be met. Scaling up of existing interventions against the two diseases to 80% and immunisation to 90% would eliminate more than two-thirds of deaths from these two diseases at a cost of US$6·715 billion by 2025. Modelling in this report shows that if all countries could attain the rates of decline of the regional leaders, then cause-specific death rates of fewer than three deaths per 1000 livebirths from pneumonia and less than one death per 1000 livebirths from diarrhoea could be achieved by 2025. These rates are those at which preventable deaths have been avoided. Increasing of awareness of the size of the problem; strengthening of leadership, intersectoral collaboration, and resource mobilisation; and increasing of efficiency through the selection of the optimum mix of a growing set of cost-effective interventions depending on local contexts are the priority actions needed to achieve the goal of ending preventable deaths from pneumonia and diarrhoea by 2025. Copyright © 2013 Elsevier Ltd. All rights reserved.

Tuberculosis mortality by industry in the United States, 1990-1999.

PubMed

Bang, K M; Weissman, D N; Wood, J M; Attfield, M D

2005-04-01

To identify occupations and industries with elevated respiratory tuberculosis (TB) mortality in the United States for the period 1990-1999, we used National Center for Health Statistics multiple-cause-of-death data, restricted to certain states for which information on decedents' usual industry and occupational information was available and limited to US residents aged > or =15 years. A total of 7686 deaths between 1990 and 1999 were attributed to respiratory TB. Proportionate mortality ratios (PMRs), adjusted for age, sex, and race, were calculated from US census occupation and industry classifications. Industries and occupations involving potential contact with infected cases (e.g., health care workers), those with silica exposure and silicosis (e.g., mining and construction), and those associated with low socioeconomic status had significantly elevated TB mortality. Overall, the pattern of findings echoes that described in various prior reports, which indicates that the potential for exposure and disease development still persists among certain worker groups. The findings should be useful in guiding occupationally targeted TB prevention programs.

AKT1 provides an essential survival signal required for differentiation and stratification of primary human keratinocytes.

PubMed

Thrash, Barry R; Menges, Craig W; Pierce, Robert H; McCance, Dennis J

2006-04-28

Keratinocyte differentiation and stratification are complex processes involving multiple signaling pathways, which convert a basal proliferative cell into an inviable rigid squame. Loss of attachment to the basement membrane triggers keratinocyte differentiation, while in other epithelial cells, detachment from the extracellular matrix leads to rapid programmed cell death or anoikis. The potential role of AKT in providing a survival signal necessary for stratification and differentiation of primary human keratinocytes was investigated. AKT activity increased during keratinocyte differentiation and was attributed to the specific activation of AKT1 and AKT2. Targeted reduction of AKT1 expression, but not AKT2, by RNA interference resulted in an abnormal epidermis in organotypic skin cultures with a thin parabasal region and a pronounced but disorganized cornified layer. This abnormal stratification was due to significant cell death in the suprabasal layers and was alleviated by caspase inhibition. Normal expression patterns of both early and late markers of keratinocyte differentiation were also disrupted, producing a poorly developed stratum corneum.

SK2 channels regulate mitochondrial respiration and mitochondrial Ca2+ uptake.

PubMed

Honrath, Birgit; Matschke, Lina; Meyer, Tammo; Magerhans, Lena; Perocchi, Fabiana; Ganjam, Goutham K; Zischka, Hans; Krasel, Cornelius; Gerding, Albert; Bakker, Barbara M; Bünemann, Moritz; Strack, Stefan; Decher, Niels; Culmsee, Carsten; Dolga, Amalia M

2017-05-01

Mitochondrial calcium ([Ca 2+ ] m ) overload and changes in mitochondrial metabolism are key players in neuronal death. Small conductance calcium-activated potassium (SK) channels provide protection in different paradigms of neuronal cell death. Recently, SK channels were identified at the inner mitochondrial membrane, however, their particular role in the observed neuroprotection remains unclear. Here, we show a potential neuroprotective mechanism that involves attenuation of [Ca 2+ ] m uptake upon SK channel activation as detected by time lapse mitochondrial Ca 2+ measurements with the Ca 2+ -binding mitochondria-targeted aequorin and FRET-based [Ca 2+ ] m probes. High-resolution respirometry revealed a reduction in mitochondrial respiration and complex I activity upon pharmacological activation and overexpression of mitochondrial SK2 channels resulting in reduced mitochondrial ROS formation. Overexpression of mitochondria-targeted SK2 channels enhanced mitochondrial resilience against neuronal death, and this effect was inhibited by overexpression of a mitochondria-targeted dominant-negative SK2 channel. These findings suggest that SK channels provide neuroprotection by reducing [Ca 2+ ] m uptake and mitochondrial respiration in conditions, where sustained mitochondrial damage determines progressive neuronal death.

SK2 channels regulate mitochondrial respiration and mitochondrial Ca2+ uptake

PubMed Central

Honrath, Birgit; Matschke, Lina; Meyer, Tammo; Magerhans, Lena; Perocchi, Fabiana; Ganjam, Goutham K; Zischka, Hans; Krasel, Cornelius; Gerding, Albert; Bakker, Barbara M; Bünemann, Moritz; Strack, Stefan; Decher, Niels; Culmsee, Carsten; Dolga, Amalia M

2017-01-01

Mitochondrial calcium ([Ca2+]m) overload and changes in mitochondrial metabolism are key players in neuronal death. Small conductance calcium-activated potassium (SK) channels provide protection in different paradigms of neuronal cell death. Recently, SK channels were identified at the inner mitochondrial membrane, however, their particular role in the observed neuroprotection remains unclear. Here, we show a potential neuroprotective mechanism that involves attenuation of [Ca2+]m uptake upon SK channel activation as detected by time lapse mitochondrial Ca2+ measurements with the Ca2+-binding mitochondria-targeted aequorin and FRET-based [Ca2+]m probes. High-resolution respirometry revealed a reduction in mitochondrial respiration and complex I activity upon pharmacological activation and overexpression of mitochondrial SK2 channels resulting in reduced mitochondrial ROS formation. Overexpression of mitochondria-targeted SK2 channels enhanced mitochondrial resilience against neuronal death, and this effect was inhibited by overexpression of a mitochondria-targeted dominant-negative SK2 channel. These findings suggest that SK channels provide neuroprotection by reducing [Ca2+]m uptake and mitochondrial respiration in conditions, where sustained mitochondrial damage determines progressive neuronal death. PMID:28282037

Experimental Proof for the Role of Nonlinear Photoionization in Plasmonic Phototherapy.

PubMed

Minai, Limor; Zeidan, Adel; Yeheskely-Hayon, Daniella; Yudovich, Shimon; Kviatkovsky, Inna; Yelin, Dvir

2016-07-13

Targeting individual cells within a heterogeneous tissue is a key challenge in cancer therapy, encouraging new approaches for cancer treatment that complement the shortcomings of conventional therapies. The highly localized interactions triggered by focused laser beams promise great potential for targeting single cells or small cell clusters; however, most laser-tissue interactions often involve macroscopic processes that may harm healthy nearby tissue and reduce specificity. Specific targeting of living cells using femtosecond pulses and nanoparticles has been demonstrated promising for various potential therapeutic applications including drug delivery via optoporation, drug release, and selective cell death. Here, using an intense resonant femtosecond pulse and cell-specific gold nanorods, we show that at certain irradiation parameters cell death is triggered by nonlinear plasmonic photoionization and not by thermally driven processes. The experimental results are supported by a physical model for the pulse-particle-medium interactions. A good correlation is found between the calculated total number and energy of the generated free electrons and the observed cell death, suggesting that femtosecond photoionization plays the dominant role in cell death.

CDIP, a novel pro-apoptotic gene, regulates TNFalpha-mediated apoptosis in a p53-dependent manner.

PubMed

Brown, Lauren; Ongusaha, Pat P; Kim, Hyung-Gu; Nuti, Shanthy; Mandinova, Anna; Lee, Ji Won; Khosravi-Far, Roya; Aaronson, Stuart A; Lee, Sam W

2007-07-25

We have identified a novel pro-apoptotic p53 target gene named CDIP (Cell Death Involved p53-target). Inhibition of CDIP abrogates p53-mediated apoptotic responses, demonstrating that CDIP is an important p53 apoptotic effector. CDIP itself potently induces apoptosis that is associated with caspase-8 cleavage, implicating the extrinsic cell death pathway in apoptosis mediated by CDIP. siRNA-directed knockdown of caspase-8 results in a severe impairment of CDIP-dependent cell death. In investigating the potential involvement of extrinsic cell death pathway in CDIP-mediated apoptosis, we found that TNF-alpha expression tightly correlates with CDIP expression, and that inhibition of TNF-alpha signaling attenuates CDIP-dependent apoptosis. We also demonstrate that TNF-alpha is upregulated in response to p53 and p53 inducing genotoxic stress, in a CDIP-dependent manner. Consistently, knockdown of TNF-alpha impairs p53-mediated stress-induced apoptosis. Together, these findings support a novel p53 --> CDIP --> TNF-alpha apoptotic pathway that directs apoptosis after exposure of cells to genotoxic stress. Thus, CDIP provides a new link between p53-mediated intrinsic and death receptor-mediated extrinsic apoptotic signaling, providing a novel target for cancer therapeutics aimed at maximizing the p53 apoptotic response of cancer cells to drug therapy.

Preconditioning in neuroprotection: From hypoxia to ischemia

PubMed Central

Li, Sijie; Hafeez, Adam; Noorulla, Fatima; Geng, Xiaokun; Shao, Guo; Ren, Changhong; Lu, Guowei; Zhao, Heng; Ding, Yuchuan; Ji, Xunming

2017-01-01

Sublethal hypoxic or ischemic events can improve the tolerance of tissues, organs, and even organisms from subsequent lethal injury caused by hypoxia or ischemia. This phenomenon has been termed hypoxic or ischemic preconditioning (HPC or IPC) and is well established in the heart and the brain. This review aims to discuss HPC and IPC with respect to their historical development and advancements in our understanding of the neurochemical basis for their neuroprotective role. Through decades of collaborative research and studies of HPC and IPC in other organ systems, our understanding of HPC and IPC-induced neuroprotection has expanded to include: early- (phosphorylation targets, transporter regulation, interfering RNA) and late- (regulation of genes like EPO, VEGF, and iNOS) phase changes, regulators of programmed cell death, members of metabolic pathways, receptor modulators, and many other novel targets. The rapid acceleration in our understanding of HPC and IPC will help facilitate transition into the clinical setting. PMID:28110083

Targeting the unmet medical need: the Abbott Laboratories oncology approach.

PubMed

Carlson, Dawn M; Steinberg, Joyce L; Gordon, Gary

2005-09-01

While significant advances in the treatment of cancer occured during the last half of the twentieth century, parallel decreases in overall cancer death rates were not observed. Cancer therapy remains an area of significant unmet medical need. Abbott's oncology research programs are focused on pioneering trageted, less toxic therapies, aimed at different aspects of tumor growth and development. Oncology drugs in development at Abbott target several mechanisms of cancer progression by interfering with multiple processes necessary for tumor growth: recruitment of a blood supply, cell proliferation, and the development of metastases. They include a selective endothelin A-receptor antagonist (atrasentan/Xinlay), 3 angiogenesis inhibitors (ABT 510, a thrombospondin mimetic: ABT-869, a multitargeted receptor tyrosine kinase inhibitor; and ABT 828, recombinant human plasminogen kringle 5), a cell proliferation inhibitor (ABT-751, an antimitotic agent), an apoptosis inducer (ABT 737, a Bcl-2 family inhibitor), and a poly(ADP-ribose)polymerase inhibitor.

AKT in cancer: new molecular insights and advances in drug development

PubMed Central

Mundi, Prabhjot S.; Sachdev, Jasgit; McCourt, Carolyn

2016-01-01

The phosphatidylinositol‐3 kinase (PI3K)–AKT pathway is one of the most commonly dysregulated pathways in all of cancer, with somatic mutations, copy number alterations, aberrant epigenetic regulation and increased expression in a number of cancers. The carefully maintained homeostatic balance of cell division and growth on one hand, and programmed cell death on the other, is universally disturbed in tumorigenesis, and downstream effectors of the PI3K–AKT pathway play an important role in this disturbance. With a wide array of downstream effectors involved in cell survival and proliferation, the well‐characterized direct interactions of AKT make it a highly attractive yet elusive target for cancer therapy. Here, we review the salient features of this pathway, evidence of its role in promoting tumorigenesis and recent progress in the development of therapeutic agents that target AKT. PMID:27232857

Prospects for TIM3-Targeted Antitumor Immunotherapy.

PubMed

Ngiow, Shin Foong; Teng, Michele W L; Smyth, Mark J

2011-11-01

New insights into the control of T-cell activation and proliferation have led to the identification of checkpoint proteins that either up- or downmodulate T-cell reactivity. Monoclonal antibody immunotherapies that are reactive with cytotoxic T lymphocyte antigen 4 or programmed death receptor 1 have shown promising therapeutic outcomes in mice and humans with established cancer, highlighting the fact that cancer immunotherapy using T-cell checkpoint inhibitors is one of the most promising new therapeutic approaches. T-cell immunoglobulin and mucin domain 3 (TIM3) is one of many similar inhibitory molecules that are gaining attention as targets, but it remains relatively poorly studied in oncology. This review discusses our recent probing of the mechanism of action of anti-TIM3 antibody against established spontaneous and experimental tumors in mice, in the context of the exciting possibility of rationally combining agents that promote tumor-specific T-cell activation, proliferation, effector function, and survival. ©2011 AACR.

East Asia review, 1976-7: Korea (South).

PubMed

Han, D W; Cho, N H

1978-09-01

The Korean fourth 5-year Economic Development Plan (1977-1981) is formulated to reduce the population growth with a population increase targeted at 16.0 in 1981, the crude birth rate at 23.9, and the crude death rate at 6.0. Incentive approaches include: 1) allocating public housing for sterilization acceptors with 2 or fewer children; 2) paying low-income people for undergoing sterilization; 3) providing tax exemption for only 2 children; 4) providing corporate tax exemptions for employee family planning services; and 5) revising family laws to give women inheritance rights. 85% of the couples practise contraception. There is a target female sterilization of 160,000 for 1978 and a deemphasization of condoms and oral contraceptives; in addition, abortion services are being increased. The program budget has increased from a 1975 budget of 3095 million won to 8512 million won (U.S. $17.7 million) in 1977.

Preventing adolescent suicide: a community takes action.

PubMed

Pirruccello, Linda M

2010-05-01

Suicide is the third leading cause of death for adolescents and young people in the United States. The etiology of suicide in this population has eluded policy makers, researchers, and communities. Although many suicide prevention programs have been developed and implemented, few are evidence-based in their effectiveness in decreasing suicide rates. In one northern California community, adolescent suicide has risen above the state's average. Two nurses led an effort to develop and implement an innovative grassroots community suicide prevention project targeted at eliminating any further teen suicide. The project consisted of a Teen Resource Card, a community resource brochure targeted at teens, and education for the public and school officials to raise awareness about this issue. This article describes this project for other communities to use as a model. Risk and protective factors are described, and a comprehensive background of adolescent suicide is provided.

Endocrine toxicity of immune checkpoint inhibitors: essential crosstalk between endocrinologists and oncologists.

PubMed

Illouz, Frédéric; Briet, Claire; Cloix, Lucie; Le Corre, Yannick; Baize, Nathalie; Urban, Thierry; Martin, Ludovic; Rodien, Patrice

2017-08-01

Two types of immune checkpoint inhibitors, both antibodies that target cytotoxic T-lymphocyte antigen-4 and those that target programmed cell death-protein 1, have been approved for use in melanoma, non-small-cell lung cancer, and renal cell carcinoma as first-line or second-line therapy. Their adverse events are primarily regarded as immune-related adverse events. We felt it was important to pinpoint and discuss certain preconceptions or misconceptions regarding thyroid dysfunction, hypophysitis, and diabetes induced by immune checkpoint inhibitors. We have identified areas of uncertainty and unmet requirements, including essential interaction between endocrinologists and oncologists. Five issues have been identified for discussion: (1) diagnosis of endocrine toxicity, (2) assessment of toxicity severity, (3) treatment of toxicity, (4) withdrawal or continuation of immunotherapy, (5) preventive action. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers

PubMed Central

LaBelle, James L.; Katz, Samuel G.; Bird, Gregory H.; Gavathiotis, Evripidis; Stewart, Michelle L.; Lawrence, Chelsea; Fisher, Jill K.; Godes, Marina; Pitter, Kenneth; Kung, Andrew L.; Walensky, Loren D.

2012-01-01

Cancer cells subvert the natural balance between cellular life and death, achieving immortality through pathologic enforcement of survival pathways and blockade of cell death mechanisms. Pro-apoptotic BCL-2 family proteins are frequently disarmed in relapsed and refractory cancer through genetic deletion or interaction-based neutralization by overexpressed antiapoptotic proteins, resulting in resistance to chemotherapy and radiation treatments. New pharmacologic strategies are urgently needed to overcome these formidable apoptotic blockades. We harnessed the natural killing activity of BCL-2–interacting mediator of cell death (BIM), which contains one of the most potent BH3 death domains of the BCL-2 protein family, to restore BH3-dependent cell death in resistant hematologic cancers. A hydrocarbon-stapled peptide modeled after the BIM BH3 helix broadly targeted BCL-2 family proteins with high affinity, blocked inhibitory antiapoptotic interactions, directly triggered proapoptotic activity, and induced dose-responsive and BH3 sequence–specific cell death of hematologic cancer cells. The therapeutic potential of stapled BIM BH3 was highlighted by the selective activation of cell death in the aberrant lymphoid infiltrates of mice reconstituted with BIM-deficient bone marrow and in a human AML xenograft model. Thus, we found that broad and multimodal targeting of the BCL-2 family pathway can overcome pathologic barriers to cell death. PMID:22622039

Radon and lung cancer: a cost-effectiveness analysis.

PubMed Central

Ford, E S; Kelly, A E; Teutsch, S M; Thacker, S B; Garbe, P L

1999-01-01

OBJECTIVES: This study examined the cost-effectiveness of general and targeted strategies for residential radon testing and mitigation in the United States. METHODS: A decision-tree model was used to perform a cost-effectiveness analysis of preventing radon-associated deaths from lung cancer. RESULTS: For a radon threshold of 4 pCi/L, the estimated costs to prevent 1 lung cancer death are about $3 million (154 lung cancer deaths prevented), or $480,000 per life-year saved, based on universal radon screening and mitigation, and about $2 million (104 lung cancer deaths prevented), or $330,000 per life-year saved, if testing and mitigation are confined to geographic areas at high risk for radon exposure. For mitigation undertaken after a single screening test and after a second confirmatory test, the estimated costs are about $920,000 and $520,000, respectively, to prevent a lung cancer death with universal screening and $130,000 and $80,000 per life-year for high risk screening. The numbers of preventable lung cancer deaths are 811 and 527 for universal and targeted approaches, respectively. CONCLUSIONS: These data suggest possible alternatives to current recommendations. PMID:10076484

Predictors of neurologic and nonneurologic death in patients with brain metastasis initially treated with upfront stereotactic radiosurgery without whole-brain radiation therapy

PubMed Central

Johnson, Adam G.; Ruiz, Jimmy; Isom, Scott; Lucas, John T.; Hinson, William H.; Watabe, Kounosuke; Laxton, Adrian W.; Tatter, Stephen B.; Chan, Michael D.

2017-01-01

Abstract Background. In this study we attempted to discern the factors predictive of neurologic death in patients with brain metastasis treated with upfront stereotactic radiosurgery (SRS) without whole brain radiation therapy (WBRT) while accounting for the competing risk of nonneurologic death. Methods. We performed a retrospective single-institution analysis of patients with brain metastasis treated with upfront SRS without WBRT. Competing risks analysis was performed to estimate the subdistribution hazard ratios (HRs) for neurologic and nonneurologic death for predictor variables of interest. Results. Of 738 patients treated with upfront SRS alone, neurologic death occurred in 226 (30.6%), while nonneurologic death occurred in 309 (41.9%). Multivariate competing risks analysis identified an increased hazard of neurologic death associated with diagnosis-specific graded prognostic assessment (DS-GPA) ≤ 2 (P = .005), melanoma histology (P = .009), and increased number of brain metastases (P<.001), while there was a decreased hazard associated with higher SRS dose (P = .004). Targeted agents were associated with a decreased HR of neurologic death in the first 1.5 years (P = .04) but not afterwards. An increased hazard of nonneurologic death was seen with increasing age (P =.03), nonmelanoma histology (P<.001), presence of extracranial disease (P<.001), and progressive systemic disease (P =.004). Conclusions. Melanoma, DS-GPA, number of brain metastases, and SRS dose are predictive of neurologic death, while age, nonmelanoma histology, and more advanced systemic disease are predictive of nonneurologic death. Targeted agents appear to delay neurologic death. PMID:27571883

USDA Forest Service, Pacific Southwest Research Station Sudden Oak Death Research Program: 2001-2005

Treesearch

Patrick J. Shea

2006-01-01

The Pacific Southwest Research Station (PSW), U.S. Department of Agriculture (USDA) Forest Service initiated the Sudden Oak Death Research (SOD) Program in late 2000. The program was prompted by late fiscal year funding dedicated directly to begin research on this newly discovered disease. The history of discovery of Phytophthora ramorum, the...

Genetic Approaches to Reveal the Connectivity of Adult-Born Neurons

PubMed Central

Arenkiel, Benjamin R.

2011-01-01

Much has been learned about the environmental and molecular factors that influence the division, migration, and programmed cell death of adult-born neurons in the mammalian brain. However, detailed knowledge of the mechanisms that govern the formation and maintenance of functional circuit connectivity via adult neurogenesis remains elusive. Recent advances in genetic technologies now afford the ability to precisely target discrete brain tissues, neuronal subtypes, and even single neurons for vital reporter expression and controlled activity manipulations. Here, I review current viral tracing methods, heterologous receptor expression systems, and optogenetic technologies that hold promise toward elucidating the wiring diagrams and circuit properties of adult-born neurons. PMID:21519388

Population-based estimate of trauma-related deaths for law enforcement personnel: Risks for death are higher and increasing over time.

PubMed

Eastman, Alexander L; Cripps, Michael W; Abdelfattah, Kareem R; Inaba, Kenji; Weiser, Thomas G; Spain, David A; Staudenmayer, Kristan L

2017-08-01

Trauma-related deaths remain an important public health problem. One group susceptible to death due to traumatic mechanisms is US law enforcement (LE). We hypothesized that LE officers experienced a higher chance of violent death compared with the general US population and that risks have increased over time. The National Institute on Occupational Safety and Health National Occupational Mortality Surveillance is a population-based survey of occupational deaths. It includes data for workers who died during 1985 to 1998 in one of 30 US states (EARLY period). Additional deaths were added from 23 US states in 1999, 2003 to 2004, 2007 to 2010 (LATE period). Mortality rates are estimated by calculating proportionate mortality ratios (PMR). A PMR above 100 is considered to exceed the average background risk for all occupations. All adults older than 18 years whose primary occupation was listed as "law enforcement worker" were included in the analysis. Law enforcement personnel were more likely to die from an injury compared with the general population (Fig. 1). The overall PMR for injury in EARLY was 111 (95% confidence interval [CI], 108-114; p < 0.01), and for LATE was 118 (95% CI, 110-127; p < 0.01). Four mechanisms of death reached statistical significance: motor vehicle traffic (MVT)-driver, MVT-other, intentional self-harm, and assault/homicide. The highest PMR in EARLY was associated with firearms (PMR, 272; 95% CI, 207-350; p < 0.01). The highest PMR in LATE was associated with death due to being a driver in an MVT (PMR, 194; 95% CI, 169-222; p < 0.01). There were differences in risk of death by race and sex. White females had the highest PMR due to assault and homicide (PMR, 317; 95% CI, 164-554; p < 0.01). All groups had similar risks of death due to intentional self-harm (PMR, 130-171). The risk of death for US LE officers is high and increasing over time, suggesting an at-risk population that requires further interventions. Targeted efforts based on risk factors, such as sex and race, may assist with the development of prevention programs for this population. Epidemiologic study, level II.

Scorched earth strategy

PubMed Central

Wrzaczek, Michael; Brosché, Mikael

2009-01-01

Programmed cell death is a common feature of developmental processes and responses to environmental cues in many multicellular organisms. Examples of programmed cell death in plants are leaf abscission in autumn and the hypersensitive response during pathogen attack. Reactive oxygen species (ROS) have been implicated in the regulation of various types of cell death.1,2 However, the precise mechanics of the involvement of ROS in the processes leading to initiation of cell death and subsequent containment are currently unknown. We recently showed the involvement of an Arabidopsis protein GRIM REAPER in the regulation of ROS-induced cell death under stress conditions.3 Our results indicated that the presence of a truncated protein primes plants for cell death in the presence of ROS leading to ozone sensitivity and increased resistance to hemibiotrophic pathogens. PMID:19820355

Bioeconomic analysis of child-targeted subsidies for artemisinin combination therapies: a cost-effectiveness analysis

PubMed Central

Klein, Eili Y.; Smith, David L.; Cohen, Justin M.; Laxminarayan, Ramanan

2015-01-01

The Affordable Medicines Facility for malaria (AMFm) was conceived as a global market-based mechanism to increase access to effective malaria treatment and prolong effectiveness of artemisinin. Although results from a pilot implementation suggested that the subsidy was effective in increasing access to high-quality artemisinin combination therapies (ACTs), the Global Fund has converted AMFm into a country-driven mechanism whereby individual countries could choose to fund the subsidy from within their country envelopes. Because the initial costs of the subsidy in the pilot countries was higher than expected, countries are also exploring alternatives to a universal subsidy, such as subsidizing only child doses. We examined the incremental cost-effectiveness of a child-targeted policy using an age-structured bioeconomic model of malaria from the provider perspective. Because the vast majority of malaria deaths occur in children, targeting children could potentially improve the cost-effectiveness of the subsidy, though it would avert significantly fewer deaths. However, the benefits of a child-targeted subsidy (i.e. deaths averted) are eroded as leakage (i.e. older individuals taking young child-targeted doses) increases, with few of the benefits of a universal subsidy gained (i.e. reductions in overall prevalence). Although potentially more cost-effective, a child-targeted subsidy must contain measures to reduce the possibility of leakage. PMID:25994293

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization.

PubMed

Pesce, Silvia; Greppi, Marco; Tabellini, Giovanna; Rampinelli, Fabio; Parolini, Silvia; Olive, Daniel; Moretta, Lorenzo; Moretta, Alessandro; Marcenaro, Emanuela

2017-01-01

Programmed death 1 (PD-1) is an immunologic checkpoint that limits immune responses by delivering potent inhibitory signals to T cells on interaction with specific ligands expressed on tumor/virus-infected cells, thus contributing to immune escape mechanisms. Therapeutic PD-1 blockade has been shown to mediate tumor eradication with impressive clinical results. Little is known about the expression/function of PD-1 on human natural killer (NK) cells. We sought to clarify whether human NK cells can express PD-1 and analyze their phenotypic/functional features. We performed multiparametric cytofluorimetric analysis of PD-1 + NK cells and their functional characterization using degranulation, cytokine production, and proliferation assays. We provide unequivocal evidence that PD-1 is highly expressed (PD-1 bright ) on an NK cell subset detectable in the peripheral blood of approximately one fourth of healthy subjects. These donors are always serologically positive for human cytomegalovirus. PD-1 is expressed by CD56 dim but not CD56 bright NK cells and is confined to fully mature NK cells characterized by the NKG2A - KIR + CD57 + phenotype. Proportions of PD-1 bright NK cells were higher in the ascites of a cohort of patients with ovarian carcinoma, suggesting their possible induction/expansion in tumor environments. Functional analysis revealed a reduced proliferative capability in response to cytokines, low degranulation, and impaired cytokine production on interaction with tumor targets. We have identified and characterized a novel subpopulation of human NK cells expressing high levels of PD-1. These cells have the phenotypic characteristics of fully mature NK cells and are increased in patients with ovarian carcinoma. They display low proliferative responses and impaired antitumor activity that can be partially restored by antibody-mediated disruption of PD-1/programmed death ligand interaction. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma

PubMed Central

Kiyasu, Junichi; Miyoshi, Hiroaki; Hirata, Akie; Arakawa, Fumiko; Ichikawa, Ayako; Niino, Daisuke; Sugita, Yasuo; Yufu, Yuji; Choi, Ilseung; Abe, Yasunobu; Uike, Naokuni; Nagafuji, Koji; Okamura, Takashi; Akashi, Koichi; Takayanagi, Ryoichi; Shiratsuchi, Motoaki

2015-01-01

Programmed cell death ligand 1 (PD-L1) is expressed on both select diffuse large B-cell lymphoma (DLBCL) tumor cells and on tumor-infiltrating nonmalignant cells. The programmed cell death 1 (PD-1)/PD-L1 pathway inhibits host antitumor responses; however, little is known about how this pathway functions in the tumor microenvironment. The aim of this study was to determine the clinicopathological impact of PD-L1+ DLBCL. We performed PD-L1/PAX5 double immunostaining in 1253 DLBCL biopsy samples and established a new definition of PD-L1+ DLBCL. We also defined the criteria for microenvironmental PD-L1+ (mPD-L1+) DLBCL (ie, PD-L1– DLBCL in which PD-L1+ nonmalignant cells are abundant in the tumor microenvironment). Of the 273 patients whose clinical information was available, quantitative analysis of PD-1+ tumor-infiltrating lymphocytes (TILs) was performed. The prevalence rates of PD-L1+ and mPD-L1+ DLBCL were 11% and 15.3%, respectively. Both PD-L1+ and mPD-L1+ DLBCL were significantly associated with non–germinal center B-cell (GCB) type and Epstein-Barr virus positivity. The number of PD-1+ TILs was significantly higher in GCB-type tumors and lower in mPD-L1– and PD-L1+ DLBCL. Patients with PD-L1+ DLBCL had inferior overall survival (OS) compared with that in patients with PD-L1– DLBCL (P = .0009). In contrast, there was no significant difference in OS between mPD-L1+ and mPD-L1– DLBCL (P = .31). The expression of PD-L1 maintained prognostic value for OS in multivariate analysis (P = .0323). This is the first report describing the clinicopathological features and outcomes of PD-L1+ DLBCL. Immunotherapy targeting the PD-1/PD-L1 pathway should be considered in this distinct DLBCL subgroup. PMID:26239088

A Comprehensive Analysis of Programmed Cell Death Ligand-1 Expression With the Clone SP142 Antibody in Non-Small-Cell Lung Cancer Patients.

PubMed

Takada, Kazuki; Toyokawa, Gouji; Okamoto, Tatsuro; Shimokawa, Mototsugu; Kozuma, Yuka; Matsubara, Taichi; Haratake, Naoki; Akamine, Takaki; Takamori, Shinkichi; Katsura, Masakazu; Shoji, Fumihiro; Oda, Yoshinao; Maehara, Yoshihiko

2017-09-01

Programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have been identified as novel targets for immunotherapy, with anti-PD-1 therapy currently the standard treatment for non-small-cell lung cancer (NSCLC) patients after the failure of first-line chemotherapy treatment. The recent phase II POPLAR and phase III OAK studies showed that atezolizumab, a representative PD-L1 inhibitor, exhibited a survival benefit compared with standard therapy in patients with NSCLC. We examined PD-L1 expression in NSCLC using the clone SP142 of POPLAR and OAK studies. PD-L1 expression in 499 surgically resected NSCLC patients was evaluated using immunohistochemistry using SP142. We set cutoff values as 1%, 5%, 10%, and 50%. The samples from 189 (37.9%), 119 (23.8%), 71 (14.2%), and 39 (7.8%) patients were positive for PD-L1 expression at cutoff values of 1%, 5%, 10%, and 50%, respectively. Fisher exact tests showed that PD-L1 positivity was significantly associated with male sex, smoking, advanced stage, the presence of vascular invasion, squamous cell carcinoma, and wild type epidermal growth factor receptor gene mutation status at all cutoff values. Univariate and multivariate survival analyses revealed that PD-L1-positive patients had a worse prognosis than PD-L1-negative patients only at the 1% cutoff value. Forest plot analyses showed that the 1% cutoff provided a more sensitive value for the prediction of postoperative prognosis. PD-L1 expression varied greatly according to different cutoff values. This study might be a useful reference to understand the results of POPLAR and OAK studies and to select patients likely to benefit from atezolizumab. Copyright © 2017 Elsevier Inc. All rights reserved.

Social marketing to plan a fall prevention program for Latino construction workers.

PubMed

Menzel, Nancy N; Shrestha, Pramen P

2012-08-01

Latino construction workers experience disparities in occupational death and injury rates. The Occupational Safety and Health Administration funded a fall prevention training program at the University of Nevada, Las Vegas in response to sharp increases in fall-related accidents from 2005 to 2007. The grant's purpose was to improve fall protection for construction workers, with a focus on Latinos. This study assessed the effectiveness of social marketing for increasing fall prevention behaviors. A multi-disciplinary team used a social marketing approach to plan the program. We conducted same day class evaluations and follow-up interviews 8 weeks later. The classes met trainee needs as evidenced by class evaluations and increased safety behaviors. However, Spanish-speaking Latinos did not attend in the same proportion as their representation in the Las Vegas population. A social marketing approach to planning was helpful to customize the training to Latino worker needs. However, due to the limitations of behavior change strategies, future programs should target employers and their obligation to provide safer workplaces. Copyright © 2012 Wiley Periodicals, Inc.

High stability of nuclear microsatellite loci during the early stages of somatic embryogenesis in Norway spruce.

PubMed

Helmersson, Andreas; von Arnold, Sara; Burg, Kornel; Bozhkov, Peter V

2004-10-01

Somatic embryos of Norway spruce (Picea abies (L.) Karst.) differentiate from proembryogenic masses (PEMs), which are subject to autodestruction through programmed cell death. In PEMs, somatic embryo formation and activation of programmed cell death are interrelated processes. We sought to determine if activation of programmed cell death in PEMs is caused by genetic aberrations during somatic embryogenesis. Based on the finding that withdrawal of auxin and cytokinin induces programmed cell death in PEMs, 1-week-old cell suspensions were cultured in medium either with or without auxin and cytokinin and then transferred to maturation medium containing abscisic acid. We analyzed the stability of three nuclear simple sequence repeat (SSR) microsatellite markers at successive stages of somatic embryogenesis in two cell lines. There were no mutations at the SSR loci at any of the successive developmental stages from PEMs to cotyledonary embryos, irrespective of whether or not the proliferation medium in which cell suspensions had been cultured contained auxin or cytokinin. The morphologies of plants regenerated from the cultures were similar, although withdrawal of auxin and cytokinin significantly stimulated the yield of both embryos and plants. We conclude, therefore, that the high genetic stability of somatic embryos in Norway spruce is unaffected by the induction of programmed cell death caused by withdrawal of auxin and cytokinin.

Calibrating the imaging and therapy performance of magneto-fluorescent gold nanoshells for breast cancer

NASA Astrophysics Data System (ADS)

Dowell, Adam; Chen, Wenxue; Biswal, Nrusingh; Ayala-Orozco, Ciceron; Giuliano, Mario; Schiff, Rachel; Halas, Naomi J.; Joshi, Amit

2012-03-01

Gold nanoshells with NIR plasmon resonance can be modified to simultaneously enhance conjugated NIR fluorescence dyes and T2 contrast of embedded iron-oxide nanoparticles, and molecularly targeted to breast and other cancers. We calibrated the theranostic performance of magneto-fluorescent nanoshells, and contrasted the performance of molecularly targeted and untargeted nanoshells for breast cancer therapy, employing MCF-7L and their HER2 overexpressing derivative MCF-7/HER2-18 breast cancer cells as in vitro model systems. Silica core gold nanoshells with plasmon resonance on ~810 nm were doped with NIR dye ICG and ~10 nm iron-oxide nanoparticles in a ~20 nm epilayer of silica. A subset of nanoshells was conjugated to antibodies targeting HER2. Cell viability with varying laser power levels in presence and absence of bare and HER2-targeted nanoshells was assessed by calcein and propidium iodide staining. For MCF-7L cells, increasing power resulted in increased cell death (F=5.63, p=0.0018), and bare nanoshells caused more cell death than HER2-targeted nanoshells or laser treatment alone (F=30.13, p<0.001). For MCF-7/HER2-18 cells, death was greater with HER2-targeted nanoshells and was independent of laser power. This study demonstrates the capability of magneto-fluorescent nanocomplexes for imaging and therapy of breast cancer cells, and the advantages of targeting receptors unique to cancer cells.

Role of a Transcriptional Regulator in Programmed Cell Death and Plant Development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Julie M. Stone

2008-09-13

The long-term goal of this research is to understand the role(s) and molecular mechanisms of programmed cell death (PCD) in the controlling plant growth, development and responses to biotic and abiotic stress. We developed a genetic selection scheme to identify A. thaliana FB1-resistant (fbr) mutants as a way to find genes involved in PCD (Stone et al., 2000; Stone et al., 2005; Khan and Stone, 2008). The disrupted gene in fbr6 (AtSPL14) responsible for the FB1-insensitivity and plant architecture phenotypes encodes a plant-specific SBP DNA-binding domain transcriptional regulator (Stone et al., 2005; Liang et al., 2008). This research plan ismore » designed to fill gaps in the knowledge about the role of SPL14 in plant growth and development. The work is being guided by three objectives aimed at determining the pathways in which SPL14 functions to modulate PCD and/or plant development: (1) determine how SPL14 functions in plant development, (2) identify target genes that are directly regulated by SPL14, and (3) identify SPL14 modifications and interacting proteins. We made significant progress during the funding period. Briefly, some major accomplishments are highlighted below: (1) To identify potential AtSPL14 target genes, we identified a consensus DNA binding site for the AtSPL14 SBP DNA-binding domain using systematic evolution of ligands by exponential selection (SELEX) and site-directed mutagenesis (Liang et al., 2008). This consensus binding site was used to analyze Affymetrix microarray gene expression data obtained from wild-type and fbr6 mutant plants to find possible AtSPL14-regulated genes. These candidate AtSPL14-regulated genes are providing new information on the molecular mechanisms linking plant PCD and plant development through modulation of the 26S proteasome. (2) Transgenic plants expressing epitope-tagged versions of AtSPL14 are being used to confirm the AtSPL14 targets (by ChIP-PCR) and further dissect the molecular interactions (Nazarenus, Liang and Stone, in preparation) (3) Double mutants generated between fbr6 and various accelerated cell death (acd) mutants indicate that sphingolipid metabolism is influenced by AtSPL14 and sphingolipidomics profiling supports this conclusion (Lin, Markham and Stone, in preparation). (4) A new set of phenotypes have been uncovered in the original fbr6-1 mutant, including a short-root phenotype related to auxin signaling and altered photosynthetic parameters related to stomatal density and conductance (Lin and Stone, in preparation; Lin, Madhavan and Stone, in preparation). Additional AtSPL14-related mutants and transgenic plants have been generated to effectively dissect the functions of AtSPL14, including a dominant negative fbr6-2 allele and transgenic plants overexpressing FBR6/AtSPL14 that display an accelerated cell death (acd) phenotype.« less

Characterization of image heterogeneity using 2D Minkowski functionals increases the sensitivity of detection of a targeted MRI contrast agent.

PubMed

Canuto, Holly C; McLachlan, Charles; Kettunen, Mikko I; Velic, Marko; Krishnan, Anant S; Neves, Andre' A; de Backer, Maaike; Hu, D-E; Hobson, Michael P; Brindle, Kevin M

2009-05-01

A targeted Gd(3+)-based contrast agent has been developed that detects tumor cell death by binding to the phosphatidylserine (PS) exposed on the plasma membrane of dying cells. Although this agent has been used to detect tumor cell death in vivo, the differences in signal intensity between treated and untreated tumors was relatively small. As cell death is often spatially heterogeneous within tumors, we investigated whether an image analysis technique that parameterizes heterogeneity could be used to increase the sensitivity of detection of this targeted contrast agent. Two-dimensional (2D) Minkowski functionals (MFs) provided an automated and reliable method for parameterization of image heterogeneity, which does not require prior assumptions about the number of regions or features in the image, and were shown to increase the sensitivity of detection of the contrast agent as compared to simple signal intensity analysis. (c) 2009 Wiley-Liss, Inc.

[Effect of family cohesion, subjective happiness and other factors on death anxiety in Korean elders].

PubMed

Jo, Kae Hwa; Song, Byung Sook

2012-10-01

The purposes of this study were to explore the effects of family cohesion and subjective happiness on death anxiety of Korean elders and to identify other factors contributing to death anxiety. The participants were 280 elders who lived in P metropolitan city. Data were collected between November 5, 2011 and January 12, 2012 using the Short Portable Mental Status Questionnaire (SPMSQ), Family Cohesion Evaluation Scale, Subjective Happiness Scale, and Fear of Death Scale (FODS). Data were analyzed using the SPSS/WIN 19.0 program. Family cohesion, marital status, religious activity, perceived health status, and subjective happiness were included in the factors affecting death anxiety of Korean elders. These variables explained 50.1% of death anxiety. The results of the study indicate that these variables should be considered in developing nursing intervention programs to decrease death anxiety and increase family cohesion and subjective happiness for life integration in Korean elders.

Mortality among Hispanic drug users in Puerto Rico.

PubMed

Robles, Rafaela R; Matos, Tomás D; Colón, Héctor M; Sahai, Hardeo; Reyes, Juan C; Marrero, C Amalia; Calderón, José M

2003-12-01

This paper assesses mortality rate for a cohort of drug users in Puerto Rico compared with that of the Island's general population, examining causes of death and estimating relative risk of death. Date and cause of death were obtained from death certificates during 1998. Vital status was confirmed through contact with subjects, family, and friends. HIV/AIDS was the major cause of death (47.7%), followed by homicide (14.6%), and accidental poisoning (6.3%). Females had higher relative risk of death than males in all age categories. Not living with a sex partner and not receiving drug treatment were related to higher mortality due to HIV/AIDS. Drug injection was the only variable explaining relative risk of death due to overdose. Puerto Rico needs to continue developing programs to prevent HIV/AIDS among drug users. Special attention should be given to young women, who appear to be in greatest need of programs to prevent early mortality.

Trends in Causes of Adult Deaths among the Urban Poor: Evidence from Nairobi Urban Health and Demographic Surveillance System, 2003-2012.

PubMed

Mberu, Blessing; Wamukoya, Marylene; Oti, Samuel; Kyobutungi, Catherine

2015-06-01

What kills people around the world and how it varies from place to place and over time is critical in mapping the global burden of disease and therefore, a relevant public health question, especially in developing countries. While more than two thirds of deaths worldwide are in developing countries, little is known about the causes of death in these nations. In many instances, vital registration systems are nonexistent or at best rudimentary, and even when deaths are registered, data on the cause of death in particular local contexts, which is an important step toward improving context-specific public health, are lacking. In this paper, we examine the trends in the causes of death among the urban poor in two informal settlements in Nairobi by applying the InterVA-4 software to verbal autopsy data. We examine cause of death data from 2646 verbal autopsies of deaths that occurred in the Nairobi Urban Health and Demographic Surveillance System (NUHDSS) between 1 January 2003 and 31 December 2012 among residents aged 15 years and above. The data is entered into the InterVA-4 computer program, which assigns cause of death using probabilistic modeling. The results are presented as annualized trends from 2003 to 2012 and disaggregated by gender and age. Over the 10-year period, the three major causes of death are tuberculosis (TB), injuries, and HIV/AIDS, accounting for 26.9, 20.9, and 17.3% of all deaths, respectively. In 2003, HIV/AIDS was the highest cause of death followed by TB and then injuries. However, by 2012, TB and injuries had overtaken HIV/AIDS as the major causes of death. When this is examined by gender, HIV/AIDS was consistently higher for women than men across all the years generally by a ratio of 2 to 1. In terms of TB, it was more evenly distributed across the years for both males and females. We find that there is significant gender variation in deaths linked to injuries, with male deaths being higher than female deaths by a ratio of about 4 to 1. We also find a fifteen percentage point increase in the incidences of male deaths due to injuries between 2003 and 2012. For women, the corresponding deaths due to injuries remain fairly stable throughout the period. We find cardiovascular diseases as a significant cause of death over the period, with overall mortality increasing steadily from 1.6% in 2003 to 8.1% in 2012, and peaking at 13.7% in 2005 and at 12.0% in 2009. These deaths were consistently higher among women. We identified substantial variations in causes of death by age, with TB, HIV/AIDS, and CVD deaths lowest among younger residents and increasing with age, while injury-related deaths are highest among the youngest adults 15-19 and steadily declined with age. Also, deaths related to neoplasms and respiratory tract infections (RTIs) were prominent among older adults 50 years and above, especially since 2005. Emerging at this stage is evidence that HIV/AIDS, TB, injuries, and cardiovascular disease are linked to approximately 73% of all adult deaths among the urban poor in Nairobi slums of Korogocho and Viwandani in the last 10 years. While mortality related to HIV/AIDS is generally declining, we see an increasing proportion of deaths due to TB, injuries, and cardiovascular diseases. In sum, substantial epidemiological transition is ongoing in this local context, with deaths linked to communicable diseases declining from 66% in 2003 to 53% in 2012, while deaths due to noncommunicable causes experienced a four-fold increase from 5% in 2003 to 21.3% in 2012, together with another two-fold increase in deaths due to external causes (injuries) from 11% in 2003 to 22% in 2012. It is important to also underscore the gender dimensions of the epidemiological transition clearly visible in the mix. Finally, the elevated levels of disadvantage of slum dwellers in our analysis relative to other population subgroups in Kenya continue to demonstrate appreciable deterioration of key urban health and social indicators, highlighting the need for a deliberate strategic focus on the health needs of the urban poor in policy and program efforts toward achieving international goals and national health and development targets.

The role of the Fas/FasL signaling pathway in environmental toxicant-induced testicular cell apoptosis: An update.

PubMed

Wang, Mei; Su, Ping

2018-04-01

The Fas/FasL signaling pathway is one of the major pathways that regulate apoptosis. Increasing studies have shown that the activation of the Fas/FasL signaling pathway is closely associated with testicular cell apoptosis. However, the mechanism involved is still unclear. We discuss recent findings regarding the molecular mechanisms by which environmental toxicants induce testicular pathology via Fas/FasL signaling. These findings suggest that Fas/FasL signaling is employed to impact the sensitivity (a response to external factors) of germ cells, disrupt steroidogenic hormone and cytokine metabolism mediated by Sertoli cells, and elicit the activation of NFAT (nuclear factor of activated T-cells) in Leydig cell apoptosis. Consequently, degeneration of testicular somatic (Sertoli and Leydig) and spermatogenic cells, leads to decreased numbers of mature sperm and subsequently translates into infertility issues. Collectively, these findings illustrate that it is beneficial to develop potential targets for a new generation of new pharmaceutical therapies that would alleviate testicular dysfunctions. BTB: blood-testis barrier; DD: death domains; DR3: death receptor 3; DR4: death receptor 4; DR5: death receptor 5; DED: death effector domain; DISC: death-inducing signaling complex; ERα: estrogen receptor alpha; FADD: Fas-associated death domain; FSH: follicle- stimulating hormone; IL-1β: interleukin 1 beta; LH: luteinizing hormone; LPS: lipopolysaccharide; mFas: membrane Fas; MMP2: matrix metalloproteinase-2; MTA1: metastasis-associated protein 1; NAC: N-acetylcysteine; NCCD: the Nomenclature Committee on Cell Death; NFAT: nuclear factor of activated T-cells; NF-kB: nuclear transcription factor-kappaB; NO: nitric oxide; NP: 4-nonylphenol; PCD: programmed cell death; PP1/PP2A: protein phosphatase 1 and 2A; ROS: reactive oxygen species; sFas: soluble Fas; T: testosterone; TGF-β: transforming growth factor-beta; THD: TNF homology domain; TIMP-2: tissue inhibitor of metalloproteinase-2; TNF: tumor necrosis factor; TNF-α: tumor necrosis factor-alpha; TNF-R1: Tumor necrosis factor receptor 1; TNFRSF1A: TNF receptor superfamily member 1A.

Economics of an adolescent meningococcal conjugate vaccination catch-up campaign in the United States.

PubMed

Ortega-Sanchez, Ismael R; Meltzer, Martin I; Shepard, Colin; Zell, Elizabeth; Messonnier, Mark L; Bilukha, Oleg; Zhang, Xinzhi; Stephens, David S; Messonnier, Nancy E

2008-01-01

In June 2005, the Advisory Committee on Immunization Practices recommended the newly licensed quadrivalent meningococcal conjugate vaccine for routine use among all US children aged 11 years. A 1-time catch-up vaccination campaign for children and adolescents aged 11-17 years, followed by routine annual immunization of each child aged 11 years, could generate immediate herd immunity benefits. The objective of our study was to analyze the cost-effectiveness of a catch-up vaccination campaign with quadrivalent meningococcal conjugate vaccine for children and adolescents aged 11-17 years. We built a probabilistic model of disease burden and economic impacts for a 10-year period with and without a program of adolescent catch-up meningococcal vaccination, followed by 9 years of routine immunization of children aged 11 years. We used US age- and serogroup-specific surveillance data on incidence and mortality. Assumptions related to the impact of herd immunity were drawn from experience with routine meningococcal vaccination in the United Kingdom. We estimated costs per case, deaths prevented, life-years saved, and quality-adjusted life-years saved. With herd immunity, the catch-up and routine vaccination program for adolescents would prevent 8251 cases of meningococcal disease in a 10-year period (a 48% decrease). Excluding program costs, this catch-up and routine vaccination program would save US$551 million in direct costs and $920 million in indirect costs, including costs associated with permanent disability and premature death. At $83 per vaccinee, the catch-up vaccination would cost society approximately $223,000 per case averted, approximately $2.6 million per death prevented, approximately $127,000 per life-year saved, and approximately $88,000 per quality-adjusted life-year saved. Targeting counties with a high incidence of disease decreased the cost per life-year saved by two-thirds. Although costly, catch-up and routine vaccination of adolescents can have a substantial impact on meningococcal disease burden. Because of herd immunity, catch-up and routine vaccination cost per life-year saved could be up to one-third less than that previously assessed for routine vaccination of children aged 11 years.

Strategic targeting of advance care planning interventions: the Goldilocks phenomenon.

PubMed

Billings, J Andrew; Bernacki, Rachelle

2014-04-01

Strategically selecting patients for discussions and documentation about limiting life-sustaining treatments-choosing the right time along the end-of-life trajectory for such an intervention and identifying patients at high risk of facing end-of-life decisions-can have a profound impact on the value of advance care planning (ACP) efforts. Timing is important because the completion of an advance directive (AD) too far from or too close to the time of death can lead to end-of-life decisions that do not optimally reflect the patient's values, goals, and preferences: a poorly chosen target patient population that is unlikely to need an AD in the near future may lead to patients making unrealistic, hypothetical choices, while assessing preferences in the emergency department or hospital in the face of a calamity is notoriously inadequate. Because much of the currently studied ACP efforts have led to a disappointingly small proportion of patients eventually benefitting from an AD, careful targeting of the intervention should also improve the efficacy of such projects. A key to optimal timing and strategic selection of target patients for an ACP program is prognostication, and we briefly highlight prognostication tools and studies that may point us toward high-value AD interventions.

Nuclear and Fluorescent Labeled PD-1-Liposome-DOX-64Cu/IRDye800CW Allows Improved Breast Tumor Targeted Imaging and Therapy.

PubMed

Du, Yang; Liang, Xiaolong; Li, Yuan; Sun, Ting; Jin, Zhengyu; Xue, Huadan; Tian, Jie

2017-11-06

The overexpression of programmed cell death-1 (PD-1) in tumors as breast cancer makes it a possible target for cancer imaging and therapy. Advances in molecular imaging, including radionuclide imaging and near-infrared fluorescence (NIRF) imaging, enable the detection of tumors with high sensitivity. In this study, we aim to develop a novel PD-1 antibody targeted positron emission tomography (PET) and NIRF labeled liposome loaded with doxorubicin (DOX) and evaluate its application for in vivo cancer imaging and therapy. IRDye800CW and 64 Cu were conjugated to liposomes with PD-1 antibody labeling, and DOX was inside the liposomes to form theranostic nanoparticles. The 4T1 tumors were successfully visualized with PD-1-Liposome-DOX- 64 Cu/IRDye800CW using NIRF/PET imaging. The bioluminescent imaging (BLI) results showed that tumor growth was significantly inhibited in the PD-1-Liposome-DOX-treated group than the IgG control. Our results highlight the potential of using dual-labeled theranostic PD-1 mAb-targeted Liposome-DOX- 64 Cu/IRDye800CW for the management of breast tumor.

7 CFR 1430.222 - Death, incompetency, or disappearance.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Death, incompetency, or disappearance. 1430.222 Section 1430.222 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT... Contract Program § 1430.222 Death, incompetency, or disappearance. In the case of death, incompetency...

7 CFR 1430.311 - Death, incompetence, or disappearance.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Death, incompetence, or disappearance. 1430.311 Section 1430.311 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT... Disaster Assistance Payment Program § 1430.311 Death, incompetence, or disappearance. In the case of death...

7 CFR 1429.112 - Death, incompetence, or disappearance.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 10 2013-01-01 2013-01-01 false Death, incompetence, or disappearance. 1429.112 Section 1429.112 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT... ASSISTANCE PAYMENT PROGRAM § 1429.112 Death, incompetence, or disappearance. (a) In the case of death...

7 CFR 1430.311 - Death, incompetence, or disappearance.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 10 2012-01-01 2012-01-01 false Death, incompetence, or disappearance. 1430.311 Section 1430.311 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT... Disaster Assistance Payment Program § 1430.311 Death, incompetence, or disappearance. In the case of death...

7 CFR 1430.311 - Death, incompetence, or disappearance.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 10 2014-01-01 2014-01-01 false Death, incompetence, or disappearance. 1430.311 Section 1430.311 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT... Disaster Assistance Payment Program § 1430.311 Death, incompetence, or disappearance. In the case of death...

7 CFR 1430.222 - Death, incompetency, or disappearance.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 10 2012-01-01 2012-01-01 false Death, incompetency, or disappearance. 1430.222 Section 1430.222 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT... Contract Program § 1430.222 Death, incompetency, or disappearance. In the case of death, incompetency...

7 CFR 1429.112 - Death, incompetence, or disappearance.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 10 2012-01-01 2012-01-01 false Death, incompetence, or disappearance. 1429.112 Section 1429.112 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT... ASSISTANCE PAYMENT PROGRAM § 1429.112 Death, incompetence, or disappearance. (a) In the case of death...

7 CFR 1429.112 - Death, incompetence, or disappearance.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 10 2014-01-01 2014-01-01 false Death, incompetence, or disappearance. 1429.112 Section 1429.112 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT... ASSISTANCE PAYMENT PROGRAM § 1429.112 Death, incompetence, or disappearance. (a) In the case of death...

7 CFR 1430.222 - Death, incompetency, or disappearance.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 10 2013-01-01 2013-01-01 false Death, incompetency, or disappearance. 1430.222 Section 1430.222 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT... Contract Program § 1430.222 Death, incompetency, or disappearance. In the case of death, incompetency...

7 CFR 1430.222 - Death, incompetency, or disappearance.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 10 2011-01-01 2011-01-01 false Death, incompetency, or disappearance. 1430.222 Section 1430.222 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT... Contract Program § 1430.222 Death, incompetency, or disappearance. In the case of death, incompetency...

7 CFR 1430.222 - Death, incompetency, or disappearance.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 10 2014-01-01 2014-01-01 false Death, incompetency, or disappearance. 1430.222 Section 1430.222 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT... Contract Program § 1430.222 Death, incompetency, or disappearance. In the case of death, incompetency...

7 CFR 1430.311 - Death, incompetence, or disappearance.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 10 2011-01-01 2011-01-01 false Death, incompetence, or disappearance. 1430.311 Section 1430.311 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT... Disaster Assistance Payment Program § 1430.311 Death, incompetence, or disappearance. In the case of death...

7 CFR 1430.311 - Death, incompetence, or disappearance.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 10 2013-01-01 2013-01-01 false Death, incompetence, or disappearance. 1430.311 Section 1430.311 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT... Disaster Assistance Payment Program § 1430.311 Death, incompetence, or disappearance. In the case of death...

Suicide Prevention among High School Students: Evaluation of a Nonrandomized Trial of a Multi-Stage Suicide Screening Program

ERIC Educational Resources Information Center

Torcasso, Gina; Hilt, Lori M.

2017-01-01

Background: Suicide is a leading cause of death among youth. Suicide screening programs aim to identify mental health issues and prevent death by suicide. Objective: The present study evaluated outcomes of a multi-stage screening program implemented over 3 school years in a moderately-sized Midwestern high school. Methods: One hundred ninety-three…

Cardioprotective activity of urocortin by preventing caspase-independent, non-apoptotic death in cultured neonatal rat cardiomyocytes exposed to ischemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takatani-Nakase, Tomoka, E-mail: nakase@mukogawa-u.ac.jp; Takahashi, Koichi, E-mail: koichi@mukogawa-u.ac.jp

Research highlights: {yields} Ischemia induces high level of iPLA{sub 2} resulting in caspase-independent myocyte death. {yields} Urocortin causes iPLA{sub 2} down-regulation leading to avoidance of non-apoptotic death. {yields} The survival-promoting effect of urocortin is abrogated by CRH receptor antagonist. -- Abstract: Caspase-independent, non-apoptotic cell death in ischemic heart disease is considered to be one of the important therapeutic targets, however, the detailed mechanisms of this cell death process are not clear. In this study, we investigated the mechanisms of non-apoptotic cell death in cultured neonatal rat cardiomyocytes during ischemia, and the cardioprotection by preventing the mechanisms. We found that ischemiamore » caused elevation of the phospholipase A{sub 2} (iPLA{sub 2}) expression in the myocytes, leading to distinctive non-apoptotic nuclear shrinkage, and cell death. Moreover, we investigated whether the potent cardioprotective corticotropin-releasing hormone (CRH), urocortin, which had been less focused on non-apoptotic cell death, inhibits the ischemic myocyte death. Ischemia-augmented nuclear shrinkage of the myocytes was suppressed by the pretreatment of {approx}10 nM urocortin before the cells were exposed to ischemia. Urocortin could significantly suppress the expression and activity of iPLA{sub 2}, resulting in preventing the ischemia-induced cell death. The survival-promoting effect of urocortin was abrogated by the CRH receptor antagonist astressin. These findings provide the first evidence linking the targets of the urocortin-mediated cardioprotection to the suppression of the caspase-independent, non-apoptotic death in cardiac myocytes exposed to ischemia.« less

In Planta Functional Analysis and Subcellular Localization of the Oomycete Pathogen Plasmopara viticola Candidate RXLR Effector Repertoire

PubMed Central

Liu, Yunxiao; Lan, Xia; Song, Shiren; Yin, Ling; Dry, Ian B.; Qu, Junjie; Xiang, Jiang; Lu, Jiang

2018-01-01

Downy mildew is one of the most destructive diseases of grapevine, causing tremendous economic loss in the grape and wine industry. The disease agent Plasmopara viticola is an obligate biotrophic oomycete, from which over 100 candidate RXLR effectors have been identified. In this study, 83 candidate RXLR effector genes (PvRXLRs) were cloned from the P. viticola isolate “JL-7-2” genome. The results of the yeast signal sequence trap assay indicated that most of the candidate effectors are secretory proteins. The biological activities and subcellular localizations of all the 83 effectors were analyzed via a heterologous Agrobacterium-mediated Nicotiana benthamiana expression system. Results showed that 52 effectors could completely suppress cell death triggered by elicitin, 10 effectors could partially suppress cell death, 11 effectors were unable to suppress cell death, and 10 effectors themselves triggered cell death. Live-cell imaging showed that the majority of the effectors (76 of 83) could be observed with informative fluorescence signals in plant cells, among which 34 effectors were found to be targeted to both the nucleus and cytosol, 29 effectors were specifically localized in the nucleus, and 9 effectors were targeted to plant membrane system. Interestingly, three effectors PvRXLR61, 86 and 161 were targeted to chloroplasts, and one effector PvRXLR54 was dually targeted to chloroplasts and mitochondria. However, western blot analysis suggested that only PvRXLR86 carried a cleavable N-terminal transit peptide and underwent processing in planta. Many effectors have previously been predicted to target organelles, however, to the best of our knowledge, this is the first study to provide experimental evidence of oomycete effectors targeted to chloroplasts and mitochondria. PMID:29706971

Novel targets for sensitizing breast cancer cells to TRAIL-induced apoptosis with siRNA delivery.

PubMed

Thapa, Bindu; Bahadur Kc, Remant; Uludağ, Hasan

2018-02-01

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in variety of cancer cells without affecting most normal cells, which makes it a promising agent for cancer therapy. However, TRAIL therapy is clinically not effective due to resistance induction. To identify novel regulators of TRAIL that can aid in therapy, protein targets whose silencing sensitized breast cancer cells against TRAIL were screened with an siRNA library against 446 human apoptosis-related proteins in MDA-231 cells. Using a cationic lipopolymer (PEI-αLA) for delivery of library members, 16 siRNAs were identified that sensitized the TRAIL-induced death in MDA-231 cells. The siRNAs targeting BCL2L12 and SOD1 were further evaluated based on the novelty and their ability to sensitize TRAIL induced cell death. Silencing both targets sensitized TRAIL-mediated cell death in MDA-231 cells as well as TRAIL resistant breast cancer cells, MCF-7. Combination of TRAIL and siRNA silencing BCL2L12 had no effect in normal human umbilical vein cells and human bone marrow stromal cell. The silencing of BCL2L12 and SOD1 enhanced TRAIL-mediated apoptosis in MDA-231 cells via synergistically activating capsase-3 activity. Hence, here we report siRNAs targeting BCL2L12 and SOD1 as a novel regulator of TRAIL-induced cell death in breast cancer cells, providing a new approach for enhancing TRAIL therapy for breast cancer. The combination of siRNA targeting BCL2L12 and TRAIL can be a highly effective synergistic pair in breast cancer cells with minimal effect on the non-transformed cells. © 2017 UICC.

The Zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim

PubMed Central

Jurado, Sabine; Gleeson, Kimberly; O’Donnell, Kristy; Izon, David J.; Walkley, Carl R.; Strasser, Andreas; Tarlinton, David M.

2012-01-01

Developing B lymphocytes expressing defective or autoreactive pre-B or B cell receptors (BCRs) are eliminated by programmed cell death, but how the balance between death and survival signals is regulated to prevent immunodeficiency and autoimmunity remains incompletely understood. In this study, we show that absence of the essential ATM (ataxia telangiectasia mutated) substrate Chk2-interacting Zn2+-finger protein (ASCIZ; also known as ATMIN/ZNF822), a protein with dual functions in the DNA damage response and as a transcription factor, leads to progressive cell loss from the pre-B stage onwards and severely diminished splenic B cell numbers in mice. This lymphopenia cannot be suppressed by deletion of p53 or complementation with a prearranged BCR, indicating that it is not caused by impaired DNA damage responses or defective V(D)J recombination. Instead, ASCIZ-deficient B cell precursors contain highly reduced levels of DYNLL1 (dynein light chain 1; LC8), a recently identified transcriptional target of ASCIZ, and normal B cell development can be restored by ectopic Dynll1 expression. Remarkably, the B cell lymphopenia in the absence of ASCIZ can also be fully suppressed by deletion of the proapoptotic DYNLL1 target Bim. Our findings demonstrate a key role for ASCIZ in regulating the survival of developing B cells by activating DYNLL1 expression, which may then modulate Bim-dependent apoptosis. PMID:22891272

42 CFR 60.39 - Death and disability claims.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Death and disability claims. 60.39 Section 60.39... ASSISTANCE LOAN PROGRAM The Lender and Holder § 60.39 Death and disability claims. (a) Death. The Secretary... death of the borrower. The holder of the loan may not attempt to collect on the loan from the borrower's...

42 CFR 60.39 - Death and disability claims.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 1 2014-10-01 2014-10-01 false Death and disability claims. 60.39 Section 60.39... ASSISTANCE LOAN PROGRAM The Lender and Holder § 60.39 Death and disability claims. (a) Death. The Secretary... death of the borrower. The holder of the loan may not attempt to collect on the loan from the borrower's...

42 CFR 60.39 - Death and disability claims.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 1 2013-10-01 2013-10-01 false Death and disability claims. 60.39 Section 60.39... ASSISTANCE LOAN PROGRAM The Lender and Holder § 60.39 Death and disability claims. (a) Death. The Secretary... death of the borrower. The holder of the loan may not attempt to collect on the loan from the borrower's...

42 CFR 60.39 - Death and disability claims.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 1 2012-10-01 2012-10-01 false Death and disability claims. 60.39 Section 60.39... ASSISTANCE LOAN PROGRAM The Lender and Holder § 60.39 Death and disability claims. (a) Death. The Secretary... death of the borrower. The holder of the loan may not attempt to collect on the loan from the borrower's...

42 CFR 60.39 - Death and disability claims.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false Death and disability claims. 60.39 Section 60.39... ASSISTANCE LOAN PROGRAM The Lender and Holder § 60.39 Death and disability claims. (a) Death. The Secretary... death of the borrower. The holder of the loan may not attempt to collect on the loan from the borrower's...

AtPDCD5 Plays a Role in Programmed Cell Death after UV-B Exposure in Arabidopsis1[OPEN

PubMed Central

Falcone Ferreyra, María Lorena; D’Andrea, Lucio; AbdElgawad, Hamada

2016-01-01

DNA damage responses have evolved to sense and react to DNA damage; the induction of DNA repair mechanisms can lead to genomic restoration or, if the damaged DNA cannot be adequately repaired, to the execution of a cell death program. In this work, we investigated the role of an Arabidopsis (Arabidopsis thaliana) protein, AtPDCD5, which is highly similar to the human PDCD5 protein; it is induced by ultraviolet (UV)-B radiation and participates in programmed cell death in the UV-B DNA damage response. Transgenic plants expressing AtPDCD5 fused to GREEN FLUORESCENT PROTEIN indicate that AtPDCD5 is localized both in the nucleus and the cytosol. By use of pdcd5 mutants, we here demonstrate that these plants have an altered antioxidant metabolism and accumulate higher levels of DNA damage after UV-B exposure, similar to levels in ham1ham2 RNA interference transgenic lines with decreased expression of acetyltransferases from the MYST family. By coimmunoprecipitation and pull-down assays, we provide evidence that AtPDCD5 interacts with HAM proteins, suggesting that both proteins participate in the same pathway of DNA damage responses. Plants overexpressing AtPDCD5 show less DNA damage but more cell death in root tips upon UV-B exposure. Finally, we here show that AtPDCD5 also participates in age-induced programmed cell death. Together, the data presented here demonstrate that AtPDCD5 plays an important role during DNA damage responses induced by UV-B radiation in Arabidopsis and also participates in programmed cell death programs. PMID:26884483

Costs and cost-effectiveness of training traditional birth attendants to reduce neonatal mortality in the Lufwanyama Neonatal Survival study (LUNESP).

PubMed

Sabin, Lora L; Knapp, Anna B; MacLeod, William B; Phiri-Mazala, Grace; Kasimba, Joshua; Hamer, Davidson H; Gill, Christopher J

2012-01-01

The Lufwanyama Neonatal Survival Project ("LUNESP") was a cluster randomized, controlled trial that showed that training traditional birth attendants (TBAs) to perform interventions targeting birth asphyxia, hypothermia, and neonatal sepsis reduced all-cause neonatal mortality by 45%. This companion analysis was undertaken to analyze intervention costs and cost-effectiveness, and factors that might improve cost-effectiveness. We calculated LUNESP's financial and economic costs and the economic cost of implementation for a forecasted ten-year program (2011-2020). In each case, we calculated the incremental cost per death avoided and disability-adjusted life years (DALYs) averted in real 2011 US dollars. The forecasted 10-year program analysis included a base case as well as 'conservative' and 'optimistic' scenarios. Uncertainty was characterized using one-way sensitivity analyses and a multivariate probabilistic sensitivity analysis. The estimated financial and economic costs of LUNESP were $118,574 and $127,756, respectively, or $49,469 and $53,550 per year. Fixed costs accounted for nearly 90% of total costs. For the 10-year program, discounted total and annual program costs were $256,455 and $26,834 respectively; for the base case, optimistic, and conservative scenarios, the estimated cost per death avoided was $1,866, $591, and $3,024, and cost per DALY averted was $74, $24, and $120, respectively. Outcomes were robust to variations in local costs, but sensitive to variations in intervention effect size, number of births attended by TBAs, and the extent of foreign consultants' participation. Based on established guidelines, the strategy of using trained TBAs to reduce neonatal mortality was 'highly cost effective'. We strongly recommend consideration of this approach for other remote rural populations with limited access to health care.

Costs and Cost-Effectiveness of Training Traditional Birth Attendants to Reduce Neonatal Mortality in the Lufwanyama Neonatal Survival Study (LUNESP)

PubMed Central

Sabin, Lora L.; Knapp, Anna B.; MacLeod, William B.; Phiri-Mazala, Grace; Kasimba, Joshua; Hamer, Davidson H.; Gill, Christopher J.

2012-01-01

Background The Lufwanyama Neonatal Survival Project (“LUNESP”) was a cluster randomized, controlled trial that showed that training traditional birth attendants (TBAs) to perform interventions targeting birth asphyxia, hypothermia, and neonatal sepsis reduced all-cause neonatal mortality by 45%. This companion analysis was undertaken to analyze intervention costs and cost-effectiveness, and factors that might improve cost-effectiveness. Methods and Findings We calculated LUNESP's financial and economic costs and the economic cost of implementation for a forecasted ten-year program (2011–2020). In each case, we calculated the incremental cost per death avoided and disability-adjusted life years (DALYs) averted in real 2011 US dollars. The forecasted 10-year program analysis included a base case as well as ‘conservative’ and ‘optimistic’ scenarios. Uncertainty was characterized using one-way sensitivity analyses and a multivariate probabilistic sensitivity analysis. The estimated financial and economic costs of LUNESP were $118,574 and $127,756, respectively, or $49,469 and $53,550 per year. Fixed costs accounted for nearly 90% of total costs. For the 10-year program, discounted total and annual program costs were $256,455 and $26,834 respectively; for the base case, optimistic, and conservative scenarios, the estimated cost per death avoided was $1,866, $591, and $3,024, and cost per DALY averted was $74, $24, and $120, respectively. Outcomes were robust to variations in local costs, but sensitive to variations in intervention effect size, number of births attended by TBAs, and the extent of foreign consultants' participation. Conclusions Based on established guidelines, the strategy of using trained TBAs to reduce neonatal mortality was ‘highly cost effective’. We strongly recommend consideration of this approach for other remote rural populations with limited access to health care. PMID:22545117

Heart failure disease management programs: a cost-effectiveness analysis.

PubMed

Chan, David C; Heidenreich, Paul A; Weinstein, Milton C; Fonarow, Gregg C

2008-02-01

Heart failure (HF) disease management programs have shown impressive reductions in hospitalizations and mortality, but in studies limited to short time frames and high-risk patient populations. Current guidelines thus only recommend disease management targeted to high-risk patients with HF. This study applied a new technique to infer the degree to which clinical trials have targeted patients by risk based on observed rates of hospitalization and death. A Markov model was used to assess the incremental life expectancy and cost of providing disease management for high-risk to low-risk patients. Sensitivity analyses of various long-term scenarios and of reduced effectiveness in low-risk patients were also considered. The incremental cost-effectiveness ratio of extending coverage to all patients was $9700 per life-year gained in the base case. In aggregate, universal coverage almost quadrupled life-years saved as compared to coverage of only the highest quintile of risk. A worst case analysis with simultaneous conservative assumptions yielded an incremental cost-effectiveness ratio of $110,000 per life-year gained. In a probabilistic sensitivity analysis, 99.74% of possible incremental cost-effectiveness ratios were <$50,000 per life-year gained. Heart failure disease management programs are likely cost-effective in the long-term along the whole spectrum of patient risk. Health gains could be extended by enrolling a broader group of patients with HF in disease management.

Involvement of miR17 pathway in glucocorticoid-induced cell death in pediatric acute lymphoblastic leukemia.

PubMed

Harada, Masako; Pokrovskaja-Tamm, Katja; Söderhäll, Stefan; Heyman, Mats; Grander, Dan; Corcoran, Martin

2012-10-01

Analysis of the microRNA transcriptome following dexa- methasone treatment of the acute lymphocytic leukemia (ALL) cell line RS4;11 showed a global down-regulation of microRNA levels. MIR17HG was rapidly down-regulated following treatment, with chromatin immunoprecipitation (ChIP) analysis demonstrating the promoter to be a direct target of glucocorticoid (GC)-transcriptional repression and revealing the miR17-92 cluster as a prime target for dexamethasone-induced repression. The loss of miR17 family expression and concomitant increases in the miR17 target Bim occurred in an additional ALL cell line SUP-B15 but not in the dexamethasone-resistant REH. Alteration of miR17 levels through up-regulation or inhibition resulted in an decrease and increase, respectively, in Bim protein levels and dexamethasone-induced cell death. Primary ex vivo ALL cells that underwent apoptosis induced by dexamethasone also down-regulated miR17 levels. Thus, down-regulation of miR17 plays an important role in glucocorticoid-induced cell death suggesting that targeting miR17 may improve the current ALL combination therapy.

Why history matters for quantitative target setting: long-term trends in socioeconomic and racial/ethnic inequities in US infant death rates (1960–2010)

PubMed Central

Krieger, Nancy; Singh, Nakul; Chen, Jarvis T.; Coull, Brent A.; Beckfield, Jason; Kiang, Mathew V.; Waterman, Pamela D.; Gruskin, Sofia

2016-01-01

Policy-oriented population health targets, such as the Millennium Development Goals and national targets to address health inequities, typically are based on trends of a decade or less. To test whether expanded timeframes might be more apt, we analyzed 50-year trends in US infant death rates (1960–2010) jointly by income and race/ethnicity. The largest annual percent changes in the infant death rate (between −4% and −10%) occurred, for all racial/ethnic groups, in the lowest income quintile between the mid-1960s and early 1980s, and in the second lowest income quintile between the mid-1960s and 1973; since the 1990s, they have hovered, in all groups, between −1% and −3%. Hence, to look back only 15 years, in 2014, to 1999, would ignore gains achieved prior to the post-1980 onset of neoliberal policies. Target setting should be informed by a deeper and more long-term appraisal of what is possible to achieve. PMID:25971237

Why history matters for quantitative target setting: Long-term trends in socioeconomic and racial/ethnic inequities in US infant death rates (1960-2010).

PubMed

Krieger, Nancy; Singh, Nakul; Chen, Jarvis T; Coull, Brent A; Beckfield, Jason; Kiang, Mathew V; Waterman, Pamela D; Gruskin, Sofia

2015-08-01

Policy-oriented population health targets, such as the Millennium Development Goals and national targets to address health inequities, are typically based on trends of a decade or less. To test whether expanded timeframes might be more apt, we analyzed 50-year trends in US infant death rates (1960-2010) jointly by income and race/ethnicity. The largest annual per cent changes in the infant death rate (between -4 and -10 per cent), for all racial/ethnic groups, in the lowest income quintile occurred between the mid-1960s and early 1980s, and in the second lowest income quintile between the mid-1960s and 1973. Since the 1990s, these numbers have hovered, in all groups, between -1 and -3 per cent. Hence, to look back only 15 years (in 2014, to 1999) would ignore gains achieved prior to the onset of neoliberal policies after 1980. Target setting should be informed by a deeper and longer-term appraisal of what is possible to achieve.

Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death.

PubMed

Philip, Naomi H; DeLaney, Alexandra; Peterson, Lance W; Santos-Marrero, Melanie; Grier, Jennifer T; Sun, Yan; Wynosky-Dolfi, Meghan A; Zwack, Erin E; Hu, Baofeng; Olsen, Tayla M; Rongvaux, Anthony; Pope, Scott D; López, Carolina B; Oberst, Andrew; Beiting, Daniel P; Henao-Mejia, Jorge; Brodsky, Igor E

2016-10-01

Caspases regulate cell death programs in response to environmental stresses, including infection and inflammation, and are therefore critical for the proper operation of the mammalian immune system. Caspase-8 is necessary for optimal production of inflammatory cytokines and host defense against infection by multiple pathogens including Yersinia, but whether this is due to death of infected cells or an intrinsic role of caspase-8 in TLR-induced gene expression is unknown. Caspase-8 activation at death signaling complexes results in its autoprocessing and subsequent cleavage and activation of its downstream apoptotic targets. Whether caspase-8 activity is also important for inflammatory gene expression during bacterial infection has not been investigated. Here, we report that caspase-8 plays an essential cell-intrinsic role in innate inflammatory cytokine production in vivo during Yersinia infection. Unexpectedly, we found that caspase-8 enzymatic activity regulates gene expression in response to bacterial infection as well as TLR signaling independently of apoptosis. Using newly-generated mice in which caspase-8 autoprocessing is ablated (Casp8DA/DA), we now demonstrate that caspase-8 enzymatic activity, but not autoprocessing, mediates induction of inflammatory cytokines by bacterial infection and a wide variety of TLR stimuli. Because unprocessed caspase-8 functions in an enzymatic complex with its homolog cFLIP, our findings implicate the caspase-8/cFLIP heterodimer in control of inflammatory cytokines during microbial infection, and provide new insight into regulation of antibacterial immune defense.

Inducing death in tumor cells: roles of the inhibitor of apoptosis proteins.

PubMed

Finlay, Darren; Teriete, Peter; Vamos, Mitchell; Cosford, Nicholas D P; Vuori, Kristiina

2017-01-01

The heterogeneous group of diseases collectively termed cancer results not just from aberrant cellular proliferation but also from a lack of accompanying homeostatic cell death. Indeed, cancer cells regularly acquire resistance to programmed cell death, or apoptosis, which not only supports cancer progression but also leads to resistance to therapeutic agents. Thus, various approaches have been undertaken in order to induce apoptosis in tumor cells for therapeutic purposes. Here, we will focus our discussion on agents that directly affect the apoptotic machinery itself rather than on drugs that induce apoptosis in tumor cells indirectly, such as by DNA damage or kinase dependency inhibition. As the roles of the Bcl-2 family have been extensively studied and reviewed recently, we will focus in this review specifically on the inhibitor of apoptosis protein (IAP) family. IAPs are a disparate group of proteins that all contain a baculovirus IAP repeat domain, which is important for the inhibition of apoptosis in some, but not all, family members. We describe each of the family members with respect to their structural and functional similarities and differences and their respective roles in cancer. Finally, we also review the current state of IAPs as targets for anti-cancer therapeutics and discuss the current clinical state of IAP antagonists.

Substrate Specificity and Possible Heterologous Targets of Phytaspase, a Plant Cell Death Protease.

PubMed

Galiullina, Raisa A; Kasperkiewicz, Paulina; Chichkova, Nina V; Szalek, Aleksandra; Serebryakova, Marina V; Poreba, Marcin; Drag, Marcin; Vartapetian, Andrey B

2015-10-09

Plants lack aspartate-specific cell death proteases homologous to animal caspases. Instead, a subtilisin-like serine-dependent plant protease named phytaspase shown to be involved in the accomplishment of programmed death of plant cells is able to hydrolyze a number of peptide-based caspase substrates. Here, we determined the substrate specificity of rice (Oryza sativa) phytaspase by using the positional scanning substrate combinatorial library approach. Phytaspase was shown to display an absolute specificity of hydrolysis after an aspartic acid residue. The preceding amino acid residues, however, significantly influence the efficiency of hydrolysis. Efficient phytaspase substrates demonstrated a remarkable preference for an aromatic amino acid residue in the P3 position. The deduced optimum phytaspase recognition motif has the sequence IWLD and is strikingly hydrophobic. The established pattern was confirmed through synthesis and kinetic analysis of cleavage of a set of optimized peptide substrates. An amino acid motif similar to the phytaspase cleavage site is shared by the human gastrointestinal peptide hormones gastrin and cholecystokinin. In agreement with the established enzyme specificity, phytaspase was shown to hydrolyze gastrin-1 and cholecystokinin at the predicted sites in vitro, thus destroying the active moieties of the hormones. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

PDT: death pathways

NASA Astrophysics Data System (ADS)

Kessel, David

2007-02-01

Cellular targets of photodynamic therapy include mitochondria, lysosomes, the endoplasmic reticulum (ER) and the plasma membrane. PDT can evoke necrosis, autophagy and apoptosis, or combinations of these, depending on the PDT dose, the site(s) of photodamage and the cellular phenotype. It has been established that loss of viability occurs even when the apoptotic program is inhibited. Studies assessing effects of ER or mitochondrial photodamage, involving loss of Bcl-2 function, indicate that low-dose PDT elicited a rapid autophagic response in L1210 cells. This was attributed to the ability of autophagy to recycle photodamaged organelles, and there was partial protection from loss of viability. This effect was not observed in L1210/Atg7, where autophagy was silenced. At higher PDT doses, apoptotic cells were observed within 60 min in both cell lines, but more so in L1210. The ability of L1210 cells to undergo autophagy did not offer protection from cell death at the higher PDT dose. Previous studies had indicated that autophagy can contribute to cell death, since L1210 cells that do not undergo an initial apoptotic response often contain multiple autophagic vacuoles 24 hr later. With L1210/Atg7, apoptosis alone may account for the loss of viability at an LD 90 PDT dose.

[Development and Evaluation of a Self-Reflection Program for Intensive Care Unit Nurses Who Have Experienced the Death of Pediatric Patients].

PubMed

Kang, Hyun Ju; Bang, Kyung Sook

2017-06-01

This study aims to develop a self-reflection program for nurses who have experienced the death of pediatric patients in the intensive care unit and to evaluate its effectiveness. The self-reflection program was developed by means of the following four steps: establishment of the goal through investigation of an initial request, drawing up the program, preliminary research, and implementation and improvement of the program. The study employed a methodological triangulation to evaluate the effectiveness of the program. Participants were 38 nurses who had experienced the death of pediatric patients (experimental group=15, control group=23); they were recruited using convenience sampling. The self-reflection program was provided over 6 weeks (6 sessions). Data were collected from April to August, 2014 and analyzed using t-tests and content analysis. The quantitative results showed that changes in personal growth (t=-6.33, p<.001) and burnout scores (z=-2.76, p=.005) were better in the experimental group compared to the control group. The qualitative results exhibited two themes, namely "personal growth" and "professional growth", and ten sub-themes. The self-reflection program developed by this study was effective in helping nurses who had experienced the death of pediatric patients to achieve personal growth through self-reflection, and it was confirmed that the program can be applied in a realistic clinical nursing setting. Furthermore, it can be recommended as an intervention program for clinical nurses. © 2017 Korean Society of Nursing Science

7 CFR 701.33 - Death, incompetency, or disappearance.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 7 2010-01-01 2010-01-01 false Death, incompetency, or disappearance. 701.33 Section... RELATED PROGRAMS PREVIOUSLY ADMINISTERED UNDER THIS PART § 701.33 Death, incompetency, or disappearance. In case of death, incompetency, or disappearance of any participant, any cost-share payment due shall...

7 CFR 760.1311 - Death, incompetence, or disappearance.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 7 2010-01-01 2010-01-01 false Death, incompetence, or disappearance. 760.1311 Section 760.1311 Agriculture Regulations of the Department of Agriculture (Continued) FARM SERVICE AGENCY... Program § 760.1311 Death, incompetence, or disappearance. (a) In the case of the death, incompetency, or...

7 CFR 1430.611 - Death, incompetence, or disappearance.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Death, incompetence, or disappearance. 1430.611... Disaster Assistance Payment Program II (DDAP-II) § 1430.611 Death, incompetence, or disappearance. In the case of death, incompetency, disappearance, or dissolution of a person that is eligible to receive...

7 CFR 1430.611 - Death, incompetence, or disappearance.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 10 2011-01-01 2011-01-01 false Death, incompetence, or disappearance. 1430.611... Disaster Assistance Payment Program II (DDAP-II) § 1430.611 Death, incompetence, or disappearance. In the case of death, incompetency, disappearance, or dissolution of a person that is eligible to receive...

7 CFR 1430.611 - Death, incompetence, or disappearance.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 10 2014-01-01 2014-01-01 false Death, incompetence, or disappearance. 1430.611... Disaster Assistance Payment Program II (DDAP-II) § 1430.611 Death, incompetence, or disappearance. In the case of death, incompetency, disappearance, or dissolution of a person that is eligible to receive...

7 CFR 760.1311 - Death, incompetence, or disappearance.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 7 2014-01-01 2014-01-01 false Death, incompetence, or disappearance. 760.1311 Section 760.1311 Agriculture Regulations of the Department of Agriculture (Continued) FARM SERVICE AGENCY... Program § 760.1311 Death, incompetence, or disappearance. (a) In the case of the death, incompetency, or...

7 CFR 760.1311 - Death, incompetence, or disappearance.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 7 2012-01-01 2012-01-01 false Death, incompetence, or disappearance. 760.1311 Section 760.1311 Agriculture Regulations of the Department of Agriculture (Continued) FARM SERVICE AGENCY... Program § 760.1311 Death, incompetence, or disappearance. (a) In the case of the death, incompetency, or...

7 CFR 760.1311 - Death, incompetence, or disappearance.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 7 2011-01-01 2011-01-01 false Death, incompetence, or disappearance. 760.1311 Section 760.1311 Agriculture Regulations of the Department of Agriculture (Continued) FARM SERVICE AGENCY... Program § 760.1311 Death, incompetence, or disappearance. (a) In the case of the death, incompetency, or...

7 CFR 1430.611 - Death, incompetence, or disappearance.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 10 2012-01-01 2012-01-01 false Death, incompetence, or disappearance. 1430.611... Disaster Assistance Payment Program II (DDAP-II) § 1430.611 Death, incompetence, or disappearance. In the case of death, incompetency, disappearance, or dissolution of a person that is eligible to receive...

7 CFR 1430.611 - Death, incompetence, or disappearance.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 10 2013-01-01 2013-01-01 false Death, incompetence, or disappearance. 1430.611... Disaster Assistance Payment Program II (DDAP-II) § 1430.611 Death, incompetence, or disappearance. In the case of death, incompetency, disappearance, or dissolution of a person that is eligible to receive...

7 CFR 760.1311 - Death, incompetence, or disappearance.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 7 2013-01-01 2013-01-01 false Death, incompetence, or disappearance. 760.1311 Section 760.1311 Agriculture Regulations of the Department of Agriculture (Continued) FARM SERVICE AGENCY... Program § 760.1311 Death, incompetence, or disappearance. (a) In the case of the death, incompetency, or...

On the origin, evolution, and nature of programmed cell death: a timeline of four billion years.

PubMed

Ameisen, J C

2002-04-01

Programmed cell death is a genetically regulated process of cell suicide that is central to the development, homeostasis and integrity of multicellular organisms. Conversely, the dysregulation of mechanisms controlling cell suicide plays a role in the pathogenesis of a wide range of diseases. While great progress has been achieved in the unveiling of the molecular mechanisms of programmed cell death, a new level of complexity, with important therapeutic implications, has begun to emerge, suggesting (i) that several different self-destruction pathways may exist and operate in parallel in our cells, and (ii) that molecular effectors of cell suicide may also perform other functions unrelated to cell death induction and crucial to cell survival. In this review, I will argue that this new level of complexity, implying that there may be no such thing as a 'bona fide' genetic death program in our cells, might be better understood when considered in an evolutionary context. And a new view of the regulated cell suicide pathways emerges when one attempts to ask the question of when and how they may have become selected during evolution, at the level of ancestral single-celled organisms.

Death and television: terror management theory and themes of law and justice on television.

PubMed

Taylor, Laramie D

2012-04-01

Based on terror management theory, it was hypothesized that media choices may be affected by the salience of death-related thoughts. Three experiments with samples of undergraduate students were conducted to investigate whether such a process would affect preferences for law and justice television programming. In the first experiment (n = 132), individuals for whom mortality had been made salient through experimental induction preferred more programs with law and justice themes than individuals for whom mortality had not been made salient. In the second experiment (n = 761), this effect was observed regardless of trust in law enforcement and only for participants induced to think about death, not those induced to think about pain. In the third experiment (n = 163), participants for whom mortality was salient who watched a crime drama that showed justice being carried out showed a diminished self-enhancing bias compared to participants who watched a version of the same program in which justice was thwarted. Results indicate that entertainment choices are influenced by thought of death beyond simply seeking distraction and that entertainment programming emphasizing justice can effectively ameliorate existential anxiety that arises from thoughts of death.

Surveillance for violent deaths - National Violent Death Reporting System, 16 states, 2010.

PubMed

Parks, Sharyn E; Johnson, Linda L; McDaniel, Dawn D; Gladden, Matthew

2014-01-17

An estimated 55,000 persons die annually in the United States as a result of violence-related injuries. This report summarizes data from CDC's National Violent Death Reporting System (NVDRS) regarding violent deaths from 16 U.S. states for 2010. Results are reported by sex, age group, race/ethnicity, marital status, location of injury, method of injury, circumstances of injury, and other selected characteristics. 2010. NVDRS collects data regarding violent deaths obtained from death certificates, coroner/medical examiner reports, law enforcement reports, and secondary sources (e.g., child fatality review team data, supplementary homicide reports, hospital data, and crime laboratory data). NVDRS data collection began in 2003 with seven states (Alaska, Maryland, Massachusetts, New Jersey, Oregon, South Carolina, and Virginia) participating; six states (Colorado, Georgia, North Carolina, Oklahoma, Rhode Island, and Wisconsin) joined in 2004, four (California, Kentucky, New Mexico, and Utah) in 2005, and two in 2010 (Ohio and Michigan), for a total of 19 states. This report includes data from 16 states that collected statewide data in 2010; data from California are not included in this report because data were not collected after 2009. Ohio and Michigan were excluded because data collection, which began in 2010, did not occur statewide until 2011. For 2010, a total of 15,781 fatal incidents involving 16,186 deaths were captured by NVDRS in the 16 states included in this report. The majority (62.8%) of deaths were suicides, followed by homicides and deaths involving legal intervention (i.e., deaths caused by law enforcement and other persons with legal authority to use deadly force, excluding legal executions) (24.4%), deaths of undetermined intent (12.2%), and unintentional firearm deaths (0.7%). Suicides occurred at higher rates among males, non-Hispanic whites, American Indians/Alaska Natives, and persons aged 45-54 years. Suicides most often occurred in a house or apartment and involved the use of firearms. Suicides were preceded primarily by a mental health or intimate partner problem, a crisis during the previous 2 weeks, or a physical health problem. Homicides occurred at higher rates among males and persons aged 20-24 years; rates were highest among non-Hispanic black males. The majority of homicides involved the use of a firearm and occurred in a house or apartment or on a street/highway. Homicides were precipitated primarily by arguments and interpersonal conflicts or in conjunction with another crime. This report provides a detailed summary of data from NVDRS for 2010. The results indicate that violent deaths resulting from self-inflicted or interpersonal violence disproportionately affected persons aged <55 years, males, and certain minority populations. For homicides and suicides, relationship problems, interpersonal conflicts, mental health problems, and recent crises were among the primary precipitating factors. Because additional information might be reported subsequently as participating states update their findings, the data provided in this report are preliminary. For the occurrence of violent deaths in the United States to be better understood and ultimately prevented, accurate, timely, and comprehensive surveillance data are necessary. NVDRS data can be used to monitor the occurrence of violence-related fatal injuries and assist public health authorities in the development, implementation, and evaluation of programs and policies to reduce and prevent violent deaths at the national, state, and local levels. NVDRS data have been used to enhance prevention programs. Examples include use of linked NVDRS data and adult protective service data to better target elder maltreatment prevention programs and improve staff training to identify violent death risks for older adults in North Carolina, use of Oklahoma VDRS homicide data to help evaluate the effectiveness of a new police and advocate intervention at domestic violence incident scenes, and data-informed changes in primary care practice in Oregon to more effectively address older adult suicide prevention. The continued development and expansion of NVDRS is essential to CDC's efforts to reduce the personal, familial, and societal impacts of violence. Further efforts are needed to increase the number of states participating in NVDRS, with an ultimate goal of full national representation.

Elongated Nanoparticle Aggregates in Cancer Cells for Mechanical Destruction with Low Frequency Rotating Magnetic Field.

PubMed

Shen, Yajing; Wu, Congyu; Uyeda, Taro Q P; Plaza, Gustavo R; Liu, Bin; Han, Yu; Lesniak, Maciej S; Cheng, Yu

2017-01-01

Magnetic nanoparticles (MNPs) functionalized with targeting moieties can recognize specific cell components and induce mechanical actuation under magnetic field. Their size is adequate for reaching tumors and targeting cancer cells. However, due to the nanometric size, the force generated by MNPs is smaller than the force required for largely disrupting key components of cells. Here, we show the magnetic assembly process of the nanoparticles inside the cells, to form elongated aggregates with the size required to produce elevated mechanical forces. We synthesized iron oxide nanoparticles doped with zinc, to obtain high magnetization, and functionalized with the epidermal growth factor (EGF) peptide for targeting cancer cells. Under a low frequency rotating magnetic field at 15 Hz and 40 mT, the internalized EGF-MNPs formed elongated aggregates and generated hundreds of pN to dramatically damage the plasma and lysosomal membranes. The physical disruption, including leakage of lysosomal hydrolases into the cytosol, led to programmed cell death and necrosis. Our work provides a novel strategy of designing magnetic nanomedicines for mechanical destruction of cancer cells.

CSF1R+ Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype.

PubMed

Candido, Juliana B; Morton, Jennifer P; Bailey, Peter; Campbell, Andrew D; Karim, Saadia A; Jamieson, Thomas; Lapienyte, Laura; Gopinathan, Aarthi; Clark, William; McGhee, Ewan J; Wang, Jun; Escorcio-Correia, Monica; Zollinger, Raphael; Roshani, Rozita; Drew, Lisa; Rishi, Loveena; Arkell, Rebecca; Evans, T R Jeffry; Nixon, Colin; Jodrell, Duncan I; Wilkinson, Robert W; Biankin, Andrew V; Barry, Simon T; Balkwill, Frances R; Sansom, Owen J

2018-05-01

Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapies including single-agent immunotherapy and has a dense desmoplastic stroma, and most patients present with advanced metastatic disease. We reveal that macrophages are the dominant leukocyte population both in human PDAC stroma and autochthonous models, with an important functional contribution to the squamous subtype of human PDAC. We targeted macrophages in a genetic PDAC model using AZD7507, a potent selective inhibitor of CSF1R. AZD7507 caused shrinkage of established tumors and increased mouse survival in this difficult-to-treat model. Malignant cell proliferation diminished, with increased cell death and an enhanced T cell immune response. Loss of macrophages rewired other features of the TME, with global changes in gene expression akin to switching PDAC subtypes. These changes were markedly different to those elicited when neutrophils were targeted via CXCR2. These results suggest targeting the myeloid cell axis may be particularly efficacious in PDAC, especially with CSF1R inhibitors. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

An in-silico investigation of anti-Chagas phytochemicals.

PubMed

McCulley, Stephanie F; Setzer, William N

2014-01-01

Over 18 million people in tropical and subtropical America are afflicted by American trypanosomiasis or Chagas disease. In humans, symptoms of the disease include fever, swelling, and heart and brain damage, usually leading to death. There is currently no effective treatment for this disease. Plant products continue to be rich sources of clinically useful drugs, and the biodiversity of the Neotropics suggests great phytomedicinal potential. Screening programs have revealed numerous plant species and phytochemical agents that have shown in-vitro or in-vivo antitrypanosomal activity, but the biochemical targets of these phytochemicals are not known. In this work, we present a molecular docking analysis of Neotropical phytochemicals, which have already demonstrated antiparasitic activity against Trypanosoma cruzi, with potential druggable protein targets of the parasite. Several protein targets showed in-silico selectivity for trypanocidal phytochemicals, including trypanothione reductase, pteridine reductase 2, lipoamide dehydrogenase, glucokinase, dihydroorotate dehydrogenase, cruzain, dihydrofolate-reductase/thymidylate-synthase, and farnesyl diphosphate synthase. Some of the phytochemical ligands showed notable docking preference for trypanothione reductase, including flavonoids, fatty-acid-derived oxygenated hydrocarbons, geranylgeraniol and the lignans ganschisandrine and eupomatenoid-6.

Elongated Nanoparticle Aggregates in Cancer Cells for Mechanical Destruction with Low Frequency Rotating Magnetic Field

PubMed Central

Shen, Yajing; Wu, Congyu; Uyeda, Taro Q. P.; Plaza, Gustavo R.; Liu, Bin; Han, Yu; Lesniak, Maciej S.; Cheng, Yu

2017-01-01

Magnetic nanoparticles (MNPs) functionalized with targeting moieties can recognize specific cell components and induce mechanical actuation under magnetic field. Their size is adequate for reaching tumors and targeting cancer cells. However, due to the nanometric size, the force generated by MNPs is smaller than the force required for largely disrupting key components of cells. Here, we show the magnetic assembly process of the nanoparticles inside the cells, to form elongated aggregates with the size required to produce elevated mechanical forces. We synthesized iron oxide nanoparticles doped with zinc, to obtain high magnetization, and functionalized with the epidermal growth factor (EGF) peptide for targeting cancer cells. Under a low frequency rotating magnetic field at 15 Hz and 40 mT, the internalized EGF-MNPs formed elongated aggregates and generated hundreds of pN to dramatically damage the plasma and lysosomal membranes. The physical disruption, including leakage of lysosomal hydrolases into the cytosol, led to programmed cell death and necrosis. Our work provides a novel strategy of designing magnetic nanomedicines for mechanical destruction of cancer cells. PMID:28529648

Engineered Proteins Program Mammalian Cells to Target Inflammatory Disease Sites.

PubMed

Qudrat, Anam; Mosabbir, Abdullah Al; Truong, Kevin

2017-06-22

Disease sites in atherosclerosis and cancer feature cell masses (e.g., plaques/tumors), a low pH extracellular microenvironment, and various pro-inflammatory cytokines such as tumor necrosis factor α (TNFα). The ability to engineer a cell to seek TNFα sources allows for targeted therapeutic delivery. To accomplish this, here we introduced a system of proteins: an engineered TNFα chimeric receptor (named TNFR1chi), a previously engineered Ca 2+ -activated RhoA (named CaRQ), vesicular stomatitis virus glycoprotein G (VSVG), and thymidine kinase. Upon binding TNFα, TNFR1chi generates a Ca 2+ signal that in turn activates CaRQ-mediated non-apoptotic blebs that allow migration toward the TNFα source. Next, the addition of VSVG, upon low pH induction, causes membrane fusion of the engineered and TNFα source cells. Finally, after ganciclovir treatment cells undergo death via the thymidine kinase suicide mechanism. Hence, we assembled a system of proteins that forms the basis of engineering a cell to target inflammatory disease sites characterized by TNFα secretion and a low-pH microenvironment. Copyright © 2017 Elsevier Ltd. All rights reserved.

42 CFR 102.33 - Death benefits.

Code of Federal Regulations, 2013 CFR

2013-10-01

... PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES VACCINES SMALLPOX COMPENSATION PROGRAM... under this Program if the Secretary determines that an otherwise eligible deceased smallpox vaccine... vaccine recipient or vaccinia contact during his or her lifetime and to his or her estate after death. (c...

42 CFR 102.33 - Death benefits.

Code of Federal Regulations, 2014 CFR

2014-10-01

... PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES VACCINES SMALLPOX COMPENSATION PROGRAM... under this Program if the Secretary determines that an otherwise eligible deceased smallpox vaccine... vaccine recipient or vaccinia contact during his or her lifetime and to his or her estate after death. (c...

42 CFR 102.33 - Death benefits.

Code of Federal Regulations, 2012 CFR

2012-10-01

... PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES VACCINES SMALLPOX COMPENSATION PROGRAM... under this Program if the Secretary determines that an otherwise eligible deceased smallpox vaccine... vaccine recipient or vaccinia contact during his or her lifetime and to his or her estate after death. (c...

42 CFR 102.33 - Death benefits.

Code of Federal Regulations, 2011 CFR

2011-10-01

... PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES VACCINES SMALLPOX COMPENSATION PROGRAM... under this Program if the Secretary determines that an otherwise eligible deceased smallpox vaccine... vaccine recipient or vaccinia contact during his or her lifetime and to his or her estate after death. (c...

Predictors of neurologic and nonneurologic death in patients with brain metastasis initially treated with upfront stereotactic radiosurgery without whole-brain radiation therapy.

PubMed

McTyre, Emory R; Johnson, Adam G; Ruiz, Jimmy; Isom, Scott; Lucas, John T; Hinson, William H; Watabe, Kounosuke; Laxton, Adrian W; Tatter, Stephen B; Chan, Michael D

2017-04-01

In this study we attempted to discern the factors predictive of neurologic death in patients with brain metastasis treated with upfront stereotactic radiosurgery (SRS) without whole brain radiation therapy (WBRT) while accounting for the competing risk of nonneurologic death. We performed a retrospective single-institution analysis of patients with brain metastasis treated with upfront SRS without WBRT. Competing risks analysis was performed to estimate the subdistribution hazard ratios (HRs) for neurologic and nonneurologic death for predictor variables of interest. Of 738 patients treated with upfront SRS alone, neurologic death occurred in 226 (30.6%), while nonneurologic death occurred in 309 (41.9%). Multivariate competing risks analysis identified an increased hazard of neurologic death associated with diagnosis-specific graded prognostic assessment (DS-GPA) ≤ 2 (P = .005), melanoma histology (P = .009), and increased number of brain metastases (P<.001), while there was a decreased hazard associated with higher SRS dose (P = .004). Targeted agents were associated with a decreased HR of neurologic death in the first 1.5 years (P = .04) but not afterwards. An increased hazard of nonneurologic death was seen with increasing age (P =.03), nonmelanoma histology (P<.001), presence of extracranial disease (P<.001), and progressive systemic disease (P =.004). Melanoma, DS-GPA, number of brain metastases, and SRS dose are predictive of neurologic death, while age, nonmelanoma histology, and more advanced systemic disease are predictive of nonneurologic death. Targeted agents appear to delay neurologic death. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Live to die another way: modes of programmed cell death and the signals emanating from dying cells

PubMed Central

Fuchs, Yaron; Steller, Hermann

2015-01-01

Preface All life ends in death, but perhaps one of life’s grander ironies is that it also depends on death. Cell-intrinsic suicide pathways, termed programmed cell death (PCD), are crucial for animal development, tissue homeostasis and pathogenesis. Originally, PCD was virtually synonymous with apoptosis, but recently, alternative PCD mechanisms have been reported. Here, we provide an overview of several distinct PCD mechanisms, namely apoptosis, autophagy and necroptosis. In addition, we discuss the complex signals emanating from dying cells, which can either fuel regeneration or instruct additional killing. Further advances in understanding the physiological role of multiple cell death mechanisms and associated signals will be important to selectively manipulate PCD for therapeutic purposes. PMID:25991373

Kennedy Space Center Coronary Heart Disease Risk Screening Program

NASA Technical Reports Server (NTRS)

Tipton, David A.; Scarpa, Philip J.

1999-01-01

The number one cause of death in the U.S. is coronary heart disease (CHD). It is probably a major cause of death and disability in the lives of employees at Kennedy Space Center (KSC) as well. The KSC Biomedical Office used a multifactorial mathematical formula from the Framingham Heart Study to calculate CHD risk probabilities for individuals in a segment of the KSC population that required medical evaluation for job certification. Those assessed to be high-risk probabilities will be targeted for intervention. Every year, several thousand KSC employees require medical evaluations for job related certifications. Most medical information for these evaluations is gathered on-site at one of the KSC or Cape Canaveral Air Station (CCAS) medical clinics. The formula used in the Framingham Heart Study allows calculation of a person's probability of acquiring CHD within 10 years. The formula contains the following variables: Age, Diabetes, Smoking, Left Ventricular Hypertrophy, Blood Pressure (Systolic or Diastolic), Cholesterol, and HDL cholesterol. The formula is also gender specific. It was used to calculate the 10-year probabilities of CHD in KSC employees who required medical evaluations for job certifications during a one-year time frame. This KSC population was profiled and CHD risk reduction interventions could be targeted to those at high risk. Population risk could also be periodically reevaluated to determine the effectiveness of intervention. A 10-year CHD risk probability can be calculated for an individual quite easily while gathering routine medical information. An employee population's CHD risk probability can be profiled graphically revealing high risk segments of the population which can be targeted for risk reduction intervention. The small audience of NASA/contractor physicians, nurses and exercise/fitness professionals at the breakout session received the lecture very well. Approximately one third indicated by a show of hands that they would be interested in implementing a similar program at their NASA Center. Questions were asked pertaining to standardization for age, the validity of using the idealized male values also for the female population, and indications of the screening test's sensitivity and specificity.

Xenon Protects Against Septic Acute Kidney Injury via miR-21 Target Signaling Pathway*

PubMed Central

Jia, Ping; Teng, Jie; Zou, Jianzhou; Fang, Yi; Wu, Xie; Liang, Mingyu

2015-01-01

Objectives: Septic acute kidney injury is one of the most common and life-threatening complications in critically ill patients, and there is no approved effective treatment. We have shown xenon provides renoprotection against ischemia-reperfusion injury and nephrotoxicity in rodents via inhibiting apoptosis. Here, we studied the effects of xenon preconditioning on septic acute kidney injury and its mechanism. Design: Experimental animal investigation. Setting: University research laboratory. Subjects: Experiments were performed with male C57BL/6 mice, 10 weeks of age, weighing 20–25 g. Interventions: We induced septic acute kidney injury by a single intraperitoneal injection of Escherichia coli lipopolysaccharide at a dose of 20 mg/kg. Mice were exposed for 2 hours to either 70% xenon or 70% nitrogen, 24 hours before the onset of septic acute kidney injury. In vivo knockdown of miR-21 was performed using locked nucleic acid-modified anti-miR, the role of miR-21 in renal protection conferred by the xenon preconditioning was examined, and miR-21 signaling pathways were analyzed. Measurements and Main Results: Xenon preconditioning provided morphologic and functional renoprotection, characterized by attenuation of renal tubular damage, apoptosis, and a reduction in inflammation. Furthermore, xenon treatment significantly upregulated the expression of miR-21 in kidney, suppressed proinflammatory factor programmed cell death protein 4 expression and nuclear factor-κB activity, and increased interleukin-10 production. Meanwhile, xenon preconditioning also suppressed the expression of proapoptotic protein phosphatase and tensin homolog deleted on chromosome 10, activating protein kinase B signaling pathway, subsequently increasing the expression of antiapoptotic B-cell lymphoma-2, and inhibiting caspase-3 activity. Knockdown of miR-21 upregulated its target effectors programmed cell death protein 4 and phosphatase and tensin homolog deleted on chromosome 10 expression, resulted in an increase in apoptosis, and exacerbated lipopolysaccharide-induced acute kidney injury. Conclusion: Our findings demonstrated that xenon preconditioning protected against lipopolysaccharide-induced acute kidney injury via activation of miR-21 target signaling pathways. PMID:25844699

MTOR-driven quasi-programmed aging as a disposable soma theory

PubMed Central

2013-01-01

If life were created by intelligent design, we would indeed age from accumulation of molecular damage. Repair is costly and limited by energetic resources, and we would allocate resources rationally. But, albeit elegant, this design is fictional. Instead, nature blindly selects for short-term benefits of robust developmental growth. “Quasi-programmed” by the blind watchmaker, aging is a wasteful and aimless continuation of developmental growth, driven by nutrient-sensing, growth-promoting signaling pathways such as MTOR (mechanistic target of rapamycin). A continuous post-developmental activity of such gerogenic pathways leads to hyperfunctions (aging), loss of homeostasis, age-related diseases, non-random organ damage and death. This model is consistent with a view that (1) soma is disposable, (2) aging and menopause are not programmed and (3) accumulation of random molecular damage is not a cause of aging as we know it. PMID:23708516

Trial watch: Immune checkpoint blockers for cancer therapy.

PubMed

Vanpouille-Box, Claire; Lhuillier, Claire; Bezu, Lucillia; Aranda, Fernando; Yamazaki, Takahiro; Kepp, Oliver; Fucikova, Jitka; Spisek, Radek; Demaria, Sandra; Formenti, Silvia C; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

2017-01-01

Immune checkpoint blockers (ICBs) are literally revolutionizing the clinical management of an ever more diversified panel of oncological indications. Although considerable attention persists around the inhibition of cytotoxic T lymphocyte-associated protein 4 (CTLA4) and programmed cell death 1 (PDCD1, best known as PD-1) signaling, several other co-inhibitory T-cell receptors are being evaluated as potential targets for the development of novel ICBs. Moreover, substantial efforts are being devoted to the identification of biomarkers that reliably predict the likelihood of each patient to obtain clinical benefits from ICBs in the absence of severe toxicity. Tailoring the delivery of specific ICBs or combinations thereof to selected patient populations in the context of precision medicine programs constitutes indeed a major objective of the future of ICB-based immunotherapy. Here, we discuss recent preclinical and clinical advances on the development of ICBs for oncological indications.

The role of OSHA violations in serious workplace accidents.

PubMed

Mendeloff, J

1984-05-01

California accident investigations for 1976 show that violations of the Occupational Safety and Health Administration's safety standards were a contributing factor in 13% to 19% of the 645 deaths reported to the workers' compensation program during that year. However, a panel of safety engineers judged that only about 50% of these violations could have been detected if an inspector had visited the day before the accident. These findings indicate that the potential gains from stronger enforcement of current standards are limited but not insignificant. The likelihood that a violation contributed to a serious accident varied considerably among accident types, industries, and size classes of plants. These findings can be used to increase the efficiency and effectiveness of the OSHA program by means of better targeting of inspections and accident investigations, more intelligent assessment of which violations should be penalized most heavily, and the provision of information to employers and workers about which violations are most consequential.

Bcl-2 Blocks a Caspase-Dependent Pathway of Apoptosis Activated by Herpes Simplex Virus 1 Infection in HEp-2 Cells

PubMed Central

Galvan, Veronica; Brandimarti, Renato; Munger, Joshua; Roizman, Bernard

2000-01-01

Earlier reports have shown that herpes simplex virus 1 (HSV-1) mutants induce programmed cell death and that wild-type virus blocks the execution of the cell death program triggered by expression of viral genes, by the Fas and tumor necrosis factor pathways, or by nonspecific stress agents. In particular, an earlier report from this laboratory showed that the mutant virus d120 lacking the genes encoding infected cell protein 4 (ICP4), the major regulatory protein of the virus, induces a caspase-3-independent pathway of apoptosis in human SK-N-SH cells. Here we report that the pathway of apoptosis induced by the d120 mutant in human HEp-2 cells is caspase dependent. Specifically, in HEp-2 cells infected with d120, (i) a broad-range inhibitor of caspase activity, z-vad-FMK, efficiently blocked DNA fragmentation, (ii) cytochrome c was released into the cytoplasm, (iii) caspase-3 was activated inasmuch as poly(ADP-ribose) polymerase was cleaved, and (iv) chromatin condensation and fragmentation of cellular DNA were observed. In parallel studies, HEp-2 cells were transfected with a plasmid encoding human Bcl-2 and a clone (VAX-3) expressing high levels of Bcl-2 was selected. This report shows that Bcl-2 blocked all of the manifestations associated with programmed cell death caused by infection with the d120 mutant. Consistent with their resistance to programmed cell death, VAX-3 cells overproduced infected cell protein 0 (ICP0). An unexpected observation was that ICP0 encoded by the d120 mutant accumulated late in infection in small, quasi-uniform vesicle-like structures in all cell lines tested. Immunofluorescence-based colocalization studies indicated that these structures were not mitochondria or components of the endoplasmic reticulum or the late endosomal compartment. These studies affirm the conclusion that HSV can induce programmed cell death at multiple steps in the course of its replication, that the d120 mutant can induce both caspase-dependent and -independent pathways of programmed cell death, and that virus-induced stimuli of programmed cell death may differ with respect to the pathway that they activate. PMID:10644366

Donation after cardiocirculatory death in Canada

PubMed Central

Shemie, Sam D.; Baker, Andrew J.; Knoll, Greg; Wall, William; Rocker, Graeme; Howes, Daniel; Davidson, Janet; Pagliarello, Joe; Chambers-Evans, Jane; Cockfield, Sandra; Farrell, Catherine; Glannon, Walter; Gourlay, William; Grant, David; Langevin, Stéphan; Wheelock, Brian; Young, Kimberly; Dossetor, John

2006-01-01

These recommendations are the result of a national, multidisciplinary, year-long process to discuss whether and how to proceed with organ donation after cardiocirculatory death (DCD) in Canada. A national forum was held in February 2005 to discuss and develop recommendations on the principles, procedures and practice related to DCD, including ethical and legal considerations. At the forum's conclusion, a strong majority of participants supported proceeding with DCD programs in Canada. The forum also recognized the need to formulate and emphasize core values to guide the development of programs and protocols based on the medical, ethical and legal framework established at this meeting. Although end-of-life care should routinely include the opportunity to donate organs and tissues, the duty of care toward dying patients and their families remains the dominant priority of health care teams. The complexity and profound implications of death are recognized and should be respected, along with differing personal, ethnocultural and religious perspectives on death and donation. Decisions around withdrawal of life-sustaining therapies, management of the dying process and the determination of death by cardiocirculatory criteria should be separate from and independent of donation and transplant processes. The recommendations in this report are intended to guide individual programs, regional health authorities and jurisdictions in the development of DCD protocols. Programs will develop based on local leadership and advance planning that includes education and engagement of stakeholders, mechanisms to assure safety and quality and public information. We recommend that programs begin with controlled DCD within the intensive care unit where (after a consensual decision to withdraw life-sustaining therapy) death is anticipated, but has not yet occurred, and unhurried consent discussions can be held. Uncontrolled donation (where death has occurred after unanticipated cardiac arrest) should only be considered after a controlled DCD program is well established. Although we recommend that programs commence with kidney donation, regional transplant expertise may guide the inclusion of other organs. The impact of DCD, including pre-and post-mortem interventions, on donor family experiences, organ availability, graft function and recipient survival should be carefully documented and studied. PMID:17124739

Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Waters, Katrina M.; Sontag, Ryan L.; Weber, Thomas J., E-mail: Thomas.Weber@pnl.gov

Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional programmore » encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ► Circadian-dependent physiological variation impacts therapeutic efficacy. ► Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ► Hepatic leukemia factor anti-death program is conserved in murine and human cells. ► Transcriptomics indicates the anti-death program results from a systems response.« less

Housing and overdose: an opportunity for the scale-up of overdose prevention interventions?

PubMed

Bardwell, Geoff; Collins, Alexandra B; McNeil, Ryan; Boyd, Jade

2017-12-06

North America is currently experiencing an overdose epidemic due to a significant increase of fentanyl-adulterated opioids and related analogs. Multiple jurisdictions have declared a public health emergency given the increasing number of overdose deaths. In the province of British Columbia (BC) in Canada, people who use drugs and who are unstably housed are disproportionately affected by a rising overdose crisis, with close to 90% of overdose deaths occurring indoors. Despite this alarming number, overdose prevention and response interventions have yet to be widely implemented in a range of housing settings. There are few examples of overdose prevention interventions in housing environments. In BC, for example, there are peer-led naloxone training and distribution programs targeted at some housing environments. There are also "supervised" spaces such as overdose prevention sites (similar to supervised consumption sites (SCS)) located in some housing environments; however, their coverage remains limited and the impacts of these programs are unclear due to the lack of evaluation work undertaken to date. A small number of SCS exist globally in housing environments (e.g., Germany), but like overdose prevention sites in BC, little is known about the design or effectiveness, as they remain under-evaluated. Implementing SCS and other overdose prevention interventions across a range of housing sites provides multiple opportunities to address overdose risk and drug-related harms for marginalized people who use drugs. Given the current overdose crisis rising across North America, and the growing evidence of the relationship between housing and overdose, the continued implementation and evaluation of novel overdose prevention interventions in housing environments should be a public health priority. A failure to do so will simply perpetuate what has proven to be a devastating epidemic of preventable death.

[The impact of patient identification on an integrated program of palliative care in Basque Country].

PubMed

Larrañaga, Igor; Millas, Jesús; Soto-Gordoa, Myriam; Arrospide, Arantzazu; San Vicente, Ricardo; Irizar, Marisa; Lanzeta, Itziar; Mar, Javier

2017-12-05

Evaluate the process and the economic impact of an integrated palliative care program. Comparative cross-sectional study. Integrated Healthcare Organizations of Alto Deba and Goierri Alto-Urola, Basque Country. Patients dead due to oncologic and non-oncologic causes in 2012 (control group) and 2015 (intervention group) liable to need palliative care according to McNamara criteria. Identification as palliative patients in primary care, use of common clinical pathways in primary and secondary care and arrange training courses for health professionals. Change in the resource use profile of patients in their last 3 months. Propensity score by genetic matching method was used to avoid non-randomization bias. The groups were compared by univariate analysis and the relationships between variables were analysed by logistic regressions and generalized linear models. One thousand and twenty-three patients were identified in 2012 and 1,142 patients in 2015. In 2015 doubled the probability of being identify as palliative patient in deaths due to oncologic (19-33%) and non-oncologic causes (7-16%). Prescriptions of opiates rise (25-68%) and deaths in hospital remained stable. Contacts per patient with primary care and home hospitalization increased, while contacts with hospital admissions decreased. Cost per patient rise 26%. The integrated palliative care model increased the identification of the target population. Relationships between variables showed that the identification had a positive impact on prescription of opiates, death outside the hospital and extension to non-oncologic diseases. Although the identification decreased admissions in hospital, costs per patient had a slight increase due to home hospitalizations. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

CDIP, a novel pro-apoptotic gene, regulates TNFα-mediated apoptosis in a p53-dependent manner

PubMed Central

Brown, Lauren; Ongusaha, Pat P; Kim, Hyung-Gu; Nuti, Shanthy; Mandinova, Anna; Lee, Ji Won; Khosravi-Far, Roya; Aaronson, Stuart A; Lee, Sam W

2007-01-01

We have identified a novel pro-apoptotic p53 target gene named CDIP (Cell Death Involved p53-target). Inhibition of CDIP abrogates p53-mediated apoptotic responses, demonstrating that CDIP is an important p53 apoptotic effector. CDIP itself potently induces apoptosis that is associated with caspase-8 cleavage, implicating the extrinsic cell death pathway in apoptosis mediated by CDIP. siRNA-directed knockdown of caspase-8 results in a severe impairment of CDIP-dependent cell death. In investigating the potential involvement of extrinsic cell death pathway in CDIP-mediated apoptosis, we found that TNF-α expression tightly correlates with CDIP expression, and that inhibition of TNF-α signaling attenuates CDIP-dependent apoptosis. We also demonstrate that TNF-α is upregulated in response to p53 and p53 inducing genotoxic stress, in a CDIP-dependent manner. Consistently, knockdown of TNF-α impairs p53-mediated stress-induced apoptosis. Together, these findings support a novel p53 → CDIP → TNF-α apoptotic pathway that directs apoptosis after exposure of cells to genotoxic stress. Thus, CDIP provides a new link between p53-mediated intrinsic and death receptor-mediated extrinsic apoptotic signaling, providing a novel target for cancer therapeutics aimed at maximizing the p53 apoptotic response of cancer cells to drug therapy. PMID:17599062

Comparative study of photothermolysis of cancer cells with nuclear-targeted or cytoplasm-targeted gold nanospheres: continuous wave or pulsed lasers

NASA Astrophysics Data System (ADS)

Huang, Xiaohua; Kang, Bin; Qian, Wei; Mackey, Megan A.; Chen, Po C.; Oyelere, Adegboyega K.; El-Sayed, Ivan H.; El-Sayed, Mostafa A.

2010-09-01

We conduct a comparative study on the efficiency and cell death pathways of continuous wave (cw) and nanosecond pulsed laser photothermal cancer therapy using gold nanospheres delivered to either the cytoplasm or nucleus of cancer cells. Cytoplasm localization is achieved using arginine-glycine-aspartate peptide modified gold nanospheres, which target integrin receptors on the cell surface and are subsequently internalized by the cells. Nuclear delivery is achieved by conjugating the gold nanospheres with nuclear localization sequence peptides originating from the simian virus. Photothermal experiments show that cell death can be induced with a single pulse of a nanosecond laser more efficiently than with a cw laser. When the cw laser is applied, gold nanospheres localized in the cytoplasm are more effective in inducing cell destruction than gold nanospheres localized at the nucleus. The opposite effect is observed when the nanosecond pulsed laser is used, suggesting that plasmonic field enhancement of the nonlinear absorption processes occurs at high localization of gold nanospheres at the nucleus. Cell death pathways are further investigated via a standard apoptosis kit to show that the cell death mechanisms depend on the type of laser used. While the cw laser induces cell death via apoptosis, the nanosecond pulsed laser leads to cell necrosis. These studies add mechanistic insight to gold nanoparticle-based photothermal therapy of cancer.

42 CFR 102.82 - Calculation of death benefits.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Calculation of death benefits. 102.82 Section 102... COMPENSATION PROGRAM Calculation and Payment of Benefits § 102.82 Calculation of death benefits. (a... paragraph (d) of this section for the death benefit available to dependents. (2) Deceased person means an...

20 CFR 638.513 - Death.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Death. 638.513 Section 638.513 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR JOB CORPS PROGRAM UNDER TITLE IV-B OF THE JOB TRAINING PARTNERSHIP ACT Center Operations § 638.513 Death. In each case of student death, the...

42 CFR 102.82 - Calculation of death benefits.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 1 2014-10-01 2014-10-01 false Calculation of death benefits. 102.82 Section 102... COMPENSATION PROGRAM Calculation and Payment of Benefits § 102.82 Calculation of death benefits. (a... paragraph (d) of this section for the death benefit available to dependents. (2) Deceased person means an...

20 CFR 638.513 - Death.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 20 Employees' Benefits 3 2011-04-01 2011-04-01 false Death. 638.513 Section 638.513 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR JOB CORPS PROGRAM UNDER TITLE IV-B OF THE JOB TRAINING PARTNERSHIP ACT Center Operations § 638.513 Death. In each case of student death, the...

42 CFR 110.82 - Calculation of death benefits.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 1 2014-10-01 2014-10-01 false Calculation of death benefits. 110.82 Section 110... COUNTERMEASURES INJURY COMPENSATION PROGRAM Calculation and Payment of Benefits § 110.82 Calculation of death... file a written selection to receive death benefits under the alternative calculation, as described in...

42 CFR 110.82 - Calculation of death benefits.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false Calculation of death benefits. 110.82 Section 110... COUNTERMEASURES INJURY COMPENSATION PROGRAM Calculation and Payment of Benefits § 110.82 Calculation of death... file a written selection to receive death benefits under the alternative calculation, as described in...

42 CFR 102.82 - Calculation of death benefits.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false Calculation of death benefits. 102.82 Section 102... COMPENSATION PROGRAM Calculation and Payment of Benefits § 102.82 Calculation of death benefits. (a... paragraph (d) of this section for the death benefit available to dependents. (2) Deceased person means an...

42 CFR 110.82 - Calculation of death benefits.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 1 2013-10-01 2013-10-01 false Calculation of death benefits. 110.82 Section 110... COUNTERMEASURES INJURY COMPENSATION PROGRAM Calculation and Payment of Benefits § 110.82 Calculation of death... file a written selection to receive death benefits under the alternative calculation, as described in...

42 CFR 110.82 - Calculation of death benefits.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 1 2012-10-01 2012-10-01 false Calculation of death benefits. 110.82 Section 110... COUNTERMEASURES INJURY COMPENSATION PROGRAM Calculation and Payment of Benefits § 110.82 Calculation of death... file a written selection to receive death benefits under the alternative calculation, as described in...

42 CFR 102.82 - Calculation of death benefits.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 1 2013-10-01 2013-10-01 false Calculation of death benefits. 102.82 Section 102... COMPENSATION PROGRAM Calculation and Payment of Benefits § 102.82 Calculation of death benefits. (a... paragraph (d) of this section for the death benefit available to dependents. (2) Deceased person means an...

20 CFR 638.513 - Death.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 20 Employees' Benefits 3 2012-04-01 2012-04-01 false Death. 638.513 Section 638.513 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR JOB CORPS PROGRAM UNDER TITLE IV-B OF THE JOB TRAINING PARTNERSHIP ACT Center Operations § 638.513 Death. In each case of student death, the...

42 CFR 102.82 - Calculation of death benefits.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 1 2012-10-01 2012-10-01 false Calculation of death benefits. 102.82 Section 102... COMPENSATION PROGRAM Calculation and Payment of Benefits § 102.82 Calculation of death benefits. (a... paragraph (d) of this section for the death benefit available to dependents. (2) Deceased person means an...

20 CFR 25.102 - How is compensation for death of a non-citizen non-resident employee paid?

Code of Federal Regulations, 2013 CFR

2013-04-01

... 20 Employees' Benefits 1 2013-04-01 2012-04-01 true How is compensation for death of a non-citizen... PROGRAMS, DEPARTMENT OF LABOR FEDERAL EMPLOYEES' COMPENSATION ACT COMPENSATION FOR DISABILITY AND DEATH OF... compensation for death of a non-citizen non-resident employee paid? If the disability causes death, the...

20 CFR 25.102 - How is compensation for death of a non-citizen non-resident employee paid?

Code of Federal Regulations, 2014 CFR

2014-04-01

... 20 Employees' Benefits 1 2014-04-01 2012-04-01 true How is compensation for death of a non-citizen... PROGRAMS, DEPARTMENT OF LABOR FEDERAL EMPLOYEES' COMPENSATION ACT COMPENSATION FOR DISABILITY AND DEATH OF... compensation for death of a non-citizen non-resident employee paid? If the disability causes death, the...

Factors affecting family satisfaction with inpatient end-of-life care.

PubMed

Sadler, Erin; Hales, Brigette; Henry, Blair; Xiong, Wei; Myers, Jeff; Wynnychuk, Lesia; Taggar, Ru; Heyland, Daren; Fowler, Robert

2014-01-01

Little data exists addressing satisfaction with end-of-life care among hospitalized patients, as they and their family members are systematically excluded from routine satisfaction surveys. It is imperative that we closely examine patient and institution factors associated with quality end-of-life care and determine high-priority target areas for quality improvement. Between September 1, 2010 and January 1, 2012 the Canadian Health care Evaluation Project (CANHELP) Bereavement Questionnaire was mailed to the next-of-kin of recently deceased inpatients to seek factors associated with satisfaction with end-of-life care. The primary outcome was the global rating of satisfaction. Secondary outcomes included rates of actual versus preferred location of death, associations between demographic factors and global satisfaction, and identification of targets for quality improvement. Response rate was 33% among 275 valid addresses. Overall, 67.4% of respondents were very or completely satisfied with the overall quality of care their relative received. However, 71.4% of respondents who thought their relative did not die in their preferred location favoured an out-of-hospital location of death. A common location of death was the intensive care unit (45.7%); however, this was not the preferred location of death for 47.6% of such patients. Multivariate Poisson regression analysis showed respondents who believed their relative died in their preferred location were 1.7 times more likely to be satisfied with the end-of-life care that was provided (p = 0.001). Items identified as high-priority targets for improvement included: relationships with, and characteristics of health care professionals; illness management; communication; and end-of-life decision-making. Nearly three-quarters of recently deceased inpatients would have preferred an out-of-hospital death. Intensive care units were a common, but not preferred, location of in-hospital deaths. Family satisfaction with end-of-life care was strongly associated with their relative dying in their preferred location. Improved communication regarding end-of-life care preferences should be a high-priority quality improvement target.

Projected health and economic impact of rotavirus vaccination in GAVI-eligible countries: 2011-2030.

PubMed

Atherly, Deborah E; Lewis, Kristen D C; Tate, Jacqueline; Parashar, Umesh D; Rheingans, Richard D

2012-04-27

Rotavirus is the leading cause of diarrheal disease in children under 5 years of age. It is responsible for more than 450,000 deaths each year, with more than 90% of these deaths occurring in low-resource countries eligible for support by the GAVI Alliance. Significant efforts made by the Alliance and its partners are providing countries with the opportunity to introduce rotavirus vaccines into their national immunization programs, to help prevent childhood illness and death. We projected the cost-effectiveness and health impact of rotavirus vaccines in GAVI-eligible countries, to assist decision makers in prioritizing resources to achieve the greatest health benefits for their populations. A decision-analytic model was used to project the health outcomes and direct costs of a birth cohort in the target population, with and without a rotavirus vaccine. Current data on disease burden, vaccine efficacy, immunization rates, and costs were used in the model. Vaccination in GAVI-eligible countries would prevent 2.46 million childhood deaths and 83 million disability-adjusted life years (DALYs) from 2011 to 2030, with annual reductions of 180,000 childhood deaths at peak vaccine uptake. The cost per DALY averted is $42 for all GAVI countries combined, over the entire period. Rotavirus vaccination would be considered very cost-effective for the entire cohort of GAVI countries, and in each country individually, as cost-effectiveness ratios are less than the gross domestic product (GDP) per capita. Vaccination is most cost-effective and has the greatest impact in regions with high rotavirus mortality. Rotavirus vaccination in GAVI-eligible countries is very cost-effective and is projected to substantially reduce childhood mortality in this population. Copyright © 2012. Published by Elsevier Ltd.

Differences in late-stage diagnosis, treatment, and colorectal cancer-related death between rural and urban African Americans and whites in Georgia.

PubMed

Hines, Robert B; Markossian, Talar W

2012-01-01

Disparities in health outcomes due to a diagnosis of colorectal cancer (CRC) have been reported for a number of demographic groups. This study was conducted to examine the outcomes of late-stage diagnosis, treatment, and cancer-related death according to race and geographic residency status (rural vs urban). This study utilized cross-sectional and follow-up data from the Surveillance, Epidemiology, and End Results (SEER) Program for all incident colon and rectal tumors diagnosed for the Atlanta and Rural Georgia Cancer Registries for the years 1992-2007. Compared to whites, African Americans had a 40% increased odds (OR, 1.40; 95% CI, 1.30-1.51) of late-stage diagnosis, a 50% decreased odds (OR, 0.50; 95% CI, 0.37-0.68) of having surgery for colon cancer, and a 67% decreased odds (OR, 0.33; 95% CI, 0.25-0.44) of receiving surgery for rectal cancer. Rural residence was not associated with late stage at diagnosis or receipt of treatment. African Americans had a slightly increased risk of death from colon cancer (HR, 1.11; 95% CI, 1.00-1.24) and a larger increased risk of death due to rectal cancer (HR, 1.24; 95% CI, 1.14-1.35). Rural residents experienced a 15% increased risk of death (HR, 1.15; 95% CI, 1.01-1.32) due to colon cancer. Further investigations should target African Americans and rural residents to gain insight into the etiologic mechanisms responsible for the poorer CRC outcomes experienced by these 2 segments of the population. © 2011 National Rural Health Association.

RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8+ T cells

PubMed Central

Duewell, P; Steger, A; Lohr, H; Bourhis, H; Hoelz, H; Kirchleitner, S V; Stieg, M R; Grassmann, S; Kobold, S; Siveke, J T; Endres, S; Schnurr, M

2014-01-01

Pancreatic cancer is characterized by a microenvironment suppressing immune responses. RIG-I-like helicases (RLH) are immunoreceptors for viral RNA that induce an antiviral response program via the production of type I interferons (IFN) and apoptosis in susceptible cells. We recently identified RLH as therapeutic targets of pancreatic cancer for counteracting immunosuppressive mechanisms and apoptosis induction. Here, we investigated immunogenic consequences of RLH-induced tumor cell death. Treatment of murine pancreatic cancer cell lines with RLH ligands induced production of type I IFN and proinflammatory cytokines. In addition, tumor cells died via intrinsic apoptosis and displayed features of immunogenic cell death, such as release of HMGB1 and translocation of calreticulin to the outer cell membrane. RLH-activated tumor cells led to activation of dendritic cells (DCs), which was mediated by tumor-derived type I IFN, whereas TLR, RAGE or inflammasome signaling was dispensable. Importantly, CD8α+ DCs effectively engulfed apoptotic tumor material and cross-presented tumor-associated antigen to naive CD8+ T cells. In comparison, tumor cell death mediated by oxaliplatin, staurosporine or mechanical disruption failed to induce DC activation and antigen presentation. Tumor cells treated with sublethal doses of RLH ligands upregulated Fas and MHC-I expression and were effectively sensitized towards Fas-mediated apoptosis and cytotoxic T lymphocyte (CTL)-mediated lysis. Vaccination of mice with RLH-activated tumor cells induced protective antitumor immunity in vivo. In addition, MDA5-based immunotherapy led to effective tumor control of established pancreatic tumors. In summary, RLH ligands induce a highly immunogenic form of tumor cell death linking innate and adaptive immunity. PMID:25012502

Ultrasonically targeted delivery into endothelial and smooth muscle cells in ex vivo arteries

PubMed Central

Hallow, Daniel M.; Mahajan, Anuj D.; Prausnitz, Mark R.

2007-01-01

This study tested the hypothesis that ultrasound can target intracellular uptake of drugs into vascular endothelial cells (ECs) at low to intermediate energy and into smooth muscle cells (SMCs) at high energy. Ultrasound-enhanced delivery has been shown to enhance and target intracellular drug and gene delivery in the vasculature to treat cardiovascular disease, but quantitative studies of the delivery process are lacking. Viable ex vivo porcine carotid arteries were placed in a solution containing a model drug, TO-PRO®-1, and Optison® microbubbles. Arteries were exposed to ultrasound at 1.1 MHz and acoustic energies of 5.0, 66, or 630 J/cm2. Using confocal microscopy and fluorescent labeling of cells, the artery endothelium and media were imaged to determine the localization and to quantify intracellular uptake and cell death. At low to intermediate ultrasound energy, ultrasound was shown to target intracellular delivery into viable cells that represented 9 – 24% of exposed ECs. These conditions also typically caused 7 – 25% EC death. At high energy, intracellular delivery was targeted to SMCs, which was associated with denuding or death of proximal ECs. This work represents the first known in-depth study to evaluate intracellular uptake into cells in tissue. We conclude that significant intracellular uptake of molecules can be targeted into ECs and SMCs by ultrasound-enhanced delivery suggesting possible applications for treatment of cardivascular diseases and dysfunctions. PMID:17291619

Compliance with guidelines and predictors of mortality in hemodialysis. Learning from Serbia patients.

PubMed

Djukanović, Ljubica; Dimković, Nada; Marinković, Jelena; Andrić, Branislav; Bogdanović, Jasmina; Budošan, Ivana; Cvetičanin, Anica; Djordjev, Kosta; Djordjević, Verica; Djurić, Živka; Lilić, Branimir Haviža; Jovanović, Nasta; Jelačić, Rosa; Knežević, Violeta; Kostić, Svetislav; Lazarević, Tatjana; Ljubenović, Stanimir; Marić, Ivko; Marković, Rodoljub; Milenković, Srboljub; Milićević, Olivera; Mitić, Igor; Mićunović, Vesna; Mišković, Milena; Pilipović, Dragana; Plješa, Steva; Radaković, Miroslava; Stanojević, Marina Stojanović; Janković, Biserka Tirmenštajn; Vojinović, Goran; Šefer, Kornelija

2015-01-01

The aims of the study were to determine the percentage of patients on regular hemodialysis (HD) in Serbia failing to meet KDOQI guidelines targets and find out factors associated with the risk of time to death and the association between guidelines adherence and patient outcome. A cohort of 2153 patients on regular HD in 24 centers (55.7% of overall HD population) in Serbia were followed from January 2010 to December 2012. The percentage of patients failing to meet KDOQI guidelines targets of dialysis dose (Kt/V>1.2), hemoglobin (>110g/L), serum phosphorus (1.1-1.8mmol/L), calcium (2.1-2.4mmol/L) and iPTH (150-300pg/mL) was determined. Cox proportional hazards analysis was used to select variables significantly associated with the risk of time to death. The patients were on regular HD for 5.3±5.3 years, dialyzed 11.8±1.9h/week. Kt/V<1.2 had 42.4% of patients, hemoglobin <110g/L had 66.1%, s-phosphorus <1.1mmol/L had 21.7% and >1.8mmol/L 28.6%, s-calcium <2.1mmol/L had 11.7% and >2.4mmol/L 25.3%, iPTH <150pg/mL had 40% and >300pg/mL 39.7% of patients. Using Cox model (adjustment for patient age, gender, duration of HD treatment) age, duration of HD treatment, hemoglobin, iPTH and diabetic nephropathy were selected as significant independent predictors of time to death. When targets of five examined parameters were included in Cox model, target for KtV, hemoglobin and iPTH were found to be significant independent predictors of time to death. Substantial proportion of patients examined failed to meet KDOQI guidelines targets. The relative risk of time to death was associated with being outside the targets for Kt/V, hemoglobin and iPTH. Copyright © 2015 The Authors. Published by Elsevier España, S.L.U. All rights reserved.

NEMO Inhibits Programmed Necrosis in an NFκB-Independent Manner by Restraining RIP1

PubMed Central

Legarda, Diana; Ting, Adrian T.

2012-01-01

TNF can trigger two opposing responses: cell survival and cell death. TNFR1 activates caspases that orchestrate apoptosis but some cell types switch to a necrotic death when treated with caspase inhibitors. Several genes that are required to orchestrate cell death by programmed necrosis have been identified, such as the kinase RIP1, but very little is known about the inhibitory signals that keep this necrotic cell death pathway in check. We demonstrate that T cells lacking the regulatory subunit of IKK, NFκB essential modifier (NEMO), are hypersensitive to programmed necrosis when stimulated with TNF in the presence of caspase inhibitors. Surprisingly, this pro-survival activity of NEMO is independent of NFκB-mediated gene transcription. Instead, NEMO inhibits necrosis by binding to ubiquitinated RIP1 to restrain RIP1 from engaging the necrotic death pathway. In the absence of NEMO, or if ubiquitination of RIP1 is blocked, necrosis ensues when caspases are blocked. These results indicate that recruitment of NEMO to ubiquitinated RIP1 is a key step in the TNFR1 signaling pathway that determines whether RIP1 triggers a necrotic death response. PMID:22848449

Death penalty for keratinocytes: apoptosis versus cornification.

PubMed

Lippens, S; Denecker, G; Ovaere, P; Vandenabeele, P; Declercq, W

2005-11-01

Homeostasis implies a balance between cell growth and cell death. This balance is essential for the development and maintenance of multicellular organisms. Homeostasis is controlled by several mechanisms including apoptosis, a process by which cells condemned to death are completely eliminated. However, in some cases, total destruction and removal of dead cells is not desirable, as when they fulfil a specific function such as formation of the skin barrier provided by corneocytes, also known as terminally differentiated keratinocytes. In this case, programmed cell death results in accumulation of functional cell corpses. Previously, this process has been associated with apoptotic cell death. In this overview, we discuss differences and similarities in the molecular regulation of epidermal programmed cell death and apoptosis. We conclude that despite earlier confusion, apoptosis and cornification occur through distinct molecular pathways, and that possibly antiapoptotic mechanisms are implicated in the terminal differentiation of keratinocytes.

Optimal Systolic Blood Pressure Target After SPRINT: Insights from a Network Meta-Analysis of Randomized Trials.

PubMed

Bangalore, Sripal; Toklu, Bora; Gianos, Eugenia; Schwartzbard, Arthur; Weintraub, Howard; Ogedegbe, Gbenga; Messerli, Franz H

2017-06-01

The optimal on-treatment blood pressure (BP) target has been a matter of debate. The recent SPRINT trial showed significant benefits of a BP target of <120 mm Hg, albeit with an increase in serious adverse effects related to low BP. PubMed, EMBASE, and CENTRAL were searched for randomized trials comparing treating with different BP targets. Trial arms were grouped into 5 systolic BP target categories: 1) <160 mm Hg, 2) <150 mm Hg, 3) <140 mm Hg, 4) <130 mm Hg, and 5) <120 mm Hg. Efficacy outcomes of stroke, myocardial infarction, death, cardiovascular death, heart failure, and safety outcomes of serious adverse effects were evaluated using a network meta-analysis. Seventeen trials that enrolled 55,163 patients with 204,103 patient-years of follow-up were included. There was a significant decrease in stroke (rate ratio [RR] 0.54; 95% confidence interval [CI], 0.29-1.00) and myocardial infarction (RR 0.68; 95% CI, 0.47-1.00) with systolic BP <120 mm Hg (vs <160 mm Hg). Sensitivity analysis using achieved systolic BP showed a 72%, 97%, and 227% increase in stroke with systolic BP of <140 mm Hg, <150 mm Hg, and <160 mm, respectively, when compared with systolic BP <120 mm Hg. There was no difference in death, cardiovascular death, or heart failure when comparing any of the BP targets. However, the point estimate favored lower BP targets (<120 mm Hg, <130 mm Hg) when compared with higher BP targets (<140 mm Hg or <150 mm Hg). BP targets of <120 mm Hg and <130 mm Hg ranked #1 and #2, respectively, as the most efficacious target. There was a significant increase in serious adverse effects with systolic BP <120 mm Hg vs <150 mm Hg (RR 1.83; 95% CI, 1.05-3.20) or vs <140 mm Hg (RR 2.12; 95% CI, 1.46-3.08). BP targets of <140 mm Hg and <150 mm Hg ranked #1 and #2, respectively, as the safest target for the outcome of serious adverse effects. Cluster plots for combined efficacy and safety showed that a systolic BP target of <130 mm Hg had optimal balance between efficacy and safety. In patients with hypertension, a on-treatment systolic BP target of <130 mm Hg achieved optimal balance between efficacy and safety. Copyright © 2017 Elsevier Inc. All rights reserved.

Effectiveness of Short-Term Death Education Programmes for Adults.

ERIC Educational Resources Information Center

Wass, Hannelore; And Others

1980-01-01

Various health and rehabilitative services staff participated in a four-day death education program. Participants in the program and a control group were given two equivalent forms of a knowledge test. The treatment group showed a higher gain score on the posttest than the control group. (RC)

Using cost-effectiveness analysis to evaluate targeting strategies: the case of vitamin A supplementation.

PubMed

Loevinsohn, B P; Sutter, R W; Costales, M O

1997-03-01

Given the demonstrated efficacy of vitamin A supplements in reducing childhood mortality, health officials now have to decide whether it would be efficient to target the supplements to high risk children. Decisions about targeting are complex because they depend on a number of factors; the degree of clustering of preventable deaths, the cost of the intervention, the side-effects of the intervention, the cost of identifying the high risk group, and the accuracy of the 'diagnosis' of risk. A cost-effectiveness analysis was used in the Philippines to examine whether vitamin A supplements should be given universally to all children 6-59 months, targeted broadly to children suffering from mild, moderate, or severe malnutrition, or targeted narrowly to pre-schoolers with moderate and severe malnutrition. The first year average cost of the universal approach was US$67.21 per death averted compared to $144.12 and $257.20 for the broad and narrow targeting approaches respectively. When subjected to sensitivity analysis the conclusion about the most cost-effective strategy was robust to changes in underlying assumptions such as the efficacy of supplements, clustering of deaths, and toxicity. Targeting vitamin A supplements to high risk children is not an efficient use of resources. Based on the results of this cost-effectiveness analysis and a consideration of alternate strategies, it is apparent that vitamin A, like immunization, should be provided to all pre-schoolers in the developing world. Issues about targeting public health interventions can usefully be addressed by cost-effectiveness analysis.

Surveillance for Violent Deaths - National Violent Death Reporting System, 17 States, 2013.

PubMed

Lyons, Bridget H; Fowler, Katherine A; Jack, Shane P D; Betz, Carter J; Blair, Janet M

2016-08-19

In 2013, more than 57,000 persons died in the United States as a result of violence-related injuries. This report summarizes data from CDC's National Violent Death Reporting System (NVDRS) regarding violent deaths from 17 U.S. states for 2013. Results are reported by sex, age group, race/ethnicity, marital status, location of injury, method of injury, circumstances of injury, and other selected characteristics. 2013. NVDRS collects data from participating states regarding violent deaths obtained from death certificates, coroner/medical examiner reports, law enforcement reports, and secondary sources (e.g., child fatality review team data, supplemental homicide reports, hospital data, and crime laboratory data). This report includes data from 17 states that collected statewide data for 2013 (Alaska, Colorado, Georgia, Kentucky, Maryland, Massachusetts, North Carolina, New Jersey, New Mexico, Ohio, Oklahoma, Oregon, Rhode Island, South Carolina, Utah, Virginia, and Wisconsin). NVDRS collates documents for each death and links deaths that are related (e.g., multiple homicides, a homicide followed by a suicide, or multiple suicides) from a single incident. For 2013, a total of 18,765 fatal incidents involving 19,251 deaths were captured by NVDRS in the 17 states included in this report. The majority (66.2%) of deaths were suicides, followed by homicides (23.2%), deaths of undetermined intent (8.8%), deaths involving legal intervention (1.2%) (i.e., deaths caused by law enforcement and other persons with legal authority to use deadly force, excluding legal executions), and unintentional firearm deaths (<1%). (The term legal intervention is a classification incorporated into the International Classification of Diseases, Tenth Revision [ICD-10] and does not denote the lawfulness or legality of the circumstances surrounding a death caused by law enforcement.) Suicides occurred at higher rates among males, non-Hispanic whites, American Indian/Alaska Natives, persons aged 45-64 years, and males aged ≥75 years. Suicides were preceded primarily by a mental health, intimate partner, or physical health problem or a crisis during the previous or upcoming 2 weeks. Homicide rates were higher among males and persons aged 15-44 years; rates were highest among non-Hispanic black males. Homicides primarily were precipitated by arguments and interpersonal conflicts, occurrence in conjunction with another crime, or were related to intimate partner violence (particularly for females). A known relationship between a homicide victim and a suspected perpetrator was most likely either that of an acquaintance or friend or an intimate partner. Legal intervention death rates were highest among males and persons aged 20-24 years and 30-34 years; rates were highest among non-Hispanic black males. Precipitating factors for the majority of legal intervention deaths were another crime, a mental health problem, or a recent crisis. Deaths of undetermined intent occurred at the highest rates among males and persons aged <1 year and 45-54 years. Substance abuse and mental or physical health problems were the most common circumstances preceding deaths of undetermined intent. Unintentional firearm death rates were higher among males, non-Hispanic whites, and persons aged persons aged 15-19 and 55-64 years; these deaths were most often precipitated by a person unintentionally pulling the trigger while playing with a firearm or while hunting. This report provides a detailed summary of data from NVDRS for 2013. The results indicate that violent deaths resulting from self-inflicted or interpersonal violence disproportionately affected persons aged <65 years, males, and certain minority populations. For homicides and suicides, intimate partner problems, interpersonal conflicts, mental health problems, and recent crises were primary precipitating factors. NVDRS data are used to monitor the occurrence of violence-related fatal injuries and assist public health authorities in the development, implementation, and evaluation of programs and policies to reduce and prevent violent deaths. For example, Utah Violent Death Reporting System (VDRS) data were used to develop policies that support children of intimate partner homicide victims, Colorado VDRS data to develop a web-based suicide prevention program targeting middle-aged men, and Rhode Island VDRS data to help guide suicide prevention efforts at workplaces. The continued development and expansion of NVDRS to include all U.S. states, territories, and the District of Columbia are essential to public health efforts to reduce the impact of violence.

75 FR 29585 - Agency Information Collection Activities: Proposed collection; Comments Requested

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-26

... Under Sentence of Death. The Department of Justice (DOJ), Office of Justice Programs, Bureau of Justice.../Collection: Capital Punishment Report of Inmates Under Sentence of Death. (3) Agency form number, if any, and... Report of Inmates Under Sentence of Death; NPS-8A Update Report of Inmates Under Sentence of Death; NPS...

20 CFR 10.414 - What reports of dependents are needed in death cases?

Code of Federal Regulations, 2011 CFR

2011-04-01

... death cases? 10.414 Section 10.414 Employees' Benefits OFFICE OF WORKERS' COMPENSATION PROGRAMS...' COMPENSATION ACT, AS AMENDED Compensation and Related Benefits Compensation for Death § 10.414 What reports of dependents are needed in death cases? If a beneficiary is receiving compensation benefits on account of an...

20 CFR 10.414 - What reports of dependents are needed in death cases?

Code of Federal Regulations, 2010 CFR

2010-04-01

... death cases? 10.414 Section 10.414 Employees' Benefits OFFICE OF WORKERS' COMPENSATION PROGRAMS...' COMPENSATION ACT, AS AMENDED Compensation and Related Benefits Compensation for Death § 10.414 What reports of dependents are needed in death cases? If a beneficiary is receiving compensation benefits on account of an...

20 CFR 10.414 - What reports of dependents are needed in death cases?

Code of Federal Regulations, 2012 CFR

2012-04-01

... death cases? 10.414 Section 10.414 Employees' Benefits OFFICE OF WORKERS' COMPENSATION PROGRAMS...' COMPENSATION ACT, AS AMENDED Compensation and Related Benefits Compensation for Death § 10.414 What reports of dependents are needed in death cases? If a beneficiary is receiving compensation benefits on account of an...

20 CFR 10.911 - How is the death gratuity payment process initiated?

Code of Federal Regulations, 2013 CFR

2013-04-01

... 20 Employees' Benefits 1 2013-04-01 2012-04-01 true How is the death gratuity payment process initiated? 10.911 Section 10.911 Employees' Benefits OFFICE OF WORKERS' COMPENSATION PROGRAMS, DEPARTMENT OF...' COMPENSATION ACT, AS AMENDED Death Gratuity § 10.911 How is the death gratuity payment process initiated? (a...

7 CFR 707.3 - Death.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 7 2011-01-01 2011-01-01 false Death. 707.3 Section 707.3 Agriculture Regulations of... Death. (a) Where any person who would otherwise be eligible to receive a payment dies before the payment... timely program application has been filed by the deceased before the death or filed in a timely way...

7 CFR 707.3 - Death.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 7 2014-01-01 2014-01-01 false Death. 707.3 Section 707.3 Agriculture Regulations of... Death. (a) Where any person who would otherwise be eligible to receive a payment dies before the payment... timely program application has been filed by the deceased before the death or filed in a timely way...

7 CFR 707.3 - Death.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 7 2012-01-01 2012-01-01 false Death. 707.3 Section 707.3 Agriculture Regulations of... Death. (a) Where any person who would otherwise be eligible to receive a payment dies before the payment... timely program application has been filed by the deceased before the death or filed in a timely way...

7 CFR 707.3 - Death.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 7 2013-01-01 2013-01-01 false Death. 707.3 Section 707.3 Agriculture Regulations of... Death. (a) Where any person who would otherwise be eligible to receive a payment dies before the payment... timely program application has been filed by the deceased before the death or filed in a timely way...

Neuroblastoma cells depend on HDAC11 for mitotic cell cycle progression and survival

PubMed Central

Thole, Theresa M; Lodrini, Marco; Fabian, Johannes; Wuenschel, Jasmin; Pfeil, Sebastian; Hielscher, Thomas; Kopp-Schneider, Annette; Heinicke, Ulrike; Fulda, Simone; Witt, Olaf; Eggert, Angelika; Fischer, Matthias; Deubzer, Hedwig E

2017-01-01

The number of long-term survivors of high-risk neuroblastoma remains discouraging, with 10-year survival as low as 20%, despite decades of considerable international efforts to improve outcome. Major obstacles remain and include managing resistance to induction therapy, which causes tumor progression and early death in high-risk patients, and managing chemotherapy-resistant relapses, which can occur years after the initial diagnosis. Identifying and validating novel therapeutic targets is essential to improve treatment. Delineating and deciphering specific functions of single histone deacetylases in neuroblastoma may support development of targeted acetylome-modifying therapeutics for patients with molecularly defined high-risk neuroblastoma profiles. We show here that HDAC11 depletion in MYCN-driven neuroblastoma cell lines strongly induces cell death, mostly mediated by apoptotic programs. Genes necessary for mitotic cell cycle progression and cell division were most prominently enriched in at least two of three time points in whole-genome expression data combined from two cell systems, and all nine genes in these functional categories were strongly repressed, including CENPA, KIF14, KIF23 and RACGAP1. Enforced expression of one selected candidate, RACGAP1, partially rescued the induction of apoptosis caused by HDAC11 depletion. High-level expression of all nine genes in primary neuroblastomas significantly correlated with unfavorable overall and event-free survival in patients, suggesting a role in mediating the more aggressive biological and clinical phenotype of these tumors. Our study identified a group of cell cycle-promoting genes regulated by HDAC11, being both predictors of unfavorable patient outcome and essential for tumor cell viability. The data indicate a significant role of HDAC11 for mitotic cell cycle progression and survival of MYCN-amplified neuroblastoma cells, and suggests that HDAC11 could be a valuable drug target. PMID:28252645

SB225002 Induces Cell Death and Cell Cycle Arrest in Acute Lymphoblastic Leukemia Cells through the Activation of GLIPR1

PubMed Central

Leal, Paulo C.; Bhasin, Manoj K.; Zenatti, Priscila Pini; Nunes, Ricardo J.; Yunes, Rosendo A.; Nowill, Alexandre E.; Libermann, Towia A.; Zerbini, Luiz Fernando; Yunes, José Andrés

2015-01-01

Acute Lymphoblastic Leukemia (ALL) is the most frequent childhood malignancy. In the effort to find new anti-leukemic agents, we evaluated the small drug SB225002 (N-(2-hydroxy-4-nitrophenyl)-N’-(2-bromophenyl)urea). Although initially described as a selective antagonist of CXCR2, later studies have identified other cellular targets for SB225002, with potential medicinal use in cancer. We found that SB225002 has a significant pro-apoptotic effect against both B- and T-ALL cell lines. Cell cycle analysis demonstrated that treatment with SB225002 induces G2-M cell cycle arrest. Transcriptional profiling revealed that SB225002-mediated apoptosis triggered a transcriptional program typical of tubulin binding agents. Network analysis revealed the activation of genes linked to the JUN and p53 pathways and inhibition of genes linked to the TNF pathway. Early cellular effects activated by SB225002 included the up-regulation of GLIPR1, a p53-target gene shown to have pro-apoptotic activities in prostate and bladder cancer. Silencing of GLIPR1 in B- and T-ALL cell lines resulted in increased resistance to SB225002. Although SB225002 promoted ROS increase in ALL cells, antioxidant N-Acetyl Cysteine pre-treatment only modestly attenuated cell death, implying that the pro-apoptotic effects of SB225002 are not exclusively mediated by ROS. Moreover, GLIPR1 silencing resulted in increased ROS levels both in untreated and SB225002-treated cells. In conclusion, SB225002 induces cell cycle arrest and apoptosis in different B- and T-ALL cell lines. Inhibition of tubulin function with concurrent activation of the p53 pathway, in particular, its downstream target GLIPR1, seems to underlie the anti-leukemic effect of SB225002. PMID:26302043

Sorafenib inhibits therapeutic induction of necroptosis in acute leukemia cells.

PubMed

Feldmann, Friederike; Schenk, Barbara; Martens, Sofie; Vandenabeele, Peter; Fulda, Simone

2017-09-15

Induction of necroptosis has emerged as an alternative approach to trigger programmed cell death, in particular in apoptosis-resistant cancer cells. Recent evidence suggests that kinase inhibitors targeting oncogenic B-RAF can also affect Receptor-interacting serine/threonine-protein kinase (RIP)1 and RIP3. Sorafenib, a multi-targeting kinase inhibitor with activity against B-RAF, is used for the treatment of acute leukemia. In the present study, we therefore investigated whether Sorafenib interferes with therapeutic induction of necroptosis in acute leukemia. Here, we report that Sorafenib inhibits necroptotic signaling and cell death in two models of necroptosis in acute leukemia. Sorafenib significantly reduces Second mitochondria-derived activator of caspases (Smac) mimetic-induced necroptosis in apoptosis-resistant acute myeloid leukemia (AML) cells as well as Smac mimetic/Tumor Necrosis Factor (TNF)α-induced necroptosis in FADD-deficient acute lymphoblastic leukemia (ALL) cells. Sub- to low micromolar concentrations of Sorafenib corresponding to its plasma levels reported in cancer patients are sufficient to inhibit necroptosis, emphasizing the clinical relevance of our findings. Furthermore, Sorafenib blocks Smac mimetic-mediated phosphorylation of mixed-lineage kinase domain-like protein (MLKL) that marks its activation, indicating that Sorafenib targets components upstream of MLKL such as RIP1 and RIP3. Intriguingly, Sorafenib reduces the Smac mimetic/TNFα-stimulated interaction of RIP1 with RIP3 and MLKL, demonstrating that it interferes with the assembly of the necrosome complex. Importantly, Sorafenib significantly protects primary, patient-derived AML blasts from Smac mimetic-induced necroptosis. By demonstrating that Sorafenib limits the anti-leukemic activity of necroptosis-inducing drugs in acute leukemia cells, our study has important implications for the use of Sorafenib in the treatment of acute leukemia.

Hospice-assisted death? A study of Oregon hospices on death with dignity.

PubMed

Campbell, Courtney S; Cox, Jessica C

2012-05-01

Nearly 90% of terminally ill patients who have used Oregon's distinctive death with dignity law to receive a medication to end their lives are enrolled in hospice care programs. In 2009-2010, we conducted a study of the policies developed by Oregon hospices to address patient inquiries and requests for death with dignity. The study examined the stated hospice values and positions and identified the boundaries to participation drawn by the hospice programs to protect personal and programmatic integrity. The boundaries were drawn around 6 key caregiving considerations: (1) language regarding physician-assisted death (PAD); (2) informed decision making by patients; (3) collaboration with physicians; (4) provision of lethal medication; (5) assistance in the patient's act of taking the medication; and (6) staff presence at the time of medication ingestion.

Effectiveness of a tailored intervention to improve cardiovascular risk management in primary care: study protocol for a randomised controlled trial.

PubMed

Huntink, Elke; Heijmans, Naomi; Wensing, Michel; van Lieshout, Jan

2013-12-17

Cardiovascular disease (CVD) is an important worldwide cause of mortality. In The Netherlands, CVD is the leading cause of death for women and the second cause of death for men. Recommendations for diagnosis and treatment of CVD are not well implemented in primary care. In this study, we aim to examine the effectiveness of a tailored implementation program targeted at practice nurses to improve healthcare for patients with (high risk for) CVD. A two-arm cluster randomized trial is planned. We offer practice nurses a tailored program to improve adherence to six specific recommendations related to blood pressure and cholesterol target values, risk profiling and lifestyle advice. Practice nurses are offered training and feedback on their motivational interviewing technique and an e-learning program on cardiovascular risk management (CVRM). They are also advised to screen for the presence and severity of depressive symptoms in patients. We also advise practice nurses to use selected E-health options (selected websites and Twitter-consult) in patients without symptoms of depression. Patients with mild depressive symptoms are referred to a physical exercise group. We recommend referring patients with major depressive symptoms for assessment and treatment of depressive symptoms if appropriate before starting CVRM. Data from 900 patients at high risk of CVD or with established CVD will be collected in 30 general practices in several geographical areas in The Netherlands. The primary outcome measure is performance of practice nurses in CVRM and reflects application of recommendations for personalized counselling and education of CVRM patients. Patients' health-related lifestyles (physical exercise, diet and smoking status) will be measured with validated questionnaires and medical record audit will be performed to document estimated CVD risk. Additionally, we will survey and interview participating healthcare professionals for exploration of processes of change. The control practices will provide usual care. Tailored interventions can improve healthcare. An understanding of the methods to reach the improved healthcare can be improved. This research contributes a share of it. Identification of the determinants of practice and developing implementation interventions were two steps which were completed. The subsequent step was implementation of the tailored intervention program. Name trial register: Nederlands trial register. Web address of trial register: http://www.trialregister.nl. Data of registration: 11 July 2013. Number of registration: NTR4069.

miR-14 regulates autophagy during developmental cell death by targeting ip3-kinase 2.

PubMed

Nelson, Charles; Ambros, Victor; Baehrecke, Eric H

2014-11-06

Macroautophagy (autophagy) is a lysosome-dependent degradation process that has been implicated in age-associated diseases. Autophagy is involved in both cell survival and cell death, but little is known about the mechanisms that distinguish its use during these distinct cell fates. Here, we identify the microRNA miR-14 as being both necessary and sufficient for autophagy during developmentally regulated cell death in Drosophila. Loss of miR-14 prevented induction of autophagy during salivary gland cell death, but had no effect on starvation-induced autophagy in the fat body. Moreover, misexpression of miR-14 was sufficient to prematurely induce autophagy in salivary glands, but not in the fat body. Importantly, miR-14 regulates this context-specific autophagy through its target, inositol 1,4,5-trisphosphate kinase 2 (ip3k2), thereby affecting inositol 1,4,5-trisphosphate (IP3) signaling and calcium levels during salivary gland cell death. This study provides in vivo evidence of microRNA regulation of autophagy through modulation of IP3 signaling. Copyright © 2014 Elsevier Inc. All rights reserved.

Understanding the socioeconomic heterogeneity in healthcare in US counties: the effect of population density, education and poverty on H1N1 pandemic mortality.

PubMed

Ponnambalam, L; Samavedham, L; Lee, H R; Ho, C S

2012-05-01

The recent outbreak of H1N1 has provided the scientific community with a sad but timely opportunity to understand the influence of socioeconomic determinants on H1N1 pandemic mortality. To this end, we have used data collected from 341 US counties to model H1N1 deaths/1000 using 12 socioeconomic predictors to discover why certain counties reported fewer H1N1 deaths compared to other counties. These predictors were then used to build a decision tree. The decision tree developed was then used to predict H1N1 mortality for the whole of the USA. Our estimate of 7667 H1N1 deaths are in accord with the lower bound of the CDC estimate of 8870 deaths. In addition to the H1N1 death estimates, we have listed possible counties to be targeted for health-related interventions. The respective state/county authorities can use these results as the basis to target and optimize the distribution of public health resources.

Unconscious Vigilance: Worldview Defense Without Adaptations for Terror, Coalition, or Uncertainty Management

PubMed Central

Holbrook, Colin; Sousa, Paulo; Hahn-Holbrook, Jennifer

2012-01-01

Individuals subtly reminded of death, coalitional challenges, or feelings of uncertainty display exaggerated preferences for affirmations and against criticisms of their cultural in-groups. Terror management, coalitional psychology, and uncertainty management theories postulate this “worldview defense” effect as the output of mechanisms evolved either to allay the fear of death, foster social support, or reduce anxiety by increasing adherence to cultural values. In 4 studies, we report evidence for an alternative perspective. We argue that worldview defense owes to unconscious vigilance, a state of accentuated reactivity to affective targets (which need not relate to cultural worldviews) that follows detection of subtle alarm cues (which need not pertain to death, coalitional challenges, or uncertainty). In Studies 1 and 2, death-primed participants produced exaggerated ratings of worldview-neutral affective targets. In Studies 3 and 4, subliminal threat manipulations unrelated to death, coalitional challenges, or uncertainty evoked worldview defense. These results are discussed as they inform evolutionary interpretations of worldview defense and future investigations of the influence of unconscious alarm on judgment. PMID:21644809

Assessment of in vitro killing assays for detecting praziquantel-induced death in Posthodiplostomum minimum metacercariae.

PubMed

Bader, Chris; Jesudoss Chelladurai, Jeba; Starling, David E; Jones, Douglas E; Brewer, Matthew T

2017-10-01

Control of parasitic infections may be achieved by eliminating developmental stages present within intermediate hosts, thereby disrupting the parasite life cycle. For several trematodes relevant to human and veterinary medicine, this involves targeting the metacercarial stage found in fish intermediate hosts. Treatment of fish with praziquantel is one potential approach for targeting the metacercaria stage. To date, studies investigating praziquantel-induced metacercarial death in fish rely on counting parasites and visually assessing morphology or movement. In this study, we investigate quantitative methods for detecting praziquantel-induced death using a Posthodiplostomum minimum model. Our results revealed that propidium iodide staining accurately identified praziquantel-induced death and the level of staining was proportional to the concentration of praziquantel. In contrast, detection of ATP, resazurin metabolism, and trypan blue staining were poor indicators of metacercarial death. The propidium iodide method offers an advantage over simple visualization of parasite movement and could be used to determine EC 50 values relevant for comparison of praziquantel sensitivity or resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

Next generation of immune checkpoint therapy in cancer: new developments and challenges.

PubMed

Marin-Acevedo, Julian A; Dholaria, Bhagirathbhai; Soyano, Aixa E; Knutson, Keith L; Chumsri, Saranya; Lou, Yanyan

2018-03-15

Immune checkpoints consist of inhibitory and stimulatory pathways that maintain self-tolerance and assist with immune response. In cancer, immune checkpoint pathways are often activated to inhibit the nascent anti-tumor immune response. Immune checkpoint therapies act by blocking or stimulating these pathways and enhance the body's immunological activity against tumors. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1(PD-L1) are the most widely studied and recognized inhibitory checkpoint pathways. Drugs blocking these pathways are currently utilized for a wide variety of malignancies and have demonstrated durable clinical activities in a subset of cancer patients. This approach is rapidly extending beyond CTLA-4 and PD-1/PD-L1. New inhibitory pathways are under investigation, and drugs blocking LAG-3, TIM-3, TIGIT, VISTA, or B7/H3 are being investigated. Furthermore, agonists of stimulatory checkpoint pathways such as OX40, ICOS, GITR, 4-1BB, CD40, or molecules targeting tumor microenvironment components like IDO or TLR are under investigation. In this article, we have provided a comprehensive review of immune checkpoint pathways involved in cancer immunotherapy, and discuss their mechanisms and the therapeutic interventions currently under investigation in phase I/II clinical trials. We also reviewed the limitations, toxicities, and challenges and outline the possible future research directions.

Construction of an anti-programmed death-ligand 1 chimeric antigen receptor and determination of its antitumor function with transduced cells

PubMed Central

Xie, Jiasen; Zhou, Zishan; Jiao, Shunchang; Li, Xiaokun

2018-01-01

A chimeric antigen receptor (CAR) is a type of fusion protein that comprises an antigen-recognition domain and signaling domains. In the present study, a programmed death-ligand 1 (PD-L1)-specific CAR, comprised of a single-chain variable fragment (scFv) derived from a monoclonal antibody, co-stimulatory domains of cluster of differentiation (CD) 28 and 4-1BB and a T-cell-activation domain derived from CD3ζ, was designed. The construction was cloned and packaged into the lentiviral vector pLVX. Flow cytometry confirmed that peripheral blood mononuclear cells were efficiently transduced and that the CAR was successfully expressed on T cells. The cytotoxicity of transduced T cells was detected using PD-L1-positive NCI-H358 bronchioalveolar carcinoma cells and A549 lung adenocarcinoma cells (with a low expression of PD-L1, only in the A549 cells). The results demonstrated mild cytotoxicity at an effector-to-target ratio of 10:1. An ELISA revealed a significant increase in the level of interferon-γ released from T cells transduced with scFv-28Bz when the cells were co-cultured with PD-L1-positive NCI-H358 cells, while interkeukin-2 and tumor necrosis factor-α levels remained unchanged. These data indicated a potential method for the treatment of solid tumors. PMID:29928397

JAK2 and genomic instability in the myeloproliferative neoplasms: a case of the chicken or the egg?

PubMed Central

Scott, Linda M.; Rebel, Vivienne I.

2012-01-01

The myeloproliferative neoplasms (MPNs) are a particularly useful model for studying mutation accumulation in neoplastic and the mechanisms of the molecular cells, understanding underlying defects our current This review summarizes acquisition. present their in patients with an MPN, and the effects of mutations targeting Janus kinase 2 (JAK2)-mediated intracellular signaling on DNA damage, and on the elimination of mutation-bearing cells by programmed cell death. Moreover, we discuss findings that suggest that the acquisition of disease-initiating mutations in hematopoietic stem cells of some MPN patients may be the consequence of an inherent genomic instability that was not previously appreciated. PMID:22641564

Deep brain stimulation for movement disorders. Considerations on 276 consecutive patients.

PubMed

Franzini, Angelo; Cordella, Roberto; Messina, Giuseppe; Marras, Carlo Efisio; Romito, Luigi Michele; Carella, Francesco; Albanese, Alberto; Rizzi, Michele; Nardocci, Nardo; Zorzi, Giovanna; Zekay, Edvin; Broggi, Giovanni

2011-10-01

The links between Stn DBS and advanced Parkinson disease, and between GPi DBS and dystonia are nearly universally accepted by the neurologists and neurosurgeons. Nevertheless, in some conditions, targets such as the ventral thalamus and the Zona Incerta may be considered to optimize the results and avoid the side effects. Positive and negative aspects of current DBS treatments justify the research of new targets, new stimulation programs and new hardware. Since 1993, at the Istituto Nazionale Neurologico "Carlo Besta" in Milan, 580 deep brain electrodes were implanted in 332 patients. 276 patients were affected by movement disorders. The DBS targets included Stn, GPi, Voa, Vop, Vim, CM-pf, cZi, IC. The long-term follow-up is reported and related to the chosen target. DBS gave a new therapeutic option to patients affected by severe movement disorders, and in some cases resolved life-threatening pathological conditions that would otherwise result in the death of the patient, such as in status dystonicus, and post-stroke hemiballismus. Nevertheless, the potential occurrence of severe complications still limit a wider use of DBS. At today, the use of DBS in severe movement disorders is strongly positive even if further investigations and studies are needed to unveil potential new applications, and to refine the selection criteria for the actual indications and targets. The experience of different targets may be useful to guide and tailor the target choice to the individual clinical condition.

3-bromopyruvate: a new targeted antiglycolytic agent and a promise for cancer therapy.

PubMed

Ganapathy-Kanniappan, S; Vali, M; Kunjithapatham, R; Buijs, M; Syed, L H; Rao, P P; Ota, S; Kwak, B K; Loffroy, R; Geschwind, J F

2010-08-01

The pyruvate analog, 3-bromopyruvate, is an alkylating agent and a potent inhibitor of glycolysis. This antiglycolytic property of 3-bromopyruvate has recently been exploited to target cancer cells, as most tumors depend on glycolysis for their energy requirements. The anticancer effect of 3-bromopyruvate is achieved by depleting intracellular energy (ATP) resulting in tumor cell death. In this review, we will discuss the principal mechanism of action and primary targets of 3-bromopyruvate, and report the impressive antitumor effects of 3-bromopyruvate in multiple animal tumor models. We describe that the primary mechanism of 3-bromopyruvate is via preferential alkylation of GAPDH and that 3-bromopyruvate mediated cell death is linked to generation of free radicals. Research in our laboratory also revealed that 3-bromopyruvate induces endoplasmic reticulum stress, inhibits global protein synthesis further contributing to cancer cell death. Therefore, these and other studies reveal the tremendous potential of 3-bromopyruvate as an anticancer agent.

Colorectal cancer chemoprevention: the potential of a selective approach.

PubMed

Ben-Amotz, Oded; Arber, Nadir; Kraus, Sarah

2010-10-01

Colorectal cancer (CRC) is a leading cause of cancer death, and therefore demands special attention. Novel recent approaches for the chemoprevention of CRC focus on selective targeting of key pathways. We review the study by Zhang and colleagues, evaluating a selective approach targeting APC-deficient premalignant cells using retinoid-based therapy and TNF-related apoptosis-inducing ligand (TRAIL). This study demonstrates that induction of TRAIL-mediated death signaling contributes to the chemopreventive value of all-trans-retinyl acetate (RAc) by sensitizing premalignant adenoma cells for apoptosis without affecting normal cells. We discuss these important findings, raise few points that deserve consideration, and may further contribute to the development of RAc-based combination therapies with improved efficacy. The authors clearly demonstrate a synergistic interaction between TRAIL, RAc and APC, which leads to the specific cell death of premalignant target cells. The study adds to the growing body of literature related to CRC chemoprevention, and provides solid data supporting a potentially selective approach for preventing CRC using RAc and TRAIL.

Acute myeloid leukemia-targeted toxin activates both apoptotic and necroptotic death mechanisms.

PubMed

Horita, Henrick; Frankel, Arthur E; Thorburn, Andrew

2008-01-01

Acute myelogenous leukemia (AML) is the second most common leukemia with approximately 13,410 new cases and 8,990 deaths annually in the United States. A novel fusion toxin treatment, diphtheria toxin GM-CSF (DT-GMCSF) has been shown to selectively eliminate leukemic repopulating cells that are critical for the formation of AML. We previously showed that DT-GMCSF treatment of U937 cells, an AML cell line, causes activation of caspases and the induction of apoptosis. In this study we further investigate the mechanisms of cell death induced by DT-GMCSF and show that, in addition to the activation of caspase-dependent apoptosis, DT-GMCSF also kills AML cells by simultaneously activating caspase-independent necroptosis. These mechanisms depend on the ability of the targeted toxin to inhibit protein synthesis, and are not affected by the receptor that is targeted or the mechanism through which protein synthesis is blocked. We conclude that fusion toxin proteins may be effective for treating AML cells whether or not they are defective in apoptosis.

Calcium regulates cell death in cancer: Roles of the mitochondria and mitochondria-associated membranes (MAMs).

PubMed

Danese, Alberto; Patergnani, Simone; Bonora, Massimo; Wieckowski, Mariusz R; Previati, Maurizio; Giorgi, Carlotta; Pinton, Paolo

2017-08-01

Until 1972, the term 'apoptosis' was used to differentiate the programmed cell death that naturally occurs in organismal development from the acute tissue death referred to as necrosis. Many studies on cell death and programmed cell death have been published and most are, at least to some degree, related to cancer. Some key proteins and molecular pathways implicated in cell death have been analyzed, whereas others are still being actively researched; therefore, an increasing number of cellular compartments and organelles are being implicated in cell death and cancer. Here, we discuss the mitochondria and subdomains of the endoplasmic reticulum (ER) that interact with mitochondria, the mitochondria-associated membranes (MAMs), which have been identified as critical hubs in the regulation of cell death and tumor growth. MAMs-dependent calcium (Ca 2+ ) release from the ER allows selective Ca 2+ uptake by the mitochondria. The perturbation of Ca 2+ homeostasis in cancer cells is correlated with sustained cell proliferation and the inhibition of cell death through the modulation of Ca 2+ signaling. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux. Copyright © 2017 Elsevier B.V. All rights reserved.

The Source of Methadone in Overdose Deaths in Western Virginia in 2004

PubMed Central

Weimer, Melissa B.; Korthuis, P. Todd; Behonick, George S.; Wunsch, Martha J.

2011-01-01

Objectives Methadone-related overdose deaths increased in the United States by 468% from 1999 to 2005. Current studies associate the nonmedical use of methadone with methadone-related deaths. This study describes medical examiner cases in rural Virginia in 2004 with methadone identified by toxicology and compares cases according to source of methadone. Methods In 2004, all intentional and unintentional poisoning deaths from the Office of The Chief Medical Examiner, Western District of Virginia, were reviewed to identify cases in which methadone was a direct or contributing cause of death. The Virginia Prescription Monitoring Program was reviewed for prescription opioids in the name of these identified decedents. Decedent participation in local opioid treatment programs (OTP) was also assessed. Results The source of methadone in the 61 methadone-related overdose deaths was mostly nonprescribed (67%), although 28% of decedents were prescribed methadone for analgesia. Only 5% of decedents were actively enrolled in an OTP. The majority of deaths were attributed to polysubstance overdose. Conclusions The majority of methadone overdose deaths in this study were related to illicit methadone use, rather than prescribed or OTP uses. Interventions to decrease methadone-related deaths should focus on reduction of nonprescription use of methadone. PMID:21844834

Control of non-apoptotic nurse cell death by engulfment genes in Drosophila.

PubMed

Timmons, Allison K; Mondragon, Albert A; Meehan, Tracy L; McCall, Kimberly

2017-04-03

Programmed cell death occurs as a normal part of oocyte development in Drosophila. For each egg that is formed, 15 germline-derived nurse cells transfer their cytoplasmic contents into the oocyte and die. Disruption of apoptosis or autophagy only partially inhibits the death of the nurse cells, indicating that other mechanisms significantly contribute to nurse cell death. Recently, we demonstrated that the surrounding stretch follicle cells non-autonomously promote nurse cell death during late oogenesis and that phagocytosis genes including draper, ced-12, and the JNK pathway are crucial for this process. When phagocytosis genes are inhibited in the follicle cells, events specifically associated with death of the nurse cells are impaired. Death of the nurse cells is not completely blocked in draper mutants, suggesting that other engulfment receptors are involved. Indeed, we found that the integrin subunit, αPS3, is enriched on stretch follicle cells during late oogenesis and is required for elimination of the nurse cells. Moreover, double mutant analysis revealed that integrins act in parallel to draper. Death of nurse cells in the Drosophila ovary is a unique example of programmed cell death that is both non-apoptotic and non-cell autonomously controlled.

Non-apoptotic cell death in animal development.

PubMed

Kutscher, Lena M; Shaham, Shai

2017-08-01

Programmed cell death (PCD) is an important process in the development of multicellular organisms. Apoptosis, a form of PCD characterized morphologically by chromatin condensation, membrane blebbing, and cytoplasm compaction, and molecularly by the activation of caspase proteases, has been extensively investigated. Studies in Caenorhabditis elegans, Drosophila, mice, and the developing chick have revealed, however, that developmental PCD also occurs through other mechanisms, morphologically and molecularly distinct from apoptosis. Some non-apoptotic PCD pathways, including those regulating germ cell death in Drosophila, still appear to employ caspases. However, another prominent cell death program, linker cell-type death (LCD), is morphologically conserved, and independent of the key genes that drive apoptosis, functioning, at least in part, through the ubiquitin proteasome system. These non-apoptotic processes may serve as backup programs when caspases are inactivated or unavailable, or, more likely, as freestanding cell culling programs. Non-apoptotic PCD has been documented extensively in the developing nervous system, and during the formation of germline and somatic gonadal structures, suggesting that preservation of these mechanisms is likely under strong selective pressure. Here, we discuss our current understanding of non-apoptotic PCD in animal development, and explore possible roles for LCD and other non-apoptotic developmental pathways in vertebrates. We raise the possibility that during vertebrate development, apoptosis may not be the major PCD mechanism.

Cancer’s Achilles’ Heel: Apoptosis and Necroptosis to the Rescue

PubMed Central

Dasgupta, Atreyi; Nomura, Motonari; Shuck, Ryan; Yustein, Jason

2016-01-01

Apoptosis, and the more recently discovered necroptosis, are two avenues of programmed cell death. Cancer cells survive by evading these two programs, driven by oncogenes and tumor suppressor genes. While traditional therapy using small molecular inhibitors and chemotherapy are continuously being utilized, a new and exciting approach is actively underway by identifying and using synergistic relationship between driver and rescue genes in a cancer cell. Through these synthetic lethal relationships, we are gaining tremendous insights into tumor vulnerabilities and specific molecular avenues for induction of programmed cell death. In this review, we briefly discuss the two cell death processes and cite examples of such synergistic manipulations for therapeutic purposes. PMID:28025559

Clinical and economic outcomes from a community hospital's antimicrobial stewardship program.

PubMed

Malani, Anurag N; Richards, Patrick G; Kapila, Shikha; Otto, Michael H; Czerwinski, Jennifer; Singal, Bonita

2013-02-01

Data from community antimicrobial stewardship programs (ASPs) are limited. We describe clinical and economic outcomes from the first year of our hospital's ASP. The ASP team comprised 2 infectious disease physicians and 3 intensive care unit pharmacists. The team prospectively audited the new starts and weekly use of 8 target antimicrobials: aztreonam, caspofungin, daptomycin, ertapenem, linezolid, meropenem, tigecycline, and voriconazole. Using administrative data, outcomes from the first year of the program, including death within 30 days of hospitalization, readmission within 30 days of discharge, and development of Clostridium difficile infection (CDI), were compared with outcomes from a similar period before institution of the program. A total of 510 antimicrobial orders were reviewed, of which 323 (63%) were appropriate, 94 (18%) prompted deescalation, 61 (12%) were denied, and 27 (5%) led to formal consultation with an infectious disease physician. On multivariate analysis, implementation of the ASP was associated with an approximate 50% reduction in the odds of developing CDI (odds ratio, 0.46; 95% confidence interval, 0.25-0.82). The ASP was not associated with decreased mortality at 30 days after discharge or readmission rate. The antimicrobial cost per patient-day decreased by 13.3%, from $10.16 to $8.81. The antimicrobial budget decreased by 15.2%, resulting in a total savings of $228,911. There was a 25.4% decrease in defined daily doses of the target antimicrobials. Implementation of the ASP was associated with significant reductions in CDI rate, antimicrobial use, and pharmacy costs. Copyright © 2013 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Mosby, Inc. All rights reserved.

Tumor suppressor roles of CENP-E and Nsl1 in Drosophila epithelial tissues.

PubMed

Clemente-Ruiz, Marta; Muzzopappa, Mariana; Milán, Marco

2014-01-01

Depletion of spindle assembly checkpoint (SAC) genes in Drosophila epithelial tissues leads to JNK-dependent programmed cell death and additional blockade of the apoptotic program drives tumorigenesis. A recent report proposes that chromosomal instability (CIN) is not the driving force in the tumorigenic response of the SAC-deficient tissue, and that checkpoint proteins exert a SAC-independent tumor suppressor role. This notion is based on observations that the depletion of CENP-E levels or prevention of Bub3 from binding to the kinetochore in Drosophila tissues unable to activate the apoptotic program induces CIN but does not cause hyperproliferation. Here we re-examined this proposal. In contrast to the previous report, we observed that depletion of CENP-E or Nsl1-the latter mediating kinetochore targeting of Bub3-in epithelial tissues unable to activate the apoptotic program induces significant levels of aneuploidy and drives tumor-like growth. The induction of the JNK transcriptional targets Wingless, a mitogenic molecule, and MMP1, a matrix metaloproteinase 1 involved in basement membrane degradation was also observed in these tumors. An identical response of the tissue was previously detected upon depletion of several SAC genes or genes involved in spindle assembly, chromatin condensation, and cytokinesis, all of which have been described to cause CIN. All together, these results reinforce the role of CIN in driving tumorigenesis in Drosophila epithelial tissues and question the proposed SAC-independent roles of checkpoint proteins in suppressing tumorigenesis. Differences in aneuploidy rates might explain the discrepancy between the previous report and our results.

Necroptosis: an alternative cell death program defending against cancer

PubMed Central

Chen, Dongshi; Yu, Jian; Zhang, Lin

2016-01-01

One of the hallmarks of cancer is resistance to programmed cell death, which maintains the survival of cells en route to oncogenic transformation and underlies therapeutic resistance. Recent studies demonstrate that programmed cell death is not confined to caspase-dependent apoptosis, but includes necroptosis, a form of necrotic death governed by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like (MLKL). Necroptosis serves as a critical cell-killing mechanism in response to severe stress and blocked apoptosis, and can be induced by inflammatory cytokines or chemotherapeutic drugs. Genetic or epigenetic alterations of necroptosis regulators such as RIP3 and cylindromatosis (CYLD), are frequently found in human tumors. Unlike apoptosis, necroptosis elicits a more robust immune response that may function as a defensive mechanism by eliminating tumor-causing mutations and viruses. Furthermore, several classes of anticancer agents currently under clinical development, such as SMAC and BH3 mimetics, can promote necroptosis in addition to apoptosis. A more complete understanding of the interplay among necroptosis, apoptosis, and other cell death modalities is critical for developing new therapeutic strategies to enhance killing of tumor cells. PMID:26968619

Antihelminthic benzimidazoles are novel HIF activators that prevent oxidative neuronal death via binding to tubulin.

PubMed

Aleyasin, Hossein; Karuppagounder, Saravanan S; Kumar, Amit; Sleiman, Sama; Basso, Manuela; Ma, Thong; Siddiq, Ambreena; Chinta, Shankar J; Brochier, Camille; Langley, Brett; Haskew-Layton, Renee; Bane, Susan L; Riggins, Gregory J; Gazaryan, Irina; Starkov, Anatoly A; Andersen, Julie K; Ratan, Rajiv R

2015-01-10

Pharmacological activation of the adaptive response to hypoxia is a therapeutic strategy of growing interest for neurological conditions, including stroke, Huntington's disease, and Parkinson's disease. We screened a drug library with known safety in humans using a hippocampal neuroblast line expressing a reporter of hypoxia-inducible factor (HIF)-dependent transcription. Our screen identified more than 40 compounds with the ability to induce hypoxia response element-driven luciferase activity as well or better than deferoxamine, a canonical activator of hypoxic adaptation. Among the chemical entities identified, the antihelminthic benzimidazoles represented one pharmacophore that appeared multiple times in our screen. Secondary assays confirmed that antihelminthics stabilized the transcriptional activator HIF-1α and induced expression of a known HIF target gene, p21(cip1/waf1), in post-mitotic cortical neurons. The on-target effect of these agents in stimulating hypoxic signaling was binding to free tubulin. Moreover, antihelminthic benzimidazoles also abrogated oxidative stress-induced death in vitro, and this on-target effect also involves binding to free tubulin. These studies demonstrate that tubulin-binding drugs can activate a component of the hypoxic adaptive response, specifically the stabilization of HIF-1α and its downstream targets. Tubulin-binding drugs, including antihelminthic benzimidazoles, also abrogate oxidative neuronal death in primary neurons. Given their safety in humans and known ability to penetrate into the central nervous system, antihelminthic benzimidazoles may be considered viable candidates for treating diseases associated with oxidative neuronal death, including stroke.

Cost-effective malaria control in Brazil. Cost-effectiveness of a Malaria Control Program in the Amazon Basin of Brazil, 1988-1996.

PubMed

Akhavan, D; Musgrove, P; Abrantes, A; d'A Gusmão, R

1999-11-01

Malaria transmission was controlled elsewhere in Brazil by 1980, but in the Amazon Basin cases increased steadily until 1989, to almost half a million a year and the coefficient of mortality quadrupled in 1977-1988. The government's malaria control program almost collapsed financially in 1987-1989 and underwent a turbulent reorganization in 1991-1993. A World Bank project supported the program from late 1989 to mid-1996, and in 1992-1993, with help from the Pan American Health Organization, facilitated a change toward earlier and more aggressive case treatment and more concentrated vector control. The epidemic stopped expanding in 1990-1991 and reversed in 1992-1996. The total cost of the program from 1989 through mid-1996 was US$616 million: US$526 million for prevention and US$90 million for treatment. Compared to what would have happened in the absence of the program, nearly two million cases of malaria and 231,000 deaths were prevented; the lives saved were due almost equally to preventing infection and to case treatment. Converting the savings in lives and in morbidity into Disability-Adjusted Life Years yields almost nine million DALYs, 5.1 million from treatment and 3.9 million from prevention. Nearly all the gain came from controlling deaths and therefore from controlling falciparum. The overall cost-effectiveness was US$2672 per life saved or US$69 per DALY, which is low compared to most previous estimates and compares favorably to many other disease control interventions. Contrary to much previous experience, case treatment appears more cost-effective than vector control, particularly where falciparum is prevalent and unfocussed insecticide spraying is relatively ineffective. Halting the epidemic by better targeted vector control and emphasizing treatment paid off in much reduced mortality from malaria and in significantly lower costs per life saved.

Benefits and harms of CT lung cancer screening strategies. A comparative modeling study for the U.S. Preventive Services Task Force

PubMed Central

de Koning, Harry J.; Meza, Rafael; Plevritis, Sylvia K.; Haaf, Kevin ten; Munshi, Vidit N.; Jeon, Jihyoun; Erdogan, Saadet Ayca; Kong, Chung Yin; Han, Summer S.; van Rosmalen, Joost; Choi, Sung Eun; Pinsky, Paul F.; Berrington de Gonzalez, Amy; Berg, Christine D.; Black, William C.; Tammemägi, Martin C.; Hazelton, William D.; Feuer, Eric J.; McMahon, Pamela M.

2014-01-01

Background The optimal screening policy for lung cancer is unknown. Objective To identify efficient CT-screening scenarios where relatively more lung cancer deaths are averted for fewer CT screens. Design Comparative modeling study using 5 independent models. Data Sources The National Lung Screening Trial, the Prostate, Lung, Colorectal and Ovarian trial, the Surveillance, Epidemiology, and End Results program, and U.S. Smoking History Generator. Target Population U.S. cohort born in 1950. Time Horizon Cohort followed from ages 45 to 90. Perspective Societal. Intervention 576 scenarios with varying eligibility criteria (age, smoking pack-years, years quit) and screening intervals. Outcome Measures Benefits: lung cancer deaths averted or life-years gained; harms: CT-exams, false positives (including biopsy/surgery), overdiagnosed cases, radiation-related deaths. Results of Best-Case Annual screening from age 55 through 80 for ever-smokers with at least 30 pack-years and ex-smokers with less than 15 years since quitting was the most advantageous strategy. It would lead to 50% (45 to 54%) of cancers being detected at an early stage (I/II); 575 screens per lung cancer death averted; a 14% (8.2 to 23.5%) lung cancer mortality reduction; 497 lung cancer deaths averted; and 5,250 life-years gained per the 100,000-member cohort. Harms would include 67,550 false-positive tests, 910 biopsies or surgeries for benign lesions and 190 overdiagnosed cancers (3.7%; 1.4 to 8.3%). Results of Sensitivity Analysis The number of cancer deaths averted for the scenario varied across models between 177 and 862, and for overdiagnosed cancers between 72 and 426. Limitations Scenarios assumed 100% screening adherence. Data derived from trials with short duration were extrapolated to life-time follow-up. Conclusion Annual CT screening for lung cancer has a favorable benefit-harm ratio for individuals aged 55 through 80 years with 30 or more pack-year exposure to smoking. PMID:24379002

34 CFR 682.510 - Determination of the borrower's death, total and permanent disability, or bankruptcy.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 34 Education 3 2010-07-01 2010-07-01 false Determination of the borrower's death, total and permanent disability, or bankruptcy. 682.510 Section 682.510 Education Regulations of the Offices of the... EDUCATION LOAN (FFEL) PROGRAM Federal Guaranteed Student Loan Programs § 682.510 Determination of the...

Death and Dying Training for Crisis Intervention.

ERIC Educational Resources Information Center

Hutchison, Theresa D.; Scherman, Avraham

This document presents a program for training volunteers to assist individuals and families who are going through a crisis related to terminal illness and death. The training is described as being both didactic and experiential. A discussion of the didactic portion of the program includes descriptions of: (1) the stages of preparatory grief as…

TRAIL enhances paracetamol-induced liver sinusoidal endothelial cell death in a Bim- and Bid-dependent manner

PubMed Central

Badmann, A; Langsch, S; Keogh, A; Brunner, T; Kaufmann, T; Corazza, N

2012-01-01

Paracetamol (acetaminophen, APAP) is a universally used analgesic and antipyretic agent. Considered safe at therapeutic doses, overdoses cause acute liver damage characterized by centrilobular hepatic necrosis. One of the major clinical problems of paracetamol-induced liver disease is the development of hemorrhagic alterations. Although hepatocytes represent the main target of the cytotoxic effect of paracetamol overdose, perturbations within the endothelium involving morphological changes of liver sinusoidal endothelial cells (LSECs) have also been described in paracetamol-induced liver disease. Recently, we have shown that paracetamol-induced liver damage is synergistically enhanced by the TRAIL signaling pathway. As LSECs are constantly exposed to activated immune cells expressing death ligands, including TRAIL, we investigated the effect of TRAIL on paracetamol-induced LSEC death. We here demonstrate for the first time that TRAIL strongly enhances paracetamol-mediated LSEC death with typical features of apoptosis. Inhibition of caspases using specific inhibitors resulted in a strong reduction of cell death. TRAIL appears to enhance paracetamol-induced LSEC death via the activation of the pro-apoptotic BH3-only proteins Bid and Bim, which initiate the mitochondrial apoptotic pathway. Taken together this study shows that the liver endothelial layer, mainly LSECs, represent a direct target of the cytotoxic effect of paracetamol and that activation of TRAIL receptor synergistically enhances paracetamol-induced LSEC death via the mitochondrial apoptotic pathway. TRAIL-mediated acceleration of paracetamol-induced cell death may thus contribute to the pathogenesis of paracetamol-induced liver damage. PMID:23254290