Case report of a cervical lipoleiomyoma with an incidentally discovered ovarian granulosa cell tumor – imaging and minimal-invasive surgical procedure

PubMed Central

Walid, M. Sami; Heaton, Richard L.

2010-01-01

Uterine lipoleiomyomas are rare benign tumors that mostly affect the uterine corpus. We are reporting the imaging and operative procedure of a very rare case of a large lipoleiomyoma of the uterine cervix combined with an occult adult ovarian granulosa cell tumor. The patient was treated with minimal invasive surgery. PMID:21063471

Detection of Occult Invasion in Melanoma In Situ.

PubMed

Bax, Michael J; Johnson, Timothy M; Harms, Paul W; Schwartz, Jennifer L; Zhao, Lili; Fullen, Douglas R; Chan, May P

2016-11-01

It is unclear why some patients with in situ melanoma develop metastases. Few reports demonstrate occult invasion with immunohistochemistry staining, which were discordant with reports interpreting such staining as false-positive. To investigate the occurrence of occult invasive disease within in situ melanoma by using methods to circumvent potential limitations in prior study designs. Unequivocal in situ melanoma without associated nevi or regression was identified using a consecutive sample of 33 cases plus 1 index case in an academic medical center. After cutting deeper into the most representative tissue block, 3 sequential slides were stained with hematoxylin-eosin (H-E), melanoma antigen (melan-A), and again with H-E. Melan-A-stained slides showing definitive invasion were double-stained with Sry-related HMg-Box gene 10 (SOX10) to confirm the melanocytic nature of the cells of interest. The study evaluated the possibilities of occult invasion detected by immunohistochemistry, sectioning deeper into the tissue block, or both. Slides were independently scored by 3 dermatopathologists with interrater reliability assessed. The study was conducted from January 1, 2012, to July 31, 2014. Assessment of the occurrence of occult invasion, diagnosis of invasion by immunohistochemistry alone vs cutting deeper into the tissue block, and occurrence of false-positive results using immunohistochemistry alone. Occult invasive melanoma was detected in 11 of 33 consecutive cases (33%) of previously diagnosed unequivocal in situ melanoma. Six of 11 melanomas (55%) were diagnosable only by immunohistochemistry. The remaining 5 tumors (45%) were diagnosable by both melan-A and H-E staining, likely as a result of simply cutting deeper into the tissue block. Four cases (12%) showed a few melan-A-positive cells in the dermis, which was insufficient for a diagnosis of invasive melanoma and most consistent on a cytomorphologic basis with occult nevi. Although rare, in situ melanoma

Occult oncocytic papillary thyroid carcinoma with lymphoid stroma (Warthin-like tumor): report of a case with concomitant mutations of BRAF V600E and V600K.

PubMed

Han, Fei; Zhang, Long; Zhang, Suxia; Zhou, Hong; Yi, Xianghua

2015-01-01

Warthin-Like tumor of the thyroid is a recently described rare variant of papillary thyroid cancer. The distinct histological feature of this variant is papillary architecture lining oncocytic epithelial cells with nuclear characteristics of papillary carcinoma, accompanied by prominent lymphocytic infiltration in the papillary stalks. Here, we present a case of occult Warthin-like papillary thyroid carcinoma, 0.5-cm in maximum dimension, underwent left thyroid lobectomy in a 65 years old Chinese woman. In this case, there was no extrathyroid extension, vascular invasion and lymphatic metastasis, as well as no complication of lymphocytic thyroiditis. Immunohistochemistry staining revealed that the tumor cells were positive for Leu-M1, HBME-1, 34βE12, and MIB-1 labeling index was low. RET/PTC expression was absent in tumor cells. Furthermore, activated point mutations of BRAF V600E and V600K were concurrently detected by DNA sequencing. Further studies are needed to elucidate the prevalence and role of BRAF(V600K) mutation in papillary thyroid carcinoma, and long-term follow-up for the patient is needed to clarify the biological behavior of this variant with dual BRAF mutations.

Occult oncocytic papillary thyroid carcinoma with lymphoid stroma (Warthin-like tumor): report of a case with concomitant mutations of BRAF V600E and V600K

PubMed Central

Han, Fei; Zhang, Long; Zhang, Suxia; Zhou, Hong; Yi, Xianghua

2015-01-01

Warthin-Like tumor of the thyroid is a recently described rare variant of papillary thyroid cancer. The distinct histological feature of this variant is papillary architecture lining oncocytic epithelial cells with nuclear characteristics of papillary carcinoma, accompanied by prominent lymphocytic infiltration in the papillary stalks. Here, we present a case of occult Warthin-like papillary thyroid carcinoma, 0.5-cm in maximum dimension, underwent left thyroid lobectomy in a 65 years old Chinese woman. In this case, there was no extrathyroid extension, vascular invasion and lymphatic metastasis, as well as no complication of lymphocytic thyroiditis. Immunohistochemistry staining revealed that the tumor cells were positive for Leu-M1, HBME-1, 34βE12, and MIB-1 labeling index was low. RET/PTC expression was absent in tumor cells. Furthermore, activated point mutations of BRAF V600E and V600K were concurrently detected by DNA sequencing. Further studies are needed to elucidate the prevalence and role of BRAFV600K mutation in papillary thyroid carcinoma, and long-term follow-up for the patient is needed to clarify the biological behavior of this variant with dual BRAF mutations. PMID:26191315

Occult hepatitis B virus infection in hematopoietic stem cell donors in a hepatitis B virus endemic area.

PubMed

Hui, Chee-kin; Sun, Jian; Au, Wing-yan; Lie, Albert K W; Yueng, Yui-hung; Zhang, Hai-ying; Lee, Nikki P; Hou, Jin-ling; Liang, Raymond; Lau, George K K

2005-06-01

The acquisition of hepatitis B virus (HBV) infection following organ transplantation from donors with occult HBV infection is an important cause of morbidity and mortality. The aim of this study is to determine the prevalence of occult HBV in allogeneic hematopoietic stem cell (HSC) transplantation donors. We performed a retrospective study on 124 consecutive hepatitis B surface antigen negative HSC donors. Their serum samples were analyzed by PCR for the pre-S/S, pre-core/core and X regions of the virus. Samples reactive by at least two PCR assays were considered HBV-DNA positive. Nineteen of the 124 HSC donors (15.3%) had occult HBV infection. Sixteen of these 19 donors with occult HBV infection (84.2%) tested positive for hepatitis B core antibody while 78 of 105 subjects (74.3%) without occult HBV infection were also positive (P=0.56). Fourteen of the 19 donors (73.7%) with occult HBV infection tested positive for hepatitis B surface antibody while 67 of the 105 subjects without occult HBV infection were also positive (P=0.45). The prevalence of occult HBV infection among HSC donors in Hong Kong is high. Anti-HBc and anti-HBs status had no significant correlation with the presence of occult HBV infection.

New perspectives in occult hepatitis C virus infection

PubMed Central

Carreño, Vicente; Bartolomé, Javier; Castillo, Inmaculada; Quiroga, Juan Antonio

2012-01-01

Occult hepatitis C virus (HCV) infection, defined as the presence of HCV RNA in liver and in peripheral blood mononuclear cells (PBMCs) in the absence of detectable viral RNA in serum by standard assays, can be found in anti-HCV positive patients with normal serum levels of liver enzymes and in anti-HCV negative patients with persistently elevated liver enzymes of unknown etiology. Occult HCV infection is distributed worldwide and all HCV genotypes seem to be involved in this infection. Occult hepatitis C has been found not only in anti-HCV positive subjects with normal values of liver enzymes or in chronic hepatitis of unknown origin but also in several groups at risk for HCV infection such as hemodialysis patients or family members of patients with occult HCV. This occult infection has been reported also in healthy populations without evidence of liver disease. Occult HCV infection seems to be less aggressive than chronic hepatitis C although patients affected by occult HCV may develop liver cirrhosis and even hepatocellular carcinoma. Thus, anti-HCV negative patients with occult HCV may benefit from antiviral therapy with pegylated-interferon plus ribavirin. The persistence of very low levels of HCV RNA in serum and in PBMCs, along with the maintenance of specific T-cell responses against HCV-antigens observed during a long-term follow-up of patients with occult hepatitis C, indicate that occult HCV is a persistent infection that is not spontaneously eradicated. This is an updated report on diagnosis, epidemiology and clinical implications of occult HCV with special emphasis on anti-HCV negative cases. PMID:22736911

Potential clinical value of PET/CT in predicting occult nodal metastasis in T1-T2N0M0 lung cancer patients staged by PET/CT

PubMed Central

Zhou, Xiang; Chen, Ruohua; Huang, Gang; Liu, Jianjun

2017-01-01

We assessed the clinical value of 2-fluoro-2-deoxyglucose (18F-FDG) PET/CT imaging for predicting occult nodal metastasis in non-small cell lung cancer (NSCLC) patients. This retrospective study included 54 patients with T1-2N0M0 NSCLC who had undergone 18F-FDG PET/CT before surgery. Occult nodal metastasis was detected in 25.9% (14/54) of the patients. Immunohistochemical analysis revealed that increased glucose transporter 1 expression was associated with occult nodal metastasis, but hexokinase 2 expression was not. Compared to the negative nodal metastasis group, the positive nodal metastasis group was associated with increased maximum standardized uptake value (SUVmax) and tumor size. Multivariate analysis indicated that SUVmax and tumor size were associated with nodal metastasis. Nodal metastasis could be predicted with a sensitivity of 92.9% and a specificity of 55.0% when the SUVmax cutoff was 4.35. When patients were divided into low-risk (tumor size ≤ 2.5 cm and SUVmax ≤ 4.35), moderate-risk (tumor size ≤ 2.5 cm and SUVmax > 4.35 or tumor size > 2.5 cm and SUVmax ≤ 4.35) and high-risk (tumor size > 2.5 cm and SUVmax > 4.35) groups, the lymph node metastasis rates were 4.3%, 22.7%, and 88.9%, respectively. These results indicate that the combination of SUVmax and tumor size has potential clinical value for predicting occult nodal metastasis in NSCLC patients. PMID:29137276

The BRAFT1799A mutation is not associated with occult contralateral carcinoma in patients with unilateral papillary thyroid microcarcinoma.

PubMed

Wan, Han-Feng; Zhang, Bin; Yan, Dan-Gui; Xu, Zhen-Gang

2015-01-01

The phenomenon of occult carcinoma maybe observed in patients with clinically unilateral papillary thyroid microcarcinoma (PTMC). Although many studies have reported that the BRAFT1799A mutation is associated with aggressive PTMC, the relationship between BRAFT1799A mutation and occult carcinoma is unclear. The aim of this study was to investigate the risk factors, including BRAFT1799A mutation, for occult contralateral carcinoma in clinically unilateral PTMC accompanied by benign nodules in the contralateral lobe. From January 2011 to December 2013,we prospectively enrolled 89 consecutive PTMC patients with clinically unilateral carcinoma accompanied by benign nodules in the contralateral lobe who received a total thyroidectomy and cervical lymph node dissection. BRAFT1799A mutation was tested by pyrosequencing on postoperative paraffin specimens. The frequency and predictive factors for occult contralateral carcinoma were analyzed with respect to the following variables: age, gender, family history, tumor size, presence of Hashimoto thyroiditis, extrathyroidal extension, central lymph node metastasis, multifocality of primary tumor, or BRAFT1799A mutation. A total of 36 patients (40.4%) had occult PTMC in the contralateral lobe. The median diameter of the occult tumors was 0.33±0.21 cm. The BRAFT1799A mutation was found in 38 cases (42.7%). According to the univariate analysis, there were no significant differences between the presence of occult contralateral carcinoma and age, gender, family history, tumor size, presence of Hashimoto thyroiditis, extrathyroidal extension, central lymph node metastasis, multifocality of primary tumor, or BRAFT1799A mutation. Using current methods, it is difficult to preoperatively identify patients with PTMC, and further research is needed to determine predictive factors for the presence of occult contralateral carcinoma in patients with unilateral PTMC.

Review: Occult hepatitis C virus infection: still remains a controversy.

PubMed

Vidimliski, Pavlina Dzekova; Nikolov, Igor; Geshkovska, Nadica Matevska; Dimovski, Aleksandar; Rostaing, Lionel; Sikole, Aleksandar

2014-09-01

Occult hepatitis C virus (HCV) infection is characterized by the presence of HCV RNA in the liver cells or peripheral blood mononuclear cells of the patients whose serum samples test negative for HCV RNA, with or without presence of HCV antibodies. The present study reviews the existing literature on the persistence of occult hepatitis C virus infection, with description of the clinical characteristics and methods for identification of occult hepatitis C. Occult hepatitis C virus infection was detected in patients with abnormal results of liver function tests of unknown origin, with HCV antibodies and HCV RNA negativity in serum, and also in patients with spontaneous or treatment-induced recovery from hepatitis C. The viral replication in the liver cells and/or peripheral blood mononuclear cells was present in all clinical presentations of occult hepatitis C. The peripheral blood mononuclear cells represent an extra-hepatic site of HCV replication. The reason why HCV RNA was not detectable in the serum of patients with occult hepatitis C, could be the low number of circulating viral particles not detectable by the diagnostic tests with low sensitivity. It is uncertain whether occult hepatitis C is a different clinical entity or just a form of chronic hepatitis C virus infection. Data accumulated over the last decade demonstrated that an effective approach to the diagnosis of HCV infection would be the implementation of more sensitive HCV RNA diagnostic assays, and also, examination of the presence of viral particles in the cells of the immune system. © 2014 Wiley Periodicals, Inc.

Identification of occult tumors by whole-specimen mapping in solitary papillary thyroid carcinoma.

PubMed

Park, Seog Yun; Jung, Yuh-S; Ryu, Chang Hwan; Lee, Chang Yoon; Lee, You Jin; Lee, Eun Kyung; Kim, Seok-Ki; Kim, Tae Sung; Kim, Tae Hyun; Jang, Jeyun; Park, Daeyoon; Dong, Seung Myung; Kang, Jae-Goo; Lee, Jin Soo; Ryu, Junsun

2015-08-01

We undertook this study to estimate an accurate incidence and spread patterns of occult papillary thyroid carcinoma (PTC) in patients with a preoperative diagnosis of solitary PTC by using whole-specimen mapping of all specimens after a total thyroidectomy. Enrolled prospectively in this whole-thyroid mapping study are 82 consecutive patients who underwent a total thyroidectomy under a preoperative diagnosis of solitary PTC. All thyroidectomy specimens were serially sectioned in 2 mm thickness and whole-thyroid mapping was carried out for additional foci of occult PTC. The frequencies of occult lesions detected in the whole and contralateral lobe were determined, and clinicopathologic factors associated with multifocality were assessed. Whole-thyroid mapping revealed 66 occult PTC lesions missed by preoperative ultrasound in 37 (45.1%) of the 82 patients. The great majority (92.5%) of the occult PTC was smaller than 3 mm in size and 25 patients (30.5%) had contralateral lesions. We found that the male sex was an independent predictor of multifocality (odds ratio (OR), 3.00; 95% CI, 1.11-8.14), adjusting for preoperative findings. Analysis with pathologic parameters showed that the male sex (OR, 5.03; 95% CI, 1.68-15.08) and extrathyroidal extensions (OR, 3.03; 95% CI, 1.03-8.95) were associated with multifocal PTC. However, none of the clinicopathologic factors evaluated predicted contralateral PTC. Our study demonstrates the diagnostic limitations of ultrasound for the detection of multifocal PTC and the need to consider the possibility of occult lesions in the management of solitary PTC, especially in male patients. © 2015 Society for Endocrinology.

Do autologous peripheral blood cell transplants provide more than hematopoietic recovery?

PubMed

Kessinger, A

1995-07-01

Bone marrow damage caused by myeloablative radiation therapy and/or chemotherapy can be repaired by intravenously infusing viable stem/progenitor cells collected from either blood or bone marrow. The hematopoietic graft product contains both stem/progenitor cells and populations of hematopoietic and nonhematopoietic (accessory) cells. The frequency of accessory cell types varies with the source of the graft product; marrow or blood. Reinfusion of these accessory cells causes effects other than the hematopoietic restoration provided by the stem/progenitor cells such as graft versus host disease and graft versus leukemia effect after allogeneic transplants. Effects of infused accessory cells in the autologous setting are less well studied and could provide ancillary advantages and/or disadvantages to the patient. Do these additional effects actually occur, and, if they do, are they more likely to appear following peripheral blood cell transplants (PBCT) or after autologous bone marrow transplants (AMBT)? Preliminary data are beginning to accumulate which suggest that reinfusion of occult tumor cells is less likely with PBCT, that immune reconstitution is different depending on the source of the autograft and that, for certain diseases, patient event-free survival following PBCT rather than ABMT may be better. However, infusion of occult tumor cells may result in re-establishment of the malignancy. If the accessory cells (including potential occult tumor cells) are eliminated from the product before transplant, will the patient have a better clinical outcome, or would benefits provided by infused accessory cells outweigh the risks of infused occult tumor cells? These controversial issues are in the very early stages of investigation.

Prognostic Value of Occult Isolated Tumour Cells within Regional Lymph Nodes of Dogs with Malignant Mammary Tumours.

PubMed

Coleto, A F; Wilson, T M; Soares, N P; Gundim, L F; Castro, I P; Guimarães, E C; Bandarra, M B; Medeiros-Ronchi, A A

2018-01-01

Canine mammary tumours (CMTs) are the most common type of neoplasm in bitches. As in women, the presence of metastasis in regional lymph nodes is an important prognostic factor in bitches with mammary carcinomas, but the clinical significance of occult isolated tumour cells (ITCs) within lymph nodes is still undefined in this species. The effectiveness of immunohistochemistry (IHC) in identifying occult ITCs and micrometastasis (MIC) was compared with that of the conventional haematoxylin and eosin staining technique. The relationship between tumour size, histological type, histological grade and the presence of metastasis was evaluated. The overall survival (OS) of female dogs with occult mammary carcinomas and ITCs within lymph nodes was analysed. Fragments of mammary carcinoma and regional lymph nodes of 59 female dogs were also evaluated. Histological sections of mammary carcinoma and lymph node samples were studied for tumour diagnosis and lymph node samples were tested by IHC using a pan-cytokeratin antibody. It was found that 35.2% of occult ITCs and 2.8% of hidden MIC were detected when IHC was used. There was a good correlation between the size of the tumour and metastasis to the lymph nodes (P = 0.77). ITCs were observed more frequently in the medullary region (60.7%) and metastases in the cortical region (44.4%). There was no significant difference in the OS between female dogs with occult ITCs and lymph nodes without ITCs. IHC can detect occult tumour cells in lymph nodes that are negative by histopathological examination. Female dogs with nodal ITCs do not have lower survival. Copyright © 2017 Elsevier Ltd. All rights reserved.

Association of preS/S Mutations with Occult Hepatitis B Virus (HBV) Infection in South Korea: Transmission Potential of Distinct Occult HBV Variants

PubMed Central

Kim, Hong; Kim, Bum-Joon

2015-01-01

Occult hepatitis B virus infection (HBV) is characterized by HBV DNA positivity but HBV surface antigen (HBsAg) negativity. Occult HBV infection is associated with a risk of HBV transmission through blood transfusion, hemodialysis, and liver transplantation. Furthermore, occult HBV infection contributes to the development of cirrhosis and hepatocellular carcinoma. We recently reported the characteristic molecular features of mutations in the preS/S regions among Korean individuals with occult infections caused by HBV genotype C2; the variants of preS and S related to severe liver diseases among chronically infected patients were also responsible for the majority of HBV occult infections. We also reported that HBsAg variants from occult-infected Korean individuals exhibit lower HBsAg secretion capacity but not reduced HBV DNA levels. In addition, these variants exhibit increased ROS-inducing capacity compared with the wild-type strain, linking HBV occult infections to liver cell damage. Taken together, our previous reports suggest the transmission potential of distinct HBV occult infection-related variants in South Korea. PMID:26084041

Association of preS/S Mutations with Occult Hepatitis B Virus (HBV) Infection in South Korea: Transmission Potential of Distinct Occult HBV Variants.

PubMed

Kim, Hong; Kim, Bum-Joon

2015-06-15

Occult hepatitis B virus infection (HBV) is characterized by HBV DNA positivity but HBV surface antigen (HBsAg) negativity. Occult HBV infection is associated with a risk of HBV transmission through blood transfusion, hemodialysis, and liver transplantation. Furthermore, occult HBV infection contributes to the development of cirrhosis and hepatocellular carcinoma. We recently reported the characteristic molecular features of mutations in the preS/S regions among Korean individuals with occult infections caused by HBV genotype C2; the variants of preS and S related to severe liver diseases among chronically infected patients were also responsible for the majority of HBV occult infections. We also reported that HBsAg variants from occult-infected Korean individuals exhibit lower HBsAg secretion capacity but not reduced HBV DNA levels. In addition, these variants exhibit increased ROS-inducing capacity compared with the wild-type strain, linking HBV occult infections to liver cell damage. Taken together, our previous reports suggest the transmission potential of distinct HBV occult infection-related variants in South Korea.

Impact of fecal occult blood on obscure gastrointestinal bleeding: Observational study

PubMed Central

Kobayashi, Yuka; Watabe, Hirotsugu; Yamada, Atsuo; Suzuki, Hirobumi; Hirata, Yoshihiro; Yamaji, Yutaka; Yoshida, Haruhiko; Koike, Kazuhiko

2015-01-01

AIM: To elucidate the association between small bowel diseases (SBDs) and positive fecal occult blood test (FOBT) in patients with obscure gastrointestinal bleeding (OGIB). METHODS: Between February 2008 and August 2013, 202 patients with OGIB who performed both capsule endoscopy (CE) and FOBT were enrolled (mean age; 63.6 ± 14.0 years, 118 males, 96 previous overt bleeding, 106 with occult bleeding). All patients underwent immunochemical FOBTs twice prior to CE. Three experienced endoscopists independently reviewed CE videos. All reviews and consensus meeting were conducted without any information on FOBT results. The prevalence of SBDs was compared between patients with positive and negative FOBT. RESULTS: CE revealed SBDs in 72 patients (36%). FOBT was positive in 100 patients (50%) and negative in 102 (50%). The prevalence of SBDs was significantly higher in patients with positive FOBT than those with negative FOBT (46% vs 25%, P = 0.002). In particular, among patients with occult OGIB, the prevalence of SBDs was higher in positive FOBT group than negative FOBT group (45% vs 18%, P = 0.002). On the other hand, among patients with previous overt OGIB, there was no significant difference in the prevalence of SBDs between positive and negative FOBT group (47% vs 33%, P = 0.18). In disease specific analysis among patients with occult OGIB, the prevalence of ulcer and tumor were higher in positive FOBT group than negative FOBT group. In multivariate analysis, only positive FOBT was a predictive factors of SBDs in patients with OGIB (OR = 2.5, 95%CI: 1.4-4.6, P = 0.003). Furthermore, the trend was evident among patients with occult OGIB who underwent FOBT on the same day or a day before CE. The prevalence of SBDs in positive vs negative FOBT group were 54% vs 13% in patients with occult OGIB who underwent FOBT on the same day or the day before CE (P = 0.001), while there was no significant difference between positive and negative FOBT group in those who underwent

Impact of fecal occult blood on obscure gastrointestinal bleeding: observational study.

PubMed

Kobayashi, Yuka; Watabe, Hirotsugu; Yamada, Atsuo; Suzuki, Hirobumi; Hirata, Yoshihiro; Yamaji, Yutaka; Yoshida, Haruhiko; Koike, Kazuhiko

2015-01-07

To elucidate the association between small bowel diseases (SBDs) and positive fecal occult blood test (FOBT) in patients with obscure gastrointestinal bleeding (OGIB). Between February 2008 and August 2013, 202 patients with OGIB who performed both capsule endoscopy (CE) and FOBT were enrolled (mean age; 63.6 ± 14.0 years, 118 males, 96 previous overt bleeding, 106 with occult bleeding). All patients underwent immunochemical FOBTs twice prior to CE. Three experienced endoscopists independently reviewed CE videos. All reviews and consensus meeting were conducted without any information on FOBT results. The prevalence of SBDs was compared between patients with positive and negative FOBT. CE revealed SBDs in 72 patients (36%). FOBT was positive in 100 patients (50%) and negative in 102 (50%). The prevalence of SBDs was significantly higher in patients with positive FOBT than those with negative FOBT (46% vs 25%, P = 0.002). In particular, among patients with occult OGIB, the prevalence of SBDs was higher in positive FOBT group than negative FOBT group (45% vs 18%, P = 0.002). On the other hand, among patients with previous overt OGIB, there was no significant difference in the prevalence of SBDs between positive and negative FOBT group (47% vs 33%, P = 0.18). In disease specific analysis among patients with occult OGIB, the prevalence of ulcer and tumor were higher in positive FOBT group than negative FOBT group. In multivariate analysis, only positive FOBT was a predictive factors of SBDs in patients with OGIB (OR = 2.5, 95%CI: 1.4-4.6, P = 0.003). Furthermore, the trend was evident among patients with occult OGIB who underwent FOBT on the same day or a day before CE. The prevalence of SBDs in positive vs negative FOBT group were 54% vs 13% in patients with occult OGIB who underwent FOBT on the same day or the day before CE (P = 0.001), while there was no significant difference between positive and negative FOBT group in those who underwent FOBT two or more days

Reflective Occultation Mask for Evaluation of Occulter Designs for Planet Finding

NASA Technical Reports Server (NTRS)

Hagopian, John; Lyon, Richard; Shiri, Shahram; Roman, Patrick

2011-01-01

Advanced formation flying occulter designs utilize a large occulter mask flying in formation with an imaging telescope to block and null starlight to allow imaging of faint planets in exosolar systems. A paper describes the utilization of subscale reflective occultation masks to evaluate formation flying occulter designs. The use of a reflective mask allows mounting of the occulter by conventional means and simplifies the test configuration. The innovation alters the test set-up to allow mounting of the mask using standard techniques to eliminate the problems associated with a standard configuration. The modified configuration uses a reflective set-up whereby the star simulator reflects off of a reflective occulting mask and into an evaluation telescope. Since the mask is sized to capture all rays required for the imaging test, it can be mounted directly to a supporting fixture without interfering with the beam. Functionally, the reflective occultation mask reflects light from the star simulator instead of transmitting it, with a highly absorptive carbon nanotube layer simulating the occulter blocking mask. A subscale telescope images the star source and companion dim source that represents a planet. The primary advantage of this is that the occulter can be mounted conventionally instead of using diffractive wires or magnetic levitation.

Radioimmune localization of occult carcinoma

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

Duda, R.B.; Zimmer, A.M.; Rosen, S.T.

1990-07-01

Patients with a rising serum carcinoembryonic antigen level and no clinical or roentgenographic evidence of recurrent or metastatic cancer present a treatment dilemma. Eleven such patients, 10 with a previously treated colorectal carcinoma and 1 with a previously treated breast carcinoma, received an injection of the anticarcinoembryonic antigen monoclonal antibody ZCE-025 labeled with the radioisotope indium 111. Nuclear scintigraphy was performed on days 3 and 5 through 7 to detect potential sites of tumor recurrence. The monoclonal antibody scan accurately predicted the presence or absence of occult malignancy in 7 (64%) patients. Second-look laparotomy confirmed the monoclonal antibody scan resultsmore » in the patients with colorectal cancer, and magnetic resonance imaging confirmed metastatic breast cancer. This study demonstrates that In-ZCE-025 can localize occult carcinoma and may assist the surgeon in facilitating the operative exploration. In-ZCE-025 assisted in the initiation of adjuvant therapy for the patient with breast cancer.« less

Circulating tumor cells in patients with testicular germ cell tumors.

PubMed

Nastały, Paulina; Ruf, Christian; Becker, Pascal; Bednarz-Knoll, Natalia; Stoupiec, Małgorzata; Kavsur, Refik; Isbarn, Hendrik; Matthies, Cord; Wagner, Walter; Höppner, Dirk; Fisch, Margit; Bokemeyer, Carsten; Ahyai, Sascha; Honecker, Friedemann; Riethdorf, Sabine; Pantel, Klaus

2014-07-15

Germ cell tumors (GCTs) represent the most frequent malignancies among young men, but little is known about circulating tumor cells (CTCs) in these tumors. Considering their heterogeneity, CTCs were investigated using two independent assays targeting germ cell tumor and epithelial cell-specific markers, and results were correlated with disease stage, histology, and serum tumor markers. CTCs were enriched from peripheral blood (n = 143 patients) and testicular vein blood (TVB, n = 19 patients) using Ficoll density gradient centrifugation. For CTC detection, a combination of germ cell tumor (anti-SALL4, anti-OCT3/4) and epithelial cell-specific (anti-keratin, anti-EpCAM) antibodies was used. In parallel, 122 corresponding peripheral blood samples were analyzed using the CellSearch system. In total, CTCs were detected in 25 of 143 (17.5%) peripheral blood samples, whereas only 11.5% of patients were CTC-positive when considering exclusively the CellSearch assay. The presence of CTCs in peripheral blood correlated with clinical stage (P < 0.001) with 41% of CTC positivity in patients with metastasized tumors and 100% in patients with relapsed and chemotherapy-refractory disease. Histologically, CTC-positive patients suffered more frequently from nonseminomatous primary tumors (P < 0.001), with higher percentage of yolk sac (P < 0.001) and teratoma (P = 0.004) components. Furthermore, CTC detection was associated with elevated serum levels of α-fetoprotein (AFP; P = 0.025), β-human chorionic gonadotropin (βHCG; P = 0.002), and lactate dehydrogenase (LDH; P = 0.002). Incidence and numbers of CTCs in TVB were much higher than in peripheral blood. The inclusion of germ cell tumor-specific markers improves CTC detection in GCTs. CTCs occur frequently in patients with more aggressive disease, and there is a gradient of CTCs with decreasing numbers from the tumor-draining vein to the periphery. ©2014 American Association for Cancer Research.

Occult Cushing's syndrome in type-2 diabetes.

PubMed

Catargi, Bogdan; Rigalleau, Vincent; Poussin, Agathe; Ronci-Chaix, Nathalie; Bex, Veronique; Vergnot, Vincent; Gin, Henri; Roger, Patrick; Tabarin, Antoine

2003-12-01

Subclinical Cushing's syndrome (SCS) caused by adrenal incidentalomas is frequently associated with overweight and insulin resistance. Metabolic syndrome X may therefore be a clue to the presence of CS. However, the incidence of CS in this situation remains unknown. We have conducted a prospective study to evaluate the prevalence of occult CS in overweight, type-2 diabetic patients devoided of specific clinical symptoms of CS. Two hundred overweight, type-2 diabetic patients, consecutively referred for poor metabolic control (HbA(1C) > 8%), were studied as inpatients. A first screening step was performed with the 1-mg overnight dexamethasone suppression test (DST) using a revised criterion for cortisol suppression (60 nmol/liter) to maximize the sensitivity of the procedure. A second confirmatory step of biochemical investigations (midnight plasma cortisol concentration, plasma cortisol circadian rhythm, morning plasma ACTH concentration, 24-h urinary free cortisol, and 4-mg i.v. DST) was performed in patients with impaired 1-mg DST. A third step of imaging studies was performed according to the results of second-step investigations. Fifty-two patients had impaired 1-mg DST. Among these, 47 were further evaluated. Thirty were considered as false positives of the 1-mg DST, whereas 17 displayed at least one additional biological abnormality of the hypothalamic-pituitary-adrenal axis. Definitive occult CS was identified in four patients (2% of the whole series) with Cushing's disease (n = 3) and surgically proven adrenal adenoma (n = 1). Definitive diagnosis remains to be established in seven additional patients (3.5%) with mild occult CS associated with unsuppressed plasma ACTH concentrations and a unilateral adrenal tumor of 10-29 mm in size showing prevalent uptake at radiocholesterol scintigraphy. In conclusion, a relatively high prevalence of occult CS was found in our study. Further studies are needed to evaluate the impact of the cure of occult CS on obesity

The incidence of occult malignancy following uterine morcellation: A ten-year single institution experience retrospective cohort study.

PubMed

Mori, Kristina M; Abaid, Lisa N; Mendivil, Alberto A; Brown, John V; Beck, Tiffany L; Micha, John P; Epstein, Howard D; Goldstein, Bram H

2018-05-01

When the Food and Drug Administration (FDA) initially reported on the parlous incidence (0.28%) of occult malignancy identified following uterine power morcellation, investigations thereafter documented their particular experience with this surgical procedure. Nevertheless, the precise risk of identifying a sarcoma following uterine morcellation remains indeterminate, primarily due to varying study patient risk factors, diagnostic criteria and operative approach. We retrospectively evaluated subjects who underwent an endoscopic hysterectomy and uterine power morcellation for the treatment of a presumptive, benign indication from January 2006 until December 2015. The primary outcome was the incidence of an occult malignancy. Secondarily, we were interested in characterizing the patients' specific clinical (age, menopausal status, body mass index (BMI)) risk factors within the context of a confirmed malignant or pre-malignant pathology. We identified 281 patients who underwent endoscopic surgery that incorporated uterine morcellation. During the study period, one subject was ultimately diagnosed with a uterine leiomyosarcoma; the overall incidence of occult malignancy was 0.36%. There were also 3 cases of uterine premalignant disease on final pathology (2 patients had complex hyperplasia with or without atypia and 1 subject was diagnosed with a smooth muscle tumor of uncertain malignant potential (an incidence of 1.1%)). We were unable to establish any relationship between patient age, uterine weight, menopausal status or BMI and the incidence of a malignant or pre-malignant pathology (P > 0.05). The rate of occult malignancy in the present investigation was similar to previously documented studies and that which has been reported by the FDA. Additional study of methods in which to enhance preoperative work-up and mitigate the surgical risk for tumor cell dissemination is warranted. Copyright © 2018 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights

Predicted occultation of Regulus

NASA Astrophysics Data System (ADS)

Waagen, Elizabeth O.

2014-03-01

The predicted occultation of Regulus (alpha Leo) by the magnitude-12.4 V asteroid (163) Erigone on 2014 March 20 at approximately 02:06 a.m. EDT (06:06 UT) is discussed. The occultation track includes Bermuda and northwest along a corridor stretching from the mid-Atlantic USA through Ontario, Canada. Unusual things about this occultation include the facts that the track includes major metropolitan areas such as New York City, and the star being occulted is one of the brightest in the Northern sky and is in a constellation pattern that makes it easy to find. The International Occultation Timing Association (IOTA) website (http://occultations.org/Regulus2014/) has comprehensive information about this predicted occultation and observing and reporting instructions, as well as links to other resources. In addition to witnessing a very rare event (Regulus is the brightest star ever to be predicted to be occulted from the USA), the possibilities for science include these three:! determining the shape of Erigone, detecting a possible companion of Erigone, and detecting the suspected white dwarf companion of Regulus. See the Alert Notice for details.

Deep shadow occulter

NASA Technical Reports Server (NTRS)

Cash, Webster (Inventor)

2010-01-01

Methods and apparatus are disclosed for occulting light. The occulter shape suppresses diffraction at any given size or angle and is practical to build because it can be made binary to avoid scatter. Binary structures may be fully opaque or fully transmitting at specific points. The diffraction suppression is spectrally broad so that it may be used with incoherent white light. An occulter may also include substantially opaque inner portion and an at least partially transparent outer portion. Such occulters may be used on the ground to create a deep shadow in a short distance, or may be used in space to suppress starlight and reveal exoplanets.

Prognostic significance of extranodal extension in head and neck squamous cell carcinoma cN0 patients with occult metastatic neck nodes.

PubMed

Lop, Joan; Rigó, Antoni; Codina, Alberto; de Juan, Julia; Quer, Miquel; León, Xavier

Extranodal extension in nodal metastases is an independent adverse prognostic factor in head and neck squamous cell carcinoma patients. However, few studies specifically address the subgroup of patients with no clinical evidence of nodal disease. We retrospectively analysed data from 348 head and neck squamous cell carcinoma patients without any previous treatment and lacking clinical or radiological evidence of neck node metastases during the initial workup, treated with an elective neck dissection between 1992-2014. The incidence of occult metastatic neck nodes with extranodal extension and the impact of extranodal extension in survival were evaluated. The proportion of patients with occult neck node metastases was 33%. Of these, 23.5% had at least one metastatic neck node with extranodal extension. There were significant differences in the disease-specific survival rate according to neck node status. Five-year disease-specific survival for patients without histopathological metastases was 90%, for patients with occult neck node metastases without extranodal extension it was 71.2%, and for patients with occult neck node metastases with extranodal extension it was 25.9% (P=.0001). The multivariate analysis revealed that the presence of occult node metastases with extranodal extension was the factor with strongest impact on survival. The inclusion of the extranodal extension as a criterion of histopathological evaluation in the 8th TNM classification edition improves the prognostic capacity compared to previous TNM editions. Appearance of metastatic neck nodes with extranodal extension is an adverse prognostic factor in head and neck squamous cell carcinoma patients without clinical evidence of regional disease during the initial workup of the tumour. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. All rights reserved.

Proteolysis during Tumor Cell Extravasation In Vitro: Metalloproteinase Involvement across Tumor Cell Types

PubMed Central

Voura, Evelyn B.; English, Jane L.; Yu, Hoi-Ying E.; Ho, Andrew T.; Subarsky, Patrick; Hill, Richard P.; Hojilla, Carlo V.; Khokha, Rama

2013-01-01

To test if proteolysis is involved in tumor cell extravasation, we developed an in vitro model where tumor cells cross an endothelial monolayer cultured on a basement membrane. Using this model we classified the ability of the cells to transmigrate through the endothelial cell barrier onto the underlying matrix, and scored this invasion according to the stage of passage through the endothelium. Metalloproteinase inhibitors reduced tumor cell extravasation by at least 35%. Visualization of protease and cell adhesion molecules by confocal microscopy demonstrated the cell surface localization of MMP-2, MMP-9, MT1-MMP, furin, CD44 and αvβ3, during the process of transendothelial migration. By the addition of inhibitors and bio-modulators we assessed the functional requirement of the aforementioned molecules for efficient migration. Proteolytic digestion occurred at the cell-matrix interface and was most evident during the migratory stage. All of the inhibitors and biomodulators affected the transition of the tumor cells into the migratory stage, highlighting the most prevalent use of proteolysis at this particular step of tumor cell extravasation. These data suggest that a proteolytic interface operates at the tumor cell surface within the tumor-endothelial cell microenvironment. PMID:24194929

[Surgical Diagnosis and Treatment of Primary Hyperthyroidism Complicated with Occult Thyroid Carcinoma].

PubMed

Wu, Xin; Yu, Jian-chun; Kang, Wei-ming; Ma, Zhi-qiang; Ye, Xin

2015-08-01

To evaluate the surgical diagnosis and treatment of primary hyperthyroidism complicated with occult thyroid carcinoma. Data of 51 cases of primary hyperthyroidism complicated with occult thyroid carcinoma admitted during January 2004 to November 2014 were analyzed retrospectively. The incidence of occult thyroid carcinoma was 5.03% in hyperthyroidism,and 47 cases (92.16%) were female. The preoperative diagnosis of all these 51 cases was primary hyperthyroidism and 11 cases were diagnosed thyroid carcinoma at the same time;25 cases were diagnosed thyroid carcinoma by frozen section and the remaining 26 cases were diagnosed by postoperative pathology. Finally,26 cases underwent subtotal thyroidectomy,4 cases underwent total thyroidectomy, and 21 cases underwent total thyroidectomy with lymphadenectomy. The tumor size ranged from 0.1 to 1.0 cm [mean:(0.63 ± 0.35) cm]. The lesions were less than or equal to 0.5 cm in 28 cases (54.9%). The follow-up lasted from 1 to 121 months [mean:(28.6 ± 22.7)months] in 43 patients,and all of them survived. Primary hyperthyroidism complicated with occult thyroid carcinoma is commonly found in female patients. Preoperative diagnosis is difficult. Ultrasound is the major examining method. Frozen section can increase the detection rate. The postoperative prognosis of hyperthyroidism complicated with occult thyroid carcinoma is satisfactory.

Prospective Evaluation of Intrahepatic Microscopic Occult Tumor Foci in Patients with Numerous Colorectal Liver Metastases.

PubMed

Vigano, Luca; Di Tommaso, Luca; Mimmo, Antonio; Sollai, Mauro; Cimino, Matteo; Donadon, Matteo; Roncalli, Massimo; Torzilli, Guido

2018-06-07

Patients with numerous colorectal liver metastases (CLM) have high risk of early recurrence after liver resection (LR). The presence of intrahepatic occult microscopic metastases missed by imaging has been hypothesized, but it has never been assessed by pathology analyses. All patients with > 10 CLM who underwent LR between September 2015 and September 2016 were considered. A large sample of liver without evidence of disease ("healthy liver") was taken from the resected specimen and sent to the pathologist. One mm-thick sections were analyzed. Any metastasis, undetected by preoperative and intraoperative imaging, but identified by the pathologist was classified as occult microscopic metastasis. Ten patients were prospectively enrolled (median number of CLM n = 15). In a per-lesion analysis, the sensitivity of computed tomography and magnetic resonance imaging was 91 and 98% respectively. The pathology examination confirmed all the CLM. All patients had an adequate sample of "healthy liver" (median number of examined blocks per sample n = 14 [5-33]). No occult microscopic metastases were detected. After a median follow-up of 15 months, 5 patients were disease-free. Recurrence was hepatic and bilobar in all patients. Clinically relevant occult microscopic disease in patients with numerous CLM is excluded. These results support the indication to resection in such patients and exclude the need for de principe major hepatectomy to increase the completeness of surgery. © 2018 S. Karger AG, Basel.

Prognostic implications of occult nodal tumour cells in stage I and II colon cancer: The correlation between micrometastasis and disease recurrence.

PubMed

Sloothaak, D A M; van der Linden, R L A; van de Velde, C J H; Bemelman, W A; Lips, D J; van der Linden, J C; Doornewaard, H; Tanis, P J; Bosscha, K; van der Zaag, E S; Buskens, C J

2017-08-01

Occult nodal tumour cells should be categorised as micrometastasis (MMs) and isolated tumour cells (ITCs). A recent meta-analysis demonstrated that MMs, but not ITCs, are prognostic for disease recurrence in patients with stage I/II colon cancer. The objective of this retrospective multicenter study was to correlate MMs and ITCs to characteristics of the primary tumour, and to determine their prognostic value in patients with stage I/II colon cancer. One hundred ninety two patients were included in the study with a median follow up of 46 month (IQR 33-81 months). MMs were found in eight patients (4.2%), ITCs in 37 (19.3%) and occult tumour cells were absent in 147 patients (76.6%). Between these groups, tumour differentiation and venous or lymphatic invasion was equally distributed. Advanced stage (pT3/pT4) was found in 66.0% of patients without occult tumour cells (97/147), 72.9% of patients with ITCs (27/37), and 100% in patients with MMs (8/8), although this was a non-significant trend. Patients with MMs showed a significantly reduced 3 year-disease free survival compared to patients with ITCs or patients without occult tumour cells (75.0% versus 88.0% and 94.8%, respectively, p = 0.005). When adjusted for T-stage, MMs independently predicted recurrence of cancer (OR 7.6 95% CI 1.5-37.4, p = 0.012). In this study, the incidence of MMs and ITCs in patients with stage I/II colon cancer was 4.2% and 19.3%, respectively. MMs were associated with an reduced 3 year disease free survival rate, but ITCs were not. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Uranus occults SAO158687. [stellar occultation and planetary parametric observation

NASA Technical Reports Server (NTRS)

Elliot, J. L.; Veverka, J.; Millis, R. L.

1977-01-01

Experience gained in obtaining atmospheric parameters, oblatenesses, and diameters of Jupiter and Mars from recent stellar occultations by these planets is used to predict what can be learned from the March 1977 occultation of the star SAO158687 by Uranus. The spectra of this star and Uranus are compared to indicate the relative instrument intensities of the two objects, the four passbands where the relative intensities are most nearly equal are listed, and expected photon fluxes from the star are computed on the assumption that it has UBVRI colors appropriate for a K5 main-sequence object. It is shown that low photon noise errors can be achieved by choosing appropriate passbands for observation, and the rms error expected for the Uranus temperature profiles obtained from the occultation light curves is calculated. It is suggested that observers of this occultation should record their data digitally for optimum time resolution.

The Occult Today: Why?

ERIC Educational Resources Information Center

Kessler, Gary E.

1975-01-01

Author offered some reflections on the "why" of the contemporary interest in the occult. He attempted to convince the reader that, if he or she has been surprised by the recent rise of occultism, sober reflection will dispell some fears and, perhaps, even convince him or her that occultism is not merely superstition. (Author/RK)

Sertoli-Leydig cell tumor

MedlinePlus

Sertoli-stromal cell tumor; Arrhenoblastoma; Androblastoma; Ovarian cancer - Sertoli-Leydig cell tumor ... The Sertoli cells are normally located in the male reproductive glands (the testes). They feed sperm cells. The Leydig cells, also ...

Studies in occultation astronomy

NASA Technical Reports Server (NTRS)

Veverka, J.

1980-01-01

Major scientific results are summarized for the following studies: (1) observations of the 8 April 1976 occultation of epsilon Geminorum by Mars; (2) studies in occultation techniques; and (3) the March 1974 occultation of Saturn by the Moon. A re-analysis of the 1974 lunar occultation of the Titan indicates that Titan is strongly limb darkened, with D approximately greater than 5800km; there is internal evidence in the data that Titan's atmosphere is inhomogeneous; and that observations are inconsistent with any sample homogeneous model atmosphere which matches the P (lambda) and Beta (lambda) observations of Titan.

Occultation studies of the Solar System

NASA Technical Reports Server (NTRS)

Millis, Robert L.

1987-01-01

The planetary occultation program began at Lowell Observatory in 1973 with a worldwide campaign to observe mutual occultations and eclipses of the Galilean Satellites. Then the temperature profile of the Martian atmosphere was measured from data taken during the occultation of epsilon Geminorum, the Rings of Uranus were discovered as they occulted SAO 158687, and the dimensions of Pallas were measured when that minor planet occulted SAO 85009. In 1979 the present grant was initiated, providing funds for portable photometric instrumentation used to observe occultations by asteroids as well as by Uranus and Neptune. Software for predicting occultations of catalog stars by asteroids, planets, and comets was written in 1983. Lowell currently provides most of the available predictions for asteroid occultations. Realizing in 1983 that the lack of a high-quality astrometric telescope dedicated to occultation work was limiting progress, an 18-inch, F/8 lens was acquired and adapted to an existing mounting at Lowell. Although acquisition of the lens and implementation of the new telescope has been accomplished primarily with non-grant funds, the instrument makes a major contribution to occultation research.

Detection of occult high graded microsatellite instabilities in MMR gene mutation negative HNPCC tumors by addition of complementary marker analysis.

PubMed

Schiemann, U; Müller-Koch, Y; Gross, M; Glas, J; Baretton, G; Muders, M; Mussack, T; Holinski-Feder, E

2005-01-28

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant tumor syndrome predisposing to predominantly colorectal and endometrial cancer. In 90% of the cases, molecular analyses reveal microsatellite instabilities due to germline mutations in DNA mismatch repair (MMR) genes, mainly MLH1, MSH2, among these tumors. Tumors from 40 HNPCC index patients (31 Amsterdam positive, 9 Bethesda positive; 21 females, 19 males; mean age 48.0 +/- 13.2 years) were examined. In contrast to the classical constellation, their tumors revealed only a microsatellite stable (MSS, n=31)--or low instable (MSI-L, n=9)--tumor phenotype following the international reference panel of 5 microsatellites. No MLH1 and MSH2 mutations were detectable. Complementary microsatellites (BAT40, D10S197, D13S153, D18S58, MYCL1) were investigated by PCR and fragment analysis to find other instabilities which might hint to the MIN-pathway of the tumors. Due to ten microsatellites in total tumors were now reclassified in 4 MSI-H (10%), 24 MSI-L (60%) and 12 in MSS (30%) phenotypes. The mean age of onset for CRCs was the lowest in the MSI-H group with 45.7 +/- 9.6 years (vs. 48.7 +/- 14.3 and 49.0 +/- 12.9 years in MSI-L and MSS group). MSI-H-and MSI-L tumors were often localized in the proximal colon (50 and 52%), whereas MSS tumors were preferentially localized in the distal colon (77%). - Complementary microsatellites help to subdive "non-classical" HNPCC in subgroups with different clinical appearance. It allows to detect occult MSI-H tumors with up to 10% and to confirm MSS tumors who seem to have a similar biological behaviour like sporadic CRC. Maybe that this genetic reclassification influence the decision of whether to offer patients chemotherapy or not, since it is known that patients with instable tumors do not benefit from chemotherapy as well as patients with microsatellite stable tumors.

New Occultation Systems and the 2005 July 11 Charon Occultation

NASA Astrophysics Data System (ADS)

Young, L. A.; French, R. G.; Gregory, B.; Olkin, C. B.; Ruhland, C.; Shoemaker, K.; Young, E. F.

2005-08-01

Charon's density is an important input to models of its formation and internal structure. Estimates range from 1.59 to 1.83 g/cm3 (Olkin et al. 2003. Icarus 164, 254), with Charon's radius as the main source of uncertainty. Reported values of Charon's radius from mutual events range from 593±13 (Buie et al. 1992, Icarus 97, 211) to 621±21 km (Young & Binzel 1994, Icarus 108), while an occultation observed from a single site gives a lower limit on the radius of 601.5 km (Walker 1980 MNRAS 192, 47; Elliot & Young 1991, Icarus 89, 244). On 2005 July 11 UT (following this abstract submission date), Charon is predicted to occult the star C313.2. If successful, this event will be the first Charon occultation observed since 1980, and the first giving multiple chords across Charon's disk. This event is expected to measure Charon's radius to 1 km. Our team is observing from three telescopes in Chile, the 4.0-m Blanco and the 0.9-m telescopes at Cerro Tololo and the 4.2-m SOAR telescope at Cerro Pachon. At SOAR, we will be using the camera from our new PHOT systems (Portable High-speed Occultation Telescopes). The PHOT camera is a Princeton Instrument MicroMAX:512BFT from Roper Scientific, a 512×512 frame-transfer CCD with a readnoise of only 3 electrons at the 100 kHz digitization rate. The camera's exposures are triggered by a custom built, compact, stand-alone GPS-based pulse-train generator. A PHOT camera and pulse-train generator were used to observe the occultation of 2MASS 1275723153 by Pluto on 2005 June 15 UT from Sommers-Bausch Observatory in Boulder Colorado; preliminary analysis shows this was at best a grazing occultation from this site and a successful engineering run for the July 11 Charon occultation. The work was supported, in part, by NSF AST-0321338 (EFY) and NASA NNG-05GF05G (LAY).

The impact of the number of occult metastatic lymph nodes on postoperative relapse of resectable esophageal cancer.

PubMed

Morimoto, J; Tanaka, H; Ohira, M; Kubo, N; Muguruma, K; Sakurai, K; Yamashita, Y; Maeda, K; Sawada, T; Hirakawa, K

2014-01-01

Clinical stage II/III esophageal cancer (EC), as defined by the Japanese Classification, relapses at a moderately high rate even after curative resection. The number of lymph node metastases is known to be associated with tumor relapse. Recently, the prognostic significance of occult metastatic lymph nodes (MLNs), as well as that of overt MLNs, has been reported. The aim of this study was to investigate the impact of the total number of MLNs including occult MLNs on postoperative relapse in clinical stage II/III EC. One hundred and five patients with clinical stage II/III EC who underwent esophagectomy accompanied by radical lymphadenectomy at the Department of Surgical Oncology in Osaka City University Hospital between January 2000 and October 2008 were included in this study. Occult MLNs, metastases not detected by hematoxylin-eosin staining, were identified by immunohistochemistry (IHC) using antipancytokeratin antibody AE1/AE3. The clinicopathological features of occult MLNs were compared between the relapse and no relapse groups. A total of 6558 lymph nodes (1357 from two-field dissection and 5201 from three-field dissection) were examined by IHC staining; 362 overt MLNs and 143 occult MLNs were detected. The number of occult MLNs increased in proportion to the International Union Against Cancer pathological (p)N-status and pStage. When the number of occult MLNs was added to the number of pNs, the number of total MLNs was associated with postoperative relapse. With respect to tumor, node, metastasis stage, 6 of 22 patients (27%) who were pathological node-negative converted to node-positive by considering total MLNs. The number of N3 patients with relapse increased markedly with restaging by total MLNs. The number of total MLNs, but not overt MLNs, was an independent prognostic factor on multivariate analysis. These results suggest that occult MLNs were often found, and they were associated with postoperative relapse of resectable esophageal cancer. The total

The Pinhole/Occulter Facility

NASA Technical Reports Server (NTRS)

Tandberg-Hanssen, E. A. (Editor); Hudson, H. S. (Editor); Dabbs, J. R. (Editor); Baity, W. A. (Editor)

1983-01-01

Scientific objectives and requirements are discussed for solar X-ray observations, coronagraph observations, studies of coronal particle acceleration, and cosmic X-ray observations. Improved sensitivity and resolution can be provided for these studies using the pinhole/occulter facility which consists of a self-deployed boom of 50 m length separating an occulter plane from a detector plane. The X-ray detectors and coronagraphic optics mounted on the detector plane are analogous to the focal plane instrumentation of an ordinary telescope except that they use the occulter only for providing a shadow pattern. The occulter plane is passive and has no electrical interface with the rest of the facility.

Tumor-Infiltrating Immune Cells Promoting Tumor Invasion and Metastasis: Existing Theories

PubMed Central

Man, Yan-gao; Stojadinovic, Alexander; Mason, Jeffrey; Avital, Itzhak; Bilchik, Anton; Bruecher, Bjoern; Protic, Mladjan; Nissan, Aviram; Izadjoo, Mina; Zhang, Xichen; Jewett, Anahid

2013-01-01

It is a commonly held belief that infiltration of immune cells into tumor tissues and direct physical contact between tumor cells and infiltrated immune cells is associated with physical destructions of the tumor cells, reduction of the tumor burden, and improved clinical prognosis. An increasing number of studies, however, have suggested that aberrant infiltration of immune cells into tumor or normal tissues may promote tumor progression, invasion, and metastasis. Neither the primary reason for these contradictory observations, nor the mechanism for the reported diverse impact of tumor-infiltrating immune cells has been elucidated, making it difficult to judge the clinical implications of infiltration of immune cells within tumor tissues. This mini-review presents several existing hypotheses and models that favor the promoting impact of tumor-infiltrating immune cells on tumor invasion and metastasis, and also analyzes their strength and weakness. PMID:23386907

Measurement of stellar occultations

NASA Astrophysics Data System (ADS)

Eberle, Andreas

2008-09-01

Whenever an asteroid occults a star, we have the opportunity to study that asteroid in great detail. As frequently shown in the past, amateur astronomers1 have the necessary equipment to measure such events successfully2. Combined with the dense net of amateur observatories and online coordination tools3 for movable stations, they can create fine grids to detect even small bodies. The analysis of these events gives us the possibility to receive high precision astrometry data, to determine the asteroids size and shape (and therefore its albedo), and even to collect information on the star itself.4 While usually a set of several light curves is required to do so, a single recording5 of (10734) Wieck's occultation of HIP 22157 on 2008 Feb 08 was sufficient to retrieve the necessary data6. 1 Observation campaigns are organized by the International Occultation Timing Association (IOTA), http://www.iota-es.de/ 2 for results see e.g. euraster.net by E. Frappa, http://www.euraster.net/ 3 Occult Watcher by H. Pavlov, http://www.hristopavlov.net/OccultWatcher/OccultWatcher.html 4 see K. Miyashita's analysis of the observation of the occultation of TYC 1886-01206-1 by Kalliope and Linus, http://www005.upp.so-net.ne.jp/k miyash/occ02/kalliope/doublestar en.html 5 recording obtained by H. Michels, MPC Station Code 240 6 using Limovie by K. Miyashita

Escape From Tumor Cell Dormancy

DTIC Science & Technology

2011-10-01

addressed using a novel organotypic bioreactor in which tumor cells can be followed for weeks to months, the process of seeding, dormancy and...and Kupffer cells (months 7-24) 3. seed bioreactors with cells (months 1-24) 4. label tumor cells for fluorescence (months 1-6) 5. label tumor... cells for mass reporting (months 3-9) Objective 2: 1. generate liver organ bioreactors for tumor cell seeding (months 3-24) 2. seed organotypic

Tumor stem cells: A new approach for tumor therapy (Review)

PubMed Central

MENG, MIN; ZHAO, XIN-HAN; NING, QIAN; HOU, LEI; XIN, GUO-HONG; LIU, LI-FENG

2012-01-01

Recent studies have demonstrated the existence of a minority of tumor cells possessing the stem cell properties of self-renewal and differentiation in leukemia and several solid tumors. However, these cells do not possess the normal regulatory mechanisms of stem cells. Following transplantation, they are capable of initiating tumorigenesis and are therefore known as ‘tumor stem cells’. Cellular origin analysis of tumor stem cells has resulted in three hypotheses: Embryonal rest hypothesis, anaplasia and maturation arrest. Several signaling pathways which are involved in carcinogenesis, including Wnt/β-catenin, Notch and Oct-4 signaling pathways are crucial in normal stem cell self-renewal decisions, suggesting that breakdown in the regulation of self-renewal may be a key event in the development of tumors. Thus, tumors can be regarded as an abnormal organ in which stem cells have escaped from the normal constraints on self-renewal, thus, leading to abnormally differentiated tumor cells that lose the ability to form tumors. This new model for maligancies has significance for clinical research and treatment. PMID:22844351

Spherical Occulter Coronagraph Cubesat

NASA Technical Reports Server (NTRS)

Davila, Joseph M. (Inventor); Rabin, Douglas M. (Inventor); Reginald, Nelson (Inventor); Gong, Qian (Inventor); Shah, Neerav (Inventor); Chamberlin, Phillip C. (Inventor)

2018-01-01

The present invention relates to a space-based instrument which provides continuous coronal electron temperature and velocity images, for a predetermined period of time, thereby improving the understanding of coronal evolution and how the solar wind and Coronal Mass Ejection transients evolve from the low solar atmosphere through the heliosphere for an entire solar rotation. Specifically, the present invention relates to using a 6U spherical occulter coronagraph CubeSat, and a relative navigational system (RNS) that controls the position of the spacecraft relative to the occulting sphere. The present invention innovatively deploys a free-flying spherical occulter, and after deployment, the actively controlled CubeSat will provide an inertial formation flying with the spherical occulter and Sun.

NK Cells, Tumor Cell Transition, and Tumor Progression in Solid Malignancies: New Hints for NK-Based Immunotherapy?

PubMed Central

Huergo-Zapico, Leticia; Parodi, Monica; Pedrazzi, Marco; Mingari, Maria Cristina; Sparatore, Bianca; Gonzalez, Segundo; Olive, Daniel; Bottino, Cristina

2016-01-01

Several evidences suggest that NK cells can patrol the body and eliminate tumors in their initial phases but may hardly control established solid tumors. Multiple factors, including the transition of tumor cells towards a proinvasive/prometastatic phenotype, the immunosuppressive effect of the tumor microenvironment, and the tumor structure complexity, may account for limited NK cell efficacy. Several putative mechanisms of NK cell suppression have been defined in these last years; conversely, the cross talk between NK cells and tumor cells undergoing different transitional phases remains poorly explored. Nevertheless, recent in vitro studies and immunohistochemical analyses on tumor biopsies suggest that NK cells could not only kill tumor cells but also influence their evolution. Indeed, NK cells may induce tumor cells to change the expression of HLA-I, PD-L1, or NKG2D-L and modulate their susceptibility to the immune response. Moreover, NK cells may be preferentially located in the borders of tumor masses, where, indeed, tumor cells can undergo Epithelial-to-Mesenchymal Transition (EMT) acquiring prometastatic phenotype. Finally, the recently highlighted role of HMGB1 both in EMT and in amplifying the recruitment of NK cells provides further hints on a possible effect of NK cells on tumor progression and fosters new studies on this issue. PMID:27294158

Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles

PubMed Central

Ma, Jingwei; Zhang, Yi; Tang, Ke; Zhang, Huafeng; Yin, Xiaonan; Li, Yong; Xu, Pingwei; Sun, Yanling; Ma, Ruihua; Ji, Tiantian; Chen, Junwei; Zhang, Shuang; Zhang, Tianzhen; Luo, Shunqun; Jin, Yang; Luo, Xiuli; Li, Chengyin; Gong, Hongwei; Long, Zhixiong; Lu, Jinzhi; Hu, Zhuowei; Cao, Xuetao; Wang, Ning; Yang, Xiangliang; Huang, Bo

2016-01-01

Developing novel approaches to reverse the drug resistance of tumor-repopulating cells (TRCs) or stem cell-like cancer cells is an urgent clinical need to improve outcomes of cancer patients. Here we show an innovative approach that reverses drug resistance of TRCs using tumor cell-derived microparticles (T-MPs) containing anti-tumor drugs. TRCs, by virtue of being more deformable than differentiated cancer cells, preferentially take up T-MPs that release anti-tumor drugs after entering cells, which in turn lead to death of TRCs. The underlying mechanisms include interfering with drug efflux and promoting nuclear entry of the drugs. Our findings demonstrate the importance of tumor cell softness in uptake of T-MPs and effectiveness of a novel approach in reversing drug resistance of TRCs with promising clinical applications. PMID:27167569

Round Cell Tumors: Classification and Immunohistochemistry.

PubMed

Sharma, Shweta; Kamala, R; Nair, Divya; Ragavendra, T Raju; Mhatre, Swapnil; Sabharwal, Robin; Choudhury, Basanta Kumar; Rana, Vivek

2017-01-01

Round cell tumors as the name suggest are comprised round cells with increased nuclear-cytoplasmic ratio. This group of tumor includes entities such as peripheral neuroectodermal tumor, rhabdomyosarcoma, synovial sarcoma, non-Hodgkin's lymphoma, neuroblastoma, hepatoblastoma, Wilms' tumor, and desmoplastic small round cell tumor. These round cells tumors are characterized by typical histological pattern, immunohistochemical, and electron microscopic features that can help in differential diagnosis. The present article describes the classification and explains the histopathology and immunohistochemistry of some important round cell tumors.

21 CFR 864.6550 - Occult blood test.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Occult blood test. 864.6550 Section 864.6550 Food... DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Manual Hematology Devices § 864.6550 Occult blood test. (a) Identification. An occult blood test is a device used to detect occult blood in urine or feces. (Occult blood is...

21 CFR 864.6550 - Occult blood test.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Occult blood test. 864.6550 Section 864.6550 Food... DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Manual Hematology Devices § 864.6550 Occult blood test. (a) Identification. An occult blood test is a device used to detect occult blood in urine or feces. (Occult blood is...

21 CFR 864.6550 - Occult blood test.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Occult blood test. 864.6550 Section 864.6550 Food... DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Manual Hematology Devices § 864.6550 Occult blood test. (a) Identification. An occult blood test is a device used to detect occult blood in urine or feces. (Occult blood is...

21 CFR 864.6550 - Occult blood test.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Occult blood test. 864.6550 Section 864.6550 Food... DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Manual Hematology Devices § 864.6550 Occult blood test. (a) Identification. An occult blood test is a device used to detect occult blood in urine or feces. (Occult blood is...

21 CFR 864.6550 - Occult blood test.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Occult blood test. 864.6550 Section 864.6550 Food... DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Manual Hematology Devices § 864.6550 Occult blood test. (a) Identification. An occult blood test is a device used to detect occult blood in urine or feces. (Occult blood is...

General Information about Pancreatic Neuroendocrine Tumors (Islet Cell Tumors)

MedlinePlus

... Islet Cell Tumors) Treatment (PDQ®)–Patient Version General Information About Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Go ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

Nitric oxide regulates tumor cell cross-talk with stromal cells in the tumor microenvironment of the liver.

PubMed

Decker, Ningling Kang; Abdelmoneim, Soha S; Yaqoob, Usman; Hendrickson, Helen; Hormes, Joe; Bentley, Mike; Pitot, Henry; Urrutia, Raul; Gores, Greg J; Shah, Vijay H

2008-10-01

Tumor progression is regulated through paracrine interactions between tumor cells and stromal cells in the microenvironment, including endothelial cells and myofibroblasts. Nitric oxide (NO) is a key molecule in the regulation of tumor-microenvironment interactions, although its precise role is incompletely defined. By using complementary in vitro and in vivo approaches, we studied the effect of endothelial NO synthase (eNOS)-derived NO on liver tumor growth and metastasis in relation to adjacent stromal myofibroblasts and matrix because liver tumors maintain a rich, vascular stromal network enriched with phenotypically heterogeneous myofibroblasts. Mice with an eNOS deficiency developed liver tumors more frequently in response to carcinogens compared with control animals. In a surgical model of pancreatic cancer liver metastasis, eNOS overexpression in the tumor microenvironment attenuated both the number and size of tumor implants. NO promoted anoikis of tumor cells in vitro and limited their invasive capacity. Because tumor cell anoikis and invasion are both regulated by myofibroblast-derived matrix, we explored the effect of NO on tumor cell protease expression. Both microarray and Western blot analysis revealed eNOS-dependent down-regulation of the matrix protease cathepsin B within tumor cells, and silencing of cathepsin B attenuated tumor cell invasive capacity in a similar manner to that observed with eNOS overexpression. Thus, a NO gradient within the tumor microenvironment influences tumor progression through orchestrated molecular interactions between tumor cells and stroma.

Emergent Stratification in Solid Tumors Selects for Reduced Cohesion of Tumor Cells: A Multi-Cell, Virtual-Tissue Model of Tumor Evolution Using CompuCell3D.

PubMed

Swat, Maciej H; Thomas, Gilberto L; Shirinifard, Abbas; Clendenon, Sherry G; Glazier, James A

2015-01-01

Tumor cells and structure both evolve due to heritable variation of cell behaviors and selection over periods of weeks to years (somatic evolution). Micro-environmental factors exert selection pressures on tumor-cell behaviors, which influence both the rate and direction of evolution of specific behaviors, especially the development of tumor-cell aggression and resistance to chemotherapies. In this paper, we present, step-by-step, the development of a multi-cell, virtual-tissue model of tumor somatic evolution, simulated using the open-source CompuCell3D modeling environment. Our model includes essential cell behaviors, microenvironmental components and their interactions. Our model provides a platform for exploring selection pressures leading to the evolution of tumor-cell aggression, showing that emergent stratification into regions with different cell survival rates drives the evolution of less cohesive cells with lower levels of cadherins and higher levels of integrins. Such reduced cohesivity is a key hallmark in the progression of many types of solid tumors.

Emergent Stratification in Solid Tumors Selects for Reduced Cohesion of Tumor Cells: A Multi-Cell, Virtual-Tissue Model of Tumor Evolution Using CompuCell3D

PubMed Central

Swat, Maciej H.; Thomas, Gilberto L.; Shirinifard, Abbas; Clendenon, Sherry G.; Glazier, James A.

2015-01-01

Tumor cells and structure both evolve due to heritable variation of cell behaviors and selection over periods of weeks to years (somatic evolution). Micro-environmental factors exert selection pressures on tumor-cell behaviors, which influence both the rate and direction of evolution of specific behaviors, especially the development of tumor-cell aggression and resistance to chemotherapies. In this paper, we present, step-by-step, the development of a multi-cell, virtual-tissue model of tumor somatic evolution, simulated using the open-source CompuCell3D modeling environment. Our model includes essential cell behaviors, microenvironmental components and their interactions. Our model provides a platform for exploring selection pressures leading to the evolution of tumor-cell aggression, showing that emergent stratification into regions with different cell survival rates drives the evolution of less cohesive cells with lower levels of cadherins and higher levels of integrins. Such reduced cohesivity is a key hallmark in the progression of many types of solid tumors. PMID:26083246

Human CD34+ cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand target both tumor cells and tumor vasculature.

PubMed

Lavazza, Cristiana; Carlo-Stella, Carmelo; Giacomini, Arianna; Cleris, Loredana; Righi, Marco; Sia, Daniela; Di Nicola, Massimo; Magni, Michele; Longoni, Paolo; Milanesi, Marco; Francolini, Maura; Gloghini, Annunziata; Carbone, Antonino; Formelli, Franca; Gianni, Alessandro M

2010-03-18

Adenovirus-transduced CD34+ cells expressing membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (CD34-TRAIL+ cells) exert potent antitumor activity. To further investigate the mechanism(s) of action of CD34-TRAIL+ cells, we analyzed their homing properties as well as antitumor and antivascular effects using a subcutaneous myeloma model in immunodeficient mice. After intravenous injection, transduced cells homed in the tumor peaking at 48 hours when 188 plus or minus 25 CD45+ cells per 10(5) tumor cells were detected. Inhibition experiments showed that tumor homing of CD34-TRAIL+ cells was largely mediated by vascular cell adhesion molecule-1 and stromal cell-derived factor-1. Both CD34-TRAIL+ cells and soluble (s)TRAIL significantly reduced tumor volume by 40% and 29%, respectively. Computer-aided analysis of TdT-mediated dUTP nick end-labeling-stained tumor sections demonstrated significantly greater effectiveness for CD34-TRAIL+ cells in increasing tumor cell apoptosis and necrosis over sTRAIL. Proteome array analysis indicated that CD34-TRAIL+ cells and sTRAIL activate similar apoptotic machinery. In vivo staining of tumor vasculature with sulfosuccinimidyl-6-(biotinamido) hexanoate-biotin revealed that CD34-TRAIL+ cells but not sTRAIL significantly damaged tumor vasculature, as shown by TdT-mediated dUTP nick end-labeling+ endothelial cells, appearance of hemorrhagic areas, and marked reduction of endothelial area. These results demonstrate that tumor homing of CD34-TRAIL+ cells induces early vascular disruption, resulting in hemorrhagic necrosis and tumor destruction.

On the reduction of occultation light curves. [stellar occultations by planets

NASA Technical Reports Server (NTRS)

Wasserman, L.; Veverka, J.

1973-01-01

The two basic methods of reducing occultation light curves - curve fitting and inversion - are reviewed and compared. It is shown that the curve fitting methods have severe problems of nonuniqueness. In addition, in the case of occultation curves dominated by spikes, it is not clear that such solutions are meaningful. The inversion method does not suffer from these drawbacks. Methods of deriving temperature profiles from refractivity profiles are then examined. It is shown that, although the temperature profiles are sensitive to small errors in the refractivity profile, accurate temperatures can be obtained, particularly at the deeper levels of the atmosphere. The ambiguities that arise when the occultation curve straddles the turbopause are briefly discussed.

Escape from Tumor Cell Dormancy

DTIC Science & Technology

2012-10-01

bioreactor has been developed (oxygen sensing) to improve monitoring of the physiological status of the cultures ; as cells are stimulated by inflammation...therapeutics but of prevention and possibly lifestyle avoidance. Herein, these issues are addressed using a novel organotypic bioreactor in which tumor cells ...months 7-24) 3. seed bioreactors with cells (months 1-24) 4. label tumor cells for fluorescence (months 1-6) 5. label tumor cells for mass

Tumor-specific CD4+ T cells develop cytotoxic activity and eliminate virus-induced tumor cells in the absence of regulatory T cells.

PubMed

Akhmetzyanova, Ilseyar; Zelinskyy, Gennadiy; Schimmer, Simone; Brandau, Sven; Altenhoff, Petra; Sparwasser, Tim; Dittmer, Ulf

2013-02-01

The important role of tumor-specific cytotoxic CD8(+) T cells is well defined in the immune control of the tumors, but the role of effector CD4(+) T cells is poorly understood. In the current research, we have used a murine retrovirus-induced tumor cell line of C57BL/6 mouse origin, namely FBL-3 cells, as a model to study basic mechanisms of immunological control and escape during tumor formation. This study shows that tumor-specific CD4(+) T cells are able to protect against virus-induced tumor cells. We show here that there is an expansion of tumor-specific CD4(+) T cells producing cytokines and cytotoxic molecule granzyme B (GzmB) in the early phase of tumor growth. Importantly, we demonstrate that in vivo depletion of regulatory T cells (Tregs) and CD8(+) T cells in FBL-3-bearing DEREG transgenic mice augments IL-2 and GzmB production by CD4(+) T cells and increases FV-specific CD4(+) T-cell effector and cytotoxic responses leading to the complete tumor regression. Therefore, the capacity to reject tumor acquired by tumor-reactive CD4(+) T cells largely depends on the direct suppressive activity of Tregs. We suggest that a cytotoxic CD4(+) T-cell immune response may be induced to enhance resistance against oncovirus-associated tumors.

Curative potential of GM-CSF-secreting tumor cell vaccines on established orthotopic liver tumors: mechanisms for the superior antitumor activity of live tumor cell vaccines.

PubMed

Tai, Kuo-Feng; Chen, Ding-Shinn; Hwang, Lih-Hwa

2004-01-01

In preclinical studies, tumor cells genetically engineered to secrete cytokines, hereafter referred to as tumor cell vaccines, can often generate systemic antitumor immunity. This study investigated the therapeutic effects of live or irradiated tumor cell vaccines that secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) on established orthotopic liver tumors. Experimental results indicated that two doses (3 x 10(7) cells per dose) of irradiated tumor cell vaccines were therapeutically ineffective, whereas one dose (3 x 10(6) cells) of live tumor cell vaccines caused complete tumor regression. In vivo depletion of CD8+ T cells, but not natural killer cells, restored tumor formation in the live vaccine-treated animals. Additionally, the treatment of cells with live vaccine induced markedly higher levels of cytotoxic T lymphocyte activity than the irradiated vaccines in the draining lymph nodes. The higher levels of cytokine and antigen loads could partly explain the superior antitumor activity of live tumor cell vaccines, but other unidentified mechanisms could also play a role in the early T cell activation in the lymph nodes. A protocol using multiple and higher dosages of irradiated tumor cell vaccines also caused significant regression of liver tumors. These results suggest that the GM-CSF-secreting tumor cell vaccines are highly promising for orthotopic liver tumors if higher levels of immune responses are elicited during early tumor development. Copyright 2004 National Science Council, ROC and S. Karger AG, Basel

Triton stellar occultation candidates - 1992-1994

NASA Technical Reports Server (NTRS)

Mcdonald, S. W.; Elliot, J. T.

1992-01-01

A search for Triton stellar occultation candidates for the period 1992-1994 has been completed with CCD strip-scanning observations. The search reached an R magnitude of about 17.4 and found 129 candidates within 1.5 arcsec of Triton's ephemeris during this period. Of these events, around 30 occultations are expected to be visible from the earth, indicating that a number of Triton occultation events should be visible from major observatories. Even the faintest of the present candidate events could produce useful occultation data if observed with a large enough telescope. The present astrometric accuracy is inadequate to identify which of these appulse events will produce occultations on the earth; further astrometry is needed to refine the predictions for positive occultation identification. To aid in selecting candidates for additional astrometric and photometric studies, finder charts and earth-based visibility charts for each event are included.

HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death.

PubMed

Aits, Sonja; Gustafsson, Lotta; Hallgren, Oskar; Brest, Patrick; Gustafsson, Mattias; Trulsson, Maria; Mossberg, Ann-Kristin; Simon, Hans-Uwe; Mograbi, Baharia; Svanborg, Catharina

2009-03-01

HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.

Metastatic potential of tumor-initiating cells in solid tumors.

PubMed

Adhikari, Amit S; Agarwal, Neeraj; Iwakuma, Tomoo

2011-01-01

The lethality of cancer is mainly caused by its properties of metastasis, drug resistance, and subsequent recurrence. Understanding the mechanisms governing these properties and developing novel strategies to overcome them will greatly improve the survival of cancer patients. Recent findings suggest that tumors are comprised of heterogeneous cell populations, and only a small fraction of these are tumorigenic with the ability to self-renew and produce phenotypically diverse tumor cell populations. Cells in this fraction are called tumor-initiating cells (TICs) or cancer stem cells (CSCs). TICs have been identified from many types of cancer. They share several similarities with normal adult stem cells including sphere-forming ability, self-renewability, and expression of stem cell surface markers and transcription factors. TICs have also been proposed to be responsible for cancer metastasis, however, scarce evidence for their metastatic potential has been provided. In this review article, we have attempted to summarize the studies which have examined the metastatic potential of TICs in solid tumors.

In Vitro Model of Tumor Cell Extravasation

PubMed Central

Jeon, Jessie S.; Zervantonakis, Ioannis K.; Chung, Seok; Kamm, Roger D.; Charest, Joseph L.

2013-01-01

Tumor cells that disseminate from the primary tumor and survive the vascular system can eventually extravasate across the endothelium to metastasize at a secondary site. In this study, we developed a microfluidic system to mimic tumor cell extravasation where cancer cells can transmigrate across an endothelial monolayer into a hydrogel that models the extracellular space. The experimental protocol is optimized to ensure the formation of an intact endothelium prior to the introduction of tumor cells and also to observe tumor cell extravasation by having a suitable tumor seeding density. Extravasation is observed for 38.8% of the tumor cells in contact with the endothelium within 1 day after their introduction. Permeability of the EC monolayer as measured by the diffusion of fluorescently-labeled dextran across the monolayer increased 3.8 fold 24 hours after introducing tumor cells, suggesting that the presence of tumor cells increases endothelial permeability. The percent of tumor cells extravasated remained nearly constant from1 to 3 days after tumor seeding, indicating extravasation in our system generally occurs within the first 24 hours of tumor cell contact with the endothelium. PMID:23437268

Progress on the occulter experiment at Princeton

NASA Astrophysics Data System (ADS)

Cady, Eric; Balasubramanian, Kunjithapatham; Carr, Michael; Dickie, Matthew; Echternach, Pierre; Groff, Tyler; Kasdin, Jeremy; Laftchiev, Christian; McElwain, Michael; Sirbu, Dan; Vanderbei, Robert; White, Victor

2009-08-01

An occulter is used in conjunction with a separate telescope to suppress the light of a distant star. To demonstrate the performance of this system, we are building an occulter experiment in the laboratory at Princeton. This experiment will use an etched silicon mask as the occulter, with some modifications to try to improve the performance. The occulter is illuminated by a diverging laser beam to reduce the aberrations from the optics before the occulter. We present the progress of this experiment and expectations for future work.

[Prediction of occult carcinoma in contralateral nodules based on the ultrasonic features of unilateral papillary thyroid carcinoma].

PubMed

Yang, L M; Li, Q; Zhao, B W; Lyu, J G; Xu, H S; Xu, L L; Li, S Y; Gao, L; Zhu, J

2017-04-07

Objective: To investigate the occurrence of occult carcinoma in contralateral lobes based on the ultrasonic features of unilateral papillary thyroid carcinoma. Methods: The study included 202 consecutives cases of unilateral papillary thyroid carcinoma with benign nodules in the contralateral lobe identified by preoperative ultrasound or fine-needle aspiration from June 2014 to December 2015. All patients received total thyroidectomies, and with postoperative pathological examination they were divided into two groups, one including 60 cases with positive occult cancer and another one consisting of 142 cases with negative occult cancer. Univariate and multivariate analyses were performed to analyze the sonographic features of unilateral papillary thyroid carcinoma relevant to the occurrence of occult carcinoma in the contralateral nodules. Results: Univariate analysis indicated occult carcinoma in the contralateral lobes was associated with Hashimoto's thyroiditis(χ(2)=3.955, P =0.047), unclear border (χ(2)=4.375, P =0.036)and multifocality in the ipsilateral(χ(2)=7.375, P =0.007), but not with tumors maximum size, location, A/T, shape, internal structure, internal echo, acoustic halo, calcification, capsular invasion and blood flow signal in the lobe with carcinoma on another side. Multivariate analysis showed unclear border ( OR =2.727, P =0.010) and multifocality in the ipsilateral( OR =2.807, P =0.005)of carcinoma were independent predictive factor for contralateral occult PTC. Conclusions: Unclear border and multifocality of PTC in the ipsilateral were closely relevant to the occurrence of occult carcinoma in the contralateral nodules.

Leydig cell tumor

MedlinePlus

Tumor - Leydig cell; Testicular tumor - Leydig; Testicular neoplasm ... your provider if you have symptoms of testicular cancer. ... Philadelphia, PA: Elsevier Saunders; 2014:chap 86. National Cancer ... cancer treatment (PDQ) - health professional version. www.cancer. ...

Several Well-observed Asteroidal Occultations in 2010

NASA Astrophysics Data System (ADS)

Timerson, Brad; Durech, J.; Abramson, H.; Brooks, J.; Caton, D.; Clark, D.; Conard, S.; Cooke, B.; Dunham, D. W.; Dunham, J.; Edberg, S.; Ellington, C.; Faircloth, J.; Herchak, S.; Iverson, E.; Jones, R.; Lucas, G.; Lyzenga, G.; Maley, P.; Martinez, L.; Menke, J.; Mroz, G.; Nolan, P.; Peterson, R.; Preston, S.; Rattley, G.; Ray, J.; Scheck, A.; Stamm, J.; Stanton, R.; Suggs, R.; Tatum, R.; Thomas, W.

2011-10-01

During 2010 IOTA observers in North America reported about 190 positive observations for 106 asteroid occultation events. For several asteroids, this included observations with multiple chords. For two events, an inversion model was available. An occultation by 16 Psyche on 2010 August 21 yielded a best-fit ellipse of 235.4 x 230.4 km. On 2010 December 24, an occultation by 93 Minerva produced a best-fit ellipse of 179.4 x 133.4 km. An occultation by 96 Aegle on 2010 October 29 yielded a best-fit ellipse of 124.9 x 88.0 km. An occultation by 105 Artemis on 2010 June 24 showed a best-fit ellipse of 125.0 x 92.0 km. An occultation by 375 Ursula on 2010 December 4 produced a best-fit ellipse of 125.0 km x 135.0 km. Of note are two events not summarized in this article. On 2010 August 31, an occultation by 695 Bella yielded a new double star. That event will be summarized in the JDSO. Finally, on 2010 April 6, an occultation of zeta Ophiuchi by 824 Anastasia was observed by 65 observers at 69 locations. Unfortunately a large shift in the path yielded only 4 chords. Results of that event, and all the events mentioned here, can be found on the North American Asteroidal Occultation Results web page.

Tumor cell migration in complex microenvironments

PubMed Central

Polacheck, William J.; Zervantonakis, Ioannis K.; Kamm, Roger D.

2012-01-01

Tumor cell migration is essential for invasion and dissemination from primary solid tumors and for the establishment of lethal secondary metastases at distant organs. In vivo and in vitro models enabled identification of different factors in the tumor microenvironment that regulate tumor progression and metastasis. However, the mechanisms by which tumor cells integrate these chemical and mechanical signals from multiple sources to navigate the complex microenvironment remain poorly understood. In this review, we discuss the factors that influence tumor cell migration with a focus on the migration of transformed carcinoma cells. We provide an overview of the experimental and computational methods that allow the investigation of tumor cell migration, and we highlight the benefits and shortcomings of the various assays. We emphasize that the chemical and mechanical stimulus paradigms are not independent and that crosstalk between them motivates the development of new assays capable of applying multiple, simultaneous stimuli and imaging the cellular migratory response in real-time. These next-generation assays will more closely mimic the in vivo microenvironment to provide new insights into tumor progression, inform techniques to control tumor cell migration, and render cancer more treatable. PMID:22926411

Stellar Occultation Studies of the Solar System

NASA Technical Reports Server (NTRS)

Elliot, James L.

1998-01-01

Earth-based observations of stellar occultations provide extremely high spatial resolution for bodies in the outer solar system, about 10,000 times better than that of traditional imaging observations. Stellar occultation data can be used to establish the structure of atmospheres and rings of solar system bodies at high spatial resolution. Airborne occultation observations are particularly effective, since the controlled mobility of the observing platform allows the observer to fly within the optimum part of the occultation shadow for most events that are visible from Earth. Airborne observations are carried out above any clouds and are nearly free of scintillation noise from the Earth's atmosphere. KAO occultation observations resulted in the first detection of gravity waves in the Martian atmosphere, discovery of the Uranian rings, the first detection of Pluto's atmosphere, the first Earth-based investigations of Triton's atmosphere, and the discovery of narrow jets from Chiron's nucleus. The first SOFIA occultation opportunity will be an investigation of Pluto's atmospheric structure in November, 2002, and will resolve a problem that has lingered since the KAO discovery observation fourteen years earlier. We plan to continue our successful airborne occultation program with the greatly enhanced capability provided by SOFIA. We propose here to replace our KAO occultation photometer with one having twice the throughput, half the noise, a somewhat wider wavelength range, four times the field of view, and ten times the frame rate to optimize its performance and to capitalize on the larger collecting area offered by SOFIA. It will also allow for simultaneous visible and IR occultation observations, greatly enriching the results that we can obtain from occultations. We call this new imaging occultation photometer HOPI (High-speed Occultation Photometer and Imager). HOPI will provide a signal-to-noise ratio two to four times that of our present photometer for a given

Mixed germ cell-sex cord-stromal tumor with a concurrent interstitial cell tumor in a ferret

PubMed Central

INOUE, Saki; YONEMARU, Kayoko; YANAI, Tokuma; SAKAI, Hiroki

2014-01-01

A 5-year-old male ferret presented with an enlarged canalicular testis in the left inguinal region. Microscopically, the enlarged testis consisted of a diffuse intimately admixed proliferation of c-kit-positive germ cell-like and Wilms tumor-1 protein-positive Sertoli cell-like components, but no Call-Exner body was detected. In addition, the compact proliferation of steroidogenic acute regulatory protein-intense positive interstitial cells was identified in a separate peripheral area of the mass. Based on histopathological and immunohistochemical findings, the tumor was diagnosed as a mixed germ cell-sex cord-stromal tumor with a concurrent interstitial cell tumor. PMID:25311985

Circulating Tumor Cell and Cell-free Circulating Tumor DNA in Lung Cancer.

PubMed

Nurwidya, Fariz; Zaini, Jamal; Putra, Andika Chandra; Andarini, Sita; Hudoyo, Achmad; Syahruddin, Elisna; Yunus, Faisal

2016-09-01

Circulating tumor cells (CTCs) are tumor cells that are separated from the primary site or metastatic lesion and disseminate in blood circulation. CTCs are considered to be part of the long process of cancer metastasis. As a 'liquid biopsy', CTC molecular examination and investigation of single cancer cells create an important opportunity for providing an understanding of cancer biology and the process of metastasis. In the last decade, we have seen dramatic development in defining the role of CTCs in lung cancer in terms of diagnosis, genomic alteration determination, treatment response and, finally, prognosis prediction. The aims of this review are to understand the basic biology and to review methods of detection of CTCs that apply to the various types of solid tumor. Furthermore, we explored clinical applications, including treatment monitoring to anticipate therapy resistance as well as biomarker analysis, in the context of lung cancer. We also explored the potential use of cell-free circulating tumor DNA (ctDNA) in the genomic alteration analysis of lung cancer.

Cytotoxic T cell clones isolated from ovarian tumor-infiltrating lymphocytes recognize multiple antigenic epitopes on autologous tumor cells.

PubMed

Ioannides, C G; Freedman, R S; Platsoucas, C D; Rashed, S; Kim, Y P

1991-03-01

CTL clones were developed from tumor infiltrating lymphocytes (TIL) from the ascites of a patient with ovarian carcinoma by coculture of TIL with autologous tumor cells and subsequent cloning in the presence of autologous tumor cells. These CTL clones expressed preferential cytolytic activity against autologous tumor cells but not against allogeneic ovarian tumor cells and the NK-sensitive cell line K562. The cytolytic activity of these CTL against autologous tumors was inhibited by anti-TCR (WT31 mAb), anti-HLA class I, and anti-CD3 mAb but not by the NK function antibody Leu 11b. Cloning of the autologous tumor cells in vitro revealed that the CTL clones of the ovarian TIL expressed differential abilities to lyse autologous tumor cell clones. The specificity analysis of these autologous tumor specific CTL suggested that they recognize several antigenic determinants present on the ovarian tumor cells. Our results indicate the presence of at least three antigenic epitopes on the tumor cells (designated OVA-1A, OVA-1B, and OVA-1C), one of which (OVA-1C) is unstable. These determinants are present either simultaneously or separately, and six types of ovarian clones can be distinguished on the basis of their expression. These results indicate that CTL of the TIL detect intratumor antigenic heterogeneity. The novel heterogeneity identified within the ovarian tumor cells in this report may be of significance for understanding cellular immunity in ovarian cancer and developing adoptive specific immunotherapeutic approaches in ovarian cancer.

Predicted occultations by Uranus - 1981-1984

NASA Technical Reports Server (NTRS)

Klemola, A. R.; Mink, D. J.; Elliot, J. L.

1981-01-01

Predictions are presented for 11 occultations by and appulses to Uranus and its ring system for ten stars from 1981 through 1984. The brightest stars are occulted on April 26, 1981 (BD - 19 deg 4222) and on April 22, 1982 (Hyd - 20 deg 51699). The ring system occults the same star twice during March 1983 (Hyd - 21 deg 64352).

Evolution of cooperation among tumor cells.

PubMed

Axelrod, Robert; Axelrod, David E; Pienta, Kenneth J

2006-09-05

The evolution of cooperation has a well established theoretical framework based on game theory. This approach has made valuable contributions to a wide variety of disciplines, including political science, economics, and evolutionary biology. Existing cancer theory suggests that individual clones of cancer cells evolve independently from one another, acquiring all of the genetic traits or hallmarks necessary to form a malignant tumor. It is also now recognized that tumors are heterotypic, with cancer cells interacting with normal stromal cells within the tissue microenvironment, including endothelial, stromal, and nerve cells. This tumor cell-stromal cell interaction in itself is a form of commensalism, because it has been demonstrated that these nonmalignant cells support and even enable tumor growth. Here, we add to this theory by regarding tumor cells as game players whose interactions help to determine their Darwinian fitness. We marshal evidence that tumor cells overcome certain host defenses by means of diffusible products. Our original contribution is to raise the possibility that two nearby cells can protect each other from a set of host defenses that neither could survive alone. Cooperation can evolve as by-product mutualism among genetically diverse tumor cells. Our hypothesis supplements, but does not supplant, the traditional view of carcinogenesis in which one clonal population of cells develops all of the necessary genetic traits independently to form a tumor. Cooperation through the sharing of diffusible products raises new questions about tumorigenesis and has implications for understanding observed phenomena, designing new experiments, and developing new therapeutic approaches.

Radio occultation experiments with INAF-IRA radiotelescopes.

NASA Astrophysics Data System (ADS)

Pluchino, S.; Schillirò, F.; Salerno, E.; Pupillo, G.

The Radio Occultation research program performed at the Medicina and Noto Radioastronomical Stations of the Istituto Nazionale di Astrofisica (INAF) - Istituto di Radioastronomia (IRA) includes observations of spacecraft by satellite and satellite by satellite events. The Lunar Radio Occultation (LRO) part of the program consists in collecting data of the lunar Total Electron Content (TEC), at different limb longitudes and at different time, in order to study long term variation of the Moon's ionosphere. The LRO program started at Medicina in September 2006 with the observation of the European probe SMART-1 during its impact on the lunar soil. It proceeded in 2007 with the observation of the lunar occultations of Saturn and Venus, and with the observation of Mars in 2008. On this occasion the probes Cassini, Venus Express, Mars Express, Mars Reconaissance Orbiter and Mars Odissey were respectively occulted by the moon. On Dec 1st 2008 a Venus lunar occultation occurred. On that occasion we performed the first Italian-VLBI (I-VLBI) tracking experiment by detecting the carrier signals coming from the Venus Express (VEX) spacecraft with both the IRA radiotelescopes together with the Matera antenna of the Italian Space Agency. The second part of the radio occultation program includes the observation of satellite by satellite occultation events, as well as mutual occultations of Jupiter satellites. These events are referred to as mutual phenomena (PHEMU). These observations are aimed to measure the radio flux variation during the occultation and to derive surface spatial characteristics such as Io's hot spots. In this work preliminary results of the Radio Occultation program will be presented.

Histologic assessment of tumor budding in preoperative biopsies to predict nodal metastasis in squamous cell carcinoma of the tongue and floor of the mouth.

PubMed

Seki, Mai; Sano, Takaaki; Yokoo, Satoshi; Oyama, Tetsunari

2016-04-01

In squamous cell carcinoma (SCC) of the tongue and the floor of the mouth (FOM), it is important to predict lymph node metastasis, including occult metastasis, before operating. The purpose of this study was for us to determine practical histopathologic parameters as predictive factors for lymph node metastasis in preoperative SCC biopsy specimens. We examined 91 cases of SCC for conventional histopathologic assessment and a new factor, tumor budding, and their relationship with lymph node metastasis. Significant factors via univariate analysis (p < .01) were budding (score ≥3) and tumor depth (≥3 mm) and these were associated with lymph node metastasis. Moreover, both budding and tumor depth significantly correlated with relapse-free survival; however, evaluating biopsy specimens often proved inaccurate for predicting true tumor depth of cancer invasion. Tumor budding using immunohistochemistry for cytokeratin should be added to routine histologic assessments as a new criterion factoring into the decision as to whether neck dissection is indicated. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1582-E1590, 2016. © 2015 Wiley Periodicals, Inc.

ME-10TUMOR MICROENVIRONMENT INFILTRATING MYELOID DERIVED SUPPRESSOR CELLS INHIBIT ANTI-TUMOR T CELL RESPONSES

PubMed Central

Kamran, Neha; Ayala, Mariela; Li, Youping; Assi, Hikmat; Candolfi, Marianela; Dzaman, Marta; Lowenstein, Pedro; Castro, Maria

2014-01-01

MDSCs represent a population of immature myeloid cells at various stages of differentiation that inhibit anti-tumor T cell-mediated responses. We demonstrate the accumulation of MDSCs in GL26 induced glioma and B16 melanoma bearing mice. Absolute numbers of Ly-6G+ (Gr-1high) MDSCs showed a 200 fold increase within the tumor microenvironment (TME) 28 days post-tumor implantation. The numbers of Ly-6C+ (Gr-1low) MDSCs also showed a similar trend within the TME. While this massive influx of MDSCs was noted within intracranial tumors, MDSC levels did not increase in the dLNs, spleen or bone marrow (BM) of intracranial tumor bearing mice. MDSCs numbers were significantly elevated in the blood of GL26 intracranial tumor bearing mice at 28 days. Mice bearing B16 tumors in the flank showed a ∼5 fold increased influx of Ly-6G+ MDSCs while the Ly6C+ MDSCs increased marginally by 1.1 fold within the tumor mass. Levels of circulating MDSCs also increased by ∼10 fold, while the levels of splenic MDSCs did not change. While both Ly-6G+ and Ly6C+ MDSCs isolated from the brain TME of GL26 intracranial tumor bearing mice inhibited antigen-specific T cell proliferation, Ly6C+ MDSC were found to be more efficient. Ly6G+ or Ly6C+ MDSCs from the bone marrow of intracranial tumor bearing mice failed to suppress antigen-specific T cell proliferation. Splenic and bone marrow MDSCs from naïve mice also did not inhibit antigen-specific T cell proliferation suggesting that TME derived factors may activate MDSCs to exert their immune-suppressive properties. Microarray analysis of glioma cell lines showed elevated levels of CXCL1 mRNA and splenic MDSCs from GL26 tumor mice showed upregulation of the CXCR2 mRNA. Preliminary experiments indicate that CXCR2 signaling mediates MDSC chemotaxis. Overall, our data suggests that strategies that inhibit MDSC recruitment to the TME and/or block their activity could enhance the T cell mediated tumor clearance.

Antitumor action of 3-bromopyruvate implicates reorganized tumor growth regulatory components of tumor milieu, cell cycle arrest and induction of mitochondria-dependent tumor cell death.

PubMed

Yadav, Saveg; Kujur, Praveen Kumar; Pandey, Shrish Kumar; Goel, Yugal; Maurya, Babu Nandan; Verma, Ashish; Kumar, Ajay; Singh, Rana Pratap; Singh, Sukh Mahendra

2018-01-15

Evidences demonstrate that metabolic inhibitor 3-bromopyruvate (3-BP) exerts a potent antitumor action against a wide range of malignancies. However, the effect of 3-BP on progression of the tumors of thymic origin remains unexplored. Although, constituents of tumor microenvironment (TME) plays a pivotal role in regulation of tumor progression, it remains unclear if 3-BP can alter the composition of the crucial tumor growth regulatory components of the external surrounding of tumor cells. Thus, the present investigation attempts to understand the effect of 3-BP administration to a host bearing a progressively growing tumor of thymic origin on tumor growth regulatory soluble, cellular and biophysical components of tumor milieu vis-à-vis understanding its association with tumor progression, accompanying cell cycle events and mode of cell death. Further, the expression of cell survival regulatory molecules and hemodynamic characteristics of the tumor milieu were analysed to decipher mechanisms underlying the antitumor action of 3-BP. Administration of 3-BP to tumor-bearing hosts retarded tumor progression accompanied by induction of tumor cell death, cell cycle arrest, declined metabolism, inhibited mitochondrial membrane potential, elevated release of cytochrome c and altered hemodynamics. Moreover, 3-BP reconstituted the external milieu, in concurrence with deregulated glucose and pH homeostasis and increased tumor infiltration by NK cells, macrophages, and T lymphocytes. Further, 3-BP administration altered the expression of key regulatory molecules involved in glucose uptake, intracellular pH and tumor cell survival. The outcomes of this study will help in optimizing the therapeutic application of 3-BP by targeting crucial tumor growth regulatory components of tumor milieu. Copyright © 2017 Elsevier Inc. All rights reserved.

Identification of Metastatic Tumor Stem Cell

DTIC Science & Technology

2010-09-01

addition to a tumor stem cell , an existence of a metastatic stem cell is predicted. Despite the critical importance of the concept, this idea has not been...isolating stem cell population from a unique set of breast tumor cell lines and by examining their metastatic behavior in an animal model. The overall...will (i) isolate stem - cell population from non-metastatic and metastatic cells of a pair of syngenic breast tumor cell lines, and test their metastatic

Tumor cell-derived microparticles polarize M2 tumor-associated macrophages for tumor progression.

PubMed

Ma, Ruihua; Ji, Tiantian; Chen, Degao; Dong, Wenqian; Zhang, Huafeng; Yin, Xiaonan; Ma, Jingwei; Liang, Xiaoyu; Zhang, Yi; Shen, Guanxin; Qin, Xiaofeng; Huang, Bo

2016-04-01

Despite identification of macrophages in tumors (tumor-associated macrophages, TAM) as potential targets for cancer therapy, the origin and function of TAM in the context of malignancy remain poorly characterized. Here, we show that microparticles (MPs), as a by-product, released by tumor cells act as a general mechanism to mediate M2 polarization of TAM. Taking up tumor MPs by macrophages is a very efficient process, which in turn results in the polarization of macrophages into M2 type, not only leading to promoting tumor growth and metastasis but also facilitating cancer stem cell development. Moreover, we demonstrate that the underlying mechanism involves the activation of the cGAS/STING/TBK1/STAT6 pathway by tumor MPs. Finally, in addition to murine tumor MPs, we show that human counterparts also possess consistent effect on human M2 polarization. These findings provide new insights into a critical role of tumor MPs in remodeling of tumor microenvironment and better understanding of the communications between tumors and macrophages.

[Progress in research of occult hepatitis B virus infection].

PubMed

Huang, X Y; Shi, Q F; Huang, T

2017-05-10

Occult hepatitis B virus infection is a worldwide public health problem, which seriously affects the clinical diagnosis of hepatitis B and threatens the safety of blood transfusion. The concept of occult hepatitis B virus infection, the pathogenesis of occult hepatitis B virus infection, the prevalence of occult hepatitis B virus infection in different groups, including healthy population and different patients, and the possibility of transmission were summarized. The prevalence of occult hepatitis B virus infection was found in healthy population and different patients, and there is possibility of occult hepatitis B virus infection to be transmitted through blood transfusion. The paper provides a comprehensive introduction of the pathogenesis and prevalence of occult hepatitis B virus infection. More attention should be paid to occult hepatitis B virus infection.

Mesenchymal stem cells in tumor development

PubMed Central

Cuiffo, Benjamin G.; Karnoub, Antoine E.

2012-01-01

Mesenchymal stem cells (MSCs) are multipotent progenitor cells that participate in the structural and functional maintenance of connective tissues under normal homeostasis. They also act as trophic mediators during tissue repair, generating bioactive molecules that help in tissue regeneration following injury. MSCs serve comparable roles in cases of malignancy and are becoming increasingly appreciated as critical components of the tumor microenvironment. MSCs home to developing tumors with great affinity, where they exacerbate cancer cell proliferation, motility, invasion and metastasis, foster angiogenesis, promote tumor desmoplasia and suppress anti-tumor immune responses. These multifaceted roles emerge as a product of reciprocal interactions occurring between MSCs and cancer cells and serve to alter the tumor milieu, setting into motion a dynamic co-evolution of both tumor and stromal tissues that favors tumor progression. Here, we summarize our current knowledge about the involvement of MSCs in cancer pathogenesis and review accumulating evidence that have placed them at the center of the pro-malignant tumor stroma. PMID:22863739

Stellar occultation studies of the solar system

NASA Technical Reports Server (NTRS)

Elliot, J. L.

1979-01-01

The paper covers the principles, observational procedures, and results relating to occultations of stars by solar system bodies other than the moon. Physical processes involved in occultations are presented including (1) extinction by ring material, (2) differential refraction by a planetary atmosphere, (3) extinction by a planetary atmosphere, and (4) Fresnel diffraction by sharp edges. It is noted that from a sufficient number of immersion and emersion timings of a stellar occultation, the radius and ellipticity of the occulting body can be accurately determined. From an occultation by a planet having an atmosphere, temperature, pressure, and number density profiles can be obtained along with information about the composition of the atmosphere and the extinction.

Method of Modeling and Simulation of Shaped External Occulters

NASA Technical Reports Server (NTRS)

Lyon, Richard G. (Inventor); Clampin, Mark (Inventor); Petrone, Peter, III (Inventor)

2016-01-01

The present invention relates to modeling an external occulter including: providing at least one processor executing program code to implement a simulation system, the program code including: providing an external occulter having a plurality of petals, the occulter being coupled to a telescope; and propagating light from the occulter to a telescope aperture of the telescope by scalar Fresnel propagation, by: obtaining an incident field strength at a predetermined wavelength at an occulter surface; obtaining a field propagation from the occulter to the telescope aperture using a Fresnel integral; modeling a celestial object at differing field angles by shifting a location of a shadow cast by the occulter on the telescope aperture; calculating an intensity of the occulter shadow on the telescope aperture; and applying a telescope aperture mask to a field of the occulter shadow, and propagating the light to a focal plane of the telescope via FFT techniques.

Occult Participation: Its Impact on Adolescent Development.

ERIC Educational Resources Information Center

Tennant-Clark, Cynthia M.; And Others

1989-01-01

Investigated relationship between occult participation, substance abuse, and level of self-esteem among 25 clinical (alcohol or drug treatment) and 25 nonclinical adolescents. Results indicated that adolescent substance abuse and occult participation were significantly related. Found significant differences between high versus low occult groups…

Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice.

PubMed

Liu, Chengwen; Lou, Yanyan; Lizée, Gregory; Qin, Hong; Liu, Shujuan; Rabinovich, Brian; Kim, Grace J; Wang, Yi-Hong; Ye, Yang; Sikora, Andrew G; Overwijk, Willem W; Liu, Yong-Jun; Wang, Gang; Hwu, Patrick

2008-03-01

A prerequisite for strong adaptive antiviral immunity is the robust initial activation of the innate immune system, which is frequently mediated by TLR-activated plasmacytoid DCs (pDCs). Natural antitumor immunity is often comparatively weak, potentially due to the lack of TLR-mediated activation signals within the tumor microenvironment. To assess whether pDCs are capable of directly facilitating effective antitumor immune responses, mice bearing established subcutaneous B16 melanoma tumors were administered TLR9-activated pDCs directly into the tumor. We found that TLR9-activated pDCs induced robust, spontaneous CTL cross-priming against multiple B16 tumor antigens, leading to the regression of both treated tumors and untreated tumors at distant contralateral sites. This T cell cross-priming was mediated by conventional DCs (cDCs) and was completely dependent upon the early recruitment and activation of NK cells at the tumor site. NK cell recruitment was mediated by CCR5 via chemokines secreted by pDCs, and optimal IFN-gamma production by NK cells was mediated by OX40L expressed by pDCs. Our data thus demonstrated that activated pDCs are capable of initiating effective and systemic antitumor immunity through the orchestration of an immune cascade involving the sequential activation of NK cells, cDCs, and CD8(+) T cells.

Apoptosis and tumor cell death in response to HAMLET (human alpha-lactalbumin made lethal to tumor cells).

PubMed

Hallgren, Oskar; Aits, Sonja; Brest, Patrick; Gustafsson, Lotta; Mossberg, Ann-Kristin; Wullt, Björn; Svanborg, Catharina

2008-01-01

HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a molecular complex derived from human milk that kills tumor cells by a process resembling programmed cell death. The complex consists of partially unfolded alpha-lactalbumin and oleic acid, and both the protein and the fatty acid are required for cell death. HAMLET has broad antitumor activity in vitro, and its therapeutic effect has been confirmed in vivo in a human glioblastoma rat xenograft model, in patients with skin papillomas and in patients with bladder cancer. The mechanisms of tumor cell death remain unclear, however. Immediately after the encounter with tumor cells, HAMLET invades the cells and causes mitochondrial membrane depolarization, cytochrome c release, phosphatidyl serine exposure, and a low caspase response. A fraction of the cells undergoes morphological changes characteristic of apoptosis, but caspase inhibition does not rescue the cells and Bcl-2 overexpression or altered p53 status does not influence the sensitivity of tumor cells to HAMLET. HAMLET also creates a state of unfolded protein overload and activates 20S proteasomes, which contributes to cell death. In parallel, HAMLET translocates to tumor cell nuclei, where high-affinity interactions with histones cause chromatin disruption, loss of transcription, and nuclear condensation. The dying cells also show morphological changes compatible with macroautophagy, and recent studies indicate that macroautophagy is involved in the cell death response to HAMLET. The results suggest that HAMLET, like a hydra with many heads, may interact with several crucial cellular organelles, thereby activating several forms of cell death, in parallel. This complexity might underlie the rapid death response of tumor cells and the broad antitumor activity of HAMLET.

The Northrop Grumman External Occulter Testbed: Preliminary Results

NASA Astrophysics Data System (ADS)

Lo, Amy; Glassman, T.; Lillie, C.

2007-05-01

We have built a subscale testbed to demonstrate and validate the performance of the New Worlds Observer (NWO), a terrestrial planet finder external-occulter mission concept. The external occulter concept allows observations of nearby exo-Earths using two spacecraft: one carrying an occulter that is tens of meters in diameter and the other carrying a generic space telescope. The occulter is completely opaque, resembling a flower, with petals having a hypergaussian profile that enable 10-10 intensity suppression of stars that potentially harbor terrestrial planets. The baseline flight NWO system has a 30 meter occulter flying 30,000 km in front of a 4 meter class telescope. Testing the flight configuration on the ground is not feasible, so we have matched the Fresnel number of the flight configuration ( 10) using a subscale occulter. Our testbed consists of an 80 meter length evacuated tube, with a high precision occulter in the center of the tube. The occulter is 4 cm in diameter, manufactured with ¼ micron metrological accuracy and less than 2 micron tip truncation. This mimics a 30 meter occulter with millimeter figure accuracy and less than centimeter tip truncation. Our testbed is an evolving experiment, and we report here the first, preliminary, results using a single wavelength laser (532 nm) as the source.

NF-κB functions as a molecular link between tumor cells and Th1/Tc1 T cells in the tumor microenvironment to exert radiation-mediated tumor suppression

PubMed Central

Simon, Priscilla S.; Bardhan, Kankana; Chen, May R.; Paschall, Amy V.; Lu, Chunwan; Bollag, Roni J.; Kong, Feng-Chong; Jin, JianYue; Kong, Feng-Ming; Waller, Jennifer L.; Pollock, Raphael E.; Liu, Kebin

2016-01-01

Radiation modulates both tumor cells and immune cells in the tumor microenvironment to exert its anti-tumor activity; however, the molecular connection between tumor cells and immune cells that mediates radiation-exerted tumor suppression activity in the tumor microenvironment is largely unknown. We report here that radiation induces rapid activation of the p65/p50 and p50/p50 NF-κB complexes in human soft tissue sarcoma (STS) cells. Radiation-activated p65/p50 and p50/p50 bind to the TNFα promoter to activate its transcription in STS cells. Radiation-induced TNFα induces tumor cell death in an autocrine manner. A sublethal dose of Smac mimetic BV6 induces cIAP1 and cIAP2 degradation to increase tumor cell sensitivity to radiation-induced cell death in vitro and to enhance radiation-mediated suppression of STS xenografts in vivo. Inhibition of caspases, RIP1, or RIP3 blocks radiation/TNFα-induced cell death, whereas inhibition of RIP1 blocks TNFα-induced caspase activation, suggesting that caspases and RIP1 act sequentially to mediate the non-compensatory cell death pathways. Furthermore, we determined in a syngeneic sarcoma mouse model that radiation up-regulates IRF3, IFNβ, and the T cell chemokines CCL2 and CCL5 in the tumor microenvironment, which are associated with activation and increased infiltration of Th1/Tc1 T cells in the tumor microenvironment. Moreover, tumor-infiltrating T cells are in their active form since both the perforin and FasL pathways are activated in irradiated tumor tissues. Consequently, combined BV6 and radiation completely suppressed tumor growth in vivo. Therefore, radiation-induced NF-κB functions as a molecular link between tumor cells and immune cells in the tumor microenvironment for radiation-mediated tumor suppression. PMID:27014915

Escape from Tumor Cell Dormancy

DTIC Science & Technology

2011-10-01

feature of the bioreactor has been developed (oxygen sensing) to improve monitoring of the physiological status of the cultures ; as cells are stimulated...Herein, these issues are addressed using a novel organotypic bioreactor in which tumor cells can be followed for weeks to months, the process of seeding... cells (months 1-6) 3. isolate human stellate and Kupffer cells (months 7-24) 3. seed bioreactors with cells (months 1-24) 4. label tumor cells for

Palifosfamide in Treating Patients With Recurrent Germ Cell Tumors

ClinicalTrials.gov

2015-06-11

Adult Central Nervous System Germ Cell Tumor; Adult Teratoma; Malignant Extragonadal Germ Cell Tumor; Malignant Extragonadal Non-Seminomatous Germ Cell Tumor; Extragonadal Seminoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Ovarian Germ Cell Tumor; Stage IV Extragonadal Non-Seminomatous Germ Cell Tumor; Stage IV Extragonadal Seminoma; Stage IV Ovarian Germ Cell Tumor

Early detection of tumor cells by innate immune cells leads to T(reg) recruitment through CCL22 production by tumor cells.

PubMed

Faget, Julien; Biota, Cathy; Bachelot, Thomas; Gobert, Michael; Treilleux, Isabelle; Goutagny, Nadège; Durand, Isabelle; Léon-Goddard, Sophie; Blay, Jean Yves; Caux, Christophe; Ménétrier-Caux, Christine

2011-10-01

In breast carcinomas, patient survival seems to be negatively affected by the recruitment of regulatory T cells (T(reg)) within lymphoid aggregates by CCL22. However, the mechanisms underpinning this process, which may be of broader significance in solid tumors, have yet to be described. In this study, we determined how CCL22 production is controlled in tumor cells. In human breast carcinoma cell lines, CCL22 was secreted at low basal levels that were strongly increased in response to inflammatory signals [TNF-α, IFN-γ, and interleukin (IL)-1β], contrasting with CCL17. Primary breast tumors and CD45(+) infiltrating immune cells appeared to cooperate in driving CCL22 secretion, as shown clearly in cocultures of breast tumor cell lines and peripheral blood mononuclear cells (PBMC) or their supernatants. We determined that monocyte-derived IL-1β and TNF-α are key players as monocyte depletion or neutralization of these cytokines attenuated secretion of CCL22. However, when purified monocytes were used, exogenous human IFN-γ was also required to generate this response suggesting a role for IFN-γ-producing cells within PBMCs. In this setting, we found that human IFN-γ could be replaced by the addition of (i) IL-2 or K562-activated natural killer (NK) cells or (ii) resting NK cells in the presence of anti-MHC class I antibody. Taken together, our results show a dialogue between NK and tumor cells leading to IFN-γ secretion, which in turn associates with monocyte-derived IL-1β and TNF-α to drive production of CCL22 by tumor cells and subsequent recruitment of T(reg). As one validation of this conclusion in primary breast tumors, we showed that NK cells and macrophages tend to colocalize within tumors. In summary, our findings suggest that at early times during tumorigenesis, the detection of tumor cells by innate effectors (monocytes and NK cells) imposes a selection for CCL22 secretion that recruits T(reg) to evade this early antitumor immune response.

Triton stellar occultation candidates: 1995-1999

NASA Technical Reports Server (NTRS)

Mcdonald, S. W.; Elliot, J. L.

1995-01-01

We have completed a search for candidates for stellar occultations by Triton over the years 1995-1999. CCd strip scan images provided star positions in the relevant sky area to a depth of about 17.5 R magnitude. Over this time period, we find that Triton passes within 1.0 arcsec of 75 stars. Appulses with geocentric minimum separations of less than 0.35 arcsec will result in stellar occultations, but further astrometry and photometry is necessary to refine individual predictions for identification of actual occultations. Finder charts are included to aid in further studies and prediction refinement. The two most promising potential occultations, Tr176 and Tr180, occur in 1997.

Treatment Option Overview (Extragonadal Germ Cell Tumors)

MedlinePlus

... Professional Extragonadal Germ Cell Tumors Treatment Extragonadal Germ Cell Tumors Treatment (PDQ®)–Patient Version General Information About Extragonadal Germ Cell Tumors Go to Health Professional Version Key Points ...

Ovarian Germ Cell Tumors Treatment

MedlinePlus

... Tube, & Primary Peritoneal Cancer Screening Research Ovarian Germ Cell Tumors Treatment (PDQ®)–Patient Version Treatment Option Overview ... types of treatment for patients with ovarian germ cell tumors. Different types of treatment are available for ...

Exploring the Solar System with Stellar Occultations

NASA Technical Reports Server (NTRS)

Elliot, J. L.; Dunham, E. W.

1984-01-01

By recording the light intensity as a function of time when a planet occults a relatively bright star, the thermal structure of the upper atmosphere of the planet can be probed. The main feature of stellar occultation observations is their high spatial resolution, typically several thousand times better than the resolution achievable with ground-based imaging. Five stellar occultations have been observed. The main results of these observations are summarized. Stellar occultations have been observed on Uranus, Mars, Pallas, Neptune and the Jovian Ring.

Blastic plasmacytoid dendritic cell neoplasm frequently shows occult central nervous system involvement at diagnosis and benefits from intrathecal therapy.

PubMed

Martín-Martín, Lourdes; Almeida, Julia; Pomares, Helena; González-Barca, Eva; Bravo, Pilar; Giménez, Teresa; Heras, Cecilia; Queizán, José-Antonio; Pérez-Ceballos, Elena; Martínez, Violeta; Alonso, Natalia; Calvo, Carlota; Álvarez, Rodolfo; Caballero, María Dolores; Orfao, Alberto

2016-03-01

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive myeloid neoplasm which shows a high rate of central nervous system (CNS) recurrence and overall survival (OS) of <1 year. Despite this, screening for CNS involvement is not routinely performed at diagnosis and intrathecal (IT) prophylaxis is not regularly administered in BPDCN. Here, we prospectively evaluated 13 consecutive BPDCN patients for the presence of CNS involvement by flow cytometry. Despite none of the patients presented with neurological symptoms, occult CNS involvement was detected in 6/10 cases evaluated at diagnosis and 3/3 studied at relapse/progression. BPDCN patients evaluated at diagnosis received IT treatment -either CNS prophylaxis (n = 4) or active therapy (n = 6)- and all but one remain alive (median follow-up of 20 months). In contrast, all three patients assessed at relapse/progression died. The potential benefit of IT treatment administered early at diagnosis on OS and CNS recurrence-free survival of BPDCN was further confirmed in a retrospective cohort of another 23 BPDCN patients. Our results show that BPDCN patients studied at diagnosis frequently display occult CNS involvement; moreover, they also indicate that treatment of occult CNS disease might lead to a dramatically improved outcome of BPDCN.

Blastic plasmacytoid dendritic cell neoplasm frequently shows occult central nervous system involvement at diagnosis and benefits from intrathecal therapy

PubMed Central

Martín-Martín, Lourdes; Almeida, Julia; Pomares, Helena; González-Barca, Eva; Bravo, Pilar; Giménez, Teresa; Heras, Cecilia; Queizán, José-Antonio; Pérez-Ceballos, Elena; Martínez, Violeta; Alonso, Natalia; Calvo, Carlota; Álvarez, Rodolfo; Caballero, María Dolores; Orfao, Alberto

2016-01-01

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive myeloid neoplasm which shows a high rate of central nervous system (CNS) recurrence and overall survival (OS) of <1 year. Despite this, screening for CNS involvement is not routinely performed at diagnosis and intrathecal (IT) prophylaxis is not regularly administered in BPDCN. Here, we prospectively evaluated 13 consecutive BPDCN patients for the presence of CNS involvement by flow cytometry. Despite none of the patients presented with neurological symptoms, occult CNS involvement was detected in 6/10 cases evaluated at diagnosis and 3/3 studied at relapse/progression. BPDCN patients evaluated at diagnosis received IT treatment -either CNS prophylaxis (n = 4) or active therapy (n = 6)- and all but one remain alive (median follow-up of 20 months). In contrast, all three patients assessed at relapse/progression died. The potential benefit of IT treatment administered early at diagnosis on OS and CNS recurrence-free survival of BPDCN was further confirmed in a retrospective cohort of another 23 BPDCN patients. Our results show that BPDCN patients studied at diagnosis frequently display occult CNS involvement; moreover, they also indicate that treatment of occult CNS disease might lead to a dramatically improved outcome of BPDCN. PMID:26840087

Treatment for occult hepatocellular carcinoma: does it offer survival advantages over symptom-driven treatment?

PubMed

Kim, Kwang Min; Kim, Jiyu; Sinn, Dong Hyun; Kim, Hye Seung; Kim, Kyunga; Kang, Wonseok; Gwak, Geum-Youn; Paik, Yong-Han; Choi, Moon Seok; Lee, Joon Hyeok; Koh, Kwang Cheol; Paik, Seung Woon

2018-04-03

In order to claim a benefit of screen-based diagnosis for asymptomatic individuals, treatment of occult disease needs to offer survival advantages compared to the treatment of symptomatic disease, yet information on this issue is scarce with regard to hepatocellular carcinoma (HCC) screening. A total of 3353 treatment-naïve, consecutive, newly diagnosed HCC patients [age: 57.9 ± 10.3, male: 2,689 (80.2%), hepatitis B virus: 2555 (76.2%)], diagnosed between 2010 and 2013 were analyzed. Data on the mode of detection was prospectively collected at the time of HCC diagnosis and was used to group patients into occult or symptomatic cases. Overall, 643 (19.2%) patients were symptomatic cases. The proportion of patients undergoing resection, radiofrequency ablation or transplantation were lower in symptomatic cases than occult cases (20.8 vs. 56.2%, p < .001). Survival was better in occult cases than symptomatic cases (71.2 vs. 30.4% at three-years, p < .001), with a multivariable-adjusted hazard ratio of 1.40 (95% confidence interval (CI), 1.24-1.58). When stratified by tumor stage, a survival benefit was not observed for patients diagnosed at modified International Union Against Cancer (mUICC) stage I, but presenting symptoms were diverse and nonspecific. In a statistical model adjusting for potential lead-time bias, the association between overall survival and the mode of detection was markedly attenuated and was no longer significant when the treatment modality was included in the model (hazard ratio, 0.94; 95% CI, 0.82-1.07). Treatment of occult disease offered a survival benefit to patients over symptomatic cases. These data support screening practices for asymptomatic individuals to diagnose occult HCC.

Occult hemorrhage in children with severe ITP.

PubMed

Flores, Adolfo; Buchanan, George R

2016-03-01

Little is known about the frequency and significance of clinically unapparent or occult hemorrhage in ITP. Therefore, we prospectively explored the sites and frequency of occult bleeding in children with severe ITP at diagnosis or upon symptomatic relapse in a prospective, single-institution cohort study of patients ≤ 18 years of age and a platelet count ≤ 10,000/mm(3) . Data collected included bleeding severity assessment, urinalysis, fecal occult blood testing, and non-contrast brain MRI. Stool and urine samples were tested within 7 days of diagnosis or symptomatic relapse. Three months after diagnosis or relapse a noncontrast brain MRI evaluated hemosiderin deposits resulting from prior localized hemorrhage. Fifty-two ITP patients were enrolled with a mean platelet count of 4,000/mm(3) . A significant occurrence of occult hemorrhage was identified in the urine (27%) compared with clinically overt hematuria (0.91%, P < 0.0005). CNS microbleeding in the superficial cortex of the left frontal lobe was identified in one child with occult bleeding in the urinary tract. There was no relationship between occult hemorrhage and bleeding manifestations on physical examination. Occult hemorrhage was not a harbinger of subsequent bleeding. Our findings suggest that occult hemorrhage occurs with greater frequency than overt bleeding in children with severe ITP. CNS microbleeding is a potential risk in this patient population. Assessment of brain microbleeds and microscopic hematuria in this patient population require additional study. © 2015 Wiley Periodicals, Inc.

Curcumin targets fibroblast–tumor cell interactions in oral squamous cell carcinoma

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

Dudás, József, E-mail: jozsef.dudas@i-med.ac.at; Fullár, Alexandra, E-mail: fullarsz@gmail.com; 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, 1085 Budapest

Co-culture of periodontal ligament fibroblasts (PDLs) and SCC-25 oral squamous carcinoma cells (OSCC) results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs) and induces epithelial-to mesenchymal transition (EMT) of OSCC tumor cells. We hypothesized that Curcumin targets this dynamic mutual interaction between CAFs and tumor cells. Normal and 2 μM Curcumin-treated co-culture were performed for 4 days, followed by analysis of tumor cell invasivity, mRNA/protein expression of EMT-markers and mediators, activity measure of matrix metalloproteinase 9 (MMP-9), and western blot analysis of signal transduction in tumor cells and fibroblasts. In Curcumin-treated co-culture, in tumor cells, the levels of nuclear factormore » κB (NFκBα) and early response kinase (ERK)—decreased, in fibroblasts, integrin αv protein synthesis decreased compared to corresponding cells in normal co-culture. The signal modulatory changes induced by Curcumin caused decreased release of EMT-mediators in CAFs and reversal of EMT in tumor cells, which was associated with decreased invasion. These data confirm the palliative potential of Curcumin in clinical application. - Graphical abstract: Co-culture of periodontal ligament fibroblasts (PDLs) and SCC-25 oral squamous carcinoma cells (OSCC) results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs) and induces epithelial-to mesenchymal transition (EMT) of tumor cells. Curcumin targets this dynamic mutual interaction between CAFs and tumor cells by inhibiting the production of EMT mediators in CAFs and by modification of intracellular signaling in tumor cells. This causes less invasivity and reversal of EMT in tumor cells. Highlights: ► Curcumin targets tumor–fibroblast interaction in head and neck cancer. ► Curcumin suppresses mediators of epithelial–mesenchymal transition. ► Curcumin decreases the invasivity of tumor cells.« less

Association of maximum standardized uptake value with occult mediastinal lymph node metastases in cN0 non-small cell lung cancer.

PubMed

Lin, Jun-Tao; Yang, Xue-Ning; Zhong, Wen-Zhao; Liao, Ri-Qiang; Dong, Song; Nie, Qiang; Weng, Si-Xian; Fang, Xiao-Jing; Zheng, Jun-Yi; Wu, Yi-Long

2016-11-01

The management of non-small cell lung cancer (NSCLC) relies on the tumour-node-metastasis (TNM) stage, and the treatment regimen differs based on the N status. Positron emission tomography-computed tomography (PET-CT) has emerged as a powerful imaging tool for the detection of various cancers with a relatively low false-negative rate. We explored predictors to identify false-negative N2 disease in PET-CT. A total of 284 consecutive cN0 patients with peripheral NSCLC who underwent PET-CT scans followed by curative intent resections were enrolled as a training set to identify predictors of occult N2 metastases by multivariable analysis. The accuracy and cut-off values for the predictors were calculated using a receiver operating characteristic curve. Clinical and pathological data were analysed retrospectively. An additional 151 patients were collected as a test set to validate the results, including the occult N2 rate and accuracy. In total, 8.5% (24/284) PET-CT-diagnosed N0 NSCLC cases had pathologically diagnosed N2 metastases. The SUV max of the primary tumour was a unique independent risk factor for occult N2 NSCLC [P = 0.003, 95% confidence interval = 0.81-0.96, odds ratio (OR) = 0.88]. Occult N2 metastases occurred more frequently in the subcarinal (16/24) and right lower paratracheal lymph nodes (12/24). Accordingly, we divided the patients into two groups by SUV max : the occult N2 rates in the SUV max of <2.6 and SUV max of ≥2.6 groups were 1.0% (1/100) and 12.5% (23/184), respectively (P = 0.001). In the test set, the occult N2 incidence rate was 9.3% (14/151), with the highest rates occurring in the subcarinal (9/14) and right lower paratracheal lymph nodes (6/14). In the two groups defined by SUV max , the occult N2 rates were 4% (2/50) and 11.9% (12/101), respectively. The SUV max of the primary tumour was an independent risk factor for occult N2 metastases in NSCLC patients diagnosed as clinical N0 by PET-CT. SUV max of ≥2.6 of the primary tumour

Primary brain tumors, neural stem cell, and brain tumor cancer cells: where is the link?

PubMed Central

Germano, Isabelle; Swiss, Victoria; Casaccia, Patrizia

2010-01-01

The discovery of brain tumor-derived cells (BTSC) with the properties of stem cells has led to the formulation of the hypothesis that neural stem cells could be the cell of origin of primary brain tumors (PBT). In this review we present the most common molecular changes in PBT, define the criteria of identification of BTSC and discuss the similarities between the characteristics of these cells and those of the endogenous population of neural stem cells (NPCs) residing in germinal areas of the adult brain. Finally, we propose possible mechanisms of cancer initiation and progression and suggest a model of tumor initiation that includes intrinsic changes of resident NSC and potential changes in the microenvironment defining the niche where the NSC reside. PMID:20045420

Targeting Tumor Oct4 to Deplete Prostate Tumor and Metastasis Initiating Cells

DTIC Science & Technology

2016-10-01

Award Number: W81XWH-13-1-0461 TITLE: Targeting Tumor Oct4 to Deplete Prostate Tumor- and Metastasis-Initiating Cells PRINCIPAL INVESTIGATOR: Daotai...29 2016 4. TITLE AND SUBTILE Targeting Tumor Oct4 to Deplete Prostate Tumor- and Metastasis-Initiating Cells 5a. CONTRACT NUMBER 5b. GRANT NUMBER...the c-MYC oncogene. POU5F1B is a pseudogene of embryonic Oct4 (POU5F1). A recent study found that tumor Oct4 found in prostate cancer cells is due

Cell migration in microengineered tumor environments.

PubMed

Um, Eujin; Oh, Jung Min; Granick, Steve; Cho, Yoon-Kyoung

2017-12-05

Recent advances in microengineered cell migration platforms are discussed critically with a focus on how cell migration is influenced by engineered tumor microenvironments, the medical relevance being to understand how tumor microenvironments may promote or suppress the progression of cancer. We first introduce key findings in cancer cell migration under the influence of the physical environment, which is systematically controlled by microengineering technology, followed by multi-cues of physico-chemical factors, which represent the complexity of the tumor environment. Recognizing that cancer cells constantly communicate not only with each other but also with tumor-associated cells such as vascular, fibroblast, and immune cells, and also with non-cellular components, it follows that cell motility in tumor microenvironments, especially metastasis via the invasion of cancer cells into the extracellular matrix and other tissues, is closely related to the malignancy of cancer-related mortality. Medical relevance of forefront research realized in microfabricated devices, such as single cell sorting based on the analysis of cell migration behavior, may assist personalized theragnostics based on the cell migration phenotype. Furthermore, we urge development of theory and numerical understanding of single or collective cell migration in microengineered platforms to gain new insights in cancer metastasis and in therapeutic strategies.

Augmentation of immune cell activity against tumor cells by Rauwolfia radix.

PubMed

Jin, Guang-Bi; Hong, Tie; Inoue, Satoshi; Urano, Tomohiko; Cho, Shigefumi; Otsu, Koji; Kitahara, Maya; Ouchi, Yasuyoshi; Cyong, Jong-Chol

2002-08-01

In this study, we investigated the effect of Rauwolfia radix on heat shock protein (HSP) 70 expression and cytotoxicity against tumor cells in activated human T cells. When activated T cells were cultured with Rauwolfia radix for 18 h, HSP70 expression after heat shock was remarkably increased, and cytotoxicity against T98G tumor cells was augmented. Moreover, Rauwolfia radix also enhanced the cytotoxicity of heat shocked activated T cells against Molt-4 and T98G tumor cells. Secretions of interferon-gamma (IFN-gamma) and tumor necrosis alpha (TNF-alpha), due to Concanavalin A (Con A) stimulation, were increased by Rauwolfia radix in activated T cells. To investigate the antitumor effect in vivo, EL-4 tumor-bearing mice were administered with Rauwolfia radix in drinking water. The survival period of the Rauwolfia radix treatment group was significantly prolonged compared with that of the control group. Reserpine, the major active ingredient of Rauwolfia radix, also enhanced the cytotoxicity of activated T cells against Molt-4 and T98G tumor cells, and prolonged the survival period of EL-4 tumor-bearing mice. Taken together, our results suggest that Rauwolfia radix can enhance the activity of immune cells against tumor cells.

Optical performance of the New Worlds Occulter

NASA Astrophysics Data System (ADS)

Arenberg, Jonathan W.; Lo, Amy S.; Glassman, Tiffany M.; Cash, Webster

2007-04-01

The New Worlds Observer (NWO) is a multiple spacecraft mission that is capable of detecting and characterizing extra-solar planets and planetary systems. NWO consists of an external occulter and a generic space telescope, flying in tandem. The external occulter has specific requirements on its shape and size, while the telescope needs no special modification beyond that required to do high-quality astrophysical observations. The occulter is a petal-shaped, opaque screen that creates a high-suppression shadow large enough to accommodate the telescope. This article reports on the optical performance of the novel New Worlds occulter design. It also introduces two new aspects of its optical performance which enhance the detectability of extra-solar planets. We also include a brief discussion of the buildability and the tolerances of the occulter. It is also shown that an occulter design can be found for any set of science requirements. We show that NWO is a viable mission concept for the study of extra-solar planets. To cite this article: J.W. Arenberg et al., C. R. Physique 8 (2007).

Targeting tumor cell motility to prevent metastasis

PubMed Central

Palmer, Trenis D.; Ashby, William J.; Lewis, John D.; Zijlstra, Andries

2011-01-01

Mortality and morbidity in patients with solid tumors invariably results from the disruption of normal biological function caused by disseminating tumor cells. Tumor cell migration is under intense investigation as the underlying cause of cancer metastasis. The need for tumor cell motility in the progression of metastasis has been established experimentally and is supported empirically by basic and clinical research implicating a large collection of migration-related genes. However, there are few clinical interventions designed to specifically target the motility of tumor cells and adjuvant therapy to specifically prevent cancer cell dissemination is severely limited. In an attempt to define motility targets suitable for treating metastasis, we have parsed the molecular determinants of tumor cell motility into five underlying principles including cell autonomous ability, soluble communication, cell-cell adhesion, cell-matrix adhesion, and integrating these determinants of migration on molecular scaffolds. The current challenge is to implement meaningful and sustainable inhibition of metastasis by developing clinically viable disruption of molecular targets that control these fundamental capabilities. PMID:21664937

Experiment D005: Star occultation navigation

NASA Technical Reports Server (NTRS)

Silva, R. M.; Jorris, T. R.; Vallerie, E. M., III

1971-01-01

The usefulness of star occultation measurements for space navigation and the determination of a horizon density profile which could be used to update atmospheric models for horizon-based measurement systems were studied. The time of occultation of a known star by a celestial body, as seen by an orbiting observer, determines a cylinder of position, the axis of which is the line through the star and the body center, and the radius of which is equal to the occulting-body radius. The dimming percentage, with respect to the altitude of this grazing ray from the star to the observer, is a percentage altitude for occultation. That is, the star can be assumed to be occulted when it reaches a predetermined percentage of its unattenuated value. The procedure used was to measure this attenuation with respect to time to determine the usefulness of the measurements for autonomous space navigation. In this experiment, the crewmembers had to accomplish star acquisition, identification, calibration, and tracking. Instrumentation was required only for measurement of the relative intensity of the star as it set into the atmosphere.

Role of Axumin PET Scan in Germ Cell Tumor

ClinicalTrials.gov

2018-05-01

Testis Cancer; Germ Cell Tumor; Testicular Cancer; Germ Cell Tumor of Testis; Germ Cell Tumor, Testicular, Childhood; Testicular Neoplasms; Testicular Germ Cell Tumor; Testicular Yolk Sac Tumor; Testicular Choriocarcinoma; Testicular Diseases; Germ Cell Cancer Metastatic; Germ Cell Neoplasm of Retroperitoneum; Germ Cell Cancer, Nos

[Isolation of circulating tumor cells in blood by means of "Isolation by SizE of Tumor cells (ISET)"].

PubMed

Liadov, V K; Skrypnikova, M A; Popova, O P

2014-01-01

There is evidence of the importance of circulating tumor cells in bloodstream as a factor of poor prognosis of cancer. The optimum method for isolating and studying of these cells is not defined. The most common methods are either based on the isolation of tumor genetic material from blood or on immune-mediated isolation of epithelial tumor cells. The first group of methods is characterized by a lack of specificity, while the latter do not allow identifying a pool of cells undergone in bloodstream epithelial-mesenchymal transformation. There is presented an overview of results of clinical trials of a new technique of isolation of tumor cells from bloodstream based on the patients' blood filtration through a membrane with defined pore sizes (ISET-Isolation by SizE of Tumor cells).

Evaluation for Occult Fractures in Injured Children

PubMed Central

French, Benjamin; Song, Lihai; Feudtner, Chris

2015-01-01

OBJECTIVES: To examine variation across US hospitals in evaluation for occult fractures in (1) children <2 years old diagnosed with physical abuse and (2) infants <1 year old with injuries associated with a high likelihood of abuse and to identify factors associated with such variation. METHODS: We performed a retrospective study in children <2 years old with a diagnosis of physical abuse and in infants <1 year old with non-motor vehicle crash–related traumatic brain injury or femur fractures discharged from 366 hospitals in the Premier database from 2009 to 2013. We examined across-hospital variation and identified child- and hospital-level factors associated with evaluation for occult fractures. RESULTS: Evaluations for occult fractures were performed in 48% of the 2502 children with an abuse diagnosis, in 51% of the 1574 infants with traumatic brain injury, and in 53% of the 859 infants with femur fractures. Hospitals varied substantially with regard to their rates of evaluation for occult fractures in all 3 groups. Occult fracture evaluations were more likely to be performed at teaching hospitals than at nonteaching hospitals (all P < .001). The hospital-level annual volume of young, injured children was associated with the probability of occult fracture evaluation, such that hospitals treating more young, injured patients were more likely to evaluate for occult fractures (all P < .001). CONCLUSIONS: Substantial variation in evaluation for occult fractures among young children with a diagnosis of abuse or injuries associated with a high likelihood of abuse highlights opportunities for quality improvement in this vulnerable population. PMID:26169425

Evaluation for Occult Fractures in Injured Children.

PubMed

Wood, Joanne N; French, Benjamin; Song, Lihai; Feudtner, Chris

2015-08-01

To examine variation across US hospitals in evaluation for occult fractures in (1) children <2 years old diagnosed with physical abuse and (2) infants <1 year old with injuries associated with a high likelihood of abuse and to identify factors associated with such variation. We performed a retrospective study in children <2 years old with a diagnosis of physical abuse and in infants <1 year old with non-motor vehicle crash-related traumatic brain injury or femur fractures discharged from 366 hospitals in the Premier database from 2009 to 2013. We examined across-hospital variation and identified child- and hospital-level factors associated with evaluation for occult fractures. Evaluations for occult fractures were performed in 48% of the 2502 children with an abuse diagnosis, in 51% of the 1574 infants with traumatic brain injury, and in 53% of the 859 infants with femur fractures. Hospitals varied substantially with regard to their rates of evaluation for occult fractures in all 3 groups. Occult fracture evaluations were more likely to be performed at teaching hospitals than at nonteaching hospitals (all P < .001). The hospital-level annual volume of young, injured children was associated with the probability of occult fracture evaluation, such that hospitals treating more young, injured patients were more likely to evaluate for occult fractures (all P < .001). Substantial variation in evaluation for occult fractures among young children with a diagnosis of abuse or injuries associated with a high likelihood of abuse highlights opportunities for quality improvement in this vulnerable population. Copyright © 2015 by the American Academy of Pediatrics.

Two tumor models of curative adoptive chemoimmunotherapy using tumor-infiltrated spleen cells with potent antitumor cytotoxicity stimulated by antigen-sharing tumors.

PubMed

Laude, M; Russo, K L; Mokyr, M B; Dray, S

1993-07-01

Previously we have established curative protocols for adoptive chemoimmunotherapy (ACIT) of mice bearing different plasmacytomas that are known to bear cross-reacting antigens: (a) the cure of mice bearing an early-stage, nonpalpable MOPC-315 tumor by a very low dose of cyclophosphamide (10 mg/kg) and cultured MOPC-315-tumor-infiltrated (TI) spleen cells (25 x 10(6)) and (b) the cure of mice bearing a late-stage, relatively drug-resistant, highly metastatic RPC-5 tumor with cyclophosphamide (100 mg/kg) and cultured RPC-5 TI spleen cells (25 x 10(6) - 50 x 10(6)). In both models, the spleen cells were obtained from mice bearing a late-stage tumor and were cultured for 5 days in the presence of polyethyleneglycol 6000 and autochthonous tumor cells as a source of tumor antigen. Here we show that RPC-5 tumor cells could substitute for MOPC-315 tumor cells in the 5-day culture of MOPC-315 TI spleen cells so that they became curative in ACIT for mice bearing an early-stage MOPC-315 tumor. Similarly, MOPC-315 tumor cells could substitute for RPC-5 tumor cells in the 5-day culture of RPC-5 TI spleen cells so that they became curative in ACIT of mice bearing a late-stage RPC-5 tumor. In addition, RPC-5 TI spleen cells cultured with either MOPC-315 or RPC-5 tumor cells were effective in curing all mice bearing an early-stage MOPC-315 tumor by ACIT. However, MOPC-315 TI spleen cells whether cultured with MOPC-315 or RPC-5 tumor cells, were much less effective than cultured RPC-5 TI spleen cells in curing mice bearing a late-stage RPC-5 tumor by ACIT (although the survival of these mice was extended significantly). Interestingly, whereas RPC-5 TI spleen cells cultured with either MOPC-315 or RPC-5 tumor cells were as effective as MOPC-315 TI spleen cells cultured under the same conditions in lysing MOPC-315 tumor cells in vitro, MOPC-315 TI spleen cells that had been cultured with either MOPC-315 or RPC-5 tumor cells exerted a much weaker in vitro cytotoxic T lymphocyte

Management of occult adrenocorticotropin-secreting bronchial carcinoids: limits of endocrine testing and imaging techniques.

PubMed

Loli, P; Vignati, F; Grossrubatscher, E; Dalino, P; Possa, M; Zurleni, F; Lomuscio, G; Rossetti, O; Ravini, M; Vanzulli, A; Bacchetta, C; Galli, C; Valente, D

2003-03-01

The differential diagnosis and the identification of the source of ACTH in occult ectopic Cushing's syndrome due to a bronchial carcinoid still represents a challenge for the endocrinologist. We report our experience in six patients with occult bronchial carcinoid in whom extensive hormonal, imaging, and scintigraphic evaluation was performed. All patients presented with hypercortisolism associated with high plasma ACTH values. The CRH test and high dose dexamethasone suppression test suggested an ectopic source of ACTH in three of six patients. During bilateral inferior petrosal sinus sampling, none of the patients showed a central to peripheral ACTH gradient. At the time of diagnosis, none of the patients had radiological evidence of the ectopic source of ACTH, whereas pentetreotide scintigraphy identified the lesion in two of four patients. Finally, a chest computed tomography scan revealed the presence of a bronchial lesion in all patients, and pentetreotide scintigraphy identified four of six lesions. In all patients a bronchial carcinoid was found and removed. In one patient with scintigraphic evidence of residual disease after two operations, radioguided surgery, using a hand-held gamma probe after iv administration of radiolabeled pentetreotide, was performed; this allowed detection and removal of residual multiple mediastinal lymph node metastases. In conclusion, our data show that there is not a single endocrine test or imaging procedure accurate enough to diagnose and localize occult ectopic ACTH-secreting bronchial carcinoids. Radioguided surgery appears to be promising in the presence of multiple tumor foci and previous incomplete removal of the tumor.

Molecular Mechanisms Underlying Occult Hepatitis B Virus Infection

PubMed Central

Samal, Jasmine; Kandpal, Manish

2012-01-01

Summary: Chronic hepatitis B virus (HBV) infection is a complex clinical entity frequently associated with cirrhosis and hepatocellular carcinoma (HCC). The persistence of HBV genomes in the absence of detectable surface antigenemia is termed occult HBV infection. Mutations in the surface gene rendering HBsAg undetectable by commercial assays and inhibition of HBV by suppression of viral replication and viral proteins represent two fundamentally different mechanisms that lead to occult HBV infections. The molecular mechanisms underlying occult HBV infections, including recently identified mechanisms associated with the suppression of HBV replication and inhibition of HBV proteins, are reviewed in detail. The availability of highly sensitive molecular methods has led to increased detection of occult HBV infections in various clinical settings. The clinical relevance of occult HBV infection and the utility of appropriate diagnostic methods to detect occult HBV infection are discussed. The need for specific guidelines on the diagnosis and management of occult HBV infection is being increasingly recognized; the aspects of mechanistic studies that warrant further investigation are discussed in the final section. PMID:22232374

ASTEROID SIZING BY RADIOGALAXY OCCULTATION AT 5 GHZ

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

Lehtinen, K.; Muinonen, K.; Poutanen, M.

Stellar occultations by asteroids observed at visual wavelengths have been an important tool for studying the size and shape of asteroids and for revising the orbital parameters of asteroids. At radio frequencies, a shadow of an asteroid on the Earth is dominated by diffraction effects. Here, we show, for the first time, that a single observation of an occultation of a compact radio source at a frequency of 5 GHz can be used to derive the effective size of the occulting object and to derive the distance between the observer and the center of the occultation path on the Earth.more » The derived diameter of the occulting object, asteroid (115) Thyra, is 75 ± 6 km. The observed occultation profile shows features that cannot be explained by diffraction of a single asteroid.« less

A population genetics perspective on the determinants of intra-tumor heterogeneity

PubMed Central

Hu, Zheng; Sun, Ruping; Curtis, Christina

2017-01-01

Cancer results from the acquisition of somatic alterations in a microevolutionary process that typically occurs over many years, much of which is occult. Understanding the evolutionary dynamics that are operative at different stages of progression in individual tumors might inform the earlier detection, diagnosis, and treatment of cancer. Although these processes cannot be directly observed, the resultant spatiotemporal patterns of genetic variation amongst tumor cells encode their evolutionary histories. Such intra-tumor heterogeneity is pervasive not only at the genomic level, but also at the transcriptomic, phenotypic, and cellular levels. Given the implications for precision medicine, the accurate quantification of heterogeneity within and between tumors has become a major focus of current research. In this review, we provide a population genetics perspective on the determinants of intra-tumor heterogeneity and approaches to quantify genetic diversity. We summarize evidence for different modes of evolution based on recent cancer genome sequencing studies and discuss emerging evolutionary strategies to therapeutically exploit tumor heterogeneity. PMID:28274726

Image Analysis of the 2012 Pluto (Near) Occultation

DTIC Science & Technology

2013-09-01

Image Analysis of the 2012 Pluto (Near) Occultation Keith T. Knox Air Force Research Laboratory ABSTRACT Imagery was gathered at the AMOS...observatory on the 3.6-meter telescope for the expected occultation of a star by the dwarf planet, Pluto , on 29 June 2012. The imagery was taken at...5 Hz for 40 minutes before and after the expected time of occultation. The initial analysis of the photometry indicated that Pluto did not occult

Oncogenic Properties of Apoptotic Tumor Cells in Aggressive B Cell Lymphoma

PubMed Central

Ford, Catriona A.; Petrova, Sofia; Pound, John D.; Voss, Jorine J.L.P.; Melville, Lynsey; Paterson, Margaret; Farnworth, Sarah L.; Gallimore, Awen M.; Cuff, Simone; Wheadon, Helen; Dobbin, Edwina; Ogden, Carol Anne; Dumitriu, Ingrid E.; Dunbar, Donald R.; Murray, Paul G.; Ruckerl, Dominik; Allen, Judith E.; Hume, David A.; van Rooijen, Nico; Goodlad, John R.; Freeman, Tom C.; Gregory, Christopher D.

2015-01-01

Summary Background Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects. Results Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased “in situ transcriptomics” analysis—gene expression profiling of laser-captured TAMs to establish their activation signature in situ—we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma. Conclusions In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy. PMID:25702581

Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma.

PubMed

Ford, Catriona A; Petrova, Sofia; Pound, John D; Voss, Jorine J L P; Melville, Lynsey; Paterson, Margaret; Farnworth, Sarah L; Gallimore, Awen M; Cuff, Simone; Wheadon, Helen; Dobbin, Edwina; Ogden, Carol Anne; Dumitriu, Ingrid E; Dunbar, Donald R; Murray, Paul G; Ruckerl, Dominik; Allen, Judith E; Hume, David A; van Rooijen, Nico; Goodlad, John R; Freeman, Tom C; Gregory, Christopher D

2015-03-02

Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects. Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased "in situ transcriptomics" analysis-gene expression profiling of laser-captured TAMs to establish their activation signature in situ-we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma. In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Identifying Tumor Progenitor Cells | Center for Cancer Research

Cancer.gov

All cells within a tumor are not identical. In fact, only a small subset appears to be capable of actually generating the tumor. These tumor-initiating cells tend to resemble normal stem cells, which have the unique ability to give rise to differentiated cells while simultaneously producing additional undifferentiated stem cells. Most chemotherapeutics affect the bulk of a tumor but spare the stem-like cells, allowing the tumor to re-grow once chemotherapy is stopped. If, however, the cancer-initiating cells could be successfully targeted, cancer recurrence could be prevented.

Occult Primary Neuroendocrine Tumor Metastasis to the Breast Detected on Screening Mammogram.

PubMed

Policeni, Fabiana; Pakalniskis, Brittany; Yang, Limin

2016-01-01

Metastatic tumors are rare in the breast. Well-differentiated neuroendocrine tumors (WDNETs) are slow-growing neoplasms that arise from neuroendocrine cells, particularly in the gastrointestinal tract and bronchial tree. Metastatic WDNET to the breast is a rare entity. We present a case report of ileal WDNET metastatic to the breast which was initially identified as a small mass in the patient's left breast on screening mammography. Targeted ultrasound identified a suspicious mass, and ultrasound-guided percutaneous core biopsy was performed. Pathology revealed metastatic WDNET. Breast magnetic resonance imaging (MRI) was then performed and demonstrated left axillary Level 2 lymphadenopathy, and liver lesions were suspicious for metastasis. The patient underwent abdominal computed tomography (CT) to evaluate for distant metastatic disease. A spiculated mass was found near the ileocecal valve, suggestive of primary ileal WDNET. In addition, CT identified multiple liver lesions, most compatible with metastasis. Indium 111 OctreoScan confirmed radiotracer uptake in the ileum consistent with primary neuroendocrine tumor. In this report, we review the imaging characteristics of metastatic WDNET to the breast by different imaging modalities including mammogram, ultrasound, and breast MRI.

Chemotherapeutic tumor microparticles combining low-dose irradiation reprogram tumor-promoting macrophages through a tumor-repopulating cell-curtailing pathway

PubMed Central

Sun, Yanling; Zheng, Zu'an; Zhang, Huafeng; Yu, Yuandong; Ma, Jingwei; Tang, Ke; Xu, Pingwei; Ji, Tiantian; Liang, Xiaoyu; Chen, Degao; Jin, Xun; Zhang, Tianzhen; Long, Zhixiong; Liu, Yuying; Huang, Bo

2017-01-01

ABSTRACT Stem cell-like tumor-repopulating cells (TRCs) have a critical role in establishing a tumor immunosuppressive microenvironment. However, means to enhance antitumor immunity by disrupting TRCs are absent. Our previous studies have shown that tumor cell-derived microparticles (T-MPs) preferentially abrogate TRCs by delivering antitumor drugs into nuclei of TRCs. Here, we show that low dose irradiation (LDI) enhances the effect of cisplatin-packaging T-MPs (Cis-MPs) on TRCs, leading to inhibiting tumor growth in different tumor models. This antitumor effect is not due to the direct killing of tumor cells but is T cell-dependent and relies on macrophages for their efficacy. The underlying mechanism is involved in therapeutic reprograming macrophages from tumor-promotion to tumor-inhibition by disrupting TRCs and curtailing their vicious education on macrophages. These findings provide a novel strategy to reset macrophage polarization and confer their function more like M1 than M2 types with highly promising potential clinical applications. PMID:28680743

Tumor cell culture on collagen-chitosan scaffolds as three-dimensional tumor model: A suitable model for tumor studies.

PubMed

Mahmoudzadeh, Aziz; Mohammadpour, Hemn

2016-07-01

Tumor cells naturally live in three-dimensional (3D) microenvironments, while common laboratory tests and evaluations are done in two-dimensional (2D) plates. This study examined the impact of cultured 4T1 cancer cells in a 3D collagen-chitosan scaffold compared with 2D plate cultures. Collagen-chitosan scaffolds were provided and passed confirmatory tests. 4T1 tumor cells were cultured on scaffolds and then tumor cells growth rate, resistance to X-ray radiation, and cyclophosphamide as a chemotherapy drug were analyzed. Furthermore, 4T1 cells were extracted from the scaffold model and were injected into the mice. Tumor growth rate, survival rate, and systemic immune responses were evaluated. Our results showed that 4T1 cells infiltrated the scaffolds pores and constructed a 3D microenvironment. Furthermore, 3D cultured tumor cells showed a slower proliferation rate, increased levels of survival to the X-ray irradiation, and enhanced resistance to chemotherapy drugs in comparison with 2D plate cultures. Transfer of extracted cells to the mice caused enhanced tumor volume and decreased life span. This study indicated that collagen-chitosan nanoscaffolds provide a suitable model of tumor that would be appropriate for tumor studies. Copyright © 2016. Published by Elsevier B.V.

Tumor Heterogeneity, Single-Cell Sequencing, and Drug Resistance.

PubMed

Schmidt, Felix; Efferth, Thomas

2016-06-16

Tumor heterogeneity has been compared with Darwinian evolution and survival of the fittest. The evolutionary ecosystem of tumors consisting of heterogeneous tumor cell populations represents a considerable challenge to tumor therapy, since all genetically and phenotypically different subpopulations have to be efficiently killed by therapy. Otherwise, even small surviving subpopulations may cause repopulation and refractory tumors. Single-cell sequencing allows for a better understanding of the genomic principles of tumor heterogeneity and represents the basis for more successful tumor treatments. The isolation and sequencing of single tumor cells still represents a considerable technical challenge and consists of three major steps: (1) single cell isolation (e.g., by laser-capture microdissection), fluorescence-activated cell sorting, micromanipulation, whole genome amplification (e.g., with the help of Phi29 DNA polymerase), and transcriptome-wide next generation sequencing technologies (e.g., 454 pyrosequencing, Illumina sequencing, and other systems). Data demonstrating the feasibility of single-cell sequencing for monitoring the emergence of drug-resistant cell clones in patient samples are discussed herein. It is envisioned that single-cell sequencing will be a valuable asset to assist the design of regimens for personalized tumor therapies based on tumor subpopulation-specific genetic alterations in individual patients.

Occult pneumomediastinum in blunt chest trauma: clinical significance.

PubMed

Rezende-Neto, J B; Hoffmann, J; Al Mahroos, M; Tien, H; Hsee, L C; Spencer Netto, F; Speers, V; Rizoli, S B

2010-01-01

Thoracic injuries are potentially responsible for 25% of all trauma deaths. Chest X-ray is commonly used to screen patients with chest injury. However, the use of computed tomography (CT) scan for primary screening is increasing, particularly for blunt trauma. CT scans are more sensitive than chest X-ray in detecting intra-thoracic abnormalities such as pneumothoraces and pneumomediastinums. Pneumomediastinum detected by chest X-ray or "overt pneumomediastinum", raises the concern of possible aerodigestive tract injuries. In contrast, there is scarce information on the clinical significance of pneumomediastinum diagnosed by CT scan only or "occult pneumomediastinum". Therefore we investigated the clinical consequences of occult pneumomediastinum in our blunt trauma population. A 2-year retrospective chart review of all blunt chest trauma patients with initial chest CT scan admitted to a level I trauma centre. Data extracted from the medical records include; demographics, occult, overt, or no pneumomediastinum, the presence of intra-thoracic aerodigestive tract injuries (trachea, bronchus, and/or esophagus), mechanism and severity of injury, endotracheal intubation, chest thoracostomy, operations and radiological reports by an attending radiologist. All patients with intra-thoracic aerodigestive tract injuries from 1994 to 2004 were also investigated. Of 897 patients who met the inclusion criteria 839 (93.5%) had no pneumomediastinum. Five patients (0.6%) had overt pneumomediastinum and 53 patients (5.9%) had occult pneumomediastinum. Patients with occult pneumomediastinum had significantly higher ISS and AIS chest (p<0.0001) than patients with no pneumomediastinum. A chest thoracostomy tube was more common (p<0.0001) in patients with occult pneumomediastinum (47.2%) than patients with no pneumomediastinum (10.4%), as well as occult pneumothorax. None of the patients with occult pneumomediastinum had aerodigestive tract injuries (95%CI 0-0.06). Follow up CT scan of

Malignant pineal germ-cell tumors: an analysis of cases from three tumor registries.

PubMed

Villano, J Lee; Propp, Jennifer M; Porter, Kimberly R; Stewart, Andrew K; Valyi-Nagy, Tibor; Li, Xinyu; Engelhard, Herbert H; McCarthy, Bridget J

2008-04-01

The exact incidence of pineal germ-cell tumors is largely unknown. The tumors are rare, and the number of patients with these tumors, as reported in clinical series, has been limited. The goal of this study was to describe pineal germ-cell tumors in a large number of patients, using data from available brain tumor databases. Three different databases were used: Surveillance, Epidemiology, and End Results (SEER) database (1973-2001); Central Brain Tumor Registry of the United States (CBTRUS; 1997-2001); and National Cancer Data Base (NCDB; 1985-2003). Tumors were identified using the International Classification of Diseases for Oncology, third edition (ICD-O-3), site code C75.3, and categorized according to histology codes 9060-9085. Data were analyzed using SAS/STAT release 8.2, SEER*Stat version 5.2, and SPSS version 13.0 software. A total of 1,467 cases of malignant pineal germ-cell tumors were identified: 1,159 from NCDB, 196 from SEER, and 112 from CBTRUS. All three databases showed a male predominance for pineal germ-cell tumors (>90%), and >72% of patients were Caucasian. The peak number of cases occurred in the 10- to 14-year age group in the CBTRUS data and in the 15- to 19-year age group in the SEER and NCDB data, and declined significantly thereafter. The majority of tumors (73%-86%) were germinomas, and patients with germinomas had the highest survival rate (>79% at 5 years). Most patients were treated with surgical resection and radiation therapy or with radiation therapy alone. The number of patients included in this study exceeds that of any study published to date. The proportions of malignant pineal germ-cell tumors and intracranial germ-cell tumors are in range with previous studies. Survival rates for malignant pineal germ-cell tumors are lower than results from recent treatment trials for intracranial germ-cell tumors, and patients that received radiation therapy in the treatment plan either with surgery or alone survived the longest.

Heat-directed tumor cell fusion.

PubMed

Brade, Anthony M; Szmitko, Paul; Ngo, Duc; Liu, Fei-Fei; Klamut, Henry J

2003-03-20

In previous studies we demonstrated that a modified human HSP70b promoter (HSE.70b) directs high levels of gene expression to tumor cells after mild hyperthermia treatment in the range of 41.5-44 degrees C. This transcriptional targeting system exhibits low basal activity at 37 degrees C, is highly induced (950-fold) after mild heat treatment (43 degrees C/30 min), and returns to basal activity levels within 12-24 hours of activation. Here we describe heat-directed targeting of an activated form of the Gibbon ape leukemia virus env protein (GALV FMG) to tumor cells. GALV FMG mediates cell-cell fusion, and when expressed in tumor cells can produce bystander effects of up to 1:200. Transient transfection of a HSE70b.GALV FMG minigene caused extensive syncytia formation in HeLa and HT-1080 cells following mild heat treatment (44 degrees C/30 min). Stable transfection into HT-1080 cells produced a cell line (HG5) that exhibits massive syncytia formation and a 60% reduction in viability relative to a vector-only control (CI1) following heat treatment in vitro. Mild hyperthermia also resulted in syncytia formation, necrosis, and complete macroscopic regression of HG5 xenograft tumors grown in the footpads of mice with severe combined immunodeficiency disorders (SCID). Median survival increased from 12.5 (in heated CI1 controls) to 52 days after a single heat treatment. Heat-directed tumor cell fusion may prove to be a highly beneficial adjunct to existing cancer treatment strategies that take advantage of the synergistic interaction between mild hyperthermia and radiation or chemotherapeutic drugs.

Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer

PubMed Central

Gupta, Harshita B; Clark, Curtis A; Yuan, Bin; Sareddy, Gangadhara; Pandeswara, Srilakshmi; Padron, Alvaro S; Hurez, Vincent; Conejo-Garcia, José; Vadlamudi, Ratna; Li, Rong; Curiel, Tyler J

2016-01-01

As tumor PD-L1 provides signals to anti-tumor PD-1+ T cells that blunt their functions, αPD-1 and αPD-L1 antibodies have been developed as anti-cancer immunotherapies based on interrupting this signaling axis. However, tumor cell-intrinsic PD-L1 signals also regulate immune-independent tumor cell proliferation and mTOR signals, among other important effects. Tumor-initiating cells (TICs) generate carcinomas, resist treatments and promote relapse. We show here that in murine B16 melanoma and ID8agg ovarian carcinoma cells, TICs express more PD-L1 versus non-TICs. Silencing PD-L1 in B16 and ID8agg cells by shRNA (‘PD-L1lo’) reduced TIC numbers, the canonical TIC genes nanog and pou5f1 (oct4), and functions as assessed by tumorosphere development, immune-dependent and immune-independent tumorigenesis, and serial transplantability in vivo. Strikingly, tumor PD-L1 sensitized TIC to interferon-γ and rapamycin in vitro. Cell-intrinsic PD-L1 similarly drove functional TIC generation, canonical TIC gene expression and sensitivity to interferon-γ and rapamycin in human ES2 ovarian cancer cells. Thus, tumor-intrinsic PD-L1 signals promote TIC generation and virulence, possibly by promoting canonical TIC gene expression, suggesting that PD-L1 has novel signaling effects on cancer pathogenesis and treatment responses. PMID:28798885

The prevalence of occult endometrial cancer in women undergoing hysterectomy for benign indications.

PubMed

Parsons, Lavanya H Palavalli; Pedersen, Rebecca; Richardson, Debra L; Kho, Kimberly A

2018-04-01

To estimate the frequency of occult endometrial cancer in women undergoing hysterectomy for benign indications. We performed a retrospective review of all patients undergoing hysterectomies for benign indications at our institution from 2006 to 2014. A departmental database was used to identify all hysterectomies performed, and institutional tumor registry was used to identify cases of endometrial carcinoma. Occult carcinomas were defined as cases with no suspicion preoperatively and histopathologic diagnosis of endometrial cancer postoperatively. A total of 6981 hysterectomies were performed for benign indications. Among these, thirteen patients (0.19%) were found to have occult endometrial cancer, with an overall rate of 1 in 537 patients (95% confidence interval 1:314-1:1008). Twelve patients had stage IA and one had stage IB disease. Median age of women found to have endometrial cancer was 50 years (range 35-72 years). The median BMI was 29.8 kg/m 2 (range 21.3-50.4 kg/m 2 ). The most common indications for hysterectomy were abnormal bleeding (47%), postmenopausal bleeding (15%), adnexal mass (15%), prolapse (15%), and endometrial hyperplasia without atypia (8%). Of the postmenopausal women that had bleeding, all patients underwent evaluation of the endometrium, however 75% of samples did not have adequate amount of endometrium to be evaluated and 25% were found to have hyperplasia. This is one of the largest single institution cohorts to examine occult malignancy. Unexpected endometrial carcinomas were found to occur in 0.19% or 1:537 (95% confidence interval 1:314-1:1008) hysterectomies for benign indications in our population. PRéCIS: Occult endometrial carcinomas are found to occur in 1:537 (0.19%) hysterectomies for benign indications. Copyright © 2018 Elsevier B.V. All rights reserved.

Occult urolithiasis in asymptomatic primary hyperparathyroidism.

PubMed

Tay, Yu-Kwang Donovan; Liu, Minghao; Bandeira, Leonardo; Bucovsky, Mariana; Lee, James A; Silverberg, Shonni J; Walker, Marcella D

2018-05-01

Recent international guidelines suggest renal imaging to detect occult urolithiasis in all patients with asymptomatic primary hyperparathyroidism (PHPT), but data regarding their prevalence and associated risk factors are limited. We evaluated the prevalence and risk factors for occult urolithiasis. Cross-sectional analysis of 96 asymptomatic PHPT patients from a university hospital in the United States with and without occult nephrolithiasis. Occult urolithiasis was identified in 21% of patients. Stone formers had 47% higher 24-hour urinary calcium excretion (p = 0.002). Although available in only a subset of patients (n = 28), activated vitamin D [1,25(OH) 2 D] was 29% higher (p = 0.02) in stone formers. There was no difference in demographics, BMI, calcium or vitamin D intake, other biochemistries, renal function, BMD, or fractures. Receiver operating characteristic curves indicated that urinary calcium excretion and 1,25(OH) 2 D had an area under the curve of 0.724 (p = 0.003) and 0.750 (p = 0.04), respectively. A urinary calcium threshold of >211mg/day provided a sensitivity of 84.2% and a specificity of 55.3% while a 1,25(OH) 2 D threshold of >91pg/mL provided a sensitivity and specificity of 62.5% and 90.0% respectively for the presence of stones. Occult urolithiasis is present in about one-fifth of patients with asymptomatic PHPT and is associated with higher urinary calcium and 1,25(OH) 2 D. Given that most patients will not have occult urolithiasis, targeted imaging in those most likely to have occult stones rather than screening all asymptomatic PHPT patients may be useful. The higher sensitivity of urinary calcium versus 1,25(OH) 2 D suggests screening those with higher urinary calcium may be an appropriate approach.

Selfish cells in altruistic cell society - a theoretical oncology.

PubMed

Chigira, M

1993-09-01

In multicellular organisms, internal evolution of individual cells is strictly forbidden and 'evolutional' DNA replication should be performed only by the sexual reproduction system. Wholistic negative control system called 'homeostasis' serves all service to germ line cells. All somatic cells are altruistic to the germ line cells. However, in malignant tumors, it seems that individual cells replicate and behave 'selfishly' and evolve against the internal microenvironment. Tumor cells only express the occult selfishness which is programmed in normal cells a priori. This phenomenon is based on the failure of identical DNA replication, and results in 'autonomy' and 'anomie' of cellular society as shown in tumor cells. Genetic programs of normal cells connote this cellular autonomy and anomie introduced by the deletion of regulators on structure genes. It is rather paradoxical that the somatic cells get their freedom from wholistic negative regulation programmed internally. However, this is not a true paradox, since multicellular organisms have clearly been evolved from 'monads' in which cells proliferate without wholistic regulation. Somatic cells revolt against germ cell DNA, called 'selfish replicator' by Dawkins. It is an inevitable destiny that the 'selfishness' coded in genome should be revenged by itself. Selfish replicator in germ cell line should be revolted by its selfishness in the expansion of somatic cells, since they have an orthogenesis to get more selfishness in order to increase their genome. Tumor heterogeneity and progression can be fully explained by this self-contradictory process which produces heterogeneous gene copies different from the original clone in the tumor, although 'selfish' gene replication is the final target of being. Furthermore, we have to discard the concept of clonality of tumor cells since genetic instability is a fundamental feature of tumors. Finally, tumor cells and proto-oncogenes can be considered as the ultimate parasite

Progress on an external occulter testbed at flight Fresnel numbers

NASA Astrophysics Data System (ADS)

Kim, Yunjong; Sirbu, Dan; Galvin, Michael; Kasdin, N. Jeremy; Vanderbei, Robert J.

2016-01-01

An external occulter is a spacecraft flown along the line-of-sight of a space telescope to suppress starlight and enable high-contrast direct imaging of exoplanets. Laboratory verification of occulter designs is necessary to validate the optical models used to design and predict occulter performance. At Princeton, we have designed and built a testbed that allows verification of scaled occulter designs whose suppressed shadow is mathematically identical to that of space occulters. The occulter testbed uses 78 m optical propagation distance to realize the flight Fresnel numbers. We will use an etched silicon mask as the occulter. The occulter is illuminated by a diverging laser beam to reduce the aberrations from the optics before the occulter. Here, we present first light result of a sample design operating at a flight Fresnel number and the mechanical design of the testbed. We compare the experimental results with simulations that predict the ultimate contrast performance.

Earth rotation derived from occultation records

NASA Astrophysics Data System (ADS)

Sôma, Mitsuru; Tanikawa, Kiyotaka

2016-04-01

We determined the values of the Earth's rotation parameter, ΔT = T T - UT, around AD 500 after confirming that the value of the tidal acceleration, dot{n}, of the lunar motion remained unchanged during the period between ancient times and the present. For determining of ΔT, we used contemporaneous occultations of planets by the Moon. In general, occultation records are not useful. However, there are some records that give us a stringent condition for the range of ΔT. Records of the lunar occultations in AD 503 and AD 513 are such examples. In order to assure the usefulness of this occultation data, we used contemporaneous annular and total solar eclipses, which have not been used in the preceding work. This is the first work in which the lunar occultation data have been used as primary data to determine the value of ΔT together with auxiliary contemporaneous annular and total solar eclipses. Our ΔT value is less than a smoothed value (Stephenson 1997) by at least 450 s. The result is consistent with our earlier results obtained from solar eclipses.

Depletion of regulatory T cells by anti-ICOS antibody enhances anti-tumor immunity of tumor cell vaccine in prostate cancer.

PubMed

Mo, Lijun; Chen, Qianmei; Zhang, Xinji; Shi, Xiaojun; Wei, Lili; Zheng, Dianpeng; Li, Hongwei; Gao, Jimin; Li, Jinlong; Hu, Zhiming

2017-10-13

ICOS + Treg cells exert important immunosuppressive effects in tumor immunity. We adopt a combination approach of ICOS + Treg cells depletion with tumor cell vaccine to evaluate anti-tumor immunity in mouse prostate cancer model. Streptavidin (SA)-mGM-CSF surface-modified RM-1 cells were prepared as the vaccine and the mouse subcutaneous prostate tumor model was used to evaluate the immunity. Tumor growth, flow cytometry, immunohistochemistry, immunofluorescence and enzyme linked immunosorbent assay (ELISA) were performed to evaluate the therapeutic effects. Our results demonstrated that SA-mGM-CSF vaccine was prepared successfully and tumor growth was inhibited. The tumor size in the combination group was much smaller than that in the vaccine with IgG mAb group. The portions of dendritic cells, CD8 + and CD4 + T cells in the mice blood and tumor tissues were increased after treatment with vaccine. There were more immune-suppressing Tregs infiltrated into tumor after treatment with tumor cell vaccine, and ICOS blocking could deplete the infiltrated Tregs, and T lymphocytes increased more dramatically in the combination therapy group. The concentrations of interferon-γ were increased in all vaccine group, the concentrations of Interleukin-10 and Interleukin-4 were much lower in the combination group. Our study demonstrated that ICOS blocking could deplete the tumor-infiltrated ICOS + Treg cells. Combining GM-CSF surface-modified RM-1 cell vaccine with Anti-ICOS antibody could induce better antitumor immunity than a vaccine alone. Copyright © 2017 Elsevier Ltd. All rights reserved.

DNA Tumor Viruses and Cell Metabolism

PubMed Central

Mushtaq, Muhammad; Darekar, Suhas

2016-01-01

Viruses play an important role in cancerogenesis. It is estimated that approximately 20% of all cancers are linked to infectious agents. The viral genes modulate the physiological machinery of infected cells that lead to cell transformation and development of cancer. One of the important adoptive responses by the cancer cells is their metabolic change to cope up with continuous requirement of cell survival and proliferation. In this review we will focus on how DNA viruses alter the glucose metabolism of transformed cells. Tumor DNA viruses enhance “aerobic” glycolysis upon virus-induced cell transformation, supporting rapid cell proliferation and showing the Warburg effect. Moreover, viral proteins enhance glucose uptake and controls tumor microenvironment, promoting metastasizing of the tumor cells. PMID:27034740

Prediction of occult lymph node metastasis in squamous cell carcinoma of the oral cavity and the oropharynx using peritumoral Prospero homeobox protein 1 lymphatic nuclear quantification.

PubMed

Mermod, Maxime; Bongiovanni, Massimo; Petrova, Tatiana V; Dubikovskaya, Elena A; Simon, Christian; Tolstonog, Genrich; Monnier, Yan

2016-09-01

The use of lymphatic vessel density as a predictor of occult lymph node metastasis (OLNM) in head and neck squamous cell carcinoma (HNSCC) has never been reported. Staining of the specific lymphatic endothelial cells nuclear marker, PROX1, as an indicator of lymphatic vessel density was determined by counting the number of positive cells in squamous cell carcinomas (SCCs) of the oral cavity and the oropharynx with clinically negative necks. Correlation with histopathological data was established. Peritumoral PROX1 lymphatic nuclear count significantly correlated with the detection of OLNM in multivariate analysis (p < .005). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of this parameter was 60%, 95%, 85%, and 90%, respectively. Peritumoral PROX1 lymphatic nuclear count in primary SCCs of the oral cavity and the oropharynx allows accurate prediction of occult lymph node metastasis. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1407-1415, 2016. © 2016 Wiley Periodicals, Inc.

Simulating Heterogeneous Tumor Cell Populations

PubMed Central

Bar-Sagi, Dafna; Mishra, Bud

2016-01-01

Certain tumor phenomena, like metabolic heterogeneity and local stable regions of chronic hypoxia, signify a tumor’s resistance to therapy. Although recent research has shed light on the intracellular mechanisms of cancer metabolic reprogramming, little is known about how tumors become metabolically heterogeneous or chronically hypoxic, namely the initial conditions and spatiotemporal dynamics that drive these cell population conditions. To study these aspects, we developed a minimal, spatially-resolved simulation framework for modeling tissue-scale mixed populations of cells based on diffusible particles the cells consume and release, the concentrations of which determine their behavior in arbitrarily complex ways, and on stochastic reproduction. We simulate cell populations that self-sort to facilitate metabolic symbiosis, that grow according to tumor-stroma signaling patterns, and that give rise to stable local regions of chronic hypoxia near blood vessels. We raise two novel questions in the context of these results: (1) How will two metabolically symbiotic cell subpopulations self-sort in the presence of glucose, oxygen, and lactate gradients? We observe a robust pattern of alternating striations. (2) What is the proper time scale to observe stable local regions of chronic hypoxia? We observe the stability is a function of the balance of three factors related to O2—diffusion rate, local vessel release rate, and viable and hypoxic tumor cell consumption rate. We anticipate our simulation framework will help researchers design better experiments and generate novel hypotheses to better understand dynamic, emergent whole-tumor behavior. PMID:28030620

[Prevalence and clinicopathological characteristics of giant cell tumors].

PubMed

Estrada-Villaseñor, E G; Linares-González, L M; Delgado-Cedillo, E A; González-Guzmán, R; Rico-Martínez, G

2015-01-01

The frequency of giant cell tumors reported in the literature is very variable. Considering that our population has its own features, which distinguish it from the Anglo-Saxon and Asian populations, we think that both the frequency and the clinical characteristics of giant cell tumors in our population are different. The major aim of this paper was to determine the frequency and clinicopathological characteristics of giant cell tumors of the bone. A cross-sectional descriptive study was conducted of the cases diagnosed at our service as giant cell tumors of the bone from January to December 2013. The electronic clinical records, radiologic records and histologic slides from each case were reviewed. Giant cell tumors represented 17% of total bone tumors and 28% of benign tumors. Patients included 13 females and 18 males. The most frequent locations of giant cell tumors were: the proximal tibia, 9 cases (29%), and the distal femur, 6 cases (19%). Forty-five percent of giant cell tumors were associated with aneurysmal bone cyst (ABC) (14 cases) and one case (3%) was malignant. The frequency of giant cell tumors in this case series was intermediate, that is, higher than the one reported in Anglo-Saxon countries (usually low), but without reaching the frequency rates reported in Asian countries (high).

Antigen localization controls T cell-mediated tumor immunity.

PubMed

Zeelenberg, Ingrid S; van Maren, Wendy W C; Boissonnas, Alexandre; Van Hout-Kuijer, Maaike A; Den Brok, Martijn H M G M; Wagenaars, Jori A L; van der Schaaf, Alie; Jansen, Eric J R; Amigorena, Sebastian; Théry, Clotilde; Figdor, Carl G; Adema, Gosse J

2011-08-01

Effective antitumor immunotherapy requires the identification of suitable target Ags. Interestingly, many of the tumor Ags used in clinical trials are present in preparations of secreted tumor vesicles (exosomes). In this study, we compared T cell responses elicited by murine MCA101 fibrosarcoma tumors expressing a model Ag at different localizations within the tumor cell in association with secreted vesicles (exosomes), as a nonsecreted cell-associated protein, or as secreted soluble protein. Remarkably, we demonstrated that only the tumor-secreting vesicle-bound Ag elicited a strong Ag-specific CD8(+) T cell response, CD4(+) T cell help, Ag-specific Abs, and a decrease in the percentage of immunosuppressive regulatory T cells in the tumor. Moreover, in a therapeutic tumor model of cryoablation, only in tumors secreting vesicle-bound Ag could Ag-specific CD8(+) T cells still be detected up to 16 d after therapy. We concluded that the localization of an Ag within the tumor codetermines whether a robust immunostimulatory response is elicited. In vivo, vesicle-bound Ag clearly skews toward a more immunogenic phenotype, whereas soluble or cell-associated Ag expression cannot prevent or even delay outgrowth and results in tumor tolerance. This may explain why particular immunotherapies based on these vesicle-bound tumor Ags are potentially successful. Therefore, we conclude that this study may have significant implications in the discovery of new tumor Ags suitable for immunotherapy and that their location should be taken into account to ensure a strong antitumor immune response.

The immunization site of cytokine-secreting tumor cell vaccines influences the trafficking of tumor-specific T lymphocytes and antitumor efficacy against regional tumors.

PubMed

Chang, Chun-Jung; Tai, Kuo-Feng; Roffler, Steve; Hwang, Lih-Hwa

2004-11-15

Tumor cells engineered to secrete cytokines, referred to as tumor cell vaccines, can often generate systemic antitumor immunity and, in many cases, cause tumor regression. We compared the efficacy of s.c. immunization or intrahepatic immunization of GM-CSF-expressing tumor cell vaccines on the growth of s.c. or orthotopic liver tumors. A chemically transformed hepatic epithelial cell line, GP7TB, derived from Fischer 344 rats, was used to generate tumor models and tumor cell vaccines. Our results demonstrated that two s.c. injections of an irradiated tumor cell vaccine significantly controlled the growth of s.c. tumors, but was completely ineffective against orthotopic liver tumors. Effector cell infiltration in liver tumors was markedly reduced compared with s.c. tumors. Enhanced apoptosis of some effector cells was observed in the liver tumors compared with the s.c. tumors. Furthermore, the T cells induced by s.c. immunization preferentially migrated to s.c. tumor sites, as demonstrated by adoptive transfer experiments. In contrast, intrahepatic immunization, using parental tumor cells admixed with adenoviruses carrying the GM-CSF gene, yielded significantly better therapeutic effects on the liver tumors than on the s.c. tumors. Adoptive transfer experiments further confirmed that the T cells induced by liver immunization preferentially migrated to the liver tumor sites. Our results demonstrate that distinct T cell populations are induced by different immunization routes. Thus, the homing behavior of T cells depends on the route of immunization and is an important factor determining the efficacy of immunotherapy for regional tumors.

Radiation induction of drug resistance in RIF-1 tumors and tumor cells

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

Hopwood, L.E.; Moulder, J.E.

1989-11-01

The RIF-1 tumor cell line contains a small number of cells (1-20 per 10(6) cells) that are resistant to various single antineoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), and adriamycin (ADR). For 5FU the frequency of drug resistance is lower for tumor-derived cells than for cells from cell culture; for MTX the reverse is true, and for ADR there is no difference. In vitro irradiation at 5 Gy significantly increased the frequency of drug-resistant cells for 5FU, MTX, and ADR. In vivo irradiation at 3 Gy significantly increased the frequency of drug-resistant cells for 5FU and MTX, but not formore » ADR. The absolute risk for in vitro induction of MTX, 5FU, and ADR resistance, and for in vivo induction of 5FU resistance, was 1-3 per 10(6) cells per Gy; but the absolute risk for in vivo induction of MTX resistance was 54 per 10(6) cells per Gy. The frequency of drug-resistant cells among individual untreated tumors was highly variable; among individual irradiated tumors the frequency of drug-resistant cells was significantly less variable. These studies provide supporting data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be due to radiation-induced drug resistance.« less

Amplification and protein overexpression of cyclin D1: Predictor of occult nodal metastasis in early oral cancer.

PubMed

Noorlag, Rob; Boeve, Koos; Witjes, Max J H; Koole, Ronald; Peeters, Ton L M; Schuuring, Ed; Willems, Stefan M; van Es, Robert J J

2017-02-01

Accurate nodal staging is pivotal for treatment planning in early (stage I-II) oral cancer. Unfortunately, current imaging modalities lack sensitivity to detect occult nodal metastases. Chromosomal region 11q13, including genes CCND1, Fas-associated death domain (FADD), and CTTN, is often amplified in oral cancer with nodal metastases. However, evidence in predicting occult nodal metastases is limited. In 158 patients with early tongue and floor of mouth (FOM) squamous cell carcinomas, both CCND1 amplification and cyclin D1, FADD, and cortactin protein expression were correlated with occult nodal metastases. CCND1 amplification and cyclin D1 expression correlated with occult nodal metastases. Cyclin D1 expression was validated in an independent multicenter cohort, confirming the correlation with occult nodal metastases in early FOM cancers. Cyclin D1 is a predictive biomarker for occult nodal metastases in early FOM cancers. Prospective research on biopsy material should confirm these results before implementing its use in routine clinical practice. © 2016 Wiley Periodicals, Inc. Head Neck 39: 326-333, 2017. © 2016 Wiley Periodicals, Inc.

Probing Titan's atmosphere with a stellar occultation

NASA Technical Reports Server (NTRS)

Hubbard, W. B.

1991-01-01

The 3 July, 1989 occultation of 28 Sgr by Titan is discussed. The star was readily detectable throughout the occultation, reaching a minimum normalized flux of about 0.05. The occultation probed Titan's atmosphere in a region not studied by the Voyager spacecraft. The region is important for the aerobraking of Titan entry probes, and direct information about its properties is important for the Cassini mission. Occultation data (normalized stellar flux vs universal time) is shown in chart form for NASA supported stations, along with data from a collaborating group at the Wise observatory in Israel. Strong scintillation data of the star is noticeable in the data records, and provides information on waves/turbulence in Titan's high atmosphere.

Io hot spots - Infrared photometry of satellite occultations

NASA Technical Reports Server (NTRS)

Goguen, J. D.; Matson, D. L.; Sinton, W. M.; Howell, R. R.; Dyck, H. M.

1988-01-01

Io's active hot spots, which are presently mapped on the basis of IR photometry of this moon's occultation by other Gallilean satellites, are obtained with greatest spatial resolution near the sub-earth point. A model is developed for the occultation lightcurves, and its fitting to the data defines the apparent path of the occulting satellite relative to Io; the mean error in apparent relative position of occulting satellites is of the order of 178 km. A heretofore unknown, 20-km diameter hot spot is noted on Io's leading hemisphere.

Strong scintillations during atmospheric occultations Theoretical intensity spectra. [radio scattering during spacecraft occultations by planetary atmospheres

NASA Technical Reports Server (NTRS)

Hinson, D. P.

1986-01-01

Each of the two Voyager spacecraft launched in 1977 has completed a reconnaissance of the Jovian and Saturnian systems. In connection with occultation experiments, strong scintillations were observed. Further theoretical work is required before these scintillations can be interpreted. The present study is, therefore, concerned with the derivation of a theory for strong scattering during atmospheric occultation experiments, taking into account as fundamental quantity of interest the spatial spectrum (or spectral density) of intensity fluctuations. Attention is given to a theory for intensity spectra, and numerical calculations. The new formula derived for Phi-i accounts for strong scattering of electromagnetic waves during atmospheric occultations.

Promotion of Tumor-Initiating Cells in Primary and Recurrent Breast Tumors

DTIC Science & Technology

2014-10-01

confer stemness . We hypothesize that inhibition of IKK/NF-κB will reduce or eliminate breast camcer TICs, blocking tumorigenesis. Furthermore, we...Korkaya H, Liu S, Wicha MS. Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Invest. 2011 Oct;121(10):3804-9. Review...cells and sub- population of cells termed cancer stem cells or tumor-initiating cells (TICs).1 The primary characteristic of TICs is their ability to

Nanoparticle Imaging of Integrins on Tumor Cells1

PubMed Central

Montet, Xavier; Montet-Abou, Karin; Reynolds, Fred; Weissleder, Ralph; Josephson, Lee

2006-01-01

Abstract Nanoparticles 10 to 100 nm in size can deliver large payloads to molecular targets, but undergo slow diffusion and/or slow transport through delivery barriers. To examine the feasibility of nanoparticles targeting a marker expressed in tumor cells, we used the binding of cyclic arginine-glycine-aspartic acid (RGD) nanoparticle targeting integrins on BT-20 tumor as a model system. The goals of this study were: 1) to use nanoparticles to image αvβ3 integrins expressed in BT-20 tumor cells by fluorescence-based imaging and magnetic resonance imaging, and, 2) to identify factors associated with the ability of nanoparticles to target tumor cell integrins. Three factors were identified: 1) tumor cell integrin expression (the αvβ3 integrin was expressed in BT-20 cells, but not in 9L cells); 2) nanoparticle pharmacokinetics (the cyclic RGD peptide cross-linked iron oxide had a blood half-life of 180 minutes and was able to escape from the vasculature over its long circulation time); and 3) tumor vascularization (the tumor had a dense capillary bed, with distances of <100 µm between capillaries). These results suggest that nanoparticles could be targeted to the cell surface markers expressed in tumor cells, at least in the case wherein the nanoparticles and the tumor model have characteristics similar to those of the BT-20 tumor employed here. PMID:16611415

OCCULT-ORSER complete conversational user-language translator

NASA Technical Reports Server (NTRS)

Ramapriyan, H. K.; Young, K.

1981-01-01

Translator program (OCCULT) assists non-computer-oriented users in setting up and submitting jobs for complex ORSER system. ORSER is collection of image processing programs for analyzing remotely sensed data. OCCULT is designed for those who would like to use ORSER but cannot justify acquiring and maintaining necessary proficiency in Remote Job Entry Language, Job Control Language, and control-card formats. OCCULT is written in FORTRAN IV and OS Assembler for interactive execution.

NKT Cells as an Ideal Anti-Tumor Immunotherapeutic

PubMed Central

Fujii, Shin-ichiro; Shimizu, Kanako; Okamoto, Yoshitaka; Kunii, Naoki; Nakayama, Toshinori; Motohashi, Shinichiro; Taniguchi, Masaru

2013-01-01

Human natural killer T (NKT) cells are characterized by their expression of an invariant T cell antigen receptor α chain variable region encoded by a Vα24Jα18 rearrangement. These NKT cells recognize α-galactosylceramide (α-GalCer) in conjunction with the MHC class I-like CD1d molecule and bridge the innate and acquired immune systems to mediate efficient and augmented immune responses. A prime example of one such function is adjuvant activity: NKT cells augment anti-tumor responses because they can rapidly produce large amounts of IFN-γ, which acts on NK cells to eliminate MHC negative tumors and also on CD8 cytotoxic T cells to kill MHC positive tumors. Thus, upon administration of α-GalCer-pulsed DCs, both MHC negative and positive tumor cells can be effectively eliminated, resulting in complete tumor eradication without tumor recurrence. Clinical trials have been completed in a cohort of 17 patients with advanced non-small cell lung cancers and 10 cases of head and neck tumors. Sixty percent of advanced lung cancer patients with high IFN-γ production had significantly prolonged median survival times of 29.3 months with only the primary treatment. In the case of head and neck tumors, 10 patients who completed the trial all had stable disease or partial responses 5 weeks after the combination therapy of α-GalCer-DCs and activated NKT cells. We now focus on two potential powerful treatment options for the future. One is to establish artificial adjuvant vector cells containing tumor mRNA and α-GalCer/CD1d. This stimulates host NKT cells followed by DC maturation and NK cell activation but also induces tumor-specific long-term memory CD8 killer T cell responses, suppressing tumor metastasis even 1 year after the initial single injection. The other approach is to establish induced pluripotent stem (iPS) cells that can generate unlimited numbers of NKT cells with adjuvant activity. Such iPS-derived NKT cells produce IFN-γ in vitro and in vivo upon

Overt and occult vidian canal involvement in juvenile angiofibroma and its possible impact on recurrence.

PubMed

Thakar, Alok; Hota, Ashutosh; Bhalla, Ashu Seth; Gupta, Siddharth Datta; Sarkar, Chitra; Kumar, Rakesh

2016-04-01

Postexcision residual disease in the vidian canal is speculated to contribute to recurrence in juvenile angiofibroma. We composed a prospective cohort of 16 consecutive patients with juvenile angiofibroma (stages IIA-IIIB). The presurgical vidian canal assessment was done by contrast-enhanced CT (1.2 mm collimation). At surgery after complete tumor excision, the vidian canal tissue was sampled for histology. Postexcision drilling of the vidian canal was done in 8 of 15 patients to remove microscopic residual disease, with a 24 to 48 month follow-up period. Presurgical radiology indicated ipsilateral vidian canal enlargement (≥3 mm)/destruction in 13 of 16 patients. Radiologically occult involvement was documented only by histology in another 1 of 16 patients. Postexcision sampling of the vidian canal noted microscopic residual tumor in 3 of 15 patients. No recurrences were noted in 8 cases (0 of 8) with postexcision drilling of the vidian canal and 2 recurrences in 7 cases (2 of 7) with no drilling (p = .20). Vidian canal involvement in juvenile angiofibroma is almost universal (14 of 16) and may be occult to CT evaluation. The site may harbor microscopic residual tumor after seemingly complete excision. Surgical attention toward it may reduce recurrences. © 2015 Wiley Periodicals, Inc. Head Neck 38: E421-425, 2016. © 2015 Wiley Periodicals, Inc.

Sizes, Shapes, and Satellites of Asteroids from Occultations

NASA Astrophysics Data System (ADS)

Waring Dunham, David; Herald, David Russell; Preston, Steve; Timerson, Bradley; Maley, Paul; Frappa, Eric; Hayamizu, Tsutomu; Talbot, John; Poro, Atila

2015-08-01

For 40 years, the sizes and shapes of dozens of asteroids have been determined from observations of asteroidal occultations. Some of the first evidence for satellites of asteroids was obtained from the early efforts; now, the orbits and sizes of some satellites discovered by other means have been refined from occultation observations. Also, several close binary stars have been discovered, and the angular diameters of some stars have been measured from analysis of these observations. The International Occultation Timing Association (IOTA) coordinates this activity worldwide, from predicting and publicizing the events, to accurately timing the occultations from as many stations as possible, and publishing and archiving the observations.The release of the Hipparcos and Tycho catalogs in 1997, from ESA’s Hipparcos space mission, revolutionized asteroidal occultation work, increasing the routine accuracy of the predictions and the annual number of observations by an order of magnitude. IOTA developed an efficient procedure for predicting the occultations using a combination of new star catalogs, based on Hipparcos and new star catalogs, generated mainly at the U. S. Naval Observatory (USNO), and new observations of asteroids relative to the improved astrometric nets mainly from USNO’s Flagstaff Astrometric Scanning Transit Telescope and JPL’s Table Mountain Observatory. In addition, many IOTA observers now use inexpensive low-light-level video cameras and specially built GPS video time inserters to accurately time the events. This automation has also allowed some observers to deploy multiple remote video stations across occultation paths. Then, one observer can record several “chords” across the asteroid. The cameras are sensitive enough that easily-hidden telescopes, many of which can be packed in standard air travel suitcases, can be used for many of the predicted occultations. IOTA’s network of regional coordinators collect and reduce the observations

Risk Factors for Predicting Occult Lymph Node Metastasis in Patients with Clinical Stage I Non-small Cell Lung Cancer Staged by Integrated Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography.

PubMed

Kaseda, Kaoru; Asakura, Keisuke; Kazama, Akio; Ozawa, Yukihiko

2016-12-01

Lymph nodes in patients with non-small cell lung cancer (NSCLC) are often staged using integrated 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). However, this modality has limited ability to detect micrometastases. We aimed to define risk factors for occult lymph node metastasis in patients with clinical stage I NSCLC diagnosed by preoperative integrated FDG-PET/CT. We retrospectively reviewed the records of 246 patients diagnosed with clinical stage I NSCLC based on integrated FDG-PET/CT between April 2007 and May 2015. All patients were treated by complete surgical resection. The prevalence of occult lymph node metastasis in patients with clinical stage I NSCLC was analysed according to clinicopathological factors. Risk factors for occult lymph node metastasis were defined using univariate and multivariate analyses. Occult lymph node metastasis was detected in 31 patients (12.6 %). Univariate analysis revealed CEA (P = 0.04), SUV max of the primary tumour (P = 0.031), adenocarcinoma (P = 0.023), tumour size (P = 0.002) and pleural invasion (P = 0.046) as significant predictors of occult lymph node metastasis. Multivariate analysis selected SUV max of the primary tumour (P = 0.049), adenocarcinoma (P = 0.003) and tumour size (P = 0.019) as independent predictors of occult lymph node metastasis. The SUV max of the primary tumour, adenocarcinoma and tumour size were risk factors for occult lymph node metastasis in patients with NSCLC diagnosed as clinical stage I by preoperative integrated FDG-PET/CT. These findings would be helpful in selecting candidates for mediastinoscopy or endobronchial ultrasound-guided transbronchial needle aspiration.

The Role of Tumor Associated Macrophage in Recurrent Growth of Tumor Stem Cell

DTIC Science & Technology

2011-09-01

recent cancer stem cell (CSC) theory, recurrent tumor must arise from a dormant tumor stem cell whose re-growth is triggered by shifting of...microenvironment. This project aims at clarifying the roles of TAM in recurrent growth of dormant stem cell in breast cancer. We hypothesize that the balance of...dormancy and recurrence is determined by the ability of the tumor stem cells to recruit TAM which in turn promotes self-renewal of the stem cell . We

Brick by brick: metabolism and tumor cell growth

PubMed Central

DeBerardinis, Ralph J.; Sayed, Nabil; Ditsworth, Dara; Thompson, Craig B.

2008-01-01

Summary Tumor cells display increased metabolic autonomy in comparison to non-transformed cells, taking up nutrients and metabolizing them in pathways that support growth and proliferation. Classical work in tumor cell metabolism focused on bioenergetics, particularly enhanced glycolysis and suppressed oxidative phosphorylation (the ‘Warburg effect’). But the biosynthetic activities required to create daughter cells are equally important for tumor growth, and recent studies are now bringing these pathways into focus. In this review, we discuss how tumor cells achieve high rates of nucleotide and fatty acid synthesis, how oncogenes and tumor suppressors influence these activities, and how glutamine metabolism enables macromolecular synthesis in proliferating cells. PMID:18387799

Tumor-stem cells interactions by fluorescence imaging

NASA Astrophysics Data System (ADS)

Meleshina, Aleksandra V.; Cherkasova, Elena I.; Sergeeva, Ekaterina; Turchin, Ilya V.; Kiseleva, Ekaterina V.; Dashinimaev, Erdem B.; Shirmanova, Marina V.; Zagaynova, Elena V.

2013-02-01

Recently, great deal of interest is investigation the function of the stem cells (SC) in tumors. In this study, we studied «recipient-tumor- fluorescent stem cells » system using the methods of in vivo imaging and laser scanning microscopy (LSM). We used adipose-derived adult stem (ADAS) cells of human lentiviral transfected with the gene of fluorescent protein Turbo FP635. ADAS cells were administrated into nude mice with transplanted tumor HeLa Kyoto (human cervical carcinoma) at different stages of tumor growth (0-8 days) intravenously or into tumor. In vivo imaging was performed on the experimental setup for epi - luminescence bioimaging (IAP RAS, Nizhny Novgorod). The results of the imaging showed localization of fluorophore tagged stem cells in the spleen on day 5-9 after injection. The sensitivity of the technique may be improved by spectral separation autofluorescence and fluorescence of stem cells. We compared the results of in vivo imaging and confocal laser scanning microscopy (LSM 510 META, Carl Zeiss, Germany). Internal organs of the animals and tumor tissue were investigated. It was shown that with i.v. injection of ADAS, bright fluorescent structures with spectral characteristics corresponding to TurboFP635 protein are locally accumulated in the marrow, lungs and tumors of animals. These findings indicate that ADAS cells integrate in the animal body with transplanted tumor and can be identified by fluorescence bioimaging techniques in vivo and ex vivo.

Clinical impact of occult hepatitis B virus infection in immunosuppressed patients

PubMed Central

Sagnelli, Evangelista; Pisaturo, Mariantonietta; Martini, Salvatore; Filippini, Pietro; Sagnelli, Caterina; Coppola, Nicola

2014-01-01

Occult hepatitis B infection (OBI), is characterized by low level hepatitis B virus (HBV) DNA in circulating blood and/or liver tissue. In clinical practice the presence of antibody to hepatitis B core antigen in hepatitis B surface antigen (HBsAg)-/anti-HBs-negative subjects is considered indicative of OBI. OBI is mostly observed in the window period of acute HBV infection in blood donors and in recipients of blood and blood products, in hepatitis C virus chronic carriers, in patients under pharmacological immunosuppression, and in those with immunodepression due to HIV infection or cancer. Reactivation of OBI mostly occurs in anti-HIV-positive subjects, in patients treated with immunosuppressive therapy in onco-hematological settings, in patients who undergo hematopoietic stem cell transplantation, in those treated with anti-CD20 or anti-CD52 monoclonal antibody, or anti-tumor necrosis factors antibody for rheumatological diseases, or chemotherapy for solid tumors. Under these conditions the mortality rate for hepatic failure or progression of the underlying disease due to discontinuation of specific treatment can reach 20%. For patients with OBI, prophylaxis with nucleot(s)ide analogues should be based on the HBV serological markers, the underlying diseases and the type of immunosuppressive treatment. Lamivudine prophylaxis is indicated in hemopoietic stem cell transplantation and in onco-hematological diseases when high dose corticosteroids and rituximab are used; monitoring may be indicated when rituximab-sparing schedules are used, but early treatment should be applied as soon as HBsAg becomes detectable. This review article presents an up-to-date evaluation of the current knowledge on OBI. PMID:25018849

Role of stem cell derived exosomes in tumor biology.

PubMed

Sharma, Aman

2018-03-15

Exosomes are nano-scale messengers loaded with bio-molecular cargo of RNA, DNA, and Proteins. As a master regulator of cellular signaling, stem cell (both normal, and cancer stem cells) secreted exosome orchestrate various autocrine and paracrine functions which alter tumor micro-environment, growth and progression. Exosomes secreted by one of the two important stem cell phenotypes in cancers a) Mesenchymal stem cells, and b) Cancer stem cells not only promote cancerous growth but also impart therapy resistance in cancer cells. In tumors, normal or mesenchymal stem cell (MSCs) derived exosomes (MSC-exo) modulate tumor hallmarks by delivering unique miRNA species to neighboring cells and help in tumor progression. Apart from regulating tumor cell fate, MSC-exo are also capable of inducing physiological processes, for example, angiogenesis, metastasis and so forth. Similarly, cancer stem cells (CSCs) derived exosomes (CSC-exo) contain stemness-specific proteins, self-renewal promoting regulatory miRNAs, and survival factors. CSC-exo specific cargo maintains tumor heterogeneity and alters tumor progression. In this review we critically discuss the importance of stem cell specific exosomes in tumor cell signaling pathways with their role in tumor biology. © 2017 UICC.

Identification of tumor-initiating cells derived from two canine rhabdomyosarcoma cell lines.

PubMed

Kishimoto, Takuya Evan; Yashima, Shoko; Nakahira, Rei; Onozawa, Eri; Azakami, Daigo; Ujike, Makoto; Ochiai, Kazuhiko; Ishiwata, Toshiyuki; Takahashi, Kimimasa; Michishita, Masaki

2017-07-07

Cancer stem cells or tumor-initiating cells (TICs) are a small subpopulation of cells that have the capacity to self-renew, differentiate and initiate tumors. These cells may function in tumor initiation, aggression and recurrence. Whether spheres derived from canine rhabdomyosarcoma cells have stem cell-like properties is unclear. We induced sphere formation in the canine rhabdomyosarcoma cell lines, CMS-C and CMS-J, and characterized the spheres in vitro and in vivo. Sphere-forming cells were more resistant to vincristine, mitoxantrone and doxorubicin than adherent cells. Xenograft transplantation demonstrated that 1 × 10 3 sphere-forming cells derived from CMS-C were sufficient for tumor formation. The sphere assay showed that the sphere-forming cells were present in these tumors. These results suggest that the spheres derived from canine rhabdomyosarcoma cells may possess characteristics of TICs. This study provides the foundation for elucidating the contribution of TICs to rhabdomyosarcoma tumorigenesis.

Peptide vaccines prevent tumor growth by activating T cells that respond to native tumor antigens.

PubMed

Jordan, Kimberly R; McMahan, Rachel H; Kemmler, Charles B; Kappler, John W; Slansky, Jill E

2010-03-09

Peptide vaccines enhance the response of T cells toward tumor antigens and represent a strategy to augment antigen-independent immunotherapies of cancer. However, peptide vaccines that include native tumor antigens rarely prevent tumor growth. We have assembled a set of peptide variants for a mouse-colon tumor model to determine how to improve T-cell responses. These peptides have similar affinity for MHC molecules, but differ in the affinity of the peptide-MHC/T-cell receptor interaction with a tumor-specific T-cell clone. We systematically demonstrated that effective antitumor responses are generated after vaccination with variant peptides that stimulate the largest proportion of endogenous T cells specific for the native tumor antigen. Importantly, we found some variant peptides that strongly stimulated a specific T-cell clone in vitro, but elicited fewer tumor-specific T cells in vivo, and were not protective. The T cells expanded by the effective vaccines responded to the wild-type antigen by making cytokines and killing target cells, whereas most of the T cells expanded by the ineffective vaccines only responded to the peptide variants. We conclude that peptide-variant vaccines are most effective when the peptides react with a large responsive part of the tumor-specific T-cell repertoire.

Precision cancer immunotherapy: optimizing dendritic cell-based strategies to induce tumor antigen-specific T-cell responses against individual patient tumors.

PubMed

Osada, Takuya; Nagaoka, Koji; Takahara, Masashi; Yang, Xiao Yi; Liu, Cong-Xiao; Guo, Hongtao; Roy Choudhury, Kingshuk; Hobeika, Amy; Hartman, Zachary; Morse, Michael A; Lyerly, H Kim

2015-05-01

Most dendritic cell (DC)-based vaccines have loaded the DC with defined antigens, but loading with autologos tumor-derived antigens would generate DCs that activate personalized tumor-specific T-cell responses. We hypothesized that DC matured with an optimized combination of reagents and loaded with tumor-derived antigens using a clinically feasible electroporation strategy would induce potent antitumor immunity. We first studied the effects on DC maturation and antigen presentation of the addition of picibanil (OK432) to a combination of zoledronic acid, tumor necrosis factor-α, and prostaglandin E2. Using DC matured with the optimized combination, we tested 2 clinically feasible sources of autologous antigen for electroloading, total tumor mRNA or total tumor lysate, to determine which stimulated more potent antigen-specific T cells in vitro and activated more potent antitumor immunity in vivo. The combination of tumor necrosis factor-α/prostaglandin E2/zoledronic acid/OK432 generated DC with high expression of maturation markers and antigen-specific T-cell stimulatory function in vitro. Mature DC electroloaded with tumor-derived mRNA [mRNA electroporated dendritic cell (EPDC)] induced greater expansion of antigen-specific T cells in vitro than DC electroloaded with tumor lysate (lysate EPDC). In a therapeutic model of MC38-carcinoembryonic antigen colon cancer-bearing mice, vaccination with mRNA EPDC induced the most efficient anti-carcinoembryonic antigen cellular immune response, which significantly suppressed tumor growth. In conclusion, mature DC electroloaded with tumor-derived mRNA are a potent cancer vaccine, especially useful when specific tumor antigens for vaccination have not been identified, allowing autologous tumor, and if unavailable, allogeneic cell lines to be used as an unbiased source of antigen. Our data support clinical testing of this strategy.

Comparison of cytotoxic T lymphocyte responses against pancreatic cancer induced by dendritic cells transfected with total tumor RNA and fusion hybrided with tumor cell

PubMed Central

Chen, Jiang; Li, Hong-Yu; Wang, Di; Shao, Xiao-Dong

2015-01-01

Pancreatic cancer (PC) is a deadly human malignancy. Dendritic cell (DC)-based immunotherapy with whole tumor antigens demonstrates potential efficiency in cancer treatment. Tumor RNA and tumor fusion hybrid cells are sources of whole tumor antigens for preparing DC tumor vaccines. However, the efficacy of these sources in eliciting immune responses against PC has not yet to be directly compared. In the present study, patient-derived PC cells and DCs were fused (DC–tumor hybrids) and primary cultured PC cell-derived total RNA was electroporated into autologous DCs (DC–tumor RNA). The antitumor immune responses induced by DC–tumor hybrids and DC–tumor RNA were compared directly. The results showed that both RNA and hybrid methodologies could induce tumor-specific cytotoxic T lymphocyte (CTL) responses, but pulsing DCs with total tumor RNA could induce a higher frequency of activated CTLs and T-helper cells than fusing DCs with autologous tumor cells. In addition, DC–tumor RNA triggered stronger autologous tumor cell lysis than DC–tumor hybrids. It could be concluded that DCs pulsed with whole tumor RNA are superior to those fused with tumor cells in priming anti-PC CTL responses. Electroporation with total tumor RNA may be more suitable for DC-based PC vaccination. PMID:25736302

The occult submucous cleft palate.

PubMed

Kaplan, E N

1975-10-01

We have studied 41 patients with classic submucous cleft and 32 cases with occult submucous cleft. Both groups have the same anatomic abnormality that leads to velar dysfunction-the insertion of the palate muscles onto the hard palate rather than onto the midline soft palate raphe. However, the occult submucous cleft palate does not have the classic triad of bifid uvula, hard palate bony notch, and furrow in the midline of the soft palate. Characteristic facial features, cephalmetric x-rays, and cine voice studies can help make a presumptive diagnosis of occult submucous cleft palate. Surgical management includes a diagnostic palate exploration to identify muscle configuration followed by levator muscle sling reconstruction, palate pushback, and pharyngeal flap. Excellent speech results are obtained except with patients having palate paresis.

Defining a New Prognostic index for Stage I Non-seminomatous Germ Cell Tumors using CXCL12 Expression and Proportion of Embryonal Carcinoma

PubMed Central

Gilbert, Duncan C; Al-Saadi, Reem; Thway, Khin; Chandler, Ian; Berney, Daniel; Gabe, Rhian; Stenning, Sally P; Sweet, Joan; Huddart, Robert; Shipley, Janet M

2015-01-01

Purpose Up to 50% of patients diagnosed with stage I non-seminomatous germ cell tumors (NSGCT) harbor occult metastases. Patients are managed by surveillance with chemotherapy at relapse or adjuvant treatment up-front. Late toxicities from chemotherapy are increasingly recognised. Based on a potential biological role in germ cells/tumors and pilot data, our aim was to evaluate tumor expression of the chemokine CXCL12 alongside previously proposed markers as clinically useful biomarkers of relapse. Experimental design Immunohistochemistry for tumor expression of CXCL12 was assessed as a biomarker of relapse alongside vascular invasion, histology (percentage embryonal carcinoma) and MIB1 staining for proliferationin formalin fixed paraffin-embedded orchidectomy samples from patients enrolled in the Medical Research Council’s TE08/22 prospective trials of surveillance in stage I NSGCT. Results TE08/TE22 trial patients had a 76.4% 2-year relapse free rate (RFR) and both CXCL12 expression and percentage embryonal carcinoma provided prognostic value independently of vascular invasion (stratified log rank test p=0.006 for both). There was no additional prognostic value for MIB1 staining. A model using CXCL12, percentage embryonal carcinoma and VI defines 3 prognostic groups that were independantly validated. Conclusions CXCL12 and percentage embryonal carcinoma both stratify patients’ relapse risk over and above vascular invasion alone. This is anticipated to improve the stratification of patients and identify high-risk cases to be considered for adjuvant therapy. PMID:26453693

Quantitative imaging of magnesium distribution at single-cell resolution in brain tumors and infiltrating tumor cells with secondary ion mass spectrometry (SIMS)

PubMed Central

Chandra, Subhash; Parker, Dylan J.; Barth, Rolf F.; Pannullo, Susan C.

2016-01-01

Glioblastoma multiforme (GBM) is one of the deadliest forms of human brain tumors. The infiltrative pattern of growth of these tumors includes the spread of individual and/or clusters of tumor cells at some distance from the main tumor mass in parts of the brain protected by an intact blood-brain-barrier. Pathophysiological studies of GBM could be greatly enhanced by analytical techniques capable of in situ single-cell resolution measurements of infiltrating tumor cells. Magnesium homeostasis is an area of active investigation in high grade gliomas. In the present study, we have used the F98 rat glioma as a model of human GBM and an elemental/isotopic imaging technique of secondary ion mass spectrometry (SIMS), a CAMECA IMS-3f ion microscope, for studying Mg distributions with single-cell resolution in freeze-dried brain tissue cryosections. Quantitative observations were made on tumor cells in the main tumor mass, contiguous brain tissue, and infiltrating tumor cells in adjacent normal brain. The brain tissue contained a significantly lower total Mg concentration of 4.70 ± 0.93 mmol/Kg wet weight (mean ± SD) in comparison to 11.64 ± 1.96 mmol/Kg wet weight in tumor cells of the main tumor mass and 10.72 ± 1.76 mmol/Kg wet weight in infiltrating tumor cells (p<0.05). The nucleus of individual tumor cells contained elevated levels of bound Mg. These observations demonstrate enhanced Mg-influx and increased binding of Mg in tumor cells and provide strong support for further investigation of GBMs for altered Mg homeostasis and activation of Mg-transporting channels as possible therapeutic targets. PMID:26703785

Axillary metastasis as first symptom of occult breast cancer: a case report.

PubMed

Frattaroli, Fabrizio Maria; Carrara, Alessandro; Conte, Anna Maria; Pappalardo, Giuseppe

2002-01-01

Axillary lymph node metastasis from an occult breast carcinoma is a rare occurrence. We report this condition in a 59-year-old woman who presented with a swelling in the right axilla. No breast mass was clinically evident. Mammography, ultrasonography and multiple random fine-needle breast biopsies yielded no pathological findings. No extramammary primary lesions were present. Axillary sampling was performed and histological examination revealed the presence of metastatic adenocarcinoma in three of the 12 dissected lymph nodes. Estrogen receptors were positive and immunohistochemistry pointed to a breast origin. All these data were suggestive of occult breast cancer. The patient refused any further treatment but accepted clinical and radiological follow-up. Eight years later mammography revealed in the same breast a 10-mm nodule containing microcalcifications, which was not evident at physical examination. The patient underwent a lumpectomy. Intraoperative histology was positive for breast carcinoma and complete axillary clearance was performed. Histological examination revealed a lobular invasive breast carcinoma and the presence of micrometastasis in one of the 23 removed lymph nodes. The patient was given radiotherapy to the breast and axilla and tamoxifen. At present, one year after the appearance of the primary tumor, she is free of disease. Based on this case report we suggest an eclectic approach in the management of patients with axillary metastasis from occult breast cancer, depending on the clinical, pathological and biological findings.

Adoptive transfer of natural killer cells promotes the anti-tumor efficacy of T cells.

PubMed

Goding, Stephen R; Yu, Shaohong; Bailey, Lisa M; Lotze, Michael T; Basse, Per H

2017-04-01

The density of NK cells in tumors correlates positively with prognosis in many types of cancers. The average number of infiltrating NK cells is, however, quite modest (approximately 30 NK cells/sq.mm), even in tumors deemed to have a "high" density of infiltrating NK cells. It is unclear how such low numbers of tumor-infiltrating NK cells can influence outcome. Here, we used ovalbumin-expressing tumor cell lines and TCR transgenic, OVA-specific cytotoxic T lymphocytes (OT-I-CTLs) to determine whether the simultaneous attack by anti-tumor CTLs and IL-2-activated NK (A-NK) cells synergistically increases the overall tumor cell kill and whether upregulation of tumor MHC class-I by NK cell-derived interferon-gamma (IFNγ) improves tumor-recognition and kill by anti-tumor CTLs. At equal E:T ratios, A-NK cells killed OVA-expressing tumor cells better than OT-I-CTLs. The cytotoxicity against OVA-expressing tumor cells increased by combining OT-I-CTLs and A-NK cells, but the increase was additive rather than synergistic. A-NK cells adenovirally-transduced to produce IL-12 (A-NK IL-12 ) produced high amounts of IFNγ. The addition of a low number of A-NK IL-12 cells to OT-I-CTLs resulted in a synergistic, albeit modest, increase in overall cytotoxicity. Pre-treatment of tumor cells with NK cell-conditioned medium increased tumor MHC expression and sensitivity to CTL-mediated killing. Pre-treatment of CTLs with NK cell-conditioned medium had no effect on CTL cytotoxicity. In vivo, MHC class-I expression by OVA-expressing B16 melanoma lung metastases increased significantly within 24-48h after adoptive transfer of A-NK IL-12 cells. OT-I-CTLs and A-NK IL-12 cells localized selectively and equally well into OVA-expressing B16 lung metastases and treatment of mice bearing 7-days-old OVA-B16 lung metastases with both A-NK IL-12 cells and OT-I-CTLs lead to a significant prolongation of survival. Thus, an important function of tumor-infiltrating NK cells may be to increase tumor

Identifying Tumor Progenitor Cells | Center for Cancer Research

Cancer.gov

All cells within a tumor are not identical. In fact, only a small subset appears to be capable of actually generating the tumor. These tumor-initiating cells tend to resemble normal stem cells, which have the unique ability to give rise to differentiated cells while simultaneously producing additional undifferentiated stem cells. Most chemotherapeutics affect the bulk of a

Prevalence of occult hepatitis C infection in chronic hemodialysis and kidney transplant patients.

PubMed

Baid-Agrawal, Seema; Schindler, Ralf; Reinke, Petra; Staedtler, Adrienne; Rimpler, Sunda; Malik, Barbara; Frei, Ulrich; Berg, Thomas

2014-05-01

Detection of hepatitis C virus (HCV) RNA in peripheral blood mononuclear cells (PBMC) and/or hepatocytes in absence of HCV RNA in serum, designated as 'occult HCV infection', has been a matter of controversy in recent years. We investigated for the first time the prevalence of occult HCV infection in large cohorts of chronic hemodialysis (CHD) and kidney transplant (KTx) patients. We enrolled 417 CHD patients, 417 KTx recipients and 2 control groups - 25 anti-HCV (antibody against HCV)-positive and HCV RNA-positive patients with chronic hepatitis C, and 40 anti-HCV-, HCV RNA-, and HBsAg-negative healthy subjects. HCV RNA was tested in serum and PBMC using a sensitive commercial assay. In CHD patients, the prevalence of anti-HCV was 3.6% (15/417) and of positive serum HCV RNA 2.4% (10/417). HCV RNA was detected in PBMC in 1/407 (0.25%) HCV serum RNA-negative patients ("occult HCV infection"). In KTx recipients, prevalence of anti-HCV was 4.8% (20/417) and of positive serum HCV RNA 4.6% (19/417). Occult HCV infection was found in 2/398 (0.5%) serum HCV RNA-negative patients. On a mean longitudinal follow-up of 30months of the 3 patients with occult HCV infection, there was no clinical or virological evidence of HCV infection. The prevalence of occult HCV infection was very low in our CHD and KTx patients, and it did not appear to be clinically relevant. Further studies in geographic populations with high HCV endemicity are required to clarify the significance of occult HCV infection in these patient groups. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Patient-Derived Antibody Targets Tumor Cells

Cancer.gov

An NCI Cancer Currents blog on an antibody derived from patients that killed tumor cells in cell lines of several cancer types and slowed tumor growth in mouse models of brain and lung cancer without evidence of side effects.

Identification of tumor-initiating cells derived from two canine rhabdomyosarcoma cell lines

PubMed Central

KISHIMOTO, Takuya Evan; YASHIMA, Shoko; NAKAHIRA, Rei; ONOZAWA, Eri; AZAKAMI, Daigo; UJIKE, Makoto; OCHIAI, Kazuhiko; ISHIWATA, Toshiyuki; TAKAHASHI, Kimimasa; MICHISHITA, Masaki

2017-01-01

Cancer stem cells or tumor-initiating cells (TICs) are a small subpopulation of cells that have the capacity to self-renew, differentiate and initiate tumors. These cells may function in tumor initiation, aggression and recurrence. Whether spheres derived from canine rhabdomyosarcoma cells have stem cell-like properties is unclear. We induced sphere formation in the canine rhabdomyosarcoma cell lines, CMS-C and CMS-J, and characterized the spheres in vitro and in vivo. Sphere-forming cells were more resistant to vincristine, mitoxantrone and doxorubicin than adherent cells. Xenograft transplantation demonstrated that 1 × 103 sphere-forming cells derived from CMS-C were sufficient for tumor formation. The sphere assay showed that the sphere-forming cells were present in these tumors. These results suggest that the spheres derived from canine rhabdomyosarcoma cells may possess characteristics of TICs. This study provides the foundation for elucidating the contribution of TICs to rhabdomyosarcoma tumorigenesis. PMID:28529244

Occult infection related hepatitis B surface antigen variants showing lowered secretion capacity

PubMed Central

Kim, Hong; Lee, Seoung-Ae; Won, You-Sub; Lee, HyunJoo; Kim, Bum-Joon

2015-01-01

AIM: To elucidate the molecular mechanisms underlying hepatitis B virus (HBV) occult infection of genotype C. METHODS: A total of 10 types of hepatitis B surface antigen (HBsAg) variants from a Korean occult cohort were used. After a complete HBV genome plasmid mutated such that it does not express HBsAg and plasmid encoding, each HBsAg variant was transiently co-transfected into HuH-7 cells. The secretion capacity and intracellular expression of the HBV virions and HBsAgs in their respective variants were analyzed using real-time quantitative polymerase chain reaction assays and commercial HBsAg enzyme-linked immunosorbent assays, respectively. RESULTS: All variants exhibited lower levels of HBsAg secretion into the medium compared with the wild type. In particular, in eight of the ten variants, very low levels of HBsAg secretion that were similar to the negative control were detected. In contrast, most variants (9/10) exhibited normal virion secretion capacities comparable with, or even higher than, the wild type. This provided new insight into the intrinsic nature of occult HBV infection, which leads to HBsAg sero-negativeness but has horizontal infectivity. Furthermore, most variants generated higher reactive oxidative species production than the wild type. This finding provides potential links between occult HBV infection and liver disease progression. CONCLUSION: The presently obtained data indicate that deficiency in the secretion capacity of HBsAg variants may have a pivotal function in the occult infections of HBV genotype C. PMID:25684944

Tumor exosomes block dendritic cells maturation to decrease the T cell immune response.

PubMed

Ning, Yongling; Shen, Kai; Wu, Qiyong; Sun, Xiao; Bai, Yu; Xie, Yewen; Pan, Jie; Qi, Chunjian

2018-07-01

Tumors can induce the generation and accumulation of immunosuppression in a tumor microenvironment, contributing to the tumor's escape from immunological surveillance. Although tumor antigen-pulsed dendritic cell can improve anti-tumor immune responses, tumor associated regulatory dendritic cells are involved in the induction of immune tolerance. The current study sought to investigate whether exosomes produced by tumor cells had any effect on DCs in immune suppression. In this study, we examined the effect of tumor exosomes on DCs and found that exosomes from LLC Lewis lung carcinoma or 4T1 breast cancer cell blocked the differentiation of myeloid precursor cells into CD11c + DCs and induced cell apoptosis. Tumor exosome treatment inhibited the maturation and migration of DCs and promoted the immune suppression of DCs. The treatment of tumor exosomes drastically decreased CD4 + IFN-γ + Th1 differentiation but increased the rates of regulatory T (Treg) cells. The immunosuppressive ability of tumor exosome-treated DCs were partially restored with PD-L1 blockage. These data suggested that PD-L1 played a role in tumor exosome-induced DC-associated immune suppression. Copyright © 2018 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Tissue Regeneration in the Chronically Inflamed Tumor Environment: Implications for Cell Fusion Driven Tumor Progression and Therapy Resistant Tumor Hybrid Cells.

PubMed

Dittmar, Thomas; Zänker, Kurt S

2015-12-19

The biological phenomenon of cell fusion in a cancer context is still a matter of controversial debates. Even though a plethora of in vitro and in vivo data have been published in the past decades the ultimate proof that tumor hybrid cells could originate in (human) cancers and could contribute to the progression of the disease is still missing, suggesting that the cell fusion hypothesis is rather fiction than fact. However, is the lack of this ultimate proof a valid argument against this hypothesis, particularly if one has to consider that appropriate markers do not (yet) exist, thus making it virtually impossible to identify a human tumor cell clearly as a tumor hybrid cell. In the present review, we will summarize the evidence supporting the cell fusion in cancer concept. Moreover, we will refine the cell fusion hypothesis by providing evidence that cell fusion is a potent inducer of aneuploidy, genomic instability and, most likely, even chromothripsis, suggesting that cell fusion, like mutations and aneuploidy, might be an inducer of a mutator phenotype. Finally, we will show that "accidental" tissue repair processes during cancer therapy could lead to the origin of therapy resistant cancer hybrid stem cells.

Study of the technique of stellar occultation

NASA Technical Reports Server (NTRS)

Hays, P. B.; Graves, M. E.; Roble, R. G.; Shah, A. N.

1973-01-01

The results are reported of a study of the stellar occultation technique for measuring the composition of the atmosphere. The intensity of starlight was monitored during the occultation using the Wisconsin stellar ultraviolet photometers aboard the Orbiting Astronomical Observatory (OAO-A2). A schematic diagram of an occultation is shown where the change in intensity at a given wavelength is illustrated. The vertical projection of the attenuation region is typically 60 km deep for molecular oxygen and 30 km deep for ozone. Intensity profiles obtained during various occultations were analyzed by first determining the tangential columm density of the absorbing gases, and then Abel inverting the column densities to obtain the number density profile. Errors are associated with each step in the inversion scheme and have been considered as an integral part of this study.

The role of tumor cell-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth.

PubMed

Bennewith, Kevin L; Huang, Xin; Ham, Christine M; Graves, Edward E; Erler, Janine T; Kambham, Neeraja; Feazell, Jonathan; Yang, George P; Koong, Albert; Giaccia, Amato J

2009-02-01

Pancreatic cancer is highly aggressive and refractory to existing therapies. Connective tissue growth factor (CTGF/CCN2) is a fibrosis-related gene that is thought to play a role in pancreatic tumor progression. However, CCN2 can be expressed in a variety of cell types, and the contribution of CCN2 derived from either tumor cells or stromal cells as it affects the growth of pancreatic tumors is unknown. Using genetic inhibition of CCN2, we have discovered that CCN2 derived from tumor cells is a critical regulator of pancreatic tumor growth. Pancreatic tumor cells derived from CCN2 shRNA-expressing clones showed dramatically reduced growth in soft agar and when implanted s.c. We also observed a role for CCN2 in the growth of pancreatic tumors implanted orthotopically, with tumor volume measurements obtained by positron emission tomography imaging. Mechanistically, CCN2 protects cells from hypoxia-mediated apoptosis, providing an in vivo selection for tumor cells that express high levels of CCN2. We found that CCN2 expression and secretion was increased in hypoxic pancreatic tumor cells in vitro, and we observed colocalization of CCN2 and hypoxia in pancreatic tumor xenografts and clinical pancreatic adenocarcinomas. Furthermore, we found increased CCN2 staining in clinical pancreatic tumor tissue relative to stromal cells surrounding the tumor, supporting our assertion that tumor cell-derived CCN2 is important for pancreatic tumor growth. Taken together, these data improve our understanding of the mechanisms responsible for pancreatic tumor growth and progression, and also indicate that CCN2 produced by tumor cells represents a viable therapeutic target for the treatment of pancreatic cancer.

Anti-tumor therapy with macroencapsulated endostatin producer cells

PubMed Central

2010-01-01

Background Theracyte is a polytetrafluoroethylene membrane macroencapsulation system designed to induce neovascularization at the tissue interface, protecting the cells from host's immune rejection, thereby circumventing the problem of limited half-life and variation in circulating levels. Endostatin is a potent inhibitor of angiogenesis and tumor growth. Continuous delivery of endostatin improves the efficacy and potency of the antitumoral therapy. The purpose of this study was to determine whether recombinant fibroblasts expressing endostatin encapsulated in Theracyte immunoisolation devices can be used for delivery of this therapeutic protein for treatment of mice bearing B16F10 melanoma and Ehrlich tumors. Results Mice were inoculated subcutaneously with melanoma (B16F10 cells) or Ehrlich tumor cells at the foot pads. Treatment began when tumor thickness had reached 0.5 mm, by subcutaneous implantation of 107 recombinant encapsulated or non-encapsulated endostatin producer cells. Similar melanoma growth inhibition was obtained for mice treated with encapsulated or non-encapsulated endostatin-expressing cells. The treatment of mice bearing melanoma tumor with encapsulated endostatin-expressing cells was decreased by 50.0%, whereas a decrease of 56.7% in tumor thickness was obtained for mice treated with non-encapsulated cells. Treatment of Ehrlich tumor-bearing mice with non-encapsulated endostatin-expressing cells reduced tumor thickness by 52.4%, whereas lower tumor growth inhibition was obtained for mice treated with encapsulated endostatin-expressing cells: 24.2%. Encapsulated endostatin-secreting fibroblasts failed to survive until the end of the treatment. However, endostatin release from the devices to the surrounding tissues was confirmed by immunostaining. Decrease in vascular structures, functional vessels and extension of the vascular area were observed in melanoma microenvironments. Conclusions This study indicates that immunoisolation devices

Anti-tumor therapy with macroencapsulated endostatin producer cells.

PubMed

Rodrigues, Danielle B; Chammas, Roger; Malavasi, Natália V; da Costa, Patrícia L N; Chura-Chambi, Rosa M; Balduino, Keli N; Morganti, Ligia

2010-03-02

Theracyte is a polytetrafluoroethylene membrane macroencapsulation system designed to induce neovascularization at the tissue interface, protecting the cells from host's immune rejection, thereby circumventing the problem of limited half-life and variation in circulating levels. Endostatin is a potent inhibitor of angiogenesis and tumor growth. Continuous delivery of endostatin improves the efficacy and potency of the antitumoral therapy. The purpose of this study was to determine whether recombinant fibroblasts expressing endostatin encapsulated in Theracyte immunoisolation devices can be used for delivery of this therapeutic protein for treatment of mice bearing B16F10 melanoma and Ehrlich tumors. Mice were inoculated subcutaneously with melanoma (B16F10 cells) or Ehrlich tumor cells at the foot pads. Treatment began when tumor thickness had reached 0.5 mm, by subcutaneous implantation of 107 recombinant encapsulated or non-encapsulated endostatin producer cells. Similar melanoma growth inhibition was obtained for mice treated with encapsulated or non-encapsulated endostatin-expressing cells. The treatment of mice bearing melanoma tumor with encapsulated endostatin-expressing cells was decreased by 50.0%, whereas a decrease of 56.7% in tumor thickness was obtained for mice treated with non-encapsulated cells. Treatment of Ehrlich tumor-bearing mice with non-encapsulated endostatin-expressing cells reduced tumor thickness by 52.4%, whereas lower tumor growth inhibition was obtained for mice treated with encapsulated endostatin-expressing cells: 24.2%. Encapsulated endostatin-secreting fibroblasts failed to survive until the end of the treatment. However, endostatin release from the devices to the surrounding tissues was confirmed by immunostaining. Decrease in vascular structures, functional vessels and extension of the vascular area were observed in melanoma microenvironments. This study indicates that immunoisolation devices containing endostatin

Surgery and Combination Chemotherapy in Treating Children With Extracranial Germ Cell Tumors

ClinicalTrials.gov

2017-12-07

Childhood Embryonal Tumor; Childhood Extracranial Germ Cell Tumor; Childhood Extragonadal Germ Cell Tumor; Childhood Malignant Ovarian Germ Cell Tumor; Childhood Malignant Testicular Germ Cell Tumor; Childhood Teratoma; Ovarian Embryonal Carcinoma; Ovarian Yolk Sac Tumor; Stage II Malignant Testicular Germ Cell Tumor; Stage IIA Ovarian Germ Cell Tumor; Stage IIB Ovarian Germ Cell Tumor; Stage IIC Ovarian Germ Cell Tumor; Stage III Malignant Testicular Germ Cell Tumor; Stage IIIA Ovarian Germ Cell Tumor; Stage IIIB Ovarian Germ Cell Tumor; Stage IIIC Ovarian Germ Cell Tumor; Testicular Choriocarcinoma and Yolk Sac Tumor; Testicular Embryonal Carcinoma

Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation

PubMed Central

Tape, Christopher J.; Ling, Stephanie; Dimitriadi, Maria; McMahon, Kelly M.; Worboys, Jonathan D.; Leong, Hui Sun; Norrie, Ida C.; Miller, Crispin J.; Poulogiannis, George; Lauffenburger, Douglas A.; Jørgensen, Claus

2016-01-01

Summary Oncogenic mutations regulate signaling within both tumor cells and adjacent stromal cells. Here, we show that oncogenic KRAS (KRASG12D) also regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analyzed heterocellular KRASG12D signaling in pancreatic ductal adenocarcinoma (PDA) cells. Tumor cell KRASG12D engages heterotypic fibroblasts, which subsequently instigate reciprocal signaling in the tumor cells. Reciprocal signaling employs additional kinases and doubles the number of regulated signaling nodes from cell-autonomous KRASG12D. Consequently, reciprocal KRASG12D produces a tumor cell phosphoproteome and total proteome that is distinct from cell-autonomous KRASG12D alone. Reciprocal signaling regulates tumor cell proliferation and apoptosis and increases mitochondrial capacity via an IGF1R/AXL-AKT axis. These results demonstrate that oncogene signaling should be viewed as a heterocellular process and that our existing cell-autonomous perspective underrepresents the extent of oncogene signaling in cancer. Video Abstract PMID:27087446

Breast conservation in the setting of contemporary multimodality treatment provides excellent outcomes for patients with occult primary breast cancer.

PubMed

Rueth, Natasha M; Black, Dalliah M; Limmer, Angela R; Gabriel, Emmanuel; Huo, Lei; Fornage, Bruno D; Dogan, Basak E; Chavez-MacGregor, Mariana; Yi, Min; Hunt, Kelly K; Strom, Eric A

2015-01-01

To evaluate recurrence and survival for patients with occult (T0N+) breast cancer who underwent contemporary treatment, assessing outcomes for breast conservation and mastectomy. We performed a single-institution review of women with occult breast cancer presenting with axillary metastasis without identifiable breast tumor or distant metastasis. We excluded patients with tumors in the axillary tail or mastectomy specimen, patients with additional nonbreast cancer diagnoses, and patients with a history of breast cancer. Breast conservation was defined as axillary node dissection with radiation therapy, without breast surgery. We evaluated patient, tumor, treatment, and outcome variables. Patients were assessed for local, regional, and distant recurrences. Overall survival was calculated using the Kaplan-Meier method. Thirty-six patients met criteria for occult breast cancer. Most of these patients (77.8 %) had N1 disease. Fifty percent of cancers (n = 18) were estrogen receptor-positive; 12 (33.3 %) were triple-negative. All patients were evaluated with mammography. Thirty-five patients had breast ultrasound (97.2 %) and 33 (91.7 %) had an MRI. Thirty-four patients (94.4 %) were treated with chemotherapy and 33 (91.7 %) with radiotherapy. Twenty-seven patients (75.0 %) were treated with breast conservation. The median follow-up was 64 months. There were no local or regional failures. One distant recurrence occurred >5 years after diagnosis, resulting in a 5-years overall survival rate of 100 %. There were no significant survival differences between patients receiving breast conservation versus mastectomy (p = 0.7). Breast conservation-performed with contemporary imaging and multimodality treatment-provides excellent local control and survival for women with T0N+ breast cancer and can be safely offered instead of mastectomy.

Microfluidic cell isolation technology for drug testing of single tumor cells and their clusters.

PubMed

Bithi, Swastika S; Vanapalli, Siva A

2017-02-02

Drug assays with patient-derived cells such as circulating tumor cells requires manipulating small sample volumes without loss of rare disease-causing cells. Here, we report an effective technology for isolating and analyzing individual tumor cells and their clusters from minute sample volumes using an optimized microfluidic device integrated with pipettes. The method involves using hand pipetting to create an array of cell-laden nanoliter-sized droplets immobilized in a microfluidic device without loss of tumor cells during the pipetting process. Using this technology, we demonstrate single-cell analysis of tumor cell response to the chemotherapy drug doxorubicin. We find that even though individual tumor cells display diverse uptake profiles of the drug, the onset of apoptosis is determined by accumulation of a critical intracellular concentration of doxorubicin. Experiments with clusters of tumor cells compartmentalized in microfluidic drops reveal that cells within a cluster have higher viability than their single-cell counterparts when exposed to doxorubicin. This result suggests that circulating tumor cell clusters might be able to better survive chemotherapy drug treatment. Our technology is a promising tool for understanding tumor cell-drug interactions in patient-derived samples including rare cells.

Recruited brain tumor-derived mesenchymal stem cells contribute to brain tumor progression.

PubMed

Behnan, Jinan; Isakson, Pauline; Joel, Mrinal; Cilio, Corrado; Langmoen, Iver A; Vik-Mo, Einar O; Badn, Wiaam

2014-05-01

The identity of the cells that contribute to brain tumor structure and progression remains unclear. Mesenchymal stem cells (MSCs) have recently been isolated from normal mouse brain. Here, we report the infiltration of MSC-like cells into the GL261 murine glioma model. These brain tumor-derived mesenchymal stem cells (BT-MSCs) are defined with the phenotype (Lin-Sca-1+CD9+CD44+CD166+/-) and have multipotent differentiation capacity. We show that the infiltration of BT-MSCs correlates to tumor progression; furthermore, BT-MSCs increased the proliferation rate of GL261 cells in vitro. For the first time, we report that the majority of GL261 cells expressed mesenchymal phenotype under both adherent and sphere culture conditions in vitro and that the non-MSC population is nontumorigenic in vivo. Although the GL261 cell line expressed mesenchymal phenotype markers in vitro, most BT-MSCs are recruited cells from host origin in both wild-type GL261 inoculated into green fluorescent protein (GFP)-transgenic mice and GL261-GFP cells inoculated into wild-type mice. We show the expression of chemokine receptors CXCR4 and CXCR6 on different recruited cell populations. In vivo, the GL261 cells change marker profile and acquire a phenotype that is more similar to cells growing in sphere culture conditions. Finally, we identify a BT-MSC population in human glioblastoma that is CD44+CD9+CD166+ both in freshly isolated and culture-expanded cells. Our data indicate that cells with MSC-like phenotype infiltrate into the tumor stroma and play an important role in tumor cell growth in vitro and in vivo. Thus, we suggest that targeting BT-MSCs could be a possible strategy for treating glioblastoma patients. © 2013 AlphaMed Press.

[Circulating tumor cells: cornerstone of personalized medicine].

PubMed

Rafii, A; Vidal, F; Rathat, G; Alix-Panabières, C

2014-11-01

Cancer treatment has evolved toward personalized medicine. It is mandatory for clinicians to ascertain tumor biological features in order to optimize patients' treatment. Identification and characterization of circulating tumor cells demonstrated a prognostic value in many solid tumors. Here, we describe the main technologies for identification and characterization of circulating tumor cells and their clinical application in gynecologic and breast cancers. Copyright © 2014. Published by Elsevier Masson SAS.

Imaging Tumor Cell Movement In Vivo

PubMed Central

Entenberg, David; Kedrin, Dmitriy; Wyckoff, Jeffrey; Sahai, Erik; Condeelis, John; Segall, Jeffrey E.

2013-01-01

This unit describes the methods that we have been developing for analyzing tumor cell motility in mouse and rat models of breast cancer metastasis. Rodents are commonly used both to provide a mammalian system for studying human tumor cells (as xenografts in immunocompromised mice) as well as for following the development of tumors from a specific tissue type in transgenic lines. The Basic Protocol in this unit describes the standard methods used for generation of mammary tumors and imaging them. Additional protocols for labeling macrophages, blood vessel imaging, and image analysis are also included. PMID:23456602

Tumor Expression of CD200 Inhibits IL-10 Production by Tumor-Associated Myeloid Cells and Prevents Tumor Immune Evasion of CTL Therapy

PubMed Central

Wang, Lixin; Liu, Jin-Qing; Talebian, Fatemeh; El-Omrani, Hani Y.; Khattabi, Mazin; Yu, Li; Bai, Xue-Feng

2010-01-01

CD200 is a cell-surface glycoprotein that functions through interaction with the CD200 receptor (CD200R) on myeloid lineage cells to regulate myeloid cell functions. Expression of CD200 has been implicated in multiple types of human cancer, however the impact of tumor expression of CD200 on tumor immunity remains poorly understood. To evaluate this issue, we generated CD200-positive mouse plasmacytoma J558 and mastocytoma P815 cells. We found that established CD200-positive tumors were often completely rejected by adoptively transferred CTL without tumor recurrence; in contrast, CD200-negative tumors were initially rejected by adoptively transferred CTL but the majority of tumors recurred. Tumor expression of CD200 significantly inhibited suppressive activity and IL-10 production by tumor-associated myeloid cells (TAMC), and as a result, more CTL accumulated in the tumor and exhibited a greater capacity to produce IFN-γ in CD200-positive tumors than in CD200-negative tumors. Neutralization of IL-10 significantly inhibited the suppressor activity of TAMC, and IL-10-deficiency allowed TAMC to kill cancer cells and their antigenic variants, which prevented tumor recurrence during CTL therapy. Thus, tumor expression of CD200 prevents tumor recurrence via inhibiting IL-10 production by TAMC. PMID:20662098

Occult Hepatitis B virus infection in previously screened, blood donors in Ile-Ife, Nigeria: implications for blood transfusion and stem cell transplantation.

PubMed

Olotu, Amadin A; Oyelese, Adesola O; Salawu, Lateef; Audu, Rosemary A; Okwuraiwe, Azuka P; Aboderin, Aaron O

2016-05-05

Hepatitis B virus (HBV) transmission through blood transfusion is reduced by screening for hepatitis B surface antigen (HBsAg). However this method cannot detect the presence of occult hepatitis B virus infection. This study sought to determine the prevalence of occult hepatitis B virus infection among blood donors in Ile-Ife, Nigeria. For the first time in Nigeria we employed an automated real-time PCR- method to investigate the prevalence of occult HBV in blood donors. Blood donors screened with HBsAg immunochromatographic rapid test kits at the blood transfusion units of two hospitals and found to be negative were recruited into the study. Questionnaires to elicit risk factors for HBV infection were administered and then 10 ml of blood was collected from each donor. Plasma samples obtained from these HBsAg negative blood donors were screened again for HBsAg using an enzyme-linked immunosorbent assay (ELISA) method, and those found negative were screened for the presence of total antibody to the HBV core antigen (anti-HBc) using ELISA method. Those positive to anti-HBc were then tested for HBV DNA, using an automated real-time PCR method. Five hundred and seven blood donors found HBsAg negative by immunochromatographic rapid test kits at both blood transfusion units, were tested for HBsAg using ELISA and 5 (1 %) were HBsAg positive. The 502 found negative were tested for anti-HBc and 354 (70.5 %) were found positive implying previous exposure to HBV and 19 (5.4 %) of the 354 anti-HBc positive had HBV DNA signifying occult HBV infection. No risk factors were found to be associated with the presence of HBV DNA among those who tested positive. Occult HBV infection exists in blood donors in Ile-Ife, Nigeria and the use of HBsAg alone for screening prospective donors will not eliminate the risk of HBV transmission in blood transfusion or stem cell transplantation.

Optimization of dendritic cell loading with tumor cell lysates for cancer immunotherapy.

PubMed

Hatfield, Paul; Merrick, Alison E; West, Emma; O'Donnell, Dearbhaile; Selby, Peter; Vile, Richard; Melcher, Alan A

2008-09-01

The immune response to cancer is critically determined by the way in which tumor cells die. As necrotic, stress-associated death can be associated with activation of antitumor immunity, whole tumor cell antigen loading strategies for dendritic cell (DC)-based vaccination have commonly used freeze-thaw "necrotic" lysates as an immunogenic source of tumor-associated antigens. In this study, the effect of such lysates on the ability of DCs to mature in response to well-established maturation stimuli was examined, and methods to enhance lysate-induced DC activation explored. Freeze-thaw lysates were prepared from murine tumor cell lines and their effects on bone marrow-derived DC maturation and function examined. Unmodified freeze-thaw tumor cell lysates inhibited the toll-like receptor-induced maturation and function of bone marrow-derived DCs, preventing up-regulation of CD40, CD86, and major histocompatibility complex class II, and reducing secretion of inflammatory cytokines [interleukin (IL)-12 p70, tumor necrosis factor-alpha, and IL-6]. Although IL-10 secretion was increased by lysate-pulsed DCs, this was not responsible for the observed suppression of IL-12. Although activation of the nuclear factor-kappaB pathway remained intact, the kinase activity of phosphorylated p38 mitogen-activated protein kinase was inhibited in lysate-pulsed DCs. Lysate-induced DC suppression was partially reversed in vitro by induction of tumor cell stress before lysis, and only DCs loaded with stressed lysates afforded protection against tumor challenge in vivo. These data suggest that ex vivo freeze-thaw of tumor cells does not effectively mimic in vivo immunogenic necrosis, and advocates careful characterization and optimization of tumor cell-derived vaccine sources for cancer immunotherapy.

Tracing the origin of disseminated tumor cells in breast cancer using single-cell sequencing.

PubMed

Demeulemeester, Jonas; Kumar, Parveen; Møller, Elen K; Nord, Silje; Wedge, David C; Peterson, April; Mathiesen, Randi R; Fjelldal, Renathe; Zamani Esteki, Masoud; Theunis, Koen; Fernandez Gallardo, Elia; Grundstad, A Jason; Borgen, Elin; Baumbusch, Lars O; Børresen-Dale, Anne-Lise; White, Kevin P; Kristensen, Vessela N; Van Loo, Peter; Voet, Thierry; Naume, Bjørn

2016-12-09

Single-cell micro-metastases of solid tumors often occur in the bone marrow. These disseminated tumor cells (DTCs) may resist therapy and lay dormant or progress to cause overt bone and visceral metastases. The molecular nature of DTCs remains elusive, as well as when and from where in the tumor they originate. Here, we apply single-cell sequencing to identify and trace the origin of DTCs in breast cancer. We sequence the genomes of 63 single cells isolated from six non-metastatic breast cancer patients. By comparing the cells' DNA copy number aberration (CNA) landscapes with those of the primary tumors and lymph node metastasis, we establish that 53% of the single cells morphologically classified as tumor cells are DTCs disseminating from the observed tumor. The remaining cells represent either non-aberrant "normal" cells or "aberrant cells of unknown origin" that have CNA landscapes discordant from the tumor. Further analyses suggest that the prevalence of aberrant cells of unknown origin is age-dependent and that at least a subset is hematopoietic in origin. Evolutionary reconstruction analysis of bulk tumor and DTC genomes enables ordering of CNA events in molecular pseudo-time and traced the origin of the DTCs to either the main tumor clone, primary tumor subclones, or subclones in an axillary lymph node metastasis. Single-cell sequencing of bone marrow epithelial-like cells, in parallel with intra-tumor genetic heterogeneity profiling from bulk DNA, is a powerful approach to identify and study DTCs, yielding insight into metastatic processes. A heterogeneous population of CNA-positive cells is present in the bone marrow of non-metastatic breast cancer patients, only part of which are derived from the observed tumor lineages.

Tissue Regeneration in the Chronically Inflamed Tumor Environment: Implications for Cell Fusion Driven Tumor Progression and Therapy Resistant Tumor Hybrid Cells

PubMed Central

Dittmar, Thomas; Zänker, Kurt S.

2015-01-01

The biological phenomenon of cell fusion in a cancer context is still a matter of controversial debates. Even though a plethora of in vitro and in vivo data have been published in the past decades the ultimate proof that tumor hybrid cells could originate in (human) cancers and could contribute to the progression of the disease is still missing, suggesting that the cell fusion hypothesis is rather fiction than fact. However, is the lack of this ultimate proof a valid argument against this hypothesis, particularly if one has to consider that appropriate markers do not (yet) exist, thus making it virtually impossible to identify a human tumor cell clearly as a tumor hybrid cell. In the present review, we will summarize the evidence supporting the cell fusion in cancer concept. Moreover, we will refine the cell fusion hypothesis by providing evidence that cell fusion is a potent inducer of aneuploidy, genomic instability and, most likely, even chromothripsis, suggesting that cell fusion, like mutations and aneuploidy, might be an inducer of a mutator phenotype. Finally, we will show that “accidental” tissue repair processes during cancer therapy could lead to the origin of therapy resistant cancer hybrid stem cells. PMID:26703575

Destruction of solid tumors by immune cells

NASA Astrophysics Data System (ADS)

López, Álvaro G.; Seoane, Jesús M.; Sanjuán, Miguel A. F.

2017-03-01

The fractional cell kill is a mathematical expression describing the rate at which a certain population of cells is reduced to a fraction of itself. In order to investigate the fractional cell kill that governs the rate at which a solid tumor is lysed by a cell population of cytotoxic CD8+ T cells (CTLs), we present several in silico simulations and mathematical analyses. When the CTLs eradicate efficiently the tumor cells, the models predict a correlation between the morphology of the tumors and the rate at which they are lysed. However, when the effectiveness of the immune cells is decreased, the mathematical function fails to reproduce the process of lysis. This limit is thoroughly discussed and a new fractional cell kill is proposed.

Role of curcumin-dependent modulation of tumor microenvironment of a murine T cell lymphoma in altered regulation of tumor cell survival

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

Vishvakarma, Naveen Kumar; Kumar, Anjani; Singh, Sukh Mahendra, E-mail: sukhmahendrasingh@yahoo.com

2011-05-01

Using a murine model of a T cell lymphoma, in the present study, we report that tumor growth retarding action of curcumin involves modulation of some crucial parameters of tumor microenvironment regulating tumor progression. Curcumin-administration to tumor-bearing host caused an altered pH regulation in tumor cells associated with alteration in expression of cell survival and apoptosis regulatory proteins and genes. Nevertheless, an alteration was also observed in biophysical parameters of tumor microenvironment responsible for modulation of tumor growth pertaining to hypoxia, tumor acidosis, and glucose metabolism. The study thus sheds new light with respect to the antineoplastic action of curcuminmore » against a tumor-bearing host with progressively growing tumor of hematological origin. This will help in optimizing application of the drug and anticancer research and therapy. - Graphical Abstract: Display Omitted« less

Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells.

PubMed

Testa, Ugo; Castelli, Germana; Pelosi, Elvira

2017-11-20

Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are associated with different mutational profiles, and possess distinct risk factors. The discovery of the molecular abnormalities underlying melanomas has led to the promising improvement of therapy, and further progress is expected in the near future. The study of melanoma precursor lesions has led to the suggestion that the pathway of tumor evolution implies the progression from benign naevi, to dysplastic naevi, to melanoma in situ and then to invasive and metastatic melanoma. The gene alterations characterizing melanomas tend to accumulate in these precursor lesions in a sequential order. Studies carried out in recent years have, in part, elucidated the great tumorigenic potential of melanoma tumor cells. These findings have led to speculation that the cancer stem cell model cannot be applied to melanoma because, in this malignancy, tumor cells possess an intrinsic plasticity, conferring the capacity to initiate and maintain the neoplastic process to phenotypically different tumor cells.

Discovery of NKT cells and development of NKT cell-targeted anti-tumor immunotherapy

PubMed Central

TANIGUCHI, Masaru; HARADA, Michishige; DASHTSOODOL, Nyambayar; KOJO, Satoshi

2015-01-01

Natural Killer T (NKT) cells are unique lymphocytes characterized by their expression of a single invariant antigen receptor encoded by Vα14Jα18 in mice and Vα24Jα18 in humans, which recognizes glycolipid antigens in association with the monomorphic CD1d molecule. NKT cells mediate adjuvant activity to activate both CD8T cells to kill MHC-positive tumor cells and NK cells to eliminate MHC-negative tumor at the same time in patients, resulting in the complete eradication of tumors without relapse. Therefore, the NKT cell-targeted therapy can be applied to any type of tumor and also to anyone individual, regardless of HLA type. Phase IIa clinical trials on advanced lung cancers and head and neck tumors have been completed and showed significantly prolonged median survival times with only the primary treatment. Another potential treatment option for the future is to use induced pluripotent stem cell (iPS)-derived NKT cells, which induced adjuvant effects on anti-tumor responses, inhibiting in vivo tumor growth in a mouse model. PMID:26194854

Cell motility and ECM proteolysis regulate tumor growth and tumor relapse by altering the fraction of cancer stem cells and their spatial scattering

NASA Astrophysics Data System (ADS)

Kumar, Sandeep; Kulkarni, Rahul; Sen, Shamik

2016-06-01

Tumors consist of multiple cell sub-populations including cancer stem cells (CSCs), transiently amplifying cells and terminally differentiated cells (TDCs), with the CSC fraction dictating the aggressiveness of the tumor and drug sensitivity. In epithelial cancers, tumor growth is influenced greatly by properties of the extracellular matrix (ECM), with cancer progression associated with an increase in ECM density. However, the extent to which increased ECM confinement induced by an increase in ECM density influences tumor growth and post treatment relapse dynamics remains incompletely understood. In this study, we use a cellular automata-based discrete modeling approach to study the collective influence of ECM density, cell motility and ECM proteolysis on tumor growth, tumor heterogeneity, and tumor relapse after drug treatment. We show that while increased confinement suppresses tumor growth and the spatial scattering of CSCs, this effect can be reversed when cells become more motile and proteolytically active. Our results further suggest that, in addition to the absolute number of CSCs, their spatial positioning also plays an important role in driving tumor growth. In a nutshell, our study suggests that, in confined environments, cell motility and ECM proteolysis are two key factors that regulate tumor growth and tumor relapse dynamics by altering the number and spatial distribution of CSCs.

A 3D Poly(ethylene glycol)-based Tumor Angiogenesis Model to Study the Influence of Vascular Cells on Lung Tumor Cell Behavior

PubMed Central

Roudsari, Laila C.; Jeffs, Sydney E.; Witt, Amber S.; Gill, Bartley J.; West, Jennifer L.

2016-01-01

Tumor angiogenesis is critical to tumor growth and metastasis, yet much is unknown about the role vascular cells play in the tumor microenvironment. In vitro models that mimic in vivo tumor neovascularization facilitate exploration of this role. Here we investigated lung adenocarcinoma cancer cells (344SQ) and endothelial and pericyte vascular cells encapsulated in cell-adhesive, proteolytically-degradable poly(ethylene) glycol-based hydrogels. 344SQ in hydrogels formed spheroids and secreted proangiogenic growth factors that significantly increased with exposure to transforming growth factor beta 1 (TGF-β1), a potent tumor progression-promoting factor. Vascular cells in hydrogels formed tubule networks with localized activated TGF-β1. To study cancer cell-vascular cell interactions, we engineered a 2-layer hydrogel with 344SQ and vascular cell layers. Large, invasive 344SQ clusters (area > 5,000 μm2, circularity < 0.25) developed at the interface between the layers, and were not evident further from the interface or in control hydrogels without vascular cells. A modified model with spatially restricted 344SQ and vascular cell layers confirmed that observed cluster morphological changes required close proximity to vascular cells. Additionally, TGF-β1 inhibition blocked endothelial cell-driven 344SQ migration. Our findings suggest vascular cells contribute to tumor progression and establish this culture system as a platform for studying tumor vascularization. PMID:27596933

A 3D Poly(ethylene glycol)-based Tumor Angiogenesis Model to Study the Influence of Vascular Cells on Lung Tumor Cell Behavior

NASA Astrophysics Data System (ADS)

Roudsari, Laila C.; Jeffs, Sydney E.; Witt, Amber S.; Gill, Bartley J.; West, Jennifer L.

2016-09-01

Tumor angiogenesis is critical to tumor growth and metastasis, yet much is unknown about the role vascular cells play in the tumor microenvironment. In vitro models that mimic in vivo tumor neovascularization facilitate exploration of this role. Here we investigated lung adenocarcinoma cancer cells (344SQ) and endothelial and pericyte vascular cells encapsulated in cell-adhesive, proteolytically-degradable poly(ethylene) glycol-based hydrogels. 344SQ in hydrogels formed spheroids and secreted proangiogenic growth factors that significantly increased with exposure to transforming growth factor beta 1 (TGF-β1), a potent tumor progression-promoting factor. Vascular cells in hydrogels formed tubule networks with localized activated TGF-β1. To study cancer cell-vascular cell interactions, we engineered a 2-layer hydrogel with 344SQ and vascular cell layers. Large, invasive 344SQ clusters (area > 5,000 μm2, circularity < 0.25) developed at the interface between the layers, and were not evident further from the interface or in control hydrogels without vascular cells. A modified model with spatially restricted 344SQ and vascular cell layers confirmed that observed cluster morphological changes required close proximity to vascular cells. Additionally, TGF-β1 inhibition blocked endothelial cell-driven 344SQ migration. Our findings suggest vascular cells contribute to tumor progression and establish this culture system as a platform for studying tumor vascularization.

Testing for Occult Heartworm Infection

PubMed Central

Stogdale, L.

1984-01-01

Heartworm infection in dogs is endemic in southern Ontario but occurs only sporadically throughout the remainder of Canada. The disease may either be associated with microfilariae in the patient's blood, a patent infection, or it may be occult. This paper describes a case of occult dirofilariasis in a dog, with emphasis on the diagnosis. A patent infection could be missed if the clinician tests an insufficient amount of blood. He should perform multiple concentration tests using either the modified Knott's technique or a filtration method. Occult infections occur in prepatent or unisexual infections, when the worms become sterile following therapy, or when the host produces antibodies that result in the destruction of the microfilariae. The recent release of a kit which detects the presence of antibodies to the adult heartworms now enables veterinarians to make an accurate diagnosis in the vast majority of dogs. PMID:17422386

Facial paralysis due to an occult parotid abscess.

PubMed

Orhan, Kadir Serkan; Demirel, Tayfun; Kocasoy-Orhan, Elif; Yenigül, Kubilay

2008-01-01

Facial paralysis associated with benign diseases of the parotid gland is very rare. It has been reported in approximately 16 cases of acute suppurative parotitis or parotid abscess. We presented a 45-year-old woman who developed facial paralysis secondary to an occult parotid abscess. Initially, there was no facial paralysis and the signs and symptoms were suggestive of acute parotitis, for which medical treatment was initiated. Three days later, left-sided facial palsy of HB (House-Brackmann) grade 5 developed. Ultrasonography revealed a pretragal, hypoechoic mass, 10x8 mm in size, causing inflammation in the surrounding tissue. Fine needle aspiration biopsy obtained from the mass revealed polymorphonuclear leukocytes and lymphocytes. No malignant cells were observed. The lesion was diagnosed as an occult parotid abscess. After a week, the mass disappeared and facial paralysis improved to HB grade 4. At the end of the first month, facial paralysis improved to HB grade 1. At three months, facial nerve function was nearly normal.

Fecal Occult Blood Test (FOBT): MedlinePlus Lab Test Information

MedlinePlus

... medlineplus.gov/labtests/fecaloccultbloodtestfobt.html Fecal Occult Blood Test (FOBT) To use the sharing features on this ... enable JavaScript. What is a Fecal Occult Blood Test? A fecal occult blood test (FOBT) looks at ...

A Digital Video System for Observing and Recording Occultations

NASA Astrophysics Data System (ADS)

Barry, M. A. Tony; Gault, Dave; Pavlov, Hristo; Hanna, William; McEwan, Alistair; Filipović, Miroslav D.

2015-09-01

Stellar occultations by asteroids and outer solar system bodies can offer ground based observers with modest telescopes and camera equipment the opportunity to probe the shape, size, atmosphere, and attendant moons or rings of these distant objects. The essential requirements of the camera and recording equipment are: good quantum efficiency and low noise; minimal dead time between images; good horological faithfulness of the image timestamps; robustness of the recording to unexpected failure; and low cost. We describe an occultation observing and recording system which attempts to fulfil these requirements and compare the system with other reported camera and recorder systems. Five systems have been built, deployed, and tested over the past three years, and we report on three representative occultation observations: one being a 9 ± 1.5 s occultation of the trans-Neptunian object 28978 Ixion (m v =15.2) at 3 seconds per frame; one being a 1.51 ± 0.017 s occultation of Deimos, the 12 km diameter satellite of Mars, at 30 frames per second; and one being a 11.04 ± 0.4 s occultation, recorded at 7.5 frames per second, of the main belt asteroid 361 Havnia, representing a low magnitude drop (Δm v = ~0.4) occultation.

Monoclonal TCR-redirected tumor cell killing.

PubMed

Liddy, Nathaniel; Bossi, Giovanna; Adams, Katherine J; Lissina, Anna; Mahon, Tara M; Hassan, Namir J; Gavarret, Jessie; Bianchi, Frayne C; Pumphrey, Nicholas J; Ladell, Kristin; Gostick, Emma; Sewell, Andrew K; Lissin, Nikolai M; Harwood, Naomi E; Molloy, Peter E; Li, Yi; Cameron, Brian J; Sami, Malkit; Baston, Emma E; Todorov, Penio T; Paston, Samantha J; Dennis, Rebecca E; Harper, Jane V; Dunn, Steve M; Ashfield, Rebecca; Johnson, Andy; McGrath, Yvonne; Plesa, Gabriela; June, Carl H; Kalos, Michael; Price, David A; Vuidepot, Annelise; Williams, Daniel D; Sutton, Deborah H; Jakobsen, Bent K

2012-06-01

T cell immunity can potentially eradicate malignant cells and lead to clinical remission in a minority of patients with cancer. In the majority of these individuals, however, there is a failure of the specific T cell receptor (TCR)–mediated immune recognition and activation process. Here we describe the engineering and characterization of new reagents termed immune-mobilizing monoclonal TCRs against cancer (ImmTACs). Four such ImmTACs, each comprising a distinct tumor-associated epitope-specific monoclonal TCR with picomolar affinity fused to a humanized cluster of differentiation 3 (CD3)-specific single-chain antibody fragment (scFv), effectively redirected T cells to kill cancer cells expressing extremely low surface epitope densities. Furthermore, these reagents potently suppressed tumor growth in vivo. Thus, ImmTACs overcome immune tolerance to cancer and represent a new approach to tumor immunotherapy.

Engineered three-dimensional microfluidic device for interrogating cell-cell interactions in the tumor microenvironment.

PubMed

Hockemeyer, K; Janetopoulos, C; Terekhov, A; Hofmeister, W; Vilgelm, A; Costa, Lino; Wikswo, J P; Richmond, A

2014-07-01

Stromal cells in the tumor microenvironment play a key role in the metastatic properties of a tumor. It is recognized that cancer-associated fibroblasts (CAFs) and endothelial cells secrete factors capable of influencing tumor cell migration into the blood or lymphatic vessels. We developed a microfluidic device that can be used to image the interactions between stromal cells and tumor cell spheroids in a three dimensional (3D) microenvironment while enabling external control of interstitial flow at an interface, which supports endothelial cells. The apparatus couples a 200-μm channel with a semicircular well to mimic the interface of a blood vessel with the stroma, and the design allows for visualization of the interactions of interstitial flow, endothelial cells, leukocytes, and fibroblasts with the tumor cells. We observed that normal tissue-associated fibroblasts (NAFs) contribute to the "single file" pattern of migration of tumor cells from the spheroid in the 3D microenvironment. In contrast, CAFs induce a rapid dispersion of tumor cells out of the spheroid with migration into the 3D matrix. Moreover, treatment of tumor spheroid cultures with the chemokine CXCL12 mimics the effect of the CAFs, resulting in similar patterns of dispersal of the tumor cells from the spheroid. Conversely, addition of CXCL12 to co-cultures of NAFs with tumor spheroids did not mimic the effects observed with CAF co-cultures, suggesting that NAFs produce factors that stabilize the tumor spheroids to reduce their migration in response to CXCL12.

Blood vessel endothelium-directed tumor cell streaming in breast tumors requires the HGF/C-Met signaling pathway

PubMed Central

Leung, E; Xue, A; Wang, Y; Rougerie, P; Sharma, V P; Eddy, R; Cox, D; Condeelis, J

2017-01-01

During metastasis to distant sites, tumor cells migrate to blood vessels. In vivo, breast tumor cells utilize a specialized mode of migration known as streaming, where a linear assembly of tumor cells migrate directionally towards blood vessels on fibronectin-collagen I-containing extracellular matrix (ECM) fibers in response to chemotactic signals. We have successfully reconstructed tumor cell streaming in vitro by co-plating tumors cells, macrophages and endothelial cells on 2.5 μm thick ECM-coated micro-patterned substrates. We found that tumor cells and macrophages, when plated together on the micro-patterned substrates, do not demonstrate sustained directional migration in only one direction (sustained directionality) but show random bi-directional walking. Sustained directionality of tumor cells as seen in vivo was established in vitro when beads coated with human umbilical vein endothelial cells were placed at one end of the micro-patterned ‘ECM fibers' within the assay. We demonstrated that these endothelial cells supply the hepatocyte growth factor (HGF) required for the chemotactic gradient responsible for sustained directionality. Using this in vitro reconstituted streaming system, we found that directional streaming is dependent on, and most effectively blocked, by inhibiting the HGF/C-Met signaling pathway between endothelial cells and tumor cells. Key observations made with the in vitro reconstituted system implicating C-Met signaling were confirmed in vivo in mammary tumors using the in vivo invasion assay and intravital multiphoton imaging of tumor cell streaming. These results establish HGF/C-Met as a central organizing signal in blood vessel-directed tumor cell migration in vivo and highlight a promising role for C-Met inhibitors in blocking tumor cell streaming and metastasis in vivo, and for use in human trials. PMID:27893712

Regulation of Ovarian Cancer Stem Cells or Tumor-Initiating Cells

PubMed Central

Kwon, Mi Jeong; Shin, Young Kee

2013-01-01

Cancer stem cells or tumor-initiating cells (CSC/TICs), which can undergo self-renewal and differentiation, are thought to play critical roles in tumorigenesis, therapy resistance, tumor recurrence and metastasis. Tumor recurrence and chemoresistance are major causes of poor survival rates of ovarian cancer patients, which may be due in part to the existence of CSC/TICs. Therefore, elucidating the molecular mechanisms responsible for the ovarian CSC/TICs is required to develop a cure for this malignancy. Recent studies have indicated that the properties of CSC/TICs can be regulated by microRNAs, genes and signaling pathways which also function in normal stem cells. Moreover, emerging evidence suggests that the tumor microenvironments surrounding CSC/TICs are crucial for the maintenance of these cells. Similarly, efforts are now being made to unravel the mechanism involved in the regulation of ovarian CSC/TICs, although much work is still needed. This review considers recent advances in identifying the genes and pathways involved in the regulation of ovarian CSC/TICs. Furthermore, current approaches targeting ovarian CSC/TICs are described. Targeting both CSC/TICs and bulk tumor cells is suggested as a more effective approach to eliminating ovarian tumors. Better understanding of the regulation of ovarian CSC/TICs might facilitate the development of improved therapeutic strategies for recurrent ovarian cancer. PMID:23528891

Tumor-associated myeloid cells as guiding forces of cancer cell stemness.

PubMed

Sica, Antonio; Porta, Chiara; Amadori, Alberto; Pastò, Anna

2017-08-01

Due to their ability to differentiate into various cell types and to support tissue regeneration, stem cells simultaneously became the holy grail of regenerative medicine and the evil obstacle in cancer therapy. Several studies have investigated niche-related conditions that favor stemness properties and increasingly emphasized their association with an inflammatory environment. Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are major orchestrators of cancer-related inflammation, able to dynamically express different polarized inflammatory programs that promote tumor outgrowth, including tumor angiogenesis, immunosuppression, tissue remodeling and metastasis formation. In addition, these myeloid populations support cancer cell stemness, favoring tumor maintenance and progression, as well as resistance to anticancer treatments. Here, we discuss inflammatory circuits and molecules expressed by TAMs and MDSCs as guiding forces of cancer cell stemness.

Ultrasound for diagnosing radiographically occult scaphoid fracture.

PubMed

Kwee, Robert M; Kwee, Thomas C

2018-04-04

To systematically review the literature on the performance of ultrasound in diagnosing radiographically occult scaphoid fracture. A systematic search was performed in the MEDLINE and Embase databases. Original studies investigating the performance of ultrasound in diagnosing radiographically occult scaphoid fracture in more than 10 patients were eligible for inclusion. Studies that included both radiographically apparent and occult scaphoid fractures (at initial radiography) were only included if independent data on radiographically occult fractures were reported. Methodological quality of the studies included was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Accuracy data were extracted. Sensitivity and specificity were pooled with a bivariate random-effects model. The inclusion criteria were met by 7 studies; total sample size comprised 314 patients. All studies, except 1, included cortical disruption of the scaphoid in their diagnostic criteria. The sensitivity and specificity of ultrasound in diagnosing radiographically occult scaphoid fracture ranged from 77.8% to 100% and from 71.4% to 100% respectively, with pooled estimates of 85.6% (95% CI: 73.9%, 92.6%) and 83.3% % (95% CI: 72.0%, 90.6%) respectively. Exclusion of two studies with a high risk of bias in any QUADAS-2 domain did not affect the pooled results. Ultrasound can diagnose radiographically occult scaphoid fracture with a fairly high degree of accuracy. Because of its relatively low costs and fairly high sensitivity, ultrasound seems more cost-effective than empiric cast immobilization and may be used when CT and MRI are not readily available.

Tumoral expression of IL-33 inhibits tumor growth and modifies the tumor microenvironment through CD8+ T and NK cells.

PubMed

Gao, Xin; Wang, Xuefeng; Yang, Qianting; Zhao, Xin; Wen, Wen; Li, Gang; Lu, Junfeng; Qin, Wenxin; Qi, Yuan; Xie, Fang; Jiang, Jingting; Wu, Changping; Zhang, Xueguang; Chen, Xinchun; Turnquist, Heth; Zhu, Yibei; Lu, Binfeng

2015-01-01

Cancer immunotherapy has shown great promise as a new standard cancer therapeutic modality. However, the response rates are limited for current approach that depends on enhancing spontaneous antitumor immune responses. Therefore, increasing tumor immunogenicity by expressing appropriate cytokines should further improve the current immunotherapy. IL-33 is a member of the IL-1 family of cytokines and is released by necrotic epithelial cells or activated innate immune cells and is thus considered a "danger" signal. The role of IL-33 in promoting type 2 immune responses and tissue inflammation has been well established. However, whether IL-33 drives antitumor immune responses is controversial. Our previous work established that IL-33 promoted the function of CD8(+) T cells. In this study, we showed that the expression of IL-33 in two types of cancer cells potently inhibited tumor growth and metastasis. Mechanistically, IL-33 increased numbers and IFN-γ production by CD8(+) T and NK cells in tumor tissues, thereby inducing a tumor microenvironment favoring tumor eradication. Importantly, IL-33 greatly increased tumor Ag-specific CD8(+) T cells. Furthermore, both NK and CD8(+) T cells were required for the antitumor effect of IL-33. Moreover, depletion of regulatory T cells worked synergistically with IL-33 expression for tumor elimination. Our studies established "alarmin" IL-33 as a promising new cytokine for tumor immunotherapy through promoting cancer-eradicating type 1 immune responses. Copyright © 2014 by The American Association of Immunologists, Inc.

Amplification of tumor inducing putative cancer stem cells (CSCs) by vitamin A/retinol from mammary tumors

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

Sharma, Rohit B.; Wang, Qingde; Khillan, Jaspal S., E-mail: khillan@pitt.edu

Highlights: •Vitamin A supports self renewal of putative CSCs from mammary tumors. •These cells exhibit impaired retinol metabolism into retinoic acid. •CSCs from mammary tumors differentiate into mammary specific cell lineages. •The cells express mammary stem cell specific CD29 and CD49f markers. •Putative CSCs form highly metastatic tumors in NOD SCID mouse. -- Abstract: Solid tumors contain a rare population of cancer stem cells (CSCs) that are responsible for relapse and metastasis. The existence of CSC however, remains highly controversial issue. Here we present the evidence for putative CSCs from mammary tumors amplified by vitamin A/retinol signaling. The cells exhibitmore » mammary stem cell specific CD29{sup hi}/CD49f{sup hi}/CD24{sup hi} markers, resistance to radiation and chemo therapeutic agents and form highly metastatic tumors in NOD/SCID mice. The cells exhibit indefinite self renewal as cell lines. Furthermore, the cells exhibit impaired retinol metabolism and do not express enzymes that metabolize retinol into retinoic acid. Vitamin A/retinol also amplified putative CSCs from breast cancer cell lines that form highly aggressive tumors in NOD SCID mice. The studies suggest that high purity putative CSCs can be isolated from solid tumors to establish patient specific cell lines for personalized therapeutics for pre-clinical translational applications. Characterization of CSCs will allow understanding of basic cellular and molecular pathways that are deregulated, mechanisms of tumor metastasis and evasion of therapies that has direct clinical relevance.« less

Chiron stellar occultation candidates: 1993-1996

NASA Technical Reports Server (NTRS)

Bus, S. J.; Wasserman, L. H.; Elliot, J. L.

1994-01-01

A photographic search was conducted for stars that may be occulted by the unusual solar system object (2060) Chiron during the period from fall 1993 through summer 1996. 44 candidates were identified to a limiting V magnitude of 16, and for which the minimum appulse separation with Chiron is predicted to be less than 2.5 arcsec. The successful observation of a stellar occultation by Chiron would give a direct measure of its diameter (currently estimated to be between 60 and 300 km), and would help considerably in constraining Chiron's surface properties and volatile makeup. If at the time of the occultation, Chiron exhibits a significant coma, there is also the potential for measuring the optical-depth profile of the dust in its inner coma.

Characterization of tumor infiltrating Natural Killer cell subset

PubMed Central

Nissan, Aviram; Darash-Yahana, Merav; Peretz, Tamar; Mandelboim, Ofer; Rachmilewitz, Jacob

2015-01-01

The presence of tumor-infiltrating Natural Killer (NK) within a tumor bed may be indicative of an ongoing immune response toward the tumor. However, many studies have shown that an intense NK infiltration, is associated with advanced disease and may even facilitate cancer development. The exact role of the tumor infiltrating NK cells and the correlation between their presence and poor prognosis remains unclear. Interestingly, during pregnancy high numbers of a specific NK subset, CD56brightCD16dim, are accumulated within first trimester deciduas. These decidual NK (dNK) cells are unique in their gene expression pattern secret angiogenic factors that induce vascular growth. In the present study we demonstrate a significant enrichment of a CD56brighCD16dim NK cells within tumors. These NK cells express several dNK markers including VEGF. Hence, this study adds new insights into the identity of tumor residual NK cells, which has clear implications for the treatment of human cancer. PMID:26079948

CD8+ T-cell responses rapidly select for antigen-negative tumor cells in the prostate.

PubMed

Bak, S Peter; Barnkob, Mike Stein; Wittrup, K Dane; Chen, Jianzhu

2013-12-01

Stimulation of patients' immune systems for the treatment of solid tumors is an emerging therapeutic paradigm. The use of enriched autologous T cells for adoptive cell therapy or vaccination with antigen-loaded dendritic cells have shown clinical efficacy in melanoma and prostate cancer, respectively. However, the long-term effects of immune responses on selection and outgrowth of antigen-negative tumor cells in specific tumor types must be determined to understand and achieve long-term therapeutic effects. In this study, we have investigated the expression of a tumor-specific antigen in situ after treatment with tumor-specific CD8(+) T cells in an autochthonous mouse model of prostate cancer. After T-cell treatment, aggregates of dead antigen-positive tumor cells were concentrated in the lumen of the prostate gland and were eventually eliminated from the prostate tissue. Despite the elimination of antigen-positive tumor cells, prostate tumor continued to grow in T-cell-treated mice. Interestingly, the remaining tumor cells were antigen negative and downregulated MHC class I expression. These results show that CD8(+) T cells are effective in eliminating antigen-bearing prostate tumor cells but they also can select for the outgrowth of antigen-negative tumor cells. These findings provide insights into the requirements for an effective cancer immunotherapy within the prostate that not only induces potent immune responses but also avoids selection and outgrowth of antigen-negative tumor cells. ©2013 AACR.

Collaboration between tumor-specific CD4+ T cells and B cells in anti-cancer immunity.

PubMed

Guy, Thomas V; Terry, Alexandra M; Bolton, Holly A; Hancock, David G; Zhu, Erhua; Brink, Robert; McGuire, Helen M; Shklovskaya, Elena; Fazekas de St. Groth, Barbara

2016-05-24

The role of B cells and antibodies in anti-tumor immunity is controversial, with both positive and negative effects reported in animal models and clinical studies. We developed a murine B16.F10 melanoma model to study the effects of collaboration between tumor-specific CD4+ T cells and B cells on tumor control. By incorporating T cell receptor transgenic T cells and B cell receptor isotype switching B cells, we were able to track the responses of tumor-reactive T and B cells and the development of anti-tumor antibodies in vivo. In the presence of tumor-specific B cells, the number of tumor-reactive CD4+ T cells was reduced in lymphoid tissues and the tumor itself, and this correlated with poor tumor control. B cells had little effect on the Th1 bias of the CD4+ T cell response, and the number of induced FoxP3+ regulatory cells (iTregs) generated from within the original naive CD4+ T cell inoculum was unrelated to the degree of B cell expansion. In response to CD4+ T cell help, B cells produced a range of isotype-switched anti-tumor antibodies, principally IgG1, IgG2a/c and IgG2b. In the absence of CD4+ T cells, B cells responded to agonistic anti-CD40 administration by switching to production of IgG2a/c and, to a lesser extent, IgG1, IgG3, IgA and IgE, which reduced the number of lung metastases after i.v. tumor inoculation but had no effect on the growth of subcutaneous tumors.

Transfer of allogeneic CD4+ T cells rescues CD8+ T cells in anti-PD-L1–resistant tumors leading to tumor eradication

PubMed Central

Arina, Ainhoa; Karrison, Theodore; Galka, Eva; Schreiber, Karin; Weichselbaum, Ralph R.; Schreiber, Hans

2017-01-01

Adoptively transferred CD8+ T cells can stabilize the size of solid tumors over long periods of time by exclusively recognizing antigen cross-presented on tumor stroma. However, these tumors eventually escape T cell–mediated growth control. The aim of this study was to eradicate such persistent cancers. In our model, the SIYRYYGL antigen is expressed by cancer cells that lack the MHC-I molecule Kb needed for direct presentation, but the antigen is picked up and cross-presented by tumor stroma. A single injection of antigen-specific 2C CD8+ T cells caused long-term inhibition of tumor growth, but without further intervention, tumors started to progress after approximately 3 months. Escape was associated with reduced numbers of circulating 2C cells. Tumor-infiltrating 2C cells produced significantly less TNFα and expressed more of the “exhaustion” markers PD-1 and Tim-3 than T cells from lymphoid organs. High-dose local ionizing radiation, depletion of myeloid-derived suppressor cells, infusions of additional 2C cells, and antibodies blocking PD-L1 did not prevent tumor escape. In contrast, adoptive transfer of allogeneic CD4+ T cells restored the numbers of circulating Ag-specific CD8+ T cells and their intratumoral function, resulting in tumor eradication. These CD4+ T cells had no antitumor effects in the absence of CD8+ T cells and recognized the alloantigen cross-presented on tumor stroma. CD4+ T cells might also be effective in cancer patients when PD1/PD-L1 blockade does not rescue intratumoral CD8+ T-cell function and tumors persist. PMID:28077434

Contralateral Prophylactic Mastectomy: Factors Predictive of Occult Malignancy or High-Risk Lesion and the Impact of MRI and Genetic Testing.

PubMed

Erdahl, Lillian M; Boughey, Judy C; Hoskin, Tanya L; Degnim, Amy C; Hieken, Tina J

2016-01-01

Despite decreasing rates of subsequent contralateral breast cancer after diagnosis of unilateral primary breast cancer, the proportion of patients electing contralateral prophylactic mastectomy (CPM) is increasing. Our aim was to identify risk factors associated with the identification of occult malignancy (OM) or high-risk lesion (HRL) in CPM to facilitate patient counseling and operative planning. We identified patients undergoing CPM in addition to mastectomy for index breast cancer between October 2008 and June 2013. Patient and tumor factors were analyzed to identify associations with OM or HRL in CPM. Among 740 CPM patients, an OM was identified in 4.1 % and an HRL was identified in 10.5 %. On multivariable analysis, factors associated with either occult finding included older age [odds ratio (OR) 1.37, per 10-year increase], invasive lobular index tumor histology (OR 2.60), progesterone receptor (PR)-positive index tumor (OR 1.79), and neoadjuvant therapy (OR 0.55). Overall, 244 patients (33 %) underwent BRCA testing, and 38 (16 %) had a deleterious mutation; 494 patients (67 %) had a preoperative breast MRI. Neither absence of a deleterious BRCA mutation nor a negative preoperative MRI decreased the likelihood of an occult finding in CPM. Although invasive cancer was identified infrequently in CPM specimens, the rate of HRL or OM in our study was 14.6 %. Older age and infiltrating lobular and PR-positive index breast cancers were associated with a higher risk of OM in CPM, while neoadjuvant therapy diminished the risk. BRCA testing and preoperative MRI were not associated with HRL or OM. This information is valuable for patient counseling and surgical planning.

Malignant perivascular epithelioid cell tumor of the retroperitoneum.

PubMed

Wu, Ji-Hua; Zhou, Jin-Lian; Cui, Yan; Jing, Qing-Ping; Shang, Le; Zhang, Jian-Zhong

2013-01-01

Perivascular epithelioid cell tumors (PEComas) are a rare type of mesenchymal neoplasms characterized by a proliferation of perivascular cells with an epithelioid phenotype and expression of myo-melanocytic markers. The majority of PEComas seem to be benign and usually their prognosis is good. Malignant cases are extremely rare, exhibiting a malignant course with local recurrences and distant metastases. We herein report a case of a malignant PEComa arising in the retroperitoneum. The patient was a 55-year-old woman experiencing abdominal discomfort for approximately one month. Ultrasound and computer tomography (CT) scans of the abdomen revealed a solid mass arising from the retroperitoneum. Microscopically, the tumor was composed of epithelioid cells mixed with spindled cells. The nucleus had significant atypia, and the mitoses were obvious. The focal intravascular tumor embolus was visible. Immunohistochemically, the epithelioid tumor cells were positive for HMB45 and Melan-A, and the spindled tumor celLs were positive for SMA and desmin. Seven months after a surgical resection, an ultrasound revealed liver metastases. In conclusion, the malignant PEComas of the retroperitoneum is a very rare neoplasm with unique morphological and immunohistochemical characteristics. It should be differentiated from other epithelioid cell tumors of the retroperitoneum.

Nondimensional Representations for Occulter Design and Performance Evaluation

NASA Technical Reports Server (NTRS)

Cady, Eric

2011-01-01

An occulter is a spacecraft with a precisely-shaped optical edges which ies in formation with a telescope, blocking light from a star while leaving light from nearby planets una ected. Using linear optimization, occulters can be designed for use with telescopes over a wide range of telescope aperture sizes, science bands, and starlight suppression levels. It can be shown that this optimization depends primarily on a small number of independent nondimensional parameters, which correspond to Fresnel numbers and physical scales and enter the optimization only as constraints. We show how these can be used to span the parameter space of possible optimized occulters; this data set can then be mined to determine occulter sizes for various mission scenarios and sets of engineering constraints.

Sizes, Shapes, and Satellites of Asteroids from Occultations

NASA Astrophysics Data System (ADS)

Dunham, David W.; Herald, David; Preston, Steve; Timerson, Brad; Maley, Paul; Frappa, Eric; Hayamizu, Tsutomu; Talbot, John; Poro, Atila

2016-01-01

For 40 years, the sizes and shapes of many dozens of asteroids have been determined from observations of asteroidal occultations, and over a thousand high-precision positions of the asteroids relative to stars have been measured. Some of the first evidence for satellites of asteroids was obtained from the early efforts; now, the orbits and sizes of some satellites discovered by other means have been refined from occultation observations. Also, several close binary stars have been discovered, and the angular diameters of some stars have been measured from analysis of these observations. The International Occultation Timing Association (IOTA) coordinates this activity worldwide, from predicting and publicizing the events, to accurately timing the occultations from as many stations as possible, and publishing and archiving the observations.

[Clinicopathologic characteristics of hemangiopericytoma/solitary fibrous tumor with giant cells].

PubMed

Wang, Hai-yan; Fan, Qin-he; Gong, Qi-xing; Wang, Zheng

2009-03-01

To study the pathological characteristics, diagnosis and differential diagnoses of hemangiopericytoma-solitary fibrous tumor with giant cells. Pathological characteristics of seven cases of orbital and extraorbital hemangiopericytoma-solitary fibrous tumors with giant cells were evaluated by HE and immunohistochemistry (EnVision method). Two cases were located in the orbit, one of which had recurred. Five cases were located in the extraorbital regions. Histologically, the tumors were well-circumscribed and composed of non-atypical, round to spindle cells with collagen deposition in the stroma. The tumors had prominent vasculatures and in areas, pseudovascular spaces lined by multinucleated giant cells lining which were also present in the stroma. Immunohistochemically, both neoplastic cells and multinucleate giant cells expressed CD34. Seven patients underwent tumor excision and were well and without tumor recurrence upon the clinical follow-up. Hemangiopericytoma-solitary fibrous tumor with giant cells is an intermediate soft tissue tumor. It typically involves the orbital or extraorbital regions. Histologically, the tumor should be distinguished from giant cell fibroblastoma, pleomorphic hyalinzing angiectatic tumor of soft part and angiomatoid fibrous histiocytoma.

Mast cells: potential positive and negative roles in tumor biology.

PubMed

Marichal, Thomas; Tsai, Mindy; Galli, Stephen J

2013-11-01

Mast cells are immune cells that reside in virtually all vascularized tissues. Upon activation by diverse mechanisms, mast cells can secrete a broad array of biologically active products that either are stored in the cytoplasmic granules of the cells (e.g., histamine, heparin, various proteases) or are produced de novo upon cell stimulation (e.g., prostaglandins, leukotrienes, cytokines, chemokines, and growth factors). Mast cells are best known for their effector functions during anaphylaxis and acute IgE-associated allergic reactions, but they also have been implicated in a wide variety of processes that maintain health or contribute to disease. There has been particular interest in the possible roles of mast cells in tumor biology. In vitro studies have shown that mast cells have the potential to influence many aspects of tumor biology, including tumor development, tumor-induced angiogenesis, and tissue remodeling, and the shaping of adaptive immune responses to tumors. Yet, the actual contributions of mast cells to tumor biology in vivo remain controversial. Here, we review some basic features of mast cell biology with a special emphasis on those relevant to their potential roles in tumors. We discuss how using in vivo tumor models in combination with models in which mast cell function can be modulated has implicated mast cells in the regulation of host responses to tumors. Finally, we summarize data from studies of human tumors that suggest either beneficial or detrimental roles for mast cells in tumors. ©2013 AACR.

Mutations Associated With Occult Hepatitis B in HIV-Positive South Africans

PubMed Central

Powell, Eleanor A.; Gededzha, Maemu P.; Rentz, Michael; Rakgole, Nare J.; Selabe, Selokela G.; Seleise, Tebogo A.; Mphahlele, M. Jeffrey; Blackard, Jason T.

2015-01-01

Occult hepatitis B is characterized by the absence of hepatitis B surface antigen (HBsAg) but the presence of HBV DNA. Because diagnosis of hepatitis B virus (HBV) typically includes HBsAg detection, occult HBV remains largely undiagnosed. Occult HBV is associated with increased risk of hepatocellular carcinoma, reactivation to chronic HBV during immune suppression, and transmission during blood transfusion and liver transplant. The mechanisms leading to occult HBV infection are unclear, although viral mutations are likely a significant factor. In this study, sera from 394 HIV-positive South Africans were tested for HBV DNA and HBsAg. For patients with detectable HBV DNA, the overlapping surface and polymerase open reading frames (ORFs) were sequenced. Occult-associated mutations—those mutations found exclusively in individuals with occult HBV infection but not in individuals with chronic HBV infection from the same cohort or GenBank references—were identified. Ninety patients (22.8%) had detectable HBV DNA. Of these, 37 had detectable HBsAg, while 53 lacked detectable surface antigen. The surface and polymerase ORFs were cloned successfully for 19 patients with chronic HBV and 30 patients with occult HBV. In total, 235 occult-associated mutations were identified. Ten occult-associated mutations were identified in more than one patient. Additionally, 15 amino acid positions had two distinct occult-associated mutations at the same residue. Occult-associated mutations were common and present in all regions of the surface and polymerase ORFs. Further study is underway to determine the effects of these mutations on viral replication and surface antigen expression in vitro. PMID:25164924

Mutations associated with occult hepatitis B in HIV-positive South Africans.

PubMed

Powell, Eleanor A; Gededzha, Maemu P; Rentz, Michael; Rakgole, Nare J; Selabe, Selokela G; Seleise, Tebogo A; Mphahlele, M Jeffrey; Blackard, Jason T

2015-03-01

Occult hepatitis B is characterized by the absence of hepatitis B surface antigen (HBsAg) but the presence of HBV DNA. Because diagnosis of hepatitis B virus (HBV) typically includes HBsAg detection, occult HBV remains largely undiagnosed. Occult HBV is associated with increased risk of hepatocellular carcinoma, reactivation to chronic HBV during immune suppression, and transmission during blood transfusion and liver transplant. The mechanisms leading to occult HBV infection are unclear, although viral mutations are likely a significant factor. In this study, sera from 394 HIV-positive South Africans were tested for HBV DNA and HBsAg. For patients with detectable HBV DNA, the overlapping surface and polymerase open reading frames (ORFs) were sequenced. Occult-associated mutations-those mutations found exclusively in individuals with occult HBV infection but not in individuals with chronic HBV infection from the same cohort or GenBank references-were identified. Ninety patients (22.8%) had detectable HBV DNA. Of these, 37 had detectable HBsAg, while 53 lacked detectable surface antigen. The surface and polymerase ORFs were cloned successfully for 19 patients with chronic HBV and 30 patients with occult HBV. In total, 235 occult-associated mutations were identified. Ten occult-associated mutations were identified in more than one patient. Additionally, 15 amino acid positions had two distinct occult-associated mutations at the same residue. Occult-associated mutations were common and present in all regions of the surface and polymerase ORFs. Further study is underway to determine the effects of these mutations on viral replication and surface antigen expression in vitro. © 2014 Wiley Periodicals, Inc.

[Therapeutic strategies targeting brain tumor stem cells].

PubMed

Toda, Masahiro

2009-07-01

Progress in stem cell research reveals cancer stem cells to be present in a variety of malignant tumors. Since they exhibit resistance to anticancer drugs and radiotherapy, analysis of their properties has been rapidly carried forward as an important target for the treatment of intractable malignancies, including brain tumors. In fact, brain cancer stem cells (BCSCs) have been isolated from brain tumor tissue and brain tumor cell lines by using neural stem cell culture methods and isolation methods for side population (SP) cells, which have high drug-efflux capacity. Although the analysis of the properties of BCSCs is the most important to developing methods in treating BCSCs, the absence of BCSC purification methods should be remedied by taking it up as an important research task in the immediate future. Thus far, there are no effective treatment methods for BCSCs, and several treatment methods have been proposed based on the cell biology characteristics of BCSCs. In this article, I outline potential treatment methods damaging treatment-resistant BCSCs, including immunotherapy which is currently a topic of our research.

Mesenchymal-Epithelial Transition and Circulating Tumor Cells in Small Cell Lung Cancer.

PubMed

Hamilton, Gerhard; Rath, Barbara

2017-01-01

Cancer patients die of metastatic disease but knowledge regarding individual steps of this complex process of intravasation, spread and extravasation leading to secondary lesions is incomplete. Subpopulations of tumor cells are supposed to undergo an epithelial-mesenchymal transition (EMT), to enter the bloodstream and eventually establish metastases in a reverse process termed mesenchymal-epithelial transition (MET). Small cell lung cancer (SCLC) represents a unique model to study metastatic spread due to early dissemination and relapse, as well as availability of a panel of circulating cancer cell (CTC) lines recently. Additionally, chemosensitive SCLC tumor cells switch to a completely resistant phenotype during cancer recurrence. In advanced disease, SCLC patients display extremely high blood counts of CTCs in contrast to other tumors, like breast, prostate and colon cancer. Local inflammatory conditions at the primary tumor site and recruitment of macrophages seem to increase the shedding of tumor cells into the circulation in processes which may proceed independently of EMT. Since millions of cells are released by tumors into the circulation per day, analysis of a limited number of CTCs at specific time points are difficult to be related to the development of metastatic lesions which may occur approximately one year later. We have obtained a panel of SCLC CTC cell line from patients with relapsing disease, which share characteristic markers of this malignancy and a primarily epithelial phenotype with unique formation of large tumorospheres, containing quiescent and hypoxic cells. Although smoking and inflammation promote EMT, partial expression of vimentin indicates a transitional state with partial EMT in these cell lines at most. The CTC lines exhibit high expression of EpCAM , absent phosphorylation of β-catenin and background levels of Snail. Provided that these tumor cells had ever undergone EMT, here in advanced disease MET seem to have occurred

Clinical relevance and biology of circulating tumor cells

PubMed Central

2011-01-01

Most breast cancer patients die due to metastases, and the early onset of this multistep process is usually missed by current tumor staging modalities. Therefore, ultrasensitive techniques have been developed to enable the enrichment, detection, isolation and characterization of disseminated tumor cells in bone marrow and circulating tumor cells in the peripheral blood of cancer patients. There is increasing evidence that the presence of these cells is associated with an unfavorable prognosis related to metastatic progression in the bone and other organs. This review focuses on investigations regarding the biology and clinical relevance of circulating tumor cells in breast cancer. PMID:22114869

General Information about Extragonadal Germ Cell Tumors

MedlinePlus

... Germ Cell Tumors Treatment (PDQ®)–Patient Version General Information About Extragonadal Germ Cell Tumors Go to Health ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

Treatment Option Overview (Ovarian Germ Cell Tumors)

MedlinePlus

... Tube, & Primary Peritoneal Cancer Screening Research Ovarian Germ Cell Tumors Treatment (PDQ®)–Patient Version Treatment Option Overview ... types of treatment for patients with ovarian germ cell tumors. Different types of treatment are available for ...

Design of an occulter testbed at flight Fresnel numbers

NASA Astrophysics Data System (ADS)

Sirbu, Dan; Kasdin, N. Jeremy; Kim, Yunjong; Vanderbei, Robert J.

2015-01-01

An external occulter is a spacecraft flown along the line-of-sight of a space telescope to suppress starlight and enable high-contrast direct imaging of exoplanets. Laboratory verification of occulter designs is necessary to validate the optical models used to design and predict occulter performance. At Princeton, we are designing and building a testbed that allows verification of scaled occulter designs whose suppressed shadow is mathematically identical to that of space occulters. Here, we present a sample design operating at a flight Fresnel number and is thus representative of a realistic space mission. We present calculations of experimental limits arising from the finite size and propagation distance available in the testbed, limitations due to manufacturing feature size, and non-ideal input beam. We demonstrate how the testbed is designed to be feature-size limited, and provide an estimation of the expected performance.

MHC-I modulation due to changes in tumor cell metabolism regulates tumor sensitivity to CTL and NK cells

PubMed Central

Catalán, Elena; Charni, Seyma; Jaime, Paula; Aguiló, Juan Ignacio; Enríquez, José Antonio; Naval, Javier; Pardo, Julián; Villalba, Martín; Anel, Alberto

2015-01-01

Tumor cells have a tendency to use glucose fermentation to obtain energy instead of mitochondrial oxidative phosphorylation (OXPHOS). We demonstrated that this phenotype correlated with loss of ERK5 expression and with reduced MHC class I expression. Consequently, tumor cells could evade cytotoxic T lymphocyte (CTL)-mediated immune surveillance, but also increase their sensitivity to natural killer (NK) cells. These outcomes were evaluated using two cellular models: leukemic EL4 cells and L929 transformed fibroblasts and their derived ρ° cell lines, which lack mitochondrial DNA. We have also used a L929 cell sub-line that spontaneously lost matrix attachment (L929dt), reminiscent of metastasis generation, that also downregulated MHC-I and ERK5 expression. MHC-I expression is lower in ρ° cells than in the parental cell lines, but they were equally sensitive to CTL. On the contrary, ρ° cells were more sensitive to activated NK cells than parental cells. On the other hand, L929dt cells were resistant to CTL and NK cells, showed reduced viability when forced to perform OXPHOS, and surviving cells increased MHC-I expression and became sensitive to CTL. The present results suggest that when the reduction in MHC-I levels in tumor cells due to glycolytic metabolism is partial, the increase in sensitivity to NK cells seems to predominate. However, when tumor cells completely lose MHC-I expression, the combination of treatments that increase OXPHOS with CTL-mediated immunotherapy could be a promising therapeutic approach. PMID:25949869

MHC-I modulation due to changes in tumor cell metabolism regulates tumor sensitivity to CTL and NK cells.

PubMed

Catalán, Elena; Charni, Seyma; Jaime, Paula; Aguiló, Juan Ignacio; Enríquez, José Antonio; Naval, Javier; Pardo, Julián; Villalba, Martín; Anel, Alberto

2015-01-01

Tumor cells have a tendency to use glucose fermentation to obtain energy instead of mitochondrial oxidative phosphorylation (OXPHOS). We demonstrated that this phenotype correlated with loss of ERK5 expression and with reduced MHC class I expression. Consequently, tumor cells could evade cytotoxic T lymphocyte (CTL)-mediated immune surveillance, but also increase their sensitivity to natural killer (NK) cells. These outcomes were evaluated using two cellular models: leukemic EL4 cells and L929 transformed fibroblasts and their derived ρ° cell lines, which lack mitochondrial DNA. We have also used a L929 cell sub-line that spontaneously lost matrix attachment (L929dt), reminiscent of metastasis generation, that also downregulated MHC-I and ERK5 expression. MHC-I expression is lower in ρ° cells than in the parental cell lines, but they were equally sensitive to CTL. On the contrary, ρ° cells were more sensitive to activated NK cells than parental cells. On the other hand, L929dt cells were resistant to CTL and NK cells, showed reduced viability when forced to perform OXPHOS, and surviving cells increased MHC-I expression and became sensitive to CTL. The present results suggest that when the reduction in MHC-I levels in tumor cells due to glycolytic metabolism is partial, the increase in sensitivity to NK cells seems to predominate. However, when tumor cells completely lose MHC-I expression, the combination of treatments that increase OXPHOS with CTL-mediated immunotherapy could be a promising therapeutic approach.

Phagocytosis of Candida albicans Enhances Malignant Behavior of Murine Tumor Cells

NASA Astrophysics Data System (ADS)

Ginsburg, Isaac; Fligiel, Suzanne E. G.; Kunkel, Robin G.; Riser, Bruce L.; Varani, James

1987-12-01

Murine tumor cells were induced to phagocytize either Candida albicans or group A streptococcal cells. The presence of microbial particles within the tumor cell cytoplasm had no effect on in vitro tumor cell growth. However, when Candida albicans-infected tumor cells were injected into syngeneic mice, they formed tumors that grew faster, invaded the surrounding normal tissue more rapidly and metastasized more rapidly than control tumor cells. Tumor cells infected with group A streptococcal particles did not grow faster or show increased malignant behavior. These data indicate that the in vivo behavior of malignant tumor cells can be modulated by microbial particles, which are often present in the microenvironment of the growing tumor.

Migratory neighbors and distant invaders: tumor-associated niche cells

PubMed Central

Wels, Jared; Kaplan, Rosandra N.; Rafii, Shahin; Lyden, David

2008-01-01

The cancer environment is comprised of tumor cells as well as a wide network of stromal and vascular cells participating in the cellular and molecular events necessary for invasion and metastasis. Tumor secretory factors can activate the migration of host cells, both near to and far from the primary tumor site, as well as promote the exodus of cells to distant tissues. Thus, the migration of stromal cells and tumor cells among specialized microenvironments takes place throughout tumor and metastatic progression, providing evidence for the systemic nature of a malignancy. Investigations of the tumor–stromal and stromal–stromal cross-talk involved in cellular migration in cancer may lead to the design of novel therapeutic strategies. PMID:18316475

Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells

PubMed Central

Castelli, Germana; Pelosi, Elvira

2017-01-01

Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are associated with different mutational profiles, and possess distinct risk factors. The discovery of the molecular abnormalities underlying melanomas has led to the promising improvement of therapy, and further progress is expected in the near future. The study of melanoma precursor lesions has led to the suggestion that the pathway of tumor evolution implies the progression from benign naevi, to dysplastic naevi, to melanoma in situ and then to invasive and metastatic melanoma. The gene alterations characterizing melanomas tend to accumulate in these precursor lesions in a sequential order. Studies carried out in recent years have, in part, elucidated the great tumorigenic potential of melanoma tumor cells. These findings have led to speculation that the cancer stem cell model cannot be applied to melanoma because, in this malignancy, tumor cells possess an intrinsic plasticity, conferring the capacity to initiate and maintain the neoplastic process to phenotypically different tumor cells. PMID:29156643

CD200-expressing human basal cell carcinoma cells initiate tumor growth.

PubMed

Colmont, Chantal S; Benketah, Antisar; Reed, Simon H; Hawk, Nga V; Telford, William G; Ohyama, Manabu; Udey, Mark C; Yee, Carole L; Vogel, Jonathan C; Patel, Girish K

2013-01-22

Smoothened antagonists directly target the genetic basis of human basal cell carcinoma (BCC), the most common of all cancers. These drugs inhibit BCC growth, but they are not curative. Although BCC cells are monomorphic, immunofluorescence microscopy reveals a complex hierarchical pattern of growth with inward differentiation along hair follicle lineages. Most BCC cells express the transcription factor KLF4 and are committed to terminal differentiation. A small CD200(+) CD45(-) BCC subpopulation that represents 1.63 ± 1.11% of all BCC cells resides in small clusters at the tumor periphery. By using reproducible in vivo xenograft growth assays, we determined that tumor initiating cell frequencies approximate one per 1.5 million unsorted BCC cells. The CD200(+) CD45(-) BCC subpopulation recreated BCC tumor growth in vivo with typical histological architecture and expression of sonic hedgehog-regulated genes. Reproducible in vivo BCC growth was achieved with as few as 10,000 CD200(+) CD45(-) cells, representing ~1,500-fold enrichment. CD200(-) CD45(-) BCC cells were unable to form tumors. These findings establish a platform to study the effects of Smoothened antagonists on BCC tumor initiating cell and also suggest that currently available anti-CD200 therapy be considered, either as monotherapy or an adjunct to Smoothened antagonists, in the treatment of inoperable BCC.

Metabolic changes in tumor cells and tumor-associated macrophages: A mutual relationship.

PubMed

Netea-Maier, Romana T; Smit, Johannes W A; Netea, Mihai G

2018-01-28

In order to adapt to the reduced availability of nutrients and oxygen in the tumor microenvironment and the increased requirements of energy and building blocks necessary for maintaining their high proliferation rate, malignant cells undergo metabolic changes that result in an increased production of lactate, nitric oxide, reactive oxygen species, prostaglandins and other byproducts of arachidonic acid metabolism that influence both the composition of the inflammatory microenvironment and the function of the tumor-associated macrophages (TAMs). In response to cues present in the TME, among which products of altered tumor cell metabolism, TAMs are also required to reprogram their metabolism, with activation of glycolysis, fatty acid synthesis and altered nitrogen cycle metabolism. These changes result in functional reprogramming of TAMs which includes changes in the production of cytokines and angiogenetic factors, and contribute to the tumor progression and metastasis. Understanding the metabolic changes governing the intricate relationship between the tumor cells and the TAMs represents an essential step towards developing novel therapeutic approaches targeting the metabolic reprogramming of the immune cells to potentiate their tumoricidal potential and to circumvent therapy resistance. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Diagnostic strategy for occult hepatitis B virus infection

PubMed Central

Ocana, Sara; Casas, Maria Luisa; Buhigas, Ingrid; Lledo, Jose Luis

2011-01-01

In 2008, the European Association for the study of the liver (EASL) defined occult hepatitis B virus infection (OBI) as the “presence of hepatitis B virus (HBV) DNA in the liver (with detectable or undetectable HBV DNA in the serum) of individuals testing hepatitis B surface antigen (HBsAg) negative by currently available assays”. Several aspects of occult HBV infection are still poorly understood, including the definition itself and a standardized approach for laboratory-based detection, which is the purpose of this review. The clinical significance of OBI has not yet been established; however, in terms of public health, the clinical importance arises from the risk of HBV transmission. Consequently, it is important to detect high-risk groups for occult HBV infection to prevent transmission. The main issue is, perhaps, to identify the target population for screening OBI. Viremia is very low or undetectable in occult HBV infection, even when the most sensitive methods are used, and the detection of the viral DNA reservoir in hepatocytes would provide the best evaluation of occult HBV prevalence in a defined set of patients. However, this diagnostic approach is obviously unsuitable: blood detection of occult hepatitis B requires assays of the highest sensitivity and specificity with a lower limit of detection < 10 IU/mL for HBV DNA and < 0.1 ng/mL for HBsAg. PMID:21472120

Portable high speed photometry systems for observing occultations

NASA Astrophysics Data System (ADS)

Elliot, J. L.; Dunham, E. W.

1986-09-01

Ring orbit studies for Uranus have been particularly fruitful because of the ability, through occultations, to obtain data of high spatial resolution at the rate of 1 to 2 times per year. The occultation program at M.I.T. involves: (1) identifying the scientific questions that can be answered by occultation events, (2) predicting the zone of visibility for the useful events, (3) maintaining and improving a set of portable high-speed photometric systems, (4) obtaining the observations, and (5) reducing the data and interpreting the results. Two stellar occultations by Uranus occurred in May 1985, and were observed with a network of large telescopes that encompassed the Northern and Southern Hemispheres. Portable quartz-oscillator time standards were used at all observatories, and were calibrated before and after each event. Observations obtained form Cerro Tololo and McDonald Observatories of the 4 May and 24 May 1985 occultations by the Uranian rings clearly show a companion to the delta ring on both the immersion and emersion traces. The occultation by Ceres that occurred on 12 November 1984 was observed. Preliminary results give a mean diameter of 933 + or - 10 km, which implies a geometric albedo, Pv = 0.07 + or - 0.01 and a density 2.7 + or - 0.3 gm cu/cm. Hence Ceres is likely composed of silicate material throughout.

First results from stellar occultations in the "GAIA era"

NASA Astrophysics Data System (ADS)

Benedetti-Rossi, G.; Vieira-Martins, R.; Sicardy, B.

2017-09-01

Stellar occultation is a powerful technique to study distant solar system bodies. It allows high angular resolution of the occulting body from the analysis of a light curve acquired with high temporal resolution with uncertainties comparable as probes. In the "GAIA era", stellar occultations is now able to obtain even more impressive results such as the presence of atmosphere, rings and topographic features.

Radiation-induced equilibrium is a balance between tumor cell proliferation and T cell-mediated killing

PubMed Central

Liang, Hua; Deng, Liufu; Chmura, Steven; Burnette, Byron; Liadis, Nicole; Darga, Thomas; Beckett, Michael A.; Lingen, Mark W.; Witt, MaryEllyn; Weichselbaum, Ralph R.; Fu, Yang-Xin

2013-01-01

Local failures following radiation therapy are multifactorial and the contributions of the tumor and the host are complex. Current models of tumor equilibrium suggest that a balance exists between cell birth and cell death due to insufficient angiogenesis, immune effects, or intrinsic cellular factors. We investigated whether host immune responses contribute to radiation induced tumor equilibrium in animal models. We report an essential role for immune cells and their cytokines in suppressing tumor cell regrowth in two experimental animal model systems. Depletion of T cells or neutralization of interferon-gamma reversed radiation-induced equilibrium leading to tumor regrowth. We also demonstrate that PD-L1 blockade augments T cell responses leading to rejection of tumors in radiation induced equilibrium. We identify an active interplay between tumor cells and immune cells that occurs in radiation-induced tumor equilibrium and suggest a potential role for disruption of the PD-L1/PD-1 axis in increasing local tumor control. PMID:23630355

Solar Occultation Retrieval Algorithm Development

NASA Technical Reports Server (NTRS)

Lumpe, Jerry D.

2004-01-01

This effort addresses the comparison and validation of currently operational solar occultation retrieval algorithms, and the development of generalized algorithms for future application to multiple platforms. initial development of generalized forward model algorithms capable of simulating transmission data from of the POAM II/III and SAGE II/III instruments. Work in the 2" quarter will focus on: completion of forward model algorithms, including accurate spectral characteristics for all instruments, and comparison of simulated transmission data with actual level 1 instrument data for specific occultation events.

Occult Intertrochanteric Fracture Mimicking the Fracture of Greater Trochanter.

PubMed

Chung, Phil Hyun; Kang, Suk; Kim, Jong Pil; Kim, Young Sung; Lee, Ho Min; Back, In Hwa; Eom, Kyeong Soo

2016-06-01

Occult intertrochanteric fractures are misdiagnosed as isolated greater trochanteric fractures in some cases. We investigated the utility of three-dimensional computed tomography (3D-CT) and magnetic resonance imaging (MRI) in the diagnosis and outcome management of occult intertrochanteric fractures. This study involved 23 cases of greater trochanteric fractures as diagnosed using plain radiographs from January 2004 to July 2013. Until January 2008, 9 cases were examined with 3D-CT only, while 14 cases were screened with both 3D-CT and MRI scans. We analyzed diagnostic accuracy and treatment results following 3D-CT and MRI scanning. Nine cases that underwent 3D-CT only were diagnosed with isolated greater trochanteric fractures without occult intertrochanteric fractures. Of these, a patient with displacement received surgical treatment. Of the 14 patients screened using both CT and MRI, 13 were diagnosed with occult intertrochanteric fractures. Of these, 11 were treated with surgical intervention and 2 with conservative management. Three-dimensional CT has very low diagnostic accuracy in diagnosing occult intertrochanteric fractures. For this reason, MRI is recommended to confirm a suspected occult intertrochanteric fracture and to determine the most appropriate mode of treatment.

Openings between Defective Endothelial Cells Explain Tumor Vessel Leakiness

PubMed Central

Hashizume, Hiroya; Baluk, Peter; Morikawa, Shunichi; McLean, John W.; Thurston, Gavin; Roberge, Sylvie; Jain, Rakesh K.; McDonald, Donald M.

2000-01-01

Leakiness of blood vessels in tumors may contribute to disease progression and is key to certain forms of cancer therapy, but the structural basis of the leakiness is unclear. We sought to determine whether endothelial gaps or transcellular holes, similar to those found in leaky vessels in inflammation, could explain the leakiness of tumor vessels. Blood vessels in MCa-IV mouse mammary carcinomas, which are known to be unusually leaky (functional pore size 1.2–2 μm), were compared to vessels in three less leaky tumors and normal mammary glands. Vessels were identified by their binding of intravascularly injected fluorescent cationic liposomes and Lycopersicon esculentum lectin and by CD31 (PECAM) immunoreactivity. The luminal surface of vessels in all four tumors had a defective endothelial monolayer as revealed by scanning electron microscopy. In MCa-IV tumors, 14% of the vessel surface was lined by poorly connected, overlapping cells. The most superficial lining cells, like endothelial cells, had CD31 immunoreactivity and fenestrae with diaphragms, but they had a branched phenotype with cytoplasmic projections as long as 50 μm. Some branched cells were separated by intercellular openings (mean diameter 1.7 μm; range, 0.3–4.7 μm). Transcellular holes (mean diameter 0.6 μm) were also present but were only 8% as numerous as intercellular openings. Some CD31-positive cells protruded into the vessel lumen; others sprouted into perivascular tumor tissue. Tumors in RIP-Tag2 mice had, in addition, tumor cell-lined lakes of extravasated erythrocytes. We conclude that some tumor vessels have a defective cellular lining composed of disorganized, loosely connected, branched, overlapping or sprouting endothelial cells. Openings between these cells contribute to tumor vessel leakiness and may permit access of macromolecular therapeutic agents to tumor cells. PMID:10751361

Malignant perivascular epithelioid cell tumor of the retroperitoneum

PubMed Central

Wu, Ji-Hua; Zhou, Jin-Lian; Cui, Yan; Jing, Qing-Ping; Shang, Le; Zhang, Jian-Zhong

2013-01-01

Perivascular epithelioid cell tumors (PEComas) are a rare type of mesenchymal neoplasms characterized by a proliferation of perivascular cells with an epithelioid phenotype and expression of myo-melanocytic markers. The majority of PEComas seem to be benign and usually their prognosis is good. Malignant cases are extremely rare, exhibiting a malignant course with local recurrences and distant metastases. We herein report a case of a malignant PEComa arising in the retroperitoneum. The patient was a 55-year-old woman experiencing abdominal discomfort for approximately one month. Ultrasound and computer tomography (CT) scans of the abdomen revealed a solid mass arising from the retroperitoneum. Microscopically, the tumor was composed of epithelioid cells mixed with spindled cells. The nucleus had significant atypia, and the mitoses were obvious. The focal intravascular tumor embolus was visible. Immunohistochemically, the epithelioid tumor cells were positive for HMB45 and Melan-A, and the spindled tumor celLs were positive for SMA and desmin. Seven months after a surgical resection, an ultrasound revealed liver metastases. In conclusion, the malignant PEComas of the retroperitoneum is a very rare neoplasm with unique morphological and immunohistochemical characteristics. It should be differentiated from other epithelioid cell tumors of the retroperitoneum. PMID:24133607

Classifying Non-Small Cell Lung Cancer by Status of Programmed Cell Death Ligand 1 and Tumor-Infiltrating Lymphocytes on Tumor Cells.

PubMed

Cui, Shaohua; Dong, Lili; Qian, Jialin; Ye, Lin; Jiang, Liyan

2018-01-01

Purpose: To explore the possible correlation between programmed death ligand 1 (PD-L1)/tumor-infiltrating lymphocytes (TIL) status and clinical factors in non-small cell lung (NSCLC). Materials and Methods: A total of 126 surgical NSCLC samples with stage I to IIIA were retrospectively collected and analyzed. Immunohistochemistry (IHC) assays were used to detect PD-L1 protein expression. PD-L1 positivity on tumor cells was defined by positive tumor cell (TC) percentage using 5% cutoff value. Results: Thirty-seven patients (29.4%), thirty patients (23.8%), six patients (4.8%) and fifty-three patients (42%) were classified as type I (PD-L1+, TIL+), type II (PD-L1-, TIL-), type III (PD-L1+, TIL-) and type IV (PD-L1-, TIL+) tumor environments according to PD-L1/TIL status, respectively. Statistical differences could be observed in factors including gender ( P <0.001), smoking status ( P <0.001), age ( P =0.002), histological types ( P <0.001), EGFR mutation ( P =0.008) and KRAS mutation ( P =0.003) across the four type tumors. Type I tumors were associated with ever smoking, non-adenocarcinoma histological types and KRAS mutation. Type II tumors were associated with female gender, never-smoking, adenocarcinoma histological types and EGFR mutation. Type III tumors were associated with ever smoking and type IV tumors were associated with female gender and EGFR mutation. Conclusion: Clinical factors associated with NSCLC microenvironment types based on PD-L1/TIL differed a lot across different types. The findings of this study may help to facilitate the understanding of the relationship between tumor microenvironment and clinical factors, and also the selecting of patients for combination immunotherapies.

Targeting Tumor Oct4 to Deplete Prostate Tumor and Metastasis Initiating Cells

DTIC Science & Technology

2017-12-01

Nie, POU5F1B, an OCT4 Retrogene, Suppresses Uncontrolled Tumor Growth. Keystone Meeting on Molecular and Cellular Basis of Growth and Regeneration...Daotai Nie. Cancer Stem Cells in Resistance to Cytotoxic Drugs: Implications in Chemotherapy. B. Bonavida (ed.), Molecular Mechanisms of Tumor Cell...retrogene of the master embryonic stem cell gene POU5F1 is associated with prostate cancer susceptibility. American journal of human genetics 94

Persistence of Multiple Tumor-Specific T-Cell Clones Is Associated with Complete Tumor Regression in a Melanoma Patient Receiving Adoptive Cell Transfer Therapy

PubMed Central

Zhou, Juhua; Dudley, Mark E.; Rosenberg, Steven A.; Robbins, Paul F.

2007-01-01

Summary The authors recently reported that adoptive immunotherapy with autologous tumor-reactive tumor infiltrating lymphocytes (TILs) immediately following a conditioning nonmyeloablative chemotherapy regimen resulted in an enhanced clinical response rate in patients with metastatic melanoma. These observations led to the current studies, which are focused on a detailed analysis of the T-cell antigen reactivity as well as the in vivo persistence of T cells in melanoma patient 2098, who experienced a complete regression of all metastatic lesions in lungs and soft tissues following therapy. Screening of an autologous tumor cell cDNA library using transferred TILs resulted in the identification of novel mutated growth arrest-specific gene 7 (GAS7) and glyceral-dehyde-3-phosphate dehydrogenase (GAPDH) gene transcripts. Direct sequence analysis of the expressed T-cell receptor beta chain variable regions showed that the transferred TILs contained multiple T-cell clonotypes, at least six of which persisted in peripheral blood for a month or more following transfer. The persistent T cells recognized both the mutated GAS7 and GAPDH. These persistent tumor-reactive T-cell clones were detected in tumor cell samples obtained from the patient following adoptive cell transfer and appeared to be represented at higher levels in the tumor sample obtained 1 month following transfer than in the peripheral blood obtained at the same time. Overall, these results indicate that multiple tumor-reactive T cells can persist in the peripheral blood and at the tumor site for prolonged times following adoptive transfer and thus may be responsible for the complete tumor regression in this patient. PMID:15614045

Giant Cell Tumor of Bone - An Overview

PubMed Central

Sobti, Anshul; Agrawal, Pranshu; Agarwala, Sanjay; Agarwal, Manish

2016-01-01

Giant Cell tumors (GCT) are benign tumors with potential for aggressive behavior and capacity to metastasize. Although rarely lethal, benign bone tumors may be associated with a substantial disturbance of the local bony architecture that can be particularly troublesome in peri-articular locations. Its histogenesis remains unclear. It is characterized by a proliferation of mononuclear stromal cells and the presence of many multi- nucleated giant cells with homogenous distribution. There is no widely held consensus regarding the ideal treatment method selection. There are advocates of varying surgical techniques ranging from intra-lesional curettage to wide resection. As most giant cell tumors are benign and are located near a joint in young adults, several authors favor an intralesional approach that preserves anatomy of bone in lieu of resection. Although GCT is classified as a benign lesion, few patients develop progressive lung metastases with poor outcomes. Treatment is mainly surgical. Options of chemotherapy and radiotherapy are reserved for selected cases. Recent advances in the understanding of pathogenesis are essential to develop new treatments for this locally destructive primary bone tumor. PMID:26894211

Different responses of tumor and normal cells to low-dose radiation

PubMed Central

Liu, Ning; Wang, Hao; Shang, Qingjun; Jiang, Peng; Zhang, Yuanmei

2013-01-01

Aim of the study We demonstrated stimulation of both erythrocyte immune function and superoxide dismutase activity in tumor-bearing mice in response to whole-body 75 mGy X-rays. In addition, we enhanced the chemotherapeutic effect by exposing tumor-bearing mice to low-dose radiation (LDR). This study aims to investigate the different responses of tumor cells and normal cells to LDR. Material and methods Survival fraction, micronucleus frequency, and cell cycle of Lewis cells and primary human fibroblast AG01522 cells were measured. S180 sarcoma cells were implanted in mice, and tumor sizes were measured in vivo. Results In response to LDR exposure in vitro, a stimulating effect was observed in AG01522 cells but not in Lewis cells. Low-dose radiation did not cause an adaptive response in the Lewis cell cycle. Lack of an LDR-induced radioadaptive response in tumor cells was observed in tumor-bearing mouse models. Furthermore, a higher apoptotic effect and lower expression of the anti-apoptosis gene Bcl-2 were found in tumor cells of tumor-bearing mice exposed to D1 + D2 than those in tumor cells of tumor-bearing mice exposed to D2 alone. Conclusions Different responses of tumor cells and normal cells to LDR were found. Low-dose radiation was found to stimulate the growth of normal cells but not of tumor cells in vitro and in vivo, which is a very important and clinically relevant phenomenon. PMID:24592123

Cell mediated therapeutics for cancer treatment: Tumor homing cells as therapeutic delivery vehicles

NASA Astrophysics Data System (ADS)

Balivada, Sivasai

Many cell types were known to have migratory properties towards tumors and different research groups have shown reliable results regarding cells as delivery vehicles of therapeutics for targeted cancer treatment. Present report discusses proof of concept for 1. Cell mediated delivery of Magnetic nanoparticles (MNPs) and targeted Magnetic hyperthermia (MHT) as a cancer treatment by using in vivo mouse cancer models, 2. Cells surface engineering with chimeric proteins for targeted cancer treatment by using in vitro models. 1. Tumor homing cells can carry MNPs specifically to the tumor site and tumor burden will decrease after alternating magnetic field (AMF) exposure. To test this hypothesis, first we loaded Fe/Fe3O4 bi-magnetic NPs into neural progenitor cells (NPCs), which were previously shown to migrate towards melanoma tumors. We observed that NPCs loaded with MNPs travel to subcutaneous melanoma tumors. After alternating magnetic field (AMF) exposure, the targeted delivery of MNPs by the NPCs resulted in a mild decrease in tumor size (Chapter-2). Monocytes/macrophages (Mo/Ma) are known to infiltrate tumor sites, and also have phagocytic activity which can increase their uptake of MNPs. To test Mo/Ma-mediated MHT we transplanted Mo/Ma loaded with MNPs into a mouse model of pancreatic peritoneal carcinomatosis. We observed that MNP-loaded Mo/Ma infiltrated pancreatic tumors and, after AMF treatment, significantly prolonged the lives of mice bearing disseminated intraperitoneal pancreatic tumors (Chapter-3). 2. Targeted cancer treatment could be achieved by engineering tumor homing cell surfaces with tumor proteases cleavable, cancer cell specific recombinant therapeutic proteins. To test this, Urokinase and Calpain (tumor specific proteases) cleavable; prostate cancer cell (CaP) specific (CaP1 targeting peptide); apoptosis inducible (Caspase3 V266ED3)- rCasp3V266ED3 chimeric protein was designed in silico. Hypothesized membrane anchored chimeric protein (rCasp3V

Pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors.

PubMed

Xin, Gang; Schauder, David M; Jing, Weiqing; Jiang, Aimin; Joshi, Nikhil S; Johnson, Bryon; Cui, Weiguo

2017-01-24

Because of insufficient migration and antitumor function of transferred T cells, especially inside the immunosuppressive tumor microenvironment (TME), the efficacy of adoptive cell transfer (ACT) is much curtailed in treating solid tumors. To overcome these challenges, we sought to reenergize ACT (ReACT) with a pathogen-based cancer vaccine. To bridge ACT with a pathogen, we genetically engineered tumor-specific CD8 T cells in vitro with a second T-cell receptor (TCR) that recognizes a bacterial antigen. We then transferred these dual-specific T cells in combination with intratumoral bacteria injection to treat solid tumors in mice. The dual-specific CD8 T cells expanded vigorously, migrated to tumor sites, and robustly eradicated primary tumors. The mice cured from ReACT also developed immunological memory against tumor rechallenge. Mechanistically, we have found that this combined approach reverts the immunosuppressive TME and recruits CD8 T cells with an increased number and killing ability to the tumors.

Pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors

PubMed Central

Xin, Gang; Schauder, David M.; Jing, Weiqing; Jiang, Aimin; Joshi, Nikhil S.; Johnson, Bryon; Cui, Weiguo

2017-01-01

Because of insufficient migration and antitumor function of transferred T cells, especially inside the immunosuppressive tumor microenvironment (TME), the efficacy of adoptive cell transfer (ACT) is much curtailed in treating solid tumors. To overcome these challenges, we sought to reenergize ACT (ReACT) with a pathogen-based cancer vaccine. To bridge ACT with a pathogen, we genetically engineered tumor-specific CD8 T cells in vitro with a second T-cell receptor (TCR) that recognizes a bacterial antigen. We then transferred these dual-specific T cells in combination with intratumoral bacteria injection to treat solid tumors in mice. The dual-specific CD8 T cells expanded vigorously, migrated to tumor sites, and robustly eradicated primary tumors. The mice cured from ReACT also developed immunological memory against tumor rechallenge. Mechanistically, we have found that this combined approach reverts the immunosuppressive TME and recruits CD8 T cells with an increased number and killing ability to the tumors. PMID:28069963

Dielectrophoretic Capture and Genetic Analysis of Single Neuroblastoma Tumor Cells

PubMed Central

Carpenter, Erica L.; Rader, JulieAnn; Ruden, Jacob; Rappaport, Eric F.; Hunter, Kristen N.; Hallberg, Paul L.; Krytska, Kate; O’Dwyer, Peter J.; Mosse, Yael P.

2014-01-01

Our understanding of the diversity of cells that escape the primary tumor and seed micrometastases remains rudimentary, and approaches for studying circulating and disseminated tumor cells have been limited by low throughput and sensitivity, reliance on single parameter sorting, and a focus on enumeration rather than phenotypic and genetic characterization. Here, we utilize a highly sensitive microfluidic and dielectrophoretic approach for the isolation and genetic analysis of individual tumor cells. We employed fluorescence labeling to isolate 208 single cells from spiking experiments conducted with 11 cell lines, including 8 neuroblastoma cell lines, and achieved a capture sensitivity of 1 tumor cell per 106 white blood cells (WBCs). Sample fixation or freezing had no detectable effect on cell capture. Point mutations were accurately detected in the whole genome amplification product of captured single tumor cells but not in negative control WBCs. We applied this approach to capture 144 single tumor cells from 10 bone marrow samples of patients suffering from neuroblastoma. In this pediatric malignancy, high-risk patients often exhibit wide-spread hematogenous metastasis, but access to primary tumor can be difficult or impossible. Here, we used flow-based sorting to pre-enrich samples with tumor involvement below 0.02%. For all patients for whom a mutation in the Anaplastic Lymphoma Kinase gene had already been detected in their primary tumor, the same mutation was detected in single cells from their marrow. These findings demonstrate a novel, non-invasive, and adaptable method for the capture and genetic analysis of single tumor cells from cancer patients. PMID:25133137

Metformin selectively affects human glioblastoma tumor-initiating cell viability

PubMed Central

Würth, Roberto; Pattarozzi, Alessandra; Gatti, Monica; Bajetto, Adirana; Corsaro, Alessandro; Parodi, Alessia; Sirito, Rodolfo; Massollo, Michela; Marini, Cecilia; Zona, Gianluigi; Fenoglio, Daniela; Sambuceti, Gianmario; Filaci, Gilberto; Daga, Antonio; Barbieri, Federica; Florio, Tullio

2013-01-01

Cancer stem cell theory postulates that a small population of tumor-initiating cells is responsible for the development, progression and recurrence of several malignancies, including glioblastoma. In this perspective, tumor-initiating cells represent the most relevant target to obtain effective cancer treatment. Metformin, a first-line drug for type II diabetes, was reported to possess anticancer properties affecting the survival of cancer stem cells in breast cancer models. We report that metformin treatment reduced the proliferation rate of tumor-initiating cell-enriched cultures isolated from four human glioblastomas. Metformin also impairs tumor-initiating cell spherogenesis, indicating a direct effect on self-renewal mechanisms. Interestingly, analyzing by FACS the antiproliferative effects of metformin on CD133-expressing subpopulation, a component of glioblastoma cancer stem cells, a higher reduction of proliferation was observed as compared with CD133-negative cells, suggesting a certain degree of cancer stem cell selectivity in its effects. In fact, glioblastoma cell differentiation strongly reduced sensitivity to metformin treatment. Metformin effects in tumor-initiating cell-enriched cultures were associated with a powerful inhibition of Akt-dependent cell survival pathway, while this pathway was not affected in differentiated cells. The specificity of metformin antiproliferative effects toward glioblastoma tumor-initiating cells was confirmed by the lack of significant inhibition of normal human stem cells (umbilical cord-derived mesenchymal stem cells) in vitro proliferation after metformin exposure. Altogether, these data clearly suggest that metformin exerts antiproliferative activity on glioblastoma cells, showing a higher specificity toward tumor-initiating cells, and that the inhibition of Akt pathway may represent a possible intracellular target of this effect. PMID:23255107

Increased IMP dehydrogenase gene expression in solid tumor tissues and tumor cell lines

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

Collart, F.R.; Chubb, C.B.; Mirkin, B.L.

1992-07-10

IMP dehydrogenase, a regulatory enzyme of guanine nucleotide biosynthesis, may play a role in cell proliferation and malignancy. To assess this possibility, we examined IMP dehydrogenase expression in a series of human solid tumor tissues and tumor cell lines in comparison with their normal counterparts. Increased IMP dehydrogenase gene expression was observed in brain tumors relative to normal brain tissue and in sarcoma cells relative to normal fibroblasts. Similarly, in several B- and T-lymphoid leukemia cell lines, elevated levels of IMP dehydrogenase mRNA and cellular enzyme were observed in comparison with the levels in peripheral blood lymphocytes. These results aremore » consistent with an association between increased IMP dehydrogenase expression and either enhanced cell proliferation or malignant transformation.« less

Identification of a Population of Epidermal Squamous Cell Carcinoma Cells with Enhanced Potential for Tumor Formation

PubMed Central

Adhikary, Gautam; Grun, Dan; Kerr, Candace; Balasubramanian, Sivaprakasam; Rorke, Ellen A.; Vemuri, Mohan; Boucher, Shayne; Bickenbach, Jackie R.; Hornyak, Thomas; Xu, Wen; Fisher, Matthew L.; Eckert, Richard L.

2013-01-01

Epidermal squamous cell carcinoma is among the most common cancers in humans. These tumors are comprised of phenotypically diverse populations of cells that display varying potential for proliferation and differentiation. An important goal is identifying cells from this population that drive tumor formation. To enrich for tumor-forming cells, cancer cells were grown as spheroids in non-attached conditions. We show that spheroid-selected cells form faster growing and larger tumors in immune-compromised mice as compared to non-selected cells. Moreover, spheroid-selected cells gave rise to tumors following injection of as few as one hundred cells, suggesting these cells have enhanced tumor-forming potential. Cells isolated from spheroid-selected tumors retain an enhanced ability to grow as spheroids when grown in non-attached culture conditions. Thus, these tumor-forming cells retain their phenotype following in vivo passage as tumors. Detailed analysis reveals that spheroid-selected cultures are highly enriched for expression of epidermal stem cell and embryonic stem cell markers, including aldehyde dehydrogenase 1, keratin 15, CD200, keratin 19, Oct4, Bmi-1, Ezh2 and trimethylated histone H3. These studies indicate that a subpopulation of cells that possess stem cell-like properties and express stem cell markers can be derived from human epidermal cancer cells and that these cells display enhanced ability to drive tumor formation. PMID:24376802

Vaccine of engineered tumor cells secreting stromal cell-derived factor-1 induces T-cell dependent antitumor responses.

PubMed

Shi, Meiqing; Hao, Siguo; Su, Liping; Zhang, Xueshu; Yuan, Jinying; Guo, Xuling; Zheng, Changyu; Xiang, Jim

2005-08-01

The CXC chemokine SDF-1 has been characterized as a T-cell chemoattractant both in vitro and in vivo. To determine whether SDF-1 expression within tumors can influence tumor growth, we transfected an expression vector pCI-SDF-1 for SDF-1 into J558 myeloma cells and tested their ability to form tumors in BALB/c. Production of biologically active SDF-1 (1.2 ng/mL) was detected in the culture supernatants of cells transfected with the expression vector pCI-SDF-1. J558 cells gave rise to a 100% tumor incidence, whereas SDF-1-expressing J558/SDF-1 tumors invariably regressed in BALB/c mice and became infiltrated with CD4(+) and CD8(+) T cells. Regression of the J558/SDF-1 tumors was dependent on both CD4(+) and CD8(+) T-cells. Our data also indicate that TIT cells containing both CD4(+) and CD8(+) T-cells within J558/SDF-1 tumors express the SDF-1 receptor CXCR4, and that SDF-1 specifically chemoattracts these cells in vitro. Furthermore, immunization of mice with engineered J558/SDF-1 cells elicited the most potent protective immunity against 0.5 x 10(6) cells J558 tumor challenge in vivo, compared to immunization with the J558 alone, and this antitumor immunity mediated by J558/SDF-1 tumor cell vaccination in vivo appeared to be dependent on CD8(+) CTL. Thus, SDF-1 has natural adjuvant activities that may augment antitumor responses through their effects on T-cells and thereby could be important in gene transfer immunotherapies for some cancers.

Functional analysis of 'a' determinant mutations associated with occult HBV in HIV-positive South Africans.

PubMed

Powell, Eleanor A; Boyce, Ceejay L; Gededzha, Maemu P; Selabe, Selokela G; Mphahlele, M Jeffrey; Blackard, Jason T

2016-07-01

Occult hepatitis B is defined by the presence of hepatitis B virus (HBV) DNA in the absence of hepatitis B surface antigen (HBsAg). Occult HBV is associated with the development of hepatocellular carcinoma, reactivation during immune suppression, and virus transmission. Viral mutations contribute significantly to the occult HBV phenotype. Mutations in the 'a' determinant of HBsAg are of particular interest, as these mutations are associated with immune escape, vaccine escape and diagnostic failure. We examined the effects of selected occult HBV-associated mutations identified in a population of HIV-positive South Africans on HBsAg production in vitro. Mutations were inserted into two different chronic HBV backbones and transfected into a hepatocyte-derived cell line. HBsAg levels were quantified by enzyme-linked immunosorbent assay (ELISA), while the detectability of mutant HBsAg was determined using an HA-tagged HBsAg expression system. Of the seven mutations analysed, four (S132P, C138Y, N146D and C147Y) resulted in decreased HBsAg expression in one viral background but not in the second viral background. One mutation (N146D) led to a decrease in HBsAg detected as compared to HA-tag, indicating that this mutation compromises the ability of the ELISA to detect HBsAg. The contribution of occult-associated mutations to the HBsAg-negative phenotype of occult HBV cannot be determined adequately by testing the effect of the mutation in a single viral background, and rigorous analysis of these mutations is required.

p53 regulates mesenchymal stem cell-mediated tumor suppression in a tumor microenvironment through immune modulation.

PubMed

Huang, Y; Yu, P; Li, W; Ren, G; Roberts, A I; Cao, W; Zhang, X; Su, J; Chen, X; Chen, Q; Shou, P; Xu, C; Du, L; Lin, L; Xie, N; Zhang, L; Wang, Y; Shi, Y

2014-07-17

p53 is one of the most studied genes in cancer biology, and mutations in this gene may be predictive for the development of many types of cancer in humans and in animals. However, whether p53 mutations in non-tumor stromal cells can affect tumor development has received very little attention. In this study, we show that B16F0 melanoma cells form much larger tumors in p53-deficient mice than in wild-type mice, indicating a potential role of p53 deficiency in non-tumor cells of the microenvironment. As mesenchymal stem cells (MSCs) are attracted to tumors and form a major component of the tumor microenvironment, we examined the potential role of p53 status in MSCs in tumor development. We found that larger tumors resulted when B16F0 melanoma cells were co-injected with bone marrow MSCs derived from p53-deficient mice rather than MSCs from wild-type mice. Interestingly, this tumor-promoting effect by p53-deficient MSCs was not observed in non-obese diabetic/severe combined immunodeficiency mice, indicating the immune response has a critical role. Indeed, in the presence of inflammatory cytokines, p53-deficient MSCs expressed more inducible nitric oxide synthase (iNOS) and exhibited greater immunosuppressive capacity. Importantly, tumor promotion by p53-deficient MSCs was abolished by administration of S-methylisothiourea, an iNOS inhibitor. Therefore, our data demonstrate that p53 status in tumor stromal cells has a key role in tumor development by modulating immune responses.

First light of an external occulter testbed at flight Fresnel numbers

NASA Astrophysics Data System (ADS)

Kim, Yunjong; Sirbu, Dan; Hu, Mia; Kasdin, Jeremy; Vanderbei, Robert J.; Harness, Anthony; Shaklan, Stuart

2017-01-01

Many approaches have been suggested over the last couple of decades for imaging Earth-like planets. One of the main candidates for creating high-contrast for future Earth-like planets detection is an external occulter. The external occulter is a spacecraft flown along the line-of-sight of a space telescope to suppress starlight and enable high-contrast direct imaging of exoplanets. The occulter is typically tens of meters in diameter and the separation from the telescope is of the order of tens of thousands of kilometers. Optical testing of a full-scale external occulter on the ground is impossible because of the long separations. Therefore, laboratory verification of occulter designs is necessary to validate the optical models used to design and predict occulter performance. At Princeton, we have designed and built a testbed that allows verification of scaled occulter designs whose suppressed shadow is mathematically identical to that of space occulters. The goal of this experiment is to demonstrate a pupil plane suppression of better than 1e-9 with a corresponding image plane contrast of better than 1e-11. The occulter testbed uses a 77.2 m optical propagation distance to realize the flight Fresnel number of 14.5. The scaled mask is placed at 27.2 m from the artificial source and the camera is located 50.0 m from the scaled mask. We will use an etched silicon mask, manufactured by the Microdevices Lab(MDL) of the Jet Propulsion Laboratory(JPL), as the occulter. Based on conversations with MDL, we expect that 0.5 μm feature size is an achievable resolution in the mask manufacturing process and is therefore likely the indicator of the best possible performance. The occulter is illuminated by a diverging laser beam to reduce the aberrations from the optics before the occulter. Here, we present first light result of a sample design operating at a flight Fresnel number and the experimental setup of the testbed. We compare the experimental results with simulations

Possible occultation by Pluto from US East Coast

NASA Astrophysics Data System (ADS)

Waagen, Elizabeth O.

2012-06-01

We have been asked to help disseminate the news of a possible occultation by Pluto visible to observers on the US East coast. Although the AAVSO does not ordinarily issue announcements of upcoming occultations, in this case the object is Pluto and the NASA New Horizons mission (http://www.nasa.gov/mission_pages/newhorizons/main/index.html) will be visiting Pluto in 2015. The information below has been supplied by Dr. Leslie Young (Southwest Research Institute), who is coordinating this observing campaign on Pluto. Dr. Young is also Deputy Project Scientist for the New Horizons mission. ALERT: Possible Pluto occultation Wednesday night (2012/06/14 03:28 UT) from US East coast. CONTACT: Leslie Young (layoung@boulder.swri.edu; work: 303-546-6057; skype: drpluto). Also see our planning pages in progress at http://wiki.boulder.swri.edu/mediawiki/index.php/2012-06-14_Pluto_occultation. Pluto's thin, nitrogen atmosphere is in vapor-pressure equilibrium with the surface ice, and changes seasonally. We've seen it double since 1988, and now we measure its pressure once or twice a year. The technique we use is stellar occultation, when a star passes behind Pluto's atmosphere. The atmosphere defocuses the starlight. By the timing of the fading of the star, we measure the pressure and temperature in Pluto's atmosphere at ~10 km resolution. MORE INFORMATION: See http://wiki.boulder.swri.edu/mediawiki/index.php/2012-06-14_Pluto_occultation.

Occultation Lightcurves for Selected Pluto Volatile Transport Models

NASA Astrophysics Data System (ADS)

Young, L. A.

2004-11-01

The stellar occultations by Pluto in 1988 and 2002 are demonstrably sensitive to changes in Pluto's atmosphere near one microbar (Elliot and Young 1992, AJ 103, 991; Elliot et al. 2003, Nature 424, 165; Sicardy 2003, Nature 424, 168). However, Pluto volatile-transport models focus on the changes in the atmospheric pressure at the surface (e.g., Hansen and Paige 1996, Icarus 20, 247; Stansberry and Yelle 1999, Icarus 141, 299). What's lacking is a connection between predictions about the surface properties and either temperature and pressure profiles measurable from stellar occultations, or the occultation light curve morphology itself. Radiative-conductive models can illuminate this connection. I will illustrate how Pluto's changing surface pressure, temperature, and heliocentric distance may affect occultation light curves for a selection of existing volatile transport models. Changes in the light curve include the presence or absence of an observable ``kink'' (or departure from an isothermal light curve), the appearance of non-zero minimum flux levels, and the detectability of the solid surface. These light curves can serve as examples of what we may anticipate during the upcoming Pluto occultation season, as Pluto crosses the galactic plane.

Enumeration of Circulating Tumor Cells and Disseminated Tumor Cells in Blood and Bone Marrow by Immunomagnetic Enrichment and Flow Cytometry (IE/FC).

PubMed

Magbanua, Mark Jesus M; Solanki, Tulasi I; Ordonez, Andrea D; Hsiao, Feng; Park, John W

2017-01-01

Enumerating circulating tumor cells (CTCs) in blood and disseminated tumor cells (DTCs) in bone marrow has shown to be clinically useful, as elevated numbers of these cells predict poor clinical outcomes. Accurate detection and quantification is, however, difficult and technically challenging because CTCs and DTCs are extremely rare. We have developed a novel quantitative detection method for enumeration of CTCs and DTCs. Our approach consists of two steps: (1) EPCAM-based immunomagnetic enrichment followed by (2) flow cytometry (IE/FC). The assay takes approximately 2 h to complete. In addition to tumor cell enumeration, IE/FC offers opportunities for direct isolation of highly pure tumor cells for downstream molecular characterization.

Interface between breast cancer cells and the tumor microenvironment using platelet-rich plasma to promote tumor angiogenesis - influence of platelets and fibrin bundles on the behavior of breast tumor cells

PubMed Central

Andrade, Sheila Siqueira; Sumikawa, Joana Tomomi; Castro, Eloísa Dognani; Batista, Fabricio Pereira; Paredes-Gamero, Edgar; Oliveira, Lilian Carolina; Guerra, Izabel Monastério; Peres, Giovani Bravin; Cavalheiro, Renan Pelluzzi; Juliano, Luiz; Nazário, Afonso Pinto; Facina, Gil; Tsai, Siu Mui; Oliva, Maria Luiza Vilela; Girão, Manoel João Batista Castello

2017-01-01

Cancer progression is associated with an evolving tissue interface of direct epithelial-tumor microenvironment interactions. In biopsies of human breast tumors, extensive alterations in molecular pathways are correlated with cancer staging on both sides of the tumor-stroma interface. These interactions provide a pivotal paracrine signaling to induce malignant phenotype transition, the epithelial-mesenchymal transition (EMT). We explored how the direct contact between platelets-fibrin bundles primes metastasis using platelet-rich plasma (PRP) as a source of growth factors and mimics the provisional fibrin matrix between actively growing breast cancer cells and the tumor stroma. We have demonstrated PRP functions, modulating cell proliferation that is tumor-subtype and cancer cell-type-specific. Epithelial and stromal primary cells were prepared from breast cancer biopsies from 21 women with different cancer subtypes. Cells supplemented with PRP were immunoblotted with anti-phospho and total Src-Tyr-416, FAK-Try-925, E-cadherin, N-cadherin, TGF-β, Smad2, and Snail monoclonal antibodies. Breast tumor cells from luminal B and HER2 subtypes showed the most malignant profiles and the expression of thrombin and other classes of proteases at levels that were detectable through FRET peptide libraries. The angiogenesis process was investigated in the interface obtained between platelet-fibrin-breast tumor cells co-cultured with HUVEC cells. Luminal B and HER2 cells showed robust endothelial cell capillary-like tubes ex vivo. The studied interface contributes to the attachment of endothelial cells, provides a source of growth factors, and is a solid substrate. Thus, replacement of FBS supplementation with PRP supplementation represents an efficient and simple approach for mimicking the real multifactorial tumor microenvironment. PMID:28187434

Interface between breast cancer cells and the tumor microenvironment using platelet-rich plasma to promote tumor angiogenesis - influence of platelets and fibrin bundles on the behavior of breast tumor cells.

PubMed

Andrade, Sheila Siqueira; Sumikawa, Joana Tomomi; Castro, Eloísa Dognani; Batista, Fabricio Pereira; Paredes-Gamero, Edgar; Oliveira, Lilian Carolina; Guerra, Izabel Monastério; Peres, Giovani Bravin; Cavalheiro, Renan Pelluzzi; Juliano, Luiz; Nazário, Afonso Pinto; Facina, Gil; Tsai, Siu Mui; Oliva, Maria Luiza Vilela; Girão, Manoel João Batista Castello

2017-03-07

Cancer progression is associated with an evolving tissue interface of direct epithelial-tumor microenvironment interactions. In biopsies of human breast tumors, extensive alterations in molecular pathways are correlated with cancer staging on both sides of the tumor-stroma interface. These interactions provide a pivotal paracrine signaling to induce malignant phenotype transition, the epithelial-mesenchymal transition (EMT). We explored how the direct contact between platelets-fibrin bundles primes metastasis using platelet-rich plasma (PRP) as a source of growth factors and mimics the provisional fibrin matrix between actively growing breast cancer cells and the tumor stroma. We have demonstrated PRP functions, modulating cell proliferation that is tumor-subtype and cancer cell-type-specific. Epithelial and stromal primary cells were prepared from breast cancer biopsies from 21 women with different cancer subtypes. Cells supplemented with PRP were immunoblotted with anti-phospho and total Src-Tyr-416, FAK-Try-925, E-cadherin, N-cadherin, TGF-β, Smad2, and Snail monoclonal antibodies. Breast tumor cells from luminal B and HER2 subtypes showed the most malignant profiles and the expression of thrombin and other classes of proteases at levels that were detectable through FRET peptide libraries. The angiogenesis process was investigated in the interface obtained between platelet-fibrin-breast tumor cells co-cultured with HUVEC cells. Luminal B and HER2 cells showed robust endothelial cell capillary-like tubes ex vivo. The studied interface contributes to the attachment of endothelial cells, provides a source of growth factors, and is a solid substrate. Thus, replacement of FBS supplementation with PRP supplementation represents an efficient and simple approach for mimicking the real multifactorial tumor microenvironment.

Not all occult papillary carcinomas are minimal

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

Allo, M.D.; Christianson, W.; Koivunen, D.

1988-12-01

Occult papillary carcinomas are characterized as small papillary tumors of less than 1.5 cm in maximum diameter, with or without bulky metastatic deposits in cervical nodes. The primary lesion is usually not palpable, and although the clinical behavior usually follows a benign course, tumors with unfavorable histologic features (invasiveness, multifocality) or extrathyroidal disease or a combination of both may not do so. In this report six cases are presented to illustrate this entity. No patient had a history of irradiation to the head or neck. All had primary lesions smaller than 1.5 cm. None had a palpable nodule or abnormalmore » thyroid scan results, and the diagnosis of thyroid cancer was based on cervical lymph node or lung biopsy specimens, which revealed papillary thyroid cancer. All of the patients underwent total or near-total thyroidectomies and were found to have small, invasive papillary lesions with additional metastases to cervical nodes noted at the time of thyroidectomy. Adjunctive treatment consisted of a 5 mCi iodine-131 scan, ablative iodine-131 therapy, and suppression with L-thyroxine. Although distant metastasis to lung or other organs is uncommon and the mortality rate is low (as in larger papillary cancers), these invasive lesions--despite their small size--have a high propensity for recurrence and should be considered to behave more like encapsulated papillary tumors with extrathyroidal extension than like their small, unencapsulated intrathyroidal counterparts.« less

Opposite Effects of Coinjection and Distant Injection of Mesenchymal Stem Cells on Breast Tumor Cell Growth.

PubMed

Zheng, Huilin; Zou, Weibin; Shen, Jiaying; Xu, Liang; Wang, Shu; Fu, Yang-Xin; Fan, Weimin

2016-09-01

: Mesenchymal stem cells (MSCs) usually promote tumor growth and metastasis. By using a breast tumor 4T1 cell-based animal model, this study determined that coinjection and distant injection of allogeneic bone marrow-derived MSCs with tumor cells could exert different effects on tumor growth. Whereas the coinjection of MSCs with 4T1 cells promoted tumor growth, surprisingly, the injection of MSCs at a site distant from the 4T1 cell inoculation site suppressed tumor growth. We further observed that, in the distant injection model, MSCs decreased the accumulation of myeloid-derived suppressor cells and regulatory T cells in tumor tissues by enhancing proinflammatory factors such as interferon-γ, tumor necrosis factor-α, Toll-like receptor (TLR)-3, and TLR-4, promoting host antitumor immunity and inhibiting tumor growth. Unlike previous reports, this is the first study reporting that MSCs may exert opposite roles on tumor growth in the same animal model by modulating the host immune system, which may shed light on the potential application of MSCs as vehicles for tumor therapy and other clinical applications. Mesenchymal stem cells (MSCs) have been widely investigated for their potential roles in tissue engineering, autoimmune diseases, and tumor therapeutics. This study explored the impact of coinjection and distant injection of allogeneic bone marrow-derived MSCs on mouse 4T1 breast cancer cells. The results showed that the coinjection of MSCs and 4T1 cells promoted tumor growth. MSCs might act as the tumor stromal precursors and cause immunosuppression to protect tumor cells from immunosurveillance, which subsequently facilitated tumor metastasis. Interestingly, the distant injection of MSCs and 4T1 cells suppressed tumor growth. Together, the results of this study revealed the dual functions of MSCs in immunoregulation. ©AlphaMed Press.

Leptin deficiency suppresses MMTV-Wnt-1 mammary tumor growth in obese mice and abrogates tumor initiating cell survival.

PubMed

Zheng, Qiao; Dunlap, Sarah M; Zhu, Jinling; Downs-Kelly, Erinn; Rich, Jeremy; Hursting, Stephen D; Berger, Nathan A; Reizes, Ofer

2011-08-01

Obesity increases both the risk and mortality associated with many types of cancer including that of the breast. In mice, obesity increases both incidence of spontaneous tumors and burden of transplanted tumors. Our findings identify leptin, an adipose secreted cytokine, in promoting increased mammary tumor burden in obese mice and provide a link between this adipokine and cancer. Using a transplantable tumor that develops spontaneously in the murine mammary tumor virus-Wnt-1 transgenic mice, we show that tumors transplanted into obese leptin receptor (LepRb)-deficient (db/db) mice grow to eight times the volume of tumors transplanted into lean wild-type (WT) mice. However, tumor outgrowth and overall tumor burden is reduced in obese, leptin-deficient (ob/ob) mice. The residual tumors in ob/ob mice contain fewer undifferentiated tumor cells (keratin 6 immunopositive) compared with WT or db/db mice. Furthermore, tumors in ob/ob mice contain fewer cells expressing phosphorylated Akt, a growth promoting kinase activated by the LepRb, compared with WT and db/db mice. In vivo limiting dilution analysis of residual tumors from ob/ob mice indicated reduced tumor initiating activity suggesting fewer cancer stem cells (CSCs). The tumor cell populations reduced by leptin deficiency were identified by fluorescence-activated cell sorting and found to express LepRb. Finally, LepRb expressing tumor cells exhibit stem cell characteristics based on the ability to form tumorspheres in vitro and leptin promotes their survival. These studies provide critical new insight on the role of leptin in tumor growth and implicate LepRb as a CSC target.

Perioperative circulating tumor cell detection: Current perspectives

PubMed Central

Kaifi, Jussuf T.; Li, Guangfu; Clawson, Gary; Kimchi, Eric T.; Staveley-O'Carroll, Kevin F.

2016-01-01

ABSTRACT Primary cancer resections and in selected cases surgical metastasectomies significantly improve survival, however many patients develop recurrences. Circulating tumor cells (CTCs) function as an independent marker that could be used in the prognostication of different cancers. Sampling of blood and bone marrow compartments during cancer resections is a unique opportunity to increase individual tumor cell capture efficiency. This review will address the diagnostic and therapeutic potentials of perioperative tumor isolation and highlight the focus of future studies on characterization of single disseminated cancer cells to identify targets for molecular therapy and immune escape mechanisms. PMID:27045201

Remnant living cells that escape cell loss in late-stage tumors exhibit cancer stem cell-like characteristics

PubMed Central

Chen, Y-L; Wang, S-Y; Liu, R-S; Wang, H-E; Chen, J-C; Chiou, S-H; Chang, C A; Lin, L-T; Tan, D T W; Lee, Y-J

2012-01-01

A balance between cell proliferation and cell loss is essential for tumor progression. Although up to 90% of cells are lost in late-stage carcinomas, the progression and characteristics of remnant living cells in tumor mass are unclear. Here we used molecular imaging to track the progression of living cells in a syngeneic tumor model, and ex vivo investigated the properties of this population at late-stage tumor. The piggyBac transposon system was used to stably introduce the dual reporter genes, including monomeric red fluorescent protein (mRFP) and herpes simplex virus type-1 thymidine kinase (HSV1-tk) genes for fluorescence-based and radionuclide-based imaging of tumor growth in small animals, respectively. Iodine-123-labeled 5-iodo-2′-fluoro-1-beta-𝒟-arabinofuranosyluracil was used as a radiotracer for HSV1-tk gene expression in tumors. The fluorescence- and radionuclide-based imaging using the single-photon emission computed tomography/computed tomography revealed that the number of living cells reached the maximum at 1 week after implantation of 4T1 tumors, and gradually decreased and clustered near the side of the body until 4 weeks accompanied by enlargement of tumor mass. The remnant living cells at late-stage tumor were isolated and investigated ex vivo. The results showed that these living cells could form mammospheres and express cancer stem cell (CSC)-related biomarkers, including octamer-binding transcription factor 4, SRY (sex-determining region Y)-box 2, and CD133 genes compared with those cultured in vitro. Furthermore, this HSV1-tk-expressing CSC-like population was sensitive to ganciclovir applied for the suicide therapy. Taken together, the current data suggested that cells escaping from cell loss in late-stage tumors exhibit CSC-like characteristics, and HSV1-tk may be considered a theranostic agent for targeting this population in vivo. PMID:23034334

The Human Cell Surfaceome of Breast Tumors

PubMed Central

da Cunha, Júlia Pinheiro Chagas; Galante, Pedro Alexandre Favoretto; de Souza, Jorge Estefano Santana; Pieprzyk, Martin; Carraro, Dirce Maria; Old, Lloyd J.; Camargo, Anamaria Aranha; de Souza, Sandro José

2013-01-01

Introduction. Cell surface proteins are ideal targets for cancer therapy and diagnosis. We have identified a set of more than 3700 genes that code for transmembrane proteins believed to be at human cell surface. Methods. We used a high-throuput qPCR system for the analysis of 573 cell surface protein-coding genes in 12 primary breast tumors, 8 breast cell lines, and 21 normal human tissues including breast. To better understand the role of these genes in breast tumors, we used a series of bioinformatics strategies to integrates different type, of the datasets, such as KEGG, protein-protein interaction databases, ONCOMINE, and data from, literature. Results. We found that at least 77 genes are overexpressed in breast primary tumors while at least 2 of them have also a restricted expression pattern in normal tissues. We found common signaling pathways that may be regulated in breast tumors through the overexpression of these cell surface protein-coding genes. Furthermore, a comparison was made between the genes found in this report and other genes associated with features clinically relevant for breast tumorigenesis. Conclusions. The expression profiling generated in this study, together with an integrative bioinformatics analysis, allowed us to identify putative targets for breast tumors. PMID:24195083

Structure of scintillations in Neptune's occultation shadow

NASA Technical Reports Server (NTRS)

Hubbard, W. B.; Lellouch, Emmanuel; Sicardy, Bruno; Brahic, Andre; Vilas, Faith

1988-01-01

An exceptionally high-quality data set from a Neptune occultation is used here to derive a number of new results about the statistical properties of the fluctuations of the intensity distribution in various parts of Neptune's occultation shadow. An approximate numerical ray-tracing model which successfully accounts for many of the qualitative aspects of the observed intensity fluctuation distribution is introduced. Strong refractive scintillation is simulated by including the effects of 'turbulence' with projected atmospheric properties allowed to vary in both the direction perpendicular and parallel to the limb, and an explicit two-dimensional picture of a typical intensity distribution throughout an occulting planet's shadow is presented. The results confirm the existence of highly anisotropic turbulence.

Revisiting the 1988 Pluto Occultation

NASA Astrophysics Data System (ADS)

Bosh, Amanda S.; Dunham, Edward W.; Young, Leslie A.; Slivan, Steve; Barba née Cordella, Linda L.; Millis, Robert L.; Wasserman, Lawrence H.; Nye, Ralph

2015-11-01

In 1988, Pluto's atmosphere was surmised to exist because of the surface ices that had been detected through spectroscopy, but it had not yet been directly detected in a definitive manner. The key to making such a detection was the stellar occultation method, used so successfully for the discovery of the Uranian rings in 1977 (Elliot et al. 1989; Millis et al. 1993) and before that for studies of the atmospheres of other planets.On 9 June 1988, Pluto occulted a star, with its shadow falling over the South Pacific Ocean region. One team of observers recorded this event from the Kuiper Airborne Observatory, while other teams captured the event from various locations in Australia and New Zealand. Preceding this event, extensive astrometric observations of Pluto and the star were collected in order to refine the prediction.We will recount the investigations that led up to this important Pluto occultation, discuss the unexpected atmospheric results, and compare the 1988 event to the recent 2015 event whose shadow followed a similar track through New Zealand and Australia.

An autologous dendritic cell canine mammary tumor hybrid-cell fusion vaccine.

PubMed

Bird, R Curtis; Deinnocentes, Patricia; Church Bird, Allison E; van Ginkel, Frederik W; Lindquist, Joni; Smith, Bruce F

2011-01-01

Mammary cancer is among the most prevalent canine tumors and frequently resulting in death due to metastatic disease that is highly homologous to human breast cancer. Most canine tumors fail to raise effective immune reactions yet, some spontaneous remissions do occur. Hybrid canine dendritic cell-tumor cell fusion vaccines were designed to enhance antigen presentation and tumor immune recognition. Peripheral blood-derived autologous dendritic cell enriched populations were isolated from dogs based on CD11c(+) expression and fused with canine mammary tumor (CMT) cells for vaccination of laboratory Beagles. These hybrid cells were injected into popliteal lymph nodes of normal dogs, guided by ultrasound, and included CpG-oligonucleotide adjuvants. Three rounds of vaccination were delivered. Significant IgG responses were observed in all vaccinated dogs compared to vehicle-injected controls. Canine IgG antibodies recognized shared CMT antigens as was demonstrated by IgG-recognition of three unrelated/independently derived CMT cell lines, and recognition of freshly isolated, unrelated, primary biopsy-derived CMT cells. A bias toward an IgG2 isotype response was observed after two vaccinations in most dogs. Neither significant cytotoxic T cell responses were detected, nor adverse or side-effects due to vaccination or due to the induced immune responses noted. These data provide proof-of-principle for this cancer vaccine strategy and demonstrate the presence of shared CMT antigens that promote immune recognition of mammary cancer.

Hypofractionation Results in Reduced Tumor Cell Kill Compared to Conventional Fractionation for Tumors With Regions of Hypoxia

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

Carlson, David J., E-mail: david.j.carlson@yale.ed; Yale University School of Medicine, Department of Therapeutic Radiology, New Haven, CT; Keall, Paul J.

2011-03-15

Purpose: Tumor hypoxia has been observed in many human cancers and is associated with treatment failure in radiation therapy. The purpose of this study is to quantify the effect of different radiation fractionation schemes on tumor cell killing, assuming a realistic distribution of tumor oxygenation. Methods and Materials: A probability density function for the partial pressure of oxygen in a tumor cell population is quantified as a function of radial distance from the capillary wall. Corresponding hypoxia reduction factors for cell killing are determined. The surviving fraction of a tumor consisting of maximally resistant cells, cells at intermediate levels ofmore » hypoxia, and normoxic cells is calculated as a function of dose per fraction for an equivalent tumor biological effective dose under normoxic conditions. Results: Increasing hypoxia as a function of distance from blood vessels results in a decrease in tumor cell killing for a typical radiotherapy fractionation scheme by a factor of 10{sup 5} over a distance of 130 {mu}m. For head-and-neck cancer and prostate cancer, the fraction of tumor clonogens killed over a full treatment course decreases by up to a factor of {approx}10{sup 3} as the dose per fraction is increased from 2 to 24 Gy and from 2 to 18 Gy, respectively. Conclusions: Hypofractionation of a radiotherapy regimen can result in a significant decrease in tumor cell killing compared to standard fractionation as a result of tumor hypoxia. There is a potential for large errors when calculating alternate fractionations using formalisms that do not account for tumor hypoxia.« less

Occult Intertrochanteric Fracture Mimicking the Fracture of Greater Trochanter

PubMed Central

Chung, Phil Hyun; Kang, Suk; Kim, Jong Pil; Kim, Young Sung; Back, In Hwa; Eom, Kyeong Soo

2016-01-01

Purpose Occult intertrochanteric fractures are misdiagnosed as isolated greater trochanteric fractures in some cases. We investigated the utility of three-dimensional computed tomography (3D-CT) and magnetic resonance imaging (MRI) in the diagnosis and outcome management of occult intertrochanteric fractures. Materials and Methods This study involved 23 cases of greater trochanteric fractures as diagnosed using plain radiographs from January 2004 to July 2013. Until January 2008, 9 cases were examined with 3D-CT only, while 14 cases were screened with both 3D-CT and MRI scans. We analyzed diagnostic accuracy and treatment results following 3D-CT and MRI scanning. Results Nine cases that underwent 3D-CT only were diagnosed with isolated greater trochanteric fractures without occult intertrochanteric fractures. Of these, a patient with displacement received surgical treatment. Of the 14 patients screened using both CT and MRI, 13 were diagnosed with occult intertrochanteric fractures. Of these, 11 were treated with surgical intervention and 2 with conservative management. Conclusion Three-dimensional CT has very low diagnostic accuracy in diagnosing occult intertrochanteric fractures. For this reason, MRI is recommended to confirm a suspected occult intertrochanteric fracture and to determine the most appropriate mode of treatment. PMID:27536653

Computed tomography and magnetic resonance imaging findings of intraorbital granular cell tumor (Abrikossoff's tumor): a case report.

PubMed

Yuan, Wei-Hsin; Lin, Tai-Chi; Lirng, Jiing-Feng; Guo, Wan-You; Chang, Fu-Pang; Ho, Donald Ming-Tak

2016-05-13

Granular cell tumors are rare neoplasms which can occur in any part of the body. Granular cell tumors of the orbit account for only 3 % of all granular cell tumor cases. Computed tomography and magnetic resonance imaging of the orbit have proven useful for diagnosing orbital tumors. However, the rarity of intraorbital granular cell tumors poses a significant diagnostic challenge for both clinicians and radiologists. We report a case of a 37-year-old Chinese woman with a rare intraocular granular cell tumor of her right eye presenting with diplopia, proptosis, and restriction of ocular movement. Preoperative orbital computed tomography and magnetic resonance imaging with contrast enhancement revealed an enhancing solid, ovoid, well-demarcated, retrobulbar nodule. In addition, magnetic resonance imaging features included an intraorbital tumor which was isointense relative to gray matter on T1-weighted imaging and hypointense on T2-weighted imaging. No diffusion restriction of water was noted on either axial diffusion-weighted images or apparent diffusion coefficient maps. Both computed tomography and magnetic resonance imaging features suggested an intraorbital hemangioma. However, postoperative pathology (together with immunohistochemistry) identified an intraorbital granular cell tumor. When intraorbital T2 hypointensity and free diffusion of water are observed on magnetic resonance imaging, a granular cell tumor should be included in the differential diagnosis of an intraocular tumor.

Dissecting social cell biology and tumors using Drosophila genetics.

PubMed

Pastor-Pareja, José Carlos; Xu, Tian

2013-01-01

Cancer was seen for a long time as a strictly cell-autonomous process in which oncogenes and tumor-suppressor mutations drive clonal cell expansions. Research in the past decade, however, paints a more integrative picture of communication and interplay between neighboring cells in tissues. It is increasingly clear as well that tumors, far from being homogenous lumps of cells, consist of different cell types that function together as complex tissue-level communities. The repertoire of interactive cell behaviors and the quantity of cellular players involved call for a social cell biology that investigates these interactions. Research into this social cell biology is critical for understanding development of normal and tumoral tissues. Such complex social cell biology interactions can be parsed in Drosophila. Techniques in Drosophila for analysis of gene function and clonal behavior allow us to generate tumors and dissect their complex interactive biology with cellular resolution. Here, we review recent Drosophila research aimed at understanding tissue-level biology and social cell interactions in tumors, highlighting the principles these studies reveal.

CD4 cells can be more efficient at tumor rejection than CD8 cells.

PubMed

Perez-Diez, Ainhoa; Joncker, Nathalie T; Choi, Kyungho; Chan, William F N; Anderson, Colin C; Lantz, Olivier; Matzinger, Polly

2007-06-15

Researchers designing antitumor treatments have long focused on eliciting tumor-specific CD8 cytotoxic T lymphocytes (CTL) because of their potent killing activity and their ability to reject transplanted organs. The resulting treatments, however, have generally been surprisingly poor at inducing complete tumor rejection, both in experimental models and in the clinic. Although a few scattered studies suggested that CD4 T "helper" cells might also serve as antitumor effectors, they have generally been studied mostly for their ability to enhance the activity of CTL. In this mouse study, we compared monoclonal populations of tumor-specific CD4 and CD8 T cells as effectors against several different tumors, and found that CD4 T cells eliminated tumors that were resistant to CD8-mediated rejection, even in cases where the tumors expressed major histocompatibility complex (MHC) class I molecules but not MHC class II. MHC class II expression on host tissues was critical, suggesting that the CD4 T cells act indirectly. Indeed, the CD4 T cells partnered with NK cells to obtain the maximal antitumor effect. These findings suggest that CD4 T cells can be powerful antitumor effector cells that can, in some cases, outperform CD8 T cells, which are the current "gold standard" effector cell in tumor immunotherapy.

Manipulating the tumor microenvironment ex vivo for enhanced expansion of tumor-infiltrating lymphocytes for adoptive cell therapy

PubMed Central

Chacon, Jessica Ann; Sarnaik, Amod A; Chen, Jie Qing; Creasy, Caitlin; Kale, Charuta; Robinson, John; Weber, Jeffrey; Hwu, Patrick; Pilon-Thomas, Shari; Radvanyi, Laszlo

2014-01-01

Purpose Cultured tumor fragments from melanoma metastases have been used for years as a source of tumor-infiltrating lymphocytes (TIL) for adoptive cell therapy. The expansion of tumor-reactive CD8+ T cells with IL-2 in these early cultures is critical in generating clinically active TIL infusion products, with a population of activated 4-1BB CD8+ T cells recently found to constitute the majority of tumor-specific T cells. Experimental Design We used an agonistic anti-4-1BB antibody added during the initial tumor fragment cultures to provide in situ 4-1BB co-stimulation. Results We found that addition of an agonistic anti-4-1BB antibody could activate 4-1BB signaling within early cultured tumor fragments and accelerated the rate of memory CD8+ TIL outgrowth that were highly enriched for melanoma antigen specificity. This was associated with NFκB activation and the induction of T-cell survival and memory genes, as well as enhanced IL-2 responsiveness, in the CD8+ T cells in the fragments and emerging from the fragments. Early provision of 4-1BB co-stimulation also affected the dendritic cells (DC) by activating NFκB in DC and promoting their maturation inside the tumor fragments. Blocking HLA class I prevented the enhanced outgrowth of CD8+ T cells with anti-4-1BB, suggesting that an ongoing HLA class I-mediated antigen presentation in early tumor fragment cultures plays a role in mediating tumor-specific CD8+ TIL outgrowth. Conclusions Our results highlight a previously unrecognized concept in TIL adoptive cell therapy that the tumor microenvironment can be dynamically regulated in the initial tumor fragment cultures to regulate the types of T cells expanded and their functional characteristics. PMID:25472998

The Role of Tumor Associated Macrophage in Recurrent Growth of Tumor Stem Cell

DTIC Science & Technology

2012-09-01

According to the recent cancer stem cell (CSC) theory, recurrent tumor must arise from a dormant tumor stem cell whose re- growth is triggered by...shifting of microenvironment. This project aims at clarifying the roles of TAM in recurrent growth of dormant stem cell in breast cancer. We hypothesize...the stem cell . We have established necessary mouse colonies and also developed the method to generate TAM. We have also shown that TAM indeed

Pediatric brain tumor cancer stem cells: cell cycle dynamics, DNA repair, and etoposide extrusion

PubMed Central

Hussein, Deema; Punjaruk, Wiyada; Storer, Lisa C.D.; Shaw, Lucy; Ottoman, Ramadan; Peet, Andrew; Miller, Suzanne; Bandopadhyay, Gagori; Heath, Rachel; Kumari, Rajendra; Bowman, Karen J.; Braker, Paul; Rahman, Ruman; Jones, George D.D.; Watson, Susan; Lowe, James; Kerr, Ian D.; Grundy, Richard G.; Coyle, Beth

2011-01-01

Reliable model systems are needed to elucidate the role cancer stem cells (CSCs) play in pediatric brain tumor drug resistance. The majority of studies to date have focused on clinically distinct adult tumors and restricted tumor types. Here, the CSC component of 7 newly established primary pediatric cell lines (2 ependymomas, 2 medulloblastomas, 2 gliomas, and a CNS primitive neuroectodermal tumor) was thoroughly characterized. Comparison of DNA copy number with the original corresponding tumor demonstrated that genomic changes present in the original tumor, typical of that particular tumor type, were retained in culture. In each case, the CSC component was approximately 3–4-fold enriched in neurosphere culture compared with monolayer culture, and a higher capacity for multilineage differentiation was observed for neurosphere-derived cells. DNA content profiles of neurosphere-derived cells expressing the CSC marker nestin demonstrated the presence of cells in all phases of the cell cycle, indicating that not all CSCs are quiescent. Furthermore, neurosphere-derived cells demonstrated an increased resistance to etoposide compared with monolayer-derived cells, having lower initial DNA damage, potentially due to a combination of increased drug extrusion by ATP-binding cassette multidrug transporters and enhanced rates of DNA repair. Finally, orthotopic xenograft models reflecting the tumor of origin were established from these cell lines. In summary, these cell lines and the approach taken provide a robust model system that can be used to develop our understanding of the biology of CSCs in pediatric brain tumors and other cancer types and to preclinically test therapeutic agents. PMID:20978004

Pediatric brain tumor cancer stem cells: cell cycle dynamics, DNA repair, and etoposide extrusion.

PubMed

Hussein, Deema; Punjaruk, Wiyada; Storer, Lisa C D; Shaw, Lucy; Othman, Ramadhan; Ottoman, Ramadan; Peet, Andrew; Miller, Suzanne; Bandopadhyay, Gagori; Heath, Rachel; Kumari, Rajendra; Bowman, Karen J; Braker, Paul; Rahman, Ruman; Jones, George D D; Watson, Susan; Lowe, James; Kerr, Ian D; Grundy, Richard G; Coyle, Beth

2011-01-01

Reliable model systems are needed to elucidate the role cancer stem cells (CSCs) play in pediatric brain tumor drug resistance. The majority of studies to date have focused on clinically distinct adult tumors and restricted tumor types. Here, the CSC component of 7 newly established primary pediatric cell lines (2 ependymomas, 2 medulloblastomas, 2 gliomas, and a CNS primitive neuroectodermal tumor) was thoroughly characterized. Comparison of DNA copy number with the original corresponding tumor demonstrated that genomic changes present in the original tumor, typical of that particular tumor type, were retained in culture. In each case, the CSC component was approximately 3-4-fold enriched in neurosphere culture compared with monolayer culture, and a higher capacity for multilineage differentiation was observed for neurosphere-derived cells. DNA content profiles of neurosphere-derived cells expressing the CSC marker nestin demonstrated the presence of cells in all phases of the cell cycle, indicating that not all CSCs are quiescent. Furthermore, neurosphere-derived cells demonstrated an increased resistance to etoposide compared with monolayer-derived cells, having lower initial DNA damage, potentially due to a combination of increased drug extrusion by ATP-binding cassette multidrug transporters and enhanced rates of DNA repair. Finally, orthotopic xenograft models reflecting the tumor of origin were established from these cell lines. In summary, these cell lines and the approach taken provide a robust model system that can be used to develop our understanding of the biology of CSCs in pediatric brain tumors and other cancer types and to preclinically test therapeutic agents.

Anterior uveal spindle cell tumor in a cat.

PubMed

Evans, Paige M; Lynch, Gwendolyn L; Dubielzig, Richard R

2010-11-01

To describe a case of anterior uveal spindle cell tumor in a cat with features similar to spindle cell tumor of blue eyed dogs. A 10-year-old female spayed domestic short-haired cat was referred for an iris mass OS. The mass was solitary, nodular, nonpigmented, located medially, and causing dyscoria. A diagnosis of a benign epithelial tumor was suggested by a FNA of the mass. The cat was lost to follow-up for 2 years, after which time she re-presented with glaucoma, blindness and grossly evident iridal mass enlargement OS. Transconjunctival enucleation was performed and the globe submitted for histopathology. Histopathology of the enucleated globe revealed the superior iris to be infiltrated and effaced by a large population of neoplastic spindle cells. The cells were arranged in streams and bundles and exhibited Antoni-A and Antoni-B tissue patterns, which are characteristic of Schwann cell tumors. Mitotic figures were rare and cellular pleomorphism moderate. Immunohistochemical staining was positive for S-100 protein and glial fibrillary acidic protein (GFAP), and negative for Melan-A. Interestingly, there was no histological evidence of glaucoma. Based on its histopathologic characteristics, this iris tumor was diagnosed as a Schwann cell variant of a peripheral nerve sheath tumor (PNST) closely resembling the spindle cell tumor of blue-eyed dogs. Anterior uveal PNST has not been previously reported in cats to the authors' knowledge. The presence of Antoni type A and type B tissue patterns along with immunohistochemical staining may facilitate a diagnosis of PNST and rule out malignant melanoma. © 2010 American College of Veterinary Ophthalmologists.

The current status and clinical value of circulating tumor cells and circulating cell-free tumor DNA in bladder cancer

PubMed Central

Soave, Armin; Rink, Michael

2017-01-01

Urothelial carcinoma of the bladder (UCB) is a complex disease, which is associated with highly aggressive tumor biologic behavior, especially in patients with muscle-invasive and advanced tumors. Despite multimodal therapy options including surgery, radiotherapy and chemotherapy, UCB patients frequently suffer from poor clinical outcome. Indeed, the potential of diverse opportunities for modern targeted therapies is not sufficiently elucidated in UCB yet. To improve the suboptimal treatment situation in UCB, biomarkers are urgently needed that help detecting minimal residual disease (MRD), predicting therapy response and subsequently prognosis as well as enabling patient stratification for further therapies and therapy monitoring, respectively. To date, decision making regarding treatment planning is mainly based on histopathologic evaluation of biopsies predominantly derived from the primary tumors and on clinical staging. However, both methods are imperfect for sufficient outcome prediction. During disease progression, individual disseminated tumor cells and consecutively metastases can acquire characteristics that do not match those of the corresponding primary tumors, and often are only hardly assessable for further evaluation. Therefore, during recent years, strong efforts were directed to establish non-invasive biomarkers from liquid biopsies. Urine cytology and serum tumor markers have been established for diagnostic purposes, but are still insufficient as universal biomarkers for decision-making and treatment of UCB patients. To date, the clinical relevance of various newly established blood-based biomarkers comprising circulating tumor cells (CTCs), circulating cell-free nucleic acids or tumor-educated platelets is being tested in cancer patients. In this review we summarize the current state and clinical application of CTCs and circulating cell-free tumor DNA originating from blood as biomarkers in patients with different UCB stages. PMID:29354496

Spindle cell oncocytomas and granular cell tumors of the pituitary are variants of pituicytoma.

PubMed

Mete, Ozgur; Lopes, Maria Beatriz; Asa, Sylvia L

2013-11-01

Pituicytomas are neoplasms that arise from pituicytes, which are specialized glia of the posterior pituitary. Pituicytes have 5 ultrastructural variants: light, dark, granular, ependymal, and oncocytic. Granular cell tumors of the pituitary gland are thought to arise from granular pituicytes. Spindle cell oncocytomas are considered to arise from folliculostellate cells, which are sustentacular cells of the adenohypophysis. Recent data suggest that, whereas pituicytes and all 3 tumor types are positive for TTF-1, folliculostellate cells are negative for TTF-1. We investigated 7 spindle cell oncocytomas, 4 pituicytomas, and 3 granular cell tumors for their genetic (BRAF(V600E) mutation and BRAF-KIAA fusion), immunohistochemical (GFAP, vimentin, S100 protein, olig2, IDH1-R132H, NF, galectin-3, chromogranin-A, CD56, EMA, CAM5.2, CD68, TTF-1, and bcl-2), and ultrastructural features to refine their classification. All tumors had nuclear positivity for TTF-1 and were negative for CAM5.2, chromogranin-A, and NF. GFAP, vimentin, S100, galectin-3, EMA, and CD68 were variably positive in the majority of the 3 tumor groups. Olig2 was only positive in 1 pituicytoma. Whereas granular cell tumors were negative for bcl-2 and CD56, pituicytomas and spindle cell oncocytomas showed variable positivity. All tumors were negative with the IDH1-R132H mutation-specific antibody, and none had evidence of BRAF alterations (BRAF(V600E) mutation and BRAF-KIAA fusion). Diffuse TTF-1 expression in nontumorous pituicytes, pituicytomas, spindle cell oncocytomas, and granular cell tumors indicates a common pituicyte lineage. The ultrastructural variants of pituicytes are reflected in these 3 morphologic variants of tumors arising from these cells. We propose the terminology "oncocytic pituicytomas" and "granular cell pituicytomas" to refine the classification of these lesions.

Vaccination with vascular progenitor cells derived from induced pluripotent stem cells elicits antitumor immunity targeting vascular and tumor cells.

PubMed

Koido, Shigeo; Ito, Masaki; Sagawa, Yukiko; Okamoto, Masato; Hayashi, Kazumi; Nagasaki, Eijiro; Kan, Shin; Komita, Hideo; Kamata, Yuko; Homma, Sadamu

2014-05-01

Vaccination of BALB/c mice with dendritic cells (DCs) loaded with the lysate of induced vascular progenitor (iVP) cells derived from murine-induced pluripotent stem (iPS) cells significantly suppressed the tumor of CMS-4 fibrosarcomas and prolonged the survival of CMS-4-inoculated mice. This prophylactic antitumor activity was more potent than that of immunization with DCs loaded with iPS cells or CMS-4 tumor cells. Tumors developed slowly in mice vaccinated with DCs loaded with iVP cells (DC/iVP) and exhibited a limited vascular bed. Immunohistochemistry and a tomato-lectin perfusion study demonstrated that the tumors that developed in the iVP-immunized mice showed a marked decrease in tumor vasculature. Immunization with DC/iVP induced a potent suppressive effect on vascular-rich CMS-4 tumors, a weaker effect on BNL tumors with moderate vasculature, and nearly no effect on C26 tumors with poor vasculature. Treatment of DC/iVP-immunized mice with a monoclonal antibody against CD4 or CD8, but not anti-asialo GM1, inhibited the antitumor activity. CD8(+) T cells from DC/iVP-vaccinated mice showed significant cytotoxic activity against murine endothelial cells and CMS-4 cells, whereas CD8(+) T cells from DC/iPS-vaccinated mice did not. DNA microarray analysis showed that the products of 29 vasculature-associated genes shared between genes upregulated by differentiation from iPS cells into iVP cells and genes shared by iVP cells and isolated Flk-1(+) vascular cells in CMS-4 tumor tissue might be possible targets in the immune response. These results suggest that iVP cells from iPS cells could be used as a cancer vaccine targeting tumor vascular cells and tumor cells.

Connexin-43 upregulation in micrometastases and tumor vasculature and its role in tumor cell attachment to pulmonary endothelium

PubMed Central

Elzarrad, M Khair; Haroon, Abu; Willecke, Klaus; Dobrowolski, Radoslaw; Gillespie, Mark N; Al-Mehdi, Abu-Bakr

2008-01-01

Background The modulation of gap junctional communication between tumor cells and between tumor and vascular endothelial cells during tumorigenesis and metastasis is complex. The notion of a role for loss of gap junctional intercellular communication in tumorigenesis and metastasis has been controversial. While some of the stages of tumorigenesis and metastasis, such as uncontrolled cell division and cellular detachment, would necessitate the loss of intercellular junctions, other stages, such as intravasation, endothelial attachment, and vascularization, likely require increased cell-cell contact. We hypothesized that, in this multi-stage scheme, connexin-43 is centrally involved as a cell adhesion molecule mediating metastatic tumor attachment to the pulmonary endothelium. Methods Tumor cell attachment to pulmonary vasculature, tumor growth, and connexin-43 expression was studied in metastatic lung tumor sections obtained after tail-vein injection into nude mice of syngeneic breast cancer cell lines, overexpressing wild type connexin-43 or dominant-negatively mutated connexin-43 proteins. High-resolution immunofluorescence microscopy and Western blot analysis was performed using a connexin-43 monoclonal antibody. Calcein Orange Red AM dye transfer by fluorescence imaging was used to evaluate the gap junction function. Results Adhesion of breast cancer cells to the pulmonary endothelium increased with cancer cells overexpressing connexin-43 and markedly decreased with cells expressing dominant-negative connexin-43. Upregulation of connexin-43 was observed in tumor cell-endothelial cell contact areas in vitro and in vivo, and in areas of intratumor blood vessels and in micrometastatic foci. Conclusion Connexin-43 facilitates metastatic 'homing' by increasing adhesion of cancer cells to the lung endothelial cells. The marked upregulation of connexin-43 in tumor cell-endothelial cell contact areas, whether in preexisting 'homing' vessels or in newly formed tumor

Connexin-43 upregulation in micrometastases and tumor vasculature and its role in tumor cell attachment to pulmonary endothelium.

PubMed

Elzarrad, M Khair; Haroon, Abu; Willecke, Klaus; Dobrowolski, Radoslaw; Gillespie, Mark N; Al-Mehdi, Abu-Bakr

2008-07-22

The modulation of gap junctional communication between tumor cells and between tumor and vascular endothelial cells during tumorigenesis and metastasis is complex. The notion of a role for loss of gap junctional intercellular communication in tumorigenesis and metastasis has been controversial. While some of the stages of tumorigenesis and metastasis, such as uncontrolled cell division and cellular detachment, would necessitate the loss of intercellular junctions, other stages, such as intravasation, endothelial attachment, and vascularization, likely require increased cell-cell contact. We hypothesized that, in this multi-stage scheme, connexin-43 is centrally involved as a cell adhesion molecule mediating metastatic tumor attachment to the pulmonary endothelium. Tumor cell attachment to pulmonary vasculature, tumor growth, and connexin-43 expression was studied in metastatic lung tumor sections obtained after tail-vein injection into nude mice of syngeneic breast cancer cell lines, overexpressing wild type connexin-43 or dominant-negatively mutated connexin-43 proteins. High-resolution immunofluorescence microscopy and Western blot analysis was performed using a connexin-43 monoclonal antibody. Calcein Orange Red AM dye transfer by fluorescence imaging was used to evaluate the gap junction function. Adhesion of breast cancer cells to the pulmonary endothelium increased with cancer cells overexpressing connexin-43 and markedly decreased with cells expressing dominant-negative connexin-43. Upregulation of connexin-43 was observed in tumor cell-endothelial cell contact areas in vitro and in vivo, and in areas of intratumor blood vessels and in micrometastatic foci. Connexin-43 facilitates metastatic 'homing' by increasing adhesion of cancer cells to the lung endothelial cells. The marked upregulation of connexin-43 in tumor cell-endothelial cell contact areas, whether in preexisting 'homing' vessels or in newly formed tumor vessels, suggests that connexin-43 can

The Treatment of the Occult in General Encyclopedias.

ERIC Educational Resources Information Center

Sonnenfeld, Gary F.

This paper is a content analysis of three general encyclopedias, "Encyclopedia Americana" (EA), "Encyclopaedia Brittanica" (EB), and "World Book Encyclopedia" (WBC), which quantifies the treatment of the occult. Entries are selected from each by starting with the article "Occultism" and tracing all…

Colorectal cancer: genetic abnormalities, tumor progression, tumor heterogeneity, clonal evolution and tumor-initiating cells.

PubMed

Testa, Ugo; Pelosi, Elvira; Castelli, Germana

2018-04-13

Colon cancer is the third most common cancer worldwide. Most colorectal cancer occurrences are sporadic, not related to genetic predisposition or family history; however, 20-30% of patients with colorectal cancer have a family history of colorectal cancer and 5% of these tumors arise in the setting of a Mendelian inheritance syndrome. In many patients, the development of a colorectal cancer is preceded by a benign neoplastic lesion: either an adenomatous polyp or a serrated polyp. Studies carried out in the last years have characterized the main molecular alterations occurring in colorectal cancers, showing that the tumor of each patient displays from two to eight driver mutations. The ensemble of molecular studies, including gene expression studies, has led to two proposed classifications of colorectal cancers, with the identification of four/five non-overlapping groups. The homeostasis of the rapidly renewing intestinal epithelium is ensured by few stem cells present at the level of the base of intestinal crypts. Various experimental evidence suggests that colorectal cancers may derive from the malignant transformation of intestinal stem cells or of intestinal cells that acquire stem cell properties following malignant transformation. Colon cancer stem cells seem to be involved in tumor chemoresistance, radioresistance and relapse.

TH9 cells in anti-tumor immunity.

PubMed

Rivera Vargas, Thaiz; Humblin, Etienne; Végran, Frédérique; Ghiringhelli, François; Apetoh, Lionel

2017-01-01

IL-9 was initially identified as a T cell growth factor with a potential oncogenic activity. Accordingly, IL-9 drives tumor growth in most hematological cancers. However, the links between IL-9 and cancer progression have been recently revisited following the discovery of T H 9 cells. T H 9 cells, which have been characterized in 2008 as a proinflammatory CD4 T cell subset that promotes protection against parasites and drives tissue inflammation in colitis, actually harbor potent IL-9-dependent anti-cancer properties in solid tumors and especially melanoma. While the molecular mechanisms underlying these observations are still being investigated, T H 9 cells were demonstrated to activate both innate and adaptive immune responses, thereby favoring anti-cancer immunity and tumor elimination. Human T H 9 cells have also been identified in cancer tissues, but their functions remain elusive. The present review aims to discuss the anti-cancer potential of T H 9 cells and their possible clinical relevance for cancer immunotherapy.

Solid tumor therapy by selectively targeting stromal endothelial cells

PubMed Central