tbuckley/cabot-search huggingface dataset:
The androgen receptor CAG repeat polymorphism and ovarian cancer risk
Authors: Monica McGrath, Shelley S. Tworoger, Susan E. Hankinson
Journal: Cancer Research (2005)

3250  Evidence from biological and epidemiologic studies suggest a role for androgens and the androgen receptor in ovarian cancer risk. The androgen receptor (AR) is a transcription factor responsible for mediating the physiological effects of androgens, and is present in normal human ovarian epithelial cells and ovarian cancer cell lines. Upon androgen binding, the androgen-AR complex interacts with coregulators and binds to specific DNA sequences in the promoter region of its target genes to influence the transcription of these androgen-responsive genes. A polymorphic CAG repeat in exon 1 of the AR gene encodes a polyglutamine tract that is inversely correlated with the transcriptional activity of this gene. We assessed the association between the functional CAG repeat polymorphism and the risk of ovarian cancer in a nested case-control study within the Nurses’ Health Study. The analysis included 135 invasive ovarian cancer cases diagnosed after blood draw in 1989 and before June 2000, and 435 controls matched on age, menopausal status, postmenopausal hormone use, and date, time, and fasting status at blood draw. The associations between the AR CAG repeat alleles and ovarian cancer risk were examined by using conditional logistic regression to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). The average repeat length and the mean repeat length of the smaller and larger AR alleles were similar in cases and controls (P >0.2). The adjusted OR for each unit increase in repeat length in the larger allele and for each unit increase in the average (CAG)n repeat length was 1.00 (95% CI, 0.92, 1.08) and 1.05 (95% CI, 0.95-1.16), respectively. In contrast, we observed a modest and marginally significant association for each one unit increase in repeat length in the larger allele and ovarian cancer risk (OR= 1.07; 95% CI, 0.99-1.16). Women with one or two long alleles (≥ 25 repeats) compared to both alleles
Cabazitaxel in docetaxel-pretreated metastatic castration resistant prostate cancer (mCRPC): Canadian experience.
Authors: Srikala S. Sridhar, Eric Winquist, Stacey Hubay, Hazem Assi, Scott R. Berry, John Stewart, Eric Levesque, Nathalie Aucoin, Piotr Czaykowski, Fred Saad
Journal: Journal of Clinical Oncology (2013)

e16082 Background: Cabazitaxel/prednisone (CbzP) improves survival in docetaxel resistant mCRPC. Canadian investigators collected safety, QoL and efficacy data in patients (pts) from a global Expanded Access Program. Methods: Following progression on or after docetaxel, all pts received cabazitaxel 25 mg/m² IV q3wkly and prednisone 10 mg daily. Safety and QoL were collected at baseline and at each cycle. Adverse events were graded according to NCI CTCAE v 4.0. Present pain intensity (PPI) and analgesic scores were assessed using the McGill-Melzack questionnaire. QoL was assessed using FACT-P and EQ 5D-3L. PSA was done at the investigator's discretion at each cycle and at the end of treatment. Results: 61 pts were enrolled at 9 centers. Median age was 65 (18% ≥ 75); 92% were ECOG 0/1; 89% had bone metastases and 21% had visceral metastases. Pts had a median of 9 cycles (median cumulative dose 675 mg/m 2 ) of prior docetaxel, and 38% had progressed on or within 3 months of it. Notably 26 pts (43%) had also received and progressed on prior Abiraterone Acetate (AA) given before (5pts), or after docetaxel (21 pts). Half the patients (51%) received &gt;6 cycles of CbzP. Median relative dose intensity was 99%. At cycle 1, 31% received prophylactic G-CSF. Main grade 3+ toxicities were anemia 9.8%, diarrhea 8.2%, fatigue 8.2% and febrile neutropenia 6.6%. Peripheral neuropathy was uncommon (4.9% ; no grade 3+). There was 1 treatment related death (1.6%) due to abdominal sepsis. Compared to baseline, PPI scores improved despite stable analgesic use and were significant at cycles 2, 4, 9 (p&lt;0.05). The FACT-P prostate specific questions showed significant improvements in the first 4 cycles (p&lt;0.05). On the EQ-5D-3L the percentage of patients reporting “no problem” for the pain domain by the last cycle increased. The PSA response rate (≥50% decrease) was 48.7% in 39 evaluable pts and was similar in AA pretreated and non-pretreated pts (47.1% and 50.0% respectively). Conclusions: In routine clinical practice, CbzP treatment was clinically manageable and toxicities were similar to the TROPIC study. PPI and QoL data support a palliative benefit of CbzP. PSA response rate was 48.7% and similar in AA pretreated and non-pretreated pts.
Clinical and morphological characteristics of BRCA-associated and sporadic breast cancer in fertile female in the Altai territory.
Authors: Valentina Dmitrievna Petrova, Svetlana Aleksandrovna Terekhova, Tatiyana Vladimirovna Sinkina, Inna Anatolievna Selezneva, Ylija Nikolaevna Dimitriadi, Natalya Aleksandrovna Ermolenko, Ulyana Aleksandrovna Boyarskih, Maxim Leonidovich Filipenko, Alexander Fedorovit Lazarev
Journal: Journal of Clinical Oncology (2013)

e12560 Background: Breast cancer (BC) for more than 10 years is the most frequent cancer in females in the Altai territory of Russian Federation. The share of patients under 40 years old varies from 2.6% to 16.0%. Genetically dependent nature of BC in young female is scientifically confirmed fact. The aim of this study was to analyze characteristics of BRCA-associated and sporadic BC in fertile females. Methods: 161 female patients of fertile age (under 40 years old) with BC were examined. Clinical, morphological and genetic (BRCA1) factors were analyzed. BRCA1 mutation was revealed in 22 patients (139 patients did not have it). Results: 82.0% of patients with BRCA1 mutations had positive family cancer history. In this group BC was diagnosed more frequently at the age of 31-35 y.o. (40.9%), while in the group of sporadic cancer – at the age of 36-40 y.o. (58.2%). Pathomorphological forms of BC were analyzed and in both groups infiltrative forms of BC were the most frequent (95.5% and 91.4% correspondingly). I stage cases of BC were diagnosed more frequently the group of sporadic cancers than in the group of BRCA-associated cancers (23.0% and 4.5% correspondingly, P&lt;0.05). Hormone status of the tumours was analyzed. BRCA-associated cancers were significantly more often ER and PR negative (87.5%, P&lt;0.05). Hyperexpression of Her2neu was not revealed in this group. In the group of patients without BRCA mutation ER and PR negative tumours were also prevalent (60.5%, P&lt;0.05). Hyperexpression of Her2neu (+++) was revealed in 6.9%. Triple negative cancers were prevalent in the both groups, while in the group of BRCA-associated cancers there were 91.7% of such tumours. The percentage of polyneoplasia in the group of patients with BRCA mutations was higher than in the group without them (12.0 and 1.0 correspondingly, P&lt;0.05). Conclusions: In females of fertile age carriage of BRCA mutations in 82.0% connected with family cancer history. In the group of sporadic cancers I stage cases of BC are more frequent. In both groups hormone receptor negative and triple negative cancer are prevalent, but in the group of BRCA-associated cancers the percentage of such tomours and polyneoplasia are significantly higher.
Long-Term Risk of Infections After Treatment of Childhood Leukemia: A Population-Based Cohort Study Using Administrative Health Data
Authors: Marie-Claude Pelland-Marcotte, Jason D. Pole, Jeremiah Hwee, Rinku Sutradhar, Michelle Science, Paul C. Nathan, Lillian Sung
Journal: Journal of Clinical Oncology (2019)

Infections are a frequent complication during childhood leukemia treatment. Little is known about the infectious risk in survivors. We compared the relative rate (RR) of infections after treatment completion between pediatric leukemia survivors and the general population.We performed a retrospective, population-based cohort study of children diagnosed with leukemia between 1992 and 2015 in Ontario, Canada, who were alive and relapse free 30 days after treatment completion (index date). Leukemia survivors were matched 5:1 with the general population by year of birth, sex, and rural status and stratified by initial treatment, including and excluding hematopoietic stem-cell transplantation (HSCT). The primary outcome was time to infections, as identified using validated diagnostic codes from administrative databases. Individuals were censored at the earliest of death, first relapse, loss to follow-up, or end of study.A total of 2,204 leukemia survivors were included and matched with 11,020 controls. The rate of infections was elevated after treatment completion compared with controls (RR, 1.51; 95% CI, 1.45 to 1.57) and at less than 1 year (RR, 1.77; 95% CI, 1.69 to 1.86); 1 to 4.99 years (RR, 1.66; 95% CI, 1.62 to 1.71), and 5 or more years (RR, 1.29; 95% CI, 1.22 to 1.36) from the index date. Among those whose initial treatment excluded HSCT, the rate remained elevated more than 5 years from the index date (RR, 1.29; 95% CI, 1.23 to 1.35). Infection-related death was significantly increased in leukemia survivors both among the entire cohort (hazard ratio, 149.3; 95% CI, 20.4 to 1,091.9) and among those without HSCT (hazard ratio, 92.7; 95% CI, 12.4 to 690.7).A significant association was found between a history of leukemia therapy and an increased risk of infections. Additional study is needed to establish which exposures in patients with leukemia lead to late infections.
Expression of decoy receptor 3 (DcR3) in androgen receptor (AR) naïve PC3 cells: A critical new target for androgen refractory prostate cancer
Authors: Musa Ali, Padma Koka, Debasis Mondal, Asim Abdel-Mageed, Krishna Agrawal
Journal: Cancer Research (2008)

4113  Over-expression of a soluble DcR3, belonging to the TNF receptor superfamily, has been reported to occur in a variety of cancer cells from malignant tumors that includes brain, breast, colon, esophagus, liver, lung, pancreas, rectum and stomach. Serum levels of DcR3 have been reported to be higher in these cancer patients and are associated with poor prognosis. DcR3 binds to TNF ligands, such as Fas ligand (FasL) and inhibits FasL induced apoptosis. DcR3 has also been shown to enhance tumor growth and metastasis. However, there are no reports to date that have shown that the expression of DcR3 occurs in prostate cancer (PCa) cells. We have therefore examined the expression of DcR3 in three different PCa cell lines that include AR responsive (LNCaP), AR independent (C4-2B), and AR naive (PC3) cells. Western blot analysis of DcR3 expression profiles in these cells indicated that DcR3 was expressed primarily in osteoclastic AR naive PC3 cells and not in other PCa cell types, suggesting that DcR3 may have a potential role in inducing osteolytic bone metastasis. RT-PCR data were consistent in that the DcR3 mRNA levels were observed only in PC3 cells and not in other PCa cell types. To assess the amount of secreted DcR3 by these cells, ELISA assays were conducted utilizing the DcR3 ELISA kit. The supernate fraction of 1x106 PC3 cell culture at 24 h showed a concentration of DcR3 at 57.3 pg/ml. Treatment of PC3 cells with DcR3 neutralizing antibody produced a concentration dependent inhibition of PC3 cell growth suggesting a direct role of DcR3 in PC3 cell growth. The IC50 value of the DcR3 antibody was 0.01 μg/mL. Utilizing algorithmic siRNA program, DNA oligonucleotide sequences were designed and two different in-house DcR3 siRNAs were synthesized. The in vitro synthesized siRNAs migrated similar to a 21-mer equal sized chemically synthesized siRNA. Targeted siRNA silencing of DcR3 in PC3 cells resulted in significant growth inhibition. Overall, these data demonstrate that expression of DcR3 in PC3 cells plays a significant role in their growth whereas targeted inhibition of this protein suppresses PC3 cell growth in vitro. These studies suggest that DcR3 may be a novel therapeutic target for inhibition of AR naive PCa cell clonal expansion in vivo.
Phase 1 Study of the Safety and Efficacy of MRG-106, a Synthetic Inhibitor of microRNA-155, in CTCL Patients
Authors: Christiane Querfeld, Francine M Foss, Lauren C. Pinter-Brown, Pierluigi Porcu, Basem M. William, Theresa Pacheco, Bradley M. Haverkos, Youn H. Kim, Joan Guitart, Ahmad S. Halwani, Jennifer DeSimone, Anita G Seto, Linda A Pestano, Aimee L Jackson, Paul J Williams, Brent A Dickinson, Judy Ruckman, Gilad Gordon, Paul Rubin, Bill S Marshall
Journal: Blood (2017)
Replacement of Polyclonal Anti-Thymocyte Globulin By Targeted Immunomodulation Is Associated with Improved Outcome of Alfa\Beta T Cell-Depleted Hematopoietic Stem Cells Transplantation in Children with Acute Leukemia
Authors: Larisa Shelikhova, Maria Ilushina, Dmitriy Balashov, Zhanna Shekhovtsova, Irina Shipitsina, Daria Shasheleva, Rimma Khismatullina, Elena Gutovskaya, Anna Bogoyavlenskaya, Sergey Blagov, Svetlana Kozlovskaya, Elena Kurnikova, Yakov Muzalevsky, Alexey Kazachenok, Dmitriy Pershin, Maria Fadeeva, Yulia Olshanskaya, Alexey Nechesnyuk, Irina Kalinina, Natalia Miakova, Dmitry Litvinov, Galina Novichkova, Alexey A. Maschan, Michael Maschan
Journal: Blood (2018)
Tobacco‐product usage as a risk factor for dental implants
Authors: Fawad Javed, Irfan Rahman, Georgios E. Romanos
Journal: Periodontology 2000 (2019)

Abstract The oral cavities of tobacco smokers and users of smokeless tobacco products are exposed to high concentrations of nicotine. A limited number of animal studies have assessed the effect of nicotine on osseointegration. Results from experimental studies have reported a statistically significant decrease, at 4 weeks of follow‐up, in bone‐to‐implant contact among rats exposed to nicotine compared with unexposed rats. Nicotine increases the production of inflammatory cytokines (such as interleukin‐6 and tumor necrosis factor‐alpha) by osteoblasts. Waterpipe, pipe, and cigarette smokers are at increased risk of developing oral cancer, periodontal disease, and alveolar bone loss. One explanation for this is that smokers (regardless of the type of tobacco product) are exposed to similar chemicals, such as nicotine, tar, oxidants, polyaromatic hydrocarbons, and carbon monoxide. Moreover, raised levels of proinflammatory cytokines have been identified in the gingival crevicular fluid of cigarette smokers with peri‐implant diseases. Therefore, it is hypothesized that nicotine and chemicals in tobacco smoke induce a state of oxidative stress in peri‐implant tissues (gingiva and alveolar bone), thereby increasing the likelihood of peri‐implant disease development via an inflammatory response, which if left uncontrolled, will result in implant failure/loss. In this regard, tobacco smoking (including cigarettes, waterpipe, and pipe) is a significant risk factor for peri‐implant diseases. The impact of vaping electronic cigarettes using nicotine‐containing e‐juices remains unknown. Habitual use of smokeless tobacco products is associated with oral inflammatory conditions, such as oral precancer, cancer, and periodontal disease. However, the effect of habitual use of smokeless tobacco products on the success and survival of dental implants remains undocumented.
Tumor as an aberrant organ: Insights from intravital microscopy.
Authors: Rakesh K. Jain
Journal: Cancer Research (2004)

A solid tumor is an aberrant organ- and not a collection of cancer cells. To unravel the complex biology of this organ, we have developed an array of imaging technologies, computer algorithms and animal models, and have integrated the resulting data using mathematical models. This undrtaking has provided unprecedented molecular, cellular, anatomical and functional insight into the pathophysiology of solid tumors and host-tumor interactions (Nature Reviews Cancer, 2002). For one example, we have shown that the cancer cells coopt the host stromal cells into producing VEGF (Cell, 1998) and TGFb (Nature Medicine, 1999), and that these activated stromal cells form a sleeve around angiogenic vessels (Nature medicine, 2001). When a treatment, such as the anti-her2/neu antibody, Herceptin, lowers the level of VEGF in breast cancer cells, the stromal cells begin to make compensatory VEGF - the net result is virtually no change in the VEGF level in tumors undergoing Herceptin treatment. Of interest, Herceptin upregulates the expression of thrombospondin, a potent endogenous angiogenesis inhibitor (Nature 2002). These findings have provided a rational basis for a clinical trial combining Herceptin with an anti-VEGF antibody Avastin. Our work has also revealed how the malfunction of the vascular and extravascular compartments in solid tumors often thwarts the effectiveness of both conventional and novel tharapies (Scientific American, 1994), and suggested counter-intuitive strategies for overcoming these barriers. For example, based on a number of studies in transplanted tumors, we have proposed a novel hypothesis that anti-angiogenic therapy can “normalize” the aberrant tumor vasculature, and improve both the delivery and the efficacy of therapeutics (Nature Medicine, 2001). Oue recent Phase I clinical trial combining Avastin with chemo- and radiation therapy in rectal carcinoma patients supports this notion (Willett et al, unpublished data). Finally, using intravital microscopy, we have shown that VEGF-C leads to lymphangiogenesis in tumors, however only the lymphatics in the tumors margin are functional, and are adequate for lymphatic metastasis (Science 2002). The lack of lymphatic function within tumors results from compression by proliferating cancer cells (Nature Biotechnology, 1997), and contributes to interstitial hypertension in tumors - a barrier to drug delivery. The collagen matrix forms another barrier to interstitial diffusion of macromolecules in tumors (Cancer Research, 2000), and the hormone relaxin can permeabilize the matrix by reorganizing the collagen matrix, as visualized by second harmonic generation microscopy (Nature Medicine, 2003). These examples underscore the importance of the systems approach to dissecting tumor biology.
Hong Kong doctors decry “excessive and abusive” use of tear gas by police during protests
Authors: Jane Parry
Journal: BMJ (2019)

Ten weeks into political protests that have shaken Hong Kong, doctors and other healthcare workers in the city have excoriated the Hong Kong Police Force for what they see as excessive and inappropriate use of tear gas and other riot control measures, such as rubber bullets and bean bag rounds.

On 13 August health workers at 13 hospitals in the city staged sit-ins to protest against police violence. “It has become clear that there is a humanitarian crisis happening right now in Hong Kong, and humanitarianism is a fundamental core value for all healthcare professionals,” said Alfred Wong Yam-hong, spokesperson for the progressive doctors’ group Medecins Inspires.

On 11 August the police fired tear gas inside the Kwai Fong Mass Transit railway station, filling the concourse with lingering smoke.

“This is inhumane. It causes mass panic, and it was a miracle that no one got killed …
Identification of a gene signature that distinguishes estrogen-receptor positive from estrogen-receptor negative breast cancers may have potential value in predicting hormone therapy response.
Authors: Ting-Hu Qiu, Aleksandra Michalowska, Eva Lee, Albert Zhou, Jeffrey Green
Journal: Cancer Research (2008)

4255  Estrogen receptor (ER) and progesterone receptor (PR) status are important factors in assessing breast cancer prognosis and treatment. Tumors which are ER positive (ER+) may initially respond to Tamoxifen anti-estrogen therapy, but often become hormone-independent. Although Tamoxifen significantly reduces tumor recurrence in certain patients with ER+ breast cancer, over time, approximately 40% of ER+ breast cancers will fail to respond or eventually develop resistance to Tamoxifen, leading to disease progression. Therefore, identification of a gene expression which could predict the response to Tamoxifen treatment would have important clinical application. Additionally, identification of genes involved in Tamoxifen resistance could provide important insights into biologic mechanisms of the non-responsiveness or aquired resistance. Using a cross-species microarray analytic approach, our lab has identified a signature of approximately 300 genes, highly predictive of the ER status of a human breast tumor. Futhermore, a subset of this signature was identified, which separated ER+ breast cancer patients into Tamoxifen responsive and Tamoxifen non-responsive groups. The expression of a set of developmentally regulated transcription factors within this signature are highly correlated with Tamoxifen treatment response or failure. A set of hoemebox genes are highly associated with ER+ status in human tumors. The roles of these genes in determining Tamoxifen response are being functionally tested in vitro by using siRNA and overexpression methods in Tamoxifen sensitive and resistant cell lines. The identification of this gene signature has potentially important implications for identifying ER+ breast cancer patients who may require additional forms of therapies since they will likely fail traditional anti-hormone treatment. Inhibition of specific genes in such tumors may be an important way to sensitize these tumors to hormone therapy.
Genetic alterations in primary melanoma in Taiwan
Authors: Y.‐S. Sheen, K.‐T. Tan, K.‐P. Tse, Y.‐H. Liao, M.‐H. Lin, J.‐S. Chen, J.‐Y. Liau, Y.‐J. Tseng, C.‐H. Lee, C.‐H. Hong, J.‐B. Liao, H.‐T. Chang, C.‐Y. Chu
Journal: British Journal of Dermatology (2019)

Acral melanoma (AM) is the most common histopathological subtype of malignant melanoma in Asians. However, differences in the mutational profiles underlying AM and nonacral cutaneous melanoma (NAM) in Asians are not well understood.To augment the understanding of the prevalence, patterns and associations of various mutations between different subtypes of melanoma.We performed comprehensive genomic profiling of 409 cancer-associated genes, using next-generation sequencing, in 66 primary melanomas comprised of 45 AMs and 21 NAMs.Most of the AMs (n = 27/45; 60%), but only five of 21 (24%) NAMs, were triple wild-type (triple-WT) tumours. Compared with AMs, NAMs exhibited a significantly higher frequency of BRAF mutations. The frequencies of NRAS/KRAS mutations, cell-cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and gains of receptor tyrosine kinase genes were significantly higher in AMs. Ulceration was found at significantly higher rates in the AMs and NAMs with cell-cycle aberrations and gains of receptor tyrosine kinase genes. Notably, cell-cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma-specific survival in the 66 patients with melanoma and especially in the 45 patients with AM. Multivariate analysis showed that lymph node metastasis and cell-cycle aberrations were independent prognostic factors of melanoma-specific survival.This study strengthens our understanding of the patterns and clinical associations of oncogenic mutations in AMs and NAMs in Asians. What's already known about this topic? Mutation frequencies of driver genes vary between melanoma subtypes. Acral melanoma is the most common subtype of melanoma in Asians. KIT mutations and copy number variations occur more frequently in the acral subtype of melanoma than in the nonacral subtype What does this study add? NRAS/KRAS mutations, cell-cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and amplifications of receptor tyrosine kinase genes were significantly enriched in acral melanoma and could be potential targets for treatment. Melanomas with cell-cycle aberrations and gains in receptor tyrosine kinase genes were significantly more likely to contain ulceration. What is the translational message? Cell-cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma-specific survival. These observations should be explored further for future drug development.