tbuckley/cabot-search huggingface dataset:
Abstract 2327: IFNgamma regulates PD-L1 expression through activating IRF1 transcription in tumor cells
Authors: Chunwan Lu, Amy V. Paschall, Priscilla S. Redd, Iryna Lebedyeva, Kebin Liu
Journal: Cancer Research (2016)

Abstract The emerging clinical success of checkpoint blockade immunotherapy in human cancer patients has highlighted the critical importance of PD-L1, a ligand for the T cell inhibitory receptor PD-1, as a molecular target in cancer immunotherapy. PD-L1 is constitutively expressed in tumor cells and is also inducible by inflammatory cytokines such as IFNgamma. It has been proposed that tumor cells may sense the elevated IFNgamma from activated host T cells as a “threat” in the tumor microenvironment and adapt it by up-regulating PD-L1. The aim of this study is to elucidate the molecular mechanism underlying IFNgamma regulation of PD-L1 expression in tumor cells. We observed that PD-L1 is constitutively expressed, albeit at low level, in multiple types of cancer cells, including pancreatic, colon, breast, and sarcoma cells. IFNgamma treatment dramatically increased PD-L1 expression level and IFNgamma up-regulates PD-L1 expression through the Jak-STAT1 signaling pathway in vitro and in vivo. Chromatin immunoprecipitation assay did not identify IFNgamma-activated pSTAT1 binding to the pd-l1 promoter. Instead, we observed that IFNgamma activates IRF1 transcription and IRF1 is required for IFNgamma-induced PD-L1 expression. Chromatin immunoprecipitation analysis shows that pSTAT1 is associated with the irf1 but not the pd-l1 promoter. Analysis of the irf1 promoter DNA sequence revealed a pSTAT1-binding consensus sequence, and electrophoretic mobility shift assay indicates that pSTAT1 directly binds to this DNA element of the irf1 promoter. Furthermore, we demonstrated that IRF1 is associated with the pd-l1 promoter chromatin near the irf1 transcription initiation site. The pd-l1 promoter region contains a putative IRF1-binding consensus sequence and electrophoretic mobility shift assay shows that IRF1 binds to this DNA element of the pd-l1 promoter region. Taken together, our data indicate that IFNgamma activates pSTAT1 that binds to the irf1 promoter to activate irf1 transcription. IFNgamma-induced IRF1 then binds to the pd-l1 promoter to activate pd-l1 transcription in tumor cells. Citation Format: Chunwan Lu, Amy V. Paschall, Priscilla S. Redd, Iryna Lebedyeva, Kebin Liu. IFNgamma regulates PD-L1 expression through activating IRF1 transcription in tumor cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2327.
Abstract 5186: Using HuTrial™ to aid in predicting a patient population of responders
Authors: Jayant Thatte, Jill Ricono, Colleen Scott, Thomas B. Broudy
Journal: Cancer Research (2016)

Abstract One of the biggest challenges in drug discovery is directing drug treatment to the correct population. Crown Bioscience currently has over 1,800 Patient derived xenograft models in &amp;gt;70 indications. These models, HuPrime® human surrogate mouse models, are reflective of the diversity of genetics, tumor heterogeneity and response in patient populations. HuPrime® models are searchable in the HuBase™ database by the expression data, copy number, mutational analysis as well as patient clinical data including diagnosis, pathology and IHC information. The vast number of models available allows one to perform surrogate clinical trials in a Phase II-like trial utilizing one patient sample per tumor bearing animal per treatment group (n = 1 studies). In this study we show reproducibility of n = 1 studies compared to the traditional preclinical mouse studies with multiple animals with the same tumor being treating with the same test agent. Further we show, the use of one patient sample per treatment allows for the expansion of the study utilizing multiple patient samples thereby reducing cost of preclinical studies. One can leverage the HuPrime® models to discover biomarkers, identify patient responder and non-responder profiles to accelerate drug development and improve chances of success in the clinic. Citation Format: Jayant Thatte, Jill Ricono, Colleen Scott, Thomas B. Broudy. Using HuTrial™ to aid in predicting a patient population of responders. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5186.
Control of GVHD by regulatory T cells depends on TNF produced by T cells and TNFR2 expressed by regulatory T cells
Authors: Mathieu Leclerc, Sina Naserian, Caroline Pilon, Allan Thiolat, Gaëlle H. Martin, Charlotte Pouchy, Claude Dominique, Yazid Belkacemi, Frédéric Charlotte, Sébastien Maury, Benoit L. Salomon, José L. Cohen
Journal: Blood (2016)
Abstract 5247: Caffeic acid phenethyl ester (CAPE) reverses aggressive breast cancer in the radiation chimera model
Authors: Coral O. Omene, Manan Patel, Irineu IllaBochaca, Mary Helen Barcellos-Hoff
Journal: Cancer Research (2016)

Abstract CAPE is the major active component of propolis, a widely available, safe, honeybee natural product with anti-inflammatory, antioxidant, and antitumor properties. We have previously shown diverse effects of CAPE in breast cancer. We postulated that CAPE may be useful in chemoprevention for women at high risk for triple-negative breast cancers (TNBC) and evaluated this in a radiation chimera mouse model in which the tumor spectrum is shifted to TNBC. The radiation chimera model consists of surgically clearing the mammary epithelium from the inguinal glands of 3-week old BALB/c mice, the mice were irradiated with 1 Gy or sham irradiated at 10-12 weeks of age, and bilaterally transplanted 3 days later with syngeneic Trp53 null mammary fragments. Mice were placed on a CAPE diet or a control diet at 1 month post transplantation that was maintained for the course of the experiment. Mammary tumor development was monitored by palpation for up to 18 months. The first tumor was resected at 1cm3 and mice monitored for tumor recurrence or second tumor formation. Tumors were immunostained for estrogen receptor (ER) status and ER negative tumors were selected from all the groups for RNA sequencing. No difference in body weight or tumor incidence was observed between mice on the CAPE versus control diet. Host irradiation significantly accelerated tumor growth rate compared to the control sham irradiated mice. CAPE treatment blocked this effect, but did not affect the control tumor growth rate. Resected tumors in CAPE treated mice recurred at significantly longer intervals (average of 40 days in the control group versus 90 days with CAPE treatment) and much less frequently than tumors from mice on a control diet. Mean expression analysis showed that CAPE induces a distinct gene expression pattern in ER negative tumors from irradiated mice. As previously described, the transcriptional profile of ER negative tumors was enriched in immune response genes in tumors from irradiated mice on a control diet. Interestingly, this difference was abrogated in mice on the CAPE diet. These findings support the potential use of CAPE to modify the aggressive behavior of TNBC. This may be due to effects on the immune system in which CAPE acts to re-establish anti tumor immunity. Thus, CAPE may be useful in chemoprevention both for women at high risk for TNBC and to prevent or delay TNBC breast cancer recurrence. Citation Format: Coral O. Omene, Manan Patel, Irineu IllaBochaca, Mary Helen Barcellos-Hoff. Caffeic acid phenethyl ester (CAPE) reverses aggressive breast cancer in the radiation chimera model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5247.
N-3 polyunsaturated fatty acids: Prophylaxis and symptomatic therapy for oxaliplatin-induced peripheral neuropathy—A randomized, double-blind placebo controlled trial.
Authors: Zohreh Ghoreishi, Mohammad hossein Somi, Hormoz Ayromlou, Mohammad Asghari Jafarabadi, Ali Esfahani
Journal: Journal of Clinical Oncology (2015)

e14504 Background: Oxaliplatin induced peripheral neuropathy (OXIPN) is the major dose-limiting side effect of oxaliplatin. N-3 PUFAs have known neuroprotective property. This study was a randomized double blind placebo controlled trial to find the possible advantages of n-3 PUFAs for preventing and reducing the severity of OXIPN in patients with colon cancer. Methods: Eligible patients with colon cancer randomly allocated to take n-3 PUFAs pearls, 640 mg t.i.d during chemotherapy with oxaliplatin and one month after the cessation of the treatment or placebo. All patients were evaluated for incidence and severity of OXIPN based on
The type of behavior and the role of relationship length in mate choice for prosociality among physically attractive individuals
Authors: Daniel Farrelly
Journal: Behavioral and Brain Sciences (2017)

Abstract Two further key aspects of prosociality as a sexual signal are explored here. First, the context in which it is used (in particular, relationship length) and, second, the different types of prosocial behaviors that exist in social interactions. Therefore, this commentary can show why prosocial behaviors are biased toward physically attractive individuals, as they can gain valuable information from them.
Total thyroidectomy versus thyroid lobectomy for papillary thyroid cancer: Comparative analysis after propensity score matching—A multicenter study.
Authors: Sayaka Kuba, Kosho Yamanouchi, Naomi Hayashida, Shigeto Maeda, Chika Sakimura, Fusako Kawakami, Hiroshi Yano, Megumi Matsumoto, Ryota Otsubo, Shuntaro Sato, Hikaru Fujioka, Tamotsu Kuroki, Takeshi Nagayasu, Susumu Eguchi
Journal: Journal of Clinical Oncology (2016)

e17556 Background: In patients with papillary thyroid carcinoma (PTC), the role of total thyroidectomy (TT) versus that of thyroid lobectomy (TL) has been controversial. Patients who undergo TT are reportedly at higher risk than those who undergo TL; therefore, accurate comparisons in observational studies require control for bias. Methods: This retrospective study was approved by our institutional review board, which waived the informed consent requirement. We evaluated 173 patients with 1–5-cm stage cN0 and cM0 PTC tumors that were treated by curative surgery during 1994–2008. We compared clinicopathological features and adverse events between the TT and TL groups. After adjusting for differences in baseline clinicopathologic factors using propensity score matching (PSM), we compared recurrence-free survival (RFS) and overall survival (OS). Results: Patients who underwent TT (n= 53) were older; had larger tumors; and more frequently had nodal metastasis, multifocal tumors, and extracapsular invasion than patients who underwent TL (n= 120). The TT group also had higher incidences of hypocalcemia that required long-term treatment (TT: 8%; TL: 0%) or recurrent laryngeal nerve paralysis (TT: 8%; TL: 3%) than the TL group. For all patients, median follow-up duration was 112 months (range: 11–250 months), 10-year RFS was 93.3% and 10-year OS was 96.7%. The treatment groups did not significantly differ in RFS (TT: 90.6%; TL: 93.0%) or OS (TT: 96.2%; TL: 96.9%) according to the extent of surgical resection after PSM. Discussion: We found no significant difference in any covariate between TT and TL after using PSM; patients with 1–5-cm stage cN0 and cM0 PTC tumors had equivalent prognoses. Despite some study limitations (retrospective design, small patient numbers and impossibility of completely excluding selection bias), PTC patients had very optimistic prognoses regardless of extent of surgery. The present study agrees with previous studies that adverse events were more frequent after TT than after TL. Conclusions: Equivalent prognoses were seen for patients with 1–5-cm stage cN0 and cM0 PTC tumors treated by TL or TT after PSM.
Abstract 1119: Tumor suppressing dual-action miRNA: Targeting Warburg effect and androgen receptor function in CRPC
Authors: Jey Sabith Ebron, Jagjit Singh, Kavleen Sikand, Eswar Shankar, Sanjay Gupta, Girish C. Shukla
Journal: Cancer Research (2016)

Abstract The ability of prostate cancer cells to alter their metabolism in a manner distinct from benign cells and energy reprogramming is a major concern in treatment of castration resistant prostate cancer (CRPC). On the other hand, development of resistance to next-generation drugs directed against the AR signaling axis (Abiraterone acetate and Enzalutamide) confers a grim prognosis. Hence, targeting aerobic glycolysis of tumor cells as well as AR signaling axis in CRPC is highly desirable. Here, we report the role of a dual-action miRNA which targets the Androgen Receptor function as well as action of key factors involved in tumor energy metabolism. In addition, the miRNA also targets the key anti-apoptotic factors and enhance the apoptosis in cultured cells. Furthermore, together with Enzalutamide, the miRNA shows a potent synergistic anti-tumor activity in 22RV1 mouse xenografts. We will present the detailed results showing the therapeutic potential of dual-action miRNA in the treatment of CRPC. Citation Format: Jey Sabith Ebron, Jagjit Singh, Kavleen Sikand, Eswar Shankar, Sanjay Gupta, Girish C. Shukla. Tumor suppressing dual-action miRNA: Targeting Warburg effect and androgen receptor function in CRPC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1119.
Case 8-1970
Authors: Richard C. Cabot, Benjamin Castleman, Betty U. McNeely, Robert W. Colman, Benjamin Castleman
Journal: New England Journal of Medicine (1970)

Presentation of CaseA sixty-five-year-old man was admitted to the hospital because of fever.Three years before admission a subdural hematoma was evacuated after an automobile accident; post-traumatic grand-mal seizures occurred and were controlled with diphenylhydantoin and phenobarbital. Subsequently, his wife noticed that he was forgetful, but he seemed well. Two weeks before entry there was the onset of nocturnal fever, with rigors and drenching sweats. Fatigue, anorexia and morning headaches developed, and he lost 14 pounds in weight.There was no history of recent travel, exposure to tuberculosis or toxins, hypotension or diabetes.The patient was obese. There was . . .
Abstract 2365: Checkpoint inhibitors and a multivalent melanoma vaccine as a novel combinatorial therapy
Authors: Rachana R. Maniyar, Neha Tuli, Robert Suriano, Jan Geliebter, Marc Wallack, Raj K. Tiwari
Journal: Cancer Research (2016)

Abstract Over 1 million cases of skin cancer are diagnosed in the US every year, of which 75% deaths result due to melanoma, one of the deadliest forms of skin cancer, arising from melanocytes. We have isolated five patient derived melanoma cell lines (MEL-V, 3MM, GLM2, Mel2, KFM) and characterized the expression of various melanoma associated antigens (MAAs). The presence of a multitude repertoire of common MAAs (Gp100, MART-1, MAGE-A1, NY-ESO-1, Tyrosinase, TRP-1 (Gp75), TRP-2, Melanotransferrin, CD71, CD146) enabled us to use composite cell membrane preparations of these cells as a multivalent vaccine. To this end, we designed a vaccinia virus vaccine that was composed of membrane lysate preparations of the five primary cells and recombinant IL-2. When tested in a pilot study, delayed type hypersensitivity and a multivalent immune response were noted. In an effort to correlate genetic lesions with MAA expression we observed that in BRAF mutant melanoma cells, treatment with a BRAFv600E inhibitor, PLX4032, enhanced the expression of MAAs making the melanoma cells more visible to the vaccination driven immune response. We also observed that melanoma cells constitutively expressed CTLA-4 as determined by Immunofluorescence and Western Blots. This expression was found on the membranes as well as in the cytoplasm in comparatively high levels on wild type as well as the BRAFV600E mutant melanoma cell lines. Further our results suggest that CTLA-4 expression on melanoma cells promotes the immunosuppressive tumor microenvironment enabling tumor evasion. Given that CTLA-4 monoclonal antibodies such as Ipilimumab are approved for clinical treatment, this study opens up a new avenue into a plausible combinatorial therapy for our vaccinia virus based vaccine with Ipilimumab for BRAF mutant as well as wild type melanoma cells. Citation Format: Rachana R. Maniyar, Neha Tuli, Robert Suriano, Jan Geliebter, Marc Wallack, Raj K. Tiwari. Checkpoint inhibitors and a multivalent melanoma vaccine as a novel combinatorial therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2365.
Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in<i>ALK</i>-Rearranged Lung Cancer
Authors: Justin F. Gainor, Leila Dardaei, Satoshi Yoda, Luc Friboulet, Ignaty Leshchiner, Ryohei Katayama, Ibiayi Dagogo-Jack, Shirish Gadgeel, Katherine Schultz, Manrose Singh, Emily Chin, Melissa Parks, Dana Lee, Richard H. DiCecca, Elizabeth Lockerman, Tiffany Huynh, Jennifer Logan, Lauren L. Ritterhouse, Long P. Le, Ashok Muniappan, Subba Digumarthy, Colleen Channick, Colleen Keyes, Gad Getz, Dora Dias-Santagata, Rebecca S. Heist, Jochen Lennerz, Lecia V. Sequist, Cyril H. Benes, A. John Iafrate, Mari Mino-Kenudson, Jeffrey A. Engelman, Alice T. Shaw
Journal: Cancer Discovery (2016)

Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib and alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALKG1202R, increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant.Secondary ALK mutations are a common resistance mechanism to second-generation ALK inhibitors and predict for sensitivity to the third-generation ALK inhibitor lorlatinib. These findings highlight the importance of repeat biopsies and genotyping following disease progression on targeted therapies, particularly second-generation ALK inhibitors. Cancer Discov; 6(10); 1118-33. ©2016 AACRSee related commentary by Qiao and Lovly, p. 1084This article is highlighted in the In This Issue feature, p. 1069.
Abstract 4306: Free IGFBP3 and the risk of liver cancer in a nested case-control study
Authors: Yasushi Adachi, Masanori Nojima, Mitsuru Mori, Yasutaka Matsunaga, Noriyuki Akutsu, Shigeru Sasaki, Takao Endo, Youichi Kurozawa, Kenji Wakai, Akiko Tamakoshi
Journal: Cancer Research (2016)

Abstract Background: Insulin-like growth factor-1 (IGF1) is a potent mitogen, whereas IGF-binding protein-3 (IGFBP3) binds and inhibits IGF1. High circulating IGF1 and low IGFBP3 are associated with increased risk of several cancers. Here we examined relations of those serum levels with the risk of hepatoma in a prospective case-control study nested in the JACC Study. Methods: A baseline survey was conducted from 1988 to 1990 and 39,242 subjects donated blood samples. Those who had been diagnosed as hepatoma were regarded as cases for nested case-control studies. Ninety-one cases and 263 controls are eligible for the present analysis. A conditional logistic model was used to estimate odds ratios (OR) for incidence of hepatoma associated with serum IGF1 and IGFBP3 levels. Results: Both IGF1 and molar ratio of IGF1/IGFBP3 were not correlated with the risk of hepatoma. After adjustment for hepatitis-viral infection, body mass index, smoking, and alcohol intake, higher molar difference of (IGFBP3 - IGF1) was associated with decreased risk of hepatoma (p for trend &amp;lt; 0.001), and peoples in the highest quintile had a lower risk (OR = 0.098; 95%CI = 0.026-0.368). In subgroup analyses, both in male and female, high molar difference of (IGFBP3 - IGF1) was associated with decreased risk of hepatoma (p for trend &amp;lt; 0.001). Both in the elderly and non-elderly, it was correlated inversely with risk of hepatoma (p for trend = 0.001, &amp;lt; 0.001, respectively). Conclusions: Molar difference of (IGFBP3 - IGF1) might associate inversely with the incidence of hepatoma. Citation Format: Yasushi Adachi, Masanori Nojima, Mitsuru Mori, Yasutaka Matsunaga, Noriyuki Akutsu, Shigeru Sasaki, Takao Endo, Youichi Kurozawa, Kenji Wakai, Akiko Tamakoshi. Free IGFBP3 and the risk of liver cancer in a nested case-control study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4306.
England’s health department avoids breaching budget on “technicality”
Authors: Nigel Hawkes
Journal: BMJ (2016)

The Department of Health for England came within a whisker of breaching the budgets given to it by parliament in 2015-16, show details released on Friday 21 July. In the event it avoided an overspend—the ultimate embarrassment to a government department—by the frantic shifting of funds and failing to disclose to the Treasury the receipt of an unexpected £417m (€500m; $550m) in national insurance contributions.

Had it made the disclosure, Her Majesty’s Treasury or parliament might have decided to subtract the £417m from funds voted to the department, turning a year end surplus of £210m into a deficit of £207m. The department said that an “administrative error” caused the failure to disclose the extra funds, and the Treasury has agreed to turn a blind eye.

The announcement of the financial near miss came on the same day that the NHS was forced to put its largest trust, Barts Health NHS Trust, into financial …