tbuckley/cabot-search huggingface dataset:
Abstract C40: Dissecting key biologic processes in pancreatic cancer metastasis using a genetically defined 3D organoid model
Authors: Fong Cheng Pan, Angie Ai-Nok Chong, Steven D. Leach, Shuibing Chen, Todd Evans
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with a dismal 5-year survival rate of 6-8% due to its late detection and limited response to treatment (1,2). Multiple combinations of genetic alterations are frequently found in human PDAC, with KRAS activating mutation representing the main driver, followed by loss of tumor-suppressor genes CDKN2A, TP53, and SMAD4 as the disease progresses (3). 90% of PDAC patients die of metastatic disease (1); however, the cellular and molecular mechanisms involved in establishing the metastatic disease are understudied compared to those involved in tumor initiation. Owing to this, improved biologic understanding of PDAC metastasis remains warranted in order to develop effective therapeutic regimens for this disease. 3D organoid cultures derived from human and mouse PDAC tumors have recently become a model of choice to study PDAC tumorigenesis, gradually replacing more commonly used 2D cancer cell lines. Organoids maintain similar gene expression profiles as the in vivo situation when cultured in a 3D matrix, and genetic manipulation is feasible. We generated a panel of isogenic murine pancreatic intraepithelial neoplasia (PanIN) and PDAC organoids containing genetic mutations commonly found in human PDAC (KRAS, TP53, SMAD4, CDKN2A), either alone or in combination, using CRISPR-Cas9 technology. Since large-scale in vitro production of these PDAC organoids is achievable, the platform can be used for a multitude of downstream analyses in vitro and in vivo, such as drug screening and metastasis-related studies. The parental of these organoids is isolated from C57/Bl6 mice, which can be orthotopically transplanted into immunocompetent mice, and the resulting tumor recapitulates human and GEMM PDAC development. In the process of systematic characterization of these organoid lines, we found that organoids with more mutations exhibit higher proliferation rates in vitro and tumor formation rates in vivo. These organoids also showed genotype-dependent organotropism during metastatic colonization. We further used this unique tool to systematically address if each combination of tumor suppressor loss utilizes distinct molecular mechanisms to drive metastasis initiation and invasion. This will allow us to identify druggable pathways that could inhibit metastasis initiation/invasion and progression. Thus, these organoids provide a powerful platform for disease modeling and drug discovery both in vitro and in vivo. Citation Format: Fong Cheng Pan, Angie Ai-Nok Chong, Steven D. Leach, Shuibing Chen, Todd Evans. Dissecting key biologic processes in pancreatic cancer metastasis using a genetically defined 3D organoid model [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C40.
Pensions: government review will “fix” annual allowance tax trap, says Hancock
Authors: Abi Rimmer
Journal: BMJ (2019)

The government has launched a review into the annual allowance taper imposed on doctors’ pensions and promised a swift and long term resolution to tackle the substantial tax burdens that are stopping many senior doctors from taking on extra work.

The taper, introduced in 2016-17, reduces the amount that high earning doctors can save in their pensions tax free. Accountants have previously told The …
Preclinical study of cytotoxicity and predictive markers of response to dual inhibition of PI3K and mTORC1/2 signaling by NVP-BEZ235 with or without paclitaxel or nab-paclitaxel as a new therapeutic strategy in pancreatic cancer cell lines.
Authors: Arturo Loaiza-Bonilla, Muaiad Kittaneh, Victor Daniel Guardiola Amado, Krisztina Kovacs, Jaime R. Merchan
Journal: Journal of Clinical Oncology (2013)

e15007 Background: Targeting the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) (PI3K-AKT-mTOR) pathway could arrest tumor growth and induce cell death in cancers that are resistant to currently available therapies. NVP-BEZ235 is an oral, targeted anticancer agent which exerts its potential activity through PI3K/mTOR dual inhibition. The paradoxical feedback activation of the PI3K/Akt pathway may compromise the efficacy of TORC1 inhibitors and provide the rationale for generating dual inhibitors in human pancreatic cancer. Methods: Kras mutant and wild-type human pancreatic cell lines were treated in vitro with BEZ235 and its combination with nab-paclitaxel. Antiproliferative effect per WST-1 assay was measured. Western blot analysis of S235/S236P-RPS6 and Akt (S473P-Akt, T308P-Akt) after exposure to BEZ235 was also performed. The potential synergistic and time-dependent effect at different concentrations of experimental agents was measured at different intervals. Results: BEZ235 reduced S473P-Akt, T308P-Akt and S235/S236P-RPS6 levels in a dose-dependent manner. Nab-paclitaxel at higher concentration exerts significant antiproliferative effects in a time-dependent fashion in pancreatic cell lines irrespective of Kras mutation status. BEZ235 in combination with nab-paclitaxel showed significant synergistic effect in a time and dose-dependent manner compared with the corresponding single drug treatments in pancreatic cancer cell lines with wild-type Kras (BxPC-3) but not in cell lines with mutant Kras (MIA PaCa-2 and PANC-1), the latter leading to a paradoxical increase in proliferation in comparison with controls, suggesting an escape pathway. Conclusions: These results provide the preclinical rationale for studies examining the synthetic lethality and escape pathways of PI3K/mTOR dual inhibition in particular subtypes of pancreatic cancer cell lines. Kras may be studied as a potential predictive biomarker of response to these agents and their combination with standard chemotherapy.
Re: Vincent Misrai, Enrique Rijo, Kevin C. Zorn, Nicolas Barry-Delongchamps, Aurelien Descazeaud. Waterjet Ablation Therapy for Treating Benign Prostatic Obstruction in Patients with Small- to Medium-size Glands: 12-month Results of the First French Aquablation Clinical Registry. Eur Urol 2019;76:667–75
Authors: Francesco Montorsi, Paolo Capogrosso, Andrea Salonia
Journal: European Urology (2019)
Publisher Correction: Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein
Authors: Sali M. K. Farhan, Daniel P. Howrigan, Liam E. Abbott, Joseph R. Klim, Simon D. Topp, Andrea E. Byrnes, Claire Churchhouse, Hemali Phatnani, Bradley N. Smith, Evadnie Rampersaud, Gang Wu, Joanne Wuu, Aleksey Shatunov, Alfredo Iacoangeli, Ahmad Al Khleifat, Daniel A. Mordes, Sulagna Ghosh, Kevin Eggan, Rosa Rademakers, Jacob L. McCauley, Rebecca Schüle, Stephan Züchner, Michael Benatar, J. Paul Taylor, Michael Nalls, Marc Gotkine, Pamela J. Shaw, Karen E. Morrison, Ammar Al-Chalabi, Bryan Traynor, Christopher E. Shaw, David B. Goldstein, Matthew B. Harms, Mark J. Daly, Benjamin M. Neale
Journal: Nature Neuroscience (2019)
Detection of disseminated tumor cells in bone marrow as an independent prognostic factor in primary ovarian cancer patients.
Authors: Pauline Wimberger, Malgorzata Banys, Sabine Kasimir-Bauer, Andreas D. Hartkopf, Natalia Krawczyk, Christian Marth, Rainer Kimmig, Hans Neubauer, Diethelm Wallwiener, Tanja N. Fehm
Journal: Journal of Clinical Oncology (2012)

5042 Background: Detection of disseminated tumor cells (DTC) in the bone marrow (BM)of breast cancer patients is associated with poor outcome. Recent studies demonstratedthat DTC may serve as a prognostic factor in ovarian cancer.The aim of our study was to evaluate the impact of BM status on survival in a large cohort of ovarian cancer patients. Methods: 365 patients with primary ovarian cancer were included into this three-center prospective study. BM aspirates were collected preoperatively from iliac crest. Disseminatedtumor cells were identified by immunocytochemistry using the pancytokeratin antibodyA45B/B3 and by cytomorphology. Patient outcomes were evaluated using a multivariable Cox regression model. Results: Disseminated tumor cells were detected in 28% of all BM aspirates. The number of CK-positive cells ranged from 1 to 42 per 2x10 6 mononuclear cells. DTC status did not correlate with any of the established clinicopathogical factors. The overall survival was significantly shorter among DTC-positive patients compared to DTC-negative patients (51 mo, 95% CI: 35 – 67 mo versus 32 mo, 95% CI: 22 – 42 mo; p = 0.003). However, disease-free survival was not related to DTC-positivity. In the multivariable analysis, BM status, FIGO stage, nodal status, resection status and age were independent predictors of reduced overall survival. Interestingly, a subset of DTCs may have stem cell properties since a subset of these cells (128 out of 228 cases) were SOX2 positive, which is an embryonic stem cell marker. Conclusions: Tumor cell dissemination into bone marrow is a common phenomenon in ovarian cancer. DTC detection has the potential to become an important biomarker for prognostication and may be included as a therapeutic target in future concepts.
Graphic Medicine—The Best of 2019
Authors: Michael J. Green, Lisa H. Plotkin, Matthew N. Noe
Journal: JAMA (2019)

This Arts and Medicine feature reviews 2 outstanding graphic novels of 2019: Kid Gloves by Lucy Knisely, about her pregnancy and its complications, and Gender Queer by Maia Kobabe, about her experience discovering she is gender nonbinary and asexual.
Advances in precision oral health
Authors: James D. Beck, Kamaira Philips, Kevin Moss, Kimon Divaris, Thiago Morelli, Steven Offenbacher
Journal: Periodontology 2000 (2019)

The concept of precision dentistry as it relates to precision medicine is relatively new to the field of oral health. Precision dentistry is a contemporary, multifaceted, data-driven approach to oral health care that uses individual characteristics to stratify similar patients into phenotypic groups. The objective is to provide clinicians with the information that will allow them to improve treatment planning and a patient's response to treatment. Providers that use a precision oral health approach would move away from using an "average treatment" for all patients with a particular diagnosis and move toward more specific treatments for patients within each diagnostic subgroup. Precision dentistry requires a method or a model that places each individual in a subgroup where each member is the same as every other member in relation to the disease of interest. Precision dentistry is a paradigm shift that requires a new way of thinking about diagnostic categories. This approach uses patients' risk factor data (including, but not limited to, genetic, environmental, and health behavioral), rather than expert opinion or clinical presentation alone, to redefine traditional categories of health and disease. We review aspects of current efforts to allow precision dentistry to be realized and focus on one of the major innovations that may help precision dentistry to be practiced by periodontists, the World Workshop Model. Another approach is the Periodontal Profile Class system. These two approaches represent examples of supervised and unsupervised learning systems, respectively. This review compares and contrasts these two learning systems for their ability to classify patients into homogeneous disease and risk groups, as well as their feasibility at achieving the objective of enabling precision dentistry. We conclude that: (a) the World Workshop Model concept of stages and grades works as expected, in that periodontal status appears to be more serious in each successive stage. In addition, the seriousness and the complexity of the disease are greater as the grade increases within each stage. Stages and grades are important for precision dentistry because they consider the risk of future disease and the prognosis, and enable practitioners to use more signs, symptoms, and other associated factors when placing a patient in a diagnostic category; (b) the assignment of stages and grades using unsupervised learning systems is superior to using supervised learning systems for the prediction of 10-year tooth loss and 3-year attachment loss progression. In addition, the unsupervised learning approach (Periodontal Profile Class stages) results in stronger associations between the periodontal phenotypes and systemic diseases and conditions (prevalent diabetes, C-reactive protein, and incident stroke). This probably occurs because an unsupervised learning model produces more data-driven, mutually exclusive, homogeneous groups than a supervised learning model.
Type 2 diabetes increases the long‐term risk of heart failure and mortality in patients with atrial fibrillation
Authors: Marija Polovina, Lars H. Lund, Dijana Đikić, Ivana Petrović‐Đorđević, Gordana Krljanac, Ivan Milinković, Ivana Veljić, Massimo F. Piepoli, Giuseppe M.C. Rosano, Arsen D. Ristić, Milika Ašanin, Petar M. Seferović
Journal: European Journal of Heart Failure (2019)
Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection
Authors: Neil J. Shah, Ghassan Al-Shbool, Matthew Blackburn, Michael Cook, Anas Belouali, Stephen V. Liu, Subha Madhavan, Aiwu Ruth He, Michael B. Atkins, Geoffrey T. Gibney, Chul Kim
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Patients with chronic viral infections including human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV) are at increased risk of developing malignancies. The safety and efficacy of ICI therapy in patients with both cancer and chronic viral infections is not well established as most clinical trials of ICIs excluded these patient populations. <h3>Methods</h3> We performed a retrospective analysis of patients with advanced-stage cancers and HIV, HBV, or HCV infection treated with ICI therapy at 5 MedStar Health hospitals from January 2011 to April 2018. <h3>Results</h3> We identified 50 patients including 16 HIV, 29 HBV/HCV, and 5 with concurrent HIV and either HBV or HCV. In the HIV cohort (<i>n</i> = 21), any grade immune-related adverse events (irAEs) were 24% with grade ≥ 3 irAEs 14%. Among 5 patients with matched pre/post-treatment results, no significant changes in HIV viral load and CD4+ T-cell counts were observed. RECIST confirmed (<i>n</i> = 18) overall response rate (ORR) was 28% with 2 complete responses (CR) and 3 partial responses (PR). Responders included 2 patients with low baseline CD4+ T-cell counts (40 and 77 cells/ul, respectively). In the HBV/HCV cohort (<i>n</i> = 34), any grade irAEs were 44% with grade ≥ 3 irAEs 29%. RECIST confirmed ORR was 21% (6 PR). Among the 6 patients with known pre/post-treatment viral titers (2 HCV and 4 HBV), there was no evidence of viral reactivation. <h3>Conclusions</h3> Our retrospective series is one of the largest case series to report clinical outcomes among HIV, HBV and HCV patients treated with ICI therapy. Toxicity and efficacy rates were similar to those observed in patients without chronic viral infections. Viral reactivation was not observed. Tumor responses occurred in HIV patients with low CD4 T-cell counts. While prospective studies are needed to validate above findings, these data support not excluding such patients from ICI–based clinical trials or treatment.
Roles of HIF1 and HIF2 in pulmonary hypertension: it all depends on the context
Authors: Gregory B. Waypa, Paul T. Schumacker
Journal: European Respiratory Journal (2019)

<b>HIF1 and HIF2 can play complementary, opposing or unrelated roles in mediating the response to low oxygen levels in different cell types. This study shows HIF2 plays a dominant role in mediating the development of PH in response to environmental hypoxia.</b>http://bit.ly/2Cy46sR
Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC
Authors: Rajashree Mishra, Mikael Åkerlund, Diana L. Cousminer, Emma Ahlqvist, Jonathan P. Bradfield, Alessandra Chesi, Kenyaita M. Hodge, Vanessa C. Guy, David J. Brillon, Richard E. Pratley, Michael R. Rickels, Adrian Vella, Fernando Ovalle, Ronald I. Harris, Olle Melander, Stephen Varvel, Hakon Hakonarson, Phillippe Froguel, John T. Lonsdale, Didac Mauricio, Nanette C. Schloot, Kamlesh Khunti, Carla J. Greenbaum, Knud B. Yderstræde, Tiinamaija Tuomi, Benjamin F. Voight, Stanley Schwartz, Bernhard O. Boehm, Leif Groop, Richard David Leslie, Struan F.A. Grant
Journal: Diabetes Care (2019)

OBJECTIVE The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region. RESEARCH DESIGN AND METHODS Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects (n = 1,985) and control subjects (n = 2,219). The same approach was applied to a LADA cohort (n = 1,428) using population-based control subjects (n = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects). RESULTS The strongest associations in the MHC class II region (rs3957146, β [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly HLA-B*39 (β [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, β [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA. CONCLUSIONS In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.
Abstract B28: Novel combination treatment designed to target both metastatic cells and proliferation in pancreatic ductal adenocarcinoma
Authors: Michelle Karl, Gabriella Russo, Bartholomew Starich, Haotian Tan, Denis Wirtz
Journal: Cancer Research (2019)

Abstract Pancreatic cancer is the 4th most common cause of cancer-related deaths in the United States, with only a 7-9% 5-year survival rate. While there are a few combination treatments that have been shown to increase overall survival by several months, gemcitabine monotherapy, which has been used to treat PDAC since 2006, is still the most commonly administered first-line treatment. Our objective is to improve patient survival by providing a novel combination therapy designed to inhibit the growth of solid tumors and prevent metastatic cancer cells from reaching secondary organs. Our lab has recently shown that secreted interleukin 6 (IL-6) and interleukin 8 (IL-8) can induce a migratory phenotype in tumorigenic, metastatic cancer cells in triple-negative breast cancer models. Cells exposed to these cytokines display enhanced invasion through stromal environments, and this phenotype can be reversed by blocking the IL-6 and IL-8 receptors with the combined treatment of tocilizumab and reparixin. We hypothesized that this simultaneous blocking of IL-6 and IL-8 receptors would improve PDAC patient outcomes when used in combination with gemcitabine by targeting both proliferation and metastasis. Preliminary results show that this combination treatment has a positive effect in in vivo PDAC models. Our novel treatment combination was able to significantly reduce the tumor size, exceeding that seen from gemcitabine monotherapy. In addition, the triple combination reduced the metastatic burden and normalized the effect of the treatment among the mice in the group. Citation Format: Michelle Karl, Gabriella Russo, Bartholomew Starich, Haotian Tan, Denis Wirtz. Novel combination treatment designed to target both metastatic cells and proliferation in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B28.
Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial
Authors: Jack Cuzick, Ivana Sestak, John F Forbes, Mitch Dowsett, Simon Cawthorn, Robert E Mansel, Sibylle Loibl, Bernardo Bonanni, D Gareth Evans, Anthony Howell
Journal: The Lancet (2019)

BackgroundTwo large clinical trials have shown a reduced rate of breast cancer development in high-risk women in the initial 5 years of follow-up after use of aromatase inhibitors (MAP.3 and International Breast Cancer Intervention Study II [IBIS-II]). Here, we report blinded long-term follow-up results for the IBIS-II trial, which compared anastrozole with placebo, with the objective of determining the efficacy of anastrozole for preventing breast cancer (both invasive and ductal carcinoma in situ) in the post-treatment period.MethodsIBIS-II is an international, randomised, double-blind, placebo-controlled trial. Postmenopausal women at increased risk of developing breast cancer were recruited and were randomly assigned (1:1) to either anastrozole (1 mg per day, oral) or matching placebo daily for 5 years. After treatment completion, women were followed on a yearly basis to collect data on breast cancer incidence, death, other cancers, and major adverse events (cardiovascular events and fractures). The primary outcome was all breast cancer.Findings3864 women were recruited between Feb 2, 2003, and Jan 31, 2012. 1920 women were randomly assigned to 5 years anastrozole and 1944 to placebo. After a median follow-up of 131 months (IQR 105–156), a 49% reduction in breast cancer was observed for anastrozole (85 vs 165 cases, hazard ratio [HR] 0·51, 95% CI 0·39–0·66, p<0·0001). The reduction was larger in the first 5 years (35 vs 89, 0·39, 0·27–0·58, p<0·0001), but still significant after 5 years (50 vs 76 new cases, 0·64, 0·45–0·91, p=0·014), and not significantly different from the first 5 years (p=0·087). Invasive oestrogen receptor-positive breast cancer was reduced by 54% (HR 0·46, 95% CI 0·33–0·65, p<0·0001), with a continued significant effect in the period after treatment. A 59% reduction in ductal carcinoma in situ was observed (0·41, 0·22–0·79, p=0·0081), especially in participants known to be oestrogen receptor-positive (0·22, 0·78–0·65, p<0·0001). No significant difference in deaths was observed overall (69 vs 70, HR 0·96, 95% CI 0·69–1·34, p=0·82) or for breast cancer (two anastrozole vs three placebo). A significant decrease in non-breast cancers was observed for anastrozole (147 vs 200, odds ratio 0·72, 95% CI 0·57–0·91, p=0·0042), owing primarily to non-melanoma skin cancer. No excess of fractures or cardiovascular disease was observed.InterpretationThis analysis has identified a significant continuing reduction in breast cancer with anastrozole in the post-treatment follow-up period, with no evidence of new late side-effects. Further follow-up is needed to assess the effect on breast cancer mortality.FundingCancer Research UK, the National Health and Medical Research Council Australia, Breast Cancer Research Foundation, Sanofi Aventis, and AstraZeneca.