tbuckley/cabot-search huggingface dataset:
The Effects of Bariatric Surgery on Islet Function, Insulin Secretion, and Glucose Control
Authors: Jonathan D Douros, Jenny Tong, David A D’Alessio
Journal: Endocrine Reviews (2019)

Abstract Although bariatric surgery was developed primarily to treat morbid obesity, evidence from the earliest clinical observations to the most recent clinical trials consistently demonstrates that these procedures have substantial effects on glucose metabolism. A large base of research indicates that bariatric surgeries such as Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), and biliopancreatic diversion (BPD) improve diabetes in most patients, with effects frequently evident prior to substantial weight reduction. There is now unequivocal evidence from randomized controlled trials that the efficacy of surgery is superior to intensive life-style/medical management. Despite advances in the clinical understanding and application of bariatric surgery, there remains only limited knowledge of the mechanisms by which these procedures confer such large changes to metabolic physiology. The improvement of insulin sensitivity that occurs with weight loss (e.g., the result of diet, illness, physical training) also accompanies bariatric surgery. However, there is evidence to support specific effects of surgery on insulin clearance, hepatic glucose production, and islet function. Understanding the mechanisms by which surgery affects these parameters of glucose regulation has the potential to identify new targets for therapeutic discovery. Studies to distinguish among bariatric surgeries on key parameters of glucose metabolism are limited but would be of considerable value to assist clinicians in selecting specific procedures and investigators in delineating the resulting physiology. This review is based on literature related to factors governing glucose metabolism and insulin secretion after the commonly used RYGB and VSG, and the less frequently used BPD and adjustable gastric banding.
Stem cell (SC) yield and transplantation results from transplant-eligible newly diagnosed multiple myeloma (TE NDMM) patients (pts) receiving daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) in the phase 3 CASSIOPEIA study.
Authors: Cyrille Hulin, Philippe Moreau, Michel Attal, Karim Belhadj, Lotfi Benboubker, Denis Caillot, Thierry Facon, Laurent Garderet, Frederique Kuhnowski, Anne-Marie Stoppa, Brigitte Kolb, Mourad Tiab, Pieter Sonneveld, Kon-Siong Jie, Matthijs Westerman, Lixia Pei, Tobias Kampfenkel, Carla De Boer, Jessica Vermeulen, Niels W.C.J. van de Donk
Journal: Journal of Clinical Oncology (2019)

8042 Background: High-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) is the standard of care in TE NDMM. In the phase 3 CASSIOPEIA study, D-VTd significantly improved stringent complete response (sCR), ≥CR, and minimal residual disease (MRD)-negative rates and reduced the risk of progression/death vs VTd in TE NDMM pts. We assessed SC yield and transplantation results among pts receiving D-VTd vs VTd induction prior to HDT/ASCT in Part 1 of CASSIOPEIA. Methods: In Part 1, TE NDMM pts ages 18-65 y were randomized 1:1 to 4 pre-transplant induction and 2 post-transplant consolidation cycles of DARA + VTd or VTd alone. After induction, pts underwent SC mobilization with cyclophosphamide 3 g/m 2 (recommended dose) and GCSF. Peripheral blood SCs were harvested based on response to mobilization. Plerixafor was given if SC collection failed at first attempt and in accordance with institutional practice. Melphalan 200 mg/m 2 IV was given as HDT prior to ASCT. Results: A total of 1085 pts were randomized (D-VTd, 543; VTd, 542). Among pts who completed mobilization (D-VTd, 506; VTd, 492), more pts receiving D-VTd vs VTd received plerixafor during mobilization (21.7% vs 7.9%). Pts underwent a median (range) of 2 (1-6) vs 1 (1-4) days of apheresis for D-VTd vs VTd. The median number of CD34 + cells collected was lower for D-VTd vs VTd (6.3×10 6 /kg vs 8.9×10 6 /kg). Nevertheless, a similar percentage of ITT pts receiving D-VTd vs VTd underwent ASCT (90.1% vs 89.3%). The median number of CD34 + cells transplanted for D-VTd vs VTd was 3.3×10 6 /kg vs 4.3×10 6 /kg. Hematopoietic reconstitution rates were high and similar for transplanted pts receiving D-VTd vs VTd (99.8% vs 99.6%). For D-VTd vs VTd, a median (range) of 13.0 (6-54) vs 13.0 (4-43) days was required to achieve sustained ANC &gt; 500 cells/mm 3 , and a median (range) of 14.0 (2-56) vs 12.0 (1-47) days was required to achieve sustained platelets &gt; 20,000 cells/mm 3 without transfusion. Conclusions: SC mobilization and collection was feasible with D-VTd induction. Adding DARA to VTd allowed successful transplantation in pts with TE NDMM. Clinical trial information: NCT02541383.
Abstract 1517: Targeting M-MDSC intrinsic enhancer reprogramming enhances the efficacy of immune checkpoint therapy in hepatocellular carcinoma
Authors: Man Liu, Jingying Zhou, Alfred Sze Lok Cheng
Journal: Cancer Research (2019)

Abstract Fibrous liver promotes an immunosuppressive environment to facilitate hepatocellular carcinoma (HCC) initiation. However, the underlying mechanisms of liver fibrosis-elicited immune evasion are poorly elucidated. Myeloid derived suppressor cells (MDSCs) play a key role in immunosuppression, leading to low responsiveness of immune checkpoint blockade (ICB). Emerging evidence highlights the pivotal role of enhancer remodeling in cell identity establishment and tumor immunity. Therefore, we aimed to determine whether enhancer remodeling participates in MDSC generation and aggressive HCC development in fibrous liver, and further explore the potential of enhancer inhibition in targeting MDSCs and improving efficacy of ICB in fibrotic HCC treatment. By a mouse hepatoma cell Hepa1-6 orthotopic fibrotic HCC mouse model, we found that monocytic MDSC (M-MDSC) subset was also dramatically expanded in murine fibrous liver and positively correlated with increased hepatic tumorigenicity. Hepatic stellate cell (HSC), as key profibrogenic stromal cell, stimulated immunosuppressive M-MDSC generation from human peripheral blood mononuclear cells (PBMCs). Mechanistically, activated HSCs initiated p38 MAPK-mediated enhancer remodeling and triggered monocyte-to-M-MDSC identity shifting. Enhancer inhibition by a clinically-trialed drug iBET-762 disrupted HSC-M-MDSC crosstalk and abrogated M-MDSC generation and immunosuppressive functions. Notably, combination of iBET-762 with anti-PD-L1 antibody significantly induced tumor-infiltrating T lymphocytes, leading to tumor eradication and prolonged host survival in fibrosis-associated HCC model. As we also showed profound suppression of HCC patient-derived M-MDSCs by enhancer inhibition, our results delineate an enhancer deregulation mechanism for M-MDSC generation in fibrous liver environment, highlighting a promising therapeutic strategy of combined enhancer and immune-checkpoint targeting for desmoplastic tumors. This project is supported by Collaborative Research Fund C4017-14G and the Focused Innovations Scheme 1907309. Citation Format: Man Liu, Jingying Zhou, Alfred Sze Lok Cheng. Targeting M-MDSC intrinsic enhancer reprogramming enhances the efficacy of immune checkpoint therapy in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1517.
Inducible Pluripotent Stem Cell–Derived Cardiomyocytes Reveal Aberrant Extracellular Regulated Kinase 5 and Mitogen-Activated Protein Kinase Kinase 1/2 Signaling Concomitantly Promote Hypertrophic Cardiomyopathy in <i>RAF1</i> -Associated Noonan Syndrome
Authors: Fabrice Jaffré, Clint L. Miller, Anne Schänzer, Todd Evans, Amy E. Roberts, Andreas Hahn, Maria I. Kontaridis
Journal: Circulation (2019)

Background: More than 90% of individuals with Noonan syndrome (NS) with mutations clustered in the CR2 domain of RAF1 present with severe and often lethal hypertrophic cardiomyopathy (HCM). The signaling pathways by which NS RAF1 mutations promote HCM remain elusive, and so far, there is no known treatment for NS-associated HCM. Methods: We used patient-derived RAF1 S257L/+ and CRISPR-Cas9–generated isogenic control inducible pluripotent stem cell (iPSC)–derived cardiomyocytes to model NS RAF1 -associated HCM and to further delineate the molecular mechanisms underlying the disease. Results: We show that mutant iPSC–derived cardiomyocytes phenocopy the pathology seen in hearts of patients with NS by exhibiting hypertrophy and structural defects. Through pharmacological and genetic targeting, we identify 2 perturbed concomitant pathways that, together, mediate HCM in RAF1 mutant iPSC–derived cardiomyocytes. Hyperactivation of mitogen-activated protein kinase kinase 1/2 (MEK1/2), but not extracellular regulated kinase 1/2, causes myofibrillar disarray, whereas the enlarged cardiomyocyte phenotype is a direct consequence of increased extracellular regulated kinase 5 (ERK5) signaling, a pathway not previously known to be involved in NS. RNA-sequencing reveals genes with abnormal expression in RAF1 mutant iPSC–derived cardiomyocytes and identifies subsets of genes dysregulated by aberrant MEK1/2 or ERK5 pathways that could contribute to the NS-associated HCM. Conclusions: Taken together, the results of our study identify the molecular mechanisms by which NS RAF1 mutations cause HCM and reveal downstream effectors that could serve as therapeutic targets for treatment of NS and perhaps other, more common, congenital HCM disorders.
Abstract 3008: PSMA glycosylation and aggressive prostate cancer progression
Authors: Tanya C. Burch, Stephen S. Mackay, Ian O. Oduor, Joseph J. Otto, Raymond S. Lance, Dean A. Troyer, Oliver John Semmes, Julius O. Nyalwidhe
Journal: Cancer Research (2019)

Abstract Introduction: Prostate cancer has a heterogeneous spectrum of clinical outcomes with phenotypes ranging from indolent asymptomatic cases to very aggressive metastatic and lethal forms. Our long term objective is to identify molecules and characterize mechanisms for PCa progression to aggressive lethal disease. PSMA, a membrane bound glycoprotein is significantly over-expressed in more aggressive and metastatic prostate carcinomas with a negative correlation with patient prognosis. The role of its glycans in disease progression and in the development of biomarkers for the disease and potential therapeutics are currently unknown. Aberrant glycosylation of glycoproteins has been observed in many malignancies, and these changes influence disease progression. Our rationale is that differential glycosylation of PSMA correlates with PCa aggressive disease progression. In this study, we characterize N-linked glycosylation profiles in disease stratified PCa cells and prostate proximal fluids show differential expression of specific PSMA conjugated glycan structures that correlates with aggressive phenotypes. Methods/Results: PSMA was isolation from PCa cell lysates and post-DRE urines by column based affinity chromatography followed by SDS-PAGE and Western Blot and Coomassie staining. The fractionated PSMA protein band was excised and processed for proteomic and glycomic analysis. Isolated PSMA was trypsin digested and treated with PNGaseF and other glycosidases to cleave of N-linked glycans from the peptides. Isolated glycans were subjected to permethylation before MALDI-TOF-MS and high resolution, high mass accuracy and high sensitivity LC/MS/MS on an Orbitrap Fusion Lumos Tribrid MS instrument with multiple fragmentation capabilities (CID, HCD, ETD and EThcD) for glycan identification and quantitation. Validation of differential glycan expression was further performed by targeted glycan based MS and lectin based biochemical technologies. Conclusions: Our preliminary studies show that there is differential expression of PSMA N-linked glycans with disease severity in prostate cancer cells and post DRE urine samples. Further analyses are currently underway using an extensive cohort of post DRE urine samples and additional studies are focusing on uncovering the mechanisms that are modulated by PSMA glycosylation that are responsible for PCa disease progression. These could assist in the development of novel diagnostic and therapeutic strategies for the disease. Citation Format: Tanya C. Burch, Stephen S. Mackay, Ian O. Oduor, Joseph J. Otto, Raymond S. Lance, Dean A. Troyer, Oliver John Semmes, Julius O. Nyalwidhe. PSMA glycosylation and aggressive prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3008.
Основные подходы к профилактике вирусного гепатита А
Authors: O.V. Oniskova, L.O. Yushchenko, V.О. Tikholaz, V.S. Oleynik, O.O. Gordiychuk, T.V. Malanina
Journal: GASTROENTEROLOGY (2019)

Профилактика вирусного гепатита А в странах со средним уровнем эндемичности остается актуальным вопросом современности. Наиболее эффективным методом профилактики в мире является вакцинация в сочетании с соблюдением удовлетворительных санитарно-гигиенических условий. Доказано, что прививки против вирусного гепатита А обеспечивают длительную и эффективную защиту, хорошо переносятся и не вызывают серьезных побочных реакций. В регионах со средним уровнем эндемичности по вирусному гепатиту А должна быть рассмотрена возможность вакцинации, особенно категорий населения, относящихся к группам риска.
Abstract 3722: Novel Optical Coherence Tomography (OCT) technology for no-invasive 3D <i>ex vivo</i> drug activity profiling
Authors: Sumeer Dhar, Akihiro Ueda, Takemitsu Muira, Yasushi Kuromi, Yuki Mori, Hiroki Fujimoto
Journal: Cancer Research (2019)

Abstract Drug discovery and early to late drug development process have relied on 2D monolayer based in vitro assay platforms and small animal models. The limitations posed by 2D in vitro assays for evaluation of targeted and immunomodulatory agents have prompted researchers to develop novel 3D in vitro and ex vivo platforms utilizing the tumor microenvironment like conditions for better understanding of mechanisms of novel targeted and immunomodulatory drug/compound entities. Therefore, rapid development of robust 3D ex vivo cell culture as drug efficacy testing system for drug discovery, development and profiling of standard of care and Immunotherapeutic molecules have led to understanding the relevance of these platforms within the scientific and clinical community. 3D ex vivo platforms are being diligently evaluated as better predictive drug efficacy testing tools in preclinical as well as clinical space in the quest for profiling of novel anticancer entities (as single or two drug combinations). Within this context, there has been growing need in improved imaging and analysis of complex 3D structures (Multicellular tumor spheroids/Organoids) containing multiple cellular components such as, Tumor cells, stromal cells, various immune cells to monitor signaling pathways and assess immune events including T cell infiltration as drug efficacy measurement. At SCREEN LifeScience, we have developed a novel OCT based technology for imaging and analysis of complex 3D structures, such as, spheroid /organoid for growth &amp; morphological profiling, quantification of internal cavities, drug sensitivity testing to capture the events leading to tumor cell death and assessing mechanism of drug action. Additionally, this technology allows us perform large tissue imaging, non-invasive monitoring of macro and sprouted neo-vasculature without the need for fluorescent staining for providing quantitative information about the vascular morphological changes, thereby allowing for the evaluation of anti-angiogenic drugs in real time. In summary, the OCT technology shown to be robust and versatile technology useful for studying multiple disease models, including cancer. Its utility in regeneration medicine is being further evaluated as a versatile non-invasive platform. Citation Format: Sumeer Dhar, Akihiro Ueda, Takemitsu Muira, Yasushi Kuromi, Yuki Mori, Hiroki Fujimoto. Novel Optical Coherence Tomography (OCT) technology for no-invasive 3D ex vivo drug activity profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3722.
Ki-67 gives additional prognostic information on St Gallen 2007 and Adjuvant! Online risk categories in early breast cancer.
Authors: S Jung, W Han, J Lee, J Yu, E Ko, E Kim, H Moon, I Park, K Hwang, D Oh, T Kim, D Noh
Journal: Cancer Research (2009)

Abstract Abstract #1086 Purpose: We sought to determine the significance of Ki-67, one of the tumor cell proliferation indexes, as a useful prognostic factor in early breast cancer.&amp;#x2028; Patients and Methods: 1,080 consecutive patients with stage I or II breast cancer operated between 1998 and 2003 were enrolled. Patients were categorized based on the 2007 St. Gallen consensus and Adjuvant! Online. The expression of Ki-67 in the tumor was assayed using immunohistochemistry (cut-off value: 10%).&amp;#x2028; Results: Univariate analysis revealed that tumor size, lymph node involvement, histologic grade, estrogen receptor, progesterone receptor, bcl-2, and Ki-67 (≥10%) were significant for both overall survival (OS) and distant metastasis-free survival (DFS). Of them, lymph node involvement and high Ki-67 expression were identified as independent prognostic factors for OS at multivariate analysis. The survivals of intermediate- and high-risk groups according to 2007 St Gallen consensus were further separated by Ki-67 expression level (5-yr DFS rate=93.3% vs 86.6% for Ki-67&amp;lt;10% and ≥10%, respectively in intermediate-risk group (p=.001); 5-yr DFS rate=83.1% vs 61.5% for Ki-67&amp;lt;10% and ≥10%, respectively in high-risk group (p=.006)). The survivals of low- and high-risk groups according to Adjuvant! Online were further separated by Ki-67 expression level [5-yr DFS rate=97.8% vs 89.5% for Ki-67&amp;lt;10% and ≥10%, respectively in low-risk group (p=.010); 5-yr DFS rate=90.4% vs 82.6% for Ki-67&amp;lt;10% and ≥10% in high-risk group (p=.005)).&amp;#x2028; Conclusion: Ki-67 was an independent prognostic factor for DFS and OS in early breast cancer, and could give additional prognostic information on the risk grouping by 2007 St Gallen consensus and Adjuvant! Online. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1086.
Maintenance with weekly carfilzomib in elderly newly diagnosed multiple myeloma (IFM 2012-03).
Authors: Arthur Bobin, Guillemette Fouquet, Alain Duhamel, Salomon Manier, Lionel Karlin, Brigitte Kolb, Mourad Tiab, Carla Araujo, Nathalie Meuleman, Jean-Valère Malfuson, Pascal Bourquard, Pascal Lenain, Arnaud Jaccard, Karim Belhadj, Michel Attal, Philippe Moreau, Herve Avet-Loiseau, Cyrille Hulin, Thierry Facon, Xavier Leleu
Journal: Journal of Clinical Oncology (2019)

8029 Background: Prolonged treatments have significantly improved survival in newly diagnosed multiple myeloma (NDMM). Lenalidomide (IMiDs), is currently approved in this indication, but remains a daily treatment, although oral, and may favor side effects in the long run. Furthermore, the use of a proteasome inhibitor (PI) is warranted in certain type of MM, such as high-risk. Carfilzomib, a second generation PI, has proved active combined with an acceptable security profile but its added benefit when given continuously is unknown. We thought to study maintenance Carfilzomib for elderly NDMM (eNDMM). Methods: The IFM 2012-03 multicenter phase I KMP (Carfilzomib, Melphalan, Prednisone) weekly study for eNDMM (≥ 65 years old) determined the maximal tolerated dose of weekly Carfilzomib at 70mg/m². We focus herein on the second part of the study with IV Carfilzomib monotherapy given at 36mg/m² for 13 cycles maintenance on an every 2 weeks schedule. Results: Thirty eNDMM were recruited in IFM 2012-03. Median age is 75, with 56% R-ISS 2 or 3 and 11% high-risk cytogenetic. With K weekly from 36 to 70mg/m², OS is reported at 93.3%, including 46.7% ≥CR; median PFS is 35.8 months and median OS was not reached. Twenty-two (73%) patients started K maintenance and 16 (73%) completed it. Four patients progressed and 2 stopped for AEs (renal amylosis, sensory neuropahty) during the maintenance phase. At maintenance completion, 50% were ≥CR. From the start of maintenance, in landmark analysis, median PFS is 28.1 months and the estimated 36-months OS approximately 70%. Conclusions: Carfilzomib monotherapy can be used safely in maintenance for 1 year in eNDMM, including for patients above 75 years. K maintenance may lead to deep response rate, certainly a most relevant prognostic factor for prolonged survival. Therefore, Carfilzomib maintenance, characterized with a simple administration modality, might be considered as an alternative to Lenalidomide and integrate the armamentarium of prolonged therapy in eNDMM. Clinical trial information: NCT02302495.
Case 20-2019: A 52-Year-Old Woman with Fever and Rash after Heart Transplantation
Authors: Michael G. Ison, Taylor A. Lebeis, Nicolas Barros, Gregory D. Lewis, Lucas R. Massoth
Journal: New England Journal of Medicine (2019)

A 52-year-old woman who had undergone orthotopic heart transplantation because of dilated cardiomyopathy was admitted to the hospital 40 days after surgery with blanching, erythematous nodules on the left leg and arm; there was no associated necrosis or ulceration. A diagnosis was made.