tbuckley/cabot-search huggingface dataset:
Abstract 1090: β-Hydroxy-β-Methylbutyrate supplementation preserves muscle mass and reduces tumor growth in obese mice
Authors: Michael F. Coleman, Kristyn A. Liu, Xiaohu Tang, Salvador Fabela, Laura M. Lashinger, Zhengrong Cui, Stephen D. Hursting
Journal: Cancer Research (2019)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) remains very challenging to treat with mean 5-year survival of approx. 6%, leading to PDAC’s status as the 4th most deadly cancer in the US. Diet induced obesity (DIO) has been shown to promote both increased incidence and growth of PDAC. Simultaneously DIO promotes muscle loss and the loss of immune surveillance in tumors. Cachexia, a chronic catabolic process in which muscle mass is lost, is a common feature of PDAC. We have previously shown that while leucine driven mTOR activation protects muscle mass in tumor bearing mice it also promotes tumor growth. Hence, we sought to test the potential of a leucine metabolite, β-hydroxy-β-methyl-butyrate, to protect against cachexia in a PDAC model while antagonizing DIO mediated tumor growth. We further sought to determine if HMB treatment would alter gemcitabine response in tumors from obese animals. Methods: C57BL/6 mice consuming either control or high fat diet, bearing Panc02 tumors, were treated with HMB alone or in combination with gemcitabine. Muscle size was determined using Feret’s diameter measured from H&amp;E stained cross sections. Immunohistochemistry staining was performed for Ki-67 and CD3. Tumor transcriptomic analysis was preformed using Affymetrics microarray. In vitro characterization HMB modulated signaling in C2C12 myotubes, Panc02 cells, and bone marrow derived macrophages treated with pro-inflammatory signaling molecules. Results: a) HMB significantly increases muscle fiber size and mTOR signaling; b) HMB reduces DIO increased tumor volume; c) HMB significantly synergizes with gemcitabine to suppress PDAC growth in obese mice; and d) HMB reverts DIO mediate immune suppression and promotes tumor immune surveillance. Discussion: Antagonism of DIO promoted PDAC tumor growth, by HMB, and promotion of immune surveillance may offer significant synergy with standard therapy or, immune targeted therapies in PDAC. Citation Format: Michael F. Coleman, Kristyn A. Liu, Xiaohu Tang, Salvador Fabela, Laura M. Lashinger, Zhengrong Cui, Stephen D. Hursting. β-Hydroxy-β-Methylbutyrate supplementation preserves muscle mass and reduces tumor growth in obese mice [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 1090.
Abstract 4165: Unstable microsatellite instability proportion among unselected ovarian and endometrial cancer patients among Korean population
Authors: Min Kyu Kim
Journal: Cancer Research (2019)

Abstract Background: There are several availability of microsatellite instability(MSI) among ovarian and endometrial cancer for detection of Lynch syndrome and biomarker of immune chemotherapeutic treatment. We investigated to know proportion of abnormal microsatellite instability (MSI-L/H). Methods: Through retrospective search,we identified 51 cases of MSI samples from ovary and endometrial cancer visiting hereditary gynecologic cancer center. Results: We found 34 ovary cancer, 13 endometrial cancer and 4 colon cancer patients. Median age was 56.6(18~78). About thirty percent have family cancer history among patient relatives (14/45(31.1%)). Early stage cancer (I~II) (4/25,16.0%) have higher incidence than late stage cancer (III~IV) (2/28,7.1%). Abnormal MSI have three serous type and endometrioid type pathology. Among abnormal MSI, we found two MSI-L and four MSI-H (6/51(11.8%)). We found one MSI-H ovary cancer,3 MSI-H endometrial cancer patients (1/34(2.9%),3/13(23.1%)). Conclusions: There are about 10 percent of abnormal MSI in this study group Citation Format: Min Kyu Kim. Unstable microsatellite instability proportion among unselected ovarian and endometrial cancer patients among Korean population [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 4165.
Prescription Patterns of Family Members After Discontinued Opioid or Benzodiazepine Therapy of Users
Authors: Michael L. Barnett, Tanner R. Hicks, Anupam B. Jena
Journal: JAMA Internal Medicine (2019)

This study uses data from a national database of privately insured individuals from 2007 to 2016 to examine first-prescription filling patterns exhibited by family members of high-volume users of opioids or benzodiazepine whose drug treatment has been discontinued.
Abstract 17303: Permanent Cardiac Pacemaker Implant Improves Sleep Habit
Authors: Sharma Kattel, Masaru Hiki, Takatoshi Kasai, Yuji Saito, Hiroyuki Daida
Journal: Circulation (2018)

Background: Permanent cardiac pacemaker is indicated in patients with symptomatic bradycardia. Its role in sleep disorder is unknown, however some patient report improvement in their sleep habit after permanent cardiac pacemaker implant. We examined the role of permanent cardiac pacemaker in relation to patients’ sleeping habits. Methods: Total of 174 patients who agreed to participate in the study were included (21 Implantable Cardioverter Defibrillator (ICD) and 153 pacemaker implants). The ICD group was used as the control group. Patients with bi-ventricular pacemaker implants for cardiac re-synchronization therapy were excluded from the study. Questionnaires about the sleep habit were evaluated before and after the device implant and analyzed using paired T test and Chi square test. Results: The indications for permanent pacemaker therapy were high grade AV block (33%), sick sinus syndrome (64%) and syncope (1%). Indications of ICD were primary or secondary sudden cardiac death prevention without history of known symptomatic bradycardia (100%). Mean Ventricular pacing was 40.39% (interquartile range: 97%) of the time in the pacemaker group. There were no baseline differences in sleep duration and quality of sleep in both the ICD and pacemaker group prior to device implant. Improved sleep habit (46% in pacemaker vs 23% in the ICD group, P=0.04) and better quality of sleep (44% in pacemaker vs 19% in ICD, P=0.01) were reported after device implant. The patients in pacemaker group reported much improvement in sleep duration (average by 30 minutes in Pacemaker vs 15 minutes in ICD, P=0.002). Conclusions: Patients who had permanent pacemaker implant for symptomatic bradycardia showed improved sleep quality and duration than the patients with ICD implant for primary or secondary sudden cardiac death prevention. Mechanisms of improved sleep habit in pacemaker group are unclear, but possibly associated with improved cardiac output with consistent heat rate during sleep from the pacemaker. Further large-scale studies are needed to validate this concept.
Abstract 266: Relationship between BAG3 expression and the cytotoxicity of laromustine in HL60 cells
Authors: Stanley R. Clarke, Allie H. Naccara, Amanda J. Loya, Sam W. Marchant, Xiaoou Wang, Thomas J. LaJoie, Jordyn N. Smith, Kevin P. Rice
Journal: Cancer Research (2019)

Abstract Laromustine is an experimental sulfonylhydrazine prodrug with clinical potential against acute myelogenous leukemia and glioblastoma multiforme. Cytotoxicity is largely due to DNA crosslinking activity from an electrophilic subspecies of laromustine generated in situ. However, methylisocyanate, another electrophile cogenerated upon base-catalyzed activation of laromustine, induces acute toxicity in cultured leukemia cells. Isocyanate-mediated cytotoxicity likely involves apoptotic processes revealed in experiments presented herein showing PARP cleavage, caspase 3/7 activation, and annexin-V staining. We demonstrate that compounds that yield methylisocyanate, including laromustine, cause substantial dysregulation of gene transcription patterns that are not observed with a derivative of laromustine that possesses the DNA crosslinking activity but not the methylisocyanate. Purified mRNA from promyelocytic HL60 cells treated with either 100 µM agent or an equivalent volume of DMSO was measured using real-time RT-PCR experiments and GeneChip analyses. Among the nearly 3,000 genes dysregulated upon exposure to both laromustine and its methylisocyanate-bearing analog, BCL2-associated athanogene 3 (BAG3) emerged as a promising candidate for further investigation. This anti-apoptotic gene was significantly upregulated in these conditions. So as to assess the significance its gene product in cell death or survival in cultured cells treated with laromustine, a stable cell line expressing an shRNA construct to knock down BAG3 was engineered from HL60 cells using lentiviruses. Preliminary evidence suggests that these cells are more susceptible to the cytotoxic effects of laromustine. These data suggest that BAG3 may be part of a defensive strategy for promyelocytic leukemia cells to survive treatment with laromustine. Citation Format: Stanley R. Clarke, Allie H. Naccara, Amanda J. Loya, Sam W. Marchant, Xiaoou Wang, Thomas J. LaJoie, Jordyn N. Smith, Kevin P. Rice. Relationship between BAG3 expression and the cytotoxicity of laromustine in HL60 cells [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 266.
Abstract 1986: Breast cancer-secreted exosomes stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumor progression
Authors: Juanjuan Li, Qi Wu, Zhiyu Li, Si Sun, Shan Zhu, Lijun Wang, Juan Wu, Yimin Zhang, Jingping Yuan, Shengrong Sun, Changhua Wang
Journal: Cancer Research (2019)

Abstract Background: Emerging evidence supports the pivotal roles of adipocytes in breast cancer progression. Beige/brown adipose tissue that activates thermogenesis is suggested to contribute to the hypermetabolic state. However, the mediators and mechanisms remain unclear. Methods: Survival probabilities for recurrence-free survival (RFS) of 106 breast cancer patients were estimated using the Kaplan-Meier method based on the immunohistochemistry results of several biomarkers. Biochemical studies were performed to characterize the novel interrelation between breast cancer cells and adipocytes. Results: In the survival analysis, high MCT4 expression in stromal adipose tissue and overexpression of CD36 or FATP1 in malignant tissue predict poor prognosis for breast cancer patients. We show that tumor-surrounding adipocytes exhibit an altered phenotype in terms of upregulated beige/brown characteristics and increased catabolism. This increase in catabolism is associated with an activated state characterized by the release of metabolites, including free fatty acids, pyruvate, lactate and ketone bodies. Likewise, tumor cells cocultivated with mature adipocytes exhibit metabolic adaptation and an aggressive phenotype in vitro and in vivo. Mechanistically, we show that tumour cells induce beige/brown differentiation and remodel metabolism in resident adipocytes by secreting exosomes that carry high levels of miRNA-144 and miRNA-126. Cancer cell-secreted miRNA-144 promotes beige/brown adipocyte characteristics by downregulating the MAP3K8/ERK1/2/PPARγ axis. We also found that exosomal miRNA-126 remodels metabolism by disrupting IRS/Glut-4 signalling, activating the AMPK/autophagy pathway and stabilizing HIF1α expression in imminent adipocytes. In vivo inhibition of miRNA-144 or miRNA-126 decreases adipocyte-induced tumour growth. Conclusions: These results demonstrate that cancer-derived exosomal miRNA-144 and miRNA-126 can reprogram the systemic energy metabolism to facilitate tumor progression by inducing beige/brown differentiation and enhancing catabolism in recipient adipocytes. Citation Format: Juanjuan Li, Qi Wu, Zhiyu Li, Si Sun, Shan Zhu, Lijun Wang, Juan Wu, Yimin Zhang, Jingping Yuan, Shengrong Sun, Changhua Wang. Breast cancer-secreted exosomes stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumor 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 1986.
Veterans Genomic Cohort Nearing 1 Million
Authors: Rita Rubin
Journal: JAMA (2019)

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Role of diet in type 2 diabetes incidence: umbrella review of meta-analyses of prospective observational studies
Authors: Manuela Neuenschwander, Aurélie Ballon, Katharina S Weber, Teresa Norat, Dagfinn Aune, Lukas Schwingshackl, Sabrina Schlesinger
Journal: BMJ (2019)

Abstract Objective To summarise the evidence of associations between dietary factors and incidence of type 2 diabetes and to evaluate the strength and validity of these associations. Design Umbrella review of systematic reviews with meta-analyses of prospective observational studies. Data sources PubMed, Web of Science, and Embase, searched up to August 2018. Eligibility criteria Systematic reviews with meta-analyses reporting summary risk estimates for the associations between incidence of type 2 diabetes and dietary behaviours or diet quality indices, food groups, foods, beverages, alcoholic beverages, macronutrients, and micronutrients. Results 53 publications were included, with 153 adjusted summary hazard ratios on dietary behaviours or diet quality indices (n=12), food groups and foods (n=56), beverages (n=10), alcoholic beverages (n=12), macronutrients (n=32), and micronutrients (n=31), regarding incidence of type 2 diabetes. Methodological quality was high for 75% (n=115) of meta-analyses, moderate for 23% (n=35), and low for 2% (n=3). Quality of evidence was rated high for an inverse association for type 2 diabetes incidence with increased intake of whole grains (for an increment of 30 g/day, adjusted summary hazard ratio 0.87 (95% confidence interval 0.82 to 0.93)) and cereal fibre (for an increment of 10 g/day, 0.75 (0.65 to 0.86)), as well as for moderate intake of total alcohol (for an intake of 12-24 g/day v no consumption, 0.75 (0.67 to 0.83)). Quality of evidence was also high for the association for increased incidence of type 2 diabetes with higher intake of red meat (for an increment of 100 g/day, 1.17 (1.08 to 1.26)), processed meat (for an increment of 50 g/day, 1.37 (1.22 to 1.54)), bacon (per two slices/day, 2.07 (1.40 to 3.05)), and sugar sweetened beverages (for an increase of one serving/day, 1.26 (1.11 to 1.43)). Conclusions Overall, the association between dietary factors and type 2 diabetes has been extensively studied, but few of the associations were graded as high quality of evidence. Further factors are likely to be important in type 2 diabetes prevention; thus, more well conducted research, with more detailed assessment of diet, is needed. Systematic review registration PROSPERO CRD42018088106.
Adult Langerhans cell histiocytosis: A contemporary single-institution series of 186 patients.
Authors: Gaurav Goyal, Marie Hu, Jason R Young, Robert Vassallo, Jay H Ryu, Nabila Nora Bennani, Mithun Vinod Shah, Karen Rech, Ronald S. Go
Journal: Journal of Clinical Oncology (2019)

7018 Background: Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm driven by MAPK-ERK mutations in majority of patients. Contemporary data on treatments and outcomes in adult LCH are lacking. Hence, we undertook this study to analyze a large cohort of adult LCH patients. Methods: This was a retrospective study of adult (≥18 years) LCH patients seen at our institution between 1998 and 2018. Results: We included 186 patients with adult LCH (median age 43; 19-88), and 54% were females. 70% of patients were diagnosed after 2007. Common presenting symptoms were cough/dyspnea (30%), rash (17%), pain/swelling in head (17%), and diabetes insipidus (10%). 70 (38%) patients had multisystem LCH, 62 (33%) had isolated pulmonary LCH, and 35 (19%) had unifocal LCH. Common sites of involvement included lung (59%), bone (37%), skin (21%), and nervous system (16%). 121 (65%) were smokers; 48% of these had lung disease, while 52% had multisystem disease. 18 of 31 tested (58%) patients had BRAF-V600E mutation. Most common first-line treatment was smoking cessation in 24 patients, and led to an overall response rate (ORR) of 83% in pulmonary lesions. Radiation therapy was used in 11 patients, and led to an ORR 82%. Surgical resection of lesion was done in 23 patients, with relapses in 24%. Systemic therapies were used in 78 (42%) patients (Table). Most common first-line systemic therapy was cladribine with ORR of 78%. Vemurafenib was used in 3 patients with BRAF-V600E, leading to an ORR of 67% . After a median follow-up of 23 months (0-261), 21 patients had died. Of these, 10 died of progressive LCH. Median OS was not reached, and mean OS was 196 months. Conclusions: This is the largest contemporary series of adult LCH. It shows that diverse clinical spectrum, ranging from benign course to a progressive multisystem disease. Although smoking cessation was an effective treatment for pulmonary LCH, a large subset required systemic chemotherapy. [Table: see text]
Chanzyme TRPM7 protects against cardiovascular inflammation and fibrosis
Authors: Francisco J Rios, Zhi-Guo Zou, Adam P Harvey, Katie Y Harvey, Ryszard Nosalski, Panagiota Anyfanti, Livia L Camargo, Silvia Lacchini, Alexey G Ryazanov, Lillia Ryazanova, Sarah McGrath, Tomasz J Guzik, Carl S Goodyear, Augusto C Montezano, Rhian M Touyz
Journal: Cardiovascular Research (2019)

Abstract Aims Transient Receptor Potential Melastatin 7 (TRPM7) cation channel is a chanzyme (channel + kinase) that influences cellular Mg2+ homeostasis and vascular signalling. However, the pathophysiological significance of TRPM7 in the cardiovascular system is unclear. The aim of this study was to investigate the role of this chanzyme in the cardiovascular system focusing on inflammation and fibrosis. Methods and results TRPM7-deficient mice with deletion of the kinase domain (TRPM7+/Δkinase) were studied and molecular mechanisms investigated in TRPM7+/Δkinase bone marrow-derived macrophages (BMDM) and co-culture systems with cardiac fibroblasts. TRPM7-deficient mice had significant cardiac hypertrophy, fibrosis, and inflammation. Cardiac collagen and fibronectin content, expression of pro-inflammatory mediators (SMAD3, TGFβ) and cytokines [interleukin (IL)-6, IL-10, IL-12, tumour necrosis factor-α] and phosphorylation of the pro-inflammatory signalling molecule Stat1, were increased in TRPM7+/Δkinase mice. These processes were associated with infiltration of inflammatory cells (F4/80+CD206+ cardiac macrophages) and increased galectin-3 expression. Cardiac [Mg2+]i, but not [Ca2+]i, was reduced in TRPM7+/Δkinase mice. Calpain, a downstream TRPM7 target, was upregulated (increased expression and activation) in TRPM7+/Δkinase hearts. Vascular functional and inflammatory responses, assessed in vivo by intra-vital microscopy, demonstrated impaired neutrophil rolling, increased neutrophil: endothelial attachment and transmigration of leucocytes in TRPM7+/Δkinase mice. TRPM7+/Δkinase BMDMs had increased levels of galectin-3, IL-10, and IL-6. In co-culture systems, TRPM7+/Δkinase macrophages increased expression of fibronectin, proliferating cell nuclear antigen, and TGFβ in cardiac fibroblasts from wild-type mice, effects ameliorated by MgCl2 treatment. Conclusions We identify a novel anti-inflammatory and anti-fibrotic role for TRPM7 and suggest that its protective effects are mediated, in part, through Mg2+-sensitive processes.
Phase 1/2 trial of cirmtuzumab and ibrutinib: Planned analysis of phase 1 CLL cohorts.
Authors: Michael Y. Choi, William G. Wierda, Hun Ju Lee, Dimitrios Tzachanis, Xen Ianopulos, Deborah Jezior, James Bradley Breitmeyer, Catriona HM Jamieson, Thomas J. Kipps
Journal: Journal of Clinical Oncology (2019)

7527 Background: Cirmtuzumab (C) is a humanized mAb that binds ROR1 and blocks Wnt5a from binding and activating ROR1 on CLL and mantle cell lymphoma (MCL); C does not bind normal adult tissues. A phase 1 trial of C showed excellent safety and inhibition of Wnt5a-ROR1 signaling. Ibrutinib (Ibr) does not inhibit the ROR1 pathway, and C+Ibr exert synergistic effects in CLL and MCL. The current clinical trial combines C+Ibr for patients (pts) with CLL and MCL. A planned analysis of the phase 1 CLL portion is presented. Methods: Eligible pts had CLL needing treatment according to iwCLL guidelines. C was given at 2, 4, 8, or 16 mg/kg q 2 wk for 8 wk, then q 28 d to 52 wk. Ibr 420 mg PO daily was started on d 28. Results: 3 pts were treated at each C dose level with age 57-86; 75% were previously treated (median 2); 3 pts had del(11q), 3 had trisomy 12, and 6 pts had unmutated IGVH genes. There were no discontinuations for toxicity and no dose limiting toxicities. Treatment with C alone and combined with Ibr was well-tolerated. One SAE occurred with C monotherapy (hospitalization for tonsillitis). Adverse events on C+Ibr were consistent with the known Ibr safety profile, with one grade 3 hyperkalemia and 1 atrial fibrillation event. All other AEs were grade 1 or 2. The overall response rate after 16-48 weeks of treatment was 67% with 1 confirmed complete response (CR) with no morphologic evidence of CLL in the marrow, 1 clinical CR, 6 partial responses (PR) and 4 stable disease. No patient had progressive disease. The typical redistributive lymphocytosis seen with Ibr was blunted, with only a 50% mean rise in ALC, rapidly returning to baseline. PRs were observed in all C dose levels. Conclusions: The combination of C+Ibr is well-tolerated and effective. CRs were observed in 2 cases, a result that would be highly unusual with Ibr monotherapy in CLL. Based on these findings, Cirm 600 mg was selected as the RP2D for the randomized phase 2 portion of this protocol, which will prospectively compare the complete response rates between C+Ibr and Ibr alone. Clinical trial information: NCT03420183.
Stereotactic body radiotherapy in locally advanced pancreatic adenocarcinoma: A single institution experience
Authors: R. Jacob, A. McDonald, U. Manne, S. Reddy, S. Vickers, M. Heslin, K. Kyanam Kabir Baig, C. Smith, G. Williams, A. Ali, O. Gbolahan, B. Rose, A. Ashlyn Everett, A. Kasi, R. Paluri
Journal: Annals of Oncology (2019)