tbuckley/cabot-search huggingface dataset:
Effect of BRCA mutation on prognosis in patients with ovarian cancer: A systematic review and meta-analysis.
Authors: Antonis Valachis, Nikolaos P. Polyzos, Apostolos Zavos, Davide Mauri, Pehr A. Lind
Journal: Journal of Clinical Oncology (2012)

5066 Background: To investigate whether the germ-line mutations of BRCA 1 and 2 in patients with ovarian cancer are associated with disease outcome. Methods: A systematic search of the literature was performed using search terms related to BRCA, ovarian cancer and prognosis. Studies were considered eligible if they reported the outcome of ovarian cancer in patients with BRCA 1 and/or 2 mutations compared with patients with sporadic ovarian cancer or / and no BRCA mutation. Cohort and case-control designs were included. Pooled Hazard Ratios (HR) were estimated with fixed or random effects models, depending on between-studies heterogeneity. Results: Of 2,340 titles identified, 26 articles met the inclusion criteria. Of these, 6 studies were excluded from the analysis due to duplication of results (n=1) and lack of data to calculate HR (n=5). Patients with BRCA 1 or 2 mutations had better survival compared with control group both in cohort (HR: 0.58, 95% Confidence Interval (CI) 0.42-0.79, p-value 0.0005) and in case-control (HR: 0.65, 95% CI 0.45-0.93, p-value = 0.02) studies. When only patients with BRCA 1 mutation were analyzed, the survival benefit remained significant (HR: 0.67, 95% CI 0.53-0.85, p-value = 0.001). Furthermore, the differential survival benefit of the mutation groups was even more evident among patients with BRCA 2 mutation (HR: 0.43, 95% CI: 0.30-0.63, p-value &lt; 0.0001). A direct comparison of patients with BRCA 1 vs. BRCA 2 mutations (4 studies) revealed a significantly better survival for BRCA 2 mutation carriers (HR: 0.53, 95% CI: 0.33-0.85, p-value = 0.009). Conclusions: Our results confirm the hypothesis that BRCA status is a prognostic factor in patients with ovarian cancer. Based on these results, the use of BRCA status as a stratifying factor in therapeutic ovarian cancer trials seems to be fully justifiable. The stronger association between survival and BRCA 2 mutation, compared with BRCA 1, suggests a different nature of the dysfunction of these 2 genes.
Diagnostic Specificity of Basal Inferoseptal Triangular Late Gadolinium Enhancement for Identification of Cardiac Sarcoidosis
Authors: Ling Kuo, Yuchi Han, David Mui, Ying Zhang, Anwar Chahal, Robert D. Schaller, David S. Frankel, Francis E. Marchlinski, Benoit Desjardins, Saman Nazarian
Journal: JACC. Cardiovascular imaging (2019)
Adapting Antibiotic Stewardship to the Community Hospital
Authors: Daniel J. Livorsi, Heather Schacht Reisinger, Edward Stenehjem
Journal: JAMA Network Open (2019)

Deverick J. Anderson, MD, MPH; Shera Watson, MPH; Rebekah W. Moehring, MD, MPH; Lauren Komarow, MS; Matthew Finnemeyer, MPH; Rebekka M. Arias, BS; Jacqueline Huvane, PhD; Carol Bova Hill, PhD; Nancie Deckard, BSN, MS; Daniel J. Sexton, MD; for the Antibacterial Resistance Leadership Group (ARLG)
Cancer-associated fibroblasts in desmoplastic tumors: emerging role of integrins
Authors: Cédric Zeltz, Irina Primac, Pugazendhi Erusappan, Jahedul Alam, Agnes Noel, Donald Gullberg
Journal: Seminars in Cancer Biology (2019)

The tumor microenvironment (TME) is a complex meshwork of extracellular matrix (ECM) macromolecules filled with a collection of cells including cancer-associated fibroblasts (CAFs), blood vessel associated smooth muscle cells, pericytes, endothelial cells, mesenchymal stem cells and a variety of immune cells. In tumors the homeostasis governing ECM synthesis and turnover is disturbed resulting in abnormal blood vessel formation and excessive fibrillar collagen accumulations of varying stiffness and organization. The disturbed ECM homeostasis opens up for new types of paracrine, cell-cell and cell-ECM interactions with large consequences for tumor growth, angiogenesis, metastasis, immune suppression and resistance to treatments. As a main producer of ECM and paracrine signals the CAF is a central cell type in these events. Whereas the paracrine signaling has been extensively studied in the context of tumor-stroma interactions, the nature of the numerous integrin-mediated cell-ECM interactions occurring in the TME remains understudied. In this review we will discuss and dissect the role of known and potential CAF interactions in the TME, during both tumorigenesis and chemoresistance-induced events, with a special focus on the "interaction landscape" in desmoplastic breast, lung and pancreatic cancers. As an example of the multifaceted mode of action of the stromal collagen receptor integrin α11β1, we will summarize our current understanding on the role of this CAF-expressed integrin in these three tumor types.
An Allosteric PRC2 Inhibitor Targeting EED Suppresses Tumor Progression by Modulating the Immune Response
Authors: Hongping Dong, Shaojun Liu, Xuejie Zhang, Sheng Chen, Lijing Kang, Yanni Chen, Shichao Ma, Xianlei Fu, Yanchao Liu, Hailong Zhang, Bin Zou
Journal: Cancer Research (2019)

Aberrant activity of polycomb repressive complex 2 (PRC2) is involved in a wide range of human cancer progression. The WD40 repeat-containing protein EED is a core component of PRC2 and enhances PRC2 activity through interaction with H3K27me3. In this study, we report the discovery of a class of pyrimidone compounds, represented by BR-001, as potent allosteric inhibitors of PRC2. X-ray co-crystallography showed that BR-001 directly binds EED in the H3K27me3-binding pocket. BR-001 displayed antitumor potency in vitro and in vivo. In Karpas422 and Pfeiffer xenograft mouse models, twice daily oral dosing with BR-001 resulted in robust antitumor activity. BR-001 was also efficacious in syngeneic CT26 colon tumor-bearing mice; oral dosing of 30 mg/kg of BR-001 led to 59.3% tumor growth suppression and increased frequency of effector CD8+ T-cell infiltrates in tumors. Pharmacodynamic analysis revealed that CXCL10 was highly upregulated, suggesting that CXCL10 triggers the trafficking of CD8+ T cells toward tumor sites. Our results demonstrate for the first time that inhibition of EED modulates the tumor immune microenvironment to induce regression of colon tumors and therefore has the potential to be used in combination with immune-oncology therapy. SIGNIFICANCE: BR-001, a potent inhibitor of the EED subunit of the PRC2 complex, suppresses tumor progression by modulating the tumor microenvironment.
An acquired high-risk chromosome instability phenotype in multiple myeloma: Jumping 1q Syndrome
Authors: Jeffrey R. Sawyer, Erming Tian, Brian A. Walker, Christopher Wardell, Janet L. Lukacs, Gael Sammartino, Clyde Bailey, Carolina D. Schinke, Sharmilan Thanendrarajan, Faith E. Davies, Gareth J. Morgan, Bart Barlogie, Maurizio Zangari, Frits van Rhee
Journal: Blood Cancer Journal (2019)

Abstract Patients with multiple myeloma (MM) accumulate adverse copy number aberrations (CNAs), gains of 1q21, and 17p deletions during disease progression. A subset of these patients develops heightened 1q12 pericentromeric instability and jumping translocations of 1q12 (JT1q12), evidenced by increased copy CNAs of 1q21 and losses in receptor chromosomes (RC). To understand the progression of these aberrations we analyzed metaphase cells of 50 patients with ≥4 CNAs of 1q21 by G-banding, locus specific FISH, and spectral karyotyping. In eight patients with ≥5 CNAs of 1q21 we identified a chromosome instability phenotype similar to that found in ICF syndrome (immunodeficiency, centromeric instability, and facial anomalies). Strikingly, the acquired instability phenotype identified in these patients demonstrates the same transient structural aberrations of 1q12 as those found in ICF syndrome, suggesting similar underlying pathological mechanisms. Four types of clonal aberrations characterize this phenotype including JT1q12s, RC deletions, 1q12-21 breakage-fusion-bridge cycle amplifications, and RC insertions. In addition, recurring transient aberrations include 1q12 decondensation and breakage, triradials, and 1q micronuclei. The acquired self-propagating mobile property of 1q12 satellite DNA drives the continuous regeneration of 1q12 duplication/deletion events. For patients demonstrating this instability phenotype, we propose the term “Jumping 1q Syndrome.”
Customized MethylC-Capture Sequencing to Evaluate Variation in the Human Sperm DNA Methylome Representative of Altered Folate Metabolism
Authors: Donovan Chan, Xiaojian Shao, Marie-Charlotte Dumargne, Mahmoud Aarabi, Marie-Michelle Simon, Tony Kwan, Janice L. Bailey, Bernard Robaire, Sarah Kimmins, Maria C. San Gabriel, Armand Zini, Clifford Librach, Sergey Moskovtsev, Elin Grundberg, Guillaume Bourque, Tomi Pastinen, Jacquetta M. Trasler
Journal: Environmental Health Perspectives (2019)

Background: The sperm DNA methylation landscape is unique and critical for offspring health. If gamete-derived DNA methylation escapes reprograming in early embryos, epigenetic defects in sperm may be transmitted to the next generation. Current techniques to assess sperm DNA methylation show bias toward CpG-dense regions and do not target areas of dynamic methylation, those predicted to be environmentally sensitive and tunable regulatory elements. Objectives: Our goal was to assess variation in human sperm DNA methylation and design a targeted capture panel to interrogate the human sperm methylome. Methods: To characterize variation in sperm DNA methylation, we performed whole genome bisulfite sequencing (WGBS) on an equimolar pool of sperm DNA from a wide cross section of 30 men varying in age, fertility status, methylenetetrahydrofolate reductase (MTHFR) genotype, and exposures. With our targeted capture panel, in individual samples, we examined the effect of MTHFR genotype (n=13 677CC, n=8 677TT), as well as high-dose folic acid supplementation (n=6, per genotype, before and after supplementation). Results: Through WGBS we discovered nearly 1 million CpGs possessing intermediate methylation levels (20–80%), termed dynamic sperm CpGs. These dynamic CpGs, along with 2 million commonly assessed CpGs, were used to customize a capture panel for targeted interrogation of the human sperm methylome and test its ability to detect effects of altered folate metabolism. As compared with MTHFR 677CC men, those with the 677TT genotype (50% decreased MTHFR activity) had both hyper- and hypomethylation in their sperm. High-dose folic acid supplement treatment exacerbated hypomethylation in MTHFR 677TT men compared with 677CC. In both cases, &gt;80% of altered methylation was found in dynamic sperm CpGs, uniquely measured by our assay. Discussion: Our sperm panel allowed the discovery of differential methylation following conditions affecting folate metabolism in novel dynamic sperm CpGs. Improved ability to examine variation in sperm DNA methylation can facilitate comprehensive studies of environment–epigenome interactions. https://doi.org/10.1289/EHP4812
Ovarian needle biopsy: A study of 84 cases with cytologic-histologic correlation.
Authors: Kimberly Nagamine, Keith Y. Terada, David Shimizu, Pamela Tauchi-Nishi
Journal: Journal of Clinical Oncology (2013)

e16501 Background: Ovarian needle biopsy (ONB) is well tolerated and underutilized. It may be employed for preoperative diagnosis and to treat symptomatic benign cysts. There is reluctance to utilize this procedure due to potential cyst rupture or seeding of malignant cells. We studied the efficacy of ONB over an 11-year period at our institution. Methods: Between January 2000 and August 2012, we retrieved 134 ONB specimens from our database. One hundred sixteen (87%) were performed by obstetrician-gynecologists, 8 (6%) by radiologists, 4 (3%) by surgeons, and 6 (4%) by other clinicians. Results: Eighty-four (63%) cases had corresponding surgical specimens, 78 (93%) of which were obtained concomitantly. Ten (12%) cases were malignant and 74 (88%) benign (Table). Sensitivity and specificity of ONB were 70% and 100%, respectively. Forty-one (53%) were benign ovarian neoplasms, and 30 (39%) were cysts. Regarding malignant lesions, 8 (80%) were primary ovarian epithelial cancers. There was 1 granulosa cell tumor and 1 metastatic lung adenocarcinoma. Three false negative cases were noted; 2 serous borderline tumors and 1 mucinous cystadenocarcinoma. These were sampling errors; no diagnostic tumor cells were present in the aspirates. Conclusions: ONB may be effective in diagnosing and treating ovarian lesions. In our study, it was highly specific and sensitive, with the exception of borderline tumors. [Table: see text]
Circumferential ileocecal valve removal for a colonic polyp using underwater endoscopic mucosal resection
Authors: Mitsuhiro Kono, Yoji Takeuchi, Koji Higashino, Noriya Uedo, Ryu Ishihara
Journal: Endoscopy (2019)

A 65-year-old man with constipation and a positive fecal occult blood test had previously undergone a colonoscopy in another hospital, which had revealed a polyp measuring 40 mm in diameter at the cecum. He was referred to our hospital for treatment of the lesion, with colonoscopy revealing a polypoid lesion on the upper lip of the ileocecal valve ([Fig. 1 a]). Because no definitive endoscopic findings suggestive of deep submucosal invasion were revealed by magnifying narrow-band imaging and chromoendoscopy, underwater endoscopic mucosal resection (UEMR) was performed using an electrosurgical snare (33-mm wide; Captivator II; Boston Scientific, Natick, Massachusetts, USA). As it was impossible to observe the distal side of the lesion when it was snared, we snared the whole ileocecal valve. Forced coagulation mode was used briefly twice and the lesion was then removed using Endocut Q mode. The lesion was completely resected along with the ileocecal valve ([Fig. 1 b]; [Video 1]). We did not perform any additional procedures, such as steroid injection, which has been reported to be effective in preventing stricture after semicircumferential removal of esophageal lesions, because there is no clear evidence regarding such use for ileocecal lesions.
Effect of Home-Based Exercise and Weight Loss Programs on Breast Cancer–Related Lymphedema Outcomes Among Overweight Breast Cancer Survivors
Authors: Kathryn H. Schmitz, Andrea B. Troxel, Lorraine T. Dean, Angela DeMichele, Justin C. Brown, Kathleen Sturgeon, Zi Zhang, Margaret Evangelisti, Bryan Spinelli, Michael J. Kallan, Crystal Denlinger, Andrea Cheville, Renate M. Winkels, Lewis Chodosh, David B. Sarwer
Journal: JAMA Oncology (2019)

To our knowledge, no randomized clinical trials have assessed the effects of the combination of weight loss and home-based exercise programs on lymphedema outcomes.To assess weight loss, home-based exercise, and the combination of weight loss and home-based exercise with clinical lymphedema outcomes among overweight breast cancer survivors.This randomized clinical trial (Women in Steady Exercise Research [WISER] Survivor clinical trial ) of 351 overweight breast cancer survivors with breast cancer-related lymphedema (BCRL) was conducted in conference rooms at academic and community hospitals and in the homes of participants from March 12, 2012, to May 28, 2016; follow-up was conducted for 1 year from the start of the intervention. Statistical analysis by intention to treat was performed from September 26, 2018, to October 28, 2018.A 52-week, home-based exercise program of strength/resistance training twice per week and 180 minutes of walking per week, a weight loss program of 20 weeks of meal replacements and 52 weeks of lifestyle modification counseling, and a combination of the home-based exercise and weight loss programs.The 12-month change in the percentage of interlimb volume difference.Of 351 participants, 90 were randomized to the control group (facility-based lymphedema care with no home-based exercise or weight loss intervention), 87 to the exercise intervention group, 87 to the weight loss intervention group, and 87 to the combined exercise and weight loss intervention group; 218 (62.1%) were white, 122 (34.8%) were black, and 11 (3.1%) were of other races or ethnicities. Median time since breast cancer diagnosis was 6 years (range, 1-29 years). Mean (SD) total upper extremity score changes from the objective clinical evaluation were -1.40 (11.10) in the control group, -2.54 (13.20) in the exercise group, -3.54 (12.88) in the weight loss group, and -3.84 (10.09) in the combined group. Mean (SD) overall upper extremity score changes from the self-report survey were -0.39 (2.33) in the control group, -0.12 (2.14) in the exercise group, -0.57 (2.47) in the weight loss group, and -0.62 (2.38) in the combined group. Weight loss from baseline was -0.55% (95% CI, -2.22% to 1.11%) in the control group, -8.06% (95% CI, -9.82% to 6.29%) in the combined group, -7.37% (95% CI, -8.90% to -5.84%) in the weight loss group, and -0.44% (95% CI, -1.81% to 0.93%) in the exercise group.Study results indicate that weight loss, home-based exercise, and combined interventions did not improve BCRL outcomes; a supervised facility-based program of exercise may be more beneficial than a home-based program for improving lymphedema outcomes.ClinicalTrials.gov identifier: NCT01515124.
Lymphopenia at diagnosis is highly prevalent in myelodysplastic syndromes and has an independent negative prognostic value in IPSS-R-low-risk patients
Authors: Tobias Silzle, Sabine Blum, Esther Schuler, Jennifer Kaivers, Martina Rudelius, Barbara Hildebrandt, Norbert Gattermann, Rainer Haas, Ulrich Germing
Journal: Blood Cancer Journal (2019)

Abstract Lymphopenia is associated with an increased mortality in several medical conditions. Its prognostic impact in myelodysplastic syndromes (MDS) is less well studied. Hence, we analyzed 1023 patients from the Düsseldorf MDS-registry with regard to the absolute lymphocyte count (ALC) at diagnosis. An ALC below the median of the population (1.2 × 10 9 /l) was associated with lower counts of neutrophils (median 1.35 vs. 1.92 × 10 9 /l, p &lt; 0.001) and platelets (median 100 vs. 138 × 10 9 /l, p &lt; 0.001) and with a significant lower overall survival in univariate analysis (whole cohort: median 36 vs. 46 months, p = 0.016; 721 patients without hematopoietic stem cell transplantation or induction chemotherapy: median 36 vs. 56 months, p = 0.001). For low-risk MDS according to IPSS-R, an ALC &lt; 1.2 × 10 9 /l was of additional prognostic value in a multivariate Cox regression model together with age (&lt; or ≥65 years) and LDH (&lt; or ≥normal value of 240 U/l; HR 1.46, 95% CI: 1.03–2.08, p = 0.033). These data support the hypothesis of subtle but clinical relevant changes of the adaptive immune system in MDS. Further studies are necessary to identify the ALC cut-off best suitable for prognostication and the mechanisms responsible for the impairment of lymphoid homeostasis in MDS.
The Respiratory Mucosa: Front and Center in Respiratory Syncytial Virus Disease
Authors: Ryan S. Thwaites, Peter J. Openshaw
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

populations that should be targeted for early detection of IPF.This is a critically important mission.Although there has been considerable progress in the development of novel therapeutic options for IPF, it is highly unlikely that any of the drugs currently in the pipeline will be able to reverse the extensive lung remodeling that is often observed when patients initially present.On the other hand, it is possible that therapeutic targeting of minimal fibrotic lesionsbefore extensive remodeling and bronchiolization have occurredwill allow complete eradication of the disease.Thus, to truly eradicate IPF, we need a paradigm shift from focusing on developing cohorts of patients already diagnosed with IPF toward cohorts of individuals highly likely to develop the disease.We could use these cohorts to develop and test algorithms for early detection.Then we could implement a multistep strategy to eradicate IPF: identification of a population with high risk for ILA and performing chest CT screenings when appropriate; in subjects with ILA, identification of patients who will develop IPF; and last, systematic study of interventions aimed at preventing progression to IPF.In an editorial in 2012 ( 9) discussing an early report on ILAs (10), Dr. David Lederer compared our traditional symptom-linked diagnosis of IPF to diagnosing coronary artery disease only after the patient presented with a myocardial infarction and called for new ways for risk prediction and early detection of IPF.Seven years later, the article by Hobbs and colleagues (8) suggests that we can move forward-that we can diagnose IPF while the horse is still in the barn.
TP-0184 Inhibits ALK2/ACVR1, Decreases Hepcidin Levels, and Demonstrates Activity in Preclinical Mouse Models of Functional Iron Deficiency
Authors: Peter Peterson, W K, Clifford Whatcott, Adam Siddiqui-Jain, Steven Weitman, Mark Kieran, David J. Bearss, Steven L. Warner
Journal: Blood (2017)
Anti-apoptotic signaling of epidermal growth factor in prostate cancer
Authors: Zhishan Huang, Despina Komninou, John Pinto, John P. Richie
Journal: Cancer Research (2004)

5177  Anti-apoptotic mechanisms have been implicated in the development of advanced prostate cancer. Prostate cancer cells LNCaP maintain viability in the absence of extracellular survival factors due to elevated levels of Akt activation. Treatment with PI3K inhibitor LY294002 suppresses Akt activity and induces apoptosis in these cells. However, epidermal growth factor (EGF) can protect LNCaP cells from apoptosis at these conditions. EGF can induce a variety of signaling cascades that have been connected to anti-apoptotic effects. It has been demonstrated that the EGF-induced anti-apoptotic signal operates upstream of the mitochondria, therefore most likely on Bcl-2 proteins. This led us to suggest that EGF may induce phosphorylation of BAD - one of the well characterized targets of Akt kinase. Since the dephosphorylation of Bad is the most probable mechanism in which LY294002 induces apoptosis, it was logical to hypothesize that EGF would either inhibit Bad dephosphorylation or induce Bad phosphorylation. Indeed, Bad was shown to be phosphorylated on Akt sites by kinases that can be activated by EGF (p90rsk, PAK). Data on Bad phosphorylation in LNCaP cells as well as anti-apoptotic effects of EGF in cells that express Bad with mutations in phosphorylation sites will be presented.