tbuckley/cabot-search huggingface dataset:
Analysis of heat shock protein HSP27 secretion in an ovarian cancer cell model and detection of cell-free HSP27 in patient blood serum sample.
Authors: Matthias B. Stope, Gerd Klinkmann, Karoline Diesing, Salvatore Delogu, Jalid Sehouli, Ioana Braicu, Sven Mahner, Andreas Greinacher, Dominique Könsgen, Alexander Mustea
Journal: Journal of Clinical Oncology (2015)

e16570 Background: Most ovarain cancer (OC) patients are diagnosed in late stages due to lack of a specific symptoms and biomarkers. New therapeutic strategies did not translate in better survival date. The cytoprotective heat shock protein HSP27 is up-regulated in numerous solid tumors and is frequently involved in cancer progression. Thus, HSP27 may represent an appropriate marker to determine the pathological status of OC. Methods: OC cell lines OVCAR-3, SKOV-3, and TOV-21G were used for cell culture experiments. HSP27 overexpression experiments were done by transfection of the plasmide pHSP27 and by cells undergoing heat-shock treatment. Intracellular and extracellular levels of HSP27 were determined by Western Blotting and ELISA, respectively. Inhibition of the protein secretory machinery was done by brefeldin A treatment. Using ELISA the presence of cell-free HSP27 in OC serum samples from TOC (Tumor Bank Ovarian Cancer) Network was determined. In this study 237 OC patients and 201 healthy women have been included. Results: pHSP27 transfection experiments demonstrated increases of intracellular HSP27 expression and were associated with significantly elevated levels of extracellular HSP27 protein. These data were affirmed by heat-shock experiments which induced endogenously expressed HSP27. Inhibition of the cellular main secretory pathway by brefeldin A demonstrated an active secretion of HSP27. Although HSP27 is actively liberated by malignant ovary cells, the cell-free HSP27 serum levels did not significantly differ from healthy female blood donors. Conclusions: The functional implications of cell-free HSP27 in body fluids of OC patients remain unclear. Due to global upregulation of heat shock proteins in malignant tissues we hypothesized that elevated HSP27 expression boosts secretion of the protein and may be a suitable biomarker candidate. Our study demonstrated an HSP27 secretion independently from cell lysis which underlines HSP27's role in OC progression. However, blood serum sample analysis did not demonstrate higher HSP27 levels in OC patients compared to control samples.
The value of clinical and translational neuroscience approaches to psychiatric illness
Authors: Juyoen Hur, Rachael M. Tillman, Andrew S. Fox, Alexander J. Shackman
Journal: Behavioral and Brain Sciences (2019)

Borsboom et al. confuse biological approaches with extreme biological reductionism and common-cause models of psychopathology. In muddling these concepts, they mistakenly throw the baby out with the bathwater. Here, we highlight recent work underscoring the unique value of clinical and translational neuroscience approaches for understanding the nature and origins of psychopathology and for developing improved intervention strategies.
Abstract P141: Association of Type of Antidepressant With Bleeding Risk in Atrial Fibrillation Patients Taking Oral Anticoagulants
Authors: Iris Yuefan Shao, J’Neka S Claxton, Pamela L Lutsey, Lin Y Chen, Richard F MacLehose, Alvaro Alonso
Journal: Circulation (2019)

Background: Inconsistent evidence suggests that concomitant use of certain antidepressants, particularly Selective Serotonin Reuptake Inhibitors (SSRIs), in patients using oral anticoagulants (OAC) might be associated with an elevated risk of bleeding. This study aims to investigate the risk of bleeding associated with initiation of different types of antidepressants among atrial fibrillation (AF) patients on OAC therapy. Methods: 72334 AF patients that started using antidepressant after initiating OAC therapy were identified from the Truven Health MarketScan Commercial and Medicare Databases for the period 2011-2015. Exposure was defined as prescription filling for SSRI, Serotonin/Norepinephrine Reuptake Inhibitors (SNRI), Serotonin Reuptake Inhibitors (SRI), Tricyclic Antidepressants (TCA) or other antidepressants. The primary outcome was incident hospitalized bleeding, defined by a validated algorithm, after antidepressant initiation. Associations of bleeding by antidepressant types were assessed using adjusted Cox proportional hazards model in pair-wise propensity score (PS) matched cohorts. PS matched cohorts for combinations of antidepressants were generated based on logistic models that included major risk factors for bleeding such as demographic information, comorbid conditions and other medication usage. Results: Among eligible patients, 57% initiated SSRI, 14% SNRI, 9% SRI, 9% TCA and 12% others. During a mean follow-up of 21 months, we identified 4035 bleeding episodes. In pair-wise comparisons, SSRI was associated with an increased risk of bleeding when compared to all other antidepressants (Table 1). In contrast, initiating SRIs was associated with small reductions in the risk of bleeding compared to all other types of antidepressants. Conclusion: Our results suggest that compared to all other antidepressants, SSRI is associated with an increased risk of bleeding. This information may be valuable to inform antidepressant choice in anticoagulated patients with AF.
Abstract 14753: Loss of Function ABCC8 Mutations Are Associated With Pulmonary Arterial Hypertension
Authors: Michael S Bohnen, Lijiang Ma, Na Zhu, Hongjian Qi, Conor McClenaghan, Claudia Gonzaga-Jauregui, Frederick E Dewey, John D Overton, Jeffrey G Reid, Alan R Shuldiner, Aris Baras, Kevin J Sampson, Marta Bleda, Charaka Hadinnapola, Matthias Haimel, Harm J Bogaard, Colin Church, Gerry Coghlan, Paul A Corris, Mélanie Eyries, J. Simon R Gibbs, Barbara Girerd, Arjan C Houweling, Marc Humbert, David G Kiely, Allan Lawrie, Rob V MacKenzie Ross, Jennifer M Martin, David Montani, Andrew J Peacock, Joanna Pepke-Zaba, Florent Soubrier, Jay Suntharalingam, Mark Toshner, Carmen M Treacy, Richard C Trembath, Anton Vonk Noordegraaf, John Wharton, Martin R Wilkins, Stephen J Wort, Katherine Yates, Stefan Gräf, Nicholas W Morrell, Usha Krishnan, Erika B Rosenzweig, Yufeng Shen, Colin G Nichols, Robert S Kass, Wendy K Chung
Journal: Circulation (2017)

Introduction: In pulmonary arterial hypertension, pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to r...
Impaired αVβ8 and TGFβ signaling lead to microglial dysmaturation and neuromotor dysfunction
Authors: Thomas D. Arnold, Carlos O. Lizama, Kelly M. Cautivo, Nicolas Santander, Lucia Lin, Haiyan Qiu, Eric J. Huang, Chang Liu, Yoh-suke Mukouyama, Louis F. Reichardt, Ann C. Zovein, Dean Sheppard
Journal: The Journal of Experimental Medicine (2019)

Microglia play a pivotal role in the coordination of brain development and have emerged as a critical determinant in the progression of neurodegenerative diseases; however, the role of microglia in the onset and progression of neurodevelopmental disorders is less clear. Here we show that conditional deletion of αVβ8 from the central nervous system (Itgb8ΔCNS mice) blocks microglia in their normal stepwise development from immature precursors to mature microglia. These “dysmature” microglia appear to result from reduced TGFβ signaling during a critical perinatal window, are distinct from microglia with induced reduction in TGFβ signaling during adulthood, and directly cause a unique neurodevelopmental syndrome characterized by oligodendrocyte maturational arrest, interneuron loss, and spastic neuromotor dysfunction. Consistent with this, early (but not late) microglia depletion completely reverses this phenotype. Together, these data identify novel roles for αVβ8 and TGFβ signaling in coordinating microgliogenesis with brain development and implicate abnormally programmed microglia or their products in human neurodevelopmental disorders that share this neuropathology.
Characterization of a Novel Human <i>MUTYH</i> Variant Causing Colonic Polyposis through Disruption of the Fe-S Cluster.
Authors: Kevin McDonnell, Joseph A. Chemler, Monica L. Marvin, Ralph H. Stern, Leon Raskin, David H. Sherman, Stephen B. Gruber
Journal: Journal of Clinical Oncology (2015)

e12514 Background: MUTYH is a human DNA repair enzyme functioning to abscise adenine residues mispaired with 8-oxo-7,8-dihydroguanine (8-oxoG) in oxidatively damaged DNA. This repair activity prevents occurrence of G:C to T:A transversions and subsequent carcinogenesis. MUTYH gene mutations underlie the autosomal, recessive cancer syndrome MUTYH-Associated Polyposis (MAP). MUTYH variants are common, and their interpretation and functional assessment inform patient management. Presently, we report a novel MUTYH variant, c.918C > G (p.C306W), occurring within the protein’s Fe-S cluster region. Functional analysis of the MUTYH Fe-S cluster has not previously been reported. We provide a functional assessment of the c.918C > G MUTYH variant relative to wild type and two well-known MUTYH mutants. Methods: Highly pure wild type, mutant and variant p.C306W MUTYH proteins were prepared with fast protein liquid chromatography (FPLC). Adenine abscission and binding activities were assessed employing capillary electrophoresis and biolayer interferometry (BLI), respectively. Integrity of the Fe-S cluster was determined with inductively coupled plasma-high resolution mass spectroscopy (ICP-HRMS). Results: The novel p.C306W MUTYH variant exhibited severe compromise of abscission and DNA binding activity. Furthermore, the Fe-S cluster of the p.C306W variant was nearly completely lacking in iron content. Conclusions: This investigation establishes the pathologic status of the MUTYH variant c.918C > G which contributes to the MAP phenotype. Additionally, this study, for the first time, investigates the Fe-S cluster region in MUTYH DNA repair and documents this region as an essential functional domain required for repair activity.
Redistribution Of Regional Lung Perfusion During Mechanical Ventilation With An Open Lung Approach Impacts Pulmonary Vascular Mechanics
Authors: João Batista Borges, Arnoldo Santos, L. Lucchetta, Göran Hedenstierna, Anders Larsson, Fernando Suarez-Sipmann
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Redistribution Of Regional Lung Perfusion During Mechanical Ventilation With An Open Lung Approach Impacts Pulmonary Vascular Mechanics
The Need to Realign Health System Processes for Patients Discharged From the Hospital—Getting Patients Home
Authors: Vincent Mor
Journal: JAMA Internal Medicine (2019)

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Abstract P332: Weight Cycling is Associated With Poorer Cardiovascular Health Assessed Using AHA’s Life’s Simple 7 in a Diverse Sample of Women Encompassing Different Life Stages
Authors: Stephanie S Byun, Natalie A Bello, Ming Liao, Nour Makarem, Brooke Aggarwal
Journal: Circulation (2019)

Introduction: Prior research has shown weight cycling, the repetitive pattern of weight loss and regain, is associated with increased CVD risk. There is limited evidence on the association of history of weight cycling (HWC) with cardiovascular health (CVH) metrics from the AHA Life’s Simple 7 (LS7). Hypothesis: We hypothesized that HWC is associated with poorer CVH in women and that these associations may vary by menopausal status and/or pregnancy history. Methods: This was a cross-sectional analysis of 485 women enrolled in the AHA Go Red for Women Strategically Focused Research Network. HWC, defined as losing and gaining ≥ 10 lbs at least once (excluding pregnancy) was self-reported. Participants were given scores of 0 (poor), 1 (moderate) or 2 (high) for each AHA LS7 metric (BMI, BP, total cholesterol, glucose, physical activity, diet and smoking). Metric scores were summed into a composite AHA LS7 CVH score: 0-8 (poor), 9-10 (moderate), 11-14 (high). Logistic regression was used to evaluate associations of HWC with AHA LS7 metrics and composite. Models were stratified by menopausal status and pregnancy history due to a statistically significant multiplicative interaction. Results: The majority of women (mean age 37±16y, BMI 26±6 kg/m 2 ), 73%, reported ≥ 1 HWC episode, and 26%, 34% and 40% of women had poor, moderate, and high CVH respectively. HWC was associated with lower odds of meeting the BMI metric or moderate or high AHA LS7 composite score, but not with other CVH metrics ( Table ). In stratified analyses, HWC was associated with lower odds of having a high AHA LS7 score in both pre- and post-menopausal women, but only in women who had never been pregnant. Conclusion: HWC was associated with lower odds of meeting the BMI metric and poorer CVH as assessed by AHA LS7 composite score. Associations were stronger in women with no pregnancy history. These findings suggest that in addition to having a healthy weight, maintaining a consistent body weight may be important for achieving ideal CVH, but they warrant prospective confirmation.
Prognostic features for testicular cancers (TCs): Can this be gleaned from pathology reports?
Authors: Sandy Srinivas, Michael Eisenberg, Eila C. Skinner
Journal: Journal of Clinical Oncology (2015)

e15550 Background: TCs are very curable cancers.Patients with stage I disease are offered surveillance, based on risk criteria, the low probability of relapse and the high curability with chemotherapy on relapse.However,pathology reporting is not consistent to guide the clinicians in making such decisions.We report our findings of pathology reports from orchiectomy specimens at our institution Methods: With IRB approval, we accessed pathology reports for patients treated between 1998-2014 with TC. Of the 656 patients in our database, we excluded extragonadal tumors, teratomas, and post chemotherapy orchiectomy. Prespecified criteria based on literature review for both histologic subtypes were set. For patients with seminoma,it was the size of the tumor and presence or absence of rete testes invasion. For patients with non-seminomatous germ cell tumors (NSGCT) presence or absence of lymphovascular invasion, % of embryonal cell and lack of yolk sac component were noted. If these were present we marked the report as having met pathology standard. We also included the year of the diagnosis and noted any changes over time. Results: We identified 330 reports from radical orchiectomy between 1998- 2014. The cohort consisted of 130(39%) with seminoma and 200 (61%) with NSGCT. Overall, adequate pathology criteria as prespecified were noted in 125 (38%) of all patients and in 24(18%) of seminomas and in 101(51%) of the NSGCT. Among those with seminomas, size was reported in 84 (65%) pathology reports.Both size and presence or absence of rete testes invasion was seen in 24(18%) . Among patients with NSGCT, all 3 criteria were met in 101(51%) of patients. Isolated LVI was most reported in 58(29%). Between 1998 and 2008 there were 176 specimens reviewed; of which 39(22%) met criteria . This increased to 56% in the years 2009-2014. Conclusions: Significant inconsistency in pathology reporting exists. Individual elements for both seminoma and nonseminoma were absent in some fraction of men suggesting a lack of standardized reporting. While improved reporting occurred over time, better communication between clinicians and pathologists are needed. Standardized templates for individual tumor types may help obviate this.
Effect of capping chemotherapy dose on chemotherapy effect in morbidly obese women with breast cancer.
Authors: David James Porter, Michelle Wilson
Journal: Journal of Clinical Oncology (2013)

1081 Background: Obesity adversely affects outcomes from adjuvant (adj) chemotherapy for breast cancer. Capping of chemotherapy dose has been implicated as one factor that may contribute to this. We postulated that if capping resulted in underdosing, this would be reflected in the incidence of dose dependent toxicities (DDT) such as mucositis and haematological toxicity. Methods: We retrospectively reviewed records of breast cancer patients (pts) commencing adj chemotherapy from 1 Jan 2010-31 Dec 2010 at the Auckland Regional Blood and Cancer Service identified using a prospective pharmacy database. Baseline characteristics, BSA, body mass index (BMI), neutrophil (ANC) nadir, relative dose intensity (RDI) and dose limiting complications (DLC) were recorded. Results: 174 pts were identified. Median age was 49 yrs (24-73). 17.8% had a BSA &gt;2. 3.2% pts with BSA&gt;2 had BMI &lt;30. 42% had a BMI ≥30 (17.9-61.0), of whom 59% had a BSA ≤2. All patients with BSA &gt;2 had dose capping. 71 pts had a DLC. Neutropenic fever/infection or treatment delays from neutropenia were more common if BSA ≤2 vs. &gt;2 (p=0.08) but not with other DDT. Treatment deferrals (18.8 vs. 16.1%) dose reductions (25.2 vs. 32.3%) and mucositis were similar in both groups. Mean baseline ANC was 4.4 in pts with BSA ≤2 and &gt;2. Mean ANC nadir was 0.8 and 1.3 respectively (p&lt;0.01). r 2 BSA vs nadir ANC was 0.012. G3/4 neutropenia was seen 76.5% of pts with BSA ≤2 vs. 44.8% if BSA &gt;2 (RR 1.3 p&lt;0.01). No pt had &gt; G1 thrombocytopenia. Mean RDI was 93.2 and 94.8 respectively (p=0.4) Conclusions: Previous studies show ANC nadirs correlate well with drug exposure (area under plasma concentration vs. time curve) but poorly with BSA. Therefore we used hematological and DDT as surrogate measures for drug exposure in pts with and without capped doses. There was more G3/4 neutropenia (p&lt;0.01) in uncapped pts but rates of other DDT were similar. Since BSA based dosing has little impact on inter-pt variability in systemic drug exposure and trials where capping was not used still show a poorer outcome in obese pts, these results suggest dose capping is a minor contributor to the worse outcomes in morbidly obese breast cancer pts having adj chemotherapy. Addressing obesity itself may be more important.
Publisher Correction: Uncoupling protein 2 reprograms the tumor microenvironment to support the anti-tumor immune cycle
Authors: Wan-Chen Cheng, Yao-Chen Tsui, Simone Ragusa, Viktor H. Koelzer, Marco Mina, Fabien Franco, Heinz Läubli, Benjamin Tschumi, Daniel Speiser, Pedro Romero, Alfred Zippelius, Tatiana V. Petrova, Kirsten Mertz, Giovanni Ciriello, Ping-Chih Ho
Journal: Nature Immunology (2019)
A fully human anti-IL-7Rα antibody promotes antitumor activity against T-cell acute lymphoblastic leukemia
Authors: Padma Akkapeddi, Rita Fragoso, Julie A. Hixon, Ana Sofia Ramalho, Mariana L. Oliveira, Tânia Carvalho, Andreas Gloger, Mattia Matasci, Francisco Corzana, Scott K. Durum, Dario Neri, Gonçalo J. L. Bernardes, João T. Barata
Journal: Leukemia (2019)

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer for which treatment options often result in incomplete therapeutic efficacy and long-term side-effects. Interleukin 7 (IL-7) and its receptor IL-7Rα promote T-ALL development and mutational activation of IL-7Rα associates with very high risk in relapsed disease. Using combinatorial phage-display libraries and antibody reformatting, we generated a fully human IgG1 monoclonal antibody (named B12) against both wild-type and mutant human IL-7Rα, predicted to form a stable complex with IL-7Rα at a different site from IL-7. B12 impairs IL-7/IL-7R-mediated signaling, sensitizes T-ALL cells to treatment with dexamethasone and can induce cell death per se. The antibody also promotes antibody-dependent natural killer-mediated leukemia cytotoxicity in vitro and delays T-cell leukemia development in vivo, reducing tumor burden and promoting mouse survival. B12 is rapidly internalized and traffics to the lysosome, rendering it an attractive vehicle for targeted intracellular delivery of cytotoxic cargo. Consequently, we engineered a B12–MMAE antibody–drug conjugate and provide proof-of-concept evidence that it has increased leukemia cell killing abilities as compared with the naked antibody. Our studies serve as a stepping stone for the development of novel targeted therapies in T-ALL and other diseases where IL-7Rα has a pathological role.