tbuckley/cabot-search huggingface dataset:
Mortality Risk and Fine Particulate Air Pollution in a Large, Representative Cohort of U.S. Adults
Authors: C. Arden Pope, Jacob S. Lefler, Majid Ezzati, Joshua D. Higbee, Julian D. Marshall, Sun-Young Kim, Matthew Bechle, Kurtis S. Gilliat, Spencer E. Vernon, Allen L. Robinson, Richard T. Burnett
Journal: Environmental Health Perspectives (2019)

Background: Evidence indicates that air pollution contributes to cardiopulmonary mortality. There is ongoing debate regarding the size and shape of the pollution–mortality exposure–response relationship. There are also growing appeals for estimates of pollution–mortality relationships that use public data and are based on large, representative study cohorts. Objectives: Our goal was to evaluate fine particulate matter air pollution (PM2.5) and mortality using a large cohort that is representative of the U.S. population and is based on public data. Additional objectives included exploring model sensitivity, evaluating relative effects across selected subgroups, and assessing the shape of the PM2.5–mortality relationship. Methods: National Health Interview Surveys (1986–2014), with mortality linkage through 2015, were used to create a cohort of 1,599,329 U.S. adults and a subcohort with information on smoking and body mass index (BMI) of 635,539 adults. Data were linked with modeled ambient PM2.5 at the census-tract level. Cox proportional hazards models were used to estimate PM2.5–mortality hazard ratios for all-cause and specific causes of death while controlling for individual risk factors and regional and urban versus rural differences. Sensitivity and subgroup analyses were conducted and the shape of the PM2.5–mortality relationship was explored. Results: Estimated mortality hazard ratios, per 10 μg/m3 long-term exposure to PM2.5, were 1.12 (95% CI: 1.08, 1.15) for all-cause mortality, 1.23 (95% CI: 1.17, 1.29) for cardiopulmonary mortality, and 1.12 (95% CI: 1.00, 1.26) for lung cancer mortality. In general, PM2.5–mortality associations were consistently positive for all-cause and cardiopulmonary mortality across key modeling choices and across subgroups of sex, age, race-ethnicity, income, education levels, and geographic regions. Discussion: This large, nationwide, representative cohort of U.S. adults provides robust evidence that long-term PM2.5 exposure contributes to cardiopulmonary mortality risk. The ubiquitous and involuntary nature of exposures and the broadly observed effects across subpopulations underscore the public health importance of breathing clean air. https://doi.org/10.1289/EHP4438
The incidence of vascular, genitourinary, and intestinal tract injuries in gynecologic oncology: An extensive, single institutional experience.
Authors: Christopher Rettenmaier, Nicholas Rettenmaier, Lisa Abaid, Alberto Mendivil, John V. Brown, John P. Micha, Katrina Lopez, Tomasz Wojciechowski, Bram Goldstein
Journal: Journal of Clinical Oncology (2012)

e15500 Background: Iatrogenic vascular, genitourinary, and intestinal tract injuries are an unfortunate consequence in gynecologic surgery because the uterus and ovaries are adjacent to critical pelvic structures. The incidence of these complications in general gynecology reportedly varies from 0.3-8.0%; conversely, in gynecologic oncology, the rate is presumably higher although the outcomes are not well documented. Methods: We reviewed the charts of gynecologic oncology patients treated at a single medical institution from January 2003 to February 2011. The following study variables were noted for evaluation: patient characteristics (age, body mass index (BMI)), medical history, cancer origin (e.g., ovarian, uterine), disease pathology, previous pelvic surgery, injury type (genitourinary, vascular or intestinal tract) and injury diagnosis (intra- or post-operative). Descriptive analyses were initially employed, followed by further evaluation of the clinicopathologic parameters via logistic regression, ANOVA and Cox proportional-hazard ratios. Results: In the current, retrospective investigation, 810 gynecologic cancer patients were identified; from this group, there were 25 (3.1%) intestinal tract, 10 (1.2%) genitourinary and 20 (2.5%) vascular injuries encountered. The logistic regression model classified correctly 84% of the injuries. Moreover, a Cox proportional hazard model revealed that cancer origin (p=0.023), previous pelvic surgery (p=.003), BMI (p=0.002) and disease stage (p &lt; 0.01) were surrogate markers for operative injury occurrence. Conclusions: The incidence of vascular, genitourinary and intestinal tract injuries in this large group of gynecologic oncology patients was quite reasonable. Fortunately, when these conditions arise, gynecologic oncologists have extensive surgical experience and are well prepared to address them. Additional study of the clinicopathologic factors that may predispose these cancer patients to a surgical complication is necessary.
Microbiota- and Radiotherapy-Induced Gastrointestinal Side-Effects (MARS) Study: A Large Pilot Study of the Microbiome in Acute and Late-Radiation Enteropathy
Authors: Miguel Reis Ferreira, H. Jervoise N. Andreyev, Kabir Mohammed, Lesley Truelove, Sharon M. Gowan, Jia Li, Sarah L. Gulliford, Julian R. Marchesi, David P. Dearnaley
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Radiotherapy is important in managing pelvic cancers. However, radiation enteropathy may occur and can be dose limiting. The gut microbiota may contribute to the pathogenesis of radiation enteropathy. We hypothesized that the microbiome differs between patients with and without radiation enteropathy. Experimental Design: Three cohorts of patients (n = 134) were recruited. The early cohort (n = 32) was followed sequentially up to 12 months post-radiotherapy to assess early radiation enteropathy. Linear mixed models were used to assess microbiota dynamics. The late cohort (n = 87) was assessed cross-sectionally to assess late radiation enteropathy. The colonoscopy cohort compared the intestinal mucosa microenvironment in patients with radiation enteropathy (cases, n = 9) with healthy controls (controls, n = 6). Fecal samples were obtained from all cohorts. In the colonoscopy cohort, intestinal mucosa samples were taken. Metataxonomics (16S rRNA gene) and imputed metataxonomics (Piphillin) were used to characterize the microbiome. Clinician- and patient-reported outcomes were used for clinical characterization. Results: In the acute cohort, we observed a trend for higher preradiotherapy diversity in patients with no self-reported symptoms (P = 0.09). Dynamically, diversity decreased less over time in patients with rising radiation enteropathy (P = 0.05). A consistent association between low bacterial diversity and late radiation enteropathy was also observed, albeit nonsignificantly. Higher counts of Clostridium IV, Roseburia, and Phascolarctobacterium significantly associated with radiation enteropathy. Homeostatic intestinal mucosa cytokines related to microbiota regulation and intestinal wall maintenance were significantly reduced in radiation enteropathy [IL7 (P = 0.05), IL12/IL23p40 (P = 0.03), IL15 (P = 0.05), and IL16 (P = 0.009)]. IL15 inversely correlated with counts of Roseburia and Propionibacterium. Conclusions: The microbiota presents opportunities to predict, prevent, or treat radiation enteropathy. We report the largest clinical study to date into associations of the microbiota with acute and late radiation enteropathy. An altered microbiota associates with early and late radiation enteropathy, with clinical implications for risk assessment, prevention, and treatment of radiation-induced side-effects. See related commentary by Lam et al., p. 6280
Circadian Clock Gene Bmal1 Regulates Bilirubin Detoxification: A Potential Mechanism of Feedback Control of Hyperbilirubinemia
Authors: Shuai Wang, Yanke Lin, Ziyue Zhou, Lu Gao, Zemin Yang, Feng Li, Baojian Wu
Journal: Theranostics (2019)

Controlling bilirubin to a low level is necessary in physiology because of its severe neurotoxicity. Therefore, it is of great interest to understand the regulatory mechanisms for bilirubin homeostasis. In this study, we uncover a critical role for circadian clock in regulation of bilirubin detoxification and homeostasis. Methods: The mRNA and protein levels of Bmal1 (a core clock gene), metabolic enzymes and transporters were measured by qPCR and Western blotting, respectively. Luciferase reporter, mobility shift and chromatin immunoprecipitation were used to investigate transcriptional gene regulation. Experimental hyperbilirubinemia was induced by injection of bilirubin or phenylhydrazine. Unconjugated bilirubin (UCB) and conjugated bilirubin were assessed by ELISA. Results: We first demonstrated diurnal variations in plasma UCB levels and in main bilirubin-detoxifying genes Ugt1a1 and Mrp2. Of note, the circadian UCB levels were antiphase to the circadian expressions of Ugt1a1 and Mrp2. Bmal1 ablation abrogated the circadian rhythms of UCB and bilirubin-induced hepatotoxicity in mice. Bmal1 ablation also decreased mRNA and protein expressions of both Ugt1a1 and Mrp2 in mouse livers, and blunted their circadian rhythms. A combination of luciferase reporter, mobility shift, and chromatin immunoprecipitation assays revealed that Bmal1 trans-activated Ugt1a1 and Mrp2 through specific binding to the E-boxes in the promoter region. Further, Bmal1 ablation caused a loss of circadian time-dependency in bilirubin clearance and sensitized mice to chemical induced-hyperbilirubinemia. Moreover, bilirubin stimulated Bmal1 expression through antagonism of Rev-erbα, constituting a feedback mechanism in bilirubin detoxification. Conclusion: These data supported a dual role for circadian clock in regulation of bilirubin detoxification, generating circadian variations in bilirubin level via direct transactivation of detoxifying genes Ugt1a1 and Mrp2, and defending the body against hyperbilirubinemia via Rev-erbα antagonism. Thereby, our study provided a potential mechanism for management of bilirubin related diseases.
Shape effect in active targeting of nanoparticles to inflamed cerebral endothelium under static and flow conditions
Authors: A. Da Silva-Candal, T. Brown, V. Krishnan, I. Lopez-Loureiro, P. Ávila-Gómez, A. Pusuluri, A. Pérez-Díaz, C. Correa-Paz, P. Hervella, J. Castillo, S. Mitragotri, F. Campos
Journal: Journal of Controlled Release (2019)

Endothelial cells represent the first biological barrier for compounds, including nanoparticles, administered via the intravascular route. In the case of ischemic stroke and other vascular diseases, the endothelium overexpresses specific markers, which can be used as molecular targets to facilitate drug delivery and imaging. However, targeting these markers can be quite challenging due to the presence of blood flow and the associated hydrodynamic forces, reducing the likelihood of adhesion to the vessel wall. To overcome these challenges, various parameters including size, shape, charge or ligand coating have been explored to increase the targeting efficiency. Geometric shape can modulate nanoparticle binding to the cell, especially by counteracting part of the hydrodynamic forces of the bloodstream encountered by the classical spherical shape. In this study, the binding affinity of polystyrene nanoparticles with two different shapes, spherical and rod-shaped, were compared. First, vascular adhesion molecule-1 (VCAM-1) was evaluated as a vascular target of inflammation, induced by lipopolysaccharide (LPS) stimulation. To evaluate the effect of nanoparticle shape on particle adhesion, nanoparticles were coated with anti-VCAM-1 and tested under static conditions in cell culture dishes coated with cerebral microvasculature cells (bEnd.3) and under dynamic flow conditions in microfluidic channels lined with hCMEC/D3 cells. Effect of particle shape on accumulation was also assessed in two in vivo models including systemic inflammation and local brain inflammation. The elongated rod-shaped particles demonstrated greater binding ability in vitro, reaching a 2.5-fold increase in the accumulation for static cultures and 1.5-fold for flow conditions. Anti-VCAM-1 coated rods exhibited a 3.5-fold increase in the brain accumulation compared to control rods. These results suggest shape offers a useful parameter in future design of drug delivery nanosystems or contrast agents for neurovascular pathologies.
Neurotrophin signaling and melanoma brain metastases.
Authors: Nicole Fortenbery, Rajappa Kenchappa, Peter A. J. Forsyth
Journal: Journal of Clinical Oncology (2013)

e13024 Background: Adult metastatic brain tumors occur more frequently than primary intracranial neoplasms. Melanoma is the third most common tumor type that metastasizes to the brain. Therefore, elucidating the underlying biological mechanisms of melanoma metastases is critical. Melanocytes and neurons share a neural ectodermal origin, and thus, melanoma may preferentially travel to the brain due to the expression of common neurotrophin receptors, namely p75 neurotrophin receptor (p75NTR) and Trks. Further, high concentrations of neurotrophic factors present in the brain may recruit metastatic melanoma. We hypothesize that neurotrophin signaling through p75NTR is required for the malignant phenotype of melanoma and melanoma brain metastases (MBM). Methods: We investigated the expression of several neutrophin receptors, signaling molecules, and neurotrophins that we hypothesize to be important in the process of MBM. Using 14 malignant melanoma cell lines and two primary MBMs grown under neurosphere conditions, we investigated the expression of these molecules using standard western blotting, flow cytometry, and RT-PCR. We also performed an in depth microarray using of 14 primary MBM patients from Moffitt’s Total Cancer Care project. Results: All melanoma lines examined have robust expression of p75NTR, Trks, and neurotrophins. We find melanoma cell lines resistant to the BRAF inhibitor, vemurafenib, have elevated expression of neurotrophins and neurotrophin receptors when compared to lines sensitive to vemurafenib. We also detect high levels of p75NTR in patient MBM, at both mRNA and protein levels. Finally, we find a significant level of expression of all 11 genes tested by microarray. Conclusions: Previous studies have demonstrated that p75NTR has a role in melanoma cell survival in vitro. Here we demonstrate p75NTR and Trk receptors have high expression in melanoma cell lines and importantly, primary MBM. These data suggest that signaling through neurotophin receptors may be important for melanoma metastases and survival in the brain. Moreover, increased expression by vemurafenib resistant lines may suggest that these cells upregulate the expression of neurotrophin signaling as a means of treatment resistant.
Basement membrane zone IgE deposition is associated with bullous pemphigoid disease severity and treatment results
Authors: A. Kamata, Y. Kurihara, T. Funakoshi, H. Takahashi, K. Kuroda, T. Hachiya, M. Amagai, J. Yamagami
Journal: British Journal of Dermatology (2019)

A subset of patients with bullous pemphigoid (BP) show deposition of IgE in the basement membrane zone (BMZ), yet the relationship between BMZ IgE and the clinical presentation of BP remains unclear. To investigate the relationship between IgE deposition, IgE levels in serum, and disease severity in patients with BP. We investigated IgE autoantibodies in 53 patients with BP by direct immunofluorescence (DIF), indirect immunofluorescence and enzyme‐linked immunosorbent assay. Of 53 patients with BP, 23 (43%) had IgE deposition, 10 (19%) of whom were IgE+ and 13 (25%) IgE± according to DIF analyses. Erosion/blister (E/B) Bullous Pemphigoid Disease Area Index (BPDAI) scores were significantly higher in IgE+ patients than in IgE− patients (n = 15), while no significant differences were found for urticaria/erythema BPDAI scores. IgE+ and IgE± patients took longer to reduce their E/B BPDAI score by 75% after systemic corticosteroid treatment. BP180‐IgE levels were significantly higher among IgE+ patients than IgE± or IgE− patients (n = 10). Total IgE levels in the serum and blood eosinophil counts did not differ between IgE+, IgE± and IgE− patients. A significant correlation was detected between BP180‐IgG and BP180‐IgE, but not between BPDAI scores and any of BP180‐IgG, BP180‐IgE or blood eosinophil count. IgE deposition in the BMZ is associated with higher E/B BPDAI scores and longer treatment periods. We conclude that IgE binding in the BMZ may contribute to BP pathogenesis by promoting blister formation. What's already known about this topic? BP180‐IgE autoantibodies have an important role in the pathogenesis of bullous pemphigoid (BP). A subset of patients with BP display deposition of IgE within the basement membrane zone (BMZ) of skin tissue. What does this study add? Patients with in vivo IgE deposition in the BMZ displayed higher erosion/blister Bullous Pemphigoid Disease Area Index (BPDAI) scores, while urticaria/erythema BPDAI scores were not significantly different. Patients with in vivo IgE deposition in the BMZ took longer to reduce their erosion/blister BPDAI score by 75% after systemic corticosteroid treatment. BP180‐specific IgE levels in serum were higher among patients with linear IgE deposition in the BMZ than in those with granular or no IgE deposition.
Regional differences in exercise training implementation in heart failure: findings from the Exercise Training in Heart Failure (ExTraHF) survey
Authors: Massimo F. Piepoli, Simone Binno, Andrew J.S. Coats, Alain Cohen‐Solal, Ugo Corrà, Constantinos H. Davos, Tiny Jaarsma, Lars Lund, David Niederseer, Francesco Orso, Giovanni Q. Villani, Piergiuseppe Agostoni, Maurizio Volterrani, Petar Seferovic
Journal: European Journal of Heart Failure (2019)
Depo-Provera: WHO set to review guidance on use by women at high HIV risk
Authors: Gareth Iacobucci
Journal: BMJ (2019)

A World Health Organization guideline development group will convene next week (29-31 July) to review recommendations for the use of contraceptive methods by women at high risk of contracting HIV.

The group will review the status of the three monthly injectable contraceptive Depo-Provera, using new evidence from a randomised clinical trial published in the Lancet last month.1 The Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial, carried out in South Africa, Kenya, Swaziland, and Zambia, was designed to settle ongoing uncertainty and debate over whether Depo-Provera increased the possibility of HIV transmission in women who used it.

The study reported no significant …
Extensive surgical resection in stage IV non-small cell lung cancer patients after tailored chemotherapy.
Authors: Huiqin Guo, Yu Zhao, Jiangyang Lu, David C. Christiani, Xihong Lin, Zhaoxi Wang
Journal: Journal of Clinical Oncology (2013)

e19080 Background: The treatment of stage IV non-small cell lung cancer patients is a problem for thoracic surgeons and the optimal treatment is discussed controversially. ERCC1, class III β-tubulin, p53, and RRM1 are predictive molecular biomarkers reported for neoadjuvant chemotherapy. Here we report a prospectively enrolled case series that patients were treated with extensive surgical resection after personalized chemotherapy tailored by these 4 markers. Methods: Patients with previously untreated stage IV NSCLC, ECOG PS of 0-2 were enrolled. The expression of ERCC1, class III β-tubulin, p53, and RRM1 was tested with IHC staining method for the tumor samples by bronchoscopy biopsy or percutaneous lung biopsy. Patients were treated with 2 of four drugs including cisplatin, taxol, gemcitabine and vinorelbine, selected by the expression of ERCC1, class III β-tubulin, RRM1 and p53, respectively. Then patients received surgical resection after evaluation with continuing adjuvant chemotherapy. A follow-up CT was performed after every 2 cycles chemotherapy and every 3 months post chemotherapy. PFS and OS were estimated by the Kaplan-Meier method. Results: 26 patients were included from May 2008 to Dec 2011 with a follow-up period 12–58 months till Nov 2011. 8 (30.8%) patients died within Follow-up period. The overall response (CR+PR) rate of tailored neoadjuvant chemotherapy was 88.5% with 23 PR. A complete resection (R0) was achieved in 24 (92.3%) patients and R1 in 2 (7.7%) patients. Median PFS was 27.0 months (95% CI: 21.0–32.9 months) and median OS was 41.6 months (95% CI: 23.1–60.0 months). Conclusions: Our study suggest extensive surgical resection in stage IV non-small cell lung cancer patients after tailored chemotherapy should be performed because it may improve survival dramatically over conservative chemotherapy. Surgery within multimodality approach will be a promise treatment option in the future.
A Novel Prognostic Factor for Allogeneic Hematopoietic Stem Cell Transplantation Based on Bone Marrow Assessment on the Day of Stem Cell Transplantation
Authors: Takahiko Sato, Naomi Kawashima, Masafumi Ito, Yoshiko Atsuta, Yusuke Kagaya, Aika Seto, Takanobu Morishita, Nobuaki Fukushima, Yukiyasu Ozawa, Koichi Miyamura
Journal: Blood (2016)
NRG1 fusion-positive lung cancers: Clinicopathologic profile and treatment outcomes from a global multicenter registry.
Authors: Michaël Duruisseaux, Stephen V. Liu, Ji-Youn Han, Valerie Gounant, Jin-Yuan Shih, Alison M. Schram, Alexa Betzig Schrock, Siraj Mahamed Ali, Fanny Magne, Isabelle Monnet, Denis Moro-Sibilot, Torsten-Gerriet Blum, Tejas Patil, Robert Charles Doebele, D. Ross Camidge, Lucia Anna Muscarella, Jacques Cadranel, Alexander E. Drilon
Journal: Journal of Clinical Oncology (2019)

9081 Background: NRG1 fusions are potentially actionable driver events enriched in NSCLCs, particularly invasive mucinous adenocarcinomas (IMAs). These fusions activate HER3/HER2, supporting the therapeutic use of HER3 and/or HER2 inhibitors, but optimal treatment strategies remain unclear. Methods: A global, multicenter network of thoracic oncologists (6 countries, 13 institutions) identified patients with pathologically confirmed NRG1 fusion-positive NSCLCs. Anonymized clinical/pathologic features and clinical outcomes were collected retrospectively. Best response to systemic therapy was determined (RECIST v1.1). PFS was calculated (Kaplan-Meier). Results: 80 NRG1 fusion-positive NSCLCs were identified. RNA-based sequencing identified 66% (n = 53/80), DNA-based sequencing 18% (n = 14/80), and FISH 16% (n = 13/80) of cases. The most common upstream partners were CD74 (45%), SLC3A2 (31%), and SDC (9%). Most patients were female (64%) and never smokers (58%). Histology was adenocarcinoma in 95% (IMA, 91%), squamous 4%, large cell neuroendocrine 1%. At diagnosis, most patients had non-metastatic disease (stage: I 33%, II 27%, III 18%, IV 22%). The lifetime frequency of brain metastases was 15%. 12 patients received the HER2 inhibitor afatinib for stage IV disease. PD was the best response in 55% (n = 6/11) of evaluable patients with 18% PR (n = 2/11) and SD 18% (n = 2/11); median PFS was 3.5 months (range 0.6-16.5 months). 19 patients received platinum-based chemotherapy; most patients had SD as their best response (47%, n = 8); PD 41% (n = 7), PR 12% (n = 2). PD-L1 was negative in the majority of tumors (79%, n = 26/33) and none had high PD-L1 expression (range 0-20%). No responses to single-agent anti-PD-1/L1 therapy were observed (PD n = 5/6, SD n = 1/6: nivolumab/atezolizumab). No responses to chemoimmunotherapy (carboplatin, pemetrexed, pembrolizumab) were observed (SD n = 4/5, PD n = 1/5). Conclusions: RNA-based testing is an important component of NRG1 fusion detection. Novel targeted therapeutic approaches are needed as overall outcomes with afatinib are poor. NRG1 fusion-positive NSCLCs do not highly express PD-L1 and outcomes with immunotherapy ± chemotherapy are poor.