tbuckley/cabot-search huggingface dataset:
The Hsp27-Mediated IkBα-NFκB Signaling Axis Promotes Radiation-Induced Lung Fibrosis
Authors: Jee-Youn Kim, Seulgi Jeon, Young Jo Yoo, Hee Jin, Hee Yeon Won, Kyeonghee Yoon, Eun Sook Hwang, Yoon-Jin Lee, Younghwa Na, Jaeho Cho, Yun-Sil Lee
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Lung fibrosis is a major side effect experienced by patients after lung cancer radiotherapy. However, effective protection strategies and underlying treatment targets remain unclear. In an effort to improve clinical outcomes, pharmacologic treatment of fibrosis is becoming increasingly popular; however, no ideal therapeutic strategy is yet available. Experimental Design: We used a mouse model to irradiate high focal (90 or 75 Gy) to 3-mm volume of the left lung. Lung tissues of mice were subjected to microarray, mRNA expression, and immunohistochemical analysis. Correlations of radiation (IR)-induced epithelial-mesenchymal transition (EMT) were validated in lung cell lines using appropriate treatments to activate or inhibit selected pathways. Results: The expression of Hsp27 was increased during IR-induced lung fibrosis in a mouse model. Inhibition of functional Hsp27 using shRNA and a synthetic small molecule inhibitor (J2) in lung cells alleviated IR-mediated EMT. The activation of NFkB pathways via direct interaction between Hsp27 and IkBα resulted in increased expressions of Twist, IL-1β, and IL-6 and facilitated IR-mediated EMT, which was identified as an underlying mechanism of Hsp27-mediated fibrosis after IR. J2 also inhibited IR-induced lung fibrosis in an orthotopic lung cancer model, and IR-induced lung fibrotic tissues from patients showed higher expression of Hsp27 than unirradiated lungs. Conclusions: Collectively, IkBα-NFkB signaling activation by Hsp27, which resulted in the facilitation of Twist, IL1β, and IL6 expression, is involved in the EMT process that is tightly connected to the development of IR-induced lung fibrosis. Our findings also suggest that inhibition of Hsp27 has the potential to become a valuable therapeutic strategy for IR-induced lung fibrosis.
COMBINATION OF ERCP AND EUS-GUIDED BILIARY DRAINAGE (CERES) VERSUS PTBD FOR MALIGNANT HILAR BILIARY OBSTRUCTION: A MULTICENTER PROSPECTIVE COMPARATIVE COHORT STUDY (THE CERES STUDY)
Authors: T Orprayoon, P Kongkam, C Boonmee, P Sodarat, O Seabmuangsai, R Romano, S Jangsirikul, W Ridtitid, P Angsuwatcharakon, T Ratanachu-ek, R Rerknimitr
Journal: Endoscopy (2019)

To prospectively compare efficacy of combination of ERCP and EUS-BD (CERES) including EUS-guided hepaticogastrostomy (EUS-HGS) and EUS-guided hepaticoduodenostomy (EUS-HDS) versus PTBD in malignant hilar biliary obstruction (MHBO).
Nivolumab for Newly Diagnosed Advanced-Stage Classic Hodgkin Lymphoma: Safety and Efficacy in the Phase II CheckMate 205 Study
Authors: Radhakrishnan Ramchandren, Eva Domingo-Domènech, Antonio Rueda, Marek Trněný, Tatyana A. Feldman, Hun Ju Lee, Mariano Provencio, Christian Sillaber, Jonathon B. Cohen, Kerry J. Savage, Wolfgang Willenbacher, Azra H. Ligon, Jing Ouyang, Robert Redd, Scott J. Rodig, Margaret A. Shipp, Mariana Sacchi, Anne Sumbul, Philippe Armand, Stephen M. Ansell
Journal: Journal of Clinical Oncology (2019)

Nivolumab, an anti-programmed death-1 monoclonal antibody, has demonstrated frequent and durable responses in relapsed/refractory classic Hodgkin lymphoma (cHL). We report results from Cohort D of the CheckMate 205 trial, which assessed nivolumab monotherapy followed by nivolumab plus doxorubicin, vinblastine, and dacarbazine (N-AVD) for newly diagnosed cHL.Patients 18 years of age or older with untreated, advanced-stage (defined as III to IV and IIB with unfavorable risk factors) cHL were eligible for Cohort D of this multicenter, noncomparative, phase II trial. Patients received nivolumab monotherapy for four doses, followed by 12 doses of N-AVD; all doses were every 2 weeks, and nivolumab was administered at 240 mg intravenously. The primary end point was safety. Efficacy end points included objective response rate and modified progression-free survival, defined as time to disease progression/relapse, death, or next therapy. Chromosome 9p24.1 alterations and programmed death-ligand 1 expression were assessed in Hodgkin Reed-Sternberg cells in evaluable patients.A total of 51 patients were enrolled and treated. At diagnosis, 49% of patients had an International Prognostic Score of 3 or greater. Overall, 59% experienced a grade 3 to 4 treatment-related adverse event. Treatment-related febrile neutropenia was reported in 10% of patients. Endocrine immune-mediated adverse events were all grade 1 to 2 and did not require high-dose corticosteroids; all nonendocrine immune-mediated adverse events resolved (most commonly, rash; 5.9%). At the end of therapy, the objective response rate (95% CI) per independent radiology review committee was 84% (71% to 93%), with 67% (52% to 79%), achieving complete remission (five patients [10%] were nonevaluable and counted as nonresponders). With a minimum follow-up of 9.4 months, 9-month modified progression-free survival was 92%. Patients with higher-level Hodgkin Reed-Sternberg programmed death-ligand 1 expression had more favorable responses to N-AVD (P = .041).Nivolumab followed by N-AVD was associated with promising efficacy and safety profiles for newly diagnosed, advanced-stage cHL.
A NEW OPTION IN ZENKER'S DIVERTICULUM ENDOSCOPIC TREATMENT
Authors: I Cunha, P Amaro, E Gravito-Soares, M Gravito-Soares, L Tomé
Journal: Endoscopy (2019)

The endoscopic treatment of Zenker's diverticulum (ZD) consists in the division of the septum that separates the diverticulum from the cervical oesophagus, a structure that includes the cricopharyngeal muscle. This septotomy is not yet standardized and may be performed using a variety of techniques and devices, from coagulation with argon-plasma to incision with forceps or diathermic knives, with variable efficacy, rate of complications and symptomatic recurrence. The aim of this study is to assess the efficacy and safety of a new endoscopic option in ZD treatment.
Microfluidic Fabrication of Biomimetic Helical Hydrogel Microfibers for Blood‐Vessel‐on‐a‐Chip Applications
Authors: Luanluan Jia, Fengxuan Han, Huili Yang, Gareth Turnbull, Jiayuan Wang, Jon Clarke, Wenmiao Shu, Mingyu Guo, Bin Li
Journal: Advanced Healthcare Materials (2019)

Abstract Nature has created many perfect helical microstructures, including DNA, collagen fibrils, and helical blood vessels, to achieve unique physiological functions. While previous studies have developed a number of microfabrication strategies, the preparation of complex helical structures and cell‐laden helical structures for biomimetic applications remains challenging. In this study, a one‐step microfluidics‐based methodology is presented for preparing complex helical hydrogel microfibers and cell‐laden helical hydrogel microfibers. Several types of complex helical structures, including multilayer helical microfibers and superhelical hollow microfibers with helical channels, are prepared by simply tuning the flow rates or modifying the geometry of microfluidic device. With the decent perfusability, the hollow microfibers may simulate the structural characteristics of helical blood vessels and create swirling blood flow in a blood‐vessel‐on‐chip setup. Such hydrogel‐based helical microstructures may potentially be used in areas such as blood vessel tissue engineering, organ‐on‐chips, drug screening, and biological actuators.
MIPSS70: Mutation-Enhanced Prognostic System for Transplant Age Patients with Primary Myelofibrosis
Authors: Alessandro M. Vannucchi, Paola Guglielmelli, Terra L. Lasho, Giada Rotunno, Carmela Mannarelli, Annalisa Pacilli, Animesh Pardanani, Elisa Rumi, Vittorio Rosti, Curtis A. Hanson, Francesco Mannelli, Rhett P. Ketterling, Naseema Gangat, Alessandro Rambaldi, Francesco Passamonti, Giovanni Barosi, Tiziano Barbui, Ayalew Tefferi
Journal: Blood (2017)
Happle–Tinschert, Curry–Jones and segmental basal cell naevus syndromes, overlapping disorders caused by somatic mutations in hedgehog signalling genes: the mosaic hedgehog spectrum
Authors: M.‐L. Lovgren, Y. Zhou, G. Hrčková, T. Dallos, I. Colmenero, S.R.F. Twigg, C. Moss
Journal: British Journal of Dermatology (2019)

Happle–Tinschert syndrome (HTS) and Curry–Jones syndrome (CJS; OMIM 601707) are rare, sporadic, multisystem disorders characterized by hypo‐ and hyperpigmented skin patches following Blaschko's lines, plus acral skeletal and other abnormalities. The blaschkoid pattern implies mosaicism, and indeed CJS was found in 2016 to be caused by a recurrent postzygotic mutation in a gene of the hedgehog signalling pathway, namely SMO, c.1234C>T, p.Leu412Phe. More recently the original case of HTS was found to carry the same somatic mutation. Despite this genetic and phenotypic overlap, two significant differences remained between the two syndromes. The histological hallmark of HTS, basaloid follicular hamartomas, is not a feature of CJS. Meanwhile, the severe gastrointestinal manifestations regularly reported in CJS had not been described in HTS. We report a patient whose phenotype was entirely consistent with HTS apart from intractable constipation, and a second patient with classic features of CJS plus early‐onset medulloblastoma, a feature of basal cell naevus syndrome (BCNS). Both had the same recurrent SMO mutation. This prompted a literature review that revealed a case with the same somatic mutation, with basaloid follicular hamartomas and other features of both CJS and BCNS. Segmental BCNS can also be caused by a somatic mutation in PTCH1. We thus demonstrate for the first time phenotypic and genetic overlap between HTS, CJS and segmental BCNS. All of these conditions are caused by somatic mutations in genes of the hedgehog signalling pathway and we therefore propose the unifying term 'mosaic hedgehog spectrum'. What's already known about this topic? Happle–Tinschert syndrome (HTS) and Curry–Jones syndrome (CJS) are rare mosaic multisystem disorders with linear skin lesions. CJS is characterized by severe constipation, which has not previously been reported in HTS. HTS is characterized by basaloid follicular hamartomas, which are not a recognized feature of CJS. The recurrent mosaic SMO mutation found in CJS was recently reported in a patient with HTS. What does this study add? We describe a patient with HTS and intractable constipation, and a case of CJS with medulloblastoma. Both patients had the same recurrent somatic SMO mutation also found in a case reported as segmental basal cell naevus syndrome. SMO functions in the hedgehog pathway, explaining phenotypic overlap between HTS, CJS and mosaic basal cell naevus syndrome. We propose the term 'mosaic hedgehog spectrum' for these overlapping conditions.
Evaluation de la prise en charge des hémorragies digestives hautes liées à l'hypertension portale dans 6hôpitaux de Kinshasa (République Démocratique du Congo)
Authors: A Tshimpi, T Ndarabu, E Loleke, A Nkodila, T Monsere, S Mbendi
Journal: Endoscopy (2019)

La prise en charge des hémorragies digestives hautes en Afrique subsaharienne semble mal codifiée et est compliquée par des difficultés d'accès à l'endoscopie digestive. Le but de notre étude était d'évaluer la prise en charge diagnostique et thérapeutique des hémorragies digestives hautes (HDH) liées à l'hypertension portale (HTP) dans 6hôpitaux de Kinshasa.
Reply to Dong<i>et al.</i>: Airway Pressure Release Ventilation: Is It Really Different in Adults and Children?
Authors: Saptharishi Lalgudi Ganesan, Muralidharan Jayashree
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

they used reference ranges to set Phigh.Furthermore, when the parameters needed to be adjusted, they also directly adjusted the parameters to a certain range.Additionally, the physiological characteristics of the respiratory system in children can be different for different ages.For example, the younger children are, the faster they breathe, and the smaller their VT.Compared with 12-year-olds, 2-month-old children have higher airway resistance, higher chest wall compliance, less alveolar area, and more abdominal breathing.All of this means that children of different ages should be ventilated in different ways, and individual APRV settings are required.Thus, we believe that the initial parameters that were inconsistent with the pathophysiology of the patients may have caused the worse outcomes in the APRV group.Third, the type of ventilator used is an important factor that is often overlooked in our daily research.In our previous study, we used a Puritan Bennett 840 ventilator (Medtronic) to deliver APRV, whereas Lalgudi Ganesan and colleagues used Hamilton Galileo (Hamilton Medical) or Servo I (MAQUET) ventilators.Different ventilators have different features-for instance, at the end of high pressure time and with the expiratory phase of a spontaneous breath, the Puritan Bennett 840 could synchronize the transition from Phigh to Plow (5).We suggest that using a single ventilator for all patients in a trial might minimize the bias caused by different types of ventilators.Finally, we are delighted to participate in this "APRV debate."To ensure a more reasonable use of APRV in adult and pediatric patients with ARDS, more evidence is needed.
Long duration of breastfeeding is associated to inflammatory breast (IBC) cancer
Authors: N. Mejri, H. El Benna, H. Rachdi, S. Labidi, H. Boussen
Journal: Annals of Oncology (2019)

Background: We aimed to evaluate the role of breastfeeding as a risk factor of IBC compared to non-IBC and according to hormonal (HR) and human epidermal growth factors receptors (HER2) receptor status. Methods: Cases of IBC (n = 160) and controls of non-IBC (n = 580) were collected from the cohort of breast cancer patients treated in two oncology centers 1:1 matched on the basis of age at cohort entry (+-2 years). Data about breastfeeding were collected, association and odds ratios were calculated. Breastfeeding was also evaluated in 3 further sub-groups: (HR+, HER2-), (HER2+, HR-) and triple negative (TN) patients. Results: Breastfeeding rate was similar between IBC and non-IBC patients (62% vs 65.3%, p = 0.57). However, breast feeding duration>12months was significantly more common in IBC vs non-IBC (30% vs 8.4%, p = 0.01). This observation was also confirmed in HR positive (32.5% vs 9.2%, p < 0.01) and HER2 positive (35.8% vs 6.35%, p < 0.01) but not in TN groups (24.3 vs 10.7, p = 0,06). We did not observe an association between breast feeding and occurrence of IBC, with an odds ratio of 1.1 [95% confidence interval (CI) 0.7-1.8], neither among HR+, HER2+ and TN groups. Odds ratio for developing IBC in breast feeding duration>12 months relative to shorter duration was 4.6 [2.9-7.2]. In HR+ tumors, it was 3.5 [1.5-8.1], and in HER2+ it was 5.7 [3-10.7]. However in TN tumors, odds ratio was not significant (2.6 [0.9-7.4]). Conclusions: Patients with breastfeeding duration>12 months, were 4.6 times more likely to develop IBC compared to non IBC. This risk became 3.5 times in HR+ and 5.7 times in HER2.This observation was not confirmed in TN tumors. Legal entity responsible for the study: Abderrahmen Mami Hospital. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Comparative Efficacy of Multicomponent Behavioral Interventions for Mild Cognitive Impairment
Authors: Kelsey T. Laird, Helen Lavretsky
Journal: JAMA Network Open (2019)

Melanie J. Chandler, PhD; Dona E. Locke, PhD; Julia E. Crook, PhD; Julie A. Fields, PhD; Colleen T. Ball, MS; Vaishali S. Phatak, PhD; Pamela M. Dean, PhD; Miranda Morris, MS; Glenn E. Smith, PhD
Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity
Authors: Marie‐Noëlle Paludetto, Florent Puisset, Etienne Chatelut, Cécile Arellano
Journal: Medicinal Research Reviews (2019)

Abstract Tyrosine kinase inhibitors (TKI) are small heterocyclic molecules targeting transmembrane and cytoplasmic tyrosine kinases that have met with considerable success in clinical oncology. TKI are associated with toxicities including liver injury that may be serious and even life‐threatening. Many of them require warnings in drug labeling against liver injury, and five of them have Black Box Warning (BBW) labels. Although drug‐induced liver injury is a matter of clinical and industrial concern, little is known about the underlying mechanisms that likely involve reactive metabolites (RM). RM are electrophiles or radicals originating from the metabolic activation of particular functional groups, known as structural alerts or toxicophores. RM are able to covalently bind to proteins and macromolecules, causing cellular damage and even cell death. If the adducted protein is the enzyme involved in RM formation, time‐dependent inhibition of the enzyme—also called mechanism‐based inhibition (MBI) or inactivation—can occur and lead to pharmacokinetic drug‐drug interactions. To mitigate RM liabilities, common practice in drug development includes avoiding structural alerts and assessing RM formation via RM trapping screens with soft and hard nucleophiles (glutathione, potassium cyanide, and methoxylamine) in liver microsomes. RM‐positive derivatives are further optimized to afford drug candidates with blocked or minimized bioactivation potential. However, different structural alerts are still commonly used scaffolds in drug design, including in TKI structures. This review focuses on the current state of knowledge of the relations among TKI structures, bioactivation pathways, RM characterization, and hepatotoxicity and cytochrome P450 MBI in vitro.
2-Hydroxypropyl-β-cyclodextrin-enhanced pharmacokinetics of cabotegravir from a nanofluidic implant for HIV pre-exposure prophylaxis
Authors: Fernanda P. Pons-Faudoa, Antons Sizovs, Nicola Di Trani, Jesus Paez-Mayorga, Giacomo Bruno, Jessica Rhudy, Madhuri Manohar, Kevin Gwenden, Cecilia Martini, Corrine Ying Xuan Chua, Greta Varchi, Mark A. Marzinke, Alessandro Grattoni
Journal: Journal of Controlled Release (2019)
The Role of Microcirculatory Dysfunction in the Pathophysiology and Treatment of Venous Leg Ulcers
Authors: Markos Klonizakis
Journal: JAMA Dermatology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Analysis of the Association Between Adverse Events and Outcome in Patients Receiving a Programmed Death Protein 1 or Programmed Death Ligand 1 Antibody
Authors: V. Ellen Maher, Laura L. Fernandes, Chana Weinstock, Shenghui Tang, Sundeep Agarwal, Michael Brave, Yang-min Ning, Harpreet Singh, Daniel Suzman, James Xu, Kirsten B. Goldberg, Rajeshwari Sridhara, Amna Ibrahim, Marc Theoret, Julia A. Beaver, Richard Pazdur
Journal: Journal of Clinical Oncology (2019)

To assess the relationship among tumor response rate, overall survival, and the development of related adverse events of special interest (AESIs) or related immune-mediated adverse events (imAEs) in patients with urothelial cancer treated with anti-programmed death protein 1 or ligand 1 (anti-PD-1/L1) antibodies.We examined seven trials in 1,747 patients with metastatic or locally advanced urothelial cancer that led to approval of an anti-PD-1/L1 antibody. Five trials enrolled patients who had received prior platinum-based therapy, and two enrolled patients who were cisplatin ineligible. The data sets were searched for AESIs, related AESIs, imAEs, and related imAEs. The relationship to study drug was determined by the investigator. ImAEs were defined as AESIs treated with topical or systemic corticosteroids.In these exploratory analyses, a related AESI was reported in 64% of responding patients and in 34% of patients who did not respond to the anti-PD-1/L1 antibody, whereas a related imAE occurred in 28% and 12% of patients who did and did not respond to study drug, respectively. In a responder analysis, an increase in overall survival was seen in patients with related AESIs compared with those with no related AESIs (hazard ratio, 0.45; 95% CI, 0.39 to 0.52). Fifty-seven percent of responding patients with a related AESI reported the AESI before documentation of response.Patients who responded to treatment with an anti-PD-1/L1 antibody were more likely to report a related AESI or related imAE. This relationship did not seem to be due to the increased duration of exposure in responding patients. Systemic corticosteroid use did not appear to affect the duration of response.
Outcomes of women at high familial risk for breast cancer in Australia: An 8-year single-centre experience
Authors: J. Lammert, A.R. Skandarajah, K. Shackleton, P. Calder, S. Thomas, G.J. Lindeman, G.B. Mann
Journal: Annals of Oncology (2019)

Background: The value of a high-risk surveillance program for mutation carriers compared to non-carriers at high familial breast cancer risk is not well understood. The Breast and Ovarian Cancer Risk Management Clinic (BOCRMC) was established to provide multimodality screening and risk management strategies. The purpose of this study was to compare breast cancer diagnoses for BRCA1, BRCA2 and other germline mutation carriers versus non-carriers attending the BOCRMC. Methods: Clinical data from mutation carriers and non-carriers with a ≥ 25% lifetime risk of developing breast cancer who attended between 2010 and 2018 were extracted from clinic records and compared. The pattern and mode of detection of breast cancers were determined. Results: A total of 206 mutation carriers and 305 non-carriers attended the BOCRMC and underwent screening on at least one occasion. Median age was 37 years. After a median follow-up of 34 months, 15 (7 invasive) breast cancers were identified in mutation carriers (median age: 45 years) and 7 (6 invasive) in non-carriers (median age: 48 years). Of these, 90.9% were detected by annual screening, while 9.1% were detected as interval cancers among BRCA1 mutation carriers. Median size of the invasive breast cancers was 11 mm. Most (76.9%) were axillary node negative. In women aged 25-49 years, the annualised breast cancer incidence rate was 1.6% in BRCA1, 1.4% in BRCA2 mutation carriers and 0.5% in non-carriers. Conclusions: Screening was effective at detecting early-stage cancers in both groups. The incidence of breast cancer events in young non-carriers was substantially higher than in the general population. This justifies ongoing management through a specialty clinic although further research to personalise risk assessment in non-carriers is required. Legal entity responsible for the study: G. Bruce Mann. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.