tbuckley/cabot-search huggingface dataset:
Dose modifications of liposomal irinotecan (nal-IRI) + 5-fluorouracil/leucovorin (5-FU/LV) in NAPOLI-1: Impact on efficacy.
Authors: Andrea Wang-Gillam, Richard Hubner, Beloo Mirakhur, Floris A de Jong, Bruce Belanger, Li-Tzong Chen
Journal: Journal of Clinical Oncology (2018)

388 Background: In NAPOLI-1 (NCT01494506), a randomized phase 3 study in patients with metastatic pancreatic cancer previously treated with gemcitabine-based therapy, nal-IRI+5-FU/LV improved overall survival (OS; primary endpoint) vs 5-FU/LV (6.1 mos vs 4.2 mos; HR = 0·67, 95% CI 0.490.92; P = 0.012). This exploratory analysis examined the impact of dose modifications or delays used to manage adverse events (AEs) on OS. The study protocol allowed ≤2 dose reductions for nal-IRI and 5-FU and for up to 3 weeks. Methods: Patient who had a dose delay or reduction within the planned first 6 weeks of the study were included. Delays were defined as any delay in dosing &gt; 3 days from target dosing date and dose reductions were defined as any reduction in dose from initial administered dose. OS was compared within the nal-IRI+5-FU/LV arm and with the 5-FU/LV arm. Comparisons were made using the cohort of 5-FU/LV and nal-IRI+5-FU/LV patients enrolled under protocol version 2. Median OS was based on Kaplan-Meier estimates and Cox regression analysis was used to calculate HRs. Results: More patients in the nal-IRI+5-FU/LV treatment group experienced AEs that required dose delay and/or reduction than in the 5-FU/LV treatment group (62% vs 33%). Within the nal-IRI+5-FU/LV arm, median OS was numerically but not significantly different between patients who did (n = 34) vs did not (n = 83) have a dose reduction (9.3 vs 5.4 mos; HR = 0.66 [95% CI 0.43, 1.01]) and for those who did (n = 49) vs did not (n = 68) have a dose delay (8.4 vs 5.6 mos; 0.82 [95% CI 0.56, 1.23]). Between treatment arms, OS was greater in the nal-IRI+5-FU/LV arm regardless of dose delay or reduction (Table). Conclusions: Dose modifications in the nal-IRI+5-FU/LV arm did not significantly impact OS compared with those who did not need a dose modification, and OS remained greater than in 5-FU/LV-treated patients. This suggests that appropriate dose modification of nal-IRI+5-FU/LV for AEs may not adversely affect outcomes. Clinical trial information: NCT01494506. [Table: see text]
Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial
Authors: Sonia Pernas, Miguel Martin, Peter A Kaufman, Marta Gil-Martin, Patricia Gomez Pardo, Sara Lopez-Tarruella, Luis Manso, Eva Ciruelos, Jose Alejandro Perez-Fidalgo, Cristina Hernando, Foluso O Ademuyiwa, Katherine Weilbaecher, Ingrid Mayer, Timothy J Pluard, Maria Martinez Garcia, Linda Vahdat, Jose Perez-Garcia, Achim Wach, Debra Barker, Samson Fung, Barbara Romagnoli, Javier Cortes
Journal: The Lancet Oncology (2018)
Incidence of Hepatitis B Virus Reactivation and Hepatotoxicity in Patients Receiving Long-term Treatment With Tumor Necrosis Factor Antagonists
Authors: Mary Patricia Pauly, Lue-Yen Tucker, Jean-Luc Szpakowski, Joanna B. Ready, David Baer, Jessica Hwang, Anna S.-F. Lok
Journal: Clinical Gastroenterology and Hepatology (2018)
IS PREOPERATIVE INTRAGASTRIC BALLOON EFFECTIVE TO DECREASE BARIATRIC SURGERY MORBIDITY, A SPANISH CLINICAL ESSAY
Authors: LR Rabago Torre, C Vicente, I Maestro, C Garcia, MD Martin Rios, M Perez, N Herrera Merino
Journal: Endoscopy (2018)

To study the usefulness of preoperative IGB-BIB® “grA” to help decrease postsurgical complications in [sleeve resection or gastric bypass]
An Immunocompetent Mouse Model of Zika Virus Infection
Authors: Matthew J. Gorman, Elizabeth A. Caine, Konstantin Zaitsev, Matthew C. Begley, James Weger-Lucarelli, Melissa B. Uccellini, Shashank Tripathi, Juliet Morrison, Boyd L. Yount, Kenneth H. Dinnon, Claudia Rückert, Michael C. Young, Zhe Zhu, Shelly J. Robertson, Kristin L. McNally, Jing Ye, Bin Cao, Indira U. Mysorekar, Gregory D. Ebel, Ralph S. Baric, Sonja M. Best, Maxim N. Artyomov, Adolfo Garcia-Sastre, Michael S. Diamond
Journal: Cell Host & Microbe (2018)
Preparing Physician-Scientists for an Evolving Research Ecosystem
Authors: Matthew E. Hirschtritt, Penny M. Heaton, Thomas R. Insel
Journal: JAMA (2018)

Physician-scientists, by combining their clinical experience with investigative skills, are uniquely poised to address critical issues in medical care and human health.However, the future of a robust physician-scientist workforce in the United States is uncertain. 1Multiple factors account for this long-standing issue, perhaps most prominently is limited federal biomedical research funding.Following strong growth of the National Institutes of Health (NIH) budget in the previous decade, from 2003 to 2015, the NIH's research-funding capacity declined by 22%. 2 Even though the 2019 federal budget proposal would increase the total NIH budget to approximately $34.8 billion, this increase will not likely compensate for the reduced funding rates for research project grants over the past 4 years. 3side from the research funding challenge, young physicians still must surmount multiple hurdles to pursue a research-predominant career, including prolonged training requirements with substantial undergraduate and medical education debt, challenges in finding and maintaining mentors, difficulty achieving Incorporating private-sector opportunities and experience into physician-scientist training may enrich and expand the scope of biomedical research.
Bawa-Garba campaign group reports progress in Scotland
Authors: Bryan Christie
Journal: BMJ (2018)

A campaign group established in Scotland in support of Hadiza Bawa-Garba, the trainee paediatrician who was erased from the medical register after being convicted of manslaughter,1 hopes to improve conditions for doctors after talks with health service leaders.

The group, which represents almost 700 doctors from all parts of the NHS in Scotland, wants to see an end to unsafe working conditions that put patients at risk and to a culture of blame and persecution when things go wrong.

Members of the group met with Paul Gray, chief executive …
A Magnetically Responsive Biomaterial System for Flexibly Regulating the Duration between Pro‐ and Anti‐Inflammatory Cytokine Deliveries
Authors: Anita E. Tolouei, Nihan Dülger, Rosa Ghatee, Stephen Kennedy
Journal: Advanced Healthcare Materials (2018)

While inflammation can be problematic, it is nonetheless necessary for proper tissue regeneration. However, it remains unclear how the magnitude and duration of the inflammatory response impacts regenerative outcome. This is partially due to the difficulty in temporally regulating macrophage phenotype at wound sites. Here, a magnetically responsive biomaterial system potentially capable of temporally regulating macrophage phenotypes through sequential, on-demand cytokine deliveries is presented. This material system is designed to (i) rapidly recruit proinflammatory macrophages (M1) through initial cytokine deliveries and (ii) subsequently transition macrophages toward anti-inflammatory phenotypes (M2s) through delayed, magnetically triggered cytokine release. Here, the ability of this system to initially deliver proinflammatory cytokines (i.e., monocyte chemoattractant protein-1 and interferon gamma), recruit, and harbor an expanding macrophage population, and delay deliveries of anti-inflammatory cytokines (i.e., IL-4 and IL-10) until the application of magnetic fields from simple hand-held magnets is demonstrated. Critically, the timing and rate of these delayed deliveries can be remotely/magnetically controlled. This biomaterial system can provide a powerful tool in (i) understanding the relationship between inflammation and regenerative outcome, (ii) developing optimized cytokine delivery strategies, and (iii) clinically implementing those optimized delivery strategies with the on-demand versatility needed to alter the course of therapies in real time.
IMPROVED ENDOSCOPIC RESECTION OF LARGE FLAT LESIONS USING AN EXTERNAL ADDITIONAL WORKING CHANNEL (AWC)
Authors: B Walter, S Schmidbaur, A Hann, A Meining
Journal: Endoscopy (2018)

En-bloc resection of lateral-spreading polyps and flat lesions larger than 2 cm in size can be challenging. EMR offers the opportunity for resection in piece-meal technique, but completeness (R0) of the resection remains unclear. In contrast, ESD is complex, time consuming and associated with a significant rate of perforation.
A predictive model for risk of early grade ≥ 3 infection in patients with multiple myeloma not eligible for transplant: analysis of the FIRST trial
Authors: Charles Dumontet, Cyrille Hulin, Meletios A. Dimopoulos, Andrew Belch, Angela Dispenzieri, Heinz Ludwig, Philippe Rodon, Jan Van Droogenbroeck, Lugui Qiu, Michele Cavo, Ann Van de Velde, Juan José Lahuerta, Olivier Allangba, Jae Hoon Lee, Eileen Boyle, Aurore Perrot, Philippe Moreau, Salomon Manier, Michel Attal, Murielle Roussel, Mohamad Mohty, Jean Yves Mary, Alexandre Civet, Bruno Costa, Antoine Tinel, Yann Gaston-Mathé, Thierry Facon
Journal: Leukemia (2018)

Infections are a major cause of death in patients with multiple myeloma. A post hoc analysis of the phase 3 FIRST trial was conducted to characterize treatment-emergent (TE) infections and study risk factors for TE grade ≥ 3 infection. The number of TE infections/month was highest during the first 4 months of treatment (defined as early infection). Of 1613 treated patients, 340 (21.1%) experienced TE grade ≥ 3 infections in the first 18 months and 56.2% of these patients experienced their first grade ≥ 3 infection in the first 4 months. Risk of early infection was similar regardless of treatment. Based on the analyses of data in 1378 patients through multivariate logistic regression, a predictive model of first TE grade ≥ 3 infection in the first 4 months retained Eastern Cooperative Oncology Group performance status and serum β2-microglobulin, lactate dehydrogenase, and hemoglobin levels to define high- and low-risk groups showing significantly different rates of infection (24.0% vs. 7.0%, respectively; P < 0.0001). The predictive model was validated with data from three clinical trials. This predictive model of early TE grade ≥ 3 infection may be applied in the clinical setting to guide infection monitoring and strategies for infection prevention.
Fight childhood obesity with multiple methods, not just more taxes, MPs hear
Authors: Adrian O’Dowd
Journal: BMJ (2018)

Nutrition experts from the NHS, academia, local government, television, and think tanks have told MPs that the ongoing battle to reduce childhood obesity must be fought on several fronts.

The introduction of a soft drinks industry levy last month was a positive step but not enough to deal with the growing obesity problem, they said during an evidence session of the parliamentary health and social care committee on 1 May.

The committee’s new inquiry into childhood obesity precedes the next chapter of the government’s Plan for Action ,1 expected later this year. MPs asked what was needed in this plan.

Jamie …
Let’s Talk About Dating—Promoting Discussions About Adolescent Dating and Early Romantic Relationships
Authors: Jane Chang, Susan L. Rosenthal
Journal: JAMA Pediatrics (2018)

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 Pediatrics 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 Pediatrics journal
Association Between Psychological Interventions and Chronic Pain Outcomes in Older Adults
Authors: Bahar Niknejad, Ruth Bolier, Charles R. Henderson, Diana Delgado, Elissa Kozlov, Corinna E. Löckenhoff, M. Carrington Reid
Journal: JAMA Internal Medicine (2018)

Chronic noncancer pain (hereafter referred to as chronic pain) is common among older adults and managed frequently with pharmacotherapies that produce suboptimal outcomes. Psychological treatments are recommended, but little information is available regarding their efficacy in older adults.To determine the efficacy of psychological interventions in older adults with chronic pain and whether treatment effects vary by participant, intervention, and study characteristics.MEDLINE, Embase, PsycINFO, and the Cochrane Library were searched from inception to March 29, 2017.Analysis included studies that (1) used a randomized trial design, (2) evaluated a psychological intervention that used cognitive behavioral modalities alone or in combination with another strategy, (3) enrolled individuals with chronic pain (pain ≥3 months) with a sample mean age of 60 years or older, and (4) reported preintervention and postintervention quantitative data.Two of the authors independently extracted data. A mixed-model meta-analysis tested the effects of treatment on outcomes. Analyses were performed to investigate the association between participant (eg, age), intervention (eg, treatment mode delivery), and study (eg, methodologic quality) characteristics with outcomes.Pain intensity was the primary outcome; secondary outcomes included pain interference, depressive symptoms, anxiety, catastrophizing beliefs, self-efficacy for managing pain, physical function, and physical health.Twenty-two studies with 2608 participants (1799 [69.0%] women) were analyzed. Participants' mean (SD) age was 71.9 (7.1) years. Differences of standardized mean differences (dD) at posttreatment were pain intensity (dD = -0.181, P = .006), pain interference (dD = -0.133, P = .12), depressive symptoms (dD = -0.128, P = .14), anxiety (dD = -0.205, P = .09), catastrophizing beliefs (dD = -0.184, P = .046), self-efficacy (dD = 0.193, P = .02), physical function (dD = 0.006, P = .96), and physical health (dD = 0.160, P = .24). There was evidence of effects persisting beyond the posttreatment assessment only for pain (dD = -0.251, P = .002). In moderator analyses, only mode of therapy (group vs individual) demonstrated a consistent effect in favor of group-based therapy.Psychological interventions for the treatment of chronic pain in older adults have small benefits, including reducing pain and catastrophizing beliefs and improving pain self-efficacy for managing pain. These results were strongest when delivered using group-based approaches. Research is needed to develop and test strategies that enhance the efficacy of psychological approaches and sustainability of treatment effects among older adults with chronic pain.
miR-339 Promotes Development of Stem Cell Leukemia/Lymphoma Syndrome via Downregulation of the <i>BCL2L11</i> and <i>BAX</i> Proapoptotic Genes
Authors: Tianxiang Hu, Yating Chong, Sumin Lu, Rebecca Wang, Haiyan Qin, Jeane Silva, Eiko Kitamura, Chang-Sheng Chang, LesleyAnn Hawthorn, John K. Cowell
Journal: Cancer Research (2018)

Abstract The development of myeloid and lymphoid neoplasms related to overexpression of FGFR1 kinases as a result of chromosome translocations depends on the promotion of a stem cell phenotype, suppression of terminal differentiation, and resistance to apoptosis. These phenotypes are related to the stem cell leukemia/lymphoma syndrome (SCLL), which arises through the effects of the activated FGFR1 kinase on gene transcription, which includes miRNA dysregulation. In a screen for miRNAs that are directly regulated by FGFR1, and which stimulate cell proliferation and survival, we identified miR-339-5p, which is highly upregulated in cells carrying various different chimeric kinases. Overexpression of miR-339-5p in SCLL cell types enhances cell survival and inhibition of its function leads to reduced cell viability. miR-339-5p overexpression protects cells from the consequences of FGFR1 inactivation, promoting cell-cycle progression and reduced apoptosis. Transient luciferase reporter assays and qRT-PCR detection of endogenous miR-339-5p expression in stably transduced cell lines demonstrated that BCR-FGFR1 can directly regulate miR-339-5p expression. This correlation between miR-339-5p and FGFR1 expression is also seen in primary human B-cell precursor acute lymphoblastic leukemia. In a screen to identify targets of miR-339-5p, we identified and verified the BCL2L11 and BAX genes, which can promote apoptosis. In vivo, SCLL cells forced to overexpress miR-339-5p show a more rapid onset of disease and poorer survival compared with parental cells expressing endogenous levels of miR-339-5p. Analysis of human primary B-cell precursor ALL shows a significant higher expression of miR339-5p compared with the two cohorts of CLL patient samples, suggesting direct roles in disease progression and supporting the evidence generated in mouse models of SCLL. Significance: Proapoptiotic genes that are direct targets of miR-339-5p significantly influence promotion and aggressive development of leukemia/lymphomas associated with FGFR1 overexpression. Cancer Res; 78(13); 3522–31. ©2018 AACR.
Neuronal atlas of the dorsal horn defines its architecture and links sensory input to transcriptional cell types
Authors: Martin Häring, Amit Zeisel, Hannah Hochgerner, Puneet Rinwa, Jon E. T. Jakobsson, Peter Lönnerberg, Gioele La Manno, Nilesh Sharma, Lotta Borgius, Ole Kiehn, Malin C. Lagerström, Sten Linnarsson, Patrik Ernfors
Journal: Nature Neuroscience (2018)
Development and validation of baseline, perioperative and at-discharge predictive models for postsurgical prosthetic joint infection
Authors: M.D. del Toro, C. Peñas, A. Conde-Albarracín, J. Palomino, F. Brun, S. Sánchez, J. Rodríguez-Baño
Journal: Clinical Microbiology and Infection (2018)
A comparison of elbasvir/grazoprevir, ledispasvir/sofosbuvir and velpatisvir/sofosbuvir therapy among people who use drugs (PWUD): real world experience
Authors: A. Alimohammadi, J. Holeksa, Y. Bhutani, A. Thiam, A. Bassi, B. Conway
Journal: Journal of Hepatology (2018)
Comparative Analysis of Human Genes Frequently and Occasionally Regulated by m<b>6</b>A Modification
Authors: Yuan Zhou, Qinghua Cui
Journal: Genomics Proteomics & Bioinformatics (2018)

Abstract The m6A modification has been implicated as an important epitranscriptomic marker, which plays extensive roles in the regulation of transcript stability, splicing, translation, and localization. Nevertheless, only some genes are repeatedly modified across various conditions and the principle of m6A regulation remains elusive. In this study, we performed a systems-level analysis of human genes frequently regulated by m6A modification (m6Afreq genes) and those occasionally regulated by m6A modification (m6Aocca genes). Compared to the m6Aocca genes, the m6Afreq genes exhibit gene importance-related features, such as lower dN/dS ratio, higher protein–protein interaction network degree, and reduced tissue expression specificity. Signaling network analysis indicates that the m6Afreq genes are associated with downstream components of signaling cascades, high-linked signaling adaptors, and specific network motifs like incoherent feed forward loops. Moreover, functional enrichment analysis indicates significant overlaps between the m6Afreq genes and genes involved in various layers of gene expression, such as being the microRNA targets and the regulators of RNA processing. Therefore, our findings suggest the potential interplay between m6A epitranscriptomic regulation and other gene expression regulatory machineries.
A large, switchable optical clearing skull window for cerebrovascular imaging
Authors: Chao Zhang, Wei Feng, Yanjie Zhao, Tingting Yu, Pengcheng Li, Tonghui Xu, Qingming Luo, Dan Zhu
Journal: Theranostics (2018)

Intravital optical imaging is a significant method for investigating cerebrovascular structure and function. However, its imaging contrast and depth are limited by the turbid skull. Tissue optical clearing has a great potential for solving this problem. Our goal was to develop a transparent skull window, without performing a craniotomy, for use in assessing cerebrovascular structure and function.
The impact of combining Selective Internal Radiation Therapy (SIRT) with Sorafenib on overall survival in patients with advanced hepatocellular carcinoma: The Soramic trial palliative cohort
Authors: J. Ricke, B. Sangro, H. Amthauer, I. Bargellini, P. Bartenstein, E. De Toni, A. Gasbarrini, H.-J. Klümpen, M. Peck-Radosavljevic, P. Popovic, O. Rosmorduc, E. Schott, M. Van Buskirk, P. Malfertheiner
Journal: Journal of Hepatology (2018)
The role of IL-6 signaling pathway in cholangiocarcinoma
Authors: T.M.L. Nguyen, K.C. Bui, T. Scholta, M. Riebold, J. Xing, V. Bhuria, L.T. Nguyen, H.S. Le, T.P. Velavan, S. Beckert, N. Malek, P. Bozko, R. Plentz
Journal: Journal of Hepatology (2018)
DNA sequencing of the small bowel adenocarcinomas to identify targetable ErbB2 mutations.
Authors: Liana Adam, Jerry Fowler, Wenhui Wu, Yao Yu, Huamin Wang, Francis A San Lucas, Chad Huff, Scott Kopetz, Paul Scheet, Michael J. Overman
Journal: Journal of Clinical Oncology (2017)

e15800 Background: Small bowel adenocarcinoma (SBA) is a rare malignancy of the digestive tract with limited knowledge about its genetic alterations. Methods: Eighteen tumor and normal matched samples were sequenced using the whole-exome-Illumina platform. Various agnostic analysis methods were used to identify relevant somatic mutations and the results were compared with the available TCGA datasets. To test potential targetable mutations we developed eight patient-derived xenografts (PDX) and three cell lines from freshly-collected primary or metastatic SBA tissues. Two kinase-activating ErbB2 mutations (V842I and Y803H) and one wild-type (wt) ErbB2 (n = 30) PDX models were used to measure the effect of Dacomitinib (Daco) on tumor growth. ErbB2-mutant tumor-derived cell lines were tested for Daco and Lapatinib (Lapa) response in-vitro. Reverse-phase-protein-arrays (RPPA) were used to identify molecular changes. Results: Several unexpected oncogenic mechanisms were suggested by the pattern of somatic mutations across the dataset, including mutations in the Notch and Hippo pathways. In addition, we found 6/18 APC truncating mutations exclusive to mutations in ZNRF3 or RNF43 genes, suggesting that non-APC wnt-activating mechanisms are important in SBA, while considered a minority in CRC. Importantly, 6/18 samples displayed ErbB2 mutations, of which 4 resided in the kinase domain, D769Y, V777L, Y803H and V842I. Nanomolar doses of both Lapa and Daco significantly inhibited ErbB2-mutants’ cell proliferation in-vitro. Target inhibition was confirmed by the RPPA results: EGFR-Y1068, ErbB2-Y1248 and PKCα-S657 dephosphorylation, PCNA reduction and PARP cleavage increase. In-vivo-administered Daco resulted in significant tumor reduction in ErbB2-V841I (39%, p = 0.03) and ErbB2-Y803H (59%, p = 0.03) tumors, and had no anti-tumor effect on wt-ErbB2 tumors. Conclusions: The generation of in-vitro and in-vivo model systems from rare cancers is possible and provides a valuable resource into understanding potentially relevant targetable mutations. Our findings suggest that SBA patients with ErbB2-activating mutations should be considered for clinical trials targeting this alteration.