tbuckley/cabot-search huggingface dataset:
<scp>TT</scp> genotype of rs10036748 in <i> <scp>TNIP</scp> 1 </i> shows better response to methotrexate in a Chinese population: a prospective cohort study
Authors: K.X. Yan, Y.J. Zhang, L. Han, Q. Huang, Z.H. Zhang, X. Fang, Z.Z. Zheng, N. Yawalkar, Y.L. Chang, Q. Zhang, L. Jin, D.F. Qian, X.Y. Li, M.S. Wu, Q.H. Xu, X.J. Zhang, J.H. Xu
Journal: British Journal of Dermatology (2019)

Methotrexate (MTX) is an efficacious treatment for psoriasis; however, its widespread application is limited by its unpredictable efficacy. To investigate the association of clinical factors and variants of psoriasis susceptibility genes with clinical responses to MTX in a prospective cohort. A total of 221 patients with psoriasis were recruited. Patients who achieved Psoriasis Area and Severity Index (PASI) improvement ≥ 75% at week 12 were defined as responders, whereas those with PASI improvement < 50% were defined as nonresponders. In 90 screening patients, genetic variants for 18 single‐nucleotide polymorphisms in 14 susceptibility genes, and HLA‐Cw6 status were initially compared for responders and nonresponders. Statistically significant associations in genetic variants were verified in all 221 patients. Overall, 49% and 45% of patients achieved PASI 75 improvement during screening and verification stages, respectively. Concomitant arthritis with psoriasis and high body mass index (BMI) negatively affect the efficacy of MTX. TT genotype of rs10036748 in TNIP1 was significantly associated with PASI 75 response at week 12 (54% and 37%, P < 0·05). A significantly higher PASI 90 response was observed in patients with TT genotype of rs10036748 (27% vs. 12%, P < 0·01) and TC/TT genotype of rs4112788 in LCE3D (25% vs. 13%, P < 0·05) at week 12 compared with those who had other genotypes. After adjustment for all confounding factors, only BMI (P < 0·05), arthritis (P < 0·05) and genotype of rs10036748 (P < 0·05) were significantly associated with clinical responses to MTX. Patients with psoriasis with TT genotype of rs10036748 in TNIP1, with lower BMI, without arthritis will achieve a better response to MTX.
ENDOSCOPIC MANAGEMENT OF DUODENAL AND JEJUNAL POLYPOSIS IN PATIENTS WITH FAMILIAL ADENOMATOUS POLYPOSIS USING DOUBLE BALLOON ENDOSCOPY
Authors: M Sekiya, H Sakamoto, T Yano, S Miyahara, M Nagayama, H Tojo, Y Kobayashi, S Shinozaki, K Sunada, A Kawarai Lefor, H Yamamoto
Journal: Endoscopy (2019)

It was reported that endoscopic treatment for colorectal polyposis can be considered in the management of Familial adenomatous polyposis (FAP) patients refusing colectomy. Despite the lifetime risk for duodenal and small bowel cancer is approximately 4%, prophylaxis is not discussed sufficiently. The aim of the study was to elucidate the long-term outcomes, safety and developing cancer after double balloon endoscopy (DBE)-assisted endoscopic treatment in FAP patients with duodenal and jejunal polyposis.
Shared Signature Dynamics Tempered by Local Fluctuations Enables Fold Adaptability and Specificity
Authors: She Zhang, Hongchun Li, James M Krieger, Ivet Bahar
Journal: Molecular Biology and Evolution (2019)

Recent studies have drawn attention to the evolution of protein dynamics, in addition to sequence and structure, based on the premise structure-encodes-dynamics-encodes-function. Of interest is to understand how functional differentiation is accomplished while maintaining the fold, or how intrinsic dynamics plays out in the evolution of structural variations and functional specificity. We performed a systematic computational analysis of 26,899 proteins belonging to 116 CATH superfamilies. Characterizing cooperative mechanisms and convergent/divergent features that underlie the shared/differentiated dynamics of family members required a methodology that lends itself to efficient analyses of large ensembles of proteins. We therefore introduced, SignDy, an integrated pipeline for evaluating the signature dynamics of families based on elastic network models. Our analysis confirmed that family members share conserved, highly cooperative (global) modes of motion. Importantly, our analysis discloses a subset of motions that sharply distinguishes subfamilies, which lie in a low-to-intermediate frequency regime of the mode spectrum. This regime has maximal impact on functional differentiation of families into subfamilies, while being evolutionarily conserved among subfamily members. Notably, the high-frequency end of the spectrum also reveals evolutionary conserved features across and within subfamilies; but in sharp contrast to global motions, high-frequency modes are minimally collective. Modulation of robust/conserved global dynamics by low-to-intermediate frequency fluctuations thus emerges as a versatile mechanism ensuring the adaptability of selected folds and the specificity of their subfamilies. SignDy further allows for dynamics-based categorization as a new layer of information relevant to distinctive mechanisms of action of subfamilies, beyond sequence or structural classifications.
The Right to Grieve
Authors: Minjee Kim
Journal: JAMA (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 HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
THER-08. RAPLINK-1 COOPERATES WITH INHIBITORS OF Bcl-2/Bcl-xl TO INDUCE APOPTOSIS IN GLIOBLASTOMA
Authors: Xujun Luo, Qi-Wen Fan, Kevan M Shokat, William A Weiss
Journal: Neuro-Oncology (2019)

BACKGROUND: Glioblastoma (GBM) has dysregulated signaling of the mTOR pathway. Rapalink-1, a bivalent inhibitor created by linking rapamycin and sapanisertib, can bind to both drug binding pockets, potently inhibits mTORC1 in vitro and in vivo. Although Rapalink-1 represents a novel path towards mTOR inhibition, cellular responses in glioblastoma are mostly cytostatic. B cell lymphoma 2 (Bcl-2) family members play a central role in programmed cell death, orchestrating pro- and anti- apoptotic signals. Pro-survival Bcl-2 family member Mcl-1 is overexpressed in GBM. We hypothesize that blockade of Bcl-2 family members in combination with RapaLink-1 will drive apoptosis in glioblastoma. METHODS: We screened a panel of prototype and clinical Bcl-2 family inhibitors, namely ABT-737, ABT-199 (Venetoclax), ABT-263(Navitoclax), and GX15-070(Obatoclax) in combination with Rapalink-1, against pediatric (SF188) and adult (LN229, SF767, U373) and GBM cell lines. We assayed cell viability, annexin V FITC flow cytometry and western blot. RESULTS: Rapalink-1 in combination with Bcl-2 family inhibitors inhibited cell viability significantly more than single drug. ABT-199, a selective inhibitor of Bcl-2, did not induce apoptosis when combined with Rapalink-1. GX15-070, a pan pro-survival Bcl-2 family inhibitor and inducer of autophagy actually blocked apoptosis when combined with RapaLink-1. ABT-737 and its clinical derivative ABT-263, both of which inhibit Bcl-2, Bcl-xl and Bcl-w, synergized with Rapalink-1 to induce apoptosis in multiple GBM cell lines, evidenced by PARP cleavage and annexin V staining. We found that Rapalink-1 potently downregulated expression of Mcl-1 and induced pro-survival members Bcl-2 and Bcl-xl, suggesting that blockade of mTORC1, Bcl-2 and Bcl-xl, in combination cooperate in driving apoptosis. These results present a preclinical strategy to drive tumor cells towards mTOR inhibition-induced cytotoxicity, offering a translatable strategy for treatment of pediatric GBM.
Tandem-genotypes: robust detection of tandem repeat expansions from long DNA reads
Authors: Satomi Mitsuhashi, Martin C. Frith, Takeshi Mizuguchi, Satoko Miyatake, Tomoko Toyota, Hiroaki Adachi, Yoko Oma, Yoshihiro Kino, Hiroaki Mitsuhashi, Naomichi Matsumoto
Journal: Genome biology (2019)

Tandemly repeated DNA is highly mutable and causes at least 31 diseases, but it is hard to detect pathogenic repeat expansions genome-wide. Here, we report robust detection of human repeat expansions from careful alignments of long but error-prone (PacBio and nanopore) reads to a reference genome. Our method is robust to systematic sequencing errors, inexact repeats with fuzzy boundaries, and low sequencing coverage. By comparing to healthy controls, we prioritize pathogenic expansions within the top 10 out of 700,000 tandem repeats in whole genome sequencing data. This may help to elucidate the many genetic diseases whose causes remain unknown.
PTSD in SJS/TEN: prevalence and risk factors
Authors: L. Hefez, K. Zaghbib, E. Sbidian, L. Valeyrie‐Allanore, M. Allain, T.A. Duong, A. Colin, F. Bellivier, H. Romano, N. Prost, K. Chazelas, O. Chosidow, P. Wolkenstein, S. Ingen‐Housz‐Oro
Journal: British Journal of Dermatology (2019)

Epidermal necrolysis is a rare and severe syndrome, mainly caused by a reaction to a medication, which causes severe blistering and sloughing of skin and mucous membranes. It includes two syndromes, Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), depending on the percentage of body surface area involved. Incidence in France is one to two cases per million people. Multiple long‐term consequences of this violent and acute disorder are known about, mostly affecting skin and eyes, but also psychological distress, called post‐traumatic stress disorder (PTSD). However, commonness and risk factors of PTSD are still largely unknown. The present study was conducted by the research team of the national reference centre for toxic bullous diseases, based in Henri Mondor hospital, Créteil, France. We aimed to assess the prevalence and the risk factors of PTSD. We included 31 adult patients admitted at the acute phase (i.e. at its most severe) of SJS/TEN from 2009 to 2013. All of them were evaluated by a psychiatrist with several psychologic scores at the acute phase and were prescribed an anti‐anxiety drug, hydroxyzine, if necessary, then patients were checked again at two, six and 12 months. The degree of post‐traumatic stress was defined by a PTSD Checklist score of greater than 44. At six months, the PTSD prevalence was 23%. Three patients developed a late PTSD at 12 months. We conclude that a systematic psychiatric evaluation is warranted at the acute phase and must be followed by a prolonged and repeated evaluation of the patients for at least one year.
UK patients who tested Kuvan for phenylketonuria will get supplies after trials end, says company
Authors: Deborah Cohen
Journal: BMJ (2019)

BioMarin, a US biotech company, has said that all UK patients who have taken part in clinical trials of sapropterin dihydrochloride (Kuvan) for phenylketonuria (PKU) will be able to continue taking the drug after the trials end.

The statement comes after the BBC’s Newsnight highlighted that some patients had not continued to receive the drug once the trials ended.1

This seemed at odds with the Declaration of Helsinki, the global research ethics agreement saying that provisions should be made “for all participants who still need an intervention identified as beneficial in the trial,” although BioMarin insisted, “To the best of our knowledge, BioMarin is treating all known ex-trial patients. If there are any ex-trial patients who are not being treated and would like to be treated, they should talk to their treating physician and apply for treatment.”

Kuvan is currently the only drug licensed to …
Reducing bias: accounting for the order of co–first authors
Authors: Arturo Casadevall, Gregg L. Semenza, Sarah Jackson, Gordon Tomaselli, Rexford S. Ahima
Journal: Journal of Clinical Investigation (2019)

Reflecting an increasing emphasis on collaborative science, the number of authors on published articles has markedly risen with time. With this trend, we see an increase in papers designating 2 or more co-first authors. To improve transparency in how such designations are made and reduce bias in the assignment of order, the JCI is now requiring an explanation for how the first-author position is determined when shared among contributing authors.
THER-25. IMMUNE ONCOLYTIC ADENOVIRUS FOR DIPG TREATMENT
Authors: Virginia Laspidea, Maider Varela-Guruceaga, Marc García-Moure, Marisol Gonzalez-Huarriz, Juan Fueyo, Candelaria Gomez-Manzano, Marta M Alonso
Journal: Neuro-Oncology (2019)

Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable pediatric brain tumor that arises in the brainstem. The median overall survival is only one year being the standard of treatment radiotherapy. Oncolytic adenoviruses have emerged as a promising therapeutic option for DIPG due to their specificity to tumor cells. Our clinical experience has shown that stimulation of an immune response against the tumor by the adenovirus is important for the effectivity of this therapy. 4-1BB is a major costimulatory receptor promoting the survival and expansion of activated T cells, as well as the generation and maintenance of memory CD8+ T cells. Since CD8+ T cells play a pivotal role in tumor immunity, enhancing 4-1BB costimulation promotes the generation of antitumor immune responses. In order to improve the antitumor immune response induced by the adenovirus, we have engineered the costimulatory molecule 4-1BBL into the genome of Delta-24-RGD (Delta-24-ACT). Delta-24-ACT was able to infect and to express viral proteins in a dose-dependent manner in murine DIPG cell lines, NP53 and XFM in vitro and in vivo. Importantly, Delta-24-ACT exerts a significant antitumoral effect in vitro, being XFM the cell line with higher sensitivity to the virus (3 days-IC50: 3.4 MOI). DIPGcells infected with Delta-24-ACT during 24 hours showed expression of 4-1BBL in the plasma membrane in around 50% of cells. Delta-24-ACT induced immunogenic cell death in DIPG cell lines showing a significant increase of calreticulin in the plasma membrane, the release of ATP and HMGB1, which are DAMPs able to trigger an adaptive immune response. All these results suggest that Delta-24-ACT is functional in DIPG models in vitro. We are currently, performing toxicity and efficacy in vivo experiments in orthotopic DIPG models. Further, in vivo studies will uncover of the suitability of this new virus for the treatment of DIPG.
DIPG-38. DIANHYDROGALACTITOL (VAL-083) WITH AZD1775 INCREASES SURVIVAL IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG), IN VIVO
Authors: Anne Steino, Xiaodong Yang, Cassie Kline, Dennis Brown, Jeff Bacha, Lei Liu, Sabine Mueller
Journal: Neuro-Oncology (2019)

VAL-083 is a bi-functional DNA-targeting agent that crosses the blood-brain barrier and accumulates in brain tumors. VAL-083 induces interstrand crosslinks leading to DNA double-strand breaks and S/G2 cell-cycle arrest. We hypothesized that by inhibiting G2 checkpoint regulator kinase Wee1, cancer cells with VAL-083 induced DNA damage would progress past the G2 checkpoint leading to premature mitosis and cancer cell death. Herein we assess the activity of VAL-083 as well as in combination with the Wee1 inhibitor AZD1775 in patient-derived model systems of DIPG. DIPG derived cell-lines SF8628 and NEM157 (H3.3K27) were treated with increasing concentrations of single agent VAL-083 and in combination with AZD1775. To determine synergistic activity, we calculated the combination index (CI) using the Chou-Talalay method. In vivo activity of VAL-083 (3 mg/kg) as single agent or in combination with AZD1775 (60 mg/kg) was assessed in an orthotopic engraftment model of DIPG (SF8628). The IC50 of single agent VAL-083 ranged from 1µM to 10µM. The combination of VAL-083 and AZD 1775 exhibited synergistic activity in SF8628 and NEM157 with CI values ranging from 0.4 to 0.95 (CI<1 indicating synergy). In vivo, single-agent VAL-083 and in combination with AZD1775 conferred significant survival benefit compared to both untreated control and single-agent AZD1775. The median survival for mice treated with VAL-083 alone was 54.5 days vs. control (44 days, p=0.0004) and the combination was 62 days vs. control (44 days, p<0.0001) or mice treated with single-agent AZD1775 (47 days, p=0.0839). Our results suggest that VAL-083 in combination with a Wee1 inhibitor such as AZD1775 might offer a promising new therapeutic strategy for children with DIPG. Ongoing studies assessing the in vivo activity in other DIPG models as well as exploring the underlying mechanism-of-action of the combination strategy will be reported.
Evolution of the Oropharynx Cancer Epidemic in the United States: Moderation of Increasing Incidence in Younger Individuals and Shift in the Burden to Older Individuals
Authors: Joseph E. Tota, Ana F. Best, Zachary S. Zumsteg, Maura L. Gillison, Philip S. Rosenberg, Anil K. Chaturvedi
Journal: Journal of Clinical Oncology (2019)

Human papillomavirus-positive oropharynx cancer incidence has increased rapidly in cohorts of US white men born during the 1930s to 1950s. It is unknown how the trajectory of the oropharynx cancer epidemic may be changing in the United States.Using US cancer registry information, we investigated whether increases in oropharynx cancer have continued into recent birth cohorts and forecasted the future burden across age, sex, and race/ethnicity subgroups. Log-linear Joinpoint regression and age-period-cohort models were used to evaluate incidence trends during 1992 to 2015 and projections through 2029.Among white men, oropharynx cancer incidence increased rapidly in individuals born during 1939 to 1955 (5.3% per 2-year birth cohort; 95% CI, 4.8% to 5.7%), but this rate of increase significantly moderated in individuals born during 1955 to 1969 (1.7% per 2-year birth cohort; 95% CI, 1.0% to 2.4%). Should these birth-cohort trends continue, from 2016 to 2029 we forecast that incidence will increase dramatically in older white men 65 to 74 years of age (from 40.7 to 71.2 per 100,000) and 75 to 84 years of age (from 25.7 to 50.1 per 100,000), moderately in white men 55 to 64 years of age (from 40.3 to 52.0 per 100,000), and remain stable in white men 45 to 54 years of age (approximately 18 per 100,000). Accounting for population growth, we project an increase in annual number of cases in the United States from 20,124 (95% CI, 19,779 to 20,469) in 2016 to 30,629 (95% CI, 29,413 to 31,845) in 2029, primarily driven by older individuals (age ≥ 65 years; from 7,976 [95% CI, 7,782 to 8,172] to 18,072 [95% CI, 17,271 to 18,895]) and white men (from 14,453 [95% CI, 14,142 to 14,764] to 22,241 [95% CI, 21,119 to 23,364]).The exponential increase in oropharynx cancer incidence in young white US men has ebbed, and modest increases are occurring/anticipated in cohorts born after 1955. Continued strong increases in incidence in cohorts born before 1955, and an approximate 50% increase in size of the US population age 65 years or older through 2029, portend a substantial shift in burden to elderly white men.
Assessment of Outcomes of Inpatient or Clinic-Based vs Home-Based Rehabilitation After Total Knee Arthroplasty
Authors: Mark A. Buhagiar, Justine M. Naylor, Ian A. Harris, Wei Xuan, Sam Adie, Adriane Lewin
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Recent publication of the largest trials to date investigating rehabilitation after total knee arthroplasty (TKA) necessitate an updated evidence review. <h3>Objective</h3> To determine whether inpatient or clinic-based rehabilitation is associated with superior function and pain outcomes after TKA compared with any home-based program. <h3>Data Sources</h3> MEDLINE, Embase, CINAHL, and PubMed were searched from inception to November 5, 2018. Search terms included<i>knee arthroplasty</i>,<i>randomized controlled trial</i>,<i>physiotherapy</i>, and<i>rehabilitation</i>. <h3>Study Selection</h3> Published randomized clinical trials of adults who underwent primary unilateral TKA and commenced rehabilitation within 6 postoperative weeks in which those receiving postacute inpatient or clinic-based rehabilitation were compared with those receiving a home-based program. <h3>Data Extraction and Synthesis</h3> Two reviewers extracted data independently and assessed data quality and validity according to the PRISMA guidelines. Data were pooled using a random-effects model. Data were analyzed from June 1, 2015, through June 4, 2018. <h3>Main Outcomes and Measures</h3> Primary outcomes were mobility (6-minute walk test [6MWT]) and patient-reported pain and function (Oxford knee score [OKS] or Western Ontario and McMaster Universities Osteoarthritis Index) reported at 10 to 12 postoperative weeks. The GRADE assessment (Grading of Recommendations, Assessment, Development, and Evaluation) was applied to the primary outcomes. <h3>Results</h3> Five unique studies involving 752 unique participants (451 [60%] female; mean [SD] age, 68.3 [8.5] years) compared clinic- and home-based rehabilitation, and 1 study involving 165 participants (112 [68%] female; mean [SD] age, 66.9 [8.0] years) compared inpatient and home-based rehabilitation. Low-quality evidence showed no clinically important difference between clinic- and home-based programs for mobility at 10 weeks (6MWT favoring home program; mean difference [MD], −11.89 m [95% CI, −35.94 to 12.16 m]) and 52 weeks (6MWT favoring home program; MD, −25.37 m [95% CI, −47.41 to −3.32 m]). Moderate-quality evidence showed no clinically important difference between clinic- and home-based programs for patient-reported pain and function at 10 weeks (OKS MD, −0.15 [95% CI, −0.35 to 0.05]) and 52 weeks (OKS MD, 0.10 [95% CI, −0.14 to 0.34]). <h3>Conclusions and Relevance</h3> Based on low- to moderate-quality evidence, no superiority of clinic-based or inpatient programs compared with home-based programs was found in the early subacute period after TKA. This evidence suggests that home-based rehabilitation is an appropriate first line of therapy after uncomplicated TKA for patients with adequate social supports.