tbuckley/cabot-search huggingface dataset:
Targeting tumour microenvironment by tyrosine kinase inhibitor
Authors: Hor-Yue Tan, Ning Wang, Wing Lam, Wei Guo, Yibin Feng, Yung-Chi Cheng
Journal: Molecular Cancer (2018)

Tumour microenvironment (TME) is a key determinant of tumour growth and metastasis. TME could be very different for each type and location of tumour and TME may change constantly during tumour growth. Multiple counterparts in surrounding microenvironment including mesenchymal-, hematopoietic-originated cells as well as non-cellular components affect TME. Thus, therapeutics that can disrupt the tumour-favouring microenvironment should be further explored for cancer therapy. Previous efforts in unravelling the dysregulated mechanisms of TME components has identified numerous protein tyrosine kinases, while its corresponding inhibitors have demonstrated potent modulatory effect on TME. Recent works have demonstrated that beyond the direct action on cancer cells, tyrosine kinase inhibitors (TKIs) have been implicated in inactivation or normalization of dysregulated TME components leading to cancer regression. Either through re-sensitizing the tumour cells or reversing the immunological tolerance microenvironment, the emergence of these TME modulatory mechanism of TKIs supports the combinatory use of TKIs with current chemotherapy or immunotherapy for cancer therapy. Therefore, an appropriate understanding on TME modulation by TKIs may offer another mode of action of TKIs for cancer treatment. This review highlights mode of kinase activation or paracrine ligand production from TME components and summarises the findings on the potential use of various TKIs on regulating TME components. At last, the combination use of current TKIs with immunotherapy in the perspectives of efficacy and safety are discussed.
Prognostic impact of elevated serum uric acid levels on long-term outcomes in patients with chronic heart failure: A post-hoc analysis of the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) trial
Authors: Alessandro Mantovani, Giovanni Targher, Pier Luigi Temporelli, Donata Lucci, Lucio Gonzini, Gian Luigi Nicolosi, Roberto Marchioli, Gianni Tognoni, Roberto Latini, Franco Cosmi, Luigi Tavazzi, Aldo Pietro Maggioni
Journal: Metabolism (2018)
RISK FACTORS FOR INCOMPLETE ENDOSCOPIC MUCOSAL RESECTION OF LARGE COLORECTAL POLYPS: PARIS IS-II
Authors: M Alburquerque Miranda, A Vargas García, I Sánchez Pérez, A Smarrelli, C Ledezma Frontado, L Vidal Plana, M Figa Francesc, F González-Huix Lladó
Journal: Endoscopy (2018)

To determine risk factors for incomplete endoscopic mucosal resection (EMRi) of colorectal sessile (Is) and/or flat (II) polyps ≥20 mm, according to the polyp features and EMR.
Vaccination Strategies During Shortages of Yellow Fever Vaccine
Authors: Scott A. Norton, David M. Morens
Journal: JAMA (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 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
Highly efficacious and specific anti-glioma chemotherapy by tandem nanomicelles co-functionalized with brain tumor-targeting and cell-penetrating peptides
Authors: Yaqin Zhu, Yu Jiang, Fenghua Meng, Chao Deng, Ru Cheng, Jian Zhang, Jan Feijen, Zhiyuan Zhong
Journal: Journal of Controlled Release (2018)
Skin inflammation and carcinogenesis enhanced in Tpl2 knockout mouse model
Authors: John Simmons, Jyotsna Pandey, Zhihong Shan, Jonathan Wiest
Journal: Cancer Research (2007)

4672  Tpl2 is a serine/threonine protein kinase implicated in the regulation of cellular proliferation, differentiation, and immune response involving chemokine-cytokine production. Tpl2 knockout mice do not display an overt phenotype and have histologically normal bone marrow, thymus, spleen, and lymph nodes. In the mouse skin carcinogenesis model, short-term (one time) application of phorbol esters (TPA) to mouse skin results in an acute inflammatory response and epidermal hyperplasia. Repeated long-term application of TPA (after initiation with DMBA) leads to tumor formation in susceptible mice. We hypothesized that loss of Tpl2 will lead to a dampened inflammatory response and loss of tumorigenic response to TPA. Tpl2 knockout mouse skins were treated with TPA over 4 to 48 hours to assess the short-term role of Tpl2 in skin inflammatory response and hyperplasia. Long-term treatment with TPA for 30 weeks, after initiation with DMBA, was performed to assess the tumorigenic potential versus wildtype controls. Unexpectedly, the inflammatory response of the knockout mice to TPA application was stronger, appeared earlier, and lasted longer than the wild type mice. This was characterized by infiltrating neutrophils, macrophages, mast cells, and occasional lymphocytes. The enhanced inflammatory response was due to differential expression of cytokines including IL-2, IL-1beta, KC, MIP-1alpha, IL-5 and G-CSF. Long-term carcinogenesis experiments reveled unexpected skin tumor development in the knockout mice after only 9 weeks of TPA application. By 30 weeks, 87% of the knockout animals had a mean of 4 tumors/animal as compared to only 17% of wild type mice with a mean of 1.25 tumors/animal. These results indicate that loss of Tpl2 has led to potentiation of a compensatory pathway. This study validates in-vitro data and indicates that potentiation of the Ras/Erk pathway may be responsible for this unchecked early inflammatory response and enhanced skin carcinogenesis in response to TPA treatment.
Randomized Phase II Trial of Carboplatin-Paclitaxel Versus Carboplatin-Paclitaxel-Trastuzumab in Uterine Serous Carcinomas That Overexpress Human Epidermal Growth Factor Receptor 2/neu
Authors: Amanda N. Fader, Dana M. Roque, Eric Siegel, Natalia Buza, Pei Hui, Osama Abdelghany, Setsuko K. Chambers, Angeles Alvarez Secord, Laura Havrilesky, David M. O’Malley, Floor Backes, Nicole Nevadunsky, Babak Edraki, Dirk Pikaart, William Lowery, Karim S. ElSahwi, Paul Celano, Stefania Bellone, Masoud Azodi, Babak Litkouhi, Elena Ratner, Dan-Arin Silasi, Peter E. Schwartz, Alessandro D. Santin
Journal: Journal of Clinical Oncology (2018)

Purpose Uterine serous carcinoma is a rare, aggressive variant of endometrial cancer. Trastuzumab is a humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2)/neu, a receptor overexpressed in 30% of uterine serous carcinoma. This multicenter, randomized phase II trial compared carboplatin-paclitaxel with and without trastuzumab in patients with advanced or recurrent uterine serous carcinoma who overexpress HER2/neu. Methods Eligible patients had primary stage III or IV or recurrent HER2/neu-positive disease. Participants were randomly assigned to receive carboplatin-paclitaxel (control arm) for six cycles with or without intravenous trastuzumab (experimental arm) until progression or unacceptable toxicity. The primary end point was progression-free survival, which was assessed for differences between treatment arms via one-sided log-rank tests. Results From August 2011 to March 2017, 61 patients were randomly assigned. Forty progression-free survival–related events occurred among 58 evaluable participants. Among all patients, median progression-free survival was 8.0 months (control) versus 12.6 months (experimental; P = .005; hazard ratio [HR], 0.44; 90% CI, 0.26 to 0.76). Similarly, median progression-free survival was 9.3 (control) versus 17.9 (experimental) months among 41 patients with stage III or IV disease undergoing primary treatment ( P = .013; HR, 0.40; 90% CI, 0.20 to 0.80) and 6.0 (control) versus 9.2 months (experimental), respectively, among 17 patients with recurrent disease ( P = .003; HR, 0.14; 90% CI, 0.04 to 0.53). Toxicity was not different between treatment arms, and no unexpected safety signals emerged. Conclusion Addition of trastuzumab to carboplatin-paclitaxel was well tolerated and increased progression-free survival. These encouraging results deserve further investigation to determine their impact on overall survival in patients with advanced or recurrent uterine serous carcinoma who overexpress HER2/neu.
ENDOSCOPIC TREATMENT OF BENIGN ESOPHAGO-BRONCHIL FISTULAS. RESULTS OF A RETROSPECTIVE STUDY IN A LARGE VOLUME CENTER
Authors: JM Gonzalez, A Debourdeau, A Benezech, M Barthet
Journal: Endoscopy (2018)

Nonmalignant esophago-respiratory fistulas (ERF) are a rare but frightening clinical situations, usually involving morbid surgery. The aim was to describe and assess the endoscopic management of benign ERF.
Prise en charge en 1 temps endoscopique (diagnostique et thérapeutique) des patients ayant une tumeur de la tête du pancréas avec ictère compressif
Authors: D Karsenti, C Locher, S Doumet, P Cabanis, I Rosa Hezode, C Mariette, P Cattan, N Molinier, P Lepicard
Journal: Endoscopy (2009)

But: La prise en charge des patients présentant une suspicion de cancer de la tête du pancréas avec compression biliaire impose souvent la réalisation de plusieurs examens endoscopiques: évaluation de la résécabilité chirurgicale par échoendoscopie (EE), ponction sous échoendoscopie et drainage biliaire. L'organisation de ces différentes étapes entraîne un délai conséquent avant l'initiation d'un traitement chirurgical ou médical. Le but de cette étude était d'évaluer la faisabilité et la morbidité d'une exploration diagnostique et thérapeutique en 1 temps associant EE diagnostique, EE ponction et CPRE.
NSAID use and somatic exomic mutations in Barrett’s esophagus
Authors: Patricia C. Galipeau, Kenji M. Oman, Thomas G. Paulson, Carissa A. Sanchez, Qing Zhang, Jerry A. Marty, Jeffrey J. Delrow, Mary K. Kuhner, Thomas L. Vaughan, Brian J. Reid, Xiaohong Li
Journal: Genome Medicine (2018)

Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to protect against tetraploidy, aneuploidy, and chromosomal alterations in the metaplastic condition Barrett's esophagus (BE) and to lower the incidence and mortality of esophageal adenocarcinoma (EA). The esophagus is exposed to both intrinsic and extrinsic mutagens resulting from gastric reflux, chronic inflammation, and exposure to environmental carcinogens such as those found in cigarettes. Here we test the hypothesis that NSAID use inhibits accumulation of point mutations/indels during somatic genomic evolution in BE. Whole exome sequences were generated from 82 purified epithelial biopsies and paired blood samples from a cross-sectional study of 41 NSAID users and 41 non-users matched by sex, age, smoking, and continuous time using or not using NSAIDs. NSAID use reduced overall frequency of point mutations across the spectrum of mutation types, lowered the frequency of mutations even when adjusted for both TP53 mutation and smoking status, and decreased the prevalence of clones with high variant allele frequency. Never smokers who consistently used NSAIDs had fewer point mutations in signature 17, which is commonly found in EA. NSAID users had, on average, a 50% reduction in functional gene mutations in nine cancer-associated pathways and also had less diversity in pathway mutational burden compared to non-users. These results indicate NSAID use functions to limit overall mutations on which selection can act and supports a model in which specific mutant cell populations survive or expand better in the absence of NSAIDs.
Quel est la prévalence des adénomes transformés parmi les adénomes sessiles festonnés coliques? Résultats d'une étude mono-centrique prospective
Authors: S Folgado Alberto, U Chaput, V Viallon, F Beuvon, B Terris, R Coriat, M Bensoussan, H Roche, M Gaudric, F Prat, S Chaussade
Journal: Endoscopy (2009)

Introduction: Les adénomes sessiles festonnés colorectaux forment un groupe hétérogène de lésions. Le risque de survenue d'une dysplasie de haut grade est mal connu. L'objectif de ce travail était de rechercher la prévalence des adénomes transformés (dysplasie de haut grade, carcinome in situ ou intra muqueux) parmi les adénomes sessiles festonnés et de les comparer aux autres types histologiques d'adénomes.
The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC)
Authors: Brandon Golding, Anita Luu, Robert Jones, Alicia M. Viloria-Petit
Journal: Molecular Cancer (2018)

Lung cancer is the leading cause of death by cancer in North America. A decade ago, genomic rearrangements in the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase were identified in a subset of non-small cell lung carcinoma (NSCLC) patients. Soon after, crizotinib, a small molecule ATP-competitive ALK inhibitor was proven to be more effective than chemotherapy in ALK-positive NSCLC patients. Crizotinib and two other ATP-competitive ALK inhibitors, ceritinib and alectinib, are approved for use as a first-line therapy in these patients, where ALK rearrangement is currently diagnosed by immunohistochemistry and in situ hybridization. The clinical success of these three ALK inhibitors has led to the development of next-generation ALK inhibitors with even greater potency and selectivity. However, patients inevitably develop resistance to ALK inhibitors leading to tumor relapse that commonly manifests in the form of brain metastasis. Several new approaches aim to overcome the various mechanisms of resistance that develop in ALK-positive NSCLC including the knowledge-based alternate and successive use of different ALK inhibitors, as well as combined therapies targeting ALK plus alternative signaling pathways. Key issues to resolve for the optimal implementation of established and emerging treatment modalities for ALK-rearranged NSCLC therapy include the high cost of the targeted inhibitors and the potential of exacerbated toxicities with combination therapies.
Dual neutralization of both interleukin 17A and interleukin 17F with bimekizumab in patients with psoriasis: Results from BE ABLE 1, a 12-week randomized, double-blinded, placebo-controlled phase 2b trial
Authors: Kim A. Papp, Joseph F. Merola, Alice B. Gottlieb, Christopher E.M. Griffiths, Nancy Cross, Luke Peterson, Christopher Cioffi, Andrew Blauvelt
Journal: Journal of the American Academy of Dermatology (2018)

Neutralizing interleukin (IL) 17F in addition to IL-17A might provide a more complete and specific approach to inhibiting inflammation.Assess the efficacy and safety of bimekizumab, a monoclonal antibody that potently and selectively neutralizes IL-17A and IL-17F, in patients with moderate-to-severe plaque psoriasis.Double-blinded, placebo-controlled phase 2b study (NCT02905006). Patients (randomized 1:1:1:1:1:1) received subcutaneous bimekizumab every 4 weeks at doses of 64 mg, 160 mg, 160 mg with 320 mg loading dose, 320 mg, 480 mg, or placebo. Primary endpoint was ≥90% reduction in Psoriasis Area Severity Index (PASI90) at week 12.There was a significant (P < .0001) dose-dependent response for PASI90 (week 12); more patients achieved PASI90 in the bimekizumab groups (46.2%-79.1%) than patients in the placebo group (0%; P < .0001 all doses). Across all doses, there were significant improvements from baseline for all secondary endpoints (PASI90 week 8, PASI75 week 12, PASI100 week 12, and Investigators Global Assessment clear or almost clear weeks 8 and 12; P ≤ .0003) compared with placebo. More bimekizumab-treated patients than placebo-treated patients achieved PASI100 (week 12) (27.9%-60.0% vs 0%; P ≤ .0002 all doses). Treatment-emergent adverse events were reported by 126 of 208 (61%) bimekizumab-treated patients and 15 of 42 (36%) placebo-treated patients.No active comparator.Dual neutralization of IL-17A and IL-17F with bimekizumab provided rapid and substantial clinical improvements in patients with psoriasis, with no unexpected or dose-related safety findings.
COMBINATION OF ERCP AND EUS-GUIDED BILIARY DRAINAGE IN HIGH-GRADE MALIGNANT HILAR BILIARY OBSTRUCTION (THE CERES STUDY): A MULTICENTER RETROSPECTIVE STUDY
Authors: R Romano, P Kongkam, C Boonmee, P Sodarat, O Seabmuangsai, S Jangsirikul, T Thongbai, W Ridtitid, P Angsuwatcharakon, R Rerknimitr
Journal: Endoscopy (2018)

To study the clinical efficacy of EUS-BD with or without ERCP in high-grade malignant hilar biliary obstruction (HG-MHBO).
Nanoparticles with high payloads of pipemidic acid, a poorly soluble crystalline drug: drug-initiated polymerization and self-assembly approach
Authors: Elisabetta Pancani, Mario Menendez-Miranda, Alexandra Pastor, François Brisset, Marie-Françoise Bernet-Camard, Didier Desmaële, Ruxandra Gref
Journal: Acta Pharmaceutica Sinica B (2018)

Nowadays, biodegradable polymers such as poly(lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA) and poly(ε-caprolactone) (PCL) remain the most common biomaterials to produce drug-loaded nanoparticles (NPs). Pipemidic acid (PIP) is a poorly soluble antibiotic with a strong tendency to crystallize. PIP incorporation in PLA/PLGA NPs was challenging because of PIP crystals formation and burst release. As PIP had a poor affinity for the NPs, an alternative approach to encapsulation was used, consisting in coupling PIP to PCL. Thus, a PCL–PIP conjugate was successfully synthesized by an original drug-initiated polymerization in a single step without the need of catalyst. PCL–PIP was characterized by NMR, IR, SEC and mass spectrometry. PCL–PIP was used to prepare self-assembled NPs with PIP contents as high as 27% (w/w). The NPs were characterized by microscopy, DLS, NTA and TRPS. This study paves the way towards the production of NPs with high antibiotic payloads by drug-initiated polymerization. Further studies will deal with the synthesis of novel polymer–PIP conjugates with ester bonds between the drug and PCL. PIP can be considered as a model drug and the strategy developed here could be extended to other challenging antibiotics or anticancer drugs and employed to efficiently incorporate them in NPs.
<i>SMAD4</i> Gene Mutation Renders Pancreatic Cancer Resistance to Radiotherapy through Promotion of Autophagy
Authors: Feng Wang, Xiaojun Xia, Chunying Yang, Jianliang Shen, Junhua Mai, Han-Cheon Kim, Dickson Kirui, Ya'an Kang, Jason B. Fleming, Eugene J. Koay, Sankar Mitra, Mauro Ferrari, Haifa Shen
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Understanding the mechanism of radioresistance could help develop strategies to improve therapeutic response of patients with PDAC. The SMAD4 gene is frequently mutated in pancreatic cancer. In this study, we investigated the role of SMAD4 deficiency in pancreatic cancer cells' response to radiotherapy. Experimental Design: We downregulated SMAD4 expression with SMAD4 siRNA or SMAD4 shRNA and overexpressed SMAD4 in SMAD4 mutant pancreatic cancer cells followed by clonogenic survival assay to evaluate their effects on cell radioresistance. To study the mechanism of radioresistance, the effects of SMAD4 loss on reactive oxygen species (ROS) and autophagy were determined by flow cytometry and immunoblot analysis, respectively. Furthermore, we measured radioresistance by clonogenic survival assay after treatment with autophagy inhibitor (Chloroquine) and ROS inhibitor (N-acetyl-l-cysteine) in SMAD4-depleted pancreatic cancer cells. Finally, the effects of SMAD4 on radioresistance were also confirmed in an orthotopic tumor model derived from SMAD4-depleted Panc-1 cells. Results: SMAD4-depleted pancreatic cancer cells were more resistant to radiotherapy based on clonogenic survival assay. Overexpression of wild-type SMAD4 in SMAD4-mutant cells rescued their radiosensitivity. Radioresistance mediated by SMAD4 depletion was associated with persistently higher levels of ROS and radiation-induced autophagy. Finally, SMAD4 depletion induced in vivo radioresistance in Panc-1-derived orthotopic tumor model (P = 0.038). More interestingly, we observed that the protein level of SMAD4 is inversely correlated with autophagy in orthotopic tumor tissue samples. Conclusions: Our results demonstrate that defective SMAD4 is responsible for radioresistance in pancreatic cancer through induction of ROS and increased level of radiation-induced autophagy. Clin Cancer Res; 24(13); 3176–85. ©2018 AACR.
Association of HLA-A*31:01 Screening With the Incidence of Carbamazepine-Induced Cutaneous Adverse Reactions in a Japanese Population
Authors: Taisei Mushiroda, Yukitoshi Takahashi, Teiichi Onuma, Yoshiaki Yamamoto, Tetsumasa Kamei, Tohru Hoshida, Katsuya Takeuchi, Kotaro Otsuka, Mitsutoshi Okazaki, Masako Watanabe, Kosuke Kanemoto, Tomohiro Oshima, Atsushi Watanabe, Shiro Minami, Kayoko Saito, Hisashi Tanii, Yasushi Shimo, Minoru Hara, Shinji Saitoh, Toshihiko Kinoshita, Masaki Kato, Naoto Yamada, Naoki Akamatsu, Toshihiko Fukuchi, Shigenobu Ishida, Shingo Yasumoto, Atsushi Takahashi, Takeshi Ozeki, Takahisa Furuta, Yoshiro Saito, Nobuyuki Izumida, Yoko Kano, Tetsuo Shiohara, Michiaki Kubo
Journal: JAMA Neurology (2018)

Carbamazepine, a commonly used antiepileptic drug, is one of the most common causes of cutaneous adverse drug reactions (cADRs) worldwide. The allele HLA-A*31:01 is reportedly associated with carbamazepine-induced cADRs in Japanese and European populations; however, the clinical utility of HLA-A*31:01 has not been evaluated.To assess the use of HLA-A*31:01 genetic screening to identify Japanese individuals at risk of carbamazepine-induced cADRs.This cohort study was conducted across 36 hospitals in Japan from January 2012 to November 2014 among 1202 patients who had been deemed suitable to start treatment with carbamazepine. Preemptive HLA-A*31:01 genetic screening was performed for 1187 participants. Patients who did not start treatment with carbamazepine or alternative drugs were excluded. Participants were interviewed once weekly for 8 weeks to monitor the development of cADRs. Data analysis was performed from June 8, 2015, to December 27, 2016.Neuropsychiatrists were asked to prescribe carbamazepine for patients who tested negative for HLA-A*31:01 and alternative drugs for those who tested positive for HLA-A*31:01.Incidence of carbamazepine-induced cADRs.Of the 1130 included patients who were prescribed carbamazepine or alternative drugs, the mean (range) age was 37.4 (0-95) years, 614 (54.3%) were men, and 198 (17.5%) were positive for HLA-A*31:01. Expert dermatologists identified 23 patients (2.0%) who had carbamazepine-induced cADRs, of which 4 patients required hospitalization. Drug-induced hypersensitivity syndrome was observed for 3 patients, maculopapular eruption for 9 patients, erythema multiforme for 5 patients, and an undetermined type of cADR for 6 patients. No patient developed Stevens-Johnson syndrome or toxic epidermal necrolysis. Compared with historical controls, the incidence of carbamazepine-induced cADRs was significantly decreased (for BioBank Japan data: incidence, 3.4%; odds ratio, 0.60; 95% CI, 0.36-1.00; P = .048; for the Japan Medical Data Centre claims database: incidence, 5.1%; odds ratio, 0.39; 95% CI, 0.26-0.59; P < .001).Preemptive HLA-A*31:01 genetic screening significantly decreased the incidence of carbamazepine-induced cADRs among Japanese patients, which suggests that it may be warranted in routine clinical practice.