tbuckley/cabot-search huggingface dataset:
Determining the prevalence of germline BAP1 mutations in malignant mesothelioma (MM).
Authors: Marjorie Glass Zauderer, Mariel A. DuBoff, Beth Siegel, Mark E. Robson, Angela G. Arnold, Janice Berliner, Megan Harlan Fleischut, Diana Mandelker, Marc Ladanyi
Journal: Journal of Clinical Oncology (2017)

e13118 Background: Somatic BAP1 mutations are very common in MM tumors (Bueno et al. Nat Genet 2016, Bott et al. Nature Genet 2011) and germline BAP1 mutations have also been shown to segregate in numerous families with clusters of malignancies including MM (Testa et al. Nat Genet 2011). However, the prevalence of germline BAP1 alterations in an unselected population of MM patients remains unknown. Methods: Unselected patients with MM were enrolled on a prospective trial (NCT01773655) to collect germline DNA, detailed family history, exposure questionnaires, and tumor tissue if available. De-identified germline DNA sequencing was performed to evaluate for the presence of BAP1 mutations. Patients with prespecified high-risk criteria (age &lt; 50 yrs, no asbestos exposure, personal/family history of choroidal nevus, uveal melanoma, melanoma, or mesothelioma, or cancer in ≥ two 1 st degree relatives) were contacted by Clinical Genetics and offered counseling and identified BAP1 testing. Results: 120 patietns with MM were enrolled. The majority are male (63%) with pleural mesothelioma (78%) and mostly epithelioid histology (75%). Sixty-seven percent met high-risk criteria for identified testing and 27 patients have consented for identified testing. Both deidentified and identified testing is ongoing. To date, among 17 patients tested, 3 have been identified with germline pathogenic BAP1 alterations. Two of those three patients had a personal history of an associated malignancy. Additional testing results will be reported at the meeting. Conclusions: Germline BAP1 mutations may be more common than previously thought among MM patients. Further work is needed to clarify those at high risk for germline mutation so they and their at-risk family members may receive testing and genetic counseling regarding their risk of malignancy. Additionally, ongoing work to define associations between genotype and phenotype should continue so that the full scope of diseases and risks are outlined for this new BAP1 associated cancer predisposition syndrome.
Eribulin mesylate (Erib) plus capecitabine (X) for adjuvant treatment in post-menopausal estrogen receptor–positive (ER+) early-stage breast cancer: Phase II, multicenter, single-arm study.
Authors: John W. Smith, Jessicca Rege, Hina Maniar, James Song, David Cox, Joyce O'Shaughnessy
Journal: Journal of Clinical Oncology (2013)

563 Background: Erib and X have both shown single agent activity in MBC; and X also has activity in ER+ adjuvant tx. This study was designed to evaluate the feasibility of the combination in the adjuvant setting. Methods: Female pts stage I-II, HER2 negative, ER+ BC received Erib at 1.4 mg/m 2 iv D1 and D8 and X at 900 mg/m 2 po bid on days 1-14 of 21 day cycle, for 4 cycles. The study was considered feasible if 80% of pts are able to achieve the target relative dose intensity (RDI) of at least 85% of the regimen and lower 95% confidence boundary (LCI) is above 70%. Results: Final results of 67pts enrolled are reported here. 88% pts completed 4 cycles of tx. Pt characteristics: Median age 62 yrs (range 28-80), ECOG 0(90%), stage 2(52%). 64/67 pts were evaluable for feasibility. The study met its primary endpoint demonstrating feasibility rate of 81%(95% LCI:71%) with average RDI of 91%. Results were mainly affected by X dose adjustments (Erib RDI-93%, X RDI-88%). X related dose reductions(24, (36%)), missed doses (57,(85%)) and discontinuations due to AE (11(16%)) were higher compared to that with Erib(14(21%), 5(8%) and 7(10%)), respectively. Most common AEs with dose reductions were gr 3/4 hand foot syndrome (HFS) (12%), neutropenia(8%), neuropathy(8%), and GI disorders(6%); and drug discontinuation were HFS(8%), neutropenia(3%), neuropathy(2%), and GI disorders(3%). Tx related AEs and SAE are reported in the Table. 14(21%) pts had an SAE with 12(18%) requiring hospitalization. Conclusions: Adjuvant tx with the Erib-X combination can be given safely with the majority of the patients able to achieve full dosing regimen. We plan to explore an alternative schedule of X(7wk on/off) with this regimen to see if it will further improve tolerability and the RDI. Clinical trial information: NCT01439282. [Table: see text]
Role of Gut Inflammation in Altering the Monocyte Compartment and Its Osteoclastogenic Potential in HLA–B27–Transgenic Rats
Authors: Cecilia Ansalone, Lotta Utriainen, Simon Milling, Carl S. Goodyear
Journal: Arthritis & Rheumatology (2017)

Objective To investigate the relationship between intestinal inflammation and the central and peripheral innate immune system in the pathogenesis of HLA–B27–associated spondyloarthritis using an HLA–B27–transgenic (B27‐Tg) rat model. Methods The myeloid compartment of the blood and bone marrow (BM) of B27‐Tg rats, as well as HLA–B7–Tg and non‐Tg rats as controls, was evaluated by flow cytometry. Plasma from rats was assessed by enzyme‐linked immunosorbent assay for levels of CCL2 and interleukin‐1α (IL‐1α). Rats were treated with antibiotics for 4 weeks, and the myeloid compartment of the blood and BM was evaluated by flow cytometry. The osteoclastogenic potential of BM‐derived cells from antibiotic‐treated rats, in the presence or absence of tumor necrosis factor (TNF), was evaluated in vitro. Results B27‐Tg rats had substantially higher numbers of circulating Lin−CD172a+CD43 low monocytes as compared to control animals, and this was significantly correlated with higher levels of plasma CCL2. Antibiotic treatment of B27‐Tg rats markedly reduced the severity of ileitis, plasma levels of CCL2 and IL‐1α, and number of BM and blood Lin−CD172a+CD43 low monocytes, a cell subset shown in the present study to have the greatest in vitro osteoclastogenic potential. Antibiotic treatment also prevented the TNF‐dependent enhancement of osteoclastogenesis in B27‐Tg rats. Conclusion Microbiota‐dependent intestinal inflammation in B27‐Tg rats directly drives the systemic inflammatory and bone‐erosive potential of the monocyte compartment.
Changes in the prevalence of human papillomavirus following a national bivalent human papillomavirus vaccination programme in Scotland: a 7-year cross-sectional study
Authors: Kimberley Kavanagh, Kevin G Pollock, Kate Cuschieri, Tim Palmer, Ross L Cameron, Cameron Watt, Ramya Bhatia, Catherine Moore, Heather Cubie, Margaret Cruickshank, Chris Robertson
Journal: The Lancet Infectious Diseases (2017)
Mutations in the netrin-1 gene cause congenital mirror movements
Authors: Aurélie Méneret, Elizabeth A. Franz, Oriane Trouillard, Thomas C. Oliver, Yvrick Zagar, Stephen P. Robertson, Quentin Welniarz, R.J. MacKinlay Gardner, Cécile Gallea, Myriam Srour, Christel Depienne, Christine L. Jasoni, Caroline Dubacq, Florence Riant, Jean-Charles Lamy, Marie-Pierre Morel, Raphael Guérois, Jessica Andreani, Coralie Fouquet, Mohamed Doulazmi, Marie Vidailhet, Guy A. Rouleau, Alexis Brice, Alain Chédotal, Isabelle Dusart, Emmanuel Roze, David Markie
Journal: Journal of Clinical Investigation (2017)

Netrin-1 is a secreted protein that was first identified 20 years ago as an axon guidance molecule that regulates midline crossing in the CNS. It plays critical roles in various tissues throughout development and is implicated in tumorigenesis and inflammation in adulthood. Despite extensive studies, no inherited human disease has been directly associated with mutations in NTN1, the gene coding for netrin-1. Here, we have identified 3 mutations in exon 7 of NTN1 in 2 unrelated families and 1 sporadic case with isolated congenital mirror movements (CMM), a disorder characterized by involuntary movements of one hand that mirror intentional movements of the opposite hand. Given the diverse roles of netrin-1, the absence of manifestations other than CMM in NTN1 mutation carriers was unexpected. Using multimodal approaches, we discovered that the anatomy of the corticospinal tract (CST) is abnormal in patients with NTN1-mutant CMM. When expressed in HEK293 or stable HeLa cells, the 3 mutated netrin-1 proteins were almost exclusively detected in the intracellular compartment, contrary to WT netrin-1, which is detected in both intracellular and extracellular compartments. Since netrin-1 is a diffusible extracellular cue, the pathophysiology likely involves its loss of function and subsequent disruption of axon guidance, resulting in abnormal decussation of the CST.
Superparamagnetic nanoparticles targeting cancer cells invading the extracellular matrix.
Authors: Samar Elachy, Wegdan Ramadan, Remon Kalsa, Nihad Abou El Azm, Tamer Refaat, Walaa Omar, Yasmine Eissa, Sanaa H Radi, Salah-Eldin Abd-El-Moneim, Tatjana Paunesku, Gayle Woloschak
Journal: Journal of Clinical Oncology (2013)

3083 Background: Metastatic cancer cells secrete matrix metalloproteinases (MMP), which allow cancer cells to burrow their way to the nearby vasculature. Therefore, MMPs are potential targets for anticancer treatment. Nanoparticles (NPs) can be crafted to adhere to the ECM and subsequently be released in response to advance of invasive cells. The objective of the study is to elucidate the interaction of cancer cells in a three-dimensional culture, with functionalized SPIONS targeted to the extracellular matrix around them. Methods: SPIONS, 15-20 nm in size were functionalized using different coatings: ficoll 400, sucrose, lysine-arginine, dextran50,000. Cellular uptake studies using cervical adenocarcinoma HeLa cell lines were performed to determine the optimum formulation taken up by the cells, using electron microscopy and Prussian blue staining for optical microscopy. Two types of extracellular matrices were used: Rat-tail Collagen type I and ECM gel from Engelbreth-Holm-Swarm murine sarcoma with NPs embedded in them. To assess the capability of cells to invade the matrix, cells were grown on the surface of the matrices for 1 week To evaluate the ability to grow, expand and migrate inside the matrix, cells were embedded within the matrix and left for 14 days. Comparison was made in the presence or absence of SPIONS. Results: Sucrose-coated SPIONS were taken up the best by HeLa cell lines as evaluated by MRI. MMP-1 Secretion allowed HeLa cell invasion of collagen type-1 matrix unidirectionally. Cells could adhere, proliferate, differentiate and migrate in the absence of SPIONS. Cells positive for MMP-9 invaded ECM gel from Engelbreth-Hol-Swarm murine sarcoma matrix also only in the absence of SPIONS. Cells that were found engulfing SPIONS showed morphological features of apoptosis as nuclear pyknosis and karryorhexis. Conclusions: Targeting NPs to the ECM surrounding cancer cells that have developed a metastatic potential represents an attractive platform for cancer therapeutics. The findings show a great promise for development of new theranostic agents, that can be directed to the tumor environment using external magnetic fields, with subsequent suppression of invasion and even destroying malignant cells.
The Treatment of Actinic Keratoses—The Rule Rather Than the Exception—Reply
Authors: Joslyn S. Kirby
Journal: JAMA Dermatology (2017)

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
Role of clove oil in solvent exchange-induced doxycycline hyclate-loaded Eudragit RS in situ forming gel
Authors: Thawatchai Phaechamud, Sai Myo Thurein, Takron Chantadee
Journal: Asian Journal of Pharmaceutical Sciences (2017)

Solvent exchange induced in situ forming gel (ISG) is the promising drug delivery system for periodontitis treatment owing to the prospect of maintaining an effective high drug level in the gingival crevicular fluid. In the present study, the influence of clove oil (CO) on the characteristics of doxycycline hyclate (DH)-loaded ISG comprising Eudragit RS (ERS) was investigated including viscosity/rheology, syringeability, in vitro gel formation/drug release, matrix formation/solvent diffusion and antimicrobial activities. CO could dissolve ERS and increase the viscosity of ISG and its hydrophobicity could also retard the diffusion of solvent and hinder the drug diffusion; thus, the minimization of burst effect and sustained drug release were achieved effectively. All the prepared ISGs comprising CO could expel through the 27-gauge needle for administration by injection and transform into matrix depot after exposure to the simulated gingival crevicular fluid. The antimicrobial activities against Staphylococcus aureus, Escherichia coli, Streptococcus mutans and Porphyromonas gingivalis were increased when the ratio of CO and N-methyl pyrrolidone (NMP) was decreased from 1:1 to 1:10 owing to higher diffusion of DH except that for C. albicans was increased as CO amount was higher. Therefore, CO could minimize the burst while prolonging the drug release of DH-loaded ERS ISG for use as a local drug delivery system for periodontitis treatment.
The Immune-microenvironment Confers Chemoresistance of Colorectal Cancer through Macrophage-Derived IL6
Authors: Yuan Yin, Surui Yao, Yaling Hu, Yuyang Feng, Min Li, Zehua Bian, Jiwei Zhang, Yan Qin, Xiaowei Qi, Leyuan Zhou, Bojian Fei, Jian Zou, Dong Hua, Zhaohui Huang
Journal: Clinical Cancer Research (2017)

Purpose: Tumor-associated macrophages (TAMs) are frequently associated with poor prognosis in human cancers. However, the effects of TAMs in colorectal cancer are contradictory. We therefore investigated the functions, mechanisms, and clinical significance of TAMs in colorectal cancer.Experimental Design: We measured the macrophage infiltration (CD68), P-gp, and Bcl2 expression in colorectal cancer tissues using IHC staining. Coculture of TAMs and colorectal cancer cells both in vitro and in vivo models was used to evaluate the effects of TAMs on colorectal cancer chemoresistance. Cytokine antibody arrays, ELISA, neutralizing antibody, and luciferase reporter assay were performed to uncover the underlying mechanism.Results: TAM infiltration was associated with chemoresistance in patients with colorectal cancer. Colorectal cancer-conditioned macrophages increased colorectal cancer chemoresistance and reduced drug-induced apoptosis by secreting IL6, which could be blocked by a neutralizing anti-IL6 antibody. Macrophage-derived IL6 activated the IL6R/STAT3 pathway in colorectal cancer cells, and activated STAT3 transcriptionally inhibited the tumor suppressor miR-204-5p. Rescue experiment confirmed that miR-204-5p is a functional target mediating the TAM-induced colorectal cancer chemoresistance. miR-155-5p, a key miRNA regulating C/EBPβ, was frequently downregulated in TAMs, resulting in increased C/EBPβ expression. C/EBPβ transcriptionally activated IL6 in TAMs, and TAM-secreted IL6 then induced chemoresistance by activating the IL6R/STAT3/miR-204-5p pathway in colorectal cancer cells.Conclusions: Our data indicate that the maladjusted miR-155-5p/C/EBPβ/IL6 signaling in TAMs could induce chemoresistance in colorectal cancer cells by regulating the IL6R/STAT3/miR-204-5p axis, revealing a new cross-talk between immune cells and tumor cells in colorectal cancer microenvironment. Clin Cancer Res; 23(23); 7375-87. ©2017 AACR.
Adjuvant Chemotherapy vs Postoperative Observation Following Preoperative Chemoradiotherapy and Resection in Gastroesophageal Cancer
Authors: Ali A. Mokdad, Adam C. Yopp, Patricio M. Polanco, John C. Mansour, Scott I. Reznik, Daniel F. Heitjan, Michael A. Choti, Rebecca R. Minter, Sam C. Wang, Matthew R. Porembka
Journal: JAMA Oncology (2017)

<h3>Importance</h3> Distant recurrence following preoperative chemoradiotherapy and resection in patients with gastroesophageal adenocarcinoma is common. Adjuvant chemotherapy may improve survival. <h3>Objective</h3> To compare adjuvant chemotherapy with postoperative observation following preoperative chemoradiotherapy and resection in patients with gastroesophageal adenocarcinoma. <h3>Design, Setting, and Participants</h3> Propensity score–matched analysis using the National Cancer Database. We included adult patients who received a diagnosis between 2006 and 2013 of clinical stage T1N1-3M0 or T2-4N0-3M0 adenocarcinoma of the distal esophagus or gastric cardia who were treated with preoperative chemoradiotherapy and curative-intent resection. Patients receiving adjuvant chemotherapy were matched by propensity score to patients undergoing postoperative observation. <h3>Exposures</h3> Adjuvant chemotherapy and postoperative observation. <h3>Main Outcomes and Measures</h3> Overall survival. <h3>Results</h3> We identified 10 086 patients (8840 [88%] male; mean [SD] age, 61 [9.5] years), 9272 in the postoperative observation group and 814 in the adjuvant chemotherapy group. Patients receiving adjuvant chemotherapy were younger (18-54 years: 252 [31%] vs 1989 [21%];<i>P</i> &lt; .001) and were more likely to have advanced disease (ypT3/4: 458 [62%] vs 3531 [46%];<i>P</i> &lt; .001; ypN+: 572 [72%] vs 3428 [39%];<i>P</i> &lt; .001), as well as shorter postoperative inpatient stays (&gt;2 weeks: 94 [13%] vs 1589 [20%];<i>P</i> &lt; .001). A total of 732 patients in the adjuvant chemotherapy group were matched by propensity score to 3660 patients in the postoperative observation group. Adjuvant chemotherapy was associated with improved overall survival compared with postoperative observation (median survival: 40 months; 95% CI, 36-46 months vs 34 months; 95% CI, 32-35 months; stratified log-rank<i>P</i> &lt; .001; hazard ratio, 0.79; 95% CI, 0.72-0.88). Overall survival at 1, 3, and 5 years was 88%, 47%, and 34% in the observation group, and 94%, 54%, and 38% in the adjuvant chemotherapy group, respectively. Adjuvant chemotherapy was associated with a survival benefit compared with postoperative observation in most patient subgroups. <h3>Conclusions and Relevance</h3> For patients with locally advanced gastroesophageal adenocarcinoma treated with preoperative chemoradiotherapy and resection, adjuvant chemotherapy was associated with improved overall survival. Our findings have important implications for the postoperative treatment of this patient group for which few data are available.
Hydropersulfides, the new kids in the COPD inflammatory town
Authors: Luis Puente-Maestu, Walther Ivan Girón-Matute
Journal: Thorax (2017)

Hydrogen sulfide (H2S) is one of several small molecules, formerly known primarily as toxic gases (such as nitric oxide (NO) and carbon monoxide) that over the past 20 years have been shown to be endogenously generated small, signalling molecules.1 2 H2S has accompanied life since its origin. Its toxicological potential, related to the inhibition of cellular respiration, has been known for centuries.3 Indeed, the Permian-Triassic mass extinction event has been linked to this toxicity. H2S has been the cause of mining, industrial and sewage accidents, as well as deaths by the inhalation of gases emanating from volcanic and sulfur-rich water wells.

In spite of this felonious record, as it happens with other primeval redox processes, ancient H2S pathways have evolved to play physiological roles in eukaryotic cells.

The rush of discovery for H2S and its derivative compounds started in the late 1980s by reports of potential biological roles of H2S in modulatory and signalling pathways.4 The associated probable health benefits generated a renewed interest in the study of H2S, as reflected in the exponential increase in the number of publications.4 

H2S is produced from L-cysteine by an array of enzymes such as cystathionine β-synthase (CBS), cystathionine γ-lyase (CGL), 3-mercaptopyruvate sulfurtransferase (3MST), cysteine aminotransferase and from …
Theranostic trial of well differentiated neuroendocrine tumors (NETs) with somatostatin antagonists <sup>68</sup>Ga-OPS202 and <sup>177</sup>Lu-OPS201.
Authors: Diane Lauren Reidy, Neeta Pandit-Taskar, Simone Krebs, Joseph A. O' Donoghue, Nitya Prabhakar Raj, Elizabeth Cruz, Hanh Pham, Alicia Lashley, Lisa Bodei, Wolfgang Weber
Journal: Journal of Clinical Oncology (2017)

4094 Background: Radiolabeled somatostatin receptor 2 (sstr2) antagonists have shown higher tumor uptake and tumor-to-organ ratios than agonists in preclinical models. We performed a phase I study to evaluate the safety and radiation dosimetry of the sstr2 antagonists 68 Ga-OPS202 and 177 Lu-OPS201 ( 68 Ga/ 177 Lu-DOTA-JR11) in patients (pts) with metastatic well differentiated NETs (NCT02609737). Efficacy data after 177 Lu-OPS201were recorded. Methods: Pts with RECIST disease progression underwent a 68 Ga-OPS202 PET/CT to confirm in-vivo binding of the sstr2 antagonists and if positive, underwent treatment with 3 doses of 177 Lu-OPS201. The first dose of 50 mCi 177 Lu-OPS201was used to calculate tumor and normal organ radiation doses. Dosimetry was then calculated to administer 177 Lu-OPS201in divided doses for the 2 nd and 3 rd fractions, 8-10 weeks apart. Results: 19 pts enrolled (primary tumors: 1 lung, 7 small bowel, 8 pancreatic NETs, 1 gastric NET, 1 rectal NET, 1 kidney). Average age was 55 y (22-73 y), 52% female; mean number of prior treatments was 3. All pts received 1 therapeutic dose of 177 Lu-OPS201, 7 pts received 2 doses. All tumors were visualized by 68 Ga-OPS202 PET/CT. With the exception of the kidneys and bladder, no organ demonstrated uptake of 68 Ga-OPS202 above background. Tumor radiation doses ranged from 0.15 Gy/mCi to 0.48 Gy/mCi. Subacute hematologic toxicity after cycle 1 was mild-moderate (G3 2/19 leukopenia that reversed before cycle 2). 4/7 (57%) pts that received the second dose of 177 Lu-OPS201had G4 hematological toxicities, which occurred 4-6 weeks after administration. G 3/4 toxicities in the four pts have resolved to G2 or lower; none of these pts demonstrated fever, infection, bleeding, or renal toxicity. Substantial efficacy was observed: 1 patient achieved a CR (1/19, 5%), 32% PR (6/19), 47% SD (9/19) and 16% POD (3/19). Median PFS has not yet been reached. Conclusions: In this trial of heavily treated NETs, preliminary data are promising for the use of 68 Ga-OPS202/ 177 Lu-OPS201 as a theranostic combination for imaging and therapy. Additional studies are planned to determine an optimal therapeutic dose and schedule. Clinical trial information: NCT02609737.
Erratum: Evaluation of the Usefulness of Recording ECG in the 3rd Intercostal Space and Prevalence of Brugada-Type ECG in Accordance with Recently Established Electrocardiographic Criteria (Circulation Journal (2004) 68, 2 (135-138))
Authors: Kenichi Hisamatsu, Hiroshi Morita, Kengo Fukushima Kusano, Shiho Takenaka, Satoshi Nagase, Kazufumi Nakamura, Tetsuro Emori, Tohru Ohe
Journal: Circulation (2004)