tbuckley/cabot-search huggingface dataset:
Using Engineered Bacteria to Characterize Infection Dynamics and Antibiotic Effects In Vivo
Authors: Laura K. Certain, Jeffrey C. Way, Matthew J. Pezone, James J. Collins
Journal: Cell Host & Microbe (2017)

Synthetic biology has focused on engineering microbes to synthesize useful products or to serve as living diagnostics and therapeutics. Here we utilize a host-derived Escherichia coli strain engineered with a genetic toggle switch as a research tool to examine in vivo replicative states in a mouse model of chronic infection, and to compare in vivo and in vitro bacterial behavior. In contrast to the effect of antibiotics in vitro, we find that the fraction of actively dividing bacteria remains relatively high throughout the course of a chronic infection in vivo and increases in response to antibiotics. Moreover, the presence of non-dividing bacteria in vivo does not necessarily lead to an antibiotic-tolerant infection, in contrast to expectations from in vitro experiments. These results demonstrate the utility of engineered bacteria for querying pathogen behavior in vivo, and the importance of validating in vitro studies of antibiotic effects with in vivo models.
Cell-specific mechanisms of TMEM16A Ca2+-activated chloride channel in cancer
Authors: Hui Wang, Liang Zou, Ke Ma, Jiankun Yu, Huizhe Wu, Minjie Wei, Qinghuan Xiao
Journal: Molecular Cancer (2017)

TMEM16A (known as anoctamin 1) Ca2+-activated chloride channel is overexpressed in many tumors. TMEM16A overexpression can be caused by gene amplification in many tumors harboring 11q13 amplification. TMEM16A expression is also controlled in many cancer cells via transcriptional regulation, epigenetic regulation and microRNAs. In addition, TMEM16A activates different signaling pathways in different cancers, e.g. the EGFR and CAMKII signaling in breast cancer, the p38 and ERK1/2 signaling in hepatoma, the Ras-Raf-MEK-ERK1/2 signaling in head and neck squamous cell carcinoma and bladder cancer, and the NFκB signaling in glioma. Furthermore, TMEM16A overexpression has been reported to promote, inhibit, or produce no effects on cell proliferation and migration in different cancer cells. Since TMEM16A exerts different roles in different cancer cells via activation of distinct signaling pathways, we try to develop the idea that TMEM16A regulates cancer cell proliferation and migration in a cell-dependent mechanism. The cell-specific role of TMEM16A may depend on the cellular environment that is predetermined by TMEM16A overexpression mechanisms specific for a particular cancer type. TMEM16A may exert its cell-specific role via its associated protein networks, phosphorylation by different kinases, and involvement of different signaling pathways. In addition, we discuss the role of TMEM16A channel activity in cancer, and its clinical use as a prognostic and predictive marker in different cancers. This review highlights the cell-type specific mechanisms of TMEM16A in cancer, and envisions the promising use of TMEM16A inhibitors as a potential treatment for TMEM16A-overexpressing cancers.
Hyaluronan assessment in tumor microenvironment using new affinity histochemistry assay and scoring method.
Authors: Jie Pu, Carrie Aldrich, Junming Zhu, Ping Jiang, Xionghua W. Wu, Thomas Müller, Paco Delgado, Michelle Quiroz, Sihem Khelifa
Journal: Journal of Clinical Oncology (2017)

e23196 Background: Enzymatic degradation of hyaluronan (HA) by PEGylated recombinant human hyaluronidase PH20 (PEGPH20) induces a remodeling of the tumor microenvironment that impacts tumor behavior and response to therapy. Ventana Medical Systems, Inc., (VMSI) and Halozyme Therapeutics co-developed the VENTANA HA RxDx Assay and a scoring method to evaluate HA in solid tumors to potentially predict which patients might better respond to the addition of PEGPH20 to cancer treatments. Methods: Using Halozyme’s novel recombinant HA binding probe altered to include a rabbit Fc region, VMSI developed a highly specific and sensitive affinity histochemistry assay that binds to HA in tissues. Histological features and staining patterns of 106 samples from Halozyme’s 109-202 Phase 2 study of PEGPH20 combined with nab-paclitaxel plus gemcitabine (AG) vs. AG alone in patients with previously untreated stage IV pancreatic ductal adenocarcinoma (PDA) with clinical outcome data were analyzed to develop a scoring method evaluating HA accumulation. Results: A novel scoring algorithm focused solely on the extracellular matrix (ECM) was developed. An ECM HA staining ≥ 50% of the entire tumor surface at any intensity defines an HA-High PDA. We recommend that a 0.05 cm x 0.2 cm uninterrupted fragment of tumor cells and associated stroma obtained using needle gauges of 16 to 20 G as the minimally required amount of tissue to assess HA in PDA. Based on verification studies performed by VMSI, including an inter-reader precision study with a 94% agreement rate, VMSI scoring method proved to be trainable, reproducible, and transferable to pathologists, supporting an IDE approval for selecting patients in the Phase 3 HALO 109-301 study. Conclusions: Performance of the VENTANA HA RxDx Assay, a robust affinity histochemical assay, has been successfully verified in PDA. Two Halozyme clinical studies in PDA (Phase 2 HALO 109-202 Stage 2 &amp; ongoing Phase 3 HALO 109-301) are expected to validate the VMSI HA scoring method in selecting patients who might better respond to the addition of PEGPH20 to cancer treatments. Current Phase 1/2 studies are exploring the utility of the VENTANA HA RxDx Assay and the pantumor potential of PEGPH20.
The paradoxes of asthma management: time for a new approach?
Authors: Paul M. O'Byrne, Christine Jenkins, Eric D. Bateman
Journal: European Respiratory Journal (2017)

Poor adherence to maintenance pharmacotherapy is a reality in asthma. Studies confirm that when symptoms worsen, most patients increase short-acting β 2 -agonist (SABA) use, instead of using controller medication. This behaviour might be attributable to several paradoxes in the current treatment approach. These paradoxes include the recommended use of a SABA bronchodilator alone at Global Initiative for Asthma (GINA) step 1, despite the fact that asthma is a chronic inflammatory disease. At step 1, the patient has autonomy and their perception of need and disease control is accepted, but at higher asthma treatment steps a fixed-dose approach is recommended, irrespective of symptom severity. The unintended consequence is the establishment of a pattern of early over-reliance on SABA. New approaches that avoid these paradoxes are needed, such as patient-adjusted therapy, in which patients adopt a symptom-driven approach using a combination reliever/controller. We propose that SABA reliever monotherapy should be replaced by a combination of inhaled corticosteroid (ICS) and formoterol, or similar rapid-onset bronchodilator, as reliever therapy for patients at GINA steps 1 or 2. This will ensure early and more regular administration of a controller medication. However, a significant body of clinical data will be needed before this approach can be approved by regulatory authorities.
SOLO3: A randomized phase III trial of olaparib versuschemotherapy in platinum-sensitive relapsed ovarian cancer patients with a germline <i>BRCA1/2</i> mutation (g<i>BRCA</i>m).
Authors: Elizabeth S. Lowe, Deepthi Jayawardene, Richard T. Penson
Journal: Journal of Clinical Oncology (2016)

TPS5598 Background: Olaparib (Lynparza) is a PARP inhibitor that can induce synthetic lethality in cancer cells with a deleterious BRCA mutation. A subgroup analysis of data from a Phase II trial of olaparib monotherapy in patients with a gBRCAm (Study 42; NCT01078662) demonstrated an objective response rate (ORR) of 46% in a small number of patients with platinum-sensitive ovarian cancer who were heavily pretreated ( ≥ 3 prior chemotherapy regimens) (Domchek et al, ASCO 2015). The approval of olaparib monotherapy (400 mg bid; capsules) in the US, based on Study 42 data, for patients with gBRCAm advanced ovarian cancer who have received ≥ 3 lines of prior chemotherapy has led to initiation of this AstraZeneca-sponsored Phase III trial in platinum-sensitive ovarian cancer patients (SOLO3; NCT02282020). Methods: SOLO3 is an open-label, randomized, controlled, multicenter study that will assess the efficacy and safety of olaparib monotherapy, compared with standard chemotherapy, in patients with relapsed high-grade serous or endometrioid ovarian cancer. Eligibility also requires a predicted deleterious gBRCAm, completion of ≥ 2 lines of platinum-based chemotherapy, and at least partial platinum sensitivity (progression ≥ 6 months after completion of the last platinum-based chemotherapy). All patients will undergo gBRCA testing (Myriad Integrated BRACAnalysis) as part of the trial. Approximately 411 subjects will be randomized (2:1) to either olaparib (300 mg bid; tablets) or physician's choice of a single standard chemotherapy agent. The primary endpoint is progression-free survival (PFS), which will be evaluated by blinded independent central review using RECIST v1.1. Tumor assessments will be performed at baseline using CT or MRI, followed by measurements every 8 weeks for 48 weeks, and then every 12 weeks. The primary analysis will commence following ~288 PFS events (~70% maturity) using a stratified log-rank test. Other endpoints include: overall survival; time from randomization to second progression (PFS2); ORR; health-related quality of life; and safety and tolerability. Enrollment began on 6 February 2015. Clinical trial information: NCT02282020.
Incorporating BEAMing technology as a liquid biopsy into clinical practice for the management of colorectal cancer patients: an expert taskforce review
Authors: J. García-Foncillas, E. Alba, E. Aranda, E. Díaz-Rubio, R. López-López, J. Tabernero, A. Vivancos
Journal: Annals of Oncology (2017)

The importance of mutation identification for advanced colorectal cancer treatment with anti-epidermal growth factor receptor agents is well established. However, due to delays in turnaround time, low-quality tissue samples, and/or lack of standardization of testing methods a significant proportion of patients are being treated without the information that Kirsten rat sarcoma and neuroblastoma rat sarcoma (RAS) testing can provide. The detection of mutated circulating tumor DNA by BEAMing technology addresses this gap in care and allows these patients to receive international guideline-recommended expanded RAS testing with rapid turnaround times. Furthermore, the overall concordance between OncoBEAM RAS colorectal cancer testing and standard of care tissue testing is very high (93.3%). This article presents an overview of the clinical utility and potential applications of this minimally invasive method, such as early detection of emergent resistance to anti-epidermal growth factor receptor therapy. If appropriately implemented, BEAMing technology holds considerable promise to enhance the quality of patient care and improve clinical outcomes.
ADARB1は概日性A‐to‐I RNA編集を介してRNA変動リズムを調節している
Authors: Terajima Hideki, Yoshitane Hikari, Kuroda Shinya, Iwasaki Wataru, Fukada Yoshitaka, Ozaki Haruka, Suzuki Yutaka, Shimba Shigeki
Journal: Nature Genetics (2017)
Pilot Study of Prognostic Impact of Pre-Allogeneic Hematopoietic Cell Transplantation (HCT) Plasma Levels of CXC-Chemokines (CXCL-4 and CXCL-7) in Patients with Myelodysplastic Syndromes (MDS)
Authors: Binod Dhakal, Tao Wang, Michael D Haagenson, Fenlu Zhu, Carolyn A. Keever-Taylor, Stephen R. Spellman, Michael R. Verneris, Katharine C. Hsu, Katharina Fleischhauer, Stephanie J. Lee, Wael Saber
Journal: Blood (2016)
MRIおよび腫瘍‐ターゲットドラッグデリバリーのための非常に高いT_2緩和性を持つ超常磁性ポリマソーム【Powered by NICT】
Authors: Liu Qiuming, Song Liwen, Chen Shuai, Gao Jingyi, Zhao Peiyu, Du Jianzhong
Journal: Biomaterials (2017)
合成ヒト心房性ナトリウム利尿ペプチド(カリペリチド)投与が有効であった重症広範前壁梗塞の1例
Authors: 山崎恭平, 上小沢護, 鈴木順, 伊藤篤, 阿部秀年, 西沢守人
Journal: Circulation (2002)
Association Between More Intensive vs Less Intensive Blood Pressure Lowering and Risk of Mortality in Chronic Kidney Disease Stages 3 to 5
Authors: Rakesh Malhotra, Hoang Anh Nguyen, Oscar Benavente, Mihriye Mete, Barbara V. Howard, Jonathan Mant, Michelle C. Odden, Carmen A. Peralta, Alfred K. Cheung, Girish N. Nadkarni, Ruth L. Coleman, Rury R. Holman, Alberto Zanchetti, Ruth Peters, Nigel Beckett, Jan A. Staessen, Joachim H. Ix
Journal: JAMA Internal Medicine (2017)

Trials in patients with hypertension have demonstrated that intensive blood pressure (BP) lowering reduces the risk of cardiovascular disease and all-cause mortality but may increase the risk of chronic kidney disease (CKD) incidence and progression. Whether intensive BP lowering is associated with a mortality benefit in patients with prevalent CKD remains unknown.To conduct a systematic review and meta-analysis of randomized clinical trials (RCTs) to investigate if more intensive compared with less intensive BP control is associated with reduced mortality risk in persons with CKD stages 3 to 5.Ovid MEDLINE, Cochrane Library, EMBASE, PubMed, Science Citation Index, Google Scholar, and clinicaltrials.gov electronic databases.All RCTs were included that compared 2 defined BP targets (either active BP treatment vs placebo or no treatment, or intensive vs less intensive BP control) and enrolled adults (≥18 years) with CKD stages 3 to 5 (estimated glomerular filtration rate <60 mL/min/1.73 m2) exclusively or that included a CKD subgroup between January 1, 1950, and June 1, 2016.Two of us independently evaluated study quality and extracted characteristics and mortality events among persons with CKD within the intervention phase for each trial. When outcomes within the CKD group had not previously been published, trial investigators were contacted to request data within the CKD subset of their original trials.All-cause mortality during the active treatment phase of each trial.This study identified 30 RCTs that potentially met the inclusion criteria. The CKD subset mortality data were extracted in 18 trials, among which there were 1293 deaths in 15 924 participants with CKD. The mean (SD) baseline systolic BP (SBP) was 148 (16) mm Hg in both the more intensive and less intensive arms. The mean SBP dropped by 16 mm Hg to 132 mm Hg in the more intensive arm and by 8 mm Hg to 140 mm Hg in the less intensive arm. More intensive vs less intensive BP control resulted in 14.0% lower risk of all-cause mortality (odds ratio, 0.86; 95% CI, 0.76-0.97; P = .01), a finding that was without significant heterogeneity and appeared consistent across multiple subgroups.Randomization to more intensive BP control is associated with lower mortality risk among trial participants with hypertension and CKD. Further studies are required to define absolute BP targets for maximal benefit and minimal harm.
mTOR Pathway Mutations and Response to Rapalogs in RCC—Letter
Authors: Juan M. Roldan-Romero, Juan F. Rodríguez-Moreno, Jesus García-Donás, Cristina Rodríguez-Antona
Journal: Clinical Cancer Research (2017)

We have read with interest the article by Kwiatkowski and colleagues ([1][1]) reporting mTOR pathway activating mutations as possible predictors of mTOR inhibitor response in renal cell carcinoma (RCC). Recent evidence indicate inferior global efficacy of rapalogs compared with new agents; however,
Altered miR‐193a‐5p expression in children with cow's milk allergy
Authors: V. D'Argenio, V. Del Monaco, L. Paparo, F. D. E. De Palma, R. Nocerino, F. D'Alessio, F. Visconte, V. Discepolo, L. Del Vecchio, F. Salvatore, R. Berni Canani
Journal: Allergy (2017)

Abstract Background Cow's milk allergy ( CMA ) is one of the most common food allergies in children. Epigenetic mechanisms have been suggested to play a role in CMA pathogenesis. We have shown that DNA methylation of Th1/Th2 cytokine genes and FoxP3 affects CMA disease course. Preliminary evidence suggests that also the mi RN ome could be implicated in the pathogenesis of allergy. Main study outcome was to comparatively evaluate mi RN ome in children with CMA and in healthy controls. Methods Peripheral blood mononuclear cells were obtained from children aged 4‐18 months: 10 CMA patients, 9 CMA patients who outgrew CMA , and 11 healthy controls. Small RNA libraries were sequenced using a next‐generation sequencing‐based approach. Functional assessment of IL ‐4 expression was also performed. Results Among the mi RNA s differently expressed, 2 were upregulated and 14 were downregulated in children with active CMA compared to healthy controls. miR‐193a‐5p resulted the most downregulated mi RNA in children with active CMA compared to healthy controls. The predicted targets of miR‐193a‐5p resulted upregulated in CMA patients compared to healthy controls. Peripheral blood CD 4 + T cells transfected with a miR193a‐5 inhibitor showed a significant upregulation of IL ‐4 mRNA and its protein expression. Children who outgrew CMA showed mi RNA ‐193a‐5p level, and its related targets expression, similar to that observed in healthy controls. Conclusions Our results suggest that miR‐193a‐5p is a post‐transcriptional regulator of IL ‐4 expression and could have a role in IgE‐mediated CMA . This mi RNA could be a novel diagnostic and therapeutic target for this common form of food allergy in childhood.
Quality indicators for end-of-life breast cancer care: Is there agreement between stakeholder groups?
Authors: P. McIntyre, E. Grunfeld, E. Mykhalovskiy, L. Cicchelli, S. F. Dent, L. Zitzelsberger, L. Paszat, C. Earle
Journal: Journal of Clinical Oncology (2006)

16034 Background: Quality indicators (QIs) are tools designed to measure quality of care and help enhance quality through identifying areas needing improvement. Breast cancer offers a disease model to examine QIs for end-of-life (EOL) care. The objective of this study was to assess agreement among stakeholder groups in two Canadian provinces on QIs for EOL breast cancer. Methods: A qualitative study design using a modified Delphi method and focus groups at each study site. After a literature review, an expert panel identified 19 QIs that were potentially measurable using administrative data. The Delphi panels and focus group sessions incorporated the 19 QIs as discussion topics in Halifax, NS and Ottawa, Ont. The Delphi panels involved a multidisciplinary group of oncology health care professionals. Separate focus groups were conducted with women with metastatic breast cancer and bereaved caregivers. All group sessions were audio-taped, transcribed verbatim, audited and a thematic analysis was conducted. Results: A total of 23 health care professionals, 16 patients, 7 bereaved caregivers participated in the study. Participants attended only one group discussion, depending on group assigned. There was good agreement on QIs among patient and caregiver groups in both cities. The need for effective communication was identified as a major theme. The Delphi process yielded overall moderate agreement with QIs among health care professionals. Conclusion: Aspects of quality EOL care important to stakeholders may not be measurable from administrative data. Results from the Delphi panels indicate that patient preferences and differences in health care delivery between different jurisdictions modulated extent of agreement with QIs. No significant financial relationships to disclose.
Evaluation of Infectious Complications after Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide Following Reduced-Intensity and Myeloablative Conditioning: A Study on Behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC) Study
Authors: Amandine Fayard, Fabien Tinquaut, Didier Blaise, Patrice Chevallier, Mauricette Michallet, Ana Berceanu, Ibrahim Yakoub-Agha, Gérard Socié, Amandine Charbonnier, Felipe Suarez, Anne Huynh, Mélanie Mercier, Claude-Eric Bulabois, Bruno Lioure, Sylvain Chantepie, Yves Beguin, Jean Henri Bourhis, Jean Valere Malfuson, Laurence Clément, Jerome Cornillon
Journal: Blood (2016)
All Types of Hemorrhagic Stroke Are Not Created Equally—Reply
Authors: Peter Brønnum Nielsen, Torben Bjerregaard Larsen, Gregory Y. H. Lip
Journal: JAMA Internal Medicine (2017)

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Thermodilution vs Estimated Fick Cardiac Output Measurement in Clinical Practice
Authors: Alexander R. Opotowsky, Edward Hess, Bradley A. Maron, Evan L. Brittain, Anna E. Barón, Thomas M. Maddox, Laith I. Alshawabkeh, Bradley M. Wertheim, Meng Xu, Tufik R. Assad, Jonathan D. Rich, Gaurav Choudhary, Ryan J. Tedford
Journal: JAMA Cardiology (2017)

Thermodilution (Td) and estimated oxygen uptake Fick (eFick) methods are widely used to measure cardiac output (CO). They are often used interchangeably to make critical clinical decisions, yet few studies have compared these approaches as applied in medical practice.To assess agreement between Td and eFick CO and to compare how well these methods predict mortality.This investigation was a retrospective cohort study with up to 1 year of follow-up. The study used data from the Veterans Affairs Clinical Assessment, Reporting, and Tracking (VA CART) program. The findings were corroborated in a cohort of patients cared for at Vanderbilt University, an academic referral center. Participants were more than 15 000 adults who underwent right heart catheterization, including 12 232 in the Veterans Affairs cohort between October 1, 2007, and September 30, 2013, and 3391 in the Vanderbilt cohort between January 1, 1998, and December 31, 2014.A single cardiac catheterization was performed on each patient with CO estimated by both Td and eFick methods. Cardiac output was indexed to body surface area (cardiac index [CI]) for all analyses.All-cause mortality over 90 days and 1 year after catheterization.Among 12 232 VA patients (mean [SD] age, 66.4 [9.9] years; 3.3% female) who underwent right heart catheterization in this cohort study, Td and eFick CI estimates correlated modestly (r = 0.65). There was minimal mean difference (eFick minus Td = -0.02 L/min/m2, or -0.4%) but wide 95% limits of agreement between methods (-1.3 to 1.3 L/min/m2, or -50.1% to 49.4%). Estimates differed by greater than 20% for 38.1% of patients. Low Td CI (<2.2 L/min/m2 compared with normal CI of 2.2-4.0 L/min/m2) more strongly predicted mortality than low eFick CI at 90 days (Td hazard ratio [HR], 1.71; 95% CI, 1.47-1.99; χ2 = 49.5 vs eFick HR, 1.42; 95% CI, 1.22-1.64; χ2 = 20.7) and 1 year (Td HR, 1.53; 95% CI, 1.39-1.69; χ2 = 71.5 vs eFick HR, 1.35; 1.22-1.49; χ2 = 35.2). Patients with a normal CI by both methods had 12.3% 1-year mortality. There was no significant additional risk for patients with a normal Td CI but a low eFick CI (12.9%, P = .51), whereas a low Td CI but normal eFick CI was associated with higher mortality (15.4%, P = .001). The results from the Vanderbilt cohort were similar in the context of a more balanced sex distribution (46.6% female).There is only modest agreement between Td and eFick CI estimates. Thermodilution CI better predicts mortality and should be favored over eFick in clinical practice.