tbuckley/cabot-search huggingface dataset:
Regulation of Fibroblast Apoptosis and Proliferation by Micro<scp>RNA</scp>‐125b in Systemic Sclerosis
Authors: Anastasiia Kozlova, Elena Pachera, Britta Maurer, Astrid Jüngel, Jörg H. W. Distler, Gabriela Kania, Oliver Distler
Journal: Arthritis & Rheumatology (2019)

To analyze the expression, regulation, and role of microRNA-125b (miR-125b) in systemic sclerosis (SSc).MiR-125b expression was assessed by quantitative polymerase chain reaction (qPCR) of RNA from dermal fibroblasts and whole skin biopsy specimens from healthy controls and SSc patients. To identify downstream effectors, RNA from healthy control fibroblasts was sequenced after miR-125b knockdown and further validated using qPCR and Western blotting. Fibrosis, apoptosis, and proliferation were assessed by Caspase-Glo 3/7 assay, Western blotting, immunofluorescence staining for cleaved caspase 3, and annexin V real-time assay in dermal fibroblasts.Expression of miR-125b was significantly down-regulated in SSc skin biopsy specimens by 53% (median fold change 0.47 [interquartile range 0.35-0.69]; P < 0.001) and in SSc dermal fibroblasts by 47% (median fold change 0.53 [interquartile range 0.36-0.58]; P < 0.001) compared to healthy control skin biopsy specimens and fibroblasts, respectively (n = 10 samples per group). Treatment with the histone deacetylase inhibitors trichostatin A and tubastatin A significantly decreased the expression of miR-125b in dermal fibroblasts. MiR-125b knockdown significantly reduced cell proliferation and α-smooth muscle actin (α-SMA) expression at the messenger RNA (mRNA) and protein levels. RNA-Seq identified BAK1, BMF, and BBC3 as potential targets of miR-125b. Quantitative PCR confirmed that knockdown of miR-125b up-regulated these genes (P < 0.01; n = 12). Bcl-2 homologous antagonist killer 1 showed the strongest induction confirmed at the protein level (P < 0.01; n = 10). Consequently, miR-125b knockdown increased apoptosis compared to scrambled control. Accordingly, miR-125b overexpression decreased apoptosis.Our findings indicate that miR-125b is down-regulated in SSc skin and primary dermal fibroblasts. MiR-125b down-regulation increases apoptosis and decreases proliferation and α-SMA expression in dermal fibroblasts, indicating that its compensatory, antifibrotic mechanism may be a potential novel therapeutic option.
How does Pseudomonas aeruginosa affect the progression of bronchiectasis?
Authors: Y-H Chai, J-F Xu
Journal: Clinical Microbiology and Infection (2019)

BackgroundPseudomonas aeruginosa is one of the most common pathogens isolated from respiratory tract specimen in patients with bronchiectasis. It is considered highly responsible for pathogenicity, progression and clinical outcomes of bronchiectasis.AimsTo summarize existing evidence on how different factors of Pseudomonas aeruginosa affect the pathogenicity, progression and clinical outcomes of bronchiectasis, so as to provide possible insights for clinical practice and related research in the future.SourcesPubMed was searched for studies pertaining to bronchiectasis and P. aeruginosa published to date, with no specific inclusion or exclusion criteria. Reference lists of retrieved reviews were searched for additional articles.ContentThis review focused on non–cystic fibrosis bronchiectasis and also provided some data on cystic fibrosis when studies in bronchiectasis were limited. We discussed various factors in relation to P. aeruginosa: virulence factors, drug resistance, regulatory systems, genomic diversity and transmission of P. aeruginosa, as well as treatment for P. aeruginosa. Their impacts on bronchiectasis and its management were discussed.ImplicationsThe impact of P. aeruginosa on bronchiectasis is definite, although conclusions in some aspects are still vague. Faced with the worrying drug-resistance status and treatment bottleneck, individualized management and novel therapies beyond the classic pathway are most likely to be a future trend. To confirm the independent or integrated impact of various factors of P. aeruginosa on bronchiectasis and to figure out all the problems mentioned, larger randomized control trials are truly needed in the future.
Journal policy on research funded by the tobacco industry
Authors: Fiona Godlee, Ruth Malone, Adam Timmis, Catherine Otto, Andrew Bush, Ian Pavord, Trish Groves
Journal: Thorax (2013)

As editors of the BMJ , Heart , Thorax and BMJ Open , we have decided that the journals will no longer consider for publication any study that is partly or wholly funded by the tobacco industry. Our new policy is consistent with those of other journals including PLoS Medicine , PLoS One , PLoS Biology ;1 Journal of Health Psychology ;2 journals published by the American Thoracic Society;3 and the BMJ 's own Tobacco Control. 4

Critics may argue—as many did when journals stopped publishing cigarette advertisements—that publishing such research does not constitute endorsing its findings and that, as long as funding sources are fully disclosed, readers can consider that information and make up their own minds about the quality of the work. Peer review should prevail, goes this line of thinking: it's not the editor's job to make these kinds of judgments. However, this view ignores the growing body of evidence that biases and research misconduct are often impossible …
Clinicopathologic analysis of a large series of microinvasive breast cancer.
Authors: Joseph W. Leach, Tamera Lillemoe, Janet Krueger
Journal: Journal of Clinical Oncology (2013)

1129 Background: Microinvasive breast cancer (Tmic) is defined by the AJCC as extension of cancer cells beyond the basement membrane with no single focus larger than 1 mm. The clinical behavior of this entity is unclear. Most series suggest that prognosis is similar to non-invasive cancer although the literature is mixed. Surgical management typically reflects invasive breast cancer including lymph node sampling. Published incidence of nodal involvement is also variable with some small series reporting incidence as high as 20%. We present a clinicopathologic review of a large series from a community practice setting. Methods: Using the AJCC definition of Tmic, we retrospectively identified all cases treated within Allina Health System from 2001-2011. Inclusion criteria included no prior history of breast cancer and available follow-up data. Data collected included ER/PR and HER2 status (when available), margin status and surgical and adjuvant therapy. Results: 118 eligible cases were identified with a mean follow-up of 3.65 years and mean age of 56.8 years (34-88). 39 were triple negative and 29 were HER2+. ER/PR data was available on all cases, HER2 on 60. 72 were treated with mastectomy. All patients underwent axillary staging. Lymph node metastasis was identified in 2 cases (one triple negative, one HER2+). In one case the metastasis measured 0.25 mm, in the other 0.4 mm. Complete axillary dissection performed on both cases demonstrated no additional lymph node involvement. Isolated tumor cells were also identified in 9 cases. 2 cases developed local recurrence following lumpectomy and radiation, both in the ipsilateral breast. One recurred with microinvasive disease, the second with DCIS only. There were no cases of metastatic recurrence and no breast cancer associated deaths. Conclusions: The clinical behavior of microinvasive breast cancer in this series is similar to DCIS. The incidence of lymph node metastasis was low (1.7%) and there were no cases of distant metastasis. Our data supports management of microinvasive breast cancer as a subset of DCIS and suggests that the benefit of routine lymph node sampling is questionable.
A phase I study of lapatinib (LPT) and cetuximab (CTX) in patients with CTX-sensitive solid tumors.
Authors: John F. Deeken, Hongkun Wang, Jimmy J. Hwang, John Marshall, Deepa Suresh Subramaniam, Aiwu Ruth He, Louis M. Weiner, Rosemarie A. Hardesty, Kenneth Steadman, Michael J. Pishvaian
Journal: Journal of Clinical Oncology (2012)

2590 Background: Preclinical research has shown that one mechanism of acquired resistance to CTX is via EGFR-ErbB2 heterodimerization, which can reactivate oncogenic pathways. LPT is a dual EGFR and ErbB2 intracellular tyrosine kinase inhibitor. A phase I translational clinical study was performed to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and clinical activity of CTX and LPT in patients with EGFR-driven solid tumor malignancies that can be treated with CTX. Methods: Patients (Pts) were enrolled in a 3+3 dose escalation trial. Prior CTX therapy was allowed. CTX was given at 400mg/m2 on Cycle 1, Day 1 (C1D1), then 250 mg/m2 weekly. LPT dose levels (DL) were (1) 750mg, (2) 1000mg, and (3) 1250mg orally daily. Rash management included daily sunblock, steroid cream, and doxycycline. Cycle length was 21 days, and patients were assessed for toxicity through the end of C2, and for efficacy after every 2 cycles. Fresh tumor biopsies were obtained at baseline and at the end of C1 to compare EGFR and ErbB2 expression levels and EGFR related pathway activation. DNA from blood samples was analyzed for pharmacogenetic (PGx) variations and correlations with toxicity and pharmacokinetics (PK). Results: Between October, 2010 to January 2012, 13 pts were enrolled, with colon (4), lung (3), head and neck (3), and anal cancers (3); 10 were evaluable for toxicity. Treatment-related toxicities of any grade included: rash (67%), diarrhea (42%), fatigue (33%), nausea/vomiting (17%), and dehydration (8%). DLTs included G3 rash in 1 of 6 pts on DL1, and G3 diarrhea despite optimal therapy in 1 of 4 pts on DL2. Enrollment to DL2 continues. Of 7 pts evaluable for response, 1 had an uPR, 3 had SD, including 1 with SD of ≥4 cycles, and 3 had DP. Both patients with uPR and prolonged SD were treated on DL1. Tumor EGFR-ErbB2 and EGFR pathway phosphorylation analyses and PGx results will be presented. Conclusions: The combination of CTX and LPT is well tolerated with expected toxicities. Efficacy was seen even on DL 1. Phase II clinical studies in CTX-sensitive diseases such as colon and head and neck cancer are planned.
Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration
Authors: David S. Liao, Federico V. Grossi, Delphine El Mehdi, Monica R. Gerber, David M. Brown, Jeffrey S. Heier, Charles C. Wykoff, Lawrence J. Singerman, Prema Abraham, Felix Grassmann, Peter Nuernberg, Bernhard H.F. Weber, Pascal Deschatelets, Robert Y. Kim, Carol Y. Chung, Ramiro M. Ribeiro, Mohamed Hamdani, Philip J. Rosenfeld, David S. Boyer, Jason S. Slakter, Cedric G. Francois
Journal: Ophthalmology (2019)

Geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), is a major cause of blindness. Even while central visual acuity remains relatively well preserved, GA often causes considerable compromise of visual function and quality of life. No treatment currently exists. We evaluated the safety and efficacy of pegcetacoplan, a complement C3 inhibitor, for treatment of GA.Prospective, multicenter, randomized, sham-controlled phase 2 study.Two hundred forty-six patients with GA.Patients with GA were assigned randomly in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg pegcetacoplan monthly or every other month (EOM) or sham intravitreal injections monthly or EOM for 12 months with follow-up at months 15 and 18. Area and growth of GA were measured using fundus autofluorescence imaging.The primary efficacy end point was mean change in square root GA lesion area from baseline to month 12. Secondary outcome measures included mean change from baseline in GA lesion area without the square root transformation, distance of GA lesion from the fovea, best-corrected visual acuity (BCVA), low-luminance BCVA, and low-luminance visual acuity deficit. The primary safety end point was the number and severity of treatment-emergent adverse events.In patients receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% confidence interval [CI], 9-49; P = 0.008) and 20% (95% CI, 0-40; P = 0.067) compared with the sham treatment group. Post hoc analysis showed that the effect was greater in the second 6 months of treatment, with observed reductions of 45% (P = 0.0004) and 33% (P = 0.009) for pegcetacoplan monthly and EOM, respectively. Two cases of culture-positive endophthalmitis and 1 case of culture-negative endophthalmitis occurred in the pegcetacoplan monthly group. New-onset investigator-determined exudative AMD was reported more frequently in pegcetacoplan-treated eyes (18/86 eyes [20.9%] and 7/79 eyes [8.9%] in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes [1.2%]).Local C3 inhibition with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham treatment. Phase 3 studies will define the efficacy and safety profile further.
Cognitive and Motor Outcomes of Children With Prenatal Opioid Exposure
Authors: Su Lynn Yeoh, John Eastwood, Ian M. Wright, Rachael Morton, Edward Melhuish, Meredith Ward, Ju Lee Oei
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Prenatal opioid exposure (POE) is one of the fastest-growing global health problems, but its association with long-term neurologic and physical development remains unknown. <h3>Objective</h3> To assess the association between POE and cognitive and motor development in children from age 6 months to 18 years. <h3>Data Sources</h3> Key search terms included<i>prenatal opioid exposure</i>,<i>neonatal abstinence syndrome</i>, and<i>neurocognitive development</i>. Studies were searched using PubMed and Embase, with no publication date restriction, through August 20, 2018. <h3>Study Selection</h3> Only published cohort studies comparing the results of age-appropriate standardized cognitive and/or motor tests between children with any POE (aged 0-18 years) with drug-free controls were included. Data that were not convertible to means and SDs were excluded. <h3>Data Extraction and Synthesis</h3> This study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Data were pooled using a random-effects model. <h3>Main Outcomes and Measures</h3> Standardized mean difference of cognitive and motor tests between POE and nonexposed children. <h3>Results</h3> Twenty-six peer-reviewed cohort studies were included. Cognitive outcomes were compared for a total of 1455 children with POE and 2982 nonexposed children across 3 age groups (mean [SE] age at cognitive testing was 13 [1.58] months for the toddler group; 4.5 [0.38] years for the preschool group; and 13 [2.36] years for the school-aged group). Motor outcomes were compared for 688 children with POE and 1500 nonexposed children up to age 6 years (mean [SD] age at motor testing, 2 [0.45] years). Standardized mean difference was lower in cognitive tests for children with POE at 0 to 2 years (<i>d</i> = −0.52; 95% CI, −0.74 to −0.31;<i>P</i> &lt; .001) and 3 to 6 years (<i>d</i> = −0.38; 95% CI, −0.69 to −0.07;<i>P</i> &lt; .001); the difference was not significant for those aged 7 to 18 years (<i>d</i> = −0.44; 95% CI, −1.16 to 0.28;<i>P</i> = .23). Motor scores were lower in children with POE (<i>d</i> = 0.49; 95% CI, 0.23-0.74;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> Prenatal opioid exposure appeared to be negatively associated with neurocognitive and physical development from age 6 months, and this association persisted until adolescence. The cause and association of this with POE or other factors (eg, withdrawal treatment) are uncertain but suggest that POE necessitates long-term support and intervention.
Evaluating Screening Participation, Follow-up, and Outcomes for Breast, Cervical, and Colorectal Cancer in the PROSPR Consortium
Authors: William E Barlow, Elisabeth F Beaber, Berta M Geller, Aruna Kamineni, Yingye Zheng, Jennifer S Haas, Chun R Chao, Carolyn M Rutter, Ann G Zauber, Brian L Sprague, Ethan A Halm, Donald L Weaver, Jessica Chubak, V Paul Doria-Rose, Sarah Kobrin, Tracy Onega, Virginia P Quinn, Marilyn M Schapira, Anna N A Tosteson, Douglas A Corley, Celette Sugg Skinner, Mitchell D Schnall, Katrina Armstrong, Cosette M Wheeler, Michael J Silverberg, Bijal A Balasubramanian, Chyke A Doubeni, Dale McLerran, Jasmin A Tiro
Journal: JNCI Journal of the National Cancer Institute (2019)

Cancer screening is a complex process encompassing risk assessment, the initial screening examination, diagnostic evaluation, and treatment of cancer precursors or early cancers. Metrics that enable comparisons across different screening targets are needed. We present population-based screening metrics for breast, cervical, and colorectal cancers for nine sites participating in the Population-based Research Optimizing Screening through Personalized Regimens consortium.We describe how selected metrics map to a trans-organ conceptual model of the screening process. For each cancer type, we calculated calendar year 2013 metrics for the screen-eligible target population (breast: ages 40-74 years; cervical: ages 21-64 years; colorectal: ages 50-75 years). Metrics for screening participation, timely diagnostic evaluation, and diagnosed cancers in the screened and total populations are presented for the total eligible population and stratified by age group and cancer type.The overall screening-eligible populations in 2013 were 305 568 participants for breast, 3 160 128 for cervical, and 2 363 922 for colorectal cancer screening. Being up-to-date for testing was common for all three cancer types: breast (63.5%), cervical (84.6%), and colorectal (77.5%). The percentage of abnormal screens ranged from 10.7% for breast, 4.4% for cervical, and 4.5% for colorectal cancer screening. Abnormal breast screens were followed up diagnostically in almost all (96.8%) cases, and cervical and colorectal were similar (76.2% and 76.3%, respectively). Cancer rates per 1000 screens were 5.66, 0.17, and 1.46 for breast, cervical, and colorectal cancer, respectively.Comprehensive assessment of metrics by the Population-based Research Optimizing Screening through Personalized Regimens consortium enabled systematic identification of screening process steps in need of improvement. We encourage widespread use of common metrics to allow interventions to be tested across cancer types and health-care settings.
Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis
Authors: Xinyu Zhou, Teng Teng, Yuqing Zhang, Cinzia Del Giovane, Toshi A Furukawa, John R Weisz, Xuemei Li, Pim Cuijpers, David Coghill, Yajie Xiang, Sarah E Hetrick, Stefan Leucht, Mengchang Qin, Jürgen Barth, Arun V Ravindran, Lining Yang, John Curry, Li Fan, Susan G Silva, Andrea Cipriani, Peng Xie
Journal: The Lancet Psychiatry (2020)
Biomodal Tumor‐Targeted and Redox‐Responsive Bi<sub>2</sub>Se<sub>3</sub> Hollow Nanocubes for MSOT/CT Imaging Guided Synergistic Low‐Temperature Photothermal Radiotherapy
Authors: Yilin Song, Yule Wang, Yan Zhu, Yu Cheng, Yidan Wang, Siyu Wang, Fengping Tan, Fan Lian, Nan Li
Journal: Advanced Healthcare Materials (2019)

Hyperthemia (>50 °C) induced heating damage of nearby normal organs and inflammatory diseases are the main challenges for photothermal therapy (PTT) of cancers. To overcome this limitation, a redox-responsive biomodal tumor-targeted nanoplatform is synthesized, which can achieve multispectral optoacoustic tomography/X-ray computed tomography imaging-guided low-temperature photothermal-radio combined therapy (PTT RT). In this study, Bi2 Se3 hollow nanocubes (HNCs) are first fabricated based on a mild cation exchange way and Kirkendall effect and then modified with hyaluronic acid (HA) through redox-cleavable linkage (-s-s-), thus enabling the HNC to target cancer cells overexpressing CD-44 and control the cargo release profile. Finally, gambogic acid (GA), a type of heat-shock protein (HSP) inhibitor, which is vital to cells resisting heating-caused damage is loaded, into Bi2 Se3 HNC. Such HNC-s-s-HA/GA under a mild NIR laser irradiation can induce efficient cancer cell apoptosis, achieving PTT under relatively low temperature (≈43 °C) with remarkable cancer cell damage efficiency. Furthermore, enhanced radiotherapy (RT) can also be experienced without depth limitation based on RT sensitizer Bi2 Se3 HNC. This research designs a facile way to synthesize Bi2 Se3 HNC-s-s-HA/GA possessing theranostic functionality and cancer cells-specific GSH, but also shows a low-temperature PTT RT method to cure tumors in a minimally invasive and highly efficient way.
Kohrt HE, Houot R, Goldstein MJ, Weiskopf K, Alizadeh AA, Brody J, Müller A, Pachynski R, Czerwinski D, Coutre S, Chao MP, Chen L, Tedder TF, Levy R. CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies. Blood. 2011;117(8):2423-2432.
Journal: Blood (2019)
Phase 1 studies assessing the safety and clinical activity of autologous and allogeneic NKG2D-based CAR-T therapy in metastatic colorectal cancer
Authors: E. Van Cutsem, J. Machiels, M. Van den Eynde, H. Prenen, A. Hendlisz, L. Shaza, J. Carrasco, J. Canon, P. Sotiropoulou, E. Breman, E. Alcantar, A. Flament
Journal: Annals of Oncology (2019)
Abstract 16554: “To Speak of Death is to Invite It”: Provider Perceptions of Palliative Care for Cardiovascular Patients in Western Kenya
Authors: Keith R Love, Elizabeth Karin, Daniel Morogo, Florence Toroitich, Juli M Boit, Allison Tarus, Felix A Barasa, Nathan E Goldstein, Myra Koech, Rajesh Vedanthan
Journal: Circulation (2017)

Introduction: Cardiovascular disease (CVD) is the global leading cause of death and a significant health burden in Kenya. While palliative care is shown to improve CVD outcomes and quality of life,...
Assessing the potential of immunotherapy in treating chronic lymphocytic leukemia through meta-analysis.
Authors: Jihad Aljabban, David Allen, Sean McDermott, Ross Wanner, Hussam Salhi, Saad A Syed, David Chen, Dexter Hadley, Dania Khoulani
Journal: Journal of Clinical Oncology (2019)

7531 Background: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and has a heterogenous presentation. CLL is known to shape the immune response to survive. Studying these processes will help gauge the potential success of immunotherapy and point to therapeutic targets. Methods: We used our Search, Tag, Analyze, Resource platform to meta-analyze patient samples from Gene Expression Omnibus. We tagged peripheral B cells from 741 CLL patients and peripheral B cell samples from 150 healthy donors as a control. We also tagged and compared B cell samples from 84 CLL progressors to 91 patients with stable CLL. Lastly, we tagged peripheral T cells from 70 CLL patients and T cells from 35 healthy donors as a control. We then analyzed the signature in Ingenuity Pathway Analysis. Results: Analysis of CLL cell samples identified T cell exhaustion signaling as our top canonical pathway. IL2, IL5, and TGFB1 were top upstream regulators. We found upregulation of PDL1, CTLA4, and Lag3, known markers for immunosuppressive B cells. FMOD, which sequesters TGFB, was also upregulated along with molecules that modulate BCR signaling such as MIR155HG. EBF1, required for B cell differentiation, and the co-stimulatory molecule CD80 were downregulated. Analysis of progressing CLL versus stable CLL highlighted metabolic changes. S-adenosyl-L-methionine biosynthesis, methionine degradation to homocysteine, cysteine biosynthesis, and acetate conversion to acetyl-CoA were top canonical pathways. No difference was seen in PDL1, CTLA4, and Lag3 expression but EBF1 was upregulated. Lastly, our T cell analysis demonstrated NFAT in regulation of the immune response as the top canonical pathway. Conclusions: Our results reinforce the promise immunotherapy can have in treatment of CLL and suggests more aggressive cases of CLL are a function of metabolic changes as opposed to differences in immune escape. We also suggest a role of NFAT in T cell exhaustion in the context of CLL.