tbuckley/cabot-search huggingface dataset:
Safety, Tolerability, and Pharmacodynamics of <scp>ABT</scp>‐122, a Tumor Necrosis Factor– and Interleukin‐17–Targeted Dual Variable Domain Immunoglobulin, in Patients With Rheumatoid Arthritis
Authors: Roy M. Fleischmann, Frank Wagner, Alan J. Kivitz, Heikki T. Mansikka, Nasser Khan, Ahmed A. Othman, Amit Khatri, Feng Hong, Ping Jiang, Melanie Ruzek, Robert J. Padley
Journal: Arthritis & Rheumatology (2017)

Objective Tumor necrosis factor ( TNF ) and interleukin‐17 ( IL ‐17) independently contribute to the pathophysiology of rheumatoid arthritis ( RA ). ABT ‐122 is a novel dual variable domain immunoglobulin that selectively and simultaneously targets human TNF and IL ‐17A. The aim of treatment with ABT ‐122 is to evoke a greater clinical response than that achieved by targeting either cytokine alone. This study was undertaken to present the pooled safety, tolerability, and exploratory pharmacodynamics of ABT ‐122 based on 2 phase I, placebo‐controlled, multiple ascending‐dose studies in patients with primarily inactive RA . Methods Patients (n = 44) receiving stable dosages of methotrexate (2.5–25 mg/week) were randomized to receive subcutaneous placebo, ABT ‐122 1 mg/kg every other week (4 doses), or ABT ‐122 0.5, 1.5, or 3 mg/kg weekly (8 doses) and were evaluated through 45 days after the last dose (day 92). Serum samples for the assessment of inflammation markers and chemokines were collected at baseline and on postdose days 3, 5, 8, 15, 29, 57, 64, 78, and 92. Results No clinically significant findings regarding the safety of ABT ‐122 were observed. The rates of treatment‐emergent adverse events ( AE s) were similar in patients receiving ABT ‐122 and those receiving placebo. Only 1 serious AE (and no systemic hypersensitivity reactions or dose‐limiting toxicities) was observed in patients treated with ABT ‐122. The incidence of infections was similar between patients treated with ABT‐122 and those receiving placebo, with no serious infection reported. The levels of CXCL 9, CXCL 10, CCL 23, and soluble E‐selectin were significantly decreased following ABT ‐122 treatment relative to placebo treatment. Although patients had essentially inactive RA , exploratory clinical parameters suggested potential antiinflammatory effects following treatment with ABT ‐122. Conclusion The results of these phase I studies suggest that dual neutralization of TNF and IL ‐17 with ABT ‐122 has characteristics acceptable for further exploration of therapeutic potential in TNF ‐ and IL ‐17A–driven immune‐mediated inflammatory diseases.
Coordination‐Accelerated “Iron Extraction” Enables Fast Biodegradation of Mesoporous Silica‐Based Hollow Nanoparticles
Authors: Liying Wang, Minfeng Huo, Yu Chen, Jianlin Shi
Journal: Advanced Healthcare Materials (2017)

Biodegradation behavior of inorganic silica-based nanoplatforms is of critical importance in their clinical translations, but still remains a great challenge in achieving this goal by composition regulation of biocompatible silica framework. In the present work, a chemical coordination-accelerated biodegradation strategy to endow hollow mesoporous silica nanoparticles (HMSNs) with unique coordination-responsive biodegradability, on-demand coordination-responsive drug releasing behavior, and significantly enhanced chemotherapeutic efficacy by directly doping iron (Fe) ions into the framework of mesoporous silica is reported. A simple but versatile dissolution-regrowth strategy has been developed to enable the framework Fe doping via chemical bonding. The deferiprone-mediated biodegradation of Fe-doped HMSNs (Fe-HMSNs) has been comprehensively evaluated both in simulated body fluid and intracellular level, which have exhibited a specific coordination-accelerated biodegradation behavior. In addition to high biocompatibility of Fe-HMSNs, the anticancer drug doxorubicin (DOX)-loaded Fe-HMSNs show enhanced tumor-suppressing effect on 4T1 mammary cancer xenograft. This work paves a new way for tuning the biodegradation performance of mesoporous silica-based nanoplatforms simply by biocompatible Fe-ion doping into silica framework based on the specific coordination property between introduced metal Fe ions with Fe-coordination proteins.
Effect of evening melatonin on the survival of patients with advanced non-small cell lung cancer (ANSCLC).
Authors: Christopher G. Lis, Robert D. Levin, James F. Grutsch, Timothy C. Birdsall, Patricia Ann Wood, Dinah Faith Q Huff, Justin Reynolds, Mary Ann Daehler, Dennis Pearl, Xiaoping Shen, David E Blask, William J. Hrushesky
Journal: Journal of Clinical Oncology (2014)

e19068 Background: Melatonin secreted only during nightly darkness promotes sleep and sets daily clocks. Cancer disrupts daily rhythms, nighttime sleep, and causes daytime fatigue. Meta-analyses report that melatonin improves cancer response and patient survival. We hypothesized that proper daily timing is essential to melatonin benefit. Methods: Eighty-four ANSCLC patients (20 Stage IIB, 64 Stage IV) from one of two centers (42 each) each receiving etoposide/cisplatin therapy, were blindly and randomly assigned to one of three arms (I, 8AM & 8PM placebo n=29; II, 8AM 20mg melatonin and 8PM placebo, n=27; III, 8AM placebo and 8PM 20mg melatonin, n=28). Each patient was followed to death; 49 were evaluable for objective response assessment by RECIST criteria. Sleep quality and quality of life (QOL) queries were made at baseline and every three months. Results: Overall survival was not significantly impacted by melatonin in a univariate analysis. Multivariate analyses reveal better survival only for those receiving evening melatonin (p=0.04, RR of death 0.454). Objective partial tumor response occurred in 10.5% of placebo, 7.7% of morning melatonin, and 29.4% of evening melatonin-treated patients. Sleep quality was enhanced and QOL declined less rapidly when PM melatonin was employed. Conclusions: Physiologic evening timing of the chronobiotic hormone melatonin is critical to its salutary effect in ANSCLC patients.
Growth Rate and Number of Spontaneous Mammary Carcinomas and Riboflavin Concentration of Liver, Muscle, and Tumor of C3H Mice as Influenced by Dietary Riboflavin
Authors: Harold P. Morris, William v. B. Robertson
Journal: JNCI Journal of the National Cancer Institute (1943)

Growth Rate and Number of Spontaneous Mammary Carcinomas and Riboflavin Concentration of Liver, Muscle, and Tumor of C3H Mice as Influenced by Dietary Riboflavin Get access Harold P. Morris, Harold P. Morris senior nutrition chemist Search for other works by this author on: Oxford Academic PubMed Google Scholar William v. B. Robertson William v. B. Robertson research fellow National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 3, Issue 5, June 1943, Pages 479–489, https://doi.org/10.1093/jnci/3.5.479 Published: 01 June 1943
Treatment intensity and duration in patients receiving first-line taxane chemotherapy for stage IV non-small cell lung cancer.
Authors: Jared Weiss, Rex W. Force, Brooke A. Pugmire, Teri Peterson, Claudio Faria, Sandra Margunato-Debay
Journal: Journal of Clinical Oncology (2015)

e19011 Background: In a phase III trial, weekly nab-paclitaxel (nab-P) plus carboplatin demonstrated a higher response rate than paclitaxel (P) every 3 weeks plus carboplatin, with less grade ≥ 3 neuropathy, neutropenia, arthralgia, and myalgia but more thrombocytopenia and anemia in patients with advanced NSCLC (Socinski et al. J Clin Oncol. 2012;30:2055-62). We hypothesized that these differences might lead to differences in cumulative dose received and regimen duration in clinical practice. Methods: Fully de-identified electronic medical records (EMRs) from October 1, 2012, to September 30, 2014, from a national EMR (OncoEMR; Altos Solutions) were analyzed. Patients receiving first-line therapy with either weekly P (P7), every 3 weeks P (P21), or weekly nab-P for stage IV NSCLC were identified. The majority of patients also received carboplatin. The total cumulative dose (mg/m2), treatment duration, and database persistence (a surrogate for overall survival) for the taxane regimens were determined. Regression and Cox proportional hazards models were used to assess the three groups with the inclusion of age, sex, race, platin use, bevacizumab use, histology, use of prior adjuvant taxanes, and comorbidities (a total of 11 degrees of freedom) to control for the potentially confounding effects of these variables. Results: A total of 475 patients had complete data. 208 patients with NSCLC received P7, 153 received P21, and 114 received nab-P. The cumulative dose was significantly greater for nab-P (932 mg vs 487 mg for P7 and 695 mg for P21; P < 0.001 for both). The median regimen duration was 104.5 days for nab-P, 69.5 days for P7, and 84.0 days for P21; P < 0.05 for both. The median database persistence after taxane initiation was significantly longer for nab-P (387 days) than for P7 (217 days) and P21 (202 days); P < 0.001 for both. Conclusions: Patients with NSCLC treated with nab-P had longer treatment duration, received a greater cumulative dose and had longer database persistence than patients treated with P7 or P21.
mTOR and HDAC Inhibitors Converge on the TXNIP/Thioredoxin Pathway to Cause Catastrophic Oxidative Stress and Regression of RAS-Driven Tumors
Authors: Clare F. Malone, Chloe Emerson, Rachel Ingraham, William Barbosa, Stephanie Guerra, Haejin Yoon, Lin L. Liu, Franziska Michor, Marcia Haigis, Kay F. Macleod, Ophélia Maertens, Karen Cichowski
Journal: Cancer Discovery (2017)

Although agents that inhibit specific oncogenic kinases have been successful in a subset of cancers, there are currently few treatment options for malignancies that lack a targetable oncogenic driver. Nevertheless, during tumor evolution cancers engage a variety of protective pathways, which may provide alternative actionable dependencies. Here, we identify a promising combination therapy that kills NF1-mutant tumors by triggering catastrophic oxidative stress. Specifically, we show that mTOR and HDAC inhibitors kill aggressive nervous system malignancies and shrink tumors in vivo by converging on the TXNIP/thioredoxin antioxidant pathway, through cooperative effects on chromatin and transcription. Accordingly, TXNIP triggers cell death by inhibiting thioredoxin and activating apoptosis signal-regulating kinase 1 (ASK1). Moreover, this drug combination also kills NF1-mutant and KRAS-mutant non-small cell lung cancers. Together, these studies identify a promising therapeutic combination for several currently untreatable malignancies and reveal a protective nodal point of convergence between these important epigenetic and oncogenic enzymes.Significance: There are no effective therapies for NF1- or RAS-mutant cancers. We show that combined mTOR/HDAC inhibitors kill these RAS-driven tumors by causing catastrophic oxidative stress. This study identifies a promising therapeutic combination and demonstrates that selective enhancement of oxidative stress may be more broadly exploited for developing cancer therapies. Cancer Discov; 7(12); 1450-63. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1355.
Slow down to strengthen sport and exercise medicine research
Authors: Thomas Bandholm, Marius Henriksen, Kristian Thorborg
Journal: British Journal of Sports Medicine (2017)

Research needs to be both trustworthy and clinically useful. It can improve treatment of patients either alone or when integrated with other evidence. However, a requirement for research to be both useful and trustworthy is that the applied research methods are of high standards. Unfortunately, this is not always the case. At least as long ago as 1994, Professor Doug Altman stated: “ We need less research, better research, and research done for the right reasons in his opinion piece ’The scandal of poor medical research’.1 In 2009, it was estimated that as much as 85% of all medical research is useless or untrustworthy, usually because it asks the wrong questions, is badly designed, not published or poorly reported.2 Research in sport and exercise medicine (SEM) is no exception.3 The competitiveness for grants, position and prestige is rising in this area of research, evidenced by the increasing number of annual SEM publications. The number of PubMed hits using ‘sports …
The impact of clinical response to anti-CTLA4 treatment on overall survival (OS) in metastatic melanoma (MM).
Authors: Xiaolan Feng, Michael Smylie, Tina Cheng, Jose Gerard Monzon, Richard M. Lee-Ying
Journal: Journal of Clinical Oncology (2014)

9080 Background: It is well known that response to anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA4) treatment can be durable in patients with MM. But it is not known whether clinical response to induction anti-CTLA4 treatment would translate into an OS benefit. Furthermore, predictors of response to anti-CTLA4 agents are not well-established. Methods: We performed a retrospective analysis on one hundred patients treated with anti-CTLA4 agents from 2006-2013 in two tertiary cancer centers in Alberta, Canada. Clinical and tumor characteristics, treatment response, toxicity, and survival data were collected through chart review. Clinicians evaluated response based on immune related response criteria. We performed Kaplan-Meier survival analysis, log-rank test and cox proportional hazards model to compare variable groups and univariable analysis using logistic regression to look for factors associated with clinical response to anti-CTLA4 agents. All statistical analyses were carried out using SAS software. Results: Striking differences in median OS (mOS) were observed in responders, defined as complete response (CR) plus partial response (PR), and non-responders defined as stable disease (SD) plus progressive disease (PD) (not reached; greater than 36.1 versus 6.9 months, 95% confidence interval (CI) 3.6-10.9, p<0.0001, respectively). A 9 fold difference in mOS was seen between patients with disease control (CR+PR+SD) and those with PD on induction treatment: 36.1 months (95%CI: 22.9-51.4) versus 4.0 months (95%CI: 3-6.7), respectively (p <0.0001). Only host-tumor immunological parameters were associated with a response to anti-CTLA4 treatment. Brisk, as opposed to non-brisk, tumor infiltrating lymphocytes in the primary tumor (p=0.003) and immune mediated side effects (p=0.048) were associated with response in univariable analysis. Conclusions: Our retrospective study, although limited by small population size, reveals that response to induction anti-CTLA4 agents is a dominant predictor for survival. Host-tumor immunological parameters may be important determinants for response to anti-CTLA4 agents, although these need to be prospectively validated.
Quality of Lymph Node Assessment and Survival Among Patients With Non–Small Cell Lung Cancer
Authors: Giye Choe, Paul Schipper
Journal: JAMA Oncology (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 Oncology 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 Oncology journal
Abstract 18889: Circulating microRNA Implicated in the TGF-β Signalling Pathway are Altered in Marfan Syndrome
Authors: Elizabeth N Robertson, Yaxin Lu, Alex Sahagian, Donna Lai, Murat Kekic, Brett Hambly, Richmond Jeremy
Journal: Circulation (2015)

Thoracic aortic aneurysms in Marfan Syndrome (MFS) caused by mutations in FBN1 are associated with altered TGF-β signaling. Regulation of gene expression can occur at the level of microRNA, which can modify signaling pathways. We hypothesized that there would be altered microRNA expression in MFS that may alter the expression of signaling proteins. Total RNA was isolated from whole blood collected in PAXgene® tubes (PreAnalytiX), from 13 MFS patients with aortic dilatation (6F, 7M; Ao Diameter 44.4±6.0mm; Age 39±12yrs) and 10 normal controls (5F, 5M; Ao Diameter 32.3±5mm; Age 34±10yrs). The RNA was reverse transcribed with Human Pool A &amp; B primers and qPCR was performed on the subsequent cDNA using TaqMan® OpenArray® Human miRNA Panels (2454 targets) (ThermoFisher). microRNA expression was considered to be significantly altered if there was &gt;2 fold change (p&lt;0.05) compared to controls. microRNA that were identified as significantly altered were then validated with qPCR using targeted primers on an additional 33 MFS patients (15F, 21M; Ao Diameter 44.2±5.0mm; Age 37±13yrs). In MFS patients, the OpenArray® identified 30 microRNA were significantly altered (22 up regulated, 8 down regulated). Of these, 12 were confirmed to be altered using targeted qPCR (Graph 1). Three of these have previously been identified as modifiers of the TGF-β signaling pathway (miR 17, miR 93, miR 93*). Three were from the let-7 family (let-7e, let-7f, let-7g), which are involved in terminal cell differentiation and have been implicated in several cardiovascular disease processes. Another three have been shown to be dysregulated in various cardiovascular disease states including atherosclerotic thoracic aortic aneurysm and left ventricular hypertrophy (miR 208, miR 486, miR 378). This study provides novel evidence for adaptive responses at the post-transcriptional level of gene expression that may modulate aneurysm development in Marfan syndrome.
Trends for prevalence and incidence of resistant hypertension: population based cohort study in the UK 1995-2015
Authors: Sarah-Jo Sinnott, Liam Smeeth, Elizabeth Williamson, Ian J Douglas
Journal: BMJ (2017)

<b>Objective</b>&nbsp;To estimate the incidence and prevalence of resistant hypertension among a UK population treated for hypertension from 1995 to 2015. <b>Design</b>&nbsp;Cohort study. <b>Setting</b>&nbsp;Electronic health records from the UK Clinical Practice Research Datalink in primary care. <b>Participants</b>&nbsp;1 317 290 users of antihypertensive drugs with a diagnosis of hypertension. <b>Main outcome measures</b>&nbsp;Resistant hypertension was defined as concurrent use of three antihypertensive drugs inclusive of a diuretic, uncontrolled hypertension (≥140/90 mm Hg), and adherence to the prescribed drug regimen, or concurrent use of four antihypertensive drugs inclusive of a diuretic and adherence to the prescribed drug regimen. To determine incidence, the numerator was new cases of resistant hypertension and the denominator was person years of those with treated hypertension and at risk of developing resistant hypertension. To determine prevalence, the numerator was total number of cases with resistant hypertension and the denominator was those with treated hypertension. Prevalence and incidence were age standardised to the 2015 hypertensive population. <b>Results</b>&nbsp;The age standardised incidence of resistant hypertension increased from 0.93 cases per 100 person years (95% confidence interval 0.87 to 1.00) in 1996 to a peak level of 2.07 cases per 100 person years (2.03 to 2.12) in 2004. Incidence then decreased to 0.42 cases per 100 person years (0.40 to 0.44) in 2015. Age standardised prevalence increased from 1.75% (95% confidence interval 1.66% to 1.83%) in 1995 to a peak of 7.76% (7.70% to 7.83%) in 2007. Prevalence then plateaued and subsequently declined to 6.46% (6.38% to 6.54%) in 2015. Compared with patients aged 65-69 years, those aged 80 or more years were more likely to have prevalent resistant hypertension throughout the study period. <b>Conclusions</b>&nbsp;Prevalent resistant hypertension has plateaued and decreased in recent years, consistent with a decrease in incidence from 2004 onwards. Despite this, resistant hypertension is common in the UK hypertensive population. Given the importance of hypertension as a modifiable risk factor for cardiovascular disease, reducing uncontrolled hypertension should remain a population health focus.
A clinical approach to genetic testing for non-specialists
Authors: Christopher Semsarian, Jodie Ingles
Journal: BMJ (2017)

#### What you need to know

A 32 year old mother of two presents to her general practitioner after the sudden death of her previously healthy 29 year old brother. Postmortem examination identified an underlying inherited cardiomyopathy, and subsequent genetic analysis of postmortem DNA found the Arg502Trp variant in the MYBPC3 gene, a common cause of hypertrophic cardiomyopathy.1 Given the familial risk, relatives were advised to seek medical attention. The woman raises questions, including what the disease risk is for herself, her two children, siblings, and parents, what the gene result means, and whether the family should pursue genetic testing. She is concerned about preventing any further sudden deaths in her family. Here we provide an overview of the basic principles of genetic testing and how these can be applied in a general clinical setting.

Inheritance of traits hails from Mendel’s pea experiments in the 1800s, where he showed that parents contribute an allele each to their offspring, with one “dominating” the other. This principle is the basis of modern medical genetics, where Mendelian diseases are inherited in families as autosomal dominant, recessive, or X linked traits (box 1). Adding to the complexity in humans, we also see incomplete penetrance—ie, the non-expression of a trait, and clinical heterogeneity, where variability in clinical characteristics due to environmental and other genetic factors occurs. While Mendelian inheritance refers to the inheritance of …