tbuckley/cabot-search huggingface dataset:
Asparagine synthetase is a biomarker of L-asparaginase activity in multiple cancer cell types
Authors: Philip Lorenzi, Daniel Webster, Natasha Caplen, John Weinstein
Journal: Clinical Cancer Research (2008)

B28  Molecular profiling can identify biomarkers that predict response to therapy in cell lines, in animal models, and in the clinic. We recently used molecular profiling and RNAi analysis to show that asparagine synthetase (ASNS) is a causal biomarker for activity of the anti-leukemia enzyme-drug L-asparaginase (L-ASP) in ovarian lines of the NCI-60 panel. Although leukemic and ovarian were the only subpanels of the NCI-60 to exhibit strong L-ASP/ASNS correlations, we nevertheless hypothesized that modulation of ASNS expression by RNAi would reveal a causal relationship between ASNS expression and L-ASP efficacy in other cancer cell types as well. In support of that hypothesis, we have now found that RNAi-mediated silencing of ASNS results in a 3- to 10,000-fold potentiation of L-ASP activity in breast, colon, CNS, prostate, melanoma, and renal cancers lines from the NCI-60 set. Interestingly, we also find that the mechanism of L-ASP potentiation by RNAi involves more than just a leftward shift of the L-ASP dose-response curve; RNAi also suppresses a rightward shift of the dose-response curve caused by ASNS up-regulation following L-ASP treatment. Those findings prompted us to investigate at the RNA and protein levels how well ASNS expression can predict L-ASP activity across multiple cancer types in the NCI-60. The most striking result was that baseline ASNS protein levels yield a strong correlation with L-ASP efficacy (r = -0.64; p = 0.012, one-tailed). These findings provide rationale for clinical evaluation of ASNS protein expression as a predictive biomarker of L-ASP efficacy across multiple cancer types.
Lack of response to intravenous sodium thiosulfate in three cases of extensive connective tissue disease-associated calcinosis cutis
Authors: P. Song, N.M. Fett, J. Lin, J.F. Merola, M. Costner, R.A. Vleugels
Journal: British Journal of Dermatology (2017)

Dystrophic calcinosis cutis is a debilitating condition of calcium salt deposition in the skin often occurring in association with connective tissue disease (CTD). Available treatments for calcinosis cutis are unsatisfactory, but given the recent use of topical and intralesional sodium thiosulfate (STS) to treat calcifying disorders, we sought to describe the use of intravenous (IV) STS for CTD-associated dystrophic calcinosis cutis. We report three patients with long-standing and extensive CTD-associated calcinosis cutis treated with IV STS after having failed multiple prior therapies. All three patients experienced fatigue and nausea with STS infusions, and none of the patients had notable clinical or symptomatic improvement of calcinosis. It remains to be seen whether the administration of IV STS earlier in the onset of calcinosis might be of benefit given that these patients all had long-standing and refractory CTD-associated calcinosis. Given the small number of patients in this series, further investigation into the use of IV STS in calcinosis cutis is warranted.
ADHD Medication and Substance-Related Problems
Authors: Patrick D. Quinn, Zheng Chang, Kwan Hur, Robert D. Gibbons, Benjamin B. Lahey, Martin E. Rickert, Arvid Sjölander, Paul Lichtenstein, Henrik Larsson, Brian M. D’Onofrio
Journal: American Journal of Psychiatry (2017)

Substance use disorders are major contributors to excess mortality among individuals with attention deficit hyperactivity disorder (ADHD), yet associations between pharmacological ADHD treatment and substance-related problems remain unclear. This study investigated concurrent and long-term associations between ADHD medication treatment and substance-related events.The authors analyzed 2005-2014 commercial health care claims from 2,993,887 (47.2% female) adolescent and adult ADHD patients. Within-individual analyses compared the risk of substance-related events (i.e., emergency department visits related to substance use disorders) during months in which patients received prescribed stimulant medication or atomoxetine relative to the risk during months in which they did not.In adjusted within-individual comparisons, relative to periods in which patients did not receive ADHD medication, male patients had 35% lower odds of concurrent substance-related events when receiving medication (odds ratio=0.65, 95% CI=0.64-0.67), and female patients had 31% lower odds of concurrent substance-related events (odds ratio=0.69, 95% CI=0.67-0.71). Moreover, male patients had 19% lower odds of substance-related events 2 years after medication periods (odds ratio=0.81, 95% CI=0.78-0.85), and female patients had 14% lower odds of substance-related events 2 years after medication periods (odds ratio=0.86, 95% CI= 0.82-0.91). Sensitivity analyses supported most findings but were less consistent for long-term associations among women.These results provide evidence that receiving ADHD medication is unlikely to be associated with greater risk of substance-related problems in adolescence or adulthood. Rather, medication was associated with lower concurrent risk of substance-related events and, at least among men, lower long-term risk of future substance-related events.
Phase I trial of paclitaxel, bevacizumab, and temsirolimus in advanced solid malignancies.
Authors: Shannon Neville Westin, Erin Stashi, Navdeep Pal, Diana L Urbauer, Filip Janku, Sarina Anne Piha-Paul, Aung Naing, Apostolia Maria Tsimberidou, Siqing Fu, David S. Hong, Vivek Subbiah, Daniel D. Karp, Robert L. Coleman, Funda Meric-Bernstam, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2016)

2573 Background: We sought to determine the MTD/recommended phase II (RP2D) dose of the combination of paclitaxel (P), bevacizumab (B), and temsirolimus (T) in patients (pts) with advanced solid tumors. Methods: Doses were escalated across 14 planned dose levels (DL) in a standard 3+3 design (Table). Responses were defined using RECIST 1.0. Results: To date, 61 pts have been enrolled. Four pts withdrew consent after one dose. Dose-limiting toxicities (DLTs) occurred at DL8 (G3 fatigue), DL10 (G3 hypertension, G4 pain), DL11 (G3 mucositis, G4 thrombocytopenia/neutropenia) and DL12 (G3 hyperglycemia). DL10 is being explored in expansion as the RP2D. Most common adverse events ( > 10%) were fatigue (74%; G3/4 5%), hypertriglyceridemia (49%, G3/4 5%), thrombocytopenia (38%, G3/4 7%), nausea (33%, G3/4 0%), mucositis (31%, G3/4 5%), constipation (30%, G3/4 0%), neutropenia (21%, G3/4 8%), diarrhea (20%, G3/4 0%), rash (16%, G3/4 0%), hypertension (13%, 02%), headache (10%, G3/4 2%), and vomiting (10%, G3/4 0%). Of 51pts evaluable for response, six had PR (12%) including NSCL (-64%, 13 months (m)), breast (-42%, 8m; -60% 3m), ovarian (-30%, 6m;), squamous cell cervical (-68%, +4m), and squamous cell tongue (-34%, 2m) cancer. Twenty pts (39%) had SD for 4 m or more including adenoid cystic (-3%, 10m), breast (-28%, 4m; +6%, 10m; +18%, 12m; -25%, 8m; -23%, 9m; -22%, 11m; +6%, 17m; +10%, 7m), chondrosarcoma (+8%, 19m; -19%, 6m), laryngeal/oropharyngeal (-19%, 5m; +12%, 7m), leiomyosarcoma (-10%, 38m; -10%, 8m), endometrial (-2%, 8m), gastric (-10%, 8m), ovarian (-20%, 18m) and renal (-10%, 7m) cancer. Conclusions: The combination of P, B, and T is well tolerated and demonstrates preliminary evidence of tumor activity in a variety of solid tumors, especially breast, gynecologic and squamous cancers. Studies to determine correlation of activity with tumor molecular profile are ongoing. Clinical trial information: NCT01187199.Dose-escalation schedule. DL B mg/kg, IV T mg IV P mg/m2 IV 1* 5 Q3W 12.5 30 Q3W 2* 7.5 Q3W 12.5 30 Q3W 3* 7.5 Q3W 20 30 Q3W 4* 7.5 Q3W 20 60 Q3W 5* 10 Q3W 20 60 Q3W 6* 10 Q3W 25 60 Q3W 7* 10 Q3W 25 80 Q3W 8* 15 Q3W 25 80 Q3W 9** 10 Q2W 25 30 QW x 3 10** 10 Q2W 25 40 QW x 3 11* 15 Q3W 25 120 Q3W 12** 10 Q2W 25 50 QW x 3 13** 10 Q2W 25 60 QW x 3 14** 10 Q2W 25 80 QW x 3 *21d cycle, ** 28d cycle
Abstract P134: Synoviolin Is a Stress-Inducible Endoplasmic/Sarcoplasmic Reticulum E3 Ubiquitin Ligase that Preserves Cardiac Function
Authors: Shirin Doroudgar, Donna J Thuerauf, Mohsin Khan, Sadia Mohsin, Mirko Völkers, Natalie Gude, Oliver J Múller, Mark A Sussman, Christopher C Glembotski
Journal: Circulation Research (2011)

We recently reported that synoviolin1 (syvn1) is a novel endoplasmic reticulum stress response (ERSR) protein that is up-regulated in the mouse heart by ATF6, a cardioprotective, nodal transcription factor of the ERSR. Syvn1 is a unique E3 ubiquitin ligase that retrotranslocates misfolded proteins from endoplasmic/sarcoplasmic reticulum (ER/SR) to the cytosol and subsequently polyubiquitinates them, targeting them for degradation. We now report that syvn1 expression is induced with tunicamycin, thapsigargin, and dithiothreitol, ER stressors that activate ATF6. Moreover, adenovirus-mediated syvn1 overexpression in neonatal rat ventricular cardiac myocytes (NRVCMs) increases contractility. Consistent with this finding, syvn1 overexpression increases calcium transient amplitude as well as diastolic calcium. We also find that syvn1 overexpression decreases secretion of MANF, a protective, anti-hypertrophic, ER/SR protein which we find is conditionally secreted when ER/SR calcium is depleted. We also report MANF as the first example of a is protein whose secretion from ventricular myocytes is conditionally dependent on ER/SR calcium. Furthermore, syvn1 reduces the growth of NRVCMs treated with the α-adrenergic agonist, phenylephrine. Moreover, while knockdown of syvn1 in NRVCMs using syvn1-targeted siRNA increases cell death, overexpression of syvn1 promotes cell survival. To investigate the roles of syvn1, in vivo , we examined the effects of syvn1 overexpression in cardiac myocytes in a mouse model of trans-aortic banding. Syvn1 overexpression, in vivo, was achieved by intravenous delivery of recombinant AAV serotype 9 (AAV9; cardiac specific serotype) with MLC2v promoter driving syvn1 expression. Baseline cardiac function, as measured by echocardiography six weeks after gene delivery, shows no difference between AAV9-control and AAV9-syvn1 treated mice. Trans-aortic banding decreases cardiac function in mice injected with AAV9-control. In contrast, cardiac function is preserved in mice injected with AAV9-syvn1. The findings in this study suggest that syvn1 is a novel stress-inducible cardiac E3 ligase with unique functions in regulating protein secretion, maintaining cell viability, and preserving cardiac function.
Pathologic Outcomes of Laparoscopic vs Open Mesorectal Excision For Rectal Cancer—Reply
Authors: Nicola de’Angelis, Aleix Martínez-Pérez, Francesco Brunetti
Journal: JAMA Surgery (2017)

In Reply We share a great enthusiasm toward laparoscopy and other minimally invasive techniques for rectal cancer surgery (eg, transanal and robotic resection).1 However, to our knowledge, a consensus on the gold-standard treatment has yet to be reached.
Reactivation of hepatitis B virus infection in patients with rheumatoid arthritis receiving tofacitinib: a real-world study
Authors: Yi-Ming Chen, Wen-Nan Huang, Yi-Da Wu, Ching-Tsai Lin, Yi-Hsing Chen, Der-Yuan Chen, Tsu-Yi Hsieh
Journal: Annals of the Rheumatic Diseases (2017)

A recent study reported long-term safety outcomes of tofacitinib for rheumatoid arthritis (RA) in global clinical trials1; the safety profile of tofacitinib exposure through 8.5 years appeared stable over time, with no new detectable safety signals. However, since most tofacitinib studies excluded patients with chronic hepatitis B (HBV) infection,1 2 the risk of HBV reactivation among tofacitinib-treated patients remains unknown.

More than two billion people globally have been infected by HBV,3 and a substantial number of patients with RA outside North America and Western Europe have coexisting HBV infection.4 HBV reactivation is a critical challenge in patients with RA receiving biological therapy5; consequently, HBV screening is recommended before initiating biologics.3 Janus kinase inhibition may counteract the suppressive effects of interferon α on viral replication6; therefore, we assessed the risk of HBV reactivation in patients receiving tofacitinib.

We established a retrospective cohort of 116 Taiwanese patients with RA who received tofacitinib at a single medical centre between April 2015 …
The Mouse Cortical Connectome, Characterized by an Ultra-Dense Cortical Graph, Maintains Specificity by Distinct Connectivity Profiles
Authors: Răzvan Gămănuţ, Henry Kennedy, Zoltán Toroczkai, Mária Ercsey-Ravasz, David C. Van Essen, Kenneth Knoblauch, Andreas Burkhalter
Journal: Neuron (2018)
Two memorable patients: What it's all about
Authors: R. Harrison
Journal: BMJ (1999)

It is 3 am and rapid eye movement sleep is destroyed by the phone. Momentarily I am confused. The apology starts… a young woman's voice. What time is it? Why me? In an Edinburgh hotel? Sense returns. Scotland was yesterday. I am at home. She is a senior house officer. I am Richard, on call consultant physician. Hello Rachel, no don't worry, I always sound like this.

Two (two?) patients need sectioning …
Calcium and Excitation-Contraction Coupling in the Heart
Authors: David A. Eisner, Jessica L. Caldwell, Kornél Kistamás, Andrew W. Trafford
Journal: Circulation Research (2017)

Cardiac contractility is regulated by changes in intracellular Ca concentration ([Ca2+]i). Normal function requires that [Ca2+]i be sufficiently high in systole and low in diastole. Much of the Ca needed for contraction comes from the sarcoplasmic reticulum and is released by the process of calcium-induced calcium release. The factors that regulate and fine-tune the initiation and termination of release are reviewed. The precise control of intracellular Ca cycling depends on the relationships between the various channels and pumps that are involved. We consider 2 aspects: (1) structural coupling: the transporters are organized within the dyad, linking the transverse tubule and sarcoplasmic reticulum and ensuring close proximity of Ca entry to sites of release. (2) Functional coupling: where the fluxes across all membranes must be balanced such that, in the steady state, Ca influx equals Ca efflux on every beat. The remainder of the review considers specific aspects of Ca signaling, including the role of Ca buffers, mitochondria, Ca leak, and regulation of diastolic [Ca2+]i.
Abstract 19595: Anatomic and Clinical Predictors of Need for Repeat Atrial Fibrillation Ablation
Authors: Yaanik B Desai, Mathew R Levy, Shahriar Iravanian, Edward C Clermont, Heval M Kelli, Robert L Eisner, Mikhael F El-Chami, Angel R Leon, David B Delurgio, Faisal M Merchant
Journal: Circulation (2016)

Introduction:  Although clinical predictors of the need for repeat procedures after catheter ablation of atrial fibrillation (AF) have been evaluated, anatomic predictors have not been well defined.   Hypothesis:  Anatomic features on cardiac magnetic resonance (CMR) imaging can identify patients most likely to require repeat ablation.   Methods:  From Jan. 2004 to Feb. 2014, 307 patients underwent CMR prior to initial AF ablation at our institution. Ablation strategies along with the need for and timing of repeat ablation were determined at the discretion of the treating physician.   Results:  Out of 307 patients, 119 (38.8%) underwent repeat ablation at a mean of 15.0 ± 19.2 months after the initial procedure. Among repeat procedures, 62% were performed primarily for recurrent AF and the remaining for left atrial tachycardias. Across the entire cohort at the initial procedure, mean age was 62.0 ± 10.8 yrs, 75% were male, 23% had persistent AF, 90% had radiofrequency ablation and the remaining had Cryoballoon ablation, without significant differences between those undergoing a single vs. repeat procedures. Other baseline clinical parameters including EF and presence of hypertension, diabetes and sleep apnea were also similar between groups. However, on CMR performed prior to the first ablation, pulmonary vein (PV) ostial diameters were significantly larger in all PVs among those requiring repeat procedures: right superior PV 19.4 ± 4.0 vs. 21.4 ± 4.5 mm (p 2 ) and left (28.0 ± 5.3 vs. 29.2 ± 6.5 cm 2 ) atrial areas were larger among those requiring repeat procedures, the differences were not significant.   Conclusions:  Among patients undergoing AF ablation, clinical variables were not significantly different between those requiring a single vs. repeat procedures. However, PV dimensions assessed by CMR were significantly larger among those likely to require repeat procedures. Further study is required to determine whether strategies at the initial ablation can be used to mitigate the increased risk of need for repeat procedures among those with larger PVs.
Abstract 10453: Fat, Fibre, Sodium Score -A Quick And Valid Tool to Measure Eating Behavior Change Patterns in Cardiac Prevention &amp; Rehabilitation Programs
Authors: Wanda Firth, Bernice Pancura, Maureen Tilley, Nicholas Giacomantonio
Journal: Circulation (2015)

Introduction: The history of nutrition scoring tools and food frequency evaluations is plagued with errors and limitations. However, there remains a need to capture outcomes for eating patterns and nutrition behavior change. Our past work led to development of a valid eating stage scoring tool but it was labor intensive and not practical for many clinic or program settings so we developed a new scoring tool. Hypothesis: The new Fat, Fibre, Sodium score is a quickly applied tool to accurately represent eating behavior and effectively measure nutrition changes, during and post cardiac rehabilitation (CR) programs. Methods: Patients attending a community CR program, participated in an intensive nutrition behavior change intervention with a dietitian. Nutrition evaluation was conducted using three methods; a general Food Score, the new self evaluation tool called the Fat Fibre Sodium score (FFSS) and thirdly,the dietitian's nutrition assessment and evaluation. Patients also had biomedical measures, exercise stress testing and anthropometrics at baseline and 3 month program completion. Results: In the General Food Score,patients went from meeting 79% to 84% of healthy eating guidelines(p&lt;0.0001). 390 patients completed the new FFSS and had improvements for each category; Fat, Fibre and Sodium (p&lt;0.0001). Fibre intake increased from 19 g/day to 27g day. The FFSS for Fibre was validated, and every 8 out of 10 patients had self-scores with 100% accuracy when compared to the dietitian evaluation (p&lt;0.001) The FFSS Fat scores went from 'moderate' to 'low' intake and while the dietitian's assessment validated the fat score at program completion, the baseline FFSS was underreported for fat intake. The sodium component of the FFSS was not valid. Impact of nutrition changes showed that a FFSS 'low fat' score at program completion led to statistically significant weight changes , and LDL lowering (p&lt;0.001)even while changes in exercise were held constant. Conclusions: The FFSS tool is easy to use and is a valid measure of eating behavior changes with fibre intake and also accurately represents dietary fat intake at program completion. Although work needs to continue on the sodium component of the FFSS, the new Fat Fibre Scoring tool can be used with confidence in CR settings.
Systematic liquid biopsy identifies novel and heterogeneous mechanisms of acquired resistance in gastrointestinal (GI) cancer patients
Authors: Aparna Parikh, Lipika Goyal, Mehlika Hazar-Rethinam, Giulia Siravegna, Lawrence Blaszkowsky, Mariangela Russo, Emily Van Seventer, Brandon Nadres, Heather Shahzade, Jeffrey Clark, Jill Allen, Iafrate A. John, David P. Ryan, Janet Murphy, Alberto Bardelli, Andrew Zhu, Theodore Hong, Ryan Corcoran
Journal: Annals of Oncology (2017)
Improvement in Right Ventricular Strain with Ambrisentan and Tadalafil Upfront Therapy in Scleroderma-associated Pulmonary Arterial Hypertension
Authors: Valentina Mercurio, Monica Mukherjee, Ryan J. Tedford, Roham T. Zamanian, Rubina M. Khair, Takahiro Sato, Omar A. Minai, Fernando Torres, Reda E. Girgis, Kelly Chin, Rachel Damico, Todd M. Kolb, Stephen C. Mathai, Paul M. Hassoun
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Laparoscopic Resection in Inflammatory Bowel Disease: Minimal Surgery, Minimal Access, and Minimal Hospital Stay
Authors: E Boyle, PF Ridgway, F Keane, P Neary
Journal: Endoscopy (2006)

Aims: Bowel resection for Inflammatory Bowel Disease (IBD) is associated with prolonged hospitalisation and significant access related trauma. The authors hypothesise that a minimal access approach confers earlier postoperative gastrointestinal recovery and reduced hospitalisation compared to conventional open resection.
A sputum gene expression signature predicts oral corticosteroid response in asthma
Authors: Bronwyn S. Berthon, Peter G. Gibson, Lisa G. Wood, Lesley K. MacDonald-Wicks, Katherine J. Baines
Journal: European Respiratory Journal (2017)

Biomarkers that predict responses to oral corticosteroids (OCS) facilitate patient selection for asthma treatment. We hypothesised that asthma patients would respond differently to OCS therapy, with biomarkers and inflammometry predicting response.Adults with stable asthma underwent a randomised controlled cross-over trial of 50 mg prednisolone daily for 10 days (n=55). A six-gene expression biomarker signature (CLC, CPA3, DNASE1L3, IL1B, ALPL and CXCR2) in induced sputum, and eosinophils in blood and sputum were assessed and predictors of response were investigated (changes in forced expiratory volume in 1 s (ΔFEV1), six-item Asthma Control Questionnaire score (ΔACQ6) or exhaled nitric oxide fraction (ΔFeNO)).At baseline, responders to OCS (n=25) had upregulated mast cell CPA3 gene expression, poorer lung function, and higher sputum and blood eosinophils. Following treatment, CLC and CPA3 gene expression was reduced, whereas DNASE1L3, IL1B, ALPL and CXCR2 expression remained unchanged. Receiver operating characteristic (ROC) analysis showed the six-gene expression biomarker signature as a better predictor of clinically significant responses to OCS than blood and sputum eosinophils.The six-gene expression signature including eosinophil and Th2 related mast cell biomarkers showed greater precision in predicting OCS response in stable asthma. Thus, a novel sputum gene expression signature highlights an additional role of mast cells in asthma, and could be a useful measurement to guide OCS therapy in asthma.