tbuckley/cabot-search huggingface dataset:
Tremelimumab and durvalumab (MEDI4736) combination for first and second-line treatment of mesothelioma patients: The NIBIT-MESO-1 study.
Authors: Luana Calabrò, Aldo Morra, Diana Giannarelli, Diego Annesi, Erica Bertocci, Riccardo Danielli, Maresa Altomonte, Anna Maria Di Giacomo, Michele Maio
Journal: Journal of Clinical Oncology (2016)

TPS8575 Background: Malignant mesothelioma (MM) has a very dismal prognosis and treatment of MM patients remains largely unsatisfactory; thus, new therapeutic approaches are eagerly awaited. In the MESOT-TREM-2008 study, the anti-CTLA-4 monoclonal antibody (mAb) tremelimumab showed initial signs of activity in pre-treated MM patients: disease control rate (DCR) was 31%, and survival rate at 1- and 2-years was 48.3% and 36.7%, respectively (Calabrò et al., Lancet Oncol, 2013). Corroborating these preliminary findings, based on pharmacokinetic analyses, an intensified schedule of tremelimumab was utilized in the follow-up study MESOT-TREM-2012. Fifty-two % of MM patients achieved a DCR (median duration 10.9 months) (Calabrò et al., Lancet Respir Med, 2015). These intriguing clinical results and the emerging efficacy of immunomodulatory mAb targeting the PD-1/PD-L1 axis in different tumor types, prompted us to design the NIBIT-MESO-1 study aimed to investigate the efficacy of tremelimumab combined with the anti-PD-L1 durvalumab in MM patients. Methods: The NIBIT-MESO-1 trial is a phase II, open-label, study that will enroll 40 unresectable, first-or second-line pleural or peritoneal MM patients with ECOG performance status 0 or 1. Patients will receive tremelimumab at 1 mg/Kg i.v. every 4 weeks (Q4W) for 4 doses, and durvalumab at 20 mg/Kg i.v. Q4W for 12 months. Patients with progressive disease during the first 12 months of treatment or in the follow-up phase may be retreated with the combination of the two drugs. Modified RECIST (Byrne et al., Ann Oncol, 2004) and RECIST 1.1 will be utilized to assess tumor responses in pleural and peritoneal MM, respectively. Primary objective is immune-related (ir)-objective response rate; secondary objectives are ir-DCR; ir-progression free-survival (PFS), overall survival, DCR, PFS, and safety. Efficacy secondary endpoints will be explored per PD-L1 expression on archivial or fresh tumor tissues. Phenotypic, functional and humoral immune-correlates will be investigated (ClinicalTrials.gov Id: NCT02588131). Fourteen MM patients have been enrolled and recruiting is ongoing. Clinical trial information: NCT02588131.
Feasibility of improving identification of familial hypercholesterolaemia in general practice: intervention development study
Authors: Nadeem Qureshi, Stephen Weng, Jennifer Tranter, Alia El-Kadiki, Joe Kai
Journal: BMJ (2016)

Objectives: To assess the feasibility of improving identification of familial hypercholesterolaemia (FH) in primary care, and of collecting outcome measures to inform a future trial.
Design: Feasibility intervention study.
Setting: 6 general practices (GPs) in central England.
Participants: 831 eligible patients with elevated cholesterol >7.5 mmol/L were identified, by search of electronic health records, for recruitment to the intervention.
Intervention:Educational session in practice; use of opportunistic computer reminders in consultations or universal postal invitation over 6 months to eligible patients invited to complete a family history questionnaire. Those fulfilling the Simon-Broome criteria for possible FH were invited for GP assessment and referred for specialist definitive diagnosis.
Outcome measures: Rates of recruitment of eligible patients, identification of patients with possible FH, referral to specialist care, diagnosis of confirmed FH in specialist care; and feasibility of collecting relevant outcome measures for a future trial.
Results: Of 173 general practices, 18 were interested in participating and 6 were recruited. From 831 eligible patients, 127 (15.3%) were recruited and completed family history questionnaires: 86 (10.7%) through postal invitation and 41 (4.9%) opportunistically. Among the 127 patients, 32 (25.6%) had a possible diagnosis of FH in primary care. Within 6 months of completing recruitment, 7 patients had had specialist assessment confirming 2 patients with definite FH (28.6%), and 5 patients with possible FH (71.4%). Potential trial outcome measures for lipid tests, statin prescribing and secondary causes of hypercholesterolaemia were extracted using automated data extraction from electronic records alone without recourse to other methods.
Conclusions: The intervention is feasible to implement in GP, and facilitates recruitment of patients with raised cholesterol for targeted assessment and identification of FH. Extracting data directly from electronic records could be used to evaluate relevant outcome measures in a future trial.
RB-independent activity of Cdk4/6 in bladder cancer.
Authors: Daniel E. Castellano, Carolina Rubio, Fernando López-Calderón, Cristina Segovia, Marta Duenas Porto, Monica Martinez-Fernandez, Irene Otero, Ray Manneh, Juan Manuel Sepúlveda, Felipe Villacampa, Jesus Paramio
Journal: Journal of Clinical Oncology (2016)

e16011 Background: MIBC is treated, in most cases, by cystectomy and platinum-based chemotherapy. Nonetheless, the metastatic spreading occurs very often with fatal consequences. Various targeted therapies are being clinically and preclinically tested for BC management. MIBC have been associated with loss of cell cycle control. Defects in the RB pathway are a major mechanisms of cell cycle deregulation in MIBC. RB1 mutations were reported in 13% of TCGA samples, although significant mutations also were noted in CDKN1A, CDKN2A, and CCND3. The CDK 4/6 complex combines with cyclin D1 to inhibit RB activity. Therapeutic targeting of this complex improves outcome in ER positive advanced breast cancer. Methods: Palbociclib (PD-0332991) is a cdk4/6 inhibitor currently tested for the treatment of other malignancies characterized by the presence of a functional RB1 gene. A series of BC cell lines of known genomic characteristics and differing in their RB1 status, were tested for their sensitivity to Palbociclib. Results: unexpectedly, we observed a similar response to Palbociclib in pRb wt and pRb mutant cell lines in vitro and in xenografts in vivo, although with different biochemical and cell cycle effects. Genomic characterization of these treated cells shows strong gene expression divergence as a consequence of Palbociclib treatment in pRb wt and mutant cells. Nonetheless, bioinformatic analyses revealed FoxM1 as a possible common regulator of some downregulated genes in both cases. Importantly, FoxM1 has been demonstrated a bona fide cdk4 substrate and may confer cis-platinum resistance. We observed reduced FoxM1 phosphorylation upon Palbociclib treatment in all cell lines tested, and also increased sensitivity to cis-platinum. Remarkably, we found that phosphorylated FoxM1 is a potential poor prognosis factor in human BC clinical samples. Conclusions: in our study we observed that the activity of Palbociclib in BC cell lines is independent on the RB1 status and showed synergistic activity with cisplatin. Future studies, using mouse models based on the genetic inactivation of Rb1 with other tumor suppressor genes, will precede the possible development of appropriate clinical trials testing the use of Palbociclib in the management of BC patients.
PS01.04: A Phase II Study of Etirinotecan Pegol (NKTR-102) in Patients with Refractory Brain Metastases and Advanced Lung Cancer
Authors: Joel W. Neal, Heather Wakelee, Sukhmani K. Padda, Sophie Bertrand, Brenda Acevedo, Alison Holmes Tisch, Judy Y. Pagtama, Scott G. Soltys, Seema Nagpal
Journal: Journal of Thoracic Oncology (2016)
Astrocytes to the rescue! Glia limitans astrocytic endfeet control CNS inflammation
Authors: Francisco J. Quintana
Journal: Journal of Clinical Investigation (2017)

The blood-brain barrier (BBB) and the glia limitans serve to prevent the migration of cells and other large molecules from the blood into the CNS. Neuroinflammatory diseases are characterized by disruption of the BBB and increased leukocyte infiltration into the CNS. In this issue of the JCI, Horng and colleagues demonstrate that astrocytes of the glia limitans induce tight junction formation in response to inflammatory cues, thereby tightening the border to limit the number of activated T cells infiltrating the CNS. Moreover, preventing the formation of this inducible barrier in mice increased disease severity in models of neuroinflammation. Together, the results of this study indicate that the inducible barrier of the glia limitans should be further explored as a therapeutic target.
Impact of Physician Specialty Mix on the Outcomes of Patients Dually Diagnosed With Diabetes and Compensated Cirrhosis
Authors: Tsai-Ling Liu, A. Sidney Barritt, Morris Weinberger, John E. Paul, Bruce Fried, Justin G. Trogdon
Journal: Diabetes Care (2017)

Liver cirrhosis, an irreversible chronic condition, was the 11th leading cause of death in the U.S. in 2012 (1). Up to 70% of patients with compensated cirrhosis have coexisting diabetes (2). Previous studies found that patients dually diagnosed with diabetes and compensated cirrhosis are often managed by primary care physicians (PCP), although the percentage who also visit specialists such as gastroenterologists (GI) and endocrinologists (ENDO) is increasing (3). Whether the mix of physician specialties visited is associated with major health events among these dually diagnosed patients is unknown. Therefore, this study investigates whether physician mix affects outcomes of patients dually diagnosed with compensated cirrhosis and diabetes. The study was reviewed and approved by the University of North Carolina at Chapel Hill Institutional Review Board.

This retrospective study analyzed MarketScan Commercial Claims and Encounters and Medicare Supplemental databases (2000–2013). A total of 18,359 adults (aged ≥18 years) with ICD-9 codes indicating both diabetes and compensated cirrhosis were classified into one of …
Telomere mediated genomic instability correlates with the clinico-pathological parameters of breast cancer
Authors: Anuradha Poonepalli, Birendranath Banerjee, Thomas Putti Choudary, Manoor Prakash Hande
Journal: Clinical Cancer Research (2007)

C52   Telomere dysfunction and chromosomal instability is associated with tumour progression in breast cancer. However, the association between telomerase activity and telomere dysfunction with tumour progression remains unclear. In the present study we quantitated the telomerase activity, telomere length and chromosomal instability in correlation with the histopathologic grades and other parameters like the estrogen and progesterone receptor status in 53 breast tissues. In addition, the expression of some telomere related genes have also been studied. Telomerase activity was found to be higher in the higher grades (grade II and III) compared to the lower grade (grade I). Telomerase activity was also detected in the paired adjacent tissues, but much lesser than the cancerous tissues. Paired adjacent tissues were found to have significantly longer terminal restriction fragments (mean ±SD and range; 8.94±2. kb and 6.8 to 13.2 kb) than in the breast tumour tissues (7.7±0.63 kb and 6.7 to 10 kb). The telomere shortening was more significant in grade 3 tumours (p  Telomere shortening in breast carcinomas was confirmed by telomere length assessment on paraffin tissue sections by quantitative FISH (Q-FISH).  The telomere shortening was also associated with telomere dysfunction in the form of increased anaphase bridge formation and this increase was significant in the higher grades. It correlated with the estrogen receptor status where it was higher in estrogen receptor negative tumours. The average expression of TRF1 mRNA was lower in the tumours than the normal tissues. Similarly Pot1 (Protection of Telomeres 1) mRNA expression was compromised in higher grades. Tankyrase 1 mRNA expression showed an increase from lower grades to higher grades. Its expression was also high in estrogen and progesterone negative tumours. Telomere dysfunction and mediated genomic instability might be of value as prognostic indicators in patients with breast cancer.  Acknowledgements: The authors acknowledge the grant support from National Medical Research Council (NMRC) Ministry of Health, National University of Singapore, Singapore.
Amyloidogenic medin induces endothelial dysfunction and vascular inflammation through the receptor for advanced glycation endproducts
Authors: Raymond Q. Migrino, Hannah A. Davies, Seth Truran, Nina Karamanova, Daniel A. Franco, Thomas G. Beach, Geidy E. Serrano, Danh Truong, Mehdi Nikkhah, Jillian Madine
Journal: Cardiovascular Research (2017)

Medin is a common amyloidogenic protein in humans that accumulates in arteries with advanced age and has been implicated in vascular degeneration. Medin's effect on endothelial function remains unknown. The aims are to assess medin's effects on human arteriole endothelial function and identify potential mechanisms underlying medin-induced vascular injury.
Response
Authors: S. L. Hart, M. A. Hoyt, M. Diefenbach, D. R. Anderson, K. M. Kilbourn, L. L. Craft, J. L. Steel, P. Cuijpers, D. C. Mohr, M. Berendsen, B. Spring, A. L. Stanton
Journal: JNCI Journal of the National Cancer Institute (2012)
Computed Tomography Scanning for Early Detection of Lung Cancer
Authors: Francine L. Jacobson, Michael T. Jaklitsch
Journal: Annual Review of Medicine (2018)

Parallel and often unrelated developments in health care and technology have all been necessary to bring about early detection of lung cancer and the opportunity to decrease mortality from lung cancer through early detection of the disease by computed tomography. Lung cancer screening programs provide education for patients and clinicians, support smoking cessation as primary prevention for lung cancer, and facilitate health care for tobacco-associated diseases, including cardiovascular and chronic lung diseases. Guidelines for lung cancer screening will need to continue to evolve as additional risk factors and screening tests are developed. Data collection from lung cancer screening programs is vital to the further development of fiscally responsible guidelines to increase detection of lung cancer, which may include small groups with elevated risk for reasons other than tobacco exposure.
Dual Conditional Loss of BLIMP-1 and p53 in B-Cells Drives B-Cell Lymphomagenesis
Authors: Antonio Sacco, Yawara Kawano, Michele Moschetta, Jihye Park, Oksana Zavidij, Michaela Reagan, Yuji Mishima, Elizabeth A. Morgan, Satoshi Takagi, Salomon Manier, Luisa Imberti, Giuseppe Rossi, Kwok Wong, Ruben D. Carrasco, Irene M. Ghobrial, Aldo M. Roccaro
Journal: Blood (2016)
Preliminary results of a phase Ib trial of savolitinib combined with gefitinib in EGFR-mutant lung cancer.
Authors: Jin-Ji Yang, Liu Yang, Andrew Farnsworth, Amir Handzel, Tanya Coleman, Shethah Morgan, Yi-Long Wu
Journal: Journal of Clinical Oncology (2016)

e20559 Background: Savolitinib (AZD6094, volitinib, HMPL-504) is a potent & selective small molecule MET inhibitor. In preclinical models the combination of savolitinib & gefitnib was more effective than either compound alone (D’Cruz et al, 2014; Zhou et al, 2013). EGFR TKI failure is frequently attributable to MET amplification. Methods: The intent of the study is to test that NSCLC pts who progressed on previous EGFR-TKI treatment, can receive treatment with gefitinib & savolitinib & potentially demonstrate an improved clinical response. This study (NCT02374645) has 2 phases: safety run-in phase (n~12) & expansion phase (n~20). Eligibility requires advanced EGFRm+ NSCLC, measurable disease, adequate PS (0-1) & organ function, progression on any prior EGFR-TKI. MET status is not required for the safety run-in but MET amplification by tumor biopsy confirmation is mandatory in the expansion phase. Data from the safety run-in phase presented here are unvalidated & preliminary. Results: As of 17 January 2016, 13pts have completed the DLT assessment with fixed dose of gefintinib 250 mg QD in combination with savolitinib at 600 mg QD (n = 6) & 800 mg QD (n = 7). No DLT in the 600mg QD cohort & a potential DLT of G3 febrile neutropenia in the 800 mg QD cohort. 11pts are evaluable for response & 12pts are evaluable for safety analysis at the data cut off. Drug-related (either gefitinib or savolitinib) adverse events most common across both dose levels were nausea (40% - G1), blood bilirubin increased (30% - G1/2), vomiting (30% - G1). Two confirmed partial responses (pts METamp neg) were reported at 12wks so far with this combination, at 18wks 1pt had PD & 1pt is ongoing. Exposure & PK parameters for gefitinib & savolitinib lie within range& align well with historical data. Conclusions: The toxicity & PK profile of savolitinib makes rational combination with gefitinib feasible in EGFRm+ NSCLC pts who failed EGFR TKI. The expansion phase in pts with MET amplification will evaluate anti-tumour activity. Reference: D’Cruz, C et al Cancer Res 2014;74(19 Suppl):Abstract nr 3114. Zhou, F et al Cancer Res 2013;73(8 Suppl):Abstract nr 971 Clinical trial information: NCT02374645.
Fructose-1,6-bisphosphatase Inhibits ERK Activation and Bypasses Gemcitabine Resistance in Pancreatic Cancer by Blocking IQGAP1–MAPK Interaction
Authors: Xin Jin, Yunqian Pan, Liguo Wang, Tao Ma, Lizhi Zhang, Amy H. Tang, Daniel D. Billadeau, Heshui Wu, Haojie Huang
Journal: Cancer Research (2017)

Abstract Dysregulation of the MAPK pathway correlates with progression of pancreatic ductal adenocarcinoma (PDAC) progression. IQ motif containing GTPase-activating protein 1 (IQGAP1) is a MAPK scaffold that directly regulates the activation of RAF, MEK, and ERK. Fructose-1,6-bisphosphatase (FBP1), a key enzyme in gluconeogenesis, is transcriptionally downregulated in various cancers, including PDAC. Here, we demonstrate that FBP1 acts as a negative modulator of the IQGAP1–MAPK signaling axis in PDAC cells. FBP1 binding to the WW domain of IQGAP1 impeded IQGAP1-dependent ERK1/2 phosphorylation (pERK1/2) in a manner independent of FBP1 enzymatic activity. Conversely, decreased FBP1 expression induced pERK1/2 levels in PDAC cell lines and correlated with increased pERK1/2 levels in patient specimens. Treatment with gemcitabine caused undesirable activation of ERK1/2 in PDAC cells, but cotreatment with the FBP1-derived small peptide inhibitor FBP1 E4 overcame gemcitabine-induced ERK activation, thereby increasing the anticancer efficacy of gemcitabine in PDAC. These findings identify a primary mechanism of resistance of PDAC to standard therapy and suggest that the FBP1–IQGAP1–ERK1/2 signaling axis can be targeted for effective treatment of PDAC. Cancer Res; 77(16); 4328–41. ©2017 AACR.
Newly Designed Silica‐Containing Redox Nanoparticles for Oral Delivery of Novel TOP2 Catalytic Inhibitor for Treating Colon Cancer
Authors: Long Binh Vong, Shinya Kimura, Yukio Nagasaki
Journal: Advanced Healthcare Materials (2017)

Although oral drug delivery is the most common route of drug administration, the conventional polymeric nanocarriers exhibit a low drug loading capacity and low stability in the gastrointestinal (GI) environments. In this study, a newly designed silica-containing redox nanoparticle (siRNP) with reactive oxygen species (ROS) scavenging capacity is developed as an ideal oral nanocarrier for a novel hydrophobic anticancer compound BNS-22 to treat colitis-associated colon cancer in vivo. Crosslinking of silica moieties significantly enhances the stability under acidic conditions and improves BNS-22 loading capacity of siRNP compared to the conventional redox nanoparticle. After oral administration to mice, BNS-22-loaded siRNP (BNS-22@siRNP) remarkably improves bioavailability and colonic tumor distribution of BNS-22. As the result, BNS-22@siRNP significantly inhibits the tumor progression in colitis-associated colon cancer mice compared to other control treatments. It is noteworthy that no systemic absorption of siRNP carrier is observed after oral administration. Interestingly, orally administered BNS-22@siRNP significantly suppresses the adverse effects of BNS-22 owing to its ROS scavenging capacity, and no other noticeable toxicities are observed in mice treated with BNS-22@siRNP although siRNP is localized in the GI tract. Our results indicate that siRNP is a promising oral drug nanocarrier for cancer therapy.
New endoscopic technique for uncontrollable bilious vomiting after gastrojejunal surgical bypass
Authors: Massimiliano Mutignani, Edoardo Forti, Francesco Pugliese, Alberto Tringali, Marcello Cintolo, Lorenzo Dioscoridi
Journal: Endoscopy (2017)

Gastrojejunal Billroth II or single Roux-en-Y reconstructions that create a defunctionalized loop, are usually performed to treat patients with unresectable periampullary tumors [1] [2]. The main adverse effect is bile reflux [3] [4], with irritation of the gastric mucosa, that can generally be controlled with prokinetic drugs [1] [2] [3] [4]. However, if the symptoms are severe, a redo surgery is the only available option described in the literature [1] [2] [3] [4].
WHAT SEPARATES AN INDIVIDUAL AT RISK OF ACL INJURY? A FIRST STEP TOWARDS AN ACL-RISK MOVEMENT PASSPORT
Authors: Raihana Sharir, Jos Vanrenterghem, Mark Robinson, Keith George
Journal: British Journal of Sports Medicine (2017)

Background Several prospective studies have suggested biomechanical risk factors for non-contact anterior cruciate ligament (ACL) injury. Ideally an individual at risk should be ranked at risk across a variety of dynamic tasks, with robust risk factors deserving an entry in the individual's “ACL risk movement passport”. Objective To determine if key prospective ACL risk factors rank individuals consistently across a variety of dynamic sporting tasks. Design Controlled laboratory study. Setting Biomechanics laboratory, Liverpool John Moores University. Patients (or Participants) Forty-one female athletes regularly participating in dynamic sports. Interventions (or Assessment of Risk Factors) 5 trials of bilateral drop vertical jumps (DVJB), single-leg hops (SLHOP), single-leg drop vertical jumps (DVJ) and sidestep (SS) tasks were performed on both dominant (DOM) and non-dominant (NONDOM) legs. Lower extremity biomechanics of each task were captured using high speed 3-dimensional motion analysis and two force platforms. Main Outcome Measurements Knee abduction angle (KAA) and knee flexion angle (KFA) at initial contact, peak knee abduction moment (KAM), and peak vertical ground reaction force (VGRF) were extracted and population rankings were compared using Spearman's correlations. Results Moderate to good correlations were observed for KAA (ρ=0.481–0.827) whereas all other variables showed low to moderate correlations (ρ&lt;0.39). DVJ and SLHOP showed moderate to high rank correlations across all risk factors. There were no systematic differences in correlation patterns between DOM and NONDOM trials. Conclusions From the existing risk factors, KAA showed most potential to providing a robust item on an individual's ACL risk movement passport. To help guide future identification of biomechanical risk factors of ACL injury, other robust ACL risk movement passport entries that show more consistent rankings across tasks deserve preference over entries that are highly task specific.