tbuckley/cabot-search huggingface dataset:
Analysis of the functional consequences of targeted exon deletion in COL7A1 reveals prospects for dystrophic epidermolysis bullosa therapy
Authors: Olivier Bornert, Tobias Kühl, Jeroen Bremer, Peter C van den Akker, Anna MG Pasmooij, Alexander Nyström
Journal: Molecular Therapy (2016)

Genetically evoked deficiency of collagen VII causes dystrophic epidermolysis bullosa (DEB)—a debilitating disease characterized by chronic skin fragility and progressive fibrosis. Removal of exons carrying frame-disrupting mutations can reinstate protein expression in genetic diseases. The therapeutic potential of this approach is critically dependent on gene, protein, and disease intrinsic factors. Naturally occurring exon skipping in COL7A1, translating collagen VII, suggests that skipping of exons containing disease-causing mutations may be feasible for the treatment of DEB. However, despite a primarily in-frame arrangement of exons in the COL7A1 gene, no general conclusion of the aptitude of exon skipping for DEB can be drawn, since regulation of collagen VII functionality is complex involving folding, intra- and intermolecular interactions. To directly address this, we deleted two conceptually important exons located at both ends of COL7A1, exon 13, containing recurrent mutations, and exon 105, predicted to impact folding. The resulting recombinantly expressed proteins showed conserved functionality in biochemical and in vitro assays. Injected into DEB mice, the proteins promoted skin stability. By demonstrating functionality of internally deleted collagen VII variants, our study provides support of targeted exon deletion or skipping as a potential therapy to treat a large number of individuals with DEB. Genetically evoked deficiency of collagen VII causes dystrophic epidermolysis bullosa (DEB)—a debilitating disease characterized by chronic skin fragility and progressive fibrosis. Removal of exons carrying frame-disrupting mutations can reinstate protein expression in genetic diseases. The therapeutic potential of this approach is critically dependent on gene, protein, and disease intrinsic factors. Naturally occurring exon skipping in COL7A1, translating collagen VII, suggests that skipping of exons containing disease-causing mutations may be feasible for the treatment of DEB. However, despite a primarily in-frame arrangement of exons in the COL7A1 gene, no general conclusion of the aptitude of exon skipping for DEB can be drawn, since regulation of collagen VII functionality is complex involving folding, intra- and intermolecular interactions. To directly address this, we deleted two conceptually important exons located at both ends of COL7A1, exon 13, containing recurrent mutations, and exon 105, predicted to impact folding. The resulting recombinantly expressed proteins showed conserved functionality in biochemical and in vitro assays. Injected into DEB mice, the proteins promoted skin stability. By demonstrating functionality of internally deleted collagen VII variants, our study provides support of targeted exon deletion or skipping as a potential therapy to treat a large number of individuals with DEB.
Ventricular Arrhythmias in Patients With a Continuous-Flow Left Ventricular Assist Device
Authors: Sing-Chien Yap, Faiz Ramjankhan, Rahat Muslem, Nicolaas de Jonge, Hans J. Kirkels, Sakir Akin, Olivier C. Manintveld, Ozcan Birim, Tamas Szili-Torok, Kadir Caliskan
Journal: Journal of the American College of Cardiology (2016)
Beta-blockers in COPD: time for reappraisal
Authors: Brian Lipworth, Jadwiga Wedzicha, Graham Devereux, Jørgen Vestbo, Mark T. Dransfield
Journal: European Respiratory Journal (2016)

The combined effects on the heart of smoking and hypoxaemia may contribute to an increased cardiovascular burden in chronic obstructive pulmonary disease (COPD). The use of beta-blockers in COPD has been proposed because of their known cardioprotective effects as well as reducing heart rate and improving systolic function. Despite the proven cardiac benefits of beta-blockers post-myocardial infarction and in heart failure they remain underused due to concerns regarding potential bronchoconstriction, even with cardioselective drugs. Initiating treatment with beta-blockers requires dose titration and monitoring over a period of weeks, and beta-blockers may be less well tolerated in older patients with COPD who have other comorbidities. Medium-term prospective placebo-controlled safety studies in COPD are warranted to reassure prescribers regarding the pulmonary and cardiac tolerability of beta-blockers as well as evaluating their potential interaction with concomitant inhaled long-acting bronchodilator therapy. Several retrospective observational studies have shown impressive reductions in mortality and exacerbations conferred by beta-blockers in COPD. However, this requires confirmation from long-term prospective placebo-controlled randomised controlled trials. The real challenge is to establish whether beta-blockers confer benefits on mortality and exacerbations in all patients with COPD, including those with silent cardiovascular disease where the situation is less clear.
Fukuoka criteria accurately predict risk for adverse outcomes during follow-up of pancreatic cysts presumed to be intraductal papillary mucinous neoplasms
Authors: Saurabh Mukewar, Nicolo de Pretis, Anupama Aryal-Khanal, Nazir Ahmed, Raghuwansh Sah, Felicity Enders, Joseph J Larson, Michael J Levy, Naoki Takahashi, Mark Topazian, Randall Pearson, Santhi S Vege, Suresh T Chari
Journal: Gut (2016)

<h3>Objective</h3> Fukuoka consensus guidelines classify pancreatic cystic lesions (PCLs) presumed to be intraductal papillary mucinous neoplasms (IPMNs) into Fukuoka positive (FP) (subgroups of high-risk (HR) and worrisome features (WFs)) and Fukuoka negative (FN) (non-HR feature/WF cysts). We retrospectively estimated 5-year risk of pancreatic cancer (PC) in FN, WF and HR cysts of patients with PCL-IPMN. <h3>Design</h3> From Mayo Clinic databases, we randomly selected 2000 patients reported to have a PCL; we excluded inflammatory or suspected non-IPMN cysts and those without imaging follow-up. We re-reviewed cross-sectional imaging and abstracted clinical and follow-up data on PCL-IPMNs. The study contained 802 patients with FN cysts and 358 with FP cysts. <h3>Results</h3> Patients with PCL-IPMN had median (IQR) follow-up of 4.2 (1.8–7.1) years. Among FN cysts, 5-year PC risk was low (2–3%) regardless of cyst size (p=0.67). After excluding events in the first 6 months, 5-year PC risk remained low (0–2%) regardless of cyst size (p=0.61). Among FP cysts, HR cysts (n=66) had greater 5-year PC risk than WF cysts (n=292) (49.7% vs 4.1%; p&lt;0.001). In HR cysts, 3-year PC risk was greatest for obstructive jaundice versus enhancing solid component or main pancreatic duct &gt;10 mm (79.8% vs 37.3% vs 39.4%, respectively; p=0.01). <h3>Conclusions</h3> Fukuoka guidelines accurately stratify PCL-IPMNs for PC risk, with FN cysts having lowest and HR cysts having greatest risk. After 6-month follow-up, WF and FN cysts had a low 5-year PC risk. Surveillance strategies should be tailored appropriately.
The pretreatment neutrophil-lymphocyte ratio (NLR) as a predictor of outcome in a cohort of metastatic pancreatic cancer patients treated with nab-paclitaxel and gemcitabine.
Authors: Jole Ventriglia, Guido Giordano, Angelica Petrillo, Maria Maddalena Laterza, Alessio Fabozzi, Beatrice Savastano, Giuseppe Tirino, Teresa Troiani, Michele Orditura, Antonio Febbraro, Fortunato Ciardiello, Ferdinando De Vita
Journal: Journal of Clinical Oncology (2015)

e15224 Background: A high neutrophil to lymphocyte ratio (NLR) is a strong predictor of poor survival in many tumors.Therefore in our study we have valuated the prognostic value of pretreatment NLR in a cohort of patients (pts) with advanced pancreatic cancer treated with Nab-paclitaxel and Gemcitabine. Methods: From January 2012 to May 2014, 41 pts with metastatic pancreatic adenocarcinoma (mPDAC) were evaluated for analysis. NLR was calculated from lymphocyte and neutrophil counts on routine blood tests taken before chemotherapy. Survival analyses were generated according to the Kaplan-Meier method. Univariate and multivariate analyses were carried out by the Cox proportional hazard model. Results: Median age of pts was 67 (range 41-77), 11 pts had an age ≥ 70 and, ECOG PS was 0-1 in 32 pts and 2 in 9 pts. Primary tumor was located to pancreatic head or body-tail in 24 (58.5%) and 17 (41.5%) pts respectively. Metastatic sites were represented by liver (60.9%), nodes (24.3%), lung (21.9%), peritoneum (9.75%) and bone (2.4%). Nine pts had received biliary stent implantation before starting chemotherapy. Median CA19.9 levels at baseline was 469 U/I (range 17,4 – 61564 U/I). These pts were divided into two groups according to NLR cut-off of 5: high ( ≥ 5.0) and low ( < 5.0). A low NLR pre-treatment was observed in 29 pts while high level of NLR was observed in 12 pts. Median Progression free survival (PFS) of pts with low NLR was 8 months (95%CI: 6.9-9.0) compared with 3 months of pts with a high NLR(95%CI: 0.8-5.1) (p: 0.005). Median Overall survival (OS) was 12 months (95%CI: 9.3-14.6) in pts with low NLR compared with 7 months (95%CI: 3.8-10.1) of patients with high NLR (p: 0.0001). On multivariate analysis, after adjusting for other clinic-pathologic factors, high NLR turned out to be an independent risk factor for poor survival (p = 0.001). Conclusions: Our results suggest that an elevated pre-treatment NLR ( ≥ 5) is an independent prognostic factor correlated to a poor PFS and OS in metastatic pancreatic cancer treated with Nab-paclitaxel and Gemcitabine. Furthermore these results justify the use of NLR as a prognostic factor for risk stratification in future studies.
Updated 2016 EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer
Authors: J. Alfred Witjes, Thierry Lebret, Eva M. Compérat, Nigel C. Cowan, Maria De Santis, Harman Maxim Bruins, Virginia Hernández, Estefania Linares Espinós, James Dunn, Mathieu Rouanne, Yann Neuzillet, Erik Veskimäe, Antoine G. van der Heijden, Georgios Gakis, Maria J. Ribal
Journal: European Urology (2016)
Effect of instructional cues on schizophrenic patients' performance on the Wisconsin Card Sorting Test
Authors: R S Goldman, B N Axelrod, L M Tompkins
Journal: American Journal of Psychiatry (1992)

Schizophrenic patients are particularly deficient on measures of executive functioning, notably the Wisconsin Card Sorting Test. This study was conducted to determine the efficacy of a cuing strategy in facilitating performance on this cognitive measure of the integrity of prefrontal brain structures and functioning.Twenty-four schizophrenic inpatients and 24 demographically matched inpatients with mood disorders were administered the Wisconsin Card Sorting Test either with instructional cues at the beginning of the task or with the standard administration procedure.There was a significant benefit of cues for the patients with affective disorders as well as for the schizophrenic patients. The schizophrenic subjects in the uncued condition maintained poor but stable performance throughout the course of the task.The study suggests that the deficit in executive functioning of schizophrenic patients may lie in the formation of concepts, not in their application.
Three cases of female anorgasmia associated with MAOIs
Authors: L M Lesko, N L Stotland, R T Segraves
Journal: American Journal of Psychiatry (1982)

Monoamine oxidase inhibitors have been associated with male retarded ejaculation and impotence. The authors describe three cases of female anorgasmia secondary to this class of antidepressants. To the author's knowledge only one incidental finding of this kind has been reported.
A transplant “immunome” screening platform defines a targetable epitope fingerprint of multiple myeloma
Authors: Aneta Schieferdecker, Anna Oberle, Benjamin Thiele, Fabian Hofmann, Markus Göthel, Sebastian Miethe, Michael Hust, Friederike Braig, Mareike Voigt, Ute-Marie von Pein, Friedrich Koch-Nolte, Friedrich Haag, Malik Alawi, Daniela Indenbirken, Adam Grundhoff, Carsten Bokemeyer, Ulrike Bacher, Nicolaus Kröger, Mascha Binder
Journal: Blood (2016)
What is asthma−COPD overlap syndrome? Towards a consensus definition from a round table discussion
Authors: Don D. Sin, Marc Miravitlles, David M. Mannino, Joan B. Soriano, David Price, Bartolome R. Celli, Janice M. Leung, Yasutaka Nakano, Hye Yun Park, Peter A. Wark, Michael E. Wechsler
Journal: European Respiratory Journal (2016)

Patients with asthma–chronic obstructive pulmonary disease overlap syndrome (ACOS) have been largely excluded from pivotal therapeutic trials and, as a result, its treatment remains poorly defined and lacking firm evidence. To date, there is no universally accepted definition of ACOS, which has made it difficult to understand its epidemiology or pathophysiology. Despite many uncertainties, there is emerging agreement that some of the key features of ACOS include persistent airflow limitation in symptomatic individuals 40 years of age and older, a well-documented history of asthma in childhood or early adulthood and a significant exposure history to cigarette or biomass smoke. In this perspective, we propose a case definition of ACOS that incorporates these key features in a parsimonious algorithm that may enable clinicians to better diagnose patients with ACOS and most importantly enable researchers to design therapeutic and clinical studies to elucidate its epidemiology and pathophysiology and to ascertain its optimal management strategies.
Engaging Patients, Health Care Professionals, and Community Members to Improve Preoperative Decision Making for Older Adults Facing High-Risk Surgery
Authors: Nicole M. Steffens, Jennifer L. Tucholka, Michael J. Nabozny, Andrea E. Schmick, Karen J. Brasel, Margaret L. Schwarze
Journal: JAMA Surgery (2016)

<h3>Importance</h3> Older patients are at greater risk for postoperative complications, yet they are less likely than younger patients to ask questions about surgery. <h3>Objective</h3> To design an intervention to improve preoperative decision making and manage postoperative expectations. <h3>Design, Setting, and Participants</h3> A Patient and Family Advisory Council (PFAC) was created to help identify preoperative decisional needs. The PFAC included 4 men and women who had previous experience with high-risk surgery as older patients or their family members; the PFAC met monthly at a local library from May 2014 to April 2015 to examine findings from a prior qualitative study and to integrate themes with PFAC members' experiences. Patient observations included 91 recorded conversations between patients and surgeons and 61 patient interviews before and after surgery. The PFAC members and other stakeholders evaluated 118 publicly available questions and selected 12 corresponding to identified needs to generate a question prompt list (QPL). Three focus groups, including 31 community members from diverse backgrounds, were conducted at community centers in Madison and Milwaukee, Wisconsin, to refine the QPL. A clinical pilot with 42 patients considering surgery was conducted in one outpatient surgical clinic in Madison. <h3>Main Outcomes and Measures</h3> Generation of a QPL to address patients' preoperative informational and decisional needs. <h3>Results</h3> Through exploration of qualitative data, the PFAC noted 3 critical problems. Patients and family members believed surgery had to be done, were surprised that postoperative recovery was difficult, and lacked knowledge about the perioperative use of advance directives. The PFAC identified a need for more information and decisional support during preoperative conversations that included clarification of treatment options, setting postoperative expectations, and advance care planning. The following 3 question prompt categories arose: "Should I have surgery?" "What should I expect if everything goes well?" and "What happens if things go wrong?" The final list included 11 questions within these domains, was understandable in English and Spanish, and was acceptable to patients in the clinic. <h3>Conclusions and Relevance</h3> Through direct engagement of stakeholders, a QPL was created to address core decisional and informational needs of surgical patients. Future testing will evaluate whether this list can be used to improve patient engagement and reduce postoperative regret and conflict about postoperative treatments.
A randomized, multicenter, phase (Ph) III study comparing carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (Dex) to LEN and Dex in patients (Pts) with relapsed multiple myeloma (MM).
Authors: P. Moreau, A. P. Palumbo, A. K. Stewart, V. Rajkumar, A. J. Jakubowiak, K. Halka, S. Goranov, H. Bumbea, K. B. Pendergrass, A. Lupu, A. Dimopoulos, A. O. Rocafiguera, J. G. Gandhi, G. Mihaylov, T. Masszi, J. Matous, G. Fonseca, R. Bryce, D. S. D. Siegel
Journal: Journal of Clinical Oncology (2011)

TPS225 Background: CFZ, a next-generation selective, irreversible epoxyketone proteasome inhibitor, has promising single-agent activity in relapsed/refractory (R/R) MM and a favorable side effect profile. CFZ is tolerable in a broad range of pts including those with baseline peripheral neuropathy (PN) or renal insufficiency. LEN/low-dose Dex (Rd) is a current standard of care for relapsed MM. While the combination of bortezomib + LEN + moderate- to high-dose Dex is active in R/R MM, it is associated with development of PN in the majority of cases, limiting extended treatment at optimal doses. Alternatively, the addition of CFZ to Rd (CRd) may provide superior activity compared to Rd alone, without additional significant toxicity. The ph 1b/2 PX-171-006 study has shown both activity and tolerability of full-dose CRd, and that prolonged treatment is possible. CRd has also shown impressive activity in the front-line setting in an ongoing, open-label independent ph 1/2b trial (NCT01029054). ASPIRE (NCT01080391) is a ph 3, randomized, open-label, multicenter study comparing CRd to Rd treatment in pts with relapsed MM. Methods: Eligible pts have an Eastern Cooperative Oncology Group performance score of 0–2 and relapsed or progressive MM following 1–3 prior treatment regimens and may be refractory to their most recent therapy. Enrollment was initiated in July 2010 with a final accrual goal of 700 patients. Pts are randomized 1:1 to receive either Rd or CRd. Treatment schedules are below. Pts will continue treatment until disease progression or unacceptable toxicity and will be followed for 30 days for safety. The primary endpoint is progression-free survival. Secondary endpoints include overall survival, overall response rate, disease control rate, duration of response, and safety. Disease outcome will be graded by study investigators using International Myeloma Working Group criteria and also be reviewed by Independent Review Committee. Cycle (28 days) CRd arm only CRd and Rd arms CFZ LEN Dex 1 20 mg/m2 IV D 1, 2; 27 mg/m2 IV D 8, 9, 15, 16 25 mg PO D 1–21 40 mg PO or IV D 1, 8, 15, 22 2–12 27 mg/m2 IV D 1, 2, 8, 9, 15, 16 13–18 27 mg/m2 IV D 1, 2, 15, 16 19+ ---
Mediterranean Diet influences breast cancer relapse: preliminary results of the SETA PROJECT.
Authors: Claudia Biasini, Camilla di Nunzio, Maria Rosa Cordani, Massimo Ambroggi, Mara Negrati, Filippo Rossi, Maria Antonia Pazzoni, Chiara Perri, Francesca Maria Cicognini, Manuela Fontana, Erminio Trevisi, Massimo Confalonieri, Luigi Cavanna
Journal: Journal of Clinical Oncology (2016)

e13039 Background: Breast cancer is a multifactorial disease and diet can affect cancer initiation. Since Mediterranean Diet may prevent cancer occurrence, we compared the recurrence of breast cancer in women treated for breast cancer. Methods: 307 women with early breast cancer and treated at the Department of Oncology, Piacenza Hospital, Italy, have been enrolled. After specific treatment and in complete remission, patients have been asked to participate the study: normal diet with dietary advice to reduce the occurrence of cancer relapse (Std-Diet) or Mediterranean Diet (Med-Diet) with nutrition education program and systematic follow-up, with the support of the dietitian. The adherence to the Mediterranean diet was determined with the Med. Score (range 0-55) proposed by Trichopoulou. BMI was recorded for each subjects. In addition a blood sample was taken, in the morning while fasting, for the determination of: glucose, cholesterol, insulin, vitamins A-D-E, sexual hormones, Ca, P, Mg, plant pigments (lycopene, β-carotene, lutein, zeaxanthin and cryptoxanthin),TNF-α, IL-1, IL-6, Reactive Oxygen Metabolites (ROM). The women received a questionnaire about quality of life sf-36 and physical activity. The comparison of cancer relapse between the 2 diets groups was carried out with the chi-squaremethod, while the correlation of data was performed with the PROC CORR of SAS 9.2. The study was approved by the Ethical Committee of the Hospital of Piacenza. Results: 199 women were included in the Std-Diet group and 108 patients in the Med-Diet group. After a median follow-up of 3 years 11 patients relapsed in the Std-Diet group, while no recurrence was observed in the Med-diet group. This difference is significant: χ²26.19; P < 0.05. The Med-Score resulted significantly correlated (r = 0.51; P < 0.01) with the β-carotene level in blood, while no significant relationship was observed with other pigments. According to this data the compliance of patients to Mediterranean diet could be estimated according to the level of pro-vitamin A. Conclusions: The adoption of a Mediterranean Diet in this study has reduced the risk of cancer recurrence. The levels of β-carotene can provide a good estimation of compliance to Mediterranean Diet.
NPM1, IDH1/2 and DNAH11 Gene Mutations Can Improve a Prognostic Stratification of Acute Myeloid Leukemia Patients with Normal Karyotype but Not Harboring FLT3/ITD Mutation.
Authors: Yeo-Kyeoung Kim, Il-Kwon Lee, Dennis Dong Hwan Kim, Chul Won Jung, Jun-Ho Jang, Hee Je Kim, Joon Ho Moon, Sang Kyun Sohn, Jong-Ho Won, Sung-Hyun Kim, Jungwon Huh, Namshin Kim, Yun Gyeong Lee, Sung-Hoon Jung, Je-Jung Lee, Hyeoung-Joon Kim
Journal: Blood (2012)
Buried adenocarcinoma hidden by normal squamous epithelium in Barrett’s esophagus: should we enlarge the margins for endoscopic resections?
Authors: Domitille Erard-Poinsot, Mathieu Pioche, Edouard Chabrun, Jérôme Rivory, Geneviève Belleannee, Valérie Hervieu, Thierry Ponchon
Journal: Endoscopy (2015)

Endoscopic submucosal dissection (ESD) is an effective technique to resect neoplasia in Barrett's esophagus, including for lesions larger than 15 mm [1]. Nevertheless, in the area surrounding the Barrett's neoplasia, buried mucosa with various grades of dysplasia or adenocarcinoma can occur under normal squamous epithelium before or after treatment (0 % – 28 %) [2] [3]. Buried components appear extremely difficult to detect endoscopically, which can result in the lesion size being underestimated [4]. Because of this invisible spread, we should enlarge our resection margins in order to avoid incomplete (R1) resections.
Enzymatic Hydrolysis of α-α Diglycylaminopropionic Acid Hydrochloride
Authors: Jose M. Gonçalves, Jesse P. Greenstein
Journal: JNCI Journal of the National Cancer Institute (1947)

Journal Article Enzymatic Hydrolysis of α-α Diglycylaminopropionic Acid Hydrochloride Get access Jose M. Gonçalves, Jose M. Gonçalves research fellow Search for other works by this author on: Oxford Academic PubMed Google Scholar Jesse P. Greenstein Jesse P. Greenstein chief biochemist 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 8, Issue 1, August 1947, Pages 25–27, https://doi.org/10.1093/jnci/8.1.25 Published: 01 August 1947 Article history Received: 29 April 1947 Published: 01 August 1947