tbuckley/cabot-search huggingface dataset:
The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency
Authors: Laura Gámez-Díaz, Dietrich August, Polina Stepensky, Shoshana Revel-Vilk, Markus G. Seidel, Mitsuiki Noriko, Tomohiro Morio, Austen J.J. Worth, Jacob Blessing, Frank Van de Veerdonk, Tobias Feuchtinger, Maria Kanariou, Annette Schmitt-Graeff, Sophie Jung, Suranjith Seneviratne, Siobhan Burns, Bernd H. Belohradsky, Nima Rezaei, Shahrzad Bakhtiar, Carsten Speckmann, Michael Jordan, Bodo Grimbacher
Journal: Journal of Allergy and Clinical Immunology (2016)
Abstract 134: Electrical Stimulation Improves Calcium Handling in Engineered Heart Tissue
Authors: Amandine Godier-Furnémont, Malte Tiburcy, Gordana Vunjak-Novakovic, Wolfram Zimmermann
Journal: Circulation Research (2012)

Purpose: Despite considerable advances in cardiac tissue engineering, morphology and functionality of engineered heart tissue (EHT) needs to be further improved, likely by making use of more “physiologic” engineering paradigms. We hypothesized that electrical stimulation may improve calcium handling in EHTs through enhanced maturation of the excitation coupling apparatus. Methods: EHTs were prepared from neonatal rat ventricular heart cells and after one week, transferred to dynamic stretchers. EHTs were cultured with (2 or 4 Hz) or without (non-stimulated ‘NS’) electrical stimulation from day 7 to 13 (Ionoptix C-Pacer: 2 ms square biphasic pulse, 4 Volts). At day 13, functional (twitch tension at 2 Hz field stimulation) were performed, and EHTs were processed for Western Blot analysis. In addition, EHT-derived single cardiomyocytes loaded with fura-2 (1 µM) were analyzed using an Ionoptix setup to assess alterations in calcium handling. Results: Culture under electrical enhanced twitch tension of EHTs (2 Hz vs. NS: 0.83 ± 0.05 vs. 0.62 ± 0.03, p&lt;0.0001, n=8/group), lowered excitation thresholds, and increased upstroke velocity. Assessment of sarcoplasmic reticulum (SR) functionality by post-rest potentiation revealed improved calcium storage capacity in EHTs (NS vs. 2 Hz vs. 4 Hz: 10.2 ± 1.4 vs. 11.7 ± 1.4 vs. 17.8 ± 1.3 % at 30 s rest; p&lt;0.05, n=7/7/5). Ryanodine (1 µM, to block SR-calcium release) reduced EHT twitch tension to 88.3 ± 2.1 % [NS] vs. 87.2 ± 2.4 % [2 Hz] vs. 75.1 ± 4.5 % [4 Hz] (n=8/group, p&lt;0.05) baseline force, indicating greater reliance on the SR for force generation, particularly in the 4 Hz stimulated group. Ryanodine receptor and SERCA protein expression increased with 4 Hz stimulation. In isolated cardiomyocytes, 4 Hz stimulated cells displayed faster upstroke velocity and relaxation times, approaching that of cardiomyocytes isolated from day 13 postnatal rats. Conclusions: Electrical stimulation of dynamically loaded EHTs contributes to increased functionality and appears to improve excitation-contraction coupling through enhanced Calcium storage and release capacity. This combined biomimetic stimulation method may overcome the sub-physiologic SR functionality of classical cell culture models.
Results of a phase 2/3 open-label, randomized trial of T138067 versus doxorubicin (DOX) in chemotherapy-naïve, unresectable hepatocellular carcinoma (HCC)
Authors: J. Posey, P. Johnson, T. Mok, M. Hirmand, S. Dahlberg, L. Kwei, T. Leung
Journal: Journal of Clinical Oncology (2005)

4035 Background: T138067 binds irreversibly and specifically to isotypes of β-tubulin, eventually inducing apoptosis. Its cytotoxicity and anti-tumor activity have been shown preclinically. Our primary study objective was to compare overall survival (OS) with T138067 vs DOX. Methods: Eligible patients (pts) had unresectable, chemotherapy-naïve HCC with Child-Pugh A or B liver disease and Karnofsky score (KS) ≥ 70%. Results: The study was closed early after recommendation from the external Data Monitoring Committee because of lack of survival benefit. Of 339 pts with available data, 169 were randomized to T138067 250 mg/m2 weekly infusion and 170 to DOX 60 mg/m2 infusion every 3 weeks: 121 from Russia, 70 China, 43 US, 41 Ukraine, and 64 other countries. Differences by country were seen in baseline Chinese University Prognostic Index (CUPI). Low CUPI (< 2) was seen for 29% of pts in Russia, 53% in China, 64% in the US, 50% in Ukraine, and 63% in other countries. 138 pts have died (median follow-up 3.1 months [mo]; maximum 15). No OS difference was seen; median 6 mo for each treatment. Ascites, KS, alpha fetoprotein (AFP), and alkaline phosphatase (AP) were all independent risk factors for OS. Hazard ratios (HR) are shown below. Symptoms, Child-Pugh score, and CUPI were not significantly associated with OS after adjusting for factors in the table. No statistically significant by-country OS differences were seen. 17% of pts had none of the 4 high-risk factors, 33% had 1 factor, 33% had 2 factors, and 17% had 3 or 4 factors. Median OS was 10 mo in pts with no factors, 9 mo for 1 factor, 5 mo for 2 factors, and 2 mo for 3 or 4 factors. Conclusions: T138067 did not improve OS compared to DOX in this population. Ascites, KS, AFP, and AP are all independent risk factors for OS. Despite baseline imbalances, no significant differences in OS by country were observed. Final data analysis is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen Amgen Amgen
Standardized treatment and follow-up protocol of hepatocellular carcinoma with transcatheter arterial chemoembolization: Survival, clinical, and tumor control outcome over 12 years at a U.S. center
Authors: E. Liapi, K. Hong, C. S. Georgiades, T. Wahlin, D. Reyes, I. R. Kamel, J. H. Geschwind
Journal: Journal of Clinical Oncology (2009)

e15522 Background: To report the outcome of the care of patients with hepatocellular carcinoma (HCC) treated with standardized transcatheter arterial chemomembolization (TACE), with a focus on tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST), progression of underlying cirrhosis [Child-Pugh (CP) score], time to progression (TTP) and survival from 1996 to 2008. Methods: TACE was performed on 365 patients in 1,035 sessions. According to a standardized protocol, all patients received imaging (MRI and/or CT) at baseline and at 4–6 weeks after each session and were clinically, biochemically and radiologically evaluated before each session. Liver disease status was evaluated before and at the end of the treatment period with the CP class system and tumor size measurements according to the RECIST. The Barcelona Clinic Liver Cancer (BCLC) classification was employed to stage patients. Three chemotherapeutic agents and lipiodol, followed by non-occlusive embolization were utilized during TACE. Complete vessel occlusion was avoided at all times. Overall survival and TTP were calculated according to the Kaplan-Meier method. The log-rank test was used to calculate differences between groups in the subgroup analysis. Results: All patients (78% male, mean age: 63.5 years) received an average of 3 TACE sessions (range: 1–10 and average interval between sessions: 75 days). Sixty six percent of patients had 3 or more tumors, with a mean tumor size at presentation of 6.9 cm. Partial response was achieved in 32 % of patients, while 65% remained stable over the course of 3 TACEs. CP class remained unchanged for 75% of patients over the above course of treatment. Median survival for the entire cohort was 20 months and TTP was 14 months. Interestingly, advanced BCLC patients achieved similar tumor response (PR:33%), TTP of 13.4 months and median survival of 13.7 months. Conclusions: Patients with HCC treated with the aforementioned standardized TACE and follow-up protocol showed durable survival, stable liver disease and effective tumor control. [Table: see text]
Prognostic impact of apoptosis-related and DNA repair gene polymorphisms in patients with advanced colorectal cancer treated with capecitabine and oxaliplatin chemotherapy
Authors: Y. Chae, J. Kim, S. Sohn, J. Moon, S. Kim, H. Ryoo, S. Bae, G. Choi, S. Jun, M. Lee
Journal: Journal of Clinical Oncology (2008)

15123 Background: Oxaliplatin-combined regimen is one of standard chemotherapy for metastatic or recurrent colorectal cancer. However, the large inter-individual variability in outcome from chemotherapy causes need to identify pharmacogenetic markers. Accordingly, the present study analyzed the impact of polymorphisms of DNA repair and apoptosis-related genes on outcome for patients with advanced colorectal cancer. Methods: Fifty-nine patients with recurred or metastatic colorectal cancer treated with capecitabine plus oxaliplatin (CapOX) combination chemotherapy were enrolled in the present study. The genomic DNA was extracted from paraffin-embedded tissue and single nucleotide polymorphisms (SNPs) of 9 DNA repair genes (NBN, MGMT, POLR2, ERCC2, RFC4, MSH2, POLE, DNMT3, and XAB2) and 14 apoptosis-related genes (LTA [Lymphotoxin alpha], TP53, BCL2, BCL2L [BCL2 ligand], BAK1, PTGS2, BID, RIPK1, FAS, FASL [FAS ligand], and caspase 6–9) determined using a PCR-RFLP assay. Results: No significant association between SNPs and chemotherapy response was found for any genes analyzed. However, the C/C genotype of BAK1 (rs5745568) was significantly correlated with a better progression-free survival (PFS) compared to the combined C/A and A/A genotype (Hazard ratio [HR]= 0.154; 95% Confidential Interval [CI]=0.038–0.627; p value=0.009), while the A/A genotype of LTA (rs1041981) was associated with a worse PFS compared to the combined C/C and C/A genotype (HR=2.835; 95% CI, 1.010–7.954; p value, 0.048) in multivariate survival analysis. However, overall survivals were not significantly different according to genotypes of BAK1 or LTA gene. Conclusion: SNPs of BAK1 and LTA was found to be correlated with PFS in patients with advanced colorectal cancer treated with CapOX. However, further study is warranted to clarify the role of apoptosis-related or DNA repair gene polymorphisms as a prognostic biomarker in colorectal cancer patients treated with chemotherapy. No significant financial relationships to disclose.
Cardiothoracic surgeon is dismissed from Cardiff hospital for gross misconduct
Authors: Clare Dyer
Journal: BMJ (2015)

A consultant cardiothoracic surgeon at the University Hospital of Wales in Cardiff has been dismissed without notice for gross misconduct after a formal investigation and hearing into allegations of bullying hospital staff.

Peter O’Keefe, 50, had been suspended from his job since April 2012 on a full salary of £120 000 (€164 000; $185 000), while locums were employed by Cardiff and Vale University Health Board to do his work.

The health board gave no details of the findings against the surgeon but confirmed that the disciplinary action “concerned his …
Mesenchymal stem cells as delivery systems for cancer and leukemia gene therapy
Authors: M. Andreeff, M. Studeny, J. Dembinski, M. Konopleva, R.-Y. Wang, H.-Y. Yang, J. Fueyo, R. E. Champlin, F. Lang, F. C. Marini
Journal: Journal of Clinical Oncology (2004)

3194 Background: We previously demonstrated that intravenously (IV) injected bone marrow-derived mesenchymal stem cells (MSC) integrate into solid tumors as stromal fibroblasts and proliferate selectively in situ. We here propose a novel cancer therapy concept based on the intratumoral drug production by gene-modified MSC. Methods: MSC were transduced with adeno (AdV)- or adeno-associated (AAV) virus carrying marker- or therapeutic genes. Gene-modified MSC were injected IV into mice carrying cancer xenografts. Results: MSC were found only in tumors, where they proliferate not in normal tissues. MSC producing human interferon-beta (IFNβ-MSC) directly inhibited the growth of metastatic A375 melanoma and MDA 231 breast carcinoma following IV injection (p=0.0073), while recombinant IFNβ protein injected subcutaneously (SC) did not (p=0.14). IFNβ-MSC doubled the survival of tumor-bearing mice (p=0.001) while SC injected IFNβ was ineffective (p=0.021 vs p=0.4). Intraperitoneal (IP) injections of IFNβ-MSC into mice with ovarian carcinomas doubled their survival (SKOV-3) and cured 70% of OVAR-3 mice. IP administration of MSC carrying a replication competent oncolytic adenovirus prolonged survival. MSC injected into the carotid artery (IA) of mice with gliomas selectively proliferated in gliomas, not in normal brain tissues. Intratumoral injection of IFNβ-MSC in vivo significantly inhibited tumor growth. In a model of chronic myelogenous leukemia in blast crisis (KBM5), interferon α (IFNα) produced in vivo by MSC induced tumor regressions and doubled the survival of mice. The melanoma differentiation-associated gene 7 (MDA7) produced by MSC, preferentially inhibited Gleevec resistant KBM5 CML blast crisis cells. Conclusions: Results suggest that gene-modified MSC selectively grow in tumors and inhibit the growth of leukemias, and metastatic cancers. Tumor inhibition required spatial proximity of MSC to the malignant cells. The findings suggest that therapeutic proteins or oncolytic replicating adenovirus have potent anti-tumor effects when produced in situ and suggest the use of MSC as tumor-selective gene therapy delivery systems. No significant financial relationships to disclose.
Abstract P060: Factors Affecting Cardiovascular Risk Perception in Subjects Submitted to a Routine Health Evaluation
Authors: Thais N Helou, Raul D Santos, Antonio G Laurinavicius, Fabio G Franco, Raquel D Conceicao, Jose A Carvalho, Antonio E Pesaro, Fernando M Silva, Mauricio Wajngarten, Marcelo Katz
Journal: Circulation (2015)

Introduction:  Cardiovascular (CV) disease remains the main cause of death worldwide and preventive measures may decrease CV adverse events. Individuals’ subjective perception of own CV risk has been pointed as a key driver for patients’ engagement on medical recommendations. However, recent studies indicate that subjects usually are hypo-perceivers and may underestimate their own CV risk. Fewer studies have evaluated the factors associated with CV risk hypo-perception. Therefore, the aim of this study was to test the association between clinical characteristics and individual’s perception of CV risk.   Hypothesis:  traditional CV risk factors would be associated with subjects’ perception of CV risk.   Methods:  Patients (n = 5,863, 47.9 ± 6.2 years, 22.1% female) who underwent a routine health evaluation, and for whom the lifetime risk score (LRS) indicated an intermediate or high CV risk were included in this analysis. All individuals subjectively rated their CV risk for the next years as low, intermediate or high, and this perception was compared to the LRS. Individuals were then classified as hypo-perceivers, i.e. perceived risk lower than estimated risk and normo-perceivers, i.e. perceived risk coincident with the estimated risk. Logistic regression analysis was performed to test the association between clinical characteristics (including CV risk factors) and individuals’ perception of risk. P   Results:  Cardiovascular risk was intermediate in 45.7% and high in 54.3% of individuals as provided by de LRS. When comparing the LRS with subjects’ perception of risk, 4,918 (83.9%) were hypo-perceivers and 945 (16.1%) were normo-perceivers. By adjusted logistic regression analysis, age (OR=1.02 [95%CI 1.01-1.04]; p=0.006), smoking (OR 2.04 [95%CI 1.43-2.91]; p   Conclusions:  Among asymptomatic individuals submitted to a routine medical evaluation there was a high prevalence of hypo-perception of CV risk. Aging, smoking, dyslipidemia, physical activity and the use of medications were associated with a higher chance of risk hypo-perception. Thus, subjects in these conditions may benefit from a more careful risk orientation on health check-ups.
Abstract P023: Risk Factors Associated with Progression of Subclinical Diastolic Dysfunction in a Multiethnic Population
Authors: Lili Zhang, Jian Shan, Cynthia Taub
Journal: Circulation (2014)

Background: Subclinical diastolic dysfunction is defined as echocardiographic evidence of left ventricular diastolic dysfunction and normal ejection fraction (EF) without congestive heart failure (HF) symptoms/diagnosis. Our study, for the first time, sought to examine risk factors associated with progression from subclinical diastolic dysfunction to overt HF in a large multiethnic population. Methods: The study population included patients with asymptomatic diastolic dysfunction and EF ≥ 50% assessed by transthoracic echocardiogram between 2003 and 2008 at Montefiore Medical Center, Bronx, NY. Patients with preexisting HF, valvular heart disease or atrial fibrillation prior were excluded. The end point was the development of HF by September 1, 2013. Multivariable adjusted Cox proportional hazards models, determined by stepwise selection method, were performed to examine risk factors associated with the development of HF. All analyses were also performed with adjustment and stratification of race. Results: A total of 7,879 patients, with 21% European Americans (EA), 36% African Americans (AA), 31% Hispanics, and 12% others or unknown, were included in the analysis. Mean follow up time was 6.3 years. Mean age of the cohort was 68±12, with 63% women. The overall cumulative probability of development of HF was 17% (19% in EA, 17% in AA, 19% in Hispanic patients) during the follow up period. In multivariable Cox proportional hazard regression analysis, renal disease (hazard ratio (HR)=1.6, 95% confidence interval (CI) 1.3-2.0, P&lt;0.001) and hemoglobin levels (HR=0.9, 95% CI 0.9-1.0, P=0.001) were significantly associated with the development of HF in overall population. In stratification analysis, age (P=0.012) and hypertension (P=0.007) were independent risk factors for HF in Hispanic patients, but not in EA and AA. Conclusions: In a large multiethnic population with subclinical diastolic dysfunction, renal disease and hemoglobin levels were independently associated with development of HF in overall population.. Age and hypertension were significant risk factors for HF only in Hispanic patients. These results may have important implications in preventing the development of HF from subclinical stage.
ETIOLOGY OF YELLOW FEVER
Authors: Hideyo Noguchi
Journal: The Journal of Experimental Medicine (1919)

The serum from a number of persons recovering from yellow fever in Guayaquil was studied with a view to establishing its possible immunological relationship with a strain of Leptospira icteroides derived from one of the yellow fever patients. For this purpose the serum of convalescents was mixed either with an organ emulsion of a passage strain, or with a culture of the organism, and inoculated intraperitoneally into guinea pigs. The Pfeiffer reaction was first studied, and then the animals were allowed to live until the controls, inoculated with the same emulsion or culture of Leptospira icteroides but without the serum, or with serum from patients suffering from other diseases than yellow fever, had died of the experimental infection with typical symptoms A positive Pfeiffer phenomenon was observed in fifteen of the eighteen convalescent cases studied, or approximately 83 per cent. Sera from ten non-immune soldiers and from two malaria patients gave uniformly negative results. Protection from an ultimate fatal infection was afforded some of the guinea pigs which received the serum of yellow fever convalescents, while the control animals succumbed to the infection with typical symptoms. In one instance, in which the serum was tested on the 2nd and the 10th days of disease, a Pfeiffer reaction was demonstrated, as well as protective property against the infection, in the specimen from the 10th but not in that from the 2nd day. From the foregoing observations of immunity reactions it appears highly probable that Leptospira icteroides is etiologically related to yellow fever.
Autologous Hematopoietic Stem/Progenitor Cell (HSPC) Therapy For Monogenic Blood Disorders: Scalable, cGMP-Compliant Process For Generating Highly Efficient Genome Edited HSPC
Authors: Gary K Lee, Lynn Truong, Travis Wood, Jill Henley, Lee Ya-Li, Ken Kim, Yuanyue Zhou, Jianbin Wang, Andreas Reik, Fyodor D Urnov, Paula Cannon, Michael C. Holmes, Dale Ando, Martin A Giedlin
Journal: Blood (2013)
Prognostic factors in adolescents and young adults (AYA) with high-risk soft tissue sarcoma (STS) treated by adjuvant chemotherapy: A study based on two pooled European Organisation for Research and Treatment of Cancer (EORTC) clinical trials
Authors: B. Kasper, M. Ouali, M. Van Glabbeke, J. Blay, V. H. Bramwell, P. J. Woll, P. Schöffski
Journal: Journal of Clinical Oncology (2009)

10573 Background: We conducted a retrospective study pooling data from two clinical trials in high risk STS patients with the objective to compare two different age groups: 15 - 29 years (AYA population) and ≥ 30 years. The aim was to determine prognostic factors for the AYA population. Methods: Patients selected for analysis were treated in two randomized trials of adjuvant chemotherapy in STS (EORTC 62771 and 62931). A total of 793 patients were included with a median follow-up (FU) of 8.74 years (AYA population: n = 161, median FU 9.46 years; patients ≥ 30 years: n = 632, median FU 8.62 years). Study endpoints were overall survival (OS) and relapse-free survival (RFS). The variables of the multivariate analysis were gender, subtype and grade, tumor size and localization (limb vs. other), absence or presence of local recurrence and treatment (control arm vs. adjuvant chemotherapy). Results: Patients’ characteristics were globally similar with two exceptions, histological subtype (p = 0.0043) and tumor size (p &lt; .0001). The commonest sarcoma subtype in the AYA population was synovial sarcoma (29 %), whereas leiomyosarcoma (18 %), malignant fibrous histiocytoma (MFH, 16 %) and liposarcoma (15 %) were more frequent in patients ≥ 30 years. For OS, independent favorable prognostic factors were low grade and small tumor size for both groups; radical resection and MFH or liposarcoma subtype were factors of favorable prognosis for patients ≥ 30 years only. For RFS, favorable prognostic factors were small tumor size and low grade for both groups; tumor location in the extremities was a factor of favorable prognosis for the AYA population only, whereas radical resection and adjuvant chemotherapy treatment were favorable factors for patients ≥ 30 years only. Conclusions: On the basis of these data, significant differences could be found concerning prognostic factors between the AYA population and older patients. Interestingly, adjuvant chemotherapy was associated with improved RFS only in patients ≥ 30 years. The results may have further implications on the treatment of STS patients in different age groups as well as the design of future clinical trials. No significant financial relationships to disclose.