tbuckley/cabot-search huggingface dataset:
Intracisternal Gtf2i Gene Therapy Ameliorates Deficits in Cognition and Synaptic Plasticity of a Mouse Model of Williams–Beuren Syndrome
Authors: Cristina Borralleras, Ignasi Sahun, Luis A Pérez-Jurado, Victoria Campuzano
Journal: Molecular Therapy (2015)

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by a heterozygous deletion of 26-28 genes at chromosome band 7q11.23. Haploinsufficiency at GTF2I has been shown to play a major role in the neurobehavioral phenotype. By characterizing the neuronal architecture in four animal models with intragenic, partial, and complete deletions of the WBS critical interval (ΔGtf2i(+/-), ΔGtf2i( -/-), PD, and CD), we clarify the involvement of Gtf2i in neurocognitive features. All mutant mice showed hypersociability, impaired motor learning and coordination, and altered anxiety-like behavior. Dendritic length was decreased in the CA1 of ΔGtf2i(+/-), ΔGtf2i ( -/-), and CD mice. Spine density was reduced, and spines were shorter in ΔGtf2i ( -/-), PD, and CD mice. Overexpression of Pik3r1 and downregulation of Bdnf were observed in ΔGtf2i(+/-), PD, and CD mice. Intracisternal Gtf2i-gene therapy in CD mice using adeno-associated virus resulted in increased mGtf2i expression and normalization of Bdnf levels, along with beneficial effects in motor coordination, sociability, and anxiety, despite no significant changes in neuronal architecture. Our findings further indicate that Gtf2i haploinsufficiency plays an important role in the neurodevelopmental and cognitive abnormalities of WBS and that it is possible to rescue part of this neurocognitive phenotype by restoring Gtf2i expression levels in specific brain areas.
O122 : Clinical impact of five large-scale screening projects for chronic hepatitis B and C in Chinese migrants in The Netherlands
Authors: S. Coenen, S. van Meer, J.M. Vrolijk, C. Richter, J.P.H. Drenth, P.P. Koopmans, H. van Soest, K.J. van Erpecum, J.E. Arends, M.A.M.T. Verhagen, P. Friederich, H.J. Flink, M.J. ter Borg, I.K. Veldhuijzen, J.G.P. Reijnders, M.C. Mostert, C.G. Dirksen, C. Schout, H.P.J. Daemen, B.W.M. Spanier
Journal: Journal of Hepatology (2015)
Abstract 345: Inadequate Coupling between Ubiquitination and the Proteasome is a Major Pathogenic Factor of Myocardial Ischemia/Reperfusion Injury
Authors: Xuejun Wang, Chengjun Hu, Yihao Tian, Hongmin Wang, Xuejun Wang
Journal: Circulation Research (2014)

Targeted removal of damaged/misfolded proteins is primarily done by the ubiquitin (Ub)-proteasome system (UPS). Generally, the UPS degrades a protein molecule via two main steps: ubiquitination of the protein and subsequent degradation of the ubiquitinated protein by the proteasome. The two steps are not always directly coupled. The proteasome can directly uptake nearby polyubiquitinated proteins via its Ub receptor subunits but extra-proteasomal Ub receptors may be required for shuttling the remote substrates to the proteasome for degradation. We have previously demonstrated that UPS function is impaired during acute myocardial ischemia/reperfusion (I/R) and this impairment plays a major role in I/R injury due to failure to timely remove damaged/misfolded proteins. The molecular underpinnings of UPS impairment in I/R injury remains poorly understood. This study shows an important role of Ubiquilin1, a bona fide extra-proteasomal Ub receptor, in cardiac ubiquitination-proteasome coupling during I/R. Mice with cardiomyocyte-restricted knockout of the Ubiquilin1 gene (CR-Ubqln1KO) or with Ubiquilin1 overexpression (Ubqln1OE) were subject to myocardial I/R created via left anterior descending artery ligation (for 30min) and subsequent release (for 24hr). The I/R induced decline of left ventricular maximum dP/dt, elevation of minimum dP/dt, and infarct size were significantly greater in CR-Ubqln1KO mice, and conversely, were markedly attenuated in Ubqln1OE mice, compared with their littermates with a respective control genotype. The accumulation of ubiquitinated proteins in I/R myocardium was increased by CR-Ubqln1KO and reduced by Ubqln1OE. Furthermore, in cultured cardiomyocytes, Ubqln1OE was able to enhance the degradation of a surrogate UPS substrate as well as a bona fide misfolded protein linked to human proteinopathy. These exciting new findings demonstrate for the first time that inadequate coupling between ubiquitination and proteasomal degradation hinders the degradation of damaged proteins in I/R myocardium and represents a major pathogenic factor to acute I/R injury. It is also suggested that facilitating the coupling is potentially a novel therapeutic strategy for reducing I/R injury.
Interleukin-6 (IL-6) as an inflammatory biomarker in patients with hepatobiliary cancers.
Authors: Sidra Anwar, Austin Miller, Gerald J. Fetterly, Renuka V. Iyer
Journal: Journal of Clinical Oncology (2015)

257 Background: IL-6 is an inflammatory cytokine that modulates growth and differentiation of tumor cells. The role of IL-6 as a biomarker in this cancer subset population remains questionable. We aimed to study IL-6 levels in patients with hepatobiliary cancer and the associated patient characteristics. Methods: Stored serum from 91 patients with treatment-naïve hepatobiliary cancers (hepatocellular carcinoma, gallbladder cancer, intra- and extra-hepatic cholangiocarcinoma) were measured for IL-6 levels. Demographics and clinical parameters were collected from retrospective chart review. IL-6 was measured in stored serum from 91 controls, matched for age, gender and BMI. Associations between baseline covariates and IL6 measurements and differences in Overall Survival (OS) were assessed using Accelerated Failure Time (AFT) models. P-values &lt;0.05 were considered statistically significant. All data analyses were generated using SAS/STAT software, Version 9.4. Results: A total of 91 cases+91 controls were analyzed: 68% males in each set. IL-6 levels were significantly higher in the cases than the controls [median: 15.2pg/ml vs 1.7pg/ml p&lt;0.01]. Amongst cancer patients the following elements were associated with significantly higher levels of IL-6: cirrhosis (AF=3.18 p&lt;0.01), uncontrolled pain (AF=1.97 p&lt;0.01), worse ECOG status (p&lt;0.01) and portal vein thrombosis (AF=1.57, p=0.03). A 3-fold increase in Alpha fetoprotein (AFP) corresponded with a 9% increase in IL-6 (AF=1.09, p=0.015). IL-6 appeared to be modestly higher in males [median: 4.47 vs 5.32 p=0.5]. IL-6 remained an independent predictor of OS after controlling for several possible confounders (AFP, Cirrhosis, portal vein thrombosis). Each 10-unit increase in IL-6 resulted in an 8% reduction in the time to death (AF=0.92 (95% CI:0.78 to 1.00) p=0.033). Conclusions: IL-6 levels are significantly elevated in hepatobiliary cancers, directly correlating with AFP. Higher IL-6 levels are associated with aggressive tumors and poorer survival. These findings suggests the potential prognostic/predictive value of IL-6 and should initiate early palliative care referrals. Anti-IL6 therapy could increase meaningful survival time for patients.
Genome-wide DNA methylation profiling in the superior temporal gyrus reveals epigenetic signatures associated with Alzheimer’s disease
Authors: Corey T. Watson, Panos Roussos, Paras Garg, Daniel J. Ho, Nidha Azam, Pavel L. Katsel, Vahram Haroutunian, Andrew J. Sharp
Journal: Genome Medicine (2016)

Alzheimer's disease affects ~13 % of people in the United States 65 years and older, making it the most common neurodegenerative disorder. Recent work has identified roles for environmental, genetic, and epigenetic factors in Alzheimer's disease risk. We performed a genome-wide screen of DNA methylation using the Illumina Infinium HumanMethylation450 platform on bulk tissue samples from the superior temporal gyrus of patients with Alzheimer's disease and non-demented controls. We paired a sliding window approach with multivariate linear regression to characterize Alzheimer's disease-associated differentially methylated regions (DMRs). We identified 479 DMRs exhibiting a strong bias for hypermethylated changes, a subset of which were independently associated with aging. DMR intervals overlapped 475 RefSeq genes enriched for gene ontology categories with relevant roles in neuron function and development, as well as cellular metabolism, and included genes reported in Alzheimer's disease genome-wide and epigenome-wide association studies. DMRs were enriched for brain-specific histone signatures and for binding motifs of transcription factors with roles in the brain and Alzheimer's disease pathology. Notably, hypermethylated DMRs preferentially overlapped poised promoter regions, marked by H3K27me3 and H3K4me3, previously shown to co-localize with aging-associated hypermethylation. Finally, the integration of DMR-associated single nucleotide polymorphisms with Alzheimer's disease genome-wide association study risk loci and brain expression quantitative trait loci highlights multiple potential DMRs of interest for further functional analysis. We have characterized changes in DNA methylation in the superior temporal gyrus of patients with Alzheimer's disease, highlighting novel loci that facilitate better characterization of pathways and mechanisms underlying Alzheimer's disease pathogenesis, and improve our understanding of epigenetic signatures that may contribute to the development of disease.
Ultrastructural Analysis of Bone Marrow Hematopoiesis in Mice Transgenic for the Thymidine Kinase Gene Driven by the IIb Promoter
Authors: Christel Poujol, Diana Tronik-Le Roux, Philippe Tropel, Valérie Roullot, Alan Nurden, Gérard Marguerie, Paquita Nurden
Journal: Blood (1998)
Juvenile Firesetters: Do the Agencies Help?
Authors: Stuart Fine, Don Louie
Journal: American Journal of Psychiatry (1979)

In an attempt to find out what was being done for juvenile firesetters in their metropolitan community the authors reviewed the records of the local fire marshal, juvenile court, and psychiatric clinic. They found that the various agencies involved with 69 juveniles over a 3-year period were unable to coordinate their efforts and were largely unsuccessful in controlling the firesetting. Because the families of firesetters seem to have many other social problems, the authors recommend early inpatient assessment and possible referral to foster homes or residential treatment settings for juvenile firesetters.
Evaluation of a breast cancer survivorship clinic that uses a group medical appointment model: Patient program evaluation and financial analysis.
Authors: Kathy Trotter, Susan M. Schneider
Journal: Journal of Clinical Oncology (2012)

90 Background: Group medical appointments have been shown to improve access, health outcomes and health care utilization rates, as well as self-management skills. A new model of breast cancer survivor care was designed and piloted at Duke Cancer Center. Survivors attended the clinic together in groups of six. An interdisciplinary group visit format in the initial part of the appointment provided surveillance, education and support, as well as formation of an individualized survivorship care plan. The first hour included review of their personal care plan and a 45-minute facilitated discussion. Afterwards, individual visits with the nurse practitioner, and dietitian, physical therapist, or social worker occurred. Methods: A 22-item Likert-type questionnaire sought opinions regarding logistics and the style and function of care delivered. 122 surveys were collected. Descriptive statistics (via SPSS v19) using ANOVA type regression were accomplished. Secondly, a retrospective two-group study of clinic financial data for follow-up patients was done. Revenues from the group medical visit by the NP were compared to those seen traditionally by the MD (N=300). Review of time to third available appointment for each clinician was also recorded. Results: 122 surveys were collected with a 86% response rate. Mean scores for all questions rated at least 4.4 of 5, with the highest score given for the confidence felt in the nurse practitioner (4.93) and the lowest for the acceptability of the wait time in the breast imaging area (4.4). Overall, 98% felt the program provided quality care and 97% were likely to recommend the clinic to other breast cancer survivors. What participants liked most about the program was sharing with other survivors. Cost benefit analysis revealed that revenues and direct costs were nearly equal between delivery models. Time to third available appointment for the primary referring oncologist, dropped from 29.4 to 26.7 days, while the NPs time remained stable at 8.7 days. Conclusions: The group visit model applied to survivor care appears feasible and highly satisfactory to participants.
A phase I study of LR-103 (1,24α(OH)2D2) in patients with refractory malignancies
Authors: H. Bailey, J. Kolesar, T. Fass, J. Weiss, J. Heideman, D. Alberti, S. Morgan-Meadow
Journal: Journal of Clinical Oncology (2006)

14608 Background: Preclinical studies of calcitriol and vitamin D analogs demonstrate potent growth inhibition of tumor cell lines. The clinical development of calcitriol and other analogs have been hindered by hypercalcemia. 1α (OH)D 2 is a Vitamin D analog which has produced objective responses in advanced androgen-independent prostate cancer patients and can be administered daily at 10mcg. LR103 is an active metabolite of 1α (OH)D 2 with equivalent anti-tumor activity and significantly less calcemic effects in preclinical studies. This phase I study explores the maximal tolerated dose and toxicity of LR-103. Methods: LR-103 was administered daily beginning at a dose of 5 μg/day with a cycle length of 14 to 28 days. Dose escalation proceeded in two stages. In step A, intra-patient dose escalation (starting dose of 5mcg daily) was allowed based on degree of toxicity regardless of attribution. Step A escalation continued until 2 patients had ≥ grade 2 toxicity at a dose level. Step B is a standard, inter-patient only, dose-escalation trial (starting dose based on Step A) with cohorts of three. Dose limiting toxicity is defined as ≥ grade 3 toxicity. Results: Nineteen patients have enrolled between May and December 2005, eight to step A and eleven to step B. During step A escalation, two patients at 15 μg/day experienced severe toxicity (grade 4 hyperuricemia and grade 3 alkaline phosphatase) and two patients at 15 μg/day experienced grade 1 hypercalcemia. Hypercalciuria has been common. No hypercalcemia ≥ grade 2 has been observed. Step B enrollment continues at 30 μg/day without hypercalcemia. Conclusions: Daily administration of LR-103 has not resulted in significant hypercalcemia to date. Dose escalation continues. No significant financial relationships to disclose.
Multilineage Hematopoietic Recovery by a Single Injection of Pegylated Recombinant Human Megakaryocyte Growth and Development Factor in Myelosuppressed Mice
Authors: Kazunori Shibuya, Hiromichi Akahori, Kazumi Takahashi, Emiko Tahara, Takashi Kato, Hiroshi Miyazaki
Journal: Blood (1998)
Proton pump inhibitors may be linked to dementia risk
Authors: Jacqui Wise
Journal: BMJ (2016)

Proton pump inhibitor use may be associated with an increased risk of dementia, a German prospective cohort study published in JAMA Neurology shows.1 These are widely used for treating gastrointestinal disease, and their use has increased among older patients.

The researchers used observational data covering 2004-11 obtained from the largest German statutory health insurer, Allgemeine Ortskrankenkasse. The insurer covers …
Effect of Positive Airway Pressure on Cardiovascular Outcomes in Coronary Artery Disease Patients with Nonsleepy Obstructive Sleep Apnea. The RICCADSA Randomized Controlled Trial
Authors: Yüksel Peker, Helena Glantz, Christine Eulenburg, Karl Wegscheider, Johan Herlitz, Erik Thunström
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Obstructive sleep apnea (OSA) is common in patients with coronary artery disease (CAD), many of whom do not report daytime sleepiness. First-line treatment for symptomatic OSA is continuous positive airway pressure (CPAP), but its value in patients without daytime sleepiness is uncertain.To determine the effects of CPAP on long-term adverse cardiovascular outcome risk in patients with CAD with nonsleepy OSA.This single-center, prospective, randomized, controlled, open-label, blinded evaluation trial was conducted between December 2005 and November 2010. Consecutive patients with newly revascularized CAD and OSA (apnea-hypopnea index ≥15/h) without daytime sleepiness (Epworth Sleepiness Scale score <10) were randomized to auto-titrating CPAP (n = 122) or no positive airway pressure (n = 122).The primary endpoint was the first event of repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality. Median follow-up was 57 months. The incidence of the primary endpoint did not differ significantly in patients who did versus did not receive CPAP (18.1% vs. 22.1%; hazard ratio, 0.80; 95% confidence interval, 0.46-1.41; P = 0.449). Adjusted on-treatment analysis showed a significant cardiovascular risk reduction in those who used CPAP for ≥4 versus <4 hours per night or did not receive treatment (hazard ratio, 0.29; 95% confidence interval, 0.10-0.86; P = 0.026).Routine prescription of CPAP to patients with CAD with nonsleepy OSA did not significantly reduce long-term adverse cardiovascular outcomes in the intention-to-treat population. There was a significant reduction after adjustment for baseline comorbidities and compliance with the treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 00519597).
Impact of radiation therapy on survival for para-aortic lymph node only recurrence in patients with uterine cervical squamous cell carcinoma
Authors: Y. Niibe, M. Oguchi, K. Hayakawa, K. Michimoto, T. Kanai, T. Jobo, H. Kuramoto, N. Unnno, K. Nimi
Journal: Journal of Clinical Oncology (2005)

5145 Background: Most patients who had any recurrent sites of cancer, have been considered to be last-stage of life. However, recent advances of clinical research reveal some patients achieve long-term survival even in recurrence cases. Furthermore, patients who had only one recurrent region, even radiation therapy could play an important role. As for uterine cervical squamous cell carcinoma, the most common recurrent site other than pelvis is para-aortic lymph node because of spreading more frequently through lymphatic route than hematogeneous one. Furthermore, improvement of diagnostic imaging enables us to detect more frequently only para-aortic lymph node recurrence. Thus, we conducted the current retrospective study. Methods: Between 1994 and 2003, about 2500 uterine cervical squamous cell carcinoma patients treated with curative intended treatments at Kitasato Univ Hsp or the Cancer Inst Hsp Japan Fdn for Cancer Rsch, Japan. Out of them, 28 patients developed para-arotic lymph node recurrence as the only site of initial tumor progression. These patients were treated with external beam radiation therapy. Radiation therapy protocol was as follows. 1.7–2.0 Gy per fraction, 5 fractions per week and median total dose was 50 Gy (40–56). Nine patients recieved adjuvant chemotherapy (6:BOMP, 2:UFT, 1: FP+TJ). Median serum SCC level was 3.6 ng/ml (1.3 - 92.8) at the detection of para-aortic recurrence. Results: Median follow-up time of all patients was 15 months (2- 62). Three-year overall survival rates of all patients was 26.4%. Stratified by adjuvant chemotherapy, 3-year overall survival rate of adjuvant chemotherapy group was 25.7% and those of radiation alone group was 27.4%, These were almost the same. However, stratified by serum SCC level (cut off level: 15 ng/ml), 3-year overall survival rate of high level group was 0% and those of low level group was 37.5%. Conclusions: The current study suggested that radiation therapy for para-aortic lymph node only recurrence in uterine cervical squamous cell carcinoma could have significant impact on overall survival. Furthermore, low level of serum SCC group could achieve better prognosis of 37.5% of 3-year overall survival. No significant financial relationships to disclose.
Role of c-erbb2 expression in non-small cell lung cancer
Authors: Z. Calikusu, Y. Yıldırım, H. Sakalli, N. Bal, Z. Akcali, O. Ozyilkan
Journal: Journal of Clinical Oncology (2008)

22044 Background: Non-small cell lung cancer is the most common causes of cancer death. To predict outcome of the lung cancer many prognostic factors are being investigated. The oncoprotein C-erb-B2 with tyrosine kinase activity is overexpressed in many tumors and its overexpression is associated with poor prognosis. In this study we evaluated the prevalence of c-erbB-2 overexpression in non-small cell lung cancer, and revealed the relation with disease prognosis. Methods: In this study, 89 patients (84 men and 4 women, age range 35-78) with non-small cell lung cancer, between 2000–2005 at Baskent University Medical Oncology Department, Adana, Turkey were evaluated. Immunohistochemical staining of c-erbB-2 was performed on paraffin-embedded sections. The scoring criteria of Clinical Trial Assay were used to evaluate staining (0 to +3). Patient's characteristics, histology and stage of the disease were obtained from clinical records. Relation between C-erbB-2 staining degrees and histology and stage of the disease compared with chi-square test. Results: In the study group, adenocarcinoma (45 patients (50.5%)) was the most common histology of non-small cell lung cancer, epidermoid carcinoma was seen in 32 patients (36%). C-erbB-2 overexpression was detected in 18 patients (20.2%). 2 patients (2.2%) exhibited strong (+3) staining and 13 patients (14.6%) exhibited moderate staining (+2) and 3 patients (3.4%) showed weak staining (+1). Seventy-one patients (89%) were c-erbB-2 negative. Median survival of patients with c-erbB-2 negative tumor was 13 months whereas; median survival of patients with c-erbB-2 positive was 6 months (p=0.02). Relative risk of death was 1.96 times higher in patients with c-erbB2 positive than those of c-erbB-2 negative (%95 CI, 1.08- 3.54; p=0.02). No correlation was found between c-erbB-2 positivity or stage of the disease or histology of the tumor (p>0.05). Conclusions: C-erbB-2 positivity may indicate shorter survival and can be regarded as unfavorable prognostic factor in non-small cell lung cancer. No significant financial relationships to disclose.