tbuckley/cabot-search huggingface dataset:
Abstract 15814: Novel Protective Mechanism of Cu Transporter ATP7A for Extracellular SOD Against Endothelial Dysfunction in Type2 Diabetes Vascular Complications
Authors: Sudhahar Varadarajan, Nazir Okur, John O'Bryan, Richard Minshall, Shane Phillips, Masuko Ushio-Fukai, Tohru Fukai
Journal: Circulation (2015)

Endothelial dysfunction induced by oxidative stress is the major vascular complication in diabetes mellitus (DM). Extracellular SOD (ecSOD), a secretory copper (Cu) enzyme, preserves endothelial function by scavenging extracellular superoxide, and its full activity requires Cu transporter ATP7A. We reported that reduced ATP7A-ecSOD pathway in vascular smooth muscle cells (VSMCs) is involved in endothelial dysfunction in type1 DM with hypoinsulinemia, but its role and mechanism in type2 DM with impaired insulin-Akt signaling is entirely unknown. Here we show that in VSMC, insulin increases ATP7A protein expression (1.8 fold) without affecting transcription by reducing ATP7A ubiquitination in a PI3K/Akt dependent manner. In organoid culture of mouse aorta, insulin increases ecSOD specific activity (47%) and ATP7A expression (1.9-fold). Insulin stimulation (2 hrs) promotes ATP7A translocation from TGN to caveolin (Cav) enriched lipid raft (C/LR) where it binds to ecSOD in PI3K/Akt dependent manner, reflecting Cu delivery to ecSOD through ATP7A at C/LR. Mechanistically, insulin increases pAkt binding to ATP7A to induce pSer-ATP7A, which is required for ATP7A translocation to C/LR. Mass spectrometry analysis identified Akt phosphorylation site of ATP7A at S1424/S1432/S1466. Of note, vascular ATP7A protein expression, ecSOD specific activity and endothelial function are impaired in Cav1 KO or Akt2 KO or ATP7Amut mice, but not Akt1 KO mice, suggesting the importance of Akt2-mediated ATP7A protein stabilization and its translocation to C/LR for ecSOD activation. Moreover, in aorta or VSMCs of high fat diet-induced type2 DM mice with impaired insulin-Akt pathway, ATP7A expression (57%) and ecSOD specific activity (53%), but not Cu/Zn SOD, are decreased. Acetylcholine-induced vasorelaxation is significantly impaired in resistant vessels of type2 DM mice, which is rescued in ATP7A-Tg/Type2 DM mice. In summary, insulin-Akt dependent ATP7A protein stabilization and translocation to C/LR promotes ecSOD activation, which prevents endothelial dysfunction in type2 DM. Thus, enhancing Akt2-ATP7A-ecSOD axis is potential therapeutic strategy for protecting against endothelial dysfunction in diabetes vascular complications.
Biopsy-driven study to identify biomarkers predictive of clinical response to second-line regorafenib in patients with metastatic colorectal cancer.
Authors: Petr Kavan, Caroline Rousseau, Francine Aubin, Adrian Langleben, Adrian Gologan, Robert Zakarian, Cyrla Hoffert, Gerald Batist
Journal: Journal of Clinical Oncology (2014)

TPS3656 Background: Biopsy-driven trials offer unique opportunities for discovery and validation of molecular signatures. We began a Phase II investigator-initiated study (IIS) to identify biomarkers (BMs) predictive of response to regorafenib in patients with metastatic colorectal cancer (mCRC) (QCROC-06; NCT01949194). Regorafenib is an oral multikinase inhibitor that targets angiogenic, stromal and oncogenic kinases. Results from the CORRECT trial suggest that some patients benefit more than others from single-agent regorafenib, but the trial was not designed to study these differences (Grothey et al. The Lancet 381: 303-312, 2012). Methods: Patients with mCRC and at least one liver metastasis available for biopsy, who have failed first-line treatment, are eligible for this study of second-line treatment with single-agent regorafenib. The primary objective is to identify BMs in blood or tissue. Secondary objectives include progression free survival, response rate and safety. Patients are accrued at four Canadian centers to collect 42 evaluable pre-treatment biopsies. Two patients have been enrolled so far. The trial is part of a portfolio of sequential biopsy-driven IIS. Patients are primarily recruited after participating in QCROC-01, a prospective study to identify BMs of resistance to first-line therapy. A biopsy taken at resistance to first-line treatment serves as the entry biopsy for QCROC-06. Another biopsy at disease progression is optional. Genomic material is isolated from all biopsies, and blood is collected regularly for analysis of VEGF polymorphism and circulating tumor DNA. BMs will be identified using targeted and global profiling approaches. We assume a maximum of 10 BMs, and an overall type 1 error of 5%, and that a disease control rate of 74% will be achieved. With 80% power, this sample size allows us to detect BM(s) if the proportion of patients with the BM(s) is ≤ 26% in non-responders and ≥ 84% in responders. Bioinformatics analysis will correlate findings with response to regorafenib. The trial is supported by Bayer HealthCare. Clinical trial information: NCT01949194.
Cytomegalovirus (CMV) Viral Load in Cord Blood (CB) Donors and Impact of Congenital Viremia on Markers of Hematopoietic Progenitor Cell (HPC) Potency
Authors: Maria S Albano, Rodica Ciubotariu, Chiseko Watanabe, Siddarth Krishnan, Michal Tarnawski, Ludy Dobrila, Andromachi Scaradavou, Pablo Rubinstein
Journal: Blood (2016)
Polyp Surveillance – Experience of a Single Gastrointestinal Endoscopy Unit
Authors: G Bennett, J Leyden, E Clarke, J Crowe, J Lennon, P MacMathuna
Journal: Endoscopy (2004)

Background: International guidelines have recommended increasing the intervals for surveillance colonoscopy in patients with a history of colorectal polyps. The American Gastroenterological Association guidelines published in February 2003 suggest 5 yearly colonoscopy for patients with small tubular adenomas.
HER3 and paxillin signaling in ER+ HER2- metastatic breast cancer (MBC) patients receiving letrozole (L) vs letrozole plus dasatinib (L+D) in a randomized phase II trial.
Authors: Joyce O'Shaughnessy, Devchand Paul, Maren K. Levin, Yunfei Wang, Nicholas N Hoke, Corinne Ramos
Journal: Journal of Clinical Oncology (2015)

517 Background: BC invasion is mediated by Src and its downstream target, the adhesion protein, paxillin (Pax). A randomized phase II trial of L + the Src inhibitor dasatinib demonstrated that L+D improved median PFS to 20 mos from 10 mos with L alone as first-line therapy for ER+ HER2-negative MBC (Paul D. SABCS 2013, S3-07). We conducted reverse phase protein microarray (RPMA) on pts’ primary BCs to identify phosphoproteins associated with recurrence and with outcome on L vs L+D. Methods: 48 pts’ FFPE primary breast cancers were acceptable for RPMA at a CLIA-certified laboratory (Theranostics Health, Rockville, MD). Immunostaining was carried out with 20 antibodies directed against HER pathway proteins, MET, Src, and Pax. Student t-test or Mann-Whitney U test and Spearman correlation coefficient (ρ) were used to assess biomarker association with PFS < 6 mos vs > 6 mos by treatment arm (unpaired 2 tails, p value). Results: Median PFS for the 48 pts was 19.2 mos for L+D (N=21) vs 9.2 mos for L (N=27). ~90% of the BCs overexpressed HER3, p-mTOR, p-4EBP1, p-JAK2, p-STAT3 and 50% overexpressed p-Pax. Across all pts, protein linkage Pearson correlations (r) showed strong associations between p-Pax & p-HER2 (r=0.74), HER3 & p-HER2 (r=0.79), p-HER1 & p-HER2 (r=0.82), HER3 & p-MET (r=0.72) and p-Pax & p-MET (SR=0.93). Evaluating all 48 pts, PFS < 6 mos was correlated with HER3 expression (p< 0.01), p-HER3 (p=0.02), p-HER2 (p=0.04) and HER1 (p=0.05). Evaluating L vs L+D pts, PFS < 6 mos was associated with HER3 (p< 0.01), p-HER3 (p=0.03), p-HER2 (p=0.07), HER1 (p=0.05), p-Pax (p=0.02), and p-Met (p=0.05) expression only in L alone pts and not in L+D pts. PFS < 6 mos with L+D was associated with p-Src (ρ=0.9, p=0.04) and p-Pax (ρ=0.71, p=0.11)]. p-Pax expression was inversely correlated with prolonged PFS in L alone (ρ= -0.7, p=0.04) but not in L+D pts. Conclusions: Primary ER+ HER2- BCs that recurred expressed high levels of HER3 and downstream phosphoproteins. HER3 overexpression correlated with p-HER2, p-HER1, p-MET, and p-Pax expression and predicted for short PFS with L alone but not with L+D. These findings suggest that dasatinib may inhibit HER3 signaling in ER+ HER2- MBC pts.
Impact of Changes Over Time in Adipokines and Inflammatory Proteins on Changes in Insulin Sensitivity, β-Cell Function, and Glycemia in Women With Previous Gestational Dysglycemia
Authors: Ravi Retnakaran, Chang Ye, Philip W. Connelly, Anthony J. Hanley, Mathew Sermer, Bernard Zinman
Journal: Diabetes Care (2017)

Adipokine dysregulation and subclinical inflammation are putative diabetogenic features of adiposity. However, while alterations in adipokines/inflammatory proteins can predict incident type 2 diabetes in longitudinal studies (1–3), evidence for causality is generally hindered by two limitations. First, there is a relative paucity of human data linking changes in adipokines/inflammatory proteins with changes in insulin sensitivity and β-cell function over time, as might be expected for causal mediators. Second, because obesity-induced changes in circulating proteins do not occur in isolation, the precise elucidation of causal mediators ideally requires consideration of multiple adipokines/inflammatory proteins simultaneously (as opposed to individually, as typically occurs in studies). Thus, to address these limitations, we evaluated changes over 2 years in adipokines (adiponectin, chemerin, retinol-binding protein 4 [RBP-4]) and inflammatory proteins (C-reactive protein [CRP], plasminogen activator inhibitor 1 [PAI-1]) in relation to changes in insulin sensitivity, β-cell function, and glycemia in women with varying degrees of recent gestational dysglycemia …
Palliative performance scale differences between patients referred by specialized cancer center and general hospitals to the palliative care center in Kuwait.
Authors: Khalid Al Saleh, Najlaa AlSayed, Wafaa Abd-El-Gawad, Sobhy Mostafa, Mohammed Mostafa, Ahmed Bedair
Journal: Journal of Clinical Oncology (2015)

e20541 Background: Palliative care is changing from just ‘end of life care’ to care delivered earlier in the disease course. Metanalysis showed that Palliative Performance Scale (PPS) is associated with increased length of survival. The Palliative Care Center (PCC) in Kuwait is the only stand-alone center in Eastern Mediterranean Region with a capacity of 92 beds. We compared clinical characteristics between patients referred from the Specialized Cancer Center and general hospitals in Kuwait to PCC. Methods: Across Sectionalsurvey was conducted since the opening of PCC in January 2011 to June 2013. Patients data on demographics, type of the cancer, PPS score and referring hospital were collected and analyzed. Results: Total number of the patients was 142. Mean agewas 61.05±14.79 years, 66 patients (47.1%) were males and 74 (52.9%) were females. The most common cancers in males were lung (n = 18, 27.3%) followed by head and neck cancers (n = 8, 12.1%) and brain tumors (n = 7, 10.6%) while in females, the most common cancers were breast cancer (n = 12, 16.7%) followed by ovarian cancer (n = 10, 13.9%) and Cancer Colon (n = 8, 11.1%). Patients with PPS score 30% were 27.9% (n = 39), 40% in 40.7% (n = 57), and 50% in 17.1% (n = 24) respectively. Patients referred from the Specialized Cancer Center had significantly higher portion of patients with PPS score > 30% (73.4%, n = 94), compared to patients coming from general hospitals (33.3%, n = 4), P value = 0.007. Conclusions: There is significant difference in PPS scores between patients referred from the Specialized Cancer Center compared to patients referred from general hospitals. We encourage that all cancer patients should be treated in Specialized Cancer Centers and earlier involvement of Palliative Care Centers to achieve better survival. Training workshops are needed for health care professionals working in general hospitals to raise awareness about earlier referral of patients to palliative care services.
AIDS Enteropathy
Authors: Reiner Ullrich, Ernst-Otto Riecken, Martin Zeitz, Klinikum Steglitz
Journal: Annals of Internal Medicine (1991)

Letters15 August 1991AIDS EnteropathyReiner Ullrich, MB, Ernst-Otto Riecken, MD, Martin Zeitz, MD, Klinikum SteglitzReiner Ullrich, MBSearch for more papers by this author, Ernst-Otto Riecken, MDSearch for more papers by this author, Martin Zeitz, MDSearch for more papers by this author, Klinikum SteglitzSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-115-4-328_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the Editors:Greenson and colleagues (1) recently defined "acquired immunodeficiency syndrome (AIDS) enteropathy" as "chronic, well-established diarrhea (> 1 month duration) for which no infectious cause can be determined after complete evaluation" but failed to find any mucosal abnormalities characteristic of such enteropathy. We find this definition inadequate for the following reasons: Intestinal dysfunction is found even at early stages of infection with the human immunodeficiency virus (HIV) and in patients without diarrhea or weight loss (2). Further, the detection of an infectious agent does not prove its causative role (3). We have recently found large proportions of both...References1. Greenson J, Belitsos P, Yardley J, and Bartlett J. AIDS enteropathy: occult enteric infections and duodenal mucosal alterations in chronic diarrhea. Ann Intern Med. 1991;114:366-72. LinkGoogle Scholar2. Ullrich R, Zeitz M, Heise W, L'age M, Höffken G, and Riecken E. Small intestinal structure and function in patients infected with human immunodeficiency virus (HIV): Evidence for HIV-induced enteropathy. Ann Intern Med. 1989;111:15-21. LinkGoogle Scholar3. Laughon B, Druckman D, and Vernon A. Prevalence of enteric pathogens in homosexual men with and without acquired immunodeficiency syndrome. Gastroenterology. 1988;94:984-93. CrossrefMedlineGoogle Scholar4. Ullrich R, Zeitz M, and Heise W. Mucosal atrophy is associated with loss of activated T cells in the duodenal mucosa of human immunodeficiency virus (HIV)-infected patients. Digestion. 1990;46(Suppl 2):302-7. CrossrefMedlineGoogle Scholar5. Zeitz M, Greene W, Peffer N, and James S. Lymphocytes isolated from the intestinal lamina propria of normal nonhuman primates have increased expression of genes associated with T cell activation. Gastroenterology. 1988;94:647-55. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: Reiner Ullrich, MB; Ernst-Otto Riecken, MD; Martin Zeitz, MD; Klinikum Steglitz PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byA Patient With Chronic Diarrhea of Unknown CauseChronic diarrhea: Causes, presentation, and mangementNew developments in acute diarrhea 15 August 1991Volume 115, Issue 4Page: 328-328KeywordsAIDSDiarrheaEnteropathiesHIVWeight loss ePublished: 1 December 2008 Issue Published: 15 August 1991 PDF downloadLoading ...
Differentiated demographic histories and local adaptations between Sherpas and Tibetans
Authors: Chao Zhang, Yan Lu, Qidi Feng, Xiaoji Wang, Haiyi Lou, Jiaojiao Liu, Zhilin Ning, Kai Yuan, Yuchen Wang, Ying Zhou, Lian Deng, Lijun Liu, Yajun Yang, Shilin Li, Lifeng Ma, Zhiying Zhang, Li Jin, Bing Su, Longli Kang, Shuhua Xu
Journal: Genome biology (2017)

The genetic relationships reported by recent studies between Sherpas and Tibetans are controversial. To gain insights into the population history and the genetic basis of high-altitude adaptation of the two groups, we analyzed genome-wide data in 111 Sherpas (Tibet and Nepal) and 177 Tibetans (Tibet and Qinghai), together with available data from present-day human populations. Sherpas and Tibetans show considerable genetic differences and can be distinguished as two distinct groups, even though the divergence between them (~3200–11,300 years ago) is much later than that between Han Chinese and either of the two groups (~6200–16,000 years ago). Sub-population structures exist in both Sherpas and Tibetans, corresponding to geographical or linguistic groups. Differentiation of genetic variants between Sherpas and Tibetans associated with adaptation to either high-altitude or ultraviolet radiation were identified and validated by genotyping additional Sherpa and Tibetan samples. Our analyses indicate that both Sherpas and Tibetans are admixed populations, but the findings do not support the previous hypothesis that Tibetans derive their ancestry from Sherpas and Han Chinese. Compared to Tibetans, Sherpas show higher levels of South Asian ancestry, while Tibetans show higher levels of East Asian and Central Asian/Siberian ancestry. We propose a new model to elucidate the differentiated demographic histories and local adaptations of Sherpas and Tibetans.
Poor prognostic factors in human papilloma virus-positive head and neck cancer: Who should not be candidate of de-escalated treatment?
Authors: Shin Hye Yoo, Chan-Young Ock, Bhumsuk Keam, Tae Min Kim, Jin Ho Kim, Yoon-Kyung Jeon, Eun-Jae Chung, Seong Keun Kwon, J. Hun Hah, Tack-Kyun Kwon, Dong-Wan Kim, Hong-Gyun Wu, Myung-Whun Sung, Dae Seog Heo
Journal: Journal of Clinical Oncology (2016)

6078 Background: Human papilloma virus (HPV)-associated locally advanced head and neck squamous carcinoma (LA HNSCC) shows favorable treatment outcome, and treatment de-escalation is actively under-investigated. However, not all the HPV+ LA HNSCCs are curable, and some of them shows poor prognosis. The purpose of this study is to identify poor prognostic factors in HPV+ LA HNSCC patients. Methods: Patients who were diagnosed as LA HNSCC and tested for HPV status from 2000 to 2015 were included in this retrospective analysis. Demographic data (age, gender), smoking status, comorbidity, and clinical information about stage, pathology, type of definite treatment were obtained. HPV typing was conducted using HPV DNA genotyping chip or liquid bead microarray. Expression of p16 was assessed by immunohistochemistry. Univariate and multivariate analyses were done with factors associated with overall survival (OS) by Cox regression analysis. Results: One hundred fifty two HPV+ LA HNSCC patients were included in this study. Male patients were 82.2% and 43.4% were current or ex-smoker. Oropharyngeal cancer was 84.2%. In univariate analysis, old age, poor performance, non-oropharynx, advanced T stage (T3, 4), N0 stage, HPV genotype 18 were significantly associated with poor OS. Smoking was not associated with OS. In multivariate analysis, poor performance (ECOG PS≥1), non-oropharyngeal location were independently associated with shorter overall survival (HR 4.82, p = 0.003; HR 7.36, p = 0.001, respectively). Furthermore, HPV genotype 18 positivity was also independent poor prognostic factor for OS in HPV+ LA HNSCC (HR 11.41, p < 0.001). Conclusions: Non-oropharyngeal cancer, poor performance status, HPV genotype 18 were independent poor prognostic factors in HPV+ LA HNSCC. These patients should not be candidate of de-escalated treatment.
The Circular RNA Interacts with STAT3, Increasing Its Nuclear Translocation and Wound Repair by Modulating Dnmt3a and miR-17 Function
Authors: Zhen-Guo Yang, Faryal Mehwish Awan, William W. Du, Yan Zeng, Juanjuan Lyu, De Wu, Shaan Gupta, Weining Yang, Burton B. Yang
Journal: Molecular Therapy (2017)

Delayed or impaired wound healing is a major health issue worldwide, especially in patients with diabetes and atherosclerosis. Here we show that expression of the circular RNA circ-Amotl1 accelerated healing process in a mouse excisional wound model. Further studies showed that ectopic circ-Amotl1 increased protein levels of Stat3 and Dnmt3a. The increased Dnmt3a then methylated the promoter of microRNA miR-17, decreasing miR-17-5p levels but increasing fibronectin expression. We found that Stat3, similar to Dnmt3a and fibronectin, was a target of miR-17-5p. Decreased miR-17-5p levels would increase expression of fibronectin, Dnmt3a, and Stat3. All of these led to increased cell adhesion, migration, proliferation, survival, and wound repair. Furthermore, we found that circ-Amotl1 not only increased Stat3 expression but also facilitated Stat3 nuclear translocation. Thus, the ectopic expressed circ-Amotl1 and Stat3 were mainly translocated to nucleus. In the presence of circ-Amotl1, Stat3 interacted with Dnmt3a promoter with increased affinity, facilitating Dnmt3a transcription. Ectopic application of circ-Amotl1 accelerating wound repair may shed light on skin wound healing clinically. Delayed or impaired wound healing is a major health issue worldwide, especially in patients with diabetes and atherosclerosis. Here we show that expression of the circular RNA circ-Amotl1 accelerated healing process in a mouse excisional wound model. Further studies showed that ectopic circ-Amotl1 increased protein levels of Stat3 and Dnmt3a. The increased Dnmt3a then methylated the promoter of microRNA miR-17, decreasing miR-17-5p levels but increasing fibronectin expression. We found that Stat3, similar to Dnmt3a and fibronectin, was a target of miR-17-5p. Decreased miR-17-5p levels would increase expression of fibronectin, Dnmt3a, and Stat3. All of these led to increased cell adhesion, migration, proliferation, survival, and wound repair. Furthermore, we found that circ-Amotl1 not only increased Stat3 expression but also facilitated Stat3 nuclear translocation. Thus, the ectopic expressed circ-Amotl1 and Stat3 were mainly translocated to nucleus. In the presence of circ-Amotl1, Stat3 interacted with Dnmt3a promoter with increased affinity, facilitating Dnmt3a transcription. Ectopic application of circ-Amotl1 accelerating wound repair may shed light on skin wound healing clinically.