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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/6
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Publication Open Access DNA methylation profiling identifies novel markers of progression in hepatitis B-related chronic liver disease(BioMed Central, 2016) Vatansever, Sezgin; Hardy, Timothy; Sarı, Aysegül Akder; Çakalağaoğlu, Fulya; Avcı, Arzu; Zeybel, Gemma Louise; Bashton, Matthew; Mathers, John C.; Ünsal, Belkis; Mann, Jelena; N/A; Department of Molecular Biology and Genetics; Department of Molecular Biology and Genetics; Zeybel, Müjdat; Karahüseyinoğlu, Serçin; Faculty Member; Faculty Member; School of Medicine; 214694; 110772Background: Chronic hepatitis B infection is characterized by hepatic immune and inflammatory response with considerable variation in the rates of progression to cirrhosis. Genetic variants and environmental cues influence predisposition to the development of chronic liver disease; however, it remains unknown if aberrant DNA methylation is associated with fibrosis progression in chronic hepatitis B. Results: To identify epigenetic marks associated with inflammatory and fibrotic processes of the hepatitis B-induced chronic liver disease, we carried out hepatic genome-wide methylation profiling using Illumina Infinium beadarrays comparing mild and severe fibrotic disease in a discovery cohort of 29 patients. We obtained 310 differentially methylated regions and selected four loci comprising three genes from the top differentially methylated regions: hypermethylation of HOXA2 and HDAC4 along with hypomethylation of PPP1R18 were significantly linked to severe fibrosis. We replicated the prominent methylation marks in an independent cohort of 102 patients by bisulfite modification and pyrosequencing. The timing and causal relationship of epigenetic modifications with disease severity was further investigated using a cohort of patients with serial biopsies. Conclusions: Our findings suggest a linkage of widespread epigenetic dysregulation with disease progression in chronic hepatitis B infection. Cpg methylation at novel genes sheds light on new molecular pathways, which can be potentially exploited as a biomarker or targeted to attenuate inflammation and fibrosis.Publication Open Access The MHC class I MICA gene is a histocompatibility antigen in kidney transplantation(Springer Nature, 2022) Carapito, Raphael; Aouadi, Ismail; Verniquet, Martin; Untrau, Meiggie; Pichot, Angelique; Beaudrey, Thomas; Bassand, Xavier; Meyer, Sebastien; Faucher, Loic; Posson, Juliane; Morlon, Aurore; Kotova, Irina; Delbos, Florent; Walencik, Alexandre; Aarnink, Alice; Kennel, Anne; Suberbielle, Caroline; Taupin, Jean-Luc; Matern, Benedict M.; Spierings, Eric; Congy-Jolivet, Nicolas; Essaydi, Arnaud; Perrin, Peggy; Blancher, Antoine; Charron, Dominique; Cereb, Nezih; Maumy-Bertrand, Myriam; Bertrand, Frederic; Garrigue, Valerie; Pernin, Vincent; Weekers, Laurent; Naesens, Maarten; Kamar, Nassim; Legendre, Christophe; Glotz, Denis; Caillard, Sophie; Ladriere, Marc; Giral, Magali; Anglicheau, Dany; Bahram, Seiamak; Süsal, Caner; Other; School of MedicineThe identity of histocompatibility loci, besides human leukocyte antigen (HLA), remains elusive. The major histocompatibility complex (MHC) class I MICA gene is a candidate histocompatibility locus. Here, we investigate its role in a French multicenter cohort of 1,356 kidney transplants. MICA mismatches were associated with decreased graft survival (hazard ratio (HR), 2.12; 95% confidence interval (CI): 1.45-3.11; P < 0.001). Both before and after transplantation anti-MICA donor-specific antibodies (DSA) were strongly associated with increased antibody-mediated rejection (ABMR) (HR, 3.79; 95% CI: 1.94-7.39; P < 0.001; HR, 9.92; 95% CI: 7.43-13.20; P < 0.001, respectively). This effect was synergetic with that of anti-HLA DSA before and after transplantation (HR, 25.68; 95% CI: 3.31-199.41; P = 0.002; HR, 82.67; 95% CI: 33.67-202.97; P < 0.001, respectively). De novo-developed anti-MICA DSA were the most harmful because they were also associated with reduced graft survival (HR, 1.29; 95% CI: 1.05-1.58; P = 0.014). Finally, the damaging effect of anti-MICA DSA on graft survival was confirmed in an independent cohort of 168 patients with ABMR (HR, 1.71; 95% CI: 1.02-2.86; P = 0.041). In conclusion, assessment of MICA matching and immunization for the identification of patients at high risk for transplant rejection and loss is warranted.Publication Open Access Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential(Nature Portfolio, 2022) Kneppers, J.; Severson, T.M.; Siefert, J.C.; Schol, P.; Joosten, S.E.P.; Yu, I.P.L.; Huang, C.F.; Morova, T.; Giambartolomei, C.; Seo, J.H.; Baca, S.C.; Carneiro, I.; Emberly, E.; Pasaniuc, B.; Jerónimo, C.; Henrique, R.; Freedman, M.L.; Wessels, L.F.A.; Bergman, A.M.; Zwart, W.; N/A; Lack, Nathan Alan; Altıntaş, Umut Berkay; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Sciences and Engineering; 120842; N/AAndrogen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients’ outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate a high level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact.Publication Open Access Treating chronic hepatitis delta: the need for surrogate markers of treatment efficacy(Elsevier, 2019) Abbas, Zaigham; Buti, Maria; Cornberg, Markus; Esteban, Rafael; Etzion, Ohad; Ganes, Edward J.; Gish, Robert G.; Glenn, Jeffrey S.; Hamids, Saeed; Heller, Theo; Koh, Christopher; Lampertico, Pietro; Lurie, Yoav; Manns, Michael; Parana, Raymundo; Rizzetto, Mario; Urban, Stephan; Wedemeyer, Heiner; Wranke, A.; Borzacov, Pinheiro L. M.; Lobato, C.; Hamid, S.; Ceausu, E.; Dalekos, G. N.; Turcanu, A.; Niro, G. A.; Lubna, F.; Abbas, M.; Ingiliz, P.; Ferenci, P.; Vanwolleghem, T.; Hayden, T.; Dashdorj, N.; Motoc, A.; Hardtke, S.; N/A; Yurtaydın, Süleyman Cihan; Faculty Member; School of MedicineChronic hepatitis delta represents the most severe form of chronic viral hepatitis. The current treatment of hepatitis delta virus (HDV) infection consists of the use of interferons and is largely unsatisfactory. Several new compounds are currently in development for the treatment of HDV infection. However, surrogate markers that can be used to develop clinical endpoints in HDV infection are not well defined. In the current manuscript, we aimed to evaluate the existing data on treatment of HDV infection and to suggest treatment goals (possible "trial endpoints") that could be used across different clinical trials.Publication Open Access Morbidity and mortality after robot-assisted radical cystectomy with intracorporeal urinary diversion in octogenarians: results from the European Association of Urology Robotic Urology Section Scientific Working Group(Wiley, 2020) Mortezavi, A.; Crippa, A.; Edeling, S.; Pokupic, S.; Dell'Oglio, P.; Montorsi, F.; D'Hondt, F.; Mottrie, A; Decaestecker, K.; Wijburg, C. J.; Collins, J.; Kelly, J. D.; Tan, W. S.; Sridhar, A.; John, H.; Schwentner, C.; Rönmark, E. P.; Wiklund, P.; Hosseini, A.; Canda, Abdullah Erdem; Faculty Member; School of Medicine; 116202Objectives: to evaluate the postoperative complication and mortality rate following laparoscopic radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) in octogenarians. Patients and methods: we conducted a retrospective analysis comparing postoperative complication and mortality rates depending on age in a consecutive series of 1890 patients who underwent RARC with ICUD for bladder cancer between 2004 and 2018 in 10 European centres. Outcomes of patients aged <80 years and those aged ≥80 years were compared with regard to postoperative complications (Clavien–Dindo grading) and mortality rate. Cancer-specific mortality (CSM) and other-cause mortality (OCM) after surgery were calculated using the non-parametric Aalen-Johansen estimator. Results: a total of 1726 patients aged <80 years and 164 aged ≥80 years were included in the analysis. The 30- and 90-day rate for high-grade (Clavien–Dindo grades III–V) complications were 15% and 21% for patients aged <80 years compared to 11% and 13% for patients aged ≥80 years (P = 0.2 and P = 0.03), respectively. In a multivariable logistic regression analysis adjusting for pre- and postoperative variables, age ≥80 years was not an independent predictor of high-grade complications (odds ratio 0.6, 95% confidence interval 0.3–1.1; P = 0.12). The non-cancer-related 90-day mortality was 2.3% for patients aged ≥80 years and 1.8% for those aged <80 years, respectively (P = 0.7). The estimated 12-month CSM and OCM rates for those aged <80 years were 8% and 3%, and for those aged ≥80 years, 15% and 8%, respectively (P = 0.009 and P < 0.001). Conclusions: the minimally invasive approach to RARC with ICUD for bladder cancer in well-selected elderly patients (aged ≥80 years) achieved a tolerable high-grade complication rate; the 90-day postoperative mortality rate was driven by cancer progression and the non-cancer-related rate was equivalent to that of patients aged <80 years. However, an increased OCM rate in this elderly group after the first year should be taken into account. These results will support clinicians and patients when balancing cancer-related vs treatment-related risks and benefits.Publication Open Access Continuous positive airway pressure treatment and anxiety in adults with coronary artery disease and nonsleepy obstructive sleep apnea in the RICCADSA trial(Elsevier, 2021) Çelik, Yeliz; Thunström, Erik; Strollo Jr., Patrick J.; Peker, Yüksel; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); 234103Background: anxiety and obstructive sleep apnea (OSA) coexist among adults with coronary artery disease (CAD) following revascularization. Continuous positive airway pressure (CPAP) is the first line treatment of OSA patients with daytime sleepiness. The current study evaluated the effect of CPAP on anxiety in CAD patients with nonsleepy OSA. Methods: two hundred forty-four revascularized CAD patients with nonsleepy OSA (apnea-hypopnea index ?15/h, Epworth Sleepiness Scale score <10) were randomly assigned to CPAP or no-CPAP between 2005 and 2010. Zung Self-rating Anxiety Scale (SAS) was administered at baseline and after 3 and 12 months with higher scores suggesting more anxiety. Results: a total of 208 patients with complete SAS scores at baseline and 12-month follow-up were included (CPAP, n = 103; no-CPAP, n = 105). In the intention-to-treat analysis, CPAP had no significant effect on the SAS scores. On-treatment analysis revealed a significant increase in the median of delta SAS score (+3.75) after three months among the participants using the device 2.8 h/day or more while there was a decline in the median of delta SAS score (?1.25) in the non-adherent or no-CPAP group (p = 0.031). The increase in the SAS score (+1.25) in the adherent group, and the decline (?1.25 points) in the non-adherent/no-CPAP group remained significant after one year (p = 0.011). Baseline SAS score predicted non-adherence [adjusted odds ratio 1.11; 95% confidence interval (CI) 1.04–1.18; p = 0.003], and there was an association between the increase in the SAS scores and accumulated CPAP hours/day [standardized ? = 0.144 (95% CI 0.005–0.695), p = 0.047]. Conclusion: our results suggest that anxiety should be considered in the management of CAD patients with nonsleepy OSA following revascularization. Clinical trial registration: NCT00519597.Publication Open Access Heterogeneity of pollen food allergy syndrome in seven Southern European countries: the @IT.2020 Multicenter Study(Wiley, 2021) Lipp, T.; Acar Şahin, A.; Aggelidis, X.; Arasi, S.; Barbalace, A.; Bourgoin, A.; Bregu, B.; Brighetti, M. A.; Caeiro, E; Çağlayan Sözmen, S.; Caminiti, L.; Charpin, D.; Couto, M.; Delgado, L.; Di Rienzo Businco, A.; Dimier, C.; Dimou, M. V.; Fonseca, J. A.; Göksel, O.; Güvensen, A.; Hernandez, D.; Hoffmann, T. M.; Jang, D. T.; Kalpaklıoğlu, F.; Lame, B.; Llusar, R.; Makris, M.; Mazon, A.; Mesonjesi, E.; Nieto, A.; Pahus, L.; Pajno, G.; Panasiti, I.; Papadopoulos, N. G.; Pellegrini, E.; Pelosi, S.; Pereira, A. M.; Pereira, M.; Pınar, N. M.; Potapova, E.; Priftanji, A.; Psarros, F.; Sfika, I.; Suarez, J.; Thibaudon, M.; Travaglini, A.; Tripodi, S.; Verdier, V.; Villella, V.; Xepapadaki, P.; Matricardi, P. M.; Dramburg, S.; Öztürk, Ayşe Bilge; Saçkesen, Cansın; Dereli, Dilek Yazıcı; Faculty Member; Faculty Member; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 147629; 182537; N/ABackground: pollen food allergy syndrome (PFAS) is a frequently underdiagnosed disease due to diverse triggers, clinical presentations, and test results. This is especially relevant in geographic areas with a broad spectrum of pollen sensitization, such as Southern Europe. Objectives: to elucidate similarities and differences ofPFAS in nine Southern European centers and identify associated characteristics and unique markers of PFAS. Methods: as part of the @IT.2020 Multicenter Study, 815 patientswith seasonal allergic rhinitis (SAR), aged 10‐60 years, were recruited in seven countries. They completed questionnaires regarding SAR, comorbidities, family history, and PFAS, underwent skin prick testing (SPT) and serum IgE testing. Results: of the 815 patients, 167 (20.5%) reported PFAS reactions.Most commonly, eliciting foods were kiwi (58, 34.7%), peach (43, 25.7%), and melon (26, 15.6%). Reported reactions were mostlylocal (216/319, 67.7%), occurring within five minutes of contact with elicitors (209/319, 65.5%). Associated characteristicsincluded positive IgE to at least one panallergen (profilin, PR‐10, or nsLTP) (p=.007), maternal PFAS (OR:3.716, p=.026), and asthma (OR:1.752, p=.073).Between centers, heterogeneity in prevalence (Marseille: 7.5% vs. Rome: 41.4%, p<.001) and of clinical characteristics was apparent. Cypress played a limited role, with only 1/22 SPT mono‐sensitized patients reporting a food‐reaction (p<.073). Conclusions: PFAS is a frequent comorbidity in Southern European SARpatients. Significant heterogeneity of clinical characteristics in PFAS patients amongst the centers was observed, and may be related to the different pollen sensitization patterns in each geographical area.IgE to panallergen(s), maternal PFAS, and asthma could be PFAS‐associated characteristics.Publication Open Access Teaching global health with simulations and case discussions in a medical student selective(BioMed Central, 2016) DallaPiazza, M.; Hopkins, M.A.; Ogedegbe, G.; DallaPiazza, M.; Hopkins, M.A.; Ogedegbe, G.; N/A; Bertelsen, Nathan; Faculty Member; School of MedicineBackground: Among US medical schools, demand for Global Health (GH) programs continues to grow. At the same time, cultural competency training has become a priority for medical students who will care for an increasingly diverse US patient population. We describe a pilot period for a new GH Selectivedesigned to introduce medical students to global medicine and enhance culturally-sensitive communication skills. Methods: As a 4-week clinical clerkship, the GH Selective was offered annually over a three-year period to a total of 33 students. Activities included clinical assignments, cultural competency and clinical skills simulations, patient case discussions in tropical medicine, journal clubs, and lectures. Faculty assessments of student performance and student evaluations of course content were focused on 6 course objectives, adapted from standardized GH objectives. Results: For each offering of the GH Selective, at least 40 faculty members and fellows volunteered over 200 teaching hours from 11 medical school departments. Student feedback was consistently positive through competency-based curricular evaluations. As a result of its successes, the course is now offered on a biannual basis. Discussion: Experiential, student-centered teaching employed in this course proved successful as an introduction to delivery of evidence-based and culturally sensitive GH. Special emphasis on working with standardized patients in interdisciplinary and cross-cultural simulations provided students with clinical skills applicable for care provided both locally and on international rotations. Conclusion: With a special emphasis on cross-cultural sensitivity, this pilot elective trained future practitioners in fund of knowledge, clinical skills, and service delivery methods in GH.Publication Open Access Changes in computed tomography findings of COVID-19 pneumonia: less extensive lung involvement with decreasing disease prevalence(Wiley, 2020) Gümüş, Terman; Cengiz, Duygu; Kartal, Furkan; Atçeken, Zeynep; Tekin, Süda; Atasoy, Kayhan Çetin; Doctor; Faculty Member; School of MedicineIt has been observed that the degree of pulmonary involvement shown in chest computed tomography (CT) scans tended to decrease as the prevalence of coronavirus disease 2019 (COVID-19) infection decreased in the Turkish population. The purpose of this study was to investigate the relationship between the disease severity based on chest CT scans and the temporal evolution of the epidemic. This study recruited 179 patients with confirmed COVID-19 disease who had received a chest CT scan between March 14 and April 28, 2020. The participants were divided into three successive temporal groups based on their date of CT examination. The early (March 14-29), mid (March 30-April 13), and late (April 14-28) groups were compared regarding the presence and extent of pulmonary involvement and CT characteristics of lesions. COVID-19 pneumonia was less extensive in participants under 45 years of age and patients presenting late in the course of epidemic (i.e., the late group) compared those presenting earlier. When each group was subcategorized on the basis of age, older patients in the late group had less extensive lung involvement than older patients in the early group. However, there was no significant difference in the extent of lung involvement in younger patients between the late and early groups. The severity of COVID-19 pneumonia appears to be variable at different temporal windows of the epidemic curve and decreases in patients presenting in the later weeks compared to the earlier weeks, particularly in older patients.Publication Open Access COVID-19 presenting with atypical Sweet's syndrome(Wiley, 2020) Altuğ, E.; Demirkesen, C.; Çelenbi, İ.; Ferhanoğlu, B.; Alper, S.; Vural, Seçil; Kocatürk Göncü, Özgür Emek; Taşkın, Banu; Faculty Member; Doctor; School of Medicine; 189340; 217219; N/A