The human blood proteome provides a holistic readout of health states through the assessment of thousands of circulating proteins. In this study, we present a pan-disease resource to enable the study of diverse disease phenotypes within a harmonized proteomics dataset. By profiling protein concentrations across 59 diseases and healthy cohorts, we identified proteins associated with age, sex, and body mass index, as well as disease-specific signatures. This study highlights shared and distinct protein patterns across conditions, demonstrating the power of a unified proteomics approach to uncover biological insights. The dataset, covering 8262 individuals and up to 5416 proteins, serves as an online resource for exploring disease-specific protein profiles and advancing precision medicine research.

Abstract Objective Turkish genome is underrepresented in large genomic databases. This study aims to evaluate the effect of allele frequency in the Turkish population in determining the clinical utility of germline findings in breast cancer, including invasive lobular carcinoma (ILC), mixed invasive ductal and lobular carcinoma (IDC‐L), and ductal carcinoma (DC). Methods Two clinic‐based cohorts from the Umraniye Research and Training Hospital (URTH) were used in this study: a cohort consisting of 132 women with breast cancer and a non‐cancer cohort consisting of 492 participants. The evaluation of the germline landscape was performed by analysis of 27 cancer genes. The frequency and type of variants in the breast cancer cohort were compared to those in the non‐cancer cohort to investigate the effect of population genetics. The variant allele frequencies in Turkish Variome and gnomAD were statistically evaluated. Results The genetic analysis identified 121 variants in the breast cancer cohort (actionable = 32, VUS = 89) and 223 variants in the non‐cancer cohort (actionable = 25, VUS = 188). The occurrence of 21 variants in both suggested a possible genetic population effect. Evaluation of allele frequency of 121 variants from the breast cancer cohort showed 22% had a significantly higher value in Turkish Variome compared to gnomAD (p < 0.0001, 95% CI) with a mean difference of 60 times (ranging from 1.37–354.4). After adjusting for variant allele frequency using the ancestry‐appropriate database, 6.7% (5/75) of VUS was reclassified to likely benign. Conclusion To our knowledge, this is the first study of population genetic effects in breast cancer subtypes in Turkish women. Our findings underscore the need for a large genomic database representing Turkish population‐specific variants. It further highlights the significance of the ancestry‐appropriate population database for accurate variant assessment in clinical settings.

Growing evidence suggests that the depletion of plasma NAD+ and glutathione (GSH) may play an important role in the development of metabolic disorders. The administration of Combined Metabolic Activators (CMA), consisting of GSH and NAD+ precursors, has been explored as a promising therapeutic strategy to target multiple altered pathways associated with the pathogenesis of the diseases. Although studies have examined the therapeutic effect of CMA that contains N-acetyl-l-cysteine (NAC) as a metabolic activator, a system-wide comparison of the metabolic response to the administration of CMA with NAC and cysteine remains lacking. In this placebo-controlled study, we studied the acute effect of the CMA administration with different metabolic activators, including NAC or cysteine with/without nicotinamide or flush free niacin, and performed longitudinal untargeted-metabolomics profiling of plasma obtained from 70 well-characterized healthy volunteers. The time-series metabolomics data revealed the metabolic pathways affected after the administration of CMAs showed high similarity between CMA containing nicotinamide and NAC or cysteine as metabolic activators. Our analysis also showed that CMA with cysteine is well-tolerated and safe in healthy individuals throughout the study. Last, our study systematically provided insights into a complex and dynamics landscape involved in amino acid, lipid and nicotinamide metabolism, reflecting the metabolic responses to CMA administration containing different metabolic activators.

NAD+ and glutathione precursors are currently used as metabolic modulators for improving the metabolic conditions associated with various human diseases, including non-alcoholic fatty liver disease, neurodegenerative diseases, mitochondrial myopathy, and age-induced diabetes. Here, we performed a one-day double blinded, placebo-controlled human clinical study to assess the safety and acute effects of six different Combined Metabolic Activators (CMAs) with 1 g of different NAD+ precursors based on global metabolomics analysis. Our integrative analysis showed that the NAD+ salvage pathway is the main source for boosting the NAD+ levels with the administration of CMAs without NAD+ precursors. We observed that incorporation of nicotinamide (Nam) in the CMAs can boost the NAD+ products, followed by niacin (NA), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), but not flush free niacin (FFN). In addition, the NA administration led to a flushing reaction, accompanied by decreased phospholipids and increased bilirubin and bilirubin derivatives, which could be potentially risky. In conclusion, this study provided a plasma metabolomic landscape of different CMA formulations, and proposed that CMAs with Nam, NMN as well as NR can be administered for boosting NAD+ levels to improve altered metabolic conditions.

Purpose: Non-invasive tests used in the screening and follow-up of celiac disease (CD) are currently below expectations because they show false negatives/positives and are not always correlated with duodenal histology. We aimed to investigate the predictive value of intestinal free fatty acid binding protein (FABP-I) which can easily be released into the circulation in the presence of enterocyte damage in a short time in CD. Methods: This study included 59 patients with CD who were not on gluten free diet (GFD)(n=24) and who were on GFD(n=35) and 52 healthy controls. Demographic variables, complete blood count, ferritin, vitamin D, calcium, phosphorus, vitamin B12, prothrombin time, INR, and serum FABP-I levels were recorded for all groups. Results: There was no difference between the groups in terms of complete blood count, ferritin, calcium, phosphorus, vitamin B12, prothrombin time and INR (all p>0.05). Mean serum FABP-I was determined as 499.2±33.3 ng/L for patients with CD who were not on GFD and as 487.7±48.0 ng/L for who were on GFD, and these values were significantly higher when compared to the healthy controls 432.2±63.8 ng/L(p<0.001). The sensitivity, specificity, positive predictive value, and negative predictive value of FABP-I for a cut-off value of 456.8 ng/L were 84.7%, 69.2%, 10.2% and 61.5%, respectively(AUC=0.785). Conclusion: This study has shown that FABP-I can serve as a non-invasive predictive marker for CD diagnosis. Overlooked diagnosis in serology-negative patients and false serology positivity for reasons other than CD will be prevented with its use in clinical practice since FABP-I directly reflects intestinal damage.

Introduction. BRCA-mutated breast cancers have specific pathological characteristics. BAP1 is a tumor suppressor gene that is important in many cancers with different pathways. The relationship between BRCA1 mutation and BAP1 immunohistochemical staining is still unclear. Our aim is to determine whether BAP1 immunohistochemical expression indicates BRCA mutation status in breast carcinomas with specific pathological characteristics. In addition, we aim to determine the histopathological characteristics of tumors according to BRCA mutations. Methods. Histomorphology, molecular subtypes and BAP1 immunohistochemical expression patterns of the BRCA1/BRCA2 mutated and non-mutated tumors were evaluated. The BAP1 immunohistochemical stain was applied to nine tumor tissues with the BRCA1 mutation, six tumor tissues with the BRCA2 mutation, and 16 tumor tissues without any BRCA mutation. Pearson's chi square test and the Fisher Freeman Halton test were used to analyze the associations between the datas. The statistical significance was considered as P value of <.05. Results. Immunohistochemical BAP1 loss was not detected in any mutated or non-mutated tumor group. BRCA1 mutated tumors had the statistically highest histopathological grade (P = .04) and BRCA1/2 mutated tumors had significant immunohistochemical triple negative expression pattern (P = .01). Conclusions. Intrinsic and histopathological characteristics may vary between BRCA1 mutated and non-BRCA1 mutated tumors. Also, BAP1 loss was not detected in BRCA mutated breast tumors because of several effects of BAP1 that are non-related with BRCA in the cell cycle.

BACKGROUND:Several risk scores have been developed to predict hepatocellular carcinoma (HCC) risk in chronic hepatitis B (CHB) patients. The majority of risk scores are based on pretreatment variables that are no longer considered risk factors for HCC development due to the suppression of hepatitis B virus replication early in the course of potent antiviral treatment in most patients. The PAGE-B score, which is based on platelet levels, age and sex, has been shown to accurately predict HCC risk in CHB patients on antiviral treatment in various populations.AIM:We aimed to evaluate the PAGE-B score in predicting HCC risk in Turkish CHB patients on antiviral treatment.METHODS:In this study, we recruited 742 CHB patients who had been treated with tenofovir disoproxil fumarate or entecavir for ≥ 1 year. Risk groups were determined according to the PAGE-B scores as follows: ≤ 9, low; 10-17, moderate and ≥ 18, high. The cumulative HCC incidences in each risk group were computed using Kaplan-Meier analysis and were compared using the log-rank test. The accuracy of the PAGE-B score in predicting HCC risk was evaluated using a time-dependent area under the receiver operating characteristic (AUROC) curve at all study time points. Univariate and multivariate logistic regression analyses were used to assess the risk factors for HCC development.RESULTS:The mean follow-up time was 54.7 ± 1.2 mo. HCC was diagnosed in 26 patients (3.5%). The cumulative HCC incidences at 1, 3, 5 and 10 years were 0%, 0%, 0% and 0.4% in the PAGE-B low-risk group; 0%, 1.2%, 1.5% and 2.1% in the PAGE-B moderate-risk group; and 5%, 11.7%, 12.5%, and 15% in the PAGE-B high-risk group, respectively (log-rank P < 0.001). The AUROCs of the PAGE-B score in the prediction of HCC development at 1, 3, 5 and 10 years were 0.977, 0.903, 0.903 and 0.865, respectively. In the multivariable analysis, older age, male sex, lower platelet levels, presence of cirrhosis, and absence of alanine aminotransferase normalization at month 6 were associated with HCC development (all P < 0.05).CONCLUSION:The PAGE-B score is a practical tool to predict HCC risk in Turkish patients with CHB and may be helpful to improve surveillance strategies.

In the sea urchin embryo, specification of the endomesoderm is accomplished by the activity of a network of regulatory genes in the vegetal hemisphere, called the endomesoderm gene regulatory network (GRN). The activation of this network is mediated primarily through the activity of the Wnt pathway, though details of pathway activation remain unclear. To gain further insight into control of endomesoderm GRN activation, we have identified a sea urchin homologue of the co-repressor Groucho (LvGroucho) that has been shown to antagonize β-catenin/Tcf activation complexes during Wnt signaling in other systems. Groucho functions by recruiting the histone deacetylase Rpd3 to the DNA template via interaction with site-specific transcription factors, resulting in localized chromatin condensation and transcriptional silencing. Our results show that the LvGroucho protein localizes to all nuclei throughout embryonic development. Interaction assays demonstrate that LvGroucho interacts with Tcf via both the Q and the WD domains of the protein. LvGroucho interacts with Tcf to antagonize the expression of key endomesoderm regulatory genes. Assays demonstrate that LvGroucho and nβ-catenin functionally compete for binding to Tcf as a major mechanism by which the Tcf-control switch is regulated. Functional analysis of the N-terminal AES197 domain of LvGroucho shows that it is sufficient to recapitulate the function of full-length LvGroucho. This finding strongly supports the conclusion that the effects of LvGro overexpression are due primarily to its interactions with Tcf and not other Groucho interacting partners, since Tcf is the only protein present in the sea urchin known to interact with AES197. Because the Q domain is unable to bind Rpd3, it was expected to behave as a dominant negative LvGroucho. Unexpectedly, overexpression of the Q domain gave functional results similar to LvGroucho and the AES197 domain. This is the first evidence for an inherent repressive function for the Q domain alone. Together, our results indicate that LvGroucho functionally competes with β-catenin for Tcf binding, and this competitive mechanism regulates one of the earliest steps in the initiation of the sea urchin endomesoderm GRN.

Next-generation sequencing (NGS) is used increasingly in hereditary cancer patients' (HCP) management. While enabling evaluation of multiple genes simultaneously, the technology brings to light the dilemma of variant interpretation. Here, we aimed to reveal the underlying reasons for the discrepancy in the evidence titles used during variant classification according to ACMG guidelines by two different bioinformatic specialists (BIs) and two different clinical geneticists (CGs). We evaluated final reports of 1920 cancer patients and 189 different variants from 285 HCP were enrolled to the study. A total of 173 of these variants were classified as pathogenic (n = 132) and likely pathogenic (n = 41) by the BI and an additional 16 variants, that were classified as VUS by at least one interpreter and their classification would change the clinical management, were compared for their evidence titles between different specialists. The attributed evidence titles and the final classification of the variants among BIs and CGs were compared. The discrepancy between P/LP final reports was 22.5%. The discordance between CGs was 30% whereas the discordance between two BIs was almost 75%. The use of PVS1, PS3, PP3, PP5, PM1, PM2, BP1, BP4 criteria markedly varied from one expert to another. This difference was particularly noticeable in PP3, PP5, and PM1 evidence and mostly in the variants affecting splice sites like BRCA1(NM_007294.4) c.4096 + 1 G > A and CHEK2(NM_007194.4) c.592 + 3 A > T. With recent advancements in precision medicine, the importance of variant interpretations is emerging. Our study shows that variant interpretation is subjective process that is in need of concrete definitions for accurate and standard interpretation.

BACKGROUND:Copy number variations (CNVs) are commonly associated with malignancies, including hereditary breast and ovarian cancers. Next generation sequencing (NGS) provides solutions for CNV detection in a single run. This study aimed to compare the accuracy of CNV detection by NGS analyzing tool against Multiplex Ligation Dependent Probe Amplification (MLPA).RESEARCH DESIGN AND METHODS:In total, 1276 cases were studied by targeted NGS panels and 691 cases (61 calls in 58 NGS-CNV positive and 633 NGS-CNV negative cases) were validated by MLPA.RESULTS:Twenty-eight (46%) NGS-CNV positive calls were consistent, whereas 33 (54%) calls showed discordance with MLPA. Two cases were detected as SNV by the NGS and CNV by the MLPA analysis. In total, 2% of the cases showed an MLPA confirmed CNV region in BRCA1/2. The results of this study showed that despite the high false positive call rate of the NGS-CNV algorithm, there were no false negative calls. The cases that were determined to be negative by the NGS and positive by the MLPA were actually carrying SNVs that were located on the MLPA probe binding sites.CONCLUSION:The diagnostic performance of NGS-CNV analysis is promising; however, the need for confirmation by different methods remains.

Bag-1 protein is a crucial target in cancer to increase the survival and proliferation of cells. The Bag-1 expression is significantly upregulated in primary and metastatic cancer patients compared to normal breast tissue. Overexpression of Bag-1 decreases the efficiency of conventional chemotherapeutic drugs, whereas Bag-1 silencing enhances the apoptotic efficiency of therapeutics, mostly in hormone-positive breast cancer subtypes. In this study, we generated stable Bag-1 knockout (KO) MCF-7 breast cancer cells to monitor stress-mediated cellular alterations in comparison to wild type (wt) and Bag-1 overexpressing (Bag-1 OE) MCF-7 cells. Validation and characterization studies of Bag-1 KO cells showed different cellular morphology with hyperactive Akt signaling, which caused stress-mediated actin reorganization, focal adhesion decrease and led to mesenchymal characteristics in MCF-7 cells. A potent Akt inhibitor, MK-2206, suppressed mesenchymal transition in Bag-1 KO cells. Similar results were obtained following the recovery of Bag-1 isoforms (Bag-1S, M, or L) in Bag-1 KO cells. The findings of this study emphasized that Bag-1 is a mediator of actin-mediated cytoskeleton organization through regulating Akt activation.

BACKGROUND The effect of hepatic steatosis on the response to antiviral therapy administered in chronic hepatitis B patients is yet to be clarified. In this study, our aim was to determine the effect of hepatic steatosis on the virological response in chronic hepatitis B patients who were treated with entecavir or tenofovir disoproxil fumarate. METHODS This retrospective cohort study was performed using the data of liver biopsy-proven chronic hepatitis B patients with or without hepatic steatosis, who received entecavir or tenofovir disoproxil fumarate treatment between 2012 and 2017. The undetectable serum hepatitis B virus deoxyribonucleic acid level under treatment was defined as the complete virological response. The predictors of virological response were determined, and it was checked whether the virological response was affected by hepatic steatosis in chronic hepatitis B patients who have undergone entecavir or tenofovir disoproxil fumarate treatment. RESULTS A total of 324 chronic hepatitis B patients, of which 203 (63%) were males, were included in the study. The median age of the patients was 42 years (range: 35-51 years). Hepatic steatosis was observed in 25% of the patients, and steatohepatitis in 4%. The median time to complete virological response was found to be 6 months (range: 3-9 months). In the full analysis model, the log hepatitis B virus deoxyribonucleic acid was determined as the factor most associated with virological response (P < .001). No statistically signifi- cant relationship was detected between hepatic steatosis and virological response (P = .409). CONCLUSION Concomitant hepatic steatosis has no significant impact on the virological response in chronic hepatitis B patients who have undergone entecavir or tenofovir disoproxil fumarate treatment.

Background: We aimed to investigate the long-term effects of tenofovir disoproxil fumarate and entecavir treatment on bone mineral density and evaluated the fracture risk assessment tool score in patients with chronic hepatitis B. Methods: A total of 58 chronic hepatitis B patients treated with tenofovir disoproxil fumarate (n = 40) and entecavir (n = 18) were included in this prospective study from 2012 to 2016. To evaluate bone mineral density, dual-X-ray absorptiometry, fracture risk assessment tool, and laboratory examinations were performed in all patients first at baseline and second at the end of the study. Results: Age, sex, body mass index, fibrosis score, and viral load were similar in both groups. The mean follow-up was 33 months in the tenofovir disoproxil fumarate group and 31 months in the entecavir group. In patients treated with entecavir, there was no statistically significant difference between baseline and second bone mineral density including lumbar spine (L) and total hip T score. In patients treated with tenofovir disoproxil fumarate, there was a significant difference in the second bone mineral density compared with baseline bone mineral density for L3 (P =.033) and the major fracture risk assessment tool score (P =.03). When patients were divided into 3 groups (normal bone mineral density, osteopenic, and osteoporotic), there was a significant increase in the number of osteopenic patients in the total hip T score after tenofovir disoproxil fumarate treatment (P =.034). Conclusion: Our results suggest a decrease in the bone mineral density for lumbar spine (L3), an increase in the number of patients with hip osteopenia, and major fracture risk assessment tool score after long-term tenofovir disoproxil fumarate treatment in patients with rechronic hepatitis B.

We present the interim results of the efficacy, immunogenicity, and safety of the two-dose schedules of TURKOVAC versus CoronaVac. This was a randomized, observer-blinded, non-inferiority trial (NCT04942405). Volunteers were 18–55 years old and randomized at a 1:1 ratio to receive either TURKOVAC or CoronaVac at Day 0 and Day 28, both of which are 3 μg/0.5 mL of inactivated severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) adsorbed to aluminum hydroxide. The primary efficacy outcome was the prevention of polymerase chain reaction (PCR)-confirmed symptomatic coronavirus disease 2019 (COVID-19) at least 14 days after the second dose in the modified per-protocol (mPP) group. Safety analyses were performed in the modified intention-to-treat (mITT) group. Between 22 June 2021 and 7 January 2022, 1290 participants were randomized. The mITT group consisted of 915 participants, and the mPP group consisted of 732 participants. During a median follow-up of 90 (IQR 86–90) days, the relative risk reduction with TURKOVAC compared to CoronaVac was 41.03% (95% CI 12.95–60.06) for preventing PCR-confirmed symptomatic COVID-19. The incidences of adverse events (AEs) overall were 58.8% in TURKOVAC and 49.7% in CoronaVac arms (p = 0.006), with no fatalities or grade four AEs. TURKOVAC was non-inferior to CoronaVac in terms of efficacy and demonstrated a good safety and tolerability profile.

Background/aim: Data on antibody response following COVID-19 in kidney transplant recipients is scarce. This crosssectional study aims to investigate the antibody response to COVID-19 among kidney transplant recipients. Materials and methods: We recruited 46 kidney transplant recipients with RT-PCR-confirmed COVID-19 and 45 recipients without COVID-19 history. We also constructed two control groups (COVID-19 positive and negative) from a historical cohort of healthcare workers. We used age and sex-based propensity score matching to select the eligible subjects to the control groups. We measured the SARS-CoV-2 IgG levels quantitatively using the Abbott ARCHITECT system. An antibody level above 1.4 S/C was defined as positivity. Results: Transplant recipients with COVID-19 had a higher BMI, and COVID-19 history in a household member was more common than that of the transplant recipient without COVID-19. IgG seropositivity rate (69.6% vs. 78.3%, p = 0.238) and the median IgG level (3.28 [IQR: 0.80-5.85] vs. 4.59 [IQR: 1.61-6.06], p = 0.499) were similar in COVID-19-positive transplant recipients and controls. Kidney transplant recipients who had a longer duration between RT-PCR and antibody testing had lower antibody levels (r = -0.532, p < 0.001). Conclusion: At the early post-COVID-19 period, kidney transplant recipients have a similar antibody response to controls. However, these patients' antibody levels and immunity should be closely monitored in the long term.

BACKGROUND:Colorectal cancer is one of the most commonly diagnosed types of cancer worldwide. An early diagnosis and detection of colon cancer and polyp can reduce mortality and morbidity from colorectal cancer. Even though there are a variety of options in screen- ing tests, the question remains on which test is the most effective for the early detection of colorectal cancer. In this prospective study, we aimed to develop a simple, useful, effective, and reliable scoring system to detect colon polyp and colorectal cancer. METHODS:We enrolled 6508 subjects over the age of 18 from 16 centers, with colonoscopy screening. The age, smoking status, alcohol consumption, body mass index, polyp incidence, polyp size, number and localization, and pathologic findings were recorded. RESULTS:The age, male gender, obesity, smoking, and family history were found as independent risk factors for adenomatous polyp. We have developed a new scoring system which can be used for these factors. With a score of 4 or above, we found the following: sensitivity 81%, specificity 40%, positive predictive value 25.68%, and negative predictive value 89.84%, for adenomatous polyp detection; and sensitivity 96%, specificity 39%, positive predictive value 3.35%, negative predictive value 99.29%, for colorectal cancer detection. CONCLUSION:Even though the first colorectal cancer screening worldwide is generally performed for individuals over 50 years of age, we recommend that screening for colorectal cancer might begin for those under 50 years of age as well. Individuals with a score ≥ 4 must be included in the screening tests for colorectal cancer.

Background and Aim:The aim of the present study was to examine the etiology of hepatocellular carcinoma (HCC) by underlying cause and determine the characteristics and clinical features of patients with HCC.Materials and Methods:The study comprised 1802 HCC patients diagnosed and followed up by Liver Diseases Outpatient Clinics in 14 tertiary centers in Turkey between 2001 and 2020.Results:The mean age was 62.3±10.7 years, and 78% of them were males. Of the patients, 82% had cirrhosis. Hepatitis B virus (HBV) infection was the most common etiology (54%), followed by hepatitis C virus (HCV) infection (19%) and nonalcoholic fatty liver disease (NAFLD) (10%). Of the patients, 56% had a single lesion. Macrovascular invasion and extrahepatic spread were present in 15% and 12% of the patients, respectively. The median serum alpha-fetoprotein level was 25.4 ng/mL. In total, 39% of the patients fulfilled the Milan Criteria. When we compared the characteristics of patients diagnosed before and after January 2016, the proportion of NAFLD-related HCC cases increased after 2016, from 6.6% to 13.4%.Conclusion:Chronic HBV and HCV infections remain the main causes of HCC in Turkey. The importance of NAFLD as a cause of HCC is increasing.