Normal Control Individuals Research Articles

Serum thymosin beta 10 level as a potential prognosis prediction of hepatocellular carcinoma and hepatic diseases

Thymosin Beta 10 (TMSB10) is a thymosin family member that has been identified as being overexpressed in a wide variety of human cancers. This study aimed to determine the expression level of TMSB10 in sera of patients with hepatocellular carcinoma (HCC) and liver cirrhosis. And to reveal the association between TMSB10 and different stages in patients with HCC. We also wanted to know how TMSB10 is predictive in HCC patients and its relation to the Barcelona Clinic's staging system. The study included 41 HCC patients, 15 liver cirrhosis patients, and 15 normal control subjects. The enzyme-linked immunosorbent assay was used to determine serum levels of TMSB10 and alpha-fetoprotein (AFP) in serum of normal control individuals and patients with liver cirrhosis and different stages of HCC, and to evaluate the relationship of AFP with TMSB10. The TMSB10 levels in patients with HCC were statistically different than in the control group and in the different stages of HCC. We found a statistically significant difference in the distribution of TMSB10 between the three study groups (p< 0.001). There was an association between TMSB10 concentration and AFP. The level of TMSB10 in the serum of the HCC subgroups was then analyzed. The TMSB10 level increased with the advance of HCC stages. The TMSB10 level in HCC patients did not correlate with levels of liver function tests including aminotransferase, aspartate aminotransferase, albumin, prothrombin, bilirubin, or alkaline phosphatase. In conclusion, serum TMSB10 levels can be used as a potential prognostic marker for clinical stages of HCC.

Evaluating the Urinary Exosome microRNA Profile of von Hippel Lindau Syndrome Patients with Clear Cell Renal Cell Carcinoma.

Renal cell carcinoma is one of the ten more common malignant tumors worldwide, with a high incidence and mortality rate. Kidney cancer frequently presents at an advanced stage, and it is almost invariably fatal. Much progress has been made in identifying molecular targets for therapy in the hope of improving survival rates, but still, we have no good markers for early detection or progression of the disease. Von Hippel Lindau syndrome (VHL) is an autosomal dominant cancer hereditary syndrome in which affected individuals are at risk of developing bilateral and multifocal renal cell carcinomas (RCC) as well as other tumors. These patients provide an ideal platform to investigate the potential of urinary exosomal miRNA biomarkers in the early development of ccRCC, as these patients are regularly imaged and tumors are actively monitored until the tumor reaches 3 cm before surgical excision. This allows for pre- and post-surgical urine collection and comparison to excised tumor tissues. Studying different biomarkers in urine can provide comprehensive molecular profiling available to patients and physicians and can be a great source of additional tumor genetic information. Pre- and postoperative urine samples were obtained from a cohort of VHL patients undergoing surveillance and surgical excision of ccRCCs, and exosomes were extracted. MicroRNA-Seq analysis was performed on miRNA extracted from both urine-derived exosomes and FFPE material from excised ccRCCs. MicroRNA-Seq analysis highlighted a significant difference in the urinary exosome-derived miRNA expression profiles between VHL patients and normal control individuals. This included decreased expression of the miR-320 family, such as miR-320a, known to be decreased in sporadic ccRCC and suppressed by the HIF1α transcription factor activated by the loss of the VHL gene. MiR-542-5p represented a potential marker of VHL-associated ccRCC that was lowly expressed in normal control urinary exosomes, significantly increased in the preoperative urinary exosomes of tumor-bearing VHL patients, and subsequently reduced to normal levels of expression after tumor excision. In concordance with this, the expression of miR-542-5p was increased in the VHL-associated ccRCC in comparison to the normal kidney. This study shows the potential for miRNA profiling of exosomes from readily available biofluids to both distinguish VHL patient urine from normal control urine microRNAs and to provide biomarkers for the presence of VHL syndrome-associated ccRCC. Further validation studies are necessary to demonstrate the utility of urinary exosome-derived miRNAs as biomarkers in kidney cancer.

Mutations in Genes Producing Nitric Oxide and Hydrogen Sulfide and Their Connection With Apoptotic Genes in Chronic Myeloid Leukemia.

Background Despite advances in chronic myeloid leukemia (CML) genetics, the role of nitric oxide (NO) and hydrogen sulfide (H2S) gene mutations and their relationship to apoptotic genes is unclear. Therefore, this study investigated NO- and H2S-producing genes' mutations and their interactions with apoptotic genes using Sanger sequencing and next-generation sequencing (NGS). Methodology A complete blood count (CBC) was carried out to measure the total number of white blood cells, while IL-6 levels were assessed in both control and CML patients using an ELISA technique.Sanger sequencing was used to analyzemutations in the CTH and NOS3 genes, whereas NGS was applied to examine mutations on all chromosomes. Results White blood cell (WBC) and granulocyte counts were significantly higher in CML patients compared to controls (p<0.0001), and monocyte counts were similarly higher (p<0.05). Interleukin-6 (IL-6) levels were significantly elevated in CML patients thancontrols (p<0.0001), indicating a possible link to CML etiology or progression. Multiple mutations have been identified in both genes, notably in CTH exon 12 and the NOS3genes VNTR, T786C, and G894T. This study also measured IL-6 concentrations using IL-6 assays, identifying its potential as a CML prognostic diagnostic. WBC counts, granulocyte counts, and mid-range absolute counts, or MID counts, were significantly higher in CML patients than in normal control individuals. NGS identified 1643 somatic and sex chromosomal abnormalities and 439 actively expressed genes in CML patients. The findings imply a genomic landscape beyond the BCR-ABL1 mutation in CML development compared to other databases. Conclusion In conclusion, this study advances the understanding of the genetic characteristics of CML by identifying mutations in the NO- and H2S-producing genes and their complex connections with genes involved in apoptosis. The comprehensive genetic profile obtained by Sanger sequencing and NGS provides possibilities for identifying novel targets for therapy and personalized treatments for CML, therefore contributing to developments in hematological diseases.

Prevalence and plasma exosome-derive microRNA diagnostic biomarker screening of adolescent idiopathic scoliosis in Yunnan Province, China.

Idiopathic scoliosis significantly affects the physical and mental health of children and adolescents, with varying prevalence rates in different regions. The occurrence of idiopathic scoliosis is associated with genetic regulation and biochemical factors, but the changes in exosome-derived miRNA profiles among idiopathic scoliosis patients remain unclear. This study aimed to determine the prevalence of idiopathic scoliosis in Yunnan Province, China, and identify key exosome-derived miRNAs in idiopathic scoliosis through a cohort study. From January 2018 to December 2020, a cross-sectional study on idiopathic scoliosis in children and adolescents was conducted in Yunnan Province. A total of 84,460 students from 13 cities and counties in Yunnan Province participated in a scoliosis screening program, with ages ranging from 7 to 19 years. After confirmation through screening and imaging results, patients with severe idiopathic scoliosis and normal control individuals were selected using propensity matching. Subsequently, plasma exosome-derived miRNA sequencing and RT-qPCR validation were performed separately. Based on the validation results, diagnostic performance analysis and target gene prediction were conducted for differential plasma exosome-derived miRNAs. The overall prevalence of idiopathic scoliosis in children and adolescents in Yunnan Province was 1.10%, with a prevalence of 0.87% in males and 1.32% in females. The peak prevalence was observed at age 13. Among patients diagnosed with idiopathic scoliosis, approximately 12.8% had severe cases, and there were more cases of double curvature than of single curvature, with thoracolumbar curvature being the most common in the single-curvature group. Sequencing of plasma exosome-derived miRNAs associated with idiopathic scoliosis revealed 56 upregulated and 153 downregulated miRNAs. Further validation analysis confirmed that hsa-miR-27a-5p, hsa-miR-539-5p, and hsa-miR-1246 have potential diagnostic value. We gained insights into the epidemiological characteristics of idiopathic scoliosis in Yunnan Province and conducted further analysis of plasma exosome-derived miRNA changes in patients with severe idiopathic scoliosis. This study has provided new insights for the prevention and diagnosis of idiopathic scoliosis, paving the way for exploring clinical biomarkers and molecular regulatory mechanisms. However, further validation and elucidation of the detailed biological mechanisms underlying these findings will be required in the future.

Pathophysiology characterization of Alzheimer's disease in South China's aging population: for the Greater-Bay-Area Healthy Aging Brain Study (GHABS).

The Guangdong-Hong Kong-Macao Greater-Bay-Area of South China has an 86million population and faces a significant challenge of Alzheimer's disease (AD). However, the characteristics and prevalence of AD in this area are still unclear due to the rarely available community-based neuroimaging AD cohort. Following the standard protocols of the Alzheimer's Disease Neuroimaging Initiative, the Greater-Bay-Area Healthy Aging Brain Study (GHABS) was initiated in 2021. GHABS participants completed clinical assessments, plasma biomarkers, genotyping, magnetic resonance imaging (MRI), β-amyloid (Aβ) positron emission tomography (PET) imaging, and tau PET imaging. The GHABS cohort focuses on pathophysiology characterization and early AD detection in the Guangdong-Hong Kong-Macao Greater Bay Area. In this study, we analyzed plasma Aβ42/Aβ40 (A), p-Tau181 (T), neurofilament light, and GFAP by Simoa in 470 Chinese older adults, and 301, 195, and 70 had MRI, Aβ PET, and tau PET, respectively. Plasma biomarkers, Aβ PET, tau PET, hippocampal volume, and temporal-metaROI cortical thickness were compared between normal control (NC), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia groups, controlling for age, sex, and APOE-ε4. The prevalence of plasma A/T profiles and Aβ PET positivity were also determined in different diagnostic groups. The aims, study design, data collection, and potential applications of GHABS are summarized. SCD individuals had significantly higher plasma p-Tau181 and plasma GFAP than the NC individuals. MCI and dementia patients showed more abnormal changes in all the plasma and neuroimaging biomarkers than NC and SCD individuals. The frequencies of plasma A+/T+ (NC; 5.9%, SCD: 8.2%, MCI: 25.3%, dementia: 64.9%) and Aβ PET positivity (NC: 25.6%, SCD: 22.5%, MCI: 47.7%, dementia: 89.3%) were reported. The GHABS cohort may provide helpful guidance toward designing standard AD community cohorts in South China. This study, for the first time, reported the pathophysiology characterization of plasma biomarkers, Aβ PET, tau PET, hippocampal atrophy, and AD-signature cortical thinning, as well as the prevalence of Aβ PET positivity in the Guangdong-Hong Kong-Macao Greater Bay Area of China. These findings provide novel insights into understanding the characteristics of abnormal AD pathological changes in South China's older population.

Serum microRNA-16 as a potential biomarker for HCV-induced hepato-cellular carcinoma in Egyptian patients

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world. Two risk factors that cause 80–90% of HCC cases globally are chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV). The diagnostic value of circulating microRNAs (miRNAs) in numerous tumors has been described. Our research assessed microRNA-16 (miR-16) as a novel biomarker in patients with HCV-induced HCC. The study included three groups. Group 1 included 55 individuals with cirrhosis caused by liver HCV infection in addition to HCC. Group 2 included 55 individuals with cirrhosis brought on by HCV infection. Group 3 included 55 normal control individuals. Expression of miR-16 in blood was assessed by real-time polymerase chain reaction (RT-PCR). The mean level of miR-16 was significantly different in the three groups, with group 1 having the greatest value (1.098 ± 0.647), followed by group 2 (1.1035 ± 0.8567) and group 3 (control subjects) having the lowest value (0.3842 ± 0.21485). The receiver operating characteristic (ROC) curve analysis showed that miR-16 had a higher diagnostic value at area under the curve (AUC) of 0.935 than alpha-feto protein (AUC of 0.859) to differentiate between HCC and control subjects. MiR-16 has a sensitivity of 81.82 % and a specificity of 69.09%, to distinguish between patients with liver cirrhosis and HCC patients. Our findings illustrated that circulating miR-16 can be proposed as a marker for detection of patients with HCV-induced HCC.

The close association of micronutrients with COVID-19

ObjectivesThe present study was conducted to explore the performance of micronutrients in the prediction and prevention of coronavirus disease 2019 (COVID-19). MethodsThis is an observational case-control study. 149 normal controls (NCs) and 214 COVID-19 patients were included in this study. Fat-soluble and water-soluble vitamins were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, and inorganic elements were detected by inductively coupled plasma-mass spectrometry (ICP-MS) analysis. A logistic regression model based on six micronutrients were constructed using DxAI platform. ResultsMany micronutrients were dysregulated in COVID-19 compared to normal control (NC). 25-Hydroxyvitamin D3 [25(OH)D3], magnesium (Mg), copper (Cu), calcium (Ca) and vitamin B6 (pyridoxic acid, PA) were significantly independent risk factors for COVID-19. The logistic regression model consisted of 25(OH)D3, Mg, Cu, Ca, vitamin B5 (VB5) and PA was developed, and displayed a strong discriminative capability to differentiate COVID-19 patients from NC individuals [area under the receiver operating characteristic curve (AUROC) = 0.901]. In addition, the model had great predictive ability in discriminating mild/normal COVID-19 patients from NC individuals (AUROC = 0.883). ConclusionsOur study showed that micronutrients were associated with COVID-19, and our logistic regression model based on six micronutrients has potential in clinical management of COVID-19, and will be useful for prediction of COVID-19 and screening of high-risk population.

Identification and functional characterization of compound heterozygous CYP11B1 gene mutations.

11β-Hydroxylase deficiency (11β-OHD) is the second leading cause of congenital adrenal hyperplasia (CAH), a rare autosomal recessive disease caused by mutations in the CYP11B1 gene. We previously reported the case of a male Chinese patient with typical 11β-OHD symptoms. Sanger sequencing revealed that the patient carried a splice-site mutation, c.595+1G>A in the CYP11B1 gene. His mother and sister harbored the heterozygous mutation, c.595+1G>A. Paradoxically, Sanger sequencing did not detect any abnormality in the CYP11B1 gene of his father and brother. Therefore, in this study, we aimed to further explore the exact genetic etiology of 11β-OHD in this pedigree and analyze the functional consequence of the c.595+1G>A mutation. Gemomic DNA was extracted from the peripheral blood leukocytes of the family members and normal control individuals, followed by quantitative real-time polymerase chain reaction (qPCR) to detect the copy number of the target CYP11B1 gene fragment. Mutation analysis was also performed via whole-exome sequencing (WES) followed by Sanger sequencing validation. In vitro minigene assay was also performed to investigate the impact of the c.595+1G>A mutation on pre-mRNA splicing. qPCR results suggested a heterozygous deletion encompassing position c.595+1 along with flanking exonic and intronic sequences in the CYP11B1 gene of the patient and his father. WES followed by Sanger sequencing verified that the patient carried compound heterozygous mutations in the CYP11B1 gene, including a novel 2840-bp deletion (c.395+661_c.1121+180del) and c.595+1G>A, while his father carried the heterozygous c.395+661_c.1121+180del mutation. No other novel CYP11B1 mutations were found in the rest of the family members. Furthermore, minigene assay revealed that the c.595+1G>A mutation resulted in a 70-bp deletion of exon 3 in the mRNA, and this altered the reading frame at amino acid 176 and created a premature stop codon at amino acid 197. We identified a novel 2840-bp-sized large deletion and confirmed that the c.595+1G>A mutation disrupts normal pre-mRNA splicing. Either mutation could significantly alter the reading frame and abolish CYP11B1 enzyme activity. Therefore, our findings widen the mutation spectrum of CYP11B1 and provide an accurate diagnosis of 11β-OHD at a molecular genetic level.

Assessment of long noncoding RNA CCAT1 using real time-polymerase chain reaction in colorectal cancer patients

Colorectal cancer (CRC) is linked to high mortality, mainly when discovered in its advanced stages. Several studies have pointed to the role of epigenetic factors in CRC and other cancers. Long non-coding RNAs (lncRNAs) are involved in the initiation, progression, metastasis, and modulation of the response to chemotherapeutic modalities of CRC as vital contributors to epigenetic mechanisms. Colon cancer-associated transcript-1 (CCAT1) is one of the lncRNAs that have been dysregulated in serum samples, providing a non-invasive route for diagnosing CRC patients. This study aimed to determine the role of CCAT1 expression as diagnostic and prognostic markers. We tested the associations of CCAT1 expression with serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9). The study included three groups: 41 patients with colorectal cancer, 39 patients with precancerous benign colorectal diseases, and 20 normal control individuals. CEA and CA 19-9 were measured by an immunoassay automated system. The expression level of CCAT1 was assessed by a real-time polymerase chain reaction. There was a statistically significant elevation of serum CEA levels in patients with CRC compared to patients with precancerous benign colorectal diseases. Furthermore, there was no statistically significant difference in serum CA 19-9 levels between all groups (p = 0.102). Interestingly, CCAT1 expression was significantly upregulated in the blood of CRC patients compared to the precancerous benign colorectal diseases group (p = 0.009) and the control group (p&lt;0.001). Also, expression of CCAT1 was significantly elevated in patients with precancerous benign colorectal diseases compared to the control group (p=0.004). In conclusion, measuring the expression level of CCAT1 is more advised than assessment of CEA and CA 19-9 for the early diagnosis and prognosis of colorectal cancer.

Conceptual saliency: Core and peripheral semantic knowledge in Alzheimer’s disease

AbstractBackgroundSemantic memory impairment in Alzheimer’s disease (AD) is indicative of an actual degradation of semantic knowledge – the conceptual and factual knowledge necessary to engage with others and the physical world – rather than merely to a retrieval deficit. Historically, studies in semantic knowledge in AD have relied on predetermined sets of stimuli to probe knowledge. The analysis presented here compares the contents, sequences and organization of lists of salient concepts generated by 19 patients at the mild to moderates stages AD and by 15 age‐matched cognitively normal control individuals by means of a free‐listing task, for two semantic categories, living kinds and man‐made objects. The free elicitation by participants prevents the imposition of a priori ideas by the experimenter, which might not correspond to the native knowledge of the specific cultural group studied.MethodData collection starts with the ‘demarcation’ of a domain of knowledge X by a sample of participants who are being asked to write the names of as many items as they can conjure up, which they think belong to that domain X. Terms that appear earlier, or with higher frequency, on free‐lists indicate high consensus among respondents (i.e., the concept is an important component of the category); those items are considered as more salient in the domain under investigation.ResultEvidence of knowledge devolution is detected in the lists of participants with AD for both semantic categories. However, the core conceptual information and central aspects of the structuration of those knowledge domains are preserved to an extent. The peripheral conceptual knowledge is showing the greatest disease impact.ConclusionThe study starts the investigation of the aspects of living kinds and artefactual categorial knowledge especially resilient as neurodegeneration sets. Semantic knowledge holds the information about what one knows. Its integrity is critical in daily functioning, and interactions with others and the world at large. Because semantic memory supports various aspects of daily life, it is a prime candidate for therapeutic targets that can lead to meaningful outcomes for both patients and their care partners.

A comparative study of interhemispheric functional connectivity in major depression and schizophrenia

BackgroundMajor depressive disorder (MDD) and schizophrenia (SZ) are serious psychiatric disorders that, despite exhibiting different diagnostic criteria, exhibit significant overlap regarding the biological and clinical features of affected patients. While prior evidence has shown that interhemispheric functional connectivity (FC) is abnormal in MDD and SZ, the particular similarities and differences that unify and characterize MDD and SZ regarding these interhemispheric FC patterns remain to be characterized. This study was thus designed to conduct an in-depth analysis of MDD- and SZ-related patterns of interhemispheric FC. MethodsThis study enrolled MDD patients, SZ patients, and normal control (NC) individuals (n = 36 each). Resting-state functional MRI (rs-fMRI) studies of these patients were conducted, after which voxel-mirrored homotopic connectivity (VMHC) was used to analyze the preprocesses rs-fMRI data. The VMHC values in these different values were then compared through one-way ANOVAs and post hoc analyses. ResultsSignificant differences were observed in both the striatum and middle frontal gyrus (MFG) when comparing these three groups. Through pairwise comparisons, MDD patients but not SZ patients exhibited reduced MFG VMHC values relative to the NC individuals. Conversely, striatum VMHC values significantly increased in SZ patients relative to NC individuals and MDD patients. ConclusionThese results support the interhemispheric functional disconnection hypothesis as a basis for the pathogenesis of MDD and SZ. The observed differences in interhemispheric FC in the MFG and striatum of MDD and SZ patients will offer a neuroimaging basis that can aid in the differential diagnosis of these debilitating conditions.

Assessment of shoulder proprioception in patients with chronic mechanical cervical pain: A comparative study.

Chronic mechanical cervical pain (CMCP) is a common disabling problem worldwide, interfering with upper extremities function. However studying the impact of CMCP on shoulder proprioception is still lacking. To investigate the impact of CMCP on shoulder proprioception in young adults compared with normal control (NC) individuals. A comparative study was conducted between two groups; 40 patients with CMCP (mean age 32.28 ± 6.586) and 40 age and sex matched NC (mean age 33.43 ± 9.021). The Biodex isokinetic dynamometer was used to assess shoulder active sense of position at 30∘ external and internal rotations. The absolute angular error was calculated for the dominant and non-dominant shoulders. The absolute angular error was significantly increased only in the CMCP at both rotation angles for both shoulders, showing a remarkable increase on the dominant shoulder and in the external rotation range compared with NC. CMCP can significantly impair shoulder proprioception, particularly on the dominant side and in external rotation range. This could emphasize the careful examination of shoulder proprioception for the early detection of shoulders at risk, to eliminate the possibility of shoulder instability and/or injury in young adults with CMCP.

Exploring Predictive Biomarkers of Relapse in Ulcerative Colitis: A Proteomics Approach.

Risk stratification of subjects with a history of inflammatory bowel disease (IBD) into those likely to relapse and those who will remain quiescent continues to be a significant challenge. The aim of this study was to investigate whether certain proteomic signature profiles or biomarkers during remission are associated with future disease relapse in patients with ulcerative colitis (UC). Endoscopic rectal samples from patients with UC in clinical, endoscopic, and histological remission at index endoscopy were collected, as well as samplers from normal control individuals. The patients were stratified to early relapsers (ERs) if they developed clinical signs of UC flare within 6 months of index endoscopy or nonrelapsers (NRs) if there was no relapse after 36 months of follow-up. The pooled rectal samples from ERs, NRs, and control individuals were subjected to nano-liquid chromatography and tandem mass spectrometry as per standard iTRAQ (isobaric tags for relative and absolute quantitation) workflow methodology. Selected proteomics-yielded candidates were subjected to orthogonal validation via immunoblotting, in a biomarker discovery exercise. Sixty-one patients were included, of whom 8 had clinical relapse within 6 months from the index endoscopy, and 43 patients had no clinical symptoms of relapse within the 36-month follow-up period. Ten patients who had clinical signs of relapse between 6 and 36 months were excluded. Seventeen control individuals were also included. Soluble proteomics analyses between ERs, NRs, and control individuals revealed a series of upregulated and downregulated proteins. Following orthogonal validation, upregulated TRX (P = .001) and IGHA1 (P = .001) were observed in ERs relative to NRs. Several novel candidate tissue biomarkers have been identified in this study, which could discriminate patients with UC at risk of early relapse from those in long-term sustained remission. Our findings may pave the way for pre-emptive UC disease monitoring and therapeutic decision making.

Differential effect of gastric bypass versus sleeve gastrectomy on insulinotropic action of endogenous incretins.

Prandial hyperinsulinemia after Roux-en-Y gastric bypass surgery (GB), and to lesser degree after sleeve gastrectomy (SG), has been attributed to rapid glucose flux from the gut and increased insulinotropic gut hormones. However, β-cell sensitivity to exogenous incretin is reduced after GB. This study examines the effect of GB versus SG on prandial glycemia and β-cell response to increasing concentrations of endogenous incretins. Glucose kinetics, insulin secretion rate (ISR), and incretin responses to 50-g oral glucose ingestion were compared between ten nondiabetic participants with GB versus nine matched individuals with SG and seven nonoperated normal glucose tolerant control individuals (CN) with and without administration of 200 mg ofsitagliptin. Fasting glucose and hormonal levels were similar among three groups. Increasing plasma concentrations of endogenous incretins by two- to three-fold diminished prandial glycemia and increased β-cell secretion in all three groups (p < 0.05), but insulin secretion per insulin sensitivity (i.e., disposition index) was increased only in GB (p < 0.05 for interaction). However, plot of the slope of ISR (from premeal to peak values) versus plasma glucagon-like peptide-1 concentration was smaller after GB compared with SG and CN. After GB, increasing incretin activity augments prandial β-cell response whereas the β-cell sensitivity to increasing plasma concentrations of endogenous incretin is diminished.

The reconfiguration pattern of individual brain metabolic connectome for Parkinson's disease identification.

18F-Fluorodeoxyglucose positron emission tomography (18F-FDG PET) is widely employed to reveal metabolic abnormalities linked to Parkinson's disease (PD) at a systemic level. However, the individual metabolic connectome details with PD based on 18F-FDG PET remain largely unknown. To alleviate this issue, we derived a novel brain network estimation method for individual metabolic connectome, that is, Jensen-Shannon Divergence Similarity Estimation (JSSE). Further, intergroup difference between the individual's metabolic brain network and its global/local graph metrics was analyzed to investigate the metabolic connectome's alterations. To further improve the PD diagnosis performance, multiple kernel support vector machine (MKSVM) is conducted for identifying PD from normal control (NC), which combines both topological metrics and connection. Resultantly, PD individuals showed higher nodal topological properties (including assortativity, modularity score, and characteristic path length) than NC individuals, whereas global efficiency and synchronization were lower. Moreover, 45 most significant connections were affected. Further, consensus connections in occipital, parietal, and frontal regions were decrease in PD while increase in subcortical, temporal, and prefrontal regions. The abnormal metabolic network measurements depicted an ideal classification in identifying PD of NC with an accuracy up to 91.84%. The JSSE method identified the individual-level metabolic connectome of 18F-FDG PET, providing more dimensional and systematic mechanism insights for PD.

Gut microbiome composition may be an indicator of preclinical Alzheimer's disease.

Alzheimer's disease (AD) pathology is thought to progress from normal cognition through preclinical disease and ultimately to symptomatic AD with cognitive impairment. Recent work suggests that the gut microbiome of symptomatic patients with AD has an altered taxonomic composition compared with that of healthy, cognitively normal control individuals. However, knowledge about changes in the gut microbiome before the onset of symptomatic AD is limited. In this cross-sectional study that accounted for clinical covariates and dietary intake, we compared the taxonomic composition and gut microbial function in a cohort of 164 cognitively normal individuals, 49 of whom showed biomarker evidence of early preclinical AD. Gut microbial taxonomic profiles of individuals with preclinical AD were distinct from those of individuals without evidence of preclinical AD. The change in gut microbiome composition correlated with β-amyloid (Aβ) and tau pathological biomarkers but not with biomarkers of neurodegeneration, suggesting that the gut microbiome may change early in the disease process. We identified specific gut bacterial taxa associated with preclinical AD. Inclusion of these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for predicting preclinical AD status when tested on a subset of the cohort (65 of the 164 participants). Gut microbiome correlates of preclinical AD neuropathology may improve our understanding of AD etiology and may help to identify gut-derived markers of AD risk.

Targeted and untargeted urinary metabolic profiling of bladder cancer

Bladder cancer (BC) is frequent cancer affecting the urinary tract and is one of the most prevalent malignancies worldwide. No biomarkers that can be used for effective monitoring of therapeutic interventions for this cancer have been identified to date. This study investigated polar metabolite profiles in urine samples from 100 BC patients and 100 normal controls (NCs) using nuclear magnetic resonance (NMR) and two methods of high-resolution nanoparticle-based laser desorption/ionization mass spectrometry (LDI-MS). Five urine metabolites were identified and quantified using NMR spectroscopy to be potential indicators of bladder cancer. Twenty-five LDI-MS-detected compounds, predominantly peptides and lipids, distinguished urine samples from BC and NCs individuals. Level changes of three characteristic urine metabolites enabled BC tumor grades to be distinguished, and ten metabolites were reported to correlate with tumor stages. Receiver-Operating Characteristics analysis showed high predictive power for all three types of metabolomics data, with the area under the curve (AUC) values greater than 0.87. These findings suggest that metabolite markers identified in this study may be useful for the non-invasive detection and monitoring of bladder cancer stages and grades.

Low XIST expression in Sertoli cells of Klinefelter syndrome patients causes high susceptibility of these cells to an extra X chromosome.

Klinefelter syndrome (KS) is the most common genetic cause of human male infertility. However, the effect of the extra X chromosome on different testicular cell types remains poorly understood. Here, we profiled testicular single-cell transcriptomes from three KS patients and normal karyotype control individuals. Among the different somatic cells, Sertoli cells showed the greatest transcriptome changes in KS patients. Further analysis showed that X-inactive-specific transcript ( XIST ), a key factor that inactivates one X chromosome in female mammals, was widely expressed in each testicular somatic cell type but not in Sertoli cells. The loss of XIST in Sertoli cells leads to an increased level of X chromosome genes, and further disrupts their transcription pattern and cellular function. This phenomenon was not detected in other somatic cells such as Leydig cells and vascular endothelial cells. These results proposed a new mechanism to explain why testicular atrophy in KS patients is heterogeneous with loss of seminiferous tubules but interstitial hyperplasia. Our study provides a theoretical basis for subsequent research and related treatment of KS by identifying Sertoli cell-specific X chromosome inactivation failure.

Evaluation of Plasma Phosphorylated Tau217 for Differentiation Between Alzheimer Disease and Frontotemporal Lobar Degeneration Subtypes Among Patients With Corticobasal Syndrome

Plasma phosphorylated tau217 (p-tau217), a biomarker of Alzheimer disease (AD), is of special interest in corticobasal syndrome (CBS) because autopsy studies have revealed AD is the driving neuropathology in up to 40% of cases. This differentiates CBS from other 4-repeat tauopathy (4RT)-associated syndromes, such as progressive supranuclear palsy Richardson syndrome (PSP-RS) and nonfluent primary progressive aphasia (nfvPPA), where underlying frontotemporal lobar degeneration (FTLD) is typically the primary neuropathology. To validate plasma p-tau217 against positron emission tomography (PET) in 4RT-associated syndromes, especially CBS. This multicohort study with 6, 12, and 24-month follow-up recruited adult participants between January 2011 and September 2020 from 8 tertiary care centers in the 4RT Neuroimaging Initiative (4RTNI). All participants with CBS (n = 113), PSP-RS (n = 121), and nfvPPA (n = 39) were included; other diagnoses were excluded due to rarity (n = 29). Individuals with PET-confirmed AD (n = 54) and PET-negative cognitively normal control individuals (n = 59) were evaluated at University of California San Francisco. Operators were blinded to the cohort. Plasma p-tau217, measured by Meso Scale Discovery electrochemiluminescence, was validated against amyloid-β (Aβ) and flortaucipir (FTP) PET. Imaging analyses used voxel-based morphometry and bayesian linear mixed-effects modeling. Clinical biomarker associations were evaluated using longitudinal mixed-effect modeling. Of 386 participants, 199 (52%) were female, and the mean (SD) age was 68 (8) years. Plasma p-tau217 was elevated in patients with CBS with positive Aβ PET results (mean [SD], 0.57 [0.43] pg/mL) or FTP PET (mean [SD], 0.75 [0.30] pg/mL) to concentrations comparable to control individuals with AD (mean [SD], 0.72 [0.37]), whereas PSP-RS and nfvPPA showed no increase relative to control. Within CBS, p-tau217 had excellent diagnostic performance with area under the receiver operating characteristic curve (AUC) for Aβ PET of 0.87 (95% CI, 0.76-0.98; P < .001) and FTP PET of 0.93 (95% CI, 0.83-1.00; P < .001). At baseline, individuals with CBS-AD (n = 12), defined by a PET-validated plasma p-tau217 cutoff 0.25 pg/mL or greater, had increased temporoparietal atrophy at baseline compared to individuals with CBS-FTLD (n = 39), whereas longitudinally, individuals with CBS-FTLD had faster brainstem atrophy rates. Individuals with CBS-FTLD also progressed more rapidly on a modified version of the PSP Rating Scale than those with CBS-AD (mean [SD], 3.5 [0.5] vs 0.8 [0.8] points/year; P = .005). In this cohort study, plasma p-tau217 had excellent diagnostic performance for identifying Aβ or FTP PET positivity within CBS with likely underlying AD pathology. Plasma P-tau217 may be a useful and inexpensive biomarker to select patients for CBS clinical trials.

Interleukin -37 in rheumatoid arthritis: Correlation with clinical severity and genetic polymorphisms in Mosul city, Iraq

The contribution of anti-inflammatory cytokines to rheumatoid arthritis (RA) is not fully comprehended. In the current research we assessed the serum concentration of interleukin (IL)-37 anti-inflammatory cytokine in RA, studied its association to disease activity score 28 (DAS28) and investigated single nucleotide polymorphism (rs2723176) of IL-37 gene as a threat for RA development. The case-control study included 60 RA patients and 30 normal control individuals. Serum IL-37 was assessed by ELISA and genotyped by "sequence-specific primer-polymerase chain reaction (SSP-PCR)". The mean IL-37 was elevated in RA patients (69.42 ng /l ± 62.99) compared to control individuals (14.66 ng /l ± 23.58, p < 0.001). IL-37 tended to increase with age where highest levels were noted in patients more than 60 years (p = 0.037). No Gender influence was found on IL-37 level (p>0.05). At best cut-off value of 31.5 ng/ l, IL-37 had a sensitivity of 73.3% and specificity of 83.3%. No correlation of IL-37 with DAS 28 score was observed (r=0.1497, p=0.2535). For IL-37 (rs2723176) gene polymorphism, C/C genotype was prevailing in both RA (90%) and normal controls (93.3%) compared to A/C or A/A. Also, no variation was found between patents and controls in regard to C/C genotype (OR = 0.643, 95% CI (0.122-3.39, p=0.603). The mean IL-37 concentration in RA patients with C/C genotype (59.70± 67.92) was not different from AC genotype (80.54± 94.18, p=0.4748). We concluded that serum IL-37 had the implication as a diagnostic marker in RA. However, it did not correlate with clinical severity of the disease. Meanwhile, IL-37 (rs2723176) gene polymorphism did not seem to be as a risk factor for RA, nor contributed to the increase of IL-37 level among patients.