Number Of Abnormalities Research Articles

The Significance of Comprehensive Metabolic Phenotypes in Cancer Risk: A Japan Multi-Institutional Collaborative Cohort (J-MICC) Study.

The present study investigated the relationship between metabolic phenotypes and the risk of cancer in a Japanese population using the criteria of metabolic phenotypes based on an examination and those based on questionnaires. We used data from 25,357 subjects for examination-based analyses and those from 53,042 subjects for questionnaire-based analyses in the Japan Multi-Institutional Collaborative Cohort Study. Metabolic phenotypes were defined by classifying subjects according to their BMI (obesity: BMI ≥25 kg/m2; normal weight: BMI <25 kg/m2) and the number of metabolic abnormalities. Metabolic abnormalities were defined according to metabolic syndrome components of the Joint Interim Statement Criteria for examination-based analyses and self-reported histories of diabetes, dyslipidemia, and hypertension for questionnaire-based analyses. Cox proportional hazards regression analyses adjusted for potential confounders were performed for total and site-specific cancer incidence according to metabolic phenotypes. Metabolically unhealthy obesity (MUHO) was significantly associated with cancer incidence in both examination-based [HR (95% CI): 1.17 (1.01-1.36)] and questionnaire-based analyses [HR (95% CI): 1.15 (1.04-1.26)]. Regarding site-specific cancer in questionnaire-based analyses, metabolically healthy obesity and MUHO were associated with colorectum and liver cancers in all subjects and with breast cancer in female subjects. Subjects with a metabolically unhealthy normal weight had a higher risk of pancreatic cancer. Moreover, MUHO was associated with corpus uteri cancer in female subjects. This prospective cohort study suggests that metabolic phenotypes are important risk factors for total and some site-specific cancers in Japanese adults.

Are metabolically healthy obese individuals really a benign cardiovascular group? An analysis of 162,590 participants with measures of arterial stiffness in UK BIOBANK

Abstract Background There is conflicting evidence as to whether so called metabolically healthy but overweight and obese individuals are at increased cardiovascular risk or mortality. Purpose We assessed whether metabolic health correlates with vascular health among these individuals using severity of arterial stiffness as a proxy for vascular health and cardiovascular risk. Methods Participants in UK Biobank with body-mass index (BMI) and arterial stiffness index (ASI) recorded at initial assessment between 2006-2010, and free from stroke and myocardial infarction and not underweight (BMI&amp;lt;18.5kg/m2) were included. Participants were stratified by BMI (normal, overweight, obese) and presence of metabolic abnormalities (hypertension, diabetes, dyslipidaemia). The primary outcome was the severity of ASI analysed using multivariate-adjusted linear regression. Results Of 162,590 participants, 55.0% were female, mean age was 57 years (SD 8), 42.5% were overweight and 24.4% obese. Within the normal BMI strata, 50.7% had ≥1 metabolic abnormality. Compared to individuals with normal BMI and no metabolic abnormalities (ref group), increased weight or metabolic abnormalities were similarly associated with higher ASI; adjusted β-coefficient [β] 0.35, 95%CI 0.30 to 0.40 for participants with normal BMI and ≥1 metabolic abnormality; β 0.32, 95%CI 0.26 to 0.37 for overweight participants without metabolic abnormalities. Obese individuals with no metabolic abnormalities had higher ASI (β 0.65; 95%CI 0.57 to 0.74) but was lower than overweight participants with metabolic abnormalities (β 0.80; 95%CI 0.75 to 0.84). Obese participants with metabolic abnormalities had the highest ASI (β 1.07; 95%CI 1.02 to 1.12) among all six metabolic combinations, p&amp;lt;0.001 for each vs ref group. Sensitivity analysis suggested higher ASI with increasing number of metabolic abnormalities within BMI categories. Conclusion Excess weight and metabolic abnormalities, are independently associated with adverse measures of vascular health to a similar degree, suggesting that the so called metabolically healthy obese are not a benign group. Primary prevention strategies should be considered in overweight, or obese individuals even if metabolic abnormalities are absent.

Prenatal diagnosis and postnatal follow-up of 15 fetuses with 16p13.11 microduplication syndrome.

The clinical phenotypes of 16p13.11 microduplication syndrome have been extensively reported in previous studies, mostly about adults and children, with limited information available on fetal cases. This study aims to explore the genotype-phenotype correlation of fetuses with 16p13.11 microduplication syndrome and analyze the characteristics of prenatal diagnosis indications and provide clinical information for prenatal and postnatal genetic counseling. We conducted a retrospective analysis of 3,451 pregnant women who underwent invasive prenatal diagnosis for SNP array between January 2018 and December 2022 at the Jinan Maternal and Child Health Hospital. Descriptive statistical analysis was performed on the prenatal diagnosis indications, pedigree analysis, pregnancy outcomes and postnatal follow-up of 15 fetuses with 16p13.11 microduplication syndrome. SNP array revealed that 15 fetuses had duplications in the 16p13.11 region with varying prenatal diagnosis indications. Among the cases, 6/15 exhibited ultrasound abnormalities, 5/15 had abnormal chromosomal copy number variations as indicated by non-invasive prenatal testing (NIPT), one case involved advanced maternal age, and 3/15 had other abnormalities. 16p13.11 microduplication syndrome was closely related to ultrasound abnormalities, especially structural abnormalities and soft marker anomalies (abnormal ultrasonic soft indicators), while the indication of NIPT could improve the detection rate of copy number variations (CNVs) in this region. Only 7/15 fetuses underwent pedigree verification, with one case of de novo 16p13.11 microduplication, and the others inherited from one parent. Pregnancy was terminated in 2/15 cases and the outcome of one case is unknown due to loss to follow-up. Among the remaining cases, only one case exhibited a ventricular septal defect, while another presented with omphalocele. No other obvious abnormalities were reported postnatally. The prenatal phenotypes of fetuses with 16p13.11 microduplication were highly associated with ultrasound abnormalities but lacked specificity. Comprehensive genetic tracing, outcome analysis, and follow-up are essential for providing accurate prenatal and postnatal genetic counseling.

Prognostic impact of next-generation sequencing on myelodysplastic syndrome: A single-center experience.

Myelodysplastic syndromes (MDS) are clinically heterogeneous disorders characterized by peripheral blood cytopenias, poor differentiation, clonal hematopoiesis, and increased risk of developing acute myeloid leukemia (AML). While somatic mutations do not currently feature in prognostic scoring systems, they may impact the clinical phenotype. In recent years, next-generation sequencing (NGS) has enabled the opportunity to identify an increasing number of genetic abnormalities, including recurrent modifications in the TP53, DNMT3A, NRAS, NPM1, RUNX1, and FLT3 genes. Bone marrow aspirate samples of 56 patients with MDS were investigated for mutations using NGS. We compared the relationship between gene mutation status and laboratory characteristics, such as certain cytopenias, the revised international prognostic scoring system, MDS subtypes, karyotypes, AML development, and overall survival. Twenty-one genes were found to have gene mutations, including ASXL1, TET2, SRSF2, EZH2, CSF3R, NRAS, ETV6, SETBP1, RUNX1, DDX41, U2AF1, JAK2, FLT3ITD, SF3B1, DNAMT3A, PHF6, TP53, CEBPA, CBL, IDH2, and GATA2. At least one point mutation occurred in 64.2% of all patients, including 58.3% of those with normal cytogenetics. Thrombocytopenia (P = .016), anemia (P = .018), decreased overall survival (P = .017), and increased AML transformation (P = .023) have been revealed to be linked to non-SF3B1 mutations. MDS are frequently associated with somatic point mutations. According to early findings, NGS panels are extremely effective instruments that provide an entirely new viewpoint on the disease for particular individuals. Future prognostications will depend more on NGS because those who exhibit normal cytogenetics may additionally have gene mutations.

Neonatal undernutrition induced by litter size expansion alters testicular parameters in adult Wistar rats.

Several models of maternal undernutrition reveal impairment of testicular development and compromise spermatogenesis in male offspring. The expansion of the litter size model, valuable for studying the impact of undernutrition on early development, has not yet been used to evaluate the consequences of early undernutrition in the adult male reproductive system. For this purpose, pups were raised in either normal litter (ten pups/dam) or large litter (LL; sixteen pups/dam). On postnatal day 90, sexual behaviour was evaluated or blood, adipose and reproductive tissues were collected for biochemical, histological and morphological analysis. Adult LL animals were lighter and thinner than controls. They showed increased food intake, but decrease of retroperitoneal white adipose tissue weight, glycaemia after oral glucose overload and plasma concentration of cholesterol. Reproductive organ weights were not altered by undernutrition, but histopathological analysis revealed an increased number of abnormal seminiferous tubules and number of immature spermatids in the tubular lumen of LL animals. These animals also showed reduction in total spermatic reserve and daily sperm production in the testes. Undernutrition decreased the number of Sertoli cells, and testosterone production was increased in the LL group. Mitochondrial activity of spermatozoa remained unchanged between experimental groups, suggesting no significant impact on the energy-related processes associated with sperm function. All animals from both experimental groups were considered sexually competent, with no significant difference in the parameters of sexual behaviour. We conclude that neonatal undernutrition induces histological and physiological testicular changes, without altering sperm quality and sexual behaviour of animals.

Characterizing the allele-specific gene expression landscape in high hyperdiploid acute lymphoblastic leukemia with BASE.

Somatic copy number variations (CNVs), including abnormal chromosome numbers and structural changes leading to gain or loss of genetic material, play a crucial role in initiation and progression of cancer. CNVs are believed to cause gene dosage imbalances and modify cis-regulatory elements, leading to allelic expression imbalances in genes that influence cell division and thereby contribute to cancer development. However, the impact of CNVs on allelic gene expression in cancer remains unclear. Allele-specific expression (ASE) analysis, a potent method for investigating genome-wide allelic imbalance profiles in tumors, assesses the relative expression of two alleles using high-throughput sequencing data. However, many existing methods for gene-level ASE detection rely on only RNA sequencing data, which present challenges in interpreting the genetic mechanisms underlying ASE in cancer. To address this issue, we developed a robust framework that integrates allele-specific copy number calls into ASE calling algorithms by leveraging paired genome and transcriptome data from the same sample. This integration enhances the interpretability of the genetic mechanisms driving ASE, thereby facilitating the identification of driver events triggered by CNVs in cancer. In this study, we utilized BASE to conduct a comprehensive analysis of ASE in high hyperdiploid acute lymphoblastic leukemia (HeH ALL), a prevalent childhood malignancy characterized by gains of chromosomes X, 4, 6, 10, 14, 17, 18, and 21. Our analysis unveiled the comprehensive ASE landscape in HeH ALL. Through a multi-perspective examination of HeH ASEs, we offer a systematic understanding of how CNVs impact ASE in HeH, providing valuable insights to guide ASE studies in cancer.

Investigating the effects of systemic thrombolysis on electrocardiography and pulmonary artery blood pressure in patients with pulmonary embolism.

We aimed to evaluate the association between electrocardiography (ECG) and echocardiographic findings in patients with pulmonary embolism (PE) before and after systemic thrombolysis. We included 38 PE patients admitted to the hospital with approved right ventricular (RV) dysfunction who were indicated for systemic thrombolysis. Indications for systemic thrombolysis were considered as patients who were either hemodynamically unstable on admission or became unstable in the course of hospital admission. Systemic thrombolysis was performed by either Reteplase or Alteplase. ECG and echocardiographic findings were documented at baseline and 12-24 h following systemic thrombolysis. Our results showed that TAPSE significantly increased while RV size and pulmonary artery systolic pressure (PAP) notably decreased after systemic thrombolysis (p < 0.001). The ECG abnormalities markedly diminished after systemic thrombolysis in PE patients (p < 0.001). Additionally, 100% of our patients had more than one ECG abnormality at baseline, while 55.3% had no ECG abnormalities after systemic thrombolysis. Further, the median number of ECG abnormalities remarkably attenuated after systemic thrombolysis (from 2.0 (1.0) to 0.0 (1.0), p < 0.001). Our results also revealed that delta RV size (r = 0.51, p = 0.001) and delta TAPSE (r = 0.4, p = 0.012) were positively correlated while mortality (r = -0.55, p = 0.001) was negatively associated with changes in the number of ECG abnormalities before and after systemic thrombolysis. We showed that systemic thrombolysis improved echocardiographic and electrocardiographic findings in PE patients. Additionally, a greater decreased number of ECG abnormalities after systemic thrombolysis was accompanied by more improvement in RV size and TAPSE and a lower mortality rate.

Clinical Outcome of Induction Treatment in the Era of Novel Agents and the Impact of the Number of High-Risk Cytogenetic Abnormalities (HRA) on Prognosis of Patients With Newly Diagnosed Multiple Myeloma (NDMM): Insights From a Multicenter Study.

In the era of novel agents, the clinical outcomes of induction treatment and the impact of the number of high-risk cytogenetic abnormalities (HRA) in newly diagnosed multiple myeloma (NDMM) need to be explored. Through this study, we aim to analyze the effectiveness of different induction treatments and explore the survival outcomes of patients with varying numbers of HRA. A total of 734 patients from seven medical centers were included in our study. Patients in the CD38 monoclonal antibody or IMiDs plus proteasome inhibitors (PI) groups had significantly superior overall survival (OS) and progression-free survival (PFS) compared to those receiving IMiDs or PI alone. Additionally, the CD38 monoclonal antibody conferred a PFS advantage over IMiDs plus PI. Patients with ≥ 2 high-risk cytogenetic abnormalities (HRA) exhibited an extremely poor prognosis and should be considered ultra-high-risk individuals in multiple myeloma (MM). The CD38 monoclonal antibody, transplantation, and achieving minimal residual disease (MRD) negativity only partly mitigated the poor prognosis in patients with HRA. Furthermore, patients with 1q21 gain/amplification (1q21+) only had a significantly worse prognosis compared to patients without HRA, and those with 1q21+ plus del17p or t(4;14) exhibited an inferior prognosis compared to those with 1q21+ alone. Our results suggested that double-hit multiple myeloma was associated with extremely poor survival outcomes, and more effective treatments needed to be explored for this particular subtype of MM.

Association between rare, genetic variants linked to autism and ultrasonography fetal anomalies in children with autism spectrum disorder

BackgroundRecent evidence suggests that certain fetal anomalies detected upon prenatal ultrasound screenings are associated with autism spectrum disorder (ASD). In this cross-sectional study, we aimed to identify genetic variants associated with fetal ultrasound anomalies (UFAs) in children with ASD.MethodsThe study included all children with ASD who are registered in the database of the Azrieli National Center of Autism and Neurodevelopment and for whom both prenatal ultrasound and whole exome sequencing (WES) data were available. We applied our in-house integrative bioinformatics pipeline, AutScore, to these WES data to prioritize rare, gene-disrupting variants (GDVs) probably contributing to ASD susceptibily. Univariate statistics and multivariable regression were used to assess the associations between UFAs and GDVs identified in these children.ResultsThe study sample comprised 126 children, of whom 43 (34.1%) had at least one UFA detected in the prenatal ultrasound scan. A total of 87 candidate ASD genetic variants were detected in 60 children, with 24 (40%) children carrying multiple variants. Children with UFAs were more likely to have loss-of-function (LoF) mutations (aOR = 2.55, 95%CI: 1.13–5.80). This association was particularly noticeable when children with structural anomalies or children with UFAs in their head and brain scans were compared to children without UFAs (any mutation: aOR = 8.28, 95%CI: 2.29–30.01; LoF: aOR = 5.72, 95%CI: 2.08–15.71 and any mutation: aOR = 6.39, 95%CI: 1.34–30.47; LoF: aOR = 4.50, 95%CI: 1.32–15.35, respectively). GDVs associated with UFAs were enriched in genes highly expressed across all tissues (aOR = 2.76, 95%CI: 1.14–6.68). There was a weak, but significant, correlation between the number of mutations and the number of abnormalities detected in the same children (r = 0.21, P = 0.016).ConclusionsThe results provide valuable insights into the potential genetic basis of prenatal organogenesis abnormalities associated with ASD and shed light on the complex interplay between genetic factors and fetal development.

Occurrence and predictors of laboratory abnormalities during outpatient parenteral antimicrobial therapy – A multicenter cohort study to inform laboratory test monitoring

ObjectivesEvidence on the optimal frequency of laboratory testing during outpatient parenteral antimicrobial therapy (OPAT) is lacking. Therefore, we investigated how often and when laboratory abnormalities occur during OPAT and which factors are associated with these abnormalities. MethodsWe performed a multicenter cohort study in four Dutch hospitals among adult patients receiving OPAT and collected routinely obtained laboratory test results. Incidence and incidence rates were calculated for various laboratory abnormalities. Survival analysis was performed to visualize the time to the first occurrence of laboratory abnormalities and Poisson regression analysis to compare the number of abnormalities in the first and second 30 OPAT days among patients receiving OPAT for ≥60 days. Predictors were identified using a multivariable Cox proportional hazard regression model. Results45.1% of 1152 included patients developed laboratory abnormalities, but only 2% led to OPAT discontinuation. Hepatotoxicity was most common (33.9 events/1000 OPAT days), with a time-dependent decrease in the occurrence of the first hepatotoxic event, while hypokalemia was rare (1.7 events/1000 OPAT days). In the subgroup of patients receiving ≥60 days of OPAT, nephrotoxicity was more common in days 31-60. We observed partly toxicity-specific associations between antibiotic type, concomitant medication, baseline laboratory values, patient characteristics, and the occurrence of laboratory abnormalities. ConclusionsWhile laboratory abnormalities are frequently observed during OPAT, they rarely lead to discontinuation of OPAT. Specific patient, treatment and laboratory characteristics were associated with the occurrence of laboratory abnormalities. Based on our results, we recommend a more personalized laboratory monitoring policy with less blood sampling.

Abstract C058: The Impact of Preferred Language on Cancer WellBeing Screen Outcomes and Supportive Care Program Touch Points

Abstract Background: Preferred language is a potential barrier to linking patients to supportive resources. At a large health system, a Wellbeing Screen (WBS) is administered to identify needs and guide referral to the Patient &amp; Family Support Program (PFSP). Abnormal WBS and number of PFSP physician touch points were compared among cancer patients with non-preferred English language (nPEL) vs. preferred English language (PEL). We hypothesized nPEL patients may have differing needs or provision of services. Methods: A single institution retrospective study evaluating WBS among all patients receiving ambulatory cancer care at one of 7 sites from 01/2021-12/2022 was performed. The WBS instrument assesses degree of impact for 15 wellbeing domains and is assigned to patients at each oncology-related visit if a WBS has not been completed within the last 30 days. PEL vs. nPEL patients were compared for percentage of abnormal screens defined as a response of moderate/severe impact on at least one domain. Number of touch points by PFSP physicians (Supportive Care Medicine; Rehabilitation; Psychiatry) were abstracted within 30 days after any abnormal WBS. Fisher’s exact test was used to calculate odds ratios and p-values. Results: A total of 12,642 patients were assigned at least one WBS during the study period, resulting in 56,821 assigned WBSs, of which 7,898 (13.9%) were assigned to nPEL patients. PEL patients were assigned a lower average number of WBSs compared to nPEL (4.4 vs. 5.3, p&amp;lt;0.001). Of all assigned WBSs, 20,191 (35.5%) were completed. Of these, 10,097 (50.0%) were abnormal with moderate/severe impact on at least one domain. WBSs completed by PEL patients had 1.42 higher odds of moderate/severe impact on at least one domain compared to nPEL (p&amp;lt;0.001) and higher odds of moderate/severe impact on 11 of the 15 individual domains (all p&amp;lt;0.01). There were 5,628 PFSP physician touch points within 30 days of the 10,097 abnormal WBS. The most frequent touch points were provided by Supportive Care Medicine (55.5%), followed by Rehabilitation (29.2%) and Psychiatry (15.4%). The nPEL group had 0.34 lower odds of having any PFSP physician touch point (p&amp;lt;0.001) and a lower average number of PFSP physician touch points (8.4 nPEL vs 16.5 PEL, p&amp;lt;0.001) compared to the PEL group. nPEL had significantly lower odds of having a touch point provided by Rehabilitation (OR 0.44) and Psychiatry (OR 0.33), but significantly higher odds of having a touch point provided by Supportive Care Medicine (OR 3.01) (all p&amp;lt;0.001). Conclusion: WBSs completed by PEL had higher odds of identifying moderate/severe impact on at least one wellbeing domain. The nPEL group had fewer PFSP physician touch points and differing odds of services from PFSP physicians compared to the PEL group. These differences may be due to bias in the screen, differences in understanding the value of services (ie., due to language barriers or cultural perception), or referral patterns. Further evaluation of non-physician PFSP services, such as Social Work, Clinical Nutrition, and Spiritual Care, is ongoing. Citation Format: Justin Kim, Scott Irwin, Kevin Tsang, Hongyu Liu, Nicholas Tatonetti, Margaret Liang. The Impact of Preferred Language on Cancer WellBeing Screen Outcomes and Supportive Care Program Touch Points [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C058.

Mechanistic target of rapamycin (mTOR) pathway in Sertoli cells regulates age-dependent changes in sperm DNA methylation

Over the past several decades, a trend toward delayed childbirth has led to increases in parental age at the time of conception. Sperm epigenome undergoes age-dependent changes increasing risks of adverse conditions in offspring conceived by fathers of advanced age. The mechanism(s) linking paternal age with epigenetic changes in sperm remain unknown. The sperm epigenome is shaped in a compartment protected by the blood-testes barrier (BTB) known to deteriorate with age. Permeability of the BTB is regulated by the balance of two mTOR complexes in Sertoli cells where mTOR complex 1 (mTORC1) promotes the opening of the BTB and mTOR complex 2 (mTORC2) promotes its integrity. We hypothesized that this balance is also responsible for age-dependent changes in the sperm epigenome. To test this hypothesis, we analyzed reproductive outcomes, including sperm DNA methylation in transgenic mice with Sertoli cell-specific suppression of mTORC1 (Rptor KO) or mTORC2 (Rictor KO). mTORC2 suppression accelerated aging of the sperm DNA methylome and resulted in a reproductive phenotype concordant with older age, including decreased testes weight and sperm counts, and increased percent of morphologically abnormal spermatozoa and mitochondrial DNA copy number. Suppression of mTORC1 resulted in the shift of DNA methylome in sperm opposite to the shift associated with physiological aging – sperm DNA methylome rejuvenation and mild changes in sperm parameters. These results demonstrate for the first time that the balance of mTOR complexes in Sertoli cells regulates the rate of sperm epigenetic aging. Thus, mTOR pathway in Sertoli cells may be used as a novel target of therapeutic interventions to rejuvenate the sperm epigenome in advanced-age fathers.

Mechanistic target of rapamycin (mTOR) pathway in Sertoli cells regulates age-dependent changes in sperm DNA methylation.

Over the past several decades, a trend toward delayed childbirth has led to increases in parental age at the time of conception. Sperm epigenome undergoes age-dependent changes increasing risks of adverse conditions in offspring conceived by fathers of advanced age. The mechanism(s) linking paternal age with epigenetic changes in sperm remain unknown. The sperm epigenome is shaped in a compartment protected by the blood-testes barrier (BTB) known to deteriorate with age. Permeability of the BTB is regulated by the balance of two mTOR complexes in Sertoli cells where mTOR complex 1 (mTORC1) promotes the opening of the BTB and mTOR complex 2 (mTORC2) promotes its integrity. We hypothesized that this balance is also responsible for age-dependent changes in the sperm epigenome. To test this hypothesis, we analyzed reproductive outcomes, including sperm DNA methylation in transgenic mice with Sertoli cell-specific suppression of mTORC1 (Rptor KO) or mTORC2 (Rictor KO). mTORC2 suppression accelerated aging of the sperm DNA methylome and resulted in a reproductive phenotype concordant with older age, including decreased testes weight and sperm counts, and increased percent of morphologically abnormal spermatozoa and mitochondrial DNA copy number. Suppression of mTORC1 resulted in the shift of DNA methylome in sperm opposite to the shift associated with physiological aging - sperm DNA methylome rejuvenation and mild changes in sperm parameters. These results demonstrate for the first time that the balance of mTOR complexes in Sertoli cells regulates the rate of sperm epigenetic aging. Thus, mTOR pathway in Sertoli cells may be used as a novel target of therapeutic interventions to rejuvenate the sperm epigenome in advanced-age fathers.

Aneuploidy of Specific Chromosomes is Beneficial to Cells Lacking Spindle Checkpoint Protein Bub3.

Accurate chromosome segregation is crucial for the proper development of all living organisms. Errors in chromosome segregation can lead to aneuploidy, characterized by an abnormal number of chromosomes, which generally impairs cell survival and growth. However, under certain stress conditions, such as in various cancers, cells with specific mutations and extra copies of advantageous chromosomes exhibit improved survival and proliferation. In our study, we discovered that cells lacking the spindle checkpoint protein Bub3 became aneuploid, retaining specific chromosomes. This finding was unexpected because although bub3 Δ cells have a higher rate of chromosome mis-segregation, they were not thought to maintain an aneuploid karyotype. We investigated whether the increased copy number of specific genes on these acquired chromosomes offered a benefit to Bub3-deficient cells. Our results revealed that several genes involved in chromosome segregation and cell cycle regulation prevented the gain of chromosomes upon Bub3-depletion, suggesting that these genes confer a survival advantage. Overall, our study demonstrates that cells lacking Bub3 selectively retain specific chromosomes to increase the copy number of genes that promote proper chromosome segregation.

O33 ARE METABOLICALLY HEALTHY OBESE INDIVIDUALS REALLY A BENIGN CARDIOVASCULAR GROUP? AN ANALYSIS OF 162,590 PARTICIPANTS WITH MEASURES OF ARTERIAL STIFFNESS IN UK BIOBANK

Background and Objective: There is conflicting evidence as to whether so called metabolically healthy but overweight and obese individuals are at increased cardiovascular risk or mortality. We assessed whether metabolic health correlates with vascular health among these individuals using arterial stiffness as a proxy for vascular health and cardiovascular risk. Methods: Participants in UK Biobank with body-mass index (BMI) and arterial stiffness index (ASI) recorded between 2006 and 2010, and free from cardiovascular diseases and not underweight (BMI&lt;18.5 kg/m2) were included. Participants were stratified by BMI and metabolic abnormalities (hypertension, diabetes, dyslipidaemia). The primary outcome was the severity of ASI analysed using multivariate-adjusted linear regression. Results: Of 162,590 participants, 55.0% were female, their mean age was 57 years (SD 8), 42.5% were overweight and 24.4% were obese. Within the normal BMI strata, 50.7% had ≥1 metabolic abnormality. Compared to individuals with normal BMI and no metabolic abnormalities (reference group), increased BMI or metabolic abnormalities were similarly associated with higher ASI: normal BMI with metabolic abnormalities (adjusted β-coefficient 0.35;95%CI 0.30 to 0.40), overweight without metabolic abnormalities (β 0.32; 95%CI 0.26 to 0.37). Obese individuals with no metabolic abnormalities had higher ASI (β 0.65; 95%CI 0.57 to 0.74) but was lower than overweight participants with metabolic abnormalities (β 0.80; 95%CI 0.75 to 0.84). Obese participants with metabolic abnormalities had the highest ASI (β 1.07; 95%CI 1.02 to 1.12) among all six metabolic combinations, p&lt;0.001 for each vs ref group. Sensitivity analysis suggested higher ASI with increasing number of metabolic abnormalities within BMI categories. Conclusions: Excess weight and metabolic abnormalities, are independently associated with adverse measures of vascular health to a similar degree, suggesting that the so called metabolically health overweight and obese are not benign groups. Primary prevention strategies should be considered in overweight, or obese individuals even if metabolic abnormalities are absent.

Exploring the function and prognostic value of RPLP0, RPLP1 and RPLP2 expression in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC) and is characterized by its heterogeneity and poor prognosis. The role of ribosomal proteins RPLP0, RPLP1 and RPLP2 in multiple cancers has been implicated. However, their function in LUAD and their correlation with the poor prognosis of LUAD remains elusive. In this study, we performed a comprehensive bioinformatic analysis of the impact of these ribosomal proteins on LUAD. Our findings reveal that RPLP0, RPLP1 and RPLP2 are overexpressed in LUAD, which are likely attributed to abnormal copy number variations and decreased methylation levels of their promoters. LUAD patients with high expression of RPLP0, RPLP1 or RPLP2 have worse clinical outcomes in terms of overall survival (OS), first progression (FP) and post-progression survival (PPS), indicating poor prognosis. Moreover, the expression of RPLP0, RPLP1 and RPLP2 affects immune cell infiltration in LUAD tissues. Finally, we identified multiple existing drugs that may inhibit the expression of RPLP1 and RPLP2. Collectively, our data implicate the oncogenic role of RPLP0, RPLP1 and RPLP2 in LUAD and underscore their prognostic value in LUAD patients.

Gut microbiota and rheumatic diseases: new insights into pathogenesis

Background: Rheumatic diseases are a group of disorders characterised by a loss of immune tolerance, which leads to chronic inflammation, degeneration or metabolic abnormalities in various organs or tissues. Despite the lack of clarity surrounding the causes of these diseases, both environmental and genetic factors play an important role. Recent research indicates that alterations in the composition of the gut microbiota, known as gut dysbiosis, may contribute to the development of a number of rheumatic diseases, including rheumatoid arthritis, systemic lupus, ankylosing spondylitis, systemic scleroderma and Sjögren's syndrome. The gut microbiota influences the balance between pro- and anti-inflammatory immune responses, which may have important implications for the pathogenesis of these diseases. Furthermore, studies have indicated that the composition of the gut microbiota may be associated with the response to therapies used to treat rheumatic diseases, thus opening up new avenues for the development of microbiota-targeted treatments for these conditions. Aim of the study: The objective of this review is to investigate the impact of the gut microbiota on the pathogenesis of rheumatic diseases and to evaluate potential therapies targeting the manipulation of the gut microbiota. Material and methods: The present study is based on literature available in scientific databases from 2019-2024, such as PubMed, Corchane Library and Google Scholar.Results and conclusions: A growing body of evidence suggests a potential link between the gut microbiota and rheumatic diseases. Patients often exhibit a reduced ratio of Firmicutes to Bacteroidetes and abnormal numbers of Bacteroides. Molecular mimicry and a potential association with short-chain fatty acids have also been observed. Further human studies are needed to more fully understand the role of the gut microbiota and potential therapeutic interventions.

The link between abnormal numbers and price movements of financial securities: How does Benford’s law predict stock returns?

This paper studies the potential effect of deviation from Benford’s law on stock return prediction. Departures from the anticipated pattern can act as early indicators of irregular market behavior or possible fraudulent activities, both of which have the potential to impact future price trends. In this study, the deviation is measured by chi-squared test statistics over the first significant digit. Preliminary results indicate no compliance between daily stock returns data from Euronext Paris and Tunisian stock markets with Benford’s distribution. Then, the impact on the returns is explored via several models: linear regression and smooth transition models with various transition variables. Empirical results show the nonlinear effect of Benford’s law on stock returns prediction. We illustrate that this law can detect and predict abnormal returns generated by fraudulent or abnormal activities in both developed and emerging markets. By using Benford’s Law to analyze leading digits, investors and analysts can effectively identify irregularities and gain valuable insights into market dynamics.

The Gender Gap in the Relationship between Metabolic Syndrome and Restrictive Ventilatory Defects.

Given the fundamental physiological differences between the sexes, this study aimed to investigate the effect of metabolic syndrome on ventilatory defects stratified by sex. We conducted a nationwide, pooled, cross-sectional study. Data from 45,788 participants (men, n = 15,859; women, n = 29,929) aged 30 years or more were obtained from the Taiwan Biobank. Age-sex-adjusted and multivariate logistic regression models were used to estimate the risk of developing impaired pulmonary function (restrictive or obstructive ventilatory defects) in individuals with or without metabolic syndromes. Separate models were also used to estimate the effect of metabolic syndrome scores and the effect of individual metabolic abnormalities on the risk of restrictive ventilatory defects. The overall prevalence of metabolic syndrome was estimated to be 15.9% in Taiwan, much higher in men than in women (18.6% versus 14.4%). A significant association was observed between metabolic syndromes and the risk of restrictive ventilatory defects. The risk of developing a restrictive ventilator defect was 35% higher in participants with metabolic syndromes (odds ratio, 1.35; 95% confidence interval, 1.26-1.45) than in those without metabolic syndromes. Elevated blood pressure and a triglycerides abnormality were important predictors of restrictive ventilator defects. Sex-stratified subgroup analyses of the individual metabolic abnormalities indicated that men with abdominal obesity and women with dysglycemia were more likely to develop restrictive ventilatory defects. Our study's evidence suggested that metabolic syndromes were important predictors of impaired pulmonary function and an increased risk of developing restrictive ventilatory defects, and its risk increased with increasing numbers of metabolic abnormalities.

Chromosomal abnormalities detected by chromosomal microarray analysis and pregnancy outcomes of 4211 fetuses with high-risk prenatal indications

With the gradual liberalization of the three-child policy and the development of assisted reproductive technology in China, the number of women with high-risk pregnancies is gradually increasing. In this study, 4211 fetuses who underwent chromosomal microarray analysis (CMA) with high-risk prenatal indications were analysed. The results showed that the overall prenatal detection rate of CMA was 11.4% (480/4211), with detection rates of 5.82% (245/4211) for abnormal chromosome numbers and 5.58% (235/4211) for copy number variants. Additionally, the detection rates of clinically significant copy number variants were 3.78% (159/4211) and 1.8% (76/4211) for variants of uncertain significance. The detection rates of fetal chromosomal abnormalities were 6.42% (30/467) for pregnant women with advanced maternal age (AMA), 6.01% (50/832) for high-risk maternal serum screening (MSS) results, 39.09% (224/573) with abnormal non-invasive prenatal testing (NIPT) results, 9.21% (127/1379) with abnormal ultrasound results, and 5.1% (49/960) for other indications. Follow-up results were available for 4211 patients, including 3677 (3677/4211, 87.32%) whose infants were normal after birth, 462 (462/4211, 10.97%) who terminated their pregnancy, 51 (51/4211, 1.21%) whose infants were abnormal after birth, and 21 (21/4211, 0.50%) who refused follow-up. The results of this study demonstrate significant variation in the diagnostic rate of chromosomal microarray analysis across different indications, providing valuable guidance for clinicians to assess the applicability of CMA technology in prenatal diagnosis.