Search Results (145)

Chromosomal microarray analysis (CMA) was performed for 40 patients with B-ALL undergoing treatment according to the ALL-2016 protocol to investigate the copy number alterations (CNAs) and copy neutral loss of heterozygosity (cnLOH) associated with minimal residual disease (MRD)-positive remission. Aberrations involving over 20,000 genes were identified, and a random forest approach was applied to isolate a subset of genes whose CNAs and cnLOH are significantly associated with poor therapeutic response. We have assembled the triple matched healthy population data and used that data as a reference, but not as a matched control. We identified a recurrent cluster of cnLOH in the 19q13.2–19q13.31 region, significantly enriched in MRD-positive patients (70% vs. 47% in the reference group vs. 16% in MRD-negative patients). This region includes the pregnancy-specific glycoprotein (PSG) gene family and the oncogene ERF, suggesting a potential role in leukemic persistence and treatment resistance. Additionally, we observed significant deletions involving 7p22.3 and 16q13, often as part of large-scale losses affecting almost the entire chromosomes 7 and 16, indicative of global chromosomal instability. These findings highlight specific genomic regions potentially involved in therapy resistance and may contribute to improved risk stratification in B-ALL. Our findings emphasize the value of high-resolution CMA in diagnostics and risk stratification and suggest that PSG genes and other candidate genes could serve as biomarkers for predicting treatment outcomes. Full article

Background: In childhood acute lymphoblastic leukemia (ALL), in addition to classical chromosomal abnormalities, loss of heterozygosity (LOH), including copy-neutral LOH, is also observed. While LOH has been described in the literature, its clinical relevance in pediatric ALL remains unclear. The aim of this study is to identify and analyze patterns of LOH, assess their frequency, and evaluate their association with clinical characteristics and early treatment response during the induction phase of the ALL protocol. Methods: The study included 853 pediatric ALL patients, of whom 120 had B-ALL LOH+ and 58 had T-ALL LOH+. LOH was analyzed using CytoScan HD SNP microarrays. Patients were stratified using multiple correspondence analysis (MCA) and hierarchical clustering on principal components (HCPC), which identified three genetically and clinically distinct clusters. Results: In B-ALL, two clusters with extensive LOH—particularly involving chromosome 9—were associated with poor prognosis and suboptimal response to therapy. In contrast, Cluster 2, characterized by CDKN2A duplication and rare LOH, showed a favorable clinical course. In T-ALL, Cluster 1 had LOH in CDKN2A but favorable outcomes; Cluster 2 exhibited biallelic CDKN2A deletion and aggressive disease; Cluster 3 lacked CDKN2A alterations and showed a genetically stable profile. LOH was common on chromosomes not typically affected by trisomy and rare on those gained. Conclusions: Our study indicates that LOH profiling can positively influence patient stratification by identifying high-risk subgroups, inform prognosis by highlighting unfavorable genetic alterations, and help predict poor treatment response in specific clinical profiles. Full article

Extending healthy lifespans is an important public health goal in societies with a long life expectancy. Late-onset hypogonadism (LOH), a condition associated with an age-related decrease in testosterone level, contributes to the onset of various diseases. Previously, we demonstrated that the oral ingestion of bean sprouts rich in the HASPIN inhibitor coumestrol increased blood testosterone levels in mice. In the present study, we showed that the oral ingestion of bean sprouts also led to increased blood testosterone levels in humans. These results suggested that bean sprouts, which are rich in coumestrol, have potential as a dietary intervention for the treatment of LOH. Full article

Background: Acute heart failure (AHF) is a major cause of hospitalizations, posing significant challenges to healthcare systems. Despite advancements in management, the rate of poor outcomes remains high globally, emphasizing the need for timely interventions. This study aimed to identify early admission-based factors predictive of poor outcomes in hospitalized AHF patients, in order to contribute to early risk stratification and optimize patient care. Methods: This retrospective single-center study analyzed routine data of adult patients hospitalized for AHF at a public university teaching hospital in Switzerland. Outcomes included in-hospital death, intensive care (ICU) treatment, and length of hospital stay (LOHS). Potential predictors were limited to routine parameters, readily available at admission. Missing predictor data was imputed and predictors were identified by means of multivariable regression analysis. Results: Data of 638 patients (median age 84 years, range 45–101 years, 50% female) were included in the study. In-hospital mortality was 7.1%, ICU admission rate 3.8%, and median LOHS was 8 days (IQR 5–12). Systolic blood pressure ≤ 100 mmHg (Odds ratio (OR) 3.8, p = 0.009), peripheral oxygen saturation ≤ 90% or oxygen supplementation (OR 5.9, p < 0.001), and peripheral edema (OR 2.7, p = 0.044) at hospital admission were identified as predictors of in-hospital death. Furthermore, a stroke or transient ischemic attack in the patient’s history (OR 3.2, p = 0.023) was associated with in-hospital death. ICU admission was associated with oxygen saturation ≤ 90% or oxygen supplementation (OR 22.9, p < 0.001). Factors linked to longer LOHS included oxygen saturation ≤ 90% or oxygen supplementation (IRR 1.2, p < 0.001), recent weight gain (IRR 1.1, p = 0.028), and concomitant chronic kidney disease (IRR 1.2, p < 0.001). Conclusions: This study validated established predictors of AHF outcomes in a Swiss cohort, highlighting the predictive value of poor perfusion status, fluid overload, and comorbidities such as chronic kidney disease. The identified predictors imply potential for developing tools to improve rapid treatment decisions. Future research should focus on the prospective external validation of the identified predictors and the design and validation of risk scores, incorporating these parameters to optimize early interventions and reduce adverse outcomes in AHF. Full article

Epilepsy is one of the most common neurological disorders. Disease etiology and pathogenesis are still not well understood. Genetic mutations are associated with 70% of epilepsies, while 30% are still enigmatic. Attempting to close the knowledge gap, we performed genetic analysis of a cohort of patients from the Middle East and North Africa, both understudied and highly consanguineous populations. Whole exome sequencing (WES) was carried out on 81 patients and their family members at a tertiary center in Qatar. We found damaging mutations in half of the patients: 15 in known epilepsy genes, and 19 in contested or unknown genes. The mutations include single nucleotide polymorphisms (SNVs), frameshifts, copy number variations (CNVs), and loss of homozygosity (LOH). Fifteen of the SNVs are novel, and seventeen are homozygous, reflective of the characteristics of the cohort. In addition, we used the WES data to type HLA alleles for 13 class I and II genes. We show that DRB3*01:01:02G is negatively associated with epilepsy, in contrast to DRB4*01:01:01G, which may be a risk allele. In addition to expanding the knowledge base of genes involved in epilepsy, our findings show that genetic predisposition, inclusive of immune genes, suggests a complex etiology. Full article

Currently, knowledge of the effects of different frequencies of administration of bedside physiotherapy programs (PTPs) on hospitalized COVID-19 patients is limited. Therefore, this study aimed to compare the effects of administering PTPs once or twice during hospitalization versus daily PTPs until discharge. Fifty-two COVID-19 patients were equally assigned to two groups, matched by gender and age (1:1 ratio). Experimental Group 1 (Ex-G1) received PTPs one to two times during hospitalization, while Experimental Group 2 (Ex-G2) received daily PTPs until discharge. The outcomes assessed included the survival rate, length of hospitalization (LoH), intensive care unit (ICU) referrals, and in-hospital complications. Most participants were classified as having mild to moderate COVID-19, with a mean age of 45 years. No significant differences were observed between the groups in all primary outcomes, including the survival rate (p = 1.000), LoH (p = 0.117), ICU referrals (p = 0.313), and complications (p = 0.555). The overall survival rate was 98%. One Ex-G2 participant was referred to the ICU, while complications occurred in two Ex-G1 and four Ex-G2 participants. In summary, for patients with mild to moderate COVID-19, one to two bedside physiotherapy sessions produced comparable results to daily physiotherapy in terms of the survival rate, LoH, ICU referrals, and in-hospital complications. Full article

Chloride plays a considerable role in physiology. This study aimed to assess the association between serum chloride and prognosis in the population of adults with acute medical conditions. A prospective cohort study was conducted in an acute medical unit. Chloride levels at admission were the main exposure factor, categorized into hypochloremia, normochloremia, and hyperchloremia. The outcomes were in-hospital mortality and length of hospital stay (LOHS). A total of 798 patients were included. The mean age was 57.3 ± 18.3 years. The prevalence of dyschloremia was 40.9%. Restricted cubic splines revealed a linear association between hypochloremia and in-hospital mortality, as well as between hypochloremia and LOHS. After adjusting for age, sex, heart failure, diabetes, sodium, bicarbonates, creatinine, and diuretic use, hypochloremia was significantly associated with in-hospital mortality (OR = 2.23; 95% CI: 1.29, 3.86, p = 0.006), but not hyperchloremia (p = 0.57). Similarly, it was associated with a longer LOHS (β = 2.19; 95% CI: 0.01, 4.39, p = 0.05), but not hyperchloremia (p = 0.8). The interaction between chloride and sodium levels was not significant (p = 0.61). Subgroup analysis showed that the effect of hypochloremia on in-hospital mortality was consistent across subgroups. The prevalence of dyschloremia in this study was high at 40.9%. Hypochloremia increased the risk of in-hospital mortality and extended the LOHS. Differentiating the effects of chloride levels from those of sodium can enhance clinical risk stratification and enable a more targeted management approach for acutely ill patients. Recognizing this distinction is essential for optimizing prognostic assessment and tailoring treatment strategies accordingly. Full article

Clear-cell renal cell carcinoma (ccRCC) is associated with the mutated von Hippel–Lindau (VHL) gene leading to the activation of hypoxia-inducible factor 1A (HIF1A) and subsequent overexpression of erythropoietin (EPO). We analyzed tumor and healthy tissues from 43 ccRCC patients after radical nephrectomy and cultured 786-O (biallelic VHL inactivation) and Caki-1 (wild-type VHL) cells in normal (21% O₂) and low oxygen (3% O₂) with 10% and 2% fetal bovine serum (FBS). DNA sequencing, including Sanger sequencing, MLPA and LOH, revealed 27 somatic mutations of VHL in ccRCC. HIF1A protein showed decreased or no expression in tumors compared to healthy tissue, independent of VHL alteration. The 786-O cells showed increased HIF1A protein expression after 48 h under low oxygen and 10% FBS. EPO and erythropoietin receptor (EPOR) were significantly decreased in ccRCC without HIF1A expression. EPO mRNA increased in the 786-O cells at 3% O₂ after 48 h, while the Caki-1 cells had low or no EPO expression. Hypoxia increased EPOR mRNA in the Caki-1 cells at 10% FBS, but decreased in the 786-O cells at 2% FBS after 48 h. JAK2/STAT5A activity was increased only in HIF1A-positive tumors. These results suggest that EPO/EPOR activation in ccRCC is mainly driven by low oxygen, not VHL regulation of hypoxia-related responses. Full article

Background/Objectives: Arterial hypertension (HT) is a leading modifiable risk factor for cardiovascular diseases, often contributing to prolonged lengths of hospital stay (LOHS), which place significant strain on healthcare systems. This study aimed to analyze the factors associated with prolonged lengths of hospital stay in patients with HT, focusing on key biochemical and clinical predictors. Methods: This retrospective study included 356 adult patients hospitalized in the Cardiology Department of the University Hospital in Wroclaw, Poland, between January 2017 and June 2021. Data collected included demographic characteristics, body mass index (BMI), comorbidities, and laboratory parameters. Logistic regression models were used to identify predictors of prolonged LOHS, defined as four or more days, and to evaluate interactions between variables. Results: Lower levels of low-density lipoprotein cholesterol (LDL-c) and elevated concentrations of high-sensitivity C-reactive protein (hsCRP) were identified as significant predictors of prolonged LOHS, with each 1 mg/dL decrease in LDL-c increasing the odds of prolonged LOHS by 1.21% (p < 0.001) and each 1 mg/L increase in hsCRP raising the odds by 3.80% (p = 0.004). An interaction between sex and heart failure (HF) was also observed. Female patients with HF had 3.995-fold higher odds of prolonged LOHS compared to females without HF (p < 0.001), while no significant difference was found among male patients with or without HF (p = 0.890). Conclusions: The predictors of prolonged LOHS in patients with HT include lower levels of LDL-c, elevated hsCRP, and the interaction between sex and heart failure (HF). Specifically, female patients with HF demonstrated significantly higher odds of prolonged LOHS compared to females without HF, while this relationship was not observed in male patients. Full article

Ovarian cancer (OC) is a highly heterogeneous malignancy, often characterized by complex genomic alterations that drive tumor progression and therapy resistance. In this paper, we report a novel de novo BRCA2 germline variant NM_000059.3:c.(8693_8695delinsGT) associated with early-onset OC that featured two regions with differential MMR (Mismatch Repair) gene expression. To date, only six cases of de novo BRCA2 variants have been reported, none of which were associated with early-onset high-grade serous OC. The immunohistochemical analysis of MMR genes revealed two distinct tumor areas, separated by a clear topographic boundary, with the heterogeneous expression of MLH1 and PMS2 proteins. Seventy-five percent of the tumor tissue showed positivity, while the remaining 25% exhibited a complete absence of expression, underscoring the spatial variability in MMR gene expression within the tumor. Integrated comparative spatial genomic profiling identified several tumor features associated with the genetic variant as regions of loss of heterozygosity (LOH) that involved BRCA2 and MLH1 genes, along with a significantly higher mutational tumor burden in the tumor area that lacked MLH1 and PMS2 expression, indicating its further molecular evolution. The following variants were acquired: c.6572C>T in NOTCH2, c.1852C>T in BCL6, c.191A>T in INHBA, c.749C>T in CUX1, c.898C>A in FANCG, and c.1712G>C in KDM6A. Integrated comparative spatial proteomic profiles revealed defects in the DNA repair pathways, as well as significant alterations in the extracellular matrix (ECM). The differential expression of proteins involved in DNA repair, particularly those associated with MMR and Base Excision Repair (BER), highlights the critical role of defective repair mechanisms in driving genomic instability. Furthermore, ECM components, such as collagen isoforms, Fibrillin-1, EMILIN-1, Prolargin, and Lumican, were found to be highly expressed in the MLH1/PMS2-deficient tumor area, suggesting a connection between DNA repair deficiencies, ECM remodeling, and tumor progression. Thus, the identification of the BRCA2 variant sheds light on the poorly understood interplay between DNA repair deficiencies and ECM remodeling in OC, providing new insights into their dual role in shaping tumor evolution and suggesting potential targets for novel therapeutic strategies. Full article

DNA methylation of tumor suppressor genes in cancer is known to be a mechanism for silencing gene expression, but much remains unknown about its extent and relationship to somatic variants at the DNA sequence level. In this study, we comprehensively analyzed DNA methylation and somatic variants of all gene regions across the genome of the major tumor suppressor genes, APC, TP53, SMAD4, and mismatch repair genes in colorectal cancer using a novel next-generation sequencing-based analysis method. The Targeted Methyl Landscape (TML) shows that DNA hypermethylation patterns of these tumor suppressor genes in colorectal cancer are more complex and widespread than previously thought. Extremely high levels of DNA methylation were observed in relatively long regions around exon 1A of APC and exon 1 and surrounding region of MLH1. DNA hypermethylation occurred whether or not somatic DNA variants were present in the tumor. Even in tumors where the loss of heterozygosity has been demonstrated by somatic variants alone, additional methylation of the same gene can occur. Our data demonstrate that somatic variants and hypermethylation of these tumor suppressor genes were considered independent, parallel events, not exclusive of each other or having one event affecting the other. Full article

Background: Unilateral (uVS) and bilateral vestibular schwannoma (bVS) are distinct disease types, yet share tumorigenic features. This study examined causative genetic alterations in three groups: patients with NF2-related schwannomatosis (NF2), young patients with uVS (≤30 years), and older patients with uVS (≥40 years). Methods: Lymphocyte and vestibular schwannoma DNA was genetically analyzed. Outcomes included gene involvement, pathogenicity classification, variant type, effect, and location, and loss of heterozygosity (LOH) of chromosome 22. Results: Among 93 patients, 17% had NF2, 39% were ≤30 years with uVS, and 44% were ≥40 years with uVS. In all patients with NF2 (100%), two or more hits were detected in the tumor DNA, whereas patients with uVS had a slightly lower detection rate (89–98%). NF2-related tumors had a higher frequency of nucleotide variants (76%), while LOH events were more common in uVS (64–69%). Variants were mostly identified in NF2, with nonsense variants over-represented in patients with NF2 (38%) and frameshift variants more prevalent in uVS (44–51%). Conclusions: Biallelic NF2 inactivation primarily drives vestibular schwannoma tumorigenesis. In patients with NF2, two pathogenic NF2 variants or one NF2 variant with LOH are common, whereas patients with uVS often exhibit one NF2 variant with LOH. Additionally, variant types differ between patient groups. Full article

Background: The 5-year prognosis of non-high-risk neuroblastomas is generally good (>90%). However, a proportion of patients show progression and succumb to their disease. We aimed to identify molecular aberrations (not incorporated in the current risk stratification) associated with overall survival (OS) and/or event-free survival (EFS) in patients diagnosed with non-high-risk neuroblastoma. Methods: We conducted a systematic search in PubMed, Embase, Cochrane and Google Scholar. Two reviewers independently and blindly screened titles/abstracts, references of protocols/reviews and full texts. Risk of bias was assessed using a customized Quality in Prognostic Studies tool. Applicability was assessed using a tool designed by the researchers. GRADE criteria were used to determine quality of evidence. Results: Sixteen studies (4718 patients) were included. A segmental chromosomal aberration (SCA) profile was associated with lower survival. 1p loss of heterozygosity (LOH) and 17q gain were associated with lower OS and EFS. 1p deletion and 2p gain were associated with lower OS, but this was not the same for EFS. 3p deletion was not associated with worse outcome. Quality of evidence was downgraded because of imprecision and publication bias and upgraded because of moderate/large effect, resulting in a moderate quality of evidence. Conclusion: The association of 1p LOH, 1p deletion, 2p gain and 17q gain with OS and EFS suggests that these SCAs may be added to the risk stratification to identify non-high-risk neuroblastomas with worse prognosis. Full article

Background/Objectives: Late-onset hypogonadism (LOH), characterized by declining testosterone levels with age, negatively affects the health of men, causing physical, psychological, and sexual dysfunction. Conventional testosterone replacement therapies have side effects, which has led to interest in natural alternatives. We investigated the effects of a standardized fermented Morinda citrifolia extract (FME) on oxidative stress-induced damage in TM3 Leydig and TM4 Sertoli cells. The cells were treated with H₂O₂ to simulate oxidative stress, followed by the FME treatment. Methods: Cytotoxicity assays, testosterone measurements, and gene and protein expression analyses were conducted to evaluate the restorative properties of FME. Results: The H₂O₂ treatment significantly decreased the cell viability, testosterone production, and the expression of proteins involved in testosterone synthesis and spermatogenesis, and the FME treatment improved testosterone production and restored the luteinizing hormone receptor, steroidogenic acute regulatory protein, CYP11A1, 3β-hydroxysteroid dehydrogenase, 17,20 desmolase, and 17β-hydroxysteroid dehydrogenase levels in the TM3 Leydig cells. It also reduced the expression of testosterone-degrading enzymes, aromatase and 5α-reductase. The FME treatment restored the levels of the androgen receptor and follicle-stimulating hormone receptor in the TM4 Sertoli cells. Conclusions: FME alleviates oxidative stress-induced damage in Leydig and Sertoli cells by promoting testosterone synthesis and spermatogenesis while regulating testosterone metabolism. These findings suggest that FME could be a promising candidate for the management of LOH symptoms. Full article

Major histocompatibility complex (MHC) class-I molecules (or Human Leucocyte Antigen class-I) play a key role in adaptive immunity against cancer. They present specific tumor neoantigens to cytotoxic T cells and provoke an antitumor cytotoxic response. The total or partial loss of HLA molecules can inhibit the immune system’s ability to detect and destroy cancer cells. Loss of heterozygosity (LOH) is a common irreversible genetic alteration that occurs in the great majority of human tumors, including breast cancer. LOH at chromosome 6, which involves HLA genes (LOH-HLA), leads to the loss of an HLA haplotype and is linked to cancer progression and a weak response to cancer immunotherapy. Therefore, the loss of genes or an entire chromosomal region which are critical for antigen presentation is of particular importance in the search for novel prognostic and clinical biomarkers in breast cancer. Here, we review the role of LOH-HLA in breast cancer, its contribution to an understanding of cancer immune escape and tumor progression, and discuss how it can be targeted in cancer therapy. Full article