An Integrated Fibrosis Signature for Predicting Survival and Immunotherapy Efficacy of Patients With Hepatocellular Carcinoma

Introduction: Fibrosis, a primary cause of hepatocellular carcinoma (HCC), is intimately associated with inflammation, the tumor microenvironment (TME), and multiple carcinogenic pathways. Currently, due to widespread inter- and intra-tumoral heterogeneity of HCC, the efficacy of immunotherapy is limited. Seeking a stable and novel tool to predict prognosis and immunotherapy response is imperative.Methods: Using stepwise Cox regression, least absolute shrinkage and selection operator (LASSO), and random survival forest algorithms, the fibrosis-associated signature (FAIS) was developed and further validated. Subsequently, comprehensive exploration was conducted to identify distinct genomic alterations, clinical features, biological functions, and immune landscapes of HCC patients.Results: The FAIS was an independent prognostic predictor of overall survival and recurrence-free survival in HCC. In parallel, the FAIS exhibited stable and accurate performance at predicting prognosis based on the evaluation of Kaplan–Meier survival curves, receiver operator characteristic curves, decision curve analysis, and Harrell’s C-index. Further investigation elucidated that the high-risk group presented an inferior prognosis with advanced clinical traits and a high mutation frequency of TP53, whereas the low-risk group was characterized by superior CD8+ T cell infiltration, a higher TIS score, and a lower TIDE score. Additionally, patients in the low-risk group might yield more benefits from immunotherapy.Conclusion: The FAIS was an excellent scoring system that could stratify HCC patients and might serve as a promising tool to guide surveillance, improve prognosis, and facilitate clinical management.

High Mutation Frequency and Significant Population Differentiation in Papaya Ringspot Virus-W Isolates

A total of 101 papaya ringspot virus-W (PRSV-W) isolates were collected from five different cucurbit hosts in six counties of Oklahoma during the 2016–2018 growing seasons. The coat protein (CP) coding region of these isolates was amplified by reverse transcription-polymerase chain reaction, and 370 clones (3–5 clones/isolate) were sequenced. Phylogenetic analysis revealed three phylogroups while host, location, and collection time of isolates had minimal impact on grouping pattern. When CP gene sequences of these isolates were compared with sequences of published PRSV isolates (both P and W strains), they clustered into four phylogroups based on geographical location. Oklahoman PRSV-W isolates formed one of the four distinct major phylogroups. The permutation-based tests, including Ks, Ks *, Z *, Snn, and neutrality tests, indicated significant genetic differentiation and polymorphisms among PRSV-W populations in Oklahoma. The selection analysis confirmed that the CP gene is undergoing purifying selection. The mutation frequencies among all PRSV-W isolates were within the range of 1 × 10−3. The substitution mutations in 370 clones of PRSV-W isolates showed a high proportion of transition mutations, which gave rise to higher GC content. The N-terminal region of the CP gene mostly contained the variable sites with numerous mutational hotspots, while the core region was highly conserved.

Comprehensive Analysis and Validation of Solute Carrier Family 25 (SLC25) in Pan-Cancer

BackgroundAs the largest gene family functioning in protein transport among human solute carriers, the SLC25 family (mitochondrial carrier family) has been reported to be associated with the genesis and development of many diseases. However, acomprehensiveexplorationfor the roles of SLC family in cancer remains lacking. MethodIn the present study, a total of 15 functional SLC25 family genes were retrieved from all current publications. And multi-dimensional analyses were systematically performed based on the transcriptome and genome data of SLC25 family from a variety of online databases for their expression, mutation and copy number variation, cancer prognosis, signaling pathways and immune cell infiltration. Validation by qPCR was further conducted for the expression of partial SLC25 family members in some tumor tissue.ResultsWe found that SLC25A7 was highly expressed in stomach adenocarcinoma, kidney chromophobeand colon adenocarcinoma, while low expressed in lung adenocarcinoma， thyroid carcinomaas well as head and neck squamous cell carcinoma. SLC25A23 was decreased in colon adenocarcinoma andhead and neck squamous cell carcinoma. SLC25A4 was down-regulated instomach adenocarcinoma,colon adenocarcinoma, kidney renal clear cell carcinoma and head and neck squamous cell carcinoma. Validation results of stomach adenocarcinoma and colon adenocarcinoma were consistent with our bioinformatic prediction. The analysis in regard to cancer-related pathways indicated that SLC25A5 was more likely to be positively associated with carcinogenic pathways such as PI3K-AKT-MTOR, MYC-TARGETS-V2 and E2F-TARGETS. Immune cells including Macrophages M2 and B cells naïve had significant association with SLC25s expression. Survival analysis demonstrated that SLC25A8 was linked to a high-risk effect on the prognosis of cervical squamous cell carcinoma and adenocarcinoma significantly. The majority of SLC25 genes showed high mutation frequency in uterine corpus endometrial carcinoma withan overall average mutation rateof 0.100189. SLC25A8 had extensive copy number variation in different cancer tissue. And SLC25A25 showed high mutation frequency in breast cancer cell lines. As forthe influence of mutation on gene expression and cancer prognosis, SLC25A4 mutation could alter its expression in uterine corpus endometrial carcinoma. Most SLC25 gene mutationmadeprominent effects on the prognosis of patients with uterine corpus endometrial carcinoma. ConclusionAll these findings suggested that the SLC25 family might be crucial to the occurrence, progression and prognosis of tumor. They had the potential to be predictive biomarkers for early diagnosis and prognosis as well as novel targets for individualized treatment of cancer.

Dissecting Highly Mutagenic Processing of Complex Clustered DNA Damage in Yeast Saccharomyces cerevisiae

Clusters of DNA damage, also called multiply damaged sites (MDS), are a signature of ionizing radiation exposure. They are defined as two or more lesions within one or two helix turns, which are created by the passage of a single radiation track. It has been shown that the clustering of DNA damage compromises their repair. Unresolved repair may lead to the formation of double-strand breaks (DSB) or the induction of mutation. We engineered three complex MDS, comprised of oxidatively damaged bases and a one-nucleotide (1 nt) gap (or not), in order to investigate the processing and the outcome of these MDS in yeast Saccharomyces cerevisiae. Such MDS could be caused by high linear energy transfer (LET) radiation. Using a whole-cell extract, deficient (or not) in base excision repair (BER), and a plasmid-based assay, we investigated in vitro excision/incision at the damaged bases and the mutations generated at MDS in wild-type, BER, and translesion synthesis-deficient cells. The processing of the studied MDS did not give rise to DSB (previously published). Our major finding is the extremely high mutation frequency that occurs at the MDS. The proposed processing of MDS is rather complex, and it largely depends on the nature and the distribution of the damaged bases relative to the 1 nt gap. Our results emphasize the deleterious consequences of MDS in eukaryotic cells.

Detection of S-HBsAg Mutations in Patients with Hematologic Malignancies

Multiple studies of hepatitis B virus (HBV) genetic variability and its relationship with the disease pathogenesis are currently ongoing, stemming from growing evidence of the clinical significance of HBV mutations. It is becoming increasingly evident that patients with hematologic malignancies may be particularly prone to a higher frequency of such mutations. The present report is the first extensive study of the prevalence of escape mutations in S-HBsAg, performed using isolates from 59 patients from hospital hematology departments with diagnoses of leukemia (n = 32), lymphoma (n = 20), multiple myeloma (n = 3), and non-tumor blood diseases (n = 4). The isolates were serologically examined for the presence of HBV markers and sequenced using either next-generation sequencing (NGS) or Sanger sequencing. Occult hepatitis B was found in 5.1% of cases. Genetic analysis of the region corresponding to S-HBsAg demonstrated an exceptionally high mutation frequency in patients with leukemias (93.4%) and lymphomas (85.0%), along with the prominent mutation heterogeneity. Additionally, more than 15 mutations in one sample were found in patients with leukemias (6.3% of cases) and lymphomas (5.0% of cases). Most of the mutations were clinically significant. The study analyzes the mutation profile of HBV in different oncohematological diseases and the frequency of individual mutations. The data strongly suggest that the NGS method, capable of detecting minor populations of HBV mutations, provides a diagnostic advantage, lays the foundation for the development of screening methods, and allows for the study of the virological and pathogenetic aspects of hepatitis B.

Association of Body Mass Index With Somatic Mutations in Breast Cancer

BackgroundThe relationship between body mass index (BMI) and the prognosis or treatment response in patients with breast cancer has been demonstrated in previous studies, but the somatic mutation profiles in breast cancer patients with different BMIs have not been explored.MethodsIn the present study, the somatic mutation profiles in 421 female breast cancer patients who were stratified into three subgroups based on BMI (normal weight, overweight/obese, and underweight) were investigated. Capture-based targeted sequencing was performed using a panel comprising 520 cancer-related genes.ResultsA total of 3547 mutations were detected in 390 genes. In breast cancer patients with different BMI statuses, the tumors exhibited high mutation frequency and burden. TP53 was the most common gene in the three groups, followed by PIK3CA, ERBB2, and CDK12. Meanwhile, the mutation hotspots in TP53 and PIK3CA were the same in the three BMI groups. More JAK1 mutations were identified in underweight patients than those in normal patients. Except for JAK1, differentially mutated genes in postmenopausal patients were completely different from those in premenopausal patients. The distribution of mutation types was significantly different among BMI groups in the postmenopausal group. Underweight patients in the postmenopausal group harbored more TP53 mutations, more amplifications, and more mutations in genes involved in the WNT signaling pathway.ConclusionsOur next-generation sequencing (NGS)-based gene panel analysis revealed the gene expression profiles of breast cancer patients with different BMI statuses. Although genes with high mutation frequency and burden were found in different BMI groups, some subtle differences could not be ignored. JAK1 mutations might play a vital role in the progression of breast cancer in underweight patients, and this needs further analysis. Postmenopausal underweight patients with breast cancer have more aggressive characteristics, such as TP53 mutations, more amplifications, and more mutations in genes involved in the WNT signaling pathway. This study provides new evidence for understanding the characteristics of breast cancer patients with different BMIs.

Ovine CD14- an immune response gene has a role against gastrointesinal nematode Haemonchus contortus -a novel report

CD14 (also known as monocyte differentiation antigen) is an important immune response gene known to be primarily responsible for innate immunity against bacterial pathogen and as pattern recognition receptor (PRR) binds with LPS (endotoxin), lipoproteins, lipotechoic acid of bacteria.So far very limited work has been conducted in parasitic immunology. In the current study, we reported the role of CD14 in parasitic immunology in livestock species (sheep) for the first time. Ovine CD14 is characterized as a horse-shoe shaped as a bent solenoid with a hydrophobic amino-terminal pocket for CD14 along with domains. High mutation frequency was observed, out of total 41 mutations identified, 23 mutations were observed to be thermodynamically unstable and 11 mutations were deleterious in nature, causing major functional alteration of important domains of CD14, an indicative for variations in individual susceptibility for sheeps against Haemonchus contortus infestations. In silico studies with molecular docking reveals a role of immune response against Haemonchus contortus in sheep, which is later confirmed with experimental evidence through differential mRNA expression analysis for sheep, which revealed better expression of CD14 in Haemonchus contortus infected sheep compared to that of healthy sheep. We confirmed the above findings with supportive evidences with haematological and biochemical analyses. Phylogenetic analysis was conducted to assess the evolutionary relationship with respect to human and observed that sheep may well be used as model organism due better genetic closeness compared to that of mouse.

Molecular Aspects of COVID-19 Differential Pathogenesis

In the absence of therapeutic interventions, and a possible vaccine candidate, the spread of COVID-19 disease and associated fatalities are on the rise. The high mutation frequency in the genomic material of these viruses supports their ability to adapt to new environments, resulting in an efficient alteration in tissue tropism and host range. Therefore, the coronavirus’ health threats could be relevant for the long-term. The epidemiological data indicate that age, sex, and cardio-metabolic disease have a significant impact on the spread and severity of COVID-19. In this review, we highlight recent updates on the pathogenesis of SARS-CoV-2 among men and women, including children. We also discuss the role of the cellular receptors and coreceptors used by the virus to enter host cells on differential infection among men, women, and cardio-metabolic patients.

SNP rs4538 CYP11B2: g.142913286G> T study in essential hypertension

Обсуждаются результаты анализа последовательности 6 экзона гена CYP11B2 в 40 образцах ДНК пациентов с диагнозом артериальная гипертензия. Выявлена высокая частота мутации в сайте rs4538 (NC_000008.11:g.142913286G>T). Частота носителей аллелей G и Т составила 0,556 и 0,444 соответственно. Уровень содержания альдостерона в сыворотке крови у обследованных в среднем составил 206,1 пг/мл; обнаружена высокая вариация в концентрациях - от 18,18 пг/мл до 933,8 пг/мл. Предварительная оценка ассоциации полиморфизма показала, что при носительстве аллельного варианта Т уровень альдостерона выше (224,0 пг/мл), чем при G (191,7 пг/мл). The paper presents results of processing sequences of 6th exon CYP11B2 taken from 40 DNA samples of patients diagnosed with arterial hypertension. Site rs4538 (NC_000008.11:g.142913286G>T, NM_000498.3:c.1120C>A) revealed a high mutation frequency. The carrier frequencies of allelic variants G and T were 0.556 and 0.444 respectively. The aldosterone content in the blood serum samples averaged 206.1 pg/ml, with high variation in concentrations ranging from 18.18 pg/ml to 933.8 pg/ml. Preliminary evaluation of polymorphism association showed that aldosterone levels were higher for allele T variant (224.0 pg/ml) than for G (191.7 pg/ml).