Abul Bashar Mir Md. Khademul Islam

Neutrophils are protumorigenic and prometastatic in tumor-bearing mice. Comprehensive single-cell RNA sequencing analyses on various tissues of naïve and tumor-bearing MMTV-PyMT (mouse mammary tumor virus-polyoma middle T antigen) mice unraveled a neutrophil reprogramming process and uncovered a strategy to selectively target reprogrammed neutrophils. Transcriptional reprogramming of neutrophils in tumor-bearing mice is initiated in the bone marrow (BM) by granulocyte colony-stimulating factor (G-CSF). Among the seven neutrophil clusters in the BM, the abundance of one cluster is markedly increased whereas another cluster is diminished in tumor-bearing mice. This reprogramming endures across tissue types including blood, tumor microenvironment, and the metastatic niche in the lungs. Thus, in all tissues tested, neutrophils derived from tumor-bearing mice are transcriptionally distinct from those derived from naïve mice. Among the genes that are markedly induced are members of the Ifitm family. We leverage this facet to selectively target reprogrammed neutrophils through treatment with Rapalink-1-an mTOR (mechanistic target of rapamycin) inhibitor-whose intake is greatly enhanced by IFITM proteins. Reprogrammed neutrophils selectively uptake Rapalink-1, which selectively eradicate them in vivo and normalized the neutrophil-to-lymphocyte ratio in tumor-bearing mice without affecting naïve neutrophils. Last, Rapalink-1 inhibited metastasis of a Rapalink-1-resistant tumor. Thus, Rapalink-1 not only could affect the primary tumor but also selectively eliminates tumor-reprogrammed neutrophils to diminish metastasis.

The online version contains supplementary material available at 10.1186/s12859-026-06382-7. The online version contains supplementary material available at 10.1186/s12859-026-06382-7.

Background: Collecting duct renal cell carcinoma (cdRCC) is a rare and aggressive renal cancer subtype. The molecular mechanisms underlying cdRCC remain poorly understood, which presents a significant challenge for the development of effective treatment strategies. Advances in genome sequencing, particularly the discovery of new genomic regions in the T2T‐CHM13 reference genome, have provided an opportunity to expand our understanding of this disease. Aims: Our study specifically aims to investigate the role of miRNAs encoded by these regions, proposing them as potential epigenetic regulators in the pathogenesis of cdRCC. Methods: We used bioinformatic pipelines and small RNA‐seq data analysis to predict novel miRNAs from the newly discovered genomic regions of T2T‐CHM13. RNA‐seq analysis of cdRCC tumors was performed to identify differentially expressed genes, and target prediction tools were used to find miRNA‐mRNA interactions. Functional enrichment analyses were conducted to characterize the biological pathways affected. Results and Discussion: Using computational approaches, we predicted 156 novel miRNAs from T2T‐CHM13's newly resolved sequences. RNA‐seq and miRNA‐mRNA interaction analyses identified 345 downregulated genes targeted by novel miRNAs and 395 downregulated genes targeted by known miRNAs. A comprehensive functional enrichment analysis of these perturbed genes revealed distinctive pathways, including cGMP‐PKG signaling, calcium signaling, adipocytokine signaling, PPAR signaling, and apelin signaling, all of which are implicated in tumorigenesis. Furthermore, Gene Ontology analysis linked miRNA‐targeted genes to disrupted cell–cell junctions and adhesion, providing a mechanistic explanation for aggressive invasion and metastasis in cdRCC. Additionally, a significant number of the target genes involved in metabolic and ion transport pathways were perturbed, explaining metabolic alterations in the cancer cells. We also identified 15 tumor suppressor genes downregulated by novel miRNAs, 6 of which were uniquely targeted, highlighting the potential of these miRNAs as cdRCC‐specific biomarkers. Conclusion: In conclusion, our study offers valuable insights into cdRCC biology from an epigenetic perspective, laying the groundwork for future research aimed at developing targeted therapies.

Lipid metabolism and the serine, one-carbon, glycine (SOG) and methionine pathways are independently and significantly correlated with estrogen receptor–negative breast cancer (ERneg BC). Here, we propose a link between lipid metabolism and ERneg BC through phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the de novo serine pathway. We demonstrate that the metabolism of the paradigmatic medium-chain fatty acid octanoic acid leads to a metabolic shift toward the SOG and methionine pathways. PHGDH plays a role in both the forward direction, contributing to the production of S-adenosylmethionine, and the reverse direction, generating the oncometabolite 2-hydroxyglutarate, leading to epigenomic reprogramming and phenotypic plasticity. The methionine cycle is closely linked to the transsulfuration pathway. Consequently, we observe that the shift increases the antioxidant glutathione, which mitigates reactive oxygen species (ROS), enabling survival of a subset of cells that have undergone DNA damage. These metabolic changes contribute to several hallmarks of cancer.

Adverse childhood experiences (ACEs) are potentially traumatic events that occur before 18 years of age. Studies emphasize the importance of childhood adversity as a risk factor for developing non-communicable diseases, including type-2 diabetes mellitus (T2DM) in adulthood. This case-control study involved 137 patients with T2DM and 134 non-diabetic adults of both genders (mean age 46.9 and 45.7 years, respectively). In addition to collecting socio-demographic, behavioral, and anthropological data, a 10-item ACE scale was utilized to gather information regarding childhood adversities, while perceived stress was assessed using the perceived stress scale-4. Fasting and 2-hour post glucose load blood sugar levels, HbA1c, and fasting lipid profiles were measured. Both univariable and multivariable binary logistic regression analyses were performed to investigate whether ACE is a potential risk factor for T2DM, with a significance level of 0.05. Around two-thirds of T2DM patients reported having ACE scores of 4 or higher, with the mean ACE score significantly higher in the case group than in the control group (3.96 vs. 3.34; p<0.0001). The logistic regression analysis found that T2DM was linked to female gender, hypertension, dyslipidemia, family history of DM, higher perceived stress, and a higher ACE score of 4 and above. After adjusting for confounding factors, individuals with an ACE score of 4 or higher had a significantly greater risk of developing T2DM (OR: 2.24; 95% CI 1.238–4.061). The study revealed a significant association between higher ACE scores and an increased risk of developing T2DM. As a recommendation, further investigation into the epigenetic mechanisms underlying this relationship is warranted.

TPO (Thyroid Peroxidase) is known to be one of the major genes involved in congenital hypothyroid patients with thyroid dyshormonogenesis. The present study aims to validate high-resolution melting (HRM) curve analysis as a substitute method for Sanger sequencing, focusing on the frequently observed non-synonymous mutations c.1117G>T, c.1193G>C, and c.2173A>C in the TPO gene in patients from Bangladesh. We enrolled 36 confirmed cases of congenital hypothyroid patients with dyshormonogenesis to establish the HRM method. Blood specimens were collected, and DNA was extracted followed by PCR and Sanger sequencing. Among the 36 specimens, 20 were pre-sequenced, and variants were characterized through Sanger sequencing. Following pre-sequencing, the 20 pre-sequenced specimens underwent real-time PCR-HRM curve analysis to determine the proper HRM condition for separating the three variations from the wild-type state into heterozygous and homozygous states. Furthermore, 16 unknown specimens were subjected to HRM analysis to validate the method. This method demonstrated a sensitivity and specificity of 100 percent in accurately discerning wild-type alleles from both homozygous and heterozygous states of c.1117G>T (23/36; 63.8%), c.1193G>C (30/36; 83.3%), and c.2173A>C (23/36; 63.8%) variants frequently encountered among 36 Bangladeshi patients. The HRM data was found to be similar to the sequencing result, thus confirming the validity of the HRM approach for TPO gene variant detection. In conclusion, HRM-based molecular technique targeting variants c.1117G>T, c.1193G>C, and c.2173A>C could be used as a high throughput, rapid, reliable, and cost-effective screening approach for the detection of all common mutations in TPO gene in Bangladeshi patients with dyshormonogenesis.

Background Sporadic amyotrophic lateral sclerosis (sALS) is a severe neurodegenerative disease characterized by continuous diminution of motor neurons in the brain and spinal cord. Earlier studies indicated that the DPP6 gene variant has a role in the development of sALS. This meta-analysis was designed to uncover the role of rs10260404 polymorphism of the DPP6 gene and its association with sALS. Methods All case–control articles published prior to October 2022 on the association between DPP6 (rs10260404) polymorphism and sALS risk were systematically extracted from different databases which include PubMed, PubMed Central, and Google Scholar. Overall odds ratios (ORs) and “95% confidence intervals (CIs)” were summarized for various genetic models. Subgroup and heterogeneity assessments were performed. Egger’s and “Begg’s tests were applied to evaluate publication bias. Trial sequential analysis (TSA) and false-positive report probability (FPRP) were performed. Results Nine case–control studies containing 4202 sALS cases and 4444 healthy controls were included in the meta-analysis. A significant association of the DPP6 (rs10260404) variant with an increased sALS risk in overall pooled subjects under allelic model [C allele vs. T allele, OR = 1.149, 95% CI (1.010–1.307), p-value = 0.035], dominant model [CC + CT vs. TT, OR = 1.165, 95% CI (1.067–1.273), p-value = 0.001], and homozygote comparison [CC vs. TT, OR = 1.421, 95% CI (1.003–2.011), p-value = 0.048] were observed. Moreover, in subgroup analysis by nationality, remarkable associations were detected in Dutch, Irish, American, and Swedish under allelic, dominant, and homozygote models. Additionally, stratification analysis by ethnicity exhibited an association with sALS risk among Caucasians and Americans under different genetic models. Interestingly, none of the models found any significant association with Asians. Conclusion The present meta-analysis indicates that DPP6 (rs10260404) polymorphism could be a candidate risk factor for sALS predisposition.

Thyroid Peroxidase ( TPO ) is known to be the major gene involved in Congenital hypothyroid patients with thyroid dyshormonogenesis. This present study aimed to establish high-resolution melting (HRM) curve analysis as a supplementary mutation detection approach of Sanger sequencing targeting commonly found mutations c.1117G>T, c.1193G>C, and c.2173A>C in the TPO gene in Bangladeshi patients. We enrolled 36 confirmed cases of congenital hypothyroid patients with dyshormonogenesis to establish the HRM method. Blood samples were collected, and genomic DNA was isolated for molecular techniques. Among the 36 specimens, 20 were pre-sequenced, and mutations were characterized through Sanger sequencing. The pre-sequenced specimens (n=20) were then subjected to real-time PCR-HRM curve analysis to get the appropriate HRM condition capable of differentiating heterozygous and homozygous states for the three mutations from the wild-type state. Furthermore, 16 unknown specimens were subjected to HRM analysis to validate the method. This method showed 100 percent sensitivity and specificity to distinguish wild-type alleles from homozygous or heterozygous states (c.1117G>T, c.1193G>C, and c.2173A>C) of alleles commonly found in Bangladeshi patients. The HRM data was found to be similar to the sequencing result, thus confirming the validity of the HRM approach for TPO gene mutation. In conclusion, the established HRM-based molecular technique targeting c.1117G>T, c.1193G>C, and c.2173A>C mutations could be used as a high throughput, rapid, reliable, and cost-effective screening approach for the detection of all common mutations in TPO gene in Bangladeshi patients with dyshormonogenesis.