Subtype Pattern Research Articles

Spatiotemporal dynamics of the developing zebrafish enteric nervous system at the whole-organ level.

Neural crest cells give rise to the neurons of the enteric nervous system (ENS) that innervate the gastrointestinal (GI) tract to regulate gut motility. The immense size and distinct subregions of the gut present a challenge to understanding the spatial organization and sequential differentiation of different neuronal subtypes. Here, we profile enteric neurons (ENs) and progenitors at single-cell resolution during zebrafish embryonic and larval development to provide a near-complete picture of transcriptional changes that accompany the emergence of ENS neurons throughout the GI tract. Multiplex spatial RNA transcript analysis identifies the temporal order and distinct localization patterns of neuronal subtypes along the length of the gut. Finally, we show that functional perturbation of select transcription factors Ebf1a, Gata3, and Satb2 alters the cell fate choice, respectively, of inhibitory, excitatory, and serotonergic neuronal subtypes in the developing ENS.

Neuronal plasticity changes in the central amygdala and prelimbic cortex network in mice with chronic unpredictable mild stress-induced depression

To explore the relationship between alterations of neural network plasticity and spatial learning and memory functions in mouse models with depression-like behaviors. C57Thy1-YFP/GAD67-GFP mice were randomized into control group (with no treatment) and chronic unpredictable mild stress (CUMS) group (n=15) subjected to CUMS for 8 weeks. Depression-like behaviors of the mice were assessed using sucrose preference test, open field test, and forced swimming test, and their spatial learning and memory abilities were evaluated using Morris water maze test. The changes in the firing patterns of different neuronal subtypes were detected in the central nucleus of the amygdala (CeA) and the prelimbic cortex (PrL) using whole-cell patch-clamp technique. Compared with the control mice, CUMS mice showed significantly decreased sucrose preference, total distance moved, number of grid-crossings, entries into the central area, and time spent in the central area in the open field test (P < 0.01). In the forced swimming test, CUMS mice exhibited obviously shortened time of struggling, swimming, and climbing with increased immobility time. In Morris water maze test, CUMS mice showed significantly increased escape latency and path length, decreased percentage of distance and swimming time within the target quadrant, and increased first entry latency into the target zone and swimming time within the opposite quadrant. Exposure to CUMS resulted in significantly enhanced energy barrier and increased absolute refractory period and inter-spike interval of glutamatergic neurons in the CeA and GABAergic neurons in the PrL, while the opposite changes were observed in GABAergic neurons in the CeA and glutamatergic neurons in the PrL. CUMS-induced depression may lead to plastic changes in the excitatory and inhibitory neuronal networks within the CeA and PrL to cause impairment of spatial learning and memory abilities in mice.

Proinflammatory Dietary Pattern and Risk of Total and Subtypes of Breast Cancer Among U.S. Women.

Dietary patterns promoting chronic inflammation, including the empirical dietary inflammatory pattern (EDIP), have been associated with certain cancers. Investigating whether this dietary pattern is associated with breast cancer-where the role of inflammation is less well-defined-could provide valuable insights and potentially improve strategies for preventing this cancer. We prospectively followed 76,386 women from Nurses' Health Study (NHS, 1984-2018) and 92,886 women from Nurses' Health Study II (NHSII, 1991-2019). Diet was assessed by food frequency questionnaires (FFQs) every 4 years, starting at baseline. The inflammatory potential of diet was evaluated using the validated EDIP based on plasma CRP, IL-6, and TNFα-R2. Higher scores indicate higher dietary inflammatory potential. Hazard ratios and 95%CIs of overall and subtypes of breast cancer were estimated using multivariable-adjusted Cox regression models. During 4,490,842 person-years of follow-up, we documented 11,026 breast cancer cases. Women in the highest, compared with the lowest, EDIP quintile were at higher breast cancer risk (HRQ5vs.Q1=1.12; 95% CI, 1.05, 1.19; P-trend<0.001). The association was stronger for ER-negative tumors (HRQ5vs.Q1=1.29; 95% CI, 1.09, 1.53; P-trend=0.003). Also, we observed that the association of EDIP with breast cancer risk differed by molecular subtype, with the strongest association observed with basal-like tumors (HRQ5vs.Q1=1.80; 95% CI, 1.20, 2.71; P-trend=0.004). Higher EDIP scores were associated with a modestly increased risk of breast cancer, which was more pronounced for ER-negative and basal-like breast tumors. These results support the hypothesis that diet-related inflammation plays a role in breast cancer etiology, particularly tumors lacking hormone receptors.

Global patterns of leukemia by subtype, age, and sex in 185 countries in 2022.

In 2022, leukemia ranked as the second most common hematological malignancy after non-Hodgkin lymphoma worldwide. However, updated global estimates of leukemia incidence by subtype are unavailable. We estimated leukemia incidences for different leukemia subtypes by country, world region, and human developmental index using data from the Cancer Incidence in Five Continents databases combined with the GLOBOCAN 2022 estimates of leukemia in 185 countries. We estimated sex-specific age-standardized rates (ASRs) per 100 000 for children (0-19 years) and adults (20+ years). In adults, the most common leukemia worldwide was AML (males:38%, ASR = 3·1; females:43%, ASR = 2·4), followed by CLL (males:28%, ASR = 2·2; females:24%, ASR = 1·3). In very high HDI countries, the ASR of CLL was higher than the ASR of AML among males (5·2 versus 4·3, respectively) and similar among females (2·9 and 3·0, respectively). In children, the most common leukemia was ALL (boys:70%, ASR = 2·4; girls:68%, ASR = 1·8) followed by AML (boys:22%, ASR = 0·76; girls:25%, ASR = 0·65). ALL proportions varied across world sub-regions from 57to78% among boys, and from 49 to 80% among girls. Our findings suggest clear geographical patterns of leukemia subtypes in adults and children. Further research into underlying causes that explain these variations is needed to support cancer control strategies for prevention and plan national healthcare needs.

Generative adversarial networks accurately reconstruct pan-cancer histology from pathologic, genomic, and radiographic latent features.

Artificial intelligence models have been increasingly used in the analysis of tumor histology to perform tasks ranging from routine classification to identification of molecular features. These approaches distill cancer histologic images into high-level features, which are used in predictions, but understanding the biologic meaning of such features remains challenging. We present and validate a custom generative adversarial network-HistoXGAN-capable of reconstructing representative histology using feature vectors produced by common feature extractors. We evaluate HistoXGAN across 29 cancer subtypes and demonstrate that reconstructed images retain information regarding tumor grade, histologic subtype, and gene expression patterns. We leverage HistoXGAN to illustrate the underlying histologic features for deep learning models for actionable mutations, identify model reliance on histologic batch effect in predictions, and demonstrate accurate reconstruction of tumor histology from radiographic imaging for a "virtual biopsy."

FOSL1 is a key regulator of a super-enhancer driving TCOF1 expression in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with an unmet clinical need, but its epigenetic regulation remains largely undefined. By performing multiomic profiling, we recently revealed distinct super-enhancer (SE) patterns in different subtypes of breast cancer and identified a number of TNBC-specific SEs that drive oncogene expression. One of these SEs, TCOF1 SE, was discovered to play an important oncogenic role in TNBC. However, the molecular mechanisms by which TCOF1 SE promotes the expression of the TCOF1 gene remain to be elucidated. Here, by using combinatorial approaches of DNA pull-down assay, bioinformatics analysis and functional studies, we identified FOSL1 as a key transcription factor that binds to TCOF1 SE and drives its overexpression. shRNA-mediated depletion of FOSL1 results in significant downregulation of TCOF1 mRNA and protein levels. Using a dual-luciferase reporter assay and ChIP-qPCR, we showed that binding of FOSL1 to TCOF1 SE promotes the transcription of TCOF1 in TNBC cells. Importantly, our data demonstrated that overexpression of FOSL1 drives the activation of TCOF1 SE. Lastly, depletion of FOSL1 inhibits tumor spheroid growth and stemness properties of TNBC cells. Taken together, these findings uncover the key epigenetic role of FOSL1 and highlight the potential of targeting the FOSL1-TCOF1 axis for TNBC treatment.

Cancer-associated fibroblast subtypes modulate the tumor-immune microenvironment and are associated with skin cancer malignancy

Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. This study dissects the intra-tumoral diversity of CAFs in basal cell carcinoma, squamous cell carcinoma, and melanoma using molecular and spatial single-cell analysis. We identify three distinct CAF subtypes: myofibroblast-like RGS5+ CAFs, matrix CAFs (mCAFs), and immunomodulatory CAFs (iCAFs). Large-cohort tissue analysis reveals significant shifts in CAF subtype patterns with increasing malignancy. Two CAF subtypes exhibit immunomodulatory properties via different mechanisms. mCAFs sythesize extracellular matrix and may restrict T cell invasion in low-grade tumors via ensheathing tumor nests, while iCAFs are enriched in late-stage tumors, and express high levels of cytokines and chemokines to aid immune cell recruitment and activation. This is supported by the induction of an iCAF-like phenotype with immunomodulatory functions in primary healthy fibroblasts exposed to skin cancer cell secretomes. Thus, targeting CAF variants holds promise to enhance immunotherapy efficacy in skin cancers.

Effect of NPM1 mutation Subtype and Co-Mutation Patterns on the Outcomes of Patients with Acute Myeloid Leukemia; A Referral Center Experience

Effect of <i>NPM1</i> mutation Subtype and Co-Mutation Patterns on the Outcomes of Patients with Acute Myeloid Leukemia; A Referral Center Experience

MFAP3L predicts tumor microenvironment status, molecular subtypes and clinical benefit in patients with bladder cancer

Bladder cancer (BLCA), ranking as the tenth most prevalent malignancy globally, imposes a substantial public health and socio-economic challenge. Despite ongoing efforts by urologists to identify novel molecular subtypes and treatment paradigms, the intrinsic heterogeneity of BLCA continues to obstruct the efficacy of current diagnostic and therapeutic evaluations, leaving a gap in the comprehensive management of BLCA. This necessitates an in-depth investigation into the BLCA tumor microenvironment (TME) to identify pivotal molecules like MFAP3L. Our research concentrated on MFAP3L, commencing with a pan-cancer analysis of its immune profile. We discovered that MFAP3L exhibits a significant negative correlation with numerous immune components and markers in BLCA, a trend not observed in other cancer types. Within the TCGA-BLCA cohort, patients were classified into High-MFAP3L and Low-MFAP3L groups according to their MFAP3L transcript levels. Our exploration into the BLCA TME delved into immune infiltration, molecular subtype patterns, and treatment preferences within these MFAP3L groups. High MFAP3L expression was linked to favorable prognoses, luminal subtypes, and low immune infiltration, inversely associated with various immune molecules and characteristics. Additionally, high MFAP3L expressors exhibited diminished immune checkpoint levels, suggesting enhanced immunotherapy tolerance and sensitivity to oncogenic pathway targeting. Conversely, low MFAP3L expression correlated with poor outcomes, basal subtypes, increased immune infiltration, and heightened gene mutation rates, alongside sensitivity to radiotherapy, EGFR-targeted treatments, and immunotherapy. Hence, MFAP3L emerges as a critical yet underexplored gene in BLCA, offering insights into immune status within the TME and aiding in molecular subtyping and therapeutic decision-making.

Glial 'omics in ischemia: Acute stroke and chronic cerebral small vessel disease.

Vascular injury and pathologies underlie common diseases including ischemic stroke and cerebral small vessel disease (CSVD). Prior work has identified a key role for glial cells, including microglia, in the multifaceted and temporally evolving neuroimmune response to both stroke and CSVD. Transcriptional profiling has led to important advances including identification of distinct gene expression signatures in ischemia-exposed, flow cytometrically sorted microglia and more recently single cell RNA sequencing-identified microglial subpopulations or clusters. There is a reassuring degree of overlap in the results from these two distinct methodologies with both identifying a proliferative and a separate type I interferon responsive microglial element. Similar patterns were later seen using multimodal and spatial transcriptomal profiling in ischemia-exposed microglia and astrocytes. Methodological advances including enrichment of specific neuroanatomic/functional regions (such as the neurovascular unit) prior to single cell RNA sequencing has led to identification of novel cellular subtypes and generation of new credible hypotheses as to cellular function based on the enhanced cell sub-type specific gene expression patterns. A ribosomal tagging strategy focusing on the cellular translatome analyses carried out in the acute phases post stroke has revealed distinct inflammation-regulating roles for microglia and astrocytes in this setting. Early spatial transcriptomics experiments using cerebral ischemia models have identified regionally distinct microglial cell clusters in ischemic core versus penumbra. There is great potential for combination of these methods for multi-omics approaches to further elucidate glial responses in the context of both acute ischemic stroke and chronic CSVD.

Cats and dogs as hosts of Blastocystis – What is the evidence?

Blastocystis is one of the most common intestinal parasites observed in human and non-human hosts. Recent meta-analyses have indicated a potential role for pets such as dogs and cats as reservoir hosts of Blastocystis, but the data underpinning this hypothesis are of mixed quality. Reviewing data for 45,894 samples tested for Blastocystis by DNA-based methods and 11,908 subtype observations, a model was developed for calculating indices that could be used for evaluating individual species as natural hosts of Blastocystis, based on weighted products of positivity rates and subtype distributions. Data from cats and dogs were analysed, using other well-sampled hosts (pig, cattle, sheep, goat, and human) as references. Data from cats and dogs meeting the inclusion criteria were entered into the model. The overall positivity rates for pigs, cattle, sheep, goats, humans, dogs, and cats were 40 %, 40 %, 35 %, 28 %, 25 %, 6 %, and 5 %, respectively, with statistically significant lower positivity rates in cats and dogs (p < 0.0001). Indices indicating Blastocystis specificity to host ranged between 0.16 (humans) and 0.49 (cattle) for the reference hosts, whereas indices for cats and dogs were only 0.01 and 0.02, respectively. Finally, indices for ST specificity to host were higher for reference hosts (range, 0.66–0.93) than for cats (0.62) and dogs (0.56). Taken together, the analyses indicate that cats and dogs are not natural or reservoir hosts of Blastocystis and that the sporadic subtype pattern observed in these hosts might indicate exposure to Blastocystis through contaminated water/feed, including Blastocystis colonizing prey animals.

Cryptosporidium species and subtypes in Norway: Predominance of C. parvum and emergence of C. mortiferum

PCR-based diagnostics has revealed the previously largely unknown Cryptosporidium transmission and infections in high-income countries. This study aimed to determine domestic and imported subtypes of Cryptosporidium species in Norway, evaluate their demographic distribution, and identify potential small outbreaks. Cryptosporidium-positive human faecal samples were obtained from six medical microbiology laboratories between February 2022 and January 2024, together with 22 Cryptosporidium-positive animal samples. Species and subtypes were identified by sequencing PCR products from gp60 and SSU rRNA genes. Most cryptosporidiosis cases occurred during late summer/early autumn, primarily in children and young adults. Of 550 human samples, 359 were successfully characterized molecularly (65%), revealing infection with 10 different Cryptosporidium species. C. parvum occurred in 245 (68%) human isolates with IIa and IId being major allele families, with distinct regional distribution patterns of common subtypes. A kindergarten outbreak with 5 cases was due to C. parvum IIaA14G1R1. C. mortiferum was identified in 33 (9.2%) human cases of which 24 were known to be of domestic origin, making it the second most common species in human autochthonous cases in Norway. All C. mortiferum isolates were of the same genotype; XIVaA20G2T1, including 13 cases from a suspected small outbreak in Trøndelag. C. hominis occurred in 68 typed cases (19%), but mostly in infections acquired abroad, with allele families Ib and If occurring most often. In conclusion, this study of recent Cryptosporidium spp. and subtypes in Norway, highlights the predominance of C. parvum and the emergence of C. mortiferum among autochthonous cases.

The longitudinal patterns of depression subtypes and stressors in depression severity in the Canadian longitudinal study on aging (CLSA).

The current study aims to characterize the longitudinal patterns of depression subtypes and investigate the associations among the stability of depression subtypes, COVID-19-related stressors, and depression severity. The study utilized data from the Canadian Longitudinal Study on Aging, which is a national, long-term study of Canadian adults aged 45 and older (n = 12,957). Latent profile analysis was used to identify latent depression subtypes. Latent transition analysis was then applied to assess the stability of these subtypes over time. Hierarchical multivariate linear regression was used to explore the relationships among these identified depression subtypes, COVID-19-related stressors, and depression severity among males and females, respectively. Distinct depression subtypes were identified. Except for atypical depression, other depression subtypes showed greater stability over time. We also found that melancholic depression (B = 9.432) and typical depression (B = 6.677) were strongly associated with depression severity during the pandemic. Health-related stressors (B = 0.840), conflict (B = 3.639), difficulties accessing resources (B = 0.927), separation from family (B = 0.840), and caregiving experience (B = 0.764), were significantly associated with increased depression severity. Sex-specific analyses also revealed differences in the associations between stressors and depression severity between males and females. This study contributes valuable insights into the latent clustering of depression subtypes and their stability. Stressors were associated with increased depression severity, with distinct associations observed among males and females. These findings have implications for targeted early interventions and integrated clinical management strategies by providing the evidence base for tailored mental health care during and after the pandemic.

Re: Metastasis and Recurrence Patterns in the Molecular Subtypes of Urothelial Bladder Cancer

Re: Metastasis and Recurrence Patterns in the Molecular Subtypes of Urothelial Bladder Cancer

MRI subtypes in Parkinson’s disease across diverse populations and clustering approaches

Parkinson’s disease (PD) is clinically heterogeneous, which suggests the existence of subtypes; however, there has been no consensus regarding their characteristics. This study included 633 PD individuals across distinct cohorts: unmedicated de novo PD, medicated PD, mild-moderate PD, and a cohort based on diagnostic work-up in clinical practice. Additionally, 233 controls were included. Clustering based on cortical and subcortical gray matter measures was conducted with and without adjusting for global atrophy in the entire PD sample and validated within each cohort. Subtypes were characterized using baseline and longitudinal demographic and clinical data. Unadjusted results identified three clusters showing a gradient of neurodegeneration and symptom severity across the entire sample and the individual cohorts. When adjusting for global atrophy eight clusters were identified in the entire sample, lacking consistency in individual cohorts. This study identified atrophy-based subtypes in PD, emphasizing the significant impact of global atrophy on subtype number, patterns, and interpretation in cross-sectional analyses.

Frequency-specific static and dynamic neural activity indices in children with different attention deficit hyperactivity disorder subtypes: a resting-state fMRI study.

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in childhood. Numerous resting-state functional magnetic resonance imaging (rs-fMRI) studies in ADHD have been performed using traditional low-frequency bands (0.01-0.08 Hz). However, the neural activity patterns of frequency subbands in ADHD still require further investigation. The purpose of this study is to explore the frequency-dependent characteristics and neural activity patterns of ADHD subtypes. We selected the ADHD combined type (ADHD-C, N = 25), ADHD inattentive type (ADHD-I, N = 26) and typically developing (TD, N = 28) children from the ADHD-200 Consortium. Based on the slow-5 band (0.01-0.027 Hz) and slow-4 band (0.027-0.073 Hz), we generated static and dynamic fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo) maps for each participant. A flexible-factorial analysis of variance model was performed on static and temporal dynamic rs-fMRI measurements within two subbands. Results revealed that the orbital-frontal gyrus, precuneus, superior temporal gyrus and angular gyrus were found to have obvious frequency band and group interaction effects. The intrinsic neural activity differences among three groups were more prominent in the slow-5 frequency band compared to the slow-4 band. In addition, the indices of significant interaction regions showed correlations with the progression of the disease and the features in slow-5 showed an advantageous diagnostic performance compared with those in slow-4. The results suggested the intrinsic neural activities of ADHD subtypes were frequency-dependent. The frequency-specific analysis of static and dynamic brain activity may provide a deeper understanding of neurophysiological dysfunction patterns in ADHD subtypes and provide supplementary information for assessing ADHD subtypes.

Longitudinal Use Patterns of Technology Subtypes During the Transition Into Early Adolescence: Results From the Adolescent Brain Cognitive Development Study

PurposeAdolescents encounter a complex digital environment, yet existing data on youth technology use rarely differentiates technology subtypes. This study maps the evolution and intricacies of youth engagement with technology subtypes. MethodsN = 11,868 participants in the Adolescent Brain Cognitive Development study followed from ages ∼9/10 to ∼13/14. We examined youths' self-reported hours per day (hr/day) of technology subtypes: TV/Movies, video games, YouTube, social media, video chat, and texting. We used descriptive statistics and multilevel logistic regression to assess cross-sectional and longitudinal use patterns of technology subtypes, agreement between child and parent reports on the child's technology use, and associations between each technology subtype and sociodemographics (child's biological sex, parent education, income, and marital status). ResultsAt age 9/10, ∼75% of youth reported minimal (<30 min/day) social technology use (social media, video chat, texting) and up to ∼1.5 hr/day of TV, video games, and YouTube. By age 13/14, TV trajectories were converging to >2 hr/day, but social technology trajectories “fanned out” into a wide range of usage rates. Child and parent reports were weakly correlated (rs range: 0.13–0.29). Using child-reported hours of technology use, increases in the subject-specific odds of using a technology >2 hr/day ranged from 25% (YouTube; 95% CI: 1.16–1.35) to 234% (social media; 95% CI: 3.14–3.55). Compared with males, females had ∼100–200% greater odds of >2 hr/day of social technologies, but ∼40–80% reduced odds of >2 hr/day of video games and YouTube. Higher parent education and income predicted significantly lower odds of >2 hr/day of use – regardless of technology subtype. DiscussionDistributions of youths' self-reported technology engagement are highly contingent on technology subtype, age, and biological sex. Future research on youth development and technology may benefit from considering youths' varied digital experiences.

Quercetin and taxifolin inhibits TMPRSS2 activity and its interaction with EGFR in paclitaxel-resistant breast cancer cells: An in silico and invitro study.

Transmembrane protease/serine (TMPRSS2), a type II transmembrane serine protease, plays a crucial role in different stages of cancer. Recent studies have reported that the triggering epidermal growth factor receptor (EGFR) activation through protease action promotes metastasis. However, there are no reports on the interaction of TMPRSS2 with EGFR, especially in triple-negative triple negative (TNBC). The current study investigates the unexplored interaction between TMPRSS2 and EGFR, which are key partners mediating metastasis. This interaction is explored for potential targeting using quercetin (QUE) and taxifolin (TAX). TMPRSS2 expression patterns in breast cancer (BC) tissues and subtypes have been predicted, with the prognostic significance assessed using the GENT2.0 database. Validation of TMPRSS2 expression was performed in normal and TNBC tissues, including drug-resistant cell lines, utilizing GEO datasets. TMPRSS2 was further validated as a predictive biomarker for FDA-approved chemotherapeutics through transcriptomic data from BC patients. The study demonstrated the association of TMPRSS2 with EGFR through in silico analysis and validates the findings in TNBC cohorts using the TIMER2.0 web server and the TCGA dataset through C-Bioportal. Molecular docking and molecular dynamic simulation studies identified QUE and TAX as best leads targeting TMPRSS2. They inhibited cell-free TMPRSS2 activity like clinical inhibitor of TMPRSS2, Camostat mesylate. In cell-based assays focused on paclitaxel-resistant TNBC (TNBC/PR), QUE and TAX demonstrated potent inhibitory activity against extracellular and membrane-bound TMPRSS2, with low IC50 values. Furthermore, ELISA and cell-based AlphaLISA assays demonstrated that QUE and TAX inhibit the interaction of TMPRSS2 with EGFR. Additionally, QUE and TAX exhibited significant inhibition of proliferation and cell cycle accompanied by notable alterations in the morphology of TNBC/PR cells. This study provides valuable insights into potential of QUE and TAX targeting TMPRSS2 overexpressing TNBC.

Microclimatic Zonation and Climatic Variability of Sikkim Himalaya

The Köppen classification of climate integrates precipitation and temperature information with natural vegetation patterns to create a precise representation of any particular region's climate. This integration depends on the empirical relationship of climate and vegetation, which indicates that distinct locations in the same class have similar vegetation attributes. Köppen climatic classification factors are explained and Sikkim's climate characteristics are regionalized based on it. The method for making representations of air temperatures and precipitation has been described, and an illustration of Sikkim's climatic zones with variability is generated as a result of these changes. The geographic pattern of climatic types and subtypes in Sikkim has been briefly addressed using an available high-resolution gridded dataset (ERA5-Land). This is described that the constraints of microclimatic zonation emanate from the empirical prerequisite of climate classifications, as well as the nature of data selection and the methodologies employed for climate variability analysis and classification. Based on the Köppen classification for the long term (1980–2021), the Sikkim Himalaya contains three primary climatic classes, particularly ETc (cold, tundra, and cool summer), Cfc (moderately warm, humid, and cool summer), and Cfb (moderately warm, humid, and warm summer). Climate variability on the basis of temperature and precipitation change with respect to 1980–2021 over the entire Sikkim Himalaya concludes that the climatic pattern of the Sikkim has been changed from cold-dry to warm-wet. The alteration in the corresponding climatic pattern is further supported by changes in LULC and NDVI. The results suggest that the precipitation change in the past two decades (1980–2000) is negative, while a significant positive change has been noticed in the recent two decades (2001–2021). Subsequently, the number of extremely wet days decreases in the entire ETc and Cfc climate zones. Regardless, the southern part of the Cfb climatic zone has experienced an increase in extremely wet days. This study's findings will significantly contribute to the development of future policies and initiatives by providing insights crucial for achieving sustainable development, environmental protection, and climate change adaptation.

Long noncoding RNA profiling unveils LINC00960 as unfavorable prognostic biomarker promoting triple negative breast cancer progression

Long noncoding RNAs (lncRNAs) play a critical role in breast cancer pathogenesis, including Triple-Negative Breast Cancer (TNBC) subtype. Identifying the lncRNA expression patterns across different breast cancer subtypes could provide valuable insights into their potential utilization as disease biomarkers and therapeutic targets. In this study, we profiled lncRNA expression in 96 breast cancer cases, revealing significant differences compared to normal breast tissue. Variations across breast cancer subtypes, including Hormone Receptor-positive (HR + ), HER2-positive (HER2 + ), HER2 + HR + , and TNBC, as well as in relation to tumor grade and patients’ age at diagnosis were observed. TNBC and HER2+ subtypes showed distinct clustering, while HER2 + HR+ tumors clustered closer to HR+ tumors based on their lncRNA profiles. Our data identified numerous enriched lncRNAs in TNBC, notably the elevated expression of LINC00960, which was subsequently validated in two additional datasets. Analysis of LINC00960 expression in an independent TNBC cohort (n = 360) revealed elevated expression of LINC00960 to correlate with cell movement, invasion, proliferation, and migration functional categories. Depletion of LINC00960 significantly reduced TNBC cell viability, colony formation, migration, and three-dimensional growth, while increasing cell death. Mechanistically, transcriptomic profiling of LINC00960-depleted cells confirmed its tumor-promoting role, likely through sponging of hsa-miR-34a-5p, hsa-miR-16-5p, and hsa-miR-183-5p, leading to the upregulation of cancer-promoting genes including BMI1, KRAS, and AKT3. Our findings highlight the distinct lncRNA expression patterns in breast cancer subtypes and underscore the crucial role for LINC00960 in promoting TNBC pathogenesis, suggesting its potential utilization as a prognostic marker and therapeutic target.