Specific Subtypes Research Articles

Size-Dependent Separation of Extracellular Vesicle Subtypes with Exodisc Enabling Proteomic Analysis in Prostate Cancer.

Extracellular vesicles (EVs) are emerging as crucial biomarkers in cancer diagnostics and therapeutics with their heterogeneity presenting both challenges and opportunities in prostate cancer research. However, existing methods for isolating and characterizing EV subtypes have been limited by inefficient separation and inadequate proteomic analysis. Here we show an optimized centrifugal microfluidic device, Exodisc, that efficiently isolates large quantities of EV subtypes from particle-enriched medium, enabling comprehensive proteomic analysis of small (EV-S, 20-200 nm) and large (EV-L, >200 nm) EVs. Using this device, we successfully separated EV-S and EV-L from prostate cancer cell lines LNCaP and PC3. Mass spectrometry-based proteomics revealed that EV proteins reflect parental cell characteristics more than EV size, with EV-L demonstrating increased expression of PSMA-correlated proteins. Our optimized protocol addresses challenges in EV isolation and characterization, providing a more effective method for studying cellular and molecular mechanisms of specific EV subtypes. This study extends the potential use of EVs as a liquid biopsy for cancer theranostics, paving the way for more precise isolation of EV subtypes and potentially leading to improved biomarker discovery and the development of personalized treatments.

An Integrated Approach Utilizing Single-Cell and Bulk RNA-Sequencing for the Identification of a Mitophagy-Associated Genes Signature: Implications for Prognostication and Therapeutic Stratification in Prostate Cancer

Introduction: Prostate cancer, notably prostate adenocarcinoma (PARD), has high incidence and mortality rates. Although typically resistant to immunotherapy, recent studies have found immune targets for prostate cancer. Stratifying patients by molecular subtypes may identify those who could benefit from immunotherapy. Methods: We used single-cell and bulk RNA sequencing data from GEO and TCGA databases. We characterized the tumor microenvironment at the single-cell level, analyzing cell interactions and identifying fibroblasts linked to mitophagy. Target genes were narrowed down at the bulk transcriptome level to construct a PARD prognosis prediction nomogram. Unsupervised consensus clustering classified PARD into subtypes, analyzing differences in clinical features, immune infiltration, and immunotherapy. Furthermore, the cellular functions of the genes of interest were verified in vitro. Results: We identified ten cell types and 160 mitophagy-related single-cell differentially expressed genes (MR-scDEGs). Strong interactions were observed between fibroblasts, endothelial cells, CD8+ T cells, and NK cells. Fibroblasts linked to mitophagy were divided into six subtypes. Intersection of DEGs from three bulk datasets with MR-scDEGs identified 26 key genes clustered into two subgroups. COX regression analysis identified seven prognostic key genes, enabling a prognostic nomogram model. High and low-risk groups showed significant differences in clinical features, immune infiltration, immunotherapy, and drug sensitivity. In prostate cancer cell lines, CAV1, PALLD, and ITGB8 are upregulated, while CLDN7 is downregulated. Knockdown of PALLD significantly inhibits the proliferation and colony-forming ability of PC3 and DU145 cells, suggesting the important roles of this gene in prostate cancer progression. Conclusions: This study analyzed mitophagy-related genes in PARD, predicting prognosis and aiding in subtype identification and immunotherapy response analysis. This approach offers new strategies for treating prostate cancer with specific molecular subtypes and helps develop potential biomarkers for personalized medicine strategies.

P-13 EXTRANODAL LYMPHOMA WITH ENDOCRINE ORGAN INVOLVEMENT: CASE REPORTS

Abstract Introduction The incidence of extranodal lymphomas has increased in the last decade, most commonly occurring in the gastrointestinal tract, head and neck, skin/soft tissue and central nervous system. We report two cases of extranodal lymphoma in the thyroid and adrenal gland. Clinical Cases A 61-year-old male patient diagnosed with Small Lymphocytic Lymphoma (CLL) was referred to us after his follow-up at the Hematology Clinic. Thyroid ultrasonography (USG) revealed a nodular ovoid lesion, that has a semisolid structure of 36x12 mm in size, with a cystic component in the center, located at the right lobe - isthmus junction, and with increased vascularity. Laboratory tests were as in Table 1. It was learned that the patient had received chemotherapy for CLL in 2009 and was in remission, and there was no family history of thyroid cancer. Since the fine needle aspiration biopsy (FNAB) was suspicious for lymphoid neoplasia, a tru-cut biopsy was performed. The flow cytometry result was found to be compatible with B-cell clonality, and the pathology result revealed mature B-cell neoplasia infiltration. Immunohistochemically, dense plasma cells were observed with CD138. Thyroidectomy was recommended to the patient, but he refused and was followed up. A 73-year-old female patient was referred to our clinic with the suspicion of adrenal insufficiency due to ongoing nausea, vomiting, and hypotension symptoms. Laboratory tests at presentation were as shown in Table 2. The patient was started on 80 mg/day methylprednisolone, which was thought to be acute adrenal insufficiency biochemically and clinically, and since hyperkalemia persisted, 0.05 mg/day fludrocortisone was added to the treatment. It was learned that the patient had been examined for abdominal pain for 6 months, and 15 mm nodular lesions were observed in both adrenal glands in the abdominal CT, but no further examination was performed. In adrenal CT, lesions measuring 41x30 mm on the right and 30x22 mm on the left at the body-medial crus level were observed in both adrenal glands, with a density higher than expected for adenoma (Figure 1). The findings were evaluated as significant in favor of nonadenomatous lesions, and due to progression in lesion sizes and high suspicion of malignancy, pheochromocytoma was excluded by checking urine catecholamines from the lesion in the right adrenal gland, and a tru-cut biopsy was performed. As a result of the pathology, the patient was diagnosed with high-grade B-cell neoplasia and hematological treatment was started. Conclusion Extranodal lymphoma involvement has been described with multiple different presentations in every tissue of the body, even within an organ system. Therefore, it should be included in the differential diagnosis of mass lesions. Tissue biopsy and immunohistochemistry are the most important methods for determining the specific subtype and cell origin.Figure 1:CT images of patientLesions in bilateral adrenal glands Table 1:Laboratory workup*Thyroid Stimulating Hormone. Table 2:Laboratory workup*Blood Urea Nitrogen,C-reactive Protein, Adrenocorticotropic hormone, Thyroid Stimulating Hormone

Gintonin Binds to Reduced LPA4 Receptor Subtype in Human Cortical Neurons in Alzheimer’s Disease Brains

Ginseng, a traditional herbal medicine with a long history of use, is known to support human health, particularly by influencing brain function. Recent studies have identified gintonin, a lysophosphatidic acid (LPA) receptor ligand derived from ginseng, as a key bioactive. However, the specific LPA receptor subtypes targeted by gintonin in the human brain to exert its anti-Alzheimer’s (AD) effects remain unclear. This study aimed to elucidate the LPA receptor subtype targeted by gintonin in the human cortex. Using a fluorescent gintonin conjugate, we investigated receptor binding in cortical samples from healthy individuals (n = 4) and AD patients (n = 4). Our results demonstrated that fluorescent gintonin selectively binds to human cortical neurons rather than glial cells and that gintonin-binding sites are co-localized with the LPA4 receptor subtype. Furthermore, the expression of LPA4 receptors was significantly reduced in the cortical neurons of AD patients. These results suggest that the LPA4 receptor may serve as a novel histopathological marker for AD and represent a promising therapeutic target for gintonin-based prevention and treatment strategies.

Important changes to the 2022 WHO classification of testicular tumours : Aguide for diagnostics

The 5thEdition of the "WHO Classification of Tumours: Urinary and Male Genital Tumours" introduces several significant updates to the classification of testicular tumours. These updates include revised terminology for special germ cell tumour subtypes (neuroectodermal and neuroendocrine tumours) of the testis. Additionally, the signet-ring stromal tumour and myoid gonadal stromal tumour have been introduced as distinct entities within the sex-cord stromal tumours. Moreover, new combined sections have been created for lymphatic neoplasms and soft tissue tumours of the urinary and male genital tract.

P0086 The role of enteric glial cells in patients with ulcerative colitis.

Abstract Background Enteric glial cells (EGCs) have traditionally been regarded as supportive cells within the enteric nervous system. However, recent studies indicate that, beyond their involvement in neural circuit formation, EGCs possess antigen-presenting capabilities and actively contribute to mucosal defense. In the mouse myenteric plexus, inflammation-inducing stimuli have been shown to trigger the expression of MHC class II on glial cells, which subsequently influences the differentiation of helper T-cell and regulatory T-cell subtypes, thereby maintaining immune homeostasis under inflammatory conditions. Nevertheless, research on EGCs in humans remains limited. Thus, this study aimed to elucidate the function and involvement of EGCs in the pathogenesis of ulcerative colitis (UC). Methods Normal colonic mucosa was obtained from histologically and macroscopically intact areas of patients with colorectal cancer (n=6). Colonic mucosa from UC patients, diagnosed based on established clinical, bacteriological, radiologic, and endoscopic criteria, was also obtained from surgically resected specimens (n=7). Lamina propria mononuclear cells were isolated through enzymatic digestion, and mesenchymal stromal fractions (CD31-CD45-EPCAM-CD90+), containing glial cells, were further isolated using flow cytometry for single-cell RNA sequencing (scRNA-seq) analysis and T cell differentiation assay. Results We identified a specific EGC population (Cluster 3: PDPN+ HLA-DR high) with high antigen-presenting capacity, which was selectively elevated at inflamed sites in UC. scRNA-seq analysis, transcription factor activity analysis, and gene-enriched pathway analysis indicated that IFNγ-STAT1 signaling activation within Cluster 3 enhances MHC class II expression. To assess T-cell effects, naive CD4+ T-cells were co-cultured with PDPN+ HLA-DR high cells isolated from UC samples. This co-culture induced differentiation into IL-10+ IL-17A+ CD4+ T-cells, with a positive correlation observed between the proportions of IL-10+ IL-17A+ CD4+ T-cells and PDPN+ HLA-DR high cells. Bulk RNA sequencing and qPCR analysis further demonstrated that PDPN+ HLA-DR high cells highly express the IL-27 subunit EBI3 and the TGF-β activator integrin αvβ8. To evaluate clinical relevance, we also examined the correlation between PDPN+ HLA-DR high cell numbers and clinical factors in 45 UC patients. Immunofluorescence staining for the glial marker CDH2 and HLA-DR revealed a negative correlation between CDH2+ HLA-DR+ cell numbers and preoperative Mayo endoscopic scores. Conclusion PDPN+ HLA-DR high glial cells are increased in inflamed areas of UC patients, suggesting a role in anti-inflammatory processes and the maintenance of immune homeostasis.

Single Cell Proteomics Reveals Specific Cellular Subtypes in Cardiomyocytes Derived from Human iPSCs and Adult Hearts.

Single cell proteomics was performed on human induced pluripotent stem cells (iPSCs), iPSC-derived cardiomyocytes, and adult cardiomyocytes. Over 700 proteins could be simultaneously measured in each cell revealing unique subpopulations. A sub-set of iPSCs expressed higher levels of Lin28a and Tra-1-60 towards the outer edge of cell colonies. In the cardiomyocytes, two distinct populations were found that exhibited complementary metabolic profiles. Cardiomyocytes from iPSCs showed a glycolysis profile while adult cardiomyocytes were enriched in proteins involved with fatty acid metabolism. Interestingly, rare single cells also co-expressed markers of both cardiac and neuronal lineages, suggesting there maybe a novel hybrid cell type in the human heart.

Amygdala-centered fusional connections characterized nonmotor symptoms in Parkinson's disease.

The importance of nonmotor symptoms in understanding the pathogenesis of the heterogeneity of Parkinson's disease has been highlighted. However, the validation of specific brain network biomarkers in nonmotor symptom subtypes is currently lacking. By performing a new approach to compute functional connectivity with structural prior using magnetic resonance imaging, the present study computed both functional connectivity and fusional connectivity features in the nonmotor symptom subtypes of Parkinson's disease, one characterized by cognitive impairment with late onset and the other depression with early onset. The functional connectivity and fusional connectivity features centered at the left amygdala were both detected. The fusional features significantly enhanced the classification performance. The amygdala-postcentral and amygdala-orbital frontal features were critical for cognitive impairment with late onset detection, while the amygdala-temporooccipital features were crucial for depression with early onset detection. Additionally, the fusional connectivity features between the amygdala and the junction sulcus of parietooccipital and temporooccipital regions contributed significantly to differentiating cognitive impairment with late onset and depression with early onset. The within-subtype correlation analysis revealed that age at onset and cognitive scores were associated with features of amygdala-somatosensory/visual-motor processing areas in cognitive impairment with late onset, while related to features of amygdala-emotional processing areas in depression with early onset. Our findings highlighted distinct amygdala-centered fusional connectivity features related to diverse nonmotor symptoms in Parkinson's disease, offering new insights for pathogenesis-targeted treatments for specific Parkinson's disease subtypes.

Trends in Breslow thickness of nodular and superficial spreading melanoma subtypes and associated factors: a twelve-year analysis from a tertiary referral center in Greece.

Primary tumor thickness is important for prognosis of melanoma patients. To enhance prevention and quantify the true burden of melanoma, better understanding of thickness patterns and associated characteristics is crucial. Previous studies have been limited to report trends and address risk factors of thickness in specific melanoma subtypes in the Greek population. We investigated associations between epidemiological characteristics and thickness for the two most common melanoma subtypes and the trends in thickness over a twelve-year period. A retrospective study of 1201 patients with histologically confirmed primary nodular and superficial spreading melanoma (SSM) diagnosed from 2010 to 2021 in "Andreas Sygros" Hospital of Cutaneous and Venereal diseases was conducted. Multiple regression was performed to examine the association of variables of interest with melanoma thickness. SSM thickness significantly increased by 2% per year (percent of change: 2.0, 95% CI: 0.2, 3.7) from 2010 to 2021, while a similar tendency for nodular melanoma (NM) thickness was indicated. Age at diagnosis was demonstrated to be a predictor of thickness for both subtypes. When considering all confounders, overall sun exposure was inversely associated with SSM thickness (PC: -6.2, 95% CI: -12.4, 0.5) and a similar association was indicated for NM (PC: -9.3, 95%CI: -21.1, 4.2). These results indicate an upward trend of SSM thickness and the associations of age at diagnosis and overall exposure to UV with thickness of both subtypes. Future research is needed to identify additional characteristics and explain differences among all melanoma types.

Early harmonies, enduring echoes—how early life experiences and personality traits shape music performance anxiety

Music performance anxiety (MPA) is a deeply personal and often debilitating experience, causing talented musicians to dread the very stages upon which they showcase their art. An increasing number of studies have addressed this anxiety phenomenon, however, definitions vary and the underlying causes remain unclear. According to the DSM-5, MPA is categorized as a specific subtype of social anxiety disorder, with a shared understanding that its development is shaped by predisposing vulnerabilities as well as external stressors and circumstances. This mini-review provides an overview of relevant literature on the multi-dimensional causes of MPA, with a particular focus on early life experiences and personality traits. It aims to address three key challenges in the field by emphasizing the importance of an enhanced investigation of formative life events, recognizing the (potentially) mediating effects of personalities, and highlighting the necessity to explore protective factors. Investigating early life experiences and personality traits in the context of MPA can deepen our understanding of its origin and development, offering valuable perspectives to tailor interventions, prevent the escalation of anxiety, and foster supportive environments conducive to the well-being and professional growth of musicians.

Exploring Genetic and Receptor-Based Dopaminergic Strategies for Antidepressant Drug Development.

The dopamine (DA) system is central to mood regulation, motivation, and reward processing, making it a critical focus for understanding Major Depressive Disorder (MDD). While the dopaminergic system's role in MDD pathophysiology has been acknowledged, gaps remain in linking specific receptor subtypes and genetic factors to depression-like phenotypes. This study explores the interplay between dopamine receptor subtypes (D1-D5) and associated genetic variations, particularly focusing on receptor heterodimers and polymorphisms influencing dopamine biosynthesis, signalling, and metabolism. A comprehensive review of molecular mechanisms highlights key findings: alterations in D1-D2 heterodimers contribute to mood dysregulation; D3 receptor downregulation correlates with depressive behaviour; and genetic polymorphisms, including those in tyrosine hydroxylase and dopamine transporter (DAT) genes, influence dopamine levels and receptor functions. Emerging data from neuroimaging and animal models confirm the pivotal role of dopamine receptor subtypes in MDD, offering insights into their therapeutic targeting. Here, we show that dopaminergic dysfunction underpins MDD's pathophysiology, with receptor-specific mechanisms presenting novel drug targets. Understanding these pathways facilitates precision medicine approaches, bridging the gap between genetic predisposition and receptor pharmacology, and paving the way for tailored antidepressant strategies with improved efficacy and reduced side effects.

Efficacy of immune checkpoint inhibitors in the treatment of soft tissue sarcoma: A systematic review and meta-analysis of clinical trials.

Soft tissue sarcomas (STS) are a heterogeneous group of tumors with diverse clinical and molecular characteristics, characterized by limited treatment options and poor prognosis. Immune checkpoint inhibitors (ICIs) have emerged as promising therapies for STS, yet comprehensive evaluations of their efficacy, especially in combination with other treatments, are scarce. We conducted a systematic review and meta-analysis of clinical trials on ICIs in STS treatment, sourced from PubMed, Embase, and the Cochrane Central Register of Controlled Trials up to May 31, 2024. The studies included both monotherapy and combination therapies with ICIs. We assessed the methodological quality using the Cochrane Risk of Bias 2 tool and the Methodological Index for Non-Randomized Studies. Data synthesis involved random-effects meta-analysis to determine pooled proportions and 95% confidence intervals (CIs) for objective response rates (ORR), disease control rates (DCR), and high-grade treatment-related adverse events (TRAEs). The analysis included 38 studies with 1349 patients covering 24 STS subtypes. The overall ORR was 16% (95% CI 0.12-0.21), DCR was 64% (95% CI 0.57-0.70), and the rate of Grade 3-5 TRAEs was 19% (95% CI 0.13-0.27). Treatments combining ICIs with tyrosine kinase inhibitors (TKIs) showed the highest efficacy (ORR 28%, 95% CI 0.18-0.40), albeit with increased adverse events. ORRs in first-line treatments were substantially higher (28%) compared to second-line treatments or beyond (11%). Subtypes like alveolar soft part sarcoma (ASPS), angiosarcoma (AS), and epithelioid sarcoma (ES) exhibited favorable responses exceeding 30%. This systematic review and meta-analysis indicate that ICIs, particularly when combined with TKIs, provide substantial therapeutic benefits in treating STS, significantly enhancing response rates in specific subtypes such as ASPS and AS. The results underscore the transformative potential of ICIs in STS treatment strategies. However, the variability across subtypes and treatment lines emphasizes the need for further randomized controlled trials to refine and personalize therapeutic approaches, ensuring optimal outcomes for patients with these diverse malignancies.

Role of Population Based Studies in Advancing our Knowledge of Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by high molecular and genomic heterogeneity. Accordingly, efforts in risk assessment and therapeutic intervention mostly target unique profiles that individualize specific MDS subtypes. In this review, we explored the contributions of population based studies accounting for MDS as a group. Large population based studies have been critical to define important details of our current knowledge of the disease. We summarized the most important population research contributions in MDS, focusing on its epidemiology, population risk factors, and relevant clinical associations. We discuss how these population data can provide vital insights to inform prevention measures, testing strategies, and treatment decisions. Population studies play an important role in guiding clinical and research efforts in MDS. Despite its complex molecular and genomic landscape, population data is integral to define the burden of disease, identify risk factors and clinical associations, and can help elucidate pathogenic mechanisms.

A clinical decision model for failed adrenal vein sampling in primary aldosteronism

ObjectivePrimary aldosteronism (PA) is a common cause of secondary hypertension with unilateral and bilateral subtypes requiring different treatments. Adrenal vein sampling (AVS) is the gold standard for subtype differentiation but can be unsuccessful by challenging right adrenal vein anatomy. This study aimed to develop a clinical decision model using only measurements from the left adrenal vein (LAV) and peripheral blood (IVC) to differentiate between PA subtypes.MethodsThe retrospective cohort study included 54 PA patients who underwent bilaterally successful AVS. The main objective was to determine optimal cut-off values for the LAV/IVC index, using ROC analysis for subtype prediction. The predictive value of this index was assessed with the Area Under the Curve (AUC). The Youden index calculated cut-off values, targeting a specificity >90% for PA subtype differentiation.ResultsThe cohort, averaging 48.5 ± 9.5 years in age, comprised 21 women and 33 men, among whom 26 presented with unilateral and 28 with bilateral disease. LAV/IVC values <1.2 indicated unilateral right-sided disease (specificity 91%, sensitivity 96%, AUC 0.98, 95% confidence interval (CI) 0.95-1.0), values 1.2-2.4 suggested bilateral disease (sensitivity 93%, specificity 64%, AUC 0.85, CI 0.73-0.96), whereas values ≥4.4 predicted unilateral left-sided disease (specificity 93%, sensitivity 60%, AUC 0.85, CI 0.73-0.96). Published literature aligns with our results on cut-off values.ConclusionsUtilizing the LAV/IVC index, over 70% of unsuccessful AVS procedures due to failed right adrenal cannulation could be interpreted with over 90% certainty regarding the PA subtype, preventing unnecessary resampling and aiding in determining the preferred treatment.

Monogenic Diabetes: Genetic Insight and Precision Therapeutics in the Management of MODY

A monogenic diabetes, specifically, the Maturity-onset diabetes of the young (MODY) is the consequence of the single-gene mutations that are responsible for transcription factors such as HNF1A and GCK taking effect on the insulin synthesis, glucose detection, and the formation of beta cells. This genetic basis necessitates a precise clinical approach for accurate diagnosis and personalized treatment, emphasizing precision medicine. Sulfonylureas are a cornerstone treatment for specific MODY subtypes, especially those with KATP channel mutations, as they enhance insulin secretion and alleviate hyperglycemia by targeting the genetic defect. Genetic testing is crucial in identifying the molecular causes of monogenic diabetes, guiding clinicians in tailoring treatment strategies to optimize therapeutic outcomes. This personalized approach integrates genetic insights with precision therapeutics, revolutionizing the management of monogenic diabetes by offering targeted treatments that improve glycemic control and long-term health outcomes. Healthcare professionals can treat patients more effectively and individually by knowing the genetic pathways behind monogenic diabetes. This advances diabetology toward more effective therapeutic strategies. Even the management of diseases can benefit from the invention of precision medicine as applied to the monogenic diabetes, which allows the personalized methods that lead to a positive effect on patients and provide better care to the patient.

Individual and County-Level Factors Associated with Severe Maternal Morbidity at Delivery: An Investigation of a Privately Insured Population in the United States, 2008 to 2018.

Few studies have explored the impact of county-level variables on severe maternal morbidity (SMM) subtypes. To address this gap, this study used a large commercial database to examine the associations between individual- and county-level factors and SMM. This retrospective cohort study used data from the Optum's deidentified Clinformatics Data Mart Database from 2008 to 2018. The primary outcomes of this study were any SMM, nontransfusion SMM, and nine specific SMM subtypes. Temporal trends in the prevalence of SMM and SMM subtypes were assessed using Joinpoint Regression. Multilevel logistic regression models were used to investigate the association of individual- and county-level factors with SMM. Between 2008 and 2018, there was not a significant change in the prevalence of any SMM (annual percent change [APC]: -0.9, 95% confidence interval [CI]: -2.2, 0.5). Significant increases in prevalence were identified for three SMM subtypes: other obstetric (OB) SMM (APC: 10.3, 95% CI: 0.1, 21.5) from 2013 to 2018, renal SMM (APC: 8.5, 95% CI: 5.5, 11.6) from 2008 to 2018, and sepsis (APC: 23.0, 95% CI: 6.5, 42.1) from 2014 to 2018. Multilevel logistic regression models revealed variability in individual and county risk factors across different SMM subtypes. Adolescent mothers (odds ratio [OR]: 2.10, 95% CI: 1.29, 3.40) and women in the 40 to 55 (OR: 1.67, 95% CI: 1.12, 2.51) age group were found to be at significant risk of other OB SMM and renal SMM, respectively. For every increase in rank within a county's socioeconomic social vulnerability index (SVI), the risk of respiratory SMM increased 2.8-fold, whereas an increase in rank in the racial/ethnic minority SVI was associated with a 1.6-fold elevated risk of blood transfusion. This study underscores the complex association between individual and county factors associated with SMM, emphasizing the need for multifaced approaches to improve maternal care. · No increase in composite SMM rates from 2008 to 2018.. · Increases in obstetric SMM subtypes and sepsis.. · Risk factor profiles may differ across SMM subtypes.. · Key risk factors: age, comorbidities, prenatal care.. · County socioeconomic status associated with respiratory SMM risk..

Childhood Maltreatment and Somatic Symptoms in Adulthood: Establishing a New Research Pathway.

Somatic symptoms, such as chronic pain, fatigue, and gastrointestinal disturbances, are commonly reported in individuals with a history of childhood maltreatment (CM), which includes various forms of abuse and neglect experienced before age 18. Although CM is strongly associated with somatic symptoms, the specific relationships between CM subtypes and these symptoms, as well as the mechanisms connecting them, remain insufficiently understood. This review examines the complex interaction between CM and somatic symptoms, which often coexist with mental disorders and significantly impact quality of life and healthcare systems. Somatic symptoms, frequently a mix of "explained" and "unexplained" conditions, are associated with personal distress and pose diagnostic challenges. CM has been linked to these symptoms through neurobiological mechanisms, such as HPA axis dysregulation and allostatic load, while theoretical models emphasize the roles of hyperawareness, cultural factors, and vulnerability in symptom development. However, existing research often fails to account for specific CM subtypes, the full range of somatic symptoms, and cultural and situational factors, leading to inconsistencies in findings. Bridging gaps in literature requires adopting the World Health Organization's CM subtype definitions and ICD-11 codes (MA00-MH2Y) to encompass a broader spectrum of somatic symptoms. Employing rigorous methodologies, such as systematic reviews and meta-analyses, is essential for advancing understanding. These approaches can enhance diagnostic accuracy, support tailored interventions, and promote a biopsychosocial framework for CM research, ultimately improving patient outcomes and alleviating societal burdens.

Suppression of dopamine receptor 2 inhibits the formation of human prostate cancer PC‑3‑derived cancer stem cell‑like cells through AMPK inhibition.

Cancer stem cells (CSCs) contribute to the resistance of intractable prostate cancer, and dopamine receptor (DR)D2 antagonists exhibit anticancer activity against prostate cancer and CSCs. Human prostate cancer PC-3 cells were used to generate CSC-like cells, serving as a surrogate system to identify the specific DR subtype the inhibition of which significantly affects prostate-derived CSCs. Additionally, the present study aimed to determine the downstream signaling molecules of this DR subtype that exert more profound effects compared with other DR subtypes. The inhibitory effects of specific antagonists or small interfering (si)RNAs on DR subtypes were compared by analyzing morphological changes of cells, expression patterns of pluripotency markers, cell growth inhibitory activities and in vitro cell invasion. L-741,626, a specific DRD2 antagonist, induced morphological changes in PC-3-derived CSC-like cells, suppressed the expression of Oct4 (a pluripotency marker), and inhibited the growth of cells and tumors. The proliferation of heterozygous null PC-3 cells, generated using the CRISPR/Cas9 method, was slow, and their sphere-forming ability was substantially reduced, indicating a diminished capacity to produce CSCs. In addition, the phosphorylation of AMPK was suppressed by DRD2 siRNA and the heterozygous knockout of DRD2 in PC-3 cells, indicating that AMPK may be a putative downstream signaling molecule involved in the production and maintenance of PC-3-derived CSC-like cells. Specific inhibition or suppression of DRD2 caused PC-3-derived CSC-like cells to lose their properties and inhibited the formation of PC-3-derived CSC-like cells, followed by inhibition of the phosphorylation of AMPK, which is considered a putative downstream signaling molecule of DRD2. Further understanding of the mechanisms by which DRD2 regulates AMPK and the effects of AMPK inhibition on the properties of PC-3-derived CSC-like cells may provide valuable insights into the identification of molecular targets for treating intractable prostate cancer wherein AMPK is constitutively activated.

Immunotherapy in Recurrent Ovarian Cancer.

It remains challenging to treat recurrent ovarian cancer effectively as traditional interventions like chemotherapy and surgery have limited long-term efficacy, highlighting an urgent need for innovative approaches. Immunotherapy offers potential advantages in modulating the immune response against tumor cells and has emerged as a promising strategy in ovarian cancer management. This review discusses various immunotherapy modalities, including active and passive immune strategies, for recurrent ovarian cancer. We systematically reviewed recent immunotherapy advances for recurrent ovarian cancer, including the efficacy and mechanisms of single and dual immune checkpoint inhibitors, checkpoint inhibitor combinations with chemotherapy or radiotherapy, anti-angiogenic agents, PARP inhibitors, antibody-drug conjugates (ADC), tumor vaccines, and adoptive cell therapies (ACT). Additionally, we assessed emerging research on biomarkers predictive of immunotherapy responsiveness in ovarian cancer. The findings indicate that immunotherapy, particularly combinations involving immune checkpoint inhibitors and other agents, demonstrates promising efficacy in recurrent ovarian cancer, with some therapies showing enhanced benefits in specific subtypes. The immune microenvironment in platinum-sensitive and -resistant cases exhibits distinct immunological profiles, influencing therapy outcomes. Several potential biomarkers have been identified, potentially aiding in patient stratification and treatment optimization. Immunotherapy significantly advances recurrent ovarian cancer treatment, with various combinations potentially improving outcomes. Further research on predictive biomarkers and immune microenvironment characteristics is crucial for personalizing immunotherapy approaches and enhancing their efficacy in managing recurrent ovarian cancer.

Spatial transcriptomic characterization of a Carnegie stage 7 human embryo.

Gastrulation marks a pivotal stage in mammalian embryonic development, establishing the three germ layers and body axis through lineage diversification and morphogenetic movements. However, studying human gastrulating embryos is challenging due to limited access to early tissues. Here we show the use of spatial transcriptomics to analyse a fully intact Carnegie stage 7 human embryo at single-cell resolution, along with immunofluorescence validations in a second embryo. Employing 82 serial cryosections and Stereo-seq technology, we reconstructed a three-dimensional model of the embryo. Our findings reveal early specification of distinct mesoderm subtypes and the presence of the anterior visceral endoderm. Notably, primordial germ cells were located in the connecting stalk, and haematopoietic stem cell-independent haematopoiesis was observed in the yolk sac. This study advances our understanding of human gastrulation and provides a valuable dataset for future research in early human development.