Utility of contrast-enhanced MRI radiomics features combined with clinical indicators for predicting induction chemotherapy response in primary central nervous system lymphoma.

PURPOSE: To assess the utility of combining contrast-enhanced magnetic resonance imaging (CE-MRI) radiomics features with clinical variables in predicting the response to induction chemotherapy (IC) for primary central nervous system lymphoma (PCNSL). METHODS: A total of 131 patients with PCNSL (101 in the training set and 30 in the testing set) who had undergone contrast-enhanced MRI scans were retrospectively analyzed. Pyradiomics was utilized to extract radiomics features, and the clinical variables of the patients were gathered. Radiomics prediction models were developed using different combinations of feature selection methods and machine learning models, and the best combination was ultimately chosen. We screened clinical variables associated with treatment outcomes and developed clinical prediction models. The predictive performance of radiomics model, clinical model, and combined model, which integrates the best radiomics model and clinical characteristics, was independently assessed and compared using Receiver Operating Characteristic (ROC) curves. RESULTS: In total, we extracted 1598 features. The best radiomics model we selected as the best utilized T-test and Recursive Feature Elimination (RFE) for feature selection and logistic regression for model building. Serum Interleukin 2 Receptor (IL-2R) and Eastern Cooperative Oncology Group (ECOG) Score were utilized to develop a clinical predictive model for assessing the response to induction chemotherapy. The results of the testing set revealed that the combined prediction model (radiomics and IL-2R) achieved the highest area under the ROC curve at 0.868 (0.683, 0.967), followed by the radiomics model at 0.857 (0.681, 0.957), and the clinical prediction model (IL-2R and ECOG) at 0.618 (0.413, 0.797). The combined model was significantly more accurate than the clinical model, with an AUC of 0.868 compared to 0.618 (P < 0.05). While the radiomics model had slightly better predictive power than the clinical model, this difference was not statistically significant (AUC, 0.857 vs. 0.618, P > 0.05). CONCLUSIONS: Our prediction model, which combines radiomics signatures from CE-MRI with serum IL-2R, can effectively stratify patients with PCNSL before high-dose methotrexate (HD-MTX) -based chemotherapy.

Prognostic Value of Sublingual Microcirculation in Sepsis: A Systematic Review and Meta-analysis.

Objectives: To investigate the relationship between sublingual microcirculation and the prognosis of sepsis. Data sources: The PubMed, Web of Science, Embase, and China National Knowledge Infrastructure (CNKI) databases were searched to identify studies published from January 2003 to November 2023. Study selection: Clinical studies examining sublingual microcirculation and the prognosis of sepsis were included. Data extraction: Sublingual microcirculation indices included the microvascular blood index (MFI), total vascular density (TVD), perfusion vascular density (PVD), perfusion vascular vessel (PPV), and heterogeneity index (HI). Prognostic outcomes included mortality and severity. Funnel plots and Egger's test were used to detect publication bias. The ability of the small vessel PPV (PPVs) to predict sepsis-related mortality was analyzed based on the summary receiver operating characteristic (SROC) curve, pooled sensitivity, and pooled specificity. Data synthesis: Twenty-five studies involving 1750 subjects were included. The TVD (95% CI 0.11-0.39), PVD (95% CI 0.42-0.88), PPV (95% CI 6.63-13.83), and MFI (95% CI 0.13-0.6) of the survival group were greater than those of the nonsurvival group. The HI in the survival group was lower than that in the nonsurvival group (95% CI -0.49 to -0.03). The TVD (95% CI 0.41-0.83), PVD (95% CI 0.83-1.17), PPV (95% CI 14.49-24.9), and MFI (95% CI 0.25-0.66) of the nonsevere group were greater than those of the severe group. Subgroup analysis revealed no significant difference in TVD between the survival group and the nonsurvival group in the small vessel subgroup. The area under the SROC curve (AUC) was 0.88. Conclusions: Sublingual microcirculation was worse among patients who died and patients with severe sepsis than among patients who survived and patients with nonsevere sepsis. PPV has a good predictive value for the mortality of sepsis patients. This study was recorded in PROSPERO (registration number: CRD42023486349).

Prognostic differences in sepsis caused by gram-negative bacteria and gram-positive bacteria: a systematic review and meta-analysis.

BACKGROUND: Bacteria are the main pathogens that cause sepsis. The pathogenic mechanisms of sepsis caused by gram-negative and gram-positive bacteria are completely different, and their prognostic differences in sepsis remain unclear. METHODS: The PubMed, Web of Science, Cochrane Library, and Embase databases were searched for Chinese and English studies (January 2003 to September 2023). Observational studies involving gram-negative (G (-))/gram-positive (G (+)) bacterial infection and the prognosis of sepsis were included. The stability of the results was evaluated by sensitivity analysis. Funnel plots and Egger tests were used to check whether there was publication bias. A meta-regression analysis was conducted on the results with high heterogeneity to identify the source of heterogeneity. A total of 6949 articles were retrieved from the database, and 45 studies involving 5586 subjects were included after screening according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Twenty-seven high-quality studies and 18 moderate-quality studies were identified according to the Newcastle‒Ottawa Scale score. There was no significant difference in the survival rate of sepsis caused by G (-) bacteria and G (+) bacteria (OR 0.95, 95% CI 0.70-1.28). Subgroup analysis according to survival follow-up time showed no significant difference. The serum concentrations of C-reactive protein (CRP) (SMD = 0.39, 95% CI 0.02-0.76), procalcitonin (SMD = 1.95, 95% CI 1.32-2.59) and tumor necrosis factor-alpha (TNF-α) (MD = 0.31, 95% CI 0.25-0.38) in the G (-) bacterial infection group were significantly higher than those in the G (+) bacterial infection group, but there was no significant difference in IL-6 (SMD = 1.33, 95% CI - 0.18-2.84) and WBC count (MD = - 0.15, 95% CI - 0.96-00.66). There were no significant differences between G (-) and G (+) bacteria in D dimer level, activated partial thromboplastin time, thrombin time, international normalized ratio, platelet count, length of stay or length of ICU stay. Sensitivity analysis of the above results indicated that the results were stable. CONCLUSION: The incidence of severe sepsis and the concentrations of inflammatory factors (CRP, PCT, TNF-α) in sepsis caused by G (-) bacteria were higher than those caused by G (+) bacteria. The two groups had no significant difference in survival rate, coagulation function, or hospital stay. The study was registered with PROSPERO (registration number: CRD42023465051).

Yttrium chloride induces ferroptosis in cardiomyocytes via iron accumulation and triggers cardiac lipid peroxidation and inflammation that cause heart adverse events in mice.

The growing presence of yttrium (Y) in the environment raises concern regarding its safety and toxicity. However, limited toxicological data are available to determine cardiotoxicity of Y and its underlying mechanisms. In the present study, yttrium chloride (YCl3) intervention with different doses was performed in male Kunming mice for the toxicological evaluation of Y in the heart. After 28 days of intragastric administration, 500 mg/kg·bw YCl3 induces iron accumulation in cardiomyocytes, and triggers ferroptosis through the glutathione peroxidase 4 (GPX4)/glutathione (GSH)/system Xc- axis via the inhibition of Nrf2 signaling pathway. This process led to cardiac lipid peroxidation and inflammatory response. Further RNA sequencing transcriptome analysis found that many genes involved in ferroptosis and lipid metabolism-related pathways were enriched. The ferroptosis induced by YCl3 in cardiomyocytes ultimately caused cardiac injury and dysfunction in mice. Our findings assist in the elucidation of the potential subacute cardiotoxicity of Y3+ and its underlying mechanisms.

Multiple neuroendocrine tumors in the stomach, duodenum and pancreas of a MEN1 patient.

Gastrinoma, a common type of GEP-NENs, is often sporadic, rarely manifested as multiple endocrine neoplasia type 1 (MEN1). We described a rare case of MEN1-related gastrinomas in the stomach, duodenum and pancreas along with lymph node metastases. The female patient had a long history of recurrent abdominal pain and diarrhea. G1 neuroendocrine tumors were diagnosed by endoscopic biopsy in the pylorus, duodenal bulb and the neck of the pancreas successively. Her symptoms lessened and serum gastrin level decreased after surgery. This case will help us learn more about MEN1-associated patients who are confirmed with multiple neuroendocrine tumors.

Autoimmune enteropathy complicated with primary biliary cholangitis.

Autoimmune enteropathy is a rare intestinal disease. Here we report an elderly female with autoimmune enteropathy and primary biliary cholangitis who presented with chronic diarrhea, malnutrition and severe hypokalemia and metabolic acidosis. Enteroscopy showed atrophied small intestinal villi with scallop-like and fissure-like changes. Hormone treatment relieved diarrhea. Four months later, she developed primary biliary cholangitis, and the liver function returned to normal after treatment with ursodeoxycholic acid, corticosteroids and immunosuppressants.

Regulation of feather follicle development and Msx2 gene SNP degradation in Hungarian white goose.

BACKGROUND: Hungarian white goose has excellent down production performance and was introduced to China in 2010. The growth and development of feather follicles has an important impact on down production. Goose feather follicles can be divided into primary and secondary feather follicles, both of which originate in the embryonic stage. Msx2 (Msh Homeobox 2) plays a regulatory role in tissues and organs such as eyes, teeth, bones and skin. However, its regulatory mechanism on goose feather follicles development remains unclear. RESULTS: Msx2 gene first increased, then decreased and increased at the end (E13, E18, E23, E28) during embryonic feather follicle development, and the expression level was the highest at E18. The pEGFP-N1-Msx2 overexpression vector and si-Msx2 siRNA vector were constructed to transfect goose embryo dermal fibroblasts. The results showed that the cell viability of ov-Msx2 group was significantly increased, and the gene expression levels of FGF5 and TGF-ß1 genes were significantly down-regulated (P < 0.05), the expressions of PCNA, Bcl2, CDK1, FOXN1 and KGF genes were significantly up-regulated (P < 0.05). After transfection of siRNA vector, the cell viability of the si-Msx2 group was significantly decreased (P < 0.01) compared with the si-NC group. TGF-ß1 expression was significantly up-regulated (P < 0.05), FGF5 expression was extremely significantly up-regulated (P < 0.01), while PCNA, Bcl2, CDK1, FOXN1 and KGF gene expression was significantly down-regulated (P < 0.05). High-throughput sequencing technology was used to mine the exon SNPs of Msx2. A total of 11 SNP loci were screened, four of the SNPs located in exon 1 were missense mutations. The feather follicle diameter of the GC genotype at the G78C site is significantly larger than that of the other two genotypes. CONCLUSIONS: Msx2 maybe inhibit the apoptosis of goose dermal fibroblasts and promotes their proliferation. G78C can be used as a potential molecular marker for downy Variety.

Systematic analysis of IL-6 as a predictive biomarker and desensitizer of immunotherapy responses in patients with non-small cell lung cancer.

BACKGROUND: Cytokines have been reported to alter the response to immune checkpoint inhibitors (ICIs) in patients with the tumor in accordance with their plasma concentrations. Here, we aimed to identify the key cytokines which influenced the responses and stimulated resistance to ICIs and tried to improve immunological response and develop novel clinical treatments in non-small cell lung cancer (NSCLC). METHODS: The promising predictive cytokines were analyzed via the multi-analyte flow assay. Next, we explored the correlation baseline level of plasma cytokines and clinical outcomes in 45 NSCLC patients treated with ICIs. The mechanism of the potential candidate cytokine in predicting response and inducing resistance to ICIs was then investigated. RESULTS: We found NSCLC with a low baseline concentration of IL-6 in plasma specimens or tumor tissues could derive more benefit from ICIs based on the patient cohort. Further analyses revealed that a favorable relationship between PD-L1 and IL-6 expression was seen in NSCLC specimens. Results in vitro showed that PD-L1 expression in the tumor was enhanced by IL-6 via the JAK1/Stat3 pathway, which induced immune evasion. Notably, an adverse correlation was found between IL-6 levels and CD8+ T cells. And a positive association between IL-6 levels and myeloid-derived suppressor cells, M2 macrophages and regulator T cells was also seen in tumor samples, which may result in an inferior response to ICIs. Results of murine models of NSCLC suggested that the dual blockade of IL-6 and PD-L1 attenuated tumor growth. Further analyses detected that the inhibitor of IL-6 stimulated the infiltration of CD8+ T cells and yielded the inflammatory phenotype. CONCLUSIONS: This study elucidated the role of baseline IL-6 levels in predicting the responses and promoting resistance to immunotherapy in patients with NSCLC. Our results indicated that the treatment targeting IL-6 may be beneficial for ICIs in NSCLC.

Yttrium chloride-induced cytotoxicity and DNA damage response via ROS generation and inhibition of Nrf2/PPARγ pathways in H9c2 cardiomyocytes.

Increasing exploration of rare-earth elements (REEs) has resulted in a high REEs' exposure risk. Owing to their persistence and accumulation of REEs in the environment, their adverse effects have caused widespread concern. However, limited toxicological data are available for the adverse effects of yttrium (Y) and its underlying mechanisms of action. In the present study, H9c2 cardiomyocytes were used in vitro model to investigate the cardiotoxicity of yttrium chloride (YCl3). Results show that YCl3 treatment resulted in reactive oxygen species (ROS) overproduction, decrease in ∆Ψm, and DNA damage. Mechanistically, we detected expression levels of protein in response to cellular DNA damage and antioxidative defense. Results indicated that the phosphorylation of histone H2AX remarkably increased in a dose-dependent manner. At a high YCl3-exposure concentration (120 µM), specific DNA damage sensors ATM/ATR-Chk1/Chk2 were significantly decreased. The protein levels of key antioxidant genes Nrf2/PPARγ/HO-1 were also remarkably inhabited. Additionally, the antioxidant N-acetyl-L-cysteine (NAC) pretreatment promoted the activation of antioxidative defense Nrf2/PPARγ signaling pathways, and prevented the production of cellular ROS, thus protecting the DNA from cleavage. Altogether, our findings suggest that YCl3 can induce DNA damage through causing intracellular ROS overproduction and inhibition of antioxidative defense, leading to cytotoxicity in H9c2 cardiomyocytes.

Discriminant Analysis under f-Divergence Measures.

In statistical inference, the information-theoretic performance limits can often be expressed in terms of a statistical divergence between the underlying statistical models (e.g., in binary hypothesis testing, the error probability is related to the total variation distance between the statistical models). As the data dimension grows, computing the statistics involved in decision-making and the attendant performance limits (divergence measures) face complexity and stability challenges. Dimensionality reduction addresses these challenges at the expense of compromising the performance (the divergence reduces by the data-processing inequality). This paper considers linear dimensionality reduction such that the divergence between the models is maximally preserved. Specifically, this paper focuses on Gaussian models where we investigate discriminant analysis under five f-divergence measures (Kullback-Leibler, symmetrized Kullback-Leibler, Hellinger, total variation, and χ2). We characterize the optimal design of the linear transformation of the data onto a lower-dimensional subspace for zero-mean Gaussian models and employ numerical algorithms to find the design for general Gaussian models with non-zero means. There are two key observations for zero-mean Gaussian models. First, projections are not necessarily along the largest modes of the covariance matrix of the data, and, in some situations, they can even be along the smallest modes. Secondly, under specific regimes, the optimal design of subspace projection is identical under all the f-divergence measures considered, rendering a degree of universality to the design, independent of the inference problem of interest.

A rare case of inflammatory pseudotumor located in the ventral of medullocervical junction. A case report and review of literature.

Inflammatory pseudotumor is a benign lesion of unknown etiology, which mimics neoplasms clinically and radiographically. It most commonly involves the lungs and orbits and is rarely reported in the central nervous system. We report a rare case of inflammatory pseudotumor located in the ventral junction of the medulla oblangta and cervical cistern, which has not been reported before as far as we know. A 61-year-old male presented with right arm weakness. MRI showed a mass located in the ventral junction of the medulla oblongata and cervical cisten. The patient was diagnosed as inflammatory pseudotumor(IPT) after surgical excision and histopathology. This tumor-like lesion was surrounding the bilateral intracranial segment of the vertebral arteries. No evidence of vascular invasion was observed. Complete surgical resection was achieved.

A Flexible Film with SnS2 Nanoparticles Chemically Anchored on 3D-Graphene Framework for High Areal Density and High Rate Sodium Storage.

The design and construction of flexible electrodes that can function at high rates and high areal capacities are essential regarding the practical application of flexible sodium-ion batteries (SIBs) and other energy storage devices, which remains significantly challenging by far. Herein, a flexible and 3D porous graphene nanosheet/SnS2 (3D-GNS/SnS2 ) film is reported as a high-performance SIB electrode. In this hybrid film, the GNS/SnS2 microblocks serve as pillars to assemble into a 3D porous and interconnected framework, enabling fast electron/ion transport; while the GNS bridges the GNS/SnS2 microblocks into a flexible framework to provide satisfactorily mechanical strength and long-range conductivity. Moreover, the SnS2 nanocrystals, which chemically bond with GNS, provide sufficient active sites for Na storage and ensure the cycling stability. Consequently, this flexible 3D-GNS/SnS2 film exhibits excellent Na-storage performances, especially in terms of high areal capacity (2.45 mAh cm-2 ) and high rates with superior stability (385 mAh g-1 at 1.0 A g-1 over 1000 cycles with ≈100% retention). A flexible SIB full cell using this anode exhibits high and stable performance under various bending situations. Thus, this work provide a feasible route to prepare flexible electrodes with high practical viability for not only SIBs but also other energy storage devices.

Toward a stabilized lattice framework and surface structure of layered lithium-rich cathode materials with Ti modification.

Layered lithium-rich oxides have several serious shortcomings such as fast voltage fading and poor cyclic stability of energy density which greatly hinder their practical applications. Fabrication of a stable framework of layered lithium-rich oxides during charging-discharging is crucial for addressing the above problems. In this work, we show that Ti modification is a promising way to realize this target with bifunctional roles. For example, it is able to substitute Mn in the lattice framework and form a stable surface layer. It therefore leads to an improved retention of energy density of the Ti-modified Li1.2Mn0.54-xTixNi0.13Co0.13O2 (x = 0.04, 0.08, and 0.15) materials during cycling. The evolution of dQ/dV curves show that the layered/spinel phase transformation is suppressed owing to the introduction of strong Ti-O bonds in the framework. In addition, SEM, TEM, and EIS results confirm that a more uniform and stable interface layer is formed on Ti-modified Li1.2Mn0.54-xTixNi0.13Co0.13O2 (x = 0.04, 0.08, and 0.15) materials compared with the Ti-free counterpart. The stable interface layer on the lithium-rich oxides is also beneficial for further reducing side reactions, resulting in stable interface layer resistance. Therefore, the improved cycling performance of the material is due to both contribution of the more stable framework and enhanced electrode/electrolyte interface by Ti modification.

Successful complementary therapy with Chinese herbal medicine in a patient with refractory symptoms from systemic lupus erythematosus: A case report.

BACKGROUND: This study presents a unique case of a patient diagnosed with systemic lupus erythematosus and a relatively rare type of traditional Chinese medicine known as Qi deficiency and cold-dampness syndrome. The patient's condition was successfully treated using a combination of complementary therapies, specifically the modified Buzhong Yiqi decoction and the Erchen decoction. CASE PRESENTATION: A 34-year-old female patient experienced intermittent arthralgia and skin rash over three years. She also developed recurrent arthralgia and skin rashes in the last month, followed by low-grade fever, vaginal bleeding, alopecia, and fatigue. The patient was diagnosed with systemic lupus erythematosus and was prescribed prednisone, tacrolimus, anti-allergic medications (ebastine and loratadine), and norethindrone. While the arthralgia improved, the low-grade fever and rash persisted and, in some instances, worsened. Based on the evaluation of tongue coating and pulses, the patient's symptoms were attributed to Qi deficiency and cold-dampness syndrome. Consequently, the modified Buzhong Yiqi decoction and the Erchen decoction were added to her treatment regimen. The former was used to tonify Qi, while the latter was employed to resolve the phlegm dampness. As a result, the patient's fever subsided after three days, and all symptoms resolved within five days. CONCLUSION: The modified Buzhong Yiqi decoction and the Erchen decoction could be considered complementary therapy in systemic lupus erythematosus patients with Qi deficiency and cold-dampness syndrome.

Demystifying the landscape of endometrial immune microenvironment in luteal-phase from cuprotosis: Implications for the mechanism and treatment of RPL.

BACKGROUND: Adaptive changes in the endometrial immune microenvironment during the luteal phase are essential for pregnancy, and their abnormalities are associated with recurrent pregnancy loss (RPL). Nevertheless, the specific mechanism is still unknown. Cuprotosis, an innovatively discovered type of programmed cell death, provides us with a pioneering perspective to decipher the landscape of luteal-phase endometrial immune microenvironment in RPL. This study aimed to analyze the immune landscape of luteal-phase endometrial microenvironment in RPL and explore the association of cuprotosis with it through integrative bioinformatics analysis. METHODS: The microarrays involving the luteal phase endometrial tissue of RPL were obtained from the GEO database. Differentially expressed genes (DEGs) of RPL were screened and key modules were detected by WGCNA. GO, KEGG, and GSEA immune enrichment analyses were performed on the DEGs in the most relevant modules to RPL. Then, the endometrial immune microenvironment landscape of RPL was analyzed, including immune infiltration analysis and correlation analysis between immune cells or immune functions. The interaction of cuprotosis-related genes (CRGs), the expression level between groups, the immune localization and their correlation with immune cells and immune function were analyzed. LASSO regression and Nomogram evaluated the diagnostic value of immune-related CRGS in RPL. Functional enrichment analysis was performed on the RPL signature CRGs. And RPL samples were grouped according to the expression of 7 RPL signature CRGs through unsupervised clustering analysis. After that, we analyzed the expression level of CRGs and immune infiltration, as well as performed immune function enrichment analysis in subtypes. In addition, we also screened potential drugs that might act on CRGs to improve the pathological mechanism of RPL. RESULTS: In this study, we uncovered that DEGs and genes in key modules derived from weighted gene co-expression network analysis (WGCNA) were involved in immune regulation. And the immune infiltration landscape of RPL was significantly different from healthy controls. Furthermore, six hub genes were screened from CRGs based on Cytohubba, and their expression profilings were verified in RPL and normal mouse samples. Besides, seven CRGs closely associated with the immune regulation of RPL were identified by Spearman correlation analysis, including SLC31A1, LIAS, DLD, DLAT, DBT, ATP7B, and ATP7A, named as immune-related CRGs. Furthermore, three subgroups clustered according to these seven genes showed significant differences in immune landscape, suggesting a remarkable effect of CRGs on immune regulation. Last but not least, we analyzed the regulation network of transcription factors, miRNAs, and CRGs, and screened potential compounds for the treatment of RPL by targeting CRGs. CONCLUSIONS: The abnormal endometrial immune microenvironment in the luteal phase was associated with the pathomechanism of RPL, and cuprotosis was closely involved in the immune microenvironment in the luteal phase endometrium of RPL. Collectively, this study revealed the potential contribution of CRGs to the pathogenesis of RPL, providing a novel breakthroughs in insights into the pathogenesis, diagnosis, and treatment of RPL.

Chromosome-level genome sequencing and multi-omics of the Hungarian White Goose (Anser anser domesticus) reveals novel miRNA-mRNA regulation mechanism of waterfowl feather follicle development.

The Hungarian White Goose (Anser anser domesticus) is an excellent European goose breed, with high feather and meat production. Despite its importance in the poultry industry, no available genome assembly information has been published. This study aimed to present Chromosome-level and functional genome sequencing of the Hungarian White Goose. The results showed that the genome assembly has a total length of 1115.82 Mb, 39 pairs of chromosomes, 92.98% of the BUSCO index, and contig N50 and scaffold N50 were up to 2.32 Mb and 60.69 Mb, respectively. Annotation of the genome assembly revealed 19550 genes, 286 miRNAs, etc. We identified 235 expanded and 1,167 contracted gene families in this breed compared with the other 16 species. We performed a positive selection analysis between this breed and four species of Anatidae to uncover the genetic information underlying feather follicle development. Further, we detected the function of miR-199-x, miR-143-y, and miR-23-z on goose embryonic skin fibroblast. In summary, we have successfully generated a highly complete genome sequence of the Hungarian white goose, which will provide a great resource to improve our understanding of gene functions and enhance the studies on feather follicle development at the genomic level.

Dermal FOXO3 activity in response to Wnt/ß-catenin signaling is required for feather follicle development of goose embryos (Anser cygnoides).

Feather is an important economic trait of poultry, and growth and development state of feathers plays an important role in the economic value of poultry. Dermal fibroblasts are required for structural integrity of the skin and for feather follicle development. How FOXO3 affects feather follicle development as skin tissues change during goose embryo (Anser cygnoides) development and growth is not well understood. Here, we demonstrate that in vitro culture of single feathers and skin tissue results in changes in feather morphological structure by adding drugs to the culture medium that affect FOXO3 expression. We used feather follicles to show that during growth, the root location of feathers, the dermis layer, affects cell proliferation and apoptosis and regulates the expression of major genes in the Wingless-types/beta-catenin (Wnt/ß-catenin) signaling pathway through the activity of FOXO3 in dermal fibroblasts. Feathers and dorsal skin tissues develop the correct structure, but feather length and width and feather follicle diameter change significantly (p < 0.05) without significant changes in feather follicle density (p > 0.05). Transfected dermal fibroblasts also showed that FOXO3 affected the formation and development of feather follicles in the embryonic stage by regulating the Wnt/ß-catenin signaling pathway. Therefore, this study reveals the critical role of dermal fibroblast-FOXO3-induced Wnt/ß-catenin signaling in promoting the formation and development of embryonic feather follicles.

Molecular subtypes of neuroendocrine carcinomas: A cross-tissue classification framework based on five transcriptional regulators.

Neuroendocrine carcinomas (NECs) are extremely lethal malignancies that can arise at almost any anatomic site. Characterization of NECs is hindered by their rarity and significant inter- and intra-tissue heterogeneity. Herein, through an integrative analysis of over 1,000 NECs originating from 31 various tissues, we reveal their tissue-independent convergence and further unveil molecular divergence driven by distinct transcriptional regulators. Pan-tissue NECs are therefore categorized into five intrinsic subtypes defined by ASCL1, NEUROD1, HNF4A, POU2F3, and YAP1. A comprehensive portrait of these subtypes is depicted, highlighting subtype-specific transcriptional programs, genomic alterations, evolution trajectories, therapeutic vulnerabilities, and clinicopathological presentations. Notably, the newly discovered HNF4A-dominated subtype-H exhibits a gastrointestinal-like signature, wild-type RB1, unique neuroendocrine differentiation, poor chemotherapeutic response, and prevalent large-cell morphology. The proposal of uniform classification paradigm illuminates transcriptional basis of NEC heterogeneity and bridges the gap across different lineages and cytomorphological variants, in which context-dependent prevalence of subtypes underlies their phenotypic disparities.