Proteogenomic insights into early-onset endometrioid endometrial carcinoma: predictors for fertility-sparing therapy response.

Endometrial carcinoma remains a public health concern with a growing incidence, particularly in younger women. Preserving fertility is a crucial consideration in the management of early-onset endometrioid endometrial carcinoma (EEEC), particularly in patients under 40 who maintain both reproductive desire and capacity. To illuminate the molecular characteristics of EEEC, we undertook a large-scale multi-omics study of 215 patients with endometrial carcinoma, including 81 with EEEC. We reveal an unexpected association between exposome-related mutational signature and EEEC, characterized by specific CTNNB1 and SIGLEC10 hotspot mutations and disruption of downstream pathways. Interestingly, SIGLEC10Q144K mutation in EEECs resulted in aberrant SIGLEC-10 protein expression and promoted progestin resistance by interacting with estrogen receptor alpha. We also identified potential protein biomarkers for progestin response in fertility-sparing treatment for EEEC. Collectively, our study establishes a proteogenomic resource of EEECs, uncovering the interactions between exposome and genomic susceptibilities that contribute to the development of primary prevention and early detection strategies for EEECs.

CCDC157 is essential for sperm differentiation and shows oligoasthenoteratozoospermia-related mutations in men.

Oligoasthenoteratospermia (OAT), characterized by abnormally low sperm count, poor sperm motility, and abnormally high number of deformed spermatozoa, is an important cause of male infertility. Its genetic basis in many affected individuals remains unknown. Here, we found that CCDC157 variants are associated with OAT. In two cohorts, a 21-bp (g.30768132_30768152del21) and/or 24-bp (g.30772543_30772566del24) deletion of CCDC157 were identified in five sporadic OAT patients, and 2 cases within one pedigree. In a mouse model, loss of Ccdc157 led to male sterility with OAT-like phenotypes. Electron microscopy revealed misstructured acrosome and abnormal head-tail coupling apparatus in the sperm of Ccdc157-null mice. Comparative transcriptome analysis showed that the Ccdc157 mutation alters the expressions of genes involved in cell migration/motility and Golgi components. Abnormal Golgi apparatus and decreased expressions of genes involved in acrosome formation and lipid metabolism were detected in Ccdc157-deprived mouse germ cells. Interestingly, we attempted to treat infertile patients and Ccdc157 mutant mice with a Chinese medicine, Huangjin Zanyu, which improved the fertility in one patient and most mice that carried the heterozygous mutation in CCDC157. Healthy offspring were produced. Our study reveals CCDC157 is essential for sperm maturation and may serve as a marker for diagnosis of OAT.

Comprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation.

Hyperthermic intraperitoneal chemotherapy's role in ovarian cancer remains controversial, hindered by limited understanding of hyperthermia-induced tumor cellular changes. This limits developing potent combinatory strategies anchored in hyperthermic intraperitoneal therapy (HIPET). Here, we perform a comprehensive multi-omics study on ovarian cancer cells under hyperthermia, unveiling a distinct molecular panorama, primarily characterized by rapid protein phosphorylation changes. Based on the phospho-signature, we pinpoint CDK1 kinase is hyperactivated during hyperthermia, influencing the global signaling landscape. We observe dynamic, reversible CDK1 activity, causing replication arrest and early mitotic entry post-hyperthermia. Subsequent drug screening shows WEE1 inhibition synergistically destroys cancer cells with hyperthermia. An in-house developed miniaturized device confirms hyperthermia and WEE1 inhibitor combination significantly reduces tumors in vivo. These findings offer additional insights into HIPET, detailing molecular mechanisms of hyperthermia and identifying precise drug combinations for targeted treatment. This research propels the concept of precise hyperthermic intraperitoneal therapy, highlighting its potential against ovarian cancer.

Protective effect of Tibetan medicine Qiwei Tiexie pills on liver injury induced by acetaminophen overdose: An integrated strategy of network pharmacology, metabolomics and transcriptomics.

BACKGROUND: Drug-induced liver injury, particularly from acetaminophen (APAP), has emerged as a significant public health concern. Unfortunately, there is currently no effective treatment strategy available. Qiwei Tiexie pills (QWTX), a traditional Tibetan medicine, have demonstrated considerable clinical efficacy in treating various liver diseases. Nevertheless, the protective effect of QWTX against drug-induced liver injury and its underlying mechanism remains poorly understood. PURPOSE: This study aimed to assess the therapeutic potential of QWTX, a Tibetan medicine, in an animal model of APAP-induced liver injury. Additionally, we sought to investigate the molecular mechanism through which QWTX exerts its effects. METHODS: We employed LC-MS and network pharmacology to predict the potential targets of QWTX in drug-induced liver injury. Subsequently, we employed HE staining, transcriptomics, metabolomics, and qRT-PCR to analyze the mechanism underlying QWTX treatment in drug-induced liver injury. RESULTS: Network pharmacology analysis revealed that the active components of QWTX are involved in inflammatory and drug metabolism-related pathways. In mouse models, pretreatment with QWTX effectively mitigated the elevated levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and inflammatory factors (IL-1ß, IL-6, and TNF-α) induced by APAP overdose. Moreover, APAP inhibited 1459 differentially expressed genes (DEGs) and 874 differential accumulation metabolites (DAMs), while QWTX promoted their expression. Conversely, APAP promoted 874 genes and 119 metabolites, which were inhibited by QWTX. Further analysis demonstrated that QWTX ameliorated the metabolic disorders induced by APAP overdose and potentially exerted a protective effect by inhibiting the expression of critical genes in crucial inflammatory pathways. QWTX also up-regulated antioxidant enzymes, thereby mitigating the oxidative stress resulting from APAP overdose. CONCLUSION: QWTX treatment effectively protects against APAP-induced liver damage in mice. Transcriptomic and metabolomic analyses further revealed that QWTX ameliorated hepatic metabolic disorders induced by APAP overdose while significantly suppressing the inflammatory response and oxidative stress associated with drug-induced liver injury. This study provides a new insight into the treatment of drug-induced liver injury by the TCM system and provides a basis for the development of new therapies for drug-induced liver injury by QWTX and its active ingredients.

Impaired dNKAP function drives genome instability and tumorigenic growth in Drosophila epithelia.

Mutations or dysregulated expression of NF-kappaB activating protein (NKAP) family genes have been found in human cancers. How NKAP family gene mutations promote tumor initiation and progression remains to be determined. Here, we characterized dNKAP, the Drosophila homolog of NKAP, and showed that impaired dNKAP function causes genome instability and tumorigenic growth in a Drosophila epithelial tumor model. dNKAP-knockdown wing imaginal discs exhibit tumorigenic characteristics, including tissue overgrowth, cell invasive behavior, abnormal cell polarity, and cell adhesion defects. dNKAP knockdown causes both R-loop accumulation and DNA damage, indicating the disruption of genome integrity. Further analysis showed that dNKAP knockdown induces c-Jun N-terminal kinase (JNK)-dependent apoptosis and causes changes in cell proliferation in distinct cell populations. Activation of the Notch and JAK/STAT signaling pathways contributes to the tumorigenic growth of dNKAP-knockdown tissues. Furthermore, JNK signaling is essential for dNKAP depletion-mediated cell invasion. Transcriptome analysis of dNKAP-knockdown tissues confirmed the misregulation of signaling pathways involved in promoting tumorigenesis and revealed abnormal regulation of metabolic pathways. dNKAP knockdown and oncogenic Ras, Notch, or Yki mutations show synergies in driving tumorigenesis, further supporting the tumor-suppressive role of dNKAP. In summary, this study demonstrates that dNKAP plays a tumor-suppressive role by preventing genome instability in Drosophila epithelia and thus provides novel insights into the roles of human NKAP family genes in tumor initiation and progression.

Fructose overconsumption impairs hepatic manganese homeostasis and ammonia disposal.

Arginase, a manganese (Mn)-dependent enzyme, is indispensable for urea generation and ammonia disposal in the liver. The potential role of fructose in Mn and ammonia metabolism is undefined. Here we demonstrate that fructose overconsumption impairs hepatic Mn homeostasis and ammonia disposal in male mice. Fructose overexposure reduces liver Mn content as well as its activity of arginase and Mn-SOD, and impairs the clearance of blood ammonia under liver dysfunction. Mechanistically, fructose activates the Mn exporter Slc30a10 gene transcription in the liver in a ChREBP-dependent manner. Hepatic overexpression of Slc30a10 can mimic the effect of fructose on liver Mn content and ammonia disposal. Hepatocyte-specific deletion of Slc30a10 or ChREBP increases liver Mn contents and arginase activity, and abolishes their responsiveness to fructose. Collectively, our data establish a role of fructose in hepatic Mn and ammonia metabolism through ChREBP/Slc30a10 pathway, and postulate fructose dietary restriction for the prevention and treatment of hyperammonemia.

Zn-Shik-PEG nanoparticles alleviate inflammation and multi-organ damage in sepsis.

Sepsis is defined as a life-threatening organ dysfunction caused by excessive formation of reactive oxygen species (ROS) and dysregulated inflammatory response. Previous studies have reported that shikonin (Shik) possess prominent anti-inflammatory and antioxidant effects and holds promise as a potential therapeutic drug for sepsis. However, the poor water solubility and the relatively high toxicity of shikonin hamper its clinical application. To address this challenge, we constructed Zn2+-shikonin nanoparticles, hereafter Zn-Shik-PEG NPs, based on an organic-inorganic hybridization strategy of metal-polyphenol coordination to improve the aqueous solubility and biosafety of shikonin. Mechanistic studies suggest that Zn-Shik-PEG NPs could effectively clear intracellular ROS via regulating the Nrf2/HO-1 pathway, meanwhile Zn-Shik-PEG NPs could inhibit NLRP3 inflammasome-mediated activation of inflammation and apoptosis by regulating the AMPK/SIRT1 pathway. As a result, the Zn-Shik-PEG NPs demonstrated excellent therapeutic efficacies in lipopolysaccharide (LPS) as well as cecal ligation puncture (CLP) induced sepsis model. These findings suggest that Zn-Shik-PEG NPs may have therapeutic potential for the treatment of other ROS-associated and inflammatory diseases.

Inhibition of SF3B1 improves the immune microenvironment through pyroptosis and synergizes with αPDL1 in ovarian cancer.

Ovarian cancer is resistant to immune checkpoint blockade (ICB) treatment. Combination of targeted therapy and immunotherapy is a promising strategy for ovarian cancer treatment benefit from an improved immune microenvironment. In this study, Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) cohorts were used to screen prognosis and cytotoxic lymphocyte infiltration-associated genes in upregulated genes of ovarian cancer, tissue microarrays were built for further verification. In vitro experiments and mouse (C57/BL6) ovarian tumor (ID8) models were built to evaluate the synergistic effect of the combination of SF3B1 inhibitor and PD-L1 antibody in the treatment of ovarian cancer. The results show that SF3B1 is shown to be overexpressed and related to low cytotoxic immune cell infiltration in ovarian cancer. Inhibition of SF3B1 induces pyroptosis in ovarian cancer cells and releases mitochondrial DNA (mtDNA), which is englobed by macrophages and subsequently activates them (polarization to M1). Moreover, pladienolide B increases cytotoxic immune cell infiltration in the ID8 mouse model as a SF3B1 inhibitor and increases the expression of PD-L1 which can enhance the antitumor effect of αPDL1 in ovarian cancer. The data suggests that inhibition of SF3B1 improves the immune microenvironment of ovarian cancer and synergizes ICB immunotherapy, which provides preclinical evidence for the combination of SF3B1 inhibitor and ICB to ovarian cancer treatment.

X-linked RBBP7 mutation causes maturation arrest and testicular tumors.

Maturation arrest (MA) is a subtype of non-obstructive azoospermia, and male infertility is a known risk factor for testicular tumors. However, the genetic basis for many affected individuals remains unknown. Here, we identified a deleterious hemizygous variant of X-linked retinoblastoma-binding protein 7 (RBBP7) as a potential key cause of MA, which was also found to be associated with the development of Leydig cell tumors. This mutation resulted in premature protein translation termination, affecting the sixth WD40 domain of the RBBP7 and the interaction of the mutated RBBP7 with histone H4. Decreased BRCA1 and increased γH2AX were observed in the proband. In mouse spermatogonial and pachytene spermatocyte-derived cells, deprivation of rbbp7 led to cell cycle arrest and apoptosis. In Drosophila, knockdown of RBBP7/Caf1-55 in germ cells resulted in complete absence of germ cells and reduced testis size, whereas knockdown of RBBP7/Caf1-55 in cyst cells resulted in hyperproliferative testicular cells. Interestingly, male infertility caused by Caf1-55 deficiency was rescued by ectopic expression of wild-type human RBBP7 but not mutant variants, suggesting the importance of RBBP7 in spermatogenesis. Our study provides insights into the mechanisms underlying the co-occurrence of MA and testicular tumors and may pave the way for innovative genetic diagnostics of these 2 diseases.

MRE11:p.K464R mutation mediates olaparib resistance by enhancing DNA damage repair in HGSOC.

BACKGROUND: Although the clinical application of PARP inhibitors has brought hope to ovarian cancer, the problem of its resistance has become increasingly prominent. Therefore, clinical experts have been focused on finding specific indicators and therapeutic targets that can be used for resistance monitoring of PARP inhibitors. RESULTS: By cfDNA detecting during Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer, we found the presence of MRE11:p.K464R mutation was strongly associated with acquired Olaparib resistance. Structural analysis revealed that the MRE11:p.K464R mutation is situated at a critical site where the MRE11 protein interacts with other biomolecules, leading to potential structural and functional abnormalities of MRE11 protein. Functionally, MRE11:p.K464R mutation enhanced the tolerance of Olaparib by reducing the DNA damage. Mechanistically, MRE11:p.K464R mutation improved the efficiency of DNA damage repair and induce Olaparib resistance by enhancing its binding activity with the interacting proteins (including RAD50 and RPS3). Among them, the enhanced binding of MRE11:p.K464R mutation to RAD50/RPS3 facilitated non-homologous end joining (NHEJ) repair in tumor cells, thereby expanding the scope of research into acquired resistance to PARP inhibitors. CONCLUSIONS: Our findings provide a theoretical basis for MRE11:p.K464R mutation as a specific indicator of resistance monitoring in Olaparib treatment, and the exploration of its resistance mechanism provides a novel insights for the formulation of combination ther therapies after Olaparib resistance.

Loss of Paip1 causes translation reduction and induces apoptotic cell death through ISR activation and Xrp1.

Regulation of protein translation initiation is tightly associated with cell growth and survival. Here, we identify Paip1, the Drosophila homolog of the translation initiation factor PAIP1, and analyze its role during development. Through genetic analysis, we find that loss of Paip1 causes reduced protein translation and pupal lethality. Furthermore, tissue specific knockdown of Paip1 results in apoptotic cell death in the wing imaginal disc. Paip1 depletion leads to increased proteotoxic stress and activation of the integrated stress response (ISR) pathway. Mechanistically, we show that loss of Paip1 promotes phosphorylation of eIF2α via the kinase PERK, leading to apoptotic cell death. Moreover, Paip1 depletion upregulates the transcription factor gene Xrp1, which contributes to apoptotic cell death and eIF2α phosphorylation. We further show that loss of Paip1 leads to an increase in Xrp1 translation mediated by its 5'UTR. These findings uncover a novel mechanism that links translation impairment to tissue homeostasis and establish a role of ISR activation and Xrp1 in promoting cell death.

NKAP acts with HDAC3 to prevent R-loop associated genome instability.

Persistent R-loop accumulation can cause DNA damage and lead to genome instability, which contributes to various human diseases. Identification of molecules and signaling pathways in controlling R-loop homeostasis provide important clues about their physiological and pathological roles in cells. Here, we show that NKAP (NF-κB activating protein) is essential for preventing R-loop accumulation and maintaining genome integrity through forming a protein complex with HDAC3. NKAP depletion causes DNA damage and genome instability. Aberrant accumulation of R-loops is present in NKAP-deficient cells and leads to DNA damage and DNA replication fork progression defects. Moreover, NKAP depletion induced R-loops and DNA damage are dependent on transcription. Consistently, the NKAP interacting protein HDAC3 exhibits a similar role in suppressing R-loop associated DNA damage and replication stress. Further analysis uncovers that HDAC3 functions to stabilize NKAP protein, independent of its deacetylase activity. In addition, NKAP prevents R-loop formation by maintaining RNA polymerase II pausing. Importantly, R-loops induced by NKAP or HDAC3 depletion are processed into DNA double-strand breaks by XPF and XPG endonucleases. These findings indicate that both NKAP and HDAC3 are novel key regulators of R-loop homeostasis, and their dysregulation might drive tumorigenesis by causing R-loop associated genome instability.

HR repair pathway plays a crucial role in maintaining neural stem cell fate under irradiation stress.

Environmental stress can cause mutation or genomic instability in stem cells which, in some cases, leads to tumorigenesis. Mechanisms to monitor and eliminate these mutant stem cells remain elusive. Here, using the Drosophila larval brain as a model, we show that X-ray irradiation (IR) at the early larval stage leads to accumulation of nuclear Prospero (Pros), resulting in premature differentiation of neural stem cells (neuroblasts, NBs). Through NB-specific RNAi screenings, we determined that it is the Mre11-Rad50-Nbs1 complex and the homologous recombination (HR) repair pathway, rather than non-homologous end-joining pathway that plays, a dominant role in the maintenance of NBs under IR stress. The DNA damage sensor ATR/mei-41 is shown to act to prevent IR-induced nuclear Pros in a WRNexo-dependent manner. The accumulation of nuclear Pros in NBs under IR stress, leads to NB cell fate termination, rather than resulting in mutant cell proliferation. Our study reveals an emerging mechanism for the HR repair pathway in maintaining neural stem cell fate under irradiation stress.

The effect of ginsenosides on liver injury in preclinical studies: a systematic review and meta-analysis.

Background: Liver injury is a severe liver lesion caused by various etiologies and is one of the main areas of medical research. Panax ginseng C.A. Meyer has traditionally been used as medicine to treat diseases and regulate body functions. Ginsenosides are the main active components of ginseng, and their effects on liver injury have been extensively reported. Methods: Preclinical studies meeting the inclusion criteria were retrieved from PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), and Wan Fang Data Knowledge Service Platforms. The Stata 17.0 was used to perform the meta-analysis, meta-regression, and subgroup analysis. Results: This meta-analysis included ginsenosides Rb1, Rg1, Rg3, and compound K (CK), in 43 articles. The overall results showed that multiple ginsenosides significantly reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST), affected oxidative stress-related indicators, such as superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GSH-Px), and catalase (CAT), and reduced levels of inflammatory factor, such as factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6). Additionally, there was a large amount of heterogeneity in the meta-analysis results. Our predefined subgroup analysis shows that the animal species, the type of liver injury model, the duration of treatment, and the administration route may be the sources of some of the heterogeneity. Conclusion: In a word, ginsenosides have good efficacy against liver injury, and their potential mechanisms of action target antioxidant, anti-inflammatory and apoptotic-related pathways. However, the overall methodological quality of our current included studies was low, and more high-quality studies are needed to confirm their effects and mechanisms further.

Potential of Medicago sativa and Perilla frutescens for overcoming the soil sickness caused by ginseng cultivation.

There are serious soil sickness in ginseng cultivation. Crop rotation is an effective agricultural management to improve soil sustainability and reduce soil sickness. To explore an appropriate ginseng rotation system, Medicago sativa (alfalfa) and Perilla frutescens (perilla) were planted on ginseng cultivation soil for 1 year to evaluate the improvement effect of both. Through chemical analysis and high-throughput sequencing technology, we found that after alfalfa and perilla cultivation for one-year, various nutrients and enzyme activities in ginseng cultivation soil were significantly improved. In addition, perilla significantly increased the diversity and richness of soil fungal communities. Cultivation of alfalfa and perilla significantly changed the composition of soil bacterial and fungal communities and significantly reduced the abundance of the potentially pathogenic fungi Ilyonectria. Further pot experiments also showed that the improved soil could significantly increase root activity of ginseng plant after two plants were planted. It should be noted that, unlike alfalfa, perilla decreased soil electrical conductivity, increased soil organic matter, soil urease, and may significantly improve the diversity and richness of soil fungal community. Moreover, in the pot experiment, the root fresh weight of ginseng cultured in perilla treated soil increased significantly. This study highlights that perilla may have better soil improvement effect than alfalfa and it has the potential to be used in the soil improvement of ginseng cultivation.

Hepatic but not Intestinal FBP1 Is Required for Fructose Metabolism and Tolerance.

Fructose intolerance in mammals is caused by defects in fructose absorption and metabolism. Fructose-1,6-bisphosphatase 1 (FBP1) is a key enzyme in gluconeogenesis, and its deficiency results in hypoglycemia as well as intolerance to fructose. However, the mechanism about fructose intolerance caused by FBP1 deficiency has not been fully elucidated. Here, we demonstrate that hepatic but not intestinal FBP1 is required for fructose metabolism and tolerance. We generated inducible knockout mouse models specifically lacking FBP1 in adult intestine or liver. Intestine-specific deletion of Fbp1 in adult mice does not compromise fructose tolerance, as evidenced by no significant body weight loss, food intake reduction, or morphological changes of the small intestine during 4 weeks of exposure to a high-fructose diet. By contrast, liver-specific deletion of Fbp1 in adult mice leads to fructose intolerance, as manifested by substantial weight loss, hepatomegaly, and liver injury after exposure to a high-fructose diet. Notably, the fructose metabolite fructose-1-phosphate is accumulated in FBP1-deficient liver after fructose challenge, which indicates a defect of fructolysis, probably due to competitive inhibition by fructose-1,6-bisphosphate and may account for the fructose intolerance. In conclusion, these data have clarified the essential role of hepatic but not intestinal FBP1 in fructose metabolism and tolerance.

Co-dependent regulation of p-BRAF and potassium channel KCNMA1 levels drives glioma progression.

BRAF mutations have been found in gliomas which exhibit abnormal electrophysiological activities, implying their potential links with the ion channel functions. In this study, we identified the Drosophila potassium channel, Slowpoke (Slo), the ortholog of human KCNMA1, as a critical factor involved in dRafGOF glioma progression. Slo was upregulated in dRafGOF glioma. Knockdown of slo led to decreases in dRafGOF levels, glioma cell proliferation, and tumor-related phenotypes. Overexpression of slo in glial cells elevated dRaf expression and promoted cell proliferation. Similar mutual regulations of p-BRAF and KCNMA1 levels were then recapitulated in human glioma cells with the BRAF mutation. Elevated p-BRAF and KCNMA1 were also observed in HEK293T cells upon the treatment of 20 mM KCl, which causes membrane depolarization. Knockdown KCNMA1 in these cells led to a further decrease in cell viability. Based on these results, we conclude that the levels of p-BRAF and KCNMA1 are co-dependent and mutually regulated. We propose that, in depolarized glioma cells with BRAF mutations, high KCNMA1 levels act to repolarize membrane potential and facilitate cell growth. Our study provides a new strategy to antagonize the progression of gliomas as induced by BRAF mutations.

Preoperative and intraoperative assessment of myometrial invasion in patients with FIGO stage I non-endometrioid endometrial carcinoma-a large-scale, multi-center, and retrospective study.

INTRODUCTION: Myometrial invasion is a prognostic factor for lymph node metastases and decreased survival in non-endometrioid endometrial carcinoma patients. Herein, we explored the mode of myometrial invasion diagnosis in FIGO stage I non-endometrioid carcinoma and evaluated the differences in diagnostic efficiency among intraoperative frozen section (IFS), intraoperative gross examination (IGE), magnetic resonance imaging (MRI), and computed tomography (CT) in clinical practice. Finally, we suggested which test should be routinely performed. METHOD: This was a historical cohort study nationwide with 30 centers in China between January 2000 and December 2019. Clinical data, including age, histology, method of myometrial invasion evaluation (MRI, CT, IGE, and IFS), and final diagnosis of postoperative paraffin sections, were collected from 490 non-endometrioid endometrial carcinoma (serous, clear cell, undifferentiated, mixed carcinoma, and carcinosarcoma) women in FIGO stage I. RESULTS: Among the 490 patients, 89.59% presented myometrial invasion. The methods reported for myometrial invasion assessment were IFS in 23.47%, IGE in 69.59%, MRI in 37.96%, and CT in 10.20% of cases. The highest concordance was detected between IFS and postoperative paraffin sections (Kappa = 0.631, accuracy = 93.04%), followed by IGE (Kappa = 0.303, accuracy = 82.40%), MRI (Kappa = 0.131, accuracy = 69.35%), and CT (Kappa = 0.118, accuracy = 50.00%). A stable diagnostic agreement between IFS and the final results was also found through the years (2000-2012: Kappa = 0.776; 2013-2014: Kappa = 0.625; 2015-2016: Kappa = 0.545; 2017-2019: Kappa = 0.652). CONCLUSION: In China, the assessment of myometrial invasion in non-endometrioid endometrial carcinoma is often performed via IGE, but the reliability is relatively low in contrast to IFS. In clinical practice, IFS is a reliable method that can help accurately assess myometrial invasion and intraoperative decision-making (lymph node dissection or not). Hence, it should be routinely performed in non-endometrioid endometrial carcinoma patients.

ConvWin-UNet: UNet-like hierarchical vision Transformer combined with convolution for medical image segmentation.

Convolutional Neural Network (CNN) plays a vital role in the development of computer vision applications. The depth neural network composed of U-shaped structures and jump connections is widely used in various medical image tasks. Recently, based on the self-attention mechanism, the Transformer structure has made great progress and tends to replace CNN, and it has great advantages in understanding global information. In this paper, the ConvWin Transformer structure is proposed, which refers to the W-MSA structure in Swin and combines with the convolution. It can not only accelerate the convergence speed, but also enrich the information exchange between patches and improve the understanding of local information. Then, it is integrated with UNet, a U-shaped architecture commonly used in medical image segmentation, to form a structure called ConvWin-UNet. Meanwhile, this paper improves the patch expanding layer to perform the upsampling operation. The experimental results on the Hubmap datasets and synapse multi-organ segmentation dataset indicate that the proposed ConvWin-UNet structure achieves excellent results. Partial code and models of this work are available at https://github.com/xmFeng-hdu/ConvWin-UNet.

The Integrator complex desensitizes cellular response to TGF-ß/BMP signaling.

Maintenance of stem cells requires the concerted actions of niche-derived signals and stem cell-intrinsic factors. Although Decapentaplegic (Dpp), a Drosophila bone morphogenetic protein (BMP) molecule, can act as a long-range morphogen, its function is spatially limited to the germline stem cell niche in the germarium. We show here that Integrator, a complex known to be involved in RNA polymerase II (RNAPII)-mediated transcriptional regulation in the nucleus, promotes germline differentiation by restricting niche-derived Dpp/BMP activity in the cytoplasm. Further results show that Integrator works in various developmental contexts to desensitize the cellular response to Dpp/BMP signaling during Drosophila development. Mechanistically, our results show that Integrator forms a multi-subunit complex with the type I receptor Thickveins (Tkv) and other Dpp/BMP signaling components and acts in a negative feedback loop to promote Tkv turnover independent of its transcriptional activity. Similarly, human Integrator subunits bind transforming growth factor ß (TGF-ß)/BMP signaling components and antagonize their activity, suggesting a conserved role of Integrator across metazoans.