The Current Understanding of Molecular Mechanisms in Adenomyosis-Associated Infertility and the Treatment Strategy for Assisted Reproductive Technology.

Adenomyosis, endometriosis of the uterus, is associated with an increased likelihood of abnormal endometrial molecular expressions thought to impair implantation and early embryo development, resulting in disrupted fertility, including the local effects of sex steroid and pituitary hormones, immune responses, inflammatory factors, and neuroangiogenic mediators. In the recent literature, all of the proposed pathogenetic mechanisms of adenomyosis reduce endometrial receptivity and alter the adhesion molecule expression necessary for embryo implantation. The evidence so far has shown that adenomyosis causes lower pregnancy and live birth rates, higher miscarriage rates, as well as adverse obstetric and neonatal outcomes. Both pharmaceutical and surgical treatments for adenomyosis seem to have a positive impact on reproductive outcomes, leading to improved pregnancy and live birth rates. In addition, adenomyosis has negative impacts on reproductive outcomes in patients undergoing assisted reproductive technology. This association appears less significant after patients follow a long gonadotropin-releasing hormone agonist (GnRHa) protocol, which improves implantation rates. The pre-treatment of GnRHa can also be beneficial before engaging in natural conception attempts. This review aims to discover adenomyosis-associated infertility and to provide patient-specific treatment options.

Californium-252 Intracavitary Radiotherapy for Primary Vaginal Carcinoma: A Retrospective Clinical Study.

Objective: To investigate the therapeutic effect of Cf-252 neutron intracavitary brachytherapy (ICBT) in the treatment of primary vaginal carcinoma of stage I-III, along with advanced complications. Methods: Between August 2009 and August 2013, 41 patients with intact primary vaginal carcinoma based on the histological diagnosis at the Second Cancer Hospital of Heilongjiang Province (Beidahuang Group General Hospital) and the Daping Hospital of the Third Military Medical University were included in this study. Among them, 32 patients were squamous cell carcinoma, and 9 adenocarcinomas. Stage I patients were treated with ICBT alone. Patients at stages II and III were treated using ICBT combined with external beam radiotherapy (EBRT). Results: The mean age, the rate of the 5-year local control, the rate of the 5-year overall survival was increased. The rate of the 5-year tumor-free survival was 56.1%, and the incidence of advanced serious complications (grade II and above radiation cystitis, proctitis, etc.) was 29.3%. Compared to later stages, early-stage patients are in better physical shape, so they are better able to withstand the toxic side effects of treatment. The local control (LC), overall survival (OS), or disease-free survival (DFS) rate in stage III patients was significantly lower than those in stage I and stage II. The rate of OS in stage I patients was 90.9% (10/11), which was significantly higher than that in all patients (56.1%; 23/41). Moreover, the mean survival time was significantly different between stage III and stage I. In addition, the survival status of squamous cell carcinoma and adenocarcinoma was also very different. Conclusion: In summary, the use of Cf-252 ICBT radiotherapy resulted in a higher rate of local control of vaginal cancer and a lower rate of recurrence, better-shrinking effect, and efficacy for advanced tumors, and has clinical prospects.

IRF8 deficiency-induced myeloid-derived suppressor cell promote immune evasion in lung adenocarcinoma.

BACKGROUND: Patients with lung adenocarcinoma (LUAD) have a low response rate to immune checkpoint blockade. It is highly important to explore the tumor immune escape mechanism of LUAD patients and expand the population of patients who may benefit from immunotherapy. METHODS: Based on 954 bulk RNA-seq data of LUAD patients and 15 single-cell RNA-seq data, the relationships between tumor immune dysfunction and exclusion (TIDE) scores and survival prognosis in each patient were calculated and evaluated, and the immune escape mechanism affecting the independent prognosis of LUAD patients was identified. Functional enrichment analysis explored the antitumour immune response and biological behavior of tumor cells among different LUAD groups. Single-cell annotation and pseudotemporal analysis were used to explore the target molecules and immune escape mechanisms of LUAD. RESULTS: Myeloid-derived suppressor cells (MDSCs) and IRF8 were identified as risk and protective factors for the independent prognosis of LUAD patients, respectively. In the tumor microenvironment of patients with high infiltration of MDSCs, the antitumor immune response is significantly suppressed, while tumor cell division, proliferation, and distant metastasis are significantly enhanced. Single-cell RNA-seq analysis revealed that IRF8 is an important regulator of MDSC differentiation in LUAD myeloid cells. In addition, IRF8 may regulate the differentiation of MDSCs through the IL6-JAK-STAT3 signalling pathway. CONCLUSIONS: IRF8 deficiency impairs the normal development of LUAD myeloid cells and induces their differentiation into MDSCs, thereby accelerating the immune escape of LUAD cells. IRF8-targeted activation to inhibit the formation of MDSCs may be a new target for immunotherapy in LUAD.

Development and validation of a clinical decision tool for preoperative micropapillary and solid pattern lung adenocarcinoma of CT≤2 cm.

BACKGROUND: Micropapillary (MP) and solid(S) pattern adenocarcinoma are highly malignant subtypes of lung adenocarcinoma. In today's era of increasingly conservative surgery for small lung cancer, effective preoperative identification of these subtypes is greatly important for surgical planning and long term survival of patients. METHODS: For this retrospective study, the presence of MP and/or S was evaluated in 2167 consecutive patients who underwent surgical resection for clinical stage IA1-2 lung adenocarcinoma. MP and/or S pattern-positive patients and negative-pattern patients were matched at a ratio of 1:3. The Lasso regression model was used for data dimension reduction and imaging signature building. Multivariate logistic regression was used to establish the predictive model, presented as an imaging nomogram. The performance of the nomogram was assessed based on calibration, identification, and clinical usefulness, and internal and external validation of the model was conducted. RESULTS: The proportion of solid components (PSC), Sphericity, entropy, Shape, bronchial honeycomb, nodule shape, sex, and smoking were independent factors in the prediction model of MP and/or S lung adenocarcinoma. The model showed good discrimination with an area under the ROC curve of 0.85. DCA demonstrated that the model could achieve good benefits for patients. RCS analysis suggested a significant increase in the proportion of MP and/or S from 11% to 48% when the PSC value was 68%. CONCLUSION: Small MP and/or S adenocarcinoma can be effectively identified preoperatively by their typical 3D and 2D imaging features.

Impact of Telemedicine on Blood Glucose Control and Ophthalmic Screenings for Patients with Diabetes in Remote Areas During the COVID-19 Pandemic: A Real-World Study in Northern Taiwan.

Introduction: The purpose of this study was to assess the impact of telemedicine on ophthalmic screening and blood glucose control for patients with diabetes in remote areas of Northern Taiwan during the coronavirus disease 2019 (COVID-19) pandemic. Methods: Telemedicine was implemented in Shiding and Wanli Districts using a 5G platform from April 2021 to December 2022. Patients with poorly controlled diabetes received real-time consultations from endocrinologists at Far Eastern Memorial Hospital, 50 km away, for medication adjustment, diet control, and lifestyle recommendations. The study also provided cloud-upload blood glucose meters for self-monitoring and regular medical advice from hospital nurses. Ophthalmic screenings included fundus imaging, external eye image, and intraocular pressure measurement, with instant communication and diagnosis by ophthalmologists through telemedicine. A satisfaction questionnaire survey was conducted. Results: The study enrolled 196 patients with diabetes. Blood glucose and glycosylated hemoglobin levels were significantly reduced after applying telemedicine (p = 0.01 and p = 0.005, respectively). Ophthalmic screenings led to hospital referrals for 16.0% with abnormal fundus images, 15.6% with severe cataract or anterior segment disorders, and 27.9% with ocular hypertension or glaucoma. Fundus screening rates remained high at 86.3% and 80.4% in 2022, mainly using telemedicine, comparable with the traditional screening rate in the past 5 years. The overall satisfaction rate was 98.5%. Conclusions: Telemedicine showed effectiveness and high satisfaction in managing diabetes and conducting ophthalmic screenings in remote areas during the COVID-19 pandemic. It facilitated early diagnosis and treatment of ocular conditions while maintaining good blood glucose control and fundus screening rates.

Lung adenocarcinoma: selection of surgical approaches in solid adenocarcinoma from the viewpoint of clinicopathologic features and tumor microenvironmental heterogeneity.

Introduction: Solid adenocarcinoma represents a notably aggressive subtype of lung adenocarcinoma. Amidst the prevailing inclination towards conservative surgical interventions for diminutive lung cancer lesions, the critical evaluation of this subtype's malignancy and heterogeneity stands as imperative for the formulation of surgical approaches and the prognostication of long-term patient survival. Methods: A retrospective dataset, encompassing 2406 instances of non-solid adenocarcinoma (comprising lepidic, acinar, and papillary adenocarcinoma) and 326 instances of solid adenocarcinoma, was analyzed to ascertain the risk factors concomitant with diverse histological variants of lung adenocarcinoma. Concurrently, RNA-sequencing data delineating explicit pathological subtypes were extracted from 261 cases in the TCGA database and 188 cases in the OncoSG database. This data served to illuminate the heterogeneity across lung adenocarcinoma (LUAD) specimens characterized by differential histological features. Results: Solid adenocarcinoma is associated with an elevated incidence of pleural invasion, microscopic vessel invasion, and lymph node metastasis, relative to other subtypes of lung adenocarcinoma. Furthermore, the tumor microenvironment (TME) in solid pattern adenocarcinoma displayed suboptimal oxygenation and acidic conditions, concomitant with augmented tumor cell proliferation and invasion capacities. Energy and metabolic activities were significantly upregulated in tumor cells of the solid pattern subtype. This subtype manifested robust immune tolerance and capabilities for immune evasion. Conclusion: This present investigation identifies multiple potential metrics for evaluating the invasive propensity, metastatic likelihood, and immune resistance of solid pattern adenocarcinoma. These insights may prove instrumental in devising surgical interventions that are tailored to patients diagnosed with disparate histological subtypes of LUAD, thereby offering valuable directional guidance.

LINC00963 Promotes Cisplatin Resistance in Esophageal Squamous Cell Carcinoma by Interacting with miR-10a to Upregulate SKA1 Expression.

Long non-coding RNA (lncRNA) is associated with a large number of tumor cellular functions together with chemotherapy resistance in a variety of tumors. LINC00963 was identified to regulate the malignant progression of various cancers. However, whether LINC00963 affects drug resistence in esophageal squamous cell carcinoma (ESCC) and the relevant molecular mechanisms have never been reported. This study aims to investigate the effect of LINC00963 on cisplatin resistance in ESCC. After detecting the level of LINC00963 in human esophageal squamous epithelial cells (HET-1 A), ESCC cells (TE-1) and cisplatin resistant cells of ESCC (TE-1/DDP), TE-1/DDP cell line and nude mouse model that interfered with LINC00963 expression were established. Then, the interaction among LINC00963, miR-10a, and SKA1 was clarified by double luciferase and RNA immunoprecipitation (RIP) assays. Meanwhile, the biological behavior changes of TE-1/DDP cells with miR-10a overexpression or SKA1 silencing were observed by CCK-8, flow cytometry, scratch, Transwell, and colony formation tests. Finally, the biological function of the LINC00963/SKA1 axis was elucidated by rescue experiments. LINC00963 was upregulated in TE-1 and TE-1/DDP cell lines. LINC00963 knockdown inhibited SKA1 expression of both cells and impaired tumorigenicity. Moreover, LINC00963 has a target relationship with miR-10a, and SKA1 is a target gene of miR-10a. MiR-10a overexpression or SKA1 silencing decreased the biological activity of TE-1/DDP cells and the expression of SKA1. Furthermore, SKA1 overexpression reverses the promoting effect of LINC00963 on cisplatin resistance of ESCC. LINC00963 regulates TE-1/DDP cells bioactivity and mediates cisplatin resistance through interacting with miR-10a and upregulating SKA1 expression.

Pan-cancer scRNA-seq analysis reveals immunological and diagnostic significance of the peripheral blood mononuclear cells.

Peripheral blood mononuclear cells (PBMCs) reflect systemic immune response during cancer progression. However, a comprehensive understanding of the composition and function of PBMCs in cancer patients is lacking, and the potential of these features to assist cancer diagnosis is also unclear. Here, the compositional and status differences between cancer patients and healthy donors in PBMCs were investigated by single-cell RNA sequencing (scRNA-seq), involving 262,025 PBMCs from 68 cancer samples and 14 healthy samples. We observed an enhanced activation and differentiation of most immune subsets in cancer patients, along with reduction of naïve T cells, expansion of macrophages, impairment of NK cells and myeloid cells, as well as tumor promotion and immunosuppression. Based on characteristics including differential cell type abundances and/or hub genes identified from weight gene co-expression network analysis (WGCNA) modules of each major cell type, we applied logistic regression to construct cancer diagnosis models. Furthermore, we found that the above models can distinguish cancer patients and healthy donors with high sensitivity. Our study provided new insights into using the features of PBMCs in non-invasive cancer diagnosis.

A Deep Learning Model Enhances Clinicians' Diagnostic Accuracy to More Than 96% for Anterior Cruciate Ligament Ruptures on Magnetic Resonance Imaging.

PURPOSE: To develop a deep learning model to accurately detect anterior cruciate ligament (ACL) ruptures on magnetic resonance imaging (MRI) and to evaluate its effect on the diagnostic accuracy and efficiency of clinicians. METHODS: A training dataset was built from MRIs acquired from January 2017 to June 2021, including patients with knee symptoms, irrespective of ACL ruptures. An external validation dataset was built from MRIs acquired from January 2021 to June 2022, including patients who underwent knee arthroscopy or arthroplasty. Patients with fractures or prior knee surgeries were excluded in both datasets. Subsequently, a deep learning model was developed and validated using these datasets. Clinicians of varying expertise levels in sports medicine and radiology were recruited, and their capacities in diagnosing ACL injuries in terms of accuracy and diagnosing time were evaluated both with and without artificial intelligence (AI) assistance. RESULTS: A deep learning model was developed based on the training dataset of 22,767 MRIs from 5 centers and verified with external validation dataset of 4,086 MRIs from 6 centers. The model achieved an area under the receiver operating characteristic curve of 0.987 and a sensitivity and specificity of 95.1%. Thirty-eight clinicians from 25 centers were recruited to diagnose 3,800 MRIs. The AI assistance significantly improved the accuracy of all clinicians, exceeding 96%. Additionally, a notable reduction in diagnostic time was observed. The most significant improvements in accuracy and time efficiency were observed in the trainee groups, suggesting that AI support is particularly beneficial for clinicians with moderately limited diagnostic expertise. CONCLUSIONS: This deep learning model demonstrated expert-level diagnostic performance for ACL ruptures, serving as a valuable tool to assist clinicians of various specialties and experience levels in making accurate and efficient diagnoses. LEVEL OF EVIDENCE: Level III, retrospective comparative case series.

pH-Responsive Sorafenib/Iron-Co-Loaded Mesoporous Polydopamine Nanoparticles for Synergistic Ferroptosis and Photothermal Therapy.

Ferroptosis has attracted significant attention as a new mechanism of cell death. Sorafenib (SRF) is widely considered a prototypical ferroptosis-inducing drug, particularly for liver cancer treatment. However, the low solubility and hydrophobic nature of SRF, along with the absence of synergistic therapeutic strategies, still limit its application in cancer treatment. Herein, we report a dual therapeutic method incorporating photothermal therapy and ferroptosis by using Fe-doped mesoporous polydopamine nanoparticles (Fe-mPDA@SRF-TPP) as a carrier for loading SRF and targeting triphenylphosphine (TPP). SRF molecules are efficiently encapsulated within the polydopamine nanospheres with a high loading ratio (80%) attributed to the porosity of Fe-mPDA, and the inherent biocompatibility and hydrophilicity of Fe-mPDA@SRF-TPP facilitate the transport of SRF to the target cancer cells. Under the external stimuli of acidic environment (pH 5.0), glutathione (GSH), and laser irradiation, Fe-mPDA@SRF-TPP shows sustained release of SRF and Fe ions with the ratio of 72 and 50% within 48 h. Fe-mPDA@SRF-TPP nanoparticles induce intracellular GSH depletion, inhibit glutathione peroxidase 4 (GPX4) activity, and generate hydroxyl radicals, all of which are essential components of the therapeutic ferroptosis process for killing MDA-MB-231 cancer cells. Additionally, the excellent near-infrared (NIR) light absorption of Fe-mPDA@SRF-TPP nanoparticles demonstrates their capability for photothermal therapy and further enhances the therapeutic efficiency. Therefore, this nanosystem provides a multifunctional therapeutic platform that overcomes the therapeutic limitations associated with standalone ferroptosis and enhances the therapeutic efficacy of SRF for breast cancer.

Single cell multi-omics reveal intra-cell-line heterogeneity across human cancer cell lines.

Human cancer cell lines have long served as tools for cancer research and drug discovery, but the presence and the source of intra-cell-line heterogeneity remain elusive. Here, we perform single-cell RNA-sequencing and ATAC-sequencing on 42 and 39 human cell lines, respectively, to illustrate both transcriptomic and epigenetic heterogeneity within individual cell lines. Our data reveal that transcriptomic heterogeneity is frequently observed in cancer cell lines of different tissue origins, often driven by multiple common transcriptional programs. Copy number variation, as well as epigenetic variation and extrachromosomal DNA distribution all contribute to the detected intra-cell-line heterogeneity. Using hypoxia treatment as an example, we demonstrate that transcriptomic heterogeneity could be reshaped by environmental stress. Overall, our study performs single-cell multi-omics of commonly used human cancer cell lines and offers mechanistic insights into the intra-cell-line heterogeneity and its dynamics, which would serve as an important resource for future cancer cell line-based studies.

Super-enhancer driven SOX2 promotes tumor formation by chromatin re-organization in nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer with a high incidence in Southern China and Southeast Asia. Patients with remote metastasis and recurrent NPC have poor prognosis. Thus, a better understanding of NPC pathogenesis may identify novel therapies to address the unmet clinical needs. METHODS: H3K27ac ChIP-seq and HiChIP was applied to understand the enhancer landscapes and the chromosome interactions. Whole genome sequencing was conducted to analyze the relationship between genomic variations and epigenetic dysregulation. CRISPRi and JQ1 treatment were used to evaluate the transcriptional regulation of SOX2 SEs. Colony formation assay, survival analysis and in vivo subcutaneous patient-derived xenograft assays were applied to explore the function and clinical relevance of SOX2 in NPC. FINDINGS: We globally mapped the enhancer landscapes and generated NPC enhancer connectomes, linking NPC specific enhancers and SEs. We found five overlapped genes, including SOX2, among super-enhancer regulated genes, survival related genes and NPC essential genes. The mRNA expression of SOX2 was repressed when applying CRISPRi targeting different SOX2 SEs or JQ1 treatment. Next, we identified a genetic variation (Chr3:181422197, G > A) in SOX2 SE which is correlated with higher expression of SOX2 and poor survival. In addition, SOX2 was highly expressed in NPC and is correlated with short survival in patients with NPC. Knock-down of SOX2 suppressed tumor growth in vitro and in vivo. INTERPRETATION: Our study demonstrated the super-enhancer landscape with chromosome interactions and identified super-enhancer driven SOX2 promotes tumorigenesis, suggesting that SOX2 is a potential therapeutic target for patients with NPC. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Innate immune response restarts adaptive immune response in tumors.

The imbalance of immune response plays a crucial role in the development of diseases, including glioblastoma. It is essential to comprehend how the innate immune system detects tumors and pathogens. Endosomal and cytoplasmic sensors can identify diverse cancer cell antigens, triggering the production of type I interferon and pro-inflammatory cytokines. This, in turn, stimulates interferon stimulating genes, enhancing the presentation of cancer antigens, and promoting T cell recognition and destruction of cancer cells. While RNA and DNA sensing of tumors and pathogens typically involve different receptors and adapters, their interaction can activate adaptive immune response mechanisms. This review highlights the similarity in RNA and DNA sensing mechanisms in the innate immunity of both tumors and pathogens. The aim is to enhance the anti-tumor innate immune response, identify regions of the tumor that are not responsive to treatment, and explore new targets to improve the response to conventional tumor therapy and immunotherapy.

ZIC2 induces pro-tumor macrophage polarization in nasopharyngeal carcinoma by activating the JUNB/MCSF axis.

Nasopharyngeal carcinoma (NPC) is a common malignant epithelial tumor of the head and neck that often exhibits local recurrence and distant metastasis. The molecular mechanisms are understudied, and effective therapeutic targets are still lacking. In our study, we found that the transcription factor ZIC2 was highly expressed in NPC. Although ZIC family members play important roles in neural development and carcinogenesis, the specific mechanism and clinical significance of ZIC2 in the tumorigenesis and immune regulation of NPC remain elusive. Here, we first reported that high expression of ZIC2 triggered the secretion of MCSF in NPC cells, induced M2 polarization of tumor-associated macrophages (TAMs), and affected the secretion of TAM-related cytokines. Mechanistically, ChIP-seq and RNA-seq analyses identified JUNB as a downstream target of ZIC2. Furthermore, ZIC2 was significantly enriched in the promoter site of JUNB and activated JUNB promoter activity, as shown by ChIP-qPCR and luciferase assays. In addition, JUNB and MCSF participated in ZIC2-induced M2 TAMs polarization. Thus, blocking JUNB and MCSF could reverse ZIC2-mediated M2 TAMs polarization. Moreover, Kaplan-Meier survival analyses indicated that high expression of ZIC2, JUNB, and CD163 was positively associated with a poor prognosis in NPC. Overexpression of ZIC2 induced tumor growth in vivo, with the increase of JUNB, MCSF secretion, and CD163. In summary, our study implies that ZIC2 induces M2 TAM polarization, at least in part through regulation of JUNB/MCSF and that ZIC2, JUNB, and CD163 can be utilized as prognostic markers for NPC and as therapeutic targets for cancer immunotherapy.

Paxlovid for hospitalized COVID-19 patients with chronic kidney disease.

BACKGROUND: COVID-19 causes significant mortality during the recent pandemic. Data regarding the effectiveness of Paxlovid on COVID-19 patients with chronic kidney disease (CKD, eGFR <90 ml/min) are limited. METHODS: A retrospective cohort study was performed on the clinical data of the hospitalized adult patients with confirmed COVID-19 infection collected at Renji Hospital from April 7, 2022 to June 21, 2022. The association of Paxlovid treatment with early (within 5 days post diagnosis) or late (5 days or later post diagnosis) initiation time with clinical outcomes was assessed by Cox proportional hazards regression model with time-dependent covariates. RESULT: 1279 of 2387 enrollees were included in the study. Patients with early initiation of Paxlovid had a lower all-cause death rate compared to those with late initiation or without Paxlovid treatment (P = 0.046). For the CKD patients with Charlson comorbidity index (CCI) > 7, the early initiation of Paxlovid was associated with a lower all-cause death rate compared to the later initiation or the lack of Paxlovid treatment (P = 0.041). Cox regression analyses revealed that eGFR (HR 4.21 [95%, CI 1.62-10.99]), Paxlovid treatment (0.32 [0.13-0.77]), CCI (4.32 [1.64-11.40]), ICU admission (2.65 [1.09-6.49]), hsCRP (3.88 [1.46-7.80]), chronic liver disease (4.02 [1.09-14.85]) were the independent risk factors for all-cause death for CKD patients after adjusting for demographics and biochemical indexes. CONCLUSIONS: All-cause death, invasive ventilation, and ICU admission were all significantly lowered by an early initiation of Paxlovid treatment in COVID-19 patients with severe CKD.

An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte-tumor cell crosstalk, local immunosuppression and tumor progression.

Dissecting and understanding the cancer ecosystem, especially that around the tumor margins, which have strong implications for tumor cell infiltration and invasion, are essential for exploring the mechanisms of tumor metastasis and developing effective new treatments. Using a novel tumor border scanning and digitization model enabled by nanoscale resolution-SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq), we identified a 500 µm-wide zone centered around the tumor border in patients with liver cancer, referred to as "the invasive zone". We detected strong immunosuppression, metabolic reprogramming, and severely damaged hepatocytes in this zone. We also identified a subpopulation of damaged hepatocytes with increased expression of serum amyloid A1 and A2 (referred to collectively as SAAs) located close to the border on the paratumor side. Overexpression of CXCL6 in adjacent malignant cells could induce activation of the JAK-STAT3 pathway in nearby hepatocytes, which subsequently caused SAAs' overexpression in these hepatocytes. Furthermore, overexpression and secretion of SAAs by hepatocytes in the invasive zone could lead to the recruitment of macrophages and M2 polarization, further promoting local immunosuppression, potentially resulting in tumor progression. Clinical association analysis in additional five independent cohorts of patients with primary and secondary liver cancer (n = 423) showed that patients with overexpression of SAAs in the invasive zone had a worse prognosis. Further in vivo experiments using mouse liver tumor models in situ confirmed that the knockdown of genes encoding SAAs in hepatocytes decreased macrophage accumulation around the tumor border and delayed tumor growth. The identification and characterization of a novel invasive zone in human cancer patients not only add an important layer of understanding regarding the mechanisms of tumor invasion and metastasis, but may also pave the way for developing novel therapeutic strategies for advanced liver cancer and other solid tumors.

EphA2 is a functional entry receptor for HCMV infection of glioblastoma cells.

Human cytomegalovirus (HCMV) infection is associated with human glioblastoma, the most common and aggressive primary brain tumor, but the underlying infection mechanism has not been fully demonstrated. Here, we show that EphA2 was upregulated in glioblastoma and correlated with the poor prognosis of the patients. EphA2 silencing inhibits, whereas overexpression promotes HCMV infection, establishing EphA2 as a crucial cell factor for HCMV infection of glioblastoma cells. Mechanistically, EphA2 binds to HCMV gH/gL complex to mediate membrane fusion. Importantly, the HCMV infection was inhibited by the treatment of inhibitor or antibody targeting EphA2 in glioblastoma cells. Furthermore, HCMV infection was also impaired in optimal glioblastoma organoids by EphA2 inhibitor. Taken together, we propose EphA2 as a crucial cell factor for HCMV infection in glioblastoma cells and a potential target for intervention.

Identification of MYB gene family and functional analysis of GhMYB4 in cotton (Gossypium spp.).

Myeloblastosis (MYB) transcription factors (TFs) form a large gene family involved in a variety of biological processes in plants. Little is known about their roles in the development of cotton pigment glands. In this study, 646 MYB members were identified in Gossypium hirsutum genome and phylogenetic classification was analyzed. Evolution analysis revealed assymetric evolution of GhMYBs during polyploidization and sequence divergence of MYBs in G. hirustum was preferentially happend in D sub-genome. WGCNA (weighted gene co-expression network analysis) showed that four modules had potential relationship with gland development or gossypol biosynthesis in cotton. Eight differentially expressed GhMYB genes were identified by screening transcriptome data of three pairs of glanded and glandless cotton lines. Of these, four were selected as candidate genes for cotton pigment gland formation or gossypol biosynthesis by qRT-PCR assay. Silencing of GH_A11G1361 (GhMYB4) downregulated expression of multiple genes in gossypol biosynthesis pathway, indicating it could be involved in gossypol biosynthesis. The potential protein interaction network suggests that several MYBs may have indirect interaction with GhMYC2-like, a key regulator of pigment gland formation. Our study was the systematic analysis of MYB genes in cotton pigment gland development, providing candidate genes for further study on the roles of cotton MYB genes in pigment gland formation, gossypol biosynthesis and future crop plant improvement.

A novel protein elicitor (PeSy1) from Saccharothrix yanglingensis induces plant resistance and interacts with a receptor-like cytoplasmic kinase in Nicotiana benthamiana.

Previously, we reported a rare actinomycete Saccharothrix yanglingensis Hhs.015 with strong biocontrol ability, which can colonize plant tissues and induce resistance, but the key elicitor and immune mechanisms were unclear. In this study, a novel protein elicitor screened from the genome of Hhs.015, PeSy1 (protein elicitor of S. yanglingensis 1), could induce a strong hypersensitive response (HR) and resistance in plants. The PeSy1 gene encodes an 11 kDa protein with 109 amino acids that is conserved in Saccharothrix species. PeSy1-His recombinant protein induced early defence events such as a cellular reactive oxygen species burst, callose deposition, and the activation of defence hormone signalling pathways, which enhanced Nicotiana benthamiana resistance to Sclerotinia sclerotiorum and Phytophthora capsici, and Solanum lycopersicum resistance to Pseudomonas syringae pv. tomato DC3000. Through pull-down and mass spectrometry, candidate proteins that interacted with PeSy1 were obtained from N. benthamiana. We confirmed the interaction between receptor-like cytoplasmic kinase RSy1 (Response to PeSy1) and PeSy1 using co-immunoprecipitation, bimolecular fluorescence complementation, and microscale thermophoresis. PeSy1 treatment promoted up-regulation of marker genes in pattern-triggered immunity. The cell death it elicited was dependent on the co-receptors NbBAK1 and NbSOBIR1, suggesting that PeSy1 acts as a microbe-associated molecular pattern from Hhs.015. Additionally, RSy1 positively regulated PeSy1-induced plants resistant to S. sclerotiorum. In conclusion, our results demonstrated a novel receptor-like cytoplasmic kinase in the plant perception of microbe-associated molecular patterns, and the potential of PeSy1 in induced resistance provided a new strategy for biological control of actinomycetes in agricultural diseases.

Adaptive immune dysfunction in patients with COVID-19 and impaired kidney function during the omicron surge.

BACKGROUND: Little is known about the characteristics of lymphocyte subsets and the association with patient outcomes in COVID-19 with and without impaired kidney function. METHODS: Lymphocyte subsets were compared in COVID-19 patients with or without kidney dysfunction. The primary outcome was a composite of all-cause mortality or intensive care unit admission. Secondary outcomes included duration of viral shedding, length of hospital stay, and acute kidney injury. RESULTS: Lymphocyte subset cell counts demonstrated the lowest in patients with severe/critical COVID-19 and kidney dysfunction. Among all lymphocyte subset parameters, Th cell count was the most significant indicator for outcomes. ROC of the combined model of Th cell count and eGFR presented better predictive value than that of the other parameters. Th cell count <394.5 cells/µl and eGFR <87.5 ml/min/1·73m2 were independently associated with poor outcomes. The propensity score matching analysis revealed consistent results. CONCLUSIONS: Reduced Th cell count and eGFR may be applied as promising predictive indicators for identifying COVID-19 patients with high risk and poor outcomes.