Crohn's disease-associated IgA nephropathy may prone to better renal outcome.

BACKGROUND AND AIM: Renal involvement in Crohn's Disease (CD) was rare in the population. Little was known between IgA nephropathy and CD. This study aimed to investigate the differences in clinical and outcome features of CD-associated IgA nephropathy (CD-IgAN) and primary IgA nephropathy (PIgAN). METHODS: Clinical data of patients diagnosed with IgAN by kidney biopsy were collected in the Sixth Affiliated Hospital of Sun Yat-sen University from January 1st, 2016 to June 1st, 2023. 17 patients with CD-IgAN and 87 patients with PIgAN were enrolled in this retrospective study. RESULTS: Compared with PIgAN patients, CD-IgAN patients had lower levels of urinary protein excretion (1.57 g per 24 h vs. 0.33 g per 24 h, p < 0.01), but higher levels of estimated glomerular filtration rate (77.63 ± 40.11 ml per min per 1.73m2 vs. 104.53 ± 32.97 ml per min per 1.73m2, p = 0.008). From the point of renal pathology of PIgAN, patients with CD-IgAN had a less incidence of tubular atrophy or interstitial fibrosis (p = 0.001). CD-IgAN patients had a higher incidence of complete remission of proteinuria (45.8% vs. 81.8%, p = 0.031) or hematuria (10.4% vs. 45.4%, p = 0.019) than PIgAN patients after twelve-month treatments. CONCLUSIONS: CD-IgAN manifests a milder progression of renal function than those PIgAN. After the treatment, proteinuria or hematuria are more prone to remit in patients with CD-IgAN.

Identification of the function of a key gene NnHCT1 in lignin synthesis in petioles of Nelumbo nucifera.

Leaf petiole or stem strength is an important agronomic trait affecting the growth of underground organs as a channel for material exchange and plays a vital role in the quality and yield of crops and vegetables. There are two different types of petioles in lotus, floating leaf petioles and vertical leaf petioles; however, the internal difference mechanism between these petioles is unclear. In this study, we investigated the differences between the initial vertical leaf petioles and the initial floating leaf petioles based on RNA sequencing (RNA-seq), and >2858 differentially expressed genes were annotated. These genes were chiefly enriched in phenylpropanoid biosynthesis, which is the source of the lignin and cellulose in petioles and stems. Lignin biology-related gene NnHCT1 was identified, and subsequent biological function validation demonstrated that the transient overexpression of NnHCT1 significantly increased the lignin and cellulose contents in lotus petioles and tobacco leaves. In contrast, silencing NnHCT1 through virus-induced gene silencing significantly reduced petiole lignin synthesis. Additionally, differentially up-regulated MYB family transcription factors were identified using RNA-seq. Yeast-one-hybrid and dual-luciferase reporter assays demonstrated that MYB4 could bind to the NnHCT1 promoter and up-regulate NnHCT1 expression. These findings demonstrate the significant potential of NnHCT1 to enhance lignin synthesis, thereby improving stem or petiole resistance to stunting and explaining the need for the study of differential petiole relationships in plants.

Combined analysis of microRNA and mRNA profiles provides insights into the pathogenic resistant mechanisms of the lotus rhizome rot.

Lotus rhizome rot caused by Fusarium oxysporum is a common vascular fungal disease in plants that significantly impacts the yield. However, only a few studies have studied the mechanism of Nelumbo nucifera responding to lotus rhizome rot. Here, we investigated the pathogenic genes and miRNAs in lotus rhizome rot to uncover the pathogenic resistant mechanisms by transcriptome and small RNA sequencing of lotus roots after inoculation with Fusarium oxysporum. GO and KEGG functional enrichment analysis showed that differential miRNAs were mostly enriched in starch and sucrose metabolism, biosynthesis of secondary metabolites, glutathione metabolism, brassinosteroid biosynthesis and flavonoid biosynthesis pathways. Twenty-seven upregulated miRNAs, 19 downregulated miRNAs and their target genes were identified. Correlation analysis found that miRNAs negatively regulate target genes, which were also enriched in starch and sucrose metabolism and glutathione metabolism pathways. Their expression was measured by reverse transcription quantitative PCR (qRT-PCR), and the results were consistent with the transcriptome analysis, thus verifying the reliability of transcriptome data. We selected three miRNAs (miRNA858-y, miRNA171-z and a novel miRNA novel-m0005-5p) to test the relationship between miRNAs and their target genes. The activity of the GUS testing assay indicated that miRNA could decrease the GUS activity by inhibiting the expression of their target genes. Collectively, this study provides a comprehensive analysis of transcriptome and small RNA sequencing of lotus root after inoculation with Fusarium oxysporum, and we identified candidate miRNAs and their target genes for breeding strategies of Nelumbo nucifera.

Network pharmacology and in vivo studies reveal the pharmacological effects and molecular mechanisms of Celastrol against acute hepatic injury induced by LPS.

Sepsis is currently the main factor of death in the ICU, and the liver, as an important organ of immunity and stable metabolism, can be acutely damaged during sepsis, and the mortality rate of patients with sepsis complicated by acute liver injury is greatly increased. Celastrol (CEL) is derived from the root bark of Tripterygium wilfordii Hook.f.. As a traditional Chinese medicine, CEL has anti-inflammatory, anti-cancer, anti-oxidant, and other biological activities. Obtain CEL and AHI intersection targets via database and construct protein-protein interaction (PPI) network by STRING. GO functional enrichment and KEGG pathway analyses were performed by R studio. Targets were finally selected to perform molecular docking simulations with CEL. In vivo experiments based on the model of AHI were established by intraperitoneal injection of Lipopolysaccharide (LPS) 4 h, and pre-treated with CEL (0.5 mg/kg, 1 mg/kg, 1.5 mg/kg). The results are as follows: 273 genes with the intersection of CEL and AHI were obtained, and GO and KEGG enrichment analysis were used to design the mechanism of inflammation, apoptosis, and oxidative stress-related injury. By constructing the PPI network selected top 10 targets are: STAT3, RELA, MAPK1, MAPK3, TP53, AKT1, HSP90AA1, JUN, TNF, MAPK14, predicted CEL protection AHI design related pathways of MAPK and PI3K/AKT-related signal pathways. In vivo experiments, CEL inhibited the activation of MAPK and PI3K/AKT related pathways, reduced inflammatory response, apoptosis, and oxidative stress, and significantly improved LPS-induced AHI. In summary, this study predicted the mechanisms involved in the protective effect of CEL on AHI through network pharmacology. In vivo, CEL inhibited MAPK and PI3K/AKT-related signaling pathways, and reduced inflammatory response, apoptosis, and oxidative stress to protect LPS-induced AHI.

Development of Nectin4/FAP-targeted CAR-T cells secreting IL-7, CCL19, and IL-12 for malignant solid tumors.

Background: Chimeric antigen receptor T (CAR-T) cell therapy has made significant advances for hematological malignancies but encounters obstacles in the treatment of solid tumors mainly due to tumor immunosuppressive microenvironment. Methods: Immunohistochemistry analysis was performed to examine the cellular expression of nectin cell adhesion molecule-4 (Nectin4) and fibroblast activation protein (FAP) in a variety of malignant solid tumors. Then, we engineered the fourth-generation Nectin4-targeted CAR-T (Nectin4-7.19 CAR-T) and FAP-targeted CAR-T (FAP-12 CAR-T) cells to evaluate their safety and efficacy in vitro and in vivo. Results: In our study, we firstly demonstrated the aberrant overexpression of Nectin4 on both primary and metastatic solid tumors and FAP on cancer-associated fibroblasts. Then, we found that our fourth-generation Nectin4-7.19 CAR-T cells expressed IL-7 and CCL19 efficiently and exhibited superior proliferation, migration, and cytotoxicity compared to the second-generation Nectin4 CAR-T cells, while FAP-12 CAR-T cells exerted their ability of targeting both murine and human FAP effectively in vitro. In a fully immune-competent mouse model of metastatic colorectal cancer, lymphodepletion pretreated mice achieved complete remission with human Nectin4-targeted murine CAR-T (Nectin4 mCAR-T) cells. In the NSG mouse model of lung metastases, Nectin4-7.19 CAR-T cells eradicated metastatic tumors and prolonged survival in combination with FAP-12 CAR-T cells. Conclusions: These findings showed that Nectin4-7.19 CAR-T cells had potential therapeutic efficacy and exerted a synergistic role with FAP-12 CAR-T cells, further demonstrating that Nectin4 and FAP were able to serve as promising targets for safe and effective CAR-T therapy of malignant solid tumors.

Effect of Chlorogenic Acid via Upregulating Resolvin D1 Inhibiting the NF-κB Pathway on Chronic Restraint Stress-Induced Liver Inflammation.

Chronic stress can cause chronic inflammatory injury to the liver. Chlorogenic acid (CGA) is known to have a wide range of biological activities and anti-inflammatory effects. Resolvin D1 (RvD1) is a polyunsaturated fatty acid derivative that has inhibitory effects on a variety of inflammatory diseases. However, whether CGA can inhibit liver inflammation in chronic stress through RvD1 remains unclear. In this work, male rats were subjected to restraint stress for 6 h every day and built a chronic stress model for 21 days. CGA (100 mg/kg) was administered intragastrically 1 h before restraint, with intraperitoneal injection of RvD1 inhibitor WRW4 (antagonist of FPR2, 0.1 mg/kg) or WRW4 solution every 2 days for 30 min before CGA administration. CGA reduced hepatic hemorrhage and inflammatory cell infiltration, alleviated hepatic injury, decreased the activation of the NF-κB pathway and the expression of interleukin 1ß, interleukin 6, and tumor necrosis factor α in the liver, and increased RvD1 in the serum and liver. The therapeutic effect of CGA was blocked after WRW4 intervention. These results suggest that the protective effects of CGA mediate the NF-κB pathway by upregulating the generation of RvD1. Above all, this research demonstrates the liver protective effect of CGA and provides a potential treatment strategy for chronic inflammatory disease.

Chlorogenic Acid Alleviates Chronic Stress-Induced Duodenal Ferroptosis via the Inhibition of the IL-6/JAK2/STAT3 Signaling Pathway in Rats.

Chronic stress causes duodenal damage, in which iron death is likely to play an important role. Chlorogenic acid (CGA), one of the most widely consumed dietary polyphenols, has been shown to protect the intestine. However, it is unclear whether CGA exerts a duodenoprotective effect in chronic stress by inhibiting ferroptosis. In this work, rats were daily exposed to restraint stress for 6 h over 21 consecutive days, with/without CGA (100 mg/kg, gavage). CGA reduced blood hepcidin, iron, reactive oxygen species (ROS), and ferroportin 1 (FPN1) levels and upregulated the levels of ferroptosis-related biomarkers (GPX4, GSH, NADPH, etc.). These results confirmed that CGA inhibited ferroptosis in the duodenum. Furthermore, the use of S3I-201 (STAT3 inhibitor) helped to further clarify the mechanism of action of CGA. Overall, CGA could reduce hepcidin production by inhibiting the IL-6/JAK2/STAT3 pathway in the liver to increase the expression of FPN1 in the duodenum, which restored iron homeostasis and inhibited ferroptosis, alleviating chronic stress-induced duodenal injury.

The adaptive evolution of Euryale ferox to the aquatic environment through paleo-hexaploidization.

Occupation of living space is one of the main driving forces of adaptive evolution, especially for aquatic plants whose leaves float on the water surface and thus have limited living space. Euryale ferox, from the angiosperm basal family Nymphaeaceae, develops large, rapidly expanding leaves to compete for space on the water surface. Microscopic observation found that the cell proliferation of leaves is almost completed underwater, while the cell expansion occurs rapidly after they grow above water. To explore the mechanism underlying the specific development of leaves, we performed sequences assembly and analyzed the genome and transcriptome dynamics of E. ferox. Through reconstruction of the three sub-genomes generated from the paleo-hexaploidization event in E. ferox, we revealed that one sub-genome was phylogenetically closer to Victoria cruziana, which also exhibits gigantic floating leaves. Further analysis revealed that while all three sub-genomes promoted the evolution of the specific leaf development in E. ferox, the genes from the sub-genome closer to V. cruziana contributed more to this adaptive evolution. Moreover, we found that genes involved in cell proliferation and expansion, photosynthesis, and energy transportation were over-retained and showed strong expression association with the leaf development stages, such as the expression divergence of SWEET orthologs as energy uploaders and unloaders in the sink and source leaf organs of E. ferox. These findings provide novel insights into the genome evolution through polyploidization, as well as the adaptive evolution regarding the leaf development accomplished through biased gene retention and expression sub-functionalization of multi-copy genes in E. ferox.

Serum amyloid a, C-reactive protein, and procalcitonin levels in children with Mycoplasma pneumoniae infection.

BACKGROUND: Mycoplasma pneumoniae (MP) is a common pathogen of community-acquired pneumonia in children. In the present study, serum amyloid A (SAA), C-reactive protein (CRP), and procalcitonin (PCT) levels in children with MP infection were analyzed and the differential diagnoses of MP evaluated. METHODS: The study included 152 children with MP infection hospitalized in Tai'an Central Hospital in Shandong Province and 50 healthy children as controls. SAA, CRP, and PCT, as well as serum immunoglobulins and T lymphocyte subsets were analyzed during the acute and convalescent phases. Among the MP-infected children, 30 cases were selected to monitor the SAA, immunoglobulins, and T lymphocyte subset levels for a week. RESULTS: The SAA, CRP, PCT, IgA, and IgM levels were significantly higher in the MP-infected group than in the control group (F(SAA) = 83.91, p < 0.05; F(CRP) = 40.79, p < 0.05; F(PCT) = 60.58, p < 0.05; F(IgA) = 43.45, p < 0.05; F(IgM) = 233.88, p < 0.05). In addition, the levels of these factors were significantly higher in the acute phase than in the convalescent phase (p < 0.05). However, significant difference was not observed in the IgG level between these two groups (p > 0.05). The CD3+ and CD4+ levels in the MP-infected group were lower than in the control group ( F(CD3+) = 60.58, P < 0.05; F(CD4+) = 89.05, p < 0.05), and the CD8+ level was higher than in the control group ( F(CD8+) = 96.96, p < 0.05). The CD3+ , CD4+ , and CD8+ levels were significantly different between the acute phase and the convalescent phase (CD3+ : acute phase vs. convalescent phase, q = 2.79, p < 0.05; CD4+ : acute phase vs. convalescent phase, q = 2.83, p < 0.05; CD8+ : acute phase vs. convalescent phase, q = 3.15, p < 0.05). The changes in serum SAA levels in the MP-infected group positively correlated with the changes in IgA, IgM, and CD8+ levels and negatively correlated with CD3+ , CD4+ , and CD4+ /CD8+ . CONCLUSION: SAA, CRP, and PCT were specific markers for diagnosing early MP infection in children. These findings are important in the differential diagnosis of MP infection and clinical guidance for MP treatment.

Effect of Superparamagnetic DMSO@γ-Fe2O3 Combined with Carmustine on Cervical Cancer.

This study aimed to investigate the effects of DMSO@γ-Fe2O3 nanomagnetic fluid thermotherapy combined with the chemotherapy drug carmustine on cervical cancer cells under a certain intensity of alternating magnetic field. And the role of Mir-590-3P in the development and progression of cervical cancer. The optimal thermotherapy concentration of γ-Fe2O3 nanomaterials on cervical cancer cells was determined by in vitro heating. In addition, the MTT colorimetric method was used to evaluate the toxic effect of γ-Fe2O3 magnetic nanoparticles on cervical cancer cells, and the optimal therapeutic concentration of carbachol on cervical cancer cells was optimized (0.015 g · L-1). The cervical cancer cells were divided into control, γ-Fe2O3 hyperthermia, chemotherapy, and DMSO@γ-Fe2O3 combined chemotherapy groups. After 2 h exposure to hypothermic conditions, flow cytometry was used to assess cell apoptosis for each group. The heating effect of the γ-Fe2O3 magnetic nanomaterials was apparent. When the concentration of γ-Fe2O3 was ≥6 g· L-1, the temperature rise above 41 °C. γ-Fe2O3 is non-toxic to cervical cancer cells and has good biocompatibility. Taking the drug concentration of IC25 as the working concentration of this study, the working concentration of carmustine was 0.015 g · L-1. Both the 41 °C heat treatment and chemotherapy alone had a killing effect on glioma and cervical cancer cells (P < 0.05). Additionally, the combined inhibitory effect of DMSO@γ-Fe2O3 nanomagnetic fluid thermotherapy and drugs at this temperature was significantly stronger than that of thermotherapy and chemotherapy alone (P < 0.05). For the control, gamma-Fe2O3 hyperthermia, chemotherapy, and DMSO@γ-Fe2O3 combined chemotherapy groups, the apoptosis rates of the cervical cancer cells were 1.4%, 18.6%, 24.12%, and 38.97%, respectively. DMSO@γ-Fe2O3 nanomagnetic fluid thermotherapy combined with the chemotherapeutic drug carmustine exerted a noticeable toxic effect on the cervical cancer cells, and DMSO@γ-Fe2O3 significantly enhanced the killing effect of carmustine on cervical cancer cells.

The BCMA-Targeted Fourth-Generation CAR-T Cells Secreting IL-7 and CCL19 for Therapy of Refractory/Recurrent Multiple Myeloma.

Chimeric antigen receptor (CAR) technology has revolutionized cancer treatment, particularly in malignant hematological tumors. Currently, the BCMA-targeted second-generation CAR-T cells have showed impressive efficacy in the treatment of refractory/relapsed multiple myeloma (R/R MM), but up to 50% relapse remains to be addressed urgently. Here we constructed the BCMA-targeted fourth-generation CAR-T cells expressing IL-7 and CCL19 (i.e., BCMA-7 × 19 CAR-T cells), and demonstrated that BCMA-7 × 19 CAR-T cells exhibited superior expansion, differentiation, migration and cytotoxicity. Furthermore, we have been carrying out the first-in-human clinical trial for therapy of R/R MM by use of BCMA-7 × 19 CAR-T cells (ClinicalTrials.gov Identifier: NCT03778346), which preliminarily showed promising safety and efficacy in first two enrolled patients. The two patients achieved a CR and VGPR with Grade 1 cytokine release syndrome only 1 month after one dose of CAR-T cell infusion, and the responses lasted more than 12-month. Taken together, BCMA-7 × 19 CAR-T cells were safe and effective against refractory/relapsed multiple myeloma and thus warranted further clinical study.

Novel method for effectively amplifying human peripheral blood T cells in vitro.

The use of chimeric antigen receptor-modified T cells (CAR T cells) is an effective therapy for advanced cancer, especially hematological malignancies, and this method has attracted widespread attention in the last several years. The type, number and vitality of the effector cells clearly play important roles in this approach. In this study, to expand the possibility of curing cancer through adoptive cell therapy (ACT), we developed a novel method for effectively obtaining abundant T cells in vitro. The fusion proteins of three cytokines, SA-hIL-2, SA-hIL-7 and SA-hIL-21, were anchored onto biotin magnetic beads to increase the number of cytokines on the surface of the magnetic beads, which increased the local concentration of cytokines and thus promoted the binding of cytokines to T cells. Next, we examined the effects of these modified magnetic beads on the proliferation rate of T cells and CD19 CAR T cells. In this study, we report the expression and purification of the active bifunctional fusion proteins SA-hIL-2, SA-hIL-7 and SA-hIL-21, which were bound to biotin magnetic beads to develop a platform that was employed to increase the local concentration of cytokines. When the cells had been cultured for 14 days, the proliferation rate of the CD3+ T cells in the group that received cytokine-coupled biotin magnetic beads (Beads-SA-CK) was higher than that of the cells in the groups that received soluble cytokines (Soluble-SA-CK) and that of the cells in the standard group (Standard-CK). We speculate that this difference may be the result of the increased expression of Bcl-2 and the increased phosphorylation of Stat5. Moreover, our results preliminarily indicate that compared with the other two treatments, Soluble-SA-CK and Standard-CK, adding cytokine-coupled biotin magnetic beads more effectively increases the proliferation rate of CD19 CAR-T cells. As expected, the CD19 CAR-T cells stimulated by Beads-SA-CK had a stronger anticancer effect than the cells stimulated by the other two treatments. An effective method of preparing abundant T cells in vitro was developed, and it may provide a novel strategy for ACT.

Tumor-Derived Exosomal miRNAs as Diagnostic Biomarkers in Non-Small Cell Lung Cancer.

BACKGROUND: Delayed diagnosis is the main obstacle to improve prognosis of non-small cell lung cancer (NSCLC). Novel biomarkers for the diagnosis of NSCLC are urgently needed. This study aimed to identify the specific exosomal miRNAs with diagnostic and prognostic potential in NSCLC patients. MATERIALS AND METHODS: Transmission electron microscopy (TEM), qNano and western blots were used to characterize the exosomes isolated from the serum of NSCLC patients (n=330) and healthy donors (n=312) by ultracentrifugation. Exosomal miRNAs were profiled by miRNA microarrays and verified by quantitative PCR (qPCR). The diagnostic accuracy was determined by receiver operating characteristic (ROC) analysis. RESULTS: A total of differential 22 miRNAs were screened out based on P < 0.05 and fold difference>2.0 by miRNA microarrays, among which, exosomal miR-5684 and miR-125b-5p were significantly down-regulated in NSCLC patients compared to healthy donors, processing favorable diagnostic efficiency for (early) NSCLC. Importantly, the exosomal miR-125b-5p were associated with metastasis (P < 0.0001), chemotherapeutic effect (P=0.007) and survival (P=0.008). CONCLUSION: Exosomal miR-5684 and miR-125b-5p levels are significantly down-regulated in NSCLC patients, and serve as the promising diagnostic and prognostic biomarkers for NSCLC.

Malignant Ovarian Tumors During Pregnancy: A Multicenter Retrospective Analysis.

PURPOSE: The aim of this study was to investigate the clinical characteristics and management of malignant ovarian tumors during pregnancy, as well as the feto-maternal outcomes and analyze the influential factors on the pregnancy outcomes. PATIENTS AND METHODS: Eighty-five patients with ovarian malignancies during pregnancy treated at 12 tertiary hospitals between 2009 and 2019 were analyzed in this study. The clinical features, histopathological characteristics, clinical management, and maternal and perinatal outcomes were retrospectively analyzed. The clinical features and managements were compared between abortion group and live birth group. RESULTS: The following diagnoses were made: 41 (48.24%) patients with borderline ovarian tumors, 18 (21.18%) patients with epithelial ovarian cancers, 17 (20.00%) patients with non-epithelial ovarian malignancies and 9 (10.59%) patients with metastatic ovarian tumors. Thirty-six (42.45%) patients underwent conservative surgical treatment. Thirty-four (40.00%) patients opted for fertility-sparing surgery, and fifteen (17.56%) patients received radical surgery. Chemotherapy was administered to 32.94% of the patients. The proportion of ovarian malignancies diagnosed in the first trimester in the abortion group was higher than that in the live birth group (P<0.05). However, tumor diameter, reproductive history, stage and surgical indications showed no significant differences between groups. A total of 67 live babies were recorded in this study, including 19 premature babies and 1 full-term newborn who died of respiratory distress. All of the BOTs were diagnosed with stage I, among whom 38 (92.68%) patients exhibited disease-free survival. Twenty-eight ovarian cancers were in stage I-II and 26 of them had disease-free survival with the longest follow-up time of 10 years. Five of the sixteen patients in advanced stage (stage III-IV) died, four of whom had metastatic tumors. CONCLUSION: Pregnant women with early-stage malignant ovarian tumors appear to have favorable outcomes. Conservative surgery is acceptable for early-stage borderline ovarian tumors during pregnancy. The gestational age of ovarian malignancy detection is key for pregnancy outcomes.

Use of peripheral blood transcriptomic biomarkers to distinguish high-grade cervical squamous intraepithelial lesions from low-grade lesions.

It is crucial to classify cervical lesions into high-grade squamous intraepithelial lesions (HSILs) and low-grade SILs (LSILs), as LSILs are conservatively treated by observation, based on an expectation of natural regression, whereas HSILs usually require electrosurgical excision. In the present study, peripheral blood gene expression profiles were analyzed to identify transcriptomic biomarkers distinguishing HSILs from LSILs. A total of 102 blood samples were collected from women with cervical SILs (66 HSIL and 36 LSIL) for microarray hybridization. Candidate gene signatures were identified using AdaBoost algorithms, and a predictive model was constructed using logistic regression to differentiate HSILs from LSILs. To correct for possible bias as a result of the limited sample size and to verify the stability of the predictive model, a two-fold cross validation and null set analysis was conducted over 1,000 iterations. The functions of the transcriptomic biomarkers were then analyzed to elucidate the pathogenesis of cervical SIL. A total of 10 transcriptomic genes (STMN3, TRPC4AP, DYRK2, AGK, KIAA0319L, GRPEL1, ZFC3H1, LYL1, ITGB1 and ARHGAP18) were identified. The predictive model based on the 10-gene panel exhibited well-discriminated power. A cross validation process using known disease status exhibited almost the same performance as that of the predictive model, whereas null-set analysis with randomly reassigned disease status exhibited much lower predictive performance for distinguishing HSILs from LSILs. These biomarkers were involved in the 'Rho GTPase cycle', 'mitochondrial protein import', 'oncogenic MAPK signaling', 'integrin cell surface interaction' and 'signaling by BRAF and RAF fusions'. In conclusion, peripheral blood gene expression analysis is a promising method for distinguishing HSILs from LSILs. The present study proposes 10 candidate genes that could be used in the future as diagnostic biomarkers and potential therapeutic targets for cervical SILs. A simple, non-invasive blood test would be clinically useful in the diagnosis and classification of patients with cervical SILs.

Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation.

The plasticity of a preexisting regulatory circuit compromises the effectiveness of targeted therapies, and leveraging genetic vulnerabilities in cancer cells may overcome such adaptations. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is characterized by oxidative phosphorylation (OXPHOS) deficiency caused by fumarate hydratase (FH) nullizyogosity. To identify metabolic genes that are synthetically lethal with OXPHOS deficiency, we conducted a genetic loss-of-function screen and found that phosphogluconate dehydrogenase (PGD) inhibition robustly blocks the proliferation of FH mutant cancer cells both in vitro and in vivo. Mechanistically, PGD inhibition blocks glycolysis, suppresses reductive carboxylation of glutamine, and increases the NADP+/NADPH ratio to disrupt redox homeostasis. Furthermore, in the OXPHOS-proficient context, blocking OXPHOS using the small-molecule inhibitor IACS-010759 enhances sensitivity to PGD inhibition in vitro and in vivo. Together, our study reveals a dependency on PGD in OXPHOS-deficient tumors that might inform therapeutic intervention in specific patient populations.

MicroRNA-149 suppresses the proliferation and increases the sensitivity of ovarian cancer cells to cisplatin by targeting X-linked inhibitor of apoptosis.

Currently, ovarian cancer is identified as one of the leading causes of cancer-associated mortality in females. Despite numerous efforts that were made on developing novel treatments for ovarian cancer, the survival rate remains unsatisfactory. Considering the important regulatory role of miRNAs in different types of cancer, the present study aims to identify a novel therapeutic target for treatment of ovarian cancer. The expression of miR-149 was detected using reverse transcription-quantitative polymerase chain reaction in cancerous and normal cells. Furthermore, the effects of miR-149 on ovarian cancer cell activities were investigated using MTT assay, colony formation, flow cytometry and western blotting analysis. In the present study, it was revealed that microRNA (miR)-149 was significantly downregulated in ovarian cancer tissues and cell lines, and that the miR-149 expression was correlated with the patient prognosis. In addition, it was observed that forced expression of miR-149 increased the sensitivity of ovarian cancer cell to cisplatin. Based on bioinformatics analysis and luciferase assay, X-linked inhibitor of apoptosis (XIAP) was identified as a direct target gene of miR-149 in ovarian cancer cells. It was also demonstrated that XIAP expression was upregulated in the ovarian cancer tissues and cell lines, while it was negatively correlated with miR-149 in these tissues and cells. Furthermore, results revealed that ectopic expression of XIAP was able to abolish the miR-149-enhanced cell sensitivity to cisplatin. In conclusion, the present study revealed that miR-149 functioned as a tumor suppressor in the progression of ovarian cancer, increasing the sensitivity of ovarian cancer cells to cisplatin treatment.

STARD: How many lymph nodals needed to be dissected in corpus carcinoma?

During corpus carcinoma surgery, there is uncertainty as to how many lymph nodes should be dissected and examined to determine lymph invasion.In this study, we evaluated a beta-binominal model in data extracted from the Surveillance, Epidemiology, and End Results (SEER) database, which contains 22,372 complete records. We quantified the relationship between examined node number and the probability of missing invaded nodes. Survival curves were used for further validation.We found that for stage T1-T4, 1, 10, 23, and 37 lymph nodes, respectively, needed to be examined to minimize the missing positive nodal probability (1-nodal staging score, NSS) to less than 5%. A hypothetical lymph node examination rate was calculated. Survival rate of T2 and T3 stage samples was significantly associated with NSS, but T1 and T4 sample survival rate was not.The currently dissected nodal should be reduced to 1 to 2 for T1, remains to 10 for T2, and increases to 23 for T3.