External validation and updating of the Rossi nomogram for predicting cesarean delivery following induction: is the Bishop score valuable?

OBJECTIVE: This study sought to validate the Rossi nomogram in a Chinese population and then to include the Bishop score to see if it has an effect on the accuracy of the nomogram. MATERIALS AND METHODS: The Rossi predictive model was applied and externally validated in a retrospective cohort from August 2017 and July 2023 in a Chinese tertiary-level medical center. For the revision and updating of the models, the regression coefficients of all the predictors (except race) were re-estimated and then the cervical Bishop score at the time of induction was added. Each model's performance was measured using the receiver-operating characteristic and calibration plots. Decision curve analysis determined the range of the probability threshold for each prediction model that would be of clinical value. RESULTS: A total of 721 women met the inclusion criteria, of whom 183 (25.4%) underwent a cesarean delivery. The calibration demonstrated the underestimation of the original model, with an area under the curve (AUC) of 0.789 (95% confidence interval [CI] 0.753-0.825, p < 0.001). After recalibrating the original model, the discriminative performance was improved from 0.789 to 0.803. Moreover, the discriminatory power of the updated model was further improved when the Bishop score at the time of induction was added to the recalibrated multivariable model. Indeed, the updated model demonstrated good calibration and discriminatory power, with an AUC of 0.811. The decision curve analysis indicated that all the models (original, recalibrated, and updated) provided higher net benefits of between 0 and 60% of the probability threshold, which indicates the benefits of using the models to make decisions concerning patients who fall within the identified range of the probability threshold. The net benefits of the updated model were higher than those of the original model and the recalibrated model. CONCLUSION: The nomogram used to predict cesarean delivery following induction developed by Rossi et al. has been validated in a Chinese population in this study. More specifically, adaptation to a Chinese population by excluding ethnicity and including the Bishop score prior to induction gave rise to better performance. The three models (original, recalibrated, and updated) offer higher net benefits when the probability threshold is between 0 and 60%.

IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis.

Cellular sensitivity to ferroptosis is primarily regulated by mechanisms mediating lipid hydroperoxide detoxification. We show that inositol-requiring enzyme 1 (IRE1α), an endoplasmic reticulum (ER) resident protein critical for the unfolded protein response (UPR), also determines cellular sensitivity to ferroptosis. Cancer and normal cells depleted of IRE1α gain resistance to ferroptosis, while enhanced IRE1α expression promotes sensitivity to ferroptosis. Mechanistically, IRE1α's endoribonuclease activity cleaves and down-regulates the mRNA of key glutathione biosynthesis regulators glutamate-cysteine ligase catalytic subunit (GCLC) and solute carrier family 7 member 11 (SLC7A11). This activity of IRE1α is independent of its role in regulating the UPR and is evolutionarily conserved. Genetic deficiency and pharmacological inhibition of IRE1α have similar effects in inhibiting ferroptosis and reducing renal ischemia-reperfusion injury in mice. Our findings reveal a previously unidentified role of IRE1α to regulate ferroptosis and suggests inhibition of IRE1α as a promising therapeutic strategy to mitigate ferroptosis-associated pathological conditions.

Clinical Experiences of Perinatal Palliative Care After a Stillbirth: A Narrative Therapy for Grief.

Narrative care for families suffering from perinatal loss is rarely provided by medical institutions in China Mainland. However, with the advancement of the Chinese narrative medicine theory and practice, the clinical significance of narrative care has been increasingly recognized. Based on the principles of Chinese narrative medicine, this narrative case study described traumatic narrative foreclosures occuring in a family suffering from stillbirth, and highlighted the multidisciplinary collaboration for practising narrative care in the process of supporting the bereaved in our hospital. Meanwhile, we advocate the establishment of a narrative care ecology by training more obsteticians and nurses with good narrative competence in purpose of helping the family experiencing perinatal losses to overcome their tramatic narrative foreclosures, increasing the chances of another successful pregnancy and childbirth as well as enhancing their quality of life.

Weekly Weight Gain in Women with Gestational Diabetes Mellitus and Neonatal Birth Weight - China, 2011-2021.

What is already known about this topic?: Elevated gestational weight gain (GWG) during pregnancy among women diagnosed with gestational diabetes mellitus (GDM) is correlated with an increased instance of large for gestational age (LGA) and macrosomia. However, it remains uncertain whether managing weekly GWG following a GDM diagnosis positively impacts fetal birth weight. What is added by this report?: Our study found that GWG following GDM diagnosis correlates positively with the risk of LGA and macrosomia among all body mass index (BMI) subgroups, especially for overweight and obese women. What are the implications for public health practice?: The results of this research highlight the importance of enforcing a more stringent regulation on GWG on a weekly basis for overweight and obese women diagnosed with GDM, particularly when considering neonatal growth.

Optimal Gestational Weight Gain for Women with Gestational Diabetes Mellitus - China, 2011-2021.

What is already known about this topic?: Joint effects of gestational weight gain (GWG) and hyperglycemia on adverse pregnancy outcomes suggest that lower optimal GWG is optimal for women with gestational diabetes mellitus (GDM). However, there is still a lack of guidelines. What is added by this report?: Optimal weekly GWG range after diagnosis of GDM for underweight, normal-weight, overweight, and obese women was 0.37-0.56 kg/week, 0.26-0.48 kg/week, 0.19-0.32 kg/week, and 0.12-0.23 kg/week, respectively. What are the implications for public health practice?: The findings may be used to inform prenatal counseling regarding optimal gestational weight gain for women with gestational diabetes mellitus, and suggest the need for weight gain management.

Identification of a novel immune landscape signature as effective diagnostic markers related to immune cell infiltration in diabetic nephropathy.

Background: The study aimed to identify core biomarkers related to diagnosis and immune microenvironment regulation and explore the immune molecular mechanism of diabetic nephropathy (DN) through bioinformatics analysis. Methods: GSE30529, GSE99325, and GSE104954 were merged with removing batch effects, and different expression genes (DEGs) were screened at a criterion |log2FC| >0.5 and adjusted P <0.05. KEGG, GO, and GSEA analyses were performed. Hub genes were screened by conducting PPI networks and calculating node genes using five algorithms with CytoHubba, followed by LASSO and ROC analysis to accurately identify diagnostic biomarkers. In addition, two different GEO datasets, GSE175759 and GSE47184, and an experiment cohort with 30 controls and 40 DN patients detected by IHC, were used to validate the biomarkers. Moreover, ssGSEA was performed to analyze the immune microenvironment in DN. Wilcoxon test and LASSO regression were used to determine the core immune signatures. The correlation between biomarkers and crucial immune signatures was calculated by Spearman analysis. Finally, cMap was used to explore potential drugs treating renal tubule injury in DN patients. Results: A total of 509 DEGs, including 338 upregulated and 171 downregulated genes, were screened out. "chemokine signaling pathway" and "cell adhesion molecules" were enriched in both GSEA and KEGG analysis. CCR2, CX3CR1, and SELP, especially for the combination model of the three genes, were identified as core biomarkers with high diagnostic capabilities with striking AUC, sensitivity, and specificity in both merged and validated datasets and IHC validation. Immune infiltration analysis showed a notable infiltration advantage for APC co-stimulation, CD8+ T cells, checkpoint, cytolytic activity, macrophages, MHC class I, and parainflammation in the DN group. In addition, the correlation analysis showed that CCR2, CX3CR1, and SELP were strongly and positively correlated with checkpoint, cytolytic activity, macrophages, MHC class I, and parainflammation in the DN group. Finally, dilazep was screened out as an underlying compound for DN analyzed by CMap. Conclusions: CCR2, CX3CR1, and SELP are underlying diagnostic biomarkers for DN, especially in their combination. APC co-stimulation, CD8+ T cells, checkpoint, cytolytic activity, macrophages, MHC class I, and parainflammation may participate in the occurrence and development of DN. At last, dilazep may be a promising drug for treating DN.

Nanoscale, antigen encounter-dependent, IL-12 delivery by CAR T cells plus PD-L1 blockade for cancer treatment.

BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapies for the treatment of hematological malignancies experienced tremendous progress in the last decade. However, essential limitations need to be addressed to further improve efficacy and reduce toxicity to assure CAR-T cell persistence, trafficking to the tumor site, resistance to an hostile tumor microenvironment (TME), and containment of toxicity restricting production of powerful but potentially toxic bioproducts to the TME; the last could be achieved through contextual release upon tumor antigen encounter of factors capable of converting an immune suppressive TME into one conducive to immune rejection. METHODS: We created an HER2-targeting CAR-T (RB-312) using a clustered regularly interspaced short palindromic repeats (CRISPR) activation (CRISPRa) system, which induces the expression of the IL-12 heterodimer via conditional transcription of its two endogenous subunits p35 and p40. This circuit includes two lentiviral constructs. The first one (HER2-TEV) expresses an anti-human epidermal growth factor receptor 2 (HER2) CAR single chain variable fragment (scFv), with CD28 and CD3z co-stimulatory domains linked to the tobacco etch virus (TEV) protease and two single guide RNAs (sgRNA) targeting the interleukin (IL)-12A and IL12B transcription start site (TSS), respectively. The second construct (LdCV) encodes linker for activation of T cells (LAT) fused to nuclease-deactivated Streptococcus Pyogenes Cas9 (dCas9)-VP64-p65-Rta (VPR) via a TEV-cleavable sequence (TCS). Activation of the CAR brings HER2-TEV in close proximity to LdCV releasing dCas9 for nuclear localization. This conditional circuit leads to conditional and reversible induction of the IL-12/p70 heterodimer. RB-312 was compared in vitro to controls (cRB-312), lacking the IL-12 sgRNAs and conventional HER2 CAR (convCAR). RESULTS: The inducible CRISPRa system activated endogenous IL-12 expression resulting in enhanced secondary interferon (FN)-γ production, cytotoxicity, and CAR-T proliferation in vitro, prolonged in vivo persistence and greater suppression of HER2+ FaDu oropharyngeal cancer cell growth compared to the conventional CAR-T cell product. No systemic IL-12 was detected in the peripheral circulation. Moreover, the combination with programmed death ligand (PD-L1) blockade demonstrated robust synergistic effects. CONCLUSIONS: RB-312, the first clinically relevant product incorporating a CRISPRa system with non-gene editing and reversible upregulation of endogenous gene expression that promotes CAR-T cells persistence and effectiveness against HER2-expressing tumors. The autocrine effects of reversible, nanoscale IL-12 production limits the risk of off-tumor leakage and systemic toxicity.

ChREBP Deficiency Suppresses Renal Inflammation and Fibrosis Via Inhibiting NLRP3 Inflammasome Activation in Diabetic Kidney Disease.

BACKGROUND AND AIM: Diabetic kidney disease (DKD) is the most-common cause of chronic renal failure and end-stage renal disease (ERSD) in diabetes mellitus (DM) patients. Renal inflammation and glomerular or interstitial fibrosis are mainly associated with the progression of DKD. Carbohydrate response element binding protein (ChREBP) is activated and transcribed in a glucose dependent manner. This study is aimed at exploring the role and underlying mechanisms of ChREBP in DKD. METHODS: ChREBP knockout mice, obtained by CRISPR Cas9 gene editing technology, were used to study the effects of ChREBP on inflammation and fibrosis in diabetic kidney of mice. Human renal tubular epithelial (HK-2) cells were cultured in a medium containing normal or high glucose levels. Additionally, the role of ChREBP in high glucose (HG)-induced NLRP3 inflammasome activation was assessed. RESULTS: We identified that renal inflammation, renal extracellular matrix deposition, and renal fibrosis were restored by ChREBP deficiency in diabetic mouse kidney. Consequently, ChREBP deficiency decreased the activation of nucleotide leukin-rich polypeptide 3 (NLRP3) inflammasome, which later restrained hyperglycemia-induced renal fibrosis. Importantly, NLRP3 inflammasome aggravated the above-mentioned renal fibrosis via TGF-ß1 expression and the signaling pathways of Smad2/3 and the p38 MAPK. Additionally, ChREBP deficiency inhibited NLRP3 inflammasome activation both in HG-induced HK-2 cells and diabetic mouse kidney. CONCLUSION: Our findings establish a critical role of ChREBP in engaging inflammation and renal fibrosis by regulating NLRP3 inflammasome activation in DKD.

Blocking REDD1/TXNIP Complex Ameliorates HG-Induced Renal Tubular Epithelial Cell Apoptosis and EMT through Repressing Oxidative Stress.

Diabetic nephropathy (DN) has become the most common secondary kidney disease causing end-stage renal disease (ESRD). Nevertheless, the underlying mechanisms responsible for DN remain largely unknown. Regulated in development and DNA damage response 1 (REDD1) is a prooxidative molecule known to contribute to diabetes mellitus and its complications. However, it has not been previously examined whether and how REDD1 can further drive renal tubular epithelial cell (RTEC) apoptosis and epithelial-to-mesenchymal transition in DN. The expression of REDD1 was elevated in the kidneys of DN patients and diabetic mice in this study. By generating the DN model in REDD1 knockout mice, we demonstrated that REDD1 deficiency significantly improved apoptosis and EMT in diabetic mice. In vitro experiments showed that REDD1 generation was induced by high glucose (HG) in HK-2 cells. Similarly, the transfection of REDD1 siRNA plasmid also suppressed HG-induced apoptosis and EMT. Furthermore, we discovered that the inhibition of REDD1 suppressed the expression of Nox4-induced HG and reactive oxygen species (ROS) synthesis in HK-2 cells. In addition, HG could induce endogenous REDD1 and TXNIP to form a powerful complex. In summary, our findings demonstrate that blocking the REDD1/TXNIP complex can prevent HG-induced apoptosis and EMT by inhibiting ROS production, highlighting REDD1 as a valuable therapeutic priority site for DN.

Value of PAPP-A combined with BMI in predicting the prognosis of gestational diabetes mellitus: an observational study.

The aim of this study was to investigate the potential of pregnancy-associated plasma protein A (PAPP-A) and clinical data in predicting gestational diabetes mellitus (GDM). Clinical data of 318 pregnant women with GDM and 200 healthy pregnant women were retrospectively analysed. The age, BMI and caesarean section in GDM were significantly higher than in normal group. Serum and placental levels of PAPP-A were significantly lower in GDM than in normal group. Pearson's correlation analysis showed that serum levels of PAPP-A were negatively correlated with BMI and blood glucose level. Binary logistic regression analysis displayed that PAPP-A were the potential factors influencing GDM. The area under the ROC curve (AUC) for PAPP-A combined with BMI in predicting GDM was 0.941, significantly higher than that of the single one. The potential of PAPP-A in the first trimester is limited in predicting GDM. PAPP-A combined with BMI is highly conductive for predicting GDM.Impact statementWhat is already known on this subject? GDM not only increases the risk of perinatal morbidity, but also results in an increased risk of long-term sequelae for both mother and child including diabetes, cardiovascular disease obesity. Previous data indicate that besides glycemic control in the second trimester, interventions initiated early in pregnancy can reduce the rate of GDM in pregnant women. The expression of PAPP-A in serum of GDM pregnant women was decreased in the first trimester. Whereas, whether PAPP-A can be as an early predictor of GDM is not clear.What do the results of this study add? The present study shows that PAPP-A MoM was less than 0.6757 in the first trimester of pregnancy is more prone to GDM. The potential of PAPP-A in the first trimester is limited in predicting GDM. PAPP-A combined with BMI is highly conductive for predicting GDM.What are the implications of these findings for clinical practice and/or further research? Early GDM prediction is crucial for prevention and management of GDM, to cope with the rising prevalence of GDM and reduce later life chronic disease of both mother and child. Based on the level of PAPP-A MoM and BMI, interventions such as lifestyle changes initiated early in pregnancy shouldbeenabledin pregnant women.

Integrated Analysis of Multiple Microarray Studies to Identify Core Gene-Expression Signatures Involved in Tubulointerstitial Injury in Diabetic Nephropathy.

Diabetic nephropathy is a leading cause of end-stage renal disease in both developed and developing countries. It is lack of specific diagnosis, and the pathogenesis remains unclarified in diabetic nephropathy, following the unsatisfactory effects of existing treatments. Therefore, it is very meaningful to find biomarkers with high specificity and potential targets. Two datasets, GSE30529 and GSE47184 from GEO based on diabetic nephropathy tubular samples, were downloaded and merged after batch effect removal. A total of 545 different expression genes screened with log2FC > 0.5 were weighted gene coexpression correlation network analysis, and green module and blue module were identified. The results of KEGG analyses both in green module and GSEA analysis showed the same two enriched pathway, focal adhesion and viral myocarditis. Based on the intersection among WGCNA focal adhesion/Viral myocarditis, GSEA focal adhesion/viral myocarditis, and PPI network, 17 core genes, ACTN1, CAV1, PRKCB, PDGFRA, COL1A2, COL6A3, RHOA, VWF, FN1, HLA-F, HLA-DPB1, ITGB2, HLA-DRA, HLA-DMA, HLA-DPA1, HLA-B, and HLA-DMB, were identified as potential biomarkers in diabetic tubulointerstitial injury and were further validated externally for expression at GSE99325 and GSE104954 and clinical feature at nephroseq V5 online platform. CMap analysis suggested that two compounds, LY-294002 and bufexamac, may be new insights for therapeutics of diabetic tubulointerstitial injury. Conclusively, it was raised that a series of core genes may be as potential biomarkers for diagnosis and two prospective compounds.

Characterization of a Novel TtLEA2 Gene From Tritipyrum and Its Transformation in Wheat to Enhance Salt Tolerance.

Late embryogenesis-abundant (LEA) proteins are critical in helping plants cope with salt stress. "Y1805" is a salt-tolerant Tritipyrum. We identified a "Y1805"-specific LEA gene that was expressed highly and sensitively under salt stress using transcriptome analysis. The novel group 2 LEA gene (TtLEA2-1) was cloned from "Y1805." TtLEA2-1 contained a 453 bp open reading frame encoding an 151-amino-acid protein that showed maximum sequence identity (77.00%) with Thinopyrum elongatum by phylogenetic analysis. It was mainly found to be expressed highly in the roots by qRT-PCR analysis and was located in the whole cell. Forty-eight candidate proteins believed to interact with TtLEA2-1 were confirmed by yeast two-hybrid analysis. These interacting proteins were mainly enriched in "environmental information processing," "glycan biosynthesis and metabolism," and "carbohydrate metabolism." Protein-protein interaction analysis indicated that the translation-related 40S ribosomal protein SA was the central node. An efficient wheat transformation system has been established. A coleoptile length of 2 cm, an Agrobacteria cell density of 0.55-0.60 OD600, and 15 KPa vacuum pressure were ideal for common wheat transformation, with an efficiency of up to 43.15%. Overexpression of TaLEA2-1 in wheat "1718" led to greater height, stronger roots, and higher catalase activity than in wild type seedlings. TaLEA2-1 conferred enhanced salt tolerance in transgenic wheat and may be a valuable gene for genetic modification in crops.

Transcriptome analysis of Auricularia fibrillifera fruit-body responses to drought stress and rehydration.

BACKGROUND: Drought stress severely restricts edible fungus production. The genus Auricularia has a rare drought tolerance, a rehydration capability, and is nutrient rich. RESULTS: The key genes and metabolic pathways involved in drought-stress and rehydration were investigated using a transcriptome analysis to clarify the relevant molecular mechanisms. In total, 173.93 Mb clean reads, 26.09 Gb of data bulk, and 52,954 unigenes were obtained. Under drought-stress and rehydration conditions, 14,235 and 8539 differentially expressed genes, respectively, were detected. 'Tyrosine metabolic', 'caffeine metabolism', 'ribosome', 'phagosome', and 'proline and arginine metabolism', as well as 'peroxisome' and 'mitogen-activated protein kinase signaling' pathways, had major roles in A. fibrillifera responses to drought stress. 'Tyrosine' and 'caffeine metabolism' might reveal unknown mechanisms for the antioxidation of A. fibrillifera under drought-stress conditions. During the rehydration process, 'diterpenoid biosynthesis', 'butanoate metabolism', 'C5-branched dibasic acid', and 'aflatoxin biosynthesis' pathways were significantly enriched. Gibberellins and γ-aminobutyric acid were important in the recovery of A. fibrillifera growth after rehydration. Many genes related to antibiotics, vitamins, and other health-related ingredients were found in A. fibrillifera. CONCLUSION: These findings suggested that the candidate genes and metabolites involved in crucial biological pathways might regulate the drought tolerance or rehydration of Auricularia, shedding light on the corresponding mechanisms and providing new potential targets for the breeding and cultivation of drought-tolerant fungi.

Pregnancy combined with severe pneumonia caused by Chlamydia psittaci infection - a case report.

OBJECTIVE: Chlamydia psittaci (Cps) feeds on gram-negative aerobic cells. Respiratory inhalation of Cps or close contact with infected animals can cause psittacosis in humans. Given its challengeable early diagnosis and rapid progression, misdiagnosis or improper antibacterial drugs may lead to multi-organ dysfunction with a high mortality. CASE REPORT: A pregnant woman at 29+1 weeks of gestational age had a fever. CT images of the chest showed lamellar consolidations in the inferior lobe of the right lung, light inflammation in the middle lobe of the right lung. Negative results were obtained from multiple times of blood and sputum culture. Next generation sequencing (NGS) results identified that Cps caused severe pneumonia, which was alleviated by specific antibiotic treatment. CONCLUSION: Cps can cause severe pneumonia in the pregnant woman and be cured through precise antibiotic treatment. NGS is efficient in the rapid identification of pathogens and accurate diagnosis when bacteriological culture fails.

Contextual reprogramming of CAR-T cells for treatment of HER2+ cancers.

BACKGROUND: Adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells combined with checkpoint inhibition may prevent T cell exhaustion and improve clinical outcomes. However, the approach is limited by cumulative costs and toxicities. METHODS: To overcome this drawback, we created a CAR-T (RB-340-1) that unites in one product the two modalities: a CRISPR interference-(CRISPRi) circuit prevents programmed cell death protein 1 (PD-1) expression upon antigen-encounter. RB-340-1 is engineered to express an anti-human epidermal growth factor receptor 2 (HER2) CAR single chain variable fragment (scFv), with CD28 and CD3ζ co-stimulatory domains linked to the tobacco etch virus (TEV) protease and a single guide RNA (sgRNA) targeting the PD-1 transcription start site (TSS). A second constructs includes linker for activation of T cells (LAT) fused to nuclease-deactivated spCas9 (dCas9)-Kruppel-associated box (KRAB) via a TEV-cleavable sequence (TCS). Upon antigen encounter, the LAT-dCas9-KRAB (LdCK) complex is cleaved by TEV allowing targeting of dCas9-KRAB to the PD-1 gene TSS. RESULTS: Here, we show that RB-340-1 consistently demonstrated higher production of homeostatic cytokines, enhanced expansion of CAR-T cells in vitro, prolonged in vivo persistence and more efficient suppression of HER2+ FaDu oropharyngeal cancer growth compared to the respective conventional CAR-T cell product. CONCLUSIONS: As the first application of CRISPRi toward a clinically relevant product, RB-340-1 with the conditional, non-gene editing and reversible suppression promotes CAR-T cells resilience to checkpoint inhibition, and their persistence and effectiveness against HER2-expressing cancer xenografts.

Improving CAR T-Cell Persistence.

Over the last decade remarkable progress has been made in enhancing the efficacy of CAR T therapies. However, the clinical benefits are still limited, especially in solid tumors. Even in hematological settings, patients that respond to CAR T therapies remain at risk of relapsing due to several factors including poor T-cell expansion and lack of long-term persistence after adoptive transfer. This issue is even more evident in solid tumors, as the tumor microenvironment negatively influences the survival, infiltration, and activity of T-cells. Limited persistence remains a significant hindrance to the development of effective CAR T therapies due to several determinants, which are encountered from the cell manufacturing step and onwards. CAR design and ex vivo manipulation, including culture conditions, may play a pivotal role. Moreover, previous chemotherapy and lymphodepleting treatments may play a relevant role. In this review, the main causes for decreased persistence of CAR T-cells in patients will be discussed, focusing on the molecular mechanisms underlying T-cell exhaustion. The approaches taken so far to overcome these limitations and to create exhaustion-resistant T-cells will be described. We will also examine the knowledge gained from several key clinical trials and highlight the molecular mechanisms determining T-cell stemness, as promoting stemness may represent an attractive approach to improve T-cell therapies.

ChREBP deficiency alleviates apoptosis by inhibiting TXNIP/oxidative stress in diabetic nephropathy.

AIMS: In the present study, we investigated the effect of carbohydrate responsive element binding protein (ChREBP) on the TXNIP/oxidative stress and apoptosis in diabetic nephropathy. METHODS: ChREBP-/- mice (8-week old) were produced using the CRISPR/Cas9 gene editing approach. Diabetes was induced in C57BL/6 mice with streptozotocin. HK-2 cells was transfected with plasmid containing either ChREBP shRNA or TXNIP siRNA. RESULTS: Renal expression of ChREBP and thioredoxin-interacting protein (TXNIP) was increased in patients with type 2 diabetes mellitus (T2DM) and diabetic mice. ChREBP deficiency improved renal function, apoptosis as well as endoplasmic reticulum (ER) stress in diabetic mice. In addition, ChREBP deficiency prevented expression levels of TXNIP and NADPH oxidase 4 (Nox4), 8-hydroxydeoxyguanosine (8-OHdG) and heme oxygenase-1 (HO-1) in diabetic kidneys. The increased urinary 8-OHdG level induced by diabetes was also attenuated in ChREBP deficiency mice. Similarly, HG was shown to induce ChREBP expression and nuclear translocation in HK-2 cells. HG-induced apoptosis was inhibited by transfection of ChREBP shRNA plasmid. Moreover, we found that knockdown of ChREBP suppressed HG-induced TXNIP and Nox4 expression, reactive oxygen species (ROS) generation and ER stress in HK-2 cells. Furthermore, TXNIP knockdown effectively abrogated HG-induced apoptosis in HK-2 cells. CONCLUSIONS: These results suggest that ChREBP deficiency prevents diabetes-induced apoptosis via inhibiting oxidative stress and ER stress, highlighting ChREBP as a potential therapy target for diabetic nephropathy.

Congenital orbital teratoma: A clinicopathologic case report.

Here we report an extremely rare case of immature congenital orbital teratoma. The ultrasound scan at the 28+1 week of gestation revealed a massive, solid, and cystic mass in the left orbital region of the fetus. The lesion site was confirmed by magnetic resonance imaging. Based on clinical examination and imaging, the diagnosis of orbital teratoma without intracranial extension was made. Histopathological examination further confirmed the diagnosis of immature teratoma. The clinical course, radiographic, and histopathological findings of this disease were also summarized.

Clinical efficacy on glycemic control and safety of mesenchymal stem cells in patients with diabetes mellitus: Systematic review and meta-analysis of RCT data.

BACKGROUND: Diabetes mellitus as a chronic metabolic disease is threatening human health seriously. Although numerous clinical trials have been registered for the treatment of diabetes with stem cells, no articles have been published to summarize the efficacy and safety of mesenchymal stem cells (MSCs) in randomized controlled trials (RCTs). METHODS AND FINDINGS: The aim of this study was to systematically review the evidence from RCTs and, where possible, conduct meta-analyses to provide a reliable numerical summary and the most comprehensive assessment of therapeutic efficacy and safety with MSCs in diabetes. PubMed, Web of Science, Ovid, the Cochrane Library and CNKI were searched. The retrieval time was from establishment of these databases to January 4, 2020. Seven RCTs were eligible for analysis, including 413 participants. Meta-analysis results showed that there were no significant differences in the reduction of fasting plasma glucose (FPG) compared to the baseline [mean difference (MD) = -1.05, 95% confidence interval (CI) (-2.26,0.16), P<0.01, I2 = 94%] and the control group [MD = -0.62, 95%CI (-1.46,0.23), P<0.01, I2 = 87%]. The MSCs treatment group showed a significant decrease in hemoglobin (Hb) A1c [random-effects, MD = -1.32, 95%CI (-2.06, -0.57), P<0.01, I2 = 90%] after treatment. Additionally, HbA1c reduced more significantly in MSC treatment group than in control group [random-effects, MD = -0.87, 95%CI (-1.53, -0.22), P<0.01, I2 = 82%] at the end of follow-up. However, as for fasting C-peptide levels, the estimated pooled MD showed that there was no significant increase [MD = -0.07, 95%CI (-0.30, 0.16), P<0.01, I2 = 94%] in MSCs treatment group compared with that in control group. Notably, there was no significant difference in the incidence of adverse events between MSCs treatment group and control group [relative risk (RR) = 0.98, 95%CI (0.72, 1.32), P = 0.02, I2 = 70%]. The most commonly observed adverse reaction in the MSC treatment group was hypoglycemia (29.95%). CONCLUSIONS: This meta-analysis revealed MSCs therapy may be an effective and safe intervention in subjects with diabetes. However, due to the limited studies, a number of high-quality as well as large-scale RCTs should be performed to confirm these conclusions.

Inhibition of NLRP3 inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy.

BACKGROUND: Nucleotide leukin-rich polypeptide 3 (NLRP3) inflammasome is documented as a potent target for treating metabolic diseases and inflammatory disorders. Our recent work demonstrated that inhibition of NLRP3 inflammasome activation inhibits renal inflammation and fibrosis in diabetic nephropathy. This study was to investigate the effect of NLRP3 inflammasome on podocyte injury and the underlying mechanism in diabetic nephropathy. METHODS: In vivo, db/db mice were treated with MCC950, a NLRP3 inflammasome specific inhibitor. NLRP3 knockout (NKO) mice were induced to diabetes by intraperitoneal injections of streptozotocin (STZ). We assessed renal function, albuminuria, podocyte injury and glomerular lipid accumulation in diabetic mice. In vitro, apoptosis, cytoskeleton change, lipid accumulation, NF-κB p65 activation and reactive oxygen species (ROS) generation were evaluated in podocytes interfered with NLRP3 siRNA or MCC950 under high glucose (HG) conditions. In addition, the effect and mechanism of IL-1ß on lipid accumulation was explored in podocytes exposed to normal glucose (NG) or HG. RESULTS: MCC950 treatment improved renal function, attenuated albuminuria, mesangial expansion, podocyte loss, as well as glomerular lipid accumulation in db/db mice. The diabetes-induced podocyte loss and glomerular lipid accumulation were reversed in NLRP3 knockout mice. The increased expression of sterol regulatory element-binding protein1 (SREBP1) and SREBP2, and decreased expression of ATP-binding cassette A1 (ABCA1) in podocytes were reversed by MCC950 treatment or NLRP3 knockout in diabetic mice. In vitro, NLRP3 siRNA or MCC950 treatment markedly inhibited HG-induced apoptosis, cytoskeleton change, lipid accumulation, NF-κB p65 activation, and mitochondrial ROS production in cultured podocytes. In addition, BAY11-7082 or tempol treatment inhibited HG-induced lipid accumulation in podocytes. Moreover, exposure of IL-1ß to podocytes induced lipid accumulation, NF-κB p65 activation and mitochondrial ROS generation. CONCLUSION: Inhibition of NLRP3 inflammasome protects against podocyte damage through suppression of lipid accumulation in diabetic nephropathy. IL-1ß/ROS/NF-κB p65 mediates diabetes-associated lipid accumulation in podocytes. The suppression of NLRP3 inflammasome activation may be an effective therapeutic approach to diabetic nephropathy.