Optimal cut-offs of depression screening tools during the COVID-19 pandemic: a systematic review.

BACKGROUND: Studies have reported an increase in the prevalence of depression during the COVID-19 pandemic. The accuracy of screening tools may change with the prevalence and distribution of a disease in a population or sample: the "Spectrum Effect". METHODS: First, we selected commonly used screening tools and developed search strategies for the inclusion of original studies during the pandemic. Second, we searched PsycINFO, EMBASE, and MEDLINE from March 2020 to September 2022 to obtain original studies that investigated the accuracy of depression screening tools during the pandemic. We then searched these databases to identify meta-analyses summarizing the accuracy of these tools conducted before the pandemic and compared the optimal cut-offs for depression screening tools during the pandemic with those before. RESULT: Four original studies evaluating the optimal cut-offs for four screening tools (Beck Depression Inventory [BDI-II], Hospital Anxiety and Depression Scale-Depression [HADS-D], Patient Health Questionnaire-9 [PHQ-9], and Geriatric Depression Scale-4 [GDS-4]) were published during the pandemic. Four meta-analyses summarizing these tools before the pandemic. We found that the optimal cut-off of BDI-II was 14 during the pandemic (23.8% depression prevalence, screening patients with Type 2 diabetes) and 14.5 before the pandemic (17.6% depression prevalence, screening psychiatric, primary care, and healthy populations); HADS-D was 10 during the pandemic (23.8% depression prevalence, screening patients with type 2 diabetes) and 7 before the pandemic (15.0% depression prevalence, screening medically ill patients); PHQ-9 was 11 during the pandemic (14.5% depression prevalence, screening university students) and 8 before the pandemic (10.9% depression prevalence, screening the unrestricted population), and GDS-4 was 1.8 during the pandemic (29.0% depression prevalence, screening adults seen in a memory clinic setting) and 3 before the pandemic (18.5% depression prevalence, screening older adults). CONCLUSION: The optimal cut-off for different screening tools may be sensitive to changes in study populations and reference standards. And potential spectrum effects that should be considered in post-COVID time which aiming to improve diagnostic accuracy.

Urinary N-acetyl-ß-d-glucosaminidase-creatine ratio is a valuable predictor for advanced diabetic kidney disease.

BACKGROUND: Many biomarkers show high diagnostic values for diabetic kidney disease (DKD), but fewer studies focus on the predictive assessment of DKD progression by blood and urinary biomarkers. AIM: This study aims to find powerful risk predictors and identifying biomarkers in blood and urine for DKD progression. METHODS: A total of 117 patients with type 2 DKD including early and advanced stages and their laboratory parameters were statistically assessed. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the significance of discriminating between early and advanced DKD, and the predictive power for advanced DKD was analyzed by regression analysis and trisector grouping. RESULTS: N-acetyl-ß-d-glucosaminidase-creatine (NAG/CR) level in advanced DKD was statistically higher than that in early DKD (p < 0.05), and there was a higher incidence of advanced DKD (72% vs. 56%) and high odds ratio (OR: 3.917, 95% CI: 1.579-10.011) of NAG/CR with ≥2.79 U/mmol compared with <2.79 U/mmol (p < 0.05). NAG/CR ratio also showed a higher area under the ROC curve of 0.727 (95% CI: 0.616-0.828, p = 0.010) with a high sensitivity (0.75) and a moderate specificity (0.66) when 1.93 U/mmol was set as the optimal cutoff value. The adjusted-multivariable analysis revealed that NAG/CR had an OR of 1.021 (95% CI: 1.024-1.038) and 2.223 (95% CI: 1.231-4.463) based on a continuous and categorical variable, respectively, for risk of advanced DKD. Moreover, the prevalence of advanced DKD exhibited an increasing tendency by an increment of the trisector of NAG/CR. CONCLUSIONS: This study suggests that NAG/CR ratio is an independent predictor for advanced DKD, and it also can be used as a powerful identifying marker between early and advanced DKD.

[The mediating effect of coping style between illness perception and fear of cancer recurrence in patients undergoing radical prostatectomy].

OBJECTIVE: To explore the mediating effect of coping style between illness perception and fear of cancer recurrence in patients undergoing radical prostatectomy. METHODS: A questionnaire survey was carried out in 254 eligible patients who underwent radical prostatectomy in the urology department of two comprehensive tertiary hospitals in Wenzhou City from June 2022 to December 2022. The questionnaires include the general data questionnaire, brief illness perception questionnaire (BIPQ), Medical Coping Modes Questionnaire (MCMQ) and Fear of Progression Questionnaire-Short Form (FoP-Q-SF). A structural equation model was used to analyze the mediating effect of coping style between illness perception and fear of cancer recurrence. RESULTS: The score of fear of cancer recurrence in prostate cancer patients is (30.08 ± 10.11). Illness perception, avoidance, and surrender coping styles could forward prediction fear of cancer recurrence (P=0.001, P=0.019, P=0.001); facing coping styles can negatively predict fear of cancer recurrence (P=0.001). Coping style played a part of the mediating role between illness perception and fear of cancer recurrence, and the mediating effect is 0.150，which accounted for 47.62% of the total effect. CONCLUSION: Coping style is a mediator between illness perception and fear of cancer recurrence in patients undergoing radical prostatectomy. Doctors and nurses should reduce patients' negative perception, guide them to adopt positive coping strategies, and thereby reduce their fear of cancer recurrence.

NOL4L, a novel nuclear protein, promotes cell proliferation and metastasis by enhancing the PI3K/AKT pathway in ovarian cancer.

Nucleolar protein 4-like (NOL4L) was first identified in acute myeloid leukaemia. Then, it was verified to be involved in cell progression in neuroblastoma. However, the functional role of NOL4L in tumor proliferation and metastasis and the underlying molecular mechanism(s) are not fully understood. Immunohistochemistry (IHC) assays were performed in patient tissues to reveal NOL4L expression profiles. Then, we knocked down NOL4L in two ovarian cancer cell lines (Skov3-ip1 and Hey), and cell-based in-vitro and in-vivo assays were subsequently conducted to gain insight into the underlying mechanism of NOL4L in ovarian cancer. We confirmed that the expression of NOL4L was higher in tumor tissues, especially in peritoneal metastatic tissues. Furthermore, we observed that NOL4L was related to prognosis in ovarian cancer patients. Next, we conducted CCK-8 assays, colony formation assays, migration and invasion experiments and wound healing assays and verified that NOL4L could promote proliferation and metastasis in ovarian cancer cells. In addition, NOL4L promoted tumor progression and metastasis in a nude mouse model. Mechanistically, we demonstrated that NOL4L influenced gene expression in the PI3K/AKT pathway. Overall, our study provides genetic and biochemical evidence that NOL4L is critical for tumor progression and metastasis in ovarian cancer cells. Thus, it could serve as a target for antimetastatic therapy in ovarian cancer.

Vaginal Repair of Cesarean Section Scar Diverticula Diagnosed in Non-pregnant Women.

STUDY OBJECTIVE: Cesarean section scar diverticulum (CSD) lead to many long-term complications. CSD is more prevalent in patients with a retroflexed uterus than in those with an anteflexed uterus. Therefore, we wanted to estimate the association between flexion of the uterus and the outcome of treatment for CSD treated by vaginal repair. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: University hospital. PATIENTS: A total of 241 women with a CSD were enrolled at the Shanghai First Maternity & Infant Hospital between May 2014 and Oct 2016. INTERVENTIONS: Vaginal excision and suture of CSD. MEASUREMENT AND MAIN RESULTS: A high failure rate was reported in remodeling of the scar by other surgeries in women with retroflexed uteri. Clinical information was obtained from medical records. Because intermenstrual bleeding was a presenting symptom of CSD, duration of menstruation was compared between groups. Patients were required to be followed at 1, 3, and 6 months to record their menstruation situation and to measure the CSD. The thickness of the residual myometrium (TRM) in the retroflexion group was much thinner than that in the anteflexion group before treatment (2.5 ± 1.2 mm vs 2.9 ± 1.1 mm, p < .05). There was no statistical difference in pretreatment menstruation duration between groups (p > .05). The duration of menstruation in the anteflexion group was 8.2 ± 2.1 days and 8.5 ± 2.1 days and in the retroflexion group was 7.6 ± 2.0 days and 7.7 ± 3.1 days at 3 and 6 months after surgery, respectively (p < .05). In all 58.6% of patients (140/239) who had a retroflexed uterus, 60.0% (84/140) reached ≤7 days of menstruation at 6 months after surgery (p < .05). Although about 40% patients still had CSD after repair, menstruation duration and TRM were improved significantly (p < .05). CONCLUSION: We propose that vaginal repair can relieve symptoms and improve TRM for CSD patients, especially for those who have a retroflexed uterus. However, 40% of patients still had a defect postoperatively.

Cesarean section scar diverticulum evaluation by saline contrast-enhanced magnetic resonance imaging: The relationship between variable parameters and longer menstrual bleeding.

AIM: This study was conducted to determine a more accurate imaging method for the diagnosis of cesarean scar diverticulum (CSD) and to identify the parameters of CSD strongly associated with prolonged menstrual bleeding. METHODS: We enrolled 282 women with a history of cesarean section (CS) who presented with prolonged menstrual bleeding between January 2012 and May 2015. Transvaginal ultrasound, general magnetic resonance imaging (MRI) and contrast-enhanced MRI were used to diagnose CSD. Five parameters were compared among the imaging modalities: length, width, depth and thickness of the remaining muscular layer (TRM) of CSD and the depth/TRM ratio. Correlation between the five parameters and days of menstrual bleeding was performed. Finally, multivariate analysis was used to determine the parameters associated with menstrual bleeding longer than 14 days. RESULTS: Contrast-enhanced MRI yielded greater length or width or thinner TRM of CSD compared with MRI and transvaginal ultrasound. CSD size did not significantly differ between women who had undergone one and two CSs. Correlation analysis revealed that CSD (P = 0.038) and TRM (P = 0.003) lengths were significantly associated with days of menstrual bleeding. Longer than 14 days of bleeding was defined by cut-off values of 2.15 mm for TRM and 13.85 mm for length. TRM and number of CSs were strongly associated with menstrual bleeding longer than 14 days. CONCLUSIONS: CE-MRI is a relatively accurate and efficient imaging method for the diagnosis of CSD. A cut-off value of TRM of 2.15 mm is the most important parameter associated with menstrual bleeding longer than 14 days.

Defect width: the prognostic index for vaginal repair of cesarean section diverticula.

PURPOSE: To evaluate the clinical parameter associated with cesarean section diverticula anatomic healing via vaginal repair management. METHODS: Observational cohort study. From Jul 2014 to Dec 2015, 143 women with CSD underwent vaginal repair surgery in Shanghai First Maternity and Infant Hospital, and 137(95.80%) were diagnosed using both transvaginal ultrasound and MRI. A total of 124 patients (86.71%) who were followed-up for more than 6 months after surgery were enrolled in this study. Excision and suture of CSD was performed through the vaginal approach. The defect sizes of the width, length, depth and TRM before or after repair were evaluated. RESULTS: The mean preoperative duration of menstruation was 14.47 ± 3.30 days and the thickness of the remaining muscular layer was 2.65 ± 1.13 mm before surgery. The study revealed that the healing effects of CSD repair stabilized 3 months after surgery. At the median follow-up time (11.28 months), CSD disappeared after surgery in 64.52% of patients (80/124), and 60.0% of patients (48/80) reached ≤7 days of menstruation. Meanwhile, for 35.48% of patients (44/124), CSD persisted at the median follow-up after surgery, and 31.82% (14/44) of these patients reached ≤7 days of menstruation(P < 0.05). TRM at a median follow-up time after vaginal repair >7.88 mm, 92.11% (70/76) of CSD disappeared. Moreover, when preoperative CSD width ≤18.85 mm indicates that only 18.75% (12/64) of patients will present with CSD after vaginal repair, as determined by MRI (95% CI 0.515-0.737). CONCLUSION: The defect width of the preoperative CSD was the prognostic index of CSD anatomical repair effect. When the preoperative CSD width >18.85 mm, we should pay more attention to the edge of the defect during vaginal repairing.

Vaginal Repair of Cesarean Section Scar Diverticula that Resulted in Improved Postoperative Menstruation.

STUDY OBJECTIVE: Owing to the increase in cesarean sections (C-sections) worldwide, long-term complications such as postmenstrual spotting, chronic pelvic pain, and C-section scar ectopic pregnancies have created a new medical era of gynecologic disease. A new type of vaginal repair is evaluated to repair C-section diverticulum (CSD) and rebuild the muscular layer to improve symptoms of abnormal uterine bleeding and decrease the risk of uterine rupture. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: University hospital. PATIENTS: A total of 121 patients with CSD diagnoses by transvaginal ultrasound (TVU) presented with postmenstrual spotting between June 2012 and March 2015. All patients had undergone at least 1 C-section delivery and had no history of postmenstrual spotting before undergoing C-section. INTERVENTION: Vaginal excision and suture of CSD. MEASUREMENT AND MAIN RESULTS: The mean duration of menstruation was 14.87 ± 3.46 days preoperatively and decreased to 8.22 ± 2.73 days at 1 month after surgery, 8.89 ± 2.67 days at 3 months after surgery, and 9.02 ± 2.47 days at 6 months after surgery (p < .01). The length, width, depth, and thickness of the remaining muscular layer (TRM) at 1 month, 3 months, and 6 months assessed by TVU also improved significantly after surgery (p < .05). However, postoperative menstruation and imaging data did not differ markedly between 3 months and 6 months, suggesting that follow-up at 3 months represents an adequate endpoint for evaluating the effectiveness of surgery. At 6 months, 80.3% of patients (94 of 117) reached ≤10 days of menstruation. Further study revealed that a TRM at 6 months of ≥8.5 mm measured by TVU (relative risk [RR], 6.418; 95% confidence interval [CI], 1.478-28.443) and an interval between CS and vaginal repair of ≤2.5 years (RR, 12.0; 95% CI, 1.541- 93.454) were good prognostic factors associated with surgery. CONCLUSION: Vaginal repair of CSD improved the symptoms of postmenstrual spotting and anatomically corrected the scars. An interval between C-section and a surgery of ≤2.5 years was optimal for vaginal repair, and a TRM at 6 months of ≥8.5 mm represented the standard healing of CSD.

Identification of distinct symptom profiles in prostate cancer patients with cancer-related cognitive impairment undergoing androgen deprivation therapy: A latent class analysis.

Objective: To identify latent classes of cognitive impairment and co-occurring symptoms (fatigue, pain, sleep disturbance, depression) as clusters in patients with prostate cancer undergoing androgen deprivation therapy and to explore the predictors among distinct latent classes. Methods: A total of 228 patients with prostate cancer were recruited in this cross-sectional study. The assessment instrument included the Perceived Cognitive Impairment Scale, the Fatigue Severity Scale, the Athens Insomnia Scale, the Brief Pain Inventory, the Patient Health Questionnaire-9, the UCLA Loneliness Scale, the International Physical Activity Questionnaire - Short Form, the Charlson comorbidity index, and General Information questionnaire. The identification of different patient subgroups was done by the latent class analysis. Results: The study identified three distinct latent classes: all low symptoms (class 1, 32%), high depression symptoms (class 2, 37.7%), and high physical symptoms (fatigue, sleep disturbance, and pain) with high cognitive impairment (class 3, 30.3%). Patients who had higher Charlson comorbidity index (P = 0.003) scores were more likely to be classified in class 3. Patients with higher loneliness scores (P < 0.001; P < 0.001) were significantly more likely to fall into class two or three than in class 1. However, having a higher level of physical activity (P = 0.014; P < 0.001) increased the likelihood of being in class 1. Conclusions: This study exhibited the inter-individual variability of symptom experience in prostate cancer patients with cognitive impairment undergoing androgen deprivation therapy. The result suggests that more emphasis should be placed on screening for fatigue, sleep disturbance, and pain, and future interventions should focus on loneliness and physical activity.

Lower circulating preptin levels in male patients with osteoporosis are correlated with bone mineral density and bone formation.

BACKGROUND: Serum preptin levels among subjects with different bone mineral densities (BMD) were measured and investigated to determine the correlation between BMD and bone-metabolic markers. METHODS: Approximately 52 elderly male patients with osteoporosis, 50 elderly men with osteopaenia, and 31 age-matched normal bone mass controls participated in the study. The serum preptin levels and bone metabolic markers were measured by enzyme-linked immunosorbent assay. The relationships between preptin levels, BMD, and metabolic parameters were also assessed. RESULTS: The serum preptin level was the lowest in the osteoporosis group and positively correlated with BMD. All the bone formation markers in the osteoporosis and osteopaenia groups were significantly reduced compared with those in the normal group. Serum preptin level was positively correlated with all the bone formation markers, whereas no correlation was observed with the bone resorption marker TRACP-5b. CONCLUSIONS: Serum preptin levels are decreased in osteoporosis and osteopaenia patients and positively correlated with BMD. Therefore, preptin is involved in the pathogenesis of osteoporosis, probably through bone formation rather than bone resorption.

PDE-5-Inhibited BMSCs Alleviate High Glucose-Induced Myocardial Fibrosis and Cardiomyocyte Apoptosis by Activating the cGMP/PKG Pathway.

BACKGROUND: Phosphodiesterase-5 (PDE-5) inhibitors have been found to play an important cardio-protective role. This study aimed to clarify the inhibitory effects of PDE-5-silenced bone marrow mesenchymal stem cells (BMSCs) on high glucose-induced myocardial fibrosis and cardiomyocyte apoptosis. METHODS: Cardiomyocytes and fibroblasts of neonatal rats were treated with high glucose (HG), and co-cultured with PDE-5-overexpressed or -knocked down BMSCs. The viability and apoptosis as well as the levels of cytokines, Cardiac troponin I and Vimentin of cardiomyocytes and fibroblasts were studied. The expressions of PDE-5, cyclic guanosine monophosphate (cGMP) and protein kinase G (PKG), in both cells were evaluated. RESULTS: BMSCs that silenced PDE-5 facilitated the viability of cardiomyocytes, decreased the viability of fibroblasts, and inhibited the apoptosis of cardiomyocytes and fibroblasts. The contents of collagen-I, collagen-III, tissue inhibitor of metalloproteinase (TIMP)-1 and Dermin in fibroblasts were decreased by the PDE-5 inhibitor, but the levels of matrix metalloproteinase (MMP)-1 in fibroblasts and troponin-I in cardiomyocytes were increased by the PDE-5 inhibitor. PDE-5 inhibitor also suppressed the expression of PDE-5 but up-regulated cGMP and PKG expression in cardiomyocytes and fibroblasts. CONCLUSIONS: PDE-5-inhibited BMSCs can decrease HG-induced myocardial fibrosis and cardiomyocyte apoptosis by activating the cGMP/PKG pathway, and may play a role in the prevention and treatment of diabetic cardiomyopathy.

Smart chitosan-based microgels for enhanced photothermal-assisted antibacterial activity.

During recent years, antibiotic-resistant bacteria have rapidly emerged owing to the irrational use of antibiotics, rendering a global problem. Currently, few studies introduce customized antibacterial nanoplatforms to overcome antibiotic-resistance according to specific characteristic of bacteria, rather than abuse of antibiotic. Herein, with regard to personalized antibacterial nanoplatform, we design a novel antibiotic delivery nanocarrier composed of polyaniline-grafted-chitosan, presenting pH-responsive, conductive, photothermal, and biodegradable properties. After treatment with divalent anion (SO42-), the negatively charged nanocarriers are obtained for improving the loading efficacy of cationic vancomycin. Meanwhile, the controlled vancomycin release is achieved by lysozyme-triggered degradation of the nanocarrier. With the assistance of photothermal effect, the photothermal-assisted antibacterial effect of the nanocarriers have been effectively enhanced rather than that of a single antibacterial effect of vancomycin. Owing to the low heat resistance of Escherichia coli, photothermal effect can break the antibiotic-resistant bacteria membrane to render the convenient antibiotic entry, leading to the improved antibacterial efficacy. Therefore, the customization of a photothermal-assisted antibacterial on account of the characteristic of specific bacteria can definitely expand our arsenal for enhancing the antibacterial effect against antibiotic-resistant bacteria.

Exosomes released from PD-L1+ tumor associated macrophages promote peritoneal metastasis of epithelial ovarian cancer by up-regulating T cell lipid metabolism.

Epithelial ovarian cancer (EOC) tends to metastasize to the peritoneum, and the prognosis of patients is poor. In the peritoneum of patients with EOC, TAMs (tumor associated macrophages) regulate the imbalance of T cell ratio and promote the progression and metastasis of EOC. However, the mechanism of peritoneal metastasis in EOC patients remains unclear. Here, we confirmed that the percentages of PD-L1+ TAMs in EOC tissues increased significantly, and TAMs-derived PD-L1+ exosomes affected the transcription factor PPARα to up-regulate the expression of CPT1A in CD8+ T cells, promote fatty acid oxidation, and increase reactive oxygen species to cause cell damage. The apoptosis of CD8+ T cells was increased, and the expressions of their exhaustion markers LAG3, TIM-3, and PD-1 were also up-regulated. TAMs affect T cell function through lipid metabolism, leading to peritoneal immune imbalance and promoting peritoneal metastasis of EOC. This study reveals the mechanism by which TAMs in the peritoneal microenvironment regulate T cell lipid metabolism through exosome delivery of PD-L1, and the effect of lipid metabolism on T cell function, reveals the molecular mechanism of tumor immune microenvironment affecting EOC metastasis, and further explores related pathways whether molecular blockade can be used as a means to intervene in disease progression is expected to establish a new strategy for the diagnosis and treatment of EOC.

Human PBMC scRNA-seq-based aging clocks reveal ribosome to inflammation balance as a single-cell aging hallmark and super longevity.

Quantifying aging rate is important for evaluating age-associated decline and mortality. A blood single-cell RNA sequencing dataset for seven supercentenarians (SCs) was recently generated. Here, we generate a reference 28-sample aging cohort to compute a single-cell level aging clock and to determine the biological age of SCs. Our clock model placed the SCs at a blood biological age to between 80.43 and 102.67 years. Compared to the model-expected aging trajectory, SCs display increased naive CD8+ T cells, decreased cytotoxic CD8+ T cells, memory CD4+ T cells, and megakaryocytes. As the most prominent molecular hallmarks at the single-cell level, SCs contain more cells and cell types with high ribosome level, which is associated with and, according to Bayesian network inference, contributes to a low inflammation state and slow aging of SCs. Inhibiting ribosomal activity or translation in monocytes validates such translation against inflammation balance revealed by our single-cell aging clock.

Stratification of diabetic kidney diseases via data-independent acquisition proteomics-based analysis of human kidney tissue specimens.

Aim: The aims of this study were to analyze the proteomic differences in renal tissues from patients with diabetes mellitus (DM) and diabetic kidney disease (DKD) and to select sensitive biomarkers for early identification of DKD progression. Methods: Pressure cycling technology-pulse data-independent acquisition mass spectrometry was employed to investigate protein alterations in 36 formalin-fixed paraffin-embedded specimens. Then, bioinformatics analysis was performed to identify important signaling pathways and key molecules. Finally, the target proteins were validated in 60 blood and 30 urine samples. Results: A total of 52 up- and 311 down-regulated differential proteins were identified as differing among the advanced DKD samples, early DKD samples, and DM controls (adjusted p<0.05). These differentially expressed proteins were mainly involved in ion transport, apoptosis regulation, and the inflammatory response. UniProt database analysis showed that these proteins were mostly enriched in signaling pathways related to metabolism, apoptosis, and inflammation. NBR1 was significantly up-regulated in both early and advanced DKD, with fold changes (FCs) of 175 and 184, respectively (both p<0.01). In addition, VPS37A and ATG4B were significantly down-regulated with DKD progression, with FCs of 0.140 and 0.088, respectively, in advanced DKD and 0.533 and 0.192, respectively, in early DKD compared with the DM control group (both p<0.01). Bioinformatics analysis showed that NBR1, VPS37A, and ATG4B are closely related to autophagy. We also found that serum levels of the three proteins and urine levels of NBR1 decreased with disease progression. Moreover, there was a significant difference in serum VPS37A and ATG4B levels between patients with early and advanced DKD (both p<0.05). The immunohistochemistry assaay exhibited that the three proteins were expressed in renal tubular cells, and NBR1 was also expressed in the cystic wall of renal glomeruli. Conclusion: The increase in NBR1 expression and the decrease in ATG4B and VPS37 expression in renal tissue are closely related to inhibition of the autophagy pathway, which may contribute to DKD development or progression. These three proteins may serve as sensitive serum biomarkers for early identification of DKD progression.

A circulating miR-19b-based model in diagnosis of human breast cancer.

Objective: Breast cancer (BC) is becoming the leading cause of cancer-related death in women all over the word. Identification of diagnostic biomarkers for early detection of BC is one of the most effective ways to reduce the mortality. Methods: Plasma samples from BC patients (n = 120) and normal controls (n = 50) were collected to determine the differentially expressed circulating miRNAs in BC patients. Binary logistic regression was applied to develop miRNA diagnostic models. Receiver operating characteristic (ROC) curves were applied to calculate the area under the curve (AUC). MMTV-PYMT mammary tumor mice were used to validate the expression change of those circulating miRNAs. Plasma samples from patients with other tumor types were collected to determine the specificity of the model in diagnosis of BC. Results: In the screening phase, 5 circulating miRNAs (miR-16, miR-17, miR-19b, miR-27a, and miR-106a) were identified as the most significantly upregulated miRNAs in plasma of BC patients. In consistence, the 5 miRNAs showed upregulation in the circulation of additional 80 BC patients in a tumor stage-dependent manner. Application of a tumor-burden mice model further confirmed upregulation of the 5 miRNAs in circulation. Based on these data, five models with diagnostic potential of BC were developed. Among the 5 miRNAs, miR-19b ranked at the top position with the highest specificity and the biggest contribution. In combination with miR-16 and miR-106a, a miR-19b-based 3-circulating miRNA model was selected as the best for further validation. Taken the samples together, the model showed 92% of sensitivity and 90% of specificity in diagnosis of BC. In addition, three other tumor types including prostate cancer, thyroid cancer and colorectal cancer further verified the specificity of the BC diagnostic model. Conclusion: The current study developed a miR-19b-based 3-miRNA model holding potential for diagnosis of BC using blood samples.

Triptolide decreases rheumatoid arthritis fibroblast-like synoviocyte proliferation, invasion, inflammation and presents a therapeutic effect in collagen-induced arthritis rats via inactivating lncRNA RP11-83J16.1 mediated URI1 and ß-catenin signaling.

OBJECTIVE: Our previous study observed that long non-coding RNA (lncRNA) RP11-83J16.1 promoted rheumatoid arthritis (RA)-fibroblast-like synoviocyte (RA-FLS) proliferation, invasion and inflammation, which was downregulated by triptolide treatment. Therefore, the present study aimed to further investigate the mechanism and interaction between triptolide and lncRNA RP11-83J16.1 in RA treatment in vitro and in vivo. METHODS: RA-FLS was isolated and treated by different concentration of triptolide and lncRNA RP11-83J16.1 overexpression plasmid. Furthermore, collagen-induced arthritis (CIA) rat model was constructed followed by triptolide and lncRNA RP11-83J16.1 overexpression plasmid treatment. RESULTS: Triptolide inhibited RA-FLS viability and lncRNA RP11-83J16.1 expression in a dose-dependent manner. Afterward, triptolide treatment inhibited RA-FLS proliferation, invasion, levels of inflammatory markers (TNF-α, IL-1ß, IL-6, MMP-3, and MMP-9), inactivated lncRNA RP11-83J16.1, URI1 and ß-catenin signaling, but promoted apoptosis. However, lncRNA RP11-83J16.1 overexpression weakened the effects of triptolide on regulating RA-FLS cell behaviors, URI1 signaling and ß-catenin signaling. In CIA model, triptolide decreased arthritis score, hyperproliferation of synovial cells, inflammation infiltration of synovial tissue, inflammatory markers (TNF-α, IL-1ß, IL-6, MMP-3, and MMP-9), inactivated lncRNA RP11-83J16.1, URI1 and ß-catenin signaling, but increased cell apoptosis rate of synovial tissue. Nevertheless, lncRNA RP11-83J16.1 curtailed the treatment effect of triptolide in CIA model. CONCLUSION: Triptolide decreases RA-FLS proliferation, invasion, inflammation and presents a therapeutic effect in CIA model via inactivating lncRNA RP11-83J16.1 mediated URI1 and ß-catenin signaling.

The high platelet counts as predictor for early foetal demise.

Objectives: Early fetal demise (absence of cardiac activity in a visible fetus) is a very common event, but there are no reliable biomarkers to predict it. The purpose of the study was to assess the association of platelet parameters with early fetal demise.Methods: In this case-control study, we included women with normal deliveries or those ultrasound diagnosed as early fetal demise. For those who were identified with early fetal demise, the platelet parameters were analyzed before the ultrasound diagnosis, which is based on the absence of either an embryo within a gestational sac or cardiac activity in a visible embryo in the 5-10 weeks of gestation. The association between the risk of early fetal demise with the women's mean platelet volume (MPV) and platelet counts was calculated by logistic regression. Duplicate measurements of platelet aggregation were performed with VerifyNow. Results: In total, 99 women identified with early fetal demise and 170 women who had an uncomplicated pregnancy with normal delivery from January 2017 and August 2020 were included in the study. We found that platelet counts in the early fetal demise group were significantly higher than healthy pregnancies. In addition, platelet reactivity is higher in the normal delivery group than those in early fetal demise group (p < .05). High levels of platelet counts resulted in an adjusted odds ratio (OR) of 2.075 (95% confidence interval [95% CI], 1.215-3.544; p = .008) for early fetal demise. Conclusions: Increased platelet counts in the first trimester may be a predictor for the risk of early fetal demise.

MicroRNA Variants and HLA-miRNA Interactions are Novel Rheumatoid Arthritis Susceptibility Factors.

Genome-wide association studies have identified >100 genetic risk factors for rheumatoid arthritis. However, the reported genetic variants could only explain less than 40% heritability of rheumatoid arthritis. The majority of the heritability is still missing and needs to be identified with more studies with different approaches and populations. In order to identify novel function SNPs to explain missing heritability and reveal novel mechanism pathogenesis of rheumatoid arthritis, 4 HLA SNPs (HLA-DRB1, HLA-DRB9, HLA-DQB1, and TNFAIP3) and 225 common SNPs located in miRNA, which might influence the miRNA target binding or pre-miRNA stability, were genotyped in 1,607 rheumatoid arthritis and 1,580 matched normal individuals. We identified 2 novel SNPs as significantly associated with rheumatoid arthritis including rs1414273 (miR-548ac, OR = 0.84, p = 8.26 × 10-4) and rs2620381 (miR-627, OR = 0.77, p = 2.55 × 10-3). We also identified that rs5997893 (miR-3928) showed significant epistasis effect with rs4947332 (HLA-DRB1, OR = 4.23, p = 0.04) and rs2967897 (miR-5695) with rs7752903 (TNFAIP3, OR = 4.43, p = 0.03). In addition, we found that individuals who carried 8 risk alleles showed 15.38 (95%CI: 4.69-50.49, p < 1.0 × 10-6) times more risk of being affected by RA. Finally, we demonstrated that the targets of the significant miRNAs showed enrichment in immune related genes (p = 2.0 × 10-5) and FDA approved drug target genes (p = 0.014). Overall, 6 novel miRNA SNPs including rs1414273 (miR-548ac, p = 8.26 × 10-4), rs2620381 (miR-627, p = 2.55 × 10-3), rs4285314 (miR-3135b, p = 1.10 × 10-13), rs28477407 (miR-4308, p = 3.44 × 10-5), rs5997893 (miR-3928, p = 5.9 × 10-3) and rs45596840 (miR-4482, p = 6.6 × 10-3) were confirmed to be significantly associated with RA in a Chinese population. Our study suggests that miRNAs might be interesting targets to accelerate understanding of the pathogenesis and drug development for rheumatoid arthritis.

Role of RP11-83J16.1, a novel long non-coding RNA, in rheumatoid arthritis.

This study aimed to explore the effects of long non-coding RNA (lncRNA) expression on rheumatoid arthritis (RA). LncRNA expression profiles were obtained from the synovial tissues of five RA patients and five age-/gender-matched controls by RNA-Seq. Six candidate lncRNAs were then chosen and their levels in synovial fluid further examined in 25 RA patients and 25 health controls using RT-qPCR. The effects of lncRNA RP11-83J16.1 overexpression and knockdown on RA fibroblast-like synoviocytes (RA-FLS) function, inflammation state, and URI1, FRAT1, and ß-catenin levels were assessed. After RNA-Seq, lncRNA expression profiles clearly distinguished RA patients from controls, and 190 upregulated lncRNAs and 131 downregulated lncRNAs were identified, which were mainly enriched in proliferative/immune/inflammatory pathways. Results of RT-qPCR showed that the levels of lncRNAs MTCO2P12, KCNQ5-IT1 and RP11-83J16.1 were increased, whereas lncRNAs LINC00570, RP11-342M1.6, and REXO1L4P were decreased in RA patients compared to controls. Notably, lncRNA RP11-83J16.1 correlated with increased inflammation and disease activity in RA patients. Additionally, lncRNA RP11-83J16.1 promoted cell proliferation, migration, invasion and inflammation, reduced apoptosis, and positively regulates cellular URI1, FRAT1 and ß-catenin expression in RA-FLS. Rescue experiments revealed that URI1 overexpression compensated for the regulatory effects of lncRNA RP11-83J16.1 knockdown in RA-FLS. In conclusion, lncRNA RP11-83J16.1, a novel lncRNA identified by RNA-Seq, correlates with increased risk and disease activity of RA, and promotes RA-FLS proliferation, migration, invasion and inflammation by regulating URI1 and downstream ß-catenin pathway components.