Association of birth weight with type 2 diabetes mellitus and the mediating role of fatty acids traits: a two-step mendelian randomization study.

BACKGROUND: Observational studies have suggested an association between birth weight and type 2 diabetes mellitus, but the causality between them has not been established. We aimed to obtain the causal relationship between birth weight with T2DM and quantify the mediating effects of potential modifiable risk factors. METHODS: Two-step, two-sample Mendelian randomization (MR) techniques were applied using SNPs as genetic instruments for exposure and mediators. Summary data from genome-wide association studies (GWAS) for birth weight, T2DM, and a series of fatty acids traits and their ratios were leveraged. The inverse variance weighted (IVW) method was the main analysis approach. In addition, the heterogeneity test, horizontal pleiotropy test, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test, and leave-one-out analysis were carried out to assess the robustness. RESULTS: The IVW method showed that lower birth weight raised the risk of T2DM (ß: -1.113, 95% CI: -1.573 ∼ -0.652). Two-step MR identified 4 of 17 candidate mediators partially mediating the effect of lower birth weight on T2DM, including ratio of polyunsaturated fatty acids to monounsaturated fatty acids (proportion mediated: 7.9%), ratio of polyunsaturated fatty acids to total fatty acids (7.2%), ratio of omega-6 fatty acids to total fatty acids (8.1%) and ratio of linoleic acid to total fatty acids ratio (6.0%). CONCLUSIONS: Our findings supported a potentially causal effect of birth weight against T2DM with considerable mediation by modifiable risk factors. Interventions that target these factors have the potential to reduce the burden of T2DM attributable to low birth weight.

The clinicopathologic and molecular features, and treatment outcome of fumarate hydratase-deficient renal cell carcinoma: a retrospective comparison with type 2 papillary renal cell carcinoma.

BACKGROUND: To compare clinicopathologic, molecular features, and treatment outcome between fumarate hydratase-deficient renal cell carcinoma (FH-dRCC) and type 2 papillary renal cell carcinoma (T2 pRCC). METHODS: Data of T2 pRCC patients and FH-dRCC patients with additional next-generation sequencing information were retrospectively analyzed. The cancer-specific survival (CSS) and disease-free survival (DFS) were primary endpoint. RESULTS: A combination of FH and 2-succino-cysteine (2-SC) increased the rate of negative predictive value of FH-dRCC. Compared with T2 pRCC cases, FH-dRCC cases displayed a greater prevalence in young patients, a higher frequency of radical nephrectomy. Seven FH-dRCC and two T2 pRCC cases received systemic therapy. The VEGF treatment was prescribed most frequently, with an objective response rate (ORR) of 22.2% and a disease control rate (DCR) of 30%. A combined therapy with VEGF and checkpoint inhibitor reported an ORR of 40% and a DCR of 100%. FH-dRCC cases showed a shortened CSS (P = 0.042) and DFS (P < 0.001). The genomic sequencing revealed 9 novel mutations. CONCLUSIONS: Coupled with genetic detection, immunohistochemical biomarkers (FH and 2-SC) can distinguish the aggressive FH-dRCC from T2 pRCC. Future research is awaited to illuminate the association between the novel mutations and the clinical phenotypes of FH-dRCC in the disease progression.

Development and validation of a nomogram for predicting the impact of tumor size on cancer-specific survival of locally advanced renal cell carcinoma: a SEER-based study.

This study was aimed to integrate tumor size with other prognostic factors into a prognostic nomogram to predict cancer-specific survival (CSS) in locally advanced (≥pT3a Nany M0) renal cell carcinoma (RCC) patients. Based on the Surveillance, Epidemiology, and End Results (SEER) database, 10,800 patients diagnosed with locally advanced RCC were collected. They were randomly divided into a training cohort (n = 7,056) and a validation cohort (n = 3,024). X-tile program was used to identify the optimal cut-off value of tumor size and age. The cut-off of age at diagnosis was 65 years old and 75 years old. The cut-off of tumor size was 54 mm and 119 mm. Univariate and multivariate Cox regression analyses were performed in the training cohort to identify independent prognostic factors for construction of nomogram. Then, the nomogram was used to predict the 1-, 3- and 5-year CSS. The performance of nomogram was evaluated by using concordance index (C-index), area under the Subject operating curve (AUC) and decision curve analysis (DCA). Moreover, the nomogram and tumor node metastasis (TNM) staging system (AJCC 8th edition) were compared. 10 variables were screened to develop the nomogram. The area under the receiver operating characteristic (ROC) curve (AUC) indicated satisfactory ability of the nomogram. Compared with the AJCC 8th edition of TNM stage, DCA showed that the nomogram had improved performance. We developed and validated a nomogram for predicting the CSS of patients with locally advanced RCC, which was more precise than the AJCC 8th edition of TNM staging system.

Serum IL-27 levels increase in subjects with hypothyroidism and are negatively correlated with the occurrence of nonalcoholic fatty liver disease.

Background: The level of serum interleukin-27 (IL-27) was significantly decreased in the obesity group. After injection of IL-27, obese mice showed significant weight loss,reduced fat accumulation, improved insulin resistance and hepatic steatosis.IL-27 plays a key role in the regulation of metabolic processes, but there are scarce data on circulating IL-27 levels in hypothyroidism. The purpose of this study was to assess the serum levels of IL-27 in patients with hypothyroidism and its relationship with NAFLD. Methods: 185 participants were included in this cross-sectional survey. According to thyroid function, the subjects were classified into three groups: euthyroidism (n = 55), subclinical hypothyroidism (n = 53), and hypothyroidism (n = 77). Serum IL-27 concentrations were measured by ELISA. Results: Serum IL27 levels were significantly higher in subclinical hypothyroidism and hypothyroidism groups than in the euthyroidism group. Serum IL27 levels had a negative correlation with HOMA-IR,FBG,TG, subcutaneous fat,and visceral fat, and had a positive correlation with HDL-C (P< 0.05). Furthermore, logistic regression analysis indicated that IL-27 levels, HOMA-IR, and visceral fat showed significant associations with NAFLD after complete adjustment (P< 0.05). ROC curves showed that theoptimal cut-off value of serum IL-27 for discriminating NAFLD was 95.87pg/mL. The area under the ROC curve was 77.3% (95% CI = 0.694-0.851, p < 0.001). Conclusions: Serum IL-27 levels demonstrated a compensatory increase in patients with subclinical hypothyroidism or hypothyroidism and showed an independent association with NAFLD. Circulating IL-27 levels could predict the occurrence of NAFLD in hypothyroidism. These results suggested that altering the circulating levels of IL-27 may be a potential therapeutic target for NAFLD.

A nomogram for predicting the risk of male breast cancer for overall survival.

Background: Male breast cancer (MBC) is a rare disease, accounting for <1% of all male carcinomas. Lack of prospective data, the current therapy for MBC is based on retrospective analysis or information that is extrapolated from studies of female patients. We constructed a nomogram model for predicting the overall survival (OS) of MBC patients and verify its feasibility using data from China. Methods: Constructed a predictive model using 1224 MBC patients from the Surveillance, Epidemiology and End Results (SEER) registry between 2010 and 2015. The performance of the model was externally validated between 2002 to 2021 using 44 MBC patients from the Fujian Medical University Union Hospital. The independent prognostic factors were selected by univariate and multivariate Cox regression analyses. The nomogram was constructed to predict individual survival outcomes for MBC patients. The discriminative power, calibration, and clinical effectiveness of the nomogram were evaluated by the receiver operating characteristic (ROC) curve, and the decision curve analysis (DCA). Results: A total of 1224 male breast cancer patients were in the training cohort and 44 in the validation cohort. T status (p<0.001), age at diagnosis (p<0.001), histologic grade (p=0.008), M status (p<0.001), ER status (p=0.001), Her2 status (p=0.019), chemotherapy (p=0.015) were independently associated with OS. The diagnostic performance of this model was evaluated and validated using ROC curves on the training and validation datasets. In the training cohort, the nomogram-predicted AUC value was 0.786 for 3-year OS and 0.767 for 5-year OS. In the validation cohort, the nomogram-predicted AUC value was 0.893 for 3-year OS and 0.895 for 5-year OS. Decision curve analysis demonstrated that the nomogram was more benefit than the AJCC stage. Conclusions: We developed a nomogram that predicts 3-year and 5-year survival in MBC patients. Validation using bootstrap sampling revealed optimal discrimination and calibration, suggesting that the nomogram may have clinical utility. The results remain reproducible in the validation cohort which included Chinese data. The model was superior to the AJCC stage system as shown in the decision curve analysis (DCA).

Clinical characteristics and overall survival prognostic nomogram for metaplastic breast cancer.

Background: Metaplastic breast cancer (MBC) is a rare breast tumor and the prognostic factors for survival in patients still remain controversial. This study aims to develop and validate a nomogram to predict the overall survival (OS) of patients with MBC. Methods: We searched the Surveillance, Epidemiology, and End Results (SEER) database for data about patients including metaplastic breast cancer and infiltrating ductal carcinoma (IDC) from 2010 to 2018. The survival outcomes of patients between MBC and IDC were analyzed and compared with the Kaplan-Meier (KM) method. MBC patients were randomly allocated to the training set and validation I set by a ratio of eight to two. Meanwhile, the performance of this model was validated again by the validation II set, which consisted of MBC patients from the Union Hospital of Fujian Medical University between 2010 and 2018. The independent prognostic factors were selected by univariate and multivariate Cox regression analyses. The nomogram was constructed to predict individual survival outcomes for MBC patients. The discriminative power, calibration, and clinical effectiveness of the nomogram were evaluated by the concordance index (C-index), the receiver operating characteristic (ROC) curve, and the decision curve analysis (DCA). Results: MBC had a significantly higher T stage (T2 and above accounting for 75.1% vs 39.9%), fewer infiltrated lymph nodes (N0 accounted for 76.2% vs 67.7%), a lower proportion of ER (22.2% vs 81.2%), PR (13.6% vs 71.4%), and HER-2(6.7% vs 17.7%) positive, radiotherapy(51.6% vs 58.0%) but more chemotherapy(67.5% vs 44.7%), and a higher rate of mastectomy(53.2% vs 36.8%), which was discovered when comparing the clinical baseline data between MBC and IDC. Age at diagnosis, T, N, and M stage, as well as surgery and radiation treatment, were all significant independent prognostic factors for overall survival (OS). In the validation I cohort, the nomogram's C-index (0.769 95% CI 0.710 -0.828) was indicated to be considerably higher than the standard AJCC model's (0.700 95% CI 0.644 -0.756). Nomogram's great predictive capability capacity further was supported by the comparatively high C-index of the validation II sets (0.728 95%CI 0.588-0.869). Conclusions: Metaplastic breast cancer is more aggressive, with a worse clinical prognosis than IDC. This nomogram is recommended for patients with MBC, both American and Chinese, which can help clinicians make more accurate individualized survival analyses.

The Effects of Non-Surgical Periodontitis Therapy on the Clinical Features and Serological Parameters of Patients Suffering from Rheumatoid Arthritis as Well as Chronic Periodontitis.

OBJECTIVE: The present study aims to evaluate the effects of basic periodontal disease therapy on the general condition and serum inflammatory indicators of patients with rheumatoid arthritis (RA) combined with chronic periodontitis (CP). METHODS: Forty patients with RA were enrolled in the study and, based on the results of an oral examination and in line with the 2018 periodontitis diagnostic criteria, they were divided into a group with CP (the RA + CP group) and a group without CP (the RA group). Twenty-nine patients with CP who attended the periodontal department of our hospital were recruited as a group with only CP (the CP group), and 20 volunteers without any systemic or periodontal disease were recruited as a healthy control group (the H group). The periodontal and joint conditions of the subjects in the four groups were recorded; anti-cyclic citrullinated protein antibodies, interleukin 6 (IL-6), C-reactive protein (CRP), the erythrocyte sedimentation rate (ESR), and rheumatoid factor levels, which reflect the severity of the RA, were detected, and the differences between the groups were analyzed. The probing depth (PD), clinical attachment loss, and sulcus bleeding index (SBI), which reflect the severity of the periodontitis, were correlated with the factor levels. The RA + CP and CP groups received therapeutic intervention, and the differences in each indicator before and six weeks after the treatment were compared, and their data were compared with those of patients in the RA group and H groups. RESULTS: Compared with the RA group, the serum expressions of ESR, CRP, and IL-6 were significantly higher in the RA + CP group. There were significant differences in the levels of PD, SBI, IL-6, and CRP in the patients receiving basic periodontal disease therapy before and after the treatment. CONCLUSION: A relatively large proportion of patients with RA have chronic periodontitis, and the local inflammatory state of CP might exacerbate the systemic inflammatory response in RA. Basic periodontal disease therapy may improve the oral condition of patients with RA and reduce the serum levels of the inflammatory factors.

A systematic review and meta-analysis of postmastectomy radiation therapy on prepectoral versus subpectoral breast reconstruction.

Background: Prepectoral breast reconstruction has once again appealed, which attributes to the introduction of acellular dermal matrices (ADMs) and mesh. Postmastectomy radiation therapy (PMRT), meanwhile, is crucial in the whole course of treatment for breast cancer patients with lymph node-positive. The impact of PMRT on outcomes after prepectoral breast reconstruction has not been clearly defined to date. This study aimed to compare the impact of PMRT on outcomes after prepectoral vs. subpectoral breast reconstruction. Methods: A comprehensive research on databases including PubMed, Embase, and Cochrane libraries was performed to retrieve literature pertaining to prepectoral breast reconstruction from database inception to October 2021. All included studies evaluated the impact of PMRT on outcomes after breast reconstruction. Only studies comparing patients who underwent prepectoral breast reconstruction with a control group who underwent subpectoral breast reconstruction were included. Data were analyzed using RevMan version 5.2. Results: A total of 4 studies were included in the meta-analysis, with a total of 394 breasts. In the setting of postmastectomy radiation therapy, 164 breasts were reconstructed with a prepectoral approach, whereas the remaining 230 breasts underwent subpectoral reconstruction. Overall, outcomes between PBR and SBR was no statistical significance in the overall complications (OR: 1.30, 95% CI: 0.35-4.85), infection (OR: 1.62, 95% CI: 0.90-2.91), seroma (OR: 1.60, 95% CI: 0.48-5.27), skin flap necrosis (OR: 0.77, 95% CI: 0.17-3.45), hematoma (OR: 0.38, 95% CI: 0.10-1.41), wound dehiscence (OR: 0.82, 95% CI: 0.36-1.85). But, included studies lacked data about the patient quality of life and satisfaction with the outcome of the reconstructed breast. Conclusions: In the setting of postmastectomy radiation therapy, prepectoral breast reconstruction is a safe and effective option.

Role of C5a and C5aR in doxorubicin-induced cardiomyocyte senescence.

Doxorubicin (DOX) is an efficacious antineoplastic drug; however, its use is limited due to its cardiotoxicity. Cardiomyocyte senescence is considered to be a key factor in the development of DOX-related cardiomyopathy. Complement component 5a (C5a) and the C5a receptor (C5aR) have been reported to play a key role in the process of cellular senescence. However, to the best of our knowledge, the exact role of C5a and C5aR in cellular senescence in the heart remains largely unknown. Reverse transcription-quantitative (RT-q)PCR and western blot assays were used to analyze the expression levels of C5a and C5aR in H9c2 embryonic rat cardiomyocytes and AC16 human cardiomyocyte-like cells. The cells were treated with DOX and a C5aR antagonist (C5aRA). The expression of TNF-α and IFN-γ was determined using ELISA and western blotting. The levels of reactive oxygen species (ROS) were also measured using ELISA. Cellular senescence was determined using senescence-associated ß-galactosidase (SA-ß-gal) staining and by analyzing the protein expression levels of p53, p16, p21 and insulin-like growth factor-binding protein 3 (IGFBP3). The expression levels of C5a and C5aR were found to be upregulated during the DOX-induced senescence of H9c2 and AC16 cardiomyocytes. Treatment with C5aRA downregulated TNF-α and IFN-γ expression, in addition to ROS levels. Furthermore, C5aRA prevented DOX-induced cellular senescence and decreased the levels of positive SA-ß-gal staining in H9c2 and AC16 cardiomyocytes, in addition to downregulating the expression levels of p53, p16, p21 and IGFBP3. C5aRA also increased the telomere length and telomerase activity in H9c2 and AC16 cardiomyocytes following DOX stimulation. In conclusion, the findings of the present study indicated that C5a and C5aR may play a key role in cardiomyocyte senescence, and treatment with C5aRA may be an effective method for preventing DOX-induced cardiomyocyte aging.

A novel polysaccharide from Hericium erinaceus: Preparation, structural characteristics, thermal stabilities, and antioxidant activities in vitro.

A novel polysaccharide fraction (HEP) from Hericium erinaceus was successively isolated and purified in the present study. We researched its structure and thermal stabilities, and further studied its antioxidant activities in vitro. The results showed that HEP was an acid heteropolysaccharide, with an average molecular weight of approximately 19.7 kDa by high-performance gel permeation chromatography. Ion chromatography indicated that HEP was mainly composed of fucose:galactose:glucose:mannose:gluconic acid (Fuc:Gal:Glu:Man:GlcA) in a molar ratio of 1:2.87:0.09:0.12:0.01. Additionally, Fourier-transformed infrared and NMR spectroscopy further demonstrated that HEP was a pyranose containing α-configuration, mainly consisting of α-1-4-Fuc and α-1-6-Gal as the main chain, with →3,6)-α-D-Man-(1→and→1,6)-Glc was branched, with α-D-GlcpA-(1 as T-terminal. The specific rotation of HEP was +55°; by the differential scanning calorimetry and the thermal stability measurement of thermogravimetric analysis for HEP showed that the pyrolysis process of HEP was mainly divided into two processes, and its melting point was 75.93℃. In vitro anti-oxidation experiments showed that HEP had a certain ability to scavenge DPPH, hydroxyl, superoxide anion, and ABTS radicals. It was found that HEP had a strong ability to scavenge DPPH-free radicals, and the highest scavenging rate could reach 91.72% ± 0.17%, which was basically equivalent to the scavenging ability of Vitamin C (Vc). Therefore, it was revealed that HEP might be used as a natural antioxidant component. PRACTICAL APPLICATIONS: A novel polysaccharide (HEP) had a potent activity possibly due to its monosaccharide composition, sugar residues, and physicochemical properties. This research proved the potential of HEP in anti-oxidation and provided the possibility of developing new natural anti-oxidation products.

Structural characterization of an acid polysaccharide from Pinellia ternata and its induction effect on apoptosis of Hep G2 cells.

In the present study, a polysaccharide fraction (PTP) was isolated and purified from the tubers of Pinellia ternata. We researched its structure and anti-tumor activity, and further studied its molecular mechanism of inducing apoptosis of Hep G2 cells. The results indicated that PTP was an acid heteropolysaccharide and the average molecular weight of PTP identified by HPGPC was 3.06 × 106 Da. Ion chromatography (IC) determined that PTP was mainly composed of Ara:Gal:Glu:Man:GlcA:GalA in a molar ratio of 6.98:16.56:7.25:2.04:1:4.16. Combined with the results of FT-IR and NMR spectroscopy, it was found that PTP is a pyranose containing α-configuration and ß-configuration, mainly consist of ß-D-Gal, α-D-Glu, α-D-Ara and ß-D-Man. By analyzing the results of MTT, cell cycle, Annexin V-FITC/PI double staining and cell morphology observation, we concluded that PTP induced dose-dependent apoptosis of Hep G2 cells via S phase arrest. In addition, mitochondrial membrane potential detection and Western blot further indicated that PTP was capable of inducing apoptosis in Hep G2 cells through an endogenous mitochondria-mediated apoptotic pathway.