Phytochemical determination and mechanistic investigation of Polygala tenuifolia root (Yuanzhi) extract for bronchitis: UPLC-MS/MS analysis, network pharmacology and in vitro/in vivo evaluation.

ETHNOPHARMACOLOGICAL RELEVANCE: Bronchitis is a respiratory disease characterized by a productive cough. Polygala tenuifolia Willd., commonly known as Yuan zhi, is a traditional Chinese herbal medicine used for relieving cough and removing phlegm. Despite its historical use, studies are lacking on the effectiveness of P. tenuifolia in treating bronchitis. Furthermore, the molecular mechanisms underlying the action of its bioactive compounds remain unknown. AIM OF THE STUDY: This study aims to identify the main bioactive compounds responsible for the effects of P. tenuifolia liquid extract (PLE) in treating bronchitis and to elucidate the associated molecular mechanisms. MATERIALS AND METHODS: The main chemical compounds in PLE were identified and determined using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The antitussive, expectorant and anti-inflammatory activities of PLE were evaluated in an ammonia-induced mouse cough model, a tracheal phenol red excretion mouse model, and a xylene-induced ear swelling mouse model, respectively. A network pharmacology analysis was conducted to investigate the associated gene targets, gene ontology, and KEGG pathways related to the main bioactives in PLE targeting bronchitis. PLE and its five bioactive compounds were assessed for their potential anti-inflammatory activities in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Western blot analysis was conducted to elucidate the associated molecular mechanisms. RESULTS: Thirty-seven compounds in PLE were identified, and twelve main compounds were further quantified in PLE using UPLC-MS/MS. PLE oral gavage administrations (0.6 and 0.12 mg/kg) for 7 days markedly reduced cough frequency, prolonged latency period of cough, reduced phlegm and inflammation in mice. The network pharmacology analysis identified 57 gene targets of PLE against bronchitis. The PI3K/AKT and MAPK signalling pathways were the top two modulated pathways. In RAW264.7 cells, PLE (12.5-50 µg/mL) significantly reduced cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α. PLE downregulated LPS-elevated protein targets in both PI3K/AKT and MAPK signaling pathways. In PLE, tenuifolin, polygalaxanthone ⅠⅠⅠ, polygalasaponin ⅩⅩⅤⅢ, tenuifoliside B, and 3,6'-Disinapoyl sucrose, were identified as the top five core components responsible for treating bronchitis. These compounds were also found to modulate the protein targets in the PI3K/AKT and MAPK signalling pathways. CONCLUSIONS: This study demonstrated the potential therapeutic effects of PLE on bronchitis by reducing cough, phlegm and inflammation. The anti-inflammatory action and molecular mechanisms of the 5 main bioactive compounds in PLE were partly validated through the in vitro assays. The findings provide valuable insights into the mechanisms underlying the traditional use of PLE for bronchitis.

Safety profiles of offspring born from early-follicular long-acting GnRH agonist protocol and daily mid-luteal GnRH agonist protocol: a retrospective study.

BACKGROUND: The gonadotropin hormone-releasing hormone agonists (GnRH-a) have been widely used for controlled ovarian stimulation in assisted reproductive technology (ART). The early-follicular long-acting GnRH-a long protocol (EFL) and the luteal phase short-acting GnRH-a long protocol (LPS) are commonly used GnRH agonist protocols. We conducted a retrospective analysis to assess and compare the rates of congenital abnormalities and safety profiles in offspring born from the EFL and LPS protocols. METHODS: We conducted a retrospective cohort study to analyze and compare neonatal data from patients who using EFL or LPS protocols at our center between January 1, 2014, and June 30, 2017. The study ultimately included 1810 neonates from 1401 cycles using the EFL protocol and 2700 neonates from 2129 cycles using the LPS protocol.The main outcome measures are gestational age at delivery, birth weight, and congenital anomaly rate.To assess the influence of various factors on congenital abnormalities, a random-effects logistic regression model was employed. RESULTS: The EFL and LPS protocols led to similar congenital anomaly rates (1.64% vs. 2.35%, P = 0.149). No significant differences were found between the two groups regarding birth weight and its categories, newborn gender and congenital anomaly rate. The results of the multivariate logistic regression model indicated no association between congenital anomaly and BMI, duration of infertility, treatment protocol, fertilization method, or embryo transfer stage. Compared with singleton pregnancies, the probability of congenital defects in multiple pregnancies was 2.64 times higher (OR: 2.64, 95% CI: 1.72-4.05, P < 0.0001). Newborns with congenital defects were born with a lower gestational age compared with full-term pregnancies. CONCLUSION: In conclusion, the EFL protocol is considered a safe option for ensuring offspring safety, comparable with the LPS protocol; however, multiple pregnancies represent an independent risk factor for congenital abnormalities. This approach can be widely adopted; however, prioritizing single embryo transfers is strongly recommended to minimize the potential risks associated with multiple pregnancies in offspring.

Fibrosis signature of anastomotic margins for predicting anastomotic stenosis in rectal cancer with neoadjuvant chemoradiotherapy and sphincter-preserving surgery.

Background: Radiation-induced colorectal fibrosis (RICF) is a common pathological alteration among patients with rectal cancer undergoing neoadjuvant chemoradiotherapy (nCRT). Anastomotic stenosis (AS) causes symptoms and negatively impacts patients' quality of life and long-term survival. In this study, we aimed to evaluate the fibrosis signature of RICF and develop a nomogram to predict the risk of AS in patients with rectal cancer undergoing nCRT. Methods: Overall, 335 pairs of proximal and distal margins were collected and randomly assigned at a 7:3 ratio to the training and testing cohorts. The RICF score was established to evaluate the fibrosis signature in the anastomotic margins. A nomogram based on the RICF score for AS was developed and evaluated by using the area under the curve, decision curve analysis, and the DeLong test. Results: The training cohort included 235 patients (161 males [68.51%]; mean age, 59.61 years) with an occurrence rate of AS of 17.4%, whereas the testing cohort included 100 patients (72 males [72.00%]; mean age, 57.17 years) with an occurrence rate of AS of 11%. The RICF total score of proximal and distal margins was significantly associated with AS (odds ratio, 3.064; 95% confidence interval [CI], 2.200-4.268; P < 0.001). Multivariable analysis revealed that the RICF total score, neoadjuvant radiotherapy, and surgical approach were independent predictors for AS. The nomogram demonstrated good discrimination in the training cohort (area under the receiver-operating characteristic curve, 0.876; 95% CI, 0.816-0.937), with a sensitivity of 68.3% (95% CI, 51.9%-81.9%) and a specificity of 85.5% (95% CI, 78.7%-89.3%). Similar results were observed in the testing cohort. Conclusions: This study results suggest that the RICF total score of anastomotic margins is an independent predictor for AS. The prediction model developed based on the RICF total score may be useful for individualized AS risk prediction in patients with rectal cancer undergoing nCRT and sphincter-preserving surgery.

Advanced effect of curcumin and resveratrol on mitigating hepatic steatosis in metabolic associated fatty liver disease via the PI3K/AKT/mTOR and HIF-1/VEGF cascade.

Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease that has no viable treatment. Curcumin (Cur) and resveratrol (Res) are two natural products that have been studied for their potential to ameliorate MAFLD. However, while these compounds have been investigated individually, their combined use and the potential for a synergistic or augmented effect remain unexplored. This study aims to investigate the effect of curcumin (Cur) and resveratrol (Res) as a potential combination therapy on MAFLD. Cur, Res and Cur+Res were tested in palmitic acid (PA)-induced-HepG2 cells. MAFLD model was established using Goto-Kakizaki rats. The animals were treated with vehicle control (model group), Cur (150 mg/kg), Res (150 mg/kg), Cur+Res (150 mg/kg, 8:2, w/w), or metformin (Met, positive control, 400 mg/kg/day) via oral gavage for 4 weeks. Wistar rats were used as the control group. Network pharmacology was conducted to elucidate the molecular actions of Cur and Res, followed by q-PCR and immunoblotting in vivo. Cur+Res exhibited synergistic effects in reducing triglyceride, total cholesterol and lipid accumulation in PA-induced HepG2 cells. The combination also markedly attenuated hepatic steatosis in the MAFLD rats. Network pharmacology illustrated that the interaction of Cur and Res was associated with the modulation of multiple molecular targets associated with the PI3K/AKT/mTOR and HIF-1 signaling pathways. Experimental results confirmed that Cur+Res nomalised the gene targets and protein expressions in the PI3K/AKT/mTOR and HIF-1 signaling pathways, including PI3K, mTOR, STAT-3, HIF-1α, and VEGF. The present study demonstrated an advanced effect of Cur and Res in combination to attenuate MAFLD, and the mechanism is at least partly associated with the modulation of the PI3K/AKT/mTOR and HIF-1 signaling pathways.

Impact of glucocorticoids on the efficacy of neoadjuvant chemoradiotherapy and survival of patients with locally advanced rectal cancer: a retrospective study.

BACKGROUND: Preclinical studies suggest that glucocorticoids (GCs) promote the proliferation and development of colorectal cancer. Because GCs are broadly prescribed for treatment-related adverse events in patients with locally advanced rectal cancer (LARC) receiving neoadjuvant chemoradiotherapy (NCRT), it's essential to assess the effect of GCs on clinical outcomes. METHODS: LARC cases treated with NCRT followed by surgery were assessed retrospectively. Evaluation of the relationship between GCs use (GCs vs. non-GCs) and neoadjuvant rectal (NAR) score (as a three-level categorical dependent variable) was performed using multivariable multinomial logistic regression (MLR). We also examined the relationship between the accumulated dose of GCs and NAR using multivariate MLR. Survival analysis of disease-free survival (DFS) and overall survival (OS) was performed using the Kaplan-Meier method. Multivariate Cox regression was used to assess confounding factors that could influence OS and DFS. RESULTS: This retrospective cohort study included 790 patients with newly diagnosed non-metastatic LARC (T3-4/N + M0) who received NCRT followed by surgery between January 2012 and April 2017. The end of the follow-up period was May 11, 2022. Among the 790 patients with LARC, 342 (43.2%) received GCs treatment and 448 (56.8%) did not during the NCRT-to-surgery period. GCs medication was significantly different between mid-NAR (8-16) and low-NAR (< 8) (odds ratio [OR], 0.615; 95% CI, 0.420-0.901; P = 0.013), and the high-NAR (> 16) and low-NAR (0.563; 0.352-0.900; 0.016). Patients exposed to GCs, had a decreased 5-year OS (GCs vs. non-GCs = 80.01% (95% CI, 75.87%-84.37%) vs. 85.30% (82.06%-88.67%), P = 0.023) and poorer 5-year DFS (73.99% (69.45%-78.82%) vs. 78.7% (75.14%-82.78%), P = 0.045). The accumulated dose of GCs was an independent risk factor for OS (hazard ratio [HR], 1.007 [1.001-1.014], 0.036) and DFS (1.010 [1.004-1.017], 0.001). CONCLUSIONS AND RELEVANCE: Our study revealed that GCs were associated with reduced efficacy of NCRT and worse clinical outcomes in patients with LARC during the NCRT-to-surgery period.

A refined prediction of early recurrence combining tumor deposits in patients with resected rectal mucinous adenocarcinoma.

PURPOSE: Early recurrence (ER) of rectal mucinous adenocarcinoma (MAC) has yet to be defined. We therefore explored risk factors for ER and constructed a predictive nomogram. METHOD: A total of 145 rectal MAC patients undergoing radical surgery were included. The minimum P value method was used to determine the optimal cut-off point to discriminate between ER and late recurrence (LR). Risk factors for ER were determined by a logistic regression analysis, and a predictive nomogram was constructed. RESULTS: A total of 62 (42.8%) patients developed tumor recurrence. The optimal time to define ER was 12 months. A pre-treatment tumor distance from the anal verge ≤ 7 cm, pathological N stage, lymphovascular invasion, tumor deposits, and time to recurrence ≤ 12 months were significantly associated with a poor post-recurrence survival in patients with recurrence. A pre-treatment serum carcinoembryonic antigen (CEA) level > 10 ng/ml, pre-treatment tumor distance from the anal verge ≤ 7 cm, pathological N + stage, perineural invasion, and tumor deposits were identified as independent risk factors associated with ER. A nomogram predicting ER was constructed (C-index 0.870). CONCLUSION: The pre-treatment serum CEA level, pre-treatment tumor distance from the anal verge, pathological N + stage, perineural invasion, and tumor deposits were significantly predictive of ER for rectal MAC patients.

Development of a Model Predicting the Outcome of In Vitro Fertilization Cycles by a Robust Decision Tree Method.

Introduction: Infertility is a worldwide problem. To evaluate the outcome of in vitro fertilization (IVF) treatment for infertility, many indicators need to be considered and the relation among indicators need to be studied. Objectives: To construct an IVF predicting model by a robust decision tree method and find important factors and their interrelation. Methods: IVF and intracytoplasmic sperm injection (ICSI) cycles between January 2010 and December 2020 in a women's hospital were collected. Comprehensive evaluation and examination of patients, specific therapy strategy and the outcome of treatment were recorded. Variables were selected through the significance of 1-way analysis between the clinical pregnant group and the nonpregnant group and then were discretized. Then, gradient boosting decision tree (GBDT) was used to construct the model to compute the score for predicting the rate of clinical pregnancy. Result: Thirty-eight variables with significant difference were selected for binning and thirty of them in which the pregnancy rate varied in different categories were chosen to construct the model. The final score computed by model predicted the clinical pregnancy rate well with the Area Under Curve (AUC) value achieving 0.704 and the consistency reaching 98.1%. Number of two-pronuclear embryo (2PN), age of women, AMH level, number of oocytes retrieved and endometrial thickness were important factors related to IVF outcome. Moreover, some interrelations among factors were found from model, which may assist clinicians in making decisions. Conclusion: This study constructed a model predicting the outcome of IVF cycles through a robust decision tree method and achieved satisfactory prediction performance. Important factors related to IVF outcome and some interrelations among factors were found.

Metabolic differences in women with premature ovarian insufficiency: a systematic review and meta-analysis.

OBJECTIVE: This review aimed to investigate the metabolic profile of women with premature ovarian insufficiency (POI) compared relative to women with normal ovarian functioning. METHODS: A systematic search of PubMed, EMBASE, and the Web of Science for observational studies published up until the 6th of July 2021 that compared the metabolic profile of POI women with a healthy control group were assessed. Mean differences (MD) and 95% confidence interval (CI) were pooled using the fixed or random effect models. RESULTS: A total of 21 studies involving 1573 women with POI and 1762 control women were included. POI patients presented significantly higher waist circumference, total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, and fasting glucose. Additionally, POI patients had marginally higher insulin level. However, the differences in systolic, and diastolic blood pressure were non-significant relative to the control group. CONCLUSIONS: POI is associated with alterations in certain metabolic parameters compared to control women. This finding highlights the importance of early screening and the lifelong management of metabolic health for women with POI.

The Effect of Lymph Node Harvest on Prognosis in Locally Advanced Middle-Low Rectal Cancer After Neoadjuvant Chemoradiotherapy.

OBJECTIVE: The purpose of this study was to investigate the relationship between lymph node harvest and the prognosis in locally advanced rectal cancer (LARC) patients after neoadjuvant chemoradiotherapy (nCRT). METHODS: Patients who were diagnosed with clinical LARC and treated with nCRT and radical surgery between June 2008 and July 2017 were included in this study. The relationship between lymph node retrieval and prognosis was analyzed. Other lymph node-related indicators were explored. RESULTS: A total of 837 patients with a median follow-up of 61 (7-139) months were included in the study. The five-year DFS and OS rates of all patients were 74.9% and 82.3%, respectively. Multivariate survival analysis suggested that dissection of ≥ 12 lymph nodes did not improve OS or DFS. 7 was selected as the best cutoff value for the total number of lymph nodes retrieved by Cox multivariate analysis (χ2 = 10.072, HR: 0.503, P=0.002). Dissection of ≥ 5 positive lymph nodes (PLNs) was an independent prognostic factor for poorer DFS (HR: 2.104, P=0.004) and OS (HR: 3.471, p<0.001). A positive lymph node ratio (LNR) of more than 0.29 was also an independent prognostic factor for poorer DFS (HR: 1.951, P=0.002) and OS (HR: 2.434, p<0.001). CONCLUSION: The recommends that at least 7 harvested lymph nodes may be more appropriate for LARC patients with nCRT. PLN and LNR may be prognostic factors for LARC patients with ypN+ after nCRT.

MiR-let-7d-3p inhibits granulosa cell proliferation by targeting TLR4 in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a typical reproductive and endocrinological disorder of women at child-bearing age. In this study, we used miRNA sequencing technology and verified miR-let-7d-3p as a vital miRNA in PCOS. RT-qPCR confirmed miR-let-7d-3p was significantly increased in granulosa cells (GCs) of PCOS. Cell counting kit-8 (CCK-8) identified the suppression of miR-let-7d-3p mimic in KGN cell proliferation and PI3K/Akt signaling pathway. Dual luciferase reporter assay proved that Toll-like receptor 4 (TLR4) was a target of miR-let-7d-3p, and TLR4 was significantly down-regulated by miR-let-7d-3p. Furthermore, over-expression of TLR4 promoted KGN cell proliferation and rescued the inhibition of miR-let-7d-3p on KGN cells. In conclusion, miR-let-7d-3p was a crucial miRNA up-regulated in GCs of PCOS, and inhibited cell proliferation by targeting TLR4 gene.

Hydrogel, a novel therapeutic and delivery strategy, in the treatment of intrauterine adhesions.

Intrauterine adhesions (IUAs) are caused by damage to the underlying lining of the endometrium. They' re related to disorder of endometrial repair. In recent years, hydrogels with controllable biological activity have been widely used for treating IUAs. They encapsulate estrogen, cytokines, cells, or exosomes, forming a delivery system to release therapeutic components for the treatment of IUAs. In addition, the hydrogel acting as a barrier can be degraded in the body automatically, reducing the risk of infection caused by secondary surgeries. In this review, we summarize the recent progress of hydrogels and their application in IUAs as both a novel alternative therapeutic and an artificial delivery strategy.

Predictive value of circulating sex hormone-binding globulin for gestational diabetes: a meta-analysis.

Aim: To detect predictive value of preconception or early pregnancy sex hormone-binding globulin (SHBG) for subsequent gestational diabetes mellitus (GDM). Materials & methods: We searched Embase, Medline, PubMed, Web of Science and Cochrane library up to January 2020. Studies assessing diagnostic performance of SHBG for GDM diagnosed by well-defined diagnostic criteria using oral glucose tolerance test. Results: Totally seven studies with 1947 women were included and 247 were diagnosed as GDM. SHBG had a combined diagnostic odds ratio of 6.68 (95% CI: 4.58-9.74), sensitivity of 0.70 (95% CI: 0.51-0.84), specificity of 0.74 (95% CI: 0.52-0.88), positive likelihood ratio of 2.49 (95% CI: 1.73-3.57) and negative likelihood ratio of 0.37 (95% CI: 0.23-0.61). The area under the summary receiver operating characteristic curve was 0.78 (95% CI: 0.74-0.82). Conclusion: SHBG had a predictive value for GDM and might improve GDM screening. However, heterogeneity between studies warrants more research into this topic.

Predictive value of the number of frozen blastocysts in live birth rates of the transferred fresh embryos.

BACKGROUND: Blastocyst development by extended culture in vitro allows the embryos to 'select' themselves, thus successful growth to the blastocyst stage is a reflection of the developmental competence of cleavage stage embryos in a cohort. The study aims to determine whether the number of frozen blastocysts is associated with live birth rates of the transferred fresh embryos. METHOD: The retrospective study included 8676 cycles of first fresh embryo transfer from January 2016 to June 2019 at a fertility center of a university hospital. The patients with ≥ 10 oocytes retrieved were divided into three groups according to the number of frozen blastocysts: 0 (group 1), 1-2 (group 2), and ≥ 3 (group 3). The primary outcome measure was the live birth. The secondary outcome measures included clinical pregnancy rates and implantation rates. Logistic regression analysis was also performed. RESULTS: Live birth rates in patients with ≥ 3 and 1-2 frozen blastocysts were 47.6% and 46.1%, respectively, which were significantly higher than that in patients without blastocyst (36.0%). The clinical pregnancy rate in group 3 was 65.1%, which was also significantly higher than the other two groups (47.0% and 59.2%). The implantation rates were 35.5%, 47.6%, and 56.0% in the three groups, respectively (P < 0.001). Compared with groups of frozen blastocysts, 0 frozen blastocyst yielded a lower rate of live birth (the adjusted odds ratio: 0.526, 95% CI: 0.469, 0.612). CONCLUSION: In patients with optimal ovarian response that retrieved ≥ 10 oocytes, fresh embryos transfer followed by having blastocysts frozen is a strong indicator of pregnancy achievement, but the number of frozen blastocysts (if not = 0) has limited value in predicting live birth rates.

Prognostic Impact of Pretreatment Elevated and Normalized Carcinoembryonic Antigen Levels After Neoadjuvant Chemoradiotherapy in Resected Locally Advanced Rectal Cancer Patients.

PURPOSE: The prognostic significance of pretreatment elevated and normalized CEA after neoadjuvant chemoradiotherapy (nCRT) was evaluated. MATERIALS AND METHODS: The characteristics of 951 locally advanced rectal cancer patients with nCRT were retrieved and were analyzed retrospectively. Pretreatment CEA levels were defined as CEA evaluated one week prior to the nCRT. CEA after nCRT was deemed as CEA measured one week before surgery. The normal CEA levels were set at <5 ng/mL. The normal CEA group was defined as patients with normal pretreatment CEA levels. The normalized CEA group was defined as patients with elevated pretreatment CEA levels and normal CEA levels after nCRT. The elevated CEA group was defined as patients with elevated pretreatment CEA levels and elevated CEA levels after nCRT. RESULTS: Compared with the elevated CEA group, the normalized CEA group was associated with better overall survival (OS) (HR: 0.625, 95%CI: 0.416-0.938, P=0.022). There was no difference between the normalized CEA group and the normal CEA group (HR: 1.143, 95%CI: 0.84-1.557, P=0.395). CONCLUSION: In conclusion, the study indicated that OS of the normalized CEA group and the normal CEA group was better than the elevated CEA group.

Identification of a MicroRNA Signature Associated With Lymph Node Metastasis in Endometrial Endometrioid Cancer.

BACKGROUND: Lymph node metastasis (LNM) is an important prognostic factor in endometrial cancer. Anomalous microRNAs (miRNAs) are associated with cell functions and are becoming a powerful tool to characterize malignant transformation and metastasis. The aim of this study was to construct a miRNA signature to predict LNM in endometrial endometrioid carcinoma (EEC). METHOD: Candidate target miRNAs related to LNM in EEC were screened by three methods including differentially expressed miRNAs (DEmiRs), weighted gene co-expression network analysis (WGCNA), and decision tree algorithms. Samples were randomly divided into the training and validation cohorts. A miRNA signature was built using a logistic regression model and was evaluated by the area under the curve (AUC) of receiver operating characteristic curve (ROC) and decision curve analysis (DCA). We also conducted pathway enrichment analysis and miRNA-gene regulatory network to look for potential genes and pathways engaged in LNM progression. Survival analysis was performed, and the miRNAs were tested whether they expressed differently in another independent GEO database. RESULT: Thirty-one candidate miRNAs were screened and a final 15-miRNA signature was constructed by logistic regression. The model showed good calibration in the training and validation cohorts, with AUC of 0.824 (95% CI, 0.739-0.912) and 0.821 (95% CI, 0.691-0.925), respectively. The DCA demonstrated the miRNA signature was clinically useful. Hub miRNAs in signature seemed to contribute to EEC progression via mitotic cell cycle, cellular protein modification process, and molecular function. MiR-34c was statistically significant in survival that a higher expression of miR-34c indicated a higher survival time. MiR-34c-3p, miR-34c-5p, and miR-34b-5p were expressed differentially in GSE75968. CONCLUSION: The miRNA signature could work as a noninvasive method to detect LNM in EEC with a high prediction accuracy. In addition, miR-34c cluster may be a key biomarker referring LNM in endometrial cancer.

Effects of Different Exposure Days to Gonadotropin-Releasing Hormone Agonist (GnRH-a) on Live Birth Rates in the Depot GnRH-a Protocol: A Retrospective Analysis of 7007 Cycles.

BACKGROUND In controlled ovarian hyperstimulation protocols worldwide, depot gonadotropin-releasing hormone agonist (GnRH-a) pretreatment is generally used for pituitary desensitization. The delay between the GnRH-a administration and starting gonadotropin treatment varies greatly, from 25 to 60 days. However, the association between exposure days to GnRH-a before the onset of gonadotropin administration and the clinical outcomes remains unknown. MATERIAL AND METHODS This retrospective study included 7007 patients who underwent fresh embryo transfers between February 2016 and July 2019. The duration of pituitary downregulation was categorized into 3 groups: group 1, ≤30 days; group 2, 31-35 days; and group 3, ≥36 days. The rates of live birth were compared as the main outcome measure. Logistic regression analysis was also performed after controlling for a range of confounders. RESULTS The number of patients in groups 1, 2, and 3 was 2001, 2824, and 2182, respectively. Group 3 (≥36 days) had a noticeably higher live birth rate (48.1%) than the other 2 groups (42.6% and 43.9%, P=0.001). The rate of live birth was remarkably enhanced in group 3 (adjusted odds ratio: 1.264, 95% confidence interval: 1.098, 1.455, P=0.001) after controlling for confounders, while the difference was not found in group 2 (P=0.512) compared with group 1. CONCLUSIONS In the depot GnRH-a protocol, live birth rates are higher among patients needing a longer time to achieve the goal of pituitary downregulation.

Effect of Hyperinsulinemia and Insulin Resistance on Endocrine, Metabolic, and Reproductive Outcomes in Non-PCOS Women Undergoing Assisted Reproduction: A Retrospective Cohort Study.

Objective: To evaluate the effect of hyperinsulinemia (HI) and insulin resistance (IR) on endocrine, metabolic, and reproductive outcomes in women without polycystic ovary syndrome (PCOS) undergoing assisted reproduction. Materials and Methods: The study included 1,104 non-PCOS women undergoing in vitro fertilization/intracytoplasmic sperm injection-fresh embryo transfer. HI was evaluated by serum fasting insulin (FIN), and IR was evaluated by homeostatic model assessment of insulin resistance index (HOMA-IR). In addition, biometric, sex hormone, and metabolic parameters were measured. Independent t-test, linear, and logistic regression examined associations between HI, IR, and endocrine, metabolic, ovarian stimulation characteristics, and reproductive outcomes. Results: Women with HI and IR had lower levels of progesterone, luteinizing hormone, follicle-stimulating hormone, estradiol, high-density lipoproteins, and increased levels of triglycerides low-density lipoproteins. For ovarian stimulation characteristics, those with HI and IR had a longer duration of stimulation, a higher total gonadotropin dose, and a lower peak estradiol level. Linear regression confirmed these associations. For reproductive outcomes, HI and IR were not associated with clinical pregnancy, live birth, and miscarriage. Conclusions: HI and IR did not impair reproductive outcomes in non-PCOS women undergoing assisted reproduction.

Prognostic Value of Pretreatment Serum CA199 in Patients with Locally Advanced Rectal Cancer Treated with CRT Followed by TME with Normal Pretreatment Carcinoembryonic Antigen Levels.

BACKGROUND: Elevated pretreatment carcinoembryonic antigen (CEA) levels are related to poor prognosis in patients with locally advanced rectal cancer (LARC) treated with neo-CRT followed by TME. In patients with normal pretreatment CEA levels, the prognostic significance of carbohydrate antigen 199 (CA199) is controversial. OBJECTIVES: The aim of this study was to explore the prognostic value of pretreatment serum CA199 in patients with LARC who had normal pretreatment CEA levels treated with neo-CRT followed by curative surgery. METHODS: A retrospective study of 456 patients with LARC treated with neo-CRT followed by TME between January 2006 and May 2017 was performed. We employed the maximal χ2 method to determine the CA199 threshold of 9.1 U/mL based on the difference in survival and divided patients into 2 groups. Group 1: patients with pretreatment s-CEA < 5 ng/mL and CA199 ≥ 9.1 U/mL. Group 2: patients with pretreatment s-CEA < 5 ng/mL and CA199 < 9.1 U/mL. Overall survival (OS) across CA199 was assessed using Cox proportional hazard regression models (PS:CEA ≥ 5 ng/mL was seen as elevated). RESULTS: Multivariate analyses demonstrated that the following factors were significantly related to OS in patients with LARC with normal pretreatment CEA levels: ypT (odds ratio [OR] 1.863, p = 0.030), ypN (OR 1.622, p = 0.026), and pretreatment CA199 levels (OR 1.886, p = 0.048). CONCLUSION: Pretreatment CA199 is an independent factor for OS in patients with LARC with normal pretreatment CEA levels, which may reach the clinic to guide individualized decision-making.

The benefit of adjuvant radiotherapy on overall survival in resected stage I to II pancreatic cancer: A propensity-adjusted analysis.

BACKGROUND: The survival time of patients with early pancreatic cancer (PC) is still disappointing, even after surgical resection. PC has an extremely poor prognosis. Herein, we aimed to investigate the survival effect of postoperative radiotherapy (PORT) on resected stage I to II PC. MATERIAL AND METHODS: A large eligible sample of patients was identified from 2010 to 2015 from the Surveillance, Epidemiology, and End Results (SEER) registry. Survival analysis was conducted to evaluate the efficiency of PORT. Propensity score matching (PSM) analysis was used to reduce selection bias and to make the groups comparable. RESULTS: A total of 3219 patients with resected stage I to II PC was included after rigid screening. The median overall survival (OS) was 26 months with PORT (n = 1055) versus 21 months with non-PORT (n = 2164) before matching (p<0.001). By multivariable analysis, PORT remained a favorable prognostic predictor for OS. In PSM analysis, receiving PORT was associated with improved OS (median, 26 months vs. 23 months; at 2 years, 51.7% vs. 46.7%; at 5 years, 23.3% vs. 17.4% (P = 0.006). After further meticulous exploration, only the stage IIB subgroup benefited from PORT (p<0.001). This result was due to the positive lymph node state (N+), whose mortality risk was cut by 23.4% (p<0.001) by PORT. CONCLUSION: Addition of PORT to the treatment of patients with resected stage I to II PC conveys a survival benefit, particularly among those with N-positive or stage IIB disease.

Nomogram Predicting Overall Survival of Resected Locally Advanced Rectal Cancer Patients with Neoadjuvant Chemoradiotherapy.

PURPOSE: The overall survival (OS) of resected locally advanced rectal cancer patients who underwent neoadjuvant chemoradiotherapy (nCRT) was significantly different, even among patients with the same tumor stage. The nomogram was designed to predict OS of rectal cancer with nCRT and divide the patients into different risk groups. MATERIALS AND METHODS: Based on materials from 911 rectal cancer patients with nCRT, the multivariable Cox regression model was carried out to select the significant prognostic factors for overall survival. And then, the nomogram was formulated using these independent prognostic factors. The discrimination of the nomogram was assessed by concordance index (C-index), calibration curves and time-dependent area under curve (AUC). The patients respective risk scores were calculated through the nomogram. The best cut-off risk score was calculated to stratify the patients. The survival curves of the two different risk cohorts were performed, which assessed the predictive ability of the nomogram. RESULTS: Age, cT stage, pretreatment CEA, pretreatment CA19-9, surgery, posttreatment CEA, posttreatment CA19-9, pT stage, pN stage and adjuvant chemotherapy were selected for the construction of the nomogram. And then the nomogram was constructed with independent prognostic factors. The C-index of the nomogram was 0.724, which showed the nomogram provided good discernment. The acceptable agreement between the predictions of nomogram and actual observations was illustrated by calibration plots for 3-, 5- and 10-year OS in the cohort. Time-dependent AUC with 6-fold cross-validation also showed consistent results of the nomogram. Risk group stratification confirmed that the nomogram had great capacity for distinguishing the prognosis. CONCLUSION: The nomogram was developed and validated to predict overall survival of resected locally advanced rectal cancer patients with nCRT. The proposed nomogram might help clinicians to develop individualized treatment strategies. However, further studies are warranted to optimize the nomogram by finding out other unknown prognostic factors, and more external validation is still required.