Sintilimab plus bevacizumab and CapeOx (BBCAPX) on first-line treatment in patients with RAS mutant, microsatellite stable, metastatic colorectal cancer: study protocol of a randomized, open-label, multicentric study.

BACKGROUND: Rat sarcoma viral oncogene homolog (RAS) gene mutation is a common molecular event in colorectal cancer (CRC). The prognosis of mCRC (metastatic colorectal cancer) patients with RAS mutation is poor and capecitabine and oxaliplatin (CapeOx) plus bevacizumab has shown to be one of the standard therapeutic regimens as first line for these patients with objective response rate (ORR) of ~ 50% and median progression-free survival (mPFS) of 8-9 months. Immunotherapy, especially anti-programmed death 1 (PD-1) monoclonal antibody has demonstrated ground-breaking results in deficient mismatch repair (dMMR) / microsatellite instability-high (MSI-H) mCRC patients. However, the response rate of in microsatellite stable (MSS) patients is extremely low. In addition, preclinical studies have demonstrated that anti-Vascular endothelial growth factor (VEGF) agents, such as bevacizumab, can induce tumor vascular normalization and enhance antitumor immunity. Previous study indicated the combination of chemotherapy, anti-VEGF agents (bevacizumab) with immune checkpoint inhibitors may have promising clinical activity in RAS mutant, MSS refractory mCRC patients. Based on these evidences, we will explore the combination of CapeOx with bevacizumab and sintilimab (anti-PD-1 monoclonal antibody) in RAS mutant, MSS mCRC patients as first-line therapy. METHODS: This is a randomized, open-label, multicentric clinical trial. In the sintilimab arm, patients will receive sintilimab in combination with CapeOx and bevacizumab. In the control arm, patients will receive CapeOx and bevacizumab. This trial will recruit 494 patients from 20 centers and randomly (1:1) disseminated into two groups. The primary endpoint is the PFS. The secondary endpoints include overall survival, safety, ORR, and disease control rate. DISCUSSION: This study may provide new ideas for optimizing oncology treatment planning for RAS mutant, MSS mCRC patients in the first-line set. TRIAL REGISTRATION: This study is short for BBCAPX and has been registered at clinicaltrials.gov registry with identifier NCT05171660.

Poly(I:C) Exacerbates Airway Goblet Cell Hyperplasia and Lung Inflammation in HDM-Exposed Balb/C Mice by YAP/FOXM1 Pathway.

INTRODUCTION: Respiratory viral infection in childhood is closely associated with asthmatic attacks. Of all predisposing factors, viral infection is the primary contributor to acute childhood asthma exacerbations. However, the mechanisms involved in viral asthma are unclear. This study attempted to provide insights into molecular mechanisms in respiratory virus-induced acute asthma exacerbations. METHODS: House dust mite (HDM) was given by intranasal administration to induce asthma in mice. Poly(I:C) was used to mimic the viral infection. A selective YAP inhibitor, verteporfin (VP), was used to investigate the role of the YAP/FOXM1 pathway. The expression of YAP, FOXM1, cytokines, and inflammatory cells in lung tissue, and bronchoalveolar lavage fluid (BALF) was determined using RT-PCR, immunohistochemical, ELISA, and flow cytometry studies. The methacholine challenge assesses airway hyperresponsiveness. In 16HBE cell experiments, we selectively inhibited YAP and FOXM1 by VP and RCM1, respectively, and detected the expression of YAP and FOXM1. RESULTS: The experimental studies have confirmed the YAP/FOXM1 pathway plays a vital role in the differentiation and proliferation of airway club cells into goblet cells and lung inflammation. Poly(I:C) upregulated the expression of FOXM1 by activating transcription factor YAP in mice airway epithelial cells and then promoted the expression of downstream transcription factors SPDEF/MUC5AC, resulting in airway mucus hypersecretion and hyperresponsiveness. In addition, Poly(I:C) facilitates the expression of inflammatory factors in lung tissue. All of these events induce asthma exacerbations. The in vitro studies have confirmed that YAP positively regulates FOXM1 in airway epithelial cells. CONCLUSION: Poly(I:C) promotes airway epithelial goblet cell hyperplasia, mucus hypersecretion, and airway hyperresponsiveness. It also upregulates the expression of inflammatory factors in lung tissue and BALF in asthmatic mice by the YAP/FOXM1 pathway, resulting in asthma attacks.

Integrin αvß6 contributes to the development of intestinal fibrosis via the FAK/AKT signaling pathway.

Intestinal fibrosis is one of the most severe complications of inflammatory bowel disease (IBD) and frequently requires surgery due to intestinal obstruction. Integrin αvß6, which is mainly regulated by the integrin ß6 subunit gene (ITGB6), is a special integrin subtype expressed only in epithelial cells. In our previous study, we found integrin αvß6 can promote the development of IBD, but the role of integrin αvß6 in intestinal fibrosis remains unclear. In this study, we observed a gradual increase of ITGB6 mRNA expression from normal region to stenotic region of IBD patients' intestinal specimens. Next, we established a dextran sulfate sodium (DSS)-induced intestinal fibrosis model and a heterotopic intestinal transplant model, and found intestinal fibrosis was decreased in ITGB6-deficient mice compared to wild-type (WT) mice. Furthermore, we performed RNA-sequencing and KEGG pathway analysis on intestinal tissues from ITGB6-overexpressing transgenic mice and WT mice, and found multiple pathways containing ITGB6, are related to the activation of focal adhesion kinase (FAK); finding was confirmed by Western blot. At last, we generated a heterotopic intestinal transplant model found the FAK/AKT pathway was inhibited in ITGB6-deficient mice. In conclusion, our data demonstrate that integrin αvß6 promotes the pathogenesis of intestinal fibrosis by FAK/AKT pathway, making integrin αvß6 a potential therapeutic target to prevent this condition.

Impact of Nursing Interventions Targeting Vital Signs and Complication Risk on Perioperative Parameters and Complication Rates in Aortic Dissection Patients.

Objective: This study aimed to investigate the impact of nursing interventions targeting vital signs and complication risk on perioperative outcomes and complications in patients diagnosed with aortic dissection. Methods: This retrospective study included patients presenting to our emergency department with acute chest pain as the primary complaint. Inclusion criteria encompassed identifiable chest pain symptoms, documented occurrence time and a time from symptom onset to blood collection of ≤ 24 hours. The cases of aortic dissection were selected from April 2018 to April 2022 and were diagnosed as major arterial dissection based on the Chinese Expert Consensus on the Criteria for the Diagnosis and Treatment of Aortic Dissection. The control group received conventional nursing care for aortic dissection, while the observation group received a nursing plan incorporating vital signs monitoring and addressing complication risk in addition to standard care. Results: All 120 enrolled patients successfully recovered and were discharged from the hospital. Age, body weight, operation time, anesthesia time, preoperative albumin levels, hypersensitive C-reactive protein (hs-CRP), and interleukin-6 (IL-6) showed no statistically significant differences between the two groups (P > .05). However, 24 hours post-operation, the observation group exhibited significantly lower IL-6 levels compared to the control group (P < .001), with no significant differences in hs-CRP levels (P > .05). Postoperative albumin levels in both aortic dissection groups significantly decreased compared to pre-surgery levels (P < .001) without statistical group differences (P > .05). Compared to controls, the observation group had reduced intraoperative sufentanil dosage, postoperative tracheal catheter extubation time, hospital stay, and costs (P < .001). No anastomotic complications occurred, and edema incidence was lower in the observation group (P = .021), with no significant differences in other complications (P > .05). Conclusions: Nursing interventions improve aortic dissection patient outcomes, reduce complications, and warrant broader clinical use.

A Multi-Target Localization and Vital Sign Detection Method Using Ultra-Wide Band Radar.

Life detection technology using ultra-wideband (UWB) radar is a non-contact, active detection technology, which can be used to search for survivors in disaster rescues. The existing multi-target detection method based on UWB radar echo signals has low accuracy and has difficulty extracting breathing and heartbeat information at the same time. Therefore, this paper proposes a new multi-target localization and vital sign detection method using ultra-wide band radar. A target recognition and localization method based on permutation entropy (PE) and K means++ clustering is proposed to determine the number and position of targets in the environment. An adaptive denoising method for vital sign extraction based on ensemble empirical mode decomposition (EEMD) and wavelet analysis (WA) is proposed to reconstruct the breathing and heartbeat signals of human targets. A heartbeat frequency extraction method based on particle swarm optimization (PSO) and stochastic resonance (SR) is proposed to detect the heartbeat frequency of human targets. Experimental results show that the PE-K means++ method can successfully recognize and locate multiple human targets in the environment, and its average relative error is 1.83%. Using the EEMD-WA method can effectively filter the clutter signal, and the average relative error of the reconstructed respiratory signal frequency is 4.27%. The average relative error of heartbeat frequency detected by the PSO-SR method was 6.23%. The multi-target localization and vital sign detection method proposed in this paper can effectively recognize all human targets in the multi-target scene and provide their accurate location and vital signs information. This provides a theoretical basis for the technical system of emergency rescue and technical support for post-disaster rescue.

Phase II study of anlotinib in combination with oxaliplatin and capecitabine for patients with RAS/BRAF wild-type metastatic colorectal adenocarcinoma as the first-line therapy.

BACKGROUND: Anlotinib, an oral small molecule tyrosine kinase inhibitor targeting VEGFR 1/2/3, FGFR 1-4, PDGFR a/ß, and c-kit, had demonstrated prolonged progression-free survival (PFS) in refractory metastatic colorectal cancer (mCRC). This multicenter, single-arm, phase II, exploratory study was conducted to evaluate the efficacy and safety of anlotinib combined with capecitabine and oxaliplatin as first-line treatment for unresectable RAS/BRAF wild-type mCRC. METHODS: Patients aged 18-75 with RAS/BRAF wild-type unresectable mCRC, without prior systemic treatment, and ECOG performance status ≤1 were enrolled. Eligible patients received capecitabine (850 mg/m2, p.o., bid, on day 1-14 every 21 days), oxaliplatin (130 mg/m2, i.v., on day 1 every 21 days), and anlotinib (12 mg, p.o., qd, on days 1-14 every 21 days) as induction therapy. Following 6 cycles of therapy, patients who achieved response or stable disease received capecitabine and anlotinib as maintenance therapy until tumor progression. The primary endpoint was objective response rate (ORR) according to RECIST (version: 1.1), and the secondary endpoints were PFS, disease control rate (DCR), duration of response (DOR), and safety. RESULTS: Between November 2019 and February 2021, 31 patients were enrolled. One patient was excluded for refusing treatment. The primary endpoint of ORR was 76.7% (95% CI, 57.7-90.1) with 1 patient achieving a complete response and 22 patients partial response. DCR was 93.3% (95% CI, 77.9-99.2). At a median follow-up of 14.1 months (95% CI, 9.9-18.3), median PFS was 11.3 months (95% CI, 7.1-14.1), and DOR was 7.9 months (95% CI, 5.5-12.7). Twenty-five (83.3%) patients experienced grade 3 or 4 treatment-emergent adverse events (TEAEs). No grade 5 TEAE was reported. The most common grade 3 or 4 TEAEs (>10%) were hypertension (15/30; 50%), neutrophil count decreased (8/30; 26.7%), and diarrhea (4/30; 13.3%). A total of 18 (60%) patients had TEAEs that resulted in dose reduction, interruptions, or delays. CONCLUSIONS: Anlotinib combined with capecitabine and oxaliplatin showed considerable ORR, DCR, PFS, and DOR in the first-line therapy of mCRC with manageable toxicity profiles. TRIAL REGISTRATION: ClinicalTrials.gov : NCT04080843.

A Vital Signs Fast Detection and Extraction Method of UWB Impulse Radar Based on SVD.

The identification of weak vital signs has always been one of the difficulties in the field of life detection. In this paper, a novel vital sign detection and extraction method with high efficiency, high precision, high sensitivity and high signal-to-noise ratio is proposed. Based on the NVA6100 pulse radar system, the radar matrix which contains several radar pulse detection signals is received. According to the characteristics of vital signs and radar matrices, the Singular Value Decomposition (SVD) is adopted to perform signal denoising and decomposition after preprocessing, and the temporal and spatial eigenvectors of each principal component are obtained. Through the energy proportion screening, the Wavelet Transform decomposition and linear trend suppression, relatively pure vital signs in each principal component, are obtained. The human location is detected by the Energy Entropy of spatial eigenvectors, and the respiratory signal and heartbeat signal are restored through a Butterworth Filter and an MTI harmonic canceller. Finally, through an analysis of the performance of the algorithm, it is proved to have the properties of efficiency and accuracy.

Research on Ultra-Wideband Radar Echo Signal Processing Method Based on P-Order Extraction and VMD.

As a new method to detect vital signs, Ultra-wideband (UWB) radar could continuously monitor human respiratory signs without contact. Aimed at addressing the problem of large interference and weak acquisition signal in radar echo signals from complex scenes, this paper adopts a UWB radar echo signal processing method that combines strong physical sign information extraction at P time and Variational Mode Decomposition (VMD) to carry out theoretical derivation. Using this novel processing scheme, respiration and heartbeat signals can be quickly reconstructed according to the selection of the appropriate intrinsic mode functions (IMFs), and the real-time detection accuracy of human respiratory signs is greatly improved. Based on an experimental platform, the data collected by the UWB radar module were first verified against the measured values obtained at the actual scene. The results of a validation test proved that our UWB radar echo signal processing method effectively eliminated the respiratory clutter signal and realized the accurate measurement of respiratory and heartbeat signals, which would prove the existence of life and further improve the quality of respiration and heartbeat signal and the robustness of detection.

Chemoenzymatic Synthesis of Heparan Sulfate Oligosaccharides having a Domain Structure.

Heparan sulfate (HS) has a domain structure in which regions that are modified by epimerization and sulfonation (NS domains) are interspersed by unmodified fragments (NA domains). There is data to support that domain organization of HS can regulate binding of proteins, however, such model has been difficult to probe. Here, we report a chemoenzymatic methodology that can provide HS oligosaccharides composed of two or more NS domains separated by NA domains of different length. It is based on the chemical synthesis of a HS oligosaccharide that enzymatically was extended by various GlcA-GlcNAc units and terminated in GlcNAc having an azido moiety at C-6 position. HS oligosaccharides having an azide and alkyne moiety could be assembled by copper catalyzed alkyne-azide cycloaddition to give compounds having various NS domains separated by unsulfonated regions. Competition binding studies showed that the length of an NA domain modulates the binding of the chemokines CCL5 and CXCL8.

Transgenic overexpression of ITGB6 in intestinal epithelial cells exacerbates dextran sulfate sodium-induced colitis in mice.

Integrins, as a large family of cell adhesion molecules, play a crucial role in maintaining intestinal homeostasis. In inflammatory bowel disease (IBD), homeostasis is disrupted. Integrin αvß6, which is mainly regulated by the integrin ß6 subunit gene (ITGB6), is a cell adhesion molecule that mediates cell-cell and cell-matrix interactions. However, the role of ITGB6 in the pathogenesis of IBD remains elusive. In this study, we found that ITGB6 was markedly upregulated in inflamed intestinal tissues from patients with IBD. Then, we generated an intestinal epithelial cell-specific ITGB6 transgenic mouse model. Conditional ITGB6 transgene expression exacerbated experimental colitis in mouse models of acute and chronic dextran sulphate sodium (DSS)-induced colitis. Survival analyses revealed that ITGB6 transgene expression correlated with poor prognosis in DSS-induced colitis. Furthermore, our data indicated that ITGB6 transgene expression increased macrophages infiltration, pro-inflammatory cytokines secretion, integrin ligands expression and Stat1 signalling pathway activation. Collectively, our findings revealed a previously unknown role of ITGB6 in IBD and highlighted the possibility of ITGB6 as a diagnostic marker and therapeutic target for IBD.

Prognostic factors for ovarian metastases in colorectal cancer patients.

PURPOSE: The aim of this study was to analyze prognostic factors for ovarian metastases (OM) in colorectal cancer (CRC) using data from a Chinese center. In addition, the study aimed at developing a new clinical scoring system for prognosis of OM of CRC patients after surgery. PATIENTS AND METHODS: Data of CRC patients with OM were collected from a single Chinese institution (n = 67). Kaplan-Meier analysis was used to evaluate cumulative survival of patients. Factors associated with prognosis of overall survival (OS) were explored using Cox's proportional hazard regression models. A scoring system to determine effectiveness of prognosis was developed. RESULTS: Median OS values for patients with or without surgery were 22 and 7 months, respectively. Size of OM, number of OM, peritoneal metastasis (PM), Peritoneal cancer index (PCI), and completeness of cytoreduction (CC) were associated with OS of patients through univariate analysis. Multivariate analysis using a Cox regression model showed that only CC was an independent predictor for OS. Three variables (the size of OM >15cm, PCI ≥ 10, and carcinoembryonic antigen (CEA) >30 ng/mL) assigned one point each were used to develop a risk score. The resulting score was used for prognosis of OS. CONCLUSION: Surgical treatment of metastatic sites is effective and safe for CRC patients with OM. CC-0 is recommended for improved prognosis. The scoring system developed in this study is effective for prediction of OS of patients after surgery.

Modular Synthesis of Heparan Sulfate Oligosaccharides Having N-Acetyl and N-Sulfate Moieties.

Heparan sulfates are structurally diverse sulfated polysaccharides that reside at the surface of all animal cells where they can interact with a multitude of proteins, thereby modulating a wide range of physiological and disease processes. We describe here a modular synthetic methodology that can provide libraries of heparan sulfate oligosaccharides that have glucosamine residues modified by different patterns of N-acetyl and N-sulfate moieties. It is based on the use of glycosyl donors that are modified at C2 by an azido- or trifluoromethylphenyl-methanimine moiety, which allowed the selective installation of α-glycosides. The amino protecting groups can be selectively unmasked by a reduction or acid treatment, allowing the installation of N-acetyl and N-sulfate moieties, respectively. In combination with the orthogonal hydroxyl protecting groups levulinic (Lev) ester, thexyldimethylsilyl (TDS) ether, allyloxycarbonate (Alloc), and 9-fluorenylmethyl carbonate (Fmoc), different patterns of O-sulfation can be installed. The methodology was applied to prepare four hexasaccharides that differ in the pattern of N- and O-sulfation. These compounds, together with a number of previously prepared HS oligosaccharides, were printed as a glycan microarray to examine the binding selectivities of several HS-binding proteins.

HNF6 promotes tumor growth in colorectal cancer and enhances liver metastasis in mouse model.

Hepatocyte nuclear factor 6 (HNF6), as a transcription factor, has been reported to be involved in cell proliferation, carcinogenesis, and tumor metastasis. Here, we demonstrated the role of HNF6 in tumor growth and liver metastasis in colorectal cancer (CRC). Through bioinformatics and clinical samples analysis, we found HNF6 messenger RNA was upregulated both in CRC primary sites and liver metastases, and its high expression indicated poor survival in CRC patients. In vitro studies confirmed that HNF6 promoted cell proliferation and colony formation. What is more, in mouse models, the xenografts grew significantly faster and liver metastasis rate was nearly 45% higher in mice injected with HNF6-overexpressing cells. Further mechanism exploration showed that HNF6 expression affected cell adhesion and conferred resistance to anoikis in CRC cells. Taken together, HNF6 expression was upregulated in CRC and closely correlated with poor survival. HNF6 promoted CRC cell proliferation and tumor growth, and may contribute to liver metastasis via conferring cell resistance to anoikis.

Fast-track multidisciplinary treatment versus conventional treatment for colorectal cancer: a multicenter, open-label randomized controlled study.

BACKGROUND: Laparoscopic surgery, fast-track perioperative treatment and XELOX chemotherapy are effective strategies for shortening the duration of hospital stay for cancer patients. This trial aimed to clarify the safety and efficacy of the fast-track multidisciplinary treatment (FTMDT) model compared to conventional surgery combined with chemotherapy in Chinese colorectal cancer patients. METHODS: This trial was a prospective randomized controlled study with a 2 × 2 balanced factorial design and was conducted at six hospitals. Patients in group 1 (FTMDT) received fast-track perioperative treatment and XELOX adjuvant chemotherapy. Patients in group 2 (conventional treatment) received conventional perioperative treatment and mFOLFOX6 adjuvant chemotherapy. Subgroups 1a and 2a had laparoscopic surgery and subgroups 1b and 2b had open surgery. The primary endpoint was total length of hospital stay during treatment. RESULTS: A total of 374 patients were randomly assigned to the four subgroups, and 342 patients were finally analyzed, including 87 patients in subgroup 1a, 85 in subgroup 1b, 86 in subgroup 2a, and 84 in subgroup 2b. The total hospital stay of group 1 was shorter than that of group 2 [13 days, (IQR, 11-17 days) vs. 23.5 days (IQR, 15-42 days), P = 0.0001]. Compared to group 2, group 1 had lower surgical costs, fewer in-hospital complications and faster recovery (all P < 0.05). Subgroup 1a showed faster surgical recovery than that of subgroup 1b (all P < 0.05). There was no difference in 5-year overall survival between groups 1 and 2 [87.1% (95% CI, 80.7-91.5%) vs. 87.1% (95% CI, 80.8-91.4%), P = 0.7420]. CONCLUSIONS: The FTMDT model, which integrates laparoscopic surgery, fast-track treatment, and XELOX chemotherapy, was the superior model for enhancing the recovery of Chinese patients with colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01080547 , registered on March 4, 2010.

Adversarial Feature Alignment: Avoid Catastrophic Forgetting in Incremental Task Lifelong Learning.

Humans are able to master a variety of knowledge and skills with ongoing learning. By contrast, dramatic performance degradation is observed when new tasks are added to an existing neural network model. This phenomenon, termed catastrophic forgetting, is one of the major roadblocks that prevent deep neural networks from achieving human-level artificial intelligence. Several research efforts (e.g., lifelong or continual learning algorithms) have proposed to tackle this problem. However, they either suffer from an accumulating drop in performance as the task sequence grows longer, or require storing an excessive number of model parameters for historical memory, or cannot obtain competitive performance on the new tasks. In this letter, we focus on the incremental multitask image classification scenario. Inspired by the learning process of students, who usually decompose complex tasks into easier goals, we propose an adversarial feature alignment method to avoid catastrophic forgetting. In our design, both the low-level visual features and high-level semantic features serve as soft targets and guide the training process in multiple stages, which provide sufficient supervised information of the old tasks and help to reduce forgetting. Due to the knowledge distillation and regularization phenomena, the proposed method gains even better performance than fine-tuning on the new tasks, which makes it stand out from other methods. Extensive experiments in several typical lifelong learning scenarios demonstrate that our method outperforms the state-of-the-art methods in both accuracy on new tasks and performance preservation on old tasks.

Extent of enhancement on multiphase contrast-enhanced CT images is a potential prognostic factor of stage I-III colon cancer.

OBJECTIVE: By evaluating extent of tumour enhancement on preoperative contrast-enhanced MDCT, we aimed to establish an imaging-based model to predict cancer-specific survival in stage I-III colon cancer. METHODS: A total of 548 stage I-III colon cancer patients who underwent curative resection from 2007 to 2013 were retrospectively included and divided into primary cohort and validation cohort according to admission time. The attenuation coefficient of each colon cancer was measured on the workstation by drawing the ROI in CT images. The enhancement ratio was calculated using maximum tumour attenuation value in triphasic MDCT scanning divided by the minimum. Patients were divided into low/high-enhancement groups according to the optimal cut-off value derived from time-dependent ROC curve. Kaplan-Meier method and COX regression analysis were adopted to evaluate prognostic value of variables. A nomogram for prognosis was conducted on the basis of a multivariate Cox proportional hazard model. RESULTS: No significant differences were observed in age, sex, pTNM stage, perioperative chemoradiotherapy, serum CEA, tumour size, tumour localisation and histologic type between low- and high-enhancement groups. The high-enhancement group had a significantly shorter cancer-specific survival rate (69.5%) than the low-enhancement group (85.9%) (p < 0.001). Subgroup analysis indicated that high-enhancement state was closely associated with increased risk of colon cancer mortality in stage I (p = 0.033), stage II (p = 0.002) and stage III (p = 0.014). Cox regression analysis indicated the extent of enhancement was an independent prognostic factor (HR 2.258, 95% CI 1.476-3.455; p < 0.001). CONCLUSIONS: The extent of tumour enhancement on MDCT can serve as a potential risk factor for stage I-III colon cancer. KEY POINTS: • Survival rates of stage I-III colon cancer vary widely even within the same stage. • Prognostic value of the extent of tumour enhancement on MDCT was assessed. • The high-enhancement group had a significantly shorter cancer-specific survival rate.

Removal of DHT can relieve polycystic ovarian but not metabolic abnormalities in DHT-induced hyperandrogenism in mice.

Polycystic ovary syndrome (PCOS) is an endocrine disorder with a high prevalence in women of childbearing age. To date, there is no method of efficiently diagnosing PCOS and curing it completely because its pathomechanism remains unclear. Here, we investigated whether metabolic abnormalities maintain the hyperandrogenism and PCOS-like ovaries and whether the symptoms induced by excess androgen are treatable. We ceased the abnormal dihydrotestosterone (DHT) stimulation to determine changes in PCOS-like mice. After ceasing DHT stimulation, the ovarian morphology and gene expression recovered from the DHT-stimulated status. However, after cessation of DHT stimulation, the hypertrophy of adipose tissues and hepatic steatosis were not significantly restored, and fat accumulation-related gene expression and serum metabolic markers in the mice were altered. These findings showed that the reproductive dysfunction was obviously relieved, but because the metabolic abnormalities were not relieved after the cessation of excess androgen for 30 days, it appears that the latter may not maintain the former.

The prognostic value of tumor-infiltrating lymphocytes in colorectal cancer differs by anatomical subsite: a systematic review and meta-analysis.

PURPOSE: In colorectal cancer (CRC), whether the immune score can be used to predict the clinical prognosis of the patient has not been completely established. Besides, the prognostic values of tumor-infiltrating lymphocytes (TILs) in different anatomical locations, counting sites, and subtypes have been controversial. The purpose of this meta-analysis is to analyze and determine the prognostic value of TILs indices including TIL subsets, infiltrating sites, and anatomical sites. METHODS: Relevant literature was obtained by searching PubMed and Google Scholar. The pooled hazard ratio (HR) of the overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) was computed to investigate the prognostic significance of CD3+, CD8+, CD45RO+, and FOXP3+ T cells. RESULTS: A total of 22 studies involving 5108 patients were included in the meta-analysis. In CC, based on T cell subtypes analysis, the final results indicated that CD8+ and FOXP3+ infiltrating cells, but not CD3+ T cells were prognostic markers for DFS and OS. In addition, with regard to the counting location of TILs, subgroup analysis revealed that only high FOXP3+ infiltrates in the tumor stroma (ST) were significantly associated with OS (HR = 0.38, 95% confidence interval (CI) = 0.22-0.67, P = 0.0007), whereas in invasive margin (IM), high density of CD3+ infiltrating cells indicated increased DFS (HR = 0.76, 95% CI = 0.62-0.93, P = 0.008). At the tumor center (TC), high CD8+ T cells infiltration was associated with improved DFS (HR = 0.50, 95% CI = 0.38-0.65, P < 0.00001). In RC, whether CSS or OS, high-density TIL was associated with improved prognosis. CONCLUSION: In a single counting site, high-density TILs reflect favorable prognostic value in CC or RC. For CC, more prospective studies are needed to verify whether different anatomical sites affect the distribution of TILs and thus the prognosis of patients. For RC, further studies should analyze the prognostic value of the immune score.

Deficiency of Gpr1 improves steroid hormone abnormality in hyperandrogenized mice.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex genetic disease with multifarious phenotypes. Many researches use dehydroepiandrosterone (DHEA) to induce PCOS in pubertal mouse models. The aim of this study was to investigate the role of GPR1 in dehydroepiandrosterone (DHEA)-induced hyperandrogenized mice. METHODS: Prepubertal C57BL/6 mice (25 days of age) and Gpr1-deficient mice were each divided into two groups and injected daily with sesame oil with or without DHEA (6 mg/100 g) for 21 consecutive days. Hematoxylin and eosin (H&E) staining was performed to determine the characteristics of the DHEA-treated ovaries. Real-time PCR was used to examine steroid synthesis enzymes gene expression. Granulosa cell was cultured to explore the mechanism of DHEA-induced, GPR1-mediated estradiol secretion. RESULTS: DHEA treatment induced some aspects of PCOS in wild-type mice, such as increased body weight, elevated serum testosterone, increased number of small, cystic, atretic follicles, and absence of corpus luteum in ovaries. However, Gpr1 deficiency significantly attenuated the DHEA-induced weight gain and ovarian phenotype, improving steroidogenesis in ovaries and estradiol synthesis in cultured granulosa cells, partially through mTOR signaling. CONCLUSIONS: In conclusion, Gpr1 deficiency leads to the improvement of steroid synthesis in mice hyperandrogenized with DHEA, indicating that GPR1 may be a therapeutic target for DHEA-induced hyperandrogenism.

IGFBP-3 Gene Methylation in Primary Tumor Predicts Recurrence of Stage II Colorectal Cancers.

OBJECTIVES: To evaluate the influence of IGFBP-3 methylation on recurrence in patients with stage II colorectal cancer (CRC) from 2 independent cohorts. BACKGROUND: The relationship between IGFBP-3 methylation in primary tumors (PTs) or lymph nodes (LNs) and risk of recurrence in patients with stage II CRC treated with surgery alone is unknown. METHODS: IGFBP-3 methylation of DNA from 115 PTs and 1641 LNs in patients with stage II CRC from 2 independent cohorts was analyzed. Forty patients developed recurrence, whereas 75 matched patients remained recurrence free for more than 2 years after surgery. Cox proportional hazard models were used to calculate hazard ratios (HRs) of recurrence, adjusted for patient and tumor characteristics. RESULTS: Methylation of IGFBP-3 in PTs was identified to be significantly associated with risk of recurrence in the training set. The signature was tested in a validation set and classified 40.7% of patients as high risk. Five-year recurrence-free survival rates were 76.4% and 58.3% for low- and high-risk patients, respectively, with an HR of 2.21 (95% confidence interval, 1.04-4.68; P = 0.039). In multivariate analysis, the signature remained the most significant prognostic factor, with an HR of 2.40 (95% confidence interval, 1.10-5.25; P = 0.029). A combined analysis of 1641 LNs from the 2 sets identified IGFBP-3 methylation in LNs was not associated with risk of recurrence. CONCLUSIONS: Detection of IGFBP-3 methylation in PTs, but not in LNs, provides a powerful tool for the identification of patients with stage II CRC at high risk of recurrence.