High patatin like phospholipase domain containing 8 expression as a biomarker for poor prognosis of colorectal cancer.

BACKGROUND: Patatin like phospholipase domain containing 8 (PNPLA8) has been shown to play a significant role in various cancer entities. Previous studies have focused on its roles as an antioxidant and in lipid peroxidation. However, the role of PNPLA8 in colorectal cancer (CRC) progression is unclear. AIM: To explore the prognostic effects of PNPLA8 expression in CRC. METHODS: A retrospective cohort containing 751 consecutive CRC patients was enrolled. PNPLA8 expression in tumor samples was evaluated by immunohistochemistry staining and semi-quantitated with immunoreactive scores. CRC patients were divided into high and low PNPLA8 expression groups based on the cut-off values, which were calculated by X-tile software. The prognostic value of PNPLA8 was identified using univariate and multivariate Cox regression analysis. The overall survival (OS) rates of CRC patients in the study cohort were compared with Kaplan-Meier analysis and Log-rank test. RESULTS: PNPLA8 expression was significantly associated with distant metastases in our cohort (P = 0.048). CRC patients with high PNPLA8 expression indicated poor OS (median OS = 35.3, P = 0.005). CRC patients with a higher PNPLA8 expression at either stage I and II or stage III and IV had statistically significant shorter OS. For patients with left-sided colon and rectal cancer, the survival curves of two PNPLA8-expression groups showed statistically significant differences. Multivariate analysis also confirmed that high PNPLA8 expression was an independent prognostic factor for overall survival (hazard ratio HR = 1.328, 95%CI: 1.016-1.734, P = 0.038). CONCLUSION: PNPLA8 is a novel independent prognostic factor for CRC. These findings suggest that PNPLA8 is a potential target in clinical CRC management.

Siglec9 + tumor-associated macrophages predict prognosis and therapeutic vulnerability in patients with colon cancer.

BACKGROUND: Siglec9 has been identified as an immune checkpoint molecule on tumor-associated macrophages (TAMs). Nevertheless, the expression profile and clinical significance of Siglec9 + TAMs in colon cancer (CC) are still not fully understood. METHODS: Two clinical cohorts from distinct medical centers were retrospectively enrolled. Immunohistochemistry and immunofluorescence were conducted to evaluate the infiltration of immune cells. Single-cell RNA sequencing and flow cytometry were utilized to identify the impact of Siglec9 + TAMs on the tumor immune environment, which was subsequently validated through bioinformatics analysis of the TCGA database. Prognosis and the benefit of adjuvant chemotherapy (ACT) were also evaluated using Cox regression analysis and the Kaplan-Meier method. RESULTS: High infiltration of Siglec9 + TAMs was associated with worse prognosis and better benefit from 6-month ACT. Siglec9 + TAMs contributed to immunoevasion by promoting the infiltration of immunosuppressive cells and the dysfunction process of CD8 + T cells. Additionally, high infiltration of Siglec9 + TAMs was associated with the mesenchymal-featured subtype and overexpression of the VEGF signaling pathway, which was validated by the strongest communication between Siglec9 + TAMs and vascular endothelial cells. CONCLUSIONS: Siglec9 + TAMs may serve as a biomarker for prognosis and response to ACT in CC. Furthermore, the immunoevasive contexture and angiogenesis stimulated by Siglec9 + TAMs suggest potential treatment combinations for CC patients.

Intratumor APOL3 delineates a distinctive immunogenic ferroptosis subset with prognosis prediction in colorectal cancer.

With the essential role of lipid transporting signaling in cancer-related immunity, apolipoprotein L3 (APOL3), a member of the apolipoprotein L gene family, demonstrated significant modulation ability in immunity. However, the expression profile and critical role of APOL3 in colorectal cancer (CRC) remain unclear. This study aimed to investigate the prognostic significance of APOL3 expression and its biological predictive value in CRC. The study enrolled multiple cohorts, consisting of 911 tumor microarray specimens of CRC patients from Zhongshan Hospital, 412 transcriptional data from The Cancer Genome Atlas, and 30 single-cell RNA sequencing (scRNA-seq) from internal and external CRC patients. APOL3 mRNA expression was directly acquired from public datasets, and APOL3 protein expression was detected using immunohistochemistry. Finally, the associations of APOL3 expression with clinical outcomes, immune context, and genomic and ferroptotic features were analyzed. Low APOL3 expression predicted poor prognosis and inferior responsiveness to 5-fluorouracil-based adjuvant chemotherapy (ACT) and targeted therapy. APOL3 fosters an immune-active microenvironment characterized by the promotion of ferroptosis, downregulation of macrophages, and upregulation of CD8+ T cell infiltration. Moreover, the expression of APOL3 in CD8+ T cells is intrinsically linked to ferroptosis and immune activation in CRC. In summary, APOL3 serves as an independent prognosticator and predictive biomarker for immunogenic ferroptosis, ACT, and targeted therapy in CRC. Furthermore, the APOL3 signaling activator could be a novel agent alone or in combination with current therapeutic strategies for CRC.

Proteomic characterization of the colorectal cancer response to chemoradiation and targeted therapies reveals potential therapeutic strategies.

Chemoradiation and targeted therapies are the major treatments for colorectal cancer (CRC); however, molecular properties associated with therapy resistance are incompletely characterized. Here, we profile the proteome of 254 tumor tissues from patients with CRC undergoing chemotherapy, chemoradiation, or chemotherapy combined with targeted therapy. Proteome-based classification reveals four subtypes featured with distinct biological and therapeutic characteristics. The integrative analysis of CRC cell lines and clinical samples indicates that immune regulation is significantly associated with drug sensitivity. HSF1 can increase DNA damage repair and cell cycle, thus inducing resistance to radiation, while high expression of HDAC6 is negatively associated with response of cetuximab. Furthermore, we develop prognostic models with high accuracy to predict the therapeutic response, further validated by parallel reaction monitoring (PRM) assay in an independent validation cohort. This study provides a rich resource for investigating the mechanisms and indicators of chemoradiation and targeted therapy in CRC.

Comparing the clinical and singleton neonatal outcomes in male infertility patients with Oligoasthenospermia, OA, or NOA following fresh ICSI-ET using different sources of sperm.

Objective: To investigate clinical and singleton newborn outcomes in fresh cycles of embryo transfer after intracytoplasmic sperm injection (ICSI-ET) with diverse sperm sources (ejaculate, epididymis, and testis) in patients with Oligoasthenospermia, obstructive azoospermia (OA) or non-obstructive azoospermia (NOA). Methods: Patients who received fresh ICSI-ET for the first time at the First Affiliated Hospital of Zhengzhou University Reproductive Medicine Center between June 2011 and June 2021 were selected for this 10-year retrospective cohort analysis. After propensity score matching, only 1630 cycles were included in the investigation of ICS-ET clinical and singleton newborn outcomes in patients with Oligoasthenospermia, OA, and NOA using sperm from diverse sperm sources. Results: After propensity score matching, our data revealed a negligible difference in baseline and cycle parameters among groups. In patients with Oligoasthenospermia and OA, different sperm sources do not appear to influence clinical pregnancy rates and live birth rates, nor do they influence newborn outcomes, such as newborn weight, premature birth rate, and neonatal sex ratio in singleton births, except for OA patients who use epididymal sperm having higher low birth weight (LBW) rates in singleton pregnancies than those who use testicular sperm. In addition, clinical pregnancy rates, live birth rates, singleton gestation birth weights, premature birth rates, and neonatal sex ratios were similar between patients with Oligoasthenospermia, OA, and NOA using testicular sperm. Conclusions: Regardless of the type of male infertility (Oligoasthenospermia, OA, NOA) or sperm sources (ejaculate, epididymis, testis), a successful ICSI-ET procedure can result in similar clinical and neonatal outcomes, such as clinical pregnancy rate, live birth rate, abortion rate, neonatal birth weight and sex ratio of singleton pregnancies.

The impact of female BMI on sperm DNA damage repair ability of oocytes and early embryonic development potential in intracytoplasmic sperm injection cycles.

Background: Obesity adversely influences the quality of oocytes and embryos and can affect DNA repair in embryos, leading to reproductive issues. However, the effects of body mass index (BMI) on DNA repair ability in oocytes during intracytoplasmic sperm injection (ICSI) cycles have not yet been investigated. Therefore, this retrospective study aimed to analyze the influence of sperm DNA damage on embryo development and reproductive outcomes in overweight/obese and normal-weight women in ICSI cycles. Methods: A total of 1,141 patients who received the first fresh ICSI cycle treatments were recruited from July 2017 to July 2021. Based on the BMI of the women, all patients were divided into normal weight (18.5≤BMI<25 kg/m2; n=824; 72.22%) and overweight/obese (BMI≥25 kg/m2; n=317; 27.78%) groups. Furthermore, according to the sperm DNA fragmentation index (DFI), these two groups were subdivided into two subgroups: DFI<30% and DFI≥30%. Results: In the normal-weight women group, the embryonic development and reproductive outcomes of ICSI cycles were not statistically different between the two subgroups (DFI<30% and DFI≥30%). However, in the overweight/obese women group, couples with a sperm DFI≥30% had a significantly lower fertilization rate (76% vs. 72.7%; p=0.027), cleavage rate (98.7% vs. 97.2%; p=0.006), and high-quality embryo rate (67.8% vs. 62.6%; p=0.006) than couples with a sperm DFI<30%. Conclusion: When injected sperm with high DFI into the oocytes of overweight/obese women, resulting in lower fertilization, cleavage, and high-quality embryo rates in ICSI cycles, and the decreased early developmental potential of embryos from overweight/obese patients may be caused by the diminished capacity of oocytes to repair sperm DNA damage.

Robotic versus open surgery for simultaneous resection of rectal cancer and liver metastases: a randomized controlled trial.

OBJECTIVE: This study aimed to compare the short-term and long-term outcomes between robotic-assisted simultaneous resection and open surgery in patients with rectal cancer and liver metastases. BACKGROUND: Open simultaneous resection of colorectal cancer and synchronous liver metastases is widely performed and the potential cure for eligible patients. However, the feasibility of robotic simultaneous resection of primary and secondary liver lesions has not been established as a treatment option for metastatic rectal cancer. PATIENTS AND METHODS: A single-center randomized controlled trial was conducted at a hospital in China. Enrolling patients were aged from 18 to 75 years and diagnosed with surgically resectable metastatic rectal cancer (distal extension to ≤15 cm from the anal margin). Patients selected for simultaneous resection were randomly assigned to have robotic or open surgery at a 1:1 ratio. The primary endpoint was the incidence rate of complications within 30 days after surgery. Secondary endpoints were bladder, sexual function, 3-year disease-free survival, and overall survival. RESULTS: A total of 171 patients were enrolled in this trial with 86 in the robotic group and 85 in the open group. As a result, patients in the robotic group demonstrated fewer complications within 30 days after surgery than those in the open group (31.4 vs. 57.6%, P =0.014) and no mortality seen in either group. Patients in the robotic group had less blood loss [mean (SD), 125.5 (38.3) vs. 211.6 (68.7) ml; P <0.001], faster bowel function recovery [mean (SD), 63.7 (27.4) vs. 93.8 (33.5) h P <0.001] and shorter hospital stay [mean (SD), 8.0 (2.2) vs. 10.7 (5.4) days; P <0.001] compared with those in the open group. The robotic group had a faster recovery of bladder and sexual function at 3 months after surgery than that of the open group. The 3-year disease-free survival rate (39.5 vs. 35.3%, P =0.739) and the 3-year overall survival rate (76.7 vs. 72.9%, P =0.712) were not statistically significant between the two groups. CONCLUSIONS: In our randomized clinical trial, robotic simultaneous resection treatment of patients with rectal cancer and liver metastases resulted in fewer surgical complications, and a faster recovery to those of open surgery. Oncological outcomes showed no significant difference between the two groups.

Deep radiomics-based fusion model for prediction of bevacizumab treatment response and outcome in patients with colorectal cancer liver metastases: a multicentre cohort study.

Background: Accurate tumour response prediction to targeted therapy allows for personalised conversion therapy for patients with unresectable colorectal cancer liver metastases (CRLM). In this study, we aimed to develop and validate a multi-modal deep learning model to predict the efficacy of bevacizumab in patients with initially unresectable CRLM using baseline PET/CT, clinical data, and colonoscopy biopsy specimens. Methods: In this multicentre cohort study, we retrospectively collected data of 307 patients with CRLM from the BECOME study (NCT01972490) (Zhongshan Hospital of Fudan University, Shanghai) and two independent Chinese cohorts (internal validation cohort from January 1, 2018 to December 31, 2018 at Zhongshan Hospital of Fudan University; external validation cohort from January 1, 2020 to December 31, 2020 at Zhongshan Hospital-Xiamen, Shanghai, and the First Hospital of Wenzhou Medical University, Wenzhou). The main inclusion criteria were that patients with CRLM had pre-treatment PET/CT images as well as colonoscopy specimens. After extracting PET/CT features with deep neural networks (DNN) and selecting related clinical factors using LASSO analysis, a random forest classifier was built as the Deep Radiomics Bevacizumab efficacy predicting model (DERBY). Furthermore, by combining histopathological biomarkers into DERBY, we established DERBY+. The performance of model was evaluated using area under the curve (AUC), sensitivity, specificity, positive predictive value, and negative predictive value. Findings: DERBY achieved promising performance in predicting bevacizumab sensitivity with an AUC of 0.77 and 95% confidence interval (CI) [0.67-0.87]. After combining histopathological features, we developed DERBY+, which had more robust accuracy for predicting tumour response in external validation cohort (AUC 0.83 and 95% CI [0.75-0.92], sensitivity 80.4%, specificity 76.8%). DERBY+ also had prognostic value: the responders had longer progression-free survival (median progression-free survival: 9.6 vs 6.3 months, p = 0.002) and overall survival (median overall survival: 27.6 vs 18.5 months, p = 0.010) than non-responders. Interpretation: This multi-modal deep radiomics model, using PET/CT, clinical data and histopathological data, was able to identify patients with bevacizumab-sensitive CRLM, providing a favourable approach for precise patient treatment. To further validate and explore the clinical impact of this work, future prospective studies with larger patient cohorts are warranted. Funding: The National Natural Science Foundation of China; Fujian Provincial Health Commission Project; Xiamen Science and Technology Agency Program; Clinical Research Plan of SHDC; Shanghai Science and Technology Committee Project; Clinical Research Plan of SHDC; Zhejiang Provincial Natural Science Foundation of China; and National Science Foundation of Xiamen.

Impact of Surgical Management for Relapse After Conversion Hepatectomy for Initially Unresectable Colorectal Liver Metastasis: A Retrospective Cohort Study.

BACKGROUND: For patients with initially unresectable colorectal liver metastasis (IU-CRLM) receiving conversion therapy, disease relapse after conversion hepatectomy is common. However, few studies have focused on the assessment and management of relapse following conversion hepatectomy for IU-CRLM. METHODS: In the retrospective cohort study, 255 patients with IU-CRLM received conversion therapy and underwent subsequent R0 resection. The treatment effects of repeated liver-directed treatment (RLDT) versus non-RLDT for liver relapse were examined. Survival analysis was evaluated with the use of Cox proportional hazards methods. The importance of RLDT was further confirmed in the propensity score matching (PSM) and subgroup analyses. RESULTS: The 5-year overall survival (OS) rate after conversion hepatectomy was 34.9%. Liver relapse was observed in 208 patients. Of these patients, 106 underwent RLDT (65 underwent repeated hepatectomy and the remainder underwent ablation treatment), while 102 received only palliative chemotherapy. The relapse patients who underwent RLDT had a significantly longer OS than those who did not (hazard ratio (HR): 0.382, 95% CI: 0.259-0.563; P<0.001). In a multivariable analysis, RLDT was independently associated to prolonged survival (HR: 0.309, 95%CI: 0.181-0.529; P<0.001). In the PSM and subgroup analyses, RLDT consistently showed evidence of prolonging OS significantly. CONCLUSION: For IU-CRLM patients with liver relapse following conversion hepatectomy, the RLDT is essential for cure and prolonged survival. To avoid missing the opportunity for RLDT, intensive disease surveillance should be proposed.

Malaria epidemiological characteristics and control in Guangzhou, China, 1950-2022.

BACKGROUND: Malaria was once widespread in Guangzhou, China. However, a series of control measures have succeeded in eliminating local malaria infections. Based on the analysis of the characteristics of malaria epidemics in Guangzhou, China, from 1950 to 2022, the changes and effectiveness of malaria control strategies and surveillance management in Guangzhou from 1950 to 2022 are described. METHODS: Data on malaria prevention and treatment in Guangzhou from 1950 to 2022 were collected, and descriptive epidemiological methods were used to analyse the prevalence of malaria, preventive and control measures taken, and the effectiveness of prevention and treatment in different periods. Data on malaria cases were obtained from the Guangzhou Centre for Disease Control and Prevention (CDC) and the China Communicable Disease Reporting System. RESULTS: The development of the malaria control system in Guangzhou has gone through four periods: 1. High malaria prevalence (1950-1979), 2. Intensive prevention and control stage (1980-2000), 3. Consolidating gains in malaria control (2001-2008), and 4. Preventing reestablishment of transmission (2009-2022). During Period 1, only medical institutions at all levels and the local CDCs, the Guangzhou CDC participated in the malaria prevention and control system, establishing a three-tier health system on malaria prevention and control. During Period 2, other types of organizations, including the agricultural sector, schools and village committees, the construction department and street committee, are involved in the malaria control system. During Period 3, more and more organizations are joining forces to prevent and control malaria. A well-established multisectoral malaria control mechanism and an improved post-elimination surveillance management system are in place. Between 1950 and 2022, a total of 420,670 cases of malaria were reported. During Period 1, there was an epidemic of malaria in the early 1950s, with an annual incidence rate of more than 10,000/100,000, including a high rate of 2887.98/100,000 in 1954. In Period 2 malaria was gradually brought under control, with the average annual malaria incidence rate dropping to 3.14/100,000. During Period 3, the incidence rate was kept below 1/100,000, and by 2009 local malaria infections were eliminated. CONCLUSION: For decades, Guangzhou has adopted different malaria control strategies and measures at different epidemic stages. Increased collaboration among civil organizations in Guangzhou in malaria control has led to a significant decline in the number of malaria cases and the elimination of indigenous malaria infections by 2009.The experience of Guangzhou can guide the development of malaria control strategies in other cities experiencing similar malaria epidemics.

Anatomical resection improves relapse-free survival in colorectal liver metastases in patients with KRAS/NRAS/BRAF mutations or right-sided colon cancer: a retrospective cohort study.

BACKGROUND: The type of liver resection (anatomical resection, AR or non-anatomical resection, NAR) for colorectal liver metastases (CRLM) is subject to debate. The debate may persist because some prognostic factors, associated with aggressive tumor biological behavior, have been overlooked. OBJECTIVE: Our study aimed to investigate the characteristics of patients who would benefit more from anatomical resection for CRLM. METHODS: Seven hundred twenty-nine patients who underwent hepatic resection of CRLM were retrospectively collected from June 2012 to May 2019. Treatment effects between AR and NAR were compared in full subgroup analyses. Tumor relapse-free survival (RFS) was evaluated by a stratified log-rank test and summarized with the use of Kaplan-Meier and Cox proportional hazards methods. RESULTS: Among 729 patients, 235 (32.2%) underwent AR and 494 (67.8%) underwent NAR. We showed favorable trends in RFS for AR compared with NAR in the patients with KRAS/NRAS/BRAF mutation (interaction P <0.001) or right-sidedness (interaction P <0.05). Patients who underwent AR had a markedly improved RFS compared with NAR in the cohorts of RAS/NRAS/BRAF mutation (median RFS 23.2 vs. 11.1 months, P <0.001) or right-sidedness (median RFS 31.6 vs. 11.5 months, P <0.001); upon the multivariable analyses, AR [gene mutation: hazard ratio (HR)=0.506, 95% CI=0.371-0.690, P <0.001; right-sidedness: HR=0.426, 95% CI=0.261-0.695, P =0.001) remained prognostic independently. In contrast, patients who underwent AR had a similar RFS compared with those who underwent NAR, in the cohorts of patients with gene wild-type tumors (median RFS 20.5 vs. 21.6 months, P =0.333). or left-sidedness (median RFS 15.8 vs. 19.5 months, P =0.294). CONCLUSIONS: CRLM patients with gene mutation or right-sidedness can benefit more from AR rather than from NAR.

Erratum: Zinc-α2-glycoprotein 1 promotes EMT in colorectal cancer by filamin A mediated focal adhesion pathway: Erratum.

[This corrects the article DOI: 10.7150/jca.35380.].

Eschar dissolution and the immunoregulator effect of keratinase on burn wounds.

At present, enzyme debridement preparation has shown a good curative effect on eschar removal of burn wounds. Keratinase has shown great potential in enzymatic debridement because of its good fibrin-degrading ability. In this study, the debridement of keratinase was examined by using a third degree burn wound model in rats. We observed the wound, and keratinase shortened the time of eschar dissolution after debridement. Histopathology and immunofluorescence staining showed that the eschar in the keratinase group became thinner, inflammatory cell infiltration in the wound increased, the fluorescence intensity of the macrophage surface marker CD68 increased, and the CD163/CD86 ratio increased. In bone marrow-derived macrophages (BMDMs), there was no significant difference in the activity of CCK-8 in cells in the keratinase group compared with the control group. The fluorescence intensity of the keratinase group was higher than that of the control group. At 12 h, the cell scratches were obviously closed. The number of migrated Transwell cells increased. Flow cytometry and immunofluorescence analysis showed increased expression of CD206 and Arg-1 and decreased expression of CD86 and iNOS. The gene expression of the Arg-1, iNOS and IL-10 was increased, as shown by qPCR. The secretion of IL-10 was increased and TNF-α was decreased, as shown by ELISA. We concluded that keratinase dissolution of eschar not only has a hydrolytic effect on eschar but may also affect immune regulation to enhance the migration and phagocytosis of macrophages, promote the polarization of macrophages, and further enhance the effect of eschar dissolution. Therefore, keratinase may have good prospects for the debridement of burn wounds.

Treatment of metastatic colorectal cancer with BRAF V600E mutation: A multicenter real-world study in China.

BACKGROUND: BRAF V600E mutant-metastatic colorectal cancer (mCRC) is characterized by its short survival time. Treatment approaches vary depending on whether or not the metastases are initially resectable. The benefit of metastasectomy remains unclear, and the optimal first-line treatment is controversial. This study aimed to describe the prognosis of BRAF V600E mutant-mCRC, analyze the recurrence pattern in resectable patients, and explore the optimal first-line treatment for unresectable patients. METHODS: Patients diagnosed with BRAF V600E mutant-mCRC between February 2014 and January 2022 in five hospitals were enrolled. Date on clinical and pathological characteristics, treatment features, and survival outcomes were collected. RESULTS: Of the 220 included patients, 64 initially resectable patients had a significantly longer overall survival (OS) (37.07 vs. 20.20 months, P < 0.001) than initially unresectable patients. Of 156 unresectable patients, 54 received doublet (FOLFOX, XELOX or FOLFIRI) or triplet (FOLFOXIRI) chemotherapies (Chemo), 55 received Chemo plus Bevacizumab (Chemo+Bev), and 33 received vemurafenib plus cetuximab and irinotecan (VIC). The VIC regimen had a better progression-free survival (PFS) (12.70 months) than the Chemo (6.70 months, P < 0.001) and Chemo+Bev (8.8 months, P = 0.044) regimens. Patients treated with VIC had the best overall response rate (60.16%, P < 0.001), disease control rate (93.94%, P < 0.001) and conversional resection rate (24.24%, P = 0.003). CONCLUSIONS: Metastasectomy is beneficial to the survival of patients with BRAF V600E mutant-mCRC. For initially unresectable patients, VIC as first-line therapy is associated with a better prognosis and efficacy than doublet and triplet chemotherapy with or without bevacizumab.

Preoperative chemotherapy prior to primary tumour resection for asymptomatic synchronous unresectable colorectal liver-limited metastases: The RECUT multicenter randomised controlled trial.

PURPOSE: Primary tumour resection (PTR) is still a selection for patients with low tumour burden and good condition, especially with conversion therapy purpose for colorectal liver-limited metastases (CRLMs). The objective was to evaluate whether pre-PTR chemotherapy could improve progression-free survival (PFS) for patients with asymptomatic synchronous unresectable CRLMs. PATIENTS AND METHODS: Patients with asymptomatic synchronous unresectable CRLMs were randomly assigned to receive pre-PTR chemotherapy (arm A) or upfront PTR (arm B). Chemotherapy regimens of mFOLFOX6 plus cetuximab, mFOLFOX6 plus bevacizumab or mFOLFOX6 alone were chosen according to the RAS genotype. The primary end-point was PFS; secondary end-points included overall survival (OS), tumour response, disease control rate (DCR), liver metastases resection rate, surgical complications and chemotherapy toxicity. RESULTS: Three hundred and twenty patients were randomly assigned to arm A (160 patients) and arm B (160 patients). Patients in arm A had significantly improved the median PFS compared with arm B (10.5 versus 9.1 months; P = 0.013). Patients in arm A also had significantly better DCR (84.4% versus 75.0%; P = 0.037). The median OS (29.4 versus 27.2 months; P = 0.058), objective response rate (ORR) (53.1% versus 45.0%; P = 0.146) and liver metastases resection rate (21.9% versus 18.1%; P = 0.402) were not significantly different. The Clavien-Dindo 3-4 complications post PTR (4.5% versus 3.8%, P = 0.759) and the incidence of grade 3/4 chemotherapy events (42.2% versus 40.4%, P = 0.744) reached no statistical significance. CONCLUSIONS: For asymptomatic synchronous unresectable CRLMs, Pre-PTR chemotherapy improved the PFS compared with upfront PTR.

Efficacy of image-enhanced endoscopy for colorectal adenoma detection: A multicenter, randomized trial.

BACKGROUND: Improved adenoma detection at colonoscopy has decreased the risk of developing colorectal cancer. However, whether image-enhanced endoscopy (IEE) further improves the adenoma detection rate (ADR) is controversial. AIM: To compare IEE with white-light imaging (WLI) endoscopy for the detection and identification of colorectal adenoma. METHODS: This was a multicenter, randomized, controlled trial. Participants were enrolled between September 2019 to April 2021 from 4 hospital in China. Patients were randomly assigned to an IEE group with WLI on entry and IEE on withdrawal (n = 2113) or a WLI group with WLI on both entry and withdrawal (n = 2098). The primary outcome was the ADR. The secondary endpoints were the polyp detection rate (PDR), adenomas per colonoscopy, adenomas per positive colonoscopy, and factors related to adenoma detection. RESULTS: A total of 4211 patients (966 adenomas) were included in the analysis (mean age, 56.7 years, 47.1% male). There were 2113 patients (508 adenomas) in the IEE group and 2098 patients (458 adenomas) in the WLI group. The ADR in two group were not significantly different [24.0% vs 21.8%, 1.10, 95% confidence interval (CI): 0.99-1.23, P = 0.09]. The PDR was higher with IEE group (41.7%) than with WLI group (36.1%, 1.16, 95%CI: 1.07-1.25, P = 0.01). Differences in mean withdrawal time (7.90 ± 3.42 min vs 7.85 ± 3.47 min, P = 0.30) and adenomas per colonoscopy (0.33 ± 0.68 vs 0.28 ± 0.62, P = 0.06) were not significant. Subgroup analysis found that with narrow-band imaging (NBI), between-group differences in the ADR, were not significant (23.7% vs 21.8%, 1.09, 95%CI: 0.97-1.22, P = 0.15), but were greater with linked color imaging (30.9% vs 21.8%, 1.42, 95%CI: 1.04-1.93, P = 0.04). the second-generation NBI (2G-NBI) had an advantage of ADR than both WLI and the first-generation NBI (27.0% vs 21.8%, P = 0.01; 27.0% vs 21.2.0%, P = 0.01). CONCLUSION: This prospective study confirmed that, among Chinese, IEE didn't increase the ADR compared with WLI, but 2G-NBI increase the ADR.

Deletion of enzymes for de novo NAD+ biosynthesis accelerated ovarian aging.

Recent advances highlight the pivotal role of nicotinamide adenine dinucleotide (NAD+ ) in ovarian aging. However, the roles of de novo NAD+ biosynthesis on ovarian aging are still unknown. Here, we found that genetic ablation of Ido1 (indoleamine-2,3-dioxygenase 1) or Qprt (Quinolinate phosphoribosyl transferase), two critical genes in de novo NAD+ biosynthesis, resulted in decreased ovarian NAD+ levels in middle-aged mice, leading to subfertility, irregular estrous cycles, reduced ovarian reserve, and accelerated aging. Moreover, we observed impaired oocyte quality, characterized by increased reactive oxygen species and spindle anomalies, which ultimately led to reduced fertilization ability and impaired early embryonic development. A transcriptomic analysis of ovaries in both mutant and wild-type mice revealed alterations in gene expression related to mitochondrial metabolism. Our findings were further supported by the observation of impaired mitochondrial distribution and decreased mitochondrial membrane potential in the oocytes of knockout mice. Supplementation with nicotinamide riboside (NR), an NAD+ booster, in mutant mice increased ovarian reserve and improved oocyte quality. Our study highlights the importance of the NAD+ de novo pathway in middle-aged female fertility.

Characteristics of leptospirosis cases, prevention and control managements 1955-2020, Guangzhou, China.

Background: Leptospirosis, which is an easily overlooked zoonotic disease, was once widespread in Guangzhou, China. However, due to the implementation of control measures, the number of cases is decreasing. Based on the characteristics of leptospirosis cases in Guangzhou, China, between 1955 and 2020, we describe the changes and achievements in prevention and control management strategies over that period. Methods: The development of the leptospirosis control system in Guangzhou occurred over three periods: Period I: 1955-1978; Period II: 1979-2000; and Period III: 2001-2020. Data about leptospirosis cases were obtained from the Guangzhou Center for Disease Control and Prevention (CDC) and national health departments. The demographic characteristics of leptospirosis patients were analyzed using descriptive statistics. Results: During Period I, only the Guangzhou CDC and medical institutions at every level participated in the leptospirosis control system. During Period II, additional types of organizations, including local CDCs, countryside committees, community committees, and the Patriotic Health Movement Commission, were involved in the control system. Additionally, strong links were established between different organizations. After entering Period III, an increasing number of departments joined the cooperation, and the management of human patients was expanded to include the management of host animals, and thus, the prevalence of leptospirosis was monitored and controlled in various ways. The leptospirosis control system in Guangzhou has been further improved. From 1955 to 2020, a total of 2501 leptospirosis cases were recorded in Guangzhou, and the number of cases decreased significantly over time, from 1608 (Period I) to 744 (Period II) and then to 149 (Period III). Conclusion: The improvements of the leptospirosis control system in Guangzhou that occurred over decades were associated with a marked decrease in the number of leptospirosis cases. Guangzhou's experience can provide guidance for other countries or cities around the world facing similar challenges.

Proteomic characteristics reveal the signatures and the risks of T1 colorectal cancer metastasis to lymph nodes.

The presence of lymph node metastasis (LNM) affects treatment strategy decisions in T1NxM0 colorectal cancer (CRC), but the currently used clinicopathological-based risk stratification cannot predict LNM accurately. In this study, we detected proteins in formalin-fixed paraffin-embedded (FFPE) tumor samples from 143 LNM-negative and 78 LNM-positive patients with T1 CRC and revealed changes in molecular and biological pathways by label-free liquid chromatography tandem mass spectrometry (LC-MS/MS) and established classifiers for predicting LNM in T1 CRC. An effective 55-proteins prediction model was built by machine learning and validated in a training cohort (N=132) and two validation cohorts (VC1, N=42; VC2, N=47), achieved an impressive AUC of 1.00 in the training cohort, 0.96 in VC1 and 0.93 in VC2, respectively. We further built a simplified classifier with nine proteins, and achieved an AUC of 0.824. The simplified classifier was performed excellently in two external validation cohorts. The expression patterns of 13 proteins were confirmed by immunohistochemistry, and the IHC score of five proteins was used to build an IHC predict model with an AUC of 0.825. RHOT2 silence significantly enhanced migration and invasion of colon cancer cells. Our study explored the mechanism of metastasis in T1 CRC and can be used to facilitate the individualized prediction of LNM in patients with T1 CRC, which may provide a guidance for clinical practice in T1 CRC.

Most patients with early-stage colorectal cancer can be treated with a minimally invasive procedure. Surgeons use a flexible tool to remove precancerous or cancerous cells, cutting the risk of death from colorectal cancer in half. But a small number of early-stage colorectal cancer patients are at risk of their cancer spreading to the lymph nodes. These patients need more extensive surgery. Clinicians use risk stratification tools to decide which patients need more extensive surgery. Unfortunately, the existing risk stratification tools are not very accurate. The current approach, which analyzes colon tissue for cancerous changes, classifies 70% to 80% of early-stage colorectal cancer patients as high risk for cancer spread. But only about 8% to 16% of patients in the high risk group have lymph node metastasis. As a result, many patients undergo unnecessary, invasive surgery. Zhuang, Zhuang, Chen, Qin, et al. developed a more accurate way to predict which patients are at risk of lymph node metastasis using proteins. In the experiments, the team analyzed the proteins in tumor samples from 143 patients with early colorectal cancer who did not have lymph node metastases and 78 patients with metastases. Zhuang et al. then used machine learning to build a prediction tool that used 55 proteins to identify patients at risk of metastases. The new approach was more accurate than existing tools and simplified versions with only nine or five proteins also performed better than existing tools. This work provides preliminary evidence that protein-based models using as few as five proteins can more accurately identify which patients are at risk of metastasis. These models may reduce the number of patients who undergo unnecessary invasive surgery. The experiments also identified potential targets for therapies to prevent or treat lymph metastases. For example, they showed that low levels of the RHOT2 protein predict metastasis.