FoxO3 regulates mouse bone mesenchymal stem cell fate and bone-fat balance during skeletal aging.

Age-related osteoporosis is characterized by an imbalance between osteogenic and adipogenic differentiation in bone mesenchymal stem cells (BMSCs). Forkhead box O 3 (FoxO3) transcription factors is involved in lifespan and cell differentiation. In this study, we explore whether FoxO3 regulates age-related bone loss and marrow fat accumulation. The expression levels of FoxO3 in BMSCs during aging were detected in vivo and in vitro. To explore the role of FoxO3 in osteogenic and adipogenic differentiation, primary BMSCs were isolated from young and aged mice. FoxO3 expression was modulated by adenoviral vector transfection. The role of FoxO3 in bone-fat balance was evaluated by alizarin red S staining, oil red O staining, quantitative reverse transcription-PCR (qRT-PCR), western blot (WB) and histological analysis. Age-related bone loss and fat deposit are associated with downregulation of FoxO3. Overexpression of FoxO3 alleviated age-related bone loss and marrow fat accumulation in aged mice. Mechanistically, FoxO3 reduced adipogenesis and enhanced osteogenesis of BMSCs via downregulation of PPAR-γ and Notch signaling respectively. In conclusion, FoxO3 is an essential factor controlling the fate of BMSCs, and is a potential target for prevention of age-related osteoporosis.

Total intracorporeal laparoscopic ileal ureter replacement in a single position for ureteral stricture based on membrane anatomy.

PURPOSE: The aim of this study was to present our initial experience and prove the feasibility of total intracorporeal laparoscopic ileal ureter replacement (TILIUR) in a single position for ureteral stricture based on membrane anatomy. MATERIALS AND METHODS: Between January 2021 and April 2023, six patients underwent TILIUR in a single position for ureteral strictures based on membrane anatomy. All patients with a past medical history underwent radical hysterectomy with bilateral pelvic lymph node dissection as well as extensive ureteral stricture due to radiotherapy. The procedure is performed completely laparoscopically. Dissection of the digestive system as well as ureteral stricture or renal pelvis is based on membrane anatomy. The surgery is performed in a single position. RESULTS: TILIUR in a single position for ureteral stricture based on membrane anatomy was successfully performed without open conversion in all patients. Among the 6 patients, 3 patients underwent combined ileal ureter replacement (IUR) and abdominal wall ostomy, 2 underwent unilateral IUR, and 1 underwent bilateral IUR. The mean length of the ileal substitution was 22.83 cm (range: 15-28). The average operative time was 458 ± 72.77 min (range 385-575 min), and the average intraoperative blood loss was 158 mL (range 50-400 mL). The median postoperative hospital stay was 15.1 d (range: 8-32). The median duration of postoperative follow-up was 15 months (range: 3-29 months). The success rate was 100%. CONCLUSIONS: TILIUR in a single position may be a promising option for ureteral stricture based on membrane anatomy in selected patients. Moreover, it has a positive effect on patients with renal insufficiency and urinary incontinence. Although IUR is difficult and risky, proficient surgeons can perform the procedure safely and effectively.

Phosphatidylethanolamine (18:2e/18:2) may inhibit adipose tissue wasting in patients with cancer cachexia by increasing lysophosphatidic acid receptor 6.

BACKGROUND: Cancer associated cachexia is characterized by the significant loss of adipose tissue, leading to devastating weight loss and muscle wasting in the majority of cancer patients. The effects and underlying mechanisms of degradation metabolites on adipocytes in cachectic patients remain poorly understood. To address this knowledge gap, we conducted a comprehensive study combining lipidomic analysis of subcutaneous and visceral adipose tissue with transcriptomics data from the database to investigate the mechanisms of lipid regulation in adipocytes. METHODS: We collected subcutaneous and visceral adipose tissue samples from cachectic and noncachectic cancer patients. Lipidomic analysis was performed to identify differentially expressed lipids in both types of adipose tissue. Additionally, transcriptomics data from the GEO database were analyzed to explore gene expression patterns in adipocytes. Bioinformatics analysis was employed to determine the enrichment of differentially expressed genes in specific pathways. Furthermore, molecular docking studies were conducted to predict potential protein targets of specific lipids, with a focus on the PI3K-Akt signaling pathway. Western blot analysis was used to validate protein levels of the identified target gene, lysophosphatidic acid receptor 6 (LPAR6), in subcutaneous and visceral adipose tissue from cachectic and noncachectic patients. RESULTS: Significant lipid differences in subcutaneous and visceral adipose tissue between cachectic and noncachectic patients were identified by multivariate statistical analysis. Cachectic patients exhibited elevated Ceramides levels and reduced CerG2GNAc1 levels (P < 0.05). A total of 10 shared lipids correlated with weight loss and IL-6 levels, enriched in Sphingolipid metabolism, GPI-anchor biosynthesis, and Glyceropholipid metabolism pathways. LPAR6 expression was significantly elevated in both adipose tissues of cachectic patients (P < 0.05). Molecular docking analysis indicated strong binding of Phosphatidylethanolamine (PE) (18:2e/18:2) to LPAR6. CONCLUSIONS: Our findings suggest that specific lipids, including PE(18:2e/18:2), may mitigate adipose tissue wasting in cachexia by modulating the expression of LPAR6 through the PI3K-Akt signaling pathway. The identification of these potential targets and mechanisms provides a foundation for future investigations and therapeutic strategies to combat cachexia. By understanding the underlying lipid regulation in adipocytes, we aim to develop targeted interventions to ameliorate the devastating impact of cachexia on patient outcomes and quality of life. Nevertheless, further studies and validation are warranted to fully elucidate the intricate mechanisms involved and translate these findings into effective clinical interventions.

Elevated 18F-FDG uptake in subcutaneous adipose tissue correlates negatively with nutritional status and prognostic survival in cachexia patients with gastric cancer.

BACKGROUND: Browning of white adipose tissue is a crucial factor contributing to adipose loss in cachexia patients, detectable via 18F-Fluorodeoxyglucose (18F-FDG) uptake. The present study elucidates the clinical relevance of 18F-FDG uptake in the subcutaneous adipose tissue of gastric cancer patients, specifically focusing on adipose browning and its implications on patient clinical parameters and prognosis. METHODS: This investigation encompassed 770 gastric cancer patients, with PET-CT imaging and clinical data meticulously combined. The 18F-FDG uptake in subcutaneous adipose tissue at the third lumbar layer was quantified, and its correlation with clinical parameters, particularly those related to nutritional status and fat metabolism, was examined. Kaplan-Meier curves were subsequently employed to probe the relationship between 18F-FDG uptake and overall survival. RESULTS: Of the 770 gastric cancer patients, 252 exhibited cancer-associated cachexia, while 518 did not. Cachectic patients demonstrated elevated 18F-FDG uptake in subcutaneous adipose tissue relative to non-cachectic patients (P < 0.001). Increased 18F-FDG uptake was also correlated with reduced plasma concentrations of albumin, prealbumin, hemoglobin, platelets, cholesterol, apolipoprotein A, low-density lipoprotein, and elevated IL-6 concentrations (all P < 0.05). A significant inverse correlation was observed between 18F-FDG uptake and BMI, albumin, low-density lipoprotein, cholesterol, and apolipoprotein A (all P < 0.05). Patients with higher 18F-FDG uptake exhibited diminished overall survival rates compared to those with lower 18F-FDG uptake (P = 0.0065). Furthermore, 18F-FDG uptake in subcutaneous adipose tissue was an independent prognostic indicator in gastric cancer patients (P = 0.028). CONCLUSIONS: Browning of subcutaneous adipose tissue was markedly elevated in cachectic gastric cancer patients compared to non-cachectic counterparts. Increased 18F-FDG uptake in subcutaneous adipose tissue in cachectic gastric cancer patients was inversely correlated with nutritional status and survival prognosis.

Immune landscape and prognostic gene signatures in gastric cancer: implications for cachexia and clinical outcomes.

Cachexia, a debilitating condition that worsens patient outcomes, often accompanies gastric cancer, a malignancy that is prevalent worldwide. The extensive research explored the interconnected molecular and immune aspects of stomach cancer, with a particular emphasis on cachexia. By employing the GEO database, we identified genes that were expressed differently in gastric cancer patients suffering from cachexia. Following the analysis of Weighted Gene Co-expression Network (WGCNA), gene modules intricately linked to particular immune cells were revealed, indicating a significantly disrupted tumor microenvironment. A strong predictive model was developed, centered around key genes such as CAMK4, SLC37A2, and BCL11B. Surprisingly, this particular model not only showed better predictive abilities in comparison to conventional clinical factors but also exhibited a strong connection with increased infiltration of macrophages and T cells. These discoveries suggest the presence of an immune-suppressing and tumor-promoting atmosphere among individuals at a greater risk. Moreover, the utilization of Gene Set Enrichment Analysis (GSEA) established a connection between the genes linked to our risk score and vital immune-related pathways, thereby strengthening the pivotal involvement of immunity in the development of gastric cancer. To summarize, our discoveries provide a more profound comprehension of the molecular and immune mechanisms that support cachexia in gastric cancer, presenting a hopeful basis for upcoming advancements in treatment.

Sarcopenia and myosteatosis diagnostic tool for gastrointestinal cancer: creatinine to cystatin C ratio as evaluation marker.

OBJECTIVE: This study aimed to develop a simplified diagnostic tool for assessing sarcopenia and myosteatosis in gastrointestinal cancer patients, focusing on the creatinine to cystatin C ratio (CCR) as an evaluation marker. METHODS: 955 patients were split into training (n = 671) and validation (n = 284) cohorts. Using logistic regression, risk factors for sarcopenia and myosteatosis were identified. The predictive capacity of the developed model was examined. The association between CCR and muscle imaging parameters, along with its impact on clinical outcomes, was analyzed. RESULTS: No significant differences were observed in baseline traits between cohorts. CCR emerged as a significant risk factor for both sarcopenia and myosteatosis. Nomograms for diagnosing these conditions demonstrated strong predictive ability, with AUC values indicating high accuracy (sarcopenia AUC: 0.865-0.872; myosteatosis AUC: 0.848-0.849). The clinical utility of the nomograms was confirmed through decision curve analysis. CCR showed significant association with muscle imaging parameters and was a reliable indicator for assessing the risk of sarcopenia, myosteatosis, and cachexia. Moreover, CCR was able to differentiate between patient survival and disease progression rates. CONCLUSION: A diagnostic tool for sarcopenia and myosteatosis in gastrointestinal cancer patients was developed, with CCR being a pivotal biomarker for disease diagnosis and prognosis prediction.

The metabolite butyrate produced by gut microbiota inhibits cachexia-associated skeletal muscle atrophy by regulating intestinal barrier function and macrophage polarization.

OBJECTIVE: Cachexia, marked by muscle atrophy, poses substantial challenges for prevention and treatment. This study delves into the unclear role of butyrate, a gut microbiota metabolite, in cachexia by examining gut microbiota and short-chain fatty acid (SCFA) profiles in human and mouse fecal samples. METHODS: We analyzed cachexia-associated gut microbiota and SCFA profiles using 16S rRNA sequencing and metabolomic techniques. Mouse cachexia models were developed with C26 cells, and LPS was used to induce muscle cell atrophy in C2C12 cells. We evaluated butyrate's in vivo effects on intestinal health, muscle preservation, inflammation, and macrophage activity. In vitro studies focused on butyrate's influence on macrophage polarization and the subsequent effects on muscle cells. RESULTS: Both cachexia patients and mice exhibited gut microbiota imbalances, irregular butyrate concentrations, and a decline in butyrate-producing bacteria. In vivo tests showed that butyrate counteract cachexia-induced muscle atrophy by adjusting the Akt/mTOR/Foxo3a and Fbox32/Trim63 pathways. These butyrate also bolstered intestinal barrier integrity, minimized endotoxin migration, and mitigated oxidative stress. Furthermore, butyrate curtailed inflammation and macrophage penetration in muscles. In vitro experimental results demonstrate that butyrate inhibit macrophage polarization towards the M1 phenotype and promote polarization towards the M2 phenotype. Both M1 and M2 macrophages influence the aforementioned pathways and oxidative stress, participating in the regulation of muscle cell atrophy. CONCLUSION: Our study delineates the intricate interplay between gut microbiota dysbiosis, butyrate fluctuations, and cachexia progression. Butyrate not only reinforces the intestinal barrier but also orchestrates macrophage polarization, mitigating muscle atrophy and averting cachexia-induced muscle deterioration. Concurrently, the M1 and M2 macrophages play pivotal roles in modulating skeletal muscle cell atrophy. This highlights the potential of utilizing the gut-derived metabolite butyrate as a promising therapeutic approach for addressing cachexia-related issues.

Unraveling the gut microbiota and short-chain fatty acids characteristics and associations in a cancer cachexia mouse model.

OBJECTIVE: Cachexia is a common pathological condition in cancer patients, affecting prognosis and treatment outcomes. The relationship between cachexia and gut microbiota and short-chain fatty acids (SCFAs) remains understudied. This research aimed to establish a cachexia mouse model and explore the gut microbiota-SCFAs connection. The study provides fundamental insights into the regulatory mechanisms of cancer cachexia and potential therapeutic strategies. METHODS: A cachexia mouse model was created using C26 cells, with relevant indicators measured. Histological and immunohistochemical analyses assessed muscle structure and protein expression. ELISA was performed to detect the levels of IL-1ß, IL-6, TNF-α, and LPS in serum to evaluate inflammation.16S rDNA sequencing and GC-MS quantified gut microbiota and SCFAs. Bioinformatics analysis identified indicator species and explored microbiota-SCFAs correlations.ROC analysis was performed to assess the potential of gut microbiota and SCFAs in identifying cachexia. RESULTS: The cachexia mouse model exhibited weight loss, muscle atrophy, and elevated inflammatory factors. Gut microbiota in cachexia mice showed decreased diversity and imbalance. Fourteen bacterial genera were identified as potential cachexia indicators. Functional prediction indicated alterations in the functional composition of gut microbial communities in cachexia mice, particularly in carbohydrate and lipid metabolism pathways. Four SCFAs showed significant changes, potentially serving as diagnostic factors. Specific microbial taxa were positively or negatively correlated with changes in SCFAs, and these microbial taxa and differential SCFAs were also correlated with inflammatory cytokines. CONCLUSION: Our study uncovers the gut microbiota and SCFAs features in a cachexia mouse model, revealing novel correlations between them. These newfound insights into the interplay between cachexia, gut microbiota, and SCFAs provide a crucial foundation for understanding the mechanisms behind cancer cachexia development and potential therapeutic approaches.

Association between cardiovascular risk factors and atrial fibrillation.

Background: The most prevalent sustained arrhythmia in medical practice, atrial fibrillation (AF) is closely associated with a high risk of cardiovascular disease. Nevertheless, the risk of AF associated with cardiovascular risk factors has not been well elucidated. We pooled all published studies to provide a better depiction of the relationship among cardiovascular risk factors with AF. Methods: Studies were searched in the MEDLINE, Web of Science, and EMBASE databases since initiation until January 15, 2022. Prospective cohort studies assessing the relationship a minimum of single cardiovascular risk factors to AF incidence were included if they contained adequate data for obtaining relative risks (RR) and 95% confidence intervals (CI). Random-effects models were utilized to perform independent meta-analyses on each cardiovascular risk factor. PROSPERO registry number: CRD42022310882. Results: A total of 17,098,955 individuals and 738,843 incident cases were reported for data from 101 studies included in the analysis. In all, the risk of AF was 1.39 (95% CI, 1.30-1.49) for obesity, 1.27 (95% CI, 1.22-1.32) per 5 kg/m2 for increase in body mass index, 1.19 (95% CI, 1.10-1.28) for former smokers, 1.23 (95% CI, 1.09-1.38) for current smokers, 1.31 (95% CI, 1.23-1.39) for diabetes mellitus, 1.68 (95% CI, 1.51-1.87) for hypertension, and 1.12 (95% CI, 0.95-1.32) for dyslipidemia. Interpretation: Adverse cardiovascular risk factors correlate with an increased risk of AF, yet dyslipidemia does not increase the risk of AF in the general population, potentially providing new insights for AF screening strategies among patients with these risk factors. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, PROSPERO identifier (CRD42022310882).

Mitophagy-mediated inflammation and oxidative stress contribute to muscle wasting in cancer cachexia.

Cancer cachexia is commonly seen in patients with malignant tumors, which usually leads to poor life quality and negatively affects long-term prognosis and survival. Mitochondria dysfunction and enhanced autophagy are well-established to play an important role in skeletal muscle wasting. However, whether mitophagy is engaged in the pathogenesis of cancer cachexia requires further investigation. This study comprised a clinical study and animal experimentation. Clinical data such as CT images and laboratory results were obtained and analyzed. Then mice model of cancer cachexia and mitophagy inhibition were established. Data including skeletal muscle mass and function, mitochondria structure and function, inflammatory factors as well as ROS concentration. Mitophagy was enhanced in cancer cachexia patients with increased inflammatory factors. Greater disruption of skeletal muscle fiber and mitochondria structure were seen in cancer cachexia, with a higher level of inflammatory factors and ROS expression in skeletal muscle. Meanwhile, ATP production was undermined, indicating a close relationship with mitophagy, inflammation, and oxidative stress in the skeletal muscle of cancer cachexia mice models. In conclusion, mitophagy is activated in cancer cachexia and may play a role in skeletal muscle atrophy, and inflammation and oxidative stress might participate in mitophagy-related skeletal muscle injury.

Evaluation and management of body composition changes in cancer patients.

Wasting in cancer patients has long been recognized as a condition that adversely affects cancer patients' quality of life, treatment tolerance, and oncological outcomes. Historically, this condition was mainly evaluated by changes in body weight. However, this approach is not quite accurate because body weight is the overall change of all body compartments. Conditions such as edema and ascites can mask the severity of muscle and adipose tissue depletion. Changes in body composition assessment in cancer patients have historically been underappreciated because of the limited availability of measurement tools. As more evidence highlighting the importance of body composition has emerged, it is imperative to apply a more precise evaluation of nutritional status and a more targeted approach to provide nutritional support for cancer patients. In this review, we will discuss the modalities for evaluating body composition and how to manage body composition changes in cancer patients.

Development and application of the Cancer Cachexia Staging Index for the diagnosis and staging of cancer cachexia.

OBJECTIVE: The current tools for evaluating cancer cachexia are either too simple to reflect the far-reaching effects of cachexia or too complicated to be used in daily practice. This study aimed to develop a cancer cachexia staging index (CCSI) that is both practical and comprehensive. METHODS: Patients with gastrointestinal cancers were prospectively included in the study. Clinical data including weight change, body composition, systematic inflammation, nutrition, and function status were entered into regression models to determine the best variable combination as well as their respective cutoff values and score distribution in the CCSI. The CCSI's ability to predict outcomes and evaluate the consequences of cachexia for patients were then assessed. RESULTS: Clinical information and test results from 10 568 patients were used to develop a CCSI composed of subjective and objective measures. Subjective measures included body mass index-adjusted weight loss grade, rate of weight loss, inflammation (neutrophil-to-lymphocyte ratio and C-reactive protein level), and prealbumin level. Objective measures included appetite status and physical status. Patients were diagnosed and stratified by the total CCSI score into 3 subgroups: no cachexia, mild or moderate cachexia, and severe cachexia. The CCSI grades showed good survival discrimination and were independently predictive of survival in multivariate analysis. Compared with the traditional Fearon criteria for diagnosing cancer cachexia, the CCSI was more accurate in predicting postoperative complications (net reclassification index [NRI], 2.8%; 95% CI, 0.0104-0.0456%), death (NRI, 10.68%; 95% CI, 0.0429-0.1708%), recurrence (NRI, 3.71%; 95% CI, 0.0082-0.0685%), and overall survival (NRI, 8.5%; 95% CI, 0.0219-0.1533%). The CCSI also had better discriminative ability than Fearon criteria in discriminating nutritional status, body composition, and systematic inflammation in patients with or without cachexia. A more detailed evaluation of a randomly selected subgroup (n = 1566) showed that CCSI grades had good discrimination of appetite and food intake status, physical function and muscle strength, symptom burden, and quality of life. CONCLUSIONS: The CCSI is a comprehensive and practical evaluation tool for cancer cachexia. It can predict postoperative outcomes and survival. The CCSI stages showed good discrimination when evaluating patients with cancer in terms of nutritional status, physical function, systematic inflammation, body composition, symptom burden, and quality of life.

Case Report: Step-by-step procedures for total intracorporeal laparoscopic kidney autotransplantation in a patient with distal high-risk upper tract urothelial carcinoma.

A 47-year-old man presented to the emergency department with right abdominal pain and a new onset of painless haematuria two weeks earlier. Urine cytology test results suggested urothelial carcinoma. Computed tomography urography (CTU) showed a filling defect in the lower right ureter with right hydronephrosis. Lymphadenopathy and any signs of metastatic disease were absent on CTU. Cystoscopy appeared normal. Creatinine level was also normal before surgery. After the treatment options were discussed, the patient chose to undergo 3D total intracorporeal laparoscopic kidney autotransplantation, bladder cuff excision, and segmental resection of the proximal two-thirds of the ureter based on the membrane anatomy concept. After more than one year of follow-up, the patient was in good health and showed no signs of haematuria. Surveillance cystoscopy and CTU examination showed no evidence of disease recurrence. Therefore, it is reasonable to assume that kidney-sparing surgery may be considered for carefully selected patients with high-grade upper tract urothelial carcinoma.

Tumor-derived semaphorin 3D promoting cancer cachexia via regulating hypothalamic pro-opiomelanocortin neurons.

Cachexia is very common in cancer patients and predicts a poor prognosis; however, the molecular basis for progress in these individuals remains unclear, especially the effect of tumors on the hypothalamus energy regulation center. To investigate the regulatory pathway of tumors associated with hypothalamic pro-opiomelanocortin (POMC) neurons known as appetite-inhibiting neurons, we conducted observations both on patients and mice models. Results showed that the highly expressed exocrine semaphorin 3D (SEMA3D) both in cachexia patients and mice was positively related to the expression of POMC and its proteolytic peptide. Compared with the control group, mice inoculated with the SEMA3D-knockout C26 cell line decreased the activity of POMC neurons resulting in a 1.3-fold increase in food intake, a 22.2% increase in body weight, and reduced skeletal muscle and fat catabolism. The effect of SEMA3D on cachexia progression can be partially alleviated by knocking-down POMC expression in the brain. In terms of mechanism, SEMA3D enhances the activity of POMC neurons by activating the expression of NRP2 (membrane receptor) and PlxnD1 (intracellular receptor). Our research revealed the overexpression of SEMA3D in tumors works as an activator of POMC neurons, which may play a vital role in suppressing appetite and promoting catabolic metabolism.

Abdominal fat and muscle distributions in different stages of colorectal cancer.

BACKGROUND: The purpose of this study is to explore the difference of abdominal fat and muscle composition, especially subcutaneous and visceral adipose tissue, in different stages of colorectal cancer (CRC). MATERIALS AND METHODS: Patients were divided into 4 groups: healthy controls (patients without colorectal polyp), polyp group (patients with colorectal polyp), cancer group (CRC patients without cachexia), and cachexia group (CRC patients with cachexia). Skeletal muscle (SM), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and intermuscular adipose tissue (IMAT) were assessed at the third lumbar level on computed tomography images obtained within 30 days before colonoscopy or surgery. One-way ANOVA and linear regression were used to analyze the difference of abdominal fat and muscle composition in different stages of CRC. RESULTS: A total of 1513 patients were divided into healthy controls, polyp group, cancer group, and cachexia group, respectively. In the development of CRC from normal mucosa to polyp and cancer, the VAT area of the polyp group was significantly higher than that of the healthy controls both in male (156.32 ± 69.71 cm2 vs. 141.97 ± 79.40 cm2, P = 0.014) and female patients (108.69 ± 53.95 cm2 vs. 96.28 ± 46.70 cm2, P = 0.044). However, no significant differences were observed of SAT area between polyp group and healthy controls in both sexes. SAT area decreased significantly in the male cancer group compared with the polyp group (111.16 ± 46.98 cm2 vs. 126.40 ± 43.52 cm2, P = 0.001), while no such change was observed in female patients. When compared with healthy controls, the SM, IMAT, SAT, and VAT areas of cachexia group was significantly decreased by 9.25 cm2 (95% CI: 5.39-13.11 cm2, P < 0.001), 1.93 cm2 (95% CI: 0.54-3.32 cm2, P = 0.001), 28.84 cm2 (95% CI: 17.84-39.83 cm2, P < 0.001), and 31.31 cm2 (95% CI: 18.12-44.51 cm2, P < 0.001) after adjusting for age and gender. CONCLUSION: Abdominal fat and muscle composition, especially SAT and VAT, was differently distributed in different stages of CRC. It is necessary to pay attention to the different roles of subcutaneous and visceral adipose tissue in the development of CRC.

Development and validation of a cancer cachexia risk score for digestive tract cancer patients before abdominal surgery.

BACKGROUND: Cancer cachexia is prevalent in digestive tract cancer patients and has significant impacts on prognosis; it is vital to identify individuals who are at risk of cancer cachexia to allow for appropriate evaluation and treatment. This study evaluated whether digestive tract cancer patients with a risk of cancer cachexia and who had a risk of adverse survival could be identified before abdominal surgery. METHODS: This large-scale cohort study involved patients who underwent abdominal surgery between January 2015 and December 2020 to treat digestive tract cancer. Participants were allocated to the development cohort, the validation cohort, or the application cohort. Univariate and multivariate analyses of the development cohort were performed to detect distinct risk variables for cancer cachexia to create a cancer cachexia risk score. The performance of the risk score across all the three cohorts was assessed through calculating the area under the receiver operating characteristic curve (AUC), as well as calibration and decision curves. We tested how well the score predicted survival outcomes in the application cohort. RESULTS: A total of 16 264 patients (median 64 years of age; 65.9% male) were included, with 8743 in the development cohort, 5828 in the validation cohort, and 1693 in the application cohort. Seven variables were identified as independent predictive factors and were included in the cancer cachexia risk score: cancer site, cancer stage, time from symptom onset to hospitalization, appetite loss, body mass index, skeletal muscle index, and neutrophil-lymphocyte ratio. The risk score predicting cancer cachexia owns a good discrimination, with the mean AUC of 0.760 (P < 0.001) in the development cohort, 0.743 (P < 0.001) in the validation cohort, and 0.751 (P < 0.001) in the application cohort, respectively, and had an excellent calibration (all P > 0.05). The decision curve analysis revealed net benefits of the risk score across a range of risk thresholds in the three cohorts. In the application cohort, compared with the high-risk group, the low-risk group experienced significantly longer overall survival [hazard ratio (HR) 2.887, P < 0.001] as well as relapse-free survival (HR 1.482, P = 0.01). CONCLUSIONS: The cancer cachexia risk score constructed and validated demonstrated good performance in identifying those digestive tract cancer patients before abdominal surgery at a higher risk of cancer cachexia and unfavourable survival. This risk score can help clinicians to enhance their capabilities to screen for cancer cachexia, assess patient prognosis, and strengthen early decision-making on targeted approaches to attune cancer cachexia for digestive tract cancer patients before abdominal surgery.

AKG induces cell apoptosis by inducing reactive oxygen species-mediated endoplasmic reticulum stress and by suppressing PI3K/AKT/mTOR-mediated autophagy in renal cell carcinoma.

BACKGROUND: Alpha-ketoglutarate (AKG) or 2-oxoglutarate is a key substance in the tricarboxylic acid cycle (TCA) and has been known to play an important role in cancerogenesis and tumor progression. Renal cell carcinoma (RCC) is the most common type of kidney cancer, and it has a high mortality rate. Autophagy is a phenomenon of self-digestion, and its significance in tumor genesis and progression remains debatable. However, the mechanisms underlying how AKG regulates autophagy in RCC remain unknown. Thus, the purpose of this study was to assess the therapeutic efficacy of AKG and its molecular mechanisms. METHODS: RCC cell lines 786O and ACHN were treated with varying doses of AKG for 24 h. CCK-8, Transwell, and scratch wound healing assays were utilized to evaluate the role of AKG in RCC cells. Autophagy protein and PI3K/AKT/mTOR pathway protein levels were analyzed by Western blot. RESULTS: AKG inhibited the proliferation of RCC cells 786O and ACHN in a dose-dependent manner according to the CCK-8 assay. In addition, flow cytometry and Western blot analysis revealed that AKG dose-dependently triggered apoptosis and autophagy in RCC cells. By promoting cell apoptosis and autophagy, AKG dramatically suppressed tumor growth. Mechanistically, AKG induces autophagy by promoting ROS generation and inhibiting the PI3K/AKT/mTOR pathway. CONCLUSIONS: The anti-tumor effect of AKG promotes autophagy in renal cancer cells via mediating ROS-PI3K/Akt/mTOR, and may be used as a potential anticancer drug for kidney cancer.

Nerve-Sparing Laparoscopic Cystoprostatectomy Based on Inferior Hypogastric Plexus Dissection: Our Initial Experience.

INTRODUCTION: The aim of this study was to implement our technique for the initial dissection of the inferior hypogastric plexus and protection of the autonomic nerve supply to the corpora cavernosa in laparoscopic radical cystoprostatectomy with an orthotopic ileal neobladder and report the initial outcomes. METHODS: Eleven normally potent patients with preoperative cT2N0 bladder cancer who underwent bilateral nerve-sparing laparoscopic cystoprostatectomy performed by the same surgeon were selected from May 2018 to September 2020. In this procedure, the anterior part of the inferior hypogastric plexus was dissected first between the prehypogastric nerve fascia and rectal proper fascia medial to the distal ureter. Then the Denonvilliers' fascia and the nerves around the prostate were preserved according to current intrafascial principles. The preliminary operative, oncologic, and functional results are presented. RESULTS: The median follow-up duration was 18 months. We observed early and late complications in 5 patients, but none exceeded grade III. Of the 11 patients, ten gained daytime continence (90.9%), and 8 (72.7%) showed nocturnal continence at the last follow-up. Regarding postoperative potency, 10 of the 11 patients (90.9%) remained potent with or without oral medications, excluding one who had partial tumescence but did not follow our recommendations regarding medication use. No local recurrence or positive surgical margins were noted. CONCLUSION: In addition to emphasizing our cavernosal nerve-sparing procedure, this report on the precise dissection and protection of the inferior hypogastric plexus could be of clinical significance, providing potentially ideal short-term functional results.

Loss of body weight and skeletal muscle negatively affect postoperative outcomes after major abdominal surgery in geriatric patients with cancer.

OBJECTIVES: Malnutrition characterized by the involuntary loss of body weight and skeletal muscle can be the result of both aging and malignancy. As a result, geriatric patients could face an increased nutritional risk. This study aimed to investigate the nutritional and functional status of geriatric patients and their association with postoperative complications. METHODS: Patients who underwent abdominal surgery for digestive cancer in our center between January 2020 and August 2021 were included in the study. Computed tomography scans were collected to evaluate muscle mass and density. Changes in body weight, muscle strength, physical performances, nutritional risk, and status were evaluated upon admission. Postoperative outcomes collected included postoperative length of stay, complications, and 30-d readmission. RESULTS: A total of 1513 patients were included for the analysis. Of these, 72.8% were at risk for malnutrition (70.3% in the non-geriatric group and 75.4% in the geriatric group; P = 0.031), and 28.9% had malnutrition according to the Subjective Global Assessment (26.0% in the non-geriatric group and 31.8% in the geriatric group; P = 0.016). Compared with younger patients, geriatric patients have decreased muscle mass (skeletal muscle index, 44.8 versus 47.4; P < 0.001) and skeletal muscle density. Significant weight loss and loss of skeletal muscle occurred concurrently in 18.8% of the patients and were more frequent in the geriatric group (22.3% versus 14.7%; P < 0.001). In multivariate analysis, an age of 65 y or older (odds ratio [OR], 1.41; 95% confidence interval [CI], 1.07-1.86; P = 0.014), a serum albumin level ≤4.11 g/dL (OR, 1.35; 95% CI, 1.03-1.77; P = 0.03), skeletal muscle loss (OR, 1.69; 95% CI, 1.28-2.24; P < 0.001), declined functional status (OR, 1.5; 95% CI, 1.14-1.98; P = 0.004), systematic inflammation (OR, 1.71; 95% CI, 1.09-2.8; P = 0.026), and significant weight loss (OR, 1.4; 95% CI, 1.06-2.85; P = 0.017) were independent predictors of overall postoperative complications. Although there was a trend of interactions between advanced age, skeletal muscle loss, and significant weight loss, multivariate analysis showed none of the interactions were significantly predictive of overall postoperative complications. CONCLUSIONS: Geriatric patients are at greater risk for malnutrition. Their declined nutritional and functional status together with advanced age could increase the risk for postoperative complications. Nutrition evaluation should be part of the preoperative workup, and timely interventions should be initiated if needed, especially in geriatric patients.

Analysis of different adipose depot gene expression in cachectic patients with gastric cancer.

PURPOSE: This study aimed to identify the differentially expressed genes (DEGs) that contributed to the different amount of fat loss between subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) among cachectic patients. METHODS: RNA sequencing was performed and bioinformatic tools were utilized to analyze the biological functions and construct regulation networks of DEGs. We presumed that iroquois homeobox 1 (IRX1) to be a hub gene and analyzed its clinical significance. Mouse model of cancer cachexia was established and differences between SAT and VAT were compared. The function of IRX1 on lipid metabolism was clarified by Oil Red O staining, qRT-PCR, and Western blotting in adipocytes. RESULTS: A total of 455 DEGs were screened between SAT and VAT in cachectic patients. Several hub genes were selected and IRX1 was presumed to contribute to the pathological difference between SAT and VAT in cancer cachexia. Patients with higher expression of IRX1 in SAT than VAT revealed significantly higher weight loss, IL-6 and TNF-α, as well as lower BMI, SAT, and VAT area. IRX1 expression in SAT was negatively correlated with SAT area. In cachectic mice, the expression of IRX1 in SAT was significantly higher than that in VAT. The inhibition effect on adipogenesis exerted by IRX1 was also proved in vitro. CONCLUSION: These data supported that DEGs contribute to the different degrees of fat loss among adipose depots in cachectic patients. IRX1 in SAT promoted fat loss by inhibiting adipocyte differentiation and adipogenesis.