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Objective: Estradiol (E(2)) is known to modulate insulin sensitivity and, consequently, glucose homeostasis. Resveratrol (RSV), an agonist of estrogen receptor (ER), has exerted antihyperglycemic effects in streptozotocin-induced type 1 diabetic rats in our previous study and was also shown to improve insulin resistance in other reports. However, it remains unknown whether activation of ER is involved in the metabolic effects of RSV via insulin-dependent and -independent mechanisms.Research Design and Methods: Male Sprague-Dawley rats were given a high cholesterol-fructose (HCF) diet for 15 weeks and were treated with RSV for either 15 days or 15 weeks.Results: Here, we show that RSV shifts the metabolic characteristics of rats on an HCF diet toward those of rats on a standard diet. RSV treatment increased insulin-stimulated whole-body glucose uptake and steady-state glucose uptake of soleus muscle and liver in HCF-fed rats as well as enhanced membrane trafficking activity of GLUT4 and increased phosphorylation of insulin receptor in insulin-resistant soleus muscles. Interestingly, the phosphorylated ER level in insulin-resistant soleus muscle was significantly elevated in rats with RSV treatment in both basal and euglycemic-hyperinsulinemic conditions. RSV exerted an insulin-like stimulatory effect on isolated soleus muscle, epididymal fat and hepatic tissue, and C2C12 myotubes. The RSV-stimulated glucose uptake in C2C12 myotubes was dependent on extracellular signal-related kinase/p38 (early phase, 1 h) and p38/phosphoinositide 3-kinase (late phase, 14 h) activation. Inhibition of ER abrogated RSV-induced glucose uptake in both early and late phases.Conclusions: Collectively, these results indicate that ER is a key regulator in RSV-stimulating insulin-dependent and -independent glucose uptake, which might account for the protective effects of RSV on diet-induced insulin resistance syndrome. [ABSTRACT FROM AUTHOR]

Obesity-induced muscle atrophy leads to physical impairment and metabolic dysfunction, which are risky for older adults. The activity of pyruvate dehydrogenase (PDH), a critical regulator of glucose metabolism, is reduced in obesity. Additionally, PDH activator dichloroacetate (DCA) improves metabolic dysfunction. However, the effects of PDH activation on skeletal muscles in obesity remain unclear. Thus, this study aimed to evaluate the effects of PDH activation by DCA treatment on obesity-induced muscle atrophy in vitro and in vivo and elucidate the possible underlying mechanisms. Results showed that PDH activation by DCA treatment ameliorated muscle loss, decreased the cross-sectional area, and reduced grip strength in C57BL/6 mice fed a high-fat diet (HFD). Elevation of muscle atrophic factors atrogin-1 and muscle RING-finger protein-1 (MuRF-1) and autophagy factors LC3BII and p62 were abrogated by DCA treatment in palmitate-treated C2C12 myotubes and in the skeletal muscles of HFD-fed mice. Moreover, p-Akt, p-FoxO1, and p-FoxO3 protein levels were reduced and p-NF-κB p65 and p-p38 MAPK protein levels were elevated in palmitate-treated C2C12 myotubes, which were restored by DCA treatment. However, the protective effects of DCA treatment against myotube atrophy were reversed by treatment with Akt inhibitor MK2206. Taken together, our study demonstrated that PDH activation by DCA treatment can alleviate obesity-induced muscle atrophy. It may serve as a basis for developing novel strategies to prevent obesity-associated muscle loss., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Colorectal cancer (CRC) represents a significant health burden worldwide, with a notable increase in early-onset colorectal cancer (EOCRC) cases, defined as those diagnosed before the age of 50 years., Materials and Methods: Using data from Taiwan's national cancer registry and a retrospective cohort from Chang Gung Memorial Hospital, this study analyzed CRC cases diagnosed between 2008 and 2019. The analysis compared the EOCRC and late-onset CRC (LOCRC) groups in terms of clinicopathological characteristics, pre-diagnostic symptoms, and survival outcomes., Results: The analysis revealed a continuous increase in the annual incidence of EOCRC, with colon cancer and rectal cancer rising by 3.2 % and 3.3 %, respectively. Patients with EOCRC presented with more aggressive disease characteristics, such as signet-ring cell adenocarcinoma, mucinous adenocarcinoma, and poorly differentiated grade. Advanced stages at diagnosis, stages III and IV, were more common with EOCRC (62.4 %) than with LOCRC (50.3 %). Patients with EOCRC reported rectal bleeding, changes in bowel habits, and abdominal pain more frequently than those in the LOCRC group. There is a strong association between stool-related symptoms and left-sided CRC. Despite similar surgical outcomes, the 5-year cancer-specific survival rate of patients with stage IV EOCRC was significantly lower than that of patients with LOCRC (32.8 % vs. 51.9 %, p = 0.012)., Conclusion: This study highlights a persistent rise in the incidence of EOCRC, with patients presenting with more aggressive disease and experiencing inferior survival. These findings underscore the importance of heightened awareness and early detection strategies for CRC, especially in younger populations, to improve the prognosis., Competing Interests: Declaration of competing interest The authors have no competing interests to declare that are relevant to the content of this article., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Conventional minimally invasive surgery requires mini-laparotomy to extract the pathological specimen. However, by using a natural orifice as the delivery route, natural orifice specimen extraction (NOSE) surgery avoids the need for a large incision. This study analyzed the short-term outcome of NOSE compared with conventional mini-laparotomy (CL) for colorectal cancer surgery., Methods: We conducted a retrospective analysis of 1,189 patients who underwent surgery for primary colorectal cancer between the cecum and upper rectum. Propensity score analyses were applied to the NOSE and CL groups in a 1:1 matched cohort., Results: After propensity score matching, each group included 201 patients. The NOSE group and CL group did not differ significantly in terms of baseline characteristics. Postoperative morbidity and mortality rates were comparable. Compared with the CL group, the NOSE group experienced a shorter time to first flatus (1.6 ± 0.8 vs. 2.0 ± 1.2 days, p < 0.001), first stool (2.7 ± 1.5 vs. 4.1 ± 1.9, p < 0.001), liquid diet (2.3 ± 1.3 vs. 3.6 ± 1.8 days, p < 0.001), soft diet (3.9 ± 2.0 vs. 5.2 ± 1.9 days, p < 0.001) and a shorter hospital stay (5.1 ± 3.5 vs. 7.4 ± 4.8 days, p < 0.001). The NOSE group exhibited lower mean pain intensity and lower highest pain intensity on postoperative days 1, 2, and 3., Conclusion: NOSE has several advantages over conventional mini-laparotomy following minimally invasive surgery for colon cancer. These advantages include reduced time to oral intake, shorter hospital stays, and less postoperative pain. NOSE can be adopted and applied to highly selective patients without additional risk of short-term complications., (© 2024. The Author(s).)

Purpose: Although minimally invasive colorectal surgery has been proven to have a shorter hospital stay and fewer short-term complications than open surgery, the advantages of laparoscopic surgery for colorectal cancer patients undergoing hemodialysis have not been validated. This study compared the outcomes of open and laparoscopic approaches in these patients., Materials and Methods: Between January 2007 and December 2020, we retrospectively analyzed the clinical data of 78 hemodialysis patients who underwent curative-intent, elective colorectal surgery. Patients were divided into two groups according to the surgical method: open and laparoscopic., Results: Postoperative morbidity (p = 0.480) and mortality (p = 0.598) rates and length of hospital stay (28.8 vs. 27.5 days, p = 0.830) were similar between the groups. However, laparoscopic surgery patients had a shorter return to clear liquid, full liquid, or soft food time than open surgery patients (p < 0.001, p = 0.007, and p = 0.002, respectively). Disease-free survival and long-term cancer-specific survival rates were also similar between the two groups (p = 0.353 and p = 0.201, respectively). Multivariate analysis revealed that intraoperative blood transfusion was a risk factor for severe complications and mortality (OR 6.055; p = 0.046), and the odds ratio (OR) of laparoscopic surgery was not significantly greater than that of open surgery (OR = 0.537, p = 0.337)., Conclusion: Although laparoscopic surgery did not result in hemodialysis patients having a shorter postoperative hospital stay, our results suggest that the laparoscopic approach is as safe as open surgery for hemodialysis patients and may be beneficial for shortening the return time to food intake., (© 2024. The Author(s).)

Vulnerable atherosclerotic plaque rupture, the leading cause of fatal atherothrombotic events, is associated with an increased risk of mortality worldwide. Peroxisome proliferator-activated receptor delta (PPARδ) has been shown to modulate vascular smooth muscle cell (SMC) phenotypic switching, and, hence, atherosclerotic plaque stability. Melatonin reportedly plays a beneficial role in cardiovascular diseases; however, the mechanisms underlying improvements in atherosclerotic plaque vulnerability remain unknown. In this study, we assessed the role of melatonin in regulating SMC phenotypic switching and its consequential contribution to the amelioration of atherosclerotic plaque vulnerability and explored the mechanisms underlying this process. We analyzed features of atherosclerotic plaque vulnerability and markers of SMC phenotypic transition in high-cholesterol diet (HCD)-fed apolipoprotein E knockout (ApoE -/- ) mice and human aortic SMCs (HASMCs). Melatonin reduced atherosclerotic plaque size and necrotic core area while enhancing collagen content, fibrous cap thickness, and smooth muscle alpha-actin positive cell coverage on the plaque cap, which are all known phenotypic characteristics of vulnerable plaques. In atherosclerotic lesions, melatonin significantly decreased the synthetic SMC phenotype and KLF4 expression and increased the expression of PPARδ, but not PPARα and PPARγ, in HCD-fed ApoE -/- mice. These results were subsequently confirmed in the melatonin-treated HASMCs. Further analysis using PPARδ silencing and immunoprecipitation assays revealed that PPARδ plays a role in the melatonin-induced SMC phenotype switching from synthetic to contractile. Collectively, we provided the first evidence that melatonin mediates its protective effect against plaque destabilization by enhancing PPARδ-mediated SMC phenotypic switching, thereby indicating the potential of melatonin in treating atherosclerosis., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Colorectal cancer (CRC) presents with varying prognoses, and identifying factors for predicting metastasis and outcomes is crucial. Perineural invasion (PNI) is a debated prognostic factor for CRC, particularly in stage I-III patients, but its role in guiding adjuvant chemotherapy for node-positive colon cancer remains uncertain., Methods: We conducted a single-center study using data from the Colorectal Section Tumor Registry Database at Chang Gung Memorial Hospital, Taiwan. This prospective study involved 3,327 CRC patients, 1,536 of whom were eligible after application of the exclusion criteria, to investigate the prognostic value of PNI in stage I-III patients and its predictive value for node-positive/negative cancer patients receiving adjuvant chemotherapy. Propensity score matching (PSM) was used to minimize selection bias, and follow-up was performed with standardized procedures., Results: PNI-positive (PNI+) tumors were associated with higher preoperative CEA levels and more frequent adjuvant chemotherapy. After PSM, PNI + tumors were associated with marginally significantly lower 5-year disease-free survival (DFS) and significantly lower overall survival (OS) rates in stages III CRC. However, no significant differences were observed in stages I and II. Subgroup analysis showed that among PNI + tumors, only poorly differentiated tumors had higher odds of recurrence. PNI did not predict outcomes in node-negative colon cancer. Adjuvant chemotherapy benefited PNI + patients with node-positive but not those with node-negative disease., Conclusions: Our study indicates that PNI is an independent poor prognostic factor in stage III colon cancer but does not predict outcomes in node-negative disease. Given the potential adverse effects of adjuvant chemotherapy, our findings discourage its use in node-negative colon cancer when PNI is present., (© 2024. The Author(s).)

Background: The primary treatment for non-metastatic rectal cancer is curative resection. However, sphincter-preserving surgery may lead to complications. This study aims to develop a predictive model for stoma non-closure in rectal cancer patients who underwent curative-intent low anterior resection., Methods: Consecutive patients diagnosed with non-metastatic rectal cancer between January 2005 and December 2017, who underwent low anterior resection, were retrospectively included in the Chang Gung Memorial Foundation Institutional Review Board. A comprehensive evaluation and analysis of potential risk factors linked to stoma non-closure were performed., Results: Out of 956 patients with temporary stomas, 10.3% (n = 103) experienced non-closure primarily due to cancer recurrence and anastomosis-related issues. Through multivariate analysis, several preoperative risk factors significantly associated with stoma non-closure were identified, including advanced age, anastomotic leakage, positive nodal status, high preoperative CEA levels, lower rectal cancer presence, margin involvement, and an eGFR below 30 mL/min/1.73m2. A risk assessment model achieved an AUC of 0.724, with a cutoff of 2.5, 84.5% sensitivity, and 51.4% specificity. Importantly, the non-closure rate could rise to 16.6% when more than two risk factors were present, starkly contrasting the 3.7% non-closure rate observed in cases with a risk score of 2 or below (p < 0.001)., Conclusion: Prognostic risk factors associated with the non-closure of a temporary stoma include advanced age, symptomatic anastomotic leakage, nodal status, high CEA levels, margin involvement, and an eGFR below 30 mL/min/1.73m2. Hence, it is crucial for surgeons to evaluate these factors and provide patients with a comprehensive prognosis before undergoing surgical intervention., (© 2024. The Author(s).)

Purpose: Low anterior resection syndrome (LARS) has had many impacts on the lives of patients and substantial differences in emotional and social functions. The aim of this study was to investigate the correlation analysis of different personality traits in rectal cancer patients with LARS after undergoing curative surgery., Methods: This study was designed as a prospective cohort study. The inclusion criteria included (1) participants diagnosed with rectal cancer who underwent surgical resection of malignant tumors and (2) ECOG 0-1. The primary outcome was the correlation between different personality traits and low anterior resection syndrome in rectal cancer patients after radical surgery. Low anterior resection syndrome incidence rates were estimated by questionnaires and personality groups by the Type A and Type D Scale-14 Personality Inventory., Results: For all 161 participants in this study, the presence of a tumor at the lower anal verge and the receipt of neoadjuvant CCRT had a statistically significant positive correlation with the LARS score at 1 month, 6 months, and 1 year (Pearson correlation coefficient = -0.283, -0.374, and - 0.205, respectively), with a p value of less than 0.05. Personalities with Type A, Type D, and Type D-SI scores had a statistically significant positive correlation with LARS score at 1 month (Pearson correlation coefficient = 0.172, 0.162, and 0,164, p value = 0.03, 0.04, and 0.04)., Conclusion: Type A and Type D personalities are highly linked to LARS. Personalized support approaches can ultimately assist rectal cancer patients in overcoming difficulties after surgery and recovery and enhance their functional outcomes., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The skin is the largest organ in the human body and serves as a barrier for protective, immune, and sensory functions. Continuous and permanent exposure to the external environment results in different levels of skin and extracellular matrix damage. During skin wound healing, the use of good dressings and addition of growth factors to the wound site can effectively modulate the rate of wound healing. A dressing containing bioactive substances can absorb wound exudates and reduce adhesion between the wound and dressing, whereas growth factors, cytokines, and signaling factors can promote cell motility and proliferation., Aim and Objectives: We prepared a functional wound dressing by combining platelet-rich plasma (PRP) and zwitterionic hydrogels. Functional wound dressings are rich in various naturally occurring growth factors that can effectively promote the healing process in various types of tissues and absorb wound exudates to reduce adhesion between wounds and dressings. Furthermore, PRP-incorporated zwitterionic hydrogels have been used to repair full-thickness wounds in Sprague-Dawley rats with diabetes (DM SD)., Materials and Methods: Fibroblasts and keratinocytes were cultured with PRP, zwitterionic hydrogels, and PRP-incorporated zwitterionic hydrogels to assess cell proliferation and specific gene expression. Furthermore, PRP-incorporated zwitterionic hydrogels were used to repair full-thickness skin defects in DM SD rats., Results: The swelling ratio of hydrogel, hydrogel + PRP1000 (108 platelets/mL), and hydrogel + PRP1000 (109 platelets/mL) groups were similar (~07.71% ± 1.396%, 700.17% ± 1.901%, 687.48% ± 4.661%, respectively) at 144 hours. The tensile strength and Young modulus of the hydrogel and hydrogel + PRP10000 groups were not significantly different. High concentrations of PRP (approximately 108 and 109 platelets/mL) effectively promoted the proliferation of fibroblasts and keratinocytes. The zwitterionic hydrogels were not cytotoxic to any cell type. High PRP concentration-incorporated zwitterionic hydrogels increased the rate of cell proliferation and significantly increased the expression of characteristic genes such as collagen, fibronectin, involucrin, and keratin. Subsequently, zwitterionic hydrogels with high PRP concentrations were used to repair full-thickness skin defects in DM SD rats, and a wound healing rate of more than 90% was recorded on day 12., Conclusions: PRP contains high concentrations of growth factors that promote cell viability, enhance specific gene expression, and have a high medical value in cell therapy. Zwitterionic hydrogels have a 3-dimensional interconnected microporous structure and can resist cell adhesion without causing cytotoxicity. Platelet-rich plasma-incorporated zwitterionic hydrogels further enhance the cellular properties and provide an effective therapeutic option for wound healing., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The relationship between plasma glial cell-derived neurotrophic factor (GDNF) or insulin-like growth factor-1 (IGF-1) levels and age-related hearing impairment (ARHI) has not been reported in humans. By cross-sectional design, 268 subjects older than 33, with normal cognitive function and normal or symmetric sensorineural hearing loss, were selected randomly. Multivariate linear regression analysis was performed to test the impact of the plasma GDNF or IGF-1 level on the pure tone threshold of low frequencies (PTA-low) and high frequencies (PTA-high), respectively. Results showed that plasma GDNF and IGF-1 levels decreased with age without statistical significance. Multivariate linear regression analysis showed that GDNF or IGF-1 levels were not significantly correlated with PTA-low or PTA-high after adjusting age, gender, body mass index, systemic diseases, habits, and noise exposure. In conclusion, plasma GDNF or IGF-1 levels were not associated with the severity of ARHI in humans. However, these findings did not support the roles of GDNF or IGF-1 genotypes on hearing., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Cysteine-cysteine chemokine receptor type 5 (CCR5) is thought to play an important role in the trafficking of lymphoid cells but has recently also been associated with AMPK signaling pathways that are implicated in energy metabolism in skeletal muscle. We hypothesized that genetic deletions of CCR5 would alter mitochondria content and exercise performance in mice. CCR5 -/- and wild-type mice with the same genetic background were subjected to endurance exercise and grip strength tests. The soleus muscle was stained with immunofluorescence for myosin heavy chain 7 (MYH7) and succinate dehydrogenase (SDH) analysis as well as the expression of genes associated with muscle atrophy and mitochondrial oxidative phosphorylation were measured using qPCR. Although there were no differences in the weight of the soleus muscle between the CCR5 -/- group and the wild-type mice, the CCR5 -/- mice showed the following muscular dysfunctions: (i) decreased MYH7 percentage and cross-section area, (ii) higher myostatin and atrogin-1 mRNA levels, (iii) dropped expression of mitochondrial DNA-encoded electron respiratory chain genes (cytochrome B, cytochrome c oxidase subunit III, and ATP synthase subunit 6) as well as mitochondrial generation genes (PPARγ and PGC-1α), and (iv) lower SDH activity and exercise performance when compared with wild-type mice. In addition, genes associated with mitochondrial biogenesis (PGC-1α, PPARγ, and MFN2) and mitochondrial complex (ND4 and Cytb) were upregulated when the skeletal muscle cell line C2C12 was exposed to cysteine-cysteine chemokine ligand 4 (a ligand of CCR5) in vitro. These findings suggested that attenuation of endurance exercise performance is related to the loss of mitochondrial content and lower SDH activity of soleus muscle in CCR5 knockout mice. The present study provides evidence indicating that the chemokine receptor CCR5 might modulate the skeletal muscle metabolic energy system during exercise., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Purpose: Vascular smooth muscle cells (SMCs) undergo phenotypic switching during sustained inflammation, contributing to an unfavourable atherosclerotic plaque phenotype. PPARδ plays an important role in regulating SMC functions; however, its role in atherosclerotic plaque vulnerability remains unclear. Here, we explored the pathological roles of PPARδ in atherosclerotic plaque vulnerability in severe atherosclerosis and elucidated the underlying mechanisms., Experimental Approach: Plasma levels of PPARδ were measured in patients with acute coronary syndrome (ACS) and stable angina (SA). SMC contractile and synthetic phenotypic markers, endoplasmic reticulum (ER) stress, and features of atherosclerotic plaque vulnerability were analysed for the brachiocephalic artery of apolipoprotein E-knockout (ApoE -/- ) mice, fed a high-cholesterol diet (HCD) and treated with or without the PPARδ agonist GW501516. In vitro, the role of PPARδ was elucidated using human aortic SMCs (HASMCs)., Key Results: Patients with ACS had significantly lower plasma PPARδ levels than those with SA. GW501516 reduced atherosclerotic plaque vulnerability, a synthetic SMC phenotype, ER stress markers, and NLRP3 inflammasome expression in HCD-fed ApoE -/- mice. ER stress suppressed PPARδ expression in HASMCs. PPARδ activation inhibited ER stress-induced synthetic phenotype development, ER stress-NLRP3 inflammasome axis activation and matrix metalloproteinase 2 (MMP2) expression in HASMCs. PPARδ inhibited NFκB signalling and alleviated ER stress-induced SMC phenotypic switching., Conclusions and Implications: Low plasma PPARδ levels may be associated with atherosclerotic plaque vulnerability. Our findings provide new insights into the mechanisms underlying the protective effect of PPARδ on SMC phenotypic switching and improvement the features of atherosclerotic plaque vulnerability., (© 2023 British Pharmacological Society.)

Purpose: The optimal timing of stoma closure during or after adjuvant chemotherapy for rectal cancer patients undergoing sphincter-preserving surgery remains unknown. This study aimed to investigate the influence of clinical and oncological outcomes depending on the timing of stoma closure., Methods: Between January 2006 and December 2015, we enrolled 244 consecutive rectal cancer patients who underwent curative-intent sphincter-preserving surgery with diverting transverse colostomy and adjuvant chemotherapy. Patients with stoma closure during (During group) adjuvant chemotherapy were compared to those who had stoma closure after adjuvant chemotherapy (After group)., Results: Parastomal hernia occurred more frequently in the after group than in the during group. (10% vs. 2.9%, p = 0.028). Overall, no significant difference was observed in overall survival (OS) or disease-free survival (DFS) between the two groups (p = 0.911 for OS, p = 0.505 for DFS). However, an inferior OS occurred if reopen surgery was performed within 30 days of stoma closure in the during group, as compared with the after group (p = 0.004). In addition, a marginally poor DFS was observed in the group of patients who received further operations due to 30-day stoma closure complications compared to the other patients (p = 0.07)., Conclusions: For rectal cancer patients who underwent sphincter-preserving surgery, attention should be given to avoid 30-day major complications after stoma reversal because patients who require reoperation during adjuvant chemotherapy may have poor long-term survival., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The standard initial treatment for metastatic colorectal cancer (mCRC) remains debated. This study investigated whether upfront primary tumor resection (PTR) or upfront systemic therapy (ST) provides better survival outcomes for patients with mCRC., Methods: The PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched for studies published at any time from January 1, 2004, to December 31, 2022. Randomized controlled trials (RCTs) and prospective or retrospective cohort studies (RCSs) utilizing propensity score matching (PSM) or inverse probability treatment weighting (IPTW) were included. We evaluated overall survival (OS) and short-term (60-day) mortality in these studies., Results: After reviewing 3,626 articles, we identified 10 studies including a total of 48,696 patients. OS differed significantly between the upfront PTR and upfront ST arms (hazard ratio [HR] 0.62; 95% CI: 0.57-0.68; p < 0.001). However, a subgroup analysis identified no significant difference in OS in RCTs (HR 0.97; 95% CI: 0.7-1.34; p = 0.83), whereas significant difference in OS occurred between the treatment arms in RCSs with PSM or IPTW (HR 0.59; 95% CI: 0.54-0.64; p < 0.001). Short-term mortality was analyzed in three RCTs, and 60-day mortality differed significantly between the treatment arms (risk ratio [RR] 3.52; 95% CI: 1.23-10.10; p = 0.02)., Conclusions: In RCTs, upfront PTR for mCRC did not improve OS and enhanced the risk of 60-day mortality. However, upfront PTR seemed to increase OS in RCSs with PSM or IPTW. Therefore, whether upfront PTR should be used for mCRC remains unclear. Further large RCTs are required., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

(1) Background: BCC is a sporadic disease that develops in areas of the skin not exposed to the sun. Perianal BCC, which occurs in the anorectal region, accounts for less than 0.2% of all BCC cases. There have been only a few reported cases of the disease, with fewer than 200 cases reported in total. Given the diagnostic challenges and potential for misdiagnosis, we conducted a systematic review of perianal basal cell carcinoma using real-world data to provide comprehensive and detailed information on the disease. (2) Methods: The study was reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 2020. Patients' clinical pathologic features, tumor characteristics, treatment modalities, and outcomes were presented. (3) Results: The results of 41 studies involving 140 patients were analyzed. The most common symptoms reported by patients at presentation were anorectal bleeding, pain, and pruritus. Ulceration was the most frequently observed tumor characteristic. The majority of patients underwent local excision as their primary treatment, with only eight patients experiencing a recurrence. Our analysis did not reveal any statistically significant differences in the outcomes of different treatment modalities. (4) Conclusions: Identifying perianal BCC poses a significant challenge as it closely resembles other anal diseases, thereby making it difficult to differentiate between the different conditions. However, a wide local excision with clear margins is considered an effective treatment option for most patients. Alternative treatments, such as radiotherapy, may be recommended for patients who are unable to undergo surgery.

Purpose: We analyzed the effectiveness, safety, and mid-term oncological outcomes of short-course radiotherapy (SCRT) and oxaliplatin-based consolidation chemotherapy in patients with locally advanced rectal cancer (LARC)., Methods: We retrospectively evaluated 64 patients with LARC who underwent SCRT and tegafox (tegafur-uracil/leucovorin plus oxaliplatin) or mFOLFOX-6 (5-fluorouracil, leucovorin, and oxaliplatin) consolidation chemotherapy before surgery between January 2015 and December 2020. Tumor response, patient compliance, toxicity, surgical outcomes, overall survival (OS), and disease-free survival (DFS) were analyzed., Results: Sixty-four patients with a mean age of 58.67 years (44 males) were included; 48 (75%) had tumors within 5 cm of the anal verge. Additionally, 93.8% of the patients underwent at least 2 months of chemotherapy, and three required dose reduction. Grade III toxicity occurred in 2 patients, and 10 had a clinical complete response and opted for non-operative management. One patient experienced tumor progression and underwent further treatment without surgery. Among the 53 patients who underwent surgery, 51 (96.2%) had sphincter preservation, 3 had Clavien-Dindo grade III complications, and no mortality occurred. The complete response rate for the entire cohort was 23.4%. Moreover, 47 patients (74.6%) had a neoadjuvant rectal score of < 16 after treatment. After a median follow-up time of 32.01 months, 6 (9.3%) had local recurrence, and 17 (26.6%) had distant metastasis. The 3-year OS, DFS and stoma-free rates were 89.5%, 65.5%, and 78.1% respectively., Conclusion: SCRT followed by oxaliplatin-based consolidation chemotherapy is safe and effective for tumor downstaging in LARC, further improving the sphincter preservation rate., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The primary treatment for metastatic colorectal cancer (mCRC) consists of targeted therapy and chemotherapy to improve survival. A molecular target drug with an anti-epidermal growth factor receptor (EGFR) antagonist is recommended when the RAS and BRAF genes are normal. About 50-70% of patients using anti-EGFR antagonists will experience skin reactions. Some studies have shown that severe skin reactions caused by anti-EGFR antagonists may be linked to overall survival (OS) and progression-free survival (PFS), but the results are still uncertain. These data of mCRC patients who underwent anti-EGFR therapy between October 2017 and October 2018 were analyzed retrospectively. A total of 111 patients were included in this study. The survival results showed that gender, age, body mass index, primary tumor site, and recurrence did not significantly affect OS and PFS. However, the first-line anti-EGFR inhibitor treatment was significantly associated with OS ( p < 0.001) and PFS ( p < 0.001). There was no significant difference in the incidence of acne between males and females in grades 1 and 2, while males have a greater risk in grades 3 and 4 than females (20.3 vs. 4.8%; p -value = 0.041). Skin toxicity was not a predictor of anti-EGFR treatment response in this investigation.

Background: Whether to ligate the inferior mesenteric artery at its root during anterior resection for sigmoid colon or rectal cancer is still under debate. This study compared the surgical outcomes, postoperative recovery, and anastomotic leakage between high and low ligation of the inferior mesenteric artery through a subgroup analysis., Methods: This was a retrospective analysis of prospectively collected data. All patients who underwent colorectal resection for rectosigmoid cancer between December 2016 and December 2019 were enrolled. According to the surgical ligation level of the inferior mesenteric artery, the patients were categorized into either the high or low ligation group. The investigated population was matched using the propensity score method., Results: Overall, 894 patients with sigmoid or rectal cancer underwent elective anterior resection with high (577 patients) or low (317 patients) ligation of the inferior mesenteric artery. After the propensity score matching, 245 patients in each group were compared. High ligation of the inferior mesenteric artery was associated with higher incidence of anastomotic leakage (14.9% vs. 5.6%, P = 0.041) for mid- to low-rectum tumors and a higher incidence of complications (8.6% vs. 3.3%, P = 0.013) of grades 1-2 according to the Clavien-Dindo classification system., Conclusion: Compared with high ligation, low ligation of the inferior mesenteric artery resulted in lower likelihood of morbidity and mortality in rectal and sigmoid cancers. Moreover, low ligation was less likely to result in anastomosis leakage in mid- to low-rectal cancers., (© 2023. The Author(s).)

Background: Second-generation antipsychotics (SGAs) is thought responsible for the metabolic abnormalities of schizophrenic patients, however, some untreated schizophrenic patients had already developed problems with glucose metabolism. The present study examined the hypothesis that schizophrenia itself but not risperidone, an extensively employed SGA, is accountable for metabolic abnormalities., Methods: A 56-day risperidone regimen (1 mg/kg/day) was employed for rats of social isolation rearing (SIR) beginning at different developmental stage (28 or 56 days after weaning, i.e., adolescent and young adulthood, respectively). Metabolic parameters including body weight, systolic blood pressure (SBP), triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol, and plasma glucose were measured at baseline, 28, and 56 days of the regimen. Oral glucose tolerance test (OGTT) was performed at the end of the regimen. Insulin function was evaluated by area under the curve (AUC) of OGTT, homeostasis model assessment-insulin resistance (HOMA-ir), and Matsuda index., Results: Our results demonstrated that: (i) SIR rats presented higher body weight, plasma triglyceride, and HOMA-ir than social controls. (ii) Higher insulin resistance was specifically presented in young adult rather than adolescent SIR rats. (iii) Adolescent drugged rats showed a lower level of LDL in day 28 of the regimen than young adult. Risperidone led to a lower LDL level in only young adult IR rats in day 56 than undrugged rats. (iv) SIR-induced dysregulation of insulin can be reversed by chronic risperidone treatment beginning at adolescence but not young adulthood., Conclusions: Our findings support the primary role of schizophrenia in metabolic abnormalities and risperidone appear beneficial when administered earlier., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

Background: Drug repurposing is a fast and effective way to develop drugs for an emerging disease such as COVID-19. The main challenges of effective drug repurposing are the discoveries of the right therapeutic targets and the right drugs for combating the disease., Methods: Here, we present a systematic repurposing approach, combining Homopharma and hierarchal systems biology networks (HiSBiN), to predict 327 therapeutic targets and 21,233 drug-target interactions of 1,592 FDA drugs for COVID-19. Among these multi-target drugs, eight candidates (along with pimozide and valsartan) were tested and methotrexate was identified to affect 14 therapeutic targets suppressing SARS-CoV-2 entry, viral replication, and COVID-19 pathologies. Through the use of in vitro (EC 50 = 0.4 μM) and in vivo models, we show that methotrexate is able to inhibit COVID-19 via multiple mechanisms., Results: Our in vitro studies illustrate that methotrexate can suppress SARS-CoV-2 entry and replication by targeting furin and DHFR of the host, respectively. Additionally, methotrexate inhibits all four SARS-CoV-2 variants of concern. In a Syrian hamster model for COVID-19, methotrexate reduced virus replication, inflammation in the infected lungs. By analysis of transcriptomic analysis of collected samples from hamster lung, we uncovered that neutrophil infiltration and the pathways of innate immune response, adaptive immune response and thrombosis are modulated in the treated animals., Conclusions: We demonstrate that this systematic repurposing approach is potentially useful to identify pharmaceutical targets, multi-target drugs and regulated pathways for a complex disease. Our findings indicate that methotrexate is established as a promising drug against SARS-CoV-2 variants and can be used to treat lung damage and inflammation in COVID-19, warranting future evaluation in clinical trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Chang, Pathak, Tzou, Luo, Hsu, Li, Lee, Chen, Huang, Yang, Hsu, Tsai, Chang, Hsu, Liu, Chin, Lin, Yang, Wu, Lee, Hsu, Liu, Chu, Wang, Wang, Huang, Lin, Hsieh, Wu Lee, Hung and Yang.)

Inflammatory reactions play a crucial role in cancer progression and may contribute to systemic inflammation. In routine clinical practice, some inflammatory biomarkers can be utilized as valuable predictors for colorectal cancer (CRC). This study aims to determine the usefulness of a novel cancer-inflammation prognostic index (CIPI) marker derived from calculating carcinoembryonic antigen (CEA) multiplied by the neutrophil-to-lymphocyte ratio (NLR) values established for non-metastatic CRCs. Between January 1995 and December 2018, 12,092 patients were diagnosed with stage I to III primary CRC and had radical resection—they were all included in this study for further investigation. There were 5996 (49.6%) patients in the low-CIPI group and 6096 (50.4%) patients in the high-CIPI group according to the cutoff value of 8. For long-term outcomes, the high-CIPI group had a significantly higher incidence of recurrence (30.6% vs. 16.0%, p < 0.001) and worse relapse-free survival (RFS) and overall survival (OS) rates (p < 0.001). High CIPI was an independent prognostic factor for RFS and OS in univariate and multivariate analyses. This research is the first to document the independent significance of CIPI as a prognostic factor for CRC. To ensure that it works, this CIPI needs to be tested on more CRC prediction models.

Some breathing indexes during sleep, including the apnea-hypopnea index, oxygen desaturation index, and oxygen saturation during sleep, can be recorded by overnight polysomnography. We aimed to investigate the association of various breathing indexes during sleep with the Epworth Sleepiness Scale (ESS) score in adults. We retrospectively collected the clinical and overnight polysomnography data of 2829 adults aged 20 years or older from November 2011 to June 2017. The association of various breathing indexes during sleep and ESS score was analyzed using univariate and multivariate logistic regression analysis for all adults (20-91 years), and in each sex and of body mass index (<26 kg/m2 vs ≥26 kg/m2). The mean ESS score was 6.2 (standard deviation = 4.3; range = 0-24) for all adults. After adjustment for age, sex, many common diseases, and health-related habits, apnea-hypopnea index, oxygen desaturation index, percentage of oxygen saturation below 90% during sleep, and percentage of oxygen saturation below 85% during sleep were significantly positively associated with ESS score in all adults, whereas mean oxygen saturation during sleep, minimal oxygen saturation during sleep, and awake oxygen saturation during sleep were significantly negatively associated with ESS score in all adults. In subgroup analysis, we found that the association between breathing indexes during sleep and ESS score was similar in both sex, but was significant in subjects of body mass index ≥ 26 kg/m2. All breathing indexes during sleep had significant positive or negative correlation with ESS score in all adults, especially in obese subjects., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

AIM: The ERAS protocol consists of multiple items that aim to improve the outcomes of patients receiving surgery. Adhering to the protocol is difficult. We wondered whether surgeons practicing the ERAS protocol in a group would improve patient outcomes. Methods: All patients who underwent colorectal resection for benign disease or malignancy from November 2017 to December 2018 were collected and reviewed retrospectively. According to the physician’s ward round strategy, the patients were categorized into two groups, either by solo practice or group practice. Results: This study enrolled 724 patients and divided them into two groups according to the practice method: group practice (n = 256) and solo practice (n = 468). The group practice cohort had less postoperative morbidity (14.0% vs. 21.4%, p = 0.048) and shorter postoperative hospital stays (mean: 6.6 ± 3.2 vs. 8.6 ± 5.5, p < 0.05) than the solo practice cohort. Group practice (p < 0.001), natural orifice specimen extraction (NOSE) procedure (p < 0.001), and blood loss >50 mL (p = 0.039) significantly affected discharge within 5 days postoperatively in multivariate analyses. Conclusions: Group practice based on a modified ERAS protocol shortens postoperative hospital stays with fewer morbidities compared with solo practice in which patients receive elective minimally invasive colorectal surgery.

The C-C chemokine motif ligand 5 (CCL5) and its receptors have recently been thought to be substantially involved in the development of obesity-associated adipose tissue inflammation and insulin resistance. However, the respective contributions of tissue-derived and myeloid-derived CCL5 to the etiology of obesity-induced adipose tissue inflammation and insulin resistance, and the involvement of monocytic myeloid-derived suppressor cells (MDSCs), remain unclear. This study used CCL5-knockout mice combined with bone marrow transplantation (BMT) and mice with local injections of shCCL5/shCCR5 or CCL5/CCR5 lentivirus into bilateral epididymal white adipose tissue (eWAT). CCL5 gene deletion significantly ameliorated HFD-induced inflammatory reactions in eWAT and protected against the development of obesity and insulin resistance. In addition, tissue (non-hematopoietic) deletion of CCL5 using the BMT method not only ameliorated adipose tissue inflammation by suppressing pro-inflammatory M-MDSC (CD11b + Ly6G - Ly6C hi ) accumulation and skewing local M1 macrophage polarization, but also recruited reparative M-MDSCs (CD11b + Ly6G - Ly6C low ) and M2 macrophages to the eWAT of HFD-induced obese mice, as shown by flow cytometry. Furthermore, modulation of tissue-derived CCL5/CCR5 expression by local injection of shCCL5/shCCR5 or CCL5/CCR5 lentivirus substantially impacted the distribution of pro-inflammatory and reparative M-MDSCs as well as macrophage polarization in bilateral eWAT. These findings suggest that an obesity-induced increase in adipose tissue CCL5-mediated signaling is crucial in the recruitment of tissue M-MDSCs and their trans-differentiation to tissue pro-inflammatory macrophages, resulting in adipose tissue inflammation and insulin resistance.

(Background) The coronavirus disease 2019 (COVID-19) that is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) carries high infectivity and mortality. Efficient intervention strategies are urgently needed. Avian immunoglobulin Y (IgY) showed efficacy against viral infection whereas the in vivo efficacy remains unclear. (Methods) We immunized laying hens with S1, S1 receptor-binding domain (S1-RBD), or S2 subunits of the SARS-CoV-2 spike (S) protein. After immunization, IgYs were collected and extracted from the egg yolks. The neutralization potential of IgYs was examined by the plaque reduction neutralization test (PRNT). The bioutility of IgYs was examined in Syrian hamsters in vivo. (Results) IgYs exhibited typical banding patterns in SDS-PAGE and Western blot and were immunoreactive against S1, S1-RBD, and S2 subunits. The plaque reduction neutralization test (PRNT) showed that all purified IgYs potently neutralized different SARS-CoV-2 strains in vitro. In Syrian hamsters, the combination of IgYs for S1-RBD and S2 subunits administered before or after SARS-CoV-2 infection effectively restored body weight loss and reduced intrapulmonary lesions and the amount of immunoreactive N protein-positive cells, which were caused by SARS-CoV-2 infection. (Conclusions) Collectively, IgYs specific for S protein subunits effectively neutralized SARS-CoV-2 in vitro and in vivo and may serve as prophylactic or therapeutic antibodies in the prevention or treatment of COVID-19.

C-C chemokine receptor type 5 (CCR5) positively contributes to the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a common metabolic liver disease associated with chronic inflammation. CCR5 signaling also facilitates the immunosuppressive activity of a group of immature myeloid cells known as granulocytic myeloid-derived suppressor cells (g-MDSCs). While both hepatocyte and g-MDSC express CCR5, how CCR5 coordinates these two distinct cell types in the hepatic microenvironment remains largely unknown. Here, we used in vivo and ex vivo approaches to define the molecular details of how CCR5 mediates the crosstalk between hepatocytes and g-MDSCs in a mouse model of NAFLD. Global CCR5-deficient mice exhibited more severe steatosis, increased hepatic gene expression of lipogenesis, and exacerbated liver damage in diet-induced obesity. Either NAFLD or CCR5-deficiency per se is causative for the increase of g-MDSCs. Purified g-MDSCs have a higher survival rate in the fatty liver microenvironment, and blockade of CCR5 significantly decreases g-MDSCs' expression of anti-inflammatory factors. On the other hand, the null of CCR5 signaling increases hepatocytes' expression of lipogenic genes in the NAFLD microenvironment. Most importantly, inhibiting g-MDSCs' CCR5 signaling in the fatty liver microenvironment dramatically reduces STAT3 signaling, lipogenic, and pro-inflammatory gene expression in primary hepatocytes. Adoptive cell transfer experiments further demonstrate that CCR5-deficient g-MDSCs mitigate hepatic lipogenic gene expression without facilitating pro-inflammatory cytokine production and liver damage in NAFLD mice. These results suggest that targeting g-MDSCs' CCR5 signaling might serve as a potential therapeutic strategy for NAFLD.

Objective: Capitation is a healthcare reimbursement scheme in which a healthcare provider equitable access to funding for services and greater flexibility and budgeting. The objectives of the study are to investigate the effect of capitation signaling on patients' perceived value and trust and on their use intention., Methods: This study was a scenario-based survey to examine interaction design, including capitation policy information and value-added health services information, which act as a combination of to test the hypotheses using signaling theory. Subject may receive the information about health services, information about a capitation policy, both of these two signals, or neither of them., Results: The results of this study show that signal capitation policy and value-added health service information positively affects patients' perceived value, but not patients' trust. When a patient receives a signal either capitation policy information or value-added health service information, their perceived value, trust, and use intention are significantly higher than those who receive neither signal., Conclusion: We suggest that high-quality healthcare institutions should consider distinguishing themselves from other low-quality providers by signaling information and allocate resources on value-added health services to enhance patients' awareness of healthy behavior and benefit from implementing a capitation payment scheme. This research contributes to healthcare stakeholders, especially policymakers and service providers, in terms of how best to engage with patients.

It is controversial whether patients who achieve clinical complete remission (cCR) of rectal cancer should be treated with the "watch and wait" (W&W) or radical resection (RR) strategy. Our study aimed to compare the survival outcomes and ostomy rate of the W&W and RR strategies. Between January 2008 and December 2015, we investigated 26 patients who achieved pathologic complete remission after undergoing RR and 36 patients who adopted the W&W strategy because of cCR. The tumor regrowth, salvage surgery, recurrence, disease-free, and overall survival (OS) rates were assessed. In our study, recurrences occurred in nine and two patients from the W&W and RR groups, respectively. Each patient in the RR group had a temporary or permanent ostomy, but only three (8.3%) had an ostomy in the W&W group. The 5-year recurrence rate was 25.0% in the W&W group and 7.7% in the RR group. Six patients (16.7%) had tumor regrowth in the W&W group, and all were resectable when regrowth. The 5-year OS rates between the two groups were nonsignificant. There is no specific risk factor for recurrence and OS. Under close surveillance, the W&W group achieved similar OS to the RR group and benefited from a lower ostomy rate., Competing Interests: Conflict of interest: There is no conflict of interest, use of off-label or unapproved drugs or products, and use of previously copyrighted material. None of the authors has any potential financial or non-financial conflicts of interest., (© 2022 Yu-Jen Hsu et al., published by De Gruyter.)

Objective: Probiotics participate in regulating oral microbiota and reducing the prevalence of oral diseases; however, clinical research on probiotics is insufficient. Therefore, in this study, we performed in vitro screening of potential oral protective probiotic strains and then evaluated the clinical efficacy of the selected strains on maintaining oral health., Materials and Methods: Fifty healthy individuals were recruited and randomly assigned into the placebo group and probiotics group, which included three strains of probiotics, Lactobacillus salivarius subs. salicinius AP-32, Lactobacillus paracasei ET-66, and Lactobacillus plantarum LPL28. Each group was blindly administered placebo or probiotics for four weeks., Results: Next-generation sequencing results showed that the oral microbiota of Lactobacillus salivarius in the oral cavity were significantly increased in subjects supplemented with mixed probiotic lozenges. The anti-bacterial activities of viable probiotics were observed within two weeks. Both IgA levels and Lactobacillus and Bifidobacterium abundances in the oral cavity were significantly increased in the experimental groups, along with a reduced formation of plaque. Most participants reported that their oral health conditions and intestinal symptoms had improved., Conclusions: Overall, our clinical study suggests that oral probiotic lozenges may enhance oral immunity, modulate oral microbiota, and improve oral health., (© 2021 Wiley Periodicals LLC.)

Background: Few studies have evaluated the feasibility and safety of intracorporeal anastomosis (IA) for left hemicolectomy. Here, we aimed to investigate the potential advantages and disadvantages of laparoscopic left hemicolectomy with IA and compare the short- and medium-term outcomes between IA and extracorporeal anastomosis (EA)., Methods: We retrospectively analyzed 133 consecutive patients who underwent laparoscopic left hemicolectomies from July 2016 to September 2019 and categorized them into the IA and EA groups. Patients with stage 4 disease and conversion to laparotomy or those lost to follow-up were excluded. Postoperative outcomes between IA and EA groups were compared. Short-term outcomes included postoperative pain score, bowel function recovery, complications, duration of hospital stay, and pathological outcome. Medium outcomes included overall survival and disease-free survival for at least 2 years., Results: After excluding ineligible patients, the remaining 117 underwent IA (n = 40) and EA (n = 77). The IA group had a shorter hospital stay, a shorter time to tolerate liquid or soft diets, and higher serum C-reactive protein level on postoperative day 3. There was no difference between two groups in operative time, postoperative pain, specimen length, or nearest margin. A 2-year overall survival (IA vs. EA: 95.0% vs. 93.5%, p = 0.747) and disease-free survival (IA vs. EA: 97.5% vs. 90.9%, p = 0.182) rates were comparable between two groups., Conclusions: Laparoscopic left hemicolectomy with IA was technically feasible, with better short-term outcomes, including shorter hospital stays and shorter time to tolerate liquid or soft diets. The IA group had higher postoperative serum C-reactive protein level; however, no complications were observed. Regarding medium-term outcomes, the overall survival and disease-free survival rates were comparable between IA and EA procedures., (© 2022. The Author(s).)

Studies have reported positive short-term and histopathological results of transanal total mesorectal excision (TaTME) for mid-low rectal cancer. The long-term oncological outcomes are diverse, and concerns regarding the high local recurrence (LR) rate of TaTME have recently increased. We retrospectively analyzed 298 consecutive patients who underwent Laparoscopic TME (LapTME) or TaTME between January 2015 and December 2019. Propensity score-matching (PSM) was performed with patients matched for demographics and stage. After PSM, 63 patients were included in each group. The TaTME group had a longer mean operative time (394 vs. 333 min, p < 0.001). The blood loss, diverting stoma rate, and conversion rate were similar. Postoperatively, TaTME and LapTME had compatible complications, recovery, and hospital stay. A similar specimen quality was detected in both groups. After a mean follow-up period of 41−47 months, TaTME had less LR than LapTME (9.5% vs. 23.8%, p = 0.031). The 3-year overall survival was 80.3% in the TaTME group and 73.6% in the LapTME group (p = 0.331). The 3-year disease-free survival (DFS) rate was 72.0% in the TaTME group and 56.6% in the LapTME group (p = 0.038). In conclusion, better DFS and fewer LR events were observed after TaTME; thus, TaTME can be considered a safe and feasible approach in patients with low rectal cancer.

Brown adipose tissue (BAT) has been considered a vital organ in response to non-shivering adaptive thermogenesis, which could be activated during cold exposure through the sympathetic nervous system (SNS) or under postprandial conditions contributing to diet-induced thermogenesis (DIT). Humans prefer to live within their thermal comfort or neutral zone with minimal energy expenditure created by wearing clothing, making shelters, or using an air conditioner to regulate their ambient temperature; thereby, DIT would become an important mechanism to counter-regulate energy intake and lipid accumulation. In addition, there has been a long interest in the intriguing possibility that a defect in DIT predisposes one to obesity and other metabolic diseases. Due to the recent advances in methodology to evaluate the functional activity of BAT and DIT, this updated review will focus on the role and regulatory mechanism of BAT biology in DIT in health and diseases and whether these mechanisms are applicable to humans.

Background: Although a temporary stoma can mitigate the severity of anastomotic leakage, some rectal cancer patients retain a permanent stoma after sphincter-preserving surgery. Therefore, this study aimed to identify independent preoperative risk factors for permanent stoma and establish a prediction model for mid-and low-rectal cancer patients who underwent sphincter-preserving surgery and temporary stoma., Methods: We retrospectively reviewed consecutive patients with non-metastatic rectal cancer between 2000 and 2015. The risk factors for permanent stomas were collected and analyzed., Results: A total of 1020 rectal cancer patients with temporary stoma were included. The overall rate of permanent stoma was 17.5% (n = 179). Cancer progression and anastomotic complications are major causes of permanent stomas. Multivariate analysis showed that preoperative risk factors such as advanced age, male sex, preoperative CEA ≥ 10 ng/ml, T4 stage, N stage, low rectal tumor, and ASA ≥ III were independent preoperative risk factors after adjustment. The ROC curve of the risk factors and permanent stoma showed an AUC of 0.689, a cut-off value of 2.5, a sensitivity of 0.689, and a specificity of 0.622. The permanent stoma rates were significantly higher between risk scores ≤ 2 and > 2 (29.9% vs. 11.3%, p < 0.001)., Conclusion: Preoperative CEA ≥ 10 ng/ml, T4 stage, N stage, low rectal tumor, advanced age, ASA ≥ III, and male sex were independent preoperative prognostic factors for a permanent stoma. The risk was higher with a score greater than two. Therefore, the risk of subsequent permanent stoma should be evaluated and informed to the patient prior to the primary surgery., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Patients with diabetes have a relatively high risk of fracture due to osteoporosis. However, the risk of osteoporosis associated with the use of oral hypoglycemic drugs and dipeptidyl peptidase-4 inhibitor (DPP-4i) by patients with diabetes is unclear. This study aimed to explore the effect of DPP-4i on the risk of osteoporosis in Taiwanese patients with type 2 diabetes mellitus (T2DM)., Methods: This study enrolled 6339 patients on DPP-4i (DPP-4i group) and 25 356 patients without DPP-4i (non-DPP-4i group). They were matched by 1:4 propensity score matching, using confounding variables including sex, age, comorbidities, medication, and index year. Cox proportional hazards analysis was used to compare hospitalization and mortality during an average follow-up period of 7 years., Results: The mean age of patients in the two groups was 66 years. Men were slightly higher in number (51.79%) than women. At the end of the follow-up period, 113 (0.36%) patients had osteoporosis, of which 15 (0.24%) were in the case group and 98 (0.39%) in the control group. The risk of all-cause osteoporosis was significantly lower in the DPP-4i group than in the non-DPP-4i group (adjusted hazard ratio [HR] 0.616; 95% confidence interval [CI] 0.358-0.961; p = 0.011). Kaplan-Meier analysis showed that the preventive effect on osteoporosis was positively correlated with the cumulative dose of DPP-4i (log-rank, p = 0.039) with the class effect., Conclusion: Compared with not using DPP-4i, the use of DPP-4i in Taiwanese T2DM patients was associated with a lower risk of osteoporosis due to the class effect, and the preventive effect was dose-dependent. However, larger prospective studies are needed to validate this finding and to explore the possible mechanism of the preventive effect of DPP-4i., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)

Background: Diabetic patients are at high risk of developing cancer. Traditional Chinese medicine (TCM) has become increasingly popular as an adjuvant treatment for patients with chronic diseases, and some studies have identified its beneficial effect in diabetic patients with cancer. The purpoes of this study was to outline the potential of TCM to attenuate hospitalization and mortality rates in diabetic patients with carcinoma  in situ  (CIS)., Methods: A total of 6,987 diabetic subjects with CIS under TCM therapy were selected from the National Health Insurance Research Database of Taiwan, along with 38,800 of 1:1 sex-, age-, and index year-matched controls without TCM therapy. Cox proportional hazard analysis was conducted to compare hospitalization and mortality rates during an average of 15 years of follow-up., Results: A total of 3,999/1,393 enrolled-subjects (28.62%/9.97%) had hospitalization/mortality, including 1,777/661 in the TCM group (25.43%/9.46%) and 2,222/732 in the control group (31.80%/10.48%). Cox proportional hazard regression analysis showed a lower rate of hospitalization and mortality for subjects in the TCM group (adjusted HR=0.536; 95% CI=0.367-0.780, P <0.001; adjusted HR=0.783; 95% CI=0.574-0.974, P  = 0.022). Kaplan-Meier analysis showed that the cumulative risk of hospitalization and mortality in the case and control groups was significantly different (log rank, P <0.001 and P  = 0.011, respectively)., Conclusions: Diabetic patients with CIS under TCM therapy were associated with lower hospitalization and mortality rates compared to those without TCM therapy. Thus, TCM application may reduce the burden of national medical resources., (© 2022 Korea Institute of Oriental Medicine. Published by Elsevier B.V.)

This study aimed to explore the safety and efficacy of neoadjuvant SCRT and tegafur−uracil/leucovorin plus oxaliplatin (TEGAFOX) for LARC in comparison to those of the modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX-6) regimen. We retrospectively evaluated 15 and 22 patients with LARC who underwent SCRT, followed by consolidation chemotherapy with TEGAFOX and mFOLFOX-6 before surgery, respectively, between January 2015 and December 2019. The primary endpoint was the tumor response rate. The secondary endpoints were compliance, toxicity, complications, overall survival (OS), and disease-free survival (DFS). The dose reduction rate was lower in the TEGAFOX group (0 vs. 9.1% (n = 2)). No grade III-IV toxicities occurred in the TEGAFOX group. Two and four patients in the TEGAFOX and mFOLFOX-6 groups, respectively, achieved clinical complete responses. The pathologic complete response rate was lower in the TEGAFOX group (7.7% vs. 17.6%). Overall, 11 (73.3%) and 17 (81.0%) patients had a neoadjuvant rectal (NAR) score of <16 in the TEGAFOX and mFOLFOX-6 groups, respectively. All patients in this study received sphincter-preservation surgery. One patient in each group developed Clavien−Dindo grade III complications. There were no significant between-group differences in the 3-year OS (81.8% vs. 84.8%, p = 0.884) and 3-year DFS (72% vs. 71.6%, p = 0.824) rates. TEGAFOX, as consolidation chemotherapy after SCRT, achieves good tumor downstaging and patient compliance in LARC. The toxicity, complications, and surgical outcomes are similar to those of mFOLFOX-6. Thus, TEGAFOX can be considered a chemotherapy option for rectal cancer treatment.

Neoadjuvant short course radiotherapy (SCRT) followed by consolidation chemotherapy (CCT) is an alternative treatment for locally advanced rectal cancer (LARC). We performed this systematic review and meta-analysis to explore the tumor response and oncological outcomes of this new approach compared to conventional chemoradiotherapy (CRT). An online search of the PubMed, Embase, and Cochrane Library databases was performed. This review included 7507 patients from 14 different cohorts. The pCR rate was higher with SCRT + CCT than that with CRT (RR: 1.60; 95% CI: 1.35−1.91; p < 0.01). SCRT + CCT provided a higher ypN0 response (RR: 1.06; 95% CI: 1.01−1.12; p = 0.02). There were no differences in R0 resection and positive CRM rates; however, more sphincter-preservation surgeries were performed in the SCRT + CCT arm (RR: 1.06; 95% CI: 1.01−1.11; p = 0.02). There was no difference in the OS and DFS between the SCRT + CCT and the CRT arms (OS: HR: 0.85, p = 0.07; DFS: HR: 0.88, p = 0.08). The compliance and toxicity were comparable between the SCRT and CRT groups. In the subgroup analysis, patients who underwent four or more cycles of CCT had better pCR and DFS events. Therefore, SCRT followed by consolidation chemotherapy might be an effective alternative treatment for LARC.

The rampageous transmission of SARS-CoV-2 has been devastatingly impacting human life and public health since late 2019. The waves of pandemic events caused by distinct coronaviruses at present and over the past decades have prompted the need to develop broad-spectrum antiviral drugs against them. In this study, our Pentarlandir ultrapure and potent tannic acids (UPPTA) showed activities against two coronaviral strains, SARS-CoV-2 and HCoV-OC43, the earliest-known coronaviruses. The mode of inhibition of Pentarlandir UPPTA is likely to act on 3-chymotrypsin-like protease (3CLpro) to prevent viral replication, as supported by results of biochemical analysis, a 3CLpro assay, and a "gain-of-function" 3CLpro overexpressed cell-based method. Even in the 3CLpro overexpressed environment, Pentarlandir UPPTA remained its antiviral characteristic. Utilizing cell-based virucidal and cytotoxicity assays, the 50% effective concentrations (EC 50 ) and 50% cytotoxicity concentration (CC 50 ) of Pentarlandir UPPTA were determined to be ∼0.5 and 52.5 μM against SARS-CoV-2, while they were 1.3 and 205.9 μM against HCoV-OC43, respectively. In the pharmacokinetic studies, Pentarlandir UPPTA was distributable at a high level to the lung tissue with no accumulation in the body, although the distribution was affected by the food effect. With further investigation in toxicology, Pentarlandir UPPTA demonstrated an overall safe toxicology profile. Taking these findings together, Pentarlandir UPPTA is considered to be a safe and efficacious pancoronal antiviral drug candidate that has been advanced to clinical development., Competing Interests: The authors declare the following competing financial interest(s): All authors, except for Po-Shiuan Hsieh and Teh-Ying Chou, are employees of SyneuRx International (Taiwan) Corp., (© 2022 The Authors. Published by American Chemical Society.)

Purpose: Although cigarette smoking is a well-known risk factor for anastomotic leakage during rectal surgery, the proper duration of smoking cessation that can decrease anastomotic leakage in patients undergoing sphincter-preserving surgery is unclear. This study aimed to investigate the optimal duration of smoking cessation that can reduce this complication., Methods: Between January 1, 2000, and December 31, 2012, we enrolled 1246 consecutive patients who underwent curative-intent sphincter-preserving surgery without preventive stoma at the Division of Colorectal Surgery of a tertiary referral center in Taiwan. Questionnaires were used to record their pre-surgical smoking status. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off duration of smoking cessation. Multivariate analysis was used to verify the effect of cigarette cessation on anastomotic leakage., Results: The ROC curve showed a cut-off value of 10.5 years of cessation duration. Therefore, the former-smoker group was further divided using a cessation duration of 10 years. The overall anastomotic leakage rate was 5.29%. However, the anastomotic leakage rate in current smokers (9.3%) and in those who quit for < 10 years (12.9%) was significantly higher than that in non-smokers (3.3%) and those who quit for ≥ 10 years (4.5%). On multivariate analysis, current smokers (p = 0.022), former smokers with < 10 years of smoking cessation (OR 2.725; p = 0.029), male sex (p = 0.015), and low rectal cancer (p < 0.001) were all independently related to the development of anastomotic leakage., Conclusion: Smoking cessation for < 10 years remains a risk factor for anastomotic leakage in patients with mid-to-low rectal cancer undergoing sphincter-preserving surgery., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The oral cavity plays a crucial role in food digestion and immune protection. Thus, maintaining oral health is necessary. Postbiotic and heat-killed probiotic cells have shown increased antibacterial potential with stable viability compared with live strains. However, clinical evidence regarding their effect on oral health is insufficient. Therefore, in this study, we tested postbiotic lozenges of Lactobacillus salivarius subsp. salicinius AP-32, L. paracasei ET-66, and L. plantarum LPL28 and heat-killed probiotic lozenges of L. salivarius subsp. salicinius AP-32 and L. paracasei ET-66 for their effect on oral health. In total, 75 healthy individuals were blindly and randomly divided into placebo, postbiotic lozenge, and heat-killed probiotic lozenge groups and were administered the respective lozenge type for 4 weeks. Postbiotic and heat-killed probiotic lozenge groups demonstrated antibacterial activities with a considerable increase in L. salivarius in their oral cavity. Furthermore, their salivary immunoglobulin A, Lactobacillus , and Bifidobacterium increased. Subjective questionnaires completed by the participants indicated that participants in both the experimental groups developed better oral health and intestinal conditions than those in the placebo group. Overall, our study revealed that a food additive in the form of an oral postbiotic or heat-killed probiotic lozenge may effectively enhance oral immunity, inhibit the growth of oral pathogens, and increase the numbers of beneficial oral microbiota.

Abstract: The adipose-derived stromal vascular fraction (SVF) is considered to be an attractive source of stem cells in cell therapy. Besides stem cells, it also contains functional cells, such as macrophages, precursor cells, somatic stem cells, and pericytes. Collagenase digestion is the most frequently used method to isolate SVF, but it is time-consuming and costly and has some problems, such as infectious agents and immune reactions. In this research, we compared the yield, cell population ratios, and cell viability when isolating SVF by the ultrasonic physics (U-SVF) method and traditional enzymatic method (E-SVF). Then, we isolated exosomes from U-SVF and E-SVF, respectively, and cocultured them with fibroblasts to investigate the potential of applying this cell secretion in wound repair. The results showed that there was no significant difference between the ultrasonic method and enzymatic method in terms of cell viability, cell numbers, or the expression of CD markers of stem cells. However, exosome analysis identified a greater number and smaller size of exosome particles obtained by U-SVF. In terms of cell proliferation efficiency, although the proliferation efficiency of U-SVF was lower than that of E-SVF. Trilineage differentiation experiments revealed that both E-SVF and U-SVF had good differentiation ability, owing to high stem cell content. Finally, E-SVF and U-SVF exosomes were cocultured with fibroblasts. The efficiency of fibroblast migration increased in the SVF exosome treated groups, and the expression of related genes (integrin α5β1) was slightly upregulated; however, the expression of FAK, AKT, ERK, and RhoA was significantly upregulated at 24 hours. From the abovementioned experiments, we found that there was no significant difference in stem cell-related characteristics between SVF isolated by ultrasonic cavitation and SVF isolated by the enzymatic method. In addition, exosomes secreted by SVF may have excellent therapeutic effect on skin injuries, which provides a new viewpoint and therapeutic strategy for soft tissue repair., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

We have previously identified Candida albicans GPH1 (orf19.7021) whose protein product was associated with C. albicans Cdc4. The GPH1 gene is a putative glycogen phosphorylase because its Saccharomyces cerevisiae homolog participates in glycogen catabolism, which involves the synthesis of β-glucan of the fungal cell wall. We made a strain whose CaCDC4 expression is repressed, and GPH1 is constitutively expressed. We established a GPH1 null mutant strain and used it to conduct the in vitro virulence assays that detect cell wall function. The in vitro virulence assay is centered on biofilm formation in which analytic procedures are implemented to evaluate cell surface hydrophobicity; competence, either in stress resistance, germ tube formation, or fibronection association; and the XTT-based adhesion and biofilm formation. We showed that the constitutively expressed GPH1 partially suppresses filamentation when the CaCDC4 expression is repressed. The C. albicans Gph1 protein is reduced in the presence of Ca Cdc4 in comparison with the absence of Ca Cdc4. Compared with the wild-type strain, the gph1 Δ/ gph1 Δ mutant displayed a reduction in the capability to form germ tubes and the cell surface hydrophobicity but an increase in binding with fibronectin. Compared with the wild-type strain, the gph1 Δ/ gph1 Δ mutant showed a rise in adhesion, the initial stage of biofilm formation, but displayed a similar capacity to form a mature biofilm. There was no major impact on the gph1 Δ/ gph1 Δ mutant regarding the conditions of cell wall damaging and TOR pathway-associated nutrient depletion. We conclude that GPH1 , adversely regulated by the filament suppressor CDC4 , contributes to cell wall function in C. albicans .

A lack of physical activity is a generally accepted risk factor for colorectal cancer. However, research on the effect of preoperative physical activity on postoperative and long-term outcomes is limited, especially in patients with stage IV colorectal cancer who underwent palliative surgery. Patients who underwent bowel resection for stage IV primary colorectal cancer between January 1995 and December 2016 were retrospectively enrolled. A total of 2185 patients were divided into two groups according to preoperative leisure-time weekly physical activity as assessed by metabolic equivalent of task (MET) values: MET < 12 ( n = 1845) and MET ≥ 12 ( n = 340). Inverse probability of treatment weighting (IPTW) was used to reduce imbalance and selection biases between the two groups. After the IPTW process, the MET < 12 group showed a higher postoperative morbidity rate (18.7% vs. 10.6%; p < 0.001) and mortality rate (2.4% vs. 0.6%; p < 0.001) than the MET ≥ 12 group. No significant difference was found in overall survival. Weekly preoperative leisure-time physical activity with MET ≥ 12 was associated with reduced short-term postoperative morbidity and mortality in patients undergoing palliative resection for metastatic colorectal cancer. However, no difference was detected in long-term survival.

Malnutrition and systemic inflammatory response (SIR) frequently occur in patients with colorectal cancer (CRC) and are associated with poor prognosis. Anti-inflammatory nutritional intervention is not only a way to restore the malnourished status but also modulate SIR. Nine experts, including colorectal surgeons, physicians and dieticians from 5 hospitals geographically distributed in Taiwan, attended the consensus meeting in Taiwan Society of Colon and Rectum Surgeons for a 3-round discussion and achieved the consensus based on a systematic literature review of clinical studies and published guidelines. The consensus recommends that assessment of nutritional risk and SIR should be performed before and after CRC treatment and appropriate nutritional and/or anti-inflammatory intervention should be adapted and provided accordingly., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ma, Hu, Huang, Chiang, Hsieh, Wang, Chiang, Hsieh, Chen and Wang.)

Chemokine (C-C motif) ligand 5 (CCL5) and CCR5, one of its receptors have been reported to be highly expressed in white adipose tissue (WAT) and are associated with the progression of inflammation and the development of insulin resistance in obese humans and mice. However, the role of CCL5/CCR5 signaling in obesity-associated dysregulation of energy metabolism remains unclear. Here, we demonstrate that global CCL5/CCR5 double knockout (DKO) mice have higher cold stress-induced energy expenditure and thermogenic function in brown adipose tissue (BAT) than wildtype (WT) mice. DKO mice have higher cold stress-induced energy expenditure and thermogenic function in BAT than WT mice. KEGG pathway analysis indicated that deletion of CCL5/CCR5 further facilitated the cold-induced expression of genes related to oxidative phosphorylation (OxPhos) and lipid metabolic pathways. In primary brown adipocytes of DKO mice, the augmentation of CL-316243-stimulated thermogenic and lipolysis responses was reversed by co-treatment with AMPKα1 and α2 short interfering RNA (siRNA). Overexpression of BAT CCL5/CCR5 genes by local lentivirus injection in WT mice suppressed cold stress-induced lipolytic processes and thermogenic activities. In contrast, knockdown of BAT CCL5/CCR5 signaling further up-regulated AMPK phosphorylation as well as thermogenic and lipolysis responses to chronic adrenergic stimuli and subsequently decreased level of body weight gain. Chronic knockdown of BAT CCL5/CCR5 signaling improved high-fat diet (HFD)-induced insulin resistance in WT mice. It is suggested that obesity-induced augmentation of adipose tissue (AT) CCL5/CCR5 signaling could, at least in part, suppress energy expenditure and adaptive thermogenesis by inhibiting AMPK-mediated lipolysis and oxidative metabolism in thermogenic AT to exacerbate the development of obesity and insulin resistance., (© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Aim: Laparoscopic anterior resection with natural orifice specimen extraction (NOSE) has favourable short-term outcomes. However, NOSE is rarely adopted for left hemicolectomy procedures. This study aimed to review the feasibility, safety and short-term outcomes of transrectal NOSE in patients undergoing laparoscopic left hemicolectomy., Method: All consecutive patients who underwent laparoscopic left hemicolectomy surgery with transrectal NOSE in a single institution between January 2018 and December 2020 were reviewed. Transrectal NOSE was performed with an enterotomy at the upper rectum. The specimen was brought out via a transanal endoscopic microsurgery scope inserted through the anus. A supplementary video demonstrates this technique. Surgical outcomes, including complications, postoperative short-term recovery and the level of pain intensity, are presented., Results: Twenty patients were reviewed. There were no immediate postoperative complications and no wound infections in these patients. The average time to tolerate a soft diet was 3.6 days, and the average postoperative hospital stay was 4.5 days. The average score on the numerical rating scale of postoperative pain was 3.0 on postoperative day 1. The median follow-up time was 23.5 months., Conclusion: Laparoscopic left hemicolectomy with transrectal NOSE is a safe and feasible procedure that leads to early postoperative recovery and a short hospital stay., (© 2021 The Association of Coloproctology of Great Britain and Ireland.)

Advanced age is a risk factor for major abdominal surgery due to a decline in physical function and increased comorbidities. Although laparoscopic surgery provides good results in most patients with colorectal cancer (CRC), its effect on elderly patients remains unclear. This study aimed to compare the short- and long-term outcomes between open and laparoscopic surgeries in elderly patients with CRC. Total 1350 patients aged ≥75 years who underwent curative resection for stage I-III primary CRC were enrolled retrospectively and were divided into open surgery (846 patients) and laparoscopy (504 patients) groups. After propensity score weighting to balance an uneven distribution, a competing risk analysis was used to analyze the short-term and long-term outcomes. Postoperative mortality rates were lower in the laparoscopy group, especially due to pulmonary complications. Postoperative hospital stay was significantly shorter in the laparoscopy group than in the open surgery group. Overall survival, disease-free survival, and competing risk analysis showed no significant differences between the two groups. Laparoscopic surgery for elderly patients with CRC significantly decreased pulmonary-related postoperative morbidity and mortality in this large cohort study. Laparoscopic surgery is a favorable method for elderly patients with CRC than open surgery in terms of less hospital stay and similar oncological outcomes.

Obesity is characterized as a complex and multifactorial excess accretion of adipose tissue accompanied with alterations in the immune and metabolic responses. Although the chemokine systems have been documented to be involved in the control of tissue inflammation and metabolism, the dual role of chemokines and chemokine receptors in the pathogenesis of the inflammatory milieu and dysregulated energy metabolism in obesity remains elusive. The objective of this review is to present an update on the link between chemokines and obesity-related inflammation and metabolism dysregulation under the light of recent knowledge, which may present important therapeutic targets that could control obesity-associated immune and metabolic disorders and chronic complications in the near future. In addition, the cellular and molecular mechanisms of chemokines and chemokine receptors including the potential effect of post-translational modification of chemokines in the regulation of inflammation and energy metabolism will be discussed in this review.