Total neoadjuvant treatment to increase the clinical complete response rate for distal locally advanced rectal cancer (TESS): A study protocol of a prospective, open-label, multicenter, single-arm, phase 2 trial.

BACKGROUND: Standard treatment of locally advanced rectal cancer (LARC) was neoadjuvant chemoradiotherapy (CRT), followed by total mesorectal excision (TME). Total neoadjuvant treatment (TNT), a new concept, attempts to deliver both systemic chemotherapy and neoadjuvant CRT prior to surgery. Patients treated with neoadjuvant chemotherapy were more likely to show higher tumor regression. The objective of this trial was to increase complete clinical rate (cCR) for LARC patients by optimizing tumor response, using TNT regimen as compared to conventional chemoradiotherapy. TESS, a prospective, open-label, multicenter, single-arm, phase 2 study, is underway. METHODS: Main inclusion criteria include cT3-4aNany or cT1-4aN+ rectal adenocarcinoma aged 18-70y; Eastern Cooperative Oncology Group (ECOG) performance 0-1; location ≤5 cm from anal verge. Ninety-eight patients will receive 2 cycles of neoadjuvant chemotherapy Capeox (capecitabine + oxaliplatin) before, during, and after radiotherapy 50Gy/25 fractions, before TME (or other treatment decisions, such as Watch and Wait strategy) and adjuvant chemotherapy capecitabine 2 cycles. Primary endpoint is the cCR rate. Secondary endpoints include ratio of sphincter preservation strategy; pathological complete response rate and tumor regression grade distribution; local recurrence or metastasis; disease-free survival; locoregional recurrence-free survival; acute toxicity; surgical complications; long-term anal function; late toxicity; adverse effect, ECOG standard score, and quality of life. Adverse events are graded per Common Terminology Criteria for Adverse Events V5.0. Acute toxicity will be monitored during antitumor treatment, and late toxicity will be monitored for 3 years from the end of the first course of antitumor treatment. DISCUSSION: The TESS trial aims to explore a new TNT strategy, which is expected to increase the rate of cCR and sphincter preservation rate. This study will provide new options and evidence for a new sandwich TNT strategy in patients with distal LARC.

Total neoadjuvant treatment and PD-1/PD-L1 checkpoint inhibitor in locally advanced rectal cancer.

For local advanced rectal cancer (LARC), total neoadjuvant treatment (TNT) has shown more complete response (CR), reduced risk of distant metastasis (DM) and increase of the sphincter preservation rate. Now it is the one and only recommendation for high-risk group of LARC according to National Comprehensive Cancer Network (NCCN) rectal cancer guideline, while it is also preferentially recommended for low-risk group of LARC. TNT is also beneficial for distant rectal cancer patients who have need for organ preservation. Even though the prognostic value of programmed cell death-ligand 1 (PD-L1) in the neoadjuvant chemoradiotherapy (NACRT) of LARC patients is undetermined yet, the combination of NACRT and programmed cell death-1 (PD-1)/PD-L1 antibodies seem bring new hope for mismatch repair proficient (pMMR)/microsatellite stable (MSS) LARC patients. Accumulating small sample sized studies have shown that combining NACRT with PD-1/PD-L1 antibody yield better short-term outcomes for pMMR/MSS LARC patients than historic data. However, ideal total dose and fractionation of radiotherapy remains one of unresolved issues in this combination setting. Thorough understanding the impact of radiotherapy on the tumor microenvironment and their interaction is needed for in-depth understanding and exquisite design of treatments combination model.

Role of ER Stress in Xenobiotic-Induced Liver Diseases and Hepatotoxicity.

The liver is a highly metabolic organ and plays a crucial role in the transportation, storage, and/or detoxication of xenobiotics. Liver damage induced by xenobiotics (e.g., heavy metal, endocrine disrupting chemicals, Chinese herbal medicine, or nanoparticles) has become a pivotal reason for liver diseases, leading to great clinical challenge and much attention for the past decades. Given that endoplasmic reticulum (ER) is the prominent organelle involved in hepatic metabolism, ER dysfunction, namely, ER stress, is clearly observed in various liver diseases. In response to ER stress, a conserved adaptive signaling pathway known as unfolded protein response (UPR) is activated to restore ER homeostasis. However, the prolonged ER stress with UPR eventually leads to the death of hepatocytes, which is a pathogenic event in many hepatic diseases. Therefore, analyzing the perturbation in the activation or inhibition of ER stress and the UPR signaling pathway is likely an effective marker for investigating the molecular mechanisms behind the toxic effects of xenobiotics on the liver. We review the role of ER stress in hepatic diseases and xenobiotic-induced hepatotoxicity, which not only provides a theoretical basis for further understanding the pathogenesis of liver diseases and the mechanisms of hepatotoxicity induced by xenobiotics but also presents a potential target for the prevention and treatment of xenobiotic-related liver diseases.

High dose chemoradiotherapy increases chance of organ preservation with satisfactory functional outcome for rectal cancer.

BACKGROUND: High dose chemoradiotherapy offers a curative chance for patients with rectal cancer that are unfit or unwilling to undergo surgical resection, yet its long-term survival and functional outcomes have been rarely investigated. METHODS: Patients with non-metastatic rectal adenocarcinoma who received pelvic radiation for curative intent from April 2006 to July 2017 were retrospectively investigated. Survival rates were analyzed using the Kaplan-Meier method. Quality of life and functional outcomes were evaluated using the EORTC quality of life questionnaire. RESULTS: A total of 57 patients were included, with a median age of 59.0 (range, 29-84) years. The numbers of patients who were diagnosed as stage I, II and III were 5 (8.8%), 16 (28.1%) and 36 (63.2%), respectively. 53 (93.0%) patients had tumor located within 5 cm from the anal verge. All patients received fluorouracil-based concurrent chemoradiotherapy with a median radiation dose of 80 (range, 60-86) Gy. All kinds of grade 3-4 adverse events occurred in 18 (31.6%) patients. 42 (73.7%) patients achieved a clinical complete response after chemoradiotherapy. After a median follow-up of 43.5 (range 14.9-163.2) months, 12 (21.1%) patients had local progression and 11 (19.3%) developed distant metastasis. The 3-year local recurrence-free survival and distant metastasis-free survival were 77.3% (95% CI, 65.7-88.8%) and 79.2% (95% CI, 68.2-90.2%), while the 3-year progression-free survival, cancer-specific survival, overall survival were 61.9% (95% CI, 48.8-75.0%), 93.1% (95% CI, 85.8-100.0%) and 91.4% (95% CI, 83.6-99.2%), respectively. For patients who had tumor located within 3 cm from the anal verge, the sphincter preservation rate was 85.3% at last follow-up. Long-term adverse events mainly were anal blood loss. 21 patients completed the quality-of-life questionnaire and had a score of the global health status of 78.57 ± 17.59. Of them, 95.2% reported no urinary incontinence and 85.7% reported no fecal incontinence. CONCLUSIONS: High dose chemoradiation demonstrated promising survival outcomes with acceptable short-term and long-term side effects, and satisfying long-term functional outcomes and quality of life. It could be considered as a non-invasive alternative for rectal cancer patients who refuse surgery.

Neoadjuvant chemoradiotherapy for patients with unresectable radically locally advanced colon cancer: a potential improvement to overall survival and decrease to multivisceral resection.

BACKGROUND: The management of unresectable locally advanced colon cancer (LACC) remains controversial, as resection is not feasible. The goal of this study was to evaluate the treatment outcomes and toxicity of neoadjuvant chemoradiotherapy (NACRT) followed with surgery and adjuvant chemotherapy in patients with unresectable radically LACC. METHODS: We included patients who were diagnosed at our institution, 2010-2018. The neoadjuvant regimen consisted of radiotherapy and capecitabine/ 5-fluorouracil-based chemotherapy. RESULTS: One hundred patients were identified. The median follow-up time was 32 months. The R0 resection rate, adjusted nonmultivisceral resection rate and bladder preservation rate were 83.0, 43.0 and 83.3%, respectively. The pCR and clinical-downstaging rates were 18, and 81.0%%, respectively. The 3-year PFS and OS rates for all patients were 68.6 and 82.1%, respectively. Seventeen patients developed grade 3-4 myelosuppression, which was the most common adverse event observed after NACRT. Tumor perforation occurred in 3 patients during NACRT. The incidence of grade 3-4 surgery-related complications was 7.0%. Postoperative anastomotic leakage was observed in 3 patients. CONCLUSIONS: NACRT followed by surgery was feasible and safe for selected patients with LACC, and can be used as a conversion treatment to achieve satisfactory downstaging, long-term survival and quality of life, with acceptable toxicities.

Enzyme-treated soy protein supplementation in low protein diet enhanced immune function of immune organs in on-growing grass carp.

A 56 days feeding trial was conducted to investigate the effects of enzyme-treated soy protein (ETSP) supplementation in low protein diets on immune function of immune organs (head kidney, spleen and skin) in on-growing grass carp. A total of 540 on-growing grass carp (initial average weight: 325.72 ± 0.60 g) were fed six diets, which included a normal protein diet (28% crude protein) and five low protein diets (26% crude protein) supplemented with graded levels of ETSP (0.0, 0.8, 1.2, 1.6 and 2.0%). At the end of feeding period, a challenge test was performed by infection with Aeromonas hydrophila for two weeks. The results indicated that (1) reducing dietary protein content from 28 to 26% decreased antibacterial substances and aggravated inflammatory responses of above three immune organs; (2) under the condition of reducing protein level in diet, 0.8-1.2% ETSP supplementation reversed these above adverse effects on immune function of above three immune organs; (3) suitable ETSP supplementation-decreased inflammatory responses were partly associated with [IκB kinase ß (IKKß)/inhibitor of κBα (IκBα)/nuclear factor kappa B (NF-κB) p65 and p52 or NF-κB p65] signaling and [target of rapamycin (TOR)/(S6K1, 4E-BP)] signaling in above three immune organs. (4) On the basis of C3 content (head kidney), C4 content (spleen) and skin hemorrhage and lesion, the optimal ETSP supplementation levels in low protein diets were estimated to be 1.48%, 1.61% and 1.03%, respectively. In summary, ETSP supplementation in low protein diets improved immune function of head kidney, spleen and skin in on-growing grass carp.

RETRACTED: The effect of combined application of pentoxifylline and vitamin E for the treatment of osteoradionecrosis of the jaws: a meta-analysis.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the corresponding author and following a translated comparative examination of the two articles for similarity. It has been concluded that duplicate publication has occurred. The significantly duplicated article of the same title by same research team is: The effect of combined application of pentoxifylline and vitamin E for the treatment of osteoradionecrosis of the jaws: A meta-analysis Chin J Stomatol Res (Electronic Edition). August 2017, Vol.11, No.4. Both articles report on a meta-analysis study and focus on the treatment of osteoradionecrosis of the jaws by pentoxifylline combined with vitamin E, with search timeframe extending 2 years later in the retracted article.

Enzyme-treated soy protein supplementation in low protein diet improved flesh tenderness, juiciness, flavor, healthiness, and antioxidant capacity in on-growing grass carp (Ctenopharyngodon idella).

An 8-week feeding trial was conducted to investigate the effects of enzyme-treated soy protein (ETSP) supplementation in low protein diets on growth performance as well as flesh sensory quality and healthiness in on-growing grass carp. A total of 540 on-growing grass carp (initial average weight 325.72 ± 0.60 g) were fed six diets, which included a normal protein diet (28% crude protein) and five low protein diets (26% crude protein) supplemented with graded levels of ETSP (0.0, 0.8, 1.2, 1.6, and 2.0%). The results showed that reducing dietary protein by 2% decreased percentage weight gain, feed intake, and flesh flavor (aspartic acid, glutamic acid, histidine, and 5'-inosinic acid contents) and healthiness-related indices (linolenic acid (LA) and docosahexaenoic acid (DHA) contents and polyunsaturated fatty acids to saturated fatty acids ratio). Under the condition of reducing dietary protein by 2%, 0.8-1.2% ETSP supplementation restored above parameters to levels equal or superior to those in 28% crude protein diet group. Although reducing dietary protein by 2% did not deteriorate flesh tenderness and juiciness, 0.8-1.2% ETSP supplementation in low protein diets also improved the two indices compared with 28% crude protein diet. Moreover, ETSP-improved flesh quality was partly related to increased muscle antioxidant enzymes activities and their mRNA levels. In addition, ESTP-enhanced antioxidant enzyme mRNA levels were partly associated with the upregulation of NF-E2-related factor 2 (Nrf2) and target of rapamycin (TOR) signaling. Collectively, 0.8-1.2% ETSP supplementation in low protein diets improved growth performance as well as flesh sensory quality and healthiness in on-growing grass carp.

Emerging protective roles of shengmai injection in septic cardiomyopathy in mice by inducing myocardial mitochondrial autophagy via caspase-3/Beclin-1 axis.

BACKGROUND: Sepsis, a life-threatening systemic syndrome related to inflammatory response, usually accompanied by major organ dysfunctions. The aim of the present study was to elucidate the role by which Shengmai injection (SMI) acts to septic cardiomyopathy. METHODS: Initially, the induced mice with septic cardiomyopathy were treated with SMI or normal saline (NS) with oe-caspase-3, and HL-1 cells were treated with oe-Beclin-1 and oe-caspase-3 and then cultured with lipopolysaccharide (LPS). Subsequently, we measured the cardiac troponin I (cTnI) level, and expression of mitochondrial autophagy protein (parkin and pink1) and myocardial cell autophagy-related proteins (LC3-II and LC3-I). Additionally, we identified the cleavage of Beclin-1 by caspase-3 and detected the changes of mitochondrial membrane potential, level of reactive oxygen species (ROS), and apoptosis of myocardial cells in myocardial tissues of mice. RESULTS: It has been demonstrated that SMI contributed to the increase of myocardial mitochondrial autophagy, reduction of cTnI level, and elevation of mitochondrial membrane potential in septic cardiomyopathy mice. Both in vitro and in vivo experiments showed that caspase-3 promoted cleavage of Beclin-1 and release of ROS, whereas repressed lipopolysaccharide (LPS)-induced mitochondrial autophagy. Furthermore, the facilitation of myocardial mitochondrial autophagy and protection of myocardial mitochondria by SMI through inhibition of cleavage Beclin-1 by caspase-3 in septic cardiomyopathy mice were also proved by in vivo experiments. CONCLUSION: Taken together, SMI could protect myocardial mitochondria by promoting myocardial mitochondrial autophagy in septic cardiomyopathy via inhibition of cleavage of Beclin-1 by caspase-3. Our study demonstrates that SMI could represent a novel target for treatment of septic cardiomyopathy.

Effect of enzymatic hydrolysate of cottonseed protein supplementation on growth performance and intestinal health of nursery pigs in Thailand.

This study investigated the effects of enzymatic hydrolysate of cottonseed protein (EHCP) supplementation on the growth performance and intestinal health of nursery pigs in Thailand. A total of 180 newly weaned piglets were randomly allocated to 3 groups with 6 replicates in each group and 10 piglets per replicate. Nursery pigs were fed three diets containing 0, 1%, and 1.5% EHCP for 28-63 days of age. The results indicated that 1% EHCP supplementation increased average daily feed intake (ADFI) and average daily gain (ADG) and decreased feed conversion rate (FCR) in the numerical, suggesting that appropriate EHCP supplementation could numerically improve growth performance of nursery pigs in Thailand. Moreover, 1% EHCP supplementation significantly decreased intestinal crypt depth and diarrhea incidence and increased intestinal villus height to crypt depth ratio and fecal consistency, suggesting that optimum EHCP supplementation could improve intestinal morphology and decreased diarrhea incidence of nursery pigs in Thailand. Furthermore, 1% EHCP supplementation significantly improved intestinal glutathione (GSH) level and superoxide dismutase (SOD) activity and indicated that optimal EHCP supplementation could improve intestinal antioxidant capacity of nursery pigs in Thailand. Optimum EHCP supplementation numerically increased growth, significantly decreased diarrhea incidence, significantly improved intestinal morphology and antioxidant capacity of nursery pig in Thailand.

Peptide supplementation to nutrient-adequate diets enhanced internal egg quality during storage in hens at peak production.

BACKGROUND: There is paucity of information on the use of dietary peptides in laying hens and its effects on egg production and quality. In the current study, peptide from enzymatic hydrolysis of soybean protein was incorporated into laying hens' diets to investigate its effect on egg production and internal egg quality. RESULTS: There were no treatment effects on egg production (average hen day production was 96%) during the experiment. Final body weight of the hens increased quadratically (P < 0.05) in response to peptide supplementation. There were no significant effects of peptide supplementation on internal egg quality of the fresh eggs. Peptide supplementation tended to increase yolk colour (P < 0.10) in eggs collected at 4 weeks of the study and stored at room temperature for 14 days. For the eggs collected at 8 weeks of the experiment and stored at room temperature for 14 days, peptide supplementation linearly increased (P < 0.05) albumen height, Haugh unit and yolk index but linearly decreased (P < 0.01) yolk width. CONCLUSION: Peptide supplementation to laying hens at peak production, receiving diets meeting their nutrient requirement, did not improve hen production but positively helped to maintain hens' body weight and egg quality during storage. © 2017 Society of Chemical Industry.

Supplementation of enzyme-treated soy protein saves dietary protein and promotes digestive and absorptive ability referring to TOR signaling in juvenile fish.

This study was conducted to evaluate the effect of enzyme-treated soy protein (ETSP) supplementation in the low-protein diet on growth performance, digestive and absorptive capacities, and related signaling molecules' gene expressions in juvenile Jian carp. The results showed that percent weight gain (PWG), specific growth rate (SGR), and feed intake (FI) were decreased by reducing dietary protein from 34 to 32% (P < 0.05). Supplying low-protein diet with optimal ETSP increased previously mentioned indices of juvenile Jian carp (P < 0.05), which also had no significant difference with the high-protein diet (34%CP) (P > 0.05). Compared with the low-protein diet, appropriate ETSP supplementation in the low-protein diet increased (P < 0.05) (1) the trypsin, lipase, and amylase activities in the hepatopancreas; (2) cholecystokinin concentration in the proximal intestine; (3) the γ-glutamyl transpeptidase (γ-GT), alkaline phosphatase (AKP), and Na+/K+-ATPase activities in all intestinal segments; and (4) the messenger RNA (mRNA) levels of trypsin, lipase, and amylase in hepatopancreas and γ-GT in the mid (MI) and distal (DI) intestine, alkaline phosphatase in MI, and Na+/K+-ATPase and target of rapamycin in all intestinal segments. At the same time, appropriate ETSP supplementation in the low-protein diet downregulated the mRNA levels of AKP in the DI and eIF4E-binding protein 2 in all intestinal segments (P < 0.05). In conclusion, adding 10 g ETSP/kg diet in the low-protein diet can restore the growth performance and digestive and absorptive abilities to the levels in group with 34% dietary protein. Supplementation of optimal ETSP in the low-protein diet enhanced the digestive and absorptive abilities and regulated the signaling molecules related to the TOR signaling pathway.

The value of the Prognostic Nutritional Index (PNI) in predicting outcomes and guiding the treatment strategy of nasopharyngeal carcinoma (NPC) patients receiving intensity-modulated radiotherapy (IMRT) with or without chemotherapy.

PURPOSE: The purpose of this study was to investigate the significance of the Prognostic Nutritional Index (PNI) in predicting prognoses and guiding treatment choices of nasopharyngeal carcinoma (NPC) patients receiving intensity-modulated radiotherapy (IMRT). METHODS: The 539 patients with newly diagnosed non-metastatic NPC were retrospectively analysed. The PNI was calculated as 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). All patients were split randomly into a training set and a testing set. Receiver operating characteristic (ROC) curves were used to identify the cut-off value of PNI and test its prognostic validity. Survival curves were calculated by Kaplan-Meier method, and differences were compared with log-rank test. RESULTS: The median follow-up time was 109.5 months. The 5-year locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), disease-specific survival (DSS) and overall survival (OS) of the whole cohort were 90.6, 85.8, 85.3 and 82.7%, respectively. The PNI cut-off value was 52.0 in the training set, which was significant in predicting DMFS, DSS and OS in the testing set. According to the PNI cut-off value, 220 patients of II-IVb stage treated by concurrent chemoradiotherapy (CCRT) were classified into PNI ≤ 52.0 and >52.0 groups and the 5-year LRRFS, DMFS, DSS, and OS of PNI ≤ 52.0 group were significantly worse than the PNI > 52.0 group. CONCLUSION: Our results suggest that the PNI is a reliable independent prognostic factor in NPC patients treated with IMRT. For stage II-IVb patients with PNI ≤ 52.0, CCRT alone does not achieve satisfactory outcomes, and further studies on treatment optimization are needed.

Effects of graded levels of dietary methionine hydroxy analogue on immune response and antioxidant status of immune organs in juvenile Jian carp (Cyprinus carpio var. Jian).

Immune response and antioxidant status of immune organs in juvenile Jian carp (Cyprinus carpio var. Jian) fed graded levels of methionine hydroxy analogue (MHA) (0, 5.1, 7.6, 10.2, 12.7, 15.3 g kg(-1) diet) for 60 days were investigated. Results indicated that head kidney index, spleen index, red and white blood cell counts significantly increased with increasing MHA levels up to a point (P < 0.05), whereupon decreased (P < 0.05). Glutathione reductase activity in head kidney and spleen, anti-hydroxy radical and glutathione-S-transferase activities in spleen, catalase activity and GSH content in head kidney significantly increased by MHA supplement, while malondialdehyde content, anti-superoxide anion, superoxide dismutase, glutathione peroxidase activities in head kidney and spleen, protein carbonyl content and catalase activity in spleen, anti-hydroxy radical activity in head kidney significantly decreased by MHA supplement. However, protein carbonyl content and glutathione-S-transferase activity in head kidney, GSH content in spleen remained unaffected. After 60-day feeding trial, a challenge study was conducted by injection of Aeromonas hydrophila for 17 days. Results showed that survival rate, leukocytes phagocytic activity, lysozyme activity, acid phosphatase activity, total iron-binding capacity, haemagglutination titre, complement 3, 4 and immunoglobulin M contents significantly increased by optimal dietary MHA supplement (P < 0.05). These data suggested that MHA affected antioxidant status of immune organs and promoted immune response in juvenile Jian carp.

The cell toxicity effect of secalonic acid D on GH3 cells and the related mechanisms.

To investigate the anti-pituitary adenoma effect of secalonic acid D (SAD) extracting from marine microorganisms, we used MTT colorimetric method to evaluate the proliferation of GH3 cells treated by SAD, the time- and dose-dependent effects and the value of IC50 were recorded. Hoechst staining, Tunel and flow cytometry methods were used to analyze the apoptosis rate of GH3 cells treated by SAD. Western blotting, RT-PCR and caspase inhibitor (Z-VAD-FMK) were used to investigate the possible mechanism of SAD induced apoptosis and the expression of growth hormone (GH). The results showed that SAD has a time- and dose-dependent effect on GH3 cells and the cytotoxic effect was mainly through apoptosis. The mechanisms were partly through the activity of caspase family and also G1/S phase block. In addition, SAD also can suppress the expression levels of growth hormone in GH3 cells, however, the RT-PCR results showed that the mechanism was not through changing the expression of GH mRNA. We concluded that SAD may be a potential anti-pituitary tumor drug and further in vivo studies should be performed.