Mucinous histology is a negative predictor of neoadjuvant chemoradiotherapy for locally advanced rectal adenocarcinoma.

BACKGROUND: Neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC). Mucinous adenocarcinoma (MAC) is a potential poor prognosis subgroup of rectal cancer. However, the predictive value of MAC in NCRT treatment of LARC is controversial. METHODS: A comprehensive literature search of PubMed, Embase, and the Cochrane Library was performed. All studies examining the effect of MAC on CRT response in LARC were included. Outcomes of MAC were compared with non-specific adenocarcinoma (AC) by using random-effects methods. Data were presented as odds ratios (ORs) with 95% confidence intervals (CIs). The main outcomes were the rates of pathological complete response (pCR), tumor and nodal down-staging, positive resection margin rate, local recurrence, and overall mortality. RESULTS: Fifteen studies containing comparative data on outcomes in a total of 9,238 patients receiving NCRT for LARC were eligible for inclusion. MAC had a reduced rate of pCR (OR, 0.38; 95% CI, 0.18-0.78) and tumor down-staging (OR, 0.31; 95% CI, 0.22-0.44) following NCRT compared with AC. MAC did not significantly affect nodal down-staging (OR, 0.42; 95% CI, 0.16-1.12) after NCRT. CONCLUSION: MAC of LARC was found to be a negative predictor of response to NCRT with lower rates of pCR and tumor down-staging for LARC. The nodal down-staging of MAC was relatively lower than that of AC, although the differences were not statistically significant.

The Role and Therapeutic Potential of Pyroptosis in Colorectal Cancer: A Review.

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. The unlimited proliferation of tumor cells is one of the key features resulting in the malignant development and progression of CRC. Consequently, understanding the potential proliferation and growth molecular mechanisms and developing effective therapeutic strategies have become key in CRC treatment. Pyroptosis is an emerging type of regulated cell death (RCD) that has a significant role in cells proliferation and growth. For the last few years, numerous studies have indicated a close correlation between pyroptosis and the occurrence, progression, and treatment of many malignancies, including CRC. The development of effective therapeutic strategies to inhibit tumor growth and proliferation has become a key area in CRC treatment. Thus, this review mainly summarized the different pyroptosis pathways and mechanisms, the anti-tumor (tumor suppressor) and protective roles of pyroptosis in CRC, and the clinical and prognostic value of pyroptosis in CRC, which may contribute to exploring new therapeutic strategies for CRC.

Diphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects.

Diphthamide is a modified histidine residue unique for eukaryotic translation elongation factor 2 (eEF2), a key ribosomal protein. Loss of this evolutionarily conserved modification causes developmental defects through unknown mechanisms. In a patient with compound heterozygous mutations in Diphthamide Biosynthesis 1 (DPH1) and impaired eEF2 diphthamide modification, we observe multiple defects in neural crest (NC)-derived tissues. Knockin mice harboring the patient's mutations and Xenopus embryos with Dph1 depleted also display NC defects, which can be attributed to reduced proliferation in the neuroepithelium. DPH1 depletion facilitates dissociation of eEF2 from ribosomes and association with p53 to promote transcription of the cell cycle inhibitor p21, resulting in inhibited proliferation. Knockout of one p21 allele rescues the NC phenotypes in the knockin mice carrying the patient's mutations. These findings uncover an unexpected role for eEF2 as a transcriptional coactivator for p53 to induce p21 expression and NC defects, which is regulated by diphthamide modification.

Impact of bariatric surgery on glucose and lipid metabolism and liver and kidney function in food-induced obese diabetic rats.

BACKGROUND: Obesity usually causes diabetes mellitus (DM) and is a serious danger to human health. Type 2 DM (T2DM) mostly occurs along with obesity. Foodborne obesity-induced DM is caused by an excessive long-term diet and surplus energy. Bariatric surgery can improve the symptoms of T2DM in some obese patients. But different types of bariatric surgery may have different effects. AIM: To investigate the effect of bariatric surgery on glucose and lipid metabolism and liver and kidney function in rats. METHODS: Male Sprague-Dawley rats aged 6-8 wk underwent Roux-en-Y gastric bypass surgery (RYGB), sleeve gastrectomy (SG), or gastric banding (GB). Glucose and insulin tolerance tests, analyses of biochemical parameters, histological examination, western blot, and quantitative real-time polymerase chain reaction were conducted. RESULTS: In comparison to the sham operation group, the RYGB, SG, and GB groups had decreased body weight and food intake, reduced glucose intolerance and insulin insensitivity, downregulated biochemical parameters, alleviated morphological changes in the liver and kidneys, and decreased levels of protein kinase C ß/ P66shc. The effect in the RYGB group was better than that in the SG and GB groups. CONCLUSION: These results suggest that RYGB, SG and GB may be helpful for the treatment of foodborne obesity-induced DM.

DMT1 differentially regulates mitochondrial complex activities to reduce glutathione loss and mitigate ferroptosis.

Mitochondria are vital for energy production and redox homeostasis, yet knowledge of relevant mechanisms remains limited. Here, through a genome-wide CRISPR-Cas9 knockout screening, we have identified DMT1 as a major regulator of mitochondria membrane potential. Our findings demonstrate that DMT1 deficiency increases the activity of mitochondrial complex I and reduces that of complex III. Enhanced complex I activity leads to increased NAD+ production, which activates IDH2 by promoting its deacetylation via SIRT3. This results in higher levels of NADPH and GSH, which improve antioxidant capacity during Erastin-induced ferroptosis. Meanwhile, loss of complex III activity impairs mitochondrial biogenesis and promotes mitophagy, contributing to suppression of ferroptosis. Thus, DMT1 differentially regulates activities of mitochondrial complex I and III to cooperatly suppress Erastin-induced ferroptosis. Furthermore, NMN, an alternative method of increasing mitochondrial NAD+, exhibits similar protective effects against ferroptosis by boosting GSH in a manner similar to DMT1 deficiency, shedding a light on potential therapeutic strategy for ferroptosis-related pathologies.

IL-33 promotes double negative T cell survival via the NF-κB pathway.

IL-33, which is a crucial modulator of adaptive immune responses far beyond type 2 response, can enhance the function of several T cell subsets and maintain the immune homeostasis. However, the contribution of IL-33 to double negative T (DNT) cell remains unappreciated. Here, we demonstrated that the IL-33 receptor ST2 was expressed on DNT cells, and that IL-33 stimulation increased DNT cells proliferation and survival in vivo and in vitro. Transcriptome sequencing analysis also demonstrated that IL-33 enhanced the biological function of DNT cells, especially effects on proliferation and survival. IL-33 promoted DNT cells survival by regulating Bcl-2, Bcl-xl and Survivin expression. IL-33-TRAF4/6-NF-κB axis activation promoted the transmission of essential division and survival signals in DNT cells. However, IL-33 failed to enhance the expression of immunoregulatory molecules in DNT cells. DNT cells therapy combined with IL-33 inhibited T cells survival and further ameliorated ConA-induced liver injury, which mainly depended on the proliferative effect of IL-33 on DNT cells in vivo. Finally, we stimulated human DNT cells with IL-33, and similar results were observed. In conclusion, we revealed a cell intrinsic role of IL-33 in the regulation of DNT cells, thereby identifying a previously unappreciated pathway supporting the expansion of DNT cells in the immune environment.

Improved Aluminum Adjuvants Eliciting Stronger Immune Response When Mixed with Hepatitis B Virus Surface Antigens.

Adjuvants can regulate the immune response triggered by vaccines. Traditional aluminum adjuvants can induce humoral immunity, but they lack the ability to effectively induce Th1 cellular immunity, which is not conducive to the development of vaccines with improved protective effects. Aluminum adjuvants from different sources may have different physicochemical properties, and therefore, completely different immune responses can be triggered. This suggests that adjuvant recognition by the immune system and its responses are closely associated with the physicochemical properties of the adjuvant itself. To test this hypothesis, in this study, we developed a new method for preparing an aluminum adjuvant. This aluminum adjuvant has a pseudoboehmite structure, strong protein adsorption capacity, and excellent suspension stability. The adjuvant was tested using the hepatitis B virus surface antigen (HBsAg) as a model antigen for immunization; the results showed that this aluminum adjuvant effectively induced not only humoral immunity but also an outstanding cellular immune response. These results provide a reference for improving the efficacy of adjuvants.

[Realization and Clinical Study of Robotic Technology in Cardiovascular Interventional Surgery].

The high incidence of cardiovascular diseases is a serious threat to human health, and endovascular surgery has become the standard treatment for most interventional cardiovascular diseases. The robotassisted endovascular surgery system further enhances surgeons' ability to perform minimally invasive endovascular procedures in interventional cardiology. This study presents a new robotic technique for coronary intervention from the perspective of clinical application. Aiming at clinical application scenarios, this scheme proposed an intuitive guide wire catheter mechanism design, which accurately and perfectly simulates the doctor's hand movements, realizes the positive and negative direction translation of the guide wire catheter, accurate torque control of the guide wire rotation and locking. The results of animal test showed that the R-OneTM has a high degree of dexterity, accuracy and stability,and meets the clinical needs.

Binding of regulatory proteins to nucleosomes is modulated by dynamic histone tails.

Little is known about the roles of histone tails in modulating nucleosomal DNA accessibility and its recognition by other macromolecules. Here we generate extensive atomic level conformational ensembles of histone tails in the context of the full nucleosome, totaling 65 microseconds of molecular dynamics simulations. We observe rapid conformational transitions between tail bound and unbound states, and characterize kinetic and thermodynamic properties of histone tail-DNA interactions. Different histone types exhibit distinct binding modes to specific DNA regions. Using a comprehensive set of experimental nucleosome complexes, we find that the majority of them target mutually exclusive regions with histone tails on nucleosomal/linker DNA around the super-helical locations ± 1, ± 2, and ± 7, and histone tails H3 and H4 contribute most to this process. These findings are explained within competitive binding and tail displacement models. Finally, we demonstrate the crosstalk between different histone tail post-translational modifications and mutations; those which change charge, suppress tail-DNA interactions and enhance histone tail dynamics and DNA accessibility.

Surgical hip dislocation for treatment of synovial chondromatosis of the hip.

PURPOSE: In the present study, we aimed to evaluate the clinical outcomes of surgical hip dislocation in patients with synovial chondromatosis (SC) of the hip. METHODS: Seven patients with primary SC of the hip treated with open synovectomy and removal of loose bodies by surgical hip dislocation from 2016 to 2019 were retrospectively reviewed. All patients had numerous and widespread loose bodies based on pre-operative images, including routine radiographs, CT, and MRI. The visual analog scale (VAS) score and Harris hip score (HHS) were collected and analyzed before and after surgery. The post-operative radiographs were reviewed to evaluate disease recurrence and osteoarthritis progression. RESULTS: The mean operative time was 61 minutes (range, 42-75 min). An average of 33 loose bodies in each patient (range, 16-67) was removed, and extra-articular pathology was found in one patient. Patients were followed up for a mean duration of 30 months (range, 18-42 months). The average VAS scores were decreased from 3.7 (range, 2-6) pre-operatively to 0.9 (range, 0-2) at the last follow-up, and the HHS was improved from 60.1 (range, 50-73) to 90.1 (range, 82-95). All results demonstrated significant improvements (P < 0.05). Post-operative radiographs showed no recurrence, osteoarthritis progression, or osteonecrosis of the femoral head in all hips. CONCLUSIONS: Surgical hip dislocation was a practical approach for managing both intra-articular and extra-articular pathologic lesions around the hip. It was an effective treatment for SC of the hip with short surgical time, good joint functions, a lower recurrence rate, and few complications.

A polymer-based zwitterionic stationary phase for hydrophilic interaction chromatography.

We describe a novel polymer-based zwitterionic stationary phase for hydrophilic interaction chromatography (HILIC). It is prepared by chemical modification of poly (glycidyl methacrylate-divinylbenzene) (GMA-DVB) by converting epoxide groups of microsphere surface to diol groups via hydrolysis, then clicking cysteine onto the microsphere with pendant double bonds of microsphere surface via "thiol-ene" click chemistry. The phase has been characterized by scanning electron micrograph, elemental analysis and zeta potential measurement. Diol and zwitterionic group (carboxylate and amine group associated with cysteine) onto the surface of GMA-DVB microspheres make them possess good hydrophilicity, as supported by effective separation towards common polar analytes. It shows good stability at alkaline solution (e.g. pH 10) and negligible bleed (e.g. only 1.7-fold blank and ~55-fold lower than a commercial silica-based polar phase tested with the minimal bleed level). Such phase exhibits specific separation selectivity to ionic analytes and simultaneous separation of anions and cations is achieved in the retention order of I- < NO3- < Choline < Br- < Cl- < K+< Na+.

Better outcomes are associated with cementless fixation in primary total knee arthroplasty in young patients: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The use of cemented and cementless fixations in primary total knee arthroplasty (TKA) in young patients is controversial. Previous reviews predominantly relied on data from retrospective studies. This systematic review and meta-analysis of randomized controlled trials (RCTs) evaluated the optimal fixation mode in TKA for young patients. METHODS: The PubMed, Embase, Medline, Web of Science, and full Cochrane Library electronic databases were searched from inception to July 2018. The outcome measurements consisted of functional outcomes (Knee Society Score [KSS], range of motion [ROM]), radiolucent lines, aseptic loosening, total complications, and reoperation rate. Study data were pooled using a random-effects model. RESULTS: Six RCTs were included in the systematic review and meta-analysis. The mean follow-up period was 12 years (range, 2-16.6 years). Cementless TKA was associated with higher KSS-function (P < .0001), higher KSS-pain (P = .005), better ROM recovery (P = .01), and fewer radiolucent lines (<1 mm) (P = .04) compared with cemented TKA. No significant intergroup differences were observed for KSS-knee, total complications, aseptic loosening, or reoperation rate. These results based on a random-effects model were unchanged by sensitivity analysis assumptions. CONCLUSION: Cementless TKA was substantially superior to cemented TKA in young patients. Although the complication and survival rates were similar between groups, better clinical outcomes were obtained with cementless fixation. Further well-designed studies with long follow-up durations are necessary to confirm our findings.

Overexpression of soybean GmPLDγ enhances seed oil content and modulates fatty acid composition in transgenic Arabidopsis.

Phospholipase D (PLD) hydrolyzes the phosphodiester bond of glycerophospholipids to yield phosphatidic acid (PA) and a free headgroup. PLDs are important for plant growth, development, and responses to external stresses. However, their roles in triacylglycerol (TAG) synthesis are still unclear. Here, we report that a soybean (Glycine max) PLDγ (GmPLDγ) is involved in glycerolipid turnover and seed oil production. GmPLDγ was targeted to mitochondria and exhibited PLD activity that was activated by oleate and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2]. Overexpression of GmPLDγ (abbreviated GmPLDγ-OE) in Arabidopsis thaliana resulted in enhanced seed weight, elevated levels of TAGs with 18-, 20-, and 22-carbon fatty acids (FAs), and altered oil-body morphology. Furthermore, the levels of membrane lipids in vegetative tissues decreased significantly, whereas no overt changes were found in mature seeds except for a decrease in the digalactosyldiacylglycerol (DGDG) level in the GmPLDγ-OE lines. Additionally, the expression of genes involved in glycerolipid metabolism was significantly upregulated in developing siliques in GmPLDγ-OE lines. Together, our data indicate a regulatory role for GmPLDγ in TAG synthesis and fatty-acid remodeling, highlighting the importance of mitochondria-directed glycerophospholipid homeostasis in seed oil accumulation.

Efficacy of Portable Accelerometer-Based Navigation Devices versus Conventional Guides in Total Knee Arthroplasty: A Meta-analysis.

Various studies have provided different conclusions regarding which component's alignment can be actually improved by a novel portable accelerometer-based navigation device (PAD) compared with the conventional guide (CON); the operative times and clinical outcomes reported by these studies also exhibited incongruity. Thus, this meta-analysis was conducted to evaluate the efficacy of PADs in total knee arthroplasty (TKA). The Web of Science, EMBASE, PubMed, MEDLINE, and Cochrane Library databases were systematically searched. Studies published till July 2018 and comparing PAD with CON in treatment with TKA were identified. Sixteen studies in which 1,551 TKAs were reported were included. Results showed that PAD was significantly superior to CON in reducing tibial component alignment out of ±3 degrees, femoral coronal angle out of ±3 degrees, and overall mechanical alignment out of ±3 degrees. PAD can also help obtain a more accurate result of femoral coronal angle (degree); however, it requires a longer operative time than the CON group. The two groups were comparable in tibial component alignment out of ±2 degrees, tibial component posterior slope out of ±3 degrees, tibial component posterior slope out of ±2 degrees, femoral coronal angle out of ±2 degrees, femoral sagittal angle out of ±3 degrees, femoral sagittal angle out of ±2 degrees, tibial component alignment (degree), tibial component posterior slope (degree), femoral sagittal angle (degree), overall mechanical alignment (degree), blood loss, Knee Society knee score, Knee Society function score, Oxford Knee Score, Short Form-36 physical component score, Short Form-36 mental component score, and range of motion. In conclusion, compared with CON, PAD can help improve the femoral coronal angle as well as decrease the outliers out of ±3 degrees in femoral/tibial coronal angles and overall mechanical alignment. However, PAD did not show significant advantages in tibial and femoral component sagittal angles out of ±3 degrees, various outliers of ±2 degrees, most mean values of component alignments, operative time, and various functional or satisfactory scores.

Genome-wide analysis and functional characterization of Acyl-CoA:diacylglycerol acyltransferase from soybean identify GmDGAT1A and 1B roles in oil synthesis in Arabidopsis seeds.

Acyl-CoA:diacylglycerol acyltransferase (DGAT) is a key enzyme in the Kennedy pathway of triacylglycerol (TAG) synthesis. It catalyzes the acyl-CoA-dependent acylation of sn-1, 2-diacylglycerol to form TAG. DGATs in soybean (Glycine max) have been reported, but their functions are largely unclear. Here we cloned three members of DGAT1 and four members of DGAT2 family from soybean, named GmDGAT1A to GmDGAT1C, and GmDGAT2A to GmDGAT2D, respectively. GmDGAT1A and GmDGAT1C were expressed at a high level in immature seeds, GmDGAT2B in mature seeds, and GmDGAT2C in older leaves. The seven genes were transformed into the H1246 quadruple mutant yeast strain, in which GmDGAT1A, GmDGAT1B, GmDGAT1C, GmDGAT2A, and GmDGAT2B had the ability to produce TAG. Six genes were transformed into Arabidopsis respectively, and constitutive expression of GmDGAT1A and GmDGAT1B resulted in an increase in oil content at the cost of reduced protein content in seeds. Overexpression of GmDGAT1A produced heavier weight of individual seed, but did not affect the weight of total seeds from a plant. Our results reveal the functions of soybean DGATs in seed oil synthesis using transgenic Arabidopsis. The implications for the biotechnological modification of the oil contents in soybeans by altering DGAT expression are discussed.

The immunoregulatory effects of CD8 T-cell-derived perforin on diet-induced nonalcoholic steatohepatitis.

The liver is a central immunologic organ with a high density of myeloid and lymphoid immune cells that play important roles in the development and progression of nonalcoholic steatohepatitis (NASH). However, the immune-cell-mediated regulation of NASH and its underlying mechanisms remain obscure. In this study, Prf1null mice showed significantly higher plasma alanine transaminase levels, with increased liver fat accumulation, lobular inflammation, and focal necrosis compared with wild-type (WT) mice after 4 wk of feeding on a methionine- and choline-deficient diet (MCD) or 16 wk of feeding on a high-fat diet. Perforin deficiency promoted the M1 polarization of infiltrated monocytes. Moreover, MCD-fed Prf1null mice exhibited increased accumulation, survival, activation, and proinflammatory cytokine production of CD8 T cells but not NK cells or CD4 T cells. Adoptive transfer of CD8 T cells or NK cells from WT or Prf1null mice, together with non-CD8 cells or non-NK cells from WT mice, indicated that CD8 T-cell-derived perforin participates in the mechanism regulating liver inflammation and thus plays a protective role in the development of NASH. Perforin-deficient CD8 T cells exhibited decreased cytotoxicity toward bone marrow-derived M1 monocytes and macrophages. According to the RNA sequencing data, the perforin deficiency inhibited cell apoptosis and enhanced the activation, migration, and proinflammatory cytokine production of CD8 T cells in mice with NASH. Furthermore, we found higher plasma soluble perforin levels and hepatic perforin expression in NASH patients, suggesting clinical relevance of the findings. We have elucidated an important role for the cytotoxic immune effector molecule perforin from CD8 T cells in restricting hepatic inflammation in mice with NASH and suggest that therapies designed to maximize the function of endogenous perforin in CD8 T cells might have potential benefits as NASH treatments.-Wang, T., Sun, G., Wang, Y., Li, S., Zhao, X., Zhang, C., Jin, H., Tian, D., Liu, K., Shi, W., Tian, Y., Zhang, D. The immunoregulatory effects of CD8 T-cell-derived perforin on diet-induced nonalcoholic steatohepatitis.