Autophagy and its role in gastrointestinal diseases.

Gastrointestinal disorders encompass a spectrum of conditions affecting various organs within the digestive system, such as the esophagus, stomach, colon, rectum, pancreas, liver, small intestine, and bile ducts. The role of autophagy in the etiology and progression of gastrointestinal diseases has garnered significant attention. This paper seeks to evaluate the impact and mechanisms of autophagy in gastrointestinal disorders by synthesizing recent research findings. Specifically, we delve into inflammation-related gastrointestinal conditions, including ul-cerative colitis, Crohn's disease, and pancreatitis, as well as gastrointestinal cancers such as esophageal, gastric, and colorectal cancers. Additionally, we provide commentary on a recent publication by Chang et al in the World Journal of Gastroenterology. Our objective is to offer fresh perspectives on the mechanisms and therapeutic approaches for these gastrointestinal ailments. This review aims to offer new perspectives on the mechanisms and therapeutic strategies for gastrointestinal disorders by critically analyzing relevant publications. As discussed, the role of autophagy in gastrointestinal diseases is complex and, at times, contentious. To harness the full therapeutic potential of autophagy in treating these conditions, more in-depth research is imperative.

N6-Methyladenosine-mediated phase separation suppresses NOTCH1 expression and promotes mitochondrial fission in diabetic cardiac fibrosis.

BACKGROUND: N6-methyladenosine (m6A) modification of messenger RNA (mRNA) is crucial for liquid-liquid phase separation in mammals. Increasing evidence indicates that liquid-liquid phase separation in proteins and RNAs affects diabetic cardiomyopathy. However, the molecular mechanism by which m6A-mediated phase separation regulates diabetic cardiac fibrosis remains elusive. METHODS: Leptin receptor-deficient mice (db/db), cardiac fibroblast-specific Notch1 conditional knockout (POSTN-Cre × Notch1flox/flox) mice, and Cre mice were used to induce diabetic cardiac fibrosis. Adeno-associated virus 9 carrying cardiac fibroblast-specific periostin (Postn) promoter-driven small hairpin RNA targeting Alkbh5, Ythdf2, or Notch1, and the phase separation inhibitor 1,6-hexanediol were administered to investigate their roles in diabetic cardiac fibrosis. Histological and biochemical analyses were performed to determine how Alkbh5 and Ythdf2 regulate Notch1 expression in diabetic cardiac fibrosis. NOTCH1 was reconstituted in ALKBH5- and YTHDF2-deficient cardiac fibroblasts and mouse hearts to study its effects on mitochondrial fission and diabetic cardiac fibrosis. Heart tissue samples from patients with diabetic cardiomyopathy were used to validate our findings. RESULTS: In mice with diabetic cardiac fibrosis, decreased Notch1 expression was accompanied by high m6A mRNA levels and mitochondrial fission. Fibroblast-specific deletion of Notch1 enhanced mitochondrial fission and cardiac fibroblast proliferation and induced diabetic cardiac fibrosis in mice. Notch1 downregulation was associated with Alkbh5-mediated m6A demethylation in the 3'UTR of Notch1 mRNA and elevated m6A mRNA levels. These elevated m6A levels in Notch1 mRNA markedly enhanced YTHDF2 phase separation, increased the recognition of m6A residues in Notch1 mRNA by YTHDF2, and induced Notch1 degradation. Conversely, epitranscriptomic downregulation rescues Notch1 expression, resulting in the opposite effects. Human heart tissues from patients with diabetic cardiomyopathy were used to validate the findings in mice with diabetic cardiac fibrosis. CONCLUSIONS: We identified a novel epitranscriptomic mechanism by which m6A-mediated phase separation suppresses Notch1 expression, thereby promoting mitochondrial fission in diabetic cardiac fibrosis. Our findings provide new insights for the development of novel treatment approaches for patients with diabetic cardiac fibrosis.

m6A control programmed cell death in cardiac fibrosis.

N6-methyladenosine (m6A) modification is closely related to cardiac fibrosis. As the most common and abundant form of mRNA modification in eukaryotes, m6A is deposited by methylases ("writers"), recognized and effected by RNA-binding proteins ("readers"), and removed by demethylases ("erasers"), achieving highly dynamic reversibility. m6A modification is involved in regulating the entire biological process of target RNA, including transcription, processing and splicing, export from the nucleus to the cytoplasm, and enhancement or reduction of stability and translation. Programmed cell death (PCD) comprises many forms and pathways, with apoptosis and autophagy being the most common. Other forms include pyroptosis, ferroptosis, necroptosis, mitochondrial permeability transition (MPT)-dependent necrosis, and parthanatos. In recent years, increasing evidence suggests that m6A modification can mediate PCD, affecting cardiac fibrosis. Since the correlation between some PCD types and m6A modification is not yet clear, this article mainly introduces the relationship between four common PCD types (apoptosis, autophagy, pyroptosis, and ferroptosis) and m6A modification, as well as their role and influence in cardiac fibrosis.

Circulating tumour cells predict recurrences and survival in head and neck squamous cell carcinoma patients.

Patients with head and neck squamous cell carcinoma (HNSCC) are at a high risk of developing recurrence and secondary cancers. This study evaluates the prognostic and surveillance utilities of circulating tumour cells (CTCs) in HNSCC. A total of 154 HNSCC patients were recruited and followed up for 4.5 years. Blood samples were collected at baseline and follow-up. CTCs were isolated using a spiral microfluid device. Recurrence and death due to cancer were assessed during the follow-up period. In patients with HNSCC, the presence of CTCs at baseline was a predictor of recurrence (OR = 8.40, p < 0.0001) and death (OR= ∞, p < 0.0001). Patients with CTCs at baseline had poor survival outcomes (p < 0.0001). Additionally, our study found that patients with CTCs in a follow-up appointment were 2.5 times more likely to experience recurrence or death from HNSCC (p < 0.05) prior to their next clinical visit. Our study highlights the prognostic and monitoring utilities of CTCs' in HNSCC patients. Early identification of CTCs facilitates precise risk assessment, guiding treatment choices and ultimately enhancing patient outcomes.

What benefit can be obtained from magnetic resonance imaging diagnosis with artificial intelligence in prostate cancer compared with clinical assessments?

The present study aimed to explore the potential of artificial intelligence (AI) methodology based on magnetic resonance (MR) images to aid in the management of prostate cancer (PCa). To this end, we reviewed and summarized the studies comparing the diagnostic and predictive performance for PCa between AI and common clinical assessment methods based on MR images and/or clinical characteristics, thereby investigating whether AI methods are generally superior to common clinical assessment methods for the diagnosis and prediction fields of PCa. First, we found that, in the included studies of the present study, AI methods were generally equal to or better than the clinical assessment methods for the risk assessment of PCa, such as risk stratification of prostate lesions and the prediction of therapeutic outcomes or PCa progression. In particular, for the diagnosis of clinically significant PCa, the AI methods achieved a higher summary receiver operator characteristic curve (SROC-AUC) than that of the clinical assessment methods (0.87 vs. 0.82). For the prediction of adverse pathology, the AI methods also achieved a higher SROC-AUC than that of the clinical assessment methods (0.86 vs. 0.75). Second, as revealed by the radiomics quality score (RQS), the studies included in the present study presented a relatively high total average RQS of 15.2 (11.0-20.0). Further, the scores of the individual RQS elements implied that the AI models in these studies were constructed with relatively perfect and standard radiomics processes, but the exact generalizability and clinical practicality of the AI models should be further validated using higher levels of evidence, such as prospective studies and open-testing datasets.

Post-treatment 18F-fludeoxyglocuse-positron emission tomography in human papillomavirus-associated oropharyngeal cancer.

BACKGROUND: Human papillomavirus association has changed the landscape of treatment for oropharyngeal squamous cell carcinoma; it remains to be seen whether current post-treatment surveillance schedules are effective. OBJECTIVE: Evaluate whether post-treatment surveillance of oropharyngeal cancer through FDG-PET imaging is modified by human papillomavirus association. METHODS: A prospective cohort analysis of retrospective data was conducted for patients undergoing treatment of oropharyngeal cancer between 2016 and 2018. This study was conducted at a single large tertiary referral center in Brisbane, Australia. RESULTS: Two-hundred and twenty-four patients were recruited for the purposes of the study, 193 (86%) with HPV-associated disease. In this cohort FDG-PET had a sensitivity of 48.3%, specificity of 72.6%, positive predictive value of 23.7%, and negative predictive value of 88.8% in detecting disease recurrence. CONCLUSIONS: FDG-PET in HPV-associated oropharyngeal cancer has significantly lower positive predictive value when compared to non-HPV-associated oropharyngeal cancer. Caution should be used when interpreting positive post-treatment FDG-PET.

[Acupuncture for treatment of tobacco withdrawal syndrome: systematic review and Meta-analysis].

OBJECTIVE: To systematically review the efficacy of acupuncture for the treatment of tobacco withdrawal syndrome. METHODS: The randomized controlled trials (RCTs) regarding acupuncture for treatment of tobacco withdrawal syndrome were searched in CNKI, Wanfang, VIP, SinoMed, PubMed, Cochrane, Medline and EMbase databases. The search period was from January 1st of 2011 to December 31st of 2021. After data extraction and bias risk assessment of the included literature, the Meta-analysis was performed using RevMan5.4.1 software. RESULTS: Totally 23 RCTs were included, including 2 120 patients. The Meta-analysis results showed that compared with medication, acupuncture showed no significant difference at improving Fagerström test for nicotine dependence (FTND) score (MD=0.16, 95%CI: -0.08, 0.41), heaviness of smoking index (HSI) score (MD=0.11, 95%CI: -0.13, 0.36), Minnesota nicotine withdrawal scale (MNWS) score (MD=0.12, 95%CI: -0.11, 1.35), questionnaire of smoking urges (QSU) score (MD=-0.30, 95%CI: -2.78, 2.18), Hamilton depression scale (HAMD) score (MD=0.76, 95%CI: -1.54, 3.06), abstinence rate (RR=0.95, 95% CI: 0.82, 1.10) and effective rate (RR=1.01, 95%CI: 0.95, 1.07). Acupuncture was superior to sham acupuncture in reducing MNWS score (MD=-4.88, 95%CI: -5.21, -4.55, P<0.000 01). Acupuncture was superior to cognitive behavioral therapy in reducing FTND score (MD=-1.41, 95%CI: -1.74, -1.08), MNWS score (MD=-4.28, 95%CI: -5.31, -3.25) and increasing abstinence rate (RR=2.19, 95%CI: 1.39, 3.45, P<0.000 01, P<0.001). CONCLUSION: Acupuncture could effectively improve tobacco withdrawal syndrome, increase abstinence rate and effective rate. Limited by the quantity and quality of the included studies, this conclusion needs to be verified by more studies.

Posttraumatic checkrein deformity following isolated Lauge-Hansen pronation external rotation stage IV malleolar fracture-a case report and literature review.

The checkrein deformity is characterized by flexion contracture of the interphalangeal joint and extension contracture of the metatarsophalangeal joint. It is a rare condition occurring after lower extremity trauma, especially a malleolar fracture. Little is known about the possible cause and therapeutic strategy. This unique case presents a 20-year-old male patient with a diagnosis of the checkrein deformity secondary to open reduction and internal fixation of a Lauge-Hansen pronation external rotation stage IV malleolar fracture. After performing a detailed physical examination, radiographic evaluation, and ultrasonography, open exploration was performed to remove the hardware and correct the deformity with sole tenolysis of the flexor hallucis longus (FHL). In the 4-month follow-up, no recurrence of the checkrein deformity was observed. This deformity was caused by FHL adhesion. Interosseous membrane injury and fibular fracture together with local hematomas increases the risk of FHL adhesion. Open exploration and tenolysis of the FHL are feasible options to correct the checkrein deformity.

[Auricular point sticking combined with transcutaneous electrical acupoint stimulation for smoking cessation：a randomized controlled trial].

OBJECTIVE: To compare the clinical efficacy between auricular point sticking combined with transcutaneous electrical acupoint stimulation (TEAS) and nicotine patch for smoking cessation. METHODS: Two hundred patients who voluntarily quit smoking were randomly divided into a combination group and a nicotine patch group, 100 cases in each group. In the combination group, auricular point sticking (Shenmen [TF4], Neifenmi [CO18], Pizhixia [AT4], Jiaogan [AH6a], etc., once every other day) combined with TEAS（Lieque [LU 7] and Zusanli [ST 36], with continuous wave, 20 Hz in frequency, 1 mA in current intensity, 30 min each time, once a day) were applied. In the nicotine patch group, nicotine patch was applied. Both groups were treated for 8 weeks. The immediate withdrawal rate and persistent withdrawal rate 8 weeks into treatment and in follow-up of 16 weeks after treatment in the two groups were compared; before treatment, 8 weeks into treatment and in follow-up of 16 weeks after treatment, the degree of nicotine dependence was evaluated by using Fagerström test for nicotine dependence (FTND); 1 week into treatment, 8 weeks into treatment and in follow-up of 16 weeks after treatment, the withdrawal symptoms and smoking craving were evaluated by using Minnesota nicotine withdrawal scale (MNWS); the safety and compliance (dropped off rate and treatment completeness) were evaluated in the two groups. RESULTS: There was no statistical significance of the differences in the immediate withdrawal rate and persistent withdrawal rate 8 weeks into treatment and during follow-up between the two groups (P>0.05). The FTND scores were decreased 8 weeks into treatment and during follow-up in the two groups compared with those before treatment (P<0.01); the FTND score during follow-up in the combination group was lower than the nicotine patch group (P<0.05). The MNWS scores were decreased 8 weeks into treatment and during follow-up in the two groups compared with those 1 week into treatment (P<0.05); the changes of MNWS scores 8 weeks into treatment and during follow-up in the combination group were greater than the nicotine patch group (P<0.05, P<0.01). There were no serious adverse reactions in either group. Eight weeks into treatment and during follow-up, the dropped off rates were all 16.0% (16/100) in the combination group, which were 20.0% (20/100) and 23.0% (23/100) in the nicotine patch group, there was no statistical significance of the differences in the two groups (P>0.05). There was no significant difference in treatment completeness between the two groups (P>0.05). CONCLUSION: Auricular point sticking combined with TEAS could effective decrease the degree of nicotine dependence, improve withdrawal symptoms in smokers, its effect is superior to nicotine patch.

Application of circulating tumour cells to predict response to treatment in head and neck cancer.

BACKGROUND: Local recurrence and metastasis remain the major causes of death in head and neck cancer (HNC) patients. Circulating tumour cells (CTCs) are shed from primary and metastatic sites into the circulation system and have been reported to play critical roles in the metastasis and recurrence of HNC. Here, we explored the use of CTCs to predict the response to treatment and disease progression in HNC patients. METHODS: Blood samples were collected at diagnosis from HNC patients (n = 119). CTCs were isolated using a spiral microfluidic device and were identified using immunofluorescence staining. Correlation of baseline CTC numbers to 13-week PET-CT data and multidisciplinary team consensus data were conducted. RESULTS: CTCs were detected in 60/119 (50.4%) of treatment naïve HNC patients at diagnosis. Baseline CTC numbers were higher in stage III vs. stage I-II p16-positive oropharyngeal cancers (OPCs) and other HNCs (p = 0.0143 and 0.032, respectively). In addition, we found that baseline CTC numbers may serve as independent predictors of treatment response, even after adjusting for other conventional prognostic factors. CTCs were detected in 10 out of 11 patients exhibiting incomplete treatment responses. CONCLUSIONS: We found that baseline CTC numbers are correlated with treatment response in patients with HNC. The expression level of cell-surface vimentin (CSV) on CTCs was significantly higher in patients with persistent or progressive disease, thus providing additional prognostic information for stratifying the risk at diagnosis in HNC patients. The ability to detect CTCs at diagnosis allows more accurate risk stratification, which in the future may be translated into better patient selection for treatment intensification and/or de-intensification strategies.

Temperature Dependence of Deformation Behaviors in High Manganese Austenitic Steel for Cryogenic Applications.

The deformation structure and its contribution to strain hardening of a high manganese austenitic steel were investigated after tensile deformation at 298 K, 77 K and 4 K by means of electron backscatter diffraction and transmission electron microscopy, exhibiting a strong dependence of strain hardening and deformation structure on deformation temperature. It was demonstrated that sufficient twinning indeed provides a high and stable strain hardening capacity, leading to a simultaneous increase in strength and ductility at 77 K compared with the tensile deformation at 298 K. Moreover, although the SFE of the steel is ~34.4 mJ/m2 at 4 K, sufficient twinning was not observed, indicating that the mechanical twinning is hard to activate at 4 K. However, numerous planar dislocation arrays and microbands can be observed, and these substructures may be a reason for multi-peak strain hardening behaviors at 4 K. They can also provide certain strain hardening capacity, and a relatively high total elongation of ~48% can be obtained at 4 K. In addition, it was found that the yield strength (YS) and ultimate tensile strength (UTS) linearly increases with the lowering of the deformation temperature from 298 K to 4 K, and the increment in YS and UTS was estimated to be 2.13 and 2.43 MPa per 1 K reduction, respectively.

The effect of retaining intact posterior capsule in congenital cataract surgery in children aged 4-8 years.

BACKGROUND: The present study sought to observe the effect of retaining intact posterior capsule in congenital cataract surgery in children aged 4-8 years. METHODS: This is a retrospective case control study. Seventy-seven children (130 eyes) aged from 4 to 8 years who underwent cataract surgery were divided into two groups. In Group A, 50 eyes underwent phacoemulsification, intraocular lens implantation and posterior capsule capsulotomy combined with anterior vitrectomy. In Group B, 80 eyes underwent cataract phacoemulsification and intraocular lens implantation. The postoperative visual acuity and the rate of complications were compared. RESULTS: In all patients, cataract surgeries were performed evenly without intraoperative complications. The follow-up time ranged from 6 months to 42 months. No apparent visual axis opacity was detected in group A during the follow-up. By the last visit, apparent visual axis opacity was detected in 31 eyes (38.75%) in group B. Among them, 9 eyes (29.03%) with mild posterior capsule opacification (PCO) were treated with Nd:YAG laser, 3 eyes (9.68%) with thick proliferative membranes were treated with posterior capsule capsulotomy combined with anterior vitrectomy and proliferative membranes in 19 eyes (61.29%) were completely aspired and the posterior capsule was retained. During follow-up, only 2 (6.45%) eyes had PCO recurrence and were treated with Nd:YAG laser. The visual acuity was significantly higher than that before surgery in all patients. CONCLUSIONS: For older children, the incidence of PCO will be low even if intact posterior capsule is retained. Either Nd:YAG laser or surgical treatment for PCO will be able to maintain good vision.

Analysis of risk factors for early stent thrombosis in the Chinese population: A multicenter restrospective study.

BACKGROUND: The predictive scoring systems for early stent thrombosis (EST) remains blank in China. The study aims to evaluate the risk factors and conduct a prediction model of EST in the Chinese population. METHODS: EST was defined as thrombosis that occurs within the first 30 days after primary percutaneous coronary intervention (PCI). Patients from ten Chinese hospitals diagnosed as stent thrombosis (ST) from January 2010 to December 2016 were retrospectively included as the study group. A control group (1 case:2 controls) was created by including patients without ST, major adverse cardiovascular events, or cerebrovascular events during follow-up. The present study evaluated 426 patients with single-vessel lesions and ultimately included 40 patients with EST and 80 control patients, who were included to identify factors that predicted EST and to develop a prediction scoring system. The other 171 patients without integrated 1:2 pair were used for external validation. RESULTS: EST was independently associated with a low hemoglobin concentration (adjusted odds ratio [OR] 0.946, 95% confidence interval [95% CI] 0.901-0.993, P=0.026), a high pre-PCI Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score (OR 1.166, 95% CI 1.049-1.297, P=0.004), and a DAPT (DAPT) duration of <30 days (OR 28.033, 95% CI 5.302-272.834, P<0.001). The simple EST prediction score provided an area under the curve (AUC) of 0.854 (95% CI 0.777-0.932, P<0.001) with 70.0% sensitivity and 90.0% specificity, and 0.742 (95% CI 0.649-0.835, P<0.001) with 54.5% sensitivity and 81.0% specificity for external validation dataset. CONCLUSIONS: EST may be independently associated with DAPT discontinuation within 30 days, a low hemoglobin concentration, and a high SYNTAX score. The scoring system also has a good ability to predict the risk of EST and may be useful in the clinical setting.

Effect of lens capsular tension ring on preventing capsular contraction syndrome in the surgery of retinitis pigmentosa combined with cataract: Retrospective case series.

PURPOSE: To observe the effect of phacoemulsification and intraocular lens (IOL) implantation with or without lens capsular tension ring (CTR) on retinitis pigmentosa (RP) combined with cataract patients. DESIGN: Retrospective cases series study. METHODS: Sixty-three cases (84 eyes) of RP with cataract were collected, including 30 males and 33 females. Phacoemulsification with 3.0 mm clear corneal incision was performed in all the patients. IOL and CTR implantation were performed in 44 eyes, and IOL implantation alone was performed in 40 eyes. All cases were followed up at 1 day, 1 week and 1, 3, 6,12 months after the surgery to compare the best-corrected visual acuity (BCVA), intraocular pressure (IOP), corneal endothelial cell count (ECC) and complications before and after the surgery. RESULTS: All surgery were successfully completed by the same physician, and IOL and CTR were all implanted in capsule without complications. The BCVA at 6 months after surgery was 0.91 ± 0.88 LogMAR, showing an improvement compared with the BCVA(1.3 ± 0.7LogMAR) before surgery and there was a statistically significant difference (P = .003). Four cases of capsule contraction syndrome (CCS) occurred in no CTR implantation group and there was no CCS in CTR group. There was a statistically significant difference in the incidence of CCS between two groups (P = .047). CONCLUSIONS: Phacoemulsification for RP combined with cataract is safe and reliable, and CTR implantation is conducive to reducing the complications caused by capsule contraction.

Prognostic Landscape of Tumor-Infiltrating T and B Cells in Human Cancer.

Recently, immunotherapy targeting tumor-infiltrating lymphocytes (TILs) has emerged as a critical and promising treatment in several types of cancer. However, not all cancer types have been tested in immunotherapeutic trials, and different patients and cancer types may have unpredictable clinical outcomes. This situation has created a particular exigency for analyzing the prognostic significance of tumor-infiltrating T cells (TIL-T) and B cells (TIL-B) across different cancer types. To address the critical role of TILs, the abundances of TIL-T and TIL-B cells, as determined by the protein levels of LCK and CD20, were analyzed across heterogeneous human malignancies. TIL-T and TIL-B cells showed varying prognostic significances across heterogeneous cancer types. Additionally, distinct distributions of TIL-T and TIL-B cells were observed in different cancer and tumor microenvironment (TME) subtypes. Next, we analyzed the cellular context for the TME communication network involving the well-acknowledgeable chemokine receptors of TIL-T and TIL-B cells, implying the functional interactions with TME. Additionally, these chemokine receptors, expressed by TIL-T and TIL-B cells, were remarkably correlated with the levels of TIL-T or TIL-B cell infiltrations across nearly all the cancer types, indicating these chemokine receptors as universal targets for up- and down-regulating the TIL-T and TIL-B cells. Lastly, we provide the prognostic landscape of TIL-T and TIL-B cells across 30 cancer types and the subgroups defined by gender, histopathology, histological grade, therapeutic approach, drug, and TME subtype, which are intended to be a resource to fuel the investigations of TILs, with important implications for cancer immunotherapy.

miR-155 facilitates calcium oxalate crystal-induced HK-2 cell injury via targeting PI3K associated autophagy.

Nephrolithiasis is one of the most common and highly recurrent diseases worldwide. Accumulating evidence revealed the elevated miR-155 levels both in serum and urine of nephrolithiasis patients. The aim of our research was to explore the role of miR-155 in CaOx-induced apoptosis in HK-2 cells. The expression levels of miR-155 in serum and renal tissues were quantified in 20 patients with nephrolithiasis using qRT-PCR assay. ELISA was performed to determine urinary levels of interleukin (IL)-1ß, IL-6 and tumor necrosis factor-alpha (TNF-α). Renal tubular cell model of CaOx nephrolithiasis was established to investigate the role and molelular mechanism of miR-155. Cell viability and apoptosis were assessed by MTT and flow cytometry, respectively. Immunofluoresent staining of LC3 autophagosome and western blotting were performed to evaluate the autophagic activity. Luciferase reporter assay was employed to verify the interaction between miR-155 and PI3KCA/Rheb. PI3K/Akt/mTOR signaling was further examined by western blotting. Serum and renal levels of miR-155 and inflammatory factors were significantly elevated in nephrolithiasis patients than in controls. CaOx treatment caused up-regulation of miR-155 and induced autophagy in renal tubular epithelial cells, while silencing miR-155 or inhibition of autophagy by 3-metheladenine (3-MA) ameliorated CaOx crystal-induced cell injury. PI3KCA and Rheb was identified as downstream targets of miR-155. Moreover, miR-155 activates autophagy and promotes cell injury through repressing PI3K/Akt/mTOR signaling pathway. Taken together, these findings demonstrated that miR-155 facilitates CaOx crystal-induced renal tubular epithelial cell injury via PI3K/Akt/mTOR-mediated autophagy, providing therapeutic targets for ameliorating cellular damage by CaOx crystals.

Implementation of electronic health records systems in surgical units and its impact on performance.

BACKGROUND: Electronic health records (EHR) systems have been utilized in New South Wales for more than a decade; however, there is no agreement as to what clinical benefits they provide. This study aims at determining whether the introduction of EHR systems resulted in changes in documentation quality and other markers of clinical performance such as post-operative length of stay (PO LOS), use of imaging modality, rates of readmission and morbidity. METHODS: A before and after study was conducted utilizing both written and electronic patient documentation in a single surgical ward. Patients who underwent appendicectomy at Blacktown Hospital had inpatient documentation collated at three distinct time-points. Documentation was then assessed against the QNOTE assessment criteria. Other markers of clinical performance assessed included PO LOS, ultrasound use, computed tomography use, rate of readmission, rate of morbidity and rate of positive histological findings. RESULTS: There was a significant (P = 0.001) improvement in QNOTE score between group 1 (6 months prior to the implementation of EHR) and group 3 (12 months after the implementation of EHR) of 9 points. PO LOS was reduced following the implementation of EHR from 1.94 to 1.37 days (P = 0.001). CONCLUSION: This study demonstrated that following the implementation of EHR system in an inpatient surgical ward, notation quality improved. It was also found that the implementation of EHR was associated with a decrease in PO LOS.

Programmed Death Ligand 1 Indicates Pre-Existing Adaptive Immune Response by Tumor-Infiltrating CD8+ T Cells in Non-Small Cell Lung Cancer.

Aberrant expression of programmed death ligand 1 (PD-L1) on tumor cells impedes antitumor immunity and instigates immune evasion. The remarkable efficacy of immune checkpoint blockade has been confirmed in various solid tumors. However, the correlation between PD-L1 expression and host immunological landscape remains of considerable controversy in non-small cell lung cancer (NSCLC). In the present study, PD-L1 expression and CD8+ tumor-infiltrating lymphocyte (TIL) infiltration levels were determined by immunohistochemistry (IHC) in tumor sections of 138 NSCLC patients. The expression level of PD-L1 was positively correlated with the abundance of CD8 + TILs (p < 0.0001). Furthermore, no constitutive expression of PD-L1 was observed in the majority of six NSCLC cell lines detected by Western blot; but exposure to interferon-γ (IFN-γ), a primary cytokine secreted by activated CD8+ T cells, prominently increased PD-L1 expression. Notably, a significantly positive association was determined within PD-L1, CD8 and IFN-γ gene expression by qRT-PCR, which was corroborated by RNA-sequencing from TCGA lung cancer dataset. These findings demonstrate that PD-L1 expression indicates an adaptive immune resistance mechanism adopted by tumor cells in the aversion of immunogenic destruction by CD8+ TILs. Both higher expression of PD-L1 and infiltration of CD8+ TILs were correlated with superior prognosis (p = 0.044 for PD-L1; p = 0.002 for CD8). Moreover, Cox multivariate regression analysis showed that the combination of PD-L1 and CD8 were independent prognostic factors, which was more accurate in prediction of prognosis in NSCLC than individually. Finally, we found that IFN-γ induced the upregulation of PD-L1 in NSCLC cells, mainly through the JAK/STAT1 signaling pathway. In conclusion, PD-L1 expression is mainly induced by activated CD8+ TILs via IFN-γ in the immune milieu and indicates pre-existing adaptive immune response in NSCLC.

RIP3 promotes colitis-associated colorectal cancer by controlling tumor cell proliferation and CXCL1-induced immune suppression.

Rationale: Necroptosis is a programmed form of non-apoptotic cell death that requires receptor-interacting protein 3 (RIP3). RIP3 has been shown to be relevant in multiple tumor types and has differential impact on tumor progression. We investigated whether RIP3 is involved in the progression of colitis-associated cancer (CAC) in mice. Methods: Tissues from colorectal cancer patients were examined for RIP3 expression. CAC was induced using azoxymethane (AOM) injection followed by dextran sodium sulfate (DSS) treatment in RIP3-deficient or wild-type mice. Colon tissues were collected and analyzed by Western blotting and gene expression profile analyses. Immune cell infiltration and CXCL1 expression were examined by flow cytometry and Real-time PCR, respectively. Results: RIP3 expression was upregulated in mouse CAC and human colon cancer. RIP3-deficient mice showed significantly attenuated colitis-associated tumorigenesis. Bone marrow transplantation experiments suggested that RIP3's function in hematopoietic cells primarily contributes to the phenotype. RIP3 supported epithelial proliferation and tumor growth via JNK signaling but had no effect on apoptosis. RIP3 deletion increased T cell accumulation and reduced infiltration by immunosuppressive subsets of myeloid cells during acute colitis and CAC. The immune-suppressive tumor microenvironment was dependent on RIP3-induced expression of the chemokine attractant CXCL1, and administration of recombinant CXCL1 during CAC restored tumorigenesis in Rip3-/- mice. Conclusion: Our results reveal an unexpected function of RIP3 in enhancing the proliferation of premalignant intestinal epithelial cells (IECs) and promoting myeloid cell-induced adaptive immune suppression. These two distinct mechanisms of RIP3-induced JNK and CXCL1 signalling contribute to CAC progression.

Receptor-Interacting Protein Kinase 3 Deficiency Recruits Myeloid-Derived Suppressor Cells to Hepatocellular Carcinoma Through the Chemokine (C-X-C Motif) Ligand 1-Chemokine (C-X-C Motif) Receptor 2 Axis.

Receptor-interacting protein kinase 3 (RIP3) is the core regulator that switches cell death from apoptosis to necrosis. However, its role in tumor immunity is unknown. In this study, decreased RIP3 expression was observed in patients with hepatocellular carcinoma (HCC), which correlates with myeloid-derived suppressor cell (MDSC) accumulation. Moreover, RIP3 is a prognosis factor for patients with HCC. We further found that RIP3 knockdown results in an increase of MDSCs and a decrease of interferon gamma-positive (IFN-γ+ ) cluster of differentiation 8-positive (CD8+ ) tumor-infiltrating lymphocytes (IFN-γ+ CD8+ T cells) in hepatoma tissues, thus promoting immune escape and HCC growth in immunocompetent mice. By phosphorylating P65Ser536 and promoting phosphorylated P65Ser536 nuclear translocation, RIP3 knockdown increases the expression of chemokine (C-X-C motif) ligand 1 (CXCL1) in HCC cells. RIP3 knockdown induces MDSC recruitment through the CXCL1-chemokine (C-X-C motif) receptor 2 (CXCR2) axis. Furthermore, a CXCR2 antagonist substantially suppresses MDSC chemotaxis and HCC growth in RIP3 knockout mice. Conclusion: RIP3 deficiency is an essential factor directing MDSC homing to HCC and promoting CXCL1/CXCR2-induced MDSC chemotaxis to facilitate HCC immune escape and HCC progression; blocking the CXCL1-CXCR2 chemokine axis may provide an immunological therapeutic approach to suppress progression of RIP3 deficiency HCC.