The volume-regulated anion channel LRRC8C suppresses T cell function by regulating cyclic dinucleotide transport and STING-p53 signaling.

The volume-regulated anion channel (VRAC) is formed by LRRC8 proteins and is responsible for the regulatory volume decrease (RVD) after hypotonic cell swelling. Besides chloride, VRAC transports other molecules, for example, immunomodulatory cyclic dinucleotides (CDNs) including 2'3'cGAMP. Here, we identify LRRC8C as a critical component of VRAC in T cells, where its deletion abolishes VRAC currents and RVD. T cells of Lrrc8c-/- mice have increased cell cycle progression, proliferation, survival, Ca2+ influx and cytokine production-a phenotype associated with downmodulation of p53 signaling. Mechanistically, LRRC8C mediates the transport of 2'3'cGAMP in T cells, resulting in STING and p53 activation. Inhibition of STING recapitulates the phenotype of LRRC8C-deficient T cells, whereas overexpression of p53 inhibits their enhanced T cell function. Lrrc8c-/- mice have exacerbated T cell-dependent immune responses, including immunity to influenza A virus infection and experimental autoimmune encephalomyelitis. Our results identify cGAMP uptake through LRRC8C and STING-p53 signaling as a new inhibitory signaling pathway in T cells and adaptive immunity.

Organ aging signatures in the plasma proteome track health and disease.

Animal studies show aging varies between individuals as well as between organs within an individual1-4, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20-50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer's disease (AD) progression independently from and as strongly as plasma pTau-181 (ref. 5), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects.

Pitavastatin sensitizes the EGFR-TKI associated resistance in lung cancer by inhibiting YAP/AKT/BAD-BCL-2 pathway.

BACKGROUND: Despite effective strategies, resistance in EGFR mutated lung cancer remains a challenge. Metabolic reprogramming is one of the main mechanisms of tumor drug resistance. A class of drugs known as "statins" inhibit lipid cholesterol metabolism and are widely used in patients with cardiovascular diseases. Previous studies have also documented its ability to improve the therapeutic impact in lung cancer patients who receive EGFR-TKI therapy. Therefore, the effect of statins on targeted drug resistance to lung cancer remains to be investigated. METHODS: Prolonged exposure to gefitinib resulted in the emergence of a resistant lung cancer cell line (PC9GR) from the parental sensitive cell line (PC9), which exhibited a traditional EGFR mutation. The CCK-8 assay was employed to assess the impact of various concentrations of pitavastatin on cellular proliferation. RNA sequencing was conducted to detect differentially expressed genes and their correlated pathways. For the detection of protein expression, Western blot was performed. The antitumor activity of pitavastatin was evaluated in vivo via a xenograft mouse model. RESULTS: PC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC9 cells, and the YAP expression was inhibited by pitavastatin administration. With YAP RNA interference, pAKT, pBAD and BCL-2 expression was decreased, while BAX expression as increased. Accordingly, YAP down-regulated significantly increased apoptosis and decreased the survival rate of gefitinib-resistant lung cancer cells. After pAKT was increased by SC79, apoptosis of YAP down-regulated cells induced by gefitinib was decreased, and the cell survival rate was increased. Mechanistically, these effects of pitavastatin are associated with the YAP pathway, thereby inhibiting the downstream AKT/BAD-BCL-2 signaling pathway. CONCLUSION: Our study provides a molecular basis for the clinical application of the lipid-lowering drug pitavastatin enhances the susceptibility of lung cancer to EGFR-TKI drugs and alleviates drug resistance.

Raddeanin A Protects the BRB Through Inhibiting Inflammation and Apoptosis in the Retina of Alzheimer's Disease.

Neuroinflammation and endothelial cell apoptosis are prominent features of blood-brain barrier (BBB) disruption, which have been described in Alzheimer's disease (AD) and can predict cognitive decline. Recent reports revealed vascular ß-amyloid (Aß) deposits, Muller cell degeneration and microglial dysfunction in the retina of AD patients. However, there has been no in-depth research on the roles of inflammation, retinal endothelial cell apoptosis, and blood-retinal barrier (BRB) damage in AD retinopathy. We found that Raddeanin A (RDA) could improve pathological and cognitive deficits in a mouse model of Alzheimer's disease by targeting ß-amyloidosis, However, the effects of RDA on AD retinal function require further study. To clarify whether RDA inhibits inflammation and apoptosis and thus improves BRB function in AD-related retinopathy. In vitro we used Aß-treated HRECs and MIO-M1 cells, and in vivo we used 3×Tg-AD mice to investigate the effect of RDA on BRB in AD-related retinopathy. We found that RDA could improve BRB function in AD-related retinopathy by inhibiting NLRP3-mediated inflammation and suppressing Wnt/ß-catenin pathway-mediated apoptosis, which is expected to improve the pathological changes in AD-related retinopathy and the quality of life of AD patients.

Severe coagulopathy and inflammation occurred after resection of giant right ventricular intimal sarcoma with cardiopulmonary bypass: a case report.

BACKGROUND: Primary malignant cardiac tumors are rare in clinic, and surgical resection under cardiopulmonary bypass (CPB) remains the main treatment. The non-physiological perfusion process of CPB leads to contact activation, and the resulting coagulopathy and systemic inflammatory response syndrome (SIRS) are common complications. However, it is difficult to predict the impact of foreign tumor fragments on this pathophysiological process once they enter the bloodstream, making this phenomenon more complex and challenging. CASE PRESENTATION: We report a case of cardiac intimal sarcoma who developed severe coagulopathy and widespread inflammation after excision of massive right ventricular tumor and replacement of tricuspid valve by median sternotomy under CPB. Although the procedure was expected to cause tumor cell necrosis and precautions were taken, uncontrolled massive postoperative bleeding, persistent fever, abnormally elevated inflammatory markers, and recurrent malignant arrhythmias occurred after surgery. In addition to common factors, the most possible underlying mechanism is contact activation triggered following surgical procedure for intimal sarcoma with CPB. CONCLUSION: Patients with intracardiac malignant tumors are at a high risk for serious contact activation during CPB. Preventive application of comprehensive anti-inflammatory measures such as drugs and adsorptive CPB technology, as well as point-of-care (POC) monitoring of coagulation status will be helpful for individualized guidance and optimization of CPB management, and improvement of patient prognosis.

Long-Term Outcomes in Patients Using Protocol-Directed Active Surveillance for Prostate Cancer.

Importance: Outcomes from protocol-directed active surveillance for favorable-risk prostate cancers are needed to support decision-making. Objective: To characterize the long-term oncological outcomes of patients receiving active surveillance in a multicenter, protocol-directed cohort. Design, Setting, and Participants: The Canary Prostate Active Surveillance Study (PASS) is a prospective cohort study initiated in 2008. A cohort of 2155 men with favorable-risk prostate cancer and no prior treatment were enrolled at 10 North American centers through August 2022. Exposure: Active surveillance for prostate cancer. Main Outcomes and Measures: Cumulative incidence of biopsy grade reclassification, treatment, metastasis, prostate cancer mortality, overall mortality, and recurrence after treatment in patients treated after the first or subsequent surveillance biopsies. Results: Among 2155 patients with localized prostate cancer, the median follow-up was 7.2 years, median age was 63 years, 83% were White, 7% were Black, 90% were diagnosed with grade group 1 cancer, and median prostate-specific antigen (PSA) was 5.2 ng/mL. Ten years after diagnosis, the incidence of biopsy grade reclassification and treatment were 43% (95% CI, 40%-45%) and 49% (95% CI, 47%-52%), respectively. There were 425 and 396 patients treated after confirmatory or subsequent surveillance biopsies (median of 1.5 and 4.6 years after diagnosis, respectively) and the 5-year rates of recurrence were 11% (95% CI, 7%-15%) and 8% (95% CI, 5%-11%), respectively. Progression to metastatic cancer occurred in 21 participants and there were 3 prostate cancer-related deaths. The estimated rates of metastasis or prostate cancer-specific mortality at 10 years after diagnosis were 1.4% (95% CI, 0.7%-2%) and 0.1% (95% CI, 0%-0.4%), respectively; overall mortality in the same time period was 5.1% (95% CI, 3.8%-6.4%). Conclusions and Relevance: In this study, 10 years after diagnosis, 49% of men remained free of progression or treatment, less than 2% developed metastatic disease, and less than 1% died of their disease. Later progression and treatment during surveillance were not associated with worse outcomes. These results demonstrate active surveillance as an effective management strategy for patients diagnosed with favorable-risk prostate cancer.

Combining Upconversion Luminescence, Photothermy, and Electrochemistry for Highly Accurate Triple-Signal Detection of Hydrogen Sulfide by Optically Trapping Single Microbeads.

The detection of hydrogen sulfide (H2S), the third gas signaling molecule, is a promising strategy for identifying the occurrence of certain diseases. However, the conventional single- or dual-signal detection can introduce false-positive or false-negative results, which ultimately decreases the diagnostic accuracy. To address this limitation, we developed a luminescent, photothermal, and electrochemical triple-signal detection platform by optically trapping the synthetic highly doped upconversion coupled SiO2 microbeads coated with metal-organic frameworks H-UCNP-SiO2@HKUST-1 (H-USH) to detect the concentration of H2S. The H-USH was first synthesized and proved to have stable structure and excellent luminescent, photothermal, and electrochemical properties. Under 980 nm optical trapping and 808 nm irradiation, H-USH showed great detection linearity, a low limit of detection, and high specificity for H2S quantification via triple-signal detection. Moreover, H-USH was captured by optical tweezers to realize quantitative detection of H2S content in serum of acute pancreatitis and spontaneously hypertensive rats. Finally, by analyzing the receiver operating characteristic (ROC) curve, we concluded that triple-signal detection of H2S was more accurate than single- or dual-signal detection, which overcame the problem of false-negative/positive results in the detection of H2S in actual serum samples.

Dietary Patterns and Risk of Gleason Grade Progression among Men on Active Surveillance for Prostate Cancer: Results from the Canary Prostate Active Surveillance Study.

Modifiable lifestyle factors, such as following a healthy dietary pattern may delay or prevent prostate cancer (PCa) progression. However, few studies have evaluated whether following specific dietary patterns after PCa diagnosis impacts risk of disease progression among men with localized PCa managed by active surveillance (AS). 564 men enrolled in the Canary Prostate Active Surveillance Study, a protocol-driven AS study utilizing a pre-specified prostate-specific antigen monitoring and surveillance biopsy regimen, completed a food frequency questionnaire (FFQ) at enrollment and had ≥ 1 surveillance biopsy during follow-up. FFQs were used to evaluate adherence to the Dietary Guidelines for Americans (Healthy Eating index (HEI))-2015, alternative Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH) dietary patterns. Multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals were estimated using Cox proportional hazards models. During a median follow-up of 7.8 years, 237 men experienced an increase in Gleason score on subsequent biopsy (grade reclassification). Higher HEI-2015, aMED or DASH diet scores after diagnosis were not associated with significant reductions in the risk of grade reclassification during AS. However, these dietary patterns have well-established protective effects on chronic diseases and mortality and remain a prudent choice for men with prostate cancer managed by AS.

Tourniquets can further reduce perioperative blood loss in patients on dexamethasone and tranexamic acid during cemented total knee arthritis: a single-center, double-blind, randomized controlled trial.

BACKGROUND: Multiple doses of dexamethasone and tranexamic acid can inhibit postoperative inflammation and reduce fibrinolysis and perioperative blood loss in total knee arthroplasty. In this single-center, double-blind, randomized clinical trial, the aim was to investigate whether applying a tourniquet to patients on dexamethasone and tranexamic acid could further reduce perioperative blood loss. MATERIALS AND METHODS: Patients who underwent cemented total knee arthroplasty at our hospital were randomized to receive a tourniquet (n = 71) or not (n = 70) during the procedure. All patients received multiple doses of dexamethasone and tranexamic acid perioperatively. The primary outcome was perioperative blood loss, while secondary outcomes were surgery duration, postoperative laboratory indices of inflammation and fibrinolysis, range of knee motion, VAS pain score, knee circumference, knee swelling rate, homologous transfusion, albumin use, and complications. RESULTS: Using a tourniquet was associated with significantly lower intraoperative blood loss (P < 0.001) and total blood loss (P = 0.007) as well as significantly shorter surgery duration (P < 0.001). In contrast, the tourniquet did not significantly affect hidden blood loss, postoperative inflammation or fibrinolysis, range of knee motion, VAS pain score, knee circumference, knee swelling rate, homologous transfusion, albumin use, or complications. CONCLUSIONS: The results of this randomized clinical trial demonstrate that applying a tourniquet during cemented total knee arthroplasty to patients receiving multiple doses of dexamethasone and tranexamic acid can further reduce perioperative blood loss without increasing the risk of inflammation, fibrinolysis, or other complications. Thus, it is advised to use tourniquets combined with dexamethasone and tranexamic acid to reduce perioperative blood loss and avoid tourniquet-related adverse events. LEVEL OF EVIDENCE: Therapeutic Level I. Trial registration Chinese Clinical Trail Registry, ChiCTR2200060567. Registered 5 June 2022-retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=171291.

SEMA4D/PlexinB1 promotes AML progression via activation of PI3K/Akt signaling.

BACKGROUND: Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. SEMA4D is a 150 kDa transmembrane protein that belongs to the IV class of the subfamily of semaphorin family. Previous studies have reported that SEMA4D is a multifunctional target in many solid tumors, involving multiple physiological systems, and there are emerging therapies to target these pathways. The role of SEMA4D in AML has not yet been explored. METHODS: The SEMA4D expression prolile, clinical data and potential prognostic analysis were acquired via the cBioPortal and GEPIA databases. SEMA4D expression was measured using real-time quantitative PCR and western blot. Cell counting kit-8 (CCK8) and flow cytometry were used to evaluate the malignant biological characteristics. RESULTS: We observed that SEMA4D was increased in AML patients and correlated with risk stratification and prognosis. Moreover, SEMA4D promotes the proliferation and inhibits apoptosis of AML cells by binding to its receptor, PlexinB1, and reduces the sensitivity of AML cells to daunorubicin. In addition, SEMA4D/PlexinB1 promotes the proliferation and survival of AML cells by activating the PI3K/Akt signaling pathway. VX15/2503, an anti-SEMA4D antibody, can inhibit the proliferation of AML cells in xenograft mouse models, thereby inhibiting the development of AML. CONCLUSION: SEMA4D will serve as a unique predictive biomarker and a possible therapeutic target in AML.

Evaluating the Outcomes of Active Surveillance in Grade Group 2 Prostate Cancer: Prospective Results from the Canary PASS Cohort.

PURPOSE: Active surveillance (AS) for grade group (GG) 2 patients is not yet well defined. We sought to compare clinical outcomes of men with GG1 and GG2 prostate cancer undergoing AS in a large prospective North American cohort. MATERIALS AND METHODS: Participants were prospectively enrolled in an AS study with protocol-directed followup at 10 centers in the U.S. and Canada. We evaluated time from diagnosis to biopsy grade reclassification and time to treatment. In men treated after initial surveillance, adverse pathology and recurrence were also analyzed. RESULTS: At diagnosis, 154 (9%) had GG2 and 1,574 (91%) had GG1. Five-year reclassification rates were similar between GG2 and GG1 (30% vs 37%, p=0.11). However, more patients with GG2 were treated at 5 years (58% vs 34%, p <0.001) and GG at diagnosis was associated with time to treatment (HR=1.41; p=0.01). Treatment rates were similar in patients who reclassified during AS, but in patients who did not reclassify, those diagnosed with GG2 underwent definitive treatment more often than GG1 (5-year treatment rates 52% and 12%, p <0.0001). In participants who underwent radical prostatectomy after initial surveillance, the adjusted risk of adverse pathology was similar (HR=1.26; p=0.4). Biochemical recurrence within 3 years of treatment for GG2 and GG1 patients was 6% for both groups. CONCLUSIONS: In patients on AS, the rate of definitive treatment is higher after an initial diagnosis of GG2 than GG1. Adverse pathology after radical prostatectomy and short-term biochemical recurrence after definitive treatment were similar between GG2 and GG1.

Outcomes of allogeneic hematopoietic stem cell transplantation for primary hemophagocytic lymphohistiocytosis in adults.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative approach for primary hemophagocytic lymphohistiocytosis (pHLH), but data on adult patients are scarce. Here we present an 8-year experience on HSCT for adult pHLH to reveal the benefits and risks in this population. A total of 29 adult pHLH patients entered this study, at a median follow-up of 29 months (3-112 months), the 5-year probability of survival was 60%. Six patients rejected HSCT, of whom 1 alive in complete response (CR). In 23 patients who underwent HSCT, 5-year survival post-HSCT overall was 73%, and in haploidentical HSCT (haplo-HSCT) cases, 71%. Patients who achieved CR at HSCT had a better outcome than those of partial response (92% vs. 47%, p = 0.013). Neither the use of HLA mismatched donor (75% vs. 72%, p = 0.996) nor the use of donor with monoallelic mutation (74% vs. 71%, p = 0.901) affected the prognosis. Hemophagocytic lymphohistiocytosis status of CR at HSCT was a positive prognostic factor. We concluded that HSCT is a promising method to cure adult-onset pHLH. Achieving CR before HSCT contributes to better outcome. Haplo-HSCT is safe and effective for adult pHLH patients, donors with monoallelic mutations in pHLH related genes but normal cytotoxic functions are reliable.

Golgi-associated microtubules are fast cargo tracks and required for persistent cell migration.

Microtubules derived from the Golgi (Golgi MTs) have been implicated to play critical roles in persistent cell migration, but the underlying mechanisms remain elusive, partially due to the lack of direct observation of Golgi MT-dependent vesicular trafficking. Here, using super-resolution stochastic optical reconstruction microscopy (STORM), we discovered that post-Golgi cargos are more enriched on Golgi MTs and also surprisingly move much faster than on non-Golgi MTs. We found that, compared to non-Golgi MTs, Golgi MTs are morphologically more polarized toward the cell leading edge with significantly fewer inter-MT intersections. In addition, Golgi MTs are more stable and contain fewer lattice repair sites than non-Golgi MTs. Our STORM/live-cell imaging demonstrates that cargos frequently pause at the sites of both MT intersections and MT defects. Furthermore, by optogenetic maneuvering of cell direction, we demonstrate that Golgi MTs are essential for persistent cell migration but not for cells to change direction. Together, our study unveils the role of Golgi MTs in serving as a group of "fast tracks" for anterograde trafficking of post-Golgi cargos.

Identification of chitin synthase activator in Aspergillus niger and its application in citric acid fermentation.

The biosynthesis of citric acid (CA) using Aspergillus niger as a carrier is influenced by mycelium morphology, which is determined by the expression level of morphology-related genes. As a key component of the fungal cell wall, chitin content has an important effect on morphogenesis, and to investigate the effects of this on fermentation performance, we used RNA interference to knockdown chitin synthase C (CHSC) and chitin synthase activator (CHS3) to obtain the single-gene mutant strains A. niger chs3 and chsC and the double mutant A. niger chs3C. We found that the CA fermentation performance of the two single mutants was significantly better than that of the double mutant. The mutant A. niger chs3-4 exhibited CA production potential compared to that of the parent strain in scale-up fermentation; we determined certain characteristics of CA high-yielding strain fermentation pellets. In addition, when chsC alone was silenced, there was very little change in chs3 mRNA levels, whereas those of chsC were significantly reduced when only chs3 was silenced. As this may be because of a synergistic effect between chsC and chs3, and we speculated that the latent activation target of CHS3 is CHSC, our results confirmed this hypothesis. This study is the first application of a separation and combination silence strategy of chitin synthase and chitin synthase activator in the morphology of A. niger CA fermentation. Furthermore, it provides new insights into the method for the morphological study of A. niger fermentation and the interaction of homologous genes. KEY POINTS: • The function of chitin synthase C (chsC) and chitin synthase activator (chs3) is tightly interrelated. • Mycelial morphology was optimized by knockdown of CHS3, resulting in the overproduction of citric acid. • The separation and combination silence strategies are promising tools for the interaction of homologous housekeeping genes.

SPAG1 promotes the development of AML by activating the ERK/MAPK signaling pathway and affects the chemotherapy sensitivity of venetoclax.

Sperm-associated antigen 1 (SPAG1) is considered to be associated with infertility and tumorigenesis. However, its function in acute myeloid leukemia (AML) remains unclear. In this study, we evaluated the expression level of SPAG1 and explored its clinical prognostic value in patients with AML, as well as its biological function in AML cells. SPAG1 is widely expressed in AML patients, resulting in a poor prognosis. However, its expression was not associated with Fms-related receptor tyrosine kinase 3 (FLT3) mutations. Utilizing the RNA interference knockdown tests, we found that SPAG1 could promote the proliferation and survival of AML cells and regulate the expression of structural maintenance of chromosomes protein 3 (SMC3), activating the ERK/MAPK signaling pathway. Furthermore, we discovered that inhibiting SPAG1 impacted AML cell susceptibility to venetoclax. In conclusion, SPAG1 may serve as a potential therapeutic target in AML.

Research Progress on the Therapeutic Effect of Polysaccharides on Non-Alcoholic Fatty Liver Disease through the Regulation of the Gut-Liver Axis.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease affecting global public health at present, which can induce cirrhosis and liver cancer in serious cases. However, NAFLD is a multifactorial disease, and there is still a lack of research on its mechanism and therapeutic strategy. With the development of the gut-liver axis theory, the association between the gut-liver axis and the pathogenesis of NAFLD has been gradually disclosed. Polysaccharides, as a kind of natural product, have the advantages of low toxicity, multi-target and multi-pathway action. It has been reported that polysaccharides can affect the gut-liver axis at multiple interrelated levels, such as maintaining the ecological balance of gut microbiota (GM), regulating the metabolites of GM and improving the intestinal barrier function, which thereby plays a protective role in NAFLD. These studies have great scientific significance in understanding NAFLD based on the gut-liver axis and developing safe and effective medical treatments. Herein, we reviewed the recent progress of polysaccharides in improving nonalcoholic fatty liver disease (NAFLD) through the gut-liver axis.

The Molecular Associations of Signet-Ring Cell Carcinoma in Colorectum: Meta-Analysis and System Review.

Background: Signet ring cell carcinoma (SC) accounts for 1% of total colorectal cancer (CRC) cases and is associated with aggressive behaviors, such as lymphatic invasion and distant metastases, resulting in poor prognosis. To date, there is still a lack of consensus on the genetic etiology underpinning this cancer subtype. This study aimed to clarify the molecular associations of SC by using meta-analysis and a systematic review. Methods: PubMed, Embase, and Cochrane Library were searched for studies evaluating the KRAS, BRAF, P53 statuses, and microsatellite instability (MSI) in CRC patients with different histological subtypes, including SC. The diagnosis of SC is defined as the signet ring cells comprising ≥50 percent of the tumor mass. By dividing the studies into subgroups based on the composition of control groups, such as classic adenocarcinoma (AC; no SC components) and non-SC (including those with SC components < 50%), the relative risk (RR) of molecular alterations for SC in each study were pooled using a random-effects model. Two reviewers identified trials for inclusion, assessed quality, and extracted data independently. Results: Data from 29 studies consisting of 9366 patients were included in this analysis. SC was associated positively with MSI (RR 1.78, 95% CI 1.34 to 2.37; 95% CI 0.77 to 4.15; p = 0.0005), BRAF mutation (RR 1.99, 95% CI 1.21 to 3.26; 95%CI 0.68 to 5.82; p = 0.0146), and negatively with KRAS mutation (RR 0.48, 95% CI 0.29 to 0.78; 95% CI 0.09 to 2.49; p = 0.0062). No association was found between SC and P53 expression (RR 0.92, 95% CI 0.76 to 1.13; 95%CI 0.61 to 1.39; p = 0.3790). Moreover, it was associated negatively with P53 gene mutations (RR 0.92, 95% CI 0.77 to 1.09; 95% CI 0.46 to 1.82; p = 0.1568), and P53 protein (RR 0.93, 95% CI 0.58 to 1.49; 95% CI 0.40 to 2.17; p = 0.6885). Conclusions: The molecular etiology of SC may be associated with the BRAF and MSI pathways. Its features, such as the high frequency of BRAF mutation, could partly explain its less favorable outcomes and limited effects of traditional chemotherapy.

Application of S-detect combined with virtual touch imaging quantification in ultrasound for diagnosis of breast mass. / S-detectè”åˆå£°è§¦è¯Šç»„ç»‡æˆåƒå®šé‡åœ¨ä¹³è ºè‚¿å—è¶ å£°è¯Šæ–­ä¸­çš„åº”ç”¨.

OBJECTIVES: Ultrasound is a safe and timely diagnosis method commonly used for breast lesion, however it depends on the operator to a certain degree. As an emerging technology, artificial intelligence can be combined with ultrasound in depth to improve the intelligence and precision of ultrasound diagnosis and avoid diagnostic errors caused by subjectivity of radiologists. This paper aims to investigate the value of artificial intelligence S-detect system combined with virtual touch imaging quantification (VTIQ) technique in the differential diagnosis of benign and malignant breast masses by conventional ultrasound (CUS). respectively, and AUCs for them were 0.74, 0.86, 0.79, and 0.94, respectively. The diagnostic accuracy of CUS+S-detect was higher than that of CUS (P<0.05). The diagnostic accuracy of CUS+S-detect was higher than that of CUS (P<0.05). The diagnostic specificity of CUS+VTIQ was higher than that of CUS (P<0.05). The diagnostic accuracy and AUC of CUS+S-detect+VTIQ were higher than those of S-detect or VTIQ applied to CUS alone (P<0.05). The sensitivities of CUS for senior radiologists, CUS for junior radiologists, CUS+S-detect+VTIQ for senior radiologists, and CUS+S-detect+VTIQ for junior radiologists were 60.00%, 80.00%, 72.73%, and 90.00%, respectively, when diagnosing benign and malignant breast masses in 50 randomly selected cases. The specificities for them was 66.67%, 76.67%, 80.00%, and 81.25%, respectively. The accuracies for them was 64.00%, 78.00%, 80.00%, and 88.00%, respectively. The AUCs for them were 0.63, 0.78, 0.88, and 0.80, respectively. Compared with the CUS for junior radiologists, the CUS+S-detect+VTIQ for junior radiologists had higher sensitivity, specificity, and accuracy (all P<0.05). The consistency of the combined application of S-detect and VTIQ for diagnosing breast masses at 2 different times was good among junior radiologists (Kappa=0.800). METHODS: CUS, S-detects, and VTIQ were used to differentially diagnose benign and malignant breast masses in 108 cases, and the final pathological results were referred to as the gold standard for classifying breast masses. The diagnostic efficacy were evaluated and compared, among the 3 methods and among S-detect applied to CUS (CUS+S-detect), VTIQ applied to CUS (CUS+VTIQ), and S-detect combined with VTIQ applied to CUS (CUS+S-detect+VTIQ). Fifty cases were acquired randomly from the collected breast masses, and 2 radiologists with different years of experience (2 and 8 years) used S-detect combined with VTIQ for the ultrasonic differential diagnosis of benign and malignant breast masses. RESULTS: The differences in sensitivity, specificity, accuracy, and the area under the receiver operating characteristic curve (AUC) of the 3 diagnostic methods of CUS, S-detect, and VTIQ were not statistically significant (all P>0.05). The sensitivities of CUS, CUS+Sdetect, CUS+VTIQ, and CUS+S-detect+VTIQ were 78.57%, 92.86%, 69.05%, and 95.24%, respectively, the specificities for them were 69.70%, 78.79%, 87.88%, and 92.42%, respectively, the accuracies for them were 73.15%, 84.26%, 80.56%, and 93.52%. CONCLUSIONS: S-detect combined with VTIQ when applied to CUS can overcome the shortcomings of separate applications and complement each other, especially for junior radiologists, and can more effectively improve the diagnostic efficacy of ultrasound for benign and malignant breast masses.

Complete genome sequence analysis of the peanut pathogen Ralstonia solanacearum strain Rs-P.362200.

BACKGROUND: Bacterial wilt caused by Ralstonia solanacearum species complex is an important soil-borne disease worldwide that affects more than 450 plant species, including peanut, leading to great yield and quality losses. However, there are no effective measures to control bacterial wilt. The reason is the lack of research on the pathogenic mechanism of bacterial wilt. RESULTS: Here, we report the complete genome of a toxic Ralstonia solanacearum species complex strain, Rs-P.362200, a peanut pathogen, with a total genome size of 5.86 Mb, encoding 5056 genes and the average G + C content of 67%. Among the coding genes, 75 type III effector proteins and 12 pseudogenes were predicted. Phylogenetic analysis of 41 strains including Rs-P.362200 shows that genetic distance mainly depended on geographic origins then phylotypes and host species, which associated with the complexity of the strain. The distribution and numbers of effectors and other virulence factors changed among different strains. Comparative genomic analysis showed that 29 families of 113 genes were unique to this strain compared with the other four pathogenic strains. Through the analysis of specific genes, two homologous genes (gene ID: 2_657 and 3_83), encoding virulence protein (such as RipP1) may be associated with the host range of the Rs-P.362200 strain. It was found that the bacteria contained 30 pathogenicity islands and 6 prophages containing 378 genes, 7 effectors and 363 genes, 8 effectors, respectively, which may be related to the mechanism of horizontal gene transfer and pathogenicity evaluation. Although the hosts of HA4-1 and Rs-P.362200 strains are the same, they have specific genes to their own genomes. The number of genomic islands and prophages in HA4-1 genome is more than that in Rs-P.36220, indicating a rapid change of the bacterial wilt pathogens. CONCLUSION: The complete genome sequence analysis of peanut bacterial wilt pathogen enhanced the information of R. solanacearum genome. This research lays a theoretical foundation for future research on the interaction between Ralstonia solanacearum and peanut.

Targeting LSD1 for acute myeloid leukemia (AML) treatment.

Targeted therapy for acute myeloid leukemia (AML) is an effective strategy, but currently there are very limited therapeutic targets for AML treatment. Histone lysine specific demethylase 1 (LSD1) is highly expressed in many cancers, impedes the differentiation of cancer cells, promotes the proliferation, metastasis and invasion of cancer cells, and is associated with poor prognosis. Targeting LSD1 has been recognized as a promising strategy for AML treatment in recent years. Based on these features, in the review, we discussed the main epigenetic drugs targeting LSD1 for AML therapy. Thus, this review focuses on the progress of LSD1 inhibitors in AML treatment, particularly those such as tranylcypromine (TCP), ORY-1001, GSK2879552, and IMG-7289 in clinical trials. These inhibitors provide novel scaffolds for designing new LSD1 inhibitors. Besides, combined therapies of LSD1 inhibitors with other drugs for AML treatment are also highlighted.