Superantigen-fused T cell engagers for tumor antigen-mediated robust T cell activation and tumor cell killing.

Inadequate T cell activation has severely limited the success of T cell engager (TCE) therapy, especially in solid tumors. Enhancing T cell activity while maintaining the tumor specificity of TCEs is the key to improving their clinical efficacy. However, currently, there needs to be more effective strategies in clinical practice. Here, we design novel superantigen-fused TCEs that display robust tumor antigen-mediated T cell activation effects. These innovative drugs are not only armed with the powerful T cell activation ability of superantigens but also retain the dependence of TCEs on tumor antigens, realizing the ingenious combination of the advantages of two existing drugs. Superantigen-fused TCEs have been preliminarily proven to have good (>30-fold more potent) and specific (>25-fold more potent) antitumor activity in vitro and in vivo. Surprisingly, they can also induce the activation of T cell chemotaxis signals, which may promote T cell infiltration and further provide an additional guarantee for improving TCE efficacy in solid tumors. Overall, this proof-of-concept provides a potential strategy for improving the clinical efficacy of TCEs.

Parallel CNN-Deep Learning Clinical-Imaging Signature for Assessing Pathologic Grade and Prognosis of Soft Tissue Sarcoma Patients.

BACKGROUND: Traditional biopsies pose risks and may not accurately reflect soft tissue sarcoma (STS) heterogeneity. MRI provides a noninvasive, comprehensive alternative. PURPOSE: To assess the diagnostic accuracy of histological grading and prognosis in STS patients when integrating clinical-imaging parameters with deep learning (DL) features from preoperative MR images. STUDY TYPE: Retrospective/prospective. POPULATION: 354 pathologically confirmed STS patients (226 low-grade, 128 high-grade) from three hospitals and the Cancer Imaging Archive (TCIA), divided into training (n = 185), external test (n = 125), and TCIA cohorts (n = 44). 12 patients (6 low-grade, 6 high-grade) were enrolled into prospective validation cohort. FIELD STRENGTH/SEQUENCE: 1.5 T and 3.0 T/Unenhanced T1-weighted and fat-suppressed-T2-weighted. ASSESSMENT: DL features were extracted from MR images using a parallel ResNet-18 model to construct DL signature. Clinical-imaging characteristics included age, gender, tumor-node-metastasis stage and MRI semantic features (depth, number, heterogeneity at T1WI/FS-T2WI, necrosis, and peritumoral edema). Logistic regression analysis identified significant risk factors for the clinical model. A DL clinical-imaging signature (DLCS) was constructed by incorporating DL signature with risk factors, evaluated for risk stratification, and assessed for progression-free survival (PFS) in retrospective cohorts, with an average follow-up of 23 ± 22 months. STATISTICAL TESTS: Logistic regression, Cox regression, Kaplan-Meier curves, log-rank test, area under the receiver operating characteristic curve (AUC)，and decision curve analysis. A P-value <0.05 was considered significant. RESULTS: The AUC values for DLCS in the external test, TCIA, and prospective test cohorts (0.834, 0.838, 0.819) were superior to clinical model (0.662, 0.685, 0.694). Decision curve analysis showed that the DLCS model provided greater clinical net benefit over the DL and clinical models. Also, the DLCS model was able to risk-stratify patients and assess PFS. DATA CONCLUSION: The DLCS exhibited strong capabilities in histological grading and prognosis assessment for STS patients, and may have potential to aid in the formulation of personalized treatment plans. TECHNICAL EFFICACY: Stage 2.

Serotonin/5-HT7 receptor provides an adaptive signal to enhance pigmentation response to environmental stressors through cAMP-PKA-MAPK, Rab27a/RhoA, and PI3K/AKT signaling pathways.

Serotonin (5-HT), a neurotransmitter, is essential for normal and pathological pigmentation processing, and its receptors may be therapeutical targets. The effect and behavior of the 5-HT7 receptor (5-HT7R) in melanogenesis in high vertebrates remain unknown. Herein, we examine the role and molecular mechanism of 5-HT7R in the pigmentation of human skin cells, human tissue, mice, and zebrafish models. Firstly, 5-HT7R protein expression decreased significantly in stress-induced depigmentation skin and vitiligo epidermis. Stressed mice received transdermal serotonin 5-HT7R selective agonists (LP-12, 0.01%) for 12 or 60 days. Mice might recover from persistent stress-induced depigmentation. The downregulation of tyrosinase (Tyr), microphthalmia-associated transcription factor (Mitf) expression, and 5-HT7R was consistently restored in stressed skin. High-throughput RNA sequencing showed that structural organization (dendrite growth and migration) and associated pathways were activated in the dorsal skin of LP-12-treated animals. 5-HT7R selective agonist, LP-12, had been demonstrated to enhance melanin production, dendrite growth, and chemotactic motility in B16F10 cells, normal human melanocytes (NHMCs), and zebrafish. Mechanistically, the melanogenic, dendritic, and migratory functions of 5-HT7R were dependent on the downstream signaling of cAMP-PKA-ERK1/2, JNK MAPK, RhoA/Rab27a, and PI3K/AKT pathway activation. Importantly, pharmacological inhibition and genetic siRNA of 5-HT7R by antagonist SB269970 partially/completely abolished these functional properties and the related activated pathways in both NHMCs and B16F10 cells. Consistently, htr7a/7b genetic knockdown in zebrafish could blockade melanogenic effects and abrogate 5-HT-induced melanin accumulation. Collectively, we have first identified that 5-HT7R regulates melanogenesis, which may be a targeted therapy for pigmentation disorders, especially those worsened by stress.

Synthesis of Asp-based lactam cyclic peptides using an amide-bonded diaminodiacid to prevent aspartimide formation.

Asp-based lactam cyclic peptides are considered promising drug candidates. However, using Fmoc solid-phase peptide synthesis (Fmoc-SPPS) for these peptides also causes aspartimide formation, resulting in low yields or even failure to obtain the target peptides. Here, we developed a diaminodiacid containing an amide bond as a ß-carboxyl-protecting group for Asp to avoid aspartimide formation. The practicality of this diaminodiacid has been illustrated by the synthesis of lactam cyclic peptide cyclo[Lys9,Asp13] KIIIA7-14 and 1Y.

Design, synthesis and triglyceride-lowering activity of tricyclic matrine derivatives for the intervention of non-alcoholic fatty liver disease.

Thirty new tricyclicmatrinic derivatives were successively synthesized and evaluated for their inhibitory activity on the accumulation of triglycerides (TG) in AML12 cells, using 12 N-m-trifluoromethylbenzenesulfonyl matrine (1) as the hit compound. Among the analogues, compound 7n possessing 11-trimethylbutylamine quaternary exerted the highest in vitro TG-lowering potency, as well as a good safety profile. 7n significantly attenuated the hepatic injury and steatosis, and ameliorated dyslipidemia and dysglycemia in the mice with non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet. Primary mechanism study revealed that upregulation of peroxisome proliferator-activated receptors α (PPARα)-carnitine palmitoyltransferase 1A (CPT1A) pathway mediated the efficacy of 7n. Our study provides powerful information for developing this kind of compound into a new class of anti-NAFLD candidates, and compound 7n is worthy of further investigation as an ideal lead compound.

The management of non-culprit vessel(s) in patients with unstable angina/non-ST elevation myocardial infarction and chronic kidney dysfunction.

BACKGROUND AND AIMS: The clinical effects of multivessel interventions in patients with unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI), multivessel disease (MVD) and chronic kidney disease (CKD) remain uncertain. This study aimed to investigate the safety and effectiveness of intervention in non-culprit lession(s) among this cohort. METHODS: We consecutively included patients diagnosed with UA/NSTEMI, MVD and CKD between January 2008 and December 2018 at our centre. After successful percutaneous coronary intervention (PCI), we compared 48-month overall mortality between those undergoing multivessel PCI (MV-PCI) through a single-procedure or staged-procedure approach and culprit vessel-only PCI (CV-PCI) after 1:1 propensity score matching. We conducted stratified analyses and tests for interaction to investigate the modifying effects of critical covariates. Additionally, we recorded the incidence of contrast-induced nephropathy (CIN) to assess the perioperative safety of the two treatment strategies. RESULTS: Of the 749 eligible patients, 271 pairs were successfully matched. Those undergoing MV-PCI had reduced all-cause mortality (hazard ratio (HR): 0.67, 95% confidence interval (CI): 0.48-0.67). Subgroup analysis showed that those with advanced CKD (estimated glomerular filtration rate (eGFR) ≤ 30 mL/min/1.73 m2 ) could not benefit from MV-PCI (P = 0.250), and the survival advantage also tended to diminish in diabetes (P interaction < 0.01; HR = 0.95, 95% CI = 0.65-1.45). Although the staged-procedure approach (N = 157) failed to bring additional survival benefits compared to single-procedure MV-PCI (N = 290) (P = 0.460), it showed a tendency to decrease the death risk. CIN risks in MV-PCI and CV-PCI groups were not significantly different (risk ratio = 1.60, 95% CI = 0.94-2.73). CONCLUSION: Among patients with UA/NSTEMI and non-diabetic CKD and an eGFR > 30 mL/min/1.73 m2 , MV-PCI was associated with a reduced risk of long-term death but did not increase the incidence of CIN during the management of MVD compared to CV-PCI. And staged procedures might be a preferable option over single-procedure MV-PCI.

Cell-Permeable Ubiquitin and Histone Tools for Studying Post-translational Modifications.

Protein post-translational modifications (PTMs) regulate nearly all biological processes in eukaryotic cells, and synthetic PTM protein tools are widely used to detect the activity of the related enzymes and identify the interacting proteins in cell lysates. Recently, the study of these enzymes and the interacting proteome has been accomplished in live cells using cell-permeable PTM protein tools. In this concept, we will introduce cell penetrating techniques, the syntheses of cell-permeable PTM protein tools, and offer some future perspective.

Ambulatory Smartwatch ECG Monitoring among Patients Undergoing Transcatheter Aortic Valve Replacement Early after Discharge: An Observational Study.

Background: As an emerging arrhythmia monitor, ambulatory smartwatch electrocardiogram (ECG) provides an option for home-based monitoring of delayed new-onset arrhythmic events after transcatheter aortic valve replacement (TAVR). We aimed to validate the diagnostic efficacy of a consumer smartwatch ECG in TAVR recipients, while further explore the occurrence rate of both tachy- and brady-arrhythmia for 30 days after discharge to support risk management. Methods: Consecutive TAVR recipients from February 26th, 2021 to December 13th, 2021 were enrolled prospectively, receiving simultaneous 24-hour Holter and 12-lead ECG compared with smartwatch ECG during hospitalization and daily smartwatch ECG collection for 30 days after discharge. Results: Among 110 patients, the efficacy of smartwatch ECG presented sensitivity and specificity in diagnosing atrial fibrillation (AF) as 1.00 and 0.97, left bundle branch block (LBBB) as 0.61 and 0.88, and right bundle branch block (RBBB) as 0.60 and 0.97, respectively, compared with 24-hour Holter; presented sensitivity and specificity in diagnosing AF as 0.88 and 1.00, LBBB as 0.90 and 0.96, and RBBB as 0.83 and 0.94, respectively, compared with 12-lead ECG. At 30-day follow-up, new-onset arrhythmia included new-onset severe conduction disturbance (SCD) (23.6%), new-onset AF (21.8%), new-onset permanent LBBB (14.5%) and new-onset permanent RBBB (0.9%); 69.2% (36/52) of early new-onset LBBB recovered at 30-day follow-up. Conclusions: The diagnostic efficacy of consumer smartwatch ECG in arrhythmic events among TAVR population was acceptable, which provided a recommendable option for home-based management. Clinical Trial Registration: "Continuously ambulatory rhythm monitoring and predictors of electrocardio-related adverse events in 30 days after transcatheter aortic valve replacement"; Identifier: ChiCTR2000041244; http://www.chictr.org.cn/showproj.aspx?proj=66324.

Total Arterial Revascularization in Diabetic Patients Undergoing Coronary Artery Bypass Graft Surgery: A Systematic Review and Meta-Analysis.

Background: Total arterial revascularization (TAR) has gradually become accepted and recognized, but its effect and safety in diabetic patients are not clear. We performed a systematic review and meta-analysis to summarize the safety and efficacy of TAR and additionally evaluated the clinical outcomes of arterial revascularization using different arterial deployments in patients with diabetes. Methods: PubMed, Embase, and the Cochrane Library databases from inception to July 2022 for studies that studied the effect of arterial revascularization in diabetic patients undergoing isolated coronary artery bypass graft (CABG) were searched. The primary outcome was long-term ( ≥ 12 months of follow-up) death by any cause. The secondary efficacy endpoints were long-term ( ≥ 12 months) cardiovascular death, early sternal wound infection (SWI) and death ( ≤ 30 days or in hospital). Risk ratios (RRs), hazard ratios (HRs), and their corresponding 95% confidence intervals (CIs) were calculated to describe short-term results and long-term survival outcomes. Two different ways were used to analyze the effect of TAR and the impact of diabetes on the clinical outcomes of TAR. Results: Thirty-five studies were included in the study, covering 178,274 diabetic patients. Compared to conventional surgery with saphenous veins, TAR was not associated with increased early mortality (RR 0.77, 95% CI 0.48-1.23) and risk of SWI (RR 0.77, 95% CI 0.46-1.28). The overall Kaplan-Meier survival curves based on reconstructed patient data indicated a significant association between TAR and reduced late mortality (HR 0.52, 95% CI 0.48-0.67) and the curves based on the propensity-score matched (PSM) analyses suggested a similar result (HR 0.74, 95% CI 0.66-0.85). TAR could also effectively decrease the risk of cardiovascular death (HR 0.42, 95% CI 0.24-0.75). Through comparing the effect of TAR in patients with and without diabetes, we found that the presence of diabetes did not elevate the risk of early adverse events (death: RR 1.50, 95% CI 0.64-3.49; SWI: RR 2.52, 95% CI 0.91-7.00). Although diabetes increased long-term mortality (HR 1.06; 95% CI 1.35-2.03), the cardiovascular death rate was similar in patients with diabetes and patients without diabetes (HR 1.09; 95% CI 0.49-2.45). Regarding the selection of arterial conduits, grafting via the bilateral internal mammary artery (BIMA) decreased the risk of overall death (HR 0.67, 95% CI 0.52-0.85) and cardiovascular death (HR 0.55, 95% CI 0.35-0.87) without resulting in a significantly elevated rate of early death (RR 0.95, 95% CI 0.82-1.11). However, the evidence from PSM studies indicated no difference between the long-term mortality of the BIMA group and that of the single internal mammary arteries (SIMA) groups (HR 0.76, 95% CI 0.52-1.11), and the risk of SWI was significantly increased by BIMA in diabetes (RR 1.65, 95% CI 1.42-1.91). The sub-analysis indicated the consistent benefit of the radial artery (RA) application in diabetic patients (HR 0.71, 95% CI 0.63-0.79) compared to saphenous vein graft. In two propensity-score-matched studies, the evidence showed that the survival outcomes of the BIMA group were similar to that of the SIMA plus RA group but that grafting via the RA reduced the risk of sternal wound infection. Conclusions: Compared with conventional surgery using SVG, TAR was associated with an enhanced survival benefit in diabetes and this long-term gain did not increase the risk of early mortality or SWI. Given the increased infection risk and controversial long-term survival gains of grafting via the BIMA in diabetes, its wide use for grafting in this cohort should be seriously considered. Compared to using the right internal mammary artery (RIMA), RA might be a similarly effective but safer option for patients with diabetes.

Performance of the Risk Scores for Predicting In-Hospital Mortality in Patients with Acute Coronary Syndrome in a Chinese Cohort.

Background: The prognosis of patients with acute coronary syndrome (ACS) varies greatly, and risk assessment models can help clinicians to identify and manage high-risk patients. While the Global Registry of Acute Coronary Events (GRACE) model is widely used, the clinical pathways for acute coronary syndromes (CPACS), which was constructed based on the Chinese population, and acute coronary treatment and intervention outcomes network (ACTION) have not yet been validated in the Chinese population. Methods: Patients with ACS who underwent coronary angiography or percutaneous coronary intervention from 2011 to 2020, were retrospectively recruited and the appropriate corresponding clinical indicators was obtained. The primary endpoint was in-hospital mortality. The performance of the GRACE, GRACE 2.0, ACTION, thrombolysis in myocardial infarction (TIMI) and CPACS risk models was evaluated and compared. Results: A total of 19,237 patients with ACS were included. Overall, in-hospital mortality was 2.2%. ACTION showed the highest accuracy in predicting discriminated risk (c-index 0.945, 95% confidence interval [CI] 0.922-0.955), but the calibration was not satisfactory. GRACE and GRACE 2.0 did not significantly differ in discrimination (p = 0.1480). GRACE showed the most accurate calibration in all patients and in the subgroup analysis of all models. CPACS (c-index 0.841, 95% CI 0.821-0.861) and TIMI (c-index 0.811, 95% CI 0.787-0.835) did not outperform (c-index 0.926, 95% CI 0.911-0.940). Conclusions: In contemporary Chinese ACS patients, the ACTION risk model's calibration is not satisfactory, although outperformed the gold standard GRACE model in predicting hospital mortality. The CPACS model developed for Chinese patients did not show better predictive performance than the GRACE model.

Improving the tumor selectivity of T cell engagers by logic-gated dual tumor-targeting.

Targeting single tumor antigens makes it difficult to provide sufficient tumor selectivity for T cell engagers (TCEs), leading to undesirable toxicity and even treatment failure, which is particularly serious in solid tumors. Here, we designed novel trispecific TCEs (TriTCEs) to improve the tumor selectivity of TCEs by logic-gated dual tumor-targeting. TriTCE can effectively redirect and activate T cells to kill tumor cells (∼18 pM EC50) by inducing the aggregation of dual tumor antigens, which was ∼70- or 750- fold more effective than the single tumor-targeted isotype controls, respectively. Further in vivo experiments indicated that TriTCE has the ability to accumulate in tumor tissue and can induce circulating T cells to infiltrate into tumor sites. Hence, TriTCE showed a stronger tumor growth inhibition ability and significantly prolonged the survival time of the mice. Finally, we revealed that this concept of logic-gated dual tumor-targeted TriTCE can be applied to target different tumor antigens. Cumulatively, we reported novel dual tumor-targeted TriTCEs that can mediate a robust T cell response by simultaneous recognition of dual tumor antigens at the same cell surface. TriTCEs allow better selective T cell activity on tumor cells, resulting in safer TCE treatment.

Chemical synthesis of on demand-activated SUMO-based probe by a photocaged glycine-assisted strategy.

The transiently-activated SUMO probes are conducive to understand the dynamic control of SENPs activity. Here, we developed a photocaged glycine-assisted strategy for the construction of on demand-activated SUMO-ABPs. The light-sensitive groups installed at G92 and G64 backbone of SUMO-2 can temporarily block probes activity and hamper aspartimide formation, respectively, which enabled the efficient synthesis of inert SUMO-2 propargylamide (PA). The probe could be activated to capture SENPs upon photo-irradiation not only in vitro but also in intact cells, providing opportunities to further perform intracellular time-resolved proteome-wide profiling of SUMO-related enzymes.

Development of an o-aminoanilide-mediated native chemical ligation-assisted DADA strategy for the synthesis of disulfide surrogate peptides.

The hydrazide-based native chemical ligation-assisted diaminodiacid (DADA) strategy is an efficient method for synthesizing large-span disulfide bridge surrogates. However, it is difficult to synthesize disulfide bond surrogates at Gln-Cys or Asn-Cys ligation sites using this strategy. Herein, we report a peptide o-aminoanilide-mediated NCL-assisted DADA strategy that enables the synthesis of large-span peptide disulfide bridge surrogates containing only Gln-Cys or Asn-Cys ligation sites. Through this strategy, we successfully synthesized disulfide bond surrogates of conotoxin vil14a and κ-hefutoxin 1. This strategy provides a new option to obtain large-span peptide disulfide bridge substitutes for native chemical ligation at Gln-Cys and Asn-Cys sites.

Synthesis of disulfide-rich C-terminal Cys-containing peptide acids through a photocleavable side-chain anchoring strategy.

A side-chain anchoring strategy has been developed as an effective method for the synthesis of C-terminal Cys-containing peptide acids. However, the application of this strategy to CCAs containing more than one disulfide bond is still hindered due to the trifluoroacetic acid (TFA) lability of the anchored side-chain groups. Herein, we report a photocleavable side-chain anchoring strategy using newly developed molecules having photocleavable side-chain protecting groups that are stable against TFA cleavage to assist in the formation of disulfide bonds. The utility of this new strategy was demonstrated by the synthesis of Riparin 1.1 and hCNP22 containing one disulfide bond and α-conotoxin Vc1.1 containing two disulfide bonds. This new strategy will provide new possibilities for the synthesis of disulfide-rich C-terminal Cys-containing peptide acids.

Correlations between geomagnetic field and global occurrence of cardiovascular diseases: evidence from 204 territories in different latitude.

BACKGROUND: The correlation between stable geomagnetic fields and unstable geomagnetic activities with mortality, incidence, and prevalence of cardiovascular diseases (CVDs) remains ambiguous. METHOD: To investigate the correlations between geomagnetic field (GMF) intensity and geomagnetic disturbance (GMD) and CVDs events in global, long-period scale, global and 204 countries and territories were included on the base of 2019 Global Burden of Disease study (GBD 2019). Data of GMF intensity, GMD frequency, CVDs events, weather and health economic indicators from 1996 to 2019 of included locations were collected. Linear regression and panel data modelling were conducted to identify the correlations between GMF intensity and CVDs events, multi-factor panel data analysis was also generated to adjust the effect of confounding factors. RESULTS: For the average data during 1996-2019, linear regression model revealed consistent positive correlations between total GMF (tGMF) intensity and mortality of total CVDs [coef = 0.009, (0.006,0.011 95%CI)], whereas negative correlations were found between horizonal GMF (hGMF) intensity and total CVD mortality [coef = -0.010 (-0.013, -0.007 95%CI)]. When considering the time trend, panel data analysis still demonstrated positive correlation between tGMF and total CVDs mortality [coef = 0.009, (0.008,0.009 95%CI)]. Concurrently, the hGMF negatively correlated with total CVDs mortality [coef = -0.008, (-0.009, -0.007 95%CI)]. When the panel models were adjusted for confounding factors, no reverse of correlation tendency was found between tGMF, hGMF and CVDs events. In high-income territories, positive correlation was found between geomagnetic storm (GMS) frequency and mortality of total CVDs [coef = 14.007,(2.785, 25.229 95%CI)], however, this positive trend faded away gradually with the latitude decreasing from polar to equator. CONCLUSIONS: Stable and long-term horizontal component of GMF may be beneficial to cardiac health. Unstable and short-term GMF called GMD could be a hazard to cardiac health. Our results suggest the importance of regular GMF in maintaining cardio-health state and the adverse impacts of GMD on cardiac health.

Synthesis and anti-HIV activity of non-nucleoside reverse-transcriptase inhibitor DB02 phosphate derivatives based on water-soluble optimization.

To improve the water solubility of anti-human immunodeficiency virus (HIV) agent DB02, an excellent non-nucleoside reverse-transcriptase inhibitor (NNRTI) obtained in our previous efforts, we designed and synthesized four phosphate derivatives of DB02 based on the molecular model of DB02 with RT. Here, the antiviral activity of these four derivatives was detected, leading to the discovery of compound P-2, which possessed a superior potency to the lead compound DB02 against wild-type HIV-1 and a variety of HIV-resistant mutant viruses significantly. Furthermore, the water solubility of P-2 was nearly 17 times higher than that of DB02, and the pharmacokinetic test in rats showed that P-2 demonstrate significantly improved oral bioavailablity of 14.6%. Our study showed that the introduction of a phosphate ester group at the end of the C-2 side chain of DB02 was beneficial to the improvement of its antiviral activity and pharmacokinetic properties, which provided a promising lead for the further development of S-DACOs type of NNRTIs.

[Effect of Calcification on the Ultrasound-Guided Radiofrequency Ablation of Papillary Thyroid Carcinoma].

Objective To investigate the effect of calcification on the ultrasound-guided radiofrequency ablation(RFA)of papillary thyroid carcinoma(PTC).Methods We retrospectively analyzed the preoperative and follow-up data of 164 patients(182 nodules)with PTC treated by percutaneous ultrasound-guided RFA in the First Medical Center of Chinese PLA General Hospital from January 1,2018 to December 31,2021.The tumor status 12 months after RFA was taken as the endpoint event.The univariate Logistic regression analysis was employed to predict the influencing factors of incomplete ablation.The factors were then included in the multivariate Logistic regression analysis for prediction of the independent risk factors of incomplete ablation.Results The maximum nodule diameter(OR=1.16,95%CI=1.04-1.29,P=0.009)and calcification ratio >2/3(OR=19.27,95%CI=4.02-92.28,P<0.001)were the factors influencing the disappearance of lesion 12 months after RFA.Conclusions PTC with calcification can be treated with ultrasound-guided RFA.In the case of calcification ratio ≤ 2/3,this therapy demonstrates the effect equivalent to that of no calcification.

[A comparative study of raw Aurantii Fructus Immaturus and bran-fried products on dryness of rats with slow-transit constipation].

The differences in dryness between raw Aurantii Fructus Immaturus(AFI) and bran-fried products were investigated based on a slow-transit constipation(STC) model. Seventy healthy SPF-grade rats were randomly divided into a blank group(K), a positive drug group(Y), a model group(M), low-and high-dose raw AFI groups(SD and SG), and low-and high-dose bran-fried AFI groups(FD and FG). During the experiment, it was found that compared with the K group, the groups with drug treatment had little effect on the daily body weight of the STC rats. The first defecation time of black stool in the M group was significantly higher than that in the K group, and the 24-hour fecal output significantly decreased starting from the 13th day, indicating successful modeling. The SG group showed a significant increase in the first defecation time, fecal water content, urine output, and water intake than other groups with drug treatment. The FG group had the highest fecal output than other groups with drug treatment. The FD group had the highest salivary secretion than other groups with drug treatment. The levels of cAMP/cGMP, VIP, 5-HT, AQP1, and AQP5 were measured in each group with drug treatment, and the expression of c-Kit and SCF mRNA in gastric antrum tissue and AQP3 mRNA in the kidney and colon were detected by RT-PCR. The results showed that the SD and SG groups had a more significant impact on AQP1, AQP5, and other water channel indexes in STC rats than the FD and FG groups. The FD and FG groups had a more significant impact on c-Kit, SCF, VIP, 5-HT, and other gastrointestinal motility indicators than the SD and SG groups. This study, through in vitro biological observations, immunological detection, and gene expression analysis, found that raw AFI had strong dryness property, while bran-fried AFI could alleviate its dryness property.

Single-Shot Solid-Phase Synthesis of Full-Length H2 Relaxin Disulfide Surrogates.

Chemical synthesis of insulin superfamily proteins (ISPs) has recently been widely studied to develop next-generation drugs. Separate synthesis of multiple peptide fragments and tedious chain-to-chain folding are usually encountered in these studies, limiting accessibility to ISP derivatives. Here we report the finding that insulin superfamily proteins (e.g. H2 relaxin, insulin itself, and H3 relaxin) incorporating a pre-made diaminodiacid bridge at A-B chain terminal disulfide can be easily and rapidly synthesized by a single-shot automated solid-phase synthesis and expedient one-step folding. Our new H2 relaxin analogues exhibit almost identical structures and activities when compared to their natural counterparts. This new synthetic strategy will expediate production of new ISP analogues for pharmaceutical studies.

Piezo1 promoted hepatocellular carcinoma progression and EMT through activating TGF-ß signaling by recruiting Rab5c.

BACKGROUND: Piezo1 has been revealed to play a regulatory role in vascular development and progression of variety tumors. However, whether and how the progression of hepatocellular carcinoma (HCC) regulated by Piezo1 remains elusive. This study aimed to elucidate the effect and mechanisms of Piezo1 in HCC. METHODS: The mRNA and protein expression level of Piezo1 in HCC samples and cell lines was determined by qRT-PCR, western blot and immunohistochemistry analyses. Two independent study cohorts containing 280 patients were analyzed to reveal the association between Piezo1 expression and clinicopathological characteristics. Series of in vitro and in vivo experiments were used to validate the function of Piezo1 in HCC. Gene set enrichment analysis (GSEA) was performed to explore the signaling pathway of Piezo1. Immunoprecipitation, immunofluorescence and in vitro and in vivo experiments were used to explore the molecular mechanism of Piezo1 in HCC progression. RESULTS: Our results demonstrated the Piezo1 expression was significantly upregulated in HCC tissues and cell lines, and upregulation of Piezo1 closely correlated with aggressive clinicopathological features and poor prognosis. Knockdown of Piezo1 in HCCLM3 and Hep3B cells significantly restrained proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of HCC cells in vitro, and tumor growth, metastasis, EMT in vivo. TGF-ß signaling pathway was most significant enriched pathway in GSEA. Finally, tumor promotion effect of Piezo1 was found to exerted through recruiting and combining Rab5c to activating TGF-ß signaling pathway. CONCLUSIONS: Piezo1 significantly related to poor prognosis and promotes progression of hepatocellular carcinoma via activating TGF-ß signaling, which suggesting that Piezo1 may serve as a novel prognostic predictor and the potential therapeutic target for HCC patients.