Syringic acid attenuates acute lung injury by modulating macrophage polarization in LPS-induced mice.

BACKGROUND: Acute lung injury (ALI) is a continuum of lung changes caused by multiple lung injuries, characterized by a syndrome of uncontrolled systemic inflammation that often leads to significant morbidity and death. Anti-inflammatory is one of its treatment methods, but there is no safe and available drug therapy. Syringic acid (SA) is a natural organic compound commonly found in a variety of plants, especially in certain woody plants and fruits. In modern pharmacological studies, SA has anti-inflammatory effects and therefore may be a potentially safe and available compound for the treatment of acute lung injury. PURPOSE: This study attempts to reveal the protective mechanism of SA against ALI by affecting the polarization of macrophages and the activation of NF-κB signaling pathway. Trying to find a safer and more effective drug therapy for clinical use. METHODS: We constructed the ALI model using C57BL/6 mice by intratracheal instillation of LPS (10 mg/kg). Histological analysis was performed with hematoxylin and eosin (H&E). The wet-dry ratio of the whole lung was measured to evaluate pulmonary edema. The effect of SA on macrophage M1-type was detected by flow cytometry. BCA protein quantification method was used to determine the total protein concentration in bronchoalveolar lavage fluid (BALF). The levels of Interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α in BALF were determined by the ELISA kits, and RT-qPCR was used to detect the expression levels of IL-6, IL-1ß and TNF-α mRNA of lung tissue. Western blot was used to detect the expression levels of iNOS and COX-2 and the phosphorylation of p65 and IκBα in the NF-κB pathway in lung tissue. In vitro experiments were conducted with RAW267.4 cell inflammation model induced by 100 ng/ml LPS and A549 cell inflammation model induced by 10 µg/ml LPS. The effects of SA on M1-type and M2-type macrophages of RAW267.4 macrophages induced by LPS were detected by flow cytometry. The toxicity of compound SA to A549 cells was detected by MTT method which to determine the safe dose of SA. The expressions of COX-2 and the phosphorylation of p65 and IκBα protein in NF-κB pathway were detected by Western blot. RESULTS: We found that the pre-treatment of SA significantly reduced the degree of lung injury, and the infiltration of neutrophils in the lung interstitium and alveolar space of the lung. The formation of transparent membrane in lung tissue and thickening of alveolar septum were significantly reduced compared with the model group, and the wet-dry ratio of the lung was also reduced. ELISA and RT-qPCR results showed that SA could significantly inhibit the production of IL-6, IL-1ß, TNF-α. At the same time, SA could significantly inhibit the expression of iNOS and COX-2 proteins, and could inhibit the phosphorylation of p65 and IκBα proteins. in a dose-dependent manner. In vitro experiments, we found that flow cytometry showed that SA could significantly inhibit the polarization of macrophages from M0 type macrophages to M1-type macrophages, while SA could promote the polarization of M1-type macrophages to M2-type macrophages. The results of MTT assay showed that SA had no obvious cytotoxicity to A549 cells when the concentration was not higher than 80 µM, while LPS could promote the proliferation of A549 cells. In the study of anti-inflammatory effect, SA can significantly inhibit the expression of COX-2 and the phosphorylation of p65 and IκBα proteins in LPS-induced A549 cells. CONCLUSION: SA has possessed a crucial anti-ALI role in LPS-induced mice. The mechanism was elucidated, suggesting that the inhibition of macrophage polarization to M1-type and the promotion of macrophage polarization to M2-type, as well as the inhibition of NF-κB pathway by SA may be the reasons for its anti-ALI. This finding provides important molecular evidence for the further application of SA in the clinical treatment of ALI.

Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells.

OBJECTIVE: Research has shown that celastrol can effectively treat a variety of diseases, yet when passing a certain dosage threshold, celastrol becomes toxic, causing complications such as liver and kidney damage and erythrocytopenia, among others. With this dichotomy in mind, it is extremely important to find ways to preserve celastrol's efficacy while reducing or preventing its toxicity. METHODS: In this study, insulin-resistant HepG2 (IR-HepG2) cells were prepared using palmitic acid and used for in vitro experiments. IR-HepG2 cells were treated with celastrol alone or in combination with N-acetylcysteine (NAC) or ferrostatin-1 (Fer-1) for 12, 24 or 48 h, at a range of doses. Cell counting kit-8 assay, Western blotting, quantitative reverse transcription-polymerase chain reaction, glucose consumption assessment, and flow cytometry were performed to measure celastrol's cytotoxicity and whether the cell death was linked to ferroptosis. RESULTS: Celastrol treatment increased lipid oxidation and decreased expression of anti-ferroptosis proteins in IR-HepG2 cells. Celastrol downregulated glutathione peroxidase 4 (GPX4) mRNA. Molecular docking models predicted that solute carrier family 7 member 11 (SLC7A11) and GPX4 were covalently bound by celastrol. Importantly, we found for the first time that the application of ferroptosis inhibitors (especially NAC) was able to reduce celastrol's toxicity while preserving its ability to improve insulin sensitivity in IR-HepG2 cells. CONCLUSION: One potential mechanism of celastrol's cytotoxicity is the induction of ferroptosis, which can be alleviated by treatment with ferroptosis inhibitors. These findings provide a new strategy to block celastrol's toxicity while preserving its therapeutic effects. Please cite this article as: Liu JJ, Zhang X, Qi MM, Chi YB, Cai BL, Peng B, Zhang DH. Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells. J Integr Med. 2024; 22(3): 286-294.

Incidence of chemotherapy-related cardiac dysfunction in cancer patients.

BACKGROUND: Cancer patients are increasingly affected by chemotherapy-related cardiac dysfunction. The reported incidence of this condition vary significantly across different studies. HYPOTHESIS: A better comprehensive understanding of chemotherapy-related cardiac dysfunction incidence in cancer patients is imperative. Therefore, we performed a meta-analysis to establish the overall incidence of chemotherapy-related cardiac dysfunction in cancer patients. METHODS: We searched articles in PubMed and EMBASE from database inception to May 1, 2023. Studies that reported the incidence of chemotherapy-related cardiac dysfunction in cancer patients were included. RESULTS: A total of 53 studies involving 35 651 individuals were finally included in the meta-analysis. The overall pooled incidence of chemotherapy-related cardiac dysfunction in cancer patients was 63.21 per 1000 person-years (95% CI: 57.28-69.14). The chemotherapy-related cardiac dysfunction incidence increased steeply within half a year of cancer chemotherapy. Also, the trend of chemotherapy-related cardiac dysfunction incidence appeared to have plateaued after a longer duration of follow-up. In addition, chemotherapy-related cardiac dysfunction incidence rates are significantly higher among patients with age ≥50 years versus patients with age <50 years (99.96 vs. 34.48 per 1000 person-years). The incidence rate of cardiac dysfunction was higher among breast cancer patients (72.97 per 1000 person-years), leukemia patients (65.21 per 1000 person-years), and lymphoma patients (55.43 per 1000 person-years). CONCLUSION: Our meta-analysis unveiled a definitive overall incidence rate of chemotherapy-related cardiac dysfunction in cancer patients. In addition, it was found that the risk of developing this condition escalates within the initial 6 months postchemotherapy, subsequently tapering off to become statistically insignificant after a duration of 6 years.

Hyperglycemia exacerbates cerebral ischemia/reperfusion injury by up-regulating autophagy through p53-Sesn2-AMPK pathway.

Hyperglycemia exacerbates ischemic brain injury by up-regulating autophagy. However, the underlying mechanisms are unknown. This study aims to determine whether hyperglycemia activates autophagy through the p53-Sesn2-AMPK signaling pathway. Rats were subjected to 30-min middle cerebral artery occlusion (MCAO) with reperfusion for 1- and 3-day under normo- and hyperglycemic conditions; and HT22 cells were exposed to oxygen deprivation (OG) or oxygen-glucose deprivation and re-oxygenation (OGD/R) with high glucose. Autophagy inhibitors, 3-MA and ARI, were used both in vivo and in vitro. The results showed that, compared with the normoglycemia group (NG), hyperglycemia (HG) increased infarct volume and apoptosis in penumbra area, worsened neurological deficit, and augmented autophagy. after MCAO followed by 1-day reperfusion. Further, HG promoted the conversion of LC-3I to LC-3II, decreased p62, increased protein levels of aldose reductase, p53, P-p53ser15, Sesn2, AMPK and numbers of autophagosomes and autolysosomes, detected by transmission electron microscopy and mRFP-GFP-LC3 molecular probe, in the cerebral cortex after ischemia and reperfusion injury in animals or in cultured HT22 cells exposed to hypoxia with high glucose content. Finally, experiments with autophagy inhibitors 3-MA and aldose reductase inhibitor (ARI) revealed that while both inhibitors reduced the number of TUNEL positive neurons and reversed the effects of hyperglycemic ischemia on LC3 and p62, only ARI decreased the levels of p53, P-p53ser15. These results suggested that hyperglycemia might induce excessive autophagy to aggravate the brain injury resulted from I/R and that hyperglycemia might activate the p53-Sesn2-AMPK signaling pathway, in addition to the classical PI3K/AKT/mTOR autophagy pathway.

Dehydroamino acid residues in bioactive natural products.

Covering: 2000 to up to 2023α,ß-Dehydroamino acids (dhAAs) are unsaturated nonproteinogenic amino acids found in a wide array of naturally occurring peptidyl metabolites, predominantly those from bacteria. Other organisms, such as fungi, higher plants and marine invertebrates, have also been found to produce dhAA-containing peptides. The α,ß-unsaturation in dhAAs has profound effects on the properties of these molecules. They display significant synthetic flexibility, readily undergoing reactions such as Michael additions, transition-metal-catalysed cross-couplings, and cycloadditions. These residues in peptides/proteins also exhibit great potential in bioorthogonal applications using click chemistry. Peptides containing contiguous dhAA residues have been extensively investigated in the field of foldamers, self-assembling supermolecules that mimic biomacromolecules such as proteins to fold into well-defined conformations. dhAA residues in these peptidyl materials tend to form a 2.05-helix. As a result, stretches of dhAA residues arrange in an extended conformation. In particular, peptidyl foldamers containing ß-enamino acid units display interesting conformational, electronic, and supramolecular aggregation properties that can be modulated by light-dependent E-Z isomerization. Among approximately 40 dhAAs found in the natural product inventory, dehydroalanine (Dha) and dehydrobutyrine (Dhb) are the most abundant. Dha is the simplest dehydro-α-amino acid, or α-dhAA, without any geometrical isomers, while its re-arranged isomer, 3-aminoacrylic acid (Aaa or ΔßAla), is the simplest dehydro-ß-amino acid, or ß-enamino acid, and displays E/Z isomerism. Dhb is the simplest α-dhAA that exhibits E/Z isomerism. The Z-isomer of Dhb (Z-Dhb) is sterically favourable and is present in the majority of naturally occurring peptides containing Dhb residues. Dha and Z-Dhb motifs are commonly found in ribosomally synthesized and post-translationally modified peptides (RiPPs). In the last decade, the formation of Dha and Dhb motifs in RiPPs has been extensively investigated, which will be briefly discussed in this review. The formation of other dhAA residues in natural products (NPs) is, however, less understood. In this review, we will discuss recent advances in the biosynthesis of peptidyl NPs containing unusual dhAA residues and cryptic dhAA residues. The proposed biosynthetic pathways of these natural products will also be discussed.

Feasibility, safety, and efficacy of task-oriented mirrored robotic training on upper-limb functions and activities of daily living in subacute poststroke patients: a pilot study.

BACKGROUND: Robotic training with high repetitions facilitates upper-limb movements but provides fewer benefits for activities of daily living. Integrating activities of daily living training tasks and mirror therapy into a robot may enhance the functional gains of robotic training. AIM: The aim of this study was to investigate the feasibility, safety, and efficacy of the task-oriented mirrored upper-limb robotic training on the upper-limb functions and activities of daily living of subacute poststroke patients. DESIGN: This study is a single-blinded, active-controlled pilot study. SETTING: The study was carried out at rehabilitation outpatient clinic and ward. POPULATION: A total of 32 subacute poststroke patients were enrolled in the study. METHODS: The enrolled patients were allocated into two groups in a ratio of 1:1. The experimental group received 4 weeks of task-oriented mirrored upper-limb robotic training, consisting of five sessions of 30-minute duration, along with 30 minutes of conventional training. The control group only received 60 minutes of conventional training. The outcome measures were the Fugl-Meyer Assessment Scale for Upper Extremity, Modified Barthel Index, Stroke Self-Efficacy Scale, System Usability Scale, and Quebec User Evaluation with Assistive Technology. RESULTS: All patients completed the full training sessions without significant adverse events related to robotic training. The task-oriented mirrored upper-limb robotic training led to increased Fugl-Meyer Assessment Scale for Upper Extremity (difference: 10.38 points, P<0.001) and Modified Barthel Index (difference: 18.38 points, P<0.001) scores, both of which exceeded the minimal clinically important difference. Intergroup analysis showed significantly higher improvements in the Fugl-Meyer Assessment Scale for Upper Extremity total scores, shoulder, wrist, and hand scores; and Modified Barthel Index scores in the experimental group than in conventional training (all P<0.05). Both groups showed significant improvements in Stroke Self-Efficacy Scale scores after the intervention (both P<0.001), but without a statistically significant intergroup difference (P>0.05). Participants in the experimental group scored an average usability perception score of 74.74 (good) and an average satisfaction score of four or more out of five. CONCLUSIONS: In general, task-oriented mirrored upper-limb robotic training appears feasible and safe for subacute poststroke rehabilitation, facilitating the recovery of upper-limb functions and activities of daily living. CLINICAL REHABILITATION IMPACT: Task-oriented mirrored upper-limb robotic training shows promise for future clinical rehabilitation and clinical trials involving subacute poststroke patients.

Integrated metasurface for efficient polarization conversion and high-gain, low-RCS EM radiation.

This paper presents an innovative design that combines the functionalities of a polarization convertor and an electromagnetic (EM) radiator into a single integrated metasurface. The metasurface consists of two identical metallic split-rings, a circular-shaped patch structure, a dielectric layer, and a reflective metallic ground. The polarization convertor component efficiently converts waves polarized in the x- or y-direction into cross-polarized waves within a frequency range of 8-13 GHz. It exhibits wideband resonances and achieves a high conversion efficiency. In the context of low-observable platforms, traditional high-gain antennas often suffer from a large radar cross section (RCS). To overcome this challenge, the same metasurface is utilized for EM radiation, enabling a high gain of 16.5 dBi while maintaining a low RCS. This is accomplished by strategically rotating the double-slotted metallic split-rings at 90 ∘, 180 ∘, and 270 ∘ in four distinct regions. Through this rotation, destructive interference cancellation occurs, resulting in wideband reduction of the RCS. Experimental results validate the effectiveness of the proposed metasurface in serving both applications, namely polarization conversion and EM radiation.

Massive bleeding from a gastric artery pseudoaneurysm in hepatocellular carcinoma treated with atezolizumab plus bevacizumab: A case report.

BACKGROUND: The combination of atezolizumab (ATZ) and bevacizumab (BVZ) was approved as first-line systemic therapy for advanced hepatocellular carcinoma (HCC) owing to its superior rates of response and patient survival. However, ATZ + BVZ is associated with increased risk of upper gastrointestinal (GI) bleeding, including arterial bleeding, which is rare and potentially fatal. We present a case of massive upper GI bleeding from a gastric pseudoaneurysm in a patient with advanced HCC who had been treated with ATZ + BVZ. CASE SUMMARY: A 67-year-old man presented with severe upper GI bleeding after atezolizumab (ATZ) + bevacizumab (BVZ) therapy for HCC. Endoscopy failed to detect the bleeding site. Digital subtraction angiography revealed a gastric artery pseudoaneurysm and contrast extravasation from the inferior splenic artery and a branch of the left gastric artery. Successful hemostasis was achieved with embolization. CONCLUSION: HCC patients who have been treated with ATZ + BVZ should be followed for 3 to 6 mo to monitor for development of massive GI bleeding. Diagnosis may require angiography. Embolization is an effective treatment.

Sacubitril/valsartan reduces susceptibility to atrial fibrillation by improving atrial remodeling in spontaneously hypertensive rats.

AIM: Sacubitril/valsartan (Sac/Val, LCZ696), the world's first angiotensin receptor-neprilysin inhibitor (ARNi), has been widely used in the treatment of heart failure. However, the use of Sac/Val in the treatment of atrial fibrillation (AF), especially AF with hypertension, has been less reported. We investigated the effect of Sac/Val on atrial remodeling and hypertension-related AF. METHODS: The AF induction rate and electrophysiological characteristics of spontaneously hypertensive rats (SHRs) treated with Sac/Val or Val were detected by rapid atrial pacing and electrical mapping/optical mapping. The whole-cell patch-clamp and Western blot were used to observe electrical/structural remodeling of atrial myocytes/tissue of rats and atrium-derived HL-1 cells cultured under 40 mmHg in vitro. RESULTS: Sac/Val was superior to Val in reducing blood pressure, myocardial hypertrophy and susceptibility of AF in SHRs. The shorten action potentials duration (APD), decreased L type calcium channel current (ICa,L) and Cav1.2, increased ultrarapid delayed rectified potassium current (Ikur) and Kv1.5 in atrial myocytes/tissue of SHRs could be better improved by Sac/Val, as well as the levels of atrial fibrosis. While the protein expression of angiotensin-converting enzyme-1 (ACE-1), angiotensin, angiotensin II type I AT1 receptor (AT1R) and neprilysin (NEP) were increased, which could be more effective ameliorated by Sac/Val than Val. Furthermore, Val + Sacubitrilat (LBQ657) (an active NEP inhibitor) was also superior to LBQ657 or Val in improving the electrical and structural remodeling of HL-1 cells through inhibiting NEP. CONCLUSION: Sac/Val can improve atrial structural and electrical remodeling induced by hypertension and reduce the AF susceptibility by inhibiting RAS and NEP. The above effects of Sac/Val were superior to Val alone.

Associations of Renal Function Trajectories and Long-Term Cardiovascular Risks Among a Population Without Chronic Kidney Disease.

Background The longitudinal trajectories of renal function have been associated with cardiovascular events in patients with chronic kidney disease (CKD). However, the change pattern of renal function in those without CKD has not yet been reported. We aim to explore patterns of renal function change in a non-CKD population and its associated risks with cardiovascular outcomes. Methods and Results The present study analyzed data from 4 prospective cohorts and was restricted to participants without baseline CKD. The primary outcome was major adverse cardiovascular events, defined as a composite of myocardial infarction, chronic heart failure, stroke, and cardiovascular deaths. We used a group-based trajectory model to identify latent groups and analyzed the associated risk with Cox regression models. The complete dates of this study were June 1, 2020, through January 1, 2021. The final sample comprised 23 760 participants (mean age, 58.63 [9.12] years, 10 618 men, and 17 799 White participants). During 20.56 years follow-up, 8328 (35.05%) first major adverse cardiovascular events happened. Four trajectories in estimated glomerular renal function and 3 patterns of CKD progression were identified. Compared with subjects assigned to class I trajectory (high to mildly decreased group), the adjusted hazard ratios of major adverse cardiovascular events for class II (normal to mildly decreased group), class III (normal to moderately decreased group), and class IV (mildly to severely decreased group) were 1.11 (95% CI, 1.01-1.23), 1.27 (95% CI, 1.14-1.40), and 1.56 (95% CI, 1.38-1.77), respectively. Likewise, participants assigned to the slow and rapid progression groups had elevated HRs for major adverse cardiovascular events (1.75 [95% CI, 1.39-2.21] and 2.19 [95% CI, 1.68-2.86], respectively) when compared with the stable group. Findings were generally consistent in stratification analysis, but significant interaction effects by age and smoking status were detected. Conclusions In this study, we identified unique trajectory groups for renal function. These findings may signal an underlying high-risk population and inspire future studies on individualized risk management.

Synthesis and Properties of Polyol Copolymer with Alternating Methacrylate-Vinyl Ether Backbone.

Radical polymerization of a tailored diphenylsilane-bridged bi-functional monomer consisting of methacrylate and vinyl ether moieties is conducted in diluted monomer concentration, in which both two moieties are consumed at almost the same rate despite their huge difference in monomer reactivity ratio. The vinyl ether content in the backbone is quantified as 45% by 1 H NMR after removal of the silane bridge. Since vinyl ether alone cannot be polymerized in such radical polymerization, it should be incorporated in an alternating fashion with methacrylate into the copolymer main chain. The cleavage of silane bridge also yields a series of polyol materials composed of ethylene glycol monovinyl ether (EGVE) and hydroxyethyl methacrylate (HEMA), and the EGVE content in the backbone can be regulated from 45% to 18% by increasing the bi-functional monomer concentration. Interestingly, although containing more than 50% HEMA units, the alternating copolymer exhibits new properties totally different from poly(HEMA), but more similar to poly(EGVE), e.g., good water solubility and a markedly low glass transition temperature (Tg ) of -31 °C, which is attributed to the major HEMA-EGVE repeating unit that replaced HEMA-HEMA consecutive segments so that the properties of poly(HEMA) such as 95 °C Tg are completely altered.

Association of healthy lifestyles on the risk of hypertension, type 2 diabetes mellitus, and their comorbidity among subjects with dyslipidemia.

Background: Adherence to a healthy lifestyle could reduce the risk of hypertension and diabetes in general populations; however, whether the associations exist in subjects with dyslipidemia remains unclear. This study aimed to investigate the integrated effect of lifestyle factors on the risk of hypertension, type 2 diabetes mellitus (T2DM), and their comorbidity among subjects with dyslipidemia. Methods: In total of 9,339 subjects with dyslipidemia were recruited from the baseline survey of the Guangzhou Heart Study. A questionnaire survey and medical examination were performed. The healthy lifestyle score (HLS) was derived from five factors: smoking, alcohol drinking, diet, body mass index, and leisure-time physical activity. Odds ratios (ORs) with 95% confidence interval (95% CI) were calculated by using the logistic regression model and the multinomial logistic regression after adjusting for confounders. Results: The prevalence of hypertension, T2DM, and their comorbidity was 47.65, 16.02, and 10.10%, respectively. Subjects with a higher HLS were associated with a lower risk of hypertension, T2DM, and their comorbidity. In comparison to the subjects with 0-2 HLS, the adjusted ORs for subjects with five HLS was 0.48 (95% CI: 0.40-0.57) and 0.67 (95% CI: 0.54-0.84) for hypertension and T2DM. Compared with subjects with 0-2 HLS and neither hypertension nor T2DM, those with five HLS had a lower risk of suffering from only one disease (OR: 0.48, 95% CI: 0.40-0.57) and their comorbidity (OR: 0.35, 95% CI: 0.26-0.47). Conclusions: The results suggest that the more kinds of healthy lifestyle, the lower the risk of hypertension, T2DM, and their comorbidity among subjects with dyslipidemia. Preventive strategies incorporating lifestyle factors may provide a more feasible approach for the prevention of main chronic diseases.

Therapeutic strategies for retention of cranioplasty titanium mesh after mesh exposure.

BACKGROUND: Titanium mesh exposure after cranioplasty is a possible complication and is usually managed by mesh removal and flap transfer, but the advantages of the rigid prosthesis are then lost. This study aimed to present our experience with negative pressure wound therapy combined with soft tissue dilation for retaining the titanium mesh in patients with mesh exposure after cranioplasty. METHODS: This retrospective study included patients treated between 01/2016 and 05/2019 at the Jiangyin Hospital Affiliated to Southeast University School of Medicine. The wound was cleaned, and a cystic space was created for the tissue dilator, which was used with a self-designed negative pressure dressing. After the target dilation was achieved, the repair was conducted while retaining the titanium mesh. RESULTS: Eight patients were included (seven males and one female; 53.6 ± 8.8 (range, 43-65) years of age). The exposed mesh area ranged from 1 × 1 to 4 × 5.5 cm. The thinning scalp area around the exposed mesh ranged from 3.6 × 3.8 to 4 × 5.5 cm. Five patients had positive wound cultures and received sensitive antibiotics. The dilator embedding time was 20-28 days. The time of negative pressure wound therapy was 25-33 days. The hospital stay was 30-41 days. Primary wound healing was achieved in all eight patients. There were no signs of recurrence after 6-18 months of follow-up. The cranial CT scans were unremarkable. CONCLUSIONS: Negative pressure wound therapy combined with soft tissue dilation for exposed titanium mesh after cranioplasty might help retain the titanium mesh.

Prognostic role of expression of angiogenesis markers in hepatocellular carcinoma: A bioinformatics analysis.

The expression of angiopoietin (ANGPT) 1, ANGPT2, vascular endothelial growth factor (VEGF) A, VEGFB, VEGFC, VEGFD, and placental growth factor (PGF) is significantly higher in tumor tissues than in normal tissues in both unpaired and paired hepatocellular carcinoma (HCC) samples. ANGPT2, VEGFB, VEGFC, and PGF are primarily involved in regulating the activation of the epithelial-mesenchymal transition pathway; ANGPT1 is primarily involved in regulating the activation of the RAS/mitogen-activated protein kinase and receptor tyrosine kinase (RTK) pathways; VEGFA is engaged in regulating the RTK activation pathway; and VEGFD is mainly involved in regulating the activation of the tuberous sclerosis protein/mammalian target of rapamycin pathway. There is a significant difference in overall survival between HCC patients with high and low expression of ANGPT2, PGF, VEGFA, and VEGFD. Disease free survival (DFS) is significantly shorter in HCC patients with high ANGPT2, PGF, and VEGFA expression than in those with low ANGPT2, PGF, and VEGFA expression.

Effect of healthy lifestyle index and lifestyle patterns on the risk of mortality: A community-based cohort study.

Background: Limited evidence was available on the association of the integrated effect of multidimensional lifestyle factors with mortality among Chinese populations. This cohort study was to examine the effect of combined lifestyle factors on the risk of mortality by highlighting the number of healthy lifestyles and their overall effects. Methods: A total of 11,395 participants from the Guangzhou Heart Study (GZHS) were followed up until 1 January 2020. Individual causes of death were obtained from the platform of the National Death Registry of China. The healthy lifestyle index (HLI) was established from seven dimensions of lifestyle, and lifestyle patterns were extracted from eight dimensions of lifestyle using principal component analysis (PCA). Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using the Cox proportional hazard regression model. Results: During 35,837 person-years of follow-up, 184 deaths (1.61%) were observed, including 64 from cardiovascular disease. After adjustment for confounders, HLI was associated with a 50% (HR: 0.50, 95% CI: 0.25-0.99) reduced risk of all-cause mortality when comparing the high (6-7 lifestyle factors) with low (0-2 lifestyle factors) categories. Three lifestyle patterns were defined and labeled as pattern I, II, and III. Lifestyle pattern II with higher factor loadings of non-smoking and low-level alcohol drinking was associated with a decreased risk of all-cause mortality (HR: 0.63, 95% CI: 0.43-0.92, P -trend = 0.023) when comparing the high with low tertiles of pattern score, after adjustment for confounders. Every 1-unit increment of pattern II score was associated with a decreased risk (HR: 0.97, 95% CI: 0.95-0.99) of all-cause mortality. The other two patterns were not associated with all-cause mortality, and the association of cardiovascular mortality risk was observed with neither HLI nor any lifestyle pattern. Conclusion: The results suggest that the more dimensions of the healthy lifestyle the lower the risk of death, and adherence to the lifestyle pattern characterized with heavier loading of non-smoking and low-level alcohol drinking reduces the risk of all-cause mortality. The findings highlight the need to consider multi-dimensional lifestyles rather than one when developing health promotion strategies.

Low level light therapy/photobiomodulation for diabetic peripheral neuropathy: protocol of a systematic review and meta-analysis.

INTRODUCTION: Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes that strongly impact the patients' quality of life and working ability. Evidence indicated that low level light therapy (LLLT)/photobiomodulation might be effective for neuropathy. However, the effect of LLLT for DPN is not clear. The objective of this systematic review and meta-analysis is to determine the effects and safety of LLLT/photobiomodulation for DPN, in comparison with other methods such as sham light, no treatment, other active treatment and LLLT as an additional treatment compared with another treatment alone. METHODS AND ANALYSIS: We will search eight databases from their inception to the date before the review submission. Randomised controlled trials (RCTs) will be included. Two reviewers will independently extract data using a structured data extraction method and assess the risk of bias in the included studies. Data will be synthesised using standardised mean difference or risk ratio with 95% CIs for continuous and dichotomous data, respectively. The primary outcome will be change in pain and secondary outcomes will include global symptom improvement, functional impairment and disability, impairment of sensation, quality of life, nerve conduction, and adverse events. Sensitivity and subgroup analysis will be employed to explore the influence of possible clinical and methodological characteristics. Publication bias will be assessed using funnel plot. We will conduct meta-analysis with RevMan V.5.4 and evaluate quality of the evidence using GRADE approach. ETHICS AND DISSEMINATION: This study does not require ethics approval. Our findings will be disseminated in the peer-reviewed publications. PROSPERO REGISTRATION NUMBER: CRD42021276056.

Short-term Outcomes of Laparoscopy-Assisted vs Open Surgery for Patients With Low Rectal Cancer: The LASRE Randomized Clinical Trial.

Importance: The efficacy of laparoscopic vs open surgery for patients with low rectal cancer has not been established. Objective: To compare the short-term efficacy of laparoscopic surgery vs open surgery for treatment of low rectal cancer. Design, Setting, and Participants: This multicenter, noninferiority randomized clinical trial was conducted in 22 tertiary hospitals across China. Patients scheduled for curative-intent resection of low rectal cancer were randomized at a 2:1 ratio to undergo laparoscopic or open surgery. Between November 2013 and June 2018, 1070 patients were randomized to laparoscopic (n = 712) or open (n = 358) surgery. The planned follow-up was 5 years. Data analysis was performed from April 2021 to March 2022. Interventions: Eligible patients were randomized to receive either laparoscopic or open surgery. Main Outcomes and Measures: The short-term outcomes included pathologic outcomes, surgical outcomes, postoperative recovery, and 30-day postoperative complications and mortality. Results: A total of 1039 patients (685 in laparoscopic and 354 in open surgery) were included in the modified intention-to-treat analysis (median [range] age, 57 [20-75] years; 620 men [59.7%]; clinical TNM stage II/III disease in 659 patients). The rate of complete mesorectal excision was 85.3% (521 of 685) in the laparoscopic group vs 85.8% (266 of 354) in the open group (difference, -0.5%; 95% CI, -5.1% to 4.5%; P = .78). The rate of negative circumferential and distal resection margins was 98.2% (673 of 685) vs 99.7% (353 of 354) (difference, -1.5%; 95% CI, -2.8% to 0.0%; P = .09) and 99.4% (681 of 685) vs 100% (354 of 354) (difference, -0.6%; 95% CI, -1.5% to 0.5%; P = .36), respectively. The median number of retrieved lymph nodes was 13.0 vs 12.0 (difference, 1.0; 95% CI, 0.1-1.9; P = .39). The laparoscopic group had a higher rate of sphincter preservation (491 of 685 [71.7%] vs 230 of 354 [65.0%]; difference, 6.7%; 95% CI, 0.8%-12.8%; P = .03) and shorter duration of hospitalization (8.0 vs 9.0 days; difference, -1.0; 95% CI, -1.7 to -0.3; P = .008). There was no significant difference in postoperative complications rate between the 2 groups (89 of 685 [13.0%] vs 61 of 354 [17.2%]; difference, -4.2%; 95% CI, -9.1% to -0.3%; P = .07). No patient died within 30 days. Conclusions and Relevance: In this randomized clinical trial of patients with low rectal cancer, laparoscopic surgery performed by experienced surgeons was shown to provide pathologic outcomes comparable to open surgery, with a higher sphincter preservation rate and favorable postoperative recovery. Trial Registration: ClinicalTrials.gov Identifier: NCT01899547.

Therapeutic experience of a pancreatic mixed serous neuroendocrine neoplasm invading peripancreatic vessels: A case report.

RATIONALE: Pancreatic mixed serous neuroendocrine neoplasm (PMSNN) is an extremely rare disease. Only a few cases on the surgical treatment of PMSNN have been reported in the literature, and it is unclear whether there is invasion of important peripancreatic vessels. PATIENT CONCERNS: We report the case of a 39-year-old female patient with PMSNN accompanied by invasion of important peripancreatic vessels. She underwent surgery and achieved satisfactory recovery. DIAGNOSIS: Abdominal enhanced CT images showed an enhanced mass with a nonenhanced cyst involving the head and body of the pancreas, which invaded important peripancreatic vessels. The lesion had been misdiagnosed and mistreated as a metastatic carcinoma before admission. INTERVENTIONS: CT 3-dimensional (3D) visualization reconstruction images showed intact peripancreatic vessels. Radical pancreatoduodenectomy was successfully performed and confirmed that the main blood vessels around the pancreas were only compressed or even wrapped by the mass, but not penetrated. OUTCOMES: The patient recovered well and was discharged on the 19th day after surgery. Pathological examination reported the diagnosis of PMSNN with the collision type combination and the well-differentiated grade 2 pancreatic neuroendocrine tumor. She was followed up for 18 months without any abnormalities. LESSONS: This case demonstrates that surgical treatment of PMSNN with invasion of peripancreatic vessels can be successful. Preoperative abdominal CT 3D visualization reconstruction is helpful in determining the degree of invasion of important peripancreatic vessels, and plays a key role in formulating an accurate surgical plan and improving patient outcome.

A ribosomally synthesised and post-translationally modified peptide containing a ß-enamino acid and a macrocyclic motif.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are structurally complex natural products with diverse bioactivities. Here we report discovery of a RiPP, kintamdin, for which the structure is determined through spectroscopy, spectrometry and genomic analysis to feature a bis-thioether macrocyclic ring and a ß-enamino acid residue. Biosynthetic investigation demonstrated that its pathway relies on four dedicated proteins: phosphotransferase KinD, Lyase KinC, kinase homolog KinH and flavoprotein KinI, which share low homologues to enzymes known in other RiPP biosynthesis. During the posttranslational modifications, KinCD is responsible for the formation of the characteristic dehydroamino acid residues including the ß-enamino acid residue, followed by oxidative decarboxylation on the C-terminal Cys and subsequent cyclization to provide the bis-thioether ring moiety mediated by coordinated action of KinH and KinI. Finally, conserved genomic investigation allows further identification of two kintamdin-like peptides among the kin-like BGCs, suggesting the occurrence of RiPPs from actinobacteria.

Development and Validation of a Deep-Learning Model to Detect CRP Level from the Electrocardiogram.

Background: C-reactive protein (CRP), as a non-specific inflammatory marker, is a predictor of the occurrence and prognosis of various arrhythmias. It is still unknown whether electrocardiographic features are altered in patients with inflammation. Objectives: To evaluate the performance of a deep learning model in detection of CRP levels from the ECG in patients with sinus rhythm. Methods: The study population came from an epidemiological survey of heart disease in Guangzhou. 12,315 ECGs of 11,480 patients with sinus rhythm were included. CRP > 5mg/L was defined as high CRP level. A convolutional neural network was trained and validated to detect CRP levels from 12 leads ECGs. The performance of the model was evaluated by calculating the area under the curve (AUC), accuracy, sensitivity, specificity, and balanced F Score (F1 score). Results: Overweight, smoking, hypertension and diabetes were more common in the High CRP group (p < 0.05). Although the ECG features were within the normal ranges in both groups, the high CRP group had faster heart rate, longer QTc interval and narrower QRS width. After training and validating the deep learning model, the AUC of the validation set was 0.86 (95% CI: 0.85-0.88) with sensitivity, specificity of 89.7 and 69.6%, while the AUC of the testing set was 0.85 (95% CI: 0.84-0.87) with sensitivity, specificity of 90.7 and 67.6%. Conclusion: An AI-enabled ECG algorithm was developed to detect CRP levels in patients with sinus rhythm. This study proved the existence of inflammation-related changes in cardiac electrophysiological signals and provided a noninvasive approach to screen patients with inflammatory status by detecting CRP levels.