Combining pathological risk factors and T, N staging to optimize the assessment for risk stratification and prognostication in low-risk stage III colon cancer.

BACKGROUND: This study aimed to investigate the combined pathological risk factors (PRFs) to stratify low-risk (pT1-3N1) stage III colon cancer (CC), providing a basis for individualized treatment in the future. PATIENTS AND METHODS: PRFs for low-risk stage III CC were identified using COX model. Low-risk stage III CC was risk-grouped combining with PRFs, and survival analysis were performed using Kaplan-Meier. The Surveillance, Epidemiology, and End Results (SEER) databases was used for external validation. RESULTS: Nine hundred sixty-two stage III CC patients were included with 634 (65.9%) as low risk and 328 (34.1%) as high risk. Poor differentiation (OS: P = 0.048; DFS: P = 0.011), perineural invasion (OS: P = 0.003; DFS: P < 0.001) and tumor deposits (OS: P = 0.012; DFS: P = 0.003) were identified as PRFs. The prognosis of low-risk CC combined with 2 PRFs (OS: HR = 3.871, 95%CI, 2.004-7.479, P < 0.001; DFS: HR = 3.479, 95%CI, 2.158-5.610, P < 0.001) or 3 PRFs (OS: HR = 5.915, 95%CI, 1.953-17.420, P = 0.002; DFS: HR = 5.915, 95%CI, 2.623-13.335, P < 0.001) was similar to that of high-risk CC (OS: HR = 3.927, 95%CI, 2.317-6.656, P < 0.001; DFS: HR = 4.132, 95%CI, 2.858-5.974, P < 0.001). In the SEER database, 18,547 CC patients were enrolled with 10,023 (54.0%) as low risk and 8524 (46.0%) as high risk. Low-risk CC combined with 2 PRFs (OS: HR = 1.857, 95%CI, 1.613-2.139, P < 0.001) was similar to that of high-risk CC without PRFs (HR = 1.876, 95%CI, 1.731-2.033, P < 0.001). CONCLUSION: Combined PRFs improved the risk stratification of low-risk stage III CC, which could reduce the incidence of undertreatment and guide adjuvant chemotherapy.

Anticancer Effect of Chlorambucil Enhanced by Chiral Phthalidyl Promoiety.

Phthalidyl promoiety has been used in several drugs, but they were all marketed in racemic form. The pharmaceutical effects of each enantiomer have not been clearly demonstrated. In this project, an anticancer chemotherapy drug, chlorambucil, was modified as enantiopure phthalidyl prodrugs. The enantiomers, together with phthalidyl unit and their racemic mixture, were then subject to the in vivo bioactivity tests against B16F10 melanoma cells. It was found that proper chirality within the promoiety had noticeably better in vivo pharmacological effects than the parent drug, the enantiomer and racemic mixture. This merit perhaps could be extended from the phthalidyl prodrugs to other chirality containing prodrugs.

Novel Sulfonamide Derivatives Containing a Piperidine Moiety as New Bactericide Leads for Managing Plant Bacterial Diseases.

Plant bacterial diseases are an intractable problem due to the fact that phytopathogens have acquired strong resistances for traditional pesticides, resulting in restricting the quality and yield of agricultural products around the world. To develop new agrochemical alternatives, we prepared a novel series of sulfanilamide derivatives containing piperidine fragments and assessed their antibacterial potency. The bioassay results revealed that most molecules displayed excellent in vitro antibacterial potency towards Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas axonopodis pv. citri (Xac). In particular, molecule C4 exhibited outstanding inhibitory activity toward Xoo with EC50 value of 2.02 µg mL-1, which was significantly better than those of the commercial agents bismerthiazol (EC50 = 42.38 µg mL-1) and thiodiazole copper (EC50 = 64.50 µg mL-1). A series of biochemical assays confirmed that compound C4 interacted with dihydropteroate synthase, and irreversibly damaged the cell membrane. In vivo assays showed that the molecule C4 presented acceptable curative and protection activities of 34.78% and 39.83%, respectively, at 200 µg mL-1, which were greater than those of thiodiazole and bismerthiazol. This study highlights the valuable insights for the excavation and development of new bactericides that can concurrently target dihydropteroate synthase and bacterial cell membranes.

Construction of a predictive model for cognitive impairment risk in patients with advanced cancer.

AIMS: The purpose of this study was to identify risk factors for cognitive impairment in advanced cancer patients and to develop predictive models based on these risk factors. BACKGROUND: Cancer-related cognitive impairment seriously affects the quality of life of advanced cancer patients. However, neural network models of cognitive impairment in patients with advanced cancer have not yet been identified. DESIGN: A cross-sectional design was used. METHODS: This study collected 494 questionnaires between January and June 2022. Statistically significant clinical indicators were selected by univariate analysis, and the artificial neural network model and logistic regression model were used for multivariate analysis. The predicted value of the model was estimated using the area under the subject's working characteristic curve. RESULT: The artificial neural network and the logistic regression models suggested that cancer course, anxiety and age were the major risk factors for cognitive impairment in advanced cancer patients. All the indexes of artificial neural network model constructed in this study are better than those of the logistic model. CONCLUSION: The artificial neural network model can better predict the risk factors of cognitive impairment in patients with advanced cancer. Better prediction will enable nurses and other healthcare professionals to provide better targeted and timely support.

Metal Free Access to Polysubstituted Pyrimidines via Nitrile Activation and [2+2+2] Cycloaddition.

Tf2 O mediated intermolecular / intramolecular [2+2+2] cycloaddition between alkynes and nitriles has been developed for efficient construction of polysubstituted pyrimidines and bicyclopyrimidines. In presence of Tf2 O, aza-allene species were generated in situ through nitrile activation and subsequently participated in the [2+2+2] cycloaddition, which was fully supported by deuteration experiments. The reaction had good substrate extensibility with moderate to excellent yield including trimethylsilylalkynes. The method was utilized as a synthetic tool in the preparation of a luminescent metal complex.

Intracranial lymphatic drainage discharges iron from the ventricles and reduce the occurrence of chronic hydrocephalus after intraventricular hemorrhage in rats.

Background: The discovery of intracranial lymphatic system provides a new theory about cerebrospinal fluid circulation. In order to investigate the role of lymphatic drainage in hydrocephalus after intraventricular hemorrhage (IVH), three parts of experiments were performed.Methods: IVH model was produced by 200ul autologous blood injection into lateral ventricle of SD male rats. Perls Prussian blue reaction was used to confirm the ability of iron drainage through deep cervical lymph nodes (DCLNs) in part I. The part II measured the volume of ventricles by MR scanner , and the part III compared the ferritin level of area surrounding ventricles by Western blotting after IVH.Results: The ability of iron drainage through DCLNs was confirmed. DCLNs-excised rats got a 19.6% higher incidence of hydrocephalus than DCLNs-preserved rats at day 28 after IVH. And DCLNs-excised group showed higher ferritin level than DCLNs-preserved group at day 3 after IVH.Conclusion: The whole experiments revealed the role of intracranial lymphatic system in discharging iron out of central nervous system at acute phase of IVH, and proved the function in alleviating and avoiding hydrocephalus at chronic phase after IVH.

[Hormesis of drugs for infectious diseases].

Hormesis, a biphasic dose-response phenomenon characterized by low-dose stimulation and high-dose inhibition, is a common feature of medicines but neglected sometime. Understanding of hormesis is essential for drug discovery and clinical application. Assessing hormetic range needs a proper experiment design including the number of doses and dose spacing, especially in the low dose zone. This article provides the shapes of hormetic dose-response curves, underlying mechanisms and the significance of hormesis for drugs of infectious diseases to facilitate drugs development and clinical applications.

[Advanced technologies in semen stain identification].

Semen stain identification is one of the crucial tasks for collection of criminal evidence by forensic techniques. Substances such as DNA and RNA contained in semen stains can serve as a source of personalized evidence targeting the suspect. Therefore, semen stain identification is vital to inferring the case attributes and the facts of the crime. The conventional methods of forensic stain identification focus on the detection of specific-function protein and/or high-content protein, such as alkaline phosphatase and PSA. Although the specificity of such protein markers is relatively high, these methods yield a limited rate of success for several factors, including poor stability, low sensitivity of the target protein, and possible subjectivity of the performer. In order to overcome these limitations, new technologies such as Raman spectroscopy, mass spectrometry for protein markers, sperm-specific aptamer, mRNA, microRNA, and DNA methylation assays have been studied and recommended by many investigators. These new technologies are paving a new ground for personalized trace analysis and even for detection of over-timed specimens.

Expression of hypoxia-inducible factor 1 alpha ameliorate myocardial ischemia in rat.

Hypoxia-inducible factor 1 alpha (HIF-1a), the upstream regulator of Vascular endothelial growth factor (VEGF), is the vital hypoxia related gene expression control factor. To evaluate HIF-1a therapeutic efficacy to acute myocardial infarction, the HIF-1a expressing recombinant Adeno-associated virus (rAAV) was constructed. The Wistar rat ischemic heart animal model was established with left anterior descending coronary artery ligation. The ischemic rats were treated with HIF-1a expressing and GFP expressing rAAVs respectively. Four weeks post the injection, the cardiac function of treated rat was compared by TM_WAVE system; size of infracted area was calculated by Evan's blue stain and capillary density was determined by CD31 immunohistochemical staining. Compare to the control group, the rats received HIF-1a expressing rAAV have smaller infracted heart size, the better heart function and higher capillary density than vehicle control group. The results show that the injection of HIF1a expressing rAAV can improve cardiac function and ameliorate acute myocardial ischemia (AMI) in rats.

A stable, reusable, and highly active photosynthetic bioreactor by bio-interfacing an individual cyanobacterium with a mesoporous bilayer nanoshell.

An individual cyanobacterium cell is interfaced with a nanoporous biohybrid layer within a mesoporous silica layer. The bio-interface acts as an egg membrane for cell protection and growth of outer shell. The resulting bilayer shell provides efficient functions to create a single cell photosynthetic bioreactor with high stability, reusability, and activity.

ErZhiTianGui Decoction alleviates age-related ovarian aging by regulating mitochondrial homeostasis and inhibiting ferroptosis.

AIM: This study was designed to investigate the pharmacological effects and mechanisms of ErZhiTianGui Decoction (EZTG) for age-related ovarian aging in mice. METHODS: This study used naturally aging mice as a model, and EZTG was used for intragastric administration. Ovarian pathological changes, as well as follicular reserve were assessed by hematoxylin and eosin staining, and serum hormone levels (anti-mullerian hormone, follicle-stimulating hormone), mitochondrial reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) damage marker 8-hydroxy-2'-deoxyguanosine(8-OHdG), and lipid peroxidation markers glutathione(GSH) and malondialdehyde(MDA) were determined by enzyme-linked immunosorbent assay. Mitochondrial membrane potential (MMP) levels in ovaries were determined using flow cytometry. The levels of PINK1 and Parkin were observed using immunofluorescence staining. Mitochondrial-derived vesicles (MDVs) and mitochondrial morphology were observed using electron microscopy. Prussian blue staining was used to observe iron ion aggregation in ovarian tissue. The Iron assay kits detected total iron levels. Western blot was used to detect the expression of proteins related to mitochondrial and ferroptosis related genes. RESULTS: After EZTG treatment, aged mice showed increased ovarian reserve, improved serum hormone levels, increased MMP, GSH levels, and decreased mitochondrial ROS, 8-OHdG, and MDA levels. Immunofluorescence staining showed decreased levels of PINK1 and Parkin, and the same trend was observed for the Western blot. Meanwhile, electron microscopy showed that EZTG improved the mitochondrial morphology in the ovaries of aged mice. EZTG also decreased the total iron and protein levels of Acyl-CoA synthetase long-chain family4 (ACSL4) and increased the protein level of glutathione peroxidase 4 (GPX4) in the ovaries of aged mice. CONCLUSIONS: EZTG can maintain PINK1/Parkin-mediated mitochondrial homeostasis, reduce the lipid peroxidation caused by the accumulation of ROS, and inhibit the occurrence of ferroptosis and delaying ovarian aging. These findings suggest that EZTG may be a promising drug for treating age-related ovarian aging in females.

Regio- and stereoselective access to highly substituted vinylphosphine oxides via metal-free electrophilic phosphonoiodination of alkynes.

In general, the P-centered ring-opening of quaternary phosphirenium salts (QPrS) predominantly leads to hydrophosphorylated products, while the C-centered ring-opening is primarily confined to intramolecular nucleophilic reactions, resulting in the formation of phosphorus-containing cyclization products instead of difunctionalized products generated through intermolecular nucleophilic processes. Here, through the promotion of ring-opening of three-member rings by iodine anions and the quenching of electronegative carbon atoms by iodine cations, we successfully synthesize ß-functionalized vinylphosphine oxides by the P-addition of QPrS intermediates generated in situ. Multiple ß-iodo-substituted vinylphosphine oxides can be obtained with exceptional regio- and stereo-selectivity by reacting secondary phosphine oxides with unactivated alkynes. In addition, a variety of ß-functionalized vinylphosphine oxides converted from C-I bonds, especially the rapid construction of benzo[b]phospholes oxides, demonstrates the significance of this strategy.

Which patients with coronary artery disease should include oral nitrates on their discharge medication list?

BACKGROUND: Which patients with coronary artery disease (CAD) should have oral nitrates on their discharge medication list after coronary angiography (CAG)? To assess the relationship between oral nitrates included in the discharge medication list and major adverse cardiovascular events (MACEs) among CAD patients, we designed this retrospective cohort study. METHODS: A total of 2979 CAD patients hospitalised in the Department of Cardiology, Affiliated Hospital of Jining Medical University from May 2013 to October 2015 were enrolled, grouped according to whether oral nitrates were included at discharge after CAG, and followed up for MACEs for a mean of 4.42 years after discharge. The primary endpoint was MACEs. Multivariate Cox proportional hazards models were used to analyses potential confounding factors. Stratified analysis was used to observe the relationship between oral nitrates and MACEs by different covariates. RESULTS: The median follow-up time was 4.61 years, and 296 (9.94%) patients experienced MACEs. Multivariate Cox proportional hazards model analysis showed no association between oral nitrates on the discharge medication list and the occurrence of MACEs among patients with CAD (p > 0.05) after adjusting for some covariates, such as SYNTAX score (hazard ratio (HR): 1.18, 95% confidence interval (CI): 0.90-1.55, p = 0.2420). Stratified analysis revealed a higher incidence of MACEs among hypertensive patients prescribed oral nitrates at discharge (HR: 1.67, 95% confidence CI: 1.13-2.46, p = 0.0046). However, prescribing nitrates at discharge for patients with low uric acid levels increased the incidence of MACEs, which showed a possible trend towards significance (HR: 1.44, 95% CI: 0.99-2.09, p = 0.0525). CONCLUSION: There was no association between oral nitrates included in the discharge medication list and the development of MACEs among patients with CAD after adjusting for some covariates, such as SYNTAX score. Oral nitrates after discharge for CAD patients combined with hypertension increased the occurrence of MACEs. Oral nitrates after discharge for CAD patients combined with low uric acid levels may increase theoccurrence of MACEs, and close monitoring for any adverse events is recommended.

Alterations of mitochondrial protein assembly and jasmonic acid biosynthesis pathway in Honglian (HL)-type cytoplasmic male sterility rice.

It has been suggested that the mitochondrial chimeric gene orfH79 is the cause for abortion of microspores in Honglian cytoplasmic male sterile rice, yet little is known regarding its mechanism of action. In this study, we used a mass spectrometry-based quantitative proteomics strategy to compare the mitochondrial proteome between the sterile line Yuetai A and its fertile near-isogenic line Yuetai B. We discovered a reduced quantity of specific proteins in mitochondrial complexes in Yuetai A compared with Yuetai B, indicating a defect in mitochondrial complex assembly in the sterile line. Western blotting showed that ORFH79 protein and ATP1 protein, an F(1) sector component of complex V, are both associated with large protein complexes of similar size. Respiratory complex activity assays and transmission electron microscopy revealed functional and morphological defects in the mitochondria of Yuetai A when compared with Yuetai B. In addition, we identified one sex determination TASSELSEED2-like protein increased in Yuetai A, leading to the discovery of an aberrant variation of the jasmonic acid pathway during the development of microspores.

Expression of survivin and livin predicts early recurrence in non-muscle invasive bladder cancer.

BACKGROUND: Survivin and livin are novel members of the inhibitor of apoptosis gene family (IAP) that controls mitotic progression and induces tumor cell invasion. This study aims to evaluate the association of both expression with clinical outcomes and risk of recurrence in patients with non-muscle invasive bladder cancer (NIMBC). PATIENTS AND METHODS: We investigated the expression of survivin and livin in 72 NMIBC samples using immunohistochemical staining (Envision Method). Survivin and livin were considered high-expressed when more than 10% of the cells expressed. The archival bladder tissue specimens from 11 normal controls were examined and studied. All patients with a follow-up of at most 5 years following initial transurethral resection (TUR) were included in the study. The association of both expression with established clinicopathologic factors and recurrence free survival (RFS) was analyzed using log-rank test and Cox regression analysis. RESUTS: Neither survivin nor livin was expressed in normal bladder urothelium. Survivin and livin were high-expressed in 84.7 and 75.0% of NIMBC. And in cases of recurrence, the high-expression (H-exp.) rates were 98.3 and 91.7% (P < 0.01), respectively. The recurrence of NIMBC was significantly associated with high expression of survivin and livin (P < 0.01, P < 0.01), and G-3 tumors had a significantly greater proportion of high survivin expression than G-1 or/and G-2 tumors (P = 0.01); however, no association was found between expression of both and age, gender, pathology stage, or adjuvant therapy. High expression of survivin (RR:9.818, 95% CI: 1.109-86.911, P = 0.040) and livin (RR: 4.199; 95% CI: 1.018-17.321; P = 0.047) was significantly powerful prognostic factors in Cox regression analysis for RFS. CONCLUSIONS: Expression of survivin and livin may influence the prognosis of NIMBC. This finding opens new perspectives for Survivin and livin prediction of early recurrence in NIMBC.

[Genetic evolution analysis of matrix protein 2 gene of avian influenza H5N1 viruses from boundary of Yunnan province].

OBJECTIVE: To elucidate the variation in characterizations and genetic evolution of the matrix protein 2 or ion channel protein(M2) genes of avian influenza subtype H5N1 viruses in the boundary region of Yunnan province from 2008 to 2012. METHODS: A total of swab samples were collected from foreign poultry such as the junction between Yunnan and Vietnam, Laos,myanmar and wild birds in boundary region of Yunnan province from 2008 to 2012 and screened by H5N1 subtype-specific multiplex RT-PCR. The M genes of H5N1 virus from the positive samples were amplified by RT-PCR and cloned into pMD18-T vectors for sequencing. The alignment and phylogenetic analysis of M2 genes were performed with sequences of the known reference strains. RESULTS: A total of 71 positive samples were found out of 1240 samples and the positive rate was 5.72%. A total of 14 different M2 sequences were obtained from 30 positive samples and were divided into 3 distinct clades or sub-clades(1.2.1, 1.2.2 and 2) by phylogenetic analysis, 5, 7 and 2, respectively. The M2 genes and Hemagglutinin(HA) genes of H5N1 viruses from the boundary region of Yunnan province had showed different relationship of genetic evolution. The substitution or mutation of key amino acids sites had been found among the domains of epitope, adamantane-resistance, and poultry or human original viral strains. CONCLUSION: The M2 genes of H5N1 subtype viruses in boundary region of Yunnan province from 2008 to 2012 showed genetic divergence and the virus of clade 1.2.2 had become dominant epidemic strain in this region.

Association of age-related hearing loss with cognitive impairment and dementia: an umbrella review.

Background: Hearing loss, cognitive impairment and dementia have become common problems for older adults. Currently, systematic reviews and meta-analyses of the association between age-related hearing loss (ARHL) with cognitive impairment and dementia may have inconsistent results. To explore and validate the association between ARHL with cognitive impairment and dementia through summarizing and evaluating existing evidence. Methods: From inception to February 01, 2023, PubMed, Web of Science, Embase, and Cochrane Library databases were systematically searched. AMSTAR 2 was used to evaluate methodological quality and GRADE system was used to evaluate evidence quality. We summarized the basic characteristics of the included studies and extracted effect data for ARHL with cognitive impairment and dementia. Forest plots were used to describe the relative risk associated with ARHL and cognitive impairment, and the relative risk associated with ARHL and dementia, respectively. Results: A total of 11 systematic reviews and meta-analyses met the inclusion criteria. Overall, the methodological quality of the included SRs/MAs was moderate and the quality of the evidence was low. The combined results found that the pooled risk ratio of ARHL and cognitive impairment was 1.30 (random-effects; 95% CI 1.16 to 1.45), and the pooled risk ratio of ARHL and dementia was 1.59 (random-effects; 95% CI 1.34 to 1.90). Conclusion: Based on the evidence reported in this umbrella review, age-related hearing loss is significantly associated with cognitive impairment and dementia. Hearing loss may be a high risk factor for cognitive impairment and dementia in older adults.

Effects of Friction Stir Welding on the Mechanical Behaviors of Extrusion-Based Additive Manufactured Polymer Parts.

The friction stir welding (FSW) of thermoplastic polymers is gradually receiving attention because of its advantages including high efficiency and pollution-free manufacturing. The extrusion-based additive manufacturing (EAM) of polymers has also become one of the main processing methods for thermoplastic parts. In this paper, a hybrid manufacturing method for the FSW process and EAM technology is proposed and explored. The effects of the FSW process using two different welding tools on the mechanical behaviors of 3D printing polymer parts were compared and investigated and the corresponding mechanism was analyzed. The results show that the appropriate welding tool is beneficial for eliminating the anisotropy and decreasing the porosity of 3D-printed parts. Therefore, the improving effects of the FSW process on the mechanical behaviors of the EAM parts are verified. The mechanism was attributed to the high-speed rotation of the welding tool with the appropriate shape, which can promote the flow of polymer melt in the welding region, leading to the formation of dense structures caused by the entanglement of the molecular chains. This study may provide some assistance in modern industrial manufacturing for the processing of large custom components.

De novo mutation of NAXE (APOAIBP)-related early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1: A case report.

BACKGROUND: Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL1) is a rare autosomal recessive severe neurometabolic disease. The aim of this study was to investigate the clinical characteristics and genetic pathogenicity of PEBEL1 caused by rare NAXE (or APOA1BP)-related defects. CASE SUMMARY: The patient was a girl aged 2 years and 10 mo. She was hospitalized due to walking disorder for > 40 d. The clinical manifestations were ataxia, motor function regression, hypotonia, and eyelid ptosis. Within 1 mo of hospitalization, she developed sigh breathing, respiratory failure, cerebellar edema and brain hernia, and finally she died. Changes were found in cranial imaging, including cerebellar edema accompanied by symmetrical myelopathy. Through whole exome sequencing, we detected NAXE compound heterozygous variation (NM 144772.3) c.733A>C (p. Lys245Gln, dbSNP: rs770023429) and novel variation c.370G>T (p.Gly124Cys) in the germline gene. The clinical features and core phenotypes of this case were consistent with 18 previously reported cases of PEBEL1. CONCLUSION: This is the first case of NAXE-related PEBEL1 with severe clinical phenotype in Mainland China. The p.Gly124Cys mutation discovered in this case has enriched the pathogenic variation spectrum of NAXE.

Rigid P-Chiral Phosphorus Ligands for Highly Selective Palladium-Catalyzed (4+2) and (4+4) Annulations.

We developed novel shackled P-chiral ligands based on 1-phosphanorbornenes and oxazolines. They were subsequently evaluated in palladium-catalyzed (4+2) annulations, producing enantioenriched tetrahydropyran scaffolds in good yields with high site selectivity and enantioselectivity. Moreover, chemoselective (4+4) products were also achieved by using acyclic imines. In addition, density functional theory calculations were performed to afford the energy profile of the Michael addition step and ring formation step. This demonstrated that the enantioselective (4+2) annulations and the chemoselective reaction between (4+2) and (4+4) products were mostly under thermodynamic control.