Outcome comparison of meniscal allograft transplantation (MAT) and meniscal scaffold implantation (MSI): A systematic review.

BACKGROUND: Although numerous studies have reported successful clinical outcomes of Meniscal allograft transplantation (MAT) or Meniscal scaffold implantation (MSI), the difference between the outcome of MAT and MSI remains unclear. PURPOSE: To compare the overall outcomes and survival rates of MAT and MSI, aiming to provide comprehensive evidence for determining the optimal treatment strategy for meniscal defects. METHODS: A systematic review was performed via a comprehensive search of PubMed, Embase, and the Cochrane Library. Studies of MAT or MSI were included according to the inclusion and exclusion criteria. The Lysholm score was chosen as the primary outcome measure, while secondary outcomes encompassed Patient-reported Outcome Measures (PROMs), Return to Sports (RTS) rates, survival rates, and complication rates. The outcomes were stratified into two groups: MAT group and MSI group, followed by statistical comparison (P<0.05). The quality of the included studies was assessed by the Cochrane Risk of Bias 2 (RoB2) assessment tool for randomized controlled trials (RCTs) and the Coleman Methodology Score (CMS) for non-randomized controlled trials. RESULTS: A total of 3932 patients (2859 MAT, 1073 MSI) in 83 studies (51 MAT, 32 MSI) had the overall significant improvement in all clinical scores. The group MSI had higher Lysholm score of both preoperative (P=0.002) and postoperative (P<0.001) than group MAT; however, the mean improvements were similar between the two groups (P=0.105). Additionally, MSI had higher improvements of IKDC (P<0.001), KOOS symptom (P=0.010), KOOS pain (P=0.036), and KOOS ADL (P=0.004) than MAT. Interestingly, MAT had higher preoperative (P=0.018) and less postoperative VAS pain (P=0.006), which was more improved in MAT (P<0.001). Compared with MAT, MSI had higher 10-year survival rate (P=0.034), similar mid-term survival rate MAT (P=0.964), and lower complication rate (P<0.001). CONCLUSION: Both MAT and MSI could have good clinical outcomes after surgery with the similar improvement in Lysholm score. MSI had higher 10-year survival rate and less complications than MAT. LEVEL OF EVIDENCE: IV, systematic review.

Biomimetic nanodrug blocks CD73 to inhibit adenosine and boosts antitumor immune response synergically with photothermal stimulation.

Combination of tumor immunotherapy with photothermal therapy (PTT) is a feasible tactic to overcome the drawback of immunotherapy such as poor immune response. Via triggering the immunogenic cells death (ICD), PTT can stimulate the activity of immune cells, but meanwhile, the level of adenosine is elevated via the CD73-induced decomposition of ATP which is overexpressed accompanying with the PTT process, resulting in negative feedback to impair the immune stimulation. Herein, we developed a novel biomimetic photothermal nanodrug to specifically block CD73 for inhibition of adenosine production and more efficient priming of the suppressive immune microenvironments. The nanodrug, named as AptEM@CBA, is constructed by encapsulation of photothermal agent black phosphorus quantum dots (BPQDs) and selective CD73 inhibitor α, ß-Methyleneadenosine 5'-diphosphate (AMPCP) in chitosan nanogels, which are further covered with aptamer AS1411 modified erythrocyte membrane (EM) for biomimetic camouflage. With AS1411 induced active targeting and EM induced long blood circulation time, the enrichment of the nanodrug tumor sites is promoted. The photothermal treatment promotes the maturation of dendritic cells. Meanwhile, the release of AMPCP suppress the adenosine generation via CD73 blockade, alleviating the impairment of adenosine to dendritic cells and suppressing regulatory T cells, synergically stimulate the activity of T cells. The combination of CD73 blockade with PTT, not only suppresses the growth of primary implanted tumors, but also boosts strong antitumor immunity to inhibit the growth of distal tumors, providing good potential for tumor photoimmunotherapy.

Causal effect of interleukin (IL)-6 on blood pressure and hypertension: A mendelian randomization study.

To examine whether circulating interleukin-6 (IL-6) levels (CirIL6) have a causal effect on blood pressure using Mendelian randomization (MR) methods. We used data from genome-wide association studies (GWAS) of European ancestry to obtain genetic instruments for circulating IL-6 levels and blood pressure measurements. We applied several robust MR methods to estimate the causal effects and to test for heterogeneity and pleiotropy. We found that circulating IL-6 had a significant positive causal effect on systolic blood pressure (SBP) and pulmonary arterial hypertension (PAH), but not on diastolic blood pressure (DBP) or hypertension. We found that as CirIL6 genetically increased, SBP increased using Inverse Variance Weighted (IVW) method (for ukb-b-20175, ß = 0.082 with SE = 0.032, P = 0.011; for ukb-a-360, ß = 0.075 with SE = 0.031, P = 0.014) and weighted median (WM) method (for ukb-b-20175, ß = 0.061 with SE = 0.022, P = 0.006; for ukb-a-360, ß = 0.065 with SE = 0.027, P = 0.014). Moreover, CirIL6 may be associated with an increased risk of PAH using WM method (odds ratio (OR) = 15.503, 95% CI, 1.025-234.525, P = 0.048), but not with IVW method. Our study provides novel evidence that circulating IL-6 has a causal role in the development of SBP and PAH, but not DBP or hypertension. These findings suggest that IL-6 may be a potential therapeutic target for preventing or treating cardiovascular diseases and metabolic disorders. However, more studies are needed to confirm the causal effects of IL-6 on blood pressure and to elucidate the underlying mechanisms and pathways.

Bridging integrator 1 fragment accelerates tau aggregation and propagation by enhancing clathrin-mediated endocytosis in mice.

The bridging integrator 1 (BIN1) gene is an important risk locus for late-onset Alzheimer's disease (AD). BIN1 protein has been reported to mediate tau pathology, but the underlying molecular mechanisms remain elusive. Here, we show that neuronal BIN1 is cleaved by the cysteine protease legumain at residues N277 and N288. The legumain-generated BIN1 (1-277) fragment is detected in brain tissues from AD patients and tau P301S transgenic mice. This fragment interacts with tau and accelerates its aggregation. Furthermore, the BIN1 (1-277) fragment promotes the propagation of tau aggregates by enhancing clathrin-mediated endocytosis (CME). Overexpression of the BIN1 (1-277) fragment in tau P301S mice facilitates the propagation of tau pathology, inducing cognitive deficits, while overexpression of mutant BIN1 that blocks its cleavage by legumain halts tau propagation. Furthermore, blocking the cleavage of endogenous BIN1 using the CRISPR/Cas9 gene-editing tool ameliorates tau pathology and behavioral deficits. Our results demonstrate that the legumain-mediated cleavage of BIN1 plays a key role in the progression of tau pathology. Inhibition of legumain-mediated BIN1 cleavage may be a promising therapeutic strategy for treating AD.

Photocatalytic ethylene production by oxidative dehydrogenation of ethane with dioxygen on ZnO-supported PdZn intermetallic nanoparticles.

The selective oxidative dehydrogenation of ethane (ODHE) is attracting increasing attention as a method for ethylene production. Typically, thermocatalysts operating at high temperatures are needed for C-H activation in ethane. In this study, we describe a low temperature ( < 140 °C) photocatalytic route for ODHE, using O2 as the oxidant. A photocatalyst containing PdZn intermetallic nanoparticles supported on ZnO is prepared, affording an ethylene production rate of 46.4 mmol g-1 h-1 with 92.6% ethylene selectivity under 365 nm irradiation. When we employ a simulated shale gas feed, the photocatalytic ODHE system achieves nearly 20% ethane conversion while maintaining an ethylene selectivity of about 87%. The robust interface between the PdZn intermetallic nanoparticles and ZnO support plays a crucial role in ethane activation through a photo-assisted Mars-van Krevelen mechanism, followed by a rapid lattice oxygen replenishment to complete the reaction cycle. Our findings demonstrate that photocatalytic ODHE is a promising method for alkane-to-alkene conversions under mild conditions.

Finite element analysis of the effect of residual lateral wall volume on postoperative stability in intertrochanteric fractures.

BACKGROUND: Lateral wall fractures represent crucial risk factors for postoperative internal fixation failure in intertrochanteric femoral fractures. However, no consensus exists on the type of lateral wall fracture requiring interventional management. This study aimed to investigate the effect of residual lateral wall volume on the postoperative stability of intertrochanteric femur fractures with associated lateral wall fractures, providing valuable reference for the clinical management of the lateral wall. METHODS: Eleven bone defect models of intertrochanteric femur fractures with varying residual lateral wall volumes were constructed using finite element analysis. These models were fixed with proximal femoral nail antirotation (PFNA). Simulations of von Mises stress and displacement distribution of the PFNA and femur during normal walking were conducted. Statistical analysis was performed to assess the correlation between volume and the maximum von Mises stresses and displacements of the PFNA and femur. RESULTS: In all 11 models, the maximum von Mises stress and displacement of the helical blade, intramedullary nail, and femur occurred at the same locations. As residual lateral wall volume increased, the maximum von Mises stress and displacement of the helical blade, intramedullary nail, and maximum femoral displacement gradually decreased. However, the overall trend of the maximum femoral von Mises stress gradually decreased. At 70% retention of the residual lateral wall volume, there was a more pronounced change in the value of the maximum stress change of the helical blade and the intramedullary nail. Statistical analysis, including the Shapiro-Wilk test and Pearson correlation analysis, demonstrated a significant negative correlation between volume and the maximum von Mises stress and displacement of the helical blade, intramedullary nail, and femur. Linear regression analysis further confirmed this significant negative correlation. CONCLUSION: Finite element analysis of the residual lateral wall revealed a significant correlation between volume and the postoperative stability of intertrochanteric femur fractures. A volume of 70% may serve as the threshold for stabilizing the residual lateral wall. Volume emerges as a novel index for evaluating the strength of the residual lateral walls.

Mitochondrial ferritin upregulation reduced oxidative stress and blood-brain-barrier disruption by maintaining cellular iron homeostasis in a neonatal rat model of germinal matrix hemorrhage.

Germinal matrix hemorrhage (GMH) is a devasting neurological disease in premature newborns. After GMH, brain iron overload associated with hemoglobin degradation contributed to oxidative stress, causing disruption of the already vulnerable blood-brain barrier (BBB). Mitochondrial ferritin (FTMT), a novel mitochondrial outer membrane protein, is crucial in maintaining cellular iron homeostasis. We aimed to investigate the effect of FTMT upregulation on oxidative stress and BBB disruption associated with brain iron overload in rats. A total of 222 Sprague-Dawley neonatal rat pups (7 days old) were used to establish a collagenase-induced GMH model and an iron-overload model of intracerebral FeCl2 injection. Deferiprone was administered via gastric lavage 1 h after GMH and given daily until euthanasia. FTMT CRISPR Knockout and adenovirus (Ad)-FTMT were administered intracerebroventricularly 48 h before GMH and FeCl2 injection, respectively. Neurobehavioral tests, immunofluorescence, Western blot, Malondialdehyde measurement, and brain water content were performed to evaluate neurobehavior deficits, oxidative stress, and BBB disruption, respectively. The results demonstrated that brain expressions of iron exporter Ferroportin (FPN) and antioxidant glutathione peroxidase 4 (GPX4) as well as BBB tight junction proteins including Claudin-5 and Zona Occulta (ZO)-1 were found to be decreased at 72 h after GMH. FTMT agonist Deferiprone attenuated oxidative stress and preserved BBB tight junction proteins after GMH. These effects were partially reversed by FTMT CRISPR Knockout. Iron overload by FeCl2 injection resulted in oxidative stress and BBB disruption, which were improved by Ad-FTMT mediated FTMT overexpression. Collectively, FTMT upregulation is neuroprotective against brain injury associated with iron overload. Deferiprone reduced oxidative stress and BBB disruption by maintaining cellular iron homeostasis partially by the upregulating of FTMT after GMH. Deferiprone may be an effective treatment for patients with GMH.

Analysis of Correlation Between Serum Oncostatin-M and Disease Severity and Mortality in Hospitalized Patients with Community-Acquired Pneumonia.

Purpose: The aim of this study was to investigate the level of serum tumor suppressor factor (Oncostatin-M, OSM) in patients with community-acquired pneumonia (CAP) and evaluate its predictive value for the severity and prognosis of pneumonia, so as to improve the ability to identify the risk of death in CAP patients. Patients and Methods: A total of 110 patients with CAP admitted to the hospital from November 2020 to November 2021 were enrolled in this prospective study. Clinical data of all patients were collected. According to the 2016 edition of "Guidelines for the Diagnosis and Treatment of Community-acquired Pneumonia in Chinese Adults", the patients were divided into non-severe CAP (NSCAP)(n=55) and severe CAP (SCAP)(n=55). At the same time, they were divided into a survival group (n=96) and a death group (n=14) by tracking the survival of patients in the hospital. The OSM concentration of CAP patients on the first day after admission was determined by enzyme-linked immunosorbent assay. All clinical data were statistically and graphed using SPSS V23.0 and Grahpad Prim 8. Results: Compared with NSCAP, patients with SCAP had higher serum OSM concentration on the day of admission, which was negatively correlated with LYM and positively correlated with WBC, NEU, CRP, IL-6, IL-8, IL-10, CURB-65 score, and PSI score. The level of OSM in the dead patient group was significantly higher than that in the surviving patient group. OSM and PSI scores were independent risk factors for in-hospital mortality in CAP patients. Kaplan-Meier survival curve showed that OSM≥76pg/mL was more advantageous in predicting mortality in patients with CAP. Conclusion: The level of the OSM is closely related to the severity and prognosis of CAP and may be a new biomarker for the prognosis of CAP patients.

Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer's disease.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein that is predominantly expressed by microglia in the brain. The proteolytic shedding of TREM2 results in the release of soluble TREM2 (sTREM2), which is increased in the cerebrospinal fluid of patients with Alzheimer's disease (AD). It remains unknown whether sTREM2 regulates the pathogenesis of AD. Here we identified transgelin-2 (TG2) expressed on neurons as the receptor for sTREM2. The microglia-derived sTREM2 binds to TG2, induces RhoA phosphorylation at S188, and deactivates the RhoA-ROCK-GSK3ß pathway, ameliorating tau phosphorylation. The sTREM2 (77-89) fragment, which is the minimal active sequence of sTREM2 to activate TG2, mimics the inhibitory effect of sTREM2 on tau phosphorylation. Overexpression of sTREM2 or administration of the active peptide rescues tau pathology and behavioral defects in the tau P301S transgenic mice. Together, these findings demonstrate that the sTREM2-TG2 interaction mediates the cross-talk between microglia and neurons. sTREM2 and its active peptide may be a potential therapeutic intervention for tauopathies including AD.

Chemical Constituents, Bioactivities, and Pharmacological Mechanisms of Dendrobium officinale: A Review of the Past Decade.

Dendrobium officinale, a plant in the Orchidaceae family, has been used in traditional Chinese medicine for thousands of years. Sweet and slightly cold in nature, it can invigorate the stomach, promote fluid production, nourish Yin, and dissipate heat. Over the past decade, more than 60 compounds have been derived from D. officinale, including flavonoids, bibenzyl, and phenanthrene. Various studies have explored the underlying pharmacological mechanisms of these compounds, which have shown antitumor, hypoglycemic, hypertensive, gastrointestinal-regulatory, visceral organ protection, antiaging, and neurorestorative effects. This paper presents a systematic review of the structural classification, biological activity, and pharmacological mechanisms of different chemical components obtained from D. officinale over the past decade. This review aims to provide a reference for future study and establish a foundation for clinical applications. Furthermore, this review identifies potential shortcomings in current research as well as potential directions and methodologies in future plant research.

Discovery, structural optimization, and anti-tumor bioactivity evaluations of betulinic acid derivatives as a new type of RORγ antagonists.

Betulinic acid (BA) is a natural pentacyclic triterpenoid that has a wide range of biological and pharmacological effects. Here, computational methods such as pharmacophore screening and reverse docking were used to predict the potential target for BA. Retinoic acid receptor-related orphan receptor gamma (RORγ) was confirmed as its target by several molecular assays as well as crystal complex structure determination. RORγ has been the focus of metabolic regulation, but its potential role in cancer treatment has only recently come to the fore. In this study, rationale optimization of BA was performed and several new derivatives were generated. Among them, the compound 22 showed stronger binding affinity with RORγ (KD = 180 nM), good anti-proliferative activity against cancer cell lines, and potent anti-tumor efficacy with a TGI value of 71.6% (at a dose of 15 mg/kg) in the HPAF-II pancreatic cancer xenograft model. Further RNA-seq analysis and cellular validation experiments supported that RORγ antagonism was closely related to the antitumor activity of BA and 22, resulting in suppression of the RAS/MAPK and AKT/mTORC1 pathway and inducing caspase-dependent apoptosis in pancreatic cancer cells. RORγ was highly expressed in cancer cells and tissues and positively correlated with the poor prognosis of cancer patients. These results suggest that BA derivatives are potential RORγ antagonists worthy of further exploration.

Efficacy and safety of autologous platelet-rich plasma for diabetic foot ulcer healing: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The occurrence of a diabetic foot ulcer (DFU) is a significant complication of diabetes that often precedes the need for amputation. Autologous platelet-rich plasma (Au-PRP), a substance abundant in various growth factors and cytokines, is increasingly being recognized as a promising method for promoting ulcer healing due to its potential similarities to the physiological wound healing process. METHODS: The databases Medline, EMBASE, PubMed, and the Cochrane Library were systematically accessed on January 26, 2023, without any consideration for the date of publication. The selection and assessment of research studies were conducted autonomously, based on predetermined criteria and methodological standards. Two researchers gathered data and evaluated the potential for bias separately. We utilize the Stata 17.0 software to conduct data analysis and generate relevant visual representations. RESULTS: The results of the meta-analysis indicate that autologous PRP has a significant positive effect on the healing rate (RR = 1.42, 95% CI 1.30-1.56, P < 0.001), reduces the healing time (MD = - 3.13, 95% CI - 5.86 to - 0.39, P < 0.001), accelerates the reduction of ulcer area (MD = 1.02, 95% CI 0.51-1.53, P < 0.001), decreases the rate of amputation (RR = 0.35, 95% CI 0.15-0.83, P < 0.001), and does not increase the incidence of adverse events (RR = 0.96, 95% CI 0.57-1.61, P > 0.05) when compared to conventional therapy. CONCLUSIONS: Au-PRP therapy has been shown to facilitate the process of wound healing and represents a viable and secure therapeutic alternative for individuals with DFU.

Islet amyloid polypeptide triggers α-synuclein pathology in Parkinson's disease.

Pathologic aggregation and prion-like propagation of α-synuclein (α-syn) are the hallmarks of Parkinson's disease (PD). Emerging evidence shows that type 2 diabetes mellitus (T2DM) is a risk factor for PD. Interestingly, T2DM is characterized by the amyloid deposition of islet amyloid polypeptide (IAPP) in the pancreas. Although T2DM and PD share pathological similarities, the underlying molecular mechanisms bridging these two diseases remain unknown. Here, we report that IAPP co-deposits with α-syn in the brains of PD patients. IAPP interacts with α-syn and accelerates its aggregation. In addition, the IAPP-seeded α-syn fibrils show enhanced seeding activity and neurotoxicity compared with pure α-syn fibrils in vitro and in vivo. Strikingly, intravenous injection of IAPP fibrils into α-syn A53T transgenic mice or human SNCA transgenic mice accelerated the aggregation of α-syn and PD-like motor deficits. Taken together, these findings support that IAPP acts as a trigger of α-syn pathology in PD, and provide a mechanistic explanation for the increased risk and faster progression of PD in patients with T2DM.

Colorable role of interleukin (IL)-6 in obesity hypertension: A hint from a Chinese adult case-control study.

BACKGROUND: Obesity and hypertension are major risk factors for cardiovascular diseases that affect millions of people worldwide. Both conditions are associated with chronic low-grade inflammation, which is mediated by cytokines such as interleukin-6 (IL-6). IL-6 is a multifunctional cytokine that can have pro-inflammatory or anti-inflammatory effects depending on the context. The exact role of IL-6 in obesity-associated hypertension is unclear. OBJECTIVE: To investigate how IL-6 affects blood pressure, inflammation, and metabolic function in obesity-hypertension using a Chinese adult case-control study. METHODS: A total of 153 participants were sorted into four subgroups according to their body mass index (BMI) and blood pressure (BP): normal healthy group (NH), just obesity group (JO), just-hypertension group (JH), and obesity-hypertension group (OH). Serum IL-6 concentrations were measured by Enzyme-linked Immunosorbent Assay (ELISA) and their correlations with anthropometric and laboratory parameters and their differences across the subgroups were examined. Multiple linear regression analysis was performed to identify the predictors of serum IL-6 concentrations in each group. RESULTS: Serum IL-6 concentrations were higher in NH group than in JO group and correlated positively with diastolic blood pressure in NH and JO groups, but not in JH and OH groups. Serum IL-6 concentrations also correlated with albumin in NH group, alkaline phosphatase in JO group, serum creatinine and fasting blood glucose in JH group. The influencing factors of serum IL-6 concentrations varied among the four groups, with gender, diastolic blood pressure and albumin being significant predictors in NH group, alkaline phosphatase in JO group, age and serum creatinine in JH group, and none in OH group. CONCLUSIONS: These results suggest that IL-6 may play diverse effects in the pathogenesis of obesity- hypertension, depending on the presence or absence of obesity and hypertension. Further studies are needed to elucidate the underlying mechanisms of IL-6 signaling and function in these diseases.

Cofilin promotes tau pathology in Alzheimer's disease.

The molecular mechanisms mediating the aggregation and transmission of tau in AD remain unclear. Here, we show that the actin-binding protein cofilin is cleaved by a cysteine protease asparagine endopeptidase (AEP) at N138 in the brains of patients with AD. The AEP-generated cofilin 1-138 fragment interacts with tau and promotes its aggregation. The mixed fibrils consisting of cofilin 1-138 and tau are more pathogenic to cells than pure tau fibrils. Furthermore, overexpression of cofilin 1-138 in the brain facilitates the propagation of pathological tau aggregates and promotes AD-like cognitive impairments in tau P301S mice. However, mice infected with adeno-associated viruses (AAVs) encoding an AEP-uncleavable cofilin mutant show attenuated tau pathology and cognitive impairments compared with mice injected with AAVs encoding wild-type cofilin. Together, these observations support the role of the cofilin 1-138 fragment in the aggregation and transmission of tau pathology during the onset and progression of AD.

CDGSH iron sulfur domain 2 over-expression alleviates neuronal ferroptosis and brain injury by inhibiting lipid peroxidation via AKT/mTOR pathway following intracerebral hemorrhage in mice.

Ferroptosis has been implicated in the pathogenesis of secondary brain injury following intracerebral hemorrhage (ICH), and regulating this process is considered a potential therapy for alleviating further brain injury. A previous study showed that CDGSH iron sulfur domain 2 (CISD2) can inhibit ferroptosis in cancer. Thus, we investigated the effects of CISD2 on ferroptosis and the mechanisms underlying its neuroprotective role in mice after ICH. CISD2 expression markedly increased after ICH. CISD2 over-expression significantly decreased the number of Fluoro-Jade C-positive neurons and alleviated brain edema and neurobehavioral deficits at 24 h after ICH. In addition, CISD2 over-expression up-regulated the expression of p-AKT, p-mTOR, ferritin heavy chain 1, glutathione peroxidase 4, ferroportin, glutathione, and glutathione peroxidase activity, which are markers of ferroptosis. Additionally, CISD2 over-expression down-regulated the levels of malonaldehyde, iron content, acyl-CoA synthetase long-chain family member 4, transferrin receptor 1, and cyclooxygenase-2 at 24 h after ICH. It also alleviated mitochondrial shrinkage and decreased the density of the mitochondrial membrane. Furthermore, CISD2 over-expression increased the number of GPX4-positive neurons following ICH induction. Conversely, knockdown of CISD2 aggravated neurobehavioral deficits, brain edema, and neuronal ferroptosis. Mechanistically, MK2206, an AKT inhibitor, suppressed p-AKT and p-mTOR and reversed the effects of CISD2 over-expression on markers of neuronal ferroptosis and acute neurological outcome. Taken together, CISD2 over-expression alleviated neuronal ferroptosis and improved neurological performance, which may be mediated through the AKT/mTOR pathway after ICH. Thus, CISD2 may be a potential target to mitigate brain injury via the anti-ferroptosis effect after ICH.

Early Effect of the Circular Model of Kidney Allocation in the United States.

BACKGROUND: In March 2021, the United States implemented a new kidney allocation system (KAS250) for deceased donor kidney transplantation (DDKT), which eliminated the donation service area-based allocation and replaced it with a system on the basis of distance from donor hospital to transplant center within/outside a radius of 250 nautical miles. The effect of this policy on kidney discards and logistics is unknown. METHODS: We examined discards, donor-recipient characteristics, cold ischemia time (CIT), and delayed graft function (DGF) during the first 9 months of KAS250 compared with a pre-KAS250 cohort from the preceding 2 years. Changes in discards and CIT after the onset of COVID-19 and the implementation of KAS250 were evaluated using an interrupted time-series model. Changes in allocation practices (biopsy, machine perfusion, and virtual cross-match) were also evaluated. RESULTS: Post-KAS250 saw a two-fold increase in kidneys imported from nonlocal organ procurement organizations (OPO) and a higher proportion of recipients with calculated panel reactive antibody (cPRA) 81%-98% (12% versus 8%; P <0.001) and those with >5 years of pretransplant dialysis (35% versus 33%; P <0.001). CIT increased (mean 2 hours), including among local OPO kidneys. DGF was similar on adjusted analysis. Discards after KAS250 did not immediately change, but we observed a statistically significant increase over time that was independent of donor quality. Machine perfusion use decreased, whereas reliance on virtual cross-match increased, which was associated with shorter CIT. CONCLUSIONS: Early trends after KAS250 show an increase in transplant access to patients with cPRA>80% and those with longer dialysis duration, but this was accompanied by an increase in CIT and a suggestion of worsening kidney discards.

Exposure to dithiocarbamate fungicide maneb in vitro and in vivo: Neuronal apoptosis and underlying mechanisms.

Maneb, a widely-used dithiocarbamate fungicide, remains in the environment and exerts adverse health effects. Epidemiological evidence shows that maneb exposure is associated with a higher risk of Parkinson's disease (PD), one of the most common neurodegenerative diseases. However, the molecular mechanisms underlying maneb-induced neurotoxicity remain unclear. Here we investigated the toxic effects and the underlying mechanisms of maneb on the degeneration of dopaminergic cells and α-synuclein in A53T transgenic mice. In SH-SY5Y cells, exposure to maneb reduces cell viability, triggers neuronal apoptosis, induces mitochondrial dysfunction, and generates reactive oxidative species (ROS) in a dose-dependent manner. Furthermore, Western blot analysis found that the mitochondrial apoptosis pathway (Bcl-2, Bax, cytochrome c, activated caspase-3) and the PKA/CREB signaling pathway (PKA, PDE10A, CREB, p-CREB) were changed by maneb both in vitro and in vivo. In addition, the activation of the mitochondrial apoptosis pathway induced by maneb was attenuated by activating PKA. Therefore, these results suggest that the PKA/CREB signaling pathway is involved in maneb-induced apoptosis. This study provides novel insights into maneb-induced neurotoxicity and the underlying mechanisms, which may serve as a guide for further toxicological assessment and standard application of maneb.

Molecular mechanism of XB130 adaptor protein mediates trastuzumab resistance in gastric cancer.

BACKGROUND: Recent studies have shown that the activation of PI3K/AKT signaling pathway is an essential molecular mechanism participating in trastuzumab resistance in HER2 + GC (gastric cancer). However, how can we effectively inhibit AKT activity associated with drug resistance during trastuzumab treatment? Screening inhibitors against the upstream receptors of PI3K/AKT signaling pathway or interacting proteins of members has become an important way. METHODS: In this study, western blot, qRT-PCR, CCK8, Co-IP and other techniques were used to explore possible mechanisms participating in trastuzumab resistance in vitro. Besides, the xenograft mouse model and GC tissue samples from patients were used to further validate the in-vitro results. RESULTS: The expression of XB130 adaptor protein was remarkably increased in GC cell lines resistant to trastuzumab, and knockdown of XB130 could reverse the resistance via downregulating p-AKT. In addition, p-SRC (Tyr416) was increased in resistant cells, which could facilitate the binding of XB130 to PI3K p85α. It was also discovered that XB130 could negatively regulate PTEN gene transcription, and thus a positive feedback loop was formed between SRC-XB130-PTEN. CONCLUSIONS: In HER2 + GC, XB130 contributes to trastuzumab resistance by stimulating the PI3K/AKT signaling pathway through binding to PI3K p85α under the mediation of SRC kinase and regulating PTEN gene transcription, and in turn forming a positive feedback loop between SRC-XB130-PTEN.

Differences in sex- and age-associated mortality in patients with anti-MDA5-positive dermatomyositis.

OBJECTIVES: The effect of sex and age on the outcomes of patients with anti-melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis (MDA5+ DM) remains unclear. This study aimed to investigate the impact of sex and age on the prognosis of patients with MDA5+ DM. METHODS: We included 251 patients (women, 156; men, 95), who were newly diagnosed with MDA5+ DM between 2014 and 2021. The outcome was 6-month all-cause mortality after the diagnosis of interstitial lung disease. Cox regression analysis was used to assess the mortality. Adjusted restricted cubic spline analysis was performed to explore the non-linear relationship between age and outcomes. RESULTS: The 6-month mortality rates of women and men were 36.5% and 46.3%, respectively. Multivariate Cox regression revealed that ≥60 years of age was significantly associated with the risk of death (hazard ratio, 2.43; 95% confidence interval, 1.02-5.78). The trend of the risk of 6-month mortality in men was relatively flat until 54 years and increased rapidly afterwards (hazard ratio, 1.14; 95% confidence interval, 1.01-1.29). In contrast, the 6-month mortality rate showed a low linear increasing trend with age among females. CONCLUSIONS: Patients with MDA5+ DM, who received contemporary treatment, had unfavourable outcomes. The 6-month mortality risk increased with age, particularly in male patients aged >54 years.