Physical Exercise Improves the Neuronal Function in Ischemic Stroke Via Microglial CB2R/P2Y12 Signaling.

Physical exercise (PE) may be the single most important and accessible lifestyle habit throughout life, it inhibits the neuroinflammatory response and protects the brain against damage. As the innate cells in brain, microglia undergo morphological and functional changes to communicate with neurons protecting the neurons from injury. Herein, aiming at exploring the effects of PE on the communication between microglia-neuron during acute ischemic cerebral infarction, we carried out running wheel training before the conduction of transient middle cerebral artery occlusion (tMCAO) in C57BL/6 J and Cx3cr1-GFP mice. We found that microglial P2Y12 expression in the peri-infarct area was decreased, microglial dynamics and microglia-neuron communications were impaired, using in vivo two-photon imaging. PE up-regulated the microglial P2Y12 expression, increased the microglial dynamics, and promoted the contacts of microglia with neurons. As a result, PE inhibited neuronal Ca2+ overloads and protected against damage of the neuronal mitochondria in acute tMCAO. Mechanistically, PE increased the cannabinoid receptor 2 (CB2R) in microglia, promoted the phosphorylation of Nrf2 (NF-E2-related factor 2) at ser-344, increased the transcription factor level of Mafk, and up-regulated the level of P2Y12, whereby PE increased the levels of CB2R to promote microglia-neuron contacts to monitor and protect neuronal function.

Superlong Metal-organic Framework Nanowire Fabricated via Steam-assisted Conversion.

1D nanomaterials have attracted great attention due to their outstanding anisotropic and linear structures. A facile method is developed to fabricate 1D copper metal-organic framework nanowires (Cu-MOF-NW) through steam-assisted conversion from Cu-MOF precursors. During the steam-assisted conversion, Cu-MOF precursor gradually dissolves in methanol steam, and then recrystallized into Cu-MOF-NW, which shows high aspect ratio of about 600 and identical crystal structure of MOF-74. As-prepared Cu-MOF-NW with multiscale porous structure can effectively remove cationic dyes even in dye mixture. Moreover, Cu-MOF-NW, as an ideal template, is calcined to form Cu nanoparticle-doped carbon nanofiber with maintaining its 1D morphology, which shows excellent electrocatalytic activity for the non-enzymatic sensing of glucose.

The effect of body weight-supported Tai Chi Yunshou on upper limb motor function in stroke survivors based on neurobiomechanical analysis: a four-arm, parallel-group, assessors-blind randomized controlled trial protocol.

Introduction: A series of functional disorders commonly occur after stroke, of which upper limb dysfunction is the most difficult to recover. The upper limb rehabilitation effect of Tai Chi Yunshou(TCY) in the later stage of stroke has been confirmed by research. Body weight support-Tai Chi Yunshou (BWS-TCY) is based on TCY exercise and robotic exoskeletons offers most flexibility in deweighting and control strategy. This study is aimed to explore the effect of BWS-TCY on upper limb motor function in stroke based on neurobiomechanics. Methods and analysis: A single-blind randomized controlled trial will be conducted on 36 stroke survivors who will be randomly assigned to three groups: experimental group, control group A and control group B. In addition, 12 healthy elderly people will be recruited into the healthy control group. Those in the experimental group will receive 20 min of CRT and 20 min of BWS-TCY training, while participants in the control group A will receive 20 min of CRT and 20 min of Robot-assisted training. Participants in the control group B will undergo 40 min of Conventional rehabilitation training (CRT) daily. All interventions will take place 5 days a week for 12 weeks, with a 12-week follow-up period. No intervention will be carried out for the healthy control group. Upper limb function will be assessed before and after the intervention using various rating scales (Fugl-Meyer Assessment, Wolf Motor Function Test, etc.), as well as neurobiomechanical analyses (surface electromyography, functional near-infrared brain function analysis system, and Xsens maneuver Capture System). Additionally, 10 healthy elderly individuals will be recruited for neurobiomechanical analysis, and the results will be compared with those of stroke survivors. Discussion: The results of this study will offer initial evidence on the effectiveness and feasibility of BWS-TCY as an early intervention for stroke rehabilitation. Positive findings from this study could contribute to the development of guidelines for the use of BWS-TCY in the early stages of stroke. Ethics and dissemination: This study has been approved by the Research Ethics Committees of the seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (Study ID: 2022-7th-HIRB-022). The results of the study will be published in a peer-reviewed journal and presented at scientific conferences. Clinical trial registration: https://clinicaltrials.gov/, ChiCTR 2200063150.

CRISPR/Cas9-mediated Nap knockout affects female reproduction and egg shape in Bombyx mori.

Insect reproductive capacity can affect effective pest control and infertility studies and has become an important focus in recent molecular genetic research. Nucleosome assembly protein (Nap) is highly conserved across multiple species and is involved in forming the sperm nucleus in many species. We used clustered regularly interspaced palindromic repeats/Cas9 technology to knockout BmNap in Bombyx mori and observed that the mutations caused female infertility, whereas male fertility was not affected. BmNap mutants grew and mated normally; however, female mutants laid smaller eggs that could not be fertilised and did not hatch. In addition, female sterility produced by the mutation could be inherited stably via male mutants; therefore, Nap could be used as a potential target for lepidopteran pest control through population regulation. In the current study, we elucidated a new function of BmNap, increased the understanding of the oogenesis regulation network in Lepidoptera and promoted the development of insect sterility technologies.

pH-Responsive, Wide Color Gamut Dynamic Color Display Enabled by PDMAEMA Brush-Based Fabry-Perot Resonant Cavity.

Dynamic color-changing materials have attracted broad interest due to their widespread applications in visual sensing, dynamic color display, anticounterfeiting, and image encryption/decryption. In this work, we demonstrate a novel pH-responsive dynamic color-changing material based on a metal-insulator-metal (MIM) Fabry-Perot (FP) cavity with a pH-responsive poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA) brush layer as the responsive insulating layer. The pH-responsive PDMAEMA brush undergoes protonation at a low pH value (pH < 6), which induces different swelling degrees in response to pH and thus refractive index and thickness change of the insulator layer of the MIM FP cavity. This leads to significant optical property changes in transmission and a distinguishable color change spanning the whole visible region by adjusting the pH value of the external environment. Due to the reversible conformational change of the PDMAEMA and the formation of covalent bonds between the PDMAEMA molecular chain and the Ag substrate, the MIM FP cavity exhibits stable performance and good reproducibility. This pH-responsive MIM FP cavity establishes a new way to modulate transmission color in the full visible region and exhibits a broad prospect of applications in dynamic color display, real-time environment monitoring, and information encryption and decryption.

Development and Validation of a Nomogram for Predicting Sepsis-Induced Coagulopathy in Septic Patients: Mixed Retrospective and Prospective Cohort Study.

BACKGROUND: Sepsis-induced coagulopathy (SIC) is a common cause of poor prognosis in critically ill patients in the intensive care unit (ICU). However, currently there are no tools specifically designed for predicting the occurrence of SIC in septic patients earlier. This study aimed to develop a predictive nomogram incorporating clinical markers and scoring systems to individually predict the probability of SIC in septic patients. METHODS: Patients consecutively recruited in the stage between January 2022 and April 2023 constituted the development cohort for retrospective analysis to internally test the nomogram, and patients in the stage between May 2023 to November 2023 constituted the validation cohort for prospective analysis to externally validate the nomogram. Univariate logistic regression analysis of the development cohort was performed firstly, and then multivariate logistic regression analysis was performed using backward stepwise method to determine the best-fitting model and obtain the nomogram from it. The nomogram was validated in an independent external validation cohort, involving discrimination and calibration. A decision curve analysis was also performed to evaluate the net benefit of the insertion decision with this nomogram. RESULTS: A total of 548 and 245 patients, 55.1 and 49.4% with SIC occurrence, were included in the development and validation cohorts, respectively. Predictors contained in the prediction nomogram included shock, platelets, and international normalized ratio (INR). Patients with shock (odds ratio [OR]: 4.499; 95% confidence interval [CI]: 2.730-7.414; p < 0.001), higher INR (OR: 349.384; 95% CI: 62.337-1958.221; p < 0.001), and lower platelet (OR: 0.985; 95% CI: 0.982-0.988; p < 0.001) had higher probabilities of SIC. The development model showed good discrimination, with an area under the receiver operating characteristic curve (AUROC) of 0.879 (95% CI: 0.850-0.908) and good calibration. Application of the nomogram in the validation cohort also gave good discrimination with an AUROC of 0.872 (95% CI: 0.826-0.917) and good calibration. The decision curve analysis of the nomogram provided better net benefit than the alternate options (intervention or no intervention). CONCLUSION: By incorporating shock, platelets, and INR in the model, this useful nomogram could be accessibly utilized to predict SIC occurrence in septic patients. However, external validation is still required for further generalizability improvement of this nomogram.

Water flush boosts performance of elemental sulfur-based denitrification packed-bed systems: Optimization and mechanisms.

Despite the promising potential of elemental sulfur-based denitrification (ESDeN) packed-bed progresses, challenges such as excessive biofilm growth and gas entrapment persist, leading to denitrification deterioration. Water flush (WF) is recognized as an effective strategy, yet its effects remain underexplored. To address this knowledge gap, this study systematically investigated WF effects on ESDeN packed-bed denitrification. Results demonstrated that controlling WF effectively regulated denitrification, achieving superior and stable rates. Compared to no WF (0.45 kgN·m-3·d-1), rates improved by 1.20 ∼ 1.56 times under low-frequency (weekly WF, 0.54 kgN·m-3·d-1) and low-intensity WF (0.54 ∼ 0.70 kgN·m-3·d-1). High-frequency (hours WF) and high-intensity WF (30 & 50 m/h) further amplified denitrification rates by 1.73 ∼ 2.29 times. The enhanced denitrifications under low-frequency/intensity WF were mainly attributed to prolonged actual hydraulic retention time (AHRT), while high-frequency/intensity WF improved both AHRT prolonging and biofilm thinning, facilitating mass transfer. This study offers a promising avenue for fine-tuning denitrification rates via strategic WF adjustments.

Blood Brain Barrier-Crossing Delivery of Felodipine Nanodrug Ameliorates Anxiety-Like Behavior and Cognitive Impairment in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder leading to cognitive decline. Excessive cytosolic calcium (Ca2+) accumulation plays a critical role in the pathogenesis of AD since it activates the NOD-like receptor family, pyrin domain containing 3 (NLRP3), switches the endoplasmic reticulum (ER) unfolded protein response (UPR) toward proapoptotic signaling and promotes Aß seeding. Herein, a liposomal nanodrug (felodipine@LND) is developed incorporating a calcium channel antagonist felodipine for Alzheimer's disease treatment through a low-intensity pulse ultrasound (LIPUS) irradiation-assisted blood brain barrier (BBB)-crossing drug delivery. The multifunctional felodipine@LND is effectively delivered to diseased brain through applying a LIPUS irradiation to the skull, which resulted in a series of positive effects against AD. Markedly, the nanodrug treatment switched the ER UPR toward antioxidant signaling, prevented the surface translocation of ER calreticulin (CALR) in microglia, and inhibited the NLRP3 activation and Aß seeding. In addition, it promoted the degradation of damaged mitochondria via mitophagy, thereby inhibiting the neuronal apoptosis. Therefore, the anxiety-like behavior and cognitive impairment of 5xFAD mice with AD is significantly ameliorated, which manifested the potential of LIPUS - assisted BBB-crossing delivery of felodipine@LND to serve as a paradigm for AD therapy based on the well-recognized clinically available felodipine.

Preparation of Free-Standing Defect-Free ZIF-8/PVA Membranes via Confined Reaction at the Quasi-Interface.

Developing a facile strategy to synthesize free-standing defect-free metal-organic framework (MOF) membranes with high separation selectivity and good mechanical stability is very appealing but challenging. Herein, by confining the reaction of metal and ligand at the quasi-interface, a representative membrane composed of a continuous ZIF-8 layer and poly(vinyl alcohol) (PVA) was fabricated. The continuous ZIF-8 layer endowed the membrane with high separation efficiency, while PVA acted as a filler to eliminate the defection, synergistically achieving high selective ion transport and good mechanical stability. The continuous defect-free ZIF-8/PVA membrane showed excellent separation performance of selective ion transport with high Li+ permeance of 17.83 mol·m-2·h-1 as well as decent Li+/Mg2+ and Li+/Ca2+ selectivities of 24.60 and 244.58, respectively. The separation performance of the ZIF-8/PVA membrane remained stable after 10% strain, indicating its good mechanical stability. This work will promote the development of MOF-based membranes in practical applications.

Endometrial large cell neuroendocrine carcinoma: A case report and literature review.

Endometrial large cell neuroendocrine carcinoma (LCNEC) is a highly malignant tumor that presents with neuroendocrine function. It is difficult to diagnose at an early stage. Moreover, the diagnosis depends on the pathological and immunohistochemical findings. It is also prone to distant metastasis, but is difficult to treat and shows poor prognosis. Presently, there exists no unified treatment plan, and the prognosis of this disease is also poor. We reported here an analysis and literature review of a case of endometrial LCNEC to facilitate the comprehension of this disease and provide help toward clinical diagnosis and treatment.

Prostate high dose-rate brachytherapy as monotherapy for low and intermediate-risk prostate cancer: Efficacy results from a randomized phase II clinical trial of one fraction of 19 Gy or two fractions of 13.5 Gy: A 9-year update.

BACKGROUND AND PURPOSE: High dose-rate (HDR) brachytherapy as a monotherapy is an accepted treatment for localized prostate cancer, but the optimal dose and fractionation schedule remain unknown. We report on the efficacy of a randomized Phase II trial comparing HDR monotherapy delivered as 27 Gy in 2 fractions vs. 19 Gy in 1 fraction with a median follow-up of 9 years. MATERIALS AND METHODS: Enrolled patients had low or intermediate-risk disease, <60 cc prostate volume and no androgen deprivation use. Patients were randomized to 27 Gy in 2 fractions delivered one week apart vs a single fraction of 19 Gy. RESULTS: 170 patients were randomized: median age 65 years, median follow-up 107 months and median baseline PSA 6.35 ng/ml. NCCN risk categories comprised low (19 %), favourable (51 %), and unfavourable intermediate risk (30 %). The median PSA at 8 years was 0.08 ng/ml in the 2-fraction arm vs. 0.89 ng/ml in the single-fraction arm. The cumulative incidence of local failure at 8 years was 11.2 % in the 2-fraction arm vs. 35.9 % in the single-fraction arm (p < 0.001). The incidence of distant failure at 8 years was 3.8 % in the 2-fraction arm and 2.5 % in the single-fraction arm (p = 0.6). CONCLUSIONS: HDR monotherapy delivered in two fractions of 13.5 Gy demonstrated a persistent cancer control rate at 8 years and was well-tolerated. Single-fraction monotherapy yielded poor oncologic control and is not recommended. These findings contribute to the ongoing discourse on optimal HDR monotherapy strategies for low and intermediate-risk prostate cancer.

The Artist's Conk Medicinal Mushroom Ganoderma applanatum (Agaricomycetes): Mycological, Mycochemical, and Pharmacological Properties: A Review.

As a commonly used Chinese herbal medicine, Ganoderma applanatum (Pers.) Pat., also known as flat-ling Ganoderma (Chinese name bianlingzhi), old mother fungus (laomujun), and old ox liver (laoniugan), has high medicinal value. It is used as an anti-cancer drug in China and Japan. Besides, it can treat rheumatic tuberculosis and has the effect of relieving pain, clearing away heat, eliminating accumulation, stopping bleeding and eliminating phlegm. The purpose of this review is to analyze the research progress systematically and comprehensively in mycology, mycochemistry and pharmacological activities of G. applanatum, and discuss the prospect of prospective research and implementation of this medicinal material. A comprehensive literature search was performed on G. applanatum using scientific databases including Web of Science, PubMed, Google Scholar, CNKI, Elsevier. Collected data from different sources was comprehensively summarized for mycology, mycochemistry and pharmacology of G. applanatum. A total of 324 compounds were recorded, the main components of which were triterpenoids, meroterpenoids, steroids, and polysaccharides. G. applanatum and its active ingredients have a variety of pharmacological effects, including anti-tumor, liver protection, hypoglycemic, anti-fat, anti-oxidation, antibacterial and other activities. Although G. applanatum is widely used in traditional medicine and has diverse chemical constituents, more studies should be carried out in animals and humans to evaluate the cellular and molecular mechanisms involved in its biological activity.

Mechanisms linking triclocarban biotransformation to functional response and antimicrobial resistome evolution in wastewater treatment systems.

Evaluating the role of antimicrobials biotransformation in the regulation of metabolic functions and antimicrobial resistance evolution in wastewater biotreatment systems is crucial to ensuring water security. However, the associated mechanisms remain poorly understood. Here, we investigate triclocarban (TCC, one of the typical antimicrobials) biotransformation mechanisms and the dynamic evolution of systemic function disturbance and antimicrobial resistance risk in a complex anaerobic hydrolytic acidification (HA)-anoxic (ANO)/oxic (O) process. We mined key functional genes involved in the TCC upstream (reductive dechlorination and amide bonds hydrolysis) and downstream (chloroanilines catabolism) biotransformation pathways by metagenomic sequencing. Acute and chronic stress of TCC inhibit the production of volatile fatty acids (VFAs), NH4+ assimilation, and nitrification. The biotransformation of TCC via a single pathway cannot effectively relieve the inhibition of metabolic functions (e.g., carbon and nitrogen transformation and cycling) and enrichment of antimicrobial resistance genes (ARGs). Importantly, the coexistence of TCC reductive dechlorination and hydrolysis pathways and subsequent ring-opening catabolism play a critical role for stabilization of systemic metabolic functions and partial control of antimicrobial resistance risk. This study provides new insights into the mechanisms linking TCC biotransformation to the dynamic evolution of systemic functions and risks, and highlights critical regulatory information for enhanced control of TCC risks in complex biotreatment systems.

The OsMOB1A-OsSTK38 kinase complex phosphorylates CYCLIN C, controlling grain size and weight in rice.

Grain size and weight are crucial yield-related traits in rice (Oryza sativa). Although certain key genes associated with rice grain size and weight have been successfully cloned, the molecular mechanisms underlying grain size and weight regulation remain elusive. Here, we identified a molecular pathway regulating grain size and weight in rice involving the MPS ONE BINDER KINASE ACTIVATOR-LIKE 1A-SERINE/THREONINE-PROTEIN KINASE 38-CYCLIN C (OsMOB1A-OsSTK38-OsCycC) module. OsSTK38 is a nuclear Dbf2-related kinase that positively regulates grain size and weight by coordinating cell proliferation and expansion in the spikelet hull. OsMOB1A interacts with and enhances the autophosphorylation of OsSTK38. Specifically, the critical role of the OsSTK38 S322 site in its kinase activity is highlighted. Furthermore, OsCycC, a component of the Mediator complex, was identified as a substrate of OsSTK38, with enhancement by OsMOB1A. Notably, OsSTK38 phosphorylates the T33 site of OsCycC. The phosphorylation of OsCycC by OsSTK38 influenced its interaction with the transcription factor KNOTTED-LIKE HOMEOBOX OF ARABIDOPSIS THALIANA 7 (OsKNAT7). Genetic analysis confirmed that OsMOB1A, OsSTK38 and OsCycC function in a common pathway to regulate grain size and weight. Taken together, our findings revealed a connection between the Hippo signalling pathway and the Cyclin-Dependent Kinase (CDK) module in eukaryotes. Moreover, they provide insights into the molecular mechanisms linked to yield-related traits and propose innovative breeding strategies for high-yielding varieties.

Molybdesum selenide-based platelet-rich plasma containing carboxymethyl chitosan/polyvinyl pyrrolidone composite antioxidant hydrogels dressing promotes the wound healing.

Excess free radicals at the wound site can cause an inflammatory response, which is not conducive to wound healing. Hydrogels with antioxidant properties can prevent inflammatory storms by scavenging free radicals from the wound site and inhibiting the release of inflammatory factors. In this study, we prepared the carboxymethyl chitosan (CMCS)/polyvinyl pyrrolidone (PVP)/Molybdenum (IV) Selenide (MoSe2), and platelet-rich plasma (PRP) (CMCS/PVP/MoSe2/PRP) hydrogels for accelerating the repair of wounds. In the hydrogels, the MoSe2 can scavenge various free radicals to reduce oxidative stress at the site of inflammation, endowed the hydrogels with antioxidant properties. Interestingly, growth factors released by PRP assisted the tissue repair by promoting the formation of new capillaries. CMCS as a backbone not only showed good biocompatibility and biodegradability but also played a significant role in maintaining the sustained release of growth factors. In addition, incorporating PVP enhanced the tissue adhesion and mechanical properties. The multifunctional composite antioxidant hydrogels have good swelling properties and biodegradability, which is completely degraded within 28 days. Thus, the antioxidant CMCS/PVP/MoSe2/PRP hydrogels provide a new idea for designing ideal multifunctional wound dressings.

Influence of Stroke Onset Location on the Efficacy of Endovascular Thrombectomy: Comparison of Outcomes Between In-hospital vs. Community-Onset Strokes.

BACKGROUND AND PURPOSE: Previous studies have suggested that patients suffering an in-hospital stroke (IHS) may face delays in treatment and worse outcomes compared to patients with community-onset strokes (COS). However, most studies occurred when intravenous thrombolysis was the primary treatment. This study aimed to examine the outcomes of patients experiencing an IHS in the endovascular thrombectomy (EVT) era. MATERIALS AND METHODS: Single-center retrospective cohort study of patients older than 18 years with acute ischemic stroke (AIS) treated with EVT within 12 hours of stroke onset from January 1, 2015, to April 30, 2021. Patients were classified into two groups: in-hospital strokes (IHS) and community-onset strokes (COS). We compared time metrics of stroke care delivery, rate of successful reperfusion, and functional outcome as scored using the modified Rankin Scale (mRS) score at 90 days (favorable outcome was defined as mRS 0-2). Differences in proportions were assessed using Fisher's exact and Chi-Square tests as appropriate. For continuous variables, differences in medians between groups were evaluated using Mann-Whitney U tests. RESULTS: A total of 676 consecutive patients were included, with 69 (10%) comprising the IHS group. IHS patients were more likely to have diabetes (36% vs. 18%, p=0.02) and less likely to receive thrombolysis (25% vs 68%, p<0.001) than the COS group but were otherwise similar. IHS patients had significantly faster overall time metrics, most notably from stroke recognition to imaging (median [IQR], 70 [38-141] min vs 121 [74-228] min, p<0.001). Successful recanalization was achieved in > 75% in both groups (p=0.39), with a median NIHSS at discharge <4 (p=0.18). The 90-day mRS was similar in both groups, with a trend of higher in-hospital mortality in the IHS group (p=0.06). CONCLUSIONS: IHS patients had shorter workflow delays to initiation of EVT compared to their community counterparts but with a similar rate of successful recanalization and clinical outcomes. Importantly, 90 day mortality and mRS scores were equivalent between IHS and COS. ABBREVIATIONS: AIS = acute ischemic stroke; LVO = large vessel occlusion; IHS= in-hospital stroke; COS= community-onset stroke; EVT= endovascular thrombectomy; CSC= comprehensive stroke center; TOAST= Trial of Org 10172 in Acute Stroke Treatment.

Microsatellite instability in mismatch repair proficient colorectal cancer: clinical features and underlying molecular mechanisms.

BACKGROUND: Both defects in mismatch repair (dMMR) and high microsatellite instability (MSI-H) have been recognised as crucial biomarkers that guide treatment strategies and disease management in colorectal cancer (CRC). As MMR and MSI tests are being widely conducted, an increasing number of MSI-H tumours have been identified in CRCs with mismatch repair proficiency (pMMR). The objective of this study was to assess the clinical features of patients with pMMR/MSI-H CRC and elucidate the underlying molecular mechanism in these cases. METHODS: From January 2015 to December 2018, 1684 cases of pMMR and 401 dMMR CRCs were enrolled. Of those patients, 93 pMMR/MSI-H were identified. The clinical phenotypes and prognosis were analysed. Frozen and paraffin-embedded tissue were available in 35 patients with pMMR/MSI-H, for which comprehensive genomic and transcriptomic analyses were performed. FINDINGS: In comparison to pMMR/MSS CRCs, pMMR/MSI-H CRCs exhibited significantly less tumour progression and better long-term prognosis. The pMMR/MSI-H cohorts displayed a higher presence of CD8+ T cells and NK cells when compared to the pMMR/MSS group. Mutational signature analysis revealed that nearly all samples exhibited deficiencies in MMR genes, and we also identified deleterious mutations in MSH3-K383fs. INTERPRETATION: This study revealed pMMR/MSI-H CRC as a distinct subgroup within CRC, which manifests diverse clinicopathological features and long-term prognostic outcomes. Distinct features in the tumour immune-microenvironment were observed in pMMR/MSI-H CRCs. Pathogenic deleterious mutations in MSH3-K383fs were frequently detected, suggesting another potential biomarker for identifying MSI-H. FUNDING: This work was supported by the Science and Technology Commission of Shanghai Municipality (20DZ1100101).

Development of erythrina-based PARP-1/FTase dual-target inhibitors against lung cancer epithelial-mesenchymal transition (EMT) in vivo and in vitro.

A novel series of erythrina derivatives as PARP-1/FTase inhibitors were synthesized, and evaluated for their biological activities. Compound T9 had excellent inhibitory effects on cell viability (A549: IC50 = 1.74 µM; A549/5-Fu: IC50 = 1.03 µM) and in vitro enzyme activities (PARP-1: IC50 = 0.40 µM; FTase: IC50 = 0.067 µM). Molecular docking and point mutation assays demonstrated the interaction of compound T9 with key amino acid residues. The compound T9 exhibited potent anti-proliferation and anti-migration capabilities against A549 and A549/5-Fu cells. PCR array and western blot results showed that compound T9 could effectively inhibit EMT-related proteins in A549 and A549/5-Fu cells, thereby inhibiting the development of lung cancer. Importantly, compound T9 could significantly inhibit tumor growth in the A549 xenograft tumor model (TGI = 65.3 %). In conclusion, this study was the first presentation of the concept of dual-target inhibitors of the PARP-1/FTase enzymes. It also provides the basis for further research and development of novel PARP-1/FTase inhibitors.

Reducing blood product wastage through the inter-hospital redistribution of near-outdate inventory.

BACKGROUND: Hospital transfusion services order blood products to satisfy orders and maintain inventory levels during unexpected periods of increased blood demand. Surplus inventory may outdate before being allocated to a recipient. Blood product outdating is the largest contributor to blood wastage. STUDY DESIGN: A province-wide redistribution program was designed and implemented to redistribute near-outdate plasma protein and related blood products from low-usage to high-usage hospitals. Program operations and details are described in this paper. Two transport container configurations were designed and validated for transport of all blood products. A cost-analysis was performed to determine the effectiveness of this redistribution program. RESULTS: A total of 130 hospital transfusion services contributed at least one near-outdate blood product for redistribution between January 2012 and March 2020. These services redistributed 15,499 products through 3412 shipments, preventing the outdating of $17,570,700 CAD worth of product. Program costs were $14,900 for shipping and $30,000 for staffing. Failed time limits or non-compliance with packing configurations resulted in $388,200 worth of blood products (97 shipments containing 816 products) being discarded. Courier transport delays was the most common reason (42/97; 43%) for transport failure. CONCLUSION: Redistributing near-outdate blood products between hospitals is a feasible solution to minimize outdating. Despite heterogeneity of Canadian blood product inventory, all products (each with unique storage and transport requirements) were successfully redistributed in one of two validated and simple containers. Total operation costs of this program were small in comparison to the $17.6 million in savings associated with preventing the discard of outdated products.