Development and validation of a nomogram for predicting critical respiratory events during early anesthesia recovery in elderly patients.

BACKGROUND: Elderly patients undergoing recovery from general anesthesia face a heightened risk of critical respiratory events (CREs). Despite this, there is a notable absence of effective predictive tools tailored to this specific demographic. This study aims to develop and validate a predictive model (nomogram) to address this gap. CREs pose significant risks to elderly patients during the recovery phase from general anesthesia, making it an important issue in perioperative care. With the increasing aging population and the complexity of surgical procedures, it is crucial to develop effective predictive tools to improve patient outcomes and ensure patient safety during post-anesthesia care unit (PACU) recovery. METHODS: A total of 324 elderly patients who underwent elective general anesthesia in a grade A tertiary hospital from January 2023 to June 2023 were enrolled. Risk factors were identified using least absolute shrinkage and selection operator (LASSO) regression. A multivariate logistic regression model was constructed and represented as a nomogram. Internal validation of the model was performed using Bootstrapping. This study followed the TRIPOD checklist for reporting. RESULTS: The indicators included in the nomogram were frailty, snoring, patient-controlled intravenous analgesia (PCIA), emergency delirium and cough intensity at extubation. The diagnostic performance of the nomogram model was satisfactory, with AUC values of 0.990 and 0.981 for the training set and internal validation set, respectively. The optimal cutoff value was determined to be 0.22, based on a Youden index of 0.911. The F1-score was 0.927, and the MCC was 0.896. The calibration curve, Brier score (0.046), and HL test demonstrated acceptable consistency between the predicted and actual results. DCA revealed high net benefits of the nomogram prediction across all threshold probabilities. CONCLUSIONS: This study developed and validated a nomogram to identify elderly patients in the PACU who are at higher risk of CREs. The identified predictive factors included frailty condition, snoring syndrome, PCIA, emergency delirium, and cough intensity at extubation. By identifying patients at higher risk of CREs early on, medical professionals can implement targeted strategies to mitigate the occurrence of complications and provide better postoperative care for elderly patients recovering from general anesthesia.

Prediction models for acute kidney injury following liver transplantation: A systematic review and critical appraisal.

OBJECTIVE: This study aims to systematically review and critical evaluation of the risk of bias and the applicability of existing prediction models for acute kidney injury post liver transplantation. DATA SOURCE: A comprehensive literature search up until February 7, 2024, was conducted across nine databases: PubMed, Web of Science, EBSCO CINAHL Plus, Embase, Cochrane Library, CNKI, Wanfang, CBM, and VIP. STUDY DESIGN: Systematic review of observational studies. EXTRACTION METHODS: Literature screening and data extraction were independently conducted by two researchers using a standardized checklist designed for the critical appraisal of prediction modelling studies in systematic reviews. The prediction model risk of bias assessment tool was utilized to assess both the risk of bias and the models' applicability. PRINCIPAL FINDINGS: Thirty studies were included, identifying 34 prediction models. External validation was conducted in seven studies, while internal validation exclusively took place in eight studies. Three models were subjected to both internal and external validation, the area under the curve ranging from 0.610 to 0.921. A meta-analysis of high-frequency predictors identified several statistically significant factors, including recipient body mass index, Model for End-stage Liver Disease score, preoperative albumin levels, international normalized ratio, and surgical-related factors such as cold ischemia time. All studies were demonstrated a high risk of bias, mainly due to the use of unsuitable data sources and inadequate detail in the analysis reporting. CONCLUSIONS: The evaluation with prediction model risk of bias assessment tool indicated a considerable bias risk in current predictive models for acute kidney injury post liver transplantation. IMPLICATIONS FOR CLINICAL PRACTICE: The recognition of high bias in existing models calls for future research to employ rigorous methodologies and robust data sources, aiming to develop and validate more accurate and clinically applicable predictive models for acute kidney injury post liver transplantation.

Association of plasma metals with resting-state functional connectivity in ischemic stroke.

BACKGROUND: Metal exposure has long been considered a significant risk factor for ischemic stroke. However, existing data on the effects of metal exposure on brain function in ischemic stroke are limited. Therefore, this study aimed to explore the correlation between exposure to various metals and changes in resting-state functional connectivity (rs-FC) in ischemic stroke patients. METHODS: This study included 28 acute ischemic stroke patients with hemiplegia and 28 matched healthy controls (HCs). All participants underwent T1-weighted MRI and 3.0 T resting-state functional magnetic resonance imaging (fMRI). After MRI acquisition, the rs-FC between 137 cortical and subcortical regions was extracted and preprocessed. Plasma levels of 19 metals were measured using inductively coupled plasma mass spectrometry (ICP-MS). The Bayesian kernel machine regression (BKMR) model and the weighted quantile sum regression (WQS) model were used to assess the overall effect of metal mixture exposure. The severity of neurological deficits in each acute ischemic stroke patient was evaluated using the National Institutes of Health Stroke Scale (NIHSS). Additionally, the associations between exposure to various metals and modifications in brain functional connectivity were determined using Pearson or Spearman correlation analysis. RESULTS: Bilateral brain connectivity was significantly decreased compared to controls and was associated with neurological impairment in ischemic stroke. In patients with ischemic stroke, the plasma concentrations of Cr (p < 0.001), Cu (p = 0.004), As (p = 0.010), Cs (p = 0.046), Rb (p = 0.041), and Sb (p = 0.001) were significantly higher than those in the HCs, whereas the plasma Tl concentrations (p = 0.022) were significantly lower. The results of the BKMR and WQS models showed that combined exposure to metal mixtures was linked to a higher risk of ischemic stroke. Cr was positively correlated with the rs-FC between the left Rolandic_Oper and the left Supp_Motor_Area (r = 0.414, p = 0.029), while negatively correlated with the rs-FC between the right Parietal_Inf and the left supramarginal (r = -0.398, p = 0.037). Cu was negatively correlated with the rs-FC between the left paracentral lobule and the left thalamus (r = -0.409, p = 0.031). Tl was positively correlated with the rs-FC between the right Parietal_Inf and the left supramarginal cortex (r = 0.590, p = 0.001). A negative correlation was observed between Cs and rs-FC between the right Cingulate_Mid and left Occipital_Sup (r = -0.429, p = 0.024). Sb was negatively correlated with the rs-FC between the left Parietal_Inf and the right SupraMarginal (r = -0.384, p = 0.044), the right Parietal_Inf and the left SupraMarginal (r = -0.583, p = 0.001), and the left SupraMarginal and the right SupraMarginal (r = -0.377, p = 0.048). CONCLUSION: Plasma levels of Cr, Cu, Tl, Cs, and Sb were associated with altered rs-FC in brain regions related to motor control, sensory integration, executive function, language processing, and emotional regulation in ischemic stroke patients with basal ganglia infarction.

Discovery of a Highly Potent, Selective and Efficacious USP7 Degrader for the Treatment of Acute Lymphoblastic Leukemia.

USP7 is an attractive therapeutic target for cancers, especially for acute lymphoblastic leukemia (ALL) with wild-type p53. Herein, we report the discovery of XM-U-14 as a highly potent, selective and efficacious USP7 proteolysis-targeting chimera degrader. XM-U-14 achieves DC50 values of 0.74 nM and Dmax of 93% in inducing USP7 degradation in RS4;11 cell lines, and also significantly inhibits ALL cell growth. XM-U-14 even at 5 mg/kg dosed daily effectively inhibits RS4;11 tumor growth with 64.7% tumor regressions and causes no signs of toxicity in mice. XM-U-14 is a promising USP7 degrader for further optimization for ALL treatment.

Methylcellulose improves dissociation quality of adult human primary cardiomyocytes.

Obtaining high-quality adult human primary cardiomyocytes (hPCM) have been technically challenging due to isolation-induced biochemical and mechanical stress. Building upon a previous tissue slicing-assisted digestion method, we introduced polymers into the digestion solution to reduce mechanical damage to cells. We found that low-viscosity methylcellulose (MC) significantly improved hPCM viability and yield. Mechanistically, it protected cells from membrane damage, which led to decreased apoptosis and mitochondrial reactive oxygen species production. MC also improved the electrophysiological properties of hPCMs by maintaining the density of sodium channels. The effects on cell viability and cell yield effects were not recapitulated by MC of larger viscosities, other cellulose derivatives, nor shear protectants polyethylene glycol and polyvinyl alcohol. Finally, MC also enhanced the isolation efficiency and the culture quality of hPCMs from diseased ventricular myocardium, expanding its potential applications. Our findings showed that the isolation quality of hPCMs can be further improved through the addition of a polymer, rendering hPCMs a more reliable cellular model for cardiac research.

Prediction models for amputation after diabetic foot: systematic review and critical appraisal.

BACKGROUND: Numerous studies have developed or validated prediction models aimed at estimating the likelihood of amputation in diabetic foot (DF) patients. However, the quality and applicability of these models in clinical practice and future research remain uncertain. This study conducts a systematic review and assessment of the risk of bias and applicability of amputation prediction models among individuals with DF. METHODS: A comprehensive search was conducted across multiple databases, including PubMed, Web of Science, EBSCO CINAHL Plus, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, Chinese Biomedical Literature Database (CBM), and Weipu (VIP) from their inception to December 24, 2023. Two investigators independently screened the literature and extracted data using the checklist for critical appraisal and data extraction for systematic reviews of prediction modeling studies. The Prediction Model Risk of Bias Assessment Tool (PROBAST) checklist was employed to evaluate both the risk of bias and applicability. RESULTS: A total of 20 studies were included in this analysis, comprising 17 development studies and three validation studies, encompassing 20 prediction models and 11 classification systems. The incidence of amputation in patients with DF ranged from 5.9 to 58.5%. Machine learning-based methods were employed in more than half of the studies. The reported area under the curve (AUC) varied from 0.560 to 0.939. Independent predictors consistently identified by multivariate models included age, gender, HbA1c, hemoglobin, white blood cell count, low-density lipoprotein cholesterol, diabetes duration, and Wagner's Classification. All studies were found to exhibit a high risk of bias, primarily attributed to inadequate handling of outcome events and missing data, lack of model performance assessment, and overfitting. CONCLUSIONS: The assessment using PROBAST revealed a notable risk of bias in the existing prediction models for amputation in patients with DF. It is imperative for future studies to concentrate on enhancing the robustness of current prediction models or constructing new models with stringent methodologies.

Unraveling Estrogen and PCSK9's Roles in Lipid Metabolism Disorders among Ovariectomized Mice.

We explore the interaction between estrogen and PCSK9 and their collective impact on lipid metabolism, especially concerning the regulation of low-density lipoprotein receptor levels. Utilizing both animal and cellular models, including ovariectomized mice and HepG2 cell lines, we demonstrate that estrogen deficiency leads to a disruption in lipid metabolism, characterized by elevated levels of total cholesterol and LDL-C. The study commences with mice undergoing ovariectomy, followed by a diet regimen comprising either high-fat diet or normal feed for a four-week duration. Key assessments include analyzing lipid metabolism, measuring PCSK9 levels in the bloodstream, and evaluating hepatic low-density lipoprotein receptor expression. We will also conduct correlation analyses to understand the relationship between PCSK9 and various lipid profiles. Further, a subset of ovariectomized mice on high-fat diet will undergo treatment with either estrogen or PCSK9 inhibitor for two weeks, with a subsequent re-evaluation of the earlier mentioned parameters. Our findings reveal that estrogen inhibits PCSK9-mediated degradation of low-density lipoprotein receptor, a process crucial for maintaining lipid homeostasis. Through a series of experiments, including immunohistochemistry and western blot analysis, we establish that PCSK9 is involved in lipid metabolism disorders caused by estrogen deficiency and that estrogen regulates PCSK9 and low-density lipoprotein receptor at post-transcriptional level. The study provides a mechanism for the involvement of PCSK9 in elucidating the disorders of lipid metabolism caused by estrogen deficiency due to perimenopause and ovarian decline.

Nonlinear Regularization Decoding Method for Speech Recognition.

Existing end-to-end speech recognition methods typically employ hybrid decoders based on CTC and Transformer. However, the issue of error accumulation in these hybrid decoders hinders further improvements in accuracy. Additionally, most existing models are built upon Transformer architecture, which tends to be complex and unfriendly to small datasets. Hence, we propose a Nonlinear Regularization Decoding Method for Speech Recognition. Firstly, we introduce the nonlinear Transformer decoder, breaking away from traditional left-to-right or right-to-left decoding orders and enabling associations between any characters, mitigating the limitations of Transformer architectures on small datasets. Secondly, we propose a novel regularization attention module to optimize the attention score matrix, reducing the impact of early errors on later outputs. Finally, we introduce the tiny model to address the challenge of overly large model parameters. The experimental results indicate that our model demonstrates good performance. Compared to the baseline, our model achieves recognition improvements of 0.12%, 0.54%, 0.51%, and 1.2% on the Aishell1, Primewords, Free ST Chinese Corpus, and Common Voice 16.1 datasets of Uyghur, respectively.

Change of function and brain activity in patients of right spastic arm paralysis combined with aphasia after contralateral cervical seventh nerve transfer surgery.

Left hemisphere injury can cause right spastic arm paralysis and aphasia, and recovery of both motor and language functions shares similar compensatory mechanisms and processes. Contralateral cervical seventh cross transfer (CC7) surgery can provide motor recovery for spastic arm paralysis by triggering interhemispheric plasticity, and self-reports from patients indicate spontaneous improvement in language function but still need to be verified. To explore the improvements in motor and language function after CC7 surgery, we performed this prospective observational cohort study. The Upper Extremity part of Fugl-Meyer scale (UEFM) and Modified Ashworth Scale were used to evaluate motor function, and Aphasia Quotient calculated by Mandarin version of the Western Aphasia Battery (WAB-AQ, larger score indicates better language function) was assessed for language function. In 20 patients included, the average scores of UEFM increased by .40 and 3.70 points from baseline to 1-week and 6-month post-surgery, respectively. The spasticity of the elbow and fingers decreased significantly at 1-week post-surgery, although partially recurred at 6-month follow-up. The average scores of WAB-AQ were increased by 9.14 and 10.69 points at 1-week and 6-month post-surgery (P < .001 for both), respectively. Post-surgical fMRI scans revealed increased activity in the bilateral hemispheres related to language centrals, including the right precentral cortex and right gyrus rectus. These findings suggest that CC7 surgery not only enhances motor function but may also improve the aphasia quotient in patients with right arm paralysis and aphasia due to left hemisphere injuries.

Skeletal muscle cystathionine γ-lyase deficiency promotes obesity and insulin resistance and results in hyperglycemia and skeletal muscle injury upon HFD in mice.

OBJECTIVES: The objective of this study was to investigate whether skeletal muscle cystathionine γ-lyase (CTH) contributes to high-fat diet (HFD)-induced metabolic disorders using skeletal muscle Cth knockout (CthΔskm) mice. METHODS: The CthΔskm mice and littermate Cth-floxed (Cthf/f) mice were fed with either HFD or chow diet for 13 weeks. Metabolomics and transcriptome analysis were used to assess the impact of CTH deficiency in skeletal muscle. RESULTS: Metabolomics coupled with transcriptome showed that CthΔskm mice displayed impaired energy metabolism and some signaling pathways linked to insulin resistance (IR) in skeletal muscle although the mice had normal insulin sensitivity. HFD led to reduced CTH expression and impaired energy metabolism in skeletal muscle in Cthf/f mice. CTH deficiency and HFD had some common pathways enriched in the aspects of amino acid metabolism, carbon metabolism, and fatty acid metabolism. CthΔskm+HFD mice exhibited increased body weight gain, fasting blood glucose, plasma insulin, and IR, and reduced glucose transporter 4 and CD36 expression in skeletal muscle compared to Cthf/f+HFD mice. Impaired mitochondria and irregular arrangement in myofilament occurred in CthΔskm+HFD mice. Omics analysis showed differential pathways enriched between CthΔskm mice and Cthf/f mice upon HFD. More severity in impaired energy metabolism, reduced AMPK signaling, and increased oxidative stress and ferroptosis occurred in CthΔskm+HFD mice compared to Cthf/f+HFD mice. DISCUSSION: Our results indicate that skeletal muscle CTH expression dysregulation contributes to metabolism disorders upon HFD.

The recent advancements in protein nanoparticles for immunotherapy.

In recent years, the advancement of nanoparticle-based immunotherapy has introduced an innovative strategy for combatting diseases. Compared with other types of nanoparticles, protein nanoparticles have obtained substantial attention owing to their remarkable biocompatibility, biodegradability, ease of modification, and finely designed spatial structures. Nature provides several protein nanoparticle platforms, including viral capsids, ferritin, and albumin, which hold significant potential for disease treatment. These naturally occurring protein nanoparticles not only serve as effective drug delivery platforms but also augment antigen delivery and targeting capabilities through techniques like genetic modification and covalent conjugation. Motivated by nature's originality and driven by progress in computational methodologies, scientists have crafted numerous protein nanoparticles with intricate assembly structures, showing significant potential in the development of multivalent vaccines. Consequently, both naturally occurring and de novo designed protein nanoparticles are anticipated to enhance the effectiveness of immunotherapy. This review consolidates the advancements in protein nanoparticles for immunotherapy across diseases including cancer and other diseases like influenza, pneumonia, and hepatitis.

Advances in therapeutic cancer vaccines: Harnessing immune adjuvants for enhanced efficacy and future perspectives.

Preventive cancer vaccines are highly effective in preventing viral infection-induced cancer, but advances in therapeutic cancer vaccines with a focus on eliminating cancer cells through immunotherapy are limited. To develop therapeutic cancer vaccines, the integration of optimal adjuvants is a potential strategy to enhance or complement existing therapeutic approaches. However, conventional adjuvants do not satisfy the criteria of clinical trials for therapeutic cancer vaccines. To improve the effects of adjuvants in therapeutic cancer vaccines, effective vaccination strategies must be formulated and novel adjuvants must be identified. This review offers an overview of the current advancements in therapeutic cancer vaccines and highlights in situ vaccination approaches that can be synergistically combined with other immunotherapies by harnessing the adjuvant effects. Additionally, the refinement of adjuvant systems using cutting-edge technologies and the elucidation of molecular mechanisms underlying immunogenic cell death to facilitate the development of innovative adjuvants have been discussed.

Incidence of dreaming during ciprofol anesthesia for painless gastroscopy.

BACKGROUND: Dreaming is often reported by patients who undergo propofol-based sedation, but there have not been any studies to date focused on the incidence of dreaming and factors associated therewith following the administration of ciprofol anesthesia in patients undergoing painless gastroscopy. The present study was thus developed with the goal of assessing the incidence of dreaming. METHODS: In total, this study enrolled 200 patients undergoing painless gastroscopy. During the procedure, patients' electroencephalographic Bispectral Index (BIS), blood pressure (BP), heart rate (HR), blood oxygen saturation (SpO2), and PETCO2 were monitored. When their MOAA/S score reached five after the procedure, patients were administered questionnaires including the Brice questionnaire and a five-point Likert Scale, and the content of any recalled dreams was also recorded. RESULTS: Overall, 27.5% of the participants in this study reported dreaming during the procedure, with most having experienced simple, pleasant dreams about everyday life. Identified predictors of dreaming during painless gastroscopy included lower ASA grade, preoperative knowledge of painless examination, a higher frequency of dreams in the month before the procedure, poor sleep quality during the month before the procedure, and shorter awakening time. Dreamers showed significantly lower BIS values at 2 min after endoscope insertion and following endoscope removal, and also showed lower minimum BIS values compared with non-dreamers. CONCLUSIONS: The postoperative dream recall incidence in this study was 27.5% among patients undergoing painless gastroscopy under ciprofol sedation anesthesia.

tiRNA-Gly-GCC-001 in major depressive disorder: Promising diagnostic and therapeutic biomarker.

BACKGROUND AND PURPOSE: In major depressive disorder (MDD), exploration of biomarkers will be helpful in diagnosing the disorder as well as in choosing a treatment and predicting the treatment response. Currently, tRNA-derived small ribonucleic acids (tsRNAs) have been established as promising non-invasive biomarker candidates that may enable a more reliable diagnosis or monitoring of various diseases. Herein, we aimed to explore tsRNA expression together with functional activities in MDD development. EXPERIMENTAL APPROACH: Serum samples were obtained from patients with MDD and healthy controls, and small RNA sequencing (RNA-Seq) was used to profile tsRNA expression. Dysregulated tsRNAs in MDD were validated by quantitative real-time polymerase chain reaction (qRT-PCR). The diagnostic utility of specific tsRNAs and the expression of these tsRNAs after antidepressant treatment were analysed. KEY RESULTS: In total, 38 tsRNAs were significantly differentially expressed in MDD samples relative to healthy individuals (34 up-regulated and 4 down-regulated). qRT-PCR was used to validate the expression of six tsRNAs that were up-regulated in MDD (tiRNA-1:20-chrM.Ser-GCT, tiRNA-1:33-Gly-GCC-1, tRF-1:22-chrM.Ser-GCT, tRF-1:31-Ala-AGC-4-M6, tRF-1:31-Pro-TGG-2 and tRF-1:32-chrM.Gln-TTG). Interestingly, serum tiRNA-Gly-GCC-001 levels exhibited an area under the ROC curve of 0.844. Moreover, tiRNA-Gly-GCC-001 is predicted to suppress brain-derived neurotrophic factor (BDNF) expression. Furthermore, significant tiRNA-Gly-GCC-001 down-regulation was evident following an 8-week treatment course and served as a promising baseline predictor of patient response to antidepressant therapy. CONCLUSION AND IMPLICATIONS: Our current work reports for the first time that tiRNA-Gly-GCC-001 is a promising MDD biomarker candidate that can predict patient responses to antidepressant therapy.

ANKRD22 promotes resolution of psoriasiform skin inflammation by antagonizing NIK-mediated IL-23 production.

Inflammation resolution is an essential process for preventing the development of chronic inflammatory diseases. However, the mechanisms that regulate inflammation resolution in psoriasis are not well understood. Here, we report that ANKRD22 is an endogenous negative orchestrator of psoriasiform inflammation because ANKRD22-deficient mice are more susceptible to IMQ-induced psoriasiform inflammation. Mechanistically, ANKRD22 deficiency leads to excessive activation of the TNFRII-NIK-mediated noncanonical NF-κB signaling pathway, resulting in the hyperproduction of IL-23 in DCs. This is due to ANKRD22 being a negative feedback regulator for NIK because it physically binds to and assists in the degradation of accumulated NIK. Clinically, ANKRD22 is negatively associated with IL-23A expression and psoriasis severity. Of greater significance, subcutaneous administration of an AAV carrying ANKRD22-overexpression vector effectively hastens the resolution of psoriasiform skin inflammation. Our findings suggest ANKRD22, an endogenous supervisor of NIK, is responsible for inflammation resolution in psoriasis, and may be explored in the context of psoriasis therapy.

Establishment of a risk prediction model for bowel preparation failure prior to colonoscopy.

BACKGROUND: This study aimed to determine the factors that contribute to the failure of bowel preparation in patients undergoing colonoscopy and to develop a risk prediction model. METHODS: A total of 1115 outpatients were included. Patients were randomly divided into two groups: the modeling group (669 patients) and the validation group (446 patients). In the modeling group, patients were further divided into two groups based on their success and failure in bowel preparation using the Boston Bowel Preparation Scale. A logistic regression analysis model was used to determine the risk factors of bowel preparation failure, which was subsequently visualized using an alignment diagram. RESULTS: After controlling for relevant confounders, multifactorial logistic regression results showed that age ≥ 60 years (OR = 2.246), male (OR = 2.449), body mass index ≥ 24 (OR = 2.311), smoking (OR = 2.467), chronic constipation (OR = 5.199), diabetes mellitus (OR = 5.396) and history of colorectal surgery (OR = 5.170) were influencing factors of bowel preparation failure. The area under the ROC curve was 0.732 in the modeling group and 0.713 in the validation group. According to the calibration plot, the predictive effect of the model and the actual results were in good agreement. CONCLUSIONS: Age ≥ 60 years, male, body mass index ≥ 24, smoking, chronic constipation, diabetes mellitus, and history of colorectal surgery are independent risk factors for bowel preparation failure. The established prediction model has a good predictive efficacy and can be used as a simple and effective tool for screening patients at high risk for bowel preparation failure.

Distinct cellular microenvironment with cytotypic effects regulates orderly regeneration of vascular tissues.

Regeneration of the architecturally complex blood vascular system requires precise temporal and spatial control of cell behaviours. Additional components must be integrated into the structure to achieve clinical success for in situ tissue engineering. Consequently, this study proposed a universal method for including any substrate type in vascular cell extracellular matrices (VCEM) via regulating selective adhesion to promote vascular tissue regeneration. The results uncovered that the VCEM worked as cell adhesion substrates, exhibited cell type specificity, and functioned as an address signal for recognition by vascular cells, which resulted in matching with the determined cells. The qPCR and immunofluorescence results revealed that a cell type-specific VCEM could be designed to promote or inhibit cell adhesion, consistenting with the expression patterns of eyes absent 3 (Eya3). In addition, a 3D vascular graft combined with VCEM which could recapitulate the vascular cell-like microenvironment was fabricated. The vascular graft revealed a prospective role for cellular microenvironment in the establishment of vascular cell distribution and tissue architecture, and potentiated the orderly regeneration and functional recovery of vascular tissues in vivo. The findings demonstrate that differential adhesion between cell types due to the cellular microenvironment is sufficient to drive the complex assembly of engineered blood vessel functional units, and underlies hierarchical organization during vascular regeneration.

Adipose tissue reconstruction facilitated with low immunogenicity decellularized adipose tissue scaffolds.

There is currently an urgent need to develop engineered scaffolds to support new adipose tissue formation and facilitate long-term maintenance of function and defect repair to further generate prospective bioactive filler materials capable of fulfilling surgical needs. Herein, adipose regeneration methods were optimized and decellularized adipose tissue (DAT) scaffolds with good biocompatibility were fabricated. Adipose-like tissues were reconstructed using the DAT and 3T3-L1 preadipocytes, which have certain differentiation potential, and the regenerative effects of the engineered adipose tissuesin vitroandin vivowere explored. The method improved the efficiency of adipose removal from tissues, and significantly shortened the time for degreasing. Thus, the DAT not only provided a suitable space for cell growth but also promoted the proliferation, migration, and differentiation of preadipocytes within it. Following implantation of the constructed adipose tissuesin vivo, the DAT showed gradual degradation and integration with surrounding tissues, accompanied by the generation of new adipose tissue analogs. Overall, the combination of adipose-derived extracellular matrix and preadipocytes for adipose tissue reconstruction will be of benefit in the artificial construction of biomimetic implant structures for adipose tissue reconstruction, providing a practical guideline for the initial integration of adipose tissue engineering into clinical medicine.

Discovery of potent PROTAC degraders of Pin1 for the treatment of acute myeloid leukemia.

Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) is overexpressed and/or overactivated in many human cancers and has been shown to play a critical role during oncogenesis. Despite the potential of Pin1 as a drug target, its successful targeting has proved to be challenging. We speculate that only blocking the enzymatic function of Pin1 with inhibitors may not be sufficient to lead to a total loss-of-function. Here, we report the discovery of P1D-34, a first-in-class and potent PROTAC degrader of Pin1, which induced Pin1 degradation with a DC50 value of 177 nM and exhibited potent degradation-dependent anti-proliferative activities in a panel of acute myeloid leukemia (AML) cell lines. In contrast, Pin1 inhibitor Sulfopin did not show activity. More significantly, P1D-34 could sensitize Bcl-2 inhibitor ABT-199 in Bcl-2 inhibitor-resistant AML cells, highlighting the potential therapeutic value of targeted Pin1 degradation for Bcl-2 inhibitor-resistant AML treatment. Further mechanism study revealed that P1D-34 led to the up-regulation of ROS pathway and down-regulation of UPR pathway to induce cell DNA damage and apoptosis. Notably, we further demonstrated that treatment with the combination formula of glucose metabolism inhibitor 2-DG and P1D-34 led to a notable synergistic anti-proliferative effect, further expanding its applicability. These data clearly reveal the practicality and importance of PROTAC as a preliminary tool compound suitable for assessment of Pin1-dependent pharmacology and a promising strategy for AML treatment.

Pembrolizumab in patients from China with microsatellite instability-high/mismatch repair deficient tumors: KEYNOTE-158.

Aim: To evaluate pembrolizumab in patients of Chinese descent with microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) tumors enrolled in KEYNOTE-158 (Cohort L). Methods: Patients with MSI-H/dMMR advanced tumors received pembrolizumab 200 mg IV Q3W. Primary end point was overall response rate (ORR). Secondary end points were duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: 24 patients were enrolled (20 were evaluable for efficacy). With median follow-up of 12.4 months, the ORR was 70%. DOR, PFS and OS were all not reached. A total of 19 (79%) patients had a treatment-related adverse event (AE; grade ≥3 in 4 [17%]), and 8 (33%) had an immune-mediated AE (grade ≥3 in (4 [17%]). Conclusion: Pembrolizumab provided meaningful and durable responses with manageable safety. These results are consistent with those reported for the global trial.