Young patient with a giant gastric bronchogenic cyst: A case report and review of literature.

BACKGROUND: Gastric bronchogenic cysts (BCs) are extremely rare cystic masses caused by abnormal development of the respiratory system during the embryonic period. Gastric bronchial cysts are rare lesions that were first reported in 1956; as of 2023, only 33 cases are available in the PubMed online database. BCs usually have no clinical symptoms in the early stage, and imaging findings also lack specificity. Therefore, they are difficult to diagnose before histopathological examination. CASE SUMMARY: A 34-year-old woman with respiratory distress presented at our hospital. Endoscopic ultrasound revealed an anechoic mass between the spleen, left kidney and gastric fundus, with hyperechogenic and soft elastography textures and with a size of approximately 6.5 cm × 4.0 cm. Furthermore, a computed tomography scan demonstrated high density between the posterior stomach and the spleen and the left kidney, with uniform internal density and a small amount of calcification. The maximum cross section was approximately 10.1 cm × 6.1 cm, and the possibility of a cyst was high. Because the imaging findings did not suggest a malignancy and because the patient required complete resection, she underwent laparotomy surgery. Intraoperatively, this cystic lesion was found to be located in the posterior wall of the large curvature of the fundus and was approximately 8 cm × 6 cm in size. Finally, the pathologists verified that the cyst in the fundus was a gastric BC. The patient recovered well, her symptoms of chest tightness disappeared, and the abdominal drain was removed on postoperative day 6, after which she was discharged on day 7 for 6 months of follow-up. She had no tumor recurrence or postoperative complications during the follow-up. CONCLUSION: This is a valuable report as it describes an extremely rare case of gastric BC. Moreover, this was a very young patient with a large BC in the stomach.

Fucosyltransferase 8 regulates adult neurogenesis and cognition of mice by modulating the Itga6-PI3K/Akt signaling pathway.

Fucosyltransferase 8 (Fut8) and core fucosylation play critical roles in regulating various biological processes, including immune response, signal transduction, proteasomal degradation, and energy metabolism. However, the function and underlying mechanism of Fut8 and core fucosylation in regulating adult neurogenesis remains unknown. We have shown that Fut8 and core fucosylation display dynamic features during the differentiation of adult neural stem/progenitor cells (aNSPCs) and postnatal brain development. Fut8 depletion reduces the proliferation of aNSPCs and inhibits neuronal differentiation of aNSPCs in vitro and in vivo, respectively. Additionally, Fut8 deficiency impairs learning and memory in mice. Mechanistically, Fut8 directly interacts with integrin α6 (Itga6), an upstream regulator of the PI3k-Akt signaling pathway, and catalyzes core fucosylation of Itga6. Deletion of Fut8 enhances the ubiquitination of Itga6 by promoting the binding of ubiquitin ligase Trim21 to Itga6. Low levels of Itga6 inhibit the activity of the PI3K/Akt signaling pathway. Moreover, the Akt agonist SC79 can rescue neurogenic and behavioral deficits caused by Fut8 deficiency. In summary, our study uncovers an essential function of Fut8 and core fucosylation in regulating adult neurogenesis and sheds light on the underlying mechanisms.

JAM-C Is Important for Lens Epithelial Cell Proliferation and Lens Fiber Maturation in Murine Lens Development.

Purpose: The underlying mechanism of congenital cataracts caused by deficiency or mutation of junctional adhesion molecule C (JAM-C) gene remains unclear. Our study aims to elucidate the abnormal developmental process in Jamc-/- lenses and reveal the genes related to lens development that JAM-C may regulate. Methods: Jamc knockout (Jamc-/-) mouse embryos and pups were generated for in vivo studies. Four key developmental stages from embryonic day (E) 12.5 to postnatal day (P) 0.5 were selected for the following experiments. Hematoxylin and eosin staining was used for histological analysis. The 5-bromo-2'-deoxyuridine (BrdU) incorporation assay and TUNEL staining were performed to label lens epithelial cell (LEC) proliferation and apoptosis, respectively. Immunofluorescence and Western blot were used to analyze the markers of lens epithelium, cell cycle exit, and lens fiber differentiation. Results: JAM-C was expressed throughout the process of lens development. Deletion of Jamc resulted in decreased lens size and disorganized lens fibers, which arose from E16.5 and aggravated gradually. The LECs of Jamc-/- lenses showed decreased quantity and proliferation, accompanied with reduction of key transcription factor, FOXE3. The fibers in Jamc-/- lenses were disorganized. Moreover, Jamc-deficient lens fibers showed significantly altered distribution patterns of Cx46 and Cx50. The marker of fiber homeostasis, γ-crystallin, was also decreased in the inner cortex and core fibers of Jamc-/- lenses. Conclusions: Deletion of JAM-C exhibits malfunction of LEC proliferation and fiber maturation during murine lens development, which may be related to the downregulation of FOXE3 expression and abnormal localization patterns of Cx46 and Cx50.

Efficient removal of cesium ions using Prussian blue loaded on magnetic porous biochar synthesized by one-step calcination.

Prussian blue (PB) is widely used for the selective removal of radioactive cesium ions (Cs+) from aqueous solutions. Due to its small size and easy dispersion in water, PB requires a carrier that is both inexpensive and easily separable. Magnetic porous biochar (MPBC) was formed by activating starch with FeCl3 through a one-step calcination method. MPBC can be used as a carrier for Prussian blue, which is easily separated from the solution. This composite material (PB/MPBC) has a rich pore structure and maintains effective surface area, which can facilitate the penetration of Cs+ into the adsorbent. Besides, PB/MPBC exhibits high selectivity and good adsorption capacity achieving a large removal capacity of 101.43 mg/g. Thus, this study provides a novel approach for preparing composites with efficient removal of Cs+.

VEGF-B prevents excessive angiogenesis by inhibiting FGF2/FGFR1 pathway.

Although VEGF-B was discovered as a VEGF-A homolog a long time ago, the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups. Notwithstanding, drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases. It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms. Using comprehensive in vitro and in vivo methods and models, we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed. Mechanistically, we unveil that VEGF-B binds to FGFR1, induces FGFR1/VEGFR1 complex formation, and suppresses FGF2-induced Erk activation, and inhibits FGF2-driven angiogenesis and tumor growth. Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway. Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels, caution is warranted when modulating VEGF-B activity to treat neovascular diseases.

Short- and long-term outcomes of single-port versus multiport laparoscopic radical gastrectomy for gastric cancer: a meta-analysis of propensity score-matched studies and randomized controlled trials.

BACKGROUND: At present, there is no convincing evidence-based medical basis for the efficacy of single-port laparoscopic gastrectomy. To make a high-quality comparison of the short- and long-term outcomes of single-port laparoscopic gastrectomy versus multiport laparoscopic gastrectomy, we performed this meta-analysis, which only included propensity score-matched studies and randomized controlled trials comparing single-port laparoscopic gastrectomy with multiport laparoscopic gastrectomy for patients with gastric cancer. METHODS: Data were retrieved from the electronic databases PubMed, EMBASE, Medline, Cochrane Library, CNKI, Wanfang and VIP up to January 2023, and the data included the outcomes of treatment after single-port laparoscopic gastrectomy and multiport laparoscopic gastrectomy. The primary outcomes were early complications, survival rate after surgery at 1 year, and survival rate after surgery at 5 years. The secondary outcomes were number of pain medications, mean operation time, estimated blood loss, hospital mortality, time to first soft fluid diet, time to first flatus, hospital stay after surgery, and retrieved number of lymph nodes. The Jadad score and Newcastle‒Ottawa scale were used to assess the quality of the included studies. RESULTS: After screening, 9 studies were finally included, including 988 patients. The meta-analysis results showed that estimated blood loss (MD=-29.35, 95% CI: -42.95-15.75, P < 0.0001), hospital stay (MD=-0.99, 95% CI:-1.82~-0.17, P = 0.02), and number of pain medications(MD=-0.65, 95% CI:-1.07~-0.23, P = 0.002) in the single-port laparoscopic gastrectomy group were better than those in the multiport laparoscopic gastrectomy group. There is no significant difference between the single-port laparoscopic gastrectomy group and the multiport laparoscopic gastrectomy group in mean operation time(MD = 5.23,95% CI:-16.58~27.04,P = 0.64), time to first soft fluid diet(MD=-0.06,95% CI: -0.30~0.18,P = 0.63), time to first flatus(MD=-0.18,95% CI:-0.43~0.07,P = 0.16), early complication(OR = 0.73,95% CI:0.50~1.09,P = 0.12), hospital mortality(OR = 1.00,95% CI:0.09~11.16,P = 1.00), retrieved number of lymph nodes(MD=-1.15, 95% CI:-2.71~0.40, P = 0.15), survival rate after surgery 1 year(OR = 2.14,95% CI:0.50~9.07,P = 0.30), and survival rate after surgery 5 year(93.7 vs. 87.6%; p = 0.689). CONCLUSION: This meta-analysis showed that single-port laparoscopic gastrectomy is both safe and feasible for laparoscopic radical gastrectomy for gastric cancer, with similar operation times and better short-term outcomes than multiport laparoscopic gastrectomy in terms of hospital stay, postoperative pain, and estimated blood loss. There was no significant difference in long-term outcomes between single-port laparoscopic gastrectomy and multiport laparoscopic gastrectomy.

Clinical outcomes and risk factor analysis of early endoscopic puncture decompression for ureterocele associated with duplex kidney in children: a single-center retrospective study.

PURPOSE: The aims of this study were to analyze the clinical outcomes of treating duplex system ureteroceles with early endoscopic puncture decompression and to identify the risk factors related to outcomes to help guide future work. MATERIALS AND METHODS: We retrospectively reviewed the clinical records of patients with ureteroceles with duplex kidney that were treated with early endoscopic puncture decompression. Charts were reviewed for demographics, preoperative imaging, surgical indications, and follow-up data. Recurrent febrile urinary tract infections (fUTIs), de novo vesicoureteral reflux (VUR), persistent high-grade VUR, unrelieved hydroureteronephrosis, and the need for further intervention were considered unfavorable outcomes. Gender, age at surgery, BMI, antenatal diagnosis, fUTIs, bladder outlet obstruction (BOO), type of ureterocele, ipsilateral VUR diagnosed before surgery, simultaneously upper-pole moiety (UM) and lower-pole moiety (LM) obstruction, the width of ureter affiliated to UM, and maximum diameter of ureterocele were all considered potential risk factors. A binary logistic regression model was used to identify the risk factors of unfavorable outcomes. RESULTS: A total of 36 patients with ureteroceles related to duplex kidney underwent endoscopic holmium laser puncture from 2015 to 2023 at our institution. After a median follow-up of 21.6 months, unfavorable outcomes developed in 17 patients (47.2%). Three patients underwent ipsilateral common-sheath ureter reimplantation and one patient underwent laparoscopic ipsilateral upper to lower ureteroureterostomy combined with recipient ureter reimplantation. Three patients underwent laparoscopic upper-pole nephrectomy. Fifteen patients suffered from recurrent UTIs were treated with oral antibiotics and eight of them were diagnosed de novo VUR according to voiding cystourethrography (VCUG). In univariate analysis, patients with simultaneously UM and LM obstruction (P = 0.003), fUTIs before surgery (P = 0.044), and ectopic ureterocele (P = 0.031) were more likely to have unfavorable outcomes. Binary logistic regression analysis showed that ectopic ureterocele (OR = 10.793, 95% CI 1.248-93.312, P = 0.031) and simultaneously UM and LM obstruction (OR = 8.304, 95% CI 1.311-52.589, P = 0.025) were identified as independent factors for unfavorable outcomes. CONCLUSIONS: Our study suggested that early endoscopic puncture decompression is not a preferred but an available treatment option to release BOO or to cure refractory UTIs. It was easier to fail if the ureterocele was ectopic or simultaneously UM and LM obstruction existed. Gender, age at surgery, BMI, antenatal diagnosis, fUTIs, bladder outlet obstruction (BOO), ipsilateral VUR diagnosed before surgery, the width of ureter affiliated to UM, and maximum diameter of ureterocele were not significantly related to the success rate of early endoscopic punctures.

PSNSleep: a self-supervised learning method for sleep staging based on Siamese networks with only positive sample pairs.

Traditional supervised learning methods require large quantities of labeled data. However, labeling sleep data according to polysomnography by well-trained sleep experts is a very tedious job. In the present day, the development of self-supervised learning methods is making significant progress in many fields. It is also possible to apply some of these methods to sleep staging. This is to remove the dependency on labeled data at the stage of representation extraction. Nevertheless, they often rely too much on negative samples for sample selection and construction. Therefore, we propose PSNSleep, a novel self-supervised learning method for sleep staging based on Siamese networks. The crucial step to the success of our method is to select appropriate data augmentations (the time shift block) to construct the positive sample pair. PSNSleep achieves satisfactory results without relying on any negative samples. We evaluate PSNSleep on Sleep-EDF and ISRUC-Sleep and achieve accuracy of 80.0% and 74.4%. The source code is publicly available at https://github.com/arthurxl/PSNSleep.

Chinese experts' consensus on the application of intensive care big data.

The development of intensive care medicine is inseparable from the diversified monitoring data. Intensive care medicine has been closely integrated with data since its birth. Critical care research requires an integrative approach that embraces the complexity of critical illness and the computational technology and algorithms that can make it possible. Considering the need of standardization of application of big data in intensive care, Intensive Care Medicine Branch of China Health Information and Health Care Big Data Society, Standard Committee has convened expert group, secretary group and the external audit expert group to formulate Chinese Experts' Consensus on the Application of Intensive Care Big Data (2022). This consensus makes 29 recommendations on the following five parts: Concept of intensive care big data, Important scientific issues, Standards and principles of database, Methodology in solving big data problems, Clinical application and safety consideration of intensive care big data. The consensus group believes this consensus is the starting step of application big data in the field of intensive care. More explorations and big data based retrospective research should be carried out in order to enhance safety and reliability of big data based models of critical care field.

Deficiency of Jamc Leads to Congenital Nuclear Cataract and Activates the Unfolded Protein Response in Mouse Lenses.

Purpose: The malfunction of junctional adhesion molecule C (JAM-C) has been reported to induce congenital cataract in humans and mice; however, specific characters and the mechanism of this cataract are still unclear. This study aimed to characterize abnormal lens development in Jamc knockout mice and clarify the underlying mechanism. Methods: Jamc knockout mice backcrossed onto the C57BL/6 genetic background were used for this research. Slit-lamp and darkfield images showed the cataract phenotype of Jamc-/- mice. Hematoxylin and eosin staining was performed to visualize the morphological and histological features. RNA sequencing was applied to detect differentially expressed genes. Quantitative RT-PCR, western blot, and immunofluorescence were used to determine the level of unfolded protein response (UPR)-related genes. TUNEL staining was utilized to label cell death. Results: Jamc knockout mice exhibited nuclear cataract with abnormal lens morphology and defective degradation of nuclei and organelles in lens fiber cells. Compared with wild-type control mice, the expression level of BiP, CHOP, TRIB3, and CHAC1, genes involved in endoplasmic reticulum stress and the UPR, were highly upregulated in Jamc-/- lenses, suggesting that abnormal lens development was accompanied by UPR activation. Moreover, increased cell death was also found in Jamc-/- lenses. Conclusions: Congenital nuclear cataract caused by Jamc deficiency is accompanied by defective degradation of nuclei and organelles in lens fiber cells, lens structure disorder, and UPR activation, suggesting that JAM-C is required for maintaining normal lens development and that UPR activation is involved in cataract formation in Jamc-deficient lenses.

Comprehensive Bioinformatics Analysis to Reveal Key RNA Targets and Hub Competitive Endogenous RNA Network of Keratoconus.

Keratoconus (KC) is the most common corneal ectatic disease, with its pathological mechanisms unclear. We mainly performed bioinformatics approaches to reveal core RNA targets and hub competitive endogenous RNA (ceRNA) network and explored the potential regulatory mechanisms of ceRNA in KC. The high-throughput sequencing datasets GSE77938 and GSE151631 were downloaded from the Gene Expression Omnibus (GEO) database. The differential expression of mRNAs and lncRNAs was identified using the DESeq2 package. Functional enrichment analyses and protein-protein interaction (PPI) were executed. Then, the hub genes were filtered and molecular docking analysis was performed. Moreover, we predicted miRNAs through a website database and validated them using quantitative PCR (qPCR). Eventually, the lncRNA-miRNA-mRNA regulatory network was constructed by Cytoscape. We revealed that 428 intersected differentially expressed mRNA (DEGs) and 68 intersected differentially expressed lncRNA (DELs) were shared between the two datasets. Functional enrichment results innovatively showed that the ubiquitin-dependent protein catabolic process was upregulated in KC. The pathway enrichment showed that DEGs were mainly involved in NF-kB signaling and neurodegenerative diseases. In addition, we uncovered the top 20 hub genes in which FBXW11, FBXO9, RCHY1, and CD36 were validated by qPCR. Particularly, a small-molecule drug triptolide was predicted by molecular docking to be a candidate drug for treating KC. Moreover, we innovatively predicted and validated four core miRNAs (miR-4257, miR-4494, miR-4263, and miR-4298) and constructed a ceRNA network that contained 165 mRNA, eight lncRNAs, and four core miRNAs. Finally, we proposed a potential regulatory mechanism for KC. Overall, we uncovered a hub ceRNA network that might underlie a critical posttranslational regulatory mechanism in KC, in which miR-4257, miR-4494, miR-4263, and miR-4298 could be valuable biomarkers and provided core RNAs therapeutic targets for KC.

NAD+ Modulates the Proliferation and Differentiation of Adult Neural Stem/Progenitor Cells via Akt Signaling Pathway.

Nicotinamide adenine dinucleotide hydrate (NAD+) acts as the essential component of the tricarboxylic citric acid (TCA) cycle and has important functions in diverse biological processes. However, the roles of NAD+ in regulating adult neural stem/progenitor cells (aNSPCs) remain largely unknown. Here, we show that NAD+ exposure leads to the reduced proliferation and neuronal differentiation of aNSPCs and induces the apoptosis of aNSPCs. In addition, NAD+ exposure inhibits the morphological development of neurons. Mechanistically, RNA sequencing revealed that the transcriptome of aNSPCs is altered by NAD+ exposure. NAD+ exposure significantly decreases the expression of multiple genes related to ATP metabolism and the PI3k-Akt signaling pathway. Collectively, our findings provide some insights into the roles and mechanisms in which NAD+ regulates aNSPCs and neuronal development.

Downregulation of AMPK dependent FOXO3 and TFEB involves in the inhibition of autophagy in diabetic cataract.

PURPOSE: Autophagy plays a crucial role in intracellular quality control of crystalline lens and AMPK has regulatory effect on autophagy. However, whether AMPK regulated autophagy is involved in diabetic cataract (DC) progression remains unknown. This study aims to investigate the AMPK-FOXO3 and AMPK-TFEB induced autophagy activity in DC patients. MATERIALS AND METHODS: First, anterior capsule specimens from DC and age-related cataract (ARC) patients were obtained to compare the expression difference of autophagy-related genes. The phosphorylation levels of AMPK, AKT, and mTOR and the expression of FOXO3 and TFEB were measured. Then, human lens epithelial cells (LECs, SRA 01/04) were cultured with 30 mM or 5.5 mM glucose, and AMPK activator (AICAR) and inhibitor (Compound C) were applied to further investigate the regulatory role of AMPK on autophagy. RESULTS: Compared with ARC patients, the expression of autophagy-related genes ATG5, FYCO1, ATG8, ATG12, Beclin1, and ULK1 in anterior capsules LECs of DC patients were significantly down-regulated. Meanwhile, AMPK and AMPK-dependent transcription factors, FOXO3 and TFEB were also inhibited. Similar results were found in high glucose (HG) treated SRA 01/04 model. Notably, this down-regulation of autophagy activity was rescued by AICAR in vitro, which was manifested by inhibition of AKT and mTOR phosphorylation and up-regulation of FOXO3, TFEB, Beclin1 and LC3B-II expression. CONCLUSIONS: Down-regulation of AMPK-FOXO3 and AMPK-TFEB induced autophagy activity was found in both LECs of anterior capsule from DC patients and SRA 01/04 cells under HG condition, which may be the underlying mechanism of DC formation. Thus, targeting AMPK-induced autophagy may be a potential therapeutic approach for diabetic cataract.

Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies.

Chimeric antigen receptor (CAR) T-cell therapy has yielded impressive outcomes and transformed treatment algorithms for hematological malignancies. To date, five CAR T-cell products have been approved by the US Food and Drug Administration (FDA). Nevertheless, some significant toxicities pose great challenges to the development of CAR T-cell therapy, most notably cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Understanding the mechanisms underlying these toxicities and establishing prevention and treatment strategies are important. In this review, we summarize the mechanisms underlying CRS and ICANS and provide potential treatment and prevention strategies.

Application of Rough Ant Colony Algorithm in Adolescent Psychology.

With the rapid development of big data, big data research in the security protection industry has been increasingly regarded as a hot spot. This article mainly aims at solving the problem of predicting the tendency of juvenile delinquency based on the experimental data of juvenile blindly following psychological crime. To solve this problem, this paper proposes a rough ant colony classification algorithm, referred to as RoughAC, which first uses the concept of upper and lower approximate sets in rough sets to determine the degree of membership. In addition, in the ant colony algorithm, we use the membership value to update the pheromone. Experiments show that the algorithm can not only solve the premature convergence problem caused by stagnation near the local optimal solution but also solve the continuous domain and combinatorial optimization problems and achieve better classification results. Moreover, the algorithm has a good effect on predicting classification and can provide guidance for predicting the tendency of juvenile delinquency.

The Roles of Inflammation in Keloid and Hypertrophic Scars.

The underlying mechanisms of wound healing are complex but inflammation is one of the determining factors. Besides its traditional role in combating against infection upon injury, the characteristics and magnitude of inflammation have dramatic impacts on the pathogenesis of scar. Keloids and hypertrophic scars are pathological scars that result from aberrant wound healing. They are characterized by continuous local inflammation and excessive collagen deposition. In this review, we aim at discussing how dysregulated inflammation contributes to the pathogenesis of scar formation. Immune cells, soluble inflammatory mediators, and the related intracellular signal transduction pathways are our three subtopics encompassing the events occurring in inflammation associated with scar formation. In the end, we enumerate the current and potential medicines and therapeutics for suppressing inflammation and limiting progression to scar. Understanding the initiation, progression, and resolution of inflammation will provide insights into the mechanisms of scar formation and is useful for developing effective treatments.

MPTP-Induced Impairment of Cardiovascular Function.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of Lewy bodies and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpC). MPTP is widely used to generate murine PD model. In addition to classical motor disorders, PD patients usually have non-motor symptoms related to autonomic impairment, which precedes decades before the motor dysfunction. This study's objective is to examine the effects of MPTP on noradrenergic neurons in the hindbrain, thereby on the cardiovascular function in mice. Adult mice received 10 mg/kg/day of MPTP (4 consecutive days) to generate PD model. Systolic blood pressure was measured by tail cuff system in conscious mice, and baroreflex sensitivity was evaluated by heart rate alteration in response to a transient increase or decrease in blood pressure induced by intravenous infusion of phenylalanine (PE) or sodium nitroprusside (SNP) in anesthetized condition, respectively. Baseline heart rate and heart rate variability were analyzed in both sham and MPTP-treated mice. Dopamine, norepinephrine, and related metabolites in the plasma and brain tissues including SNpC, locus coeruleus (LC), rostroventrolateral medulla (RVLM), and nucleus tractus solitarii (NTS) were measured by liquid chromatography-mass spectrometry (LC-MS). Tyrosine hydroxylase-positive (TH+) neurons in above nuclei were quantified by immunoreactivities. We found that in addition to the loss of TH+ neurons in SNpC, MPTP treatment induced a dramatic reduction of TH+ cell counts in the LC, RVLM, and NTS. These are associated with significant decreases of dopamine, norepinephrine, and epinephrine in above nuclei. Meanwhile, MPTP induced a lasting effect of baroreflex desensitization, tachycardia, and decreased heart rate variability compared to the sham mice. Notably, MPTP treatment elevated sympathetic outflow and suppressed parasympathetic tonicity according to the heart rate power spectrum analysis. Our results indicate that the loss of TH+ neurons in the brainstem by MPTP treatment led to impaired autonomic cardiovascular function. These results suggest that MPTP treatment can be used to study the autonomic dysfunction in murine model.

Challenges and Clinical Strategies of CAR T-Cell Therapy for Acute Lymphoblastic Leukemia: Overview and Developments.

Chimeric antigen receptor (CAR) T-cell therapy exhibits desirable and robust efficacy in patients with acute lymphoblastic leukemia (ALL). Stimulated by the revolutionized progress in the use of FDA-approved CD19 CAR T cells, novel agents with CAR designs and targets are being produced in pursuit of superior performance. However, on the path from bench to bedside, new challenges emerge. Accessibility is considered the initial barrier to the transformation of this patient-specific product into a commercially available product. To ensure infusion safety, profound comprehension of adverse events and proactive intervention are required. Additionally, resistance and relapse are the most critical and intractable issues in CAR T-cell therapy for ALL, thus precluding its further development. Understanding the limitations through up-to-date insights and characterizing multiple strategies will be critical to leverage CAR T-cell therapy flexibly for use in clinical situations. Herein, we provide an overview of the application of CAR T-cell therapy in ALL, emphasizing the main challenges and potential clinical strategies in an effort to promote a standardized set of treatment paradigms for ALL.

Mechanisms of Relapse After CD19 CAR T-Cell Therapy for Acute Lymphoblastic Leukemia and Its Prevention and Treatment Strategies.

Chimeric antigen receptor (CAR) T-cell therapy is highly effective in the treatment of B-cell acute lymphoblastic leukemia (ALL) or B-cell lymphoma, providing alternative therapeutic options for patients who failed to respond to conventional treatment or relapse. Moreover, it can bridge other therapeutic strategies and greatly improve patient prognosis, with broad applicable prospects. Even so, 30-60% patients relapse after treatment, probably due to persistence of CAR T-cells and escape or downregulation of CD19 antigen, which is a great challenge for disease control. Therefore, understanding the mechanisms that underlie post-CAR relapse and establishing corresponding prevention and treatment strategies is important. Herein, we discuss post-CAR relapse from the aspects of CD19-positive and CD19-negative and provide some reasonable prevention and treatment strategies.

Rational Design of Cancer Nanomedicine: Nanoproperty Integration and Synchronization.

Current cancer nanomedicines can only mitigate adverse effects but fail to enhance therapeutic efficacies of anticancer drugs. Rational design of next-generation cancer nanomedicines should aim to enhance their therapeutic efficacies. Taking this into account, this review first analyzes the typical cancer-drug-delivery process of an intravenously administered nanomedicine and concludes that the delivery involves a five-step CAPIR cascade and that high efficiency at every step is critical to guarantee high overall therapeutic efficiency. Further analysis shows that the nanoproperties needed in each step for a nanomedicine to maximize its efficiency are different and even opposing in different steps, particularly what the authors call the PEG, surface-charge, size and stability dilemmas. To resolve those dilemmas in order to integrate all needed nanoproperties into one nanomedicine, stability, surface and size nanoproperty transitions (3S transitions for short) are proposed and the reported strategies to realize these transitions are comprehensively summarized. Examples of nanomedicines capable of the 3S transitions are discussed, as are future research directions to design high-performance cancer nanomedicines and their clinical translations.