Accessory hepatic vein recanalization for Budd-Chiari syndrome: a systematic review and meta-analysis.

BACKGROUND: Budd-Chiari syndrome (BCS) results when the outflow of the hepatic vein (HV) is obstructed. BCS patients exhibiting an accessory HV (AHV) that is dilated but obstructed can achieve significant alleviation of liver congestion after undergoing AHV recanalization. This meta-analysis was developed to explore the clinical efficacy of AHV recanalization in patients with BCS. MATERIALS AND METHODS: PubMed, Embase, and Wanfang databases were searched for relevant studies published as of November 2022, and RevMan 5.3 and Stata 12.0 were used for pooled endpoint analyses. RESULTS: Twelve total studies were identified for analysis. Pooled primary clinical success, re-stenosis, 1- and 5-year primary patency, 1- and 5-year secondary patency, 1-year overall survival (OS), and 5-year OS rates of patients in these studies following AHV recanalization were 96%, 17%, 91%, 75%, 98%, 91%, 97%, and 96%, respectively. Patients also exhibited a significant reduction in AHV pressure after recanalization relative to preoperative levels (P < 0.00001). Endpoints exhibiting significant heterogeneity among these studies included, AHV pressure (I2 = 95%), 1-year primary patency (I2 = 51.2%), and 5-year primary patency (I2 = 62.4%). Relative to HV recanalization, AHV recanalization was related to a lower rate of re-stenosis (P = 0.002) and longer primary patency (P < 0.00001), but was not associated with any improvements in clinical success (P = 0.88) or OS (P = 0.29) relative to HV recanalization. CONCLUSIONS: The present meta-analysis highlights AHV recanalization as an effective means of achieving positive long-term outcomes in patients affected by BCS, potentially achieving better long-term results than those associated with HV recanalization.

Mitigating the impact of bisphenol A exposure on mortality: Is diet the key? A cohort study based on NHANES.

Bisphenol A (BPA) is a widespread environmental pollutant linked to detrimental effects on human health and reduced life expectancy following chronic exposure. This prospective cohort study aimed to examine the association between BPA exposure and mortality in American adults and to explore the potential mitigating effects of dietary quality on BPA-related mortality. This study utilized data from 8761 American adults in the 2003-2016 National Health and Nutrition Examination Survey (NHANES). Urinary BPA levels were employed to assess BPA exposure, and dietary quality was evaluated using the Healthy Eating Index-2015 (HEI-2015). All-cause, cardiovascular disease (CVD), and cancer mortality statuses were determined until December 31, 2019, resulting in a cumulative follow-up of 80,564 person-years. The results showed that the highest tertile of urinary BPA levels corresponded to a 36% increase in all-cause mortality and a 62% increase in CVD mortality compared to the lowest tertile. In contrast, the highest tertile of HEI-2015 scores was associated with a 29% reduction in all-cause mortality relative to the lowest tertile. Although no significant interaction was found between HEI-2015 scores and urinary BPA levels concerning mortality, the association between HEI-2015 scores and both all-cause and CVD mortality was statistically significant at low urinary BPA levels. Continuous monitoring of BPA exposure is crucial for evaluating its long-term adverse health effects. Improving dietary quality can lower all-cause mortality and decrease the risk of all-cause and CVD mortality at low BPA exposure levels. However, due to the limited protective effect of dietary quality against BPA exposure, minimizing BPA exposure remains a vital goal.

Reliability of a human pose tracking algorithm for measuring upper limb joints: comparison with photography-based goniometry.

BACKGROUND: Range of motion (ROM) measurements are essential for diagnosing and evaluating upper extremity conditions. Clinical goniometry is the most commonly used methods but it is time-consuming and skill-demanding. Recent advances in human tracking algorithm suggest potential for automatic angle measuring from RGB images. It provides an attractive alternative for at-distance measuring. However, the reliability of this method has not been fully established. The purpose of this study is to evaluate if the results of algorithm are as reliable as human raters in upper limb movements. METHODS: Thirty healthy young adults (20 males, 10 females) participated in this study. Participants were asked to performed a 6-motion task including movement of shoulder, elbow and wrist. Images of movements were captured by commercial digital cameras. Each movement was measured by a pose tracking algorithm (OpenPose) and compared with the surgeon-measurement results. The mean differences between the two measurements were compared. Pearson correlation coefficients were used to determine the relationship. Reliability was investigated by the intra-class correlation coefficients. RESULTS: Comparing this algorithm-based method with manual measurement, the mean differences were less than 3 degrees in 5 motions (shoulder abduction: 0.51; shoulder elevation: 2.87; elbow flexion:0.38; elbow extension:0.65; wrist extension: 0.78) except wrist flexion. All the intra-class correlation coefficients were larger than 0.60. The Pearson coefficients also showed high correlations between the two measurements (p < 0.001). CONCLUSIONS: Our results indicated that pose estimation is a reliable method to measure the shoulder and elbow angles, supporting RGB images for measuring joint ROM. Our results presented the possibility that patients can assess their ROM by photos taken by a digital camera. TRIAL REGISTRATION: This study was registered in the Clinical Trials Center of The First Affiliated Hospital, Sun Yat-sen University (2021-387).

Dynamic Compression Promotes the Matrix Synthesis of Nucleus Pulposus Cells Through Up-Regulating N-CDH Expression in a Perfusion Bioreactor Culture.

BACKGROUND/AIMS: An adequate matrix production of nucleus pulposus (NP) cells is an important tissue engineering-based strategy to regenerate degenerative discs. Here, we mainly aimed to investigate the effects and mechanism of mechanical compression (i.e., static compression vs. dynamic compression) on the matrix synthesis of three-dimensional (3D) cultured NP cells in vitro. METHODS: Rat NP cells seeded on small intestinal submucosa (SIS) cryogel scaffolds were cultured in the chambers of a self-developed, mechanically active bioreactor for 10 days. Meanwhile, the NP cells were subjected to compression (static compression or dynamic compression at a 10% scaffold deformation) for 6 hours once per day. Unloaded NP cells were used as controls. The cellular phenotype and matrix biosynthesis of NP cells were investigated by real-time PCR and Western blotting assays. Lentivirus-mediated N-cadherin (N-CDH) knockdown and an inhibitor, LY294002, were used to further investigate the role of N-CDH and the PI3K/Akt pathway in this process. RESULTS: Dynamic compression better maintained the expression of cell-specific markers (keratin-19, FOXF1 and PAX1) and matrix macromolecules (aggrecan and collagen II), as well as N-CDH expression and the activity of the PI3K/Akt pathway, in the 3D-cultured NP cells compared with those expression levels and activity in the cells grown under static compression. Further analysis showed that the N-CDH knockdown significantly down-regulated the expression of NP cell-specific markers and matrix macromolecules and inhibited the activation of the PI3K/Akt pathway under dynamic compression. However, inhibition of the PI3K/Akt pathway had no effects on N-CDH expression but down-regulated the expression of NP cell-specific markers and matrix macromolecules under dynamic compression. CONCLUSION: Dynamic compression increases the matrix synthesis of 3D-cultured NP cells compared with that of the cells under static compression, and the N-CDH-PI3K/Akt pathway is involved in this regulatory process. This study provides a promising strategy to promote the matrix deposition of tissue-engineered NP tissue in vitro prior to clinical transplantation.

N-Cadherin Attenuates High Glucose-Induced Nucleus Pulposus Cell Senescence Through Regulation of the ROS/NF-κB Pathway.

BACKGROUND/AIMS: Diabetes mellitus (DM) is a potential etiology of disc degeneration. N-cadherin (N-CDH) helps maintain the cell viability, cell phenotype and matrix biosynthesis of nucleus pulposus (NP) cells. Here, we mainly aimed to investigate whether N-CDH can attenuate high glucose-induced NP cell senescence and its potential mechanism. METHODS: Rat NP cells were cultured in a base culture medium and base culture medium with a 0.2 M glucose concentration. Recombinant lentiviral vectors were used to enhance N-CDH expression in NP cells. Senescence-associated ß-galactosidase (SA-ß-Gal) activity was measured by SA-ß-Gal staining. NP cell proliferation was evaluated by CCK-8 assay. Telomerase activity and intracellular reactive oxygen species (ROS) content were tested by specific chemical kits according to the manufacturer's instructions. G0/G1 cell cycle arrest was evaluated by flow cytometry. Real-time PCR and Western blotting were used to analyze mRNA and protein expressions of senescence markers (p16 and p53) and matrix macromolecules (aggrecan and collagen II). Additionally, p-NF-κB expression was also analyzed by Western blotting to evaluate NF-κB pathway activity. RESULTS: High glucose significantly decreased N-CDH expression, increased ROS generation and NF-κB pathway activity, and promoted NP cell senescence, which was reflected in the increase in SA-ß-Gal activity and senescence marker (p16 and p53) expression, compared to the control group. High glucose decreased telomerase activity and cell proliferation potency. However, N-CDH overexpression partially attenuated NP cell senescence, decreased ROS content and inhibited the activation of the NF-κB pathway under the high glucose condition. CONCLUSION: High glucose decreases N-CDH expression and promotes NP cell senescence. N-CDH overexpression can attenuate high glucose-induced NP cell senescence through the regulation of the ROS/ NF-κB pathway. This study suggests that N-CDH is a potential therapeutic target to slow DM-mediated disc NP degeneration.

Intracellular endogenous glutathione detection and imaging by a simple and sensitive spectroscopic off-on probe.

Glutathione (GSH) exhibits many cellular functions in human pathologies. A sensitive and simple method capable of assaying GSH would be useful to understand the mechanism of GSH-related diseases. In this study, a new colorimetric and fluorescent off-on probe, 3-oxo-3H-phenoxazin-7-ylthiophene-2-carboxylate, is constructed, synthesized and applied to determine fluctuations in intracellular GSH levels selectively and sensitively. The latent fluorescent probe is designed by reacting resorufin with thiophenecarboxylate and shows high sensitivity (LOD 8.9 × 10-7 M) and off-on fluorescent response to GSH over other different physiological species in pH 7.4 buffer solutions. A new reaction mechanism based on the cut-through of thiophenecarboxylate in the probe by GSH is confirmed via the HPLC (high performance liquid chromatography) and MS (mass spectrometry) analytical methods. Moreover, the probe is successfully applied to image GSH in A549 cells and indicates fluctuations in GSH levels under the stimulation of chemicals and drugs, which is verified by the investigation of the cell lysate with a commonly used commercial assay kit. As a result, it is feasible to monitor the levels of GSH in biosamples.

Electrochemical Determination of Nitrite by Au Nanoparticle/Graphene-Chitosan Modified Electrode.

A highly sensitive nitrite (NO2−) electrochemical sensor is fabricated using glassy carbon electrode modified with Au nanoparticle and grapheme oxide. Briefly, this electrochemical sensor was prepared by drop-coating graphene oxide-chitosan mixed film on the surface of the electrode and then electrodepositing a layer of Au nanoparticle using cyclic voltammetry. The electrochemical behavior of NO2− on the sensor was investigated by cyclic voltammetry and amperometric i-t curve. The results showed that the sensor exhibited better electrocatalytic activity for NO2− in 0.1 mol/L phosphate buffer solution (PBS) (pH 5.0). The oxidation peak current was positively correlated with NO2− concentration in the ranges of 0.9 µM to 18.9 µM. The detection limit was estimated to be 0.3 µM. In addition, the interference of some common ions (e.g., NO3−, CO32−, SO42−, Cl−, Ca2+ and Mg2+) and oxidizable compound including sodium sulfite and ascorbic acid in the detection of nitrite was also studied. The results show that this sensor is more sensitive and selective to NO2−. Therefore, this electrochemical sensor provided an effective tool for the detection of NO2−.

A CT-based diagnostic nomogram and survival analysis for differentiating grade 3 pancreatic neuroendocrine tumors from pancreatic ductal adenocarcinomas.

Objective: To construct a CT-based diagnostic nomogram for distinguishing grade 3 pancreatic neuroendocrine tumors (G3 PNETs) from pancreatic ductal adenocarcinomas (PDACs) and assess their respective survival outcomes. Methods: Patients diagnosed with G3 PNETs (n = 30) and PDACs (n = 78) through surgery or biopsy from two medical centers were retrospectively identified. Demographic and radiological information, including age, gender, tumor diameter, shape, margin, dilatation of pancreatic duct, and invasive behavior, were carefully collected. A nomogram was established after univariate and multivariate logistic regression analyses. The Kaplan-Meier survival was performed to analyze their survival outcomes. Results: Factors with a p-value <0.05, including age, CA 19-9, pancreatic duct dilatation, irregular shape, ill-defined margin, pancreatic atrophy, combined pancreatitis, arterial/portal enhancement ratio, were included in the multivariate logistic analysis. The independent predictive factors, including age (OR, 0.91; 95% CI, 0.85-0.98), pancreatic duct dilatation (OR, 0.064; 95% CI, 0.01-0.32), and portal enhancement ratio (OR, 1,178.08; 95% CI, 5.96-232,681.2) were determined to develop a nomogram. The internal calibration curve and decision curve analysis demonstrate that the nomogram exhibits good consistency and discriminative capacity in distinguishing G3 PNETs from PDACs. Patients diagnosed with G3 PNETs exhibited considerably better overall survival outcomes compared to those diagnosed with PDACs (median survival months, 42 vs. 9 months, p < 0.001). Conclusions: The nomogram model based on age, pancreatic duct dilatation, and portal enhancement ratio demonstrates good accuracy and discriminative ability effectively predicting the probability of G3 PNETs from PDACs. Furthermore, patients with G3 PNETs exhibit better prognosis than PDACs.

Combinational therapy of CAR T-cell and HDT/ASCT demonstrates impressive clinical efficacy and improved CAR T-cell behavior in relapsed/refractory large B-cell lymphoma.

BACKGROUND: Approximately two-thirds of patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) do not respond to or relapse after anti-CD19 chimeric antigen receptor T (CAR T)-cell therapy, leading to poor outcomes. Previous studies have suggested that intensified lymphodepletion and hematological stem cell infusion can promote adoptively transferred T-cell expansion, enhancing antitumor effects. Therefore, we conducted a phase I/II clinical trial in which CNCT19 (an anti-CD19 CAR T-cell) was administered after myeloablative high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT) in patients with R/R LBCL. METHODS: Transplant-eligible patients with LBCL who were refractory to first-line immunochemotherapy or experiencing R/R status after salvage chemotherapy were enrolled. The study aimed to evaluate the safety and efficacy of this combinational therapy. Additionally, frozen peripheral blood mononuclear cell samples from this trial and CNCT19 monotherapy studies for R/R LBCL were used to evaluate the impact of the combination therapy on the in vivo behavior of CNCT19 cells. RESULTS: A total of 25 patients with R/R LBCL were enrolled in this study. The overall response and complete response rates were 92.0% and 72.0%, respectively. The 2-year progression-free survival rate was 62.3%, and the overall survival was 68.5% after a median follow-up of 27.0 months. No unexpected toxicities were observed. All cases of cytokine release syndrome were of low grade. Two cases (8%) experienced grade 3 or higher CAR T-cell-related encephalopathy syndrome. The comparison of CNCT19 in vivo behavior showed that patients in the combinational therapy group exhibited enhanced in vivo expansion of CNCT19 cells and reduced long-term exhaustion formation, as opposed to those receiving CNCT19 monotherapy. CONCLUSIONS: The combinational therapy of HDT/ASCT and CNCT19 demonstrates impressive efficacy, improved CNCT19 behavior, and a favorable safety profile. TRIAL REGISTRATION NUMBERS: ChiCTR1900025419 and NCT04690192.

Up-to-date literature review and issues of sedation during digestive endoscopy.

Sedation is common during digestive endoscopy to provide comfort and pain relief for patients. However, the use of sedation in endoscopy also poses potential risks, and recent issues have been raised regarding its safety and administration. This literature review paper will discuss the most recent developments in the field of sedation in digestive endoscopy, including the adverse events that might be associated with sedation and how to manage it, the legal issues associated with administration, the impact of COVID-19 on sedation practices, and sedation in special situations. It will also touch upon the current guidelines and recommendations for sedation, including the importance of patient selection and monitoring and the need for training and certification for endoscopists administering sedation. The review will also analyse studies evaluating the safety and efficacy of various sedation techniques, including propofol, midazolam, and others. It will examine the benefits and drawbacks of these agents.

Mechanistic insights into the role of probiotics in modulating immune cells in ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is a persistent inflammatory disorder that affects the gastrointestinal tract, mainly the colon, which is defined by inflammatory responses and the formation of ulcers. Probiotics have been shown to directly impact various immune cells, including dendritic cells (DCs), macrophages, natural killer (NK) cells, and T and B cells. By interacting with cell surface receptors, they regulate immune cell activity, produce metabolites that influence immune responses, and control the release of cytokines and chemokines. METHODS: This article is a comprehensive review wherein we conducted an exhaustive search across published literature, utilizing reputable databases like PubMed and Web of Science. Our focus centered on pertinent keywords, such as "UC," 'DSS," "TNBS," "immune cells," and "inflammatory cytokines," to compile the most current insights regarding the therapeutic potential of probiotics in managing UC. RESULTS: This overview aims to provide readers with a comprehensive understanding of the effects of probiotics on immune cells in relation to UC. Probiotics have a crucial role in promoting the proliferation of regulatory T cells (Tregs), which are necessary for preserving immunological homeostasis and regulating inflammatory responses. They also decrease the activation of pro-inflammatory cells like T helper 1 (Th1) and Th17 cells, contributing to UC development. Thus, probiotics significantly impact both direct and indirect pathways of immune cell regulation in UC, promoting Treg differentiation, inhibiting pro-inflammatory cell activation, and regulating cytokine and chemokine release. CONCLUSION: Probiotics demonstrate significant potential in modulating the immune reactions in UC. Their capacity to modulate different immune cells and inflammation-related processes makes them a promising therapeutic approach for managing UC. However, further studies are warranted to optimize their use and fully elucidate the molecular mechanisms underlying their beneficial effects in UC treatment.

Preoperative computed tomography-guided transscapular sens-cure needle localization for pulmonary nodule located behind the scapula.

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) is an approach that is commonly used to resect pulmonary nodules (PNs). However, when these PNs are located behind the scapula, a transscapular access approach is generally required. In this study, the safety, efficacy, and feasibility of preoperative computed tomography (CT)-guided Sens-cure needle (SCN) localization was assessed for PNs located behind the scapula. METHODS: From January 2020 - June 2022, a total of 122 PN patients in our hospital underwent preoperative CT-guided SCN localization and subsequent VATS resection, of whom 12 (9.8%) exhibited PNs behind the scapula necessitating a transscapular approach for this localization procedure. RESULTS: This study included 12 patients, each of whom had one PN located behind the scapula. The CT-guided transscapular SCN localization approach was successful in all patients, and no complications near the operative site were observed. The median localization time was 12 min, and 2 (16.7%) and 1 (8.3%) patients respectively developed pneumothorax and pulmonary hemorrhage after the localization procedure was complete. Wedge resection procedures for these PNs achieved technical success in all cases. Four patients were diagnosed with invasive adenocarcinomas and subsequently accepted lobectomy and systematic lymph node dissection. The median VATS duration and the median blood loss was 80 min and 10 mL, respectively. In total, 3, 5, and 4 PNs were respectively diagnosed as benign, mini-invasive adenocarcinomas, and invasive adenocarcinomas. CONCLUSION: Preoperative CT-guided transscapular SCN localization represents a safe, straightforward, and effective means of localizing PNs present behind the scapula.

Validity and Reliability of a Depth Camera-Based Quantitative Measurement for Joint Motion of the Hand.

Purpose: Quantitative measurement of hand motion is essential in evaluating hand function. This study aimed to investigate the validity and reliability of a novel depth camera-based contactless automatic measurement system to assess hand range of motion and its potential benefits in clinical applications. Methods: Five hand gestures were designed to evaluate the hand range of motion using a depth camera-based measurement system. Seventy-one volunteers were enrolled in performing the designed hand gestures. Then, the hand range of motion was measured with the depth camera and manual procedures. System validity was evaluated based on 3 dimensions: repeatability, within-laboratory precision, and reproducibility. For system reliability, linear evaluation, the intraclass correlation coefficient, paired t -test and bias were employed to test the consistency and difference between the depth camera and manual procedures. Results: When measuring phalangeal length, repeatability, within-laboratory precision, and reproducibility were 2.63%, 12.87%, and 27.15%, respectively. When measuring angles of hand motion, the mean repeatability and within-laboratory precision were 1.2° and 3.3° for extension of 5 digits, 2.7° and 10.2° for flexion of 4 fingers, and 3.1° and 5.3° for abduction of 4 metacarpophalangeal joints, respectively. For system reliability, the results showed excellent consistency (intraclass correlation coefficient = 0.823; P < .05) and good linearity with the manual procedures (r = 0.909-0.982, approximately; P < .001). Besides, 78.3% of the measurements were clinically acceptable. Conclusions: Our depth camera-based evaluation system provides acceptable validity and reliability in measuring hand range of motion and offers potential benefits for clinical care and research in hand surgery. However, further studies are required before clinical application. Clinical relevance: This study suggests a depth camera-based contactless automatic measurement system holds promise for assessing hand range of motion in hand function evaluation, diagnosis, and rehabilitation for medical staff. However, it is currently not adequate for all clinical applications.

Precision and accuracy of measuring finger motion with a depth camera: a cross-sectional study of healthy participants.

The purpose of this cross-sectional study was to determine the precision and accuracy of the measurement of finger motion with a depth camera. Fifty-five healthy adult hands were included. Measurements were done with a depth camera and compared with traditional manual goniometer measurements. Repeated measuring showed that the overall repeatability and reproducibility of extension measured with the depth camera were within 3° and 4° and that of flexion were within 13° and 14°. Compared with traditional manual goniometry, biases of extension of all finger joints and flexion of metacarpophalangeal joints were less than 5°, and the average bias of flexion of proximal and distal interphalangeal joints was 29°. We conclude that the measurement of finger extension and flexion of the metacarpophalangeal joints with a depth camera was reliable, but improvement is required in the precision and accuracy of interphalangeal joint flexion.

The Impact of Cellular Therapies on Gastrointestinal Diseases: Applications and Challenges.

Gastrointestinal diseases are highly prevalent, and their burden significantly impacts the quality of life of affected individuals. Inflammatory and immune-mediated intestinal diseases usually have a chronic course without adequate therapeutic modalities. Although much has been reported to comprehend these diseases, many remain resistant and refractory to conventional treatment approaches. Therefore, recent approaches to cellular therapy using stem cells, like hematopoietic stem cells and mesenchymal stem cells, and other cellular immunosuppressive modalities, like T-regulatory cells, were introduced and investigated in treating gastrointestinal diseases. We aimed to conduct a literature review to discuss the applications and challenges of cellular therapeutics in gastrointestinal diseases. Evidence from published clinical trials supports the safety and efficacy of cellular treatment in different immune-mediated and inflammatory gastrointestinal diseases. They can offer a longer duration of remission, being able to adjust the dysregulated immune system. However, there are various challenges to be considered by future trials, including the limitations of current clinical trials, challenges in retrieval and application of these therapeutics, and their mutagenesis potential.

JAG1 is correlated to suppressive immune microenvironment and predicts immunotherapy resistance in lung adenocarcinoma.

Background: The current exploration of the tumor immune microenvironment is enthusiastic, but few studies explored the impact of angiogenesis on the immune microenvironment. Immunotherapy combined with anti-angiogenesis therapy has become one of the first-line treatment for lung adenocarcinoma. Our study aimed to explore the reasons for resistance of immunotherapy, and explore markers for immunotherapy combined with anti-angiogenesis therapy. Methods: First, by unsupervised clustering of 36 angiogenesis-related genes in lung adenocarcinoma patients from TCGA database, AGS1 and AGS2 groups were distinguished with significantly different clinical outcomes. Secondly, the immune microenvironment and metabolic characteristics were analyzed. Next, we used the GDSC and GEO database to analyze therapeutic responses. Then, through multivariate Cox regression, the hub gene: JAG1, significantly related to prognosis was selected, and further verified by multi-omics data. Finally, we validated that patient with high JAG1 expression had a low immune-infiltrating tumor microenvironment through single-cell transcriptomic data. Results: Compared with the AGS1 group, AGS2 showed an immune "cold" phenotype with lower lymphocyte infiltration, and was associated with worse prognoses. At the same time, the immunosuppressive TGF-ß response was significantly higher in AGS2. Furthermore, the glycolysis ability of the AGS2 was stronger than AGS1. The expression of JAG1 was significantly higher in the AGS2, and was significantly negatively correlated with the degree of immune infiltration, accompanying with higher glycolytic capacity. The above results indicate that patients with high expression of JAG1 may lead to immunosuppressive phenotype due to its strong glycolytic capacity, thus making immunotherapy resistance. Conclusion: Patients with high expression of JAG1 enhanced glycolytic capacity was likely to cause suppressed immune microenvironment. JAG1 may be a marker for resistance of immunotherapy. Combining anti-angiogenesis therapy could be considered to improve the prognosis of those patients.

Impact of NSCLC metabolic remodeling on immunotherapy effectiveness.

It is known that metabolic reprogramming (MR) contributes to tumorigenesis through the activation of processes that support survival of cells, proliferation, and grow in the tumor microenvironment. In order to keep the tumor proliferating at a high rate, metabolic pathways must be upregulated, and tumor metabolism must be adapted to meet this requirement. Additionally, immune cells engage in metabolic remodeling to maintain body and self-health. With the advent of immunotherapy, the fate of individuals suffering from non-small cell lung cancer (NSCLC) has been transformed dramatically. MR may have a profound influence on their prognosis. The aim of this review is to summarize current research advancements in metabolic reprogramming and their impact on immunotherapy in NSCLC. Moreover, we talk about promising approaches targeting and manipulating metabolic pathways to improve cancer immunotherapy's effectiveness in NSCLC.

A novel and efficient CD22 CAR-T therapy induced a robust antitumor effect in relapsed/refractory leukemia patients when combined with CD19 CAR-T treatment as a sequential therapy.

BACKGROUND: CD19 chimeric antigen receptor (CAR) therapy has achieved impressive success in relapsed or refractory (R/R) B-cell malignancies, but relapse due to antigen escape is increasingly appearing reported. As the expression profile of CD22 is similar to that of CD19, CD22 has become a candidate target when CD19 CAR-T therapy fails. METHODS: A novel CD22 CAR incorporating scFv derived from an HIB22 hybridoma which bound the first and second Ig-like extracellular domains of CD22 antigen was constructed. Preclinical investigation of the CD22 CAR-T therapy against B-cell malignancies was evaluated by coculturing CD22 CAR-T cells with tumor cell lines or primary blasts from patients in vitro and using a xenograft mouse model in vivo. Further clinical study of CD22/CD19 CAR-T sequential therapy was conducted in 4 R/R adult B-cell acute lymphoblastic leukemia (B-ALL) patients. RESULTS: The novel CD22 CAR-T treatment had specific cytotoxicity to CD22 + target cells, and the survival time of mice in the CD22 CAR-T treatment group was significantly prolonged. Furthermore, it's validated that sequential CD22/CD19 CAR-T therapy was significantly superior than single CD19 or CD22 CAR-T treatment in a relapse xenograft model. All 4 patients achieved complete remission (CR) with negative minimal residual disease (MRD), including 3 patients who had received prior CD19-related immunotherapy. The proliferation of CD19 and CD22 CAR-T cells was observed respectively in vivo, and 3 of the 4 patients experienced cytokine release syndrome (CRS); 2 of these patients had grade 1 CRS and 1 had grade 3 CRS. Long term follow-up showed that 3 of the 4 (75%) patients had sustained CR for up to 1 year. Analysis of antigen expression in the relapsed patients demonstrated that loss or diminution of CD19 and CD22 expression might cause antigen escape from CAR-T surveillance. CONCLUSIONS: In summary, the novel CD22 CAR-T therapy was validated with antitumor effects both in vitro and in vivo. Furthermore, our study demonstrated the safety and robust efficacy of sequential CD22/CD19 CAR-T therapy in xenograft models and clinical trials, especially as the salvage treatment for R/R B-ALL patients with antigen loss or in whom anti-CD19 related immunotherapy failure failed. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR): ChiCTR1900025419, Supplementarily registered 26 August, 2019.