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Neuromodulation techniques have emerged as promising approaches for treating a wide range of neurological disorders, precisely delivering electrical stimulation to modulate abnormal neuronal activity. While leveraging the unique capabilities of AI holds immense potential for responsive neurostimulation, it appears as an extremely challenging proposition where real-time (low-latency) processing, low-power consumption, and heat constraints are limiting factors. The use of sophisticated AI-driven models for personalized neurostimulation depends on the back-telemetry of data to external systems (e.g. cloud-based medical mesosystems and ecosystems). While this can be a solution, integrating continuous learning within implantable neuromodulation devices for several applications, such as seizure prediction in epilepsy, is an open question. We believe neuromorphic architectures hold an outstanding potential to open new avenues for sophisticated on-chip analysis of neural signals and AI-driven personalized treatments. With more than three orders of magnitude reduction in the total data required for data processing and feature extraction, the high power- and memory-efficiency of neuromorphic computing to hardware-firmware co-design can be considered as the solution-in-the-making to resource-constraint implantable neuromodulation systems. This perspective introduces the concept of Neuromorphic Neuromodulation , a new breed of closed-loop responsive feedback system. It highlights its potential to revolutionize implantable brain-machine microsystems for patient-specific treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

Abstract: Chimeric antigen receptor (CAR) T-cell therapies have demonstrated transformative efficacy in treating B-cell malignancies. However, high costs and manufacturing complexities hinder their widespread use. To overcome these hurdles, we have developed the VivoVec platform, a lentiviral vector capable of generating CAR T cells in vivo. Here, we describe the incorporation of T-cell activation and costimulatory signals onto the surface of VivoVec particles (VVPs) in the form of a multidomain fusion protein and show enhanced in vivo transduction and improved CAR T-cell antitumor functionality. Furthermore, in the absence of lymphodepleting chemotherapy, administration of VVPs into nonhuman primates resulted in the robust generation of anti-CD20 CAR T cells and the complete depletion of B cells for >10 weeks. These data validate the VivoVec platform in a translationally relevant model and support its transition into human clinical testing, offering a paradigm shift in the field of CAR T-cell therapies., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction: Structural and functional abnormalities in the cortical-striatal network (CSN) are hypothesised to play a key role in the pathogenesis of neurological disease-associated fatigue. Some small-scale functional MRI (fMRI) studies have suggested that poststroke fatigue (PSF) is related to focal functional connectivity (FC) changes. To date, there has been no published large-scale fMRI study on PSF. This planned study will examine the role of the CSN FC on PSF., Methods and Analysis: The planned study will be a prospective cohort study conducted at the Neurology Unit of the Prince of Wales Hospital. We will recruit 738 participants. The project duration will be 36 months. A psychiatrist will administer the Fatigue Severity Scale (FSS) at 3 months (P1) following the index stroke. PSF is defined as an FSS Score≥4.0. PSF severity will be defined by the FSS total score at P1. Participants with PSF at P1 will undergo two follow-up assessments at 9 (P2) and 15 (P3) months post stroke. PSF remission at P2 or P3 will be defined as a 50% reduction in FSS. Participants will undergo MRI examinations within 2 weeks of the 3-month poststroke assessment. Structural MRI, resting-state fMRI and diffusion tensor imaging will be performed. FC, structural connectivity, infarcts, cerebral microbleeds and white matter hyperintensities will be analysed. For the primary analysis, the effect of PSF on the FC, structural connectivity and diffusion metrics of CSN of stroke survivors, voxel-wise two-sample t-tests will be performed with FDR correction for multiple comparison and significance level set at p<0.05., Ethics and Dissemination: Ethical approval was obtained from the Joint Chinese University of Hong Kong-New Territories East Cluster clinical research ethics committee. The study findings will be shared through peer-reviewed journal publications, national and international conferences and social media platforms., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study introduces two models, ConvLSTM2D-liquid time-constant network (CLTC) and ConvLSTM2D-closed-form continuous-time neural network (CCfC), designed for abnormality identification using electrocardiogram (ECG) data. Trained on the Telehealth Network of Minas Gerais (TNMG) subset dataset, both models were evaluated for their performance, generalizability capacity, and resilience. They demonstrated comparable results in terms of F1 scores and AUROC values. The CCfC model achieved slightly higher accuracy, while the CLTC model showed better handling of empty channels. Remarkably, the models were successfully deployed on a resource-constrained microcontroller, proving their suitability for edge device applications. Generalization capabilities were confirmed through the evaluation on the China Physiological Signal Challenge 2018 (CPSC) dataset. The models' efficient resource utilization, occupying 70.6% of memory and 9.4% of flash memory, makes them promising candidates for real-world healthcare applications. Overall, this research advances abnormality identification in ECG data, contributing to the progress of AI in healthcare., (© 2024. The Author(s).)

Background: Vaccine-related acute myocarditis is recognized as a rare and specific vaccine complication following mRNA-based COVID-19 vaccinations. The precise mechanisms remain unclear. We hypothesized that natural killer (NK) cells play a central role in its pathogenesis., Methods: Samples from 60 adolescents with vaccine-related myocarditis were analyzed, including pro-inflammatory cytokines, cardiac troponin T, genotyping, and immunophenotyping of the corresponding activation subsets of NK cells, monocytes, and T cells. Results were compared with samples from 10 vaccinated individuals without myocarditis and 10 healthy controls., Findings: Phenotypically, high levels of serum cytokines pivotal for NK cells, including interleukin-1β (IL-1β), interferon α2 (IFN-α2), IL-12, and IFN-γ, were observed in post-vaccination patients with myocarditis, who also had high percentage of CD57 + NK cells in blood, which in turn correlated positively with elevated levels of cardiac troponin T. Abundance of the CD57 + NK subset was particularly prominent in males and in those after the second dose of vaccination. Genotypically, killer cell immunoglobulin-like receptor (KIR) KIR2DL5B(-)/KIR2DS3(+)/KIR2DS5(-)/KIR2DS4del(+) was a risk haplotype, in addition to single-nucleotide polymorphisms related to the NK cell-specific expression quantitative trait loci DNAM-1 and FuT11, which also correlated with cardiac troponin T levels in post-vaccination patients with myocarditis., Conclusion: Collectively, these data suggest that NK cell activation by mRNA COVID-19 vaccine contributed to the pathogenesis of acute myocarditis in genetically and epidemiologically vulnerable subjects., Funding: This work was funded by the Hong Kong Collaborative Research Fund (CRF) 2020/21 and the CRF Coronavirus and Novel Infectious Diseases Research Exercises (reference no. C7149-20G)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Chimeric antigen receptor (CAR) designs that incorporate pharmacologic control are desirable; however, designs suitable for clinical translation are needed. We designed a fully human, rapamycin-regulated drug product for targeting CD33+ tumors called dimerizaing agent-regulated immunoreceptor complex (DARIC33). T cell products demonstrated target-specific and rapamycin-dependent cytokine release, transcriptional responses, cytotoxicity, and in vivo antileukemic activity in the presence of as little as 1 nM rapamycin. Rapamycin withdrawal paused DARIC33-stimulated T cell effector functions, which were restored following reexposure to rapamycin, demonstrating reversible effector function control. While rapamycin-regulated DARIC33 T cells were highly sensitive to target antigen, CD34+ stem cell colony-forming capacity was not impacted. We benchmarked DARIC33 potency relative to CD19 CAR T cells to estimate a T cell dose for clinical testing. In addition, we integrated in vitro and preclinical in vivo drug concentration thresholds for off-on state transitions, as well as murine and human rapamycin pharmacokinetics, to estimate a clinically applicable rapamycin dosing schedule. A phase I DARIC33 trial has been initiated (PLAT-08, NCT05105152), with initial evidence of rapamycin-regulated T cell activation and antitumor impact. Our findings provide evidence that the DARIC platform exhibits sensitive regulation and potency needed for clinical application to other important immunotherapy targets.

γδ-T cells are innate-like T cells with dual antitumor activities. They can directly eradicate tumor cells and function as immunostimulatory cells to promote antitumor immunity. Previous studies have demonstrated that small extracellular vesicles (EVs) derived from γδ-T cells (γδ-T-EVs) inherited the dual antitumor activities from their parental cells. However, it remains unknown whether γδ-T-EVs can be designed as tumors vaccine to improve therapeutic efficacy. Here, we found that γδ-T-EVs had immune adjuvant effects on antigen-presenting cells, as revealed by enhanced expression of antigen-presenting and co-stimulatory molecules, secretion of pro-inflammatory cytokines and antigen-presenting ability of DCs after γδ-T-EVs treatment. The γδ-T-EVs-based vaccine was designed by loading tumor-associated antigens (TAAs) into γδ-T-EVs. Compared with γδ-T-EVs, the γδ-T-EVs-based vaccine effectively promoted more tumor-specific T-cell responses. In addition, the vaccine regimen preserved direct antitumor effects and induced tumor cell apoptosis. Interestingly, the allogeneic γδ-T-EVs-based vaccine showed comparable preventive and therapeutic antitumor effects to their autologous counterparts, indicating a better way of centralization and standardization in clinical practice. Furthermore, the allogeneic γδ-T-EVs-based vaccine displayed advantages over the DC-EVs-based vaccine through their dual antitumor activities. This study provides a proof-of-concept for using the allogeneic γδ-T-EVs-based vaccine in cancer control., (© 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

The outer circulation of tropical cyclones (TCs) on the western North Pacific has been reported to substantially influence the atmospheric environment over the Guangdong-Hong Kong-Macau Greater Bay Area (GBA) of China, whereas dynamic evolution and redistribution of water vapor and aerosol in the atmospheric boundary layer (ABL) responding to moving TCs have yet to be understood. This study aims to answer three key research questions related to the influences of the approaching TCs: (1) how do water vapor and aerosol particles over the GBA change during the TC approaching stage? (2) how does the ABL in terms of vertical wind structure respond to the approaching TCs? and (3) how does turbulence influence the vertical profile of aerosol during the approaching stage? Based on an intensive analysis of three-year reanalysis and Doppler LiDAR data, this study identified a dry-polluted time over the GBA when a TC was located at ~1000 km away on South China Sea. Before that, horizontal wind has consistently come from the northeast, creating a favorable condition for weak transboundary air pollution to the GBA. During the dry-polluted time, the highest surface PM 2.5 concentration was resulted from the enhanced downdraft and early-stage wind shear, i.e., stronger wind started occurring at upper-level ABL, while the further turbulent mixing induced by wind shear enhancement and updrafts recovery pumped surface pollution upward to the upper level when TCs became closer. Our findings are expected to improve both weather and PM 2.5 forecasts under the impacts of approaching TCs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Steve H.L. Yim reports financial support was provided by Dr. Stanley Ho Medical Development Foundation. Steve H.L. Yim reports financial support was provided by Government of Singapore Ministry of Education. Steve H.L. Yim reports financial support was provided by Earth Observatory of Singapore at NTU., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Optimal perioperative fluid management is crucial, with over- or under-replacement associated with complications. There are many strategies for fluid therapy, including liberal fluid therapy (LFT), restrictive fluid therapy (RFT) and goal-directed fluid therapy (GDT), without a clear consensus as to which is better. We aimed to find out which is the more effective fluid therapy option in adult surgical patients undergoing non-vascular abdominal surgery in the perioperative period. This study is a systematic review and network meta-analysis (NMA) with node-splitting analysis of inconsistency, sensitivity analysis and meta-regression. We conducted a literature search of Pubmed, Cochrane Library, EMBASE, Google Scholar and Web of Science. Only studies comparing restrictive, liberal and goal-directed fluid therapy during the perioperative phase in major non-cardiac surgery in adult patients will be included. Trials on paediatric patients, obstetric patients and cardiac surgery were excluded. Trials that focused on goal-directed therapy monitoring with pulmonary artery catheters and venous oxygen saturation (SvO2), as well as those examining purely biochemical and laboratory end points, were excluded. A total of 102 randomised controlled trials (RCTs) and 78 studies (12,100 patients) were included. NMA concluded that goal-directed fluid therapy utilising FloTrac was the most effective intervention in reducing the length of stay (LOS) (surface under cumulative ranking curve (SUCRA) = 91%, odds ratio (OR) = -2.4, 95% credible intervals (CrI) = -3.9 to -0.85) and wound complications (SUCRA = 86%, OR = 0.41, 95% CrI = 0.24 to 0.69). Goal-directed fluid therapy utilising pulse pressure variation was the most effective in reducing the complication rate (SUCRA = 80%, OR = 0.25, 95% CrI = 0.047 to 1.2), renal complications (SUCRA = 93%, OR = 0.23, 95% CrI = 0.045 to 1.0), respiratory complications (SUCRA = 74%, OR = 0.42, 95% CrI = 0.053 to 3.6) and cardiac complications (SUCRA = 97%, OR = 0.067, 95% CrI = 0.0058 to 0.57). Liberal fluid therapy was the most effective in reducing the mortality rate (SUCRA = 81%, OR = 0.40, 95% CrI = 0.12 to 1.5). Goal-directed therapy utilising oesophageal Doppler was the most effective in reducing anastomotic leak (SUCRA = 79%, OR = 0.45, 95% CrI = 0.12 to 1.5). There was no publication bias, but moderate to substantial heterogeneity was found in all networks. In preventing different complications, except mortality, goal-directed fluid therapy was consistently more highly ranked and effective than standard (SFT), liberal or restricted fluid therapy. The evidence grade was low quality to very low quality for all the results, except those for wound complications and anastomotic leak., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Yang et al.)

Introduction: Two doses of inactivated SARS-CoV-2 vaccine CoronaVac cannot elicit high efficacy against symptomatic COVID-19, especially against the Omicron variant, but that can be improved by a third dose in adults. The use of a third dose of CoronaVac in adolescents may be supported by immunobridging studies in the absence of efficacy data., Methods: With an immunobridging design, our study (NCT04800133) tested the non-inferiority of the binding and neutralizing antibodies and T cell responses induced by a third dose of CoronaVac in healthy adolescents (N=94, median age 14.2 years, 56% male) compared to adults (N=153, median age 48.1 years, 44% male). Responses against wild-type (WT) and BA.1 SARS-CoV-2 were compared in adolescents. Safety and reactogenicity were also monitored., Results: A homologous third dose of CoronaVac further enhanced antibody response in adolescents compared to just 2 doses. Adolescents mounted non-inferior antibody and T cell responses compared to adults. Although S IgG and neutralizing antibody responses to BA.1 were lower than to WT, they remained detectable in 96% and 86% of adolescents. T cell responses to peptide pools spanning only the mutations of BA.1 S, N and M in adolescents were preserved, increased, and halved compared to WT respectively. No safety concerns were identified., Discussion: The primary vaccination series of inactivated SARS-CoV-2 vaccines for adolescents should include 3 doses for improved humoral immunogenicity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Leung, Cohen, Mu, Rosa Duque, Cheng, Wang, Wang, Zhang, Zhang, Tam, Lam, Chan, Chaothai, Kwan, Chan, Li, Luk, Tsang, Chu, Wong, Mori, Leung, Valkenburg, Peiris, Tu and Lau.)

Mononuclear rare-earth metal alkyl complexes supported by tetradentate dianionic bis(amino-oxazoline) ligands have been synthesized, and their reactivity toward small molecules and catalytic performance on ring-opening polymerization have been studied. Treatment of Ln(CH 2 SiMe 3 ) 3 (THF) 2 (Ln = Sc, Y; THF = tetrahydrofuran) with the bis(amino-oxazoline) proligand H 2 L afforded the corresponding rare-earth metal monoalkyl complexes L-Ln(CH 2 SiMe 3 )(THF) x (Ln = Sc, x = 0 ( 1 ); Ln = Y, x = 1 ( 2 )). The isopropyl-substituted Sc alkyl complex L'-Sc(CH 2 SiMe 3 ) ( 3 ) and the analogue Y silylamide complex L-Y[N(SiHMe 2 ) 2 ] ( 4 ) have been prepared by a similar method. Complexes 1 and 2 were stable in solution at room temperature but transformed gradually at elevated temperature to give a nucleophilic addition product for Sc ( 5 ) and an oxazoline ring-opened dimeric complex for Y ( 6 ). Reactions of 1 with elemental sulfur and selenium each led to insertion of one chalcogen into the Sc-C bond, and the corresponding six-coordinate mononuclear chalcogenolate complexes L-Sc(ECH 2 SiMe 3 )(THF) (E = S ( 7 ), Se ( 8 )) were isolated. Treatment of 1 with an equimolar amount of aniline yielded the Sc anilide complex L-Sc(NHC 6 H 5 ) ( 9 ), whereas the reaction of 1 with [NHEt 3 ][BPh 4 ] afforded the Sc ion-pair [L-Sc][BPh 4 ] ( 10 ), which upon recrystallization led to formation of a THF-solvated product [L-Sc(THF)][BPh 4 ] ( 11 ). Single-crystal X-ray diffraction analyses of complexes 1 - 3 , 7 - 9 , and 11 revealed the flexible coordination capability of the tetradentate bis(amino-oxazoline) ligand of upholding a mononuclear metal center via a torsion of the diaminobiphenyl axis. Complexes 1 - 4 were active catalysts for initiating the ring-opening polymerization of rac -lactide with good activity (TOF up to 3204 h -1 ) and heteroselectivity ( P r = 0.65-0.71). This study highlights the applicability of the well-defined tetradentate bis(amino-oxazoline) ligands for mononuclear rare-earth metal complexation and shed light on the new potential of rare-earth metal catalysts bearing this type of easily derivatizable polydentate ligand.

Despite the expanding portfolio of targeted therapies for adults with acute myeloid leukemia (AML), direct implementation in children is challenging due to inherent differences in underlying genetics. Here we established the pharmacologic profile of pediatric AML by screening myeloblast sensitivity to approved and investigational agents, revealing candidates of immediate clinical relevance. Drug responses ex vivo correlated with patient characteristics, exhibited age-specific alterations, and concorded with activities in xenograft models. Integration with genomic data uncovered new gene-drug associations, suggesting actionable therapeutic vulnerabilities. Transcriptome profiling further identified gene-expression signatures associated with on- and off-target drug responses. We also demonstrated the feasibility of drug screening-guided treatment for children with high-risk AML, with two evaluable cases achieving remission. Collectively, this study offers a high-dimensional gene-drug clinical data set that could be leveraged to research the unique biology of pediatric AML and sets the stage for realizing functional precision medicine for the clinical management of the disease., Significance: We conducted integrated drug and genomic profiling of patient biopsies to build the functional genomic landscape of pediatric AML. Age-specific differences in drug response and new gene-drug interactions were identified. The feasibility of functional precision medicine-guided management of children with high-risk AML was successfully demonstrated in two evaluable clinical cases. This article is highlighted in the In This Issue feature, p. 476., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Age-specific incidence of acute myocarditis/pericarditis in adolescents following Comirnaty vaccination in Asia is lacking. This study aimed to study the clinical characteristics and incidence of acute myocarditis/pericarditis among Hong Kong adolescents following Comirnaty vaccination., Methods: This is a population cohort study in Hong Kong that monitored adverse events following immunization through a pharmacovigilance system for coronavirus disease 2019 (COVID-19) vaccines. All adolescents aged between 12 and 17 years following Comirnaty vaccination were monitored under the COVID-19 vaccine adverse event response and evaluation program. The clinical characteristics and overall incidence of acute myocarditis/pericarditis in adolescents following Comirnaty vaccination were analyzed., Results: Between 14 June 2021 and 4 September 2021, 33 Chinese adolescents who developed acute myocarditis/pericarditis following Comirnaty vaccination were identified. In total, 29 (87.88%) were male and 4 (12.12%) were female, with a median age of 15.25 years. And 27 (81.82%) and 6 (18.18%) cases developed acute myocarditis/pericarditis after receiving the second and first dose, respectively. All cases are mild and required only conservative management. The overall incidence of acute myocarditis/pericarditis was 18.52 (95% confidence interval [CI], 11.67-29.01) per 100 000 persons vaccinated. The incidence after the first and second doses were 3.37 (95% CI, 1.12-9.51) and 21.22 (95% CI, 13.78-32.28 per 100 000 persons vaccinated, respectively. Among male adolescents, the incidence after the first and second doses were 5.57 (95% CI, 2.38-12.53) and 37.32 (95% CI, 26.98-51.25) per 100 000 persons vaccinated., Conclusions: There is a significant increase in the risk of acute myocarditis/pericarditis following Comirnaty vaccination among Chinese male adolescents, especially after the second dose., Competing Interests: Potential conflict of interest. C. C. has received grants outside of the submitted work from the Food and Health Bureau of the Hong Kong Government, Hong Kong Research Grants Council, Hong Kong Innovation and Technology Commission, Pfizer, IQVIA, and Amgen; and a personal fee from Primevigilance Ltd. A. S. Y. L. received grants outside of the submitted work from the Health and Medical Research Fund, Food and Health Bureau of the Hong Kong Government Special Administrative Region. M. Y. N. has received funding/education grants from the Food and Health Bureau of the Hong Kong Government, Radiological Society of North America, GE, Lode, Arterys, Bayer, Circle Cardiovascular Imaging and TeraRecon; honoraria for education activities from Boehringer Ingelheim; reports the following leadership roles: Vice Chair of the Education Committee for Society of Cardiovascular Magnetic Resonance and Member of the Corporate Relations Committee for Society of Cardiovascular Computed Tomography. G. C. F. C. is the CMO of Xellera and advisor of Pangenia. Y. L. L. received Government funding for COVID-19 Vaccinations in Adolescents (COVA) and is the Chairman of the Scientific Committee on Vaccine Preventable Diseases, Centre for Health Protection, HKSAR. I. W. has received research funding outside of the submitted work from Amgen, Bristol-Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, Hong Kong Research Grants Council, Hong Kong Health and Medical Research Fund, National Institute for Health Research in England, European Commission, and National Health and Medical Research Council in Australia (Research grants on pharmacoepidemiology to The University of Hong Kong outside of the submitted work); consultancy fee for advising IQVIA on pharmacoepidemiology studies outside of the submitted work; payment for expert testimony from Appeal Court in Hong Kong (expert report on effects of cannabis outside of the submitted work); and speaker fees from Janssen and Medicine in the previous 3 years; reports the following leadership roles: Member of Pharmacy and Poisons Board (this is the regulatory agency in pharmaceutical product licensing), Member of the Expert Committee on Clinical Events Assessment Following COVID-19 Immunization (advise the Hong Kong Government on safety of COVID-19 vaccines), and Member of the Advisory Panel on COVID-19 Vaccines of the Hong Kong Government (advise the Hong Kong Government on the emergency use of COVID-19 vaccines). He is also an independent nonexecutive director of Jacobson Medical in Hong Kong (salaried). P. I. has received grants outside of the submitted work from the Food and Health Bureau of the Hong Kong Government, Hong Kong Research Grants Council, and Hong Kong Jockey Club Charities Trust. M. T. Y. L. reports receiving Honorarium for a talk on ADHD. W. K. C. N. reports personal honoraria for Guerbet online lecture on pediatric cardiac imaging; holds 100 shares in Moderna stock, 50 shares in Biotech stock since April, owned 100 shares in Pfizer stock from July 2020 to January 2021. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Patients with type 2 diabetes mellitus (T2DM) have an increased risk of cancer. The effect of glucose metabolism on γδ T cells and their impact on tumor surveillance remain unknown. Here, we showed that high glucose induced Warburg effect type of bioenergetic profile in Vγ9Vδ2 T cells, leading to excessive lactate accumulation, which further inhibited lytic granule secretion by impairing the trafficking of cytolytic machinery to the Vγ9Vδ2 T-cell-tumor synapse by suppressing AMPK activation and resulted in the loss of antitumor activity in vitro, in vivo and in patients. Strikingly, activating the AMPK pathway through glucose control or metformin treatment reversed the metabolic abnormalities and restored the antitumor activity of Vγ9Vδ2 T cells. These results suggest that the impaired antitumor activity of Vγ9Vδ2 T cells induced by dysregulated glucose metabolism may contribute to the increased cancer risk in T2DM patients and that metabolic reprogramming by targeting the AMPK pathway with metformin may improve tumor immunosurveillance., (© 2022. The Author(s), under exclusive licence to CSI and USTC.)

We present an interim analysis of a registered clinical study (NCT04800133) to establish immunobridging with various antibody and cellular immunity markers and to compare the immunogenicity and reactogenicity of 2-dose BNT162b2 and CoronaVac in healthy adolescents as primary objectives. One-dose BNT162b2, recommended in some localities for risk reduction of myocarditis, is also assessed. Antibodies and T cell immune responses are non-inferior or similar in adolescents receiving 2 doses of BNT162b2 (BB, N = 116) and CoronaVac (CC, N = 123) versus adults after 2 doses of the same vaccine (BB, N = 147; CC, N = 141) but not in adolescents after 1-dose BNT162b2 (B, N = 116). CC induces SARS-CoV-2 N and N C-terminal domain seropositivity in a higher proportion of adolescents than adults. Adverse reactions are mostly mild for both vaccines and more frequent for BNT162b2. We find higher S, neutralising, avidity and Fc receptor-binding antibody responses in adolescents receiving BB than CC, and a similar induction of strong S-specific T cells by the 2 vaccines, in addition to N- and M-specific T cells induced by CoronaVac but not BNT162b2, possibly implying differential durability and cross-variant protection by BNT162b2 and CoronaVac, the 2 most used SARS-CoV-2 vaccines worldwide. Our results support the use of both vaccines in adolescents., (© 2022. The Author(s).)

Research in cancer diagnostics has recently established its footing and significance in the biosensor sphere, emphasizing the idea of a unique probe design used as a sensor and actuator, to identify the presence of protein, DNA, RNA, or miRNA. The fluorescein isothiocyanate (FITC) probe and biotinylated probe are designed for a two-pronged approach to the detection of the urinary miR-21 and miR-141, both of which have demonstrated significance in the development and progression of colorectal cancer, a leading cause of mortality and morbidity. The remainder of the apparatus is composed of a modified screen-printed carbon electrode (SPCE), to which the probes adhere, that transduces signals via the redox reaction between H2O2 and HRP, measured with chronoamperometry and cyclic voltammetry. The precise nature of our ultra-non-invasive biosensor makes for a highly sensitive and practical cancer detector, concluded by the significance when establishing disease presence (miR-21 p-value = 0.0176, miR-141 p-value = 0.0032), disease follow-up (miR-21 p-value = 0.00154, miR141 p-value < 0.0005), and even disease severity. This article hopes to emphasize the potential of an additional clinical tool for the management of colorectal cancer.

Background: Many syndromes are associated with exaggerated inflammation. Children with hyperinflammatory syndromes often present with vague and non-specific symptoms that pose diagnostic and management challenges. The recent literature seems biased towards referring these syndromes only to the multisystem inflammatory syndrome in children (MIS-C) that is associated with COVID-19. The purpose of this paper is to provide an updated narrative review on the pathophysiology, manifestations and management approaches for common hyperinflammatory syndromes., Methods: An extensive PubMed search of all publications in the English literature was performed with Clinical Queries for various hyperinflammatory syndromes and conditions using the undermentioned Medical Subject Headings: "hyperinflammation", "hyperinflammatory syndromes", "sepsis syndrome", "severe inflammatory response syndrome" and "acute respiratory distress syndrome". Categories were limited to reviews and clinical trials for the age range from birth to 18 years., Results: The criteria, presentation and management of these hyperinflammatory syndromes are described. Hyperinflammatory syndromes refer to a basket of inflammatory syndromes often associated with multisystem involvement and aberrant cytokine release and should be differentiated from autoinflammatory, autoimmune and hyperimmune syndromes. The major subtypes of hyperinflammatory syndromes, including macrophage activation syndrome, haemophagocytic lymphohistiocytosis, cytokine release syndrome and cytokine storm syndrome, are described. MIS-C associated with SARS-CoV-2 represents the latest addition. It must be understood that the syndrome is not exclusive to COVID-19 but could be caused by various viral infections. Early recognition, prompt and proactive treatment can reduce potential complications and improve outcomes and survival rates in paediatric patients. Anti-inflammatory medications for the management of these syndromes are described., Conclusion: The incidence of these hyperinflammatory conditions is generally low in comparison to other disease conditions. Except for paediatric inflammatory multisystem syndrome/MIS-C, the mortality is high and the hospital stay is prolonged in affected patients. Acute and critical care physicians must be aware of these conditions and their initial management. Corticosteroids are often used in the initial phrase but various disease-specific drugs and biologics are needed in subsequent management and expert management of these often-difficult conditions is crucial., Competing Interests: Disclosure and potential conflicts of interest: KLH and AKCL are associate editors of Drugs in Context and confirm that this article has no other conflicts of interest otherwise. This manuscript was sent out for independent peer review. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2022/05/dic.2022-2-1-COI.pdf, (Copyright © 2022 Hon KL, Leung AKC, Leung WH, Leung KKY, Cheong KN, Lee PPW.)

Competing Interests: Disclosure: The authors declare no conflict of interest.

Approximately 25% of colorectal cancer (CRC) patients will develop metastatic (m)CRC despite treatment interventions. In this setting, tumor cells are attracted to the epidermal growth factor receptor ( EGFR ) oncogene. Kirsten rat sarcoma (RAS) 2 viral oncogene homolog ( KRAS ) mutations were reported to drive CRC by promoting cancer progression in activating Wnt/β-catenin and RAS/extracellular signal-regulated kinase (ERK) pathways. In addition, KRAS is associated with almost 40% of patients who acquire resistance to EGFR inhibitors in mCRC. Multiple studies have demonstrated that cancer stem cells (CSCs) promote tumorigenesis, tumor growth, and resistance to therapy. One of the most common CSC prognostic markers widely reported in CRC is a cluster of differentiation 44 (CD44), which regulates matrix metalloproteinases 7/9 (MMP7/9) to promote tumor progression and metastasis; however, the molecular role of CD44 in CRC is still unclear. In invasive CRC, overexpression of MMP7 was reported in tumor cells compared to normal cells and plays a crucial function in CRC cetuximab and oxaliplatin resistance and distant metastasis. Here, we utilized a bioinformatics analysis and identified overexpression of KRAS/MMP7/CD44 oncogenic signatures in CRC tumor tissues compared to normal tissues. In addition, a high incidence of mutations in KRAS and CD44 were associated with some of the top tumorigenic oncogene's overexpression, which ultimately promoted a poor response to chemotherapy and resistance to some FDA-approved drugs. Based on these findings, we explored a computational approach to drug repurposing of the drug, sulfasalazine, and our in silico molecular docking revealed unique interactions of sulfasalazine with the KRAS/MMP7/CD44 oncogenes, resulting in high binding affinities compared to those of standard inhibitors. Our in vitro analysis demonstrated that sulfasalazine combined with cisplatin reduced cell viability, colony, and sphere formation in CRC cell lines. In addition, sulfasalazine alone and combined with cisplatin suppressed the expression of KRAS/MMP7/CD44 in DLD-1 and HCT116 cell lines. Thus, sulfasalazine is worthy of further investigation as an adjuvant agent for improving chemotherapeutic responses in CRC patients.

Background: Radiotherapy is the first-line treatment for patients nasopharyngeal carcinoma (NPC), but its therapeutic efficacy is poor in some patients due to radioresistance. Adoptive T cell-based immunotherapy has also shown promise to control NPC; however, its antitumor efficacy may be attenuated by an immunosuppressive tumor microenvironment. Exosomes derived from γδ-T cells (γδ-T-Exos) have potent antitumor potentials. However, it remains unknown whether γδ-T-Exos have synergistic effect with radiotherapy and preserve their antitumor activities against NPC in an immunosuppressive tumor microenvironment., Methods: γδ-T-Exos were stained with fluorescent membrane dye, and their interactions with NPC were determined both in vitro and in vivo. NPC cell deaths were detected after treatment with γδ-T-Exos and/or irradiation. Moreover, effects of γδ-T-Exos on radioresistant cancer stem-like cells (CSCs) were determined. The therapeutic efficacy of combination therapy using γδ-T-Exos and irradiation on NPC tumor progression was also monitored in vivo. Finally, the tumor-killing and T cell-promoting activities of γδ-T-Exos were determined under the culture in immunosuppressive NPC supernatant., Results: γδ-T-Exos effectively interacted with NPC tumor cells in vitro and in vivo. γδ-T-Exos not only killed NPC cells in vitro, which was mainly mediated by Fas/Fas ligand (FasL) and death receptor 5 (DR5)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathways, but also controlled NPC tumor growth and prolonged tumor-bearing mice survival in vivo. Furthermore, γδ-T-Exos selectively targeted the radioresistant CD44 +/high CSCs and induced profound cell apoptosis. The combination of γδ-T-Exos with radiotherapy overcame the radioresistance of CD44 +/high NPC cells and significantly improved its therapeutic efficacy against NPC in vitro and in vivo. In addition, γδ-T-Exos promoted T-cell migration into NPC tumors by upregulating CCR5 on T cells that were chemoattracted by CCR5 ligands in the NPC tumor microenvironment. Although NPC tumor cells secreted abundant tumor growth factor beta to suppress T-cell responses, γδ-T-Exos preserved their direct antitumor activities and overcame the immunosuppressive NPC microenvironment to amplify T-cell antitumor immunity., Conclusions: γδ-T-Exos synergized with radiotherapy to control NPC by overcoming the radioresistance of NPC CSCs. Moreover, γδ-T-Exos preserved their tumor-killing and T cell-promoting activities in the immunosuppressive NPC microenvironment. This study provides a proof of concept for a novel and potent strategy by combining γδ-T-Exos with radiotherapy in the control of NPC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: We evaluated whether combining a humanized antidisialoganglioside monoclonal antibody (hu14.18K322A) throughout therapy improves early response and outcomes in children with newly diagnosed high-risk neuroblastoma., Patients and Methods: We conducted a prospective, single-arm, three-stage, phase II clinical trial. Six cycles of induction chemotherapy were coadministered with hu14.18K322A, granulocyte-macrophage colony-stimulating factor (GM-CSF), and low-dose interleukin-2 (IL-2). The consolidation regimen included busulfan and melphalan. When available, an additional cycle of parent-derived natural killer cells with hu14.18K322A was administered during consolidation (n = 31). Radiation therapy was administered at the end of consolidation. Postconsolidation treatment included hu14.18K322A, GM-CSF, IL-2, and isotretinoin. Early response was assessed after the first two cycles of induction therapy. End-of-induction response, event-free survival (EFS), and overall survival (OS) were evaluated., Results: Sixty-four patients received hu14.18K322A with induction chemotherapy. This regimen was well tolerated, with continuous infusion narcotics. Partial responses (PRs) or better after the first two chemoimmunotherapy cycles occurred in 42 of 63 evaluable patients (66.7%; 95% CI, 55.0 to 78.3). Primary tumor volume decreased by a median of 75% (range, 100% [complete disappearance]-5% growth). Median peak hu14.18K322A serum levels in cycle one correlated with early response to therapy ( P = .0154, one-sided t -test). Sixty of 62 patients (97%) had an end-of-induction partial response or better. No patients experienced progressive disease during induction. The 3-year EFS was 73.7% (95% CI, 60.0 to 83.4), and the OS was 86.0% (95% CI, 73.8 to 92.8), respectively., Conclusion: Adding hu14.18K322A to induction chemotherapy improved early objective responses, significantly reduced tumor volumes in most patients, improved end-of-induction response rates, and yielded an encouraging 3-year EFS. These results, if validated in a larger study, may be practice changing., Competing Interests: Barry L. ShulkinConsulting or Advisory Role: Navidea Matthew KrasinConsulting or Advisory Role: Debiopharm Group Michael W. BishopConsulting or Advisory Role: Fennec PharmaResearch Funding: Pfizer Fariba NavidResearch Funding: Bayer (Inst) Brandon TriplettTravel, Accommodations, Expenses: Miltenyi Biotec Stephen D. GilliesEmployment: LinkedUp BioscienceLeadership: LinkedUp BioscienceStock and Other Ownership Interests: Provenance BiopharmaceuticalsConsulting or Advisory Role: Delos Capital PartnersPatents, Royalties, Other Intellectual Property: Patent owner not related to this paper Alice YuLeadership: OPKO HealthStock and Other Ownership Interests: OPKO Health/GeneDxHonoraria: EUSA PharmaConsulting or Advisory Role: OBI PharmaSpeakers' Bureau: EUSA PharmaResearch Funding: United Therapeutics (Inst)Patents, Royalties, Other Intellectual Property: Globo H-Diphtheria toxoid vaccine for cancer therapy, NKT stimulatory phenyl-glycolipids for cancer therapy and vaccine adjuvant, Cancer targeting peptides, Methods for suppressing cancer by inhibition of TMCC3Travel, Accommodations, Expenses: EUSA Pharma Paul M. SondelResearch Funding: Invenra Inc (Inst)Patents, Royalties, Other Intellectual Property: I have partial interest in patents related to my work at the University of Wisconsin-Madison WI, which are held by and managed by the University of Wisconsin Foundation. I am an unpaid medical advisor to Invenra Inc, a monoclonal antibody biotech firm in Madison WI. My UW laboratory is collaborating with Invenra and receiving research reagents from them for mutual researchUncompensated Relationships: Invenra Wing H. LeungEmployment: Miltenyi Biotec Alberto PappoHonoraria: Bayer, RocheConsulting or Advisory Role: Merck, Loxo/Bayer, EUSA Pharma, DebbioNo other potential conflicts of interest were reported.

Background: B-precursor cell acute lymphoblastic leukemia (B-ALL) in adults is an aggressive and challenging condition, and patients with relapsed/refractory (R/R) disease after allogeneic stem cell transplantation (SCT), or noncandidates for SCT, have a particularly poor prognosis. The authors investigated the activity of the Fc-modified anti-CD19 antibody tafasitamab in adults with R/R B-ALL (NCT01685021)., Methods: Adults with R/R B-ALL received single-agent tafasitamab 12 mg/kg weekly for up to four 28-day cycles. Patients with complete remission (with or without neutrophil/platelet recovery; complete remission [CR] or complete remission with incomplete count recovery [CRi]) after cycles 2, 3, or 4 could continue tafasitamab every 2 weeks for up to 3 further months. The primary end point was overall response rate (ORR)., Results: Twenty-two patients were treated (median, 2 prior lines of therapy; range, 1-8). Six patients completed 2 cycles, and 2 of these patients responded for an ORR of 9%; 16 patients (73%) progressed before their first response assessment. Responses lasted 8 and 4 weeks in the 2 patients with CR and minimal residual disease (MRD)-negative CRi, respectively. Tafasitamab produced rapid B-cell/blast depletion in 21 of 22 patients within 1 to 2 weeks of first administration. Tafasitamab was well tolerated, with the most frequent adverse events being infusion-related reactions (59.1%) and fatigue (40.9%). Grade 3 to 4 febrile neutropenia (22.7%) was the most common hematologic adverse event., Conclusions: Tafasitamab monotherapy was associated with clinical activity in a subset of patients with R/R B-ALL, including short-lasting CR and MRD-negative CRi. Given its favorable tolerability profile, further development of tafasitamab in chemoimmunotherapy combinations and MRD settings should be explored., (© 2021 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)