Multifaceted Carbonized Metal-Organic Frameworks Synergize with Immune Checkpoint Inhibitors for Precision and Augmented Cuproptosis Cancer Therapy.

The discovery of cuproptosis, a copper-dependent mechanism of programmed cell death, has provided a way for cancer treatment. However, cuproptosis has inherent limitations, including potential cellular harm, the lack of targeting, and insufficient efficacy as a standalone treatment. Therefore, exogenously controlled combination treatments have emerged as key strategies for cuproptosis-based oncotherapy. In this study, a Cu2-xSe@cMOF nanoplatform was constructed for combined sonodynamic/cuproptosis/gas therapy. This platform enabled precise cancer cotreatment, with external control allowing the selective induction of cuproptosis in cancer cells. This approach effectively prevented cancer metastasis and recurrence. Furthermore, Cu2-xSe@cMOF was combined with the antiprogrammed cell death protein ligand-1 antibody (aPD-L1), and this combination maximized the advantages of cuproptosis and immune checkpoint therapy. Additionally, under ultrasound irradiation, the H2Se gas generated from Cu2-xSe@cMOF induced cytotoxicity in cancer cells. Further, it generated reactive oxygen species, which hindered cell survival and proliferation. This study reports an externally controlled system for cuproptosis induction that combines a carbonized metal-organic framework with aPD-L1 to enhance cancer treatment. This precision and reinforced cuproptosis cancer therapy platform could be valuable as an effective therapeutic agent to reduce cancer mortality and morbidity in the future.

Improving self-dependency in Pakistan: Experience of a locally prepared automated PD machine.

The increasing burden of haemodialysis on healthcare systems merits efforts to make peritoneal dialysis (PD) more accessible to the population in need of kidney replacement therapy. Automated PD (APD) may be a suitable alternative to continuous ambulatory peritoneal dialysis for home dialysis especially for children, elderly and patients who lead a busy schedule in their jobs thus leaving more time for personal and family activities during the day. Recently, a local bioengineering company took the initiative to develop a locally manufactured, low-cost APD cycler in Pakistan, with an aim to improve the self-dependency and home-based kidney replacement therapy. We herein present our first experience of APD on this locally manufactured APD cycler. It was an investigator-led study on the utility of a locally manufactured APD cycler and the safety and efficacy of the standard operating procedures developed and adopted by the study authors. A total of eight patients agreed to participate in this study extending from September 2021 to August 2022. There were four male and four female patients, and the mean age was 52.5 + 19.71 years. The locally manufactured cycler provided more than 1600 h of APD sessions. The APD sessions were well tolerated with only a few instances of minor mechanical and software issues that did not require termination of therapy. There were no episodes of peritonitis; however, one of the patients had an episode of exit site and tunnel infection that did not seem to be related to the procedure. Our experience with locally manufactured APD cycler was successful and without major adverse events. We believe the locally produced APD cycler is a viable cost-effective option for patients requiring PD and may herald a new era of self-dependency for patients considering or undergoing PD in Pakistan.

Black Phosphorus Quantum Dot Loaded Bioinspired Nanoplatform Synergized with aPD-L1 for Multimode Cancer Immunotherapy.

Efforts to prolong the blood circulation time and bypass immune clearance play vital roles in improving the therapeutic efficacy of nanoparticles (NPs). Herein, a multifunctional nanoplatform (BPP@RTL) that precisely targets tumor cells is fabricated by encapsulating ultrasmall phototherapeutic agent black phosphorus quantum dot (BPQD), chemotherapeutic drug paclitaxel (PTX), and immunomodulator PolyMetformin (PM) in hybrid membrane-camouflaged liposomes. Specifically, the hybrid cell membrane coating derived from the fusion of cancer cell membrane and red blood cell membrane displays excellent tumor targeting efficiency and long blood circulation property due to the innate features of both membranes. After collaboration with aPD-L1-based immune checkpoint blockade therapy, a boosted immunotherapeutic effect is obtained due to elevated dendritic cell maturation and T cell activation. Significantly, laser-irradiated BPP@RTL combined with aPD-L1 effectively eliminates primary tumors and inhibits lung metastasis in 4T1 breast tumor model, offering a promising treatment plan to develop personalized antitumor strategy.

Transition between peritoneal dialysis modalities: Impact on blood pressure levels and drug prescription in a national multicentric cohort.

BACKGROUND: Hypertension is a leading cause of kidney failure, affects most dialysis patients and associates with adverse outcomes. Hypertension can be difficult to control with dialysis modalities having differential effects on sodium and water removal. There are two main types of peritoneal dialysis (PD), automated peritoneal dialysis (APD) and continuous ambulatory peritoneal dialysis (CAPD). It is unknown whether one is superior to the other in controlling blood pressure (BP). Therefore, the aim of our study was to analyse the impact of switching between these two PD modalities on BP levels in a nationally representative cohort. METHODS: This was a cohort study of patients on PD from 122 dialysis centres in Brazil (BRAZPD II study). Clinical and laboratory data were collected monthly throughout the study duration. We selected all patients who remained on PD at least 6 months and 3 months on each modality at minimum. We compared the changes in mean systolic/diastolic blood pressures (SBP/DBP) before and after modality transition using a multilevel mixed-model where patients were at first level and their clinics at the second level. RESULTS: We analysed data of 848 patients (814 starting on CAPD and 34 starting on APD). The SBP decreased by 4 (SD 22) mmHg when transitioning from CAPD to APD (p < 0.001) and increased by 4 (SD 21) mmHg when transitioning from APD to CAPD (p = 0.38); consistent findings were seen for DBP. There was no significant change in the number of antihypertensive drugs prescribed before and after transition. CONCLUSIONS: Transition between PD modalities seems to directly impact on BP levels. Further studies are needed to confirm if switching to APD could be an effective treatment for uncontrolled hypertension among CAPD patients.

Is Percentage Improvement in Anteroposterior Pelvic Diameter a Valuable Marker for Successful Drainage Postpyeloplasty in Isolated Pediatric Pelvi-ureteric Junction Obstruction.

Context: Pelvic-ureteric junction obstruction (PUJO) causes urine stasis in the renal pelvis and progressive kidney damage. Postpyeloplasty improvement of renal function and urinary drainage is assessed by diuretic isotope renogram and ultrasonography. Renograms are expensive and have radiation exposure. This study explores whether ultrasound parameters such as percentage improvement in anteroposterior pelvic diameter (PI-APD) is a valuable markers for successful pediatric pyeloplasties. Aims: The aim of this study was to identify patients who would benefit from ultrasound monitoring of PI-APD alone instead of diuretic isotope renal scan for postoperative follow-up of pyeloplasty. Settings and Design: This was a retrospective descriptive study. Subjects and Methods: We analyzed 127 pediatric pyeloplasties performed and under follow-up between June 2016 and May 2021. We recorded the postoperative ultrasound and isotope renogram parameters. PI-APD (preoperative AP diameter - postoperative AP diameter)/preoperative AP diameter × 100) was compared with improvement in renogram parameters (differential renal function, Tmax, curve pattern, and retention) to look for a correlation between them. Statistical Analysis Used: SPSS version 20.5, Chi-square and paired t-test were used for statistical analysis. Results: About 73.2% of patients were males, with most cases detected antenatally (76.4%). The majority was left-sided PUJO (67.7%). The mean age at surgery was 30.8 months. We identified a statistically significant correlation between the ultrasound parameter PI-APD and the renogram parameter Tmax. There is no significant correlation between PI-APD and other renogram parameters. Conclusions: In patients whose ultrasound parameter PI-APD is >40% and renal parenchymal thickness has increased, isotope renograms can be avoided for follow-up of postpyeloplasty patients.

Auditory processing disorder: an online survey of hearing healthcare professionals' knowledge and practices.

OBJECTIVE: To investigate (1) the current level of awareness and knowledge on Auditory Processing Disorder (APD) among Audiologists and other hearing healthcare professionals; (2) current practices in screening, diagnosis, and management of APD in children and adults across the UK; (3) professional's acceptance of APD assessment and diagnosis. DESIGN: An online survey was disseminated through the British Academy of Audiology and ENT UK. STUDY SAMPLE: A total of 191 hearing healthcare professionals responded to the survey. RESULTS: Overall, while 63% of the respondents considered themselves to be adequately informed about APD, only 4% viewed themselves as very informed on the topic. Fewer than half of the respondents report screening (31%), diagnosing (14%), or managing (36%) cases of APD. For screening APD, professionals most commonly use auditory processing tests in adults and take case histories in children, whereas routine audiological procedures are the primary method for diagnosing APD in both adults and children. Although modifying the listening environment is a widely recommended management strategy for APD, half of the respondents indicated that a diagnosis of APD has no implications for patient management. CONCLUSIONS: There is a critical need to promote APD-related training to ensure they can provide appropriate referrals and management.

Spatiotemporal Visualization of Photogenerated Carriers on an Avalanche Photodiode Surface Using Ultrafast Scanning Electron Microscopy.

The spatiotemporal evolution of photogenerated charge carriers on surfaces and at interfaces of photoactive materials is an important issue for understanding fundamental physical processes in optoelectronic devices and advanced materials. Conventional optical probe-based microscopes that provide indirect information about the dynamic behavior of photogenerated carriers are inherently limited by their poor spatial resolution and large penetration depth. Herein, we develop an ultrafast scanning electron microscope (USEM) with a planar emitter. The photoelectrons per pulse in this USEM can be two orders of magnitude higher than that of a tip emitter, allowing the capture of high-resolution spatiotemporal images. We used the contrast change of the USEM to examine the dynamic nature of surface carriers in an InGaAs/InP avalanche photodiode (APD) after femtosecond laser excitation. It was observed that the photogenerated carriers showed notable longitudinal drift, lateral diffusion, and carrier recombination associated with the presence of photovoltaic potential at the surface. This work demonstrates an in situ multiphysics USEM platform with the capability to stroboscopically record carrier dynamics in space and time.

Scheduling of Remote Monitoring for Peritoneal Dialysis Patients.

Peritoneal dialysis (PD) is performed as a home-based treatment and in this context, telemedicine has been proven helpful for improving clinicians' surveillance and maintaining PD patients in their home setting. The new e-health devices make remote patient monitoring (RPM) for automated peritoneal dialysis (APD) treatment possible, evaluating the data at the end of every treatment and adapting the prescription at distance if necessary. This paper aims to share a method for improving clinical surveillance and enabling PD patients to receive their treatment at home. In the present case series, we delineate the clinical protocol of the Vicenza PD Center regarding patient characteristics, timing, and the purpose of the APD-RPM. We present the Vicenza PD Center's experience, illustrating its application through three case reports as exemplars. Telemedicine helps to carefully allocate healthcare resources while removing the barriers to accessing care. However, there is a risk of data overload, as some data might not be analyzed because of an increased workload for healthcare professionals. A proactive physician's attitude towards the e-health system has to be supported by clinical instructions and legislative rules. International and national guidelines may suggest which patients should be candidates for RPM, which parameters should be monitored, and with what timing. According to our experience, we suggest that the care team should define a workflow that helps in formulating a correct approach to RPM, adequately utilizing resources. The workflow has to consider the different needs of patients, in order to assure frequent remote control for incident or unstable patients, while prevalent and stable patients can perform their home treatment more independently, helped by periodic and deferred clinical supervision.

Structure of human GPR119-Gs complex binding APD597 and characterization of GPR119 binding agonists.

The rhodopsin-like receptor GPR119 plays a crucial role in glucose homeostasis and is an emerging target for the treatment of type 2 diabetes mellitus. In this study, we analyzed the structure of GPR119 with the agonist APD597 bound and in complex with the downstream G protein trimer by single particle cryo-electron microscopy (cryo-EM). Structural comparison in combination with function assay revealed the conservative and specific effects of different kinds of GPR119 agonists. The activation mechanism of GPR119 was analyzed by comparing the conformational changes between the inactive and active states. The interaction between APD597 derivatives and synthetic agonists with GPR119 was analyzed by molecular docking technique, and the necessary structural framework was obtained. The above conclusions can provide structural and theoretical basis for the development of therapeutic drugs for type 2 diabetes mellitus.

Nanoscale Metal-Organic Frameworks-Mediated Degradation of Mutant p53 Proteins and Activation of cGAS-STING Pathway for Enhanced Cancer Immunotherapy.

Activating cGAS-STING pathway has great potential to achieve effective antitumor immunotherapy. However, mutant p53 (mutp53), a commonly observed genetic alteration in over 50% of human cancer, will impede the therapeutic performance of the cGAS-STING pathway. Herein, multifunctional ZIF-8@MnO2 nanoparticles are constructed to degrade mutp53 and facilitate the cGAS-STING pathway. The synthesized ZIF-8@MnO2 can release Zn2+ and Mn2+ in cancer cells to induce oxidative stress and cytoplasmic leakage of fragmented mitochondrial double-stranded DNAs (dsDNAs). Importantly, the released Zn2+ induces variable degradation of multifarious p53 mutants through proteasome ubiquitination, which can alleviate the inhibitory effects of mutp53 on the cGAS-STING pathway. In addition, the released Mn2+ further increases the sensitivity of cGAS to dsDNAs as immunostimulatory signals. Both in vitro and in vivo results demonstrate that ZIF-8@MnO2 effectively promotes the cGAS-STING pathway and synergizes with PD-L1 checkpoint blockades, leading to remarkable regression of local tumors as well as distant metastases of breast cancer. This study proposes an inorganic metal ion-based nanoplatform to enhance the cGAS-STING-mediated antitumor immunotherapy, especially to those tumors with mutp53 expression.

Acquired perforating dermatosis in patients on peritoneal dialysis: a report of 3 cases.

Background: Acquired perforating dermatosis (APD) is a heterogeneous group of unfrequented diseases (2.5 cases for 100,000 habitants) associated with multiple pathologies like end-stage renal disease and other concomitant conditions such as diabetes mellitus (DM). Case Description: We described 3 cases of APD in patients on peritoneal dialysis (PD), one of them with a giant variant of reactive perforating collagenosis (RPC). The first case is a 28-year-old man with chronic kidney disease on PD and a lousy control of disturbances of calcium and phosphorus metabolism that develops an APD. The second case is a 44-year-old man with DM, chronic kidney disease (CKD) on PD, and poor control of disturbances of calcium and phosphorus metabolism that develops an RPC. The third case is a 58-year-old man with DM, rheumatoid arthritis, hypothyroidism, CKD and bad control of calcium and phosphorus metabolism that develops a giant variant of RPC with poor evolution. Conclusions: CKD and concomitant conditions such as DM present an increased risk of developing APD. Poor control of calcium and phosphorus metabolism is frequently found in patients with CKD and seems to be related to the development of APD in our cases. With the description of these cases, we want to emphasize the importance of knowing this rare disease, in order to promptly refer to Dermatology and start treatment.

Factors Influencing the Choice of Automated Peritoneal Dialysis Treatment by Patients Receiving Home Peritoneal Dialysis.

Objective: This study was conducted to understand the influencing factors for home peritoneal dialysis patients choosing APD and to provide a scientific basis for improving the completion rate of APD treatment and the follow-up of peritoneal dialysis patients. Methods: The study was a cross-sectional questionnaire-based study. A total of 588 patients on peritoneal dialysis were randomly selected from 6 regions in Fujian Province in southern China using a stratified cluster sampling method. Results: The mean age of the patients were 56.5 ± 14.73 years. In the univariate analysis, knowledge, user experience and family support were the factors that affected patients' choice of APD (all P < 0.05) and were positively correlated with the treatment utilization rate. In the multivariate analysis, 3 factors (treatment with APD, knowledge of APD, and family support) remained significantly associated not choosing APD. The selection rate for APD was 2.594 times higher among patients who had received APD than among patients who had never received APD. The selection rate for patients with "a lot of knowledge" about APD was 10.75 times that of patients with "no knowledge". Conclusion: Patients' knowledge of APD, experience in application and family support were the main factors affecting the choice of APD as a treatment mode (P < 0.05) and were positively correlated with the treatment utilization rate. Further studies are needed to improve the APD treatment completion rates by modulation the above-mentioned factors. Relevance to Clinical Practice: This study provides scientific evidence for improving APD treatment completion rates and improving patient quality of life.

Prominence of bioresponsive DNA nanococoons in tackling post-surgery cancer recurrence.

Post-surgery cancer recurrence is one of the reasons for increased cancer cases. The effective usage of the enhanced permeability and retention effect of a nanocarrier infused with the bioresponsive release mechanism of checkpoint inhibitors (aPD1 and aCTLA4) can become a boon to mankind. DNA nanococoons (DNCs) comprising cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG-ODNs) with potent immunostimulatory effects can significantly enhance anti-cancer activity. Triglycerylmonostearate (TGMS) with enzymatic cleavage potential at the wound sites of tumor resection, upon caging with restriction enzyme (HhaI) followed by attaching to DNCs, makes the immunotherapy bioresponsive. Hhal-TGMS-DNCs-aPD1 triggered by the inflammation at the wound site undergoes enzymatic cleavage, releases the restriction enzyme, converts DNCs to CpG ODNs sequentially and with sustained aPD1 release exerts an appreciable anti-cancer effect.

Cardiac safety assessment of a novel recombinant bispecific antibody targeting the ether-à-go-go related gene 1 (hERG1)-ß1 integrin macromolecular complex.

Introduction: In the last decades, mounting evidence has pointed out the human ether-á-go-go-related gene (hERG1) potassium channel as a novel biomarker in human cancers. However, hERG1 sustains the cardiac repolarizing current IKr and its blockade can induce a prolonged QT interval at the ECG, which increases the risk of life-threatening arrhythmias. This represents a major hindrance for targeting hERG1 for antineoplastic therapeutic purposes. Based on our discovery that hERG1 resides in a macromolecular complex with the ß1 subunit of integrin adhesion receptors only in tumors, and not in the heart, we generated (and patented WO2019/015936) a novel engineered, single chain, bispecific antibody in the format of a diabody (scDb-hERG1-ß1). This antibody has been proven to target with high affinity the hERG1/ß1 integrin complex and to exert a good antineoplastic activity in preclinical mouse models. Methods: In the present study, we evaluated the cardiac safety of the scDb-hERG1-ß1, determining the action potential duration (APD) of human cardiomyocytes, either atrial (from valve-disease patients) or ventricular (from aortic stenosis patients). Cardiac cells were incubated in vitro with i) the scDb-hERG1-ß1, ii) the full length anti-hERG1 monoclonal antibody (mAb-hERG1) and iii) its single chain Fragment variable derivative (scFv-hERG1), from which the scDb-hERG1-ß1 was assembled. All the tests were performed before and after treatment with the specific hERG1 blocker E4031. In addition, we have performed preliminary experiments, analyzing the effects of the scDb-hERG1/ß1 in vivo measuring the QT interval length of the surface ECG after its injection intravenously in farm-pigs. Results: The scDb-hERG1-ß1 did not produce any lengthening of APD compared to control (vehicle) conditions, either in atrial or ventricular cardiomyocytes, whereas both the hERG1-mAb and the scFv-hERG1 produced a significant APD prolongation. The addition of E4031 further prolonged APD. The scDb-hERG1-ß1 did not produce any alterations of the QT (and QTc) interval values, once injected intravenously in farm pigs. Discussion: Overall, the above evidences plead for the cardiac safety of the scDb-hERG1-ß1, suggesting that an application of this antibody for anti-cancer therapy will be untainted by cardiotoxicity.

Injectable microenvironment-responsive hydrogels with redox-activatable supramolecular prodrugs mediate ferroptosis-immunotherapy for postoperative tumor treatment.

Immunotherapy is an emerging antitumor modality with high specificity and persistence, but its application for resected tumor treatment is impeded by the low availability of tumor-specific antigens and strong immunosuppression in the wound margin. Here a nanoengineered hydrogel is developed for eliciting robust cooperative ferroptosis-immunotherapeutic effect on resected tumors. Specifically, ß-cyclodextrin (ß-CD) is first grafted onto oxidized sodium alginate (OSA) through Schiff base ligation, which could trap cRGD-modified redox-responsive Withaferin prodrugs (WA-cRGD) to obtain the hydrogel building blocks (Gel@WA-cRGD). Under Ca2+-mediated crosslinking, Gel@WA-cRGD rapidly forms physiologically stable hydrogels, of which the porous network is used to deliver programmed cell death ligand 1 antibodies (aPD-L1). After injection into the post-surgical wound cavity, the ß-CD-entrapped WA-cRGD is detached by the local acidity and specifically internalized by residual tumor cells to trigger ferroptosis, thus releasing abundant damage-associated molecular patterns (DAMPs) and tumor-derived antigens for activating the antigen-presenting cell-mediated cross-presentation and downstream cytotoxic T cell (CTL)-mediated antitumor responses. Furthermore, aPD-L1 could block PD-1/PD-L1 interaction and enhance the effector function of CTLs to overcome tumor cell-mediated immunosuppression. This cooperative hydrogel-based antitumor strategy for ferroptosis-immunotherapy may serve as a generally-applicable approach for postoperative tumor management. STATEMENT OF SIGNIFICANCE: To overcome the immunosuppressive microenvironment in resected solid tumors for enhanced patient survival, here we report a nanoengineered hydrogel incorporated supramolecular redox-activatable Withaferin prodrug and PD-L1 antibody, which could elicit robust cooperative ferroptosis-immunotherapeutic effect against residual tumor cells in the surgical bed to prevent tumor relapse, thus offering a generally-applicable approach for postoperative tumor management.

Tumor-associated macrophages trigger MAIT cell dysfunction at the HCC invasive margin.

Mucosal-associated invariant T (MAIT) cells represent an abundant innate-like T cell subtype in the human liver. MAIT cells are assigned crucial roles in regulating immunity and inflammation, yet their role in liver cancer remains elusive. Here, we present a MAIT cell-centered profiling of hepatocellular carcinoma (HCC) using scRNA-seq, flow cytometry, and co-detection by indexing (CODEX) imaging of paired patient samples. These analyses highlight the heterogeneity and dysfunctionality of MAIT cells in HCC and their defective capacity to infiltrate liver tumors. Machine-learning tools were used to dissect the spatial cellular interaction network within the MAIT cell neighborhood. Co-localization in the adjacent liver and interaction between niche-occupying CSF1R+PD-L1+ tumor-associated macrophages (TAMs) and MAIT cells was identified as a key regulatory element of MAIT cell dysfunction. Perturbation of this cell-cell interaction in ex vivo co-culture studies using patient samples and murine models reinvigorated MAIT cell cytotoxicity. These studies suggest that aPD-1/aPD-L1 therapies target MAIT cells in HCC patients.

Avalanche Photodiodes and Silicon Photomultipliers of Non-Planar Designs.

Conventional designs of an avalanche photodiode (APD) have been based on a planar p-n junction since the 1960s. APD developments have been driven by the necessity to provide a uniform electric field over the active junction area and to prevent edge breakdown by special measures. Most modern silicon photomultipliers (SiPM) are designed as an array of Geiger-mode APD cells based on planar p-n junctions. However, the planar design faces an inherent trade-off between photon detection efficiency and dynamic range due to loss of an active area at the cell edges. Non-planar designs of APDs and SiPMs have also been known since the development of spherical APDs (1968), metal-resistor-semiconductor APDs (1989), and micro-well APDs (2005). The recent development of tip avalanche photodiodes (2020) based on the spherical p-n junction eliminates the trade-off, outperforms the planar SiPMs in the photon detection efficiency, and opens new opportunities for SiPM improvements. Furthermore, the latest developments in APDs based on electric field-line crowding and charge-focusing topology with quasi-spherical p-n junctions (2019-2023) show promising functionality in linear and Geiger operating modes. This paper presents an overview of designs and performances of non-planar APDs and SiPMs.

Disposition and Mass Balance of Etrasimod in Healthy Subjects and In Vitro Determination of the Enzymes Responsible for Its Oxidative Metabolism.

Etrasimod (APD334) is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator (S1P1,4,5 ) in development for treatment of various immune-mediated inflammatory disorders. The disposition and mass balance of a single 2-mg [14 C]etrasimod dose were evaluated in 8 healthy males. An in vitro study was also conducted to identify etrasimod's oxidative metabolizing enzymes. Peak concentrations of etrasimod and total radioactivity in plasma and whole blood were typically reached 4-7 hours postdose. Etrasimod constituted 49.3% of total radioactivity plasma exposure, with multiple minor/trace metabolites making up the remainder. Etrasimod was slowly cleared mainly via biotransformation, predominantly by oxidative metabolism, with unchanged etrasimod recovered in feces accounting for only 11.2% of the dose and none in urine. The mean apparent terminal half-lives of etrasimod and total radioactivity in plasma were 37.8 and 89.0 hours, respectively. Mean cumulative recovery of radioactivity in excreta over 336 hours was 86.9% of the dose, mostly in feces. The prevalent metabolites eliminated in feces were M3 (hydroxy-etrasimod) and M36 (oxy-etrasimod sulfate), accounting for 22.1% and 18.9% of the dose, respectively. From in vitro reaction phenotyping, the predominant enzymes involved in the oxidation of etrasimod were CYP2C8, CYP2C9, and CYP3A4, with minor contributions from CYP2C19 and CYP2J2.

Auditory Discrimination-A Missing Piece of Speech and Language Development: A Study on 6-9-Year-Old Children with Auditory Processing Disorder.

Auditory discrimination, the hearing ability crucial for speech and language development, allowing one to perceive changes in volume, duration and frequency of sounds, was assessed for 366 participants with normal peripheral hearing: 220 participants with auditory processing disorders (APD) and 146 typically developing (TD) children, all aged 6-9 years. Discrimination of speech was tested with nonsense words using the phoneme discrimination test (PDT), while pure tones-with the frequency pattern test (FPT). The obtained results were statistically analyzed and correlated. The median of the FPT results obtained by participants with APD was more than twice lower than those of TD (20% vs. 50%; p < 0.05), similarly in the PDT (21 vs. 24; p < 0.05). The FPT results of 9-year-old APD participants were worse than the results of TD 6-year-olds (30% vs. 40%; p < 0.05), indicating that the significant FPT deficit strongly suggests APD. The process of auditory discrimination development does not complete with the acquisition of phonemes but continues during school age. Physiological phonemes discrimination is not yet equalized among 9-year-olds. Nonsense word tests allow for reliable testing of phoneme discrimination. APD children require testing with PDT and FPT because both test results allow for developing individual therapeutic programs.

Live-attenuated Japanese encephalitis virus inhibits glioblastoma growth and elicits potent antitumor immunity.

Glioblastomas (GBMs) are highly aggressive brain tumors that have developed resistance to currently available conventional therapies, including surgery, radiation, and systemic chemotherapy. In this study, we investigated the safety of a live attenuated Japanese encephalitis vaccine strain (JEV-LAV) virus as an oncolytic virus for intracerebral injection in mice. We infected different GBM cell lines with JEV-LAV to investigate whether it had growth inhibitory effects on GBM cell lines in vitro. We used two models for evaluating the effect of JEV-LAV on GBM growth in mice. We investigated the antitumor immune mechanism of JEV-LAV through flow cytometry and immunohistochemistry. We explored the possibility of combining JEV-LAV with PD-L1 blocking therapy. This work suggested that JEV-LAV had oncolytic activity against GBM tumor cells in vitro and inhibited their growth in vivo. Mechanistically, JEV-LAV increased CD8+ T cell infiltration into tumor tissues and remodeled the immunosuppressive GBM microenvironment that is non-conducive to immunotherapy. Consequently, the results of combining JEV-LAV with immune checkpoint inhibitors indicated that JEV-LAV therapy improved the response of aPD-L1 blockade therapy against GBM. The safety of intracerebrally injected JEV-LAV in animals further supported the clinical use of JEV-LAV for GBM treatment.