Early prediction of sudden cardiac death risk with Nested LSTM based on electrocardiogram sequential features.

Electrocardiogram (ECG) signals are very important for heart disease diagnosis. In this paper, a novel early prediction method based on Nested Long Short-Term Memory (Nested LSTM) is developed for sudden cardiac death risk detection. First, wavelet denoising and normalization techniques are utilized for reliable reconstruction of ECG signals from extreme noise conditions. Then, a nested LSTM structure is adopted, which can guide the memory forgetting and memory selection of ECG signals, so as to improve the data processing ability and prediction accuracy of ECG signals. To demonstrate the effectiveness of the proposed method, four different models with different signal prediction techniques are used for comparison. The extensive experimental results show that this method can realize an accurate prediction of the cardiac beat's starting point and track the trend of ECG signals effectively. This study holds significant value for timely intervention for patients at risk of sudden cardiac death.

Integrative Analyses of Bulk and Single-Cell RNA Seq Identified the Shared Genes in Acute Respiratory Distress Syndrome and Rheumatoid Arthritis.

Acute respiratory distress syndrome (ARDS), a progressive status of acute lung injury (ALI), is primarily caused by an immune-mediated inflammatory disorder, which can be an acute pulmonary complication of rheumatoid arthritis (RA). As a chronic inflammatory disease regulated by the immune system, RA is closely associated with the occurrence and progression of respiratory diseases. However, it remains elusive whether there are shared genes between the molecular mechanisms underlying RA and ARDS. The objective of this study is to identify potential shared genes for further clinical drug discovery through integrated analysis of bulk RNA sequencing datasets obtained from the Gene Expression Omnibus database, employing differentially expressed genes (DEGs) analysis and weighted gene co-expression network analysis (WGCNA). The hub genes were identified through the intersection of common DEGs and WGCNA-derived genes. The Random Forest (RF) and least absolute shrinkage and selection operator (LASSO) algorithms were subsequently employed to identify key shared target genes associated with two diseases. Additionally, RA immune infiltration analysis and COVID-19 single-cell transcriptome analysis revealed the correlation between these key genes and immune cells. A total of 59 shared genes were identified from the intersection of DEGs and gene clusters obtained through WGCNA, which analyzed the integrated gene matrix of ALI/ARDS and RA. The RF and LASSO algorithms were employed to screen for target genes specific to ALI/ARDS and RA, respectively. The final set of overlapping genes (FCMR, ADAM28, HK3, GRB10, UBE2J1, HPSE, DDX24, BATF, and CST7) all exhibited a strong predictive effect with an area under the curve (AUC) value greater than 0.8. Then, the immune infiltration analysis revealed a strong correlation between UBE2J1 and plasma cells in RA. Furthermore, scRNA-seq analysis demonstrated differential expression of these nine target genes primarily in T cells and NK cells, with CST7 showing a significant positive correlation specifically with NK cells. Beyond that, transcriptome sequencing was conducted on lung tissue collected from ALI mice, confirming the substantial differential expression of FCMR, HK3, UBE2J1, and BATF. This study provides unprecedented evidence linking the pathophysiological mechanisms of ALI/ARDS and RA to immune regulation, which offers novel understanding for future clinical treatment and experimental research.

Primary Human Breast Cancer-Associated Endothelial Cells Favor Interactions with Nanomedicines.

Cancer nanomedicines predominately rely on transport processes controlled by tumor-associated endothelial cells to deliver therapeutic and diagnostic payloads into solid tumors. While the dominant role of this class of endothelial cells for nanoparticle transport and tumor delivery has been established in animal models, there is a need to probe the translational potential of these findings in human cells. Using primary human breast cancer as a model, we explored and quantified the differential interactions of normal and tumor-associated endothelial cells with clinically relevant nanomedicine formulations. We determined that primary human breast cancer-associated endothelial cells exhibited up to ∼2 times higher nanoparticle uptake than normal human mammary microvascular endothelial cells. In addition, super-resolution imaging studies revealed a significantly higher intracellular vesicle number for tumor-associated endothelial cells, indicating a substantial increase in cellular transport activities. RNA sequencing and gene expression analysis indicated the upregulation of transport-related genes, especially motor protein genes, in tumor-associated endothelial cells. Collectively, our results demonstrate that primary human breast cancer-associated endothelial cells exhibit enhanced interactions with nanomedicines. Our findings suggest that these cells potentially play a significant role in nanoparticle tumor delivery in human patients. Engineering nanoparticles that leverage the translational potential of tumor-associated endothelial cell-mediated transport into human solid tumors may lead to the development of a new class of clinical cancer nanomedicines that are safer and more effective. This article is protected by copyright. All rights reserved.

Spatiotemporal characterization of PM2.5, O3, and trace gases associated with east Asian continental outflows via drone sounding.

East Asian continental outflows with PM2.5, O3, and other species may determine the baseline conditions and affect the air quality in downwind areas via long-range transport (LRT). To gain insight into the impact and spatiotemporal characteristics of airborne pollutants in East Asian continental outflows, a versatile multicopter drone sounding platform was used to simultaneously observe PM2.5, O3, CO2, and meteorological variables (temperature, specific humidity, pressure, and wind vector) above the northern tip of Taiwan, Cape Fuiguei, which often encounters continental outflows during winter monsoon periods. By coordinating hourly high-spatial-resolution profiles provided by drone soundings, WRF/CMAQ model air quality predictions, HYSPLIT-simulated backward trajectories, and MERRA-2 reanalysis data, we analyzed two prominent phenomena of airborne pollutants in continental outflows to better understand their physical/chemical characteristics. First, we found that pollutants were well mixed within a sounding height of 500 m when continental outflows passed through and completely enveloped Cape Fuiguei. Eddies induced by significant fluctuations in wind speeds coupled with minimal temperature inversion and LRT facilitated vertical mixing, possibly resulting in high homogeneity of pollutants within the outflow layer. Second, the drone soundings indicated exceptionally high O3 concentrations (70-100 ppbv) but relatively low concentrations of PM2.5 (10-20 µg/m3), CO2 (420-425 ppmv), and VOCs in some air masses. The low levels of PM2.5, CO2, and VOCs ruled out photochemistry as the cause of the formation of high-level O3. Further coordination of spatiotemporal data with air mass trajectories and O3 cross sections provided by MERRA-2 suggested that the high O3 concentrations could be attributed to stratospheric intrusion and advection via continental outflows. High-level O3 concentrations persisted in the lower troposphere, even reaching the surface, suggesting that stratospheric intrusion O3 may be involved in the rising trend in O3 concentrations in parts of East Asia in recent years in addition to surface photochemical factors.

Numb positively regulates Hedgehog signaling at the ciliary pocket.

Hedgehog (Hh) signaling relies on the primary cilium, a cell surface organelle that serves as a signaling hub for the cell. Using proximity labeling and quantitative proteomics, we identify Numb as a ciliary protein that positively regulates Hh signaling. Numb localizes to the ciliary pocket and acts as an endocytic adaptor to incorporate Ptch1 into clathrin-coated vesicles, thereby promoting Ptch1 exit from the cilium, a key step in Hh signaling activation. Numb loss impedes Sonic hedgehog (Shh)-induced Ptch1 exit from the cilium, resulting in reduced Hh signaling. Numb loss in spinal neural progenitors reduces Shh-induced differentiation into cell fates reliant on high Hh activity. Genetic ablation of Numb in the developing cerebellum impairs the proliferation of granule cell precursors, a Hh-dependent process, resulting in reduced cerebellar size. This study highlights Numb as a regulator of ciliary Ptch1 levels during Hh signal activation and demonstrates the key role of ciliary pocket-mediated endocytosis in cell signaling.

The diagnostic value of tenascin-C in acute aortic syndrome.

OBJECTIVES: Misdiagnosis of acute aortic syndrome (AAS) significantly increases mortality. Tenascin-C (TN-C) is an extracellular matrix glycoprotein related to cardiovascular injury. The elevation of TN-C in AAS and whether it can discriminate sudden-onset of acute chest pain in Chinese remains unclear. METHODS: We measured the plasma concentration of TN-C by ELISA in a cohort of 376 patients with chest or back pain. Measures to discriminate AAS from acute coronary syndrome (ACS) were compared and calculated. RESULTS: From October 2016 to September 2021, 376 undiagnosed patients with chest or back pain were enrolled. 166 of them were finally diagnosed as AAS, 100 were ACS and 110 without cardiovascular diseases (NCV). TN-C was significantly elevated in AAS at 18.18 ng/mL (IQR: 13.10-27.68) compared with 7.51 ng/mL (IQR: 5.67-11.38) in ACS (P < 0.001) and 3.68 ng/mL (IQR: 2.50-5.29) in NCV (P < 0.001). There was no significant difference in TN-C level among the subtypes of AAS. Of the 166 AAS patients, the peaked level of TN-C was at acute stage (P = 0.012), then a slight of decrease was observed at subacute stage. The area under receiver operating characteristic curve for AAS patients versus NCV was 0.979 (95% CI: 0.964-0.994) for TN-C. At a cutoff level of 11.474 ng/mL, TN-C has a sensitivity of 76.0%, specificity of 85.5%, accuracy of 82.0%, positive predictive value (PPV) of 76.0%, negative predictive value (NPV) of 85.5%. Diagnostic performance of TN-C was superior to D-dimer and hs-cTnT. CONCLUSIONS: The concentration of serum TN-C in AAS patients was significantly higher than that in ACS patients and NCV. TN-C could be a new biomarker to distinguish AAS patients in the early stage after symptoms onset from other pain diseases.

Perceived HRM and turnover intentions of elderly care workers: perspective from person-job fit and institutional ownership.

BACKGROUND: Although the phenomenon of high turnover rate in the elderly care industry has existed for a long time, there are few studies that have constructed frameworks to comprehensively analyze the strength of the effects of various factors on the turnover intention of elderly care workers.. This study analyzed the impact of different types of perceived human resource management practices on elderly care workers' turnover intentions and whether this relationship is moderated by person-job fit and ownership of elderly care institutions. METHODS: This is a cross-sectional and regional survey study. The study included questionnaire survey data from a total of 305 elderly care workers from 42 elderly care institutions in 21 provinces in China during June to September 2021. Descriptive statistics, Pearson correlation coefficient, multiple regression, and heterogeneity analyses were performed. RESULTS: Perceived work environment ( ß =-0.5164, p< 0.01), perceived occupational protection ( ß =-0.3390, p< 0.01), perceived welfare benefits ( ß = -0.2620, p< 0.01) and perceived competency training ( ß = -0.1421, p< 0.1) were all significantly and negatively related to turnover intentions, the quality of perceived work environment has the greatest impact on elderly care workers' turnover intentions. Under the moderating effects of person-job fit and ownership of elderly care institutions, there existed heterogeneity between perceived human resource management and turnover intentions among elderly care workers. High level of person-job fit and elderly care institutions' public feature can effectively weaken the negative impact of each type of perceived human resource management on turnover intention among elderly care workers. CONCLUSIONS: The managers of elderly care institutions should optimize the management mechanism, typically pay attention to elderly care workers' working environment, formulate and improve the professional standards and job requirements for elderly care workers, promote the public welfare value of nursing care services, and strengthen the sense of honor and responsibility of elderly care workers to reduce the turnover rate.

Influence of vaccination on critical COVID-19 patients with acute respiratory failure: a retrospective cohort study.

BACKGROUND: Despite vaccines' effectiveness in reducing COVID-19 infection rates and disease severity, their impact on critical patients presenting with acute respiratory failure is elusive. The aim of this study was to further investigate the influence of vaccination on mortality rates among severely ill COVID-19 patients experiencing acute respiratory failure. METHODS: This retrospective cohort study was carried out at a tertiary medical center in Taiwan. From April to September 2022, patients who tested positive for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through reverse transcription polymerase chain reaction (RT-PCR) and subsequently experienced acute respiratory failure were included in the study. Baseline characteristics, including vaccination history, along with information regarding critical illness and clinical outcomes, were gathered and compared between patients who received the vaccine and those who did not. RESULTS: A total of 215 patients with COVID-19 exhibiting acute respiratory failure, as confirmed via RT‒PCR, were included in the analysis. Of this cohort, sixty-six (30.7%) patients died within 28 days. Neither administration of the vaccine nor achievement of primary series vaccination status had a significantly different effect on 28 day mortality, number of viral shedding events, acute respiratory distress syndrome (ARDS) incidence or other clinical outcomes. Patients who received the booster vaccine and completed the primary series showed a tendency of increased 28 days of ventilator-free status, though this difference was not statistically significant (p = 0.815). CONCLUSIONS: Vaccination status did not significantly influence mortality rates, the occurrence of ARDS, or the viral shedding duration in COVID-19 patients with acute respiratory failure.

Design of smart temperature-sensitive terpolymeric hydrogel for multi-applications in liquid chromatography.

Hydrogels with a unique three-dimensional network structure have been widely used in a variety of fields. However, hydrogels are prone to swelling under water-rich conditions, which severely limits their application in liquid chromatography. Therefore, producing a hydrogel with reliable performance and good mechanical property is essential. Smart temperature-sensitive chromatographic packings have attracted extensive attentions in recent years. In this work, sodium 4-styrenesulfonate and 1-octadecene were introduced into the poly(N-isopropylacrylamide) hydrogel to improve mechanical property and separation performance. As a consequence, a smart temperature-sensitive terpolymeric hydrogel modified silica stationary phase (ION-hydrogel@SiO2) was synthesized for multimode liquid chromatographic separation. It was found that this new ION-hydrogel@SiO2 column exhibited excellent chromatographic separation ability for a wide range of analytes. To a certain extent, this new column has a higher chromatographic separation efficiency compared to the commercial C18 column and XAmide column. Moreover, the use of low proportion of organic phase in chromatographic separation is conducive to the realization of green chromatography. By investigating the chromatographic separation mechanism, it has been demonstrated that the hydrogen bonding interaction is primarily responsible for the temperature-sensitive behavior of the hydrogel. Finally, the ION-hydrogel@SiO2 column was used for the determination of pyridoxine in the commercially available tablet samples. In conclusion, this study presents a feasible idea for the development of novel copolymer hydrogels as liquid chromatographic stationary phases.

Chromatin context-dependent regulation and epigenetic manipulation of prime editing.

We set out to exhaustively characterize the impact of the cis-chromatin environment on prime editing, a precise genome engineering tool. Using a highly sensitive method for mapping the genomic locations of randomly integrated reporters, we discover massive position effects, exemplified by editing efficiencies ranging from ∼0% to 94% for an identical target site and edit. Position effects on prime editing efficiency are well predicted by chromatin marks, e.g., positively by H3K79me2 and negatively by H3K9me3. Next, we developed a multiplex perturbational framework to assess the interaction of trans-acting factors with the cis-chromatin environment on editing outcomes. Applying this framework to DNA repair factors, we identify HLTF as a context-dependent repressor of prime editing. Finally, several lines of evidence suggest that active transcriptional elongation enhances prime editing. Consistent with this, we show we can robustly decrease or increase the efficiency of prime editing by preceding it with CRISPR-mediated silencing or activation, respectively.

Dihydroartemisinin is an inhibitor of trained immunity through Akt/mTOR/HIF1α signaling pathway.

Trained immunity is mechanistically defined as the metabolically and epigenetically mediated long-term functional adaptation of the innate immune system, characterized by a heightened response to a secondary stimulation. Given appropriate activation, trained immunity represents an attractive anti-infective therapeutic target. Nevertheless, excessive immune response and subsequent inflammatory cascades may contribute to pathological tissue damage, indicating that the negative impacts of trained immunity appear to be significant. In this study, we show that innate immune responses such as the production of extracellular traps, pro-inflammatory cytokines, and autophagy-related proteins were markedly augmented in trained BMDMs. Furthermore, heat-killed C. albicans priming promotes the activation of the AIM2 inflammasome, and AIM2-/- mice exhibit impaired memory response induced by heat-killed C. albicans. Therefore, we establish that the AIM2 inflammasome is involved in trained immunity and emerges as a promising therapeutic target for potentially deleterious effects. Dihydroartemisinin can inhibit the memory response induced by heat-killed C. albicans through modulation of mTOR signaling and the AIM2 inflammasome. The findings suggest that dihydroartemisinin can reduce the induction of trained immunity by heat-killed C. albicans in C57BL/6 mice. Dihydroartemisinin is one such therapeutic intervention that has the potential to treat of diseases characterized by excessive trained immunity.

Green moisture-electric generator based on supramolecular hydrogel with tens of milliamp electricity toward practical applications.

Moisture-electric generators (MEGs) has emerged as promising green technology to achieve carbon neutrality in next-generation energy suppliers, especially combined with ecofriendly materials. Hitherto, challenges remain for MEGs as direct power source in practical applications due to low and intermittent electric output. Here we design a green MEG with high direct-current electricity by introducing polyvinyl alcohol-sodium alginate-based supramolecular hydrogel as active material. A single unit can generate an improved power density of ca. 0.11 mW cm-2, a milliamp-scale short-circuit current density of ca. 1.31 mA cm-2 and an open-circuit voltage of ca. 1.30 V. Such excellent electricity is mainly attributed to enhanced moisture absorption and remained water gradient to initiate ample ions transport within hydrogel by theoretical calculation and experiments. Notably, an enlarged current of ca. 65 mA is achieved by a parallel-integrated MEG bank. The scalable MEGs can directly power many commercial electronics in real-life scenarios, such as charging smart watch, illuminating a household bulb, driving a digital clock for one month. This work provides new insight into constructing green, high-performance and scalable energy source for Internet-of-Things and wearable applications.

The impact of COVID-19 restrictions on motorcycle crashes in Taiwan.

Taiwan is one of the countries with the highest motorcycle per capita globally, and motorcycle crashes are predominant among traffic crashes. This study examines the impact of coronavirus disease 2019 restrictions on motorcycle crashes. We analyzed the trend of motorcycle crashes in Taipei City from 2019 to 2020 using the dataset provided by the Department of Transportation, Taipei City Government, Taiwan. We found 47,108 and 51,441 motorcycle crashes in 2019 and 2020, involving 61,141 and 67,093 motorcycles, respectively. Mopeds had the highest risk in 2020, followed by heavy motorcycles [≥550 cubic capacity (cc)] and scooters compared to 2019. Food delivery motorcycle crashes increased for scooters (0.93% in 2019 to 3.45% in 2020, P < .0001) and heavy motorcycles (250 < cc < 550) (0.90% in 2019 to 3.38% in 2020, P < .0001). While fatalities remained under 1%, 30% to 51% of motorcyclists sustained injuries. Food delivery with scooters or heavy motorcycles (250 < cc < 550) was significantly associated with motorcyclist injuries and deaths. Compared with 2019, the adjusted odds ratios of motorcyclist injuries and deaths in 2020 were 1.43 (95% confidence interval = 1.05-1.94) for heavy motorcycles (≥550 cc) and 1.07 (95% confidence interval = 1.04-1.09) for scooters. This study shows that coronavirus disease 2019 restrictions was associated with elevated risks of crashes, injuries, and deaths among motorcyclists, reflecting the general preference for private transport over public transport. The popularity of food delivery services also contributed to increased motorcycle crashes.

Acute right extremity deep vein thrombosis and left-sided inferior vena cava thrombosis treated by percutaneous mechanical thrombectomy (PMT) combined with catheter directed thrombolysis (CDT): A case report.

INTRODUCTION: Left-sided inferior vena cava (IVC) is an uncommon condition with a prevalence rate of 0.2% to 0.5%. Most of them remain asymptomatic and are discovered incidentally. The patient condition in this case is critical, and conventional procedures are not applicable. The surgical approach being considered is innovative, but it carries significant risks and uncertain therapeutic efficacy. PATIENT CONCERNS: A 42-year-old male presented with acute right lower extremity pain with swelling for 2 days. DIAGNOSIS: The patient was subsequently diagnosed with acute right lower extremity deep vein thrombosis, inferior vena cava thrombosis, and a left-sided IVC. INTERVENTIONS: Based on the treatment guidelines for lower extremity deep venous thrombosis. OUTCOMES: We successfully cured him with percutaneous mechanic thrombectomy (PMT) combined with catheter directed thrombolysis (CDT). CONCLUSION AND SIGNIFICANCE: The relatively low incidence of left-sided IVC does not diminish the significance of its identification. PMT combined with CDT is a safe way to treat acute thrombosis. It provides a new approach for similar patients in the future.

Bilateral keratitis associated with afatinib therapy.

This case discussed a significant ocular side effect, bilateral keratitis, which could be induced by afatinib, an irreversible epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). We explored the disease progression of a 52-year-old, stage IV nasopharyngeal carcinoma male patient, who was under afatinib treatment and had experienced progressive bilateral eye dryness and tenderness on increasing afatinib from 40 mg every other day to 40 mg daily. Clinical examination noted bilateral visual acuity reduction, diffuse superficial punctate keratopathy in the right eye, and a central epithelial defect in the left eye. Seidel test results were negative for both eyes, with no corneal infiltration, lagophthalmos, anterior chamber cell precipitation, or retinal lesion. Symptoms subsequently resolved after reducing the frequency of afatinib used, along with intensive ocular hydration. In summary, this case highlighted afatinib's potential link to bilateral keratitis, and early afatinib dose adjustment with supportive medication could significantly reverse the condition.

Understanding physical exercise among individuals with substance use disorders using an integrated theoretical perspective of the health action process approach and theory of planned behavior.

Introduction: Physical exercise is considered a useful non-pharmacological adjunctive treatment for promoting recovery from substance use disorders (SUD). However, adherence to physical exercise treatments is low, and little is known about what factors are associated with the initiation and maintenance of physical exercise behaviors. The aim of this study was to explore the psychosocial factors underlying these behaviors in individuals with SUD using an integrated theoretical model based on the health action process approach (HAPA) and the theory of planned behavior (TPB). Methods: A total of 1,197 individuals with SUDs (aged 37.20 ± 8.62 years) were recruited from 10 compulsory isolation drug rehabilitation centers in Zhejiang Province via convenience sampling according to a set of inclusion criteria. Self-reported data were collected to assess task self-efficacy (TSE), maintenance self-efficacy (MSE), recovery self-efficacy (RSE), outcome expectations (OE), action planning (AP), coping planning (CP), social support (SS), subjective norms (SN), attitude behavior (AB), behavioral intention (BI), perceived behavioral control (PBC), risk perception (RP), exercise stage, and exercise behavior in this integrated model. ANOVA and structural equation modeling (SEM) were used to evaluate this model. Results: One-way ANOVA revealed that the majority of the moderating variables were significantly different in the exercise phase. Further SEM showed that the model fit the data and revealed several important relationships. TSE, RP, SS, AB, and SN were indirectly associated with physical exercise behavior in individuals with SUD through the BI in the SUD initiation stage. In addition, PBC was directly related to physical exercise behavior in individuals with SUD. In the maintenance stage, MSE, AP, CP and exercise behavior were significantly related. Moreover, AP and CP were mediators of BI and MSE. Conclusion: This study is the first attempt to integrate patterns of physical exercise behavior in individuals with SUD. The HAPA-TPB integration model provides a useful framework for identifying determinants of physical exercise behavioral intentions and behaviors in individuals with SUD and for explaining and predicting the initiation and maintenance of physical exercise behaviors in these individuals. Moreover, the model provides scientific guidance for the enhancement of physical exercise adherence in individuals with SUD.

A practical synthesis of nitrone-derived C5a-functionalized isofagomines as protein stabilizers to treat Gaucher disease.

Isofagomine (IFG) and its analogues possess promising glycosidase inhibitory activities. However, a flexible synthetic strategy toward both C5a-functionalized IFGs remains to be explored. Here we show a practical synthesis of C5a-S and R aminomethyl IFG-based derivatives via the diastereoselective addition of cyanide to cyclic nitrone 1. Nitrone 1 was conveniently prepared on a gram scale and in high yield from inexpensive (-)-diethyl D-tartrate via a straightforward method, with a stereoselective Michael addition of a nitroolefin and a Nef reaction as key steps. A 268-membered library (134 × 2) of the C5a-functionalized derivatives was submitted to enzyme- or cell-based bio-evaluations, which resulted in the identification of a promising ß-glucocerebrosidase (GCase) stabilizer demonstrating a 2.7-fold enhancement at 25 nM in p.Asn370Ser GCase activity and a 13-fold increase at 1 µM in recombinant human GCase activity in Gaucher cell lines.

Bispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial.

Despite the high therapeutic response achieved with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapy in relapsed and refractory multiple myeloma (R/R MM), primary resistance and relapse exist with single-target immunotherapy. Here, we design bispecific BC19 CAR T cells targeting BCMA/CD19 and evaluate antimyeloma activity in vitro and in vivo. Preclinical results indicate that BC19 CAR specifically recognize target antigens, and BC19 CAR T cells mediate selective killing of BCMA or CD19-positive cancer cells. BC19 CAR T cells also exhibit potent antigen-specific anti-tumor activity in xenograft mouse models. We conduct an open-label, single-arm, phase I/II study of BC19 CAR T cells in 50 patients with R/R MM (ChiCTR2000033567). The primary endpoint was safety. BC19 CAR T cells are well tolerated with grade 3 or higher cytokine release syndrome in 8% of patients and grade 1 neurotoxic events in 4% of patients, which meet the pre-specified primary endpoint. Secondary endpoints include overall response rate (92%), median progression-free survival (19.7 months), median overall survival (19.7 months) and median duration of response (not reached). Our study demonstrates that bispecific BC19 CAR T cells are feasible, safe and effective in treating patients with R/R MM.

Mitochondrial DNA-Activated cGAS-STING Signaling in Environmental Dry Eye.

Purpose: The cGAS-STING pathway has been shown to be an important mediator of inflammation. There is emerging evidence of the importance of this signaling cascade in a variety of inflammatory diseases settings. Here, we present evidence that the mitochondrial DNA (mtDNA) damage-mediated cGAS-STING pathway plays an important role in the induction of inflammation in environmental dry eye (DE). Methods: RT-qPCR and Western blot were used to assess the induction of the cGAS-STING pathway and inflammatory cytokines in environmental DE mouse model, primary human corneal epithelial cells (pHCECs), and patients with DE. RNA sequencing was used to determine mRNA expression patterns of high osmotic pressure (HOP)-stimulated pHCECs. mtDNA was detected with electron microscopy, flow cytometry, and immunofluorescent staining. mtDNA was isolated and transfected into pHCECs for evaluating the activation of the cGAS-STING pathway. Results: The expression levels of cGAS, STING, TBK1, IRF3, and IFNß were significantly increased in an environmental DE model and HOP-stimulated pHCECs. The STING inhibitor decreased the expression of inflammatory factors in DE. An upregulation of STING-mediated immune responses and IRF3 expression mediated by TBK1 were observed in the HOP group. HOP stimulation induced mitochondrial oxidative damage and the leakage of mtDNA into the cytoplasm. Then, mtDNA activated the cGAS-STING pathway and induced intracytoplasmic STING translocated to the Golgi apparatus. Finally, we also found activated cGAS-STING signaling in the human conjunctival blot cell of patients with DE. Conclusions: Our findings suggest that the cGAS-STING pathway is activated by recognizing cytoplasmic mtDNA leading to STING translocation, further exacerbating the development of inflammation in environmental DE.

The normative values of pain thresholds in healthy Taiwanese.

OBJECTIVE: Quantitative sensory testing is widely used in clinical and research settings to assess the sensory functions of healthy subjects and patients. It is of importance to establish normative values in a healthy population to provide reference for studies involving patients. Given the absence of normative values for pain thresholds in Taiwan, the aim of this study was to report the normative values for future reference in the Taiwanese population and compare the differences between male and female participants. METHODS: Healthy adults without any chronic or acute pain condition were recruited. The pain thresholds were assessed over the cephalic (supraorbital area and masseter muscle) and extracephalic (medio-volar forearm and thenar eminence) areas. The heat, cold, mechanical punctate, and pressure pain thresholds were measured with a standardized protocol. Comparisons between male and female participants were performed. RESULTS: One hundred and thirty healthy participants (55 males: 30.4 ± 7.4 years; 75 females: 30.5 ± 8.1 years) finished the assessments. Male participants were less sensitive to mechanical stimuli, including pressure over masseter muscle (male vs. female: 178.5 ± 56.7 vs. 156.6 ± 58.4 kPa, p = .034) and punctate over medio-volar forearm (male vs. female: 116.4 ± 45.2 vs. 98.7 ± 65.4 g, p = .011), compared to female participants. However, female participants were less sensitive to cold stimuli, indicated by lower cold pain thresholds over the supraorbital area (male vs. female: 18.6 ± 8.4 vs. 13.6 ± 9.3°C, p = .004), compared to male participants. No significant differences were found between sexes in other pain threshold parameters. CONCLUSIONS: We provided the normative values of healthy male and female adults in Taiwan. This information is crucial for comparison in future pain-related studies to identify potential hypoalgesia or hyperalgesia of tested subjects.