Aromaticity Tuning of Heavy-Atom-Free Photosensitizers for Singlet Fission-Enhanced Immunogenic Photodynamic Oncotherapy.

The quantum yield of reactive oxygen species is of central importance for the development of organic photosensitizers and photodynamic therapy (PDT). A common molecular design approach for optimizing organic photosensitizers involves the incorporation of heavy atoms into their backbones. However, this raises concerns regarding heightened dark cytotoxicity and a shortened triplet-state lifetime. Herein, we demonstrate a heavy-atom-free (HAF) photosensitizer design strategy founded on the singlet fission (SF) mechanism for cancer PDT. Through the "single-atom surgery" approach to deleting oxygen atoms in pyrazino[2,3-g]quinoxaline skeleton photosensitizers, photosensitizers PhPQ and TriPhPQ are produced with Huckel's aromaticity and Baird's aromaticity in the ground state and triplet state, respectively, enabling the generation of two triplet excitons through SF. The SF process endows photosensitizer PhPQ with an ultrahigh triplet-state quantum yield (186%) and an outstanding 1O2 quantum yield (177%). Notably, HAF photosensitizers PhPQ and TriPhPQ enhanced PDT efficacy and potentiated αPD-L1 immune check blockade therapy in vivo, which show their promise for translational oncology treatment.

The effects of delayed appropriate antimicrobial therapy on children with Staphylococcus aureus blood infection.

Early appropriate antimicrobial therapy plays a critical role for patients with Staphylococcus aureus bloodstream infection (SAB). We aim to determine the optimal time-window for appropriate antimicrobial therapy and evaluate the effects of delayed therapy on adverse clinical outcomes (in-hospital mortality, sepsis, and septic shock) in children with SAB by propensity score matching (PSM) analysis. Receiver-operating characteristic was used to determine the cut-off point of the time to appropriate therapy (TTAT), the patients were divided into timely and delayed appropriate antimicrobial therapy (delayed therapy) groups accordingly. The PSM was used to balance the characteristics between the two groups, controlling the effects of potential confounders. Kaplan-Meier methods and Cox proportional hazards regression were applied to the matched groups to analyze the association between delayed therapy and clinical outcomes. Inverse probability of treatment weighting and propensity score covariate adjustment were also performed to investigate the sensitivity of the results under different propensity score-based approaches. In total, 247 patients were included in this study. The optimal cut-off point of TTAT was identified as 6.4 h, with 85.0% sensitivity and 69.2% specificity (AUC 0.803, 95% confidence interval 0.702-0.904). Eighty-seven (35.22%) of the 247 patients who received delayed therapy (TTAT ≥ 6.4 h) had higher in-hospital mortality (19.54% vs 1.88%, p < 0.001), higher incidences of sepsis (44.83% vs 15.00%, p < 0.001) and septic shock (32.18% vs 6.25%, p < 0.001) when compared to timely therapy (TTAT < 6.4 h) patients. After PSM analysis, a total of 134 episodes (67 in each of the two matched groups) were further analyzed. No statistically significant difference was observed in in-hospital mortality between delayed and timely -therapy groups (log-rank test, P = 0.157). Patients with delayed therapy had a higher incidence of sepsis or septic shock than those with timely therapy (log-rank test, P = 0.009; P = 0.018, respectively). Compared to the timely-therapy group, the hazard ratio and 95% confidence interval in delayed-therapy group were 2.512 (1.227-5.144, P = 0.012) for sepsis, 3.109 (1.166-8.290, P = 0.023) for septic shock.    Conclusion: Appropriate therapy delayed 6.4 h may increase the incidence of sepsis and septic shock, with similar in-hospital mortality in patients with SAB. What is Known: • Staphylococcus aureus (S. aureus) is a major cause of bloodstream infections in children. Undoubtedly, early antimicrobial application plays a critical role in the treatment of children with Staphylococcus aureus bloodstream infections (SAB). • However, rapid, and aggressive administration of antimicrobials may lead to the overuse of these drugs and the emergence of multidrug-resistant microorganisms. Therefore, it is crucial to determine the optimal time-window for appropriate antimicrobial administration in children with SAB. Unfortunately, the optimal time-window for appropriate antimicrobial administration in children with SAB remains unclear. What is New: • Determining the optimal time-window for appropriate antimicrobial administration in patients with matched data variables is particularly important. The Propensity score matching (PSM) analysis effectively controls for confounding factors to a considerable extent when assessing the impact of treatment, thereby approximating the effects observed in randomized controlled trials. • To our knowledge, this is the first study using PSM method to assess the effects of delayed appropriate antimicrobial therapy on adverse outcomes in children with SAB. In low-risk populations with SAB, a delay of 6.4 h in appropriate therapy might increase the occurrence rate for sepsis and septic shock; however, no correlation has been found between this delay and an increased risk for hospital mortality.

Discovery of KT-413, a Targeted Protein Degrader of IRAK4 and IMiD Substrates Targeting MYD88 Mutant Diffuse Large B-Cell Lymphoma.

Developing therapies for the activated B-cell like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL) remains an area of unmet medical need. A subset of ABC DLBCL tumors is driven by activating mutations in myeloid differentiation primary response protein 88 (MYD88), which lead to constitutive activation of interleukin-1 receptor associated kinase 4 (IRAK4) and cellular proliferation. IRAK4 signaling is driven by its catalytic and scaffolding functions, necessitating complete removal of this protein and its escape mechanisms for complete therapeutic suppression. Herein, we describe the identification and characterization of a dual-functioning molecule, KT-413 and show it efficiently degrades IRAK4 and the transcription factors Ikaros and Aiolos. KT-413 achieves concurrent degradation of these proteins by functioning as both a heterobifunctional degrader and a molecular glue. Based on the demonstrated activity and safety of KT-413 in preclinical studies, a phase 1 clinical trial in B-cell lymphomas, including MYD88 mutant ABC DLBCL, is currently underway.

Sulforaphane decreases oxidative stress and inhibits NLRP3 inflammasome activation in a mouse model of ulcerative colitis.

Excessive oxidative stress and NLRP3 inflammasome activation are considered the main drivers of inflammatory bowel disease (IBD), and inhibition of inflammasomes ameliorates clinical symptoms and morphological manifestations of IBD. Herein, we examined the roles of NLRP3 activation in IBD and modulation of NLRP3 by sulforaphane (SFN), a compound with multiple pharmacological activities that is extracted from cruciferous plants. To simulate human IBD, we established a mouse colitis model by administering dextran sodium sulfate in the drinking water. SFN (25, 50 mg·kg-1·d-1, ig) or the positive control sulfasalazine (500 mg/kg, ig) was administered to colitis-affected mice for 7 days. Model mice displayed pathological alterations in colon tissue as well as classic symptoms of colitis beyond substantial tissue inflammation. Expression of NLRP3, ASC, and caspase-1 was significantly elevated in the colonic epithelium. The expression of NLRP3 inflammasomes led to activation of downstream proteins and increases in the cytokines IL-18 and IL-1ß. SFN administration either fully or partially reversed these changes, thus restoring IL-18 and IL-1ß, substantially inhibiting NLRP3 activation, and decreasing inflammation. SFN alleviated the inflammation induced by LPS and NLRP3 agonists in RAW264.7 cells by decreasing the levels of reactive oxygen species. In summary, our results revealed the pathological roles of oxidative stress and NLRP3 in colitis, and indicated that SFN might serve as a natural NLRP3 inhibitor, thereby providing a new strategy for alternative colitis treatment.

Association between homocysteine and blood pressure in the NHANES 2003-2006: the mediating role of Vitamin C.

Background: The yearly escalation in hypertension prevalence signifies a noteworthy public health challenge. Adhering to a nutritious diet is crucial for enhancing the quality of life among individuals managing hypertension. However, the relationship between vitamin C and hypertension, as well as homocysteine, remains unclear. Objective: The primary aim of this investigation was to scrutinize the potential mediating role of Vitamin C in the association between homocysteine levels and blood pressure, utilizing data extracted from the National Health and Nutrition Examination Survey (NHANES) database. Methods: A total of 7,327 participants from the NHANES 2003-2006 were enrolled in this cross-sectional survey. The main information was obtained using homocysteine, Vitamin C, systolic blood pressure (SBP) and diastolic blood pressure (DBP). Correlation analysis was used to assess the correlation between homocysteine, SBP, DBP and vitamin C. Linear regression analysis was utilized to determine the ß value (ß) along with its 95% confidence intervals (CIs). Mediation analysis was performed to investigate whether the relationship between homocysteine and blood pressure was mediated by Vitamin C, and to quantify the extent to which Vitamin C contributed to this association. Results: The results manifested that the homocysteine was positively associated with SBP (r = 0.24, p < 0.001) and DBP (r = 0.03, p < 0.05), while negatively correlated with Vitamin C (r = -0.008, p < 0.001). Vitamin C was found to be negatively associated with SBP (r = -0.03, p < 0.05) and DBP (r = 0.11, p < 0.001). Mediation effect analysis revealed that a partial mediation (indirect effect: 0.0247[0.0108-0.0455], p < 0.001) role accounting for 11.5% of total effect, among homocysteine and SBP. However, the mediating effect of Vitamin C between homocysteine and DBP was not statistically significant. Conclusion: Hypertension patients should pay attention to homocysteine and Vitamin C level. What is more, hypertension patients ought to formulate interventions for Vitamin C supplementation as well as homocysteine reduce strategies to lower blood pressure.

Liver injury and prolonged hospitalization as indicators of severity in patients with adenovirus infections.

BACKGROUND: Adenovirus (ADV) is a prevalent infective virus in children, accounting for around 5-10% of all cases of acute respiratory illnesses and 4-15% of pneumonia cases in children younger than five years old. Without treatment, severe ADV pneumonia could result in fatality rates of over 50% in cases of emerging strains or disseminated disease. This study aims to uncover the relationship of clinical indicators with primary ADV infection severity, regarding duration of hospitalization and liver injury. METHODS: In this retrospective study, we collected and analyzed the medical records of 1151 in-patients who met the inclusion and exclusion criteria. According to duration of hospitalization, all patients were divided into three groups. Then the difference and correlation of clinical indicators with ADV infection were analyzed, and the relationship among liver injury, immune cells and cytokines was evaluated. RESULTS: The study revealed that patients with a duration of hospitalization exceeding 14 days had the highest percentage of abnormalities across most indicators. This was in contrast to the patients with a hospitalization duration of either less than or equal to 7 days or between 7 and 14 days. Furthermore, correlation analysis indicated that a longer duration of body temperature of ≥ 39°C, bilateral lung lobes infiltration detected by X ray, abnormal levels of AST, PaO2, and SPO2, and a lower age were all predictive of longer hospital stays. Furthermore, an elevated AST level and reduced liver synthesis capacity were related with a longer hospital stay and higher ADV copy number. Additionally, AST/ALT was correlated positively with IFN-γ level and IFN-γ level was only correlated positively with CD4+ T cells. CONCLUSIONS: The study provided a set of predicting indicators for longer duration of hospitalization, which responded for primary severe ADV infection, and elucidated the possible reason for prolonged duration of hospitalization attributing to liver injury via higher ADV copy number, IFN-γ and CD4+ T cells, which suggested the importance of IFN-γ level and liver function monitoring for the patients with primary severe ADV infection.

ESCO2's oncogenic role in human tumors: a pan-cancer analysis and experimental validation.

PURPOSE: Establishment of sister chromatid cohesion N-acetyltransferase 2 (ESCO2) is involved in the mitotic S-phase adhesins acetylation and is responsible for bridging two sister chromatids. However, present ESCO2 cancer research is limited to a few cancers. No systematic pan-cancer analysis has been conducted to investigate its role in diagnosis, prognosis, and effector function. METHODS: We thoroughly examined the ESCO2 carcinogenesis in pan-cancer by combining public databases such as The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), UALCAN and Tumor Immune Single-cell Hub (TISCH). The analysis includes differential expression analysis, survival analysis, cellular effector function, gene mutation, single cell analysis, and tumor immune cell infiltration. Furthermore, we confirmed ESCO2's impacts on clear cell renal cell carcinoma (ccRCC) cells' proliferative and invasive capacities in vitro. RESULTS: In our study, 30 of 33 cancer types exhibited considerably greater levels of ESCO2 expression in tumor tissue using TCGA and GTEx databases, whereas acute myeloid leukemia (LAML) exhibited significantly lower levels. Kaplan-Meier survival analyses in adrenocortical carcinoma (ACC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), mesothelioma (MESO), and pancreatic adenocarcinoma (PAAD) demonstrated that tumor patients with high ESCO2 expression have short survival periods. However, in thymoma (THYM), colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ), ESCO2 was a favorable prognostic factor. Moreover, ESCO2 expression positively correlates with tumor stage and tumor size in several cancers, including LIHC, KIRC, KIRP and LUAD. Function analysis revealed that ESCO2 participates in mitosis, cell cycle, DNA damage repair, and other processes. CDK1 was identified as a downstream gene regulated by ESCO2. Furthermore, ESCO2 might also be implicated in immune cell infiltration. Finally, ESCO2'S knockdown significantly inhibited the A498 and T24 cells' proliferation, invasion, and migration. CONCLUSIONS: In conclusion, ESCO2 is a possible pan-cancer biomarker and oncogene that can reliably predict the prognosis of cancer patients. ESCO2 was also implicated in the cell cycle and proliferation regulation. In a nutshell, ESCO2 is a therapeutically viable and dependable target.

Risk of cardiovascular death in patients with hepatocellular carcinoma based on the Fine-Gray model.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common types of cancers worldwide, ranking fifth among men and seventh among women, resulting in more than 7 million deaths annually. With the development of medical technology, the 5-year survival rate of HCC patients can be increased to 70%. However, HCC patients are often at increased risk of cardiovascular disease (CVD) death due to exposure to potentially cardiotoxic treatments compared with non-HCC patients. Moreover, CVD and cancer have become major disease burdens worldwide. Thus, further research is needed to lessen the risk of CVD death in HCC patient survivors. AIM: To determine the independent risk factors for CVD death in HCC patients and predict cardiovascular mortality (CVM) in HCC patients. METHODS: This study was conducted on the basis of the Surveillance, Epidemiology, and End Results database and included HCC patients with a diagnosis period from 2010 to 2015. The independent risk factors were identified using the Fine-Gray model. A nomograph was constructed to predict the CVM in HCC patients. The nomograph performance was measured using Harrell's concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and area under the ROC curve (AUC) value. Moreover, the net benefit was estimated via decision curve analysis (DCA). RESULTS: The study included 21545 HCC patients, of whom 619 died of CVD. Age (< 60) [1.981 (1.573-2.496), P < 0.001], marital status (married) [unmarried: 1.370 (1.076-1.745), P = 0.011], alpha fetoprotein (normal) [0.778 (0.640-0.946), P = 0.012], tumor size (≤ 2 cm) [(2, 5] cm: 1.420 (1.060-1.903), P = 0.019; > 5 cm: 2.090 (1.543-2.830), P < 0.001], surgery (no) [0.376 (0.297-0.476), P < 0.001], and chemotherapy(none/unknown) [0.578 (0.472-0.709), P < 0.001] were independent risk factors for CVD death in HCC patients. The discrimination and calibration of the nomograph were better. The C-index values for the training and validation sets were 0.736 and 0.665, respectively. The AUC values of the ROC curves at 2, 4, and 6 years were 0.702, 0.725, 0.740 in the training set and 0.697, 0.710, 0.744 in the validation set, respectively. The calibration curves showed that the predicted probabilities of the CVM prediction model in the training set vs the validation set were largely consistent with the actual probabilities. DCA demonstrated that the prediction model has a high net benefit. CONCLUSION: Risk factors for CVD death in HCC patients were investigated for the first time. The nomograph served as an important reference tool for relevant clinical management decisions.

Predictive effect of triglyceride-glucose index on No-Reflow Phenomenon in patients with type 2 diabetes mellitus and acute myocardial infarction undergoing primary percutaneous coronary intervention.

OBJECTIVE: Triglyceride glucose (TyG) index is considered as a new alternative marker of insulin resistance and a clinical predictor of type 2 diabetes mellitus (T2DM) combined with coronary artery disease. However, the prognostic value of TyG index on No-Reflow (NR) Phenomenon in T2DM patients with acute myocardial infarction (AMI) remains unclear. METHODS: In this retrospective study, 1683 patients with T2DM and AMI underwent primary percutaneous coronary intervention (PCI) were consecutively included between January 2014 and December 2019. The study population was divided into two groups as follows: Reflow (n = 1277) and No-reflow (n = 406) group. The TyG index was calculated as the ln [fasting triglycerides (mg/dL)×fasting plasma glucose (mg/dL)/2].Multivariable logistic regression models and receiver-operating characteristic curve analysis were conducted to predict the possible risk of no-reflow. Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI) were calculated to determine the ability of the TyG index to contribute to the baseline risk model. RESULTS: Multivariable logistic regression models revealed that the TyG index was positively associated with NR[OR,95%CI:5.03,(2.72,9.28),p<0.001] in patients with T2DM and AMI. The area under the curve (AUC) of the TyG index predicting the occurrence of NR was 0.645 (95% CI 0.615-0.673; p < 0.001)], with the cut-off value of 8.98. The addition of TyG index to a baseline risk model had an incremental effect on the predictive value for NR [net reclassification improvement (NRI): 0.077(0.043to 0.111), integrated discrimination improvement (IDI): 0.070 (0.031to 0.108), all p < 0.001]. CONCLUSIONS: High TyG index was associated with an increased risk of no-reflow after PCI in AMI patients with T2DM. The TyG index may be a valid predictor of NR phenomenon of patients with T2DM and AMI. Early recognition of NR is critical to improve outcomes with AMI and T2DM patients.

Confined Transport Behavior of Biomolecules within Tilted Nanopores.

The transport behavior of biomolecules at the confined nanoscale is very different from that of the bulk state. Numerous disease diagnostics and targeted drug treatments are performed based on nanochannels in cells. The specific structure and shape of nanochannels play an important role in the behavior and efficiency of substance transport. In this paper, we fabricated nanopores with different tilt angles and the same diameters using focused ion beam. The capture frequency and the blocking current amplitude of λ-DNA within large-angle nanopores decrease obviously, suggesting an increase in the energy barrier of large-angle nanopores and the fact that they stretch biomolecules to thinness. Most importantly, large-angle nanopores slow down λ-DNA transport by 2-4 times. MD simulations find that the sloped electroosmotic flow inside the tilted nanopores is the main factor contributing to the transport phenomena. The increase in the capture time of biomolecules by nanopores assists in obtaining more biological information from the current trajectories. Our study provides a new understanding of substance transport in specially shaped nanopores, which can be instrumental in providing fresh inspiration and approaches to the biomedical field.

Development and Evaluation of Refreshable Braille Display and Active Touch-Reading System for Digital Reading of the Visually Impaired.

The traditional way of reading through Braille books is constraining the reading experience of blind or visually impaired (BVI) in the digital age. In order to improve the reading convenience of BVI, this paper proposes a low-cost and refreshable Braille display device, and solves the problems of high energy consumption and low latching force existing in existing devices. Further, the Braille display device was combined with the 3D Systems Touch device to develop an active Braille touch-reading system for digital reading of BVI with the help of the CHAI3D virtual environment. Firstly, according to the actual needs of BVI to touch and read the Braille dots, this paper utilizes the beam structure to provide a full latching function for the raised Braille dot without energy consumption. Through theoretical derivation and finite element analysis, the performance of the Braille dot actuator is optimized to provide sufficient feedback force and latching force for finger's touch-reading. Then, this paper designs a virtual Braille interactive environment based on the CHAI3D, and combines the sense of touch with audio to effectively improve the recognition accuracy and reading efficiency of BVI for Braille through the multi-modal presentation of Braille information. The performance test results of the device show that the average lifting force of the Braille dot actuator is 101.67 mN, the latching force is over 5 N, and the average refresh frequency is 17.1 Hz, which meets the touch-reading needs of BVI. User experiments show that the average accuracy rate of BVI subjects in identifying digitized Braille is 95.5%, and subjects have a high subjective evaluation of the system.

SERCA1 Overexpression in Skeletal Muscle Attenuates Muscle Atrophy and Improves Motor Function in a Mouse Model of ALS.

Background: Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of muscle mass and muscle function. Previous work from our lab demonstrated that skeletal muscles from a mouse model of ALS show elevated intracellular calcium (Ca2+) levels and heightened endoplasmic reticulum (ER) stress. Objective: To investigate whether overexpression of sarcoplasmic reticulum (SR) Ca2+ ATPase 1 (SERCA1) in skeletal muscle would improve intracellular Ca2+ handling, attenuate ER stress, and improve motor function ALS transgenic mice. Methods: B6SJL-Tg (SOD1*G93A)1Gur/J (ALS-Tg) mice were bred with skeletal muscle α-actinin SERCA1 overexpressing mice to generate wild type (WT), SERCA1 overexpression (WT/+SERCA1), ALS-Tg, and SERCA1 overexpressing ALS-Tg (ALS-Tg/+SERCA1) mice. Motor function (grip test) was assessed weekly and skeletal muscles were harvested at 16 weeks of age to evaluate muscle mass, SR-Ca2+ ATPase activity, levels of SERCA1 and ER stress proteins - protein disulfide isomerase (PDI), Grp78/BiP, and C/EBP homologous protein (CHOP). Single muscle fibers were also isolated from the flexor digitorum brevis muscle to assess changes in resting and peak Fura-2 ratios. Results: ALS-Tg/+SERCA1 mice showed improved motor function, delayed onset of disease, and improved muscle mass compared to ALS-Tg. Further, ALS-Tg/+SERCA1 mice returned levels of SERCA1 protein and SR-Ca2+ ATPase activity back to levels in WT mice. Unexpectedly, SERCA-1 overexpression increased levels of the ER stress maker Grp78/BiP in both WT and ALS-Tg mice, while not altering protein levels of PDI or CHOP. Lastly, single muscle fibers from ALS-Tg/+SERCA1 had similar resting but lower peak Fura-2 levels (at 30 Hz and 100 Hz) compared to ALS-Tg mice. Conclusions: These data indicate that SERCA1 overexpression attenuates the progressive loss of muscle mass and maintains motor function in ALS-Tg mice while not lowering resting Ca2+ levels or ER stress.

Machine learning-coupled tactile recognition with high spatiotemporal resolution based on cross-striped nanocarbon piezoresistive sensor array.

Flexible pressure sensor arrays have been playing important roles in various applications of human-machine interface, including robotic tactile sensing, electronic skin, prosthetics, and human-machine interaction. However, it remains challenging to simultaneously achieve high spatial and temporal resolution in developing pressure sensor arrays for tactile sensing with robust function to achieve precise signal recognition. This work presents the development of a flexible high spatiotemporal piezoresistive sensor array (PRSA) by coupling with machine learning algorithms to enhance tactile recognition. The sensor employs cross-striped nanocarbon-polymer composite as an active layer, though screen printing manufacture processes. A miniaturized signal readout circuit and transmission board is developed to achieve high-speed acquisition of distributed pressure signals from the PRSA. Test results indicate that the developed PRSA platform simultaneously possesses the characteristics of high spatial resolution up to 1.5 mm, fast temporal resolution of about 5 ms, and long-term durability with a variation of less than 2%. The PRSA platform also exhibits excellent performance in real-time visualization of multi-point touch, mapping embossed shapes, and tracking motion trajectory. To test the performance of PRSA in recognizing different shapes, we acquired pressure images by pressing the finger-type device coated with PRSA film on different embossed shapes and implementing the T-distributed Stochastic Neighbor Embedding model to visualize the distinction between images of different shapes. Then we adopted a one-layer neural network to quantify the discernibility between images of different shapes. The analysis results show that the PRSA could capture the embossed shapes clearly by one contact with high discernibility up to 98.9%. Collectively, the PRSA as a promising platform demonstrates its promising potential for robotic tactile sensing.

Epitranscriptional regulation of TGF-ß pseudoreceptor BAMBI by m6A/YTHDF2 drives extrinsic radioresistance.

Activation of TGF-ß signaling serves as an extrinsic resistance mechanism that limits the potential for radiotherapy. Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) antagonizes TGF-ß signaling and is implicated in cancer progression. However, the molecular mechanisms of BAMBI regulation in immune cells and its impact on antitumor immunity after radiation have not been established. Here, we show that ionizing radiation (IR) specifically reduces BAMBI expression in immunosuppressive myeloid-derived suppressor cells (MDSCs) in both murine models and humans. Mechanistically, YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2) directly binds and degrades Bambi transcripts in an N6-methyladenosine-dependent (m6A-dependent) manner, and this relies on NF-κB signaling. BAMBI suppresses the tumor-infiltrating capacity and suppression function of MDSCs via inhibiting TGF-ß signaling. Adeno-associated viral delivery of Bambi (AAV-Bambi) to the tumor microenvironment boosts the antitumor effects of radiotherapy and radioimmunotherapy combinations. Intriguingly, combination of AAV-Bambi and IR not only improves local tumor control, but also suppresses distant metastasis, further supporting its clinical translation potential. Our findings uncover a surprising role of BAMBI in myeloid cells, unveiling a potential therapeutic strategy for overcoming extrinsic radioresistance.

Three-dimensional ultrashort echo time magnetic resonance imaging in pediatric patients with pneumonia: a comparative study.

BACKGROUND: UTE has been used to depict lung parenchyma. However, the insufficient discussion of its performance in pediatric pneumonia compared with conventional sequences is a gap in the existing literature. The objective of this study was to compare the diagnostic value of 3D-UTE with that of 3D T1-GRE and T2-FSE sequences in young children diagnosed with pneumonia. METHODS: Seventy-seven eligible pediatric patients diagnosed with pneumonia at our hospital, ranging in age from one day to thirty-five months, were enrolled in this study from March 2021 to August 2021. All patients underwent imaging using a 3 T pediatric MR scanner, which included three sequences: 3D-UTE, 3D-T1 GRE, and T2-FSE. Subjective analyses were performed by two experienced pediatric radiologists based on a 5-point scale according to six pathological findings (patchy shadows/ground-glass opacity (GGO), consolidation, nodule, bulla/cyst, linear opacity, and pleural effusion/thickening). Additionally, they assessed image quality, including the presence of artifacts, and evaluated the lung parenchyma. Interrater agreement was assessed using intraclass correlation coefficients (ICCs). Differences among the three sequences were evaluated using the Wilcoxon signed-rank test. RESULTS: The visualization of pathologies in most parameters (patchy shadows/GGO, consolidation, nodule, and bulla/cyst) was superior with UTE compared to T2-FSE and T1 GRE. The visualization scores for linear opacity were similar between UTE and T2-FSE, and both were better than T1-GRE. In the case of pleural effusion/thickening, T2-FSE outperformed the other sequences. However, statistically significant differences between UTE and other sequences were only observed for patchy shadows/GGO and consolidation. The overall image quality was superior or at least comparable with UTE compared to T2-FSE and T1-GRE. Interobserver agreements for all visual assessments were significant and rated "substantial" or "excellent." CONCLUSIONS: In conclusion, UTE MRI is a useful and promising method for evaluating pediatric pneumonia, as it provided better or similar visualization of most imaging findings compared with T2-FSE and T1-GRE. We suggest that the UTE MRI is well-suited for pediatric population, especially in younger children with pneumonia who require longitudinal and repeated imaging for clinical care or research and are susceptible to ionizing radiation.

IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial.

Toll-like receptor-driven and interleukin-1 (IL-1) receptor-driven inflammation mediated by IL-1 receptor-associated kinase 4 (IRAK4) is involved in the pathophysiology of hidradenitis suppurativa (HS) and atopic dermatitis (AD). KT-474 (SAR444656), an IRAK4 degrader, was studied in a randomized, double-blind, placebo-controlled phase 1 trial where the primary objective was safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics and clinical activity in patients with moderate to severe HS and in patients with moderate to severe AD. KT-474 was administered as a single dose and then daily for 14 d in 105 healthy volunteers (HVs), followed by dosing for 28 d in an open-label cohort of 21 patients. Degradation of IRAK4 was observed in HV blood, with mean reductions after a single dose of ≥93% at 600-1,600 mg and after 14 daily doses of ≥95% at 50-200 mg. In patients, similar IRAK4 degradation was achieved in blood, and IRAK4 was normalized in skin lesions where it was overexpressed relative to HVs. Reduction of disease-relevant inflammatory biomarkers was demonstrated in the blood and skin of patients with HS and patients with AD and was associated with improvement in skin lesions and symptoms. There were no drug-related infections. These results, from what, to our knowledge, is the first published clinical trial using a heterobifunctional degrader, provide initial proof of concept for KT-474 in HS and AD to be further confirmed in larger trials. ClinicalTrials.gov identifier: NCT04772885 .

A Breath-Based In Vitro Diagnostics for Lower Respiratory Tract Infection.

Lower Respiratory Tract Infections (LRTIs) represent the leading cause of death due to infectious diseases. Current diagnostic modalities primarily depend on clinical symptoms and lack specificity, especially in light of common colonization without overt infection. To address this, we developed a noninvasive diagnostic approach that employs BreathBiomics™, an advanced human breath sampling system, to detect protease activities induced by bacterial infection in the lower respiratory tract. Specifically, we engineered a high-sensitivity and high-specificity molecular sensor for human neutrophil elastase (HNE). The sensor undergoes cleavage in the presence of HNE, an event that is subsequently detected via Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS). Application of this methodology to clinical samples, breath specimens collected from intubated patients with LRTIs, demonstrated the detection of the cleaved sensor by MALDI-TOF MS. Our findings indicate that this novel approach offers a noninvasive and specific diagnostic strategy for people with LRTIs.

Single-cell analysis reveals the immune heterogeneity and interactions in lungs undergoing hepatic ischemia-reperfusion.

Hepatic ischemia-reperfusion IR (HIR) is an unavoidable pathophysiological process during liver transplantation, resulting in systematic sterile inflammation and remote organ injury. Acute lung injury (ALI) is a serious complication after liver transplantation with high postoperative morbidity and mortality. However, the underlying mechanism is still unclear. To assess the phenotype and plasticity of various cell types in the lung tissue microenvironment after HIR at the single-cell level, single-cell RNA sequencing (scRNA-seq) was performed using the lungs from HIR-induced mice. In our results, we identified 23 cell types in the lungs after HIR and found that this highly complex ecosystem was formed by subpopulations of bone marrow-derived cells that signaled each other and mediated inflammatory responses in different states and different intervals. We described the unique transcriptional profiles of lung cell clusters and discovered two novel cell subtypes (Tspo+Endothelial cells and Vcan+ monocytes), as well as the endothelial cell-immune cell and immune cell-T cell clusters interactome. In addition, we found that S100 calcium binding protein (S100a8/a9), specifically and highly expressed in immune cell clusters of lung tissues and exhibited detrimental effects. Finally, the cellular landscape of the lung tissues after HIR was established, highlighting the heterogeneity and cellular interactions between major immune cells in HIR-induced lungs. Our findings provided new insights into the mechanisms of HIR-induced ALI and offered potential therapeutic target to prevent ALI after liver transplantation.