Influence of diamond particle size on the properties of diamond/Al composites fabricated by filtration extrusion.

High-content diamond/Al composites have great potential for application as heat dissipation substrates in high-power electronic devices due to their superior thermal properties. This study addresses the persistent challenge of efficiently and economically preparing high-content diamond/Al composites. The filtration extrusion technique as a novel approach for fabricating these composites and explore the critical impact of diamond particle size on the extrusion process and the resulting microstructures. Our findings reveal that extrusion force remains minimal at the onset of the process but escalates sharply with an increase in diamond content, peaking upon completion of extrusion. Notably, larger diamond particles precipitate a more abrupt rise in extrusion force during displacement. The composites' density and thermal conductivity exhibit an initial increase followed by a decline as the diamond particle size is incremented, while the thermal expansion coefficient shows a progressive rise with size enlargement. These insights are pivotal for optimizing the fabrication parameters to achieve high-performance diamond/Al composites for thermal management applications.

Treatment options for tumor progression after initial immunotherapy in advanced non-small cell lung cancer: A real-world study.

OBJECTIVE: Whether to continue administering immunotherapy to patients with advanced non-small cell lung cancer (NSCLC) who have experienced tumor progression remains controversial after immunotherapy. The aims were to explore survival outcomes after further immunotherapy post-progression and to determine the optimal combination therapy in such cases. METHODS: Overall, 507 patients with NSCLC who underwent immunotherapy and experienced tumor progression were retrospectively divided into Immuno-combination and No-immuno groups according to whether additional combination therapy involving immunotherapy was administered post-progression. Progression-free survival (PFS) and overall survival (OS) were evaluated. Subgroup analyses were performed according to the different treatment regimens for patients in the Immuno-combination group. RESULTS: After propensity score matching, there were 150 patients in the No-immuno group and 300 patients in the Immuno combination group. Superior PFS was observed in the Immuno-combination group compared with those in the No-immuno group (6-month PFS: 25.3 % vs. 60.6 %; 12-month PFS: 6.7 % vs. 24.4 %; P < 0.001). Similar intergroup differences were observed for OS (12-month OS: 22.3 % vs. 69.4 %; 18-month OS: 6.4 % vs. 40.4 %; P < 0.001). Superior PFS outcomes were observed in the Immuno+Antiangiogenic group compared with the Immuno+Chemo group (6-month PFS: 51.3 % vs. 71.5 %; 12-month PFS: 23.1 % vs. 25.7 %; P = 0.017). Similar differences in OS were observed between those same subgroups (12-month OS: 62.1 % vs. 77.9 %; 18-month OS: 33.3 % vs. 48.7 %; P = 0.006). CONCLUSION: Patients with NSCLC experiencing tumor progression post-immunotherapy can still benefit from further treatment, with immunotherapy combined with antiangiogenic therapy the most efficacious option.

Peptide and Protein Cysteine Modification Enabled by Hydrosulfuration of Ynamide.

Efficient functionalization of peptides and proteins has widespread applications in chemical biology and drug discovery. However, the chemoselective and site-selective modification of proteins remains a daunting task. Herein, a highly efficient chemo-, regio-, and stereoselective hydrosulfuration of ynamide was identified as an efficient method for the precise modification of peptides and proteins by uniquely targeting the thiol group of cysteine (Cys) residues. This novel method could be facilely operated in aqueous buffer and was fully compatible with a wide range of proteins, including small model proteins and large full-length antibodies, without compromising their integrity and functions. Importantly, this reaction provides the Z-isomer of the corresponding conjugates exclusively with superior stability, offering a precise approach to peptide and protein therapeutics. The potential application of this method in peptide and protein chemical biology was further exemplified by Cys-bioconjugation with a variety of ynamide-bearing functional molecules such as small molecule drugs, fluorescent/affinity tags, and PEG polymers. It also proved efficient in redox proteomic analysis through Cys-alkenylation. Overall, this study provides a novel bioorthogonal tool for Cys-specific functionalization, which will find broad applications in the synthesis of peptide/protein conjugates.

Efficacy and safety of laser ablation and microwave ablation to treat papillary thyroid microcarcinoma: A retrospective study.

OBJECTIVE: To retrospectively analyze the efficacy and safety of laser ablation (LA) and microwave ablation (MWA) in the treatment of papillary thyroid microcarcinoma (PTMC). METHODS: This was a retrospective study of 103 patients (109 nodules) who underwent thermal ablation for PTMC between October 2019 and March 2023; 61 underwent LA and 48 underwent MWA. The mean patients' age was 43.50 ± 12.42 years. After ablation, changes in tumor size at different time points, local recurrence, new lesions, lymph node metastasis, and complications were evaluated and recorded. The feasibility, success rate, and safety of LA and MWA were analyzed. RESULTS: Complete absence of enhancement on contrast-enhanced ultrasonography was observed in all target tumors after ablation. At the last follow-up, the mean volume of the PTMC nodules decreased from 0.09 ± 0.09 to 0.03 ± 0.03 ml (LA group) and from 0.11 ± 0.10 to 0.06 ± 0.08 ml (MWA group) (both, P < 0.05). There was no significant difference in volume change between the groups (P (groups): 0.520; P (groups over time): 0.423), indicating similar efficacy between the groups. There was also no significant difference in the volume reduction rate between the groups during follow-up, except for at 3 months (P = 0.023). The complication rates did not differ between the LA group (8.2 %) and MWA group (6.3 %) (P > 0.05). CONCLUSION: During the short-term follow-up, ultrasound-guided LA and MWA were effective and safe for PTMC, and there were no significant differences in treatment outcomes between the methods.

Real-time coloration control of gallium-based strips through cold rolling.

Cold rolling has been used as a real-time surface oxidation control method to create colored strips on flexible substrates. By controlling the extrusion rate in real time, a variety of colored strips have been fabricated on Ga-based liquid metal (LM) strips. X-ray photoelectron spectroscopy (XPS) analysis shows that the surfaces of the colored strips, which were obtained through extrusion rate control of LM-Al, consist primarily of metal oxide composites, including Ga2O3, Ga2O, Al2O3, SnO2, and In2O3. The colors of the strip surfaces are directly correlated with the oxide film thickness. Additionally, these cold-rolled colored thin strips demonstrate high conductivity and have significant potential for use as conductive flexible components with indicator functions in the flexible electronics realm.

Common endocrine system adverse events associated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs), a novel anti-tumor therapeutic modality, are monoclonal antibodies targeting certain immune checkpoints (ICs) that reactivate T cells to achieve anti-tumor immunity by targeting, binding, and blocking ICs. Targeted inhibitory antibodies against the ICs cytotoxic T-lymphocyte antigen and programmed death receptor-1 have demonstrated efficacy and durable anti-tumor activity in patients with cancer. ICs may prevent autoimmune reactions. However, ICIs may disrupt ICs properties and trigger autoimmune-related adverse reactions involving various organ systems including the cardiovascular, pulmonary, gastrointestinal, renal, musculoskeletal, dermal, and endocrine systems. Approximately 10% of patients with damage to target organs such as the thyroid, pituitary, pancreas, and adrenal glands develop endocrine system immune-related adverse events (irAEs) such as thyroid dysfunction, pituitary gland inflammation, diabetes mellitus, and primary adrenal insufficiency. However, the symptoms of immunotherapy-associated endocrine system irAEs may be nonspecific and similar to those of other treatment-related adverse reactions, and failure to recognize them early may lead to death. Timely detection and treatment of immunotherapy-associated endocrine irAEs is essential to improve the efficacy of immunotherapy, prognosis, and the quality of life of patients. This study aimed to review the mechanisms by which ICIs cause endocrine irAEs providing guidance for the development of appropriate management protocols. Here, we discuss (1) the biological mechanisms of ICs in tumorigenesis and progression, focusing on cytotoxic T-lymphocyte antigen and programmed cell death-1/programmed cell death-ligand 1; and (2) the epidemiology, clinical symptoms, diagnosis, and treatment of four immunotherapy-related endocrine complications.

Lathyrol reduces the RCC invasion and incidence of EMT via affecting the expression of AR and SPHK2 in RCC mice.

OBJECTIVE: To investigate the effects of Lathyrol on the expression of androgen receptor (AR) and sphingosine kinase 2 (SPHK2) in renal cell carcinoma (RCC) mice and to further explore the mechanism by which Lathyrol inhibits the invasion and incidence of epithelial-mesenchymal transition (EMT). METHODS: An RCC xenograft mouse model was constructed, and the mice were randomly divided into a model group, an experiment group and a negative control group. The experiment group was intragastrically gavaged with Lathyrol solution (20 mg/kg), the model group was intragastrically gavaged with 0.9% NaCl (same volume as that used in the experiment group), and the negative control group was injected intraperitoneally with 2 mg/kg cisplatin aqueous solution. Changes in the body weight and tumor volume of the mice were recorded. Western blot (WB) was used to assess the protein expression levels of AR, p-AR, CYP17A1, PARP1, E-cadherin, N-cadherin, vimentin, α-SMA, ß-catenin, and ZO-1. Protein expression levels of SPHK2, metal matrix protease 2 (MMP2), MMP9 and urokinase-type plasminogen activator (uPA) in tumor tissues were assessed by immunohistochemistry (IHC). AR expression in tumor tissues was assessed after immunofluorescence (IF) staining. RESULTS: After 14 days of drug administration, compared with that in the model group, the tumor volumes in the negative control and experiment groups were lower; the difference in tumor volume among the model, control and experiment groups was statistically significant (P < 0.05). The differences in body weight among the three groups were not statistically significant (P > 0.05). In the model group, the protein expression levels of AR, p-AR, CYP17A1, SPHK2, and PARP1 were relatively increased, the protein expression levels of E-cadherin and ZO-1 were relatively reduced (P < 0.05), and the protein expression levels of N-cadherin, ß-catenin, vimentin, and α-SMA were relatively increased (P < 0.05). In the negative control and experiment groups, the protein expression levels of AR, p-AR, CYP17A1, SPHK2, and PARP1 were relatively decreased (P < 0.05), the protein expression levels of E-cadherin and ZO-1 were relatively increased (P < 0.05), and the protein expression levels of N-cadherin, ß-catenin, vimentin and α-SMA were relatively decreased (P < 0.05). CONCLUSION: Lathyrol and cisplatin inhibit the proliferation of RCC xenografts, reduce the protein expression levels of AR, CYP17A1, SPHK2, PARP1, E-cadherin, and ZO-1 in tumor tissues (P < 0.05), and promote the protein expression levels of N-cadherin, ß-catenin, vimentin and α-SMA (P < 0.05). Therefore, Lathyrol reduces RCC invasion and EMT by affecting the expression of AR and SPHK2 in RCC mice.

Intelligent Assist Office Blood Pressures (IOBP) versus awake ambulatory monitoring and conventional auscultatory office readings in Chinese primary medical institutions.

To practice standardized office blood pressure (OBP) measurement guidelines pragmatically, we developed an intelligent assisted OBP (IOBP) measurement system in the Chinese community, which can automatically obtain two or three BP values after a 5-min rest before the patients visit the doctor and transfer values to the community medical network in real time. We conducted a comparative study to investigate the agreement among IOBP, awake ambulatory BP (ABP), and conventional auscultatory OBP at different BP levels. Participants were divided into three groups according to BP, with 120/80 mmHg and 160/100 mmHg as the cut-off points. Attended IOBP, unattended IOBP, and auscultatory OBP were randomly measured before ABP monitoring. In total, 245 participants were included in the analysis. The mean systolic attended/unattended IOBP, auscultatory OBP, and awake ABP were 135.0, 136.7, 135.6, and 136.2 mmHg, respectively. Bland-Altman analysis revealed a bias of -1.1 and 0.5 mmHg for systolic attended/unattended IOBP compared with awake ABP in the overall sample. For auscultatory OBP, the bias was -0.4 (attended) and 1.2 mmHg (unattended). The discrepancy between the systolic attended/unattended IOBP and awake ABP was inconsistent at different BP levels. In Group 1 the values were -8.4 and -6.9 mmHg, whereas in Group 3, the values were 9.4 and 10.0 mmHg. BP measured using the IOBP measurement system was in accordance with awake ABP and conventional OBP, and can be a good choice in the Chinese community.

Fatty acid de novo biosynthesis in plastids: Key enzymes and their critical roles for male reproduction and other processes in plants.

Fatty acid de novo biosynthesis in plant plastids is initiated from acetyl-CoA and catalyzed by a series of enzymes, which is required for the vegetative growth, reproductive growth, seed development, stress response, chloroplast development and other biological processes. In this review, we systematically summarized the fatty acid de novo biosynthesis-related genes/enzymes and their critical roles in various plant developmental processes. Based on bioinformatic analysis, we identified fatty acid synthase encoding genes and predicted their potential functions in maize growth and development, especially in anther and pollen development. Finally, we highlighted the potential applications of these fatty acid synthases in male-sterility hybrid breeding, seed oil content improvement, herbicide and abiotic stress resistance, which provides new insights into future molecular crop breeding.

Longtime evolution and stationary response of a stochastic tumor-immune system with resting T cells.

In this paper, we take the resting T cells into account and interpret the progression and regression of tumors by a predator-prey like tumor-immune system. First, we construct an appropriate Lyapunov function to prove the existence and uniqueness of the global positive solution to the system. Then, by utilizing the stochastic comparison theorem, we prove the moment boundedness of tumor cells and two types of T cells. Furthermore, we analyze the impact of stochastic perturbations on the extinction and persistence of tumor cells and obtain the stationary probability density of the tumor cells in the persistent state. The results indicate that when the noise intensity of tumor perturbation is low, tumor cells remain in a persistent state. As this intensity gradually increases, the population of tumors moves towards a lower level, and the stochastic bifurcation phenomena occurs. When it reaches a certain threshold, instead the number of tumor cells eventually enter into an extinct state, and further increasing of the noise intensity will accelerate this process.

Ynamide Coupling Reagents: Origin and Advances.

Since the pioneering work of Curtius and Fischer, chemical peptide synthesis has witnessed a century's development and evolved into a routine technology. However, it is far from perfect. In particular, it is challenged by sustainable development because the state-of-the-art of peptide synthesis heavily relies on legacy reagents and technologies developed before the establishment of green chemistry. Over the past three decades, a broad range of efforts have been made for greening peptide synthesis, among which peptide synthesis using unprotected amino acid represents an ideal and promising strategy because it does not require protection and deprotection steps. Unfortunately, C → N peptide synthesis employing unprotected amino acids has been plagued by undesired polymerization, while N → C inverse peptide synthesis with unprotected amino acids is retarded by severe racemization/epimerization owing to the iterative activation and aminolysis of high racemization/epimerization susceptible peptidyl acids. Consequently, there is an urgent need to develop innovative coupling reagents and strategies with novel mechanisms that can address the long-standing notorious racemization/epimerization issue of peptide synthesis.This Account will describe our efforts in discovery of ynamide coupling reagents and their application in greening peptide synthesis. Over an eight-year journey, ynamide coupling reagents have evolved into a class of general coupling reagents for both amide and ester bond formation. In particular, the superiority of ynamide coupling reagents in suppressing racemization/epimerization enabled them to be effective for peptide fragment condensation, and head-to-tail cyclization, as well as precise incorporation of thioamide substitutions into peptide backbones. The first practical inverse peptide synthesis using unprotected amino acids was successfully accomplished by harnessing such features and taking advantage of a transient protection strategy. Ynamide coupling reagent-mediated ester bond formation enabled efficient intermolecular esterification and macrolactonization with preservation of α-chirality and the configuration of the conjugated α,ß-C-C double bond. To make ynamide coupling reagents readily available with reasonable cost and convenience, we have developed a scalable one-step synthetic method from cheap starting materials. Furthermore, a water-removable ynamide coupling reagent was developed, offering a column-free purification of the target coupling product. In addition, the recycle of ynamide coupling reagent was accomplished, thereby paving the way for their sustainable industrial application.As such, this Account presents the whole story of the origin, mechanistic insights, preparation, synthetic applications, and recycle of ynamide coupling reagents with a perspective that highlights their future impact on peptide synthesis.

Biomimetic Design of a New Semi-Rigid Spatial Mesh Antenna Reflector.

The reflective surface accuracy (RSA) of traditional space mesh antennas typically ranges from 0.2 to 6 mmRMS. To improve the RSA, an active control scheme can be employed, although it presents challenges in determining the installation position of the actuator. In this study, we propose a novel design for a semi-rigid cable mesh that combines rigid members and a flexible woven mesh, drawing inspiration from both rigid ribbed antennas and biomimicry. Initially, we investigate the planar mesh topology of spider webs and determine the bionic cable surface's mesh topology based on the existing hexagonal meshing method, with RSA serving as the evaluation criterion. Subsequently, through motion simulations and careful observation, we establish the offset angle as the key design parameter for the bionic mesh and complete the design of the bionic cable mesh accordingly. Finally, by analyzing the impact of the node quantity on RSA, we determine a layout scheme for the flexible woven mesh with a variable number of nodes, ultimately settling for 26 nodes. Our results demonstrate that the inclusion of numerous rigid components on the bionic cable mesh surface offers viable installation positions for the actuator of the space mesh antenna. The reflector accuracy achieved is 0.196 mmRMS, slightly surpassing the lower limit of reflector accuracy observed in most traditional space-space mesh antennas. This design presents a fresh research perspective on combining active control schemes with reflective surfaces, offering the potential to enhance the RSA of traditional rigid rib antennas to a certain extent.

Survival benefit of adjuvant chemotherapy after resection of Stage I lung adenocarcinoma containing micropapillary components.

BACKGROUND: The usefulness of postoperative adjuvant chemotherapy (ACT) for patients with stage I lung adenocarcinoma with micropapillary (MIP) components remains unclear. We analyzed whether postoperative ACT could reduce recurrence in patients with stage I lung adenocarcinoma with MIP components, thereby improving their overall survival (OS) and disease-free survival (DFS). METHODS: Data for patients with pathologically confirmed stage I lung adenocarcinoma with MIP components from January 2012 to December 2018 were retrospectively analyzed. OS and DFS were analyzed in groups and subgroups. RESULTS: Overall, 259 patients were enrolled. Patients who received ACT in stage IA showed significantly better survival than did those with no-adjuvant chemotherapy (NACT); (5-year OS 89.4% vs. 73.6%, p < 0.001; 5-year DFS 87.2% vs. 66.0%, p = 0.008). A difference was also observed for in-stage IB patients (5-year OS 82.0% vs. 51.8%, p = 0.001; 5-year DFS 76.0% vs. 41.11 %, p = 0.004). In subgroup analysis based on the proportion of MIP components, patients with 1%-5% MIP components had a significantly better prognosis in the ACT group than in the NACT group (5-year OS 82.4% vs. 66.0%, p = 0.005; 5-year DFS 76.5% vs. 49.1%, p = 0.032). A similar difference was observed for patients with MIP ≥5% (5-year OS 80.7% vs. 47.8%, p = 0.009; 5-year DFS 73.11% vs. 43.5%, p = 0.007). CONCLUSION: Among patients with stage I lung adenocarcinoma with MIP components, those who received ACT showed significant survival benefits compared to those without ACT. Patients with lung adenocarcinoma with MIP components could benefit from ACT when the MIP was ≥1%.

Clinical implications and predictive value of the creatinine­cystatin C ratio in patients with multiple myeloma and renal impairment.

The creatinine (Cr)-cystatin C ratio (CCR) at the time of cancer diagnosis is associated with survival; however, to the best of our knowledge, the association between this ratio and mortality in patients with multiple myeloma and renal impairment (RI) is unclear. Therefore, the present study aimed to assess this association, as well as disease prognosis and the clinical significance of the CCR in patients with multiple myeloma and RI. The present retrospective study included 191 patients diagnosed with multiple myeloma and RI between 2012 and 2022. The predictive value of the CCR was evaluated using area under the receiver operating characteristic curve (AUC) values. The factors affecting overall survival (OS) were assessed using uni- and multivariate logistic regression analyses. The effect of the CCR on survival was evaluated using a Cox regression model and the Kaplan-Meier method. There was a significant association between low CCR and poor progression-free survival (PFS) and overall survival (OS). The 1-, 2- and 3-year PFS and OS rates in patients with a low CCR were significantly lower than those in patients with a high CCR. The 1-, 2- and 3-year AUC values of the CCR were 0.712, 0.764 and 0.746 respectively. Multivariate analysis revealed sex, age, Cr levels, CCR and C-reactive protein levels as independent prognostic factors affecting OS rates. The CCR is a potential prognostic indicator in patients with multiple myeloma with RI and is associated with clinical stages.

Inverse Peptide Synthesis Using Transient Protected Amino Acids.

Peptide therapeutics have experienced a rapid resurgence over the past three decades. While a few peptide drugs are biologically produced, most are manufactured via chemical synthesis. The cycle of prior protection of the amino group of an α-amino acid, activation of its carboxyl group, aminolysis with the free amino group of a growing peptide chain, and deprotection of the N-terminus constitutes the principle of conventional C → N peptide chemical synthesis. The mandatory use of the Nα-protecting group invokes two additional operations for incorporating each amino acid, resulting in poor step- and atom-economy. The burgeoning demand in the peptide therapeutic market necessitates cost-effective and environmentally friendly peptide manufacturing strategies. Inverse peptide chemical synthesis using unprotected amino acids has been proposed as an ideal and appealing strategy. However, it has remained unsuccessful for over 60 years due to severe racemization/epimerization during N → C peptide chain elongation. Herein, this challenge has been successfully addressed by ynamide coupling reagent employing a transient protection strategy. The activation, transient protection, aminolysis, and in situ deprotection were performed in one pot, thus offering a practical peptide chemical synthesis strategy formally using unprotected amino acids as the starting material. Its robustness was exemplified by syntheses of peptide active pharmaceutical ingredients. It is also amenable to fragment condensation and inverse solid-phase peptide synthesis. The compatibility to green solvents further enhances its application potential in large-scale peptide production. This study offered a cost-effective, operational convenient, and environmentally benign approach to peptides.

Safety and efficacy of remote ischemic conditioning for spontaneous intracerebral hemorrhage (SERIC-ICH): A multicenter, randomized, parallel-controlled clinical trial study design and protocol.

BACKGROUND: Previous studies have revealed that remote ischemic conditioning (RIC) may have a neuroprotective function. However, the potential benefit of RIC for patients with ICH remain unclear. OBJECTIVE: The primary aim of this study is to assess the safety and efficacy of RIC for patients with ICH. METHODS: The Safety and Efficacy of RIC for Spontaneous ICH (SERIC-ICH) is an ongoing prospective, randomized, multicenter, parallel-controlled, and blinded-endpoint clinical trial. The study will enroll an estimated 2000 patients aged ⩾18 years within 24 h after ICH onset, with National Institutes of Health Stroke Scale ⩾6 and Glasgow Coma Scale ⩾8 upon presentation. The patients will be randomly assigned to the RIC or control groups (1:1) and will be treated with cuffs inflated to a pressure of 200 or 60 mmHg, respectively, twice daily for 7 days. Each RIC treatment will consist of four cycles of arm ischemia for 5 min, followed by reperfusion for another 5 min, for a total procedure time of 35 min. The primary efficacy outcome measure is the proportion of patients with good functional outcomes (modified Rankin scale 0-2) at 180 days. The safety outcome measures will include all adverse events and severe adverse events occurring in the course of the study. DISCUSSION: RIC is an inexpensive intervention and might be a strategy to improve outcomes in patients with ICH. The SERIC-ICH trial will investigate whether RIC treatment can be applied as an adjuvant treatment in the acute phase of ICH and identify safety issues.

Enacted Stigma Influences Bereavement Coping Among Children Orphaned by Parental AIDS: A Longitudinal Study with Network Analysis.

Purpose: The study aims to understand how enacted stigma influences bereavement coping at the style (scale) level and the specific pathways at the strategy (item) level. Methods: The longitudinal data of 755 children orphaned by parental Acquired Immune Deficiency Syndrome (AIDS) in rural China were used. Grief processing and deliberate grief avoidance were measured at wave 1 (baseline) and wave 2 (one-year follow-up) to reflect bereavement coping in the contexts of being with family members, being with friends, being with community members, and being alone. Enacted stigma that measured at wave 1 was used to assess the experienced stigma of these AIDS-orphaned children. Network analyses were run following regressions. Results: Controlling for demographics and baseline-level bereavement coping, multivariate regressions revealed that enacted stigma at wave 1 significantly predicted grief processing and deliberate grief avoidance at wave 2. Network analyses showed that, for grief processing, stigma increased searching for meaning alone and with friends and expressing feelings to community members, which then provoked the same strategy across contexts. Meanwhile, stigma triggered the deliberate grief avoidance network by initially suppressing the expression of feelings to community members. Conclusion: Enacted stigma contributes to bereavement coping. Stigma stirs up complex feelings but forces AIDS-orphaned children to suppress expressions, and it increases needs to process grief through meaning making but cuts supporting forces by promoting avoidance. Interventions are imperative to reduce stigma, improve emotion regulation, and facilitate meaning making for people bereaved by stigmatized deaths.

The Combined Effects of Hourly Multi-Pollutant on the Risk of Ambulance Emergency Calls: A Seven-Year Time Series Study.

BACKGROUND: Ambulance emergency calls (AECs) are seen as a more suitable metric for syndromic surveillance due to their heightened sensitivity in reflecting the health impacts of air pollutants. Limited evidence has emphasized the combined effect of hourly air pollutants on AECs. This study aims to investigate the combined effects of multipollutants (i.e., PM2.5, PM10, Ozone, NO2, and SO2) on all-cause and cause-specific AECs by using the quantile g-computation method. METHODS: We used ambulance emergency dispatch data, air pollutant data, and meteorological data from between 1 January 2013 and 31 December 2019 in Shenzhen, China, to estimate the associations of hourly multipollutants with AECs. We followed a two-stage analytic protocol, including the distributed lag nonlinear model, to examine the predominant lag for each air pollutant, as well as the quantile g-computation model to determine the associations of air pollutant mixtures with all-cause and cause-specific AECs. RESULTS: A total of 3,022,164 patients were identified during the study period in Shenzhen. We found that each interquartile range increment in the concentrations of PM2.5, PM10, Ozone, NO2, and SO2 in 0-8 h, 0-8 h, 0-48 h, 0-28 h, and 0-24 h was associated with the highest risk of AECs. Each interquartile range increase in the mixture of air pollutants was significantly associated with a 1.67% (95% CI, 0.12-3.12%) increase in the risk of all-cause AECs, a 1.81% (95% CI, 0.25-3.39%) increase in the risk of vascular AECs, a 1.77% (95% CI, 0.44-3.11%) increase in reproductive AECs, and a 2.12% (95% CI, 0.56-3.71%) increase in AECs due to injuries. CONCLUSIONS: We found combined effects of pollutant mixtures associated with an increased risk of AECs across various causes. These findings highlight the importance of targeted policies and interventions to reduce air pollution, particularly for PM, Ozone, and NO2 emissions.

Administration of a glypican-3 peptide increases the infiltration and cytotoxicity of CD8+ T cells against testicular yolk sac tumor, associated with enhancing the intratumoral cGAS/STING signaling.

BACKGROUND: Glypican-3 (GPC3) is highly expressed in testicular yolk sac tumor (TYST). GPC3 has been evaluated as a cancer vaccine for some types of tumors, but little is known on the effects of GPC3 peptide-based therapy on TYST. Here, we evaluated the antitumor effect of GPC3144-152 on TYST and its potential mechanisms. METHODS: GPC3144-152 -specific CD8+ T cells were induced by vaccine immunization and examined by ELISPOT. The CD8+ T cells were purified for testing their cytotoxicity in vitro against TYST cells by CCK-8 and TUNEL assays and in vivo against tumor growth. The influence of GPC3144-152 loading and/or cGAS silencing on the tumor growth, apoptosis and cGAS/STING signaling was tested by immunohistochemistry, immunofluorescence, flow cytometry, and Western blot. RESULTS: Vaccination with GPC3144-152 induced tumor-specific CD8+ T cells that secreted high levels of IFN-γ and granzyme B, and had potent cytotoxicity against TYST in a dose-dependent manner. Adoptive transfer of CD8+ T cells and treatment with GPC3144-152 significantly inhibited the growth of TYST tumors, but less effective for cGAS-silenced TYST tumors in vivo. Treatment with GPC3144-152 enhanced the infiltration of CD8+ T cells into the tumor environment and their cytotoxicity against TYST tumors in vivo by up-regulating granzyme B and IFN-ß expression, but down-regulating GPC3 expression in the tumors. Co-culture of CD8+ T cells with TYST in the presence of exogenous GPC3144-152 enhanced peptide-specific CD8+ T-cell cytotoxicity in vitro, accompanied by enhancing cGAS, γH2AX, TBK1, and IRF3 phosphorylation in TYST cells, but less effective in cGAS-silenced TYST cells. CONCLUSIONS: These data indicated that GPC3 peptide-specific CD8+ T cells had potent antitumor activity against TYST tumor, particularly for combined treatment with the peptide, which was partially dependent on the intratumoral cGAS/STNG signaling. GPC3 peptide vaccine may be valuable for the combination treatment of TYST.