Tubeimoside-I, an inhibitor of HSPD1, enhances cytotoxicity of oxaliplatin by activating ER stress and MAPK signaling pathways in colorectal cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Tubeimoside-I (TBM) promotes various cancer cell death by increasing the reactive oxygen species (ROS) production. However, the specific molecular mechanisms of TBM and its impact on oxaliplatin-mediated anti-CRC activity are not yet fully understood. AIM OF THE STUDY: To elucidate the therapeutic effect and underlying molecular mechanism of TBM on oxaliplatin-mediated anti-CRC activity. MATERIALS AND METHODS: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing assays and flow cytometry were conducted to investigate the changes in cell phenotypes and ROS generation. Real-time quantitative PCR (qRT-PCR) and western blotting were performed to detect the expressions of related mRNA and proteins. Finally, mouse xenograft models demonstrated that synergistic anti-tumor effects of combined treatment with TBM and oxaliplatin. RESULTS: The synergistic enhancement of the anti-tumor effects of oxaliplatin in colon cancer cells by TBM involved in the regulation of ROS-mediated endoplasmic reticulum (ER) stress, C-jun-amino-terminal kinase (JNK), and p38 MAPK signaling pathways. Mechanistically, TBM increased ROS generation in colon cancer cells by inhibiting heat shock protein 60 (HSPD1) expression. Knocking down HSPD1 increased TBM-induced antitumor activity and ROS generation in colon cancer cells. The mouse xenograft tumor models further validated that the combination therapy exhibited stronger anti-tumor effects than monotherapy alone. CONCLUSIONS: Combined therapy with TBM and oxaliplatin might be an effective therapeutic strategy for some CRC patients.

Interception behaviors of mixed chlorinated hydrocarbons in groundwater by DDAC-amended LPBs: Control mechanism and CFD simulation.

Low permeability barrier has emerged as a promising, cost-effective technology for anti-seepage and pollution mitigation in geotechnical engineering. However, its efficacy in organic pollution sites, particularly those contaminated with chlorinated hydrocarbons (CHCs) pales in comparison to its performance in areas contaminated by heavy metals. In order to rectify this deficiency, a novel bentonite backfill, modified with dihexadecyl dimethyl ammonium chloride (DDAC) and designated as DDAC-LPB, is proposed for use in low permeability barriers to contain CHCs in groundwater at contaminated sites. A series of rigid-wall permeability tests, mechanical properties tests, and diffusion tests were conducted to investigate the impact of CHCs solution on hydraulic conductivity, unconfined compression strength and adsorption properties of the LPB, respectively. The results reveal that LPB containing 10 % DDAC modified bentonite exhibits excellent impermeability and mechanical workability, with a 2-5 fold increase in adsorption capacity, primarily driven by the hydrophobic interaction between CHCs and DDAC. Moreover, this study has innovatively applied computational fluid dynamics simulation to the field of solute transport modeling to evaluate the performance of DDAC-LPB in containing CHCs within lateral flowing groundwater. This novel approach was benchmarked against the widely embraced convection-diffusion equation modeling method, demonstrating a significant improvement in predictive accuracy. In a typical field scenario, the breakthrough time for CHCs using the DDAC-LPB technique ranged from 25.3 to 25.5 years, with a barrier thickness of 1 m. This duration satisfactorily aligns with the expected service life of real-world projects. Overall, the DDAC-LPB has demonstrated superior performance and practical applicability in enhancing the containment of CHCs in contaminated groundwater.

Unexpected transient atrioventricular block and slow junctional rhythm using pulsed field ablation for slow pathway modification: excited or cautious for ablators.

BACKGROUND: Data regarding the effects of pulsed field ablation (PFA) on atrioventricular nodal reentrant tachycardia (AVNRT) are limited. OBJECTIVE: To evaluate the outcomes of PFA for AVNRT, and its impact on dual-pathway electrophysiology. METHODS: A larger cohort of patients with typical AVNRT underwent slow pathway (SP) modification (SPM) using a focal PFA catheter in a biphasic/bipolar manner. The primary endpoints were the efficacy and safety of PFA during the procedure and 6-month follow-up. RESULTS: The acute success of SPM was achieved in all 40 patients. The total ablation time was 7.9±3.8 seconds for 6.4±2.2 ablation sites (ASs). Slow junctional rhythm (SJR) was induced in 32 (80%) patients lasting 28.9±10.3 seconds in 3.0±1.1 ASs per patient. SP was located 11.1±1.2 mm from the largest His activation (LHA). At 9 ASs, SJR could be reinduced after an increase of contact force (CF) from 1.3±0.5g to 6.4±1.3g (P<0.0001). Transient atrioventricular block (AVB) was recorded in 7(17.5%) patients (1 second-degree and 6 third-degree AVB) lasting 435.3±227.4 seconds, with a shorter AS-LHA distance than patients without AVB (7.7±0.6 mm vs. 11.3±1 mm, P<0.0001). PFA-related delayed atrial-His (n=6) and His-atrial (n=1) conduction preceded transient AVB with a constant His-ventricular interval. Normal PR interval was restored within 24 hours. All patients maintained sinus rhythm without any significant adverse events during 6-month follow-up. CONCLUSION: Despite the high efficiency of PFA for SPM, the notable incidence of transient AVB warranted caution when applying it near the His bundle. SJR frequently occurred during SPM and was dependent on moderate CF.

Solar-Driven Evaporator With "Starburst Turbine" Design Featuring Directional Salt Crystallization, Antibacterial, and Catalytic Multifunctionality for Efficient Water Purification.

Facing the global challenge of water scarcity, solar-driven desalination is considered a sustainable technology for obtaining freshwater from seawater. However, issues such as uncontrolled salt crystallization and bacterial contamination limit its efficiency and practicality. This study proposes an innovative solar-driven evaporator designed to address these challenges using optimized shape design and advanced photothermal materials. Based on finite element analyses, cylindrical evaporators with a "Starburst Turbine" shape are designed and fabricated, achieving directional salt crystallization and a record-breaking water collection rate of 3.56 kg m-2 h-1 and an evaporation rate of 4.57 kg m-2 h-1 under one sun illumination. During continuous 60-h illumination tests, the evaporator maintained a stable evaporation rate, attributed to its excellent directional salt crystallization capability. Additionally, the evaporator demonstrates superior photodynamic antibacterial performance and photocatalytic degradation of organic pollutants. Under one sun illumination for 1 h, it achieves 100% sterilization of S. aureus and E. coli, and a 95.4% degradation of methylene blue (MB), demonstrating its potential to purify various wastewater types. These findings underscore the significant scientific and practical value of integrating antibacterial and photocatalytic functions into solar water purification materials, providing a sustainable solution to global water scarcity challenges and environmental protection.

A Phase Ib Study of Linperlisib in the Treatment of Patients with Relapsed and/or Refractory Peripheral T-cell Lymphoma.

PURPOSE: Relapsed and/or refractory peripheral T-cell lymphoma (r/r PTCL) is an aggressive and heterogeneous hematologic malignancy with high unmet need. Previously, PI3K inhibitors were shown to be efficacious in B- and T-cell lymphomas, but as a drug class, these agents have frequently been observed to have tolerability limitations. Next-generation agents that improve the tolerability while maintaining efficacy are desirable. PATIENTS AND METHODS: A phase Ib clinical study was conducted with the oral PI3K-delta isoform-selective small-molecule inhibitor, linperlisib, in patients with r/r PTCL, and the clinical benefit was explored by the evaluation of safety and efficacy. RESULTS: In this clinical study, 43 patients with r/r PTCL in China were treated with continuous dosing of 80-mg linperlisib once a day. Treatment-related adverse events (AE) were manageable. The most frequently reported grade 3 AE were neutropenia (21%), pneumonia (11.6%), and hypertriglyceridemia (7%). All other AE were either absent or reported in <5% of the patients. Linperlisib treatment for these patients with r/r PTCL, consisting of the major PTCL subtypes, was observed to have a 60.5% overall response rate with 35% complete responses and led to a median duration of response of 11.1 months, median progression-free survival of 11.8 months, and a median overall survival of >38 months (not reached). CONCLUSIONS: With the very promising clinical activity against r/r PTCL, the results of this study support the further investigation of linperlisib for the treatment of r/r PTCL.

Efficacy and safety of camrelizumab plus apatinib in patients with advanced esophageal squamous cell carcinoma previously treated with immune checkpoint inhibitors (CAP 02 Re-challenge): A single-arm, phase II study.

BACKGROUND: With the increasing use of immune checkpoint inhibitors (ICIs) in advanced esophageal squamous cell carcinoma (ESCC), there remains an unmet need for options to address disease progression after prior ICIs. This single-arm phase II study evaluated the efficacy and safety of re-challenge with camrelizumab plus apatinib in patients with advanced ESCC who were previously treated with ICIs. METHODS: This study enrolled patients aged 18-75 years with unresectable locally advanced, locally recurrent, or distant metastatic ESCC who received prior ICIs. Patients received intravenous camrelizumab 200 mg every 2 weeks and oral apatinib 250 mg daily until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was the investigator-assessed confirmed objective response rate (ORR). RESULTS: Between September 1, 2021 and March 29, 2023, 49 eligible patients were enrolled and received treatment. Among the 49 patients, the confirmed ORR was 10.2 % (95 % CI 3.4-22.2), the disease control rate (DCR) was 69.4 % (54.6-81.7), the median progression-free survival (PFS) was 4.6 months (95 % CI 3.8-6.5) and overall survival (OS) was 7.5 months (5.5-13.6). Grade ≥ 3 treatment-related adverse events occurred in 17 patients (34.7 %). No treatment-related deaths occurred. CONCLUSIONS: This study showed that the confirmed ORR was modest and did not reach clinically meaningful improvement for patients with ESCC who were previously treated with ICIs, with a manageable safety profile.

Synthesis, structure, spectra, cytotoxicity and photo induced NO release of four isomeric nitrosylruthenium complexes.

Four isomeric nitrosyl ruthenium complexes [RuCl(2mqn)(Val)(NO)] (1-4) were prepared (2mqn, 2-methyl-8-hydroxyquinoline; Val, L-valine) and characterized by 1H NMR, 13C NMR, absorption spectrum, electrospray ionization mass spectrometry, and X-ray crystal diffraction. Time-resolved FT-IR and fluorescence spectroscopy were used to monitor photo-induced NO release in solution, while NO released in living cells was imaged using a selective fluorescent probe. The isomeric complexes showed different levels of cytotoxicity against HeLa cells, and slightly photo-enhanced anti-proliferative activity was observed. The isomeric complexes 1-4 inhibited the growth of HeLa cells by inducing apoptosis and promoted cell cycle arrest in the S phase. Furthermore, they showed relatively lower cytotoxicity against the human liver cell line HL-7702. The different spatial configurations of the complexes is close related with the selective binding of the isomeric complexes with serum albumin, which provide insight into the potential applications of the nitrosyl ruthenium complexes.

Comparative efficacy of cryoablation versus robot-assisted partial nephrectomy in the treatment of cT1 renal tumors: a systematic review and meta-analysis.

PURPOSE: This study utilizes a meta-analytic approach to investigate the effects of cryoablation and robot-assisted partial nephrectomy on perioperative outcomes, postoperative renal function, and oncological results in patients. METHODS: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Four electronic databases (PubMed, Embase, Web of Science, and the Cochrane Library database) were systematically searched to identify relevant studies published in English up to November 2023. The primary outcomes were perioperative results, complications, postoperative renal function and oncologic outcomes. Review Manager 5.4 was used for this analysis. RESULTS: This study included a total of 10 studies comprising 2,011 patients. Compared to RAPN (Robot-Assisted Partial Nephrectomy), the CA (Cryoablation) group had a shorter hospital stay [MD -1.76 days; 95% CI -3.12 to -0.41; p = 0.01], less blood loss [MD -104.60 ml; 95% CI -152.58 to -56.62; p < 0.0001], and fewer overall complications [OR 0.62; 95% CI 0.45 to 0.86; p = 0.004], but a higher recurrence rate [OR 7.83; 95% CI 4.32 to 14.19; p < 0.00001]. There were no significant differences between the two groups in terms of operative time, minor complications (Clavien-Dindo Grade 1-2), major complications (Clavien-Dindo Grade 3-5), changes in renal function at 12 months post-operation, RFS (Recurrence-Free Survival), and OS (Overall Survival). CONCLUSION: The evidence provided by this meta-analysis indicates that the therapeutic effects of Cryoablation (CA) are similar to those of Robot-Assisted Partial Nephrectomy (RAPN) in terms of perioperative outcomes and renal function. However, the recurrence rate of tumors treated with CA is significantly higher. SYSTEMATIC REVIEW REGISTRATION: The study has been registered on the International Prospective Register of Systematic Reviews (PROSPERO: CRD42023465846).

Targeting IL-33 reprograms the tumor microenvironment and potentiates antitumor response to anti-PD-L1 immunotherapy.

BACKGROUND: The main challenge against patients with cancer to derive benefits from immune checkpoint inhibitors targeting PD-1/PD-L1 appears to be the immunosuppressive tumor microenvironment (TME), in which IL-33/ST2 signal fulfills critical functions. However, whether IL-33 limits the therapeutic efficacy of anti-PD-L1 remains uncertain. METHODS: Molecular mechanisms of IL-33/ST2 signal on anti-PD-L1 treatment lewis lung carcinoma tumor model were assessed by RNA-seq, ELISA, WB and immunofluorescence (IF). A sST2-Fc fusion protein was constructed for targeting IL-33 and combined with anti-PD-L1 antibody for immunotherapy in colon and lung tumor models. On this basis, bifunctional fusion proteins were generated for PD-L1-targeted blocking of IL-33 in tumors. The underlying mechanisms of dual targeting of IL-33 and PD-L1 revealed by RNA-seq, scRNA-seq, FACS, IF and WB. RESULTS: After anti-PD-L1 administration, tumor-infiltrating ST2+ regulatory T cells (Tregs) were elevated. Blocking IL-33/ST2 signal with sST2-Fc fusion protein potentiated antitumor efficacy of PD-L1 antibody by enhancing T cell responses in tumor models. Bifunctional fusion protein anti-PD-L1-sST2 exhibited enhanced antitumor efficacy compared with combination therapy, not only inhibited tumor progression and extended the survival, but also provided long-term protective antitumor immunity. Mechanistically, the superior antitumor activity of targeting IL-33 and PD-L1 originated from reducing immunosuppressive factors, such as Tregs and exhausted CD8+ T cells while increasing tumor-infiltrating cytotoxic T lymphocyte cells. CONCLUSIONS: In this study, we demonstrated that IL-33/ST2 was involved in the immunosuppression mechanism of PD-L1 antibody therapy, and blockade by sST2-Fc or anti-PD-L1-sST2 could remodel the inflammatory TME and induce potent antitumor effect, highlighting the potential therapeutic strategies for the tumor treatment by simultaneously targeting IL-33 and PD-L1.

TIGIT: Will it be the next star therapeutic target like PD-1 in hematological malignancies?

Research on the mechanism and application of checkpoint inhibitory receptors in hematologic diseases has progressed rapidly. However, in the treatment of relapserefractory (R/R) hematologic malignancies and anti-programmed cell death protein 1 (PD-1), patients who are resistant to anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) are in urgent need of alternative therapeutic targets. T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) has a broad prospect as an inhibitory receptor like PD-1, but its more specific mechanism of action and application in hematologic diseases still need to be further studied. In this review, we discuss the mechanism of TIGIT pathway, combined effects with other immune checkpoints, immune-related therapy, the impact of TIGIT on hematopoietic stem cell transplantation (HSCT) and the tumor microenvironment (TME) provides a potential therapeutic target for hematologic malignancies.

Enhanced Preoperative Planning for Intracranial Aneurysms Through Multimodal Image Fusion of Silent/Time-of-Magnetic Resonance Angiography and Computed Tomography Using 3DSlicer: A Comparative Efficacy Analysis With Computed Tomography Angiography.

OBJECTIVE: This study evaluates the effectiveness of multimodal image fusion (MIF) using silent and time-of-flight (TOF) magnetic resonance angiography (MRA) and computed tomography (CT) for preoperative planning in patients with intracranial aneurysms who have contraindications to contrast media. MATERIALS AND METHODS: A retrospective study included 40 patients with intracranial aneurysms, diagnosed using three-dimensional computed tomography angiography (CTA). These patients underwent both Silent and TOF MRA scans, followed by a CTA scan. The multi-image fusion (MIF) technique, applied using 3DSlicer software, integrated the silent/TOF-MRA with CT images for preoperative assessment. This study compared the image quality, aneurysm detection sensitivity, and anatomic accuracy of the MIF images with those of three-dimensional CTA. RESULTS: Silent-MRA-CT fusion images demonstrated higher sensitivity (95.5%) and lower false negative rates (4.5%) compared with TOF-MRA-CT. Furthermore, silent-MRA-CT fusion images outperformed TOF-MRA-CT in terms of signal homogeneity, venous signal interference suppression, and aneurysm visibility (all P < 0.05). The interclass correlation coefficient and kappa values for aneurysm morphology and shape indicated superior measurement consistency and shape concordance of silent-MRA-CT with CTA compared with TOF-MRA-CT (all P < 0.01). CONCLUSION: This study supports the use of silent/TOF-MRA-CT fusion imaging as a reliable alternative to CTA, noting that silent-MRA-CT closely mirrors CTA. Contrast-free MRA-CT fusion images have the potential to be used for preoperative planning in patients with intracranial aneurysms who have contraindications to contrast.

Establishment and evaluation of MIRA-qPCR assay for the rapid and sensitively detection of Mycoplasma pneumoniae.

Aim: Mycoplasma pneumoniae (MP) is a common cause of respiratory infections, and its incidence has increased post-COVID-19 due to "immune debt." Real-time quantitative polymerase chain reaction (qPCR) is the standard for detecting MP, but it has a lengthy detection time. This study aimed to establish a highly sensitive rapid detection method for MP.Materials & methods: We developed an integrated assay combining multienzyme isothermal rapid amplification (MIRA) with qPCR, referred to as MIRA-qPCR, for the rapid detection of MP, delivering results within approximately 40 min.Results: The analytic sensitivity of the MIRA-qPCR assay was 10 copies per reaction, and it exhibited no cross-reactivity with other respiratory pathogens, ensuring high specificity. Clinical sample analysis demonstrated higher sensitivity for MIRA-qPCR compared to qPCR reported in the literature, and 100% concordance with commercial qPCR kit.Conclusion: The MIRA-qPCR method established in this study is a promising tool for the clinical detection of MP, offering significant advantages for the rapid diagnosis of MP infections.

Mycoplasma pneumoniae is a bacteria that can make us sick. It mainly affects the lungs and can cause a sickness called "walking pneumonia". This is because it can make you poorly, but not so badly that you are unable to walk around. This bacteria spreads when someone that is infected sneezes or coughs. It is important that M. pneumoniae can be diagnosed quickly. This article looks at a new, fast way to identify infection called MIRA-quantitative PCR.

Association of overall survival benefit of radiotherapy with progression-free survival after chemotherapy for diffuse large B-cell lymphoma: A systematic review and meta-analysis.

Objective: To evaluate whether improved progression-free survival (PFS) from radiotherapy (RT) translates into an overall survival (OS) benefit for diffuse large B-cell lymphoma (DLBCL). Methods: A systematic literature search identified randomized controlled trials (RCTs) and retrospective studies that compared combined-modality therapy (CMT) with chemotherapy (CT) alone. Weighted regression analyses were used to estimate the correlation between OS and PFS benefits. Cohen's kappa statistic assessed the consistency between DLBCL risk-models and PFS patterns. Furthermore, the benefit trend of RT was analyzed by fitting a linear regression model to the pooled hazard ratio (HR) according to the PFS patterns. Results: For both 7 RCTs and 52 retrospective studies, correlations were found between PFS HR (HRPFS) and OS HR (HROS) at trial level (r = 0.639-0.876), and between PFS and OS rates at treatment-arm level, regardless of CT regimens (r = 0.882-0.964). Incorporating RT into CT increased about 18% of PFS, and revealed a different OS benefit profile. Patients were stratified into four CT-generated PFS patterns (>80%, >60-80%, >40-60%, and ≤40%), which was consistent with risk-stratified subgroups (kappa > 0.6). Absolute gain in OS from RT ranged from ≤5% at PFS >80% to about 21% at PFS ≤40%, with pooled HROS from 0.70 (95% CI, 0.51-0.97) to 0.48 (95% CI, 0.36-0.63) after rituximab-based CT. The OS benefit of RT was predominant in intermediate- and high-risk patients with PFS ≤ 80%. Conclusion: We demonstrated a varied OS benefit profile of RT to inform treatment decisions and clinical trial design.

Thiourea enhanced oxidase-like activity of CeO2/CuxO nanozyme for fluorescence/colorimetric detection of thiourea and glutathione.

A novel fluorescence/colorimetric dual-mode sensor, based on enhancement of the oxidase-like activity of CeO2/CuxO nanozyme towards the oxidation of o-phenylenediamine (OPD) induced by thiourea (TU), has been proposed for TU detection. The catalytic activity enhancement on CeO2/CuxO can be attributed to the strong electron-donation ability of TU, which promoted hydroxyl radical generation and amplified OPD oxidization with enhanced dual-signal readout. By integrating a portable paper-chip and smartphone system, this CeO2/CuxO-OPD system achieved on-site visual colorimetric analysis of TU. The dual-mode sensor demonstrated high sensitivity and specificity in recognizing TU, with a detection limit (LOD) of 1.90 µM and a linear range (LR) 2.5-80 µM in fluorescent mode; as well as an LOD of 6.69 µM and an LR 10-250 µM in colorimetric mode. Furthermore, the CeO2/CuxO-TU-OPD system has been designed for dual-mode glutathione (GSH) detection with enhanced sensitivity, achieving an LOD of 0.19 µM and an LR 0.5-10 µM in fluorescent mode; as well as an LOD of 1.24 µM and an LR 1.25-25 µM in colorimetric mode. Additionally, GSH discrimination (fluorescent mode) was successfully achieved in different biological samples, showing good consistency with the standard method. The recoveries ranged from 96.8 % to 116.7 % in serum samples and from 97.3 % to 107.7 % in cell lysates, with RSDs less than 2 %. This work not only introduced a novel approach to enhance oxidase-like activity of nanozymes but also provided an efficient field-suitable tool for enhanced dual-mode response towards TU and GSH.

Association of benzodiazepine and Z-hypnotic use with cardiovascular disease risk: insights from a prospective study of 10 million people in China.

AIM: To assess the association between Benzodiazepines (BZDs) or Z-hypnotic use and cardiovascular diseases (CVD) incidence in residents in Beijing, China. METHODS: We included 2,415,573 individuals with a prescription record for BZDs or Z-hypnotics in the Beijing Medical Claim Data for Employees database during 2010-2017, and 8,794,356 non-users with other prescriptions for the same period. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional risk models for 712,850 exposed and 712,850 unexposed participants who were matched 1:1 by propensity score. RESULTS: BZDs or Z-hypnotics users had a higher risk of CVD than non-users, with an HR of 1.11 (95% CI: 1.10, 1.13). Compared with non-users, those who used them for less than 3 months had the lowest risk of CVD, and those for more than 5 years had the highest risk, with HRs of 0.50 (0.48, 0.51) and 1.78 (1.72, 1.83), respectively. The risk of CVD was relatively low in those who used only one of the long-acting BZDs, short-acting BZDs, or Z-hypnotics compared to unexposed individuals. Individuals exposed to all three types of drugs had the highest risk, 2.33 (2.22, 2.44) times that of non-users. Users below the median dose had a lower risk of CVD compared to non-users, whereas users exceeding the median dose had an increased risk. CONCLUSION: BZD or Z-hypnotic use in general was nominally associated with an elevated risk of CVD. However, for short-term, single-type, and low-to-moderate-dose users, not only did this elevated risk disappear, but drug use also demonstrated a protective effect.

SARS-CoV-2 reactivates fungal-associated Hemophagocytic lymphohistiocytosis: Case report and review of the literature.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease characterized by the uncontrolled activation of the immune system, resulting in a high clinical mortality rate. A 56-year-old Chinese female presented at the emergency room with symptoms including fever, fatigue, nausea, vomiting, cough, shortness of breath, and chest tightness. Laboratory investigations demonstrated decreased levels of white blood cells, hemoglobin, and platelets while interleukin-6 and ferritin exhibited significant elevations. She was subsequently admitted to the hematology department, where she was diagnosed with HLH caused by a Candida infection. Following treatment with antifungal agents, glucocorticoids, antiemetics, diuretics, and hepatoprotective therapy, the patient's condition has shown improvement. However, after being infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the patient experienced a reactivation of HLH, resulting in a more severe clinical presentation and complications compared to the initial onset. Although the patient's condition improved after the administration of antiviral drugs, etoposide, glucocorticoids, cyclosporin, and intravenous immunoglobulin, this case highlights the possibility of disease reactivation during the recovery phase of HLH. This should raise the attention of medical professionals.

Revealing an Extended Adsorption/Insertion-Filling Sodium Storage Mechanism in Petroleum Coke-Derived Amorphous Carbon.

Amorphous carbon holds great promise as anode material for sodium-ion batteries due to its cost-effectiveness and good performance. However, its sodium storage mechanism, particularly the insertion process and origin of plateau capacity, remains controversial. Here, an extended adsorption/insertion-filling sodium storage mechanism is proposed using petroleum coke-derived amorphous carbon as a multi-microcrystalline model. Combining in situ X-ray diffraction, in situ Raman, theoretical calculations, and neutron scattering, the effective storage form and location of sodium ions in amorphous carbon are revealed. The sodium adsorption at defect sites leads to a high-potential sloping capacity. The sodium insertion process occurs in both the pseudo-graphite phase (d002 > 0.370 nm) and graphite-like phase (0.345 ≤ d002 < 0.370 nm) rather than the graphite phase, contributing to low-potential sloping capacity. The sodium filling into accessible closed pores forms quasi-metallic sodium clusters, contributing to plateau capacity. The threshold of the effective interlayer spacing for sodium insertion is extended to 0.345 nm, breaking the consensus of insertion interlayer threshold and enhancing understanding of closed pore filling. The extended adsorption/insertion-filling mechanism explains the sodium storage behavior of amorphous carbon with different microstructures, providing theoretical guidance for the rational design of high-performance amorphous carbon anodes.

Therapeutic targeting of GDF11 in muscle atrophy: Insights and strategies.

The exploration of novel therapeutic avenues for skeletal muscle atrophy is imperative due to its significant health impact. Recent studies have spotlighted growth differentiation factor 11 (GDF11), a TGFß superfamily member, for its rejuvenating role in reversing age-related tissue dysfunction. This review synthesizes current findings on GDF11, elucidating its distinct biological functions and the ongoing debates regarding its efficacy in muscle homeostasis. By addressing discrepancies in current research outcomes and its ambiguous role due to its homological identity to myostatin, a negative regulator of muscle mass, this review aims to clarify the role of GDF11 in muscle homeostasis and its potential as a therapeutic target for muscle atrophy. Through a thorough examination of GDF11's mechanisms and effects, this review provides insights that could pave the way for innovative treatments for muscle atrophy, emphasizing the need and strategies to boost endogenous GDF11 levels for therapeutic potential.

crVDAC3 alleviates ferroptosis by impeding HSPB1 ubiquitination and confers trastuzumab deruxtecan resistance in HER2-low breast cancer.

AIMS: With the wide application of trastuzumab deruxtecan (T-DXd), the survival of HER2-low breast cancer patients is dramatically improved. However, resistance to T-DXd still exists in a subset of patients, and the molecular mechanism remains unclear. METHODS: An in vivo shRNA lentiviral library functional screening was performed to identify potential circular RNA (crRNA) that mediates T-DXd resistance. RNA pull-down, mass spectrometry, RNA immunoprecipitation, and co-immunoprecipitation assays were conducted to investigate the molecular mechanism. Ferroptosis was detected using C11-BODIPY, Liperfluo, FerroOrange staining, glutathione quantification, malondialdehyde quantification, and transmission electron microscopy. Molecular docking, virtual screening, and patient-derived xenograft (PDX) models were used to validate therapeutic agents. RESULTS: VDAC3-derived crRNA (crVDAC3) ranked first in functional shRNA library screening. Knockdown of crVDAC3 increased the sensitivity of HER2-low breast cancer cells to T-DXd treatment. Further mechanistic research revealed that crVDAC3 specifically binds to HSPB1 protein and inhibits its ubiquitination degradation, leading to intracellular accumulation and increased levels of HSPB1 protein. Notably, suppression of crVDAC3 dramatically increases excessive ROS levels and labile iron pool accumulation. Inhibition of crVDAC3 induces ferroptosis in breast cancer cells by reducing HSPB1 expression, thereby mediating T-DXd resistance. Through virtual screening and experimental validation, we identified that paritaprevir could effectively bind to crVDAC3 and prevent its interaction with HSPB1 protein, thereby increasing ubiquitination degradation of HSPB1 protein to overcome T-DXd resistance. Finally, we validated the enhanced therapeutic efficacy of T-DXd by paritaprevir in a HER2-low PDX model. CONCLUSION: This finding reveals the molecular mechanisms underlying T-DXd resistance in HER2-low breast cancer. Our study provides a new strategy to overcome T-DXd resistance by inhibiting the interaction between crVDAC3 and HSPB1 protein.