Short-Range Graphitic Nanodomains in Hypocrystalline Carbon Nanotubes Realize Fast Potassium Ion Migration and Multidirection Stress Release.

Defect-rich carbon materials are considered as one of the most promising anodes for potassium-ion batteries due to their enormous adsorption sites of K+ , while the realization of both rate capability and cycling stability is still greatly limited by unstable electrochemical kinetics and inevitable structure degradation. Herein, an Fe3+ -induced hydrothermal-pyrolysis strategy is reported to construct well-tailored hybrid carbon nanotubes network architecture (PP-CNT), in which the short-range graphitic nanodomains are in-situ localized in the pea pod shape hypocrystalline carbon. The N,O codoped hypocrystalline carbon region contributes to abundant defect sites for potassium ion storage, ensuring high reversible capacity. Meanwhile, the short-range graphitic nanodomains with expanded interlayer spacing facilitate stable K+ migration and fast electron transfer. Furthermore, the finite element analysis confirms the volume expansion caused by K+ intercalation can be availably buffered due to the multidirection stress release effect of the unique porous pea pod shape, endowing carbon nanotubes with superior structural integrity. Consequently, the PP-CNT anode exhibits superior potassium-storage performance, including high reversible capacity, exceptional rate capability, and ultralong cycling stability. This work opens a new avenue for the fabrication of advanced carbon materials for achieving durable and fast potassium storage.

Monitoring the Micro-Structural Evolution Mechanism of Next-Generation Ultra-High-Energy All-Nitrogen Materials: A Molecular Dynamic Study.

Micro-structural evolution mechanisms of next-generation ultra-high-energy all-nitrogen materials under the extreme conditions of high temperature coupled with high pressure were revealed by state-of-the-art ab initio molecular dynamics studies based on highest-nitrogen-content energetic material 2,2'-azobis(5-azidotetrazole). The results indicate that there are three primary initial uni-molecular decomposition pathways, namely, tetrazole ring opening, azido group elimination, and the breaking of the N-N bond between the azo group and azidotetrazole. In complicated global decomposition reactions, there exists the formation of nitrogen-rich clusters and all-nitrogen species. Lowering the temperature or increasing the pressure is conducive to increasing the N content in the nitrogen-rich cluster and widening the time distribution for the cluster. Abundant all-nitrogen species N4, N5, N6, N7, N8, N9, N10, and N13 were formed, and their detailed evolutionary process and construction mechanisms were enunciated. We innovatively constructed a series of next-generation ultra-high-energy all-nitrogen materials, which are expected to realize the controllable construction of next-generation ultra-high-energy all-nitrogen materials under extreme conditions.

Metal Salts of 4-Chloro-3,5-dinitropyrazole for Promising Eco-Friendly Primary Colors Pyrotechnics.

The construction and design of pyrotechnics with superior performance is not only a task of great significance but also a tremendous challenge. In this regard, we present the syntheses of novel green primary colors pyrotechnics (red, green, and blue light-generating pyrotechnics) by employing 4-chloro-3,5-dinitropyrazole (CDNP) as a multifunctional raw material. CDNP contains a flame enhancer, oxygen-rich functional group, and nitrogen heterocyclic combustibles, which contribute to the high performance of the pyrotechnics. The characteristic elements (strontium, barium, and copper) that impart color to the flame are combined with the CDNP to synthesize the primary colors pyrotechnics by an "all-in-one" strategy. The structures of three energetic metal salts (EMS-1, EMS-2, and EMS-3) are completely characterized, and their thermal stability, sensitivity, ignition performance, and color purity are systematically evaluated. All EMSs show excellent thermal stability and low mechanical sensitivities (>330 °C, >40 J, >360 N). Moreover, the EMSs demonstrate successful ignition and combustion under laser conditions and roasting test conditions, producing bright characteristic flames. Chromaticity analysis reveals that the three EMSs possess good color purities of 91, 80, and 70%, respectively. Consequently, the three integrated pyrotechnics exhibit exceptional combustion properties, highlighting their potential for use in various pyrotechnic applications.

Unraveling the Intercorrelation Between Micro/Mesopores and K Migration Behavior in Hard Carbon.

Pore-structure design with increased ion-diffusion ability is usually regarded as an effective strategy to improve K-storage performance in hard carbon (HC). However, the relationship between porous structure and K+ migration behavior remains unclear and requires further exploration. Herein, a series of chemically activated hard carbon spheres (denoted as AHCSs) with controllable micro/mesopores structure are successfully synthesized to explore intercorrelation between micro/mesopores and K migration behavior. The experimental results indicate AHCSs have two different K+ storage ways, that is, adsorption behavior at high potential region and intercalation process at low potential region. These behaviors are closely related to the pores structure evolution: the micropores afford extra active sites for efficient K-ions adsorption, and therefore positive correlation between micropores and adsorption-contributed capacity is confirmed; the mesopores permit more K-ions intercalation/deintercalation by offering adequate pathways, and as a result positive correlations between mesopores and intercalation-contributed capacity as well as initial Coulombic efficiency are revealed. All these together contribute to achieving excellent reversible capacity, and exceptional rate capability with an ultra-long cycle lifespan in PIBs, and simultaneously exhibit a high energy density as well as considerable cycling stability for potassium-ion full cells. These results promote a fundamental understanding of K+ migration behaviors in hard carbon.

Interconnected 3D carbon network with enhanced reaction kinetics and architecture stability for advanced potassium-ion hybrid capacitors.

Due to their high energy/power densities and ultralong cycle lifespan, potassium-ion hybrid capacitors (PIHCs) have attracted increasing research interest for large-scale energy storage systems. However, the kinetics mismatch between the battery-type anodes and capacitor-type cathodes severely hampers the further development of PIHCs. Herein, the kinetics-enhanced N-doped amorphous porous carbon with an interconnected three-dimensional (3D) network (marked as NPC) is reported. The existence of an amorphous configuration can provide numerous storage potassium sites, while the interconnected 3D network contributes to electron transfer, thus improving the reversible capacity and reaction kinetics of NPC. The expanded carbon interlayer spacing, well-established porous structure and plentiful active sites induced by N-doping greatly boost the structural stability and further increase kinetics. Benefiting from these structure merits, the NPC electrode delivers a high capacity (257.7 mA h g-1 at 0.5 A g-1), an excellent rate capability (199.5 mA h g-1 at 2 A g-1), and an extraordinary cycling stability over 3000 cycles at 2 A g-1. Moreover, coupling with activated carbon (AC) cathode and NPC anode, the assembled PIHCs exhibit ultra-large energy/ultra-high power density (177.3 W h kg-1 and 19348.3 W kg-1) with a long cycling life (81.6% capacity retention after 3000 cycles).

Construction of Coplanar Bicyclic Backbones for 1,2,4-Triazole-1,2,4-Oxadiazole-Derived Energetic Materials.

Combining different nitrogen-rich heterocycles into a molecule can fine-tune its energetic performance and physical properties as well as its safety for use in energetic materials. Here, 1,2,4-oxadiazole was incorporated into 1,2,4-triazole to construct new energetic backbones. 3-(5-Amino-1H-1,2,4-triazol-3-yl)-1,2,4-oxadiazol-5-amine (5) was designed and synthesized. Nitramino-functionalized N-(5-(5-amino-1,2,4-oxadiazol-3-yl)-3H-1,2,4-triazol-3-yl)nitramide (6) and N-(5-(5-(nitramino)-1,2,4-oxadiazol-3-yl)-3H-1,2,4-triazol-3-yl)nitramide (7) were also obtained, and two series of corresponding nitrogen-rich salts were prepared, leading to the creation of new energetic compounds. All derivatives were fully characterized, and five of them were further confirmed by X-ray diffraction. The theoretical calculations, energetic performance, safety, and the main decomposition gaseous products of 1,2,4-triazole-1,2,4-oxadiazole-derived energetic materials were studied. Compound 7 and its dihydroxylammonium salt (7 c) exhibited prominent detonation performance comparable to that of RDX while possessing satisfying thermal stabilities and mechanical sensitivities.

Circ_0055625 knockdown inhibits tumorigenesis and improves radiosensitivity by regulating miR-338-3p/MSI1 axis in colon cancer.

BACKGROUND: Radiotherapy is a main therapeutic method for cancers, including colon cancer. In the current study, we aim to explore the effects of circular RNA (circRNA) circ_0055625 in the progression and radiosensitivity of colon cancer and the underlying mechanism. METHODS: The expression of circ_0055625 and musashi homolog 1 (MSI1) mRNA was detected by quantitative real-time polymerase chain reaction (qRT-PCR). MSI1 protein expression was determined by Western blot. Cell proliferation was assessed by cell counting kit-8 (CCK-8) and colony formation assays. Cell survival fraction, apoptosis, and invasion were investigated by colony formation assay, flow cytometry analysis, and transwell invasion assay, respectively. Cell migration was detected by wound-healing and transwell migration assays. The binding relationship between microRNA-338-3p (miR-338-3p) and circ_0055625 or MSI1 was predicted by online databases and identified by Dual-Luciferase Reporter Assay. The effects of circ_0055625 silencing on the tumor formation and radiosensitivity of colon cancer in vivo were explored by in vivo tumor formation assay. RESULTS: Circ_0055625 and MSI1 were upregulated in colon cancer tissues and cells relative to control groups. Radiation treatment apparently increased the expression of circ_0055625 and MSI1 in colon cancer cells. Circ_0055625 knockdown or MSI1 silencing repressed cell proliferation, migration, and invasion and promoted cell apoptosis and radiosensitivity in colon cancer. Also, circ_0055625 silencing-mediated effects were attenuated by MSI1 overexpression. Additionally, circ_0055625 silencing reduced MSI1 expression, which could be attenuated by miR-338-3p inhibitor. Mechanically, circ_0055625 acted as a sponge for miR-338-3p to regulate MSI1. Furthermore, circ_0055625 knockdown hindered tumor growth and improved radiosensitivity in vivo. CONCLUSION: Circ_0055625 repression inhibited the progression and radioresistance of colon cancer by downregulating MSI1 through sponging miR-338-3p. This result might provide a theoretical basis for improving the therapy of colon cancer with radiation.

Fe-induced carbon nanotube/amorphous carbon polyhedral frame for superior potassium storage.

In todays energy field, the long-term development of lithium-ion batteries has been limited due to the scarcity and high cost of lithium resources. On the other hand, research towards of potassium-ion batteries (KIBs) is on the rise. Herein, we synthesize Fe-induced carbon nanotube/nitrogen-doped carbon (FNC) derived from metal-organic frameworks as a promising anode for KIBs. The carbon nanotubes can enhance the electronic conductivity and increase the contact area, thus improving the rate performance. Additionally, the amorphous carbon polyhedral frame can boost the electrochemical stability. Therefore, the FNC electrode exhibits a high reversible capacity (a charge capability of 268 mAh g-1 after 200 cycles at 0.1 A g-1) and an excellent rate performance.

CoSe2/N-doped carbon porous nanoframe as an anode material for potassium-ion storage.

Transition metal selenides (TMS), on account of their relatively high theoretical capacity, unique electrical properties, easy compositing and low cost, are considered to be a candidate anode material for potassium-ion batteries. However, the cycling stability of TMS is unsatisfactory owing to the large intercalation/deintercalation of K ions. Herein, a CoSe2/N-doped carbon porous frame (CoSe2@NC) is successfully synthesized through a simple mixing and sintering approach and displays excellent potassium storage performance. Plentiful C-N bonds in the precursor can induce the formation of homogeneous N-doped carbon matrix and C-N-Co bonds, thus endowing robust structure and high electronic conductivity for superior cycling stability. Therefore, the unique porous nanoframe suppresses volume expansion and provides more diffusion paths for K ions. After 1000 cycles at 50 mA g-1, a high capacity of 311.3 mA h g-1 is acquired. When the current density increases to 500 mA g-1, the CoSe2@NC can still maintain a capacity of 184.5 mA h g-1 after 1000 cycles. The high performance, easy compositing and low cost of the CoSe2@NC make it a favorable material for application in KIBs.

Effects of Beta-Blockers on Cardiovascular Events and Mortality in Dialysis Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: The effects of beta-blockers are uncertain in dialysis patients. Except antihypertension, ß-blockers may play a unique cardiovascular protective role in the population. This meta-analysis aimed to explore the effects of ß-blockers therapy in adult patients treated with dialysis. METHODS: We searched MEDLINE, EMBASE, and the Cochrane library from inception to May 2018 for randomized controlled trials (RCTs) and observational studies about the role of ß-blockers on all-cause mortality, cardiovascular mortality, cardiovascular events, or hospitalizations in dialysis population. RESULTS: Three RCTs and 9 observational studies met the predefined inclusion criteria. The RCTs showed significant association between ß-blockers and reduced all-cause mortality (n = 363; risk ratio [RR] 0.73; 95% CI 0.54-0.97), cardiovascular mortality (n = 314; RR 0.44; 95% CI 0.29-0.68), cardiovascular events (n = 363; RR 0.52; 95% CI 0.31-0.88), or hospitalizations (n = 314; RR 0.61; 95% CI 0.48-0.78) in dialysis patients. The observational studies showed significant difference in all-cause mortality (n = 35,233; hazard ratio [HR] 0.86; 95% CI 0.80-0.92) between ß-blockers and no ß-blockers therapy in patients with dialysis, while the studies showed no difference in cardiovascular mortality (n = 19,413; HR 0.79; 95% CI 0.57-1.11), or cardiovascular events (n = 87,060; HR 0.79; 95% CI 0.50-1.26). CONCLUSIONS: ß-blockers seem to be associated with reduced mortality in patients on dialysis. Both the statistical heterogeneity in observational studies and the small number of participants and studies in RCTs limit the strength of these findings. Video Journal Club "Cappuccino with Claudio Ronco" at  https://www.karger.com/Journal/ArticleNews/496083?sponsor=52.

The Enormous Potential of Sodium/Potassium-Ion Batteries as the Mainstream Energy Storage Technology for Large-Scale Commercial Applications.

Cost-effectiveness plays a decisive role in sustainable operating of rechargeable batteries. As such, the low cost-consumption of sodium-ion batteries (SIBs) and potassium-ion batteries (PIBs) provides a promising direction for "how do SIBs/PIBs replace Li-ion batteries (LIBs) counterparts" based on their resource abundance and advanced electrochemical performance. To rationalize the SIBs/PIBs technologies as alternatives to LIBs from the unit energy cost perspective, this review gives the specific criteria for their energy density at possible electrode-price grades and various battery-longevity levels. The cost ($ kWh-1 cycle-1) advantage of SIBs/PIBs is ascertained by the cheap raw-material compensation for the cycle performance deficiency and the energy density gap with LIBs. Furthermore, the cost comparison between SIBs and PIBs, especially on cost per kWh and per cycle, is also involved. This review explicitly manifests the practicability and cost-effectiveness toward SIBs are superior to PIBs whose commercialization has so far been hindered by low energy density. Even so, the huge potential on sustainability of PIBs, to outperform SIBs, as the mainstream energy storage technology is revealed as long as PIBs achieve long cycle life or enhanced energy density, the related outlook of which is proceeded as the next development directions for commercial applications.

The efficacy and safety of neoadjuvant chemoradiotherapy combined with immunotherapy for locally advanced rectal cancer patients: a systematic review.

Background: Several studies have explored the effectiveness of PD-1/PD-L1 inhibitors combined with neoadjuvant chemoradiotherapy (nCRT) in the treatment of locally advanced rectal cancer(LARC), particularly in microsatellite stable(MSS) or mismatch repair proficient(pMMR) LARC patients. We undertook a single-arm systematic review to comprehensively evaluate the advantages and potential risks associated with the use of PD-1/PD-L1 inhibitors in conjunction with nCRT for patients diagnosed with locally advanced rectal cancer. Methods: The PubMed, Embase, Cochrane Library, ClinicalTrials.gov, ASCO and ESMO were searched for related studies. The main outcomes were pathologic complete response (pCR), major pathological response (MPR), anal preservation, and adverse effects (AEs). Results: Fourteen articles including 533 locally advanced rectal cancer (LARC) patients were analyzed. The pooled pCR, MPR, and anal preservation rates were 36%, 66% and 86%. Grade ≥3 adverse events occurred in 20%. Subgroup analysis showed that; dMMR/MSI-H had a pooled pCR (100%) and MPR (100%), pMMR/MSS had a pooled pCR (38%) and MPR (60%); the short-course radiotherapy and long-course radiotherapy had pooled pCR rates of 51% and 30%, respectively. The rates of pCR for the concurrent and sequential immuno-chemoradiotherapy subgroups at 30% and 40%, mirroring pCR rates for the PD-L1 and PD-1 inhibitor subgroups were 32% and 40%, respectively. Conclusion: In cases of locally advanced rectal cancer, PD-1/PD-L1 inhibitors combined with neoadjuvant chemoradiotherapy have shown promising response rates and acceptable toxicity profiles. PD-1/PD-L1 inhibitors combined with neoadjuvant chemoradiotherapy hence has a positive outcome even in MSS LARC patients. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/#myprospero, identifier CRD42023465380.

Structure and performance regulation of energetic complexes through multifunctional molecular self-assembly.

The design of novel energetic compounds constitutes a pivotal research direction within the field of energetic materials. However, exploring the intricate relationship between their molecular structure and properties, in order to uncover their potential applications, remains a challenging endeavor. Therefore, employing multi-molecule assembly techniques to modulate the structure and performance of energetic materials holds immense significance. This approach enables the creation of a new generation of energetic materials, fueling research and development efforts in this field. In this study, a series of coordination compounds are synthesized by utilizing tetranitroethide (TNE) as an anion, which possesses a high nitrogen and oxygen content. The synthesis involves the synergistic modification between metal ions and small molecule ligands. Characterization of the obtained compounds is carried out using various techniques, including single crystal X-ray diffraction, IR spectroscopy, elemental analysis, and simultaneous TG-DSC analysis. Additionally, the energy of formation for these compounds is calculated using bomb calorimetry, based on the heat of combustion. The detonation performances of the compounds are determined through calculations using the EXPLO 5 software, and their sensitivities to external stimuli are evaluated.

Fabrication, Characterization, and Performance Evaluation of Thermally Stable [5,6]-Fused Bicyclic Energetic Materials.

In recent decades, there has been considerable interest in investigating advanced energetic materials characterized by high stability and favorable energetic properties. Nevertheless, reconciling the conflicting balance between high energy and the insensitivity of such materials through traditional approaches, which involve integrating fuel frameworks and oxidizing groups into an organic molecule, presents significant challenges. In this study, we employed a promising method to fabricate high-energy-density materials (HEDMs) through the intermolecular assembly of variously substituted purines with a high-energy oxidant. Purines are abundant in nature and are readily available. A series of advanced energetic materials with a good balance between energy and sensitivity were prepared by the simple and effective self-assembly of purines with high-energy oxidants. Notably, these compounds exhibit incredibly improved crystal densities (1.80-2.00 g·cm-3) and good detonation performance (D: 7072-8358 m·s-1; P: 19.82-34.56 GPa). In comparison to RDX, these self-assembled energetic materials exhibit reduced mechanical sensitivities and enhanced thermal stabilities. Compounds 1-5 demonstrate both high energy and low sensitivity, indicating that self-assembly represents a straightforward and effective approach for developing advanced energetic materials with a balanced combination of energy and safety. Moreover, this study offers an avenue for synthesizing energetic materials based on naturally occurring compounds assembled through intermolecular attractions, thereby achieving a balance between energy and sensitivity along with versatile functionality.

Hydrogen Sulfide Inhibited Sympathetic Activation in D-Galactose-Induced Aging Rats by Upregulating Klotho and Inhibiting Inflammation in the Paraventricular Nucleus.

The present study aimed to explore the central relationship between cardiovascular conditions and aging. D-galactose (D-gal) was utilized to induce an accelerated aging model and to evaluate the effects of hydrogen sulfide (H2S) on aging-related cardiovascular risk factors and mechanisms. Eight-week-old Sprague Dawley rats were given an intraperitoneal injection of 250 mg/kg D-gal every day with or without H2S (56 µmol/kg) for 12 weeks. We found that D-gal treatment induced a noticeably aging-related increase in p16, p53 and p21 protein levels and senescence-associated beta-galactosidase staining. In addition, the level of noradrenalin was increased, accompanied by enhanced blood pressure and renal sympathetic nerve activity in aged rats. The greater sympathetic responses were related with the increased level of inflammation. The decreased level of klotho in the paraventricular nucleus neuron also contributed to sympathetic activation in D-gal-induced aged rats. However, the exogenous administration of H2S attenuated the sympathetic activity in aged rats, as evidenced by the decreased blood pressure, renal sympathetic nerve activity and noradrenalin level. The ameliorated cellular senescence, inflammation and heightened klotho in the paraventricular nucleus were attributed to the protective effects of H2S. The present study provides further evidence for the drug development of H2S for the prevention or treatment of the aging-associated cardiovascular diseases.

Melatonin suppresses sympathetic vasomotor tone through enhancing GABAA receptor activity in the hypothalamus.

Introduction: Melatonin (5-methoxy-N-acetyl-tryptamine) is a circadian hormone synthesized and secreted by the pineal gland. In addition to regulating circadian rhythms of many physiological functions, melatonin is involved in regulating autonomic nervous function and blood pressure. Hypothalamus paraventricular nucleus (PVN), receiving melatonin projections from the superchiasmatic nucleus, is a critical brain region to regulate neuroendocrine and cardiovascular function. Here, we determined the synaptic mechanisms involved in the effect of melatonin on the sympathetic outflow and blood pressure. Methods and Results: Microinjection of melatonin into the PVN produced a depressor effect and decreased renal sympathetic nerve activity (RSNA). While microinjection of luzindole, a non-selective melatonin receptor antagonist, into the PVN did not change melatonin-induced sympathoinhibition, GABAA receptor antagonist bicuculline eliminated melatonin-induced sympathoinhibition. Furthermore, melatonin decreased firing rate of retrogradely labeled PVN neurons which project to the rostral ventrolateral medulla (RVLM), an effect was not altered by luzindole but eliminated by bicuculline. Melatonin significantly increased the amplitude of spontaneous and evoked GABAergic inhibitory synaptic currents, as well as GABA-induced currents. Conclusion: These data suggest that melatonin in the PVN suppresses sympathetic vasomotor tone through enhancing GABAA receptor activity. This study provides novel information for understanding the cellular mechanisms involved in the effect of melatonin on regulating blood pressure and sympathetic output.

Exosomal Circ_FMN2 Derived from the Serum of Colorectal Cancer Patients Promotes Cancer Progression by miR-338-3p/MSI1 Axis.

BACKGROUND: Colorectal cancer (CRC) is a common malignancy of the gastrointestinal tract with high incidence and mortality. Exosomal circular RNA (circRNA) has been shown to be associated with the malignant progression of cancers, including CRC. Circ_0005100 (named as circ_FMN2) has been shown to promote CRC cell proliferation and migration. However, whether exosomal circ_FMN2 participated in CRC progression remains unclear. METHODS: Exosomes were isolated from the serum of CRC patients and then identified using transmission electron microscope. Western blot assay was used to test the protein levels of exosome markers, proliferation-related marker, metastasis-related markers and musashi-1 (MSI1). The expression levels of circ_FMN2, microRNA (miR)-338-3p and MSI1 were detected by qPCR. Flow cytometry, colony formation assay, MTT assay, and transwell assay were employed to measure cell cycle, apoptosis, colony formation ability, viability, migration and invasion. Dual-luciferase reporter assay was performed to assess the interaction between miR-338-3p and circ_FMN2 or MSI1. BALB/c nude mice was used to conduct animal experiments. RESULTS: Circ_FMN2 was overexpressed in the exosomes of CRC patient's serums and CRC cells. Overexpressed exosomal circ_FMN2 could promote CRC cell proliferation, metastasis, and suppress apoptosis. Circ_FMN2 acted as miR-338-3p sponge. MiR-338-3p overexpression reversed the promotion effect of circ_FMN2 on CRC progression. MSI1 was found to be a target of miR-338-3p, and its overexpression revoked the inhibitory effect of miR-338-3p on CRC progression. Furthermore, exosomal circ_FMN2 overexpression also could facilitate CRC tumor growth in vivo. CONCLUSION: Exosomal circ_FMN2 accelerated CRC progression through miR-338-3p/MSI1 axis, revealing that exosomal circ_FMN2 might be a target for CRC treatment.

Neoadjuvant sintilimab plus chemotherapy for locally advanced resectable esophageal squamous cell carcinoma: a prospective, single-arm, phase II clinical trial (CY-NICE).

Background: Adding immune checkpoint inhibitors (ICIs) to the chemotherapy has shown significant clinical benefits in neoadjuvant treatment of locally advanced esophageal squamous cell carcinoma (ESCC). Sintilimab is one such ICI used for treatment. Herein, we designed a trial to evaluate the safety and efficacy of sintilimab combined with paclitaxel and platinum for locally advanced resectable ESCC. Methods: Patients with locally advanced resectable (stage II-III) ESCC were enrolled and received at least two cycles of neoadjuvant therapy with sintilimab (200 mg on day 1) plus platinum-based chemotherapy in each 3-week cycle followed by esophagectomy. The primary endpoint of the trial was the pathological complete response (pCR) rate. The secondary endpoints were the major pathological response (MPR) rate, the objective response rate (ORR), the treatment-related adverse events (TRAEs), the immune-related adverse events (irAEs) and quality of life (QOL). Besides, relapse-free survival (RFS), overall survival (OS) were exploratory endpoints. Forty-three cases were needed to be enrolled in this trial. It was assumed the regimen of the neoadjuvant sintilimab plus chemotherapy would achieve a pCR rate of 30.5%. Results: Between March 2021 and January 2023, a total of 43 patients (41 men and 2 women) were enrolled, including 11 cases (25.6%) of clinical stage II and 32 cases (74.4%) of clinical stage III at baseline. All the 43 patients completed two cycles of neoadjuvant therapy, and 32 patients received McKeown radical resection for esophageal cancer. The pCR rate was 28.1% (9/32), which was below the 30.5% reference cutoff value, and the MPR rate was 37.5% (12/32). According to RECIST 1.1, four patients (4/43, 9.3%) had a complete response (CR), 21 patients (21/43, 48.8%) had a partial response (PR), ORR was 58.1% (25/43). The incidence of ≥ grade 3 TRAEs was 23.3% (10/43) and there were no ≥ grade 4 TRAEs. Conclusions: Sintilimab plus platinum-based chemotherapy as neoadjuvant therapy is safe, feasible and effective in locally advanced resectable ESCC, suggesting a supportive rationale for its further evaluation in randomized clinical trials. Trial Registration: Chinese Clinical Trial Registry identifier: ChiCTR2200056558.

Melittin induces ferroptosis and ER stress-CHOP-mediated apoptosis in A549 cells.

Melittin is a natural polypeptide present in bee venom, with significant anti-tumor activity. Melittin has been reported to induce cell death in lung carcinoma cell line A549 cells, suggesting an excellent potential for treating lung cancer. However, the core mechanism underlying melittin-induced cell death in A549 cells remains unclear. This work reports that melittin induces reactive oxygen species (ROS) burst, upregulates intracellular Fe2+ levels, disrupts the glutathione-glutathione peroxidase 4 antioxidant system, and increases lipid peroxide accumulation, eventually inducing cell death, indicating that ferroptosis may be involved in the antitumor effects of melittin in A549 cells. Furthermore, A549 cells treated with the ferroptosis inhibitors ferrostatin-1 and deferoxamine demonstrated that these inhibitors could reverse the cell death induced by melittin, further confirming that melittin induces A549 cell death via ferroptosis. Furthermore, the results also illustrated that melittin activated the endoplasmic reticulum (ER) stress-CHOP (C/EBP homologous protein) apoptotic signal, closely associated with high-level intracellular ROS. The ER stress inhibitor, 4-Phenylbutyric acid, was used to confirm that ER stress-CHOP apoptotic signaling is another molecular mechanism of melittin-induced A549 cell death. Thus, our results demonstrate that ferroptosis and ER stress-CHOP signaling are key molecular mechanisms of melittin-induced cell death in lung cancer.KEY POLICY HIGHLIGHTSMelittin upregulates intracellular Fe2+ levels, leading to the accumulation of lipid peroxides in A549 cells.Melittin disrupts the glutathione-glutathione peroxidase 4 antioxidant system in A549 cells.Melittin induces activation of endoplasmic reticulum stress-C/EBP homologous protein apoptosis signal.Ferroptosis and ER stress are the core molecular mechanisms underlying melittin-induced cell death in A549 cells.