Effect of volatile versus propofol anaesthesia on major complications and mortality after cardiac surgery: a multicentre randomised trial.

BACKGROUND: The comparative effectiveness of volatile anaesthesia and total intravenous anaesthesia (TIVA) in terms of patient outcomes after cardiac surgery remains a topic of debate. METHODS: Multicentre randomised trial in 16 tertiary hospitals in China. Adult patients undergoing elective cardiac surgery were randomised in a 1:1 ratio to receive volatile anaesthesia (sevoflurane or desflurane) or propofol-based TIVA. The primary outcome was a composite of predefined major complications during hospitalisation and mortality 30 days after surgery. RESULTS: Of the 3123 randomised patients, 3083 (98.7%; mean age 55 yr; 1419 [46.0%] women) were included in the modified intention-to-treat analysis. The composite primary outcome was met by a similar number of patients in both groups (volatile group: 517 of 1531 (33.8%) patients vs TIVA group: 515 of 1552 (33.2%) patients; relative risk 1.02 [0.92-1.12]; P=0.76; adjusted odds ratio 1.05 [0.90-1.22]; P=0.57). Secondary outcomes including 6-month and 1-yr mortality, duration of mechanical ventilation, length of ICU and hospital stay, and healthcare costs, were also similar for the two groups. CONCLUSIONS: Among adults undergoing cardiac surgery, we found no difference in the clinical effectiveness of volatile anaesthesia and propofol-based TIVA. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-IOR-17013578).

Radiofrequency radiation reshapes tumor immune microenvironment into antitumor phenotype in pulmonary metastatic melanoma by inducing active transformation of tumor-infiltrating CD8+ T and NK cells.

Immunosuppression by the tumor microenvironment is a pivotal factor contributing to tumor progression and immunotherapy resistance. Priming the tumor immune microenvironment (TIME) has emerged as a promising strategy for improving the efficacy of cancer immunotherapy. In this study we investigated the effects of noninvasive radiofrequency radiation (RFR) exposure on tumor progression and TIME phenotype, as well as the antitumor potential of PD-1 blockage in a model of pulmonary metastatic melanoma (PMM). Mouse model of PMM was established by tail vein injection of B16F10 cells. From day 3 after injection, the mice were exposed to RFR at an average specific absorption rate of 9.7 W/kg for 1 h per day for 14 days. After RFR exposure, lung tissues were harvested and RNAs were extracted for transcriptome sequencing; PMM-infiltrating immune cells were isolated for single-cell RNA-seq analysis. We showed that RFR exposure significantly impeded PMM progression accompanied by remodeled TIME of PMM via altering the proportion and transcription profile of tumor-infiltrating immune cells. RFR exposure increased the activation and cytotoxicity signatures of tumor-infiltrating CD8+ T cells, particularly in the early activation subset with upregulated genes associated with T cell cytotoxicity. The PD-1 checkpoint pathway was upregulated by RFR exposure in CD8+ T cells. RFR exposure also augmented NK cell subsets with increased cytotoxic characteristics in PMM. RFR exposure enhanced the effector function of tumor-infiltrating CD8+ T cells and NK cells, evidenced by increased expression of cytotoxic molecules. RFR-induced inhibition of PMM growth was mediated by RFR-activated CD8+ T cells and NK cells. We conclude that noninvasive RFR exposure induces antitumor remodeling of the TIME, leading to inhibition of tumor progression, which provides a promising novel strategy for TIME priming and potential combination with cancer immunotherapy.

Management of esophageal cancer in patients with a right aortic arch or double aortic arch: a case series of 34 cases.

BACKGROUND: Few cases describing patients with a right aortic arch (RAA) or double aortic arch (DAA) and esophageal cancer (EC) have been reported. METHODS: We analyzed RAA and DAA cases treated with esophagectomy in our center's database and reported in English-language studies until April 1, 2023. Our study assessed the malformation characteristics and surgical details of EC patients with RAA and DAA. RESULTS: We extracted data of 24 EC patients with RAAs and 10 EC patients with DAAs. In both groups, the patients were more likely to be Japanese and male, to have squamous cell carcinoma and to have tumors located in the upper thoracic esophagus or middle thoracic esophagus. Left thoracotomy was commonly applied for RAA patients. For DAA patients, the proportions of left-sided and right-sided approaches were similar. Esophagectomy under video-assisted thoracoscopic surgery (VATS) in RAA or DAA patients had been performed on a routine basis in recent years. There were two anastomotic leakages in each group. Specifically, Kommerell diverticulum rupture occurred in 1 RAA patient; gastric tube dilation occurred in 1 DAA patient; and recurrent laryngeal nerve (RLN) injury occurred in 2 RAA patients. The postoperative course was uneventful for most patients in both cohorts. CONCLUSIONS: Esophageal carcinoma is rarely seen in patients with an RAA or DAA. To adequately dissect superior mediastinal LNs, an auxiliary incision (such as sternotomy), the left door open method or a preceding cervical procedure should be used appropriately. Esophagectomy, whether via thoracotomy or thoracoscopic surgery, can be performed safely for both RAA and DAA.

Thermostable vacuum foam dried Newcastle disease vaccine: Process optimization and pilot-scale study.

Vacuum foam drying (VFD) has been shown to improve the thermostability and long-term shelf life of Newcastle Disease Virus (NDV). This study optimized the VFD process to improve the shelf life of NDV at laboratory-scale and then tested the optimized conditions at pilot-scale. The optimal NDV to T5 formulation ratio was determined to be 1:1 or 3:2. Using the 1:1 virus to formulation ratio, the optimal filling volumes were determined to be 13-17% of the vial capacity. The optimized VFD process conditions were determined to be at a shelf temperature of 25℃ with a minimum overall drying time of 44 h. The vaccine samples prepared using these optimized conditions at laboratory-scale exhibited virus titer losses of ≤ 1.0 log10 with residual moisture content (RMC) below 3%. Furthermore, these samples were transported for 97 days around China at ambient temperature without significant titer loss, thus demonstrating the thermostability of the NDV-VFD vaccine. Pilot-scale testing of the NDV-VFD vaccine at optimized conditions showed promising results for up-scaling the process as the RMC was below 3%. However, the virus titer loss was slightly above 1.0 log10 (approximately 1.1 log10). Therefore, the NDV-VFD process requires further optimization at pilot scale to obtain a titer loss of ≤ 1.0 log10. Results from this study provide important guidance for possible industrialization of NDV-VFD vaccine in the future. KEY POINTS: • The process optimization and scale-up test of thermostable NDV vaccine prepared through VFD is reported for the first time in this study. • The live attenuated NDV-VFD vaccine maintained thermostability for 97 days during long distance transportation in summer without cold chain conditions. • The optimized NDV-VFD vaccine preparations evaluated at pilot-scale maintained acceptable levels of infectivity after preservation at 37℃ for 90 days, which demonstrated the feasibility of the vaccine for industrialization.

Individualized Positive End-expiratory Pressure on Postoperative Atelectasis in Patients with Obesity: A Randomized Controlled Clinical Trial.

BACKGROUND: Individualized positive end-expiratory pressure (PEEP) guided by dynamic compliance improves oxygenation and reduces postoperative atelectasis in nonobese patients. The authors hypothesized that dynamic compliance-guided PEEP could also reduce postoperative atelectasis in patients undergoing bariatric surgery. METHODS: Patients scheduled to undergo laparoscopic bariatric surgery were eligible. Dynamic compliance-guided PEEP titration was conducted in all patients using a downward approach. A recruitment maneuver (PEEP from 10 to 25 cm H2O at 5-cm H2O step every 30 s, with 15-cm H2O driving pressure) was conducted both before and after the titration. Patients were then randomized (1:1) to undergo surgery under dynamic compliance-guided PEEP (PEEP with highest dynamic compliance plus 2 cm H2O) or PEEP of 8 cm H2O. The primary outcome was postoperative atelectasis, as assessed with computed tomography at 60 to 90 min after extubation, and expressed as percentage to total lung tissue volume. Secondary outcomes included Pao2/inspiratory oxygen fraction (Fio2) and postoperative pulmonary complications. RESULTS: Forty patients (mean ± SD; 28 ± 7 yr of age; 25 females; average body mass index, 41.0 ± 4.7 kg/m2) were enrolled. Median PEEP with highest dynamic compliance during titration was 15 cm H2O (interquartile range, 13 to 17; range, 8 to 19) in the entire sample of 40 patients. The primary outcome of postoperative atelectasis (available in 19 patients in each group) was 13.1 ± 5.3% and 9.5 ± 4.3% in the PEEP of 8 cm H2O and dynamic compliance-guided PEEP groups, respectively (intergroup difference, 3.7%; 95% CI, 0.5 to 6.8%; P = 0.025). Pao2/Fio2 at 1 h after pneumoperitoneum was higher in the dynamic compliance-guided PEEP group (397 vs. 337 mmHg; group difference, 60; 95% CI, 9 to 111; P = 0.017) but did not differ between the two groups 30 min after extubation (359 vs. 375 mmHg; group difference, -17; 95% CI, -53 to 21; P = 0.183). The incidence of postoperative pulmonary complications was 4 of 20 in both groups. CONCLUSIONS: Postoperative atelectasis was lower in patients undergoing laparoscopic bariatric surgery under dynamic compliance-guided PEEP versus PEEP of 8 cm H2O. Postoperative Pao2/Fio2 did not differ between the two groups.

Insights into C-C Bond Cleavage Mechanisms in Dichloroacetonitrile Formation during Chlorination of Long-Chain Primary Amines, Amino Acids, and Dipeptides.

Dichloroacetonitrile (DCAN) as one of the potentially prioritized regulated DBPs has drawn great attention; however, understanding its formation, especially the C-C bond cleavage mechanisms, is limited. In this study, DCAN formation mechanisms from long-chain primary amines, amino acids, and dipeptides during chlorination were investigated by a combined computational and experimental approach. The results indicate that nitriles initially generate for all of the above precursors, then they undergo ß-C-hydroxylation or/and α-C-chlorination processes, and finally, DCAN is produced through the Cα-Cß bond cleavage. For the first time, the underlying mechanism of the C-C bond cleavage was unraveled to be electron transfer from the O- anion into its attached C atom in the chlorinated nitriles, leading to the strongly polarized Cα-Cß bond heterocleavage and DCAN- formation. Moreover, DCAN molar yields of precursors studied in the present work were found to be determined by their groups at the γ-site of the amino group, where the carbonyl group including -CO2-, -COR, and -CONHR, the aromatic group, and the -OH group can all dramatically facilitate DCAN formation by skipping over or promoting the time-consuming ß-C-hydroxylation process and featuring relatively lower activation free energies in the C-C bond cleavage. Importantly, 4-amino-2-hydroxybutyric acid was revealed to possess the highest DCAN yield among all the known aliphatic long-chain precursors to date during chlorination. Additionally, enonitriles, (chloro-)isocyanates, and nitriles can be generated during DCAN formation and should be of concern due to their high toxicities.

Value of the modified semiquantitative classification in predicting outcomes in children with Henoch-Schönlein purpura nephritis.

BACKGROUND: The modified semiquantitative classification (SQC) is a new pathological classification for Henoch-Schönlein purpura nephritis (HSPN), and its prognostic value with regard to the outcomes of HSPN is unclear. METHODS: We performed a retrospective review of 249 patients with biopsy-proven HSPN admitted to the Children's Hospital of Chongqing Medical University. In addition to the International Study of Kidney Disease in Children (ISKDC) classification, renal biopsy specimens were also reevaluated according to the SQC. RESULTS: During the follow-up period of 2.9 (1.0-6.9) years, 14 (5.6%) patients reached the poor outcome at the end of follow-up. The SQC activity and chronicity indexes were positively correlated with the clinical manifestations, conventional pathology grades, and 24-h urinary protein (24hUP). The difference in the areas under the curve between the total biopsy SQC scores and ISKDC classification was 0.12 (p = .001, 95% CI: 0.0485-0.192). In the receiver operating characteristic (ROC) curve analysis of 1-year, 3-year, and 5-year poor outcomes and total biopsy SQC scores, a total biopsy score ≥10 was associated with a higher risk of an adverse outcome. CONCLUSION: Our study suggests that the SQC indexes are clearly correlated with the clinical and pathological findings of HSPN. The SQC is more sensitive than ISKDC classification for the prediction of the long-term outcomes of HSPN in children.

A three-dimensional composite film-modified electrode based on polyoxometalates and ionic liquid-decorated carbon nanotubes for the determination of L-tyrosine in food.

A stable and innovative composite film-modified electrode based on Dawson polyoxometalates H8P2Mo16V2O62 (P2Mo16V2) and ionic liquid (BMIMBr)-decorated carbon nanotubes, annotated as PEI/(P2Mo16V2/BMIMBr-CNTs)8, has been constructed by using the layer-by-layer self-assembly (LBL) method for the determination of L-tyrosine. The combination of three active components not only offers higher conductivity to facilitate rapid electron transfer, but also avoids the accumulation of P2Mo16V2 to expand the contact area and increase the reactive active sites. The modified electrode exhibits outstanding sensing performance for determination of Tyr with wide linear determination range of 5.8×10-7 M ~ 1.2×10-4 M, low determination limit of 1.7×10-7M (S/N=3), high selectivity for common interferences, and excellent stability at the potential of +0.78 V (vs. Ag/AgCl (3 M KCl)). The relative standard deviation (RSD) of 4.3% for five groups of parallel experiments shows the satisfactory repeatability of PEI/(P2Mo16V2/BMIMBr-CNTs)8. In addition, for determination of Tyr, the PEI/(P2Mo16V2/BMIMBr-CNTs)8 shows good recoveries of 98.8-99.8% in meat floss, which can be feasible in practical application.

[Chrysin alleviates cerebral ischemia-reperfusion injury by inhibiting ferroptosis in rats].

The purpose of this study is to investigate whether chrysin reduces cerebral ischemia-reperfusion injury(CIRI) by inhi-biting ferroptosis in rats. Male SD rats were randomly divided into a sham group, a model group, high-, medium-, and low-dose chrysin groups(200, 100, and 50 mg·kg~(-1)), and a positive drug group(Ginaton, 21.6 mg·kg~(-1)). The CIRI model was induced in rats by transient middle cerebral artery occlusion(tMCAO). The indexes were evaluated and the samples were taken 24 h after the operation. The neurological deficit score was used to detect neurological function. The 2,3,5-triphenyl tetrazolium chloride(TTC) staining was used to detect the cerebral infarction area. Hematoxylin-eosin(HE) staining and Nissl staining were used to observe the morphological structure of brain tissues. Prussian blue staining was used to observe the iron accumulation in the brain. Total iron, lipid pero-xide, and malondialdehyde in serum and brain tissues were detected by biochemical reagents. Real-time quantitative polymerase chain reaction(RT-qPCR), immunohistochemistry, and Western blot were used to detect mRNA and protein expression of solute carrier fa-mily 7 member 11(SLC7A11), transferrin receptor 1(TFR1), glutathione peroxidase 4(GPX4), acyl-CoA synthetase long chain family member 4(ACSL4), and prostaglandin-endoperoxide synthase 2(PTGS2) in brain tissues. Compared with the model group, the groups with drug intervention showed restored neurological function, decreased cerebral infarction rate, and alleviated pathological changes. The low-dose chrysin group was selected as the optimal dosing group. Compared with the model group, the chrysin groups showed reduced content of total iron, lipid peroxide, and malondialdehyde in brain tissues and serum, increased mRNA and protein expression levels of SLC7A11 and GPX4, and decreased mRNA and protein expression levels of TFR1, PTGS2, and ACSL4. Chrysin may regulate iron metabolism via regulating the related targets of ferroptosis and inhibit neuronal ferroptosis induced by CIRI.

A pilot study: Gut microbiota, metabolism and inflammation in hypertensive intracerebral haemorrhage.

AIMS: In recent years, the incidence rate of hypertensive intracerebral haemorrhage (HICH) has been increasing, accompanied by high mortality and morbidity, which has brought a heavy burden to the social economy. However, the pathogenesis of HICH is still unclear. This study intends to explore the mechanism of gut microbiota metabolism and inflammation in the process of HICH to provide a theoretical basis for the diagnosis and treatment of HICH. METHODS AND RESULTS: HE staining showed that the brain tissues of model group had obvious oedema injury, which indicated that the HICH model was successfully constructed. ELISA analysis showed that IL-1ß and TNF-α levels in blood and brain tissues were significantly increased, and IL-10 level was significantly decreased in blood. IHC analysis showed that microglia and macrophages were activated in the model group. 16S rRNA sequence showed that the diversity of gut microbiota in HICH patients decreased. Also, the microbiota belonging to Firmicutes, Proteobacteria and Verrucomicrobia changed significantly. LC-MS/MS analysis showed that the metabolic phenotype of HICH patients changed. Also, the 3,7-dimethyluric acid- and 7-methylxanthine-related metabolic pathways of caffeine metabolism pathways were downregulated in patients with HICH. Bacteroides was negatively correlated with the IL-1ß and TNF-α levels. Blautia was negatively correlated with the IL-1ß and TNF-α levels, and positively correlated with the IL-10 level. Akkermansia was negatively correlated with the 3,7-dimethyluric acid and 7-methylxanthine. CONCLUSION: Our study suggested that HICH was accompanied by the increased inflammation marker levels in peripheral blood and brain, decreased gut microbiota diversity, altered gut metabolic phenotype and downregulation of caffeine metabolism pathway. SIGNIFICANCE AND IMPACT OF THE STUDY: Our study reported that HICH accompanied by the increased inflammation, decreased gut microbiota diversity and altered gut metabolic phenotype. Due to the number of patients, this work was a pilot study.

A sustainable phosphorus management in agriculture: Assessing trade-offs between human health risks and nutritional yield regarding heavy metals in maize grain.

High-quality products in sustainable agriculture require both limited health risks and sufficient dietary nutrients. Phosphorus (P) as a finite and non-renewable resource is widely used in agriculture, usually exerting influence on the accumulation of heavy metals (HMs) in soil and crops. The present research explores, for the first time, the combined effects of long-term P fertilizer and repeated zinc (Zn) application in field on the human health risks and nutritional yield regarding trace elements in maize grain. A field experiment was conducted using maize with six P application rates (0, 12.5, 25, 50, 100, and 200 kg P ha-1) and two Zn application rates (0 and 11.4 kg Zn ha-1). The results showed that the concentrations of Zn, copper (Cu), and lead (Pb) in the maize grain were significantly affected by P application and can be further affected by Zn application. The concentrations of chromium (Cr) and arsenic (As) showed opposite tendency as affected by P fertilizer rates while did not affected by additional Zn application. Zn application decreased the cadmium (Cd) concentration at high P levels and Pb concentration at low P levels, particularly. No HMs contamination or direct health risk was found in maize grain after receiving long-term P and repeated Zn fertilizer. The threshold hazard quotient of an individual and all investigated HMs in this study were acceptable for human digestion of maize grain. While the carcinogenic risk of Cr was non-negligible in case of maize was taken as one of daily staple food for local residents. Combination use of P (25 kg ha-1) and Zn fertilizer on maize enhanced its nutritional supply ability regarding Zn and Cu, and simultaneously mitigated potential human health risks associated with Cd and Pb.

Maslinic Acid: A New Compound for the Treatment of Multiple Organ Diseases.

Maslinic acid (MA) is a pentacyclic triterpene acid, which exists in many plants, including olive, and is highly safe for human beings. In recent years, it has been reported that MA has anti-inflammatory, antioxidant, anti-tumor, hypoglycemic, neuroprotective and other biological activities. More and more experimental data has shown that MA has a good therapeutic effect on multiple organ diseases, indicating that it has great clinical application potential. In this paper, the extraction, purification, identification and analysis, biological activity, pharmacokinetics in vivo and molecular mechanism of MA in treating various organ diseases are reviewed. It is hoped to provide a new idea for MA to treat various organ diseases.

[Exploration of mechanism of "simultaneous treatment of brain and heart" of Naoxintong Capsules based on Toll-like receptor signaling pathway].

This study aims to explore the mechanism of "simultaneous treatment of the brain and the heart" of Naoxintong Capsules(NXT) under cerebral ischemia based on Toll-like receptor(TLR) signaling pathway.Male SD rats were randomized into sham operation group, model group, NXT group, and positive drug group.Middle cerebral artery occlusion(MCAO) model rats were used in model group, NXT group, and positive drug group, respectively.Neurological function was scored with the Bederson scale, and brain infarct rate was measured by 2,3,5-triphenyltetrazolium chloride(TTC) staining.Brain edema was detected with wet-dry weight method.Hematoxylin-eosin(HE) staining and TdT-mediated dUTP nick-end labeling(TUNEL) staining were used to observe and count apoptotic cardiocytes.In addition, serum myocardial enzymes were measured.The expression of 8 TLR signaling pathway-related proteins interferon-α(IFN-α), interferon regulatory factor-3(IRF3), interferon regulatory factor-7(IRF7), TLR2, TLR4, TLR7, TLR9, and tumor necrosis factor-α(TNF-α) in the cerebral cortex and heart of rats was detected by Western blot. Brain infarct rate, neurological function score, and brain water content in NXT group decreased significantly compared with those in the model group. At the same time, the reduction in apoptosis rate of cardiocytes and the content of serum aspartate aminotransferase(AST), alanine aminotransferase(ALT), creatine kinase(CK), and lactate dehydrogenase(LDH) were decreased in the NXT group.Systems pharmacological results and previous research showed that TLR signaling pathway played an important role in immune inflammatory response.The study of TLR signaling pathway and related proteins is helpful to elucidate the mechanism of "simultaneous treatment of the brain and the heart". Western blot results showed that NXT significantly inhibited the expression of IRF3, IRF7, TLR2, TLR7, and TNF-α in cerebral cortex and heart under cerebral ischemia.Cerebral ischemia influences cardiac functions, and TLR signaling pathway is one of the pathways for "simultaneous treatment of the brain and the heart" of NXT.

PAR1 and PAR4 exert opposite effects on tumor growth and metastasis of esophageal squamous cell carcinoma via STAT3 and NF-κB signaling pathways.

BACKGROUND: Esophageal carcinogenesis is a multifactorial process in which genetic and environmental factors interact to activate intracellular signals, leading to the uncontrolled survival and growth of esophageal squamous cell carcinoma (ESCC) cells. The intracellular pathways of ESCC cells could be regulated by proteinase activated-receptors (PARs), which are comprised of four receptors (i.e., PAR-1, PAR-2, PAR-3, and PAR-4). Therefore, the function and possible mechanism of PAR1 and PAR4 in the progression of ECSS were explored in our study. METHODS: First, we detected the expression levels of PAR1 and PAR4 in 27 cases of ESCC specimens and cell lines by RT-qPCR, IHC and western blot. Meanwhile, the correlation between PAR1/PAR4 expression levels, clinicopathological characteristics, and disease free survival was analyzed. Then, we constructed PAR1/PAR4 knockdown cell models and investigated the role of PAR1/PAR4 knockdown on the proliferation, apoptosis, changes of calcium flow, and metastasis of ESCC cells via MTT, flow cytometry, transwell and wound healing assays in vitro. Further, an experimental metastasis model in vivo was established to explore the role of stable PAR1/PAR4 knockdown on the growth and metastasis of ESCC cells. Finally, the role of nSMase2 in the activation of NF-κB induced by PAR4 and the role of NF-κB and STAT3 signaling pathways in the PAR1/PAR4-mediated tumor promoting or suppressive functions were measured by immunoprecipitation, western blot and immunofluorescence assays. RESULTS: First, the integrated results demonstrated the expression levels of PAR1 and PAR4 are inversely proportional in ESCC. PAR1 potently enhanced tumor growth and metastasis, while PAR4 had an inhibitory effect. Further, the co-activation of STAT3 and NF-κB was involved in the PAR1 activation-induced tumor promoting effect, while only NF-κB participated in the PAR4 activation-induced tumor inhibitory effect in ESCC. To be specific, FAK/PI3K/AKT/STAT3/NF-κB signaling mediated PAR1 activation-induced tumor promoting effect and nSMase2/MAPK/NF-κB signaling mediated PAR4 activation-induced tumor inhibitory effect. CONCLUSIONS: Overall, the study has provided new insights into the potential implication of PAR1 and PAR4 in the pathogenesis of ESCC. Besides, FAK/PI3K/AKT/STAT3/NF-κB and nSMase2/MAPK/NF-κB pathways may be novel targets for regulating tumor growth and metastasis in ESCC patients.

A novel near-infrared triggered dual-targeted nanoplatform for mitochondrial combined photothermal-chemotherapy of cancer in vitro.

A combination of photothermal-chemotherapy has received widespread attention in drug delivery systems for cancer treatment. However, the combination therapy operated in subcellular organelles, such as mitochondria, has been rarely reported. Herein, we designed a novel near-infrared (NIR) triggered dual-targeted nanoplatform (FA/TPP-DINPs) based on mitochondrial combined photothermal-chemotherapy by co-loading FDA-approved NIR dye indocyanine green (ICG) and anticancer drug doxorubicin (DOX). The resulting nanoparticles showed a monodispersed sphere and excellent colloidal stability. Specially, the simultaneous introduction of targeted ligands folic acid (FA) and triphenylphosphine (TPP) to nanoparticles significantly promoted the cellular internalization and mitochondrial co-localization of nanoparticles. Moreover, the encapsulated dye could convert NIR light into heat with high efficiency, which makes the FA/TPP-DINPs an effective platform for mitochondrial combination therapy with chemotherapy drug DOX. Meanwhile, the thermal expansion in response to the change of temperature after sustained 808 nm laser irradiation could cause the disintegration of nanoparticles, which triggered the rapid release of DOX from nanoparticles. As expected, the prepared FA/TPP-DINPs exhibited evidently enhanced cytotoxicity and preeminent combination therapy efficiency on MCF-7 cells. Thus, the NIR triggered dual-targeted nanoplatform provides a new drug delivery strategy for mitochondrial combined photothermal-chemotherapy of cancer.

Organoplatinum-Substituted Polyoxometalate Inhibits ß-amyloid Aggregation for Alzheimer's Therapy.

Aggregated ß-amyloid (Aß) is widely considered as a key factor in triggering progressive loss of neuronal function in Alzheimer's disease (AD), so targeting and inhibiting Aß aggregation has been broadly recognized as an efficient therapeutic strategy for curing AD. Herein, we designed and prepared an organic platinum-substituted polyoxometalate, (Me4 N)3 [PW11 O40 (SiC3 H6 NH2 )2 PtCl2 ] (abbreviated as PtII -PW11 ) for inhibiting Aß42 aggregation. The mechanism of inhibition on Aß42 aggregation by PtII -PW11 was attributed to the multiple interactions of PtII -PW11 with Aß42 including coordination interaction of Pt2+ in PtII -PW11 with amino group in Aß42 , electrostatic attraction, hydrogen bonding and van der Waals force. In cell-based assay, PtII -PW11 displayed remarkable neuroprotective effect for Aß42 aggregation-induced cytotoxicity, leading to increase of cell viability from 49 % to 67 % at a dosage of 8 µm. More importantly, the PtII -PW11 greatly reduced Aß deposition and rescued memory loss in APP/PS1 transgenic AD model mice without noticeable cytotoxicity, demonstrating its potential as drugs for AD treatment.

Biostable L-DNA-Templated Aptamer-Silver Nanoclusters for Cell-Type-Specific Imaging at Physiological Temperature.

The high susceptibility of the natural D-conformation of DNA (D-DNA) to nucleases greatly limits the application of DNA-templated silver nanoclusters (Ag NCs) in biological matrixes. Here we demonstrate that the L-conformation of DNA (L-DNA), the enantiomer of D-DNA, can also be used for the preparation of aptamer-Ag NCs. The extraordinary resistance of L-DNA to nuclease digestion confers much higher biostability to these NCs than those templated by D-DNA, thus making cell-type-specific imaging possible at physiological temperatures, using at least 100-times lower Ag NC concentration than reported D-DNA-templated ones. The L-DNA-templated metal NC probes with enhanced biostability might promote the applications of metal nanocluster probes in complex biological systems.

Preoperative camrelizumab combined with chemotherapy for borderline resectable ESCC: A single-arm, prospective, phase 2 study.

BACKGROUND: We investigated the safety and efficacy of preoperative camrelizumab combined with chemotherapy for treating thoracic borderline resectable esophageal squamous cell carcinoma (Br-ESCC) (ChiCTR2200056728). METHODS: Patients with thoracic Br-ESCC received intravenous camrelizumab plus chemotherapy and underwent esophagectomy. The primary endpoint was the pathologic complete response (pCR) rate. We introduced computed tomography and endoscopic examination into the diagnostic criteria to increase its reproducibility. Additionally, we defined a new resection status, Rbr+/-, for Br-ESCC. FINDINGS: Thirty-one patients with Br-ESCC were ultimately enrolled in this study. Overall, 71.0% (22/31) of the patients underwent esophagectomy. R0 resection was achieved in 81.8% of patients (18/22). pCR and major pathological response were observed in 40.9% (9/22) and 63.6% (14/22) of the resected patients, respectively. Eighteen R0 resection patients were redefined according to our Rbr definition; 61.1% (11/18) were classified as Rbr+ resection, and 38.9% (7/18) were classified as Rbr- resection. With a median postoperative follow-up of 17.9 months, 4 patients out of 11 who underwent Rbr+ resection experienced local recurrence (2 of whom achieved pCR). However, no patients (0/7) who underwent Rbr- resection experienced local recurrence. CONCLUSIONS: Esophagectomy after neoadjuvant immunochemotherapy is a promising radical treatment for Br-ESCC. R0 resection was achieved in 81.8% of patients, and a pCR was observed in 40.9% of resected patients. Even after complete excision, Rbr+ resection leads to a higher rate of local recurrence in patients with Br-ESCC. FUNDING: This study was supported by the Key Scientific Research Projects of the Institutions of Higher Learning in Henan Province (no. 21A320032).

Preoperative administration of camrelizumab combined with chemotherapy for borderline resectable esophageal squamous cell carcinoma (BRES-1): study protocol of a single-arm, open-label, phase II study.

Background: The prognosis and first-line treatment response of patients with borderline resectable esophageal squamous cell carcinoma (ESCC) are unsatisfactory. We are conducting the borderline resectable esophageal squamous (BRES-1) study to evaluate the safety and efficacy of camrelizumab combined with chemotherapy in patients with borderline resectable ESCC. Methods: A total of 30 patients with borderline resectable ESCC will be enrolled in the BRES-1 study. These patients will undergo three stages of treatment: neoadjuvant therapy, surgery, and adjuvant therapy. Preoperative therapies will include camrelizumab, cisplatin, and nab-paclitaxel. Preoperative therapies will include camrelizumab, which will be given every 3 weeks for 6 weeks at a dose of 200 mg (baseline weight <50 kg, 3 mg/kg), nab-paclitaxel (130 mg/m2 on days 1 and 8 of one period with 21 days, a total of two cycles), and cisplatin (75 mg/m2 on day 1 of one period with 21 days, a total of two cycles). Patients will undergo esophagectomy 3-6 weeks after completing the neoadjuvant treatment. Three weeks after surgery, camrelizumab combined with chemotherapy will continue to be used for two cycles of maintenance therapy. Then, only camrelizumab will be administered for an entire year. The primary endpoint of this study will be pathological complete response (pCR). Discussion: The BRES-1 trial will evaluate the efficacy and safety of camrelizumab combined with chemotherapy for patients with borderline resectable ESCC. Translational research will explore perioperative complications and drug-related adverse events (AEs). Trial Registration: ChiCTR, ChiCTR2200056728. Registered 11 February 2022. https://www.chictr.org.cn/index.aspx.