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Ferroptosis is a unique regulated cell death defined by the intracellular iron overload and distinct biological features compared with other well-known programmed cell death. Ferroptosis can be triggered by many causes including decreased expression of glutathione (GSH), inhibition of the function of glutathione-dependent peroxidase 4 (GPX4), and system x c – , all of which finally lead to the over-accumulation of lipid peroxides in the cell. Ferroptosis has been reported to play an important role in the pathophysiological process of various cancers. In recent years, much evidence also proved that ferroptosis is involved in the progress of cerebral stroke. In this review, we summarized the characteristics of ferroptosis and the potential relationship between ferroptosis and ischemic and hemorrhagic stroke, to provide new targets and ideas for the therapy of stroke.

Oral administration is a desirable alternative of parenteral administration due to the convenience and increased compliance to patients, especially for chronic diseases that require frequent administration. The oral drug delivery is a dynamic research field despite the numerous challenges limiting their effective delivery, such as enzyme degradation, hydrolysis and low permeability of intestinal epithelium in the gastrointestinal (GI) tract. pH-Responsive carriers offer excellent potential as oral therapeutic systems due to enhancing the stability of drug delivery in stomach and achieving controlled release in intestines. This review provides a wide perspective on current status of pH-responsive oral drug delivery systems prepared mainly with organic polymers or inorganic materials, including the strategies used to overcome GI barriers, the challenges in their development and future prospects, with focus on technology trends to improve the bioavailability of orally delivered drugs, the mechanisms of drug release from pH-responsive oral formulations, and their application for drug delivery, such as protein and peptide therapeutics, vaccination, inflammatory bowel disease (IBD) and bacterial infections.

Therapies that targeted PD-1 have shown remarkable rates of durable clinical responses in patients with various tumor types. However, the extent and knowledge of pulmonary toxicities associated with PD-1 blockade, mainly manifested as pneumonitis, remains obscure. In this study, a total of 6360 subjects from 16 phase II/III clinical trials were pooled for meta-analysis to evaluate the overall incidence and risk of PD-1 inhibitors-related pneumonitis in cancer patients. The incidence of pneumonitis during anti-PD-1 immunotherapy was 2.92% (95%CI: 2.18–3.90%) for all-grade and 1.53% (95%CI: 1.15–2.04%) for high-grade pneumonitis. Compared with routine chemotherapy, PD-1 inhibitors were associated with a significant increased risk of pneumonitis. Moreover, among the types of tumor treated with PD-1 inhibitors, the melanoma patients have the lowest incidence of pneumonitis, while the non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) patients have the highest. Furthermore, no significant differences were detected in the incidences of all- and high-grade pneumonitis between high-dose and low-dose groups of PD-1 inhibitors. In conclusion, PD-1 inhibitors were probably associated with an increased risk of pneumonitis in a dose-independent manner, compared with routine chemotherapeutic agents. The frequency and severity of treatment-mediated pneumonitis was quite different in patients with various tumor types.

Background. Spinal cord injury (SCI) is one of the serious neurological diseases that occur in young people with high morbidity and disability. However, there is still a lack of effective treatments for it. Stem cell (SC) treatment of SCI has gradually become a new research hotspot over the past decades. This article is aimed at reviewing the research progress of SC therapy for SCI. Methods. Review the literature and summarize the effects, strategies, related mechanisms, safety, and clinical application of different SC types and new approaches in combination with SC in SCI treatment. Results. A large number of studies have focused on SC therapy for SCI, most of which showed good effects. The common SC types for SCI treatment include mesenchymal stem cells (MSCs), hematopoietic stem cells (HSCs), neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and embryonic stem cells (ESCs). The modes of treatment include in vivo and in vitro induction. The pathways of transplantation consist of intravenous, transarterial, nasal, intraperitoneal, intrathecal, and intramedullary injections. Most of the SC treatments for SCI use a number of cells ranging from tens of thousands to millions. Early or late SC administration, application of immunosuppressant or not are still controversies. Potential mechanisms of SC therapy include tissue repair and replacement, neurotrophy, and regeneration and promotion of angiogenesis, antiapoptosis, and anti-inflammatory. Common safety issues include thrombosis and embolism, tumorigenicity and instability, infection, high fever, and even death. Recently, some new approaches, such as the pharmacological activation of endogenous SCs, biomaterials, 3D print, and optogenetics, have been also developed, which greatly improved the application of SC therapy for SCI. Conclusion. Most studies support the effects of SC therapy on SCI, while a few studies do not. The cell types, mechanisms, and strategies of SC therapy for SCI are very different among studies. In addition, the safety cannot be ignored, and more clinical trials are required. The application of new technology will promote SC therapy of SCI.

Tigecycline is regarded as the last line of defense to combat multidrug-resistant Klebsiella pneumoniae . However, increasing utilization has led to rising drug resistance and treatment failure. Here, we design a D-alpha tocopheryl polyethylene glycol succinate-modified and S-thanatin peptide-functionalized nanorods based on calcium phosphate nanoparticles for tigecycline delivery and pneumonia therapy caused by tigecycline-resistant Klebsiella pneumoniae . After incubation with bacteria, the fabricated nanorods can enhance tigecycline accumulation in bacteria via the inhibitory effect on efflux pumps exerted by D-alpha tocopheryl polyethylene glycol succinate and the targeting capacity of S-thanatin to bacteria. The synergistic antibacterial capacity between S-thanatin and tigecycline further enhances the antibacterial activity of nanorods, thus overcoming the tigecycline resistance of Klebsiella pneumoniae . After intravenous injection, nanorods significantly reduces the counts of white blood cells and neutrophils, decreases bacterial colonies, and ameliorates neutrophil infiltration events, thereby largely increasing the survival rate of mice with pneumonia. These findings may provide a therapeutic strategy for infections caused by drug-resistant bacteria. Overproduction of efflux pumps represents an important mechanism of Klebsiella pneumonia resistance to tigecycline. Here, the authors design TPGS- and S-thanatin functionalized nanorods loaded with tigecycline to increase drug accumulation inside bacteria and overcome bacterial resistance.

Continuous Renal Replacement Therapy (CRRT) is more and more widely used in patients for various indications recent years. It is still intricate for clinicians to decide a suitable empiric antimicrobial dosing for patients receiving CRRT. Inappropriate doses of antimicrobial agents may lead to treatment failure or drug resistance of pathogens. CRRT factors, patient individual conditions and drug pharmacokinetics/pharmacodynamics are the main elements effecting the antimicrobial dosing adjustment. With the development of CRRT techniques, some antimicrobial dosing recommendations in earlier studies were no longer appropriate for clinical use now. Here, we reviewed the literatures involving in new progresses of antimicrobial dosages, and complied the updated empirical dosing strategies based on CRRT modalities and effluent flow rates. The following antimicrobial agents were included for review: flucloxacillin, piperacillin/tazobactam, ceftriaxone, ceftazidime/avibactam, cefepime, ceftolozane/tazobactam, sulbactam, meropenem, imipenem, panipenem, biapenem, ertapenem, doripenem, amikacin, ciprofloxacin, levofloxacin, moxifloxacin, clindamycin, azithromycin, tigecycline, polymyxin B, colistin, vancomycin, teicoplanin, linezolid, daptomycin, sulfamethoxazole/trimethoprim, fluconazole, voriconazole, posaconzole, caspofungin, micafungin, amphotericin B, acyclovir, ganciclovir, oseltamivir, and peramivir.

In this work, the structural and mechanical characteristics of Cu50Zr43Al7 bulk metallic glass (BMG) fabricated by selective laser melting (SLM) are studied and the impacts from the SLM process are clarified. Cu50Zr43Al7 alloy specimens were manufactured by the SLM method from corresponding gas-atomized amorphous powders. The as-built specimens were examined in terms of phase structure, morphologies, thermal properties and mechanical behavior. The x-ray diffraction and differential scanning calorimetry results showed that structural relaxation and partial crystallization co-exist in the as-fabricated Cu50Zr43Al7 glassy samples. The nano- and micro- hardness and the elastic modulus of the SLM-fabricated Cu50Zr43Al7 BMG were higher than CuZrAl ternary BMGs with similar compositions prepared by conventional mold casting, which can be attributed to the structural relaxation in the former sample. However, the macro compressive strength of the SLM-fabricated Cu50Zr43Al7 BMG was only 1044 MPa mainly due to its porosity. This work suggests that the SLM process induced changes in structural and mechanical properties are significant and cannot be neglected in the fabrication of BMGs.

Background The nephrotoxicity associated with polymyxins is a critical safety concern in clinical practice. The aim of this study was to compare the nephrotoxicity of patients treated with colistin sulfate (CS) and colistin methanesulfonate (CMS). Methods Data on inpatients who received intravenous colistin (CS) or colistin methanesulfonate (CMS) for over 72 h were collected from January to December 2023. The primary outcome was the incidence of acute kidney injury (AKI) associated with polymyxins, while the secondary outcome was 30-day all-cause mortality. Furthermore, Cox proportional hazard regression analysis was used to identify the risk factors of polymyxin-induced AKI. Results A total of 291 patients were included in this study. The overall incidence of AKI was significantly higher in patients who received CMS compared to those who received CS in the unmatched cohort (29.70% vs. 7.37%) and in the propensity score matching (PSM) cohort (26.30% vs. 10.00%), respectively. However, 30-day all-cause mortality was significantly higher in the CS cohort than in the CMS cohort before (27.37% vs. 15.84%) and after (33.75% vs. 15.00%) PSM. CMS therapy and a lower baseline estimated glomerular filtration rate (eGFR) were identified as independent risk factors for polymyxin-induced AKI. Conclusions This was the first study to investigate the nephrotoxicity difference between CS and CMS to our best knowledge. In this study, the incidence rate of AKI was significantly lower in the CS cohort compared with the CMS cohort, however, 30-day all-cause mortality rate was significantly higher in the CS cohort than in the CMS cohort. Further validation of these findings requires more prospective multicentre studies with a large sample size.

Venetoclax has emerged as a breakthrough for treatment of leukemia with a wide interindividual variability in pharmacokinetics. Herein, a rapid, sensitive, and reliable UPLC-MS/MS method for quantification of venetoclax in plasma was developed and validated. The method was operated in the multiple-reaction monitoring (MRM) mode to detect venetoclax at m/z transition 868.5 > 321.0 and IS at 875.5 > 321.0, respectively. Protein precipitation prior to injection into the LC-MS/MS and the analyte was separated on an ACQUITY UPLC BEH C18 column by gradient elution with acetonitrile and 0.1% formic acid in water. Linear calibration curves were obtained in the range of 25–8000 ng/mL. The specificity, recovery, matrix effect, and stability also met the acceptance criteria of FDA guidance. The method was successfully applied to analyze plasma in acute myeloid leukemia (AML) patients. The peak plasma concentration (Cmax) of venetoclax in Chinese AML patient was 2966.0 ± 1595.0 ng/mL while the trough concentration (Cmin) was 1018.0 ± 729.4 ng/mL. Additionally, Cmax and Cmin showed a positive correlation with AST levels. Furthermore, Cmax was significantly higher in the older patients. The present method can be applied for TDM of venetoclax in treatment of hematological cancers.

With the surge of big data applications and the worsening of the memory-wall problem, the memory system, instead of the computing unit, becomes the commonly recognized major concern of computing. However, this “memory-centric” common understanding has a humble beginning. More than three decades ago, the memory-bounded speedup model is the first model recognizing memory as the bound of computing and provided a general bound of speedup and a computing-memory trade-off formulation. The memory-bounded model was well received even by then. It was immediately introduced in several advanced computer architecture and parallel computing textbooks in the 1990’s as a must-know for scalable computing. These include Prof. Kai Hwang’s book “Scalable Parallel Computing” in which he introduced the memory-bounded speedup model as the Sun-Ni’s Law, parallel with the Amdahl’s Law and the Gustafson’s Law. Through the years, the impacts of this model have grown far beyond parallel processing and into the fundamental of computing. In this article, we revisit the memory-bounded speedup model and discuss its progress and impacts in depth to make a unique contribution to this special issue, to stimulate new solutions for big data applications, and to promote data-centric thinking and rethinking.