Zinc-Iron Bimetallic Peroxides Modulate the Tumor Stromal Microenvironment and Enhance Cell Immunogenicity for Enhanced Breast Cancer Immunotherapy Therapy.

Immunotherapy has emerged as a potential approach for breast cancer treatment. However, the rigid stromal microenvironment and low immunogenicity of breast tumors strongly reduce sensitivity to immunotherapy. To sensitize patients to breast cancer immunotherapy, hyaluronic acid-modified zinc peroxide-iron nanocomposites (Fe-ZnO2@HA, abbreviated FZOH) were synthesized to remodel the stromal microenvironment and increase tumor immunogenicity. The constructed FZOH spontaneously generated highly oxidative hydroxyl radicals (·OH) that degrade hyaluronic acid (HA) in the tumor extracellular matrix (ECM), thereby reshaping the tumor stromal microenvironment and enhancing blood perfusion, drug penetration, and immune cell infiltration. Furthermore, FZOH not only triggers pyroptosis through the activation of the caspase-1/GSDMD-dependent pathway but also induces ferroptosis through various mechanisms, including increasing the levels of Fe2+ in the intracellular iron pool, downregulating the expression of FPN1 to inhibit iron efflux, and activating the p53 signaling pathway to cause the failure of the SLC7A11-GSH-GPX4 signaling axis. Upon treatment with FZOH, 4T1 cancer cells undergo both ferroptosis and pyroptosis, exhibiting a strong immunogenic response. The remodeling of the tumor stromal microenvironment and the immunogenic response of the cells induced by FZOH collectively compensate for the limitations of cancer immunotherapy and significantly enhance the antitumor immune response to the immune checkpoint inhibitor αPD-1. This study proposes a perspective for enhancing immune therapy for breast cancer.

Oncolytic mineralized bacteria as potent locally administered immunotherapeutics.

Oncolytic bacteria can trigger innate immune activity. However, the antitumour efficacy of inactivated bacteria is poor, and attenuated live bacteria pose substantial safety risks. Here we show that intratumourally injected paraformaldehyde-fixed bacteria coated with manganese dioxide potently activate innate immune activity, modulate the immunosuppressive tumour microenvironment and trigger tumour-specific immune responses and abscopal antitumour responses. A single intratumoural administration of mineralized Salmonella typhimurium suppressed the growth of multiple types of subcutaneous and orthotopic tumours in mice, rabbits and tree shrews and protected the cured animals against tumour rechallenge. We also show that mineralized bacteria can be administered via arterial embolization to treat orthotopic liver cancer in rabbits. Our findings support the further translational testing of oncolytic mineralized bacteria as potent and safe antitumour immunotherapeutics.

Association between haemoglobin-to-red blood cell distribution width ratio at admission and all-cause mortality in adult patients with sepsis in an intensive care unit: a secondary analysis of the MIMIC-IV database.

OBJECTIVE: The association between haemoglobin-to-red blood cell distribution width ratio (HRR) and all-cause mortality remains poorly understood. This study aimed to examine the influence of HRR at the time of admission mortality over 1 year and 30 days in patients with sepsis. DESIGN: This was a secondary analysis. SETTING: This study was conducted in intensive care units (ICUs). PARTICIPANTS: Adult patients with sepsis were identified and included from an intensive care database based on eligibility criteria. PRIMARY OUTCOME AND MEASURE: The primary outcome was the rate of death within 1 year. The secondary outcome was the death rate within 30 days. RESULTS: A total of 4233 patients with sepsis who met the inclusion criteria were analysed, excluding those ineligible. These participants were divided into quartiles based on their HRR at admission. The overall mortality rates at 1 year and 30 days were 42.9% and 25.5%, respectively. A significant inverse association was observed between HRR quartiles and all-cause mortality (p<0.001). Pairwise comparisons using Kaplan-Meier analysis showed significant differences in 1-year mortality rates across the quartiles. However, no significant difference was detected in 30-day mortality between the Q3 and Q4 groups (p=0.222). Multivariate Cox regression analysis demonstrated that a higher HRR at ICU admission was independently associated with reduced mortality at 1 year (HR, 0.935; 95% CI 0.913 to 0.958; p<0.001) and 30 days (HR, 0.969; 95% CI 0.939 to 0.999; p=0.043). Furthermore, restricted cubic spline models indicated a non-linear relationship between HRR and mortality at both 1 year and 30 days (p<0.001 for both). CONCLUSIONS: This retrospective analysis demonstrated that the HRR at the time of admission was a significant prognostic marker for long-term mortality in patients with sepsis.

Application of CRISPR/Cas13a-based biosensors in serum marker detection.

The detection of serum markers is important for the early diagnosis and monitoring of diseases, but conventional detection methods have the problem of low specificity or sensitivity. CRISPR/Cas13a-based biosensors have the characteristics of simple detection methods and high sensitivity, which have a certain potential to solve the problems of conventional detection. This paper focuses on the research progress of CRISPR/Cas13a-based biosensors in serum marker detection, introduces the principles and applications of fluorescence, electrochemistry, colorimetric, and other biosensors based on CRISPR/Cas13a in the detection of serum markers, compares and analyzes the differences between the above CRISPR/Cas13a-based biosensors, and looks forward to the future development direction of CRISPR/Cas13a-based biosensors.

Aptamers targeting SARS-CoV-2 nucleocapsid protein exhibit potential anti pan-coronavirus activity.

Emerging and recurrent infectious diseases caused by human coronaviruses (HCoVs) continue to pose a significant threat to global public health security. In light of this ongoing threat, the development of a broad-spectrum drug to combat HCoVs is an urgently priority. Herein, we report a series of anti-pan-coronavirus ssDNA aptamers screened using Systematic Evolution of Ligands by Exponential Enrichment (SELEX). These aptamers have nanomolar affinity with the nucleocapsid protein (NP) of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and also show excellent binding efficiency to the N proteins of both SARS, MERS, HCoV-OC43 and -NL63 with affinity KD values of 1.31 to 135.36 nM. Such aptamer-based therapeutics exhibited potent antiviral activity against both the authentic SARS-CoV-2 prototype strain and the Omicron variant (BA.5) with EC50 values at 2.00 nM and 41.08 nM, respectively. The protein docking analysis also evidenced that these aptamers exhibit strong affinities for N proteins of pan-coronavirus and other HCoVs (-229E and -HKU1). In conclusion, we have identified six aptamers with a high pan-coronavirus antiviral activity, which could potentially serve as an effective strategy for preventing infections by unknown coronaviruses and addressing the ongoing global health threat.

Deteriorated sleep quality and associate factors in patients with type 2 diabetes mellitus complicated with diabetic peripheral neuropathy.

Objectives: To understand the sleep quality and its influencing factors in patients with type 2 diabetes mellitus (T2DM) who suffered diabetic peripheral neuropathy (DPN), and provide evidence for clinicians to carry out comprehensive intervention measures to improve the sleep quality of patients. Methods: Patients who were admitted to the Endocrinology Department of Affiliated Hospital of Zunyi Medical University were recruited from May to December 2022, and the investigation were conducted by face-to-face interview. The questionnaires included PSQI questionnaire and influencing factors, such as lifestyle and health status. Results: Among the 193 patients, 40.4% of the patients never took physical examination, 56.5% of the patients had duration of illness greater than 5 years, 61.7% of the patients had had an operation, 10.4% of the patients had bad dietary status, and 55.4% of the patients had physical pain. In addition, the PSQI general score was 8.34 ± 3.98, the occurrence rate of poor sleep quality (PSQI ≥ 8) was 54.4%, and the results showed that sleep quality of the physical pain group was worse than the no pain group. Moreover, the results of multivariate analysis revealed that the factors affecting sleep quality were lower frequency of exercise, bad dietary status, lower frequency of physical examination, longer duration of illness, and smoking, and the OR and 95% CI were [1.40, 1.04∼1.89], [3.42, 1.86∼6.29], [1.49, 1.01∼2.20], [1.78, 1.09∼2.92], [2.38, 1.17∼4.88], respectively. Conclusion: Patients with DPN have higher risk of poor sleep quality. Moreover, there were many risk factors associated with poor sleep quality, clinicians and health policymakers should timely detect and effectively intervene in these factors to improve the sleep quality, which is important to enhance the quality of life of T2DM patients complicated with DPN.

Immunotherapy combined with local therapy in the late-line treatment of repair-proficient (pMMR)/microsatellite stable (MSS) metastatic colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignancies, and at the initial visit, most patients are diagnosed with metastatic CRC (mCRC). However, immunotherapy is only and highly effective in a very small proportion of patients with mCRC having mismatch repair defect (dMMR)/high microsatellite instability, and the majority of the patients with mCRC having mismatch repair proficient (pMMR)/microsatellite stability (MSS) cannot benefit from it. At present, many clinical studies of immunotherapy combined with tyrosine kinase inhibitors (TKIs) are trying to regulate the immune microenvironment of pMMR/MSS mCRC, transforming a "cold tumor" into a "hot tumor," which has not only surprising effects but also certain limitations, i.e., the response could not be specific to metastasis. Therefore, regarding the bottleneck encountered by immunotherapy in patients with patients pMMR/MSS mCRC, this study summarized current research and possible mechanisms of immunotherapy combined with local therapy for metastasis, including radiotherapy, ablation, and transcatheter arterial chemoembolization.

Single-cell and bulk RNA sequencing reveals Anoikis related genes to guide prognosis and immunotherapy in osteosarcoma.

Anoikis resistance, a notable factor in osteosarcoma, plays a significant role in tumor invasion and metastasis. This study seeks to identify a distinct gene signature that is specifically associated with the anoikis subcluster in osteosarcoma. Clinical, single-cell, and transcriptional data from TARGET and GEO datasets were used to develop a gene signature for osteosarcoma based on the anoikis subcluster. Univariate Cox and LASSO regression analyses were employed. The signature's predictive value was evaluated using time-dependent ROC and Kaplan-Meier analyses. Functional enrichment analyses and drug sensitivity analyses were conducted. Validation of three modular genes was performed using RT-qPCR and Western blotting. Signature (ZNF583, CGNL1, CXCL13) was developed to predict overall survival in osteosarcoma patients, targeting the anoikis subcluster. The signature demonstrated good performance in external validation. Stratification based on the signature revealed significantly different prognoses. The signature was an independent prognostic factor. The low-risk group showed enhanced immune cell infiltration and improved immune function. Drug sensitivity analysis indicated efficacy of chemotherapy agents. Prognostic nomograms incorporating the signature provided greater predictive accuracy and clinical utility. Signatures related to the anoikis subcluster play a significant role in osteosarcoma progression. Incorporating these findings into clinical decision-making can improve osteosarcoma treatment and patient outcomes.

Improving the therapeutic efficacy of oncolytic viruses for cancer: targeting macrophages.

Oncolytic viruses (OVs) for cancer treatment are in a rapid stage of development, and the direct tumor lysis and activation of a comprehensive host immune response are irreplaceable advantages of cancer immunotherapy. However, excessive antiviral immune responses also restrict the spread of OVs in vivo and the infection of tumor cells. Macrophages are functionally diverse innate immune cells that phagocytose tumor cells and present antigens to activate the immune response, while also limiting the delivery of OVs to tumors. Studies have shown that the functional propensity of macrophages between OVs and tumor cells affects the overall therapeutic effect of oncolytic virotherapy. How to effectively avoid the restrictive effect of macrophages on OVs and reshape the function of tumor-associated macrophages in oncolytic virotherapy is an important challenge we are now facing. Here, we review and summarize the complex dual role of macrophages in oncolytic virotherapy, highlighting how the functional characteristics of macrophage plasticity can be utilized to cooperate with OVs to enhance anti-tumor effects, as well as highlighting the importance of designing and optimizing delivery modalities for OVs in the future.

Elucidating the Mechanism of Fe Incorporation in In Situ Synthesized Co-Fe Oxygen-Evolving Nanocatalysts.

Ni- and Co-based catalysts with added Fe demonstrate promising activity in the oxygen evolution reaction (OER) during alkaline water electrolysis, with the presence of Fe in a certain quantity being crucial for their enhanced performance. The mode of incorporation, local placement, and structure of Fe ions in the host catalyst, as well as their direct/indirect contribution to enhancing the OER activity, remain under active investigation. Herein, the mechanism of Fe incorporation into a Co-based host was investigated using an in situ synthesized Co-Fe catalyst in an alkaline electrolyte containing Co2+ and Fe3+. Fe was found to be uniformly incorporated, which occurs solely after the anodic deposition of the Co host structure and results in exceptional OER activity with an overpotential of 319 mV at 10 mA cm-2 and a Tafel slope of 28.3 mV dec-1. Studies on the lattice structure, chemical oxidation states, and mass changes indicated that Fe is incorporated into the Co host structure by replacing the Co3+ sites with Fe3+ from the electrolyte. Operando Raman measurements revealed that the presence of doped Fe in the Co host structure reduces the transition potential of the in situ Co-Fe catalyst to the OER-active phase CoO2. The findings of our facile synthesis of highly active and stable Co-Fe particle catalysts provide a comprehensive understanding of the role of Fe in Co-based electrocatalysts, covering aspects that include the incorporation mode, local structure, placement, and mechanistic role in enhancing the OER activity.

Research progress of nanovaccine in anti-tumor immunotherapy.

Tumor vaccines aim to activate dormant or unresponsive tumor-specific T lymphocytes by using tumor-specific or tumor-associated antigens, thus enhancing the body's natural defense against cancer. However, the effectiveness of tumor vaccines is limited by the presence of tumor heterogeneity, low immunogenicity, and immune evasion mechanisms. Fortunately, multifunctional nanoparticles offer a unique chance to address these issues. With the advantages of their small size, high stability, efficient drug delivery, and controlled surface chemistry, nanomaterials can precisely target tumor sites, improve the delivery of tumor antigens and immune adjuvants, reshape the immunosuppressive tumor microenvironment, and enhance the body's anti-tumor immune response, resulting in improved efficacy and reduced side effects. Nanovaccine, a type of vaccine that uses nanotechnology to deliver antigens and adjuvants to immune cells, has emerged as a promising strategy for cancer immunotherapy due to its ability to stimulate immune responses and induce tumor-specific immunity. In this review, we discussed the compositions and types of nanovaccine, and the mechanisms behind their anti-tumor effects based on the latest research. We hope that this will provide a more scientific basis for designing tumor vaccines and enhancing the effectiveness of tumor immunotherapy.

Preparation of capsaicin-loaded ultrafine fiber film and its application in the treatment of oral ulcers in rats.

A drug-loaded diaphragm is an easy-to-use and effective drug delivery system that is often used to treat mouth ulcers. In this study, an ultrafine fiber film loaded with capsaicin was successfully prepared using the electrospinning technology. poly-L-lactic acid and gelatin were selected as the matrix materials to form the composite fiber, and trifluoroethanol was used as a co-solvent for poly-L-lactic acid, gelatin and capsaicin to prepare the spinning solution, which was simple to fabricate. The prepared fiber films were characterized based on their microscopic morphology and tested to derive their mechanical properties. Thereafter, the capsaicin release behavior of the film was investigated. In vitro experiments revealed certain anti-inflammatory and antibacterial abilities while animal experiments revealed that the capsaicin-loaded ultrafine fiber film could promote the healing of oral ulcers in rats. Healing of the tongue tissue in rats administered 10% capsaicin-loaded fiber film was found to be better than that in rats administered the commercial dexamethasone patch. Overall, this development strategy may prove to be promising for the development of oral ulcer patch formulations.

Total Synthesis of abeo-Steroids via Cycloaddition Strategy.

ConspectusSteroids continue to play a significant role in organic chemistry, medicinal chemistry, and drug discovery due to their important biological activities and diverse intriguing structures. Although synthetic organic chemists have successfully constructed and elaborated the classical [6-6-6-5] tetracyclic steroid skeleton for nearly a century, synthesis of the unusual rearranged steroids, particularly abeo-steroids with a medium-sized ring, remains a challenge in the synthetic community. Furthermore, the structures of abeo-steroids are complex and diverse, containing a seven-membered ring embedded in the fused or bridged A/B ring system and possessing numerous stereogenic centers. Besides their structural complexity, various abeo-steroids have shown remarkable biological activities. However, the relative scarcity of abeo-steroids in natural sources has impeded the systematic evaluation of their biological activities. In addition, direct strategies to build the core structures of abeo-steroids are very rare, partially because of the high ring-strain energies of their rearranged A/B ring systems. Therefore, the development of direct and efficient synthetic approaches to these complex molecules is highly desired.Our long-standing interest in the total synthesis of abeo-steroids and the development of new cycloaddition reactions for streamlining complex molecule synthesis have led us to develop a series of unique and powerful intramolecular cycloaddition strategies to access a diverse array of highly strained abeo-steroids. These strategies include Ru-catalyzed [5 + 2] cycloaddition, acid-promoted type I [5 + 2] cycloaddition, Rh-catalyzed [2 + 2 + 1] cycloaddition, and type II [5 + 2] cycloaddition. Since 2018, we have accomplished the first total syntheses of five synthetically challenging abeo-steroids, i.e., bufogargarizins A and B, phomarol, bufospirostenin A, and cyclocitrinol, thus facilitating the evaluation of their pharmacological potentials. In this Account, we summarize our laboratory's systematic efforts in the total synthesis of these abeo-steroids via cycloaddition strategies. We highlight the efficiency and versatility of each cycloaddition strategy for constructing structurally complex abeo-steroid cores by forming the A/B ring system. The evolution of each strategy and key lessons learned from the synthetic journey are also discussed. We believe that our unique perspective in this field will promote advances in the total synthesis of abeo- and related steroids.

A fluoropolymer bifunctional solid membrane interface for improving the discharge duration in aqueous Al-air batteries.

Herein, a fluoropolymer bifunctional solid membrane interface (SMI) for an aqueous Al-air battery is proposed, which inhibits anodic self-corrosion, while concurrently reducing the accumulation of undesirable by-products. A battery using the SMI exhibits a remarkable anticorrosion efficiency of 81.31% and achieves an astonishing battery lifetime improvement rate of 184.37% under the condition of 5 min intermittent discharge.

Study of Oncolytic Virus Preservation and Formulation.

In recent years, oncolytic viruses (OVs) have emerged as an effective means of treating cancer. OVs have multiple oncotherapeutic functions including specifically infecting and lysing tumor cells, initiating immune cell death, attacking and destroying tumor angiogenesis and triggering a broad bystander effect. Oncolytic viruses have been used in clinical trials and clinical treatment as drugs for cancer therapy, and as a result, oncolytic viruses are required to have long-term storage stability for clinical use. In the clinical application of oncolytic viruses, formulation design plays a decisive role in the stability of the virus. Therefore, this paper reviews the degradation factors and their degradation mechanisms (pH, thermal stress, freeze-thaw damage, surface adsorption, oxidation, etc.) faced by oncolytic viruses during storage, and it discusses how to rationally add excipients for the degradation mechanisms to achieve the purpose of maintaining the long-term stability of oncolytic viral activity. Finally, the formulation strategies for the long-term formulation stability of oncolytic viruses are discussed in terms of buffers, permeation agents, cryoprotectants, surfactants, free radical scavengers, and bulking agent based on virus degradation mechanisms.

Adhesive Composite Microspheres with Dual Antibacterial Strategies for Infected Wound Healing.

Skin damage and infection pose a severe challenge to human health. Construction of a novel versatile dressing with good anti-infection and healing-promoting abilities is greatly expected. In this paper, nature-source-based composite microspheres with dual antibacterial mechanisms and bioadhesive features by microfluidics electrospray for infected wound healing is developed. The microspheres enable sustained release of copper ions, which not only show long-term antibacterial properties, but also play important role in wound-healing-related angiogenesis. Additionally, the microspheres are coated with polydopamine via self-polymerization, which renders the microspheres adhesive to the wound surface, and further enhance the antibacterial ability through photothermal energy conversion. Based on the dual antibacterial strategies provided by copper ions and polydopamine as well as the bioadhesive property, the composite microspheres exhibit excellent anti-infection and wound healing performances in a rat wound model. These results, along with the nature-source-based composition and biocompatibility, indicate the great potential of the microspheres in clinical wound repair.