Amorphous conversion in pyrolytic symmetric trinuclear nickel clusters trigger trifunctional electrocatalysts.

The pursuit of multifunctional electrocatalysts holds significant importance due to their comprehension of material chemistry. Amorphous materials are particularly appealing, yet they pose challenges in terms of rational design due to their structural disorder and thermal instability. Herein, we propose a strategy that entails the tandem (low-temperature/250-350 °C) pyrolysis of molecular clusters, enabling preservation of the local short-range structures of the precursor Schiff base nickel (Ni3[2(C21H24N3Ni1.5O6)]). The temperature-dependent residuals demonstrate exceptional activity and stability for at least three distinct electrocatalytic processes, including the oxygen evolution reaction (η10 = 197 mV), urea oxidation reaction (η10 = 1.339 V), and methanol oxidation reaction (1358 mA cm-2 at 0.56 V). Three distinct nickel atom motifs are discovered for three efficient electrocatalytic reactions (Ni1 and Ni1' are preferred for UOR/MOR, while Ni2 is preferred for OER). Our discoveries pave the way for the potential development of multifunctional electrocatalysts through disordered engineering in molecular clusters under tandem pyrolysis.

Trimethyl chitosan-cysteine-based nanoparticles as an effective delivery system for portulacerebroside A in the management of hepatocellular carcinoma cells in vitro and in vivo.

Portulacerebroside A (PCA), a cerebroside compound extracted from Portulaca oleracea L., has been shown to suppress hepatocellular carcinoma (HCC) cells. This study aims to investigate the effectiveness of trimethyl chitosan-cysteine (TMC-Cys) nanocarrier in delivering PCA for HCC management and to elucidate the molecular mechanisms behind PCA's function. TMC-Cys nanocarriers notably augmented PCA's function, diminishing the proliferation, migration, and invasiveness of HCC cells in vitro, reducing hepatocellular tumorigenesis in immunocompetent mice, and impeding metastasis of xenograft tumours in nude mice. Comprehensive bioinformatics analyses, incorporating Super-PRED systems alongside pathway enrichment analysis, pinpointed toll-like receptor 4 (TLR4) and epidermal growth factor receptor (EGFR) as two promising targets of PCA, enriched in immune checkpoint pathway. PCA/nanocarrier (PCA) reduced levels of TLR4 and EGFR and their downstream proteins, including programmed cell death ligand 1, thereby increasing populations and activity of T cells co-cultured with HCC cells in vitro or in primary HCC tumours in mice. However, these effects were counteracted by additional artificial activation of TLR4 and EGFR. In conclusion, this study provides novel evidence of PCA's function in immunomodulation in addition to its direct tumour suppressive effect. TMC-Cys nanocarriers significantly enhance PCA efficacy, indicating promising application as a drug delivery system.

Four lathyrane diterpenoids from the seeds of Euphorbia lathyris.

Four new diterpenoids, including three secolathyrane diterpenoids (1-3) and one lathyrane diterpenoid (4), together with seven known diterpenoids, were obtained in the shelled seeds of Euphorbia lathyris. In particular, 1-3 possess a rare split ring structure, and currently only one compound with the same skeleton has been identified in E. lathyris. Compound 4 furnishes an unprecedented oxygen bridge structure. The structures were identified using various spectral techniques, including NMR, HR-ESI-MS, single-crystal X-ray diffraction and calculated electronic circular dichroism (ECD). The biosynthetic pathway of 1-4 was inferred. Furthermore, the cytotoxic activities of all compounds (1-11) were measured on three human tumor cells. New compounds 2 and 3 showed moderate cytotoxic activities against U937 cells with IC50 values of 22.18 and 25.41 µM, respectively.

Double crosslinking decellularized bovine pericardium of dialdehyde chondroitin sulfate and zwitterionic copolymer for bioprosthetic heart valves with enhanced antithrombogenic, anti-inflammatory and anti-calcification properties.

Due to the increasing aging population and the advancements in transcatheter aortic valve replacement (TAVR), the use of bioprosthetic heart valves (BHVs) in patients diagnosed with valvular disease has increased substantially. Commercially available glutaraldehyde (GA) cross-linked biological valves suffer from reduced durability due to a combination of factors, including the high cell toxicity of GA, subacute thrombus, inflammation and calcification. In this study, oxidized chondroitin sulfate (OCS), a natural polysaccharide derivative, was used to replace GA to cross-link decellularized bovine pericardium (DBP), carrying out the first crosslinking of DBP to obtain OCS-BP. Subsequently, the zwitterion radical copolymerization system was introduced in situ to perform double cross-linking to obtain double crosslinked BHVs with biomimetic modification (P(APM/MPC)-OCS-BP). P(APM/MPC)-OCS-BP presented enhanced mechanical properties, collagen stability and enzymatic degradation resistance due to double crosslinking. The ex vivo AV-shunt assay and coagulation factors test suggested that P(APM/MPC)-OCS-BP exhibited excellent anticoagulant and antithrombotic properties due to the introduction of P(APM/MPC). P(APM/MPC)-OCS-BP also showed good HUVEC-cytocompatibility due to the substantial reduction of its residual aldehyde group. The subcutaneous implantation also demonstrated that P(APM/MPC)-OCS-BP showed a weak inflammatory response due to the anti-inflammatory effect of OCS. Finally, in vivo and in vitro results revealed that P(APM/MPC)-OCS-BP exhibited an excellent anti-calcification property. In a word, this simple cooperative crosslinking strategy provides a novel solution to obtain BHVs with good mechanical properties, and HUVEC-cytocompatibility, anti-coagulation, anti-inflammatory and anti-calcification properties. It might be a promising alternative to GA-fixed BP and exhibited good prospects in clinical applications.

MARS an improved de novo peptide candidate selection method for non-canonical antigen target discovery in cancer.

Understanding the nature and extent of non-canonical human leukocyte antigen (HLA) presentation in tumour cells is a priority for target antigen discovery for the development of next generation immunotherapies in cancer. We here employ a de novo mass spectrometric sequencing approach with a refined, MHC-centric analysis strategy to detect non-canonical MHC-associated peptides specific to cancer without any prior knowledge of the target sequence from genomic or RNA sequencing data. Our strategy integrates MHC binding rank, Average local confidence scores, and peptide Retention time prediction for improved de novo candidate Selection; culminating in the machine learning model MARS. We benchmark our model on a large synthetic peptide library dataset and reanalysis of a published dataset of high-quality non-canonical MHC-associated peptide identifications in human cancer. We achieve almost 2-fold improvement for high quality spectral assignments in comparison to de novo sequencing alone with an estimated accuracy of above 85.7% when integrated with a stepwise peptide sequence mapping strategy. Finally, we utilize MARS to detect and validate lncRNA-derived peptides in human cervical tumour resections, demonstrating its suitability to discover novel, immunogenic, non-canonical peptide sequences in primary tumour tissue.

Crohn's disease as the intestinal manifestation of pan-lymphatic dysfunction: An exploratory proposal based on basic and clinical data.

Crohn's disease (CD) is caused by immune, environmental, and genetic factors. It can involve the entire gastrointestinal tract, and although its prevalence is rapidly increasing its etiology remains unclear. Emerging biological and small-molecule drugs have advanced the treatment of CD; however, a considerable proportion of patients are non-responsive to all known drugs. To achieve a breakthrough in this field, innovations that could guide the further development of effective therapies are of utmost urgency. In this review, we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases, and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data. The supporting evidence is fully summarized, including the existence of lymphatic system dysfunction, recognition of the inside-out model, disorders of immune cells, changes in cell plasticity, partial overlap of the underlying mechanisms, and common gut-derived fatty and bile acid metabolism. Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases, especially CD, as this model is good at presenting and mimicking lymphatic dysfunction. More importantly, the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.

A Portable Self-Powered Electrochemical Sensor Based on Zinc-Air Battery for Detection of Hydrogen Sulfide.

The self-powered electrochemical sensor (SPES), an analytical sensing device without external power supply, is integrated with the dual function of power supply and detection performance, which lay the foundation for the development of intelligent and portable electrochemical sensing devices. Herein, a novel SPES based on a zinc-air battery was constructed for the detection of hydrogen sulfide (H2S) in the lysate of colon cancer cells. Typically, an Fe/Fe3C@graphene foam with oxygen reduction performance was used to construct SPES based on a zinc-air battery (ZAB-SPES), which brings the open-circuit voltage to 1.30 V. Among them, the poisoning effect of H2S causes the catalytic performance of the oxygen reduction catalyst to decrease, causing a significant decrease in the discharge voltage of ZAB. Based on this principle, ZAB-SPES was constructed for the detection of H2S using a digital multimeter. The proposed ZAB-SPES demonstrated good selectivity and reproducibility for detecting H2S compared to the results of the H2S-specific fluorescence probe. This strategy enriches the idea of constructing a self-powered sensor and a digital multimeter as detection devices, providing technical support for the portability of SPESs.

Reducing Cholesterol Level in Live Macrophages Improves Delivery Performance by Enhancing Blood Shear Stress Adaptation.

In recent years, live-cell-based drug delivery systems have gained considerable attention. However, shear stress, which accompanies blood flow, may cause cell death and weaken the delivery performance. In this study, we found that reducing cholesterol in macrophage plasma membranes enhanced their tumor targeting ability by more than 2-fold. Our study demonstrates that the reduced cholesterol level deactivated the mammalian target of rapamycin (mTOR) and consequently promoted the nuclear translocation of transcription factor EB (TFEB), which in turn enhanced the expression of superoxide dismutase (SOD) to reduce reactive oxygen species (ROS) induced by shear stress. A proof-of-concept system using low cholesterol macrophages attached to MXene (e.g., l-RX) was fabricated. In a melanoma mouse model, l-RX and laser irradiation treatments eliminated tumors with no recurrences observed in mice. Therefore, cholesterol reduction is a simple and effective way to enhance the targeting performance of macrophage-based drug delivery systems.

A multicenter retrospective analysis: Factors influencing hepatic adverse events induced by immunotherapy in advanced liver cancer.

OBJECTIVES: To analyze the clinical characteristics and influencing factors of hepatotoxicity in patients with advanced hepatocellular carcinoma (HCC) treated with programmed cell death protein-1 (PD-1) inhibitors, and to provide a theoretical basis for the treatment of immune-related hepatotoxicity in patients with advanced HCC. METHODS: Retrospective analysis of clinical data of patients with advanced HCC from February 2021 to February 2023, in order to summarize and statistically analyze the influencing factors of immune-related liver adverse reactions. RESULTS: A total of 135 patients met the inclusion criteria, among whom 46 patients experienced varying degrees of immune-related liver adverse reactions, with an incidence rate of 34.1% (46/135). The time range of immune-related liver adverse reactions was 3-26 weeks, with a median time of 4 weeks. The age range of immune-related liver adverse reactions was 34-73 years, with a median age of 62 years. Statistical analysis of the influencing factors and liver adverse reactions showed that age, total bilirubin level, and Child-Pugh (C-P) grading were influencing factors for the occurrence of liver adverse reactions (p < .05), and among these three influencing factors, the proportion of males with ≥2 influencing factors was higher than that of females; liver function C-P B was an independent influencing factor for liver adverse reactions (p < .05). CONCLUSION: For male patients over 60 years old, with bilirubin levels ≥51 µmol/L and liver function C-P B, close observation of the occurrence of immune-related adverse reactions during treatment is recommended.

3D Molybdenum Disulfide Nanospheres Loaded with Metformin to Enhance SCPP Scaffolds for Bone Regeneration.

Conventional strontium-doped calcium polyphosphate (SCPP) ceramics have attracted a lot of attention due to good cytocompatibility and controlled degradation. However, their poor mechanical strength, brittleness, and difficulty in eliminating unavoidable postoperative inflammation and bacterial infections in practical applications limit their further clinical application. In this study, carboxylated molybdenum disulfide nanospheres (MoS2-COOH) were first prepared via a one-step hydrothermal method. The optimal doping concentration of MoS2-COOH was then incorporated into SCPP to overcome its poor mechanical strength. To further enhance the anti-inflammatory properties of scaffolds, metformin (MET) was loaded onto MoS2-COOH through covalent bond cross-linking (MoS2-MET). Then MoS2-MET was doped into SCPP (SCPP/MoS2-MET) according to the previously obtained concentration, resulting in the controlled and sustained release of MET from the SCPP/MoS2-MET scaffolds for 21 days in vitro. The SCPP/MoS2-MET scaffolds were shown to have good biological activity in vitro to promote stem cell proliferation and the potential to promote mineralization in vitro. It also showed good osteoimmunomodulatory activity could reduce the expression of proinflammatory factors and effectively induce the differentiation of BMSCs under inflammatory conditions, upregulating the expression of relevant osteoblastic cytokines. In addition, SCPP/MoS2-MET scaffolds could effectively inhibit Staphylococcus aureus and Escherichia coli. In vivo experiments also demonstrated better osteogenic potential of SCPP/MoS2-MET scaffolds compared with the other scaffold-samples. Thus, the introduction of carboxylated molybdenum disulfide nanospheres is a promising approach to improve the properties of SCPP and may provide a new modification strategy for inert ceramic scaffolds and the construction of multifunctional composite scaffolds for bone tissue engineering.

Dopamine and cyclic adenosine monophosphate-regulated phosphoprotein with an apparent Mr of 32000 promotes colorectal cancer growth.

BACKGROUND: Dopamine and cyclic adenosine monophosphate (cAMP)-regulated phosphoprotein with an apparent Mr of 32000 (DARPP-32) is a protein that is involved in regulating dopamine and cAMP signaling pathways in the brain. However, recent studies have shown that DARPP-32 is also expressed in other tissues, including colorectal cancer (CRC), where its function is not well understood. AIM: To explore the effect of DARPP-32 on CRC progression. METHODS: The expression levels of DARPP-32 were assessed in CRC tissues using both quantitative polymerase chain reaction and immunohistochemistry assays. The proliferative capacity of CRC cell lines was evaluated with Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays, while apoptosis was measured by flow cytometry. The migratory and invasive potential of CRC cell lines were determined using wound healing and transwell chamber assays. In vivo studies involved monitoring the growth rate of xenograft tumors. Finally, the underlying molecular mechanism of DARPP-32 was investigated through RNA-sequencing and western blot analyses. RESULTS: DARPP-32 was frequently upregulated in CRC and associated with abnormal clinicopathological features in CRC. Overexpression of DARPP-32 was shown to promote cancer cell proliferation, migration, and invasion and reduce apoptosis. DARPP-32 knockdown resulted in the opposite functional effects. Mechanistically, DARPP-32 may regulate the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway in order to carry out its biological function. CONCLUSION: DARPP-32 promotes CRC progression via the PI3K/AKT signaling pathway.

H3.1K27me1 loss confers Arabidopsis resistance to Geminivirus by sequestering DNA repair proteins onto host genome.

The H3 methyltransferases ATXR5 and ATXR6 deposit H3.1K27me1 to heterochromatin to prevent genomic instability and transposon re-activation. Here, we report that atxr5 atxr6 mutants display robust resistance to Geminivirus. The viral resistance is correlated with activation of DNA repair pathways, but not with transposon re-activation or heterochromatin amplification. We identify RAD51 and RPA1A as partners of virus-encoded Rep protein. The two DNA repair proteins show increased binding to heterochromatic regions and defense-related genes in atxr5 atxr6 vs wild-type plants. Consequently, the proteins have reduced binding to viral DNA in the mutant, thus hampering viral amplification. Additionally, RAD51 recruitment to the host genome arise via BRCA1, HOP2, and CYCB1;1, and this recruitment is essential for viral resistance in atxr5 atxr6. Thus, Geminiviruses adapt to healthy plants by hijacking DNA repair pathways, whereas the unstable genome, triggered by reduced H3.1K27me1, could retain DNA repairing proteins to suppress viral amplification in atxr5 atxr6.

Promoting Stem Cell Mechanosensing and Osteogenesis by Hybrid Soft Fibers.

Bone regenerative biomaterials are essential in treating bone defects as they serve as extracellular matrix (ECM) mimics, creating a favorable environment for cell attachment, proliferation, and differentiation. However, the currently used bone regenerative biomaterials mostly exhibit high stiffness, which may lead to difficulties in degradation and thus increase the risk of foreign body ingestion. In this study, we prepared soft fibrous scaffolds modified with Zn-MOF-74 nanoparticles via electrostatic spinning. The soft fibers (only 1 kPa) permit remodeling under cellular adhesive force, optimizing the mechanical cues in the microenvironment to support cell adhesion and mechanosensing. In addition, the incorporation of Zn-MOF-74 nanoparticles enables the stable and sustained release of zinc ions, promoting stem cell mechanotransduction and osteogenic differentiation. Therefore, the hybrid soft fibers facilitate the regeneration of new bone in the rat femoral defect model, which provides a promising approach for regenerative medicine.

A synergistic strategy of dual-crosslinking and loading intelligent nanogels for enhancing anti-coagulation, pro-endothelialization and anti-calcification properties in bioprosthetic heart valves.

Currently, glutaraldehyde (GA)-crosslinked bioprosthetic heart valves (BHVs) still do not guarantee good biocompatibility and long-term effective durability for clinical application due to their subacute thrombus, inflammation, calcification, tearing and limited durability. In this study, double-modified xanthan gum (oxidized/vinylated xanthan gum (O2CXG)) was acquired from xanthan gum for subsequent double crosslinking and modification platform construction. Sulfonic acid groups with anticoagulant properties were also introduced through the free radical polymerization of vinyl sulfonate (VS) and vinyl on O2CXG. Taking advantage of the drug-loading function of xanthan gum, the treated pericardium was further loaded with inflammation-triggered dual drug-loaded nanogel (heparin (Hep) and atorvastatin (Ator)). Mechanical properties of O2CXG-crosslinked porcine pericardium (O2CXG-PP) were significantly improved via the first network formed by Schiff base bonds and the second C-C bonds network. Due to the presence of sulfonic acid groups as well as the dual drug release from nanogels under the stimulation of H2O2, the hemocompatibility, anti-inflammatory, pro-endothelialization and anti-calcification properties of the crosslinked pericardium modified with nanogels loaded with Hep and Ator (O2CXG+VS+(Hep+Ator) nanogel-PP) was significantly better than that of GA-crosslinked PP (GA-PP). The collaborative strategy of double crosslinking and sequential release of anticoagulant/endothelium-promoting drugs triggered by inflammation could effectively meet the requirement of enhanced multiple performance and long-term durability of bioprosthetic heart valves and provide a valuable pattern for multi-functionalization of blood contacting materials. STATEMENT OF SIGNIFICANCE: Currently, glutaraldehyde-crosslinked bioprosthetic heart valves (BHVs) are subject to subacute thrombus, inflammation, calcification and tearing, which would not guarantee good biocompatibility and long-term effective durability. We developed a cooperative strategy of double crosslinking and surface modification in which double-modified xanthan gum plays a cornerstone. The mechanical properties of this BHV were significantly improved via the first network formed by Schiff base bonds and the second C-C bonds network. Inflammation-triggered combination delivery of heparin and atorvastatin has been demonstrated to enhance anticoagulation, anti-inflammatory and pro-endothelialization of BHVs by utilizing local inflammatory response. The collaborative strategy could effectively meet the requirement of enhanced multiple performance and long-term durability of BHVs and provide a valuable pattern for the multi-functionalization of blood-contacting materials.

Effects of chronic liver disease on the outcomes of simultaneous resection of colorectal cancer with synchronous liver metastases: a propensity score matching study.

Introduction: Given the rising prevalence of chronic liver disease (CLD), it is increasingly important to understand its impact on surgical outcomes. Our aim was to evaluate the impact of CLD on short-term outcomes in patients with colorectal cancer and synchronous liver metastases undergoing simultaneous surgery. Methods: We retrospectively reviewed patients with colorectal cancer and liver metastases who underwent simultaneous resection between January 2013 and June 2022. Patients were divided into the CLD and non-CLD groups. Data regarding short-term surgical outcomes were compared between the two groups. Results: A total of 187 patients were included. After propensity score matching, there were 42 patients in each group, and the basic characteristics of the two groups were similar. Patients with CLD had a significantly greater incidence of postoperative complications (47.6% vs. 26.2%; P = 0.042). The operation times of the CLD and non-CLD groups were similar (297 vs. 307.5 min, P = 0.537), and the blood loss was comparable between the two groups (250 vs. 155 ml, P = 0.066). No significant differences were observed between the two groups in pneumonia (P > 0.999), urinary infection rate (P > 0.999), ileus rate (P = 0.474), wound infection rates (P > 0.999), abdominal infection rate (P = 0.533), anastomotic leakage rate (P > 0.999), digestive hemorrhage rate (P > 0.999), bile leakage rate (P > 0.999), hepatic hemorrhage rate (P > 0.999), reoperation rate (P > 0.999), intensive care rate (P > 0.999), or severe liver failure (P > 0.999). There were no deaths in the two groups. CLD significantly prolonged the length of hospital stay (P = 0.011). Discussion: CLD is an important factor affecting postoperative complications in patients with colorectal cancer liver metastases undergoing simultaneous surgery. Considering the large number of patients with CLD in China, more attention and medical care should be provided to patients with CLD who require simultaneous resection of colorectal cancer with synchronous liver metastases.

dECM based dusal-responsive vascular graft with enzyme-controlled adenine release for long-term patency.

Rapid occlusion is the culprit leading to implantation failure of biological blood vessels. Although adenosine is a clinical-proven drug to overcome the problem, its short half-life and turbulent burst-release limit its direct application. Thus, a pH/temperature dual-responsive blood vessel possessed controllable long-term adenosine secretion was constructed based on acellular matrix via compact crosslinking by oxidized chondroitin sulfate (OCSA) and functionalized with apyrase and acid phosphatase. These enzymes, as adenosine micro-generators, controlled the adenosine release amount by "real-time-responding" to acidity and temperature of vascular inflammation sites. Additionally, the macrophage phenotype was switched from M1 to M2, and related factors expression proved that adenosine release was effectively regulated with the severity of inflammation. What's more, the ultra-structure for degradation resisting and endothelialization accelerating was also preserved by their "double-crosslinking". Therefore, this work suggested a new feasible strategy providing a bright future of long-term patency for transplanted blood vessels.

Research on essential performance of oxidized chitosan-crosslinked acellular porcine aorta modified with bioactive SCPP/DOPA for esophageal scaffold with enhanced mechanical strength, biocompatibility and anti-inflammatory.

Acellular porcine aorta (APA) is an excellent candidate for an implanted scaffold but needs to be modified with appropriate cross-linking agent to increase its mechanical property and storage time in vitro as well as to give itself some bioactivities and eliminate its antigenicity for acting as a novel esophageal prosthesis. In this paper, a polysaccharide crosslinker (oxidized chitosan, OCS) was prepared by oxidizing chitosan using NaIO4 and further used to fix APA to prepare a novel esophageal prosthesis (scaffold). And then the surface modification with dopamine (DOPA) and strontium-doped calcium polyphosphate (SCPP) were performed one after another to prepare DOPA/OCS-APA and SCPP-DOPA/OCS-APA to improve the biocompatibility and inhibit inflammation of the scaffolds. The results showed that the OCS with a feeding ratio of 1.5:1.0 and a reaction time of 24 h had a suitable molecular weight and oxidation degree, almost no cytotoxicity and good cross-linking effect. Compared with glutaraldehyde (GA) and genipin (GP), OCS-fixed APA could provide a more suitable microenvironment for cell proliferation. The vital cross-linking characteristics and cytocompatibility of SCPP-DOPA/OCS-APA were evaluated. Results suggested that SCPP-DOPA/OCS-APA exhibited suitable mechanical properties, excellent resistance to enzymatic degradation/acid degradation, suitable hydrophilicity, and the ability to promote the proliferation of Human normal esophageal epithelial cells (HEECs) and inhibit inflammation in vitro. In vivo tests also confirmed that SCPP-DOPA/OCS-APA could diminish the immunological response to samples and had a positive impact on bioactivity and anti-inflammatory. In conclusion, SCPP-DOPA/OCS-APA could act as an effective, bioactive artificial esophageal scaffold and be expected to be used for clinical in the future.

The Efficacy and Safety of Telerehabilitation for Fibromyalgia: Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Fibromyalgia is a chronic pain syndrome characterized by persistent and widespread musculoskeletal pain. Telerehabilitation is a promising treatment for patients with fibromyalgia through long-term monitoring, intervention, supervision, consultation, and education. OBJECTIVE: This study aimed to perform a comprehensive systematic review and meta-analysis of the efficacy and safety of telerehabilitation in patients with fibromyalgia. METHODS: Randomized controlled trials (RCTs) related to fibromyalgia and telerehabilitation were systematically searched in the PubMed, PEDro, Cochrane Library, ScienceDirect, Ovid MEDLINE, Embase, and Web of Science databases from inception to November 13, 2022. Two independent researchers screened the literatures and evaluated the methodological quality using the Cochrane Risk of Bias Tool. The outcome measures included the Fibromyalgia Impact Questionnaire scale, pain intensity, depression, pain catastrophizing, quality of life (QoL), and adverse events. Pooled effect sizes were calculated by Stata SE 15.1; a fixed effects model was used when I2<50%, whereas a random effects model was used when I2≥50%. RESULTS: A total of 14 RCTs with 1242 participants were included in this meta-analysis. The pooled results indicated that the telerehabilitation improved the Fibromyalgia Impact Questionnaire score (weighted mean difference -8.32, 95% CI -11.72 to -4.91; P<.001), pain intensity (standardized mean difference [SMD] -0.62, 95% CI -0.76 to -0.47; P<.001), depression levels (SMD -0.42, 95% CI -0.62 to -0.22; P<.001), pain catastrophizing (weighted mean difference -5.81, 95% CI -9.40 to -2.23; P=.001), and QoL (SMD 0.32, 95% CI 0.18 to 0.47; P<.001) in patients with fibromyalgia compared to control interventions. Only 1 RCT reported a mild adverse event of telerehabilitation; the other 13 RCTs did not mention this. CONCLUSIONS: Telerehabilitation can improve the symptoms and QoL of fibromyalgia. However, the safety of telerehabilitation remains uncertain due to the lack of sufficient evidence for the management of fibromyalgia. More rigorously designed trials are needed in the future to verify the safety and efficacy of telerehabilitation in fibromyalgia. TRIAL REGISTRATION: PROSPERO CRD42022338200; https://tinyurl.com/322keukv.

Novel canonical and non-canonical viral antigens extend current targets for immunotherapy of HPV-driven cervical cancer.

Current immunotherapeutic approaches for human papillomavirus (HPV)-driven cervical cancer target the viral oncogenes E6 and E7. We report viral canonical and alternative reading frame (ARF)-derived sequences presented on cervical tumor cells, including antigens encoded by the conserved viral gene E1. We confirm immunogenicity of the identified viral peptides in HPV-positive women, and women with cervical intraepithelial neoplasia. We observe consistent transcription of the E1, E6, and E7 genes in 10 primary cervical tumor resections from the four most common high-risk HPV subtypes (HPV16, 18, 31, and 45), suggesting the suitability of E1 as therapeutic target. We finally confirm HLA presentation of canonical peptides derived from E6 and E7, and ARF-derived viral peptides from a reverse-strand transcript spanning the HPV E1 and E2 genes in primary human cervical tumor tissue. Our results extend currently known viral immunotherapeutic targets in cervical cancer and highlight E1 as an important cervical cancer antigen.