A Novel Anti-CD38 Monoclonal Antibody for Treating Immune Thrombocytopenia.

BACKGROUND: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibody-mediated platelet destruction. Treatment with CM313, a novel anti-CD38 monoclonal antibody, can result in targeted clearance of CD38-positive cells, including plasma cells. METHODS: We conducted a phase 1-2, open-label study to evaluate the safety and efficacy of CM313 in adult patients with ITP. CM313 was administered intravenously at a dose of 16 mg per kilogram of body weight every week for 8 weeks, followed by a 16-week follow-up period. The primary outcomes were adverse events and documentation of two or more consecutive platelet counts of at least 50×109 per liter within 8 weeks after the first dose of CM313. The status of peripheral-blood immune cells in patients and changes in the mononuclear phagocytic system in passive mouse models of ITP receiving anti-CD38 therapy were monitored. RESULTS: Of the 22 patients included in the study, 21 (95%) had two consecutive platelet counts of at least 50×109 per liter during the treatment period, with a median cumulative response duration of 23 weeks (interquartile range, 17 to 24). The median time to the first platelet count of at least 50×109 per liter was 1 week (range, 1 to 3). The most common adverse events that occurred during the study were infusion-related reaction (in 32% of the patients) and upper respiratory tract infection (in 32%). After CD38-targeted therapy, the percentage of CD56dimCD16+ natural killer cells, the expression of CD32b on monocytes in peripheral blood, and the number of macrophages in the spleen of the passive mouse models of ITP all decreased. CONCLUSIONS: In this study, anti-CD38 targeted therapy rapidly boosted platelet levels by inhibiting antibody-dependent cell-mediated cytotoxicity on platelets, maintained long-term efficacy by clearing plasma cells, and was associated with mainly low-grade toxic effects. (Funded by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences and others; ClinicalTrials.gov number, NCT05694767).

Metabolomics profile and machine learning prediction of treatment responses in immune thrombocytopenia: A prospective cohort study.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by antibody-mediated platelet destruction and impaired platelet production. The mechanisms underlying ITP and biomarkers predicting the response of drug treatments are elusive. We performed a metabolomic profiling of bone marrow biopsy samples collected from ITP patients admission in a prospective study of the National Longitudinal Cohort of Hematological Diseases. Machine learning algorithms were conducted to discover novel biomarkers to predict ITP patient treatment responses. From the bone marrow biopsies of 91 ITP patients, we quantified a total of 4494 metabolites, including 1456 metabolites in the positive mode and 3038 metabolites in the negative mode. Metabolic patterns varied significantly between groups of newly diagnosed and chronic ITP, with a total of 876 differential metabolites involved in 181 unique metabolic pathways. Enrichment factors and p-values revealed the top metabolically enriched pathways to be sphingolipid metabolism, the sphingolipid signalling pathway, ubiquinone and other terpenoid-quinone biosynthesis, thiamine metabolism, tryptophan metabolism and cofactors biosynthesis, the phospholipase D signalling pathway and the phosphatidylinositol signalling system. Based on patient responses to five treatment options, we screened several metabolites using the Boruta algorithm and ranked their importance using the random forest algorithm. Lipids and their metabolism, including long-chain fatty acids, oxidized lipids, glycerophospholipids, phosphatidylcholine and phosphatidylethanolamine biosynthesis, helped differentiate drug treatment responses. In conclusion, this study revealed metabolic alterations associated with ITP in bone marrow supernatants and a potential biomarker predicting the response to ITP.

Single-dose rituximab plus glucocorticoid versus cyclophosphamide plus glucocorticoid in patients with newly diagnosed acquired hemophilia A: A multicenter, open-label, randomized noninferiority trial.

Acquired hemophilia A (AHA) is a rare but serious bleeding disorder. Randomized controlled trial (RCT) comparing the efficacy of immunosuppression therapy for AHA lacks. We conducted the first multicenter RCT aiming to establish whether the single-dose rituximab combination regimen was noninferior to the cyclophosphamide combination regimen. From 2017 to 2022, 63 patients with newly diagnosed AHA from five centers were randomly assigned 1:1 to receive glucocorticoid (methylprednisolone 0.8 mg/kg per day for the first 3 weeks and then tapered) plus single-dose rituximab (375 mg/m2 ; n = 31) or plus cyclophosphamide (2 mg/kg per day until inhibitor becomes negative, for a maximum of 5 weeks; n = 32). The primary outcome was complete remission (CR, defined as FVIII activity ≥50 IU/dL, FVIII inhibitor undetectable, immunosuppression tapered and no bleeding for 24 h without bypassing agents) rate measured within 8 weeks. The noninferiority margin was an absolute difference of 20%. Twenty-four (77.4%) patients in the rituximab group and 22 (68.8%) patients in the cyclophosphamide group achieved CR, which showed the noninferiority of the single-dose rituximab-based regimen (absolute difference = -8.67%, lower limit of the 95% confidence interval = -13.11%; Pnoninferiority = 0.005). No difference was found in the incidence of treatment-related adverse events. Single-dose rituximab plus glucocorticoid regimen showed similar efficacy and safety, without a reported risk of secondary malignancies or reproductive toxicity seen in cyclophosphamide, it might be recommended as a first-line therapy for AHA, especially in China where there is a young age trend in AHA patients. This trial was registered at ClinicalTrials.gov as #NCT03384277.

Health risk assessment of heavy metals based on source analysis and Monte Carlo in the downstream basin of the Zishui.

In this study, stone coal mines in the lower reaches of the Zijiang River were adopted as the research object. To analyze the spatial distribution, sources, and health risks of heavy metals in the surrounding soil of stone coal mines, 82 topsoil samples were collected in the study area, and the contents of 8 heavy metals including Cd, Hg, As, Cr, Pb, Cu, Ni, and Zn were determined. The spatial distribution of heavy metals was analyzed using ArcGIS, and the pollution sources of heavy metals were identified using Positive matrix factorization (PMF). Then, Monte Carlo and health risk assessment models were used to evaluate the health risks of different populations. The results showed that the average content of heavy metals followed the order of Zn > Cr > Pb > Cu > Ni > As > Cd > Hg, and the contents of all heavy metals were higher than the soil background values of Hunan Province. The high-value areas of heavy metals content were mostly concentrated in the central region close to areas with a notable concentration of stone coal mines. PMF identified four pollution sources, namely, mining activities (26.9%), atmospheric deposition (18.8%), natural sources (32.8%) and agricultural sources (21.5%). The carcinogenic and non-carcinogenic risks for children were higher than those for adults, with As and Cd posing higher carcinogenic risks to children. Based on the source of health risks, it was determined that the health risks could be primarily attributed to agricultural sources, and As was the main heavy metal causing health risks. This study provides theoretical support for treating heavy metal pollution in mining basins.

Sonopiezoelectric Nanomedicine and Materdicine.

Endogenous electric field is ubiquitous in a multitude of important living activities such as bone repair, cell signal transduction, and nerve regeneration, signifying that regulating the electric field in organisms is highly beneficial to maintain organism health. As an emerging and promising research direction, piezoelectric nanomedicine and materdicine precisely activated by ultrasound with synergetic advantages of deep tissue penetration, remote spatiotemporal selectivity, and mechanical-electrical energy interconversion, have been progressively utilized for disease treatment and tissue repair by participating in the modulation of endogenous electric field. This specific nanomedicine utilizing piezoelectric effect activated by ultrasound is typically regarded as "sonopiezoelectric nanomedicine". This comprehensive review summarizes and discusses the substantially employed sonopiezoelectric nanomaterials and nanotherapies to provide an insight into the internal mechanism of the corresponding biological behavior/effect of sonopiezoelectric biomaterials in versatile disease treatments. This review primarily focuses on the sonopiezoelectric biomaterials for biosensing, drug delivery, tumor therapy, tissue regeneration, antimicrobia, and further illuminates the underlying sonopiezoelectric mechanism. In addition, the challenges and developments/prospects of sonopiezoelectric nanomedicine are analyzed for promoting the further clinical translation. It is earnestly expected that this kind of nanomedicine/biomaterials-enabled sonopiezoelectric technology will provoke the comprehensive investigation and promote the clinical development of the next-generation multifunctional materdicine.

Clinical features and current treatment status of essential thrombocythemia in older adults: a multicenter real-world study in China.

Approximately half of patients diagnosed with essential thrombocythemia (ET) are older adults (aged ≥ 60 years), but to date, little is known about the clinical and molecular characteristics of older patients diagnosed according to the 2016 World Health Organization criteria. We retrospectively collected clinical and molecular data from 282 older (≥ 60 years) and 621 younger ET patients (18-59 years) in China from March 1, 2012 to November 1, 2021 and summarized the clinical characteristics and treatment of these older ET patients. Compared to younger patients, older patients had a higher incidence of the JAK2V617F mutation (P = 0.001), a lower incidence of CALR mutations (P = 0.033) and a higher rate of epigenetic mutations (P < 0.001), TP53 mutations (P = 0.005), and RNA splicing mutations (P < 0.001). Older patients had not only a higher incidence of thrombosis but also a higher incidence of bleeding events. Furthermore, older patients had a significantly higher mortality rate after disease progression (P = 0.050) or after thrombotic events (P = 0.013). Risk factors for thrombosis or prognosis were significantly different between older patients and the entire ET cohort. In older patients, non-driver mutations contributed significantly to thrombotic complications and a poor prognosis, while the JAK2V617F mutation was a risk factor for overall survival but not for thrombotic events. The application of interferon in older ET patients was not inferior to that of hydroxyurea in terms of efficacy and safety. Older patients presented unique characteristics different from those of younger patients, which could provide new information for formulating more appropriate treatment and follow-up strategies.

Machine learning analyses constructed a novel model to predict recurrent thrombosis in adults with essential thrombocythemia.

The current study involving 318 essential thrombocythemia (ET) patients with prior thrombosis was designed to identify risk factors that were predictive of recurrent thrombosis. The whole cohort was randomly split into derivation and validation cohorts. The random forest method, support vector machine with built-in recursive feature elimination model, and logistic multivariable analysis were performed in the derivation cohort, and cardiovascular risk factor (CVF) and RBC distribution width with standard deviation (RDW-SD) were finally selected as independent predictors. Subsequently we devise a 3-tiered model (low risk: 0 points; intermediate risk: 1-1.5 points; and high risk: 2.5 points) and it showed good discrimination in all cohorts. Moreover, the model was significantly correlated with rethrombosis-free survival (rTFS) (p = 0.0007 in the derivation cohort; p = 0.0019 in the validation cohort). In the whole cohort, cytoreductive therapy was more effective than antiplatelet agents alone for 10-year rTFS (p = 0.0336). No significant difference in 10-year rTFS was observed among interferon (IFN), hydroxyurea (HU), and IFN + HU therapy (p = 0.444). The present study helps identify individuals who need close monitoring and provides valuable risk signals for recurrence in ET patients with prior thrombosis.

Dynamics and competition of CRISPR-Cas9 ribonucleoproteins and AAV donor-mediated NHEJ, MMEJ and HDR editing.

Investigations of CRISPR gene knockout editing profiles have contributed to enhanced precision of editing outcomes. However, for homology-directed repair (HDR) in particular, the editing dynamics and patterns in clinically relevant cells, such as human iPSCs and primary T cells, are poorly understood. Here, we explore the editing dynamics and DNA repair profiles after the delivery of Cas9-guide RNA ribonucleoprotein (RNP) with or without the adeno-associated virus serotype 6 (AAV6) as HDR donors in four cell types. We show that editing profiles have distinct differences among cell lines. We also reveal the kinetics of HDR mediated by the AAV6 donor template. Quantification of T50 (time to reach half of the maximum editing frequency) indicates that short indels (especially +A/T) occur faster than longer (>2 bp) deletions, while the kinetics of HDR falls between NHEJ (non-homologous end-joining) and MMEJ (microhomology-mediated end-joining). As such, AAV6-mediated HDR effectively outcompetes the longer MMEJ-mediated deletions but not NHEJ-mediated indels. Notably, a combination of small molecular compounds M3814 and Trichostatin A (TSA), which potently inhibits predominant NHEJ repairs, leads to a 3-fold increase in HDR efficiency.

Ultrathin Supratrochlear Artery Cutaneous Branch Flaps for Large Defects Around Eyebrows.

BACKGROUND: The key point of repairing large defects around eyebrows is to keep the eyebrow undistorted. The limited skin elevates the application difficulty of conventional methods such as direct suture or local flap. Forehead pedicle flaps do well in tension control. However, most of them are too thick for defects because the frontalis muscle must be included. Recently, 1 stable supratrochlear artery cutaneous branch was found, which provides an opportunity to make an ultrathin forehead flap with a good blood supply. This study aims to investigate whether the supratrochlear artery cutaneous branch flap could perform good esthetic reconstruction for defects around the eyebrow. METHODS: The authors retrospectively included 15 patients whose defect around the eyebrows was repaired by the supratrochlear artery cutaneous branch flap from June 2017 to June 2020. The authors followed up about their flap color and texture, scar, abnormal sensation, any complication, recurrence, and patient satisfaction for at least 6 months online or face-to-face. RESULTS: All of the flaps survived, without distortion of the eyebrows or inner canthi. Similar flap color, texture, and thickness with the nearby skin were obtained, except 2 patients reported pigmentation. Donor and receptor scars were acceptable. There was no recurrence or other complications. All of the patients were satisfied with the surgery effect. CONCLUSIONS: The supratrochlear artery cutaneous branch flap is a valuable alternative method to repair large defects around the eyebrows. It can avoid facial distortion and achieve good esthetic outcomes in single-stage surgery.

Electron Transport Properties of Graphene/WS2 Van Der Waals Heterojunctions.

Van der Waals heterojunctions of two-dimensional atomic crystals are widely used to build functional devices due to their excellent optoelectronic properties, which are attracting more and more attention, and various methods have been developed to study their structure and properties. Here, density functional theory combined with the nonequilibrium Green's function technique has been used to calculate the transport properties of graphene/WS2 heterojunctions. It is observed that the formation of heterojunctions does not lead to the opening of the Dirac point of graphene. Instead, the respective band structures of both graphene and WS2 are preserved. Therefore, the heterojunction follows a unique Ohm's law at low bias voltages, despite the presence of a certain rotation angle between the two surfaces within the heterojunction. The transmission spectra, the density of states, and the transmission eigenstate are used to investigate the origin and mechanism of unique linear I-V characteristics. This study provides a theoretical framework for designing mixed-dimensional heterojunction nanoelectronic devices.

Preoperative clinical characteristics for differentiating malignant transformation from torsion of mature cystic teratoma.

This retrospective study was conducted in 27 patients with malignant transformation of mature cystic teratoma（MT-MCT）and 125 ovarian teratoma patients with torsion who underwent surgery in the First Affiliated Hospital of Wenzhou Medical University from 2008 to 2019. The incidence of MT-MCT in this study was 0.79%. The 3-year overall survival (OS) rate was 69.6 ± 9.6%. The 3-year progression-free survival (PFS) rate was 58.3 ± 9.6%. Kaplan-Meier survival analysis indicated that patients with squamous cell carcinoma (SCC) had significantly shorter OS compared with non-SCC patients. Older age (OR 1.076, 95% CI 1.041-1.111), higher platelet (PLT) level (OR 1.012, 95% CI 1.005-1.020) and lower neutrophil-to-lymphocyte ratio (NLR) level (OR 0.794, 95% CI 0.647-0.915) were independent predictors of MT-MCT. The area under the curve (AUC) for the combined use of age, PLT count and NLR was 0.921 (95% confidence interval 0.877-0.964; p < 0.001), with a sensitivity of 92.6% and a specificity of 80.8%.

[Network Meta-analysis of oral Chinese patent medicine in adjuvant treatment of rotavirus gastroenteritis in children].

This study aimed to evaluate the efficacy and safety of various oral Chinese patent medicines in the adjuvant treatment of rotavirus gastroenteritis(RVGE) in children based on network Meta-analysis. Randomized controlled trial(RCT) of oral Chinese patent medicine in the adjuvant treatment of RVGE in children was retrieved from the databases such as CNKI, Wanfang, VIP, SinoMed, PubMed, Cochrane Library, EMbase, and Web of Science from database inception to October 22, 2022. The quality of the included RCT was evaluated according to the Cochrane risk-of-bias tool, and the data were analyzed by RevMan 5.4 and Stata 16 software. Sixty-three RCTs were included, with 11 oral Chinese patent medicines involved, including Xingpi Yanger Granules, Weichang'an Pills, Qiuxieling Mixture, Erxieting Granules, and Changyanning Granules/Syrup. The results of the network Meta-analysis showed that in terms of clinical total effective rate, the top 3 optimal interventions were Changyanning Granules/Syrup, Xiaoer Guangpo Zhixie Oral Liquid, and Xiaoer Shuangjie Zhixie Granules combined with conventional western medicine. In terms of the anti-diarrheal time, the top 3 optimal interventions were Shenling Baizhu Granules, Qiuxieling Mixture, and Shuangling Zhixie Oral Liquid combined with conventional western medicine. In terms of the antiemetic time, the top 3 optimal interventions were Changyanning Granules/Syrup, Xingpi Yanger Granules, and Xiaoer Shuangjie Zhixie Granules combined with conventional western medicine. In terms of the antipyretic time, the top 3 optimal interventions were Shenling Baizhu Granules, Xiaoer Shuangjie Zhixie Granules, and Qiuxieling Mixture combined with conventional western medicine. In terms of the negative conversion rate of rotavirus, the top 3 optimal interventions were Xingpi Yanger Granules, Erxieting Granules, and Cangling Zhixie Oral Liquid combined with conventional western medicine. In terms of reducing creatine kinase isoenzyme MB(CK-MB) level, the top 3 optimal interventions were Weichang'an Pills, Xingpi Yanger Granules, and Xiaoer Shuangjie Zhixie Granules combined with conventional western medicine. In terms of adverse reactions, no se-rious adverse reactions were reported in all studies. Oral Chinese patent medicines in the adjuvant treatment of children with RVGE have their own advantages, Specifically, Changyanning Granules/Syrup + conventional western medicine focuses on improving the clinical total effective rate and shortening the antiemetic time, Shenling Baizhu Granules + conventional western medicine on shortening the anti-diarrheal time and antipyretic time, Xingpi Yanger Granules + conventional western medicine on improving the negative conversion rate of rotavirus, and Weichang'an Pills + conventional western medicine on reducing the CK-MB level. Limited by the quantity and quality of literature included in this study, the results need to be verified by high-quality RCT with a larger sample size.

Nanomedicine-Enabled Chemical Regulation of Reactive X Species for Versatile Disease Treatments.

Reactive X species (RXS), encompassing elements such as O, N, C, S, Se, Cl, Br, I, and H, play vital roles in cell biology and physiological function, impacting cellular signal transduction, metabolic regulation, and disease processes. The redox unbalance of RXS is firmly implicated in an assortment of physiological and pathological disorders, including cancer, diabetes, cardiovascular disease, and neurodegenerative diseases. However, the intricate nature and multifactorial dependence of RXS pose challenges in comprehending and precisely modulating their biological behavior. Nanomaterials with distinct characteristics and biofunctions offer promising avenues for generating or scavenging RXS to maintain redox homeostasis and advance disease therapy. This minireview provides a tutorial summary of the relevant chemistry and specific mechanisms governing different RXS, focusing on cellular metabolic regulation, stress responses, and the role of nanomedicine in RXS generation and elimination. The challenges associated with chemically regulating RXS for diverse disease treatments are further discussed along with the future prospects, aiming to facilitate the clinical translation of RXS-based nanomedicine and open new avenues for improved therapeutic interventions.

Reticular Chemistry-Enabled Sonodynamic Activity of Covalent Organic Frameworks for Nanodynamic Cancer Therapy.

The development of covalent organic framework (COF) sonosensitizers with intrinsic sonodynamic effects is highly desirable. However, such COFs are generally constructed using small-molecule photosensitizers. Herein, we report that the reticular chemistry-based synthesis of COFs from two inert monomers yields a COF-based sonosensitizer (TPE-NN) with inherent sonodynamic activity. Subsequently, a nanoscale COF TPE-NN is fabricated and embedded with copper (Cu)-coordinated sites to obtain TPE-NN-Cu. Results show that Cu coordination can enhance the sonodynamic effect of TPE-NN, whereas ultrasound (US) irradiation for sonodynamic therapy can augment the chemodynamic efficacy of TPE-NN-Cu. Consequently, TPE-NN-Cu upon US irradiation shows high-performance anticancer effects based on mutually reinforced sono-/chemo-nanodynamic therapy. This study reveals the backbone-originated sonodynamic activity of COFs and proposes a paradigm of intrinsic COF sonosensitizers for nanodynamic therapy.

Cu2+ -Chelatable and ROS-Scavenging MXenzyme as NIR-II-Triggered Blood-Brain Barrier-Crossing Nanocatalyst against Alzheimer's Disease.

Transition-metal dyshomeostasis has been identified as a critical pathogenic factor for the aggregates of amyloid-beta (Aß) peptide, which is associated with the onset and progression of Alzheimer's disease (AD). Excessive transition-metal ions, especially copper ion (Cu2+ ), catalyze the formation of reactive oxygen species (ROS), triggering neuroinflammation and neuronal cell apoptosis. Therefore, developing a robust chelating agent can not only efficiently bind toxic Cu2+ , but also simultaneously scavenge the over-generated ROS that is urgently needed for AD treatment. In this work, a 2D niobium carbide (Nb2 C) MXene-based nano-chelator is constructed and its performance in suppressing Cu2+ -induced accumulation of aggregated Aß peptide and acting as a nanozyme (MXenzyme) with powerful antioxidant property to scavenge excess cellular ROS is explored, and the intrinsic mechanism is revealed by computational simulation. Importantly, the benign photothermal effect of Nb2 C MXenzyme demonstrates the facilitated permeability of the blood-brain barrier under near-infrared laser irradiation, conquering limitations of the most conventional anti-AD therapeutic agents. This work not only demonstrates a favorable strategy for combating AD by engineering Nb2 C MXenzyme-based neuroprotective nano-chelator, but also paves a distinct insight for extending the biomedical applications of MXenes in treating transition-metal dyshomeostasis-and ROS-mediated central nervous system diseases.

Clinical characteristics and prognosis analysis of uterine sarcoma: a single-institution retrospective study.

BACKGROUND: Uterine sarcomas are rare and aggressive gynaecologic malignancies, characterized by a relatively high recurrence rate and poor prognosis. The aim of this study was to investigate the clinicopathological features and explore the prognostic factors of these malignancies. METHODS: This was a single-institution, retrospective study. We reviewed the medical records of 155 patients with pathologically confirmed uterine sarcomas including uterine leiomyosarcoma (ULMS), low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS), undifferentiated uterine sarcoma (UUS) and adenosarcoma (AS) between 2006 and 2022. A total of 112 patients who underwent surgery between January 2006 and April 2019 were included in the survival analysis. The current study recorded the clinicopathological, treatment and outcome data to determine clinical characteristics and survival. RESULTS: The most common histopathological type was ULMS (63/155, 40.64%), followed by LG-ESS (56/155, 36.13%) and HG-ESS (16/155, 10.32%). The mean age at diagnosis of all patients was 49.27±48.50 years and 32.90% (51/155) of patients were postmenopausal. Fifteen patients underwent fast-frozen sectioning, 63(54.78%) were diagnosed with malignancy, 29(25.22%) were highly suspected of malignancy that needed further clarification and 23(14.84%) were diagnosed with benign disease. A total of 124(80%) patients underwent total hysterectomy (TH) and salpingo-oophorectomy. Multivariate analyses showed that histological type and tumour size were independent prognostic factors both for overall survival (OS) (p<0.001 and P=0.017, respectively) and progression-free survival (PFS) (p<0.001 and P=0.018, respectively). Tumour stage was only significantly associated with PFS (P=0.002). Elevated preoperative NLR, PLR and postmenopausal status were significantly correlated with shorter PFS and OS in univariate analysis, but no statistically significant difference was found in multivariate analysis. CONCLUSIONS: In patients with uterine sarcoma, in comparison to LMS and LG-ESS, UUS and HG-ESS tend to present as more aggressive tumour with poorer outcomes. Furthermore, larger tumour (>7.5 cm) were an important predictor of shorter PFS and OS.

Engineering defected 2D Pd/H-TiO2 nanosonosensitizers for hypoxia alleviation and enhanced sono-chemodynamic cancer nanotherapy.

BACKGROUND: Sonodynamic therapy (SDT) is a burgeoning modality for cancer therapy owing to its high tissue-penetrating capability, controllability and safety. Whereas, the undesirable reactive oxygen species (ROS) yield of sonosensitizers and tumor hypoxia are two vulnerable spots of SDT. Therefore, it is an advisable strategy to augment ROS level and simultaneously relieve hypoxia for SDT to arrive its full potential in cancer treatment. RESULTS: In this work, the defected two-dimensional (2D) Pd/H-TiO2 nanosheets (NSs) with triple antineoplastic properties were dexterously elaborated and engineered using a facile one-pot Pd-catalyzed hydrogenation tactic by loading a tiny amount of Pd and then inletting hydrogen flow at atmospheric pressure and temperature. The 2D black Pd/H-TiO2 NSs with oxygen defects exerted eximious SDT effect based on the decreased bandgap that made it easier for the separation of electrons and holes when triggered by ultrasound as theoretically guided by density functional theory calculations. Additionally, Pd/H-TiO2 NSs could serve as Fenton-like agents because of the presence of oxygen defects, facilitating the conversion of hydrogen peroxide into hydroxyl radicals for exerting the chemodynamic therapy (CDT). Simultaneously, the introduced tiny Pd component possessed catalase-like activity responsible for oxygen production to ameliorate hypoxic condition and thus contributed to improving SDT and CDT efficacies. Both in vitro and in vivo results provided compelling evidences of high ROS yield and aggrandized sono-chemodynamic effect of Pd/H-TiO2 nanosonosensitizers with the detailed underlying mechanism investigation by RNA sequencing. CONCLUSION: This work delves the profound potential of Pd-catalyzed hydrogenated TiO2 on oncotherapy, and the effective antineoplastic performance and ignorable therapeutic toxicity make it a powerful competitor among a cornucopia of nanosonosensitizers.

[Evidence mapping of clinical research on traditional Chinese medicine in treatment of diabetic foot].

The present study comprehensively summarized the clinical randomized controlled trials(RCTs) and systematic reviews/Meta-analyses of traditional Chinese medicine(TCM) in the treatment of diabetic foot by evidence mapping and clarified the distribution of evidence in this field.CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase, and Web of Science were searched for clinical RCTs and systematic reviews on TCM in the treatment of diabetic foot published in the past ten years.The evidence was analyzed and displayed in the form of text combined with figures and tables.AMSTAR was used for the quality evaluation of systematic reviews.A total of 1 037 clinical RCTs and 20 systematic reviews/Meta-analyses were included.The overall publishing trend was stable, and the scale of RCTs was small.TCM interventions for diabetic foot mainly included external application and foot bath.Much attention was paid to the outcome indicators including total effective rate, ankle brachial index(ABI), and TCM syndromes, while less attention to neuropathy scores, emotional psychology, and long-term prognosis.The overall quality of systematic reviews was low, and the majority of studies indicated that TCM had potential efficacy in treating diabetic foot, and there was still a lack of clear clinical evidence of efficacy.TCM has both advantages and problems in the treatment of diabetic foot.At present, there is still a lack of high-quality research, suggesting that more large-sample, multi-center RCTs should be launched in the future, and the quality of related systematic reviews/Meta-analyses should be improved to fully explore and give full play to the advantages of TCM in the treatment of diabetic foot, and promote the development of the clinical and evidence-based medicine of TCM in the treatment of diabetic foot.

A Sonication-Activated Valence-Variable Sono-Sensitizer/Catalyst for Autography Inhibition/Ferroptosis-Induced Tumor Nanotherapy.

The effective deployment of reactive oxygen species (ROS)-mediated oncotherapy in practice remains challenging, mired by uncontrollable catalytic processes, stern reaction conditions and safety concerns. Herein, we develop a copper nanodot integrating sonodynamic and catalytic effects within one active center, which responds to exogenous ultrasound (US) and endogenous H2 O2 stimuli. US irradiation induces the valence conversion from CuII to CuI catalyzing H2 O2 into ⋅OH for chemodynamic therapy. Meanwhile, valence transformation results in electron-hole pairs separation, promoting ROS generation for sonodynamic therapy. Notably, copper nanodots not only block lysosome fusion and degradation leading to autophagy flux blockage, but also interfere with the glutathione peroxidase 4 and cystine-glutamate antiporter SLC7A11 function achieving ferroptosis. Furthermore, reversible valence changes, inherent hydrophilicity and renal clearance ultrasmall size guarantee biosafety.

Probing Atomic-Scale Fracture of Grain Boundaries in Low-symmetry 2D Materials.

Grain boundaries (GBs) play a central role in the fracture of polycrystals. However, the complexity of GBs and the difficulty in monitoring the atomic structure evolution during fracture greatly limit the understanding of the GB mechanics. Here, in situ aberration-corrected scanning transmission electron microscopy and density functional theory calculations are combined to investigate the fracture mechanics in low-symmetry, polycrystalline, 2D rhenium disulfide (ReS2 ), unveiling the distinctive crack behaviors at different GBs with atomic resolution. Brittle intergranular fracture prefers to rip through the GBs that are parallel to the Re chains of at least one side of the GBs. In contrast, those GBs, which do not align with Re chains on either side of the GBs, are highly resistant to fracture, impeding or deflecting the crack propagation. These results disclose the GB type-dependent mechanical failure of anisotropic 2D polycrystals, providing new ideas for material reinforcement and controllable cutting via GB engineering.