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RNA interference screening identified XPO1 (exportin 1) among the 55 most vulnerable targets in multiple myeloma (MM). XPO1 encodes CRM1, a nuclear export protein. XPO1 expression increases with MM disease progression. Patients with MM have a higher expression of XPO1 compared with normal plasma cells ( P <0.04) and to patients with monoclonal gammopathy of undetermined significance/smoldering MM ( P <0.0001). The highest XPO1 level was found in human MM cell lines (HMCLs). A selective inhibitor of nuclear export compound KPT-276 specifically and irreversibly inhibits the nuclear export function of XPO1 . The viability of 12 HMCLs treated with KTP-276 was significantly reduced. KPT-276 also actively induced apoptosis in primary MM patient samples. In gene expression analyses, two genes of probable relevance were dysregulated by KPT-276: cell division cycle 25 homolog A ( CDC25A ) and bromodomain-containing protein 4 (BRD4), both of which are associated with c-MYC pathway. Western blotting and reverse transcription-PCR confirm that c-MYC, CDC25A and BRD4 are all downregulated after treatment with KPT-276. KPT-276 reduced monoclonal spikes in the Vk*MYC transgenic MM mouse model, and inhibited tumor growth in a xenograft MM mouse model. A phase I clinical trial of an analog of KPT-276 is ongoing in hematological malignancies including MM.

AbstractObjectiveTo determine whether a single low dose of esketamine administered after childbirth reduces postpartum depression in mothers with prenatal depression.DesignRandomised, double blind, placebo controlled trial with two parallel arms.SettingFive tertiary care hospitals in China, 19 June 2020 to 3 August 2022.Participants364 mothers aged ≥18 years who had at least mild prenatal depression as indicated by Edinburgh postnatal depression scale scores of ≥10 (range 0-30, with higher scores indicating worse depression) and who were admitted to hospital for delivery.InterventionsParticipants were randomly assigned 1:1 to receive either 0.2 mg/kg esketamine or placebo infused intravenously over 40 minutes after childbirth once the umbilical cord had been clamped.Main outcome measuresThe primary outcome was prevalence of a major depressive episode at 42 days post partum, diagnosed using the mini-international neuropsychiatric interview. Secondary outcomes included the Edinburgh postnatal depression scale score at seven and 42 days post partum and the 17 item Hamilton depression rating scale score at 42 days post partum (range 0-52, with higher scores indicating worse depression). Adverse events were monitored until 24 hours after childbirth.ResultsA total of 364 mothers (mean age 31.8 (standard deviation 4.1) years) were enrolled and randomised. At 42 days post partum, a major depressive episode was observed in 6.7% (12/180) of participants in the esketamine group compared with 25.4% (46/181) in the placebo group (relative risk 0.26, 95% confidence interval (CI) 0.14 to 0.48; P<0.001). Edinburgh postnatal depression scale scores were lower in the esketamine group at seven days (median difference −3, 95% CI −4 to −2; P<0.001) and 42 days (−3, −4 to −2; P<0.001). Hamilton depression rating scale scores at 42 days post partum were also lower in the esketamine group (−4, −6 to −3; P<0.001). The overall incidence of neuropsychiatric adverse events was higher in the esketamine group (45.1% (82/182) v 22.0% (40/182); P<0.001); however, symptoms lasted less than a day and none required drug treatment.ConclusionsFor mothers with prenatal depression, a single low dose of esketamine after childbirth decreases major depressive episodes at 42 days post partum by about three quarters. Neuropsychiatric symptoms were more frequent but transient and did not require drug intervention.Trial registrationClinicalTrials.gov NCT04414943.

The ultimate goal of phototherapy based on nanoparticles, such as photothermal therapy (PTT) which generates heat and photodynamic therapy (PDT) which not only generates reactive oxygen species (ROS) but also induces a variety of anti-tumor immunity, is to kill tumors. In addition, due to strong efficacy in clinical treatment with minimal invasion and negligible side effects, it has received extensive attention and research in recent years. In this paper, the generations of nanomaterials in PTT and PDT are described separately. In clinical application, according to the different combination pathway of nanoparticles, it can be used to treat different diseases such as tumors, melanoma, rheumatoid and so on. In this paper, the mechanism of pathological treatment is described in detail in terms of inducing apoptosis of cancer cells by ROS produced by PDT, immunogenic cell death to provoke the maturation of dendritic cells, which in turn activate production of CD4+ T cells, CD8+T cells and memory T cells, as well as inhibiting heat shock protein (HSPs), STAT3 signal pathway and so on.

Radiotherapy (RT) is a major treatment for malignant tumors. The latest data show that >70% of patients with malignant tumors need RT at different periods. Skin changes can be experienced by up to 95% of patients who underwent RT. Inflammation and oxidative stress (OS) have been shown to be generally associated with radiation-induced skin reactions (RISRs). Inflammatory response and OS interact and promote each other during RISRs. Severe skin reactions often have a great impact on the progress of RT. The treatment of RISRs is particularly critical because advanced RT technology can also lead to skin reactions. RISRs are classified into acute and chronic reactions. The treatment methods for acute RISRs include steroid treatment, creams, ointments, and hydrocolloid dressings, depending on the reaction grading. Chronic RISRs includes chronic ulcerations, telangiectasias, and fibrosis of the skin, and advanced treatments such as mesenchymal stem cells, hyperbaric oxygen therapy, superoxide dismutase, and low-intensity laser therapy can be considered. Here, we review and summarize the important mechanisms that cause RISRs as well as the standard and advanced treatments for RISRs.

ObjectiveThere is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of Trametes robinophila Murr (Huaier granule) to address this unmet need.Design and resultsA total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS rate in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI −12.59 to −2.50; p=0.0018), respectively.ConclusionsThis is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group.Trial registration NCT01770431; Post-results.

Several recent studies link parental environments to phenotypes in subsequent generations. Here, we investigate the mechanism by which paternal diet affects offspring metabolism. Protein restriction in mice affects small RNA levels in mature sperm, with decreased let-7 levels and increased levels of 5' fragments of glycine tRNAs. tRNA fragments are scarce in testicular sperm, but are gained as sperm mature in the epididymis. Epididymosomes-vesicles that fuse with sperm during epididymal transit-carry RNA payloads matching those of mature sperm, and deliver RNAs to immature sperm in vitro. Functionally, tRNA-Gly-GCC fragments repress genes associated with the endogenous retroelement MERVL, both in ES cells and embryos. Our results shed light on small RNA biogenesis, and its dietary regulation, during post-testicular sperm †

In the primary report of the SYSUCC-001 trial, 1 year of metronomic capecitabine improved 5-year disease-free survival in patients with operable triple-negative breast cancer. Here, we provide updated 10-year disease-free survival and overall survival data from extended follow-up, together with an exploratory analysis of FOXC1 as a potential predictive biomarker. This post-hoc, long-term analysis of an open-label, multicentre, phase 3 trial was conducted at 13 centres in China. Eligible women with stage T1b–3 N0–3c M0 triple-negative breast cancer who had completed standard adjuvant therapy were randomly assigned (1:1) to receive oral metronomic capecitabine 650 mg/m2 twice daily for 1 year or observation. Here, we report 10-year follow-up data, including all of the original prespecified trial endpoints: disease-free survival (primary outcome), overall survival, distant disease-free survival, and locoregional recurrence-free survival analysed in the full analysis set. Exploratory biomarker analysis of FOXC1 was undertaken using immunohistochemistry on baseline tumour samples. This trial is registered with ClinicalTrials.gov, NCT01112826, and is complete. Between April 23, 2010, and Dec 31, 2016, 443 participants were enrolled and randomly assigned, of whom 434 initiated the intervention as assigned and were included in the primary analysis (221 in the capecitabine group, 213 in the observation group). As of data cutoff for this analysis (March 31, 2025), 420 (97%) participants had available follow-up data and the median duration of follow-up was 116·0 months (IQR 96·0–134·8). The updated 10-year disease-free survival was significantly higher in the capecitabine group than in the observation group (78·1% vs 66·6%; hazard ratio [HR] 0·61; 95% CI 0·43–0·88; p=0·0074). 10-year overall survival was not significantly different between the two groups (82·4% vs 73·7%; HR 0·67; 95% CI 0·45–1·01; p=0·058). The 10-year distant disease-free survival rates were 78·1% versus 66·5% (HR 0·61; 95% CI 0·43–0·88; p=0·0075) and 10-year locoregional recurrence-free survival rates were 81·6% versus 69·9% (0·60; 0·40–0·89; p=0·011). The FOXC1 biomarker cohort comprised 338 (78%) patients (171 [51%] from the capecitabine group, 167 [49%] from the observation group). In FOXC1-high patients (n=149), capecitabine conferred superior disease-free survival (HR 0·33; 95% CI 0·16–0·68; p=0·0027) and overall survival (0·25; 0·10–0·62; p=0·0028) compared with observation, whereas the FOXC1-low subgroup (n=189) showed no benefit with capecitabine versus observation. In this exploratory, long-term analysis, extended adjuvant metronomic capecitabine provided durable disease-free survival benefit in early triple-negative breast cancer, although the findings should be interpreted with caution given the post-hoc nature of the analysis. Patients with FOXC1-high tumours showed a survival advantage with capecitabine versus observation; if this finding is validated, FOXC1-driven patient selection might be useful to optimise therapeutic responses. National Natural Science Foundation of China and Guangdong Esophageal Cancer Institute Science and Technology Program. For the Chinese translation of the abstract see Supplementary Materials section.

Background: Rheumatoid arthritis (RA) joint inflammation severely affects joint function and quality of life in patients and leads to joint deformities and limb disability. The non-steroidal anti-inflammatory drugs used in the treatment of RA do not fully control the progression of joint inflammation and bone destruction and have notable adverse reactions. Traditional Chinese medicine formula JuanBiQiangGu Granules (JBQG) are commonly used for the treatment of RA inflammation and delay of bone destruction, but has not been evaluated through high-quality clinical studies. There is a pressing need for well-designed, randomized, parallel, controlled clinical studies to evaluate the exact effect of JBQG on RA joint inflammation and improvement of patient quality of life. Methods: This is a randomized, parallel, controlled clinical study in which 144 patients with rheumatoid arthritis who met the inclusion criteria were randomly assigned to 2 groups in a 1:1 ratio. The JBQG group received methotrexate 7.5 mg qw and JBQG granules 8 mg tid, while the MTX group received methotrexate 7.5 mg qw. The endpoint was 12 weeks after treatment. Relevant indices at baseline, 4 weeks, 8 weeks, and 12 weeks after treatment were observed and recorded, and DAS28-ESR, HAQ-DI, and Sharp scores were recorded for each patient. Blood samples were collected to test for CRP, ESR, TNF-α, IL-1β, IL-6, IL-17, and INF-γ, and adverse reactions and liver and kidney function (AST, ALT, Cr, BUN) were recorded for safety assessment. After 12 weeks of treatment, the effect of JBQG granules on disease activity, improvement in bone damage, and patient quality of life scores and safety in RA patients were evaluated. Results: A total of 144 subjects completed treatment (71 in the JBQG group and 73 in the MTX group) and were included in the analysis. At baseline, there were no significant differences between the groups in terms of the observed indicators ( p > 0.05). After treatment, 76.06% of patients in the JBQG group had DAS28-ESR levels below or equal to Low, including 45.07% in Remission and 5.63% in High, compared to 53.1% in the MTX group below or equal to Low, 12.33% in Remission, and 17.81% in High. CRP was significantly reduced (8.54 ± 5.87 vs. 11.86 ± 7.92, p < 0.05, p = 0.005), ESR was significantly reduced (15.1 ± 6.11 vs. 21.96 ± 9.19, p < 0.0001), TNF-α was significantly reduced (1.44 ± 0.83 vs. 1.85 ± 1.07, p < 0.05, p = 0.011), IL-17 was significantly reduced (0.53 ± 0.33 vs. 0.71 ± 0.38, p < 0.05, p = 0.004), and INF-γ was significantly reduced (3.2 ± 1.51 vs. 3.89 ± 1.77, p < 0.05, p = 0.014). The median (IQR) OPG in the JBQG group was 2.54 (2.21–3.01), significantly higher than in the MTX group 2.06 (1.81–2.32), p < 0.0001), and the median (IQR) β -CTX in the JBQG group was 0.4 (0.32–0.43), significantly lower than in the MTX group 0.55 (0.47–0.67), p < 0.0001). The median (IQR) VSA scores were 2 (1–3), a decrease from 3 (2–4) in the MTX group ( p < 0.0001). The median (IQR) Sharp scores were 1 (1–2), a decrease from 2 (1–2) in the MTX group, but the difference was not statistically significant ( p > 0.05, p = 0.28). The median (IQR) HAQ-DI scores were 11 (8–16), significantly lower than in the MTX group 26 (16–30) ( p < 0.0001). The median (IQR) AST in the JBQG group was 16 (12–20), with a significant difference compared to the MTX group 19 (13–25) ( p < 0.01, p = 0.004); the median (IQR) ALT in the JBQG group was 14 (10–18), with a significant difference compared to the MTX group 16 (11–22.5) ( p < 0.05, p = 0.015). There were no statistically significant differences in Cr or BUN ( p > 0.05). Conclusion: JuanBiQiangGu Granules can be used to treat patients with rheumatoid arthritis, alleviate joint inflammation, reduce the incidence of adverse reactions to methotrexate, and has good safety. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/index.html ; identifier: ChiCTR2100046373.

Nickel-based catalysts are most commonly used in industrial alkaline water electrolysis. However, it remains a great challenge to address the sluggish reaction kinetics and severe deactivation problems of hydrogen evolution reaction (HER). Here, we show a Cu-doped Ni catalyst implanted with Ni-O-VOx sites (Ni(Cu)VOx) for alkaline HER. The optimal Ni(Cu)VOx electrode exhibits a near-zero onset overpotential and low overpotential of 21 mV to deliver –10 mA cm −2 , which is comparable to benchmark Pt/C catalyst. Evidence for the formation of Ni-O-VOx sites in Ni(Cu)VOx is established by systematic X-ray absorption spectroscopy studies. The VOx can cause a substantial dampening of Ni lattice and create an enlarged electrochemically active surface area. First-principles calculations support that the Ni-O-VOx sites are superactive and can promote the charge redistribution from Ni to VOx, which greatly weakens the H-adsorption and H 2 release free energy over Ni. This endows the Ni(Cu)VOx electrode high HER activity and long-term durability. Producing H 2 from water using electricity and earth-abundant elements is necessary for worldwide renewable fuel production, yet most electrocatalysts have sluggish activities or poor stabilities. Here, authors show vanadium oxide modified copper-doped nickel to enable active and durable H 2 evolution.

Regulating the fluorescent properties of organic small molecules in a controlled and dynamic manner has been a fundamental research goal. Although several strategies have been exploited, realizing multi-color molecular emission from a single fluorophore remains challenging. Herein, we demonstrate an emissive system by combining pyrene fluorophore and acylhydrazone units, which can generate multi-color switchable fluorescent emissions at different assembled states. Two kinds of supramolecular tools, amphiphilic self-assembly and γ-cyclodextrin mediated host-guest recognition, are used to manipulate the intermolecular aromatic stacking distances, resulting in the tunable fluorescent emission ranging from blue to yellow, including a pure white-light emission. Moreover, an external chemical signal, amylase, is introduced to control the assembly states of the system on a time scale, generating a distinct dynamic emission system. The dynamic properties of this multi-color fluorescent system can be also enabled in a hydrogel network, exhibiting a promising potential for intelligent fluorescent materials. Regulating fluorescent properties of small molecules in a controlled manner has been a fundamental research goal but realizing multi-color emission from a single fluorophore remains challenging. Here the authros demonstrate that combined pyrene fluorophore and acylhydrazone units show multi-color switchable fluorescent at different assembled states.