HDAC Inhibition Increases CXCL12 Secretion to Recruit Natural Killer Cells in Peripheral T Cell Lymphoma.

Peripheral T cell lymphoma (PTCL) is a heterogeneous and aggressive disease with a poor prognosis. Histone deacetylase (HDAC) inhibitors have shown inhibitory effects on PTCL. A better understanding of the therapeutic mechanism underlying the effects of HDAC inhibitors could help improve treatment strategies. Here, we found that high expression of HDAC3 is associated with poor prognosis in PTCL. HDAC3 inhibition suppressed lymphoma growth in immunocompetent mice but not in immunodeficient mice. HDAC3 deletion delayed the progression of lymphoma, reduced the lymphoma burden in the thymus, spleen, and lymph nodes, and prolonged the survival of mice bearing MNU-induced lymphoma. Furthermore, inhibiting HDAC3 promoted the infiltration and enhanced the function of natural killer (NK) cells. Mechanistically, HDAC3 mediated ATF3 deacetylation, enhancing its transcriptional inhibitory activity. Targeting HDAC3 enhanced CXCL12 secretion through an ATF3-dependent pathway to stimulate NK cell recruitment and activation. Finally, HDAC3 suppression improved the response of PTCL to conventional chemotherapy. Collectively, this study provides insights into the mechanism by which HDAC3 regulates ATF3 activity and CXCL12 secretion, leading to immune infiltration and lymphoma suppression. Combining HDAC3 inhibitors with chemotherapy may be a promising strategy for treating PTCL. Key words: Histone deacetylases (HDACs), Natural killer (NK) cells, Peripheral T cell lymphoma (PTCL).

Impermeability and Durability of Self-Compacting Concrete Prepared with Aeolian Sand and Recycled Coarse Aggregate.

Self-compacting concrete has seen extensive application in both engineering and construction. In order to save building resources, aeolian sand-recycled coarse aggregate self-compacting concrete (ARSCC) is created by partially substituting recycled coarse aggregates (RCA) and aeolian sand (AS) for natural coarse aggregates. For ten groups with different mechanical and durable properties, this study examined the effects of sulfate erosion, chloride penetration resistance, and related impermeability, as well as AS replacement ratios of 20%, 40%, and 60% and RCA replacement ratios of 25%, 50%, and 75% in ARSCC and a control group (A0-R0). According to the study's findings, after sulfate attack, the highest relative dynamic elastic modulus and corrosion resistance factor were obtained with the 20% AS replacement ratio and 50% RCA replacement ratio (A20-R50). The highest impermeability grade and lowest electric flux were obtained with the 20% AS replacement ratio and 25% RCA replacement ratio (A20-R25). X-ray diffraction (XRD) and mercury intrusion porosimetry (MIP) revealed that the addition of aeolian sand and recycled coarse aggregates improved the pore structure of the SCC and increased the densification of the self-compacting concrete, particularly following sulfate attack. This study highlights the importance of recycled aggregates and aeolian sand in engineering applications and the sustainable growth of the concrete industry, both of which support resource conservation and environmental protection.

Salvianolic-Acid-B-Loaded HA Self-Healing Hydrogel Promotes Diabetic Wound Healing through Promotion of Anti-Inflammation and Angiogenesis.

Inflammatory dysfunction and angiogenesis inhibition are two main factors leading to the delayed healing of diabetic wounds. Hydrogels with anti-inflammatory and angiogenesis-promoting effects have been considered as promising wound care materials. Herein, a salvianolic acid B (SAB)-loaded hyaluronic acid (HA) self-healing hydrogel (HA/SAB) with anti-inflammatory and pro-angiogenesis capacities for diabetic wound healing is reported. The HA hydrogel was prepared via the covalent cross-linking of aldehyde groups in oxidized HA (OHA) and hydrazide groups in adipic dihydrazide (ADH)-modified HA (HA-ADH) with the formation of reversible acylhydrazone bonds. The obtained HA hydrogel exhibited multiple favorable properties such as porous structures, excellent self-healing properties, a sustainable release capacity of SAB, as well as excellent cytocompatibility. In addition, the effects of the SAB-loaded HA self-healing hydrogel were investigated via a full-thickness skin defect model using diabetic rats. The HA/SAB hydrogel showed enhanced skin regeneration effects with accelerated wound closure, shorter remaining dermal space length, thicker granulation tissue formation, and more collagen deposition. Furthermore, reduced inflammatory response and enhanced vascularization were found with HA/SAB2.5 hydrogel-treated wounds, indicating that the hydrogel promotes diabetic wound healing through the promotion of anti-inflammation and angiogenesis. Our results suggest that the fabricated SAB-loaded HA self-healing hydrogel is promising as a wound dressing for the treatment of diabetic wounds.

Post-transplantation cyclophosphamide combined with tacrolimus and low-dose post-engraftment anti-thymoglobulin as GVHD prophylaxis for patients undergoing peripheral blood stem cell transplantation from haploidentical family donor: A single center analysis.

Introduction: Post-transplantation cyclophosphamide (PT-Cy) use is a recent graft-versus-host disease (GVHD) prophylaxis strategy for patients undergoing allogeneic stem cell transplantation (allo-HSCT). PT-Cy combined with two immunosuppressants is now widely used after haplo-identical (haplo) and HLA-matched peripheral blood stem cell (PBSC) transplantations with promising GVHD and relapsefree survival (GRFS) probabilities. Although appealing, these results may benefit from improvement notably outside matched sibling donor transplantation, and should be investigated in various ethnic populations. Methods: Therefore, we report our experience of GVHD prophylaxis regimen combining PT-Cy and tacrolimus with addition of post-engraftment low-dose anti-thymocyte globulin (ATG) in allogeneic stem cell transplantation from haplo-identical donors (Haplo). Sixtyseven patients were included in the analysis. All patients received myeloablative or intensified sequential conditioning regimen. Results: The median follow-up was 521 (range, 10~991) days. The cumulative incidences of 100-day grade II-IV acute GVHD was 14.9±4.4%, and no case of grade III-IV acute GVHD was documented. The cumulative incidences of 2-yearchronic GVHD and moderate-to-severe chronic GVHD were 25.4±5.4% and 11.9±4%, respectively. The non-relapse mortality at day+100 and 2year were 7.5±3.2% and 9.0±3.5%, respectively. The cumulative incidence of relapse at 2year was 16±6.4%. The 2-year probability of DFS and OS were 73.8% (95%CI, 61.5~88.4%) and 72.5% (95% CI, 57.1~92.1%), respectively. The 2-year GRFS was estimated as 63.6% (95%CI, 50.6~80%). Discussion: Our results suggested that a combination of PT-Cy, tacrolimus, and low-dose post-engraftment ATG was a promising GVHD prophylaxis with low incidence of acute GVHD in the haplo-transplantation setting.

Targeting HDAC3 to overcome the resistance to ATRA or arsenic in acute promyelocytic leukemia through ubiquitination and degradation of PML-RARα.

Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML-RARα, which recruits corepressor complexes, including histone deacetylases (HDACs), to suppress cell differentiation and promote APL initiation. All-trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) or chemotherapy highly improves the prognosis of APL patients. However, refractoriness to ATRA and ATO may occur, which leads to relapsed disease in a group of patients. Here, we report that HDAC3 was highly expressed in the APL subtype of AML, and the protein level of HDAC3 was positively associated with PML-RARα. Mechanistically, we found that HDAC3 deacetylated PML-RARα at lysine 394, which reduced PIAS1-mediated PML-RARα SUMOylation and subsequent RNF4-induced ubiquitylation. HDAC3 inhibition promoted PML-RARα ubiquitylation and degradation and reduced the expression of PML-RARα in both wild-type and ATRA- or ATO-resistant APL cells. Furthermore, genetic or pharmacological inhibition of HDAC3 induced differentiation, apoptosis, and decreased cellular self-renewal of APL cells, including primary leukemia cells from patients with resistant APL. Using both cell line- and patient-derived xenograft models, we demonstrated that treatment with an HDAC3 inhibitor or combination of ATRA/ATO reduced APL progression. In conclusion, our study identifies the role of HDAC3 as a positive regulator of the PML-RARα oncoprotein by deacetylating PML-RARα and suggests that targeting HDAC3 could be a promising strategy to treat relapsed/refractory APL.

Fabrication of Fibrin/Polyvinyl Alcohol Scaffolds for Skin Tissue Engineering via Emulsion Templating.

In the search for a novel and scalable skin scaffold for wound healing and tissue regeneration, we fabricated a class of fibrin/polyvinyl alcohol (PVA) scaffolds using an emulsion templating method. The fibrin/PVA scaffolds were formed by enzymatic coagulation of fibrinogen with thrombin in the presence of PVA as a bulking agent and an emulsion phase as the porogen, with glutaraldehyde as the cross-linking agent. After freeze drying, the scaffolds were characterized and evaluated for biocompatibility and efficacy of dermal reconstruction. SEM analysis showed that the formed scaffolds had interconnected porous structures (average pore size e was around 330 µm) and preserved the nano-scale fibrous architecture of the fibrin. Mechanical testing showed that the scaffolds' ultimate tensile strength was around 0.12 MPa with an elongation of around 50%. The proteolytic degradation of scaffolds could be controlled over a wide range by varying the type or degree of cross-linking and by fibrin/PVA composition. Assessment of cytocompatibility by human mesenchymal stem cell (MSC) proliferation assays shows that MSC can attach, penetrate, and proliferate into the fibrin/PVA scaffolds with an elongated and stretched morphology. The efficacy of scaffolds for tissue reconstruction was evaluated in a murine full-thickness skin excision defect model. The scaffolds were integrated and resorbed without inflammatory infiltration and, compared to control wounds, promoted deeper neodermal formation, greater collagen fiber deposition, facilitated angiogenesis, and significantly accelerated wound healing and epithelial closure. The experimental data showed that the fabricated fibrin/PVA scaffolds are promising for skin repair and skin tissue engineering.

Trichloroethylene remediation using zero-valent iron with kaolin clay, activated carbon and bacteria.

Nanoscale particles of zero-valent iron were used to form a permeable reactive barrier whose performance in dechlorinating a solution of trichloroethylene was compared with that of a barrier formed from limestone. The iron was combined with kaolin by calcination. The test liquid contained sewage sludge, and also added NH4Cl and KH2PO4. The average removal rates of trichloroethylene and phosphorus over 365 days both exceeded 94%. Chemical oxygen demand was reduced by 92% and ammonium nitrogen by 43.6%. All were significantly greater than the removals with the limestone barrier. The ceramsite barrier retained 85% of its effectiveness even after 365 days of use. Dechloromonas sp. was the main dechlorinating bacterium, but its removal ability is limited. The removal of trichloroethylene in such a barrier mainly depends on reduction by the zero-valent iron and biodegradation. The results show that the prepared ceramsite is stable and effective in removing trichloroethylene from water. It is a promising in-situ remediation material for groundwater.

The Signaling Pathways Induced by Exosomes in Promoting Diabetic Wound Healing: A Mini-Review.

Impaired healing of diabetic wounds harms patients' quality of life and even leads to disability and death, which is an urgent issue to be solved clinically. Despite the great progress that has been achieved, it remains a worldwide challenge to develop effective therapeutic treatments for diabetic wounds. Recently, exosomes have attracted special attention because they can be involved in immune response, antigen presentation, cell migration, cell differentiation, tumor invasion and other processes. Meanwhile, exosomes have been proven to hold great potential in the treatment of diabetic wounds. Mechanistic studies of exosomes based on signaling pathways could not only help to uncover the mechanisms by which exosomes promote diabetic wound healing but could also provide a theoretical basis for the clinical application of exosomes. Herein, our mini-review aims to summarize the progress of research on the use of various exosomes derived from different cell types to promote diabetic wound healing, with a focus on the classical signaling pathways, including PI3K/Akt, Wnt, NF-κB, MAPK, Notch, Nrf2, HIF-1α/VEGF and TGF-ß/Smad. The results show that exosomes could regulate these signaling pathways to down-regulate inflammation, reduce oxidative stress, increase angiogenesis, promote fibroblast proliferation, induce re-epithelization and inhibit scar formation, making exosomes attractive candidates for the treatment of diabetic wounds.

Efficacy and safety of microwave ablation for benign breast lesions: a systematic review and meta-analysis.

Aim: We performed a systematic review and meta-analysis to evaluate the efficacy and safety of microwave ablation (MWA) for benign breast lesions. Material and methods: PubMed, Embase, Web of Science, Cochrane Library databases, China National Knowledge Infrastructure, and Wanfang Data Knowledge Service Platform databases were searched. Results: A total of 10 studies were included, giving a sample size of 1241 patients and 2729 benign breast lesions. The first complete ablation success rate was 96%. The volume reduction ratio (VRR) after 3/6/12 months was 47.4%, 62.1%, and 85.8%, respectively. After 12 months, the lesion disappearance rate was 53.6%, and the efficiency rate was 99%. The rate of excellent cosmesis was 88% and the rate of good cosmesis was 10%. The complication rate was 2%. Conclusions: MWA is safe and effective for treating benign breast lesions. It can be a promising minimally invasive choice for benign breast lesions.

The preventive and therapeutic effects of probiotics on mastitis: A systematic review and meta-analysis.

Acute mastitis is one of the main reasons why breastfeeding women stop breastfeeding, and medication should be used with caution. Considering the uncertainty of mastitis infection and the indications of antibiotic use, as well as the problem of drug resistance and the safety of medication during lactation, probiotics have become an alternative treatment choice. However, a meta-analysis of the effects of probiotics in preventing and treating lactational mastitis is still lacking. Therefore, we searched six electronic databases and the sites of clinical trial registration, a total of six randomized controlled trials were included in this meta-analysis, which showed that oral probiotics during pregnancy can reduce the incidence of mastitis (RR: 0.49, 95% CI: 0.35 to 0.69; p<0.0001). After oral administration of probiotics, the counts of bacteria in the milk of healthy people and mastitis patients were both significantly reduced (in healthy people: MD: -0.19, 95% CI: -0.23 to -0.16, p<0.00001; in mastitis patients: MD: -0.89, 95% CI: -1.34 to -0.43, p = 0.0001). These indicate that to a certain extent, probiotics are beneficial in reducing the incidence rate of mastitis during lactation and some related mastitis symptoms. However, high-quality multicenter clinical trials are still needed to support this result.

Selenium mediated host plant-mite conflict: defense and adaptation.

BACKGROUND: Selenium has shown effectiveness in protecting plants from herbivores. However, some insects have evolved adaptability to selenium. RESULTS: Selenium accumulation in host plants protected them against spider mite feeding. Selenium showed toxic effects on spider mites by reducing growth and interfering with reproduction. After 40 generations on selenium-rich plants, a Tetranychus cinnabarinus strain (Tc-Se) developed adaptability to selenium, with an increased rate of population growth and enhanced ability for selenium metabolism. The high expression of two genes (GSTd07 and SPS1) in the selenium metabolism pathway might be involved in selenium metabolism in spider mites. After GSTd07 and SPS1 were silenced, the selenium adaptability decreased. Recombinant GSTd07 protein promoted the reaction between sodium selenite and glutathione (GSH) and increased the production of sodium selenite metabolites. The results indicated that GSTd07 was involved in the first step of selenium metabolism. CONCLUSION: Plants can resist spider mite feeding by accumulating selenium. Spider mites subjected to long-term selenium exposure can adapt to selenium by increasing the expression of key genes involved in selenium metabolism. These results elucidate the mechanism of the interaction between mites and host plants mediated by selenium. This study of the interaction between selenium-mediated host plants and spider mites may lead to the development of new and less toxic methods for the prevention and control of spider mites. © 2021 Society of Chemical Industry.

The signaling pathways and targets of traditional Chinese medicine and natural medicine in triple-negative breast cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Triple-negative breast cancer (TNBC) has a poorer prognosis than other subtypes due to its strong invasion and higher risk of distant metastasis. Traditional Chinese medicine (TCM) and natural medicine have the unique advantages of multitargets and small side-effects and may be used as long-term complementary and alternative therapies. AIM OF THE REVIEW: The present article summarizes the classical signaling pathways and potential targets by the action of TCM and natural medicine (including extracts, active constituents and formulas) on TNBC and provides evidence for its clinical efficacy. METHODS: The literature information was acquired from the scientific databases PubMed, Web of Science and CNKI from January 2010 to June 2020, and it was designed to elucidate the internal mechanism and role of TCM and natural medicine in the treatment of TNBC. The search key words included "Triple negative breast cancer" or "triple negative breast carcinoma", "TNBC" and "traditional Chinese medicine" or "Chinese herbal medicine", "medicinal plant", "natural plant", and "herb". RESULTS: We described the antitumor activity of TCM and natural medicine in TNBC based on different signaling pathways. Plant medicine and herbal formulas regulated the related gene and protein expression via pathways such as PI3K/AKT/mTOR, MAPK and Wnt/ß-catenin, which inhibit the growth, proliferation, migration, invasion and metastasis of TNBC cells. CONCLUSION: The inhibitory effect of TCM and natural medicine on tumors was reflected in multiple levels and multiple pathways, providing reasonable evidence for new drug development. To make TCM and natural medicine widely and flexibly used in clinical practice, the efficacy, safety and mechanism of action need more in-depth experimental research.

Therapies for cognitive impairment in breast cancer survivors treated with chemotherapy: A protocol for systematic review.

OBJECTIVE: The aim of this systematic review was to evaluate the effect of therapies for cognitive impairment on patients' perceived cognitive function in breast cancer survivors with chemotherapy-related cognitive impairment. METHOD: A literature search of PubMed, Embase, and the Cochrane Library was conducted up to April 2019. Search terms included breast cancer, chemotherapy, and cognitive impairment. RESULT: Six randomized controlled trials with a total of 305 patients were included in this review. A total of 6 randomized controlled trials using various treatments (Tibetan sound meditation, donepezil, memory and attention adaptation training, aerobic exercise, acupuncture, Qigong) for chemotherapy-related cognitive impairment met the eligibility criteria and were included. This review showed that meditative interventions (Tibetan sound meditation, Qigong) and cognitive therapy (memory and attention adaptation training) may partially improve some aspects of patients' perceived (self-reported) cognitive functioning, particularly patients' perceived cognitive impairment and ability. CONCLUSION: In this systematic review, the results showed that meditative interventions (Tibetan sound meditation, Qigong) and cognitive therapy (memory and attention adaptation training) may be optional therapies. We hope to have more randomized controlled trials to support this result in the future.

Statistical Method Based on Bayes-Type Empirical Score Test for Assessing Genetic Association with Multilocus Genotype Data.

Simultaneous testing of multiple genetic variants for association is widely recognized as a valuable complementary approach to single-marker tests. As such, principal component regression (PCR) has been found to have competitive power. We focus on exploring a robust test for an unknown genetic mode of all SNPs, an unknown Hardy-Weinberg equilibrium (HWE) in a population, and a large number of all SNPs. First, we propose a new global test by means of the use of codominant codes for all markers and PCR. The new global test is built on an empirical Bayes-type score statistic for testing marginal associations with each single marker. The new global test gains power by robustly exploiting the Hardy-Weinberg equilibrium in the control population and effectively using linkage disequilibrium among test markers. The new global test reduces to PCR when the genotype for each marker is coded as the number of minor alleles. This connection lends insight into the power of the new global test relative to PCR and some other popular multimarker test methods. Second, we propose a robust test method based on the new global test and the ordinary PCR test built on a prospective score statistic for testing marginal associations with each single marker when the genotype for each marker is coded as the number of minor alleles by taking the minimum p value of these two tests. Finally, through extensive simulation studies and analysis of the association between pancreatic cancer and some genes of interest, we show that the proposed robust test method has desirable power and can often identify association signals that may be missed by existing methods.

Genomic and GeneChip expression profiling reveals the inhibitory effects of Amorphophalli Rhizoma in TNBC cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Amorphophalli Rhizoma has been widely used as an adjuvant treatment for advanced or metastatic breast cancer, pancreatic cancer, hepatoma, and malignant lymphoma, but its molecular mechanism of action for treatment of metastatic triple-negative breast cancer (TNBC) is generally poorly understood. AIM OF THE STUDY: To investigate genomic changes related to the inhibitory effect of Amorphophalli Rhizoma and to elucidate the molecular mechanism of this inhibition in MDA-MB-231 TNBC cells. MATERIALS AND METHODS: Gene chip analysis was employed to explore genomic changes caused by Amorphophalli Rhizoma in TNBC cells. Potential classical signaling pathways, upstream regulators, functions, regulatory effects and gene interaction networks were analyzed by Ingenuity Pathway Analysis (IPA). Real-time quantitative PCR (RT-qPCR) and RNA interference (RNAi) assays were used to clarify the roles of potential target genes. RESULTS: In total, 536 significantly upregulated and 648 significantly downregulated genes were identified between the group treated with Amorphophalli Rhizoma extract and that treated with vehicle. Many of these differentially expressed genes (DEGs) in TNBC cells are involved in DNA replication, recombination and repair, the cell cycle, and cellular assembly and organization. Attenuation of KNL1, OLFML2A, RTKN2 and SGO1 gene expression by Amorphophalli Rhizoma significantly induced cell cycle arrest and suppressed cell proliferation and migration. CONCLUSIONS: The inhibitory effects of Amorphophalli Rhizoma in TNBC cells likely occur through regulation of the spindle checkpoint, chromosomal and centrosomal instability, and cell membrane stability.

Adaptive Group-combined P-values Test for Two-sample Location Problem with Applications to Microarray Data.

The purpose of this article is to propose a test for two-sample location problem in high-dimensional data. In general highdimensional case, the data dimension can be much larger than the sample size and the underlying distribution may be far from normal. Existing tests requiring explicit relationship between the data dimension and sample size or designed for multivariate normal distributions may lose power significantly and even yield type I error rates strayed from nominal levels. To overcome this issue, we propose an adaptive group p-values combination test which is robust against both high dimensionality and normality. Simulation studies show that the proposed test controls type I error rates correctly and outperforms some existing tests in most situations. An Ageing Human Brain Microarray data are used to further exemplify the method.

Testing Association between Mixed Type Outcomes and Covariates Jointly by the Use of a Latent Variable.

Multiple outcomes are often collected simultaneously in biomedical fields in order to identify whether a continuous response and an ordinal response are associated with some covariates simultaneously. Here we propose a joint statistical model by the use of a latent variable underlying the ordinal response. Asymptotic results are obtained and a jointly test is proposed for testing the continuous response and the ordinal response are associated with some covariates simultaneously. Extensive simulations and real data analysis results indicate more efficient performances of the proposed method than that of the combined p-values method.

Three-Dimensional MoS2 @CNT/RGO Network Composites for High-Performance Flexible Supercapacitors.

Two-dimensional atomically thick materials, reduced graphene oxide (RGO), and layered molybdenum disulfide (MoS2 ) have been investigated as potential novel energy storage materials because of their distinct physicochemical properties. These materials suffer, however, from rapid capacity decay and low rate capability. This study describes a facile, binder-free approach to fabricate large-scale, 3D network structured MoS2 @carbon nanotube (CNT)/RGO composites for application in flexible supercapacitor devices. The as-obtained composites possess a hierarchical porosity, and an interconnected framework. The electrochemical supercapacitive measurements of the MoS2 @CNT/RGO electrode show a high specific capacitance of 129 mF cm-2 at 0.1 mA cm-2 . The symmetric supercapacitor devices based on the as-obtained composites exhibit a long lifetime (94.7 % capacitance retention after 10 000 cycles), and a high electrochemical performance (29.7 mF cm-2 ). The present experimental findings will lead to scalable, binder-free synthesis of MoS2 @CNT/RGO hybrid electrodes, with enhanced, flexible, supercapacitive performance, in portable and wearable energy storage devices.