Search

While post-transplant cyclophosphamide (PTCy) is commonly used as graft-versus-host disease (GvHD) prophylaxis in haploidentical stem cell transplantation (haplo-HSCT), its dose remains a matter of debate due to side effect concerns. Standard dose of 100 mg/kg associated with tacrolimus and post-engraftment anti-thymocyte globulin (ATG) was used as the reference GvHD prophylaxis in our center and had demonstrated encouraging results. Though PTCy 80 mg/kg was shown to be feasible in patients in reduced-intensity conditioning, whether it exerts equivalent GvHD prophylactic efficacy in myeloablative conditioning (MAC) setting has not been confirmed. Here, we retrospectively analyzed the efficacy and safety of PTCy 80 mg/kg combined with tacrolimus and post-engraftment ATG as GvHD prophylaxis in patients aged more than 55 years or with cardiac antecedents or HCT-CI score >2 undergoing haplo-HSCT with MAC. The cumulative incidence of grade III-IV aGvHD at day 100 and moderate-to-severe cGvHD at 1 year was 4.8% ± 3.4% and 19.9% ± 7.0%, respectively. When compared with patients receiving the reference regimen, patients from the PTCy 80 mg/kg group had similar incidence of GvHDs and survival as their younger counterparts. Thus, PTCy 80 mg/kg seems to be feasible for patients treated with MAC conditioning regimens in haplo-HSCT, inviting further investigation notably in frail patients.

The Tian Shan is one of the world's largest intracontinental orogens and provides an excellent example for deciphering the intracontinental responses to the tectonics of plate boundaries. Despite its significance, the timing and driving mechanism of the Cenozoic mountain building of the Tian Shan in the context of the India–Eurasia collision remain controversial. In this study, Cenozoic stratigraphy of the Tiereke section along the western Kuqa Depression of the northern Tarim Basin on the south foreland of Eastern Tian Shan (east of 80°E) has been investigated. The results indicate that the Cenozoic deposition of the Tiereke region sequentially experienced a transgression from the Kumugeliemu Group to the Suweiyi Formation and a regression from the Suweiyi to the Kuqa Formations. Based on the contact relationships and conglomerate textures, three stages of high-energy alluvial deposition have been identified in the lower Kumugeliemu Group, upper Jidike and Kangcun–Kuqa Formations, respectively. These sedimentary events were interpreted to represent phases of Eastern Tian Shan mountain building at c. 54 Ma, c. 27 Ma and since c. 9.7 Ma according to previous magnetostratigraphic results, which were possibly related to the initial India–Eurasia collision, the collision between the India and Tarim lithospheric mantles, and the basinward propagation of deformation, respectively. Thematic collection: This article is part of the Mesozoic and Cenozoic tectonics, landscape and climate change collection available at: https://www.lyellcollection.org/topic/collections/mesozoic-and-cenozoic-tectonics-landscape-and-climate-change [ABSTRACT FROM AUTHOR]

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.

Prostate cancer (PCa) is one of the leading causes of death for men worldwide. Unlike some other types of cancer, there is a lack of targeted therapy for prostate cancer patients that can kill cancer cells but do much less damage to the normal tissue. In this paper, we report on an adenoviral vector enhanced prostate cancer specific transferrin conjugated drug targeted therapy. In particular, a functional PCa-specific gene probe is introduced to drive and up-regulate the transferrin receptor expression on the PCa via adenoviral vector. As a result, significantly enhanced accumulation of nanoscale transferrin-doxorubicin (Tf-DOX) protein drug conjugates and concomitant notably elevated PCa tumor inhibition are observed. This conceptual strategy provides the proof-of-concept for the targeted therapy of PCa that is highly desired but not yet developed.

Cartilage tissue engineering provides a promising method for the repair of articular cartilage defects, requiring appropriate biological scaffolds and necessary growth factors to enhance the efficiency of cartilage regeneration. Here, a silk fibroin (SF) microcarrier and a clematis triterpenoid saponin delivery SF (CTS-SF) microcarrier were prepared by the high-voltage electrostatic differentiation and lyophilization method, and chondrocytes were carried under the simulated microgravity condition by a rotating cell culture system. SF and CTS-SF microspheres were relatively uniform in size and had a porous structure with good swelling and cytocompatibility. Further, CTS-SF microcarriers could sustainably release CTSs in the monitored 10 days. Compared with the monolayer culture, chondrocytes under the microgravity condition maintained a better chondrogenic phenotype and showed better proliferation ability after culture on microcarriers. Moreover, the sustained release of CTS from CTS-SF microcarriers upregulated transforming growth factor-β, Smad2, and Smad3 signals, contributing to promote chondrogenesis. Hence, the biophysical effects of microgravity and bioactivities of CTS-ST were used for chondrocyte expansion and phenotype maintenance in vitro. With prolonged expansion, SF- and CTS-SF-based microcarrier–cell composites were directly implanted in vivo to repair rabbit articular defects. Gross evaluations, histopathological examinations, and biochemical analysis indicated that SF- and CTS-SF-based composites exhibited cartilage-like tissue repair compared with the nontreated group. Further, CTS-SF-based composites displayed superior hyaline cartilage-like repair that integrated with the surrounding cartilage better and higher cartilage extracellular matrix content. In conclusion, these results provide an alternative preparation method for drug-delivered SF microcarrier and a culture method for maintaining the chondrogenic phenotype of seed cells based on the microgravity environment. CTS showed its bioactive function, and the application of CTS-SF microcarriers can help repair and regenerate cartilage defects.

Self-sensing cementitious materials are critical to smart structural health monitoring with the piezoresistivity as an indicator for internal stress and cracks in the structure, which have been frequently utilized as functional coatings in engineering practices. To facilitate the automatic deployment of self-sensing cementitious materials, the compatibility with robotic spraying has been systematically investigated in this study. Pre- and post-spraying evaluations have been conducted for the mixtures with carbon fibers at different dosages, including rheology, tackiness, compressive strengths, and electromechanical responses. On this basis, the addition of 0.4 vol.% carbon fiber was confirmed as the optimal dosage with both competent spraying performance and self-sensing function in the corresponding mixture. Furthermore, the porosity characteristics and fiber agglomeration of the designed mixtures were quantitatively assessed by micro computed tomography (micro-CT), which suggested their relationship to the mechanical and self-sensing properties. Apart from the structural application potential of the developed self-sensing mixture, this study also provides detailed guidance for the optimization of other value-added robotic sprayable cementitious materials.

Internal tandem duplication mutations of the FMS-like tyrosine kinase-3 (FLT3-ITDs) occur in 25%–30% of patients with acute myeloid leukemia (AML) and are associated with dismal prognosis. Although FLT3 inhibitors have demonstrated initial clinical efficacy, the overall outcome of patients with FLT3-ITD AML remains poor, highlighting the urgency to develop more effective treatment strategies. In this study, we reveal that FLT3 inhibitors reduced protein stability of the anti-cancer protein p53, resulting in drug resistance. Blocking p53 degradation with proteasome inhibitors restores intracellular p53 protein levels and, in combination with FLT3-ITD inhibitors, shows superior therapeutic effects against FLT3-ITD AML in cells, mouse models, and patients. These data suggest that this combinatorial therapeutic approach may represent a promising strategy to target FLT3-ITD AML.

Background In recent years, the focus of traditional Chinese medicine (TCM) research has gradually shifted from pure chemical research to looking at the combination of chemistry with the life sciences. However, due to the complexity of the chemical composition of Chinese medicinal plants, understanding material structure through in vivo and in vitro studies is a bottleneck in biological analysis. Nuclear magnetic resonance (NMR) spectroscopy has numerous unique advantages over other analytical techniques, and has developed into a crucial tool in Chinese medicine research. This review aims to analyze and summarize the application of NMR under the multiple fields of TCM.Methods The online databases PubMed, Web of Science, Embase, Cochrane Library, and CNKI were using the search terms “Nuclear magnetic resonance spectrometry,” “NMR,”“Chinese medicine,” “TCM,” “Herbal medicine,” were from January 1, 2010 to June 1, 2023Results The research scopes were 375 after being selected. The latest applications of NMR to TCM including its application to metabolomics, structural identification and efficacy exploration, and authentication and quality control. There were 116 articles on metabolism, 196 articles on compound structure identification and 63 articles on quality control. The metabolomic study of NMR is in line with the multicomponent, multitarget, and overall comprehensive effect of TCM. The structural identification of the chemical components of TCM is more helpful for the discovery of other biologically active substances with high efficacy and few side effects. NMR provides support in quality control and planting site selection of TCM.Conclusion NMR has become an essential tool and makes great contributions to the field of TCM research, the innovation in the application of NMR technology will aid with the research on the material basis of TCM.

ABSTRACTTumor markers of bladder cancer (BC) have been investigated for many years, but the clinical treatment based on these biomarkers is still unsatisfactory. STK32C, a member of the serine/threonine protein kinase of AGC superfamily, was first found to be highly expressed in brain tissues; however, the role of STK32C in malignant disease has not been determined. Data from TCGA database showed that the STK32C gene is overexpressed in BC and a number of other human tumors. In the current study, immunohistochemistry revealed that high expression of STK32C protein in tumor tissues was significantly associated with poor clinico pathologic features and a short relapse-free survival (RFS) in patients with BC. Slicing of STK32C inhibited tumor cell proliferation, migration and invasion in vitro. In vivoanimal experiments demonstrated that knocking-down of STK32C restricted the growth of tumor cells in mice. Finally, microarray analysis revealed that silencing of STK32C inhibited the activity of the HMGB1 pathway and regulated the expression of key genes in this pathway. In conclusion, our study showed novel promoting roles for STK32C in human tumors, which may provide a new therapeutic target for the patients with BC.

The ambitious goal of limiting end-of-century temperature rise relative to pre-industry level below 1.5 °C will offer both great challenges and opportunities in terms of curbing energy use and CO2emissions for the building sector of China. This paper simulates the long-term trend (2010–2100) of energy consumption and CO2emissions of the building sector in China, within the framework of 1.5 °C climate target, with application of GCAM-TU model. The impacts of energy efficiency improvement and carbon policy on energy savings and emission reductions are also explored. The results show that direct CO2emissions from the building sector would have to peak around 2030, and cumulative emissions during 2015–2100 would be limited to 48.2 Gt CO2in the 1.5 °C-consistent scenario. The share of electricity in building’s energy consumption by the mid-century would be 8.9% higher than that under 2 °C scenario. Accelerating efficiency improvement would create significant energy savings relative to the reference scenario, especially in space heating and cooling. However, the emission reductions required by the 1.5 °C temperature increase limit cannot be effectively achieved without the collaboration of economic-wide carbon policy, which would play important role in the deep decarbonization of the energy system. Finally, it is suggested that policy makers should further strengthen technological efficiency improvement in the building sector to help enhance energy performance, while carefully devising prospective carbon policies to facilitate fast and early mitigation.

Trace levels of antibiotics in water bodies could present a public health risk. However, advanced oxidation can potentially transform trace antibiotics; therefore, this study investigates the degradation of typical pharmaceuticals such as ofloxacin (OFL) in aqueous solution by the UV/H2O2advanced oxidation process. The results show that OFL could be rapidly degraded by UV/H2O2, and that the degradation process is dependent on the H2O2concentration and on the initial concentrations of OFL. The pseudo-first-order rate constant (k) of OFL is significantly improved by ·OH generated by H2O2; however, with an increased OFL concentration, the k declines. In actual water bodies, the rate constant of OFL is lower than that in ultrapure water. Further analysis has indicated that the acidic and basic environments or the existence of natural organic matter and chloride ion inhibit the degradation of OFL. The experimental results indicate that the laboratory results could not be extended directly to actual water treatment without further consideration. Six degradation products of OFL were determined by ultra-performance liquid chromatography-high resolution mass spectrometry. The degradation pathways mainly encompass ring openings at both the piperazinyl substituent and the quinolone moiety.

A new griseofulvin derivative, 4′-demethoxy-4′-N-isopentylisogriseofulvin (1), three new indole alkaloids, 2-demethylcyclopiamide E (2), 2-demethylsperadine F (3), and clopiamine C (4), and five known metabolites (5–9) were isolated from Penicillium griseofulvumCPCC 400528. Compound 1is the first reported griseofulvin analogue with an N-isopentane group and the first example of a naturally occurring N-containing griseofulvin analogue. Their structures and absolute configurations were elucidated through extensive spectroscopic analyses, calculated ECD, and single-crystal X-ray diffraction (Cu Kα). The possible biogenetic pathway of 1–3was proposed. Compounds 1, 2, and 5exhibited anti-HIV activities with IC50values of 33.2, 20.5, and 12.6 μM, respectively.

We present a new three‐dimensional velocity model of the crust in the eastern margin of the Tibetan Plateau. The model describes the velocity structure of the Sichuan basin and surrounding thrust belts. The model consists of 3‐D surfaces representing major geologic unit contacts and faults and is parameterized with Vpvelocity‐depth functions calibrated using sonic logs. The model incorporates data from 1166 oil wells, industry isopach maps, geological maps, and a digital elevation model. The geological surfaces were modeled based on structure contour maps for various units from oil wells and seismic reflection profiles. These surfaces include base Quaternary, Mesozoic, Paleozoic, and Proterozoic horizons. The horizons locally exhibit major offsets that are compatible with the locations and displacements of important faults systems. This layered, upper crustal 3‐D model extends down to 10–15 km depth and illustrates lateral and vertical variations of velocity that reflect the complex evolution of tectonics and sedimentation in the basin. The model also incorporates 3‐D descriptions of Vsand density for sediments that are obtained from empirical relationships with Vpusing direct measurements of these properties in borehole logs. To illustrate the impact of our basin model on earthquake hazards assessment, we use it to calculate ground motions and compare these with observations for the 2013 Lushan earthquake. The result demonstrates the effects of basin amplification in the western Sichuan basin. The Sichuan CVM model is intended to facilitate fault systems analysis, strong ground motion prediction, and earthquake hazards assessment for the densely populated Sichuan region. We present a high‐resolution seismic velocity model for Sichuan basinVp structure reflects complex tectonic and sedimentation processThe model applied effectively in the seismic hazard assessment

The extreme modern elevation of the Tianshan Mountains reflects the Cenozoic deformation. Apatite Fission Track (AFT) chronometry is widely used to study the latest cooling stages caused by tectonic process or by exhumation in the uppermost crust. However, uncertainties remain over timing constraints on thermal history of the Tianshan Mountains since the Cenozoic though a great mount of dating work had been done in this area. To address this issue, modern river sands from the drainage basin on the piedmont of the Tianshan Mountains were sampled to integrate regional information. Single grains were dated with the AFT method, and then different grain-age components were identified to provide thermochronological constraints of their sources. Combined with discussion of previous dataset, our results show the multi-staged rapid cooling cluster at 46-32, 25-24, 19-13, 8-6, and ∼3 Ma, respectively. We interpreted these cooling events as a result of interplays between the Cenozoic tectonic uplift of the mountains and regional climate change.

New technologies are in urgent need of unconventional hydrocarbon exploration and development in China. This paper provides a brief introduction and analysis of a new three-dimensional (3D) geomechanical restoration method developed in recent years. After an in-depth discussion on the technical principle and specific characteristics of the fields, we designed a feasible workflow for two oil–gas fields with great unconventional oil–gas resource potentials in China (Weiyuan and Jiulongshan oil–gas fields of Sichuan). After discussing the major challenges and limitations of the new technology, we also suggest its research efforts and future application prospect. It is shown that the new technology will be an effective method to facilitate the exploration and development of unconventional oil and gas resources in China.

The Oxford classification of immunoglobulin A (IgA) nephropathy (IgAN) provides a histopathologic grading system that is associated with kidney disease outcomes independent of clinical features. We evaluated the Oxford IgAN classification in a large cohort of patients from China.

Six novel phototoxins, phaeosphaerins A–F (1–6), together with six known perylenequinones were isolated from an endolichenic fungus Phaeosphaeriasp. Their structures were determined unequivocally on the basis of comprehensive analysis of MS and NMR data as well as electronic circular dichroism calculations. These toxins kill cancer cells in vitro with accumulation in lysosomes, and the killing effects were potently intensified in the presence of light.

Mesangial cells are the main source of renal interstitial fibrosis in diabetic nephropathy (DN). Interferon-? (IFN-?) is a key cytokine that may play a potential therapeutic role in reducing fibrosis. Here, we focus on the effects of IFN-? on human mesangial cells (HMCs) treated with high glucose. This study shows that IFN-? phosphorylates STAT1, suppresses HMC proliferation, and down-regulates mRNA and protein levels of transforming growth factor-ß1 (TGF-ßl) and connective tissue growth factor (CTGF) in HMCs treated with high glucose. The regulation of P-STAT1 could change HMC proliferation and the expression of fibrotic cytokines TGF-ß1 and CTGF in HMCs. These data indicate that IFN-y could activate STAT1 to suppress the increase in TGF-ß1 and CTGF synthesis in HMCs induced by high glucose. This paper may lead to new therapeutic treatments of DN.

ABSTRACTTuberculosis is a common disease worldwide. However, it now is clear that tuberculosis can affect the kidney more insidiously. We describe a case of lumbar tuberculosis associated with simultaneous membranous nephropathy and interstitial nephritis, in which recovery of renal function occurred after treatment with steroids in addition to antituberculosis agents.

With the development of the food industry and the improvement of the living standard, people's diet structure has changed gradually. Excessive diet with high calorie and high protein could cause dyspepsia. Aim of our study is to discuss the effect of yogurt on gastrointestinal motility of dyspepsia mice. Mice were randomly divided into four groups: normal group, model group, Chinese medical group (Drug group), and yogurt group. The mice of normal group were given ordinary feed, the rest of groups were given high protein and high calorie feed and administered through gastric intubation with 52% milk solution to establish dyspeptic model from day 1 to 4. the gastric emptying rate, intestinal propulsion rate, intestinal muscle tension, small intestinal contraction frequency and motilin were measured. Compared with the normal group, the gastric emptying rate, small intestinal propulsion rate, small intestine muscle tension, the small intestine contraction frequency and the motilin concentration were decreased in the model group, Compared with the model group, the intestine muscle tension in the yogurt group was increased, the difference has statistical significance(p<0.05), in addition, the gastric emptying rate in yogurt group was increased(p<0.05),the small intestine contraction frequency and the motilin of yogurt group were increased.Yogurt could improve gastrointestinal motility of dyspepsia mice.

No relevant conflicts of interest to declare.

Deconinck: PFIZER: Research Funding; ALEXION: Other: Travel for international congress; JANSSEN: Other: Travel for international congress; NOVARTIS: Other: Travel for international congress; LFB loboratory: Consultancy; ROCHE: Research Funding; CHUGAI: Other: Travel for international congress.