Nanoscale Structure, Interactions, and Dynamics of Centromere Nucleosomes.

Centromeres are specific segments of chromosomes comprising two types of nucleosomes: canonical nucleosomes containing an octamer of H2A, H2B, H3, and H4 histones and CENP-A nucleosomes in which H3 is replaced with its analogue CENP-A. This modification leads to a difference in DNA wrapping (∼121 bp), considerably less than 147 bp in canonical nucleosomes. We used atomic force microscopy (AFM) and high-speed AFM (HS-AFM) to characterize nanoscale features and dynamics for both types of nucleosomes. For both nucleosomes, spontaneous asymmetric unwrapping of DNA was observed, and this process occurs via a transient state with ∼100 bp DNA wrapped around the core, followed by a rapid dissociation of DNA. Additionally, HS-AFM revealed higher stability of CENP-A nucleosomes compared with H3 nucleosomes in which dissociation of the histone core occurs prior to the nucleosome dissociation. These results help elucidate the differences between these nucleosomes and the potential biological necessity for CENP-A nucleosomes.

MCA Parallel Anatomic Scanning MR Imaging-Guided Recanalization of a Chronic Occluded MCA by Endovascular Treatment.

Basi-parallel anatomic scanning has been widely used for assessing the vascular morphology of vertebral basilar arteries. Previous studies have demonstrated its efficacy in evaluating the morphology of the MCA, which we refer to as MCA parallel anatomic scanning MR imaging (MCPAS). In this study, we present our experience with the application of MCPAS in patients with MCA occlusion. Endovascular treatment was performed on the patients with intact MCA morphology visible in on MCPAS, with no intracranial hemorrhage, occlusion, or other complications observed. No severe stenosis or re-occlusion was observed at the 12-month postoperative follow-up. In conclusion, MCPAS is an effective method for assessing the outer contour of an occlusive MCA. Endovascular treatment can be considered a safe and efficient option for patients who show a favorable MCA through MCPAS assessment.

Homoharringtonine may help improve the outcomes of venetoclax and azacitidine in AML1-ETO positive acute myeloid leukemia.

PURPOSE: T(8;21)(q22;q22.1)/AML1-ETO positive acute myeloid leukemia (AE-AML) is sensitive to conventional chemotherapy with a favorable prognosis. However, recent small case reports suggest the limited effectiveness of venetoclax (VEN) and hypomethylating agents (HMA) in treating AE-AML. The aim of this retrospective study was to evaluate the effectiveness of VEN plus AZA (VA) in AE-AML and explore whether adding homoharringtonine (HHT) to VA (VAH) could improve the response. METHODS: Patients who received VEN plus AZA and HHT (VAH) or VEN plus AZA (VA) regimens were included in this retrospective study. The endpoints of this study were to evaluate the rate of composite complete remission (CRc), measurable residual disease (MRD), event-free survival (EFS), overall survival (OS), and relapse between VAH and VA groups. RESULTS: A total of 32 AE-AML patients who underwent VA or VAH treatments (newly diagnosed with VA, ND-VA, n = 8; relapsed/refractory with VA, R/R-VA, n = 10; relapsed/refractory with VAH, R/R-VAH, n = 14) were included. The CR (complete remission) /CRi (CR with incomplete count recovery) rate of ND-VA, R/R-VA and R/R-VAH were 25%, 10%, and 64.3%, respectively. Measurable residual disease (MRD) negative was observed in 66.7% of R/R-VAH and none of VA-R/R patients. Co-occurring methylation mutations are associated with poor outcomes with VA but exhibit a more favorable response with VAH treatment. Additionally, patients with c-kit mutation presented inferior outcomes with both VEN-based regimens. All regimens were tolerated well by all patients. CONCLUSION: Our data confirmed the poor response of VA in AE-AML, whether used as frontline or salvage therapy. Adding HHT to VA may improve outcomes and enhance the efficacy of VEN in this population.

Discovery of Novel HDAC3 Inhibitors with PD-L1 Downregulating/Degrading and Antitumor Immune Effects.

Targeting the programmed cell death-1/ligand 1 (PD-1/PD-L1) pathway is one of the most promising cancer treatment strategies. Studies have shown that HDAC inhibitors can enhance the antitumor immune response by modulating the expression of PD-L1. Herein, we designed and synthesized a series of novel hydrazide-based small molecule HDAC inhibitors; among them, compound HQ-30 showed selective HDAC3 inhibition (IC50 = 89 nM) and remarkable PD-L1-degrading activity (DC50 = 5.7 µM, Dmax = 80% at 10 µM). Further studies revealed that HQ-30 induced the degradation of PD-L1 by regulating cathepsin B (CTSB) in the lysosomes. Further, HQ-30 could enhance the infiltration of CD3+ CD4+ helper T and CD3+ CD8+ cytotoxic T cells in tumors, thus activating the tumor immune microenvironment. Moreover, HQ-30 possessed a benign toxicity profile (LD50 > 1000 mg/kg) and favorable pharmacokinetic properties (F = 57%). Taken together, HQ-30 is worthy of further investigation as a small molecule-based epigenetic modulator of tumor immunotherapy.

Complex impact of metals on the fate of disinfection by-products in drinking water pipelines: A systematic review.

Metals in the drinking water distribution system (DWDS) play an important role on the fate of disinfection by-products (DBPs). They can increase the formation of DBPs through several mechanisms, such as enhancing the proportion of reactive halogen species (RHS), catalysing the reaction between natural organic matter (NOM) and RHS through complexation, or by increasing the conversion of NOM into DBP precursors. This review comprehensively summarizes these complex processes, focusing on the most important metals (copper, iron, manganese) in DWDS and their impact on various DBPs. It organizes the dispersed 'metals-DBPs' experimental results into an easily accessible content structure and presents their underlying common or unique mechanisms. Furthermore, the practically valuable application directions of these research findings were analysed, including the toxicity changes of DBPs in DWDS under the influence of metals and the potential enhancement of generalization in DBP model research by the introduction of metals. Overall, this review revealed that the metal environment within DWDS is a crucial factor influencing DBP levels in tap water.

Self-assembled Au-CQDs nanofluids with excellent solar absorption and medium-high temperature stability for solar energy harvesting.

Nanofluids-based direct absorption solar collectors are promising candidates for medium-high-temperature solar energy harvesting. However, nanofluids' complicated preparation process and undesirable high-temperature stability have hindered their practical applications. Herein, we propose a facile method for synthesizing gold/carbon quantum dots (Au-CQDs) nanofluids by directly carbonizing the base fluid and spontaneously assembling with Au nanoparticles (AuNPs) triggered by high temperatures. The results indicate that the self-assembled Au-CQDs nanofluids can maintain high stability at 110 °C for 100 h without precipitation and keep excellent photothermal conversion performance under 10 sun irradiation. The concentration and particle size of AuNPs are crucial factors affecting the self-assembly process. By modulating the microscopic morphologies of the self-assembled nanoparticles, the extinction coefficient of the prepared nanofluids is up to 88.7 % at a low loading of 30 ppm. The nanofluids can reach an equilibrium temperature of 50 °C under 1 sun irradiation, 10.4 °C higher than the base fluid due to the enhanced plasmonic effects and stability resulting from the CQDs dotted AuNPs. This work offers a new strategy to fabricate highly stable nanofluids with excellent light absorption properties for efficient solar thermal applications.

The role of tumor-associated macrophages in the radioresistance of esophageal cancer cells via regulation of the VEGF-mediated angiogenic pathway.

Tumor-associated macrophages (TAMs) are known to promote tumor growth, invasion, metastasis, and protumor angiogenesis, but the role of TAMs in evading radiotherapy in esophagus cancer remains unclear. In this study, we first induced TAMs from human monocytes (THP-1) and identified using immunofluorescence and Western blotting assays. We then co-cultured them with human esophageal cancer cell lines. CCK-8, colony formation, Transwell, scratch test, and TUNEL assays showed that TAMs could promote proliferation, survival rate, invasion, migration, and radioresistance and could inhibit apoptosis of the esophageal squamous carcinoma cell lines KYSE-150 and TE-1 before and after radiotherapy both in vivo and in vitro. Using LV-VEGFA-RNAi lentiviral vectors, we also found that TAMs could increase the expression of VEGFA and that inhibition of VEGFA could inhibit the biological function caused by TAMs. Finally, a Western blotting assay was used to evaluate the expression of various factors underlying the mechanism of TAMs. VEGFA, MAPK, P-MAPK, BCL-2, and Snail proteins were found to be overexpressed in co-cultured groups, whereas after VEGFA inhibition, MAPK, P-MAPK, BCL-2, and Snail proteins were found to be significantly downregulated in the radiotherapy group. These study results offer important information regarding the mechanism of radioresistance in esophageal cancer.

Kiwifruit resistance to gray mold is enhanced by yeast-induced modulation of the endophytic microbiome.

The influence of endophytic microbial community on plant growth and disease resistance is of considerable importance. Prior research indicates that pre-treatment of kiwifruit with the biocontrol yeast Debaryomyces hansenii suppresses gray mold disease induced by Botrytis cinerea. However, the specific underlying mechanisms remain unclear. In this study, Metagenomic sequencing was utilized to analyze the composition of the endophytic microbiome of kiwifruit under three distinct conditions: the healthy state, kiwifruit inoculated with B. cinerea, and kiwifruit treated with D. hansenii prior to inoculation with B. cinerea. Results revealed a dominance of Proteobacteria in all treatment groups, accompanied by a notable increase in the relative abundance of Actinobacteria and Firmicutes. Ascomycota emerged as the major dominant group within the fungal community. Treatment with D. hansenii induced significant alterations in microbial community diversity, specifically enhancing the relative abundance of yeast and exerting an inhibitory effect on B. cinerea. The introduction of D. hansenii also enriched genes associated with energy metabolism and signal transduction, positively influencing the overall structure and function of the microbial community. Our findings highlight the potential of D. hansenii to modulate microbial dynamics, inhibit pathogenic organisms, and positively influence functional attributes of the microbial community.

Discovery of 4-phenyl-1H-indazole derivatives as novel small-molecule inhibitors targeting the PD-1/PD-L1 interaction.

The inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway with small molecules is a promising approach for cancer immunotherapy. Herein, novel small molecules compounds bearing various scaffolds including thiophene, thiazole, tetrahydroquinoline, benzimidazole and indazole were designed, synthesized and evaluated for their inhibitory activity against the PD-1/PD-L1 interaction. Among them, compound Z13 exhibited the most potent activity with IC50 of 189.6 nM in the homogeneous time-resolved fluorescence (HTRF) binding assay. Surface plasmon resonance (SPR) assay demonstrated that Z13 bound to PD-L1 with high affinity (KD values of 231 nM and 311 nM for hPD-L1 and mPD-L1, respectively). In the HepG2/Jurkat T co-culture cell model, Z13 decreased the viability rate of HepG2 cells in a concentration-dependent manner. In addition, Z13 showed significant in vivo antitumor efficacy (TGI = 52.6 % at 40 mg/kg) without obvious toxicity in the B16-F10 melanoma model. Furthermore, flow cytometry analysis demonstrated that Z13 inhibited tumor growth in vivo by activating the tumor immune microenvironment. These findings indicate that Z13 is a promising PD-1/PD-L1 inhibitor deserving further investigation.

Selective Phosphate Adsorption Using Topologically Regulated Binary-Defect Metal-Organic Frameworks: Essential Role of Interfacial Electron Mobility.

Metal-organic framework (MOF)-modified biochars (BC) have gained recognition as potent adsorbents for phosphate. However, essential insights into the electronic interfacial state of the MOFs remain lacking. In this study, we propose a novel topological transformation strategy to directionally regulate the interfacial electronic states of BC/MOFs composites. The optimized BC/MOFs exhibited an excellent selective phosphate adsorption capacity of 188.68 mg·g-1, coupled with rapid sorption kinetics of 6.81 mg·(g·min0.5)-1 in simulated P-laden wastewater. When challenged with real bioeffluent, such efficacy was still maintained (5 mg·L-1, 25.92 mg·g-1). This superior performance was due to the Fe(III) → Fe(II) transition, promoting electron mobility and leading to the anchoring of Mg(II) to form specific coordination unsaturated sites (Mg-CUS) for phosphate adsorption. Importantly, the simultaneous regulation of binary defects further enhances electron mobility, resulting in the formation of sp3 unequal hybrid orbitals with a stronger internal coupling capability between Mg 3s in Mg-CUS and O 2p in phosphate. Furthermore, the high electron affinity of Mg effectively promotes electron cycling, endowing BC/MOFs with a distinct self-healing capability to facilitate phosphate desorption. The outcomes of this study provide novel perspectives for electronic regulated phosphate adsorption.

Transformation and environmental chemical characteristics of hazardous trace elements in an 800 t/d waste incineration thermal power plant.

The hazardous trace elements (HTEs) emitted during the municipal solid waste incineration (MSWI) process have been widely concerned. In this work, the bottom ash (BA), heat recovery boiler ash (HA), and ash after desulfurization (SA) were collected to explore the occurrence forms of HTEs in the three types of ash and their relationship with minerals and leaching characteristics. The results show that the volatility of the seven studied HTEs follows the order of Cd, As > Ni, Zn > Pb > Cr, Cu. In the process of BA â†’ HA â†’ SA, the content of Cd, As, Zn, and Pb shows an increasing trend. The seven HTEs are mainly in the forms of chlorides and oxides. There is an obvious relationship between the occurrence forms and simulated existence form of HTEs. SiO2 and CaCO3 are the major mineral components in the three ashes, while SA also contains chlorine-containing compounds which are easily leached out. The risk assessment code and soluble ratio show that HTEs in SA are more leachable than BA and HA, where Cd, Pb and Ni need to be addressed to reduce their impact on soil or water during subsequent landfill treatment of SA.

Clinical and genetic characteristics predict outcomes of acute myeloid leukemia patients with FLT3 mutations receiving venetoclax-based therapy.

BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disease, and its heterogeneity is associated with treatment response. Despite the demonstrated success of venetoclax (VEN)-based therapy for AML, the effect of FLT3 mutations on the efficacy of the therapy is poorly understood. We aimed to compare the efficacy of VEN-based therapy between FLT3-mutated (FLT3mut ) and FLT3 wild-type (FLT3wt ) patients and identify the predictors of efficacy in FLT3mut patients. METHODS: A total of 266 AML patients (127 newly diagnosed [ND] and 139 refractory/relapsed [R/R]) receiving VEN-based regimens were enrolled in this study. A retrospective analysis was performed, and the treatment responses and overall survival (OS) of FLT3mut and FLT3wt patients were compared. Logistic regression and Cox proportional hazards model were applied to examine the clinical and genetic predictors of outcomes. RESULTS: With a median of two cycles of VEN-based therapy, for the ND AML cohort, the FLT3mut group had a comparable composite complete remission (CRc) rate with the FLT3wt group (79.3% vs. 61.2%, p = 0.072). For the R/R AML cohort, the FLT3mut group exhibited a lower CRc rate than the FLT3wt group. With a median follow-up of 8.6 months (95% confidence interval [CI], 8.0-10), the median OS observed in the FLT3mut and FLT3wt groups for both cohorts were close (14.0 vs. 19.9 months, p = 0.356; 10.0 vs. 11.9 months, p = 0.680). For the ND AML cohort, in FLT3mut patients, MRD-positive and RNA-splicing mutation predicted inferior survival (hazard ratio [HR], 10.3; 95% CI: 2.0-53.8; p = 0.006; HR 11.3; 95% CI: 1.2-109.3; p = 0.036, respectively). For the R/R AML cohort, in FLT3mut patients, adverse ELN risk was associated with an inferior response (odds ratio [OR], 0.2; 95% CI: 0.1-0.8; p = 0.025), whereas NPM1 co-mutation was associated with a superior response (57.1%; OR, 6.7; 95% CI: 1.5-30.1; p = 0.014). CR/CRi predicted a better survival (HR 0.2; 95% CI: 0.1-0.8; p = 0.029), while DNMT3A mutation predicted an inferior survival (HR, 4.6; 95% CI: 1.4-14.9; p = 0.011). CONCLUSIONS: FLT3 mutations may influence response to VEN-based therapy in R/R AML patients but not in ND AML patients. Furthermore, clinical and genetic characteristics could predict outcomes of FLT3mut patients receiving VEN-based therapy.

[Establishment and verification of a prognostic nomogram for survival of tongue squamous cell carcinoma patients who underwent cervical dissection].

OBJECTIVE: To evaluate the prognostic significance of inflammatory biomarkers, prognostic nutritional index and clinicopathological characteristics in tongue squamous cell carcinoma (TSCC) patients who underwent cervical dissection. METHODS: The retrospective cohort study consisted of 297 patients undergoing tumor resection for TSCC between January 2017 and July 2018. The study population was divided into the training set and validation set by 7 :3 randomly. The peripheral blood indices of interest were preoperative neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), systemic inflammation score (SIS) and prognostic nutritional index (PNI). Kaplan-Meier survival analysis and multivariable Cox regression analysis were used to evaluate independent prognostic factors for overall survival (OS) and disease-specific survival (DSS). The nomogram's accuracy was internally validated using concordance index, receiver operating characteristic (ROC) curve, area under the curve (AUC), calibration plot and decision curve analysis. RESULTS: According to the univariate Cox regression analysis, clinical TNM stage, clinical T category, clinical N category, differentiation grade, depth of invasion (DOI), tumor size and pre-treatment PNI were the prognostic factors of TSCC. Multivariate Cox regression analysis revealed that pre-treatment PNI, clinical N category, DOI and tumor size were independent prognostic factors for OS or DSS (P < 0.05). Positive neck nodal status (N≥1), PNI≤50.65 and DOI > 2.4 cm were associated with the poorer 5-year OS, while a positive neck nodal status (N≥1), PNI≤50.65 and tumor size > 3.4 cm were associated with poorer 5-year DSS. The concordance index of the nomograms based on independent prognostic factors was 0.708 (95%CI, 0.625-0.791) for OS and 0.717 (95%CI, 0.600-0.834) for DSS. The C-indexes for external validation of OS and DSS were 0.659 (95%CI, 0.550-0.767) and 0.780 (95%CI, 0.669-0.890), respectively. The 1-, 3- and 5-year time-dependent ROC analyses (AUC = 0.66, 0.71 and 0.72, and AUC = 0.68, 0.77 and 0.79, respectively) of the nomogram for the OS and DSS pronounced robust discriminative ability of the model. The calibration curves showed good agreement between the predicted and actual observations of OS and DSS, while the decision curve confirmed its pronounced application value. CONCLUSION: Pre-treatment PNI, clinical N category, DOI and tumor size can potentially be used to predict OS and DSS of patients with TSCC. The prognostic nomogram based on these variables exhibited good accurary in predicting OS and DSS in patients with TSCC who underwent cervical dissection. They are effective tools for predicting survival and helps to choose appropriate treatment strategies to improve the prognosis.

Sorafenib plus triplet therapy with venetoclax, azacitidine and homoharringtonine for refractory/relapsed acute myeloid leukemia with FLT3-ITD: A multicenter phase 2 study.

BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (R/R AML) and FLT3-internal tandem duplication (FLT3-ITD) respond infrequently to salvage chemotherapy. OBJECTIVE: To investigate the efficacy of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as a salvage therapy in this population. METHODS: This multicenter, single-arm, phase 2 study was conducted at 12 hospitals across China. Eligible patients had R/R AML with FLT3-ITD (aged 18-65 years) who were treated with VAH. The primary endpoint was composite complete remission (CRc) after two cycles. Secondary outcomes included the overall response rate (ORR), safety, and survival. RESULTS: Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom were enrolled. The median patient age was 47 years (interquartile range [IQR] 31-57). CRc was 76.5% with ORR of 82.4%. At a median follow-up of 17.7 months (IQR, 8.7-24.7), the median duration of CRc was not reached (NR), overall survival was 18.1 months (95% confidence interval [CI], 11.8-NR) and event-free survival was 11.4 months (95% CI, 5.6-NR). Grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92.2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%), and sepsis in 6 (11.8%) patients. Treatment-related death occurred in two (3.9%) patients. CONCLUSIONS: The sorafenib plus VAH regimen was well tolerated and highly active against R/R AML with FLT3-ITD. This regimen may be a suitable therapeutic option for this population, but larger population trials are needed to be explored. TRIAL REGISTRATION: Clinical Trials Registry: NCT04424147.

Chinese expert consensus on the management of patients with hematologic malignancies infected with SARS-CoV-2.

In December 2022, the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became dominant in China due to its high infectivity and lower mortality rate. The risk of critical illness and mortality among patients with hematologic malignancies who contracted SARS-CoV-2 was particularly high. The aim of this study was to draft a consensus to facilitate effective treatments for these patients based on the type and severity of the disease. Following the outbreak of the novel coronavirus in China, a steering committee consisting of experienced hematologists was formed by the Specialized Committee of Oncology and Microecology of the Chinese Anti-Cancer Association. The expert group drafted a consensus on the management and intervention measures for different types of hematologic malignancies based on the clinical characteristics of the Omicron variant of the SARS-CoV-2 infection, along with relevant guidelines and literature. The expert group drafted independent recommendations on several important aspects based on the epidemiology of the Omicron variant in China and the unique vulnerability of patients with hematologic malignancies. These included prophylactic vaccinations for those with hematologic malignancies, the use of plasma from blood donors who recovered from the novel coronavirus infection, the establishment of negative pressure wards, the use of steady-state mobilization of peripheral blood hematopoietic stem cells, the provision of psychological support for patients and medical staff, and a focus on maintaining a healthy intestinal microecology.

Dirac semimetal-assisted near-field radiative thermal rectifier and thermostat based on phase transition of vanadium dioxide.

The near-field thermal radiation has broad application prospects in micro-nano-scale thermal management technology. In this paper, we report the Dirac semimetal-assisted (AlCuFe quasicrystal) near-field radiative thermal rectifier (DSTR) and thermostat (DST), respectively. The DSTR is made of a Dirac semimetal-covered vanadium dioxide (VO2) plate and silicon dioxide (SiO2) plate separated by a vacuum gap. The left and right sides of DST are consisted of the SiO2 covered with Dirac semimetal, and the intermediate plate is the VO2. The strong coupling of the surface electromagnetic modes between the Dirac semimetal, SiO2, and insulating VO2 leads to enhance near-field radiative transfer. In the DSTR, the net radiative heat flux of VO2 in the insulating state is much larger than that in metallic state. When the vacuum gap distance d=100 nm, Fermi level EF=0.20 eV, and film thickness t=12 nm, the global rectification factor of DSTR is 3.5, which is 50% higher than that of structure without Dirac semimetal. In the DST, the equilibrium temperature of the VO2 can be controlled accurately to achieve the switching between the metallic and insulating state of VO2. When the vacuum gap distance d=60 nm, intermediate plate thickness δ=30 nm, and film thickness t=2 nm, with the modulation of Fermi level between 0.05-0.15 eV, the equilibrium temperature of VO2 can be controlled between 325-371 K. In brief, when the crystalline state of VO2 changes between the insulating and metallic state with temperature, the active regulation of near-field thermal radiation can be realized in both two-body and three-body parallel plate structure. This work will pave a way to further improve performance of near-field radiative thermal management and modulation.

Development and validation of a new risk assessment model for immunomodulatory drug-associated venous thrombosis among Chinese patients with multiple myeloma.

BACKGROUND: Individuals with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs) are at risk of developing venous thromboembolism (VTE), a serious complication. There is no established clinical model for predicting VTE in the Chinese population. We develop a new risk assessment model (RAM) for IMiD-associated VTE in Chinese MM patients. METHODS: We retrospectively selected 1334 consecutive MM patients receiving IMiDs from 16 medical centers in China and classified them randomly into the derivation and validation cohorts. A multivariate Cox regression model was used for analysis. RESULTS: The overall incidence of IMiD-related VTE in Chinese MM patients was 6.1%. Independent predictive factors of VTE (diabetes, ECOG performance status, erythropoietin-stimulating agent use, dexamethasone use, and VTE history or family history of thrombosis) were identified and merged to develop the RAM. The model identified approximately 30% of the patients in each cohort at high risk for VTE. The hazard ratios (HRs) were 6.08 (P < 0.001) and 6.23 (P < 0.001) for the high-risk subcohort and the low-risk subcohort, respectively, within both the derivation and validation cohorts. The RAM achieved satisfactory discrimination with a C statistic of 0.64. The stratification approach of the IMWG guidelines yielded respective HRs of 1.77 (P = 0.053) and 1.81 (P = 0.063). The stratification approach of the SAVED score resulted in HRs of 3.23 (P = 0.248) and 1.65 (P = 0.622), respectively. The IMWG guideline and the SAVED score-based method yielded C statistics of 0.58 and 0.51, respectively. CONCLUSIONS: The new RAM outperformed the IMWG guidelines and the SAVED score and could potentially guide the VTE prophylaxis strategy for Chinese MM patients.

Identification of the Immune Landscapes and Follicular Helper T Cell-Related Genes for the Diagnosis of Age-Related Macular Degeneration.

BACKGROUND: Age-related macular degeneration (AMD) is a progressive ocular ailment causing age-associated vision deterioration, characterized by dysregulated immune cell activity. Notably, follicular helper T (Tfh) cells have emerged as pivotal contributors to AMD pathogenesis. Nonetheless, investigations into Tfh-associated gene biomarkers for this disorder remain limited. METHODS: Utilizing gene expression data pertinent to AMD procured from the Gene Expression Omnibus (GEO) repository, we employed the "DESeq2" R software package to standardize and preprocess expression levels. Concurrently, CIBERSORT analysis was utilized to compute the infiltration proportions of 22 distinct immune cell types. Subsequent to weighted gene correlation network analysis (WGCNA), coupled with differential expression scrutiny, we pinpointed genes intricately linked with Tfh cells. These potential genes underwent further screening using the MCODE function within Cytoscape software. Ultimately, a judicious selection of pivotal genes from these identified clusters was executed through the LASSO algorithm. Subsequently, a diagnostic nomogram was devised based on these selected genes. RESULTS: Evident Tfh cell disparities between AMD and control cohorts were observed. Our amalgamated analysis, amalgamating differential expression data with co-expression patterns, unveiled six genes closely associated with Tfh cells in AMD. Subsequent employment of the LASSO algo-rithm facilitated identification of the most pertinent genes conducive to predictive modeling. From these, GABRB3, MFF, and PROX1 were elected as prospective diagnostic biomarkers for AMD. CONCLUSIONS: This investigation discerned three novel biomarker genes, linked to inflammatory mechanisms and pivotal in diagnosing AMD. Further exploration of these genes holds potential to foster novel therapeutic modalities and augment comprehension of AMD's disease trajectory.

Hypomethylating agents plus modified priming regimens compared with venetoclax-based regimens based on molecular characteristics for newly diagnosed patients with acute myeloid leukemia: a multi-center cohort study.

Venetoclax (VEN)-based regimens are the standard of care for elderly or unfit patients with newly diagnosed (ND) acute myeloid leukemia (AML). Some single-arm studies have implied that hypomethylating agents (HMAs) plus priming regimens may potentially provide an alternative therapeutic approach, owing to encouraging efficacy seen. However, no comparative data exists yet regarding these two treatment approaches. In this retrospective multi-center cohort study, we enrolled 294 ND AML patients, allocating 167 to the HMA + priming group and 127 to the VEN-based group. Treatment response and overall survival (OS) were compared between groups. Molecular subgroup analyses were also conducted. With a median of two cycles for HMA + priming group, the overall response (ORR) was 65.3%, including 55.1% complete remission (CR), 9.6% CR with incomplete hematologic recovery (CRi) and 0.6% morphologic leukemia-free state (MLFS). With a median of two cycles for VEN-based group, the ORR was 70.9%, including 46.5% CR, 18.9% CRi, and 5.5% MLFS. Response differences (ORR or CR/CRi) between groups were not significant (p > 0.05). With a median follow-up of 10.1 months, median OSs were similar between groups (20.9 vs 16.3 months, p = 0.41). However, VEN regimens demonstrated superior CR/CRi for patients with mutations in FLT3, IDH1/2, and NPM1 compared to HMA + priming (80.0% vs 35.0%, p = 0.01; 90.9% vs 65.5%, p = 0.02; 90.9% and 65.5%, p = 0.02, respectively). In conclusion, HMAs plus modified priming regimens might be a potential alternative therapeutic approach for patients with ND AML, but VEN-based regimens presented predominance in specific molecular subgroups. Molecular characteristics contribute to guiding choice of treatment.