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The establishment of epiblast-derived pluripotent stem cells (PSCs) from cattle, which are important domestic animals that provide humans with milk and meat while also serving as bioreactors for producing valuable proteins, poses a challenge due to the unclear molecular signaling required for embryonic epiblast development and maintenance of PSC self-renewal. Here, we selected six key stages of bovine embryo development (E5, E6, E7, E10, E12, and E14) to track changes in pluripotency and the dependence on signaling pathways via modified single-cell transcription sequencing technology. The remarkable similarity of the gene expression patterns between cattle and pigs during embryonic lineage development contributed to the successful establishment of bovine epiblast stem cells (bEpiSCs) using 3i/LAF (WNTi, GSK3βi, SRCi, LIF, Activin A, and FGF2) culture system. The generated bEpiSCs exhibited consistent expression patterns of formative epiblast pluripotency genes and maintained clonal morphology, normal karyotypes, and proliferative capacity for more than 112 passages. Moreover, these cells exhibited high-efficiency teratoma formation as well as the ability to differentiate into various cell lineages. The potential of bEpiSCs for myogenic differentiation, primordial germ cell like cells (PGCLCs) induction, and as donor cells for cell nuclear transfer was also assessed, indicating their promise in advancing cell-cultured meat production, gene editing, and animal breeding. [ABSTRACT FROM AUTHOR]

As the world's first oral nuclear export inhibitor, selinexor is increasingly being used in clinical applications for malignant tumors. However, there is no extensive exploration on selinexor's adverse events (ADEs), necessitating a real-word assessment of its clinical medication safety. FAERS data (July 2019–June 2023) were searched for selinexor ADE reports across all indications. Use the system organ class (SOC) and preferred terms (PT) from the medical dictionary for regulatory activities (MedDRA) to describe, categorize, and statistic ADEs. Disproportionality analysis was employed through calculation of reporting odds ratio (ROR) and proportional reporting ratio (PRR). Based on total of 4392 selinexor related ADE reports as the primary suspect (PS), of which 2595 instances were severe outcomes. The predominant ADEs included gastrointestinal disorders, myelosuppression symptoms, and various nonspecific manifestations. 124 signals associated with selinexor ADE were detected, and 10 of these top 15 signals were not included into the instructions. Our study provides real-world evidence regarding the drug safety of selinexor, which is crucial for clinicians to safeguard patients’ health. [ABSTRACT FROM AUTHOR]

The vulnerability of plant xylem to embolism can be described as the water potential at which xylem conductivity is lost by 50% (P50). According to the traditional hypothesis of hydraulic vulnerability segmentation, the difference in vulnerability to embolism between branches and roots is positive (P50 root−branch > 0). It is not clear whether this occurs broadly across species or how segmentation might vary across aridity gradients. We compiled hydraulic and anatomical datasets from branches and roots across 104 woody species (including new measurements from 10 species) in four biomes to investigate the relationships between P50 root–branch and environmental factors associated with aridity. We found a positive P50 root–branch relationship across species, and evidence that P50 root–branch increases with aridity. Branch xylem hydraulic conductivity transitioned from more efficient (e.g., wider conduit, higher hydraulic conductivity) to safer (e.g., narrower conduit, more negative P50) in response to the increase of aridity, while root xylem hydraulic conductivity remained unchanged across aridity gradients. Our results demonstrate that the hydraulic vulnerability difference between branches and roots is more positive in species from arid regions, largely driven by modifications to branch traits. [ABSTRACT FROM AUTHOR]

Introduction: Cardiovascular diseases present a great burden for survivors of hematologic malignancy (HM). However, the effect of pulmonary hypertension (PH) on the clinical outcome of patients with HM remains unknown. This study aims to evaluate the prognostic potential of PH in patients with HM and explore the related clinical determinants. Methods: This retrospective study included 220 patients with HM and PH and 220 controls without PH, the case-matching cohort analysis was performed based on age, sex, the year of diagnosis and disease type. The baseline characteristics and overall survival (OS) of the patients with HM with or without PH were compared. The cumulative overall survival was analyzed using the Kaplan–Meier curves and the log-rank test. Multivariate Cox proportional hazard models were conducted to identify the predictors of OS. Results: PH was found in 11.98% (302/2520) of the patients with HM. The PH group had lower levels of hemoglobin, platelet, albumin, fibrinogen and B cell count; whereas the levels of lactate dehydrogenase, N terminal pro B type natriuretic peptide, d-dimer, fibrinogen degradation products and C-reactive protein were higher. Additionally, the PH group had a higher prevalence of atrial fibrillation. Survival analysis revealed that the PH group had an inferior OS compared to the non-PH group (16.9 vs. 37.6 months, p = 0.002). Further subgroup analysis revealed that the severe PH group had the worst OS, followed by the moderate and the mild PH groups (8.7 vs. 14.7 vs. 23.7 months, p < 0.001). Multivariate analysis showed that PH was an independent predictor for unfavorable clinical outcomes. Conclusions: Coexisting PH was associated with inferior clinical outcomes in patients with HM, and the severe PH group had the worst prognosis. The study may provide additional risk stratification for patients with HM. [ABSTRACT FROM AUTHOR]

Purpose: A barrier to widespread adoption of chimeric antigen receptor (CAR) T-cell therapy is toxicity. To address this, we recently developed a novel antibody-T-cell receptor (AbTCR) platform (trademarked as ARTEMIS®) which was designed to leverage natural immune receptor signaling and regulation. The AbTCR platform includes a gamma/delta (γδ) TCR-based AbTCR construct and a separate co-stimulatory molecule, both engineered to be tumor-specific. Here, we aim to assess the safety and preliminary efficacy of a CD19-directed AbTCR T-cell therapy. Methods: We generated ET019003 T cells, which are autologous CD19-directed AbTCR T cells. We then conducted an early phase I study to evaluate the safety and preliminary efficacy of ET019003 T cells for the treatment of CD19-positive relapsed/refractory (r/r) B-cell lymphoma. Results: Sixteen patients enrolled in this study and 12 patients were treated. Of the 12 patients treated, 6 patients (50%) achieved a complete response (CR), and 4 (33%) achieved a partial response (PR) (best objective response rate [ORR] of 83%). CRs were durable, including 2 patients with ongoing CRs for 22.7 months and 23.2 months. ET019003 was well-tolerated with an attractive safety profile. No patients experienced severe (grade ≥ 3) cytokine release syndrome (CRS) and only 1 patient experienced immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade. Significant elevations of cytokine levels were not seen, even in patients with marked expansion of ET019003 T cells. Conclusion: This study provides initial clinical validation of the AbTCR platform as a novel cancer treatment with the potential to provide durable clinical benefit with low toxicity. Trial registration: NCT03642496; Date of registration: August 22, 2018. [ABSTRACT FROM AUTHOR]

Glioma is the most common tumor of the central nervous system, and its poor prognosis can be linked to hypoxia and gene inactivation. Na+/Ca2+ exchanger 2 (NCX2) is expressed only in the normal brain and not in other tissues or glioma. We constructed a hypoxic microenvironment to more accurately understand the effect of NCX2 in glioma. Our previous experiments confirmed that NCX2 inhibited the growth of U87 cells in nude mice, indicating that NCX2 is a potential tumor suppressor gene. Malignant tumor cells are often exposed to an anoxic environment. To more accurately understand the effect of NCX2 in glioma, we constructed a hypoxic microenvironment. To detect the localization of NCX2 in transfected U87 cells, immunofluorescence was used. We tested the function of NCX2 in glioma, i.e., how it contributes to the cytosolic Ca2+ homeostasis by X-Rhod-1. We tested the cell proliferation of NCX2 in glioma in hypoxic using Cell counting kit-8 (CCK8). Cell migration and invasion were evaluated in 24-well transwell matrigel-coated or non-matrigel-coated in hypoxia. NCX2 promoted the proliferation of U87 cells in the hypoxic microenvironment. It inhibited the invasion and migration abilities of U87 cells. We demonstrated that NCX2 was located on the cell membrane and that it reduced intracellular Ca2+ levels and reactivated P53 and PTEN. We further demonstrated that NCX2 impaired cell invasion through the HIF-1α pathway in glioma. The results indicated that NCX2 plays a key role in glioma formation and tumor invasion functionality. [ABSTRACT FROM AUTHOR]

Introduction: Patients with multiple myeloma (MM) can develop cardiac abnormalities, predisposing them to the development of heart failure, arrhythmias, or infarction with poor prognosis. The purpose of this study is to evaluate the prognostic potential of electrocardiographic (ECG) parameters in patients with MM.Methods: This study retrospectively included patients with MM from January 2010 to December 2018 in the First Affiliated Hospital of Xi'an Jiao Tong University. Univariate and multivariate Cox proportional hazard models were conducted to evaluate the relationship between ECG parameters and all-cause mortality in patients with MM.Results: A total of 409 patients were included (mean age 61.3 ± 9.7 years, 59.2% male). The relationship between ECG parameters (including PR interval, voltage, QRS axis, QRS duration, and QTc interval) and all-cause mortality in patients with MM was evaluated. Overall, patients with QTc interval ≥ 400 ms have a significantly higher all-cause mortality compared to those with QTc interval < 400 ms (P < 0.001). When stratified by the International Staging System (ISS), this relationship was true for stages II and III (P < 0.01), but not stage I (P > 0.05). Patients with MM and QRS duration ≥ 120 ms had a higher all-cause mortality compared to those with QRS duration < 120 ms for women (P < 0.01) but not for men (P > 0.05). PR interval, voltage, and QRS axis did not predict mortality.Conclusion: QTc interval was independently associated with all-cause mortality in patients with MM, especially when QTc interval was more than 400 ms in more advanced stages II and III. ECG parameters may provide prognostic potential in patients with MM and aid risk stratification of these patients. [ABSTRACT FROM AUTHOR]

Purpose: Trimetazidine has been shown to prevent the risk of contrast-induced nephropathy (CIN) in patients with renal dysfunction undergoing percutaneous coronary intervention (PCI). However, the effect of trimetazidine on CIN in unselected patients is unknown. We aimed to evaluate the effect of trimetazidine on preventing CIN in unselected patients treated with PCI. Methods: 2154 consecutive patients were enrolled and divided into the trimetazidine (n = 529) and non-trimetazidine group (n = 1625). Patients in the trimetazidine group received trimetazidine 20 mg thrice daily starting at least 24 h before the procedure and continuing until discharge. The primary outcome was CIN. Results: CIN was observed in 197 (9.2%) patients. The incidence of CIN was similar between two groups (9.1% vs. 9.2%, P = 0.947). After adjusting for other potential risk factors, trimetazidine did not significantly reduce the risk of CIN (OR = 0.70, 95% CI 0.46–1.08, P = 0.104). The results remained similar when using the alternate definitions of CIN and different subgroup analysis based on diabetes or chronic kidney disease. In additional, no significant difference between two groups was found with respect to in-hospital major adverse clinical events (1.89% vs. 1.66%, P > 0.05). Conclusions: Trimetazidine did not exert significant renal protective effect on preventing CIN and in hosptial major adverse clinical events in unselected patients undergoing PCI. [ABSTRACT FROM AUTHOR]

Benzene bridged Ti incorporated periodic mesoporous organosilicas (Ti-PMOs) was prepared following an in situ hydrothermal method by using P123 as a structure directing agent in acidic condition, tetrabutyl titanate (TBOT) as titanium source, tetraethoxysilane (TEOS) as inorganic Si-source and 1, 4-bis(triethoxysilyl)benzene (BTEB) as organic Si-source. The effects of preparation conditions of Ti-PMOs, mole ratio of TEOS/BTEB and ageing time, on the catalytic performance for the cyclohexene epoxidation with tertbutyl hydroperoxide as an oxidant agent were investigated. By means of a variety of characterized method, the results showed that the proper mole ratio of TEOS/BTEB was 3:1, which was favor of maintaining good mesoporous structure, ageing time of preparation mixture solution was a key factor to improve the catalytic performance of Ti-PMOs. NH3-TPD indicated that sample prepared at ageing time 48 h had more readily exposed active titanium site, which significantly improve the selectivity of cyclohexene oxide to 97.7% from 37.7% at 24 h ageing time. The hydrophobic group of benzene bridged on the pore wall was benefit for the approach of cyclohexene and formation of the active tetravalent titanium. [ABSTRACT FROM AUTHOR]

A new composite catalyst was constructed by immobilizing active site N,N-dihydroxypyromellitimide (NDHPI) on the co-catalyst Co-doped mesoporous sieve SBA-15 through the chemical bond with the 3-(glycidoxypropyl) trimethoxysilicane used as the silylation agent. The catalyst was characterized by various means. The new catalyst showed significantly higher activity in toluene aerobic oxidation at 90 °C with acetonitrile as a solvent or under solvent-free condition compared with the NDHPI and co-catalyst independent system. The effects of the reaction conditions such as temperature, oxygen pressure, catalyst amount on the toluene oxidation over the immobilized catalyst were also investigated. After reuse for three times, the composite catalyst kept the activity without loss of Co from SBA-15. Graphical Abstract: A new composite catalyst was constructed by immobilizing active site N,N-dihydroxypyromellitimide (NDHPI) on the co-catalyst Co-doped mesoporous sieve SBA-15 through the chemical bond with the 3-(glycidoxypropyl) trimethoxysilicane used as the silylation agent. The catalyst was characterized by various means. The catalytic performance of the composite was evaluated in toluene aerobic oxidation and the reuseability of the catalyst was also investigated. [ABSTRACT FROM AUTHOR]

Arsenic trioxide (ATO) combined with dexamethasone, melphalan or other cytostatic agents had been used to treat refractory or relapsed multiple myeloma (MM) patients. We assessed the safety and efficacy of ATO combined with vindesine/cyclophosphamide/melphalan/prednisone (VCMP) or vindesine/doxorubicin/dexamethsone (VAD) chemotherapy for MM patients who failed more than two different prior regimens. All patients received ATO (0.25 mg/kg day) for 10 days/cycle combined with VCMP or VAD in 30-day cycles. Vindesine (1.4 mg/m) was given intravenously on day 1, cyclophosphamide (400 mg/m day) was given intravenously on days 2, 4, 6, 8, 10, melphalan (6 mg/day) and prednisone (1 mg/kg day) were given orally day 1 to day 10 for VCMP regimen. VAD regimen consisted of vindesine 1 mg/day and doxorubicin 10 mg/day intravenously drip for 4 days with oral dexamethasone 40 mg/day for days 1-4, 9-12, 17-20. Patients who completed at least one cycle were evaluated for response to treatment. Objective responses occurred in 35 of 63 (56 %) patients, including seven complete, 14 partial and 14 minor responses. Median progression-free survival and overall survival were 6 and 23 months respectively. 12 patients had elevated serum creatinine levels (SCr) at baseline, and 9 of 12 (75 %) showed decreased SCr levels during treatment. Frequent Grade 3/4 non-hematological adverse events included arrhythmia, hypertension, fatigue and neuropathy. These results indicate that ATO combined with VCMP or VAD was effective and well tolerated as a new therapeutic option for patients with relapsed or refractory MM. [ABSTRACT FROM AUTHOR]

Tetra-arsenic tetra-sulfide (AsS) is an arsenic compound with antitumor activity, especially in acute promyelocytic leukemia (APL) that are resistant to retinoic acid (RA). Although recent studies have revealed that the therapeutic action of AsS is closely associated with the induction of cellular apoptosis, the exact molecular mechanism underlying this action in RA-resistant APL remains to be clarified. In this study, we found that AsS-induced apoptosis was accompanied by reduced mRNA and protein expression of SET gene in RA-resistant NB4-R1 cells. Moreover, RNAi knockdown of SET gene further promoted AsS-induced apoptosis, while SET overexpression recovered the cell viability, suggesting that AsS induces apoptosis through the reduction of SET protein in NB4-R1 cells. We also observed that the knockdown of SET gene resulted in the upregulation of protein phosphatase 2 (PP2A) expression and the downregulation of promyelocytic leukemia and retinoic acid receptor α fusion gene (PML-RARα) expression, which were enhanced by AsS treatments. By contrast, overexpression of SET gene resulted in PP2A downregulation and PML-RARα upregulation, which were abolished by AsS pretreatment. Since PP2A is a proapoptotic factor and PML-RARα is an antiapoptotic factor, our results suggest that AsS-induced apoptosis in RA-resistant NB4-R1 cells is through the downregulation of SET protein expression, which, in turn, increases PP2A and reduces PML-RARα expressions to lead to cell apoptosis. [ABSTRACT FROM AUTHOR]

The early diverged Magnoliaceae shows a historical temperate-tropical distribution among lineages indicating divergent evolution, yet which ecophysiological traits are phylogenetically conserved, and whether these traits are involved in correlated evolution remain unclear. Integrating phylogeny and 20 ecophysiological traits of 27 species, from the four largest sections of Magnoliaceae, we tested the phylogenetic signals of these traits and the correlated evolution between trait pairs. Phylogenetic niche conservatism (PNC) in water-conducting and nutrient-use related traits was identified, and correlated evolution of several key functional traits was demonstrated. Among the three evergreen sections of tropical origin, Gwillimia had the lowest hydraulic-photosynthetic capacity and the highest drought tolerance compared with Manglietia and Michelia. Contrastingly, the temperate centred deciduous section, Yulania, showed high rates of hydraulic conductivity and photosynthesis at the cost of drought tolerance. This study elucidated the regulation of hydraulic and photosynthetic processes in the temperate-tropical adaptations for Magnoliaceae species, which led to strong phylogenetic signals and PNC in ecophysiological traits across divergent lineages of Magnoliaceae. [ABSTRACT FROM AUTHOR]

Purpose: The role of therapeutic drug monitoring (TDM) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients receiving letermovir has not yet been clarified. This study is to explore letermovir trough concentration (Cmin) correlation with its clinical efficacy and adverse events, and factors affecting its plasma concentrations.A prospective, non-interventional study was performed in allo-HSCT recipients receiving letermovir prophylaxis. Plasma concentrations were determined using high-performance liquid chromatography-tandem mass spectrometry. Data analysis was performed using logistic regression, linear regression, and classification and regression tree (CART) models.701 trough concentrations from 71 recipients were included, uncovering pronounced intra- and inter-individual variability in letermovir Cmin. During 24-week follow-up, CMV infection incidence was 16.4%. A significant correlation was identified between letermovir Cmin and its clinical efficacy, and the CART model showed an increased risk of CMV infection when Cmin ≤ 2731 ng/mL. However, no clear correlation was found between Cmin and adverse events. Gastrointestinal graft-versus-host disease, cyclosporine Cmin, gender, and concomitant medications, including mycophenolate mofetil, ondansetron, caspofungin, and methylprednisolone, may impact letermovir Cmin. Additionally, coadministration with cyclosporine injection significantly decreased median letermovir Cmin compared with cyclosporine capsules (2311 vs. 3386 ng/mL). Moreover, with the extension of time post-transplant, trough concentrations of both cyclosporine and letermovir significantly decreased.TDM for letermovir may be beneficial in allo-HSCT recipients considering the variability in letermovir Cmin and its correlation with clinical efficacy. Moreover, drug interactions and the effects of changes in cyclosporine dosage forms or concentrations require careful monitoring for their effect on letermovir Cmin.Methods: The role of therapeutic drug monitoring (TDM) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients receiving letermovir has not yet been clarified. This study is to explore letermovir trough concentration (Cmin) correlation with its clinical efficacy and adverse events, and factors affecting its plasma concentrations.A prospective, non-interventional study was performed in allo-HSCT recipients receiving letermovir prophylaxis. Plasma concentrations were determined using high-performance liquid chromatography-tandem mass spectrometry. Data analysis was performed using logistic regression, linear regression, and classification and regression tree (CART) models.701 trough concentrations from 71 recipients were included, uncovering pronounced intra- and inter-individual variability in letermovir Cmin. During 24-week follow-up, CMV infection incidence was 16.4%. A significant correlation was identified between letermovir Cmin and its clinical efficacy, and the CART model showed an increased risk of CMV infection when Cmin ≤ 2731 ng/mL. However, no clear correlation was found between Cmin and adverse events. Gastrointestinal graft-versus-host disease, cyclosporine Cmin, gender, and concomitant medications, including mycophenolate mofetil, ondansetron, caspofungin, and methylprednisolone, may impact letermovir Cmin. Additionally, coadministration with cyclosporine injection significantly decreased median letermovir Cmin compared with cyclosporine capsules (2311 vs. 3386 ng/mL). Moreover, with the extension of time post-transplant, trough concentrations of both cyclosporine and letermovir significantly decreased.TDM for letermovir may be beneficial in allo-HSCT recipients considering the variability in letermovir Cmin and its correlation with clinical efficacy. Moreover, drug interactions and the effects of changes in cyclosporine dosage forms or concentrations require careful monitoring for their effect on letermovir Cmin.Results: The role of therapeutic drug monitoring (TDM) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients receiving letermovir has not yet been clarified. This study is to explore letermovir trough concentration (Cmin) correlation with its clinical efficacy and adverse events, and factors affecting its plasma concentrations.A prospective, non-interventional study was performed in allo-HSCT recipients receiving letermovir prophylaxis. Plasma concentrations were determined using high-performance liquid chromatography-tandem mass spectrometry. Data analysis was performed using logistic regression, linear regression, and classification and regression tree (CART) models.701 trough concentrations from 71 recipients were included, uncovering pronounced intra- and inter-individual variability in letermovir Cmin. During 24-week follow-up, CMV infection incidence was 16.4%. A significant correlation was identified between letermovir Cmin and its clinical efficacy, and the CART model showed an increased risk of CMV infection when Cmin ≤ 2731 ng/mL. However, no clear correlation was found between Cmin and adverse events. Gastrointestinal graft-versus-host disease, cyclosporine Cmin, gender, and concomitant medications, including mycophenolate mofetil, ondansetron, caspofungin, and methylprednisolone, may impact letermovir Cmin. Additionally, coadministration with cyclosporine injection significantly decreased median letermovir Cmin compared with cyclosporine capsules (2311 vs. 3386 ng/mL). Moreover, with the extension of time post-transplant, trough concentrations of both cyclosporine and letermovir significantly decreased.TDM for letermovir may be beneficial in allo-HSCT recipients considering the variability in letermovir Cmin and its correlation with clinical efficacy. Moreover, drug interactions and the effects of changes in cyclosporine dosage forms or concentrations require careful monitoring for their effect on letermovir Cmin.Conclusion: The role of therapeutic drug monitoring (TDM) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients receiving letermovir has not yet been clarified. This study is to explore letermovir trough concentration (Cmin) correlation with its clinical efficacy and adverse events, and factors affecting its plasma concentrations.A prospective, non-interventional study was performed in allo-HSCT recipients receiving letermovir prophylaxis. Plasma concentrations were determined using high-performance liquid chromatography-tandem mass spectrometry. Data analysis was performed using logistic regression, linear regression, and classification and regression tree (CART) models.701 trough concentrations from 71 recipients were included, uncovering pronounced intra- and inter-individual variability in letermovir Cmin. During 24-week follow-up, CMV infection incidence was 16.4%. A significant correlation was identified between letermovir Cmin and its clinical efficacy, and the CART model showed an increased risk of CMV infection when Cmin ≤ 2731 ng/mL. However, no clear correlation was found between Cmin and adverse events. Gastrointestinal graft-versus-host disease, cyclosporine Cmin, gender, and concomitant medications, including mycophenolate mofetil, ondansetron, caspofungin, and methylprednisolone, may impact letermovir Cmin. Additionally, coadministration with cyclosporine injection significantly decreased median letermovir Cmin compared with cyclosporine capsules (2311 vs. 3386 ng/mL). Moreover, with the extension of time post-transplant, trough concentrations of both cyclosporine and letermovir significantly decreased.TDM for letermovir may be beneficial in allo-HSCT recipients considering the variability in letermovir Cmin and its correlation with clinical efficacy. Moreover, drug interactions and the effects of changes in cyclosporine dosage forms or concentrations require careful monitoring for their effect on letermovir Cmin. [ABSTRACT FROM AUTHOR]