An ERK5-NRF2 Axis Mediates Senescence-Associated Stemness and Atherosclerosis.

BACKGROUND: ERK5 (extracellular signal-regulated kinase 5) is a dual kinase transcription factor containing an N-terminal kinase domain and a C-terminal transcriptional activation domain. Many ERK5 kinase inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions about the role of the catalytic activity of ERK5 in proliferation and inflammation. We aimed to investigate how ERK5 reprograms myeloid cells to the proinflammatory senescent phenotype, subsequently leading to atherosclerosis. METHODS: A ERK5 S496A (dephosphorylation mimic) knock in (KI) mouse model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9), and atherosclerosis was characterized by hypercholesterolemia induction. The plaque phenotyping in homozygous ERK5 S496A KI and wild type (WT) mice was studied using imaging mass cytometry. Bone marrow-derived macrophages were isolated from hypercholesterolemic mice and characterized using RNA sequencing and functional in vitro approaches, including senescence, mitochondria reactive oxygen species, and inflammation assays, as well as by metabolic extracellular flux analysis. RESULTS: We show that atherosclerosis was inhibited in ERK5 S496A KI mice. Furthermore, ERK5 S496 phosphorylation mediates both senescence-associated secretory phenotype and senescence-associated stemness by upregulating AHR (aryl hydrocarbon receptor) in plaque and bone marrow-derived macrophages isolated from hypercholesterolemic mice. We also discovered that ERK5 S496 phosphorylation could induce NRF2 (NFE2-related factor 2) SUMOylation at a novel K518 site to inhibit NRF2 transcriptional activity without altering ERK5 catalytic activity and mediates oxidized LDL (low-density lipoprotein)-induced senescence-associated secretory phenotype. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) also inhibited ERK5 S496 phosphorylation, suggesting the involvement of ERK5 S496 phosphorylation in the anti-inflammatory effects of these ERK5 kinase inhibitors. CONCLUSIONS: We discovered a novel mechanism by which the macrophage ERK5-NRF2 axis develops a unique senescence-associated secretory phenotype/stemness phenotype by upregulating AHR to engender atherogenesis. The finding of senescence-associated stemness phenotype provides a molecular explanation to resolve the paradox of senescence in proliferative plaque by permitting myeloid cells to escape the senescence-induced cell cycle arrest during atherosclerosis formation.

Comparative physiological and transcriptome analysis between potassium-deficiency tolerant and sensitive sweetpotato genotypes in response to potassium-deficiency stress.

BACKGROUND: Sweetpotato is a typical ''potassium (K+) favoring'' food crop, which root differentiation process needs a large supply of potassium fertilizer and determine the final root yield. To further understand the regulatory network of the response to low potassium stress, here we analyze physiological and biochemical characteristics, and investigated root transcriptional changes in two sweetpotato genotypes, namely, - K tolerant "Xu32" and - K susceptible"NZ1". RESULT: We found Xu32 had the higher capability of K+ absorption than NZ1 with better growth performance, higher net photosynthetic rate and higher chlorophyll contents under low potassium stress, and identified 889 differentially expressed genes (DEGs) in Xu32, 634 DEGs in NZ1, 256 common DEGs in both Xu32 and NZ1. The Gene Ontology (GO) term in molecular function enrichment analysis revealed that the DEGs under low K+ stress are predominately involved in catalytic activity, binding, transporter activity and antioxidant activity. Moreover, the more numbers of identified DEGs in Xu32 than that in NZ1 responded to K+-deficiency belong to the process of photosynthesis, carbohydrate metabolism, ion transport, hormone signaling, stress-related and antioxidant system may result in different ability to K+-deficiency tolerance. The unique genes in Xu32 may make a great contribution to enhance low K+ tolerance, and provide useful information for the molecular regulation mechanism of K+-deficiency tolerance in sweetpotato. CONCLUSIONS: The common and distinct expression pattern between the two sweetpotato genotypes illuminate a complex mechanism response to low potassium exist in sweetpotato. The study provides some candidate genes, which can be used in sweetpotato breeding program for improving low potassium stress tolerance.

Efficacy and safety of avatrombopag in Chinese children with persistent and chronic primary immune thrombocytopenia: A multicentre observational retrospective study in China.

Avatrombopag (AVA) is a novel thrombopoietin receptor agonist (TPO-RA) that has been recently approved as a second-line therapy for immune thrombocytopenia (ITP) in adults; however, its safety and efficacy data in children are lacking. Here, we demonstrated the efficacy and safety of AVA as second-line therapy in children with ITP. A multicentre, retrospective, observational study was conducted in children with persistent or chronic ITP who did not respond to or relapsed from previous treatment and were treated with AVA for at least 12 weeks between August 2020 and December 2022. The outcomes were the responses (defined as achieving a platelet count ≥30 × 109/L, twofold increase in platelet count from baseline and absence of bleeding), including rapid response within 4 weeks, sustained response at weeks 12 and 24, bleeding control and adverse events (AEs). Thirty-four (18 males) patients with a mean age of 6.3 (range: 1.9-15.3) years were enrolled. The median number of previous treatment types was four (range: 1-6), and 41.2% patients switched from other TPO-RAs. Within 4 weeks, overall response (OR) was achieved in 79.4% patients and complete response (CR, defined as a platelet count ≥100 × 109/L and the absence of bleeding) in 67.7% patients with a median response time of 7 (range: 1-27) days. At 12 weeks, OR was achieved in 88.2%, CR in 76.5% and sustained response in 44% of patients. At 24 weeks, 22/34 (64.7%) patients who achieved a response and were followed up for 24 weeks were evaluated; 12/22 (54.55%) achieved a sustained response. During AVA therapy, median platelet counts increased by week 1 and were maintained throughout the treatment period. The proportion of patients with grade 1-3 bleeding decreased from 52.95% at baseline to 2.94% at 12 weeks, while concomitant ITP medications decreased from 36.47% at baseline to 8.82% at 12 weeks, with only 9 (26.47%) patients receiving rescue therapy 23 times within 12 weeks. There were 61.8% patients with 59 AEs: 29.8% with Common Terminology Criteria for Adverse Events grade 1 and the rest with grade 2. These findings show that AVA could achieve a rapid and sustained response in children with persistent or chronic ITP as a second-line treatment, with good clinical bleeding control and reduction of concomitant ITP therapy, without significant AEs.

Deleterious variant in FAM71D cause male infertility with asthenoteratospermia.

Asthenoteratospermia is a significant cause of male infertility. FAM71D (Family with sequence similarity 71, member D), as a novel protein exclusively expressed in the testis, has been found to be associated with sperm motility. However, the association of FAM71D mutation with male infertility has yet to be examined. Here, we conducted whole-exome sequencing and identified a homozygous missense mutation c.440G > A (p. Arg147Gln) of FAM71D in an asthenoteratospermia-affected man from a consanguineous family. The FAM71D variant is extremely rare in human population genome databases and predicted to be deleterious by multiple bioinformatics tools. Semen analysis indicated decreased sperm motility and obvious morphological abnormalities in sperm cells from the FAM71D-deficient man. Immunofluorescence assays revealed that the identified FAM71D mutation had an important influence on the assembly of sperm structure-related proteins. Furthermore, intra-cytoplasmic sperm injection (ICSI) treatment performed on the infertile man with FAM71D variant achieved a satisfactory outcome. Overall, our study identified FAM71D as a novel causative gene for male infertility with asthenoteratospermia, for which ICSI treatment may be suggested to acquire good prognosis. All these findings will provide effective guidance for genetic counselling and assisted reproduction treatments of asthenoteratospermia-affected subjects.

The role of age and AMH on cumulative live birth rates over multiple frozen-thawed embryo transfer cycles: a study based on low prognosis patients of POSEIDON 3 and 4 groups.

BACKGROUND: Among the POSEIDON criteria, group 3 and group 4 have an expected low prognosis. For those patients with inadequate ovary reserve, embryo accumulated from consecutive oocyte retrieval cycles for multiple frozen-thawed embryo transfers (FET) has become more common. It is necessary to inform them of the pregnancy outcomes after single or multiple FET cycles before the treatment. However few studies about cumulative live birth rate (CLBR) for those with low prognosis have been reported. METHODS: This retrospective study included 4712 patients undergoing frozen embryo transfer cycles from July 2015 to August 2020. Patients were stratified as POSEIDON group 3, group 4, control 1 group (< 35 years) and control 2 group (≥ 35 years). The primary outcome is CLBRs up to six FET cycles and the secondary outcomes were LBRs per transfer cycle. Optimistic approach was used for the analysis of CLBRs and the depiction of cumulative incidence curves. RESULTS: Under optimistic model analyses, control 1 group exhibited the highest CLBR (93.98%, 95%CI 91.63-95.67%) within 6 FET cycles, followed by the CLBR from women in POSEIDON group 3(92.51%, 95%CI 77.1-97.55)was slightly lower than that in control 1 group. The CLBR of POSEIDON group 4(55% ,95%CI 39.34-70.66%)was the lowest and significantly lower than that of control 2 group(88.7%, 95%CI 80.68-96.72%). Further, patients in POSEIDON group 4 reached a CLBR plateau after 5 FET cycles. CONCLUSIONS: The patients of POSEIDON group 3 may not be considered as traditional "low prognosis" in clinical practice as extending the number of FET cycles up to 6 can archive considerably CLBR as control women. While for the POSEIDON group 4, a simple repeat of the FET cycle is not recommended after four failed FET cycles, some strategies such as PGT-A may be beneficial.

Effects of gene polymorphisms on delayed MTX clearance, toxicity, and metabolomic changes after HD-MTX treatment in children with acute lymphoblastic leukemia.

This study aims to assess the role of methotrexate-related gene polymorphisms in children with acute lymphoblastic leukemia (ALL) during high-dose methotrexate (HD-MTX) therapy and to explore their effects on serum metabolites before and after HD-MTX treatment. The MTHFR 677C>T, MTHFR 1298A>C, ABCB1 3435C>T, and GSTP1 313A>G genotypes of 189 children with ALL who received chemotherapy with the CCCG-ALL-2020 regimen from January 2020 to April 2023 were analyzed, and toxic effects were reported according to the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Fasting peripheral blood serum samples were collected from 27 children before and after HD-MTX treatment, and plasma metabolites were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS). The results of univariate and multivariate analyses showed that MTHFR 677C>T and ABCB1 3435 C>T gene polymorphisms were associated with the delayed MTX clearance (P < 0.05) and lower platelet count after treatment in children with MTHFR 677 mutation compared with wild-type ones (P < 0.05), and pure mutations in ABCB1 3435 were associated with higher serum creatinine levels (P < 0.05). No significant association was identified between MTHFR 677C>T, MTHFR 1298A>C, ABCB1 3435 C>T, and GSTP1 313A>G genes and hepatotoxicity or nephrotoxicity (P > 0.05). However, the serum metabolomic analysis indicated that the presence of the MTHFR 677C > T gene polymorphism could potentially contribute to delayed MTX clearance by influencing L-phenylalanine metabolism, leading to the occurrence of related toxic side effects. CONCLUSION: MTHFR 677C>T and ABCB1 3435 C>T predicted the risk of delayed MTX clearance during HD-MTX treatment in children with ALL. Serum L-phenylalanine levels were significantly elevated after HD-MTX treatment in children with the MTHFR 677C>T mutation gene. TRIAL REGISTRATION: This study was registered at the Chinese Clinical Trial Registry (registration number: ChiCTR2000035264; registration: 2020/08/05; https://www.chictr.org.cn/ ). WHAT IS KNOWN: • MTX-related genes play an important role in MTX pharmacokinetics and toxicity, but results from different studies are inconsistent and the mechanisms involved are not clear. WHAT IS NEW: • Characteristics, prognosis, polymorphisms of MTX-related genes, and metabolite changes were comprehensively evaluated in children treated with HD-MTX chemotherapy. • Analysis revealed that both heterozygous and pure mutations in MTHFR 677C>T resulted in a significantly increased risk of delayed MTX clearance, and that L-phenylalanine has the potential to serve as a predictive marker for the metabolic effects of the MTHFR 677C>T polymorphism.

Road-MobileSeg: Lightweight and Accurate Road Extraction Model from Remote Sensing Images for Mobile Devices.

Current road extraction models from remote sensing images based on deep learning are computationally demanding and memory-intensive because of their high model complexity, making them impractical for mobile devices. This study aimed to develop a lightweight and accurate road extraction model, called Road-MobileSeg, to address the problem of automatically extracting roads from remote sensing images on mobile devices. The Road-MobileFormer was designed as the backbone structure of Road-MobileSeg. In the Road-MobileFormer, the Coordinate Attention Module was incorporated to encode both channel relationships and long-range dependencies with precise position information for the purpose of enhancing the accuracy of road extraction. Additionally, the Micro Token Pyramid Module was introduced to decrease the number of parameters and computations required by the model, rendering it more lightweight. Moreover, three model structures, namely Road-MobileSeg-Tiny, Road-MobileSeg-Small, and Road-MobileSeg-Base, which share a common foundational structure but differ in the quantity of parameters and computations, were developed. These models varied in complexity and were available for use on mobile devices with different memory capacities and computing power. The experimental results demonstrate that the proposed models outperform the compared typical models in terms of accuracy, lightweight structure, and latency and achieve high accuracy and low latency on mobile devices. This indicates that the models that integrate with the Coordinate Attention Module and the Micro Token Pyramid Module surpass the limitations of current research and are suitable for road extraction from remote sensing images on mobile devices.

Exploring Preclinical Experiments with Different Fat Types for Autologous Fat Grafting.

BACKGROUND: Autologous fat transplantation has been a cornerstone of tissue regeneration for decades. However, there is no standardized selection system or criteria for fat graft selection, often relying heavily on the surgeon's experience. OBJECTIVES: This study aimed to investigate various types of fat derivatives, both in vitro and in vivo at the same condition. METHODS: We collected traditional fat granules of different sizes and SVF-gel, evaluating the viability of ADSCs isolated from them and their performance after grafting into mice. RESULTS: Large fat granules exhibited more complete adipocyte structures, and the isolated ADSCs demonstrated superior differentiation, proliferation, and secretion capacities. They also showed excellent volume retention after 12 weeks. In contrast, ADSCs isolated from SVF-gel displayed lower vitality. However, grafts from SVF-gel exhibited the highest volume maintenance rate among the four groups after 12 weeks, closely resembling normal adipose tissue and displaying significant vascularization. Compared to large fat granule and SVF-gel group, medium and small fat granule grafts exhibited lower volume retention and less angiogenesis. CONCLUSIONS: Through preclinical studies, the flexible clinical use of different fat grafts can be tailored to their unique characteristics. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Treatment of Chin Retrusion With Botulinum Toxin Plus Hyaluronic Acid Filler in Comparison With Hyaluronic Acid Filler Alone: A Randomized, Evaluator-Blinded, Controlled Study.

BACKGROUND: Hyaluronic acid (HA) has already been widely administered for chin augmentation. Patients with chin retrusion frequently present with increased chin hypertonia. Monotherapy with HA falls short in addressing the multifaceted cosmetic concerns associated with chin retrusion. OBJECTIVES: This study aimed to investigate the clinical efficacy and safety of the combination therapy involving botulinum toxin (BTX) and HA in the treatment of chin retrusion. METHODS: We enrolled patients with moderate to severe chin retrusion for 9 months of follow-up after they received either combined treatment with BTX plus HA or monotreatment with HA. We also calculated the surface-volume coefficient with 3-dimensional digital scanning technique, and evaluated outcomes based on the Allergan Chin Retrusion Scale (ACRS), the Global Aesthetic Improvement Scale (GAIS), and treatment-related adverse events (TRAEs). RESULTS: A total of 50 patients were recruited and randomized to the treatment group (BTX plus HA) or control group (HA alone) in a 1:1 ratio. Patients in the treatment group exhibited significantly higher surface-volume coefficients during the first 6 months (P < .05). ACRS scores and responder rates in the 2 groups remained similar throughout the follow-up (P > .05). Within the initial 3 months, the GAIS responder rate in the treatment group was significantly higher than that in the control group (P < .05). Mild TRAEs were observed in both groups, and subsided within 7 days. There was no increase in adverse effects with the combined treatment. CONCLUSIONS: In comparison to monotherapy, the combined treatment not only improved the surface-volume coefficient of hyaluronic acid but also achieved similar ACRS scores with less HA volume. Furthermore, the combination treatment yielded superior treatment outcomes for individuals with chin retrusion.

Dissecting the PRSS37 interactome and potential mechanisms leading to ADAM3 loss in PRSS37-null sperm.

A disintegrin and metalloproteinase 3 (ADAM3) is a sperm membrane protein critical for sperm migration from the uterus into the oviduct and sperm-egg binding in mice. Disruption of PRSS37 results in male infertility concurrent with the absence of mature ADAM3 from cauda epididymal sperm. However, how PRSS37 modulates ADAM3 maturation remains largely unclear. Here, we determine the PRSS37 interactome by GFP immunoprecipitation coupled with mass spectrometry in PRSS37-EGFP knock-in mice. Three molecular chaperones (CLGN, CALR3 and PDILT) and three ADAM proteins (ADAM2, ADAM6B and ADAM4) were identified to be interacting with PRSS37. Coincidently, five of them (except ADAM4) have been reported to interact with ADAM3 precursor and regulate its maturation. We further demonstrated that PRSS37 also interacts directly with ADAM3 precursor and its deficiency impedes the association between PDILT and ADAM3. This could contribute to improper translocation of ADAM3 to the germ cell surface, leading to ADAM3 loss in PRSS37-null mature sperm. The understanding of the maturation mechanisms of pivotal sperm plasma membrane proteins will pave the way toward novel strategies for contraception and the treatment of unexplained male infertility.

Bioactive Injectable and Self-Healing Hydrogel Via Cell-Free Fat Extract for Endometrial Regeneration.

The damaged endometrium and the formation of fibrosis are key barriers to pregnancy and further lead to infertility. However, how to promote endometrium repair is always a challenge. Here, a bioactive injectable and self-healing hydrogel is developed by physically combination of thiolated polyethylene (PEG), Cu2+ and cell-free fat extract (CEFFE, CF) for endometrial regeneration and fertility. By inheriting the advantages of various active proteins contained in CEFFE, it could induce the overall repair of endometrial microenvironment for intrauterine adhesion (IUA). In vitro, CF@Cu-PEG reduces endometrial cell apoptosis by more than 50%, and increases angiogenesis by 92.8%. In the IUA mouse, injection of CF@Cu-PEG significantly reduces the rate of uterine hydrometra and prevents the formation of endometrial fibrosis. Remarkably, CF@Cu-PEG contributes to the repair of endometrial microstructure, especially increases the number of endometrial pinopodes, significantly improves endometrial receptivity, and increases the pregnancy rate of IUA mice from 7.14% to 66.67%. In summary, through the physically combination of CEFFE and Cu-PEG, the construction of loaded bioactive injectable hydrogel not only inhibits the IUA, but also induces the self-repair of endometrial cells in situ and improves fertility, providing a new strategy for IUA repair in clinical application.

MYB6/bHLH13-AbSUS2 involved in sugar metabolism regulates root hair initiation of Abies beshanzuensis.

Root hair is regarded as a pivotal complementary survival tactic for mycorrhizal plant like Abies beshanzuensis when symbiosis is disrupted. Relatively little is known about the mechanism underlying root hair morphogenesis in plant species that are strongly dependent on mycorrhizal symbiosis. Many of these species are endangered, and this knowledge is critical for ensuring their survival. Here, a MYB6/bHLH13-sucrose synthase 2 (AbSUS2) module was newly identified and characterized in A. beshanzuensis using bioinformatics, histochemistry, molecular biology, and transgenesis. Functional, expression pattern, and localization analysis showed that AbSUS2 participated in sucrose synthesis and was involved in root hair initiation in A. beshanzuensis. Additionally, the major enzymatic product of AbSUS2 was found to suppress root hair initiation in vitro. Our data further showed that a complex involving the transcription factors AbMYB6 and AbbHLH13 directly interacted with the promoter of AbSUS2 and strengthened its expression, thereby inhibiting root hair initiation in response to exogenous sucrose. Our findings offer novel insights into how root hair morphogenesis is regulated in mycorrhizal plants and also provide a new strategy for the preservation of endangered mycorrhizal plant species.

Development of a two-beveled-fiber polarized fiber-optic Raman probe coupled with a ball lens for in vivo superficial epithelial Raman measurements in endoscopy.

We report on the development of a two-beveled-fiber polarized (TBFP) fiber-optic Raman probe coupled with a ball lens for in vivo superficial epithelial Raman measurements in endoscopy. The two-beveled fibers positioned symmetrically along a ball lens, in synergy with paired parallel-polarized polarizers integrated between the fibers and the ball lens, maximize the Raman signal excitation and collection from the superficial epithelium where gastrointestinal (GI) precancer arises. Monte Carlo (MC) simulations and two-layer tissue phantom experiments show that the probe developed detects ∼90% of the Raman signal from the superficial epithelium. The suitability of the probe developed for rapid (<3 s) superficial epithelial Raman measurements is demonstrated on fresh swine esophagus, stomach, and colon tissues, followed by their differentiation with high accuracies (92.1% for esophagus [sensitivity: 89.3%, specificity: 93.2%], 94.1% for stomach [sensitivity: 86.2%, specificity: 97.2%], and 94.1% for colon [sensitivity: 93.2%, specificity: 94.7%]). The presented results suggest the great potential of the developed probe for enhancing in vivo superficial epithelial Raman measurements in endoscopy.

PELI2 regulates early B-cell progenitor differentiation and related leukemia via the IL-7R expression.

Little is known about the transition mechanisms that govern early lymphoid lineage progenitors from common lymphoid progenitors (CLPs). Pellino2 (PELI2) is a newly discovered E3 ubiquitin ligase, which plays important roles in inflammation and immune system. However, the physiological and molecular roles of PELI2 in the differentiation of immune cells are largely unknown. Here, by using a conditional knockout mouse model, we demonstrated that PELI2 is required for the early B-cell development and stressed hematopoiesis. PELI2 interacted with and stabilized PU.1 via K63- polyubiquitination to regulate IL-7R expression. The defects of B cell development induced by PELI2 deletion were restored by overexpression of PU.1. Similarly, PELI2 promoted TCF3 protein stability via K63- polyubiquitination to regulate IL-7R expression, which is required for the proliferation of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells. These results underscore the significance of PELI2 in both normal B lymphopoiesis and malignant B-cell acute lymphoblastic leukemia via the regulation of IL-7R expression, providing a potential therapeutic approach for BCP-ALL.

Causes of death and treatment-related mortality in newly diagnosed childhood acute lymphoblastic leukemia treatment with Chinese Children's Cancer Group study ALL-2015.

To investigate the possible risk factors for death at post-treatment in children with acute lymphoblastic leukemia (ALL). A multivariate competing risk analysis was performed to retrospectively analyze the data of children with ALL who died after treatment with CCCG-ALL-2015 in China and to determine the possible risk factors for death at post-treatment in children with ALL. Age at the first diagnosis of ≥10 years; final risk level of high-risk; D19 minimal residual disease (MRD) (≥0.01%) and D46 MRD (≥0.01%); genetic abnormalities, such as KMT2A-rearrangement, c-Myc rearrangement, and PDGFRB rearrangement; and the presence of CNS3 (all P values, <0.05) were identified as independent risk factors, whereas the risk level at the first diagnosis of low-risk (LR) and ETV6::RUNX1 positivity was considered as independent protective factors of death in children with ALL. Among the 471 cases of death, 45 cases were treated with CCCG-ALL-2015 only, and 163 (34.61%) were treatment-related, with 62.42% due to severe infections. 55.83% of treatment-related mortality (TRM) occurred in the early phase of treatment (induction phase). TRM has a significant impact on the overall survival of pediatric patients with ALL. Moreover, the CCCG-ALL-2015 regimen has a better safety profile for treating children with ALL, with rates close to those in developed countries (registration number: ChiCTR-IPR-14005706; date of registration: June 4, 2014).

Downregulation of SEPTIN11 inhibits endometrial epithelial cell adhesive function in patients with elevated peripheral blood natural killer cell counts.

RESEARCH QUESTION: What is the underlying mechanism of IVF and embryo transfer (IVF-ET) failure in patients with elevated peripheral blood natural killer cell (pNK) counts? DESIGN: Patients undergoing IVF-ET cycles for tubal obstruction or pelvic adhesion (n = 486) were assigned to three groups: high (CD56+CD16+pNK >30% [n = 49]); medium (15< CD56+CD16+pNK ≤30% [n = 211]); and normal pNK groups (5≤ CD56+CD16+pNK ≤15% [n = 226]). Their general condition, previous pregnancy history and IVF outcomes were compared. Uterine fluid and endometrial tissue from patients in the high and normal pNK groups were collected during the mid-secretory phase and studied to elucidate the molecular mechanism underlying impaired endometrial receptivity. RESULTS: The highest incidence of IVF-ET cycles (P < 0.0001) and biochemical pregnancy losses (P < 0.0001), and lowest implantation and clinical pregnancy rates (both P < 0.0001), were observed in patients with pNK over 30%. No significant difference was found in the number of previous miscarriages and rate of spontaneous miscarriage in IVF outcomes. Lower Septin11 (SEPT11) expression in the uterine fluid and endometrial epithelial cells (EEC), and higher endometrial IFN-γ, was observed in patients with high pNK. Ishikawa cell and human endometrial epithelial cell (HEEC) adhesion was inhibited after SEPT11 knock-down. Elevated IFN-γ decreased the SEPT11 protein levels in Ishikawa cells and HEECs. CONCLUSIONS: CD56+CD16+pNK above 30% may be a threshold for adverse IVF-ET outcomes. Low SEPT11 expression in EEC inhibits cell adhesion, which may cause impaired endometrial receptivity in patients with elevated pNK. The level of SEPT11 in mid-secretory uterine fluid could serve as a non-invasive marker to assess endometrial receptivity in these patients.

IgD/FcδR is involved in T-cell acute lymphoblastic leukemia and regulated by IgD-Fc-Ig fusion protein.

T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis as a result of severe immunosuppression and rapid tumor progression with resistance to conventional chemotherapy. Excessive IgD may play a role in T cell activation via IgD Fc receptor (FcδR). Here we aimed to investigate the effects of IgD in T-ALL and demonstrated the potential benefit by targeting IgD/FcδR in T-ALL patients with IgD-Fc-Ig fusion protein. In T-ALL patients' blood samples and cell lines, the level of IgD, the percentage of FcδR expressing cells and the binding affinity were determined by flow cytometry. T cell viability, proliferation and apoptosis were analyzed. A mouse xenograft model was used to evaluate the in vivo effect of IgD-Fc-Ig, an IgD-FcδR blocker. The levels of serum IgD and FcδR were abnormally increased in part of T-ALL patients and IgD could induce over-proliferation and inhibit apoptosis of T-ALL cells in vitro. FcδR was constitutively expressed on T-ALL cells. IgD-Fc-Ig showed similar binding affinity to FcδR and selectively blocked the stimulation effect of IgD on T-ALL cells in vitro. In vivo study exhibited that IgD-Fc-Ig may also have therapeutic benefit. IgD-Fc-Ig administration inhibited human T-ALL growth and extended survival in xenograft T-ALL mice. In conclusion, this work supports the idea of targeting IgD/FcδR in T-ALL patients with excessive IgD. IgD-Fc-Ig fusion protein might be a potential biological drug with high selectivity for T-ALL treatment.

A clinical phase I dose-finding design with adaptive shrinking boundaries for drug combination trials.

BACKGROUND: Combinations of drugs are becoming increasingly common in oncology treatment. In some cases, patients can benefit from the interaction between two drugs, although there is usually a higher risk of developing toxicity. Due to drug-drug interactions, multidrug combinations often exhibit different toxicity profiles than those of single drugs, leading to a complex trial scenario. Numerous methods have been proposed for the design of phase I drug combination trials. For example, the two-dimensional Bayesian optimal interval design for combination drug (BOINcomb) is simple to implement and has desirable performance. However, in scenarios where the lowest and starting dose is close to being toxic, the BOINcomb design may tend to allocate more patients to overly toxic doses, and select an overly toxic dose combination as the maximum tolerated dose combination. METHOD: To improve the performance of BOINcomb in the above extreme scenarios, we widen the range of variation of the boundaries by setting the self-shrinking dose escalation and de-escalation boundaries. We refer to the new design as adaptive shrinking Bayesian optimal interval design for combination drug (asBOINcomb). We conduct a simulation study to evaluate the performance of the proposed design using a real clinical trial example. RESULTS: Our simulation results show that asBOINcomb is more accurate and stable than BOINcomb, especially in some extreme scenarios. Specifically, in all ten scenarios, the percentage of correct selection is higher than the BOINcomb design within 30 to 60 patients. CONCLUSION: The proposed asBOINcomb design is transparent and simple to implement and can reduce the trial sample size while maintaining accuracy compared with the BOINcomb design.

Hepatobiliary calculi associated with ceftriaxone treatment: An analysis of FAERS data from 2004 to 2021.

INTRODUCTION: The role of gender, age, dose and other factors in the adverse reaction process of pseudocholelithiasis caused by ceftriaxone is controversial. In this study, we further explored potential risk factors using the FAERS database. METHODS: The reported odds ratio (ROR) and the information component (IC) of specific candidate factors were calculated by using the ROR method and the Bayesian confidence promotion neural network (BCPNN) method respectively to detect potential risk factors in adverse events(AEs) of ceftriaxone and hepatobiliary calculi(HBC). One candidate factor will be considered as a suspicious signal, or potential risk factors if its lower limit of 95% confidence interval of ROR (ROR025) is greater than 1 and its lower limit of 95% confidence interval of IC (IC025) is greater than 0. RESULTS: A total of 764 AEs of HBC were used to this analysis to evaluate candidate risk factors: Age group, Gender, Dose. Child (1-12 years): male ROR025 = 6.64, IC025 = 2.42, female ROR025 = 6.66, IC025 = 2.40. Adolescent group (12-18 years): male ROR025 = 5.47, IC025 = 2.08; elderly (≥65 years): female ROR025 = 1.25, IC025 = 0.22. CONCLUSIONS: Gender was not detected as a risk factor for HBC caused by ceftriaxone. However, Male infants, male children, female children, adolescent male, and elderly female were potential risk factors for HBC caused by ceftriaxone based on criteria ROR025 > 1 and IC025 > 0.

Enhancement of soil high-molecular-weight polycyclic aromatic hydrocarbon degradation by Fusarium sp. ZH-H2 using different carbon sources.

High-molecular-weight PAHs (HMW-PAHs) in soil cannot be easily degraded. However, nutrient supplementation could stimulate the growth of exogenously added strains to enhance the degradation of HMW-PAHs in polluted soil. This study evaluated the applicability of Fusarium sp. ZH-H2, a polycyclic aromatic hydrocarbon (PAH)-degrading strain isolated by our research group, for the bioremediation of contaminated soil from the Hebei coal mining area in China. A soil incubation experiment was conducted to investigate the effect of two carbon sources and different carbon, nitrogen, and phosphorus (C:N:P) ratios on the remediation of high-molecular-weight PAHs (HMW-PAHs) in soil by Fusarium sp. ZH-H2, as well as the induction of lignin peroxidase activity. Our findings indicated that the HDF2 treatment (equal parts of humic acid and starch as carbon sources at a 50:1:0.5 C:N:P ratio) enhanced the removal rate of total HMW-PAHs from soil, reaching a maximum removal rate of 37.15 %. The removal rates of Pyr (a 4-ring PAH), BaP (a 5-ring PAH), and BghiP (a 6-ring PAH) were the highest in HDF2 treatment, and the removal rates were 39.51 %, 54.63 %, and 38.60 %, respectively. Compared with the ZH-H2 treatment, different carbon sources and C:N:P ratios significantly induced soil lignin peroxidase activity and the HDF2 treatment also resulted in the highest enzyme activity (up to 34.68 U/L). Furthermore, there was a significant or highly significant linear positive correlation between the removal rate of HMW-PAHs and enzyme activity in all cases. Our findings suggest that the optimal HMW-PAH degradation performance and enhancement of lignin peroxidase activity by ZH-H2 were achieved when both starch and humic acid were used as carbon sources at a C:N:P ratio of 50:1:0.5.