Ribosomal translation of fluorinated non-canonical amino acids for de novo biologically active fluorinated macrocyclic peptides.

Fluorination has emerged as a promising strategy in medicinal chemistry to improve the pharmacological profiles of drug candidates. Similarly, incorporating fluorinated non-canonical amino acids into macrocyclic peptides expands chemical diversity and enhances their pharmacological properties, from improved metabolic stability to enhanced cell permeability and target interactions. However, only a limited number of fluorinated non-canonical amino acids, which are canonical amino acid analogs, have been incorporated into macrocyclic peptides by ribosomes for de novo construction and target-based screening of fluorinated macrocyclic peptides. In this study, we report the ribosomal translation of a series of distinct fluorinated non-canonical amino acids, including mono-to tri-fluorinated variants, as well as fluorinated l-amino acids, d-amino acids, ß-amino acids, etc. This enabled the de novo discovery of fluorinated macrocyclic peptides with high affinity for EphA2, and particularly the identification of those exhibiting broad-spectrum activity against Gram-negative bacteria by targeting the BAM complex. This study not only expands the scope of ribosomally translatable fluorinated amino acids but also underscores the versatility of fluorinated macrocyclic peptides as potent therapeutic agents.

EGFR kinase domain duplication in lung adenocarcinoma with systemic and intracranial response to a double-dose of furmonertinib: a case report and literature review.

Background: EGFR kinase domain duplication (EGFR-KDD) is an infrequent oncogenic driver mutation in lung adenocarcinoma. It may be a potential target benefit from EGFR-tyrosine kinase inhibitors (TKIs) treatment. Case presentation: A 66-year-old Chinese male was diagnosed with lung adenocarcinoma in stage IVb with brain metastases. Next-generation sequencing revealed EGFR-KDD mutation. The patient received furmonertinib 160mg daily for anti-cancer treatment and obtained therapeutic efficacy with partial response (PR). Progression-free survival (PFS) duration from monotherapy was 16 months. With slow progressions, combined radiotherapy and anti-vascular targeted therapy also brought a continuous decrease in the tumors. The patient has an overall survival (OS) duration of more than 22 months and still benefits from double-dose furmonertinib. Conclusions: This report provided direct evidence for the treatment of EGFR-KDD to use furmonertinib. A Large-scale study is needed to confirm this preliminary finding.

Clinical efficacy of CO2 fractional laser combined with compound betamethasone in treating vitiligo and its impact on inflammatory factors.

Objective: To analyze the clinical efficacy of CO2 fractional laser combined with compound betamethasone in treating vitiligo and its impact on inflammatory factors. Methods: The clinical treatment effects, levels of inflammatory factors [interleukin-17 (IL-17), interferon-gamma (IFN-γ), interleukin-10 (IL-10)], prognosis regarding repigmentation and relapse, psychological health (satisfaction). Results: ① Clinical treatment effects: the total effective rate in Group A was 92.73%, Group B was 74.55%, and Group C was 67.27%, with Group A showing significantly higher effectiveness than Groups B and C (p < 0.05). ② Inflammatory factors: prior to treatment, there was no significant difference in IL-17, IFN-γ, and IL-10 levels among the three groups (p > 0.05); after 3 and 6 months of treatment, the levels of IL-17 and IFN-γ decreased significantly while IL-10 levels increased significantly across all three groups, with Group A showing a more pronounced change compared to Groups B and C (p < 0.05). ③ Prognosis regarding repigmentation and relapse: after 3 and 6 months of treatment, Group A exhibited significantly higher repigmentation rates compared to Groups B and C (p < 0.05); in terms of relapse, Group A had a relapse rate of 5.45%, Group B had 21.82%, and Group C had 23.64%, with Group A showing significantly lower relapse rates compared to Groups B and C (p < 0.05). ④ Quality of life and psychological health: at the end of the 6 month follow-up, the quality of life and psychological health of patients in Group A were significantly higher than those in Groups B and C (p < 0.05). ⑤ Occurrence of adverse reactions: the incidence of adverse reactions was 12.73% in Group A, 10.91% in Group B, and 9.09% in Group C, with no significant difference observed among the three groups (p > 0.05). Conclusion: The application of CO2 fractional laser combined with compound betamethasone in vitiligo patients demonstrates significant efficacy. Compared to sole treatment with CO2 fractional laser or compound betamethasone injections, this combined approach further improves the levels of inflammatory factors in vitiligo patients, reduces the risk of relapse, enhances skin repigmentation, improves quality of life, psychological well-being, without increasing the risk of related adverse reactions. This combined approach merits clinical promotion and application.

Circulating tumor DNA assisting lymphoma genetic feature profiling and identification.

INTRODUCTION: Lymphoma tissue biopsies cannot fully capture genetic features due to accessibility and heterogeneity. We aimed to assess the applicability of circulating tumor DNA (ctDNA) for genomic profiling and disease surveillance in classic Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), and diffuse large B-cell lymphoma (DLBCL). METHODS: Tumor tissue and/or liquid biopsies of 49 cHLs, 32 PMBCLs, and 74 DLBCLs were subject to next-generation sequencing targeting 475 genes. The concordance of genetic aberrations in ctDNA and paired tissues was investigated, followed by elevating ctDNA-based mutational landscapes and the correlation between ctDNA dynamics and radiological response/progression. RESULTS: ctDNA exhibited high concordance with tissue samples in cHL (78%), PMBCL (84%), and DLBCL (78%). In cHL, more unique mutations were detected in ctDNA than in tissue biopsies (P < 0.01), with higher variant allele frequencies (P < 0.01). Distinct genomic features in cHL, PMBCL, and DLBCL, including STAT6, SOCS1, BTG2, and PIM1 alterations, could be captured by ctDNA alone. Prevalent PD-L1/PD-L2 amplifications were associated with more concomitant alterations in PMBCL (P < 0.01). Moreover, ctDNA fluctuation could reflect treatment responses and indicate relapse before imaging diagnosis. CONCLUSIONS: Lymphoma genomic profiling by ctDNA was concordant with that by tumor tissues. ctDNA might also be applied in lymphoma surveillance.

Evaluation of comprehensive early warning for higher education institutions' cloud model of simulated enterprise management cockpit.

The cross-disciplinary virtually simulated platform for enterprise management in universities' new business courses is an initiative practical framework based on scenario-driven tasks. However, there is a prominent conflict between the rapid operating cycle of simulation enterprises plus their fierce competitions and the strategic demand for real-time analysis for operational data. Based on such demand, this study takes the development method of the simulated enterprise management cockpit from Guangzhou Huashang College as an example. It adopts the combined weighting method based on cloud models to determine indicator weights, then qualitative and quantitative data analyses are conducted from five aspects: "business, finance and operation", "customer management and marketing", "internal operational objectives", "product development strategy", along with "team building and management". This approach achieves a comprehensive evaluation and early warning of the enterprise management process. Specifically, the subjective weights are determined by the Analytic Hierarchy Process, while the objective weights by the entropy weight method, finally verified by cloud model evaluation of its overall indicator performance. The design can evaluate the comprehensive performance of enterprise management indicators and students' activity participation through the cloud-based application and the digital cockpit, so as to fully presents the enterprise's overall management level, along with judgement of whether it is reasonable through pointers in different colors. In addition, apparent indicator-related characteristics are also utilized to assess future decision-making directions. Finally, this comprehensive approach can timely optimize operation strategies and facilitate budget allocation for future development.

Investigation on activation characterization, secondary electron yield, and surface resistance of novel quinary alloy Ti-Zr-V-Hf-Cu non-evaporable getters.

The performance of next-generation particle accelerators has been adversely affected by the occurrence of electron multipacting and vacuum instabilities. Particularly, minimization of secondary electron emission (SEE) and reduction of surface resistance are two critical issues to prevent some of the phenomena such as beam instability, reduction of beam lifetime, and residual gas ionization, all of which occur as a result of these adverse effects in next-generation particle accelerators. For the first time, novel quinary alloy Ti-Zr-V-Hf-Cu non-evaporable getter (NEG) films were prepared on stainless steel substrates by using the direct current magnetron sputtering technique to reduce surface resistance and SEE yield with an efficient pumping performance. Based on the experimental findings, the surface resistance of the quinary Ti-Zr-V-Hf-Cu NEG films was established to be 6.6 × 10-7 Ω m for sample no. 1, 6.4 × 10-7 Ω m for sample no. 2, and 6.2 × 10-7 Ω m for sample no. 3. The δmax measurements recorded for Ti-Zr-V-Hf-Cu NEG films are 1.33 for sample no. 1, 1.34 for sample no. 2, and 1.35 for sample no. 3. Upon heating the Ti-Zr-V-Hf-Cu NEG film to 150 °C, the XPS spectra results indicated that there are significant changes in the chemical states of its constituent metals, Ti, Zr, V, Hf, and Cu, and these chemical state changes continued with heating at 180 °C. This implies that upon heating at 150 °C, the Ti-Zr-V-Hf-Cu NEG film becomes activated, showing that novel quinary NEG films can be effectively employed as getter pumps for generating ultra-high vacuum conditions.

Evaluation of post-activation mandibular remodelling in children with craniofacial microsomia treated with distraction osteogenesis.

OBJECTIVE: Patients with type IIA craniofacial microsomia (CFM) may benefit from mandibular distraction osteogenesis (MDO) treatment during childhood; however, remodelling of the mandible during the consolidation phase, which may affect the short-term outcomes of MDO, has not yet been quantitatively analysed using computed tomography. Therefore, we aimed to investigate bone remodelling of the mandible in children with type IIA CFM treated with MDO before distractor removal and the factors that influence ramus vertical elongation efficiency. MATERIALS AND METHODS: Twenty-three children with unilateral CFM were studied between 2020 and 2024. Longitudinal computed tomography data (preoperative, end of active phase and at pre-distractor removal) were analysed. Condyle positions and the mandibular cant were analysed using a paired-sample t test. The relapse rates of vertical lengthening and mandibular cant were calculated. The correlation between distraction efficiency and preoperative craniofacial morphology was analysed. RESULTS: The condyle on the affected side moved upwards and backwards by 28.84 ± 4.08 and 2.85 ± 4.33 mm, respectively during the active phase but lost 7.66 ± 2.64 mm of vertical extension during the consolidation phase. The relapse rates for vertical extension of the condyle and occlusal plane were 27% and 35%, respectively. The ratio of mandibular ramus height was positively related to EV. CONCLUSIONS: In children with CFM, attention should be paid to vertical elongation instability and relapse of mandibular inclination during consolidation. Severe mandibular ramus hypoplasia is a preoperative risk factor for vertical skeletal relapse during consolidation. Further efforts are required to reduce the stress that leads to relapse.

Ribosomal Incorporation of Lithocholic Acid into Peptides for the De Novo Discovery Of Peptide-Lithocholic Acid Hybrid Macrocyclic Peptides.

Peptide-bile acid hybrids offer promising drug candidates due to enhanced pharmacological properties, such as improved protease resistance and oral bioavailability. However, it remains unknown whether bile acids can be incorporated into peptide chains by the ribosome to produce a peptide-bile acid hybrid macrocyclic peptide library for target-based de novo screening. In this study, we achieved the ribosomal incorporation of lithocholic acid (LCA)-d-tyrosine into peptide chains. This led to the construction of a peptide-LCA hybrid macrocyclic peptide library, which enabled the identification of peptides TP-2C-4L3 (targeting Trop2) and EP-2C-4L5 (targeting EphA2) with strong binding affinities. Notably, LCA was found to directly participate in binding to EphA2 and confer on the peptides improved stability and resistance to proteases. Cell staining experiments confirmed the high specificity of the peptides for targeting Trop2 and EphA2. This study highlights the benefits of LCA in peptides and paves the way for de novo discovery of stable peptide-LCA hybrid drugs.

Prevalence and risk factors of postoperative delirium in tumor patients after free flap reconstruction: A systematic review and meta-analysis of case-control studies.

BACKGROUND: Postoperative delirium is a severe complication of flap transplantation surgery, adversely affecting surgical prognoses. The intricate pathophysiology of postoperative delirium renders the elucidation of its risk factors challenging. This research aims to delineate the prevalence and the specific risk factors of postoperative delirium in patients with cancer undergoing free flap reconstruction through a systematic review and meta-analysis to enlighten proactive prevention measures. METHODS: The researchers systematically queried both the international and Chinese databases. Searches were performed for publications from inception until September 14, 2023, using the terms "free tissue flaps," "delirium," "neoplasms," and "risk factors." Data synthesis and statistical analysis were conducted using Stata SE (version 15.0) to calculate the combined effect size for identified risk factors. Reported outcomes included weighted mean differences or odds ratios with their respective 95% confidence intervals. RESULTS: Twelve case-control studies were included (ntotal = 3,256). Among them, 515 patients developed postoperative delirium after free flap surgery, compared with 2,741 patients who did not. The outcomes suggest that the risk factors include but are not limited to age, male, late neoplasm staging, use of hypnotic or antipsychotic, history of background diseases, psychiatric review, tracheotomy, and impaired wound healing. In contrast, early neoplasm staging and others are the protective factors with statistical significance. Multivariate analysis further identified significant correlations between preoperative albumin, perioperative blood transfusion, sleep disturbance, postoperative visual analog scale, postoperative albumin, smoking, and the appearance of postoperative delirium. CONCLUSION: The determined risk factors were grouped into preoperative, intraoperative, and postoperative categories substantiated by current data to present instructions for postoperative delirium prevention.

Epidemic patterns of the different influenza virus types and subtypes/lineages for 10 years in Chongqing, China, 2010-2019.

To optimize seasonal influenza control and prevention programs in regions with potentially complicated seasonal patterns. Descriptive epidemiology was used to analyze the etiology of influenza, and chi-square tests were used to compare the epidemic patterns among different influenza virus types and subtypes/lineages. From January 2010 to December 2019, a total of 63,626 ILI cases were reported in Chongqing and 14,136 (22.22%) were laboratory-confirmed influenza cases. The proportions of specimens positive for influenza A and influenza B were 13.32% (8,478/63,626) and 8.86% (5,639/63,626), respectively. The proportion of positive specimens for influenza A reached the highest in winter (23.33%), while the proportion of positive specimens for influenza B reached the highest in spring (11.88%). Children aged 5-14 years old had the highest proportion of positive specimens for influenza. The influenza virus types/subtypes positive was significantly different by seasons and age groups (P<.001), but not by gender (p = .436). The vaccine strains were matched to the circulating influenza virus strains in all other years except for 2018 (vaccine strain was B/Colorado/06/2017; circulating strain was B/Yamagata). The study showed significant variations in epidemic patterns, including seasonal epidemic period and age distributions, among different influenza types, subtypes/lineages in Chongqing. Influenza vaccines matched to the circulating influenza virus strain in nine of the ten years. To prevent and mitigate the influenza outbreaks in this area, high risk population, especially children aged 5-14 years, are encouraged to get vaccinated against influenza before the epidemic seasons.

[The Effecacy and Safety of Daratumumab Based Regimens in Relapsed/Refractory Multiple Myeloma: A Single-Center Real-World Data Analysis].

OBJECTIVE: To investigate the efficacy and safety of daratumumab based regimens in relapse and/or refractory multiple myeloma (RRMM) in the real world, as well as the impact of daratumumab on stem cell collection and engraftment. METHODS: The clinical data of patients with RRMM who received daratumumab in hematology department of the First Affiliated Hospital of Xiamen University from February 2019 to March 2023 and had evaluable efficacy were retrospective analysis. RESULTS: All 43 RRMM patients were treated with daratumumab-based combination regimens, including Dd, DVd, DRd, Dkd, DId, and Dara-DECP. With median follow-up time 10.1 (2.1-36.6) months, the best overall response rate (ORR) was 74.4% and a best complete response rate (CR) was 25.6%. 1-year overall survival rate (OS) was 84.5%. The most common severe hematologic adverse events (Grade>3) are 3/4 grade leukopenia（18.6%）, and the most common severe non-hematologic adverse events were infusion-related reactions (IRRs， 20.9%) and infections（7.0%）. Multivariate prognostic analysis showed that extramedullary infiltration was an independent adverse prognostic factor affecting OS （P =0.004）. The use of daratumumab has no effect on stem cell collection, or engraftment. CONCLUSION: Daratumumab is safe and effective in RRMM.

Bioinformatics Analysis of Hub Genes in Craniofacial Microsomia Combined With Congenital Heart Disease.

OBJECTIVE: The primary objective of this study was to investigate potential mechanisms and explore hub genes of craniofacial microsomia (CFM) patients associated with congenital heart defects (CHD). METHODS: Initially, the authors acquired target gene data related to CFM and congenital cardiac anomalies. Subsequently, the authors established a protein-protein interaction (PPI) network. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses and molecular complex detection were conducted using Metascape. Finally, the authors hub genes were screened by the cytoHubba plugin. RESULTS: A total of 43 CFM genes and 120 optimal CHD candidate genes were selected. The PPI networks for pathogenic genes contained 163 nodes and 1179 edges. Functional enrichment analysis largely focused on tissue formation and development. Five modules were identified from the PPI network, and 7 hub genes were screened out. The genes most relevant to CFM associated with congenital cardiac anomalies pathogenesis included fibroblast growth factor 3, GATA binding protein 3, nuclear factor of activated T cells 1, histone cell cycle regulator, EPAS1, mitogen-activated protein kinase 1, and CRK like proto-oncogene, adaptor protein. CONCLUSIONS: This study identified some significant hub genes, pathways, and modules of CFM associated with CHD by bioinformatics analyses. Our findings indicate that gene subfamilies fibroblast growth factor 3, GATA binding protein 3, nuclear factor of activated T cells 1, histone cell cycle regulator, EPAS1, mitogen-activated protein kinase 1, and CRK like proto-oncogene, adaptor protein may have had significant involvement in both CFM and CHD.

Identification of bioactive ingredients and potential mechanisms of flowers of Hosta Plantaginea in treating pneumonia based on network pharmacology and experimental validation.

Flowers of Hosta plantaginea (H. plantaginea), a widely utilized medicinal herb in Mongolian medicine, holds a significant historical background in terms of its medicinal applications. This herb is renowned for its ability to clear heat and detoxify the body, alleviate cough, and provide relief to the throat. However, the active ingredients and the potential mechanism of action remain ambiguity. The objective of this study was to conduct a comprehensive analysis of the efficacy of H. plantaginea in treating pneumonia, identify its active ingredients and unveil the pharmacological mechanism in the treatment of pneumonia. In vivo experiments demonstrate the plant's anti-pneumonia properties, while mass spectrometry analysis identifies 62 chemicals, with 14 absorbed into the bloodstream. Network pharmacology and Venn analysis reveal 195 targets of 52 active ingredients, with 49 gene targets common to H. plantaginea and pneumonia. Protein-protein interaction (PPI) network construction and enrichment analysis highlight the key targets and pathways such as AKT, EGFR, IL-17. Western blotting confirms downregulation of these pathways, indicating the anti-inflammatory effects of H. plantaginea in treating acute lung injury. Our findings showed that the treatment of ALI with the H. plantaginea exerts its anti-inflammatory effects through multiple components, targets, and pathways. This study established a solid experimental foundation for investigating the various components, targets, and pathways involved in the treatment of pneumonia using H. plantaginea. It offers valuable insights from multiple perspectives and can serve as a reference for the clinical application of this plant in pneumonia treatment.

The first diagnosis of Severe Fever with Thrombocytopenia Syndrome caused by tick-borne Severe Fever with Thrombocytopenia Syndrome virus in Chongqing, China: A case report and literature review.

BACKGROUND: Severe Fever with Thrombocytopenia Syndrome (SFTS) is a tick-borne disease caused by the SFTS virus (SFTSV) which has the potential to become a pandemic and is currently a major public health concern. CASE PRESENTATION: We present the case of a 74-year-old female from an urban area of Chongqing, with leukocytopenia, thrombocytopenia, organ function, inflammatory, blood coagulation, and immune abnormalities. SFTSV infection was confirmed through molecular detection and metagenomic next-generation sequencing (mNGS) analysis, indicating a diagnosis of SFTS due to the patient's history of tick bites. The patient received symptomatic and supportive therapy, including antibiotics, antiviral treatment, and antifungal therapy, and finally discharged from the hospital on day 18. CONCLUSIONS: This study highlights the need for increased awareness, early diagnosis, and prompt treatment for tick-borne SFTS. It also provides a comprehensive understanding of the disease's characteristics, pathogenesis, detection methods, and available treatments.

HAMP predicts a pivotal role in modulating the malignant behaviors of non-small cell lung cancer cells.

BACKGROUND: Hepcidin antimicrobial peptide (HAMP) is a small peptide hormone recognized for its role in iron metabolism and cancer treatment. The purpose of this study was to examine the influence of HAMP in NSCLC. METHODS: The profile of NSCLC cells and tissues was characterized via HAMP. Gain- or loss-of-function cell models of HAMP were constructed, and CCK8, colony formation, and Transwell analyses were used to confirm the influence of HAMP on NSCLC cells. Upstream and downstream HAMP mechanisms in NSCLC were also analysed. Dual-luciferase reporter and pull-down assays confirmed the associations of miR-873-5p with HAMP, miR-873-5p, and the lncRNA KCNQ1OT1/SNHG14/XIST. Moreover, a xenograft model was established in nude mice for confirming the role of HAMP in NSCLC cell growth. RESULTS: In addition, HAMP expression increased in NSCLC cells and tissues. In terms of cellular functions, the HAMP-overexpressing group exhibited elevated NSCLC cell proliferation, invasion, and migration. HAMP knockdown reversed these changes. Bioinformatics analysis indicated that miR-873-5p targeted HAMP, which affected the nuclear factor kappa B (NF-κB) pathway in NSCLC. HAMP activated the NF-κB pathway, which was negatively modulated by miR-873-5p. NF-κB inhibitor JSH-23 can partly suppress the proliferation, invasion, and migration in HAMP-overexpressed cells. Moreover, miR-873-5p was the target miRNA of long noncoding RNAs (lncRNAs), which included KCNQ1OT1, SNHG14, and XIST, and these three lncRNAs promoted HAMP. CONCLUSION: Noncoding RNA-mediated HAMP promotes NSCLC cell proliferation, migration, and invasion by initiating the NF-κB pathway.

Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia.

OBJECTIVE: In B-cell acute lymphoblastic leukemia (B-ALL), current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50% of cases, underscoring the urgent need for new therapeutic regimens for this patient population. The present study aimed to determine whether HZX-02-059, a novel dual-target inhibitor targeting both phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) and tubulin, is lethal to B-ALL cells and is a potential therapeutic for B-ALL patients. METHODS: Cell proliferation, vacuolization, apoptosis, cell cycle, and in-vivo tumor growth were evaluated. In addition, Genome-wide RNA-sequencing studies were conducted to elucidate the mechanisms of action underlying the anti-leukemia activity of HZX-02-059 in B-ALL. RESULTS: HZX-02-059 was found to inhibit cell proliferation, induce vacuolization, promote apoptosis, block the cell cycle, and reduce in-vivo tumor growth. Downregulation of the p53 pathway and suppression of the phosphoinositide 3-kinase (PI3K)/AKT pathway and the downstream transcription factors c-Myc and NF-κB were responsible for these observations. CONCLUSION: Overall, these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.

Sparse Action Tube Detection.

Action tube detection is a challenging task as it requires not only to locate action instances in each frame, but also link them in time. Existing action tube detection methods often employ multi-stage pipelines with complex designs and time-consuming linking procedure. In this paper, we present a simple end-to-end action tube detection method, termed as Sparse Tube Detector (STDet). Unlike those dense action detectors, our core idea is to use a set of learnable tube queries and directly decode them into action tubes (i.e., a set of tracked boxes with action label) from video content. This sparse detection paradigm shares several advantages. First, the large number of hand-crafted anchor candidates in dense action detectors is greatly reduced to a small number of learnable tubes, which results in a more efficient detection framework. Second, our learnable tube queries directly attend the whole video content, which endows our method with the capacity of capturing long-range information for action detection. Finally, our action detector is an end-to-end tube detection without requiring the linking procedure, which directly and explicitly predicts the action boundary instead of depending on the linking strategy. Extensive experiments shows that our STDet outperforms the previous state-of-the-art methods on two challenging untrimmed video action detection datasets of UCF101-24 and MultiSports. We hope our method will be an simple end-to-end tube detection baseline and can inspire new ideas in this direction.

Effect of prior lenalidomide or daratumumab exposure on hematopoietic stem cell collection and reconstitution in multiple myeloma.

BACKGROUND: The roles of Lenalidomide (Len) and Daratumumab (Dara) in multiple myeloma treatment are well-established, yet their influences on hematopoietic stem cell harvesting and reconstitution remain disputed. METHODS: We conducted a systematic database review to identify cohort studies or RCTs evaluating the effect of the use of Len or Dara on hematopoietic stem cell collection and peripheral blood count recovery in multiple myeloma patients. Effects on hematopoietic collection or reconstitution were estimated by comparing standardized mean differences (SMD) and mean differences (MD), or median differences. RESULTS: Eighteen relevant studies were identified, summarizing mobilization results. For Len, data from 13 studies were summarized, including total CD34+ cell yield, collection failure rate, and time to neutrophil and platelet engraftment. Results indicated that Len exposure led to decreased stem cell collection [SMD=-0.23, 95% CI (-0.34, -0.12)]. However, collection failure (<2×106) could be mitigated by plerixafor [OR=2.14, 95% CI (0.96, 4.77)]. For Dara, two RCTs and three cohort studies were included, showing that Dara exposure resulted in a reduction in total stem cells even with optimized plerixafor mobilization [SMD=-0.75, 95% CI (-1.26, -0.23)], and delayed platelet engraftment recovery [MD=1.20, 95% CI (0.73, 1.66)]. CONCLUSIONS: Our meta-analysis offers a comprehensive view of Len and Dara's impacts on hematopoietic stem cell collection and reconstitution in multiple myeloma. Len usage could lead to reduced stem cell collection, counteracted by plerixafor mobilization. Dara usage could result in diminished stem cell collection and delayed platelet engraftment.

Lactate acid promotes PD-1+ Tregs accumulation in the bone marrow with high tumor burden of Acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) displayed poor response to programmed death-1 (PD-1) blockade therapy. Regulatory T cells (Tregs) was one of major immunosuppressive components in Tumor microenvironment and plays a vital role in the resistance of immunotherapy. Coinhibitory receptors regulate function of regulatory Tregs and are associated with resistance of PD-1 blockade. However, the coinhibitory receptors expression and differentiated status of Tregs in AML patients remain to be unclear. METHODS: Phenotypic determination of Tregs and CD8+ T cells in bone marrow of healthy donors and AML patients was performed by flow cytometry. Coculture experiments of AML and Tregs in vitro were performed and the concentrations of lactate acid (LA) in the supernatant were examined by ELISA. RESULTS: More Tregs differentiated into effector subsets in AML patients. However, PD-1 and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) expression on Tregs were comparable in healthy donors and AML patients. Further analysis showed that PD-1+ and PD-1+TIGIT+Tregs are more abundant in the bone marrow of patients with higher leukemic load. Moreover, PD-1+ Tregs accumulation was associated with higher level of senescent CD4+ T cells and increased frequencies of exhausted CD4+ as well as CD8+ T cells. Notably, neither Tregs nor their effector subsets were decreased among patients in complete remission. PD-1 expression was significantly downregulated in Tregs after achieving complete remission. Mechanistically, both AML cell line (KG-1α) and primary AML blasts produced high concentration of LA. Blockade of LA by lactate transporter inhibitor abrogated the upregulation of PD-1 by AML cells. CONCLUSION: PD-1+ Tregs accumulation in bone marrow in higher leukemic burden setting was linked to lactate acid secreted by AML blasts and decreased after disease remission. Our findings provided a novel insight into Tregs in AML and possible mechanism for resistance of PD-1 blockade in AML.

The novel miR-873-5p-YWHAE-PI3K/AKT axis is involved in non-small cell lung cancer progression and chemoresistance by mediating autophagy.

Non-small cell lung cancer (NSCLC) encompasses approximately 85% of all lung cancer cases and is the foremost cancer type worldwide; it is prevalent in both sexes and known for its high fatality rate. Expanding scientific inquiry underscores the indispensability of microRNAs in NSCLC. Here, we probed the impact of miR-873-5p on NSCLC development and chemoresistance. qRT‒PCR was used to measure the miR-873-5p level in NSCLC cells with or without chemoresistance. A model of miR-873-5p overexpression was constructed. The proliferation and viability of NSCLC cells were evaluated through CCK8 and colony formation experiments. Cell migration and invasion were monitored via Transwell assays. Western blotting was used to determine the levels of YWHAE, PI3K, AKT, EMT, apoptosis, and autophagy-related proteins. The sensitivity of NSCLC cells to the chemotherapeutic agent gefitinib was assessed. Additionally, the correlation of YWHAE with miR-873-5p was validated via a dual-luciferase reporter assay and RNA immunoprecipitation (RIP). Overexpressed miR-873-5p suppressed migration, proliferation, invasion, and EMT while concurrently stimulating apoptotic processes. miR-873-5p was downregulated in NSCLC cells resistant to gefitinib. Upregulating miR-873-5p reversed gefitinib resistance by inducing autophagy. YWHAE was confirmed to be a downstream target of miR-873-5p. YWHAE overexpression promoted the malignant behaviors of NSCLC cells and boosted tumor growth, while these effects were reversed following miR-873-5p overexpression. Subsequent investigations revealed that overexpressing YWHAE promoted PI3K/AKT pathway activation, with miR-873-5p displaying inhibitory effects on the YWHAE-mediated PI3K/AKT signaling cascade. miR-873-5p affects proliferation, invasion, migration, EMT, autophagy, and chemoresistance in NSCLC by controlling the YWHAE/PI3K/AKT axis.