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关键词： HIV   PHAT   Primary HIV-associated thrombocytopenia  

摘要： Primary HIV-associated thrombocytopenia (PHAT) is an isolated thrombocytopenia in HIV-positive individuals in the absence of secondary causes. The presence of certain Human Leukocyte Antigens (HLA) has been linked to individuals' immune response to HIV and the development of immune-mediated thrombocytopenic disorders. Considering the established associations between HLA and HIV infection and HLA and immune-mediated thrombocytopenias, we hypothesise that specific HLA alleles may also increase the risk of developing PHAT, a condition that links both HIV and immune-mediated thrombocytopenia. Therefore, the study aimed to determine the frequency of high-resolution HLA alleles in patients presenting with possible PHAT. Following a detailed screening process, we evaluated the HLA profiles of 43 participants with probable PHAT using the Axiom Precision Medicine Diversity Array (PMDA) Kit on the GeneTitan Multi-Channel instrument. No single HLA allele was found to be more prominent in our PHAT population. However, 93.02% of participants had both HIV-protective and HIV-susceptible alleles. The potential mechanism causing thrombocytopenia to be the only clinically relevant haematological abnormality in these patients remains to be explored. We concluded that the presence of both an HIV-protective and HIV-susceptibility allele in the same individual may cause antagonistic immune reactions, resulting in thrombocytopenia in HIV-positive individuals. We propose future long-term follow-up studies to determine the progression and outcome in patients with PHAT.

关键词： combined exercise   obese   older women   body composition   GDF-15   apelin-12   IL-15  

摘要： Background: The purpose of this study was to investigate the effects of a 16-week exercise program combining aerobic and resistance training on body composition, growth differentiation factor-15 (GDF-15), apelin-12, and interleukin-15 (IL-15) in older Korean women according to obesity status. Methods: Participants were divided into obesity (n = 15) and normal-weight groups (n = 14). A walking exercise was performed at 60-70% heart rate reserve (RPE 13-15). The bodyweight resistance exercises were progressively intensified over 16 weeks. Analysis methods included two-way repeated measures ANOVA, ANCOVA, and paired and independent t-tests. Results: Significant main effects of time and group were observed in body weight (p < 0.001), and both groups demonstrated significant within-group reductions in body mass index (BMI) (obese: p < 0.001;normal-weight: p < 0.05), along with significant between-group differences (p < 0.001). The percentage of body fat significantly decreased over time (p < 0.01) and differed between groups (p < 0.001). GDF-15 exhibited a significant group x time interaction (p < 0.05) and a main group effect (p < 0.05). Although no statistically significant changes were observed in Apelin-12 levels, an opposite trend was identified between groups, with an increase in the obese group and a decrease in the normal-weight group. For IL-15, no significant interaction effect was found between the groups. Conclusions: The 16-week combined exercise intervention improved key markers of body composition, particularly in obese older women, and led to increased GDF-15, indicating potential metabolic benefits. While changes in apelin-12 and IL-15 were not statistically significant, the findings support the utility of combined exercise for mitigating fat accumulation and promoting healthy aging in older adults.

关键词： Ovarian Cancer   Hematologic Malignancies   Chimeric antigen receptor - CAR   JAK-STAT   T cell  

摘要： Background While chimeric antigen receptor (CAR)-T cell therapy exhibits a robust therapeutic efficacy against B-cell malignancies and multiple myeloma, its efficacy and safety have not been established for acute myeloid leukemia (AML) and solid tumors due to the paucity of established target antigens. Some AML and solid tumor cells express tumor necrosis factor (TNF), which is initially expressed on the cell surface prior to *** In this study, we obtained monoclonal antibodies against the N-terminal fragment of TNF (TNF-NTF) that remains on the cell surface after shedding. We then generated CAR-T cells to target TNF-NTF using the antibody sequence. To enhance the therapeutic efficacy of TNF-NTF CAR-T cells, we further engineered the previously developed chimeric cytokine receptor consisting of GP130, IL6R, and constitutively active IL7R with the M452L mutation (G6/7R).Results TNF-NTF CAR-T cells efficiently lysed TNF-expressing leukemia cells in vitro, while showing limited antitumor efficacy in vivo due to poor expansion and persistence. Activated T cells upregulate TNF, which was recognized by TNF-NTF CAR-T cells and led to fratricide. Genetic knockout (KO) of TNF significantly enhanced the viability and proliferation of TNF-NTF CAR-T cells, while slightly reducing their cytotoxic activity. In addition, ectopic expression of G6/7R improved the effector function of TNF-NTF CAR-T cells through constitutive activation of janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling. The G6/7R-expressing TNF-KO TNF-NTF CAR-T cells exhibited superior persistence and durable antileukemic efficacy in vivo compared with parental CAR-T cells. We also confirmed that TNF-NTF CAR-T cells can target primary AML cells, including a leukemia-initiating population with colony-forming capacity. Unlike CD33, targeting TNF-NTF did not show cytotoxicity against normal hematopoietic stem/progenitor cells. Finally, we demonstrated the curative effi

摘要： Lipid nanoparticle (LNP)-mediated mRNA delivery has emerged as a powerful platform for both immunostimulatory and immunomodulatory applications. However, the influence of local immunometabolic cues on the intracellular fate and translational efficiency of mRNA-LNPs remains poorly understood. In this study, we investigated how interferon-gamma (IFN-γ), a potent inducer of indoleamine 2,3-dioxygenase 1 (IDO1), and tryptophan (Trp) deprivation independently and combinatorially affect mRNA-LNP function in DC2.4 dendritic cells. These two cues are canonical drivers of immunoregulatory microenvironments, particularly those that favor tolerogenic dendritic cell programming and the induction of regulatory T cells. Using dual-reporter mRNA constructs and high-resolution confocal imaging, we show that IFN-γ stimulation reduces total cellular mRNA uptake and lysosomal accumulation without affecting translation efficiency and endosomal escape efficiency. Whereas Trp deprivation also reduces the overall cellular uptake of mRNA-LNPs, it also significantly impairs protein synthesis from mRNA-LNPs and modestly reduces endosomal escape, despite having minimal impact on lysosomal mRNA levels. Spatial compartmentalization analysis revealed that IFN-γ and Trp limitation disrupt distinct steps in the delivery-translation cascade, acting independently but additively to suppress the ultimate protein translation from mRNA-LNPs in DC2.4 dendritic cells. These findings highlight the importance of considering local metabolic and cytokine contexts when deploying mRNA-LNPs for immunological applications. Our work provides mechanistic insights into how immunoregulatory environments impair the delivery and translation of mRNA-LNPs, suggesting strategies to tune delivery outcomes for tolerogenic purposes.

关键词： Triple-negative breast cancer   KIF20A   The IL-17 signaling pathway   bioinformatic analysis  

摘要： Background: Triple-negative breast cancer (TNBC), the only breast cancer subtype lacking effective targeted therapies, is associated with a poor prognosis. Emerging evidence highlights the oncogenic role of kinesin family member 20A (KIF20A) in human malignancies, though its mechanistic contributions to TNBC progression remain poorly understood. Methods: Candidate target genes were screened via bioinformatic analysis. Following KIF20A knockdown, we utilized cell counting kit-8, 5-Ethynyl-2 '-deoxyuridine staining, transwell, and wound healing assays to assess TNBC cell viability, proliferative capacity, migratory ability, and invasive potential of TNBC cells. In vivo, we measured the volume, weight, and proliferation of solid tumors. Moreover, the downstream pathway of KIF20A was screened by bioinformatic analysis and validated by an agonist and an inhibitor for the interleukin 17 (IL-17) pathway. The expression levels of proteins associated with the IL-17 pathway were assessed via Western blot. Results: KIF20A, highly overexpressed in TNBC, was screened out as a promising target gene. In vitro, KIF20A knockdown significantly impaired TNBC cell viability, proliferation, migration, and invasion. In vivo, KIF20A knockdown suppressed the growth and proliferation of solid tumors in nude mice xenograft models. Mechanistically, the IL-17 signaling pathway was screened out and the expression of proteins in this pathway was suppressed by KIF20A knockdown. The agonist for the IL-17 signaling countered the impact of KIF20A knockdown on TNBC progression. Direct inhibition of IL-17 showed a similar effect as KIF20A silencing on TNBC cells. Conclusion: KIF20A downregulation suppresses TNBC progression via the inactivation of the IL-17 signaling pathway, suggesting KIF20A as a potential therapeutic target for TNBC.

关键词： acute myeloid leukemia   allogeneic hematopoietic cell transplantation   donor cell dose   CD34-positive cells   measurable residual disease   relapse  

摘要： Background: The impact of donor graft cell composition on post-HCT outcomes in AML remains controversial. Furthermore, it is unknown whether this interacts with pre-HCT MRD status. We evaluated the impact of CD34+ and CD3+ cell doses on outcomes of myeloablative conditioning (MAC) HCT in patients with myelodysplastic neoplasm (MDS)/AML or AML with and without detectable MRD in pre-HCT bone marrow specimens. Methods: We utilized an electronic database to identify all adults >= 18 years with MDS/AML or AML who underwent MAC and received 10/10 HLA-matched sibling or unrelated donor mobilized PBSC allografts in first morphologic remission between 2006 and 2023 at the University of Washington/Fred Hutchinson Cancer Center. Results: Among 385 adults, we found a progressive decrease in relapse incidence and improved survival with increasing CD34+ doses up to a threshold of 5.61 x 106/kg, above which the relapse risk no longer decreased. After multivariable adjustment, a low CD34+ dose was associated with increased risk of relapse as well as lower overall and relapse-free survival. Similar results were obtained for patients with and without pre-HCT MRD. Higher CD3+ doses were linearly associated with an increased incidence of moderate-severe chronic GVHD. Conclusions: Our data identify a non-linear relationship between CD34+ cell dose and relapse risk in AML patients undergoing myeloablative allogeneic HCT, with no apparent added benefit beyond a CD34+ dose threshold. Our findings suggest that donor graft composition impacts outcomes in adults with AML undergoing allogeneic HCT after MAC, independent of pre-HCT MRD status;however, additional studies are needed for other donor cell scenarios.

关键词： Treg cells   amyotrophic lateral sclerosis (ALS)   biomarker   immunomodulation   low-dose IL-2  

摘要： Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease caused by motor neuron loss. In a recent Phase 2b trial, Bensimon and colleagues report that the addition of low-dose interleukin 2 (LD-IL-2) immunotherapy to standard of care (SOC) shows promise in enhancing immune tolerance and improving survival in individuals with slower disease progression.

关键词： Gastrointestinal cancers   Flavonoids   Ferroptosis   Iron-metabolism   Cell death   Natural compounds   AA   arachidonic acid   AC   auriculasin   ACSL4   acyl-CoA synthetase long chain family member 4   AdA   adrenic acid   AF   amentoflavone   AIFM1   apoptosis-inducing factor mitochondria-associated 1   AIM2   absent in melanoma 2   AKT   protein kinase B (also known as PKB)   ALOX   arachidonate lipoxygenase   AMPK   5′ adenosine monophosphate-activated protein kinase   APAP   acetaminophen   ASC   apoptosis-associated speck-like protein containing a caspase activation and recruitment domain   ATF2   activating transcription factor 2   ATG   protein kinase B   Bak   B-cell leukemia lymphoma 2 antagonist killer 1   Bax   B-cell leukemia lymphoma 2 associated X   Bcl-2   B-cell leukemia lymphoma 2   Bid   BH3-interacting domain death agonist   CAPN2   calpain 2   CASP1   caspase-1   CASP3   caspase-3   CBR1   carbonyl reductase 1   CL   cardiolipin   CoA   coenzyme A   CoQ10H2   reduced coenzyme Q10   CRC   colorectal cancer   CRISPR-Cas9   clustered regularly interspaced short palindromic repeats–CRISPR-associated protein 9   CYP   cytochrome P450   DAMP   damage-associated molecular patterns   DFO   deferoxamine   DISC   death-inducing signaling complex   DMT1   divalent metal transporter 1   DR   death receptor   FAC   ferric ammonium citrate   FADD   Fas-associated death domain   FasR   Fas receptor   FasL   Fas ligand   FDA   Food and Drug Administration   Fe   2   ferrous iron   Fe   3   ferric iron   FIN56   ferroptosis inducer 56   FINS   ferroptosis inducers   FOXO3   forkhead box O3   FPN   ferroportin   FR2   ferroportin 2   FSP1   ferroptosis suppressor protein 1   FTH1   ferritin heavy chain 1   GADD34   growth arrest and DNA damage–inducible protein   GC   gastric cancer   GCN2   general control nonderepressible 2   GI   gastrointestinal   GPX4   glutathione peroxidase 4   GSDMD   gasdermin D   GSH   glutathione   GSR   glutathione disulfide reductase   GSSG   glutathione disulfide   GSTP1   glutathione S-transferase Pi 1   HCC   hepatocellular carcinoma   HMOX1   heme oxygenase-1 gene   HO-1   heme oxygenase-1   IASPP   inhibitor of apoptosis-stimulating protein of p53   IBS   inflammatory bowel syndrome   IKE   imidazole ketone erastin   IL-1   interleukin-1  

摘要： Background The incidence of early-onset gastrointestinal cancer in individuals under 50 has been rising at an alarming rate in recent years. A major challenge in standard therapeutic interventions is the ability of cancer cells to evade apoptosis, which leads to chemoresistance and promotes cancer progression and metastasis. As a result, non-apoptotic forms of cell death, such as ferroptosis, have gained considerable attention as potential therapeutic interventions. Ferroptosis is a unique cell death characterized by iron-dependent lipid peroxidation and regulated through multiple signaling pathways. Cancer cells rely more on iron and are more sensitive to ferroptosis than normal cells. Recently, interest has surged in using natural compounds, particularly flavonoids, as anticancer agents. Flavonoids are increasingly recognized as potent inducers of ferroptosis, offering new therapeutic strategies in cancer therapy. Aim of the review This review provides a detailed overview of current preclinical evidence on the therapeutic potential of flavonoids that induce ferroptosis in gastrointestinal cancers. First, the general mechanisms of ferroptosis are described, followed by an overview of synthetic compounds or small-molecule modulators. Then, flavonoids are introduced and described in terms of their classification, chemical structure, and anticancer activity. Finally, the gaps, challenges, and future scope of research are addressed. Key scientific concepts of review Flavonoid modulators of ferroptosis target GPX4, the system Xc − , lipid metabolism, and iron metabolism pathways, in addition to various other pathways, to initiate the cell death process and inhibit carcinogenesis. We hypothesize that flavonoid-induced ferroptosis presents a strategic intervention in cancer therapy, serving as both anticancer agents and sensitizers to enhance the efficacy of current treatments.