IRF4-BLOC1S5: the first rearrangement gene identified in TEMPI syndrome.

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CT radiomics analysis discriminates pulmonary lesions in patients with pulmonary MALT lymphoma and non-pulmonary MALT lymphoma.

PURPOSE: The aim of this study is to create and validate a radiomics model based on CT scans, enabling the distinction between pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma and other pulmonary lesion causes. METHODS: Patients diagnosed with primary pulmonary MALT lymphoma and lung infections at Fuzhou Pulmonary Hospital were randomly assigned to either a training group or a validation group. Meanwhile, individuals diagnosed with primary pulmonary MALT lymphoma and lung infections at Fujian Provincial Cancer Hospital were chosen as the external test group. We employed ITK-SNAP software for delineating the Region of Interest (ROI) within the images. Subsequently, we extracted radiomics features and convolutional neural networks using PyRadiomics, a component of the Onekey AI software suite. Relevant radiomic features were selected to build an intelligent diagnostic prediction model utilizing CT images, and the model's efficacy was assessed in both the validation group and the external test group. RESULTS: Leveraging radiomics, ten distinct features were carefully chosen for analysis. Subsequently, this study employed the machine learning techniques of Logistic Regression (LR), Support Vector Machine (SVM), and k-Nearest Neighbors (KNN) to construct models using these ten selected radiomics features within the training groups. Among these, SVM exhibited the highest performance, achieving an accuracy of 0.868, 0.870, and 0.90 on the training, validation, and external testing groups, respectively. For LR, the accuracy was 0.837, 0.863, and 0.90 on the training, validation, and external testing groups, respectively. For KNN, the accuracy was 0.884, 0.859, and 0.790 on the training, validation, and external testing groups, respectively. CONCLUSION: We established a noninvasive radiomics model utilizing CT imaging to diagnose pulmonary MALT lymphoma associated with pulmonary lesions. This model presents a promising adjunct tool to enhance diagnostic specificity for pulmonary MALT lymphoma, particularly in populations where pulmonary lesion changes may be attributed to other causes.

Diverse rescue potencies of p53 mutations to ATO are predetermined by intrinsic mutational properties.

Tumor suppressor p53 is inactivated by thousands of heterogeneous mutations in cancer, but their individual druggability remains largely elusive. Here, we evaluated 800 common p53 mutants for their rescue potencies by the representative generic rescue compound arsenic trioxide (ATO) in terms of transactivation activity, cell growth inhibition, and mouse tumor-suppressive activities. The rescue potencies were mainly determined by the solvent accessibility of the mutated residue, a key factor determining whether a mutation is a structural one, and the temperature sensitivity, the ability to reassemble the wild-type DNA binding surface at a low temperature, of the mutant protein. A total of 390 p53 mutants were rescued to varying degrees and thus were termed as type 1, type 2a, and type 2b mutations, depending on the degree to which they were rescued. The 33 type 1 mutations were rescued to amounts comparable to the wild type. In PDX mouse trials, ATO preferentially inhibited growth of tumors harboring type 1 and type 2a mutants. In an ATO clinical trial, we report the first-in-human mutant p53 reactivation in a patient harboring the type 1 V272M mutant. In 47 cell lines derived from 10 cancer types, ATO preferentially and effectively rescued type 1 and type 2a mutants, supporting the broad applicability of ATO in rescuing mutant p53. Our study provides the scientific and clinical communities with a resource of the druggabilities of numerous p53 mutations (www.rescuep53.net) and proposes a conceptual p53-targeting strategy based on individual mutant alleles rather than mutation type.

Adoptive immune transfer from donors offers Anti-HBV protection to HBsAb-negative patients after Allo-HSCT.

Adoptive transfer of hepatitis B virus (HBV) immunity may occur following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we investigated the adoptive transfer of HBV immunity in 112 patients without HBV surface antibody (HBsAb) (HBsAb-) at the time of their first allo-HSCT. After allo-HSCT, HBV-DNA（87.5%） and HBsAg（11.1%%）cleared in HBsAg+ patients. All HBsAg- patients acquired HBsAb immediately. Nevertheless, HBsAb titers subsequently declined, and 39/67 (58.2%) patients lost HBsAb during follow-up. The 5-year overall survival (OS) was better in patients who lost HBsAb. Multivariate analysis showed that the independent risk factors for OS were lack of cytomegalovirus (CMV) clearance, acute graft-versus-host disease (aGVHD), and no HBsAb loss. Overall, adoptive immune transfer offers anti-HBV protection to patients without HBsAb, as they acquire HBsAb and clear HBV-DNA and HBsAg, while HBsAb loss after allo-HSCT predicts better survival.

SPAG5 as a novel biomarker and potential therapeutic target via regulating AKT pathway in multiple myeloma.

SPAG5, as a spindle-associated protein in mitosis, has been observed to have oncogenic activities in solid tumors. Here, we identified that SPAG5 expression was correlated with the deterioration of plasma cell malignancy and SPAG5 overexpression (OE) predicted unfavorable outcomes in multiple myeloma (MM). SPAG5 knockdown led to anti-MM effects in MM cell lines and animal xenograft models by regulating cell growth and apoptosis. Furthermore, gene set enrichment analysis (GSEA) revealed that PI3K/AKT/mTOR pathway was enriched in MM samples with highly expressed SPAG5 from GSE datasets. There was a concurrent downregulation of phosphorylation levels in the AKT/mTOR pathway. Yet OE of SPAG5 could restore the cell growth and p-AKT levels in MM cells after treatment with the AKT inhibitor MK2206. Taken together, SPAG5 could serve as a novel biomarker, and targeting the SPAG5 might have therapeutic potential in MM.

Association of iKIR-mismatch model and donor aKIRs with better outcome in haploidentical hematopoietic stem cell transplantation for acute myeloid leukemia.

Objectives: Killer cell immunoglobulin like receptor (KIR) can trigger the alloreactivity of NK cells. However, there is no clear consensus as to their function. Here, we investigated the potential influence of KIR mismatch and KIR alleles on the outcome of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in acute myeloid leukemia (AML) patients. Method: Data from 79 AML patients treated with haplo-HSCT were retrospectively analyzed. HLA-C genotyping was determined by the PCR-rSSO method. KIR, HLA-A and HLA-B genotyping was performed by the PCR-SSP method. Cox proportional hazards model and Kaplan-Meier survival curves were used for analysis. Results: Both KIR ligand mismatch (KLM) group and KIR receptor-ligand mismatch (RLM) group were associated with a decreased risk in aGVHD and relapse rate (RR), and better overall survival (OS) compared to the KIR ligand matching and receptor-ligand matching groups, respectively (aGVHD: KLM: p=0.047, HR:0.235; RLM: p<0.001, HR:0.129; RR: KLM: p=0.049, HR:0.686, RLM: p=0.017, HR:0.200;OS:KLM: p=0.012, HR: 0.298, RLM: p=0.021, HR:0.301). RLM was more accurate at predicting relapse and aGVHD compared with KLM (aGVHD: p=0.009; RR: p=0.039). Patients with greater number of donor activating KIRs (aKIR) had a lower incidence of aGVHD and relapse, and the benefits correlated with the increase in the number of donor aKIRs (aGVHD: p=0.019, HR:0.156; RR: p=0.037, HR:0.211). Patients with RLM and the highest number of donor aKIRs had the lowest RR, lowest incidence of aGVHD and best OS. Conclusions: Both KLM and RLM reduced the risk of aGVHD and relapse after haplo-HSCT in AML patients, and RLM showed superiority in predicting HSCT outcome. The synergistic effects of RLM and donor aKIRs can provide a better donor selection strategy to improve haplo-HSCT outcome in AML patients.

JaponiconeA induces apoptosis of bortezomib-sensitive and -resistant myeloma cells in vitro and in vivo by targeting IKK.

OBJECTIVE: Multiple myeloma (MM) remains incurable with high rates of relapse. New therapeutic drugs are therefore urgently needed to improve the prognosis. JaponiconeA (JA), a natural product isolated from Inula japonica Thunb, has shown good anti-MM potential. A comprehensive study should therefore be conducted to identify both the in vitro and in vivo mechanisms of the anti-MM effects of JA. METHODS: CCK8 assays and flow cytometry were used to detect the proliferation, apoptosis, and cell cycle of MM cell lines when treated with JA. In vivo experiments were conducted using subcutaneous xenograft mouse models. We also identified possible targets and the mechanism of JA using RNA-seq and c-Map databases, and identified the specific targets of JA in bortezomib-sensitive and -resistant MM cell lines using CETSA, DARTS, and rescue experiments. Furthermore, JA and bortezomib were used separately or together to characterize their possible synergistic effects. RESULTS: In vitro, JA inhibited proliferation, and induced apoptosis and G2/M phase arrest in MM cell lines, and selectively killed primary CD138+ MM cells. In vivo, JA also demonstrated a strong anti-tumor effect with no observable toxicity. In addition, JA showed synergetic effects in combination with bortezomib, and enhanced the anti-tumor effect of bortezomib in bortezomib-resistant cells. CETSA and DARTS confirmed direct binding of JA to NF-κB inhibitor kinase beta (IKKß), and overexpression of IKKß or knockdown of IκBα partially rescued the apoptosis induced by JA. CONCLUSIONS: JA exhibited strong anti-tumor effects in MM. It sensitized myeloma cells to bortezomib and overcame NF-κB-induced drug resistance by inhibiting IKKß, providing a new treatment strategy for MM patients.

Arsenic trioxide and bortezomib interact synergistically to induce apoptosis in chronic myelogenous leukemia cells resistant to imatinib mesylate through Bcr/Abl­dependent mechanisms.

Arsenic trioxide (As2O3) and the proteasome inhibitor bortezomib (BTZ) have been used successfully to treat acute promyelocytic leukemia and multiple myeloma. Their synergistic effects with other anticancer drugs have been widely studied. In this study, interactions between As2O3 and BTZ were examined in imatinib­resistant Bcr/Abl+ (K562r) cells. Co­treatment of K562r cells with subtoxic concentrations of As2O3 (2 µM) and BTZ (24 nM) resulted in a synergistic enhancement in growth inhibition and apoptosis, as demonstrated by increased annexin V staining. These events were associated with activation of protein kinase Cδ, poly ADP­ribose polymerase cleavage and caspase­3 activation, along with downregulation of Bcr/Abl mRNA and Bcr/Abl protein expression levels during apoptosis. In addition, reactive oxygen species were downregulated during combined treatment in K562r cells. Collectively, these findings suggest that BTZ and As2O3 act synergistically to induce apoptosis in K562r cells. Therefore, further studies are required to assess the potential of BTZ and As2O3 combinatory treatment of chronic myeloid leukemia, particularly using imatinib­resistant Bcr/Abl+ clones.