Abstract Tumor necrosis factor (TNF) receptor–associated factor (TRAF)–interacting protein with forkhead-associated domain B (TIFAB), an inhibitor of NF-κB signaling, plays critical roles in hematopoiesis, myelodysplastic neoplasms, and leukemia. We previously demonstrated that Tifab enhances KMT2A::MLLT3–driven acute myeloid leukemia (AML) by either upregulating Hoxa9 or through ubiquitin-specific peptidase 15–mediated downregulation of p53 signaling. In this study, we show that Tifab deletion in KMT2A::MLLT3–induced AML impairs leukemia stem/progenitor cell (LSPC) engraftment, glucose uptake, and mitochondrial function. Gene set enrichment analysis reveals that Tifab deletion downregulates MYC, HOXA9/MEIS1, mTORC1 signaling, and genes involved in glycolysis and oxidative phosphorylation. By comparing genes upregulated in TIFAB-overexpressing LSPCs with those downregulated upon Tifab deletion, we identify hepatocyte nuclear factor 4 alpha (Hnf4a) as a key TIFAB target, regulated through the inhibition of NF-κB component RelB, which suppresses Hnf4a in leukemia cells. HNF4A, a nuclear receptor involved in organ development, metabolism, and tumorigenesis, rescues the metabolic defects caused by Tifab deletion and enhances leukemia cell engraftment. Conversely, Hnf4a knockdown attenuates TIFAB-mediated enhancement of LSPC function. These findings highlight the critical role of the TIFAB-HNF4A axis in KMT2A::MLLT3–induced AML and uncover a novel regulator in leukemia biology.

Cancer remains a formidable adversary, challenging medical advancements with its dismal prognosis, low cure rates and high mortality rates. Within this intricate landscape, long non‑coding RNAs (lncRNAs) emerge as pivotal players, orchestrating proliferation and migration of cancer cells. Harnessing the potential of lncRNAs as therapeutic targets and prognostic markers holds immense promise. The present comprehensive review delved into the molecular mechanisms underlying the involvement of lncRNAs in the onset and progression of the top five types of cancer. By meticulously examining lncRNAs across diverse types of cancer, it also uncovered their distinctive roles, highlighting their exclusive oncogenic effects or tumor suppressor properties. Notably, certain lncRNAs demonstrate diverse functions across different cancers, confounding the conventional understanding of their roles. Furthermore, the present study identified lncRNAs exhibiting aberrant expression patterns in numerous types of cancer, presenting them as potential indicators for cancer screening and diagnosis. Conversely, a subset of lncRNAs manifests tissue‑specific expression, hinting at their specialized nature and untapped significance in diagnosing and treating specific types of cancer. The present comprehensive review not only shed light on the intricate network of lncRNAs but also paved the way for further research and clinical applications. The unraveled molecular mechanisms offer a promising avenue for targeted therapeutics and personalized medicine, combating cancer proliferation, invasion and metastasis.

The intricate web of cancer biology is governed by the active participation of long non-coding RNAs (lncRNAs), playing crucial roles in cancer cells' proliferation, migration, and drug resistance. Pioneering research driven by machine learning algorithms has unveiled the profound ability of specific combinations of lncRNAs to predict the prognosis of cancer patients. These findings highlight the transformative potential of lncRNAs as powerful therapeutic targets and prognostic markers. In this comprehensive review, we meticulously examined the landscape of lncRNAs in predicting the prognosis of the top five cancers and other malignancies, aiming to provide a compelling reference for future research endeavours. Leveraging the power of machine learning techniques, we explored the predictive capabilities of diverse lncRNA combinations, revealing their unprecedented potential to accurately determine patient outcomes.

Hypoxia-exposed lung cancer-released exosomal microRNA-23a (miR-23a) has been shown to enhance angiogenesis as well as vascular permeability, contributing to the close correlation between exosomal miR-23a and tumorigenesis. The current study aimed to investigate whether gastric cancer (GC) cell-derived exosomal miR-23a could induce angiogenesis and to elucidate the potential mechanisms associated with the process. Differentially expressed miRNAs in GC were initially screened from the Gene Expression Omnibus database. Target genes were selected following miRNA-mRNA prediction and subsequently verified by dual luciferase reporter assay. RT-qPCR was conducted to detect miR-23a and PTEN expression in GC tissues, cells and exosomes. Human umbilical venous endothelial cells (HUVECs) were co-cultured with GC cell-derived exosomes to assess the angiogenesis mediated by exosomes in vitro. Additionally, PTEN was overexpressed in HUVECs to analyze the mechanism by which miR-23a regulates angiogenesis. miR-23a was highly expressed in GC tissues and cells and GC cell-derived exosomes. Angiogenesis was promoted by the co-culture of HUVECs and GC cells-derived exosomes, as evidenced by the increased expression of VEGF but decreased expression of TSP-1. PTEN was targeted by miR-23a and was lowly expressed in GC tissues. In a co-culture system, miR-23a carried by GC cells-derived exosomes promoted angiogenesis via the repression of PTEN. Collectively, GC cell-derived exosomal miR-23a could promote angiogenesis and provide blood supply for growth of GC cells. This study contributes to advancement of miRNA-targeted therapeutics.

Acute myeloid leukemia (AML) is maintained by self-renewing leukemic stem cells (LSCs). A fundamental problem in treating AML is that conventional therapy fails to eliminate LSCs, which can reinitiate leukemia. Heat shock transcription factor 1 (HSF1), a central regulator of the stress response, has emerged as an important target in cancer therapy. Using genetic Hsf1 deletion and a direct HSF1 small molecule inhibitor, we show that HSF1 is specifically required for the maintenance of AML, while sparing steady-state and stressed hematopoiesis. Mechanistically, deletion of Hsf1 dysregulates multifaceted genes involved in LSC stemness and suppresses mitochondrial oxidative phosphorylation through downregulation of succinate dehydrogenase C (SDHC), a direct HSF1 target. Forced expression of SDHC largely restores the Hsf1 ablation-induced AML developmental defect. Importantly, the growth and engraftment of human AML cells are suppressed by HSF1 inhibition. Our data provide a rationale for developing efficacious small molecules to specifically target HSF1 in AML.

We previously showed stabilization of NIK-induced activation of NF-κB non-canonical signaling suppresses MLL-AF9-induced AML. In the current study, we demonstrate that deletion of NF-κB non-canonical RelB prevents the inhibitory effect of NIK stabilization in MLL-AF9 AML. Mechanistically, RelB suppresses its direct target, TIFAB, which is upregulated in human AML and correlates negatively with the survival of AML patients. Forced expression of TIFAB reverses NIK-induced impaired AML development through downregulation of RelB and upregulation of HOXA9. Consistent with upregulation of HOXA9, gene set enrichment analysis shows that forced expression of TIFAB blocks myeloid cell development, upregulates leukemia stem cell signature and induces similar gene expression patterns to those of HOXA9-MEIS1 and HOXA9-NUP98, and upregulates oxidative phosphorylation. Accordingly, forced expression of HOXA9 also largely releases the inhibitory impact of NIK stabilization via downregulation of RelB and upregulation of RelA. Our data suggest that NIK/RelB suppresses MLL-AF9-induced AML mainly through downregulation of TIFAB/HOXA9.

Background. We aimed to examine the differences of clinical characteristics between patients with ischemic stroke with active cancer and those without cancer to develop a clinical score for predicting the presence of occult cancer in patients with ischemic stroke. Methods. This retrospective study enrolled consecutive adult patients with acute ischemic stroke who were admitted to our department between December 2017 and January 2019. The demographic, clinical, laboratory, and neuroimaging characteristics were compared between patients with ischemic stroke with active cancer and those without cancer. Multivariate analysis was performed to identify independent factors associated with active cancer. Subsequently, a predictive score was developed using the areas under the receiver operating characteristic curves based on these independent factors. Finally, Bayesian decision theory was applied to calculate the posterior probability of active cancer for finding the best scoring system. Results. Fifty-three (6.63%) of 799 patients with ischemic stroke had active cancer. The absence of a history of hyperlipidemia (odds ratio OR=0.17, 95% confidence interval (CI): 0.06–0.48, P<0.01), elevated serum fibrinogen (OR=1.72, 95% CI: 1.33–2.22, P<0.01) and D-dimer levels (OR=1.43, 95% CI: 1.24–1.64, P <0.01), and stroke of undetermined etiology (OR=22.87, 95% CI: 9.91–52.78, P<0.01) were independently associated with active cancer. A clinical score based on the absence of hyperlipidemia, serum fibrinogen level of ≥4.00 g/L, and D-dimer level of ≥2.00 μg/mL predicted active cancer with an area under the curve of 0.83 (95% CI: 0.77–0.89, P<0.01). The probability of active cancer was 59% at a supposed prevalence of 6.63%, if all three independent factors were present in a patient with ischemic stroke. Conclusions. We devised a clinical score to predict active cancer in patients with ischemic stroke based on the absence of a history of hyperlipidemia and elevated serum D-dimer and fibrinogen levels. The use of this score may allow for early intervention. Further research is needed to confirm the implementation of this score in clinical settings.

Key Points Common progenitor cells exist in clonally related concomitant chronic lymphocytic leukemia and acute myeloid leukemias. CLL cells dedifferentiated to clonally related myeloid cells posttransplantation.

Lung adenocarcinoma (LUAD) is one of the major types of lung cancer. Tumor-infiltrating immune cells (TIICs) are positively associated with overall survival (OS) in LUAD. The SPARC/osteonectin, cwcv and kazal-like domains proteoglycan 2 (SPOCK2) is a complex type of secreted proteoglycan involved in forming a protective barrier against viral infection. The purpose of this study was to investigate the relationship between SPOCK2 and TIICs and the prognostic role of SPOCK2 in LUAD. The GEPIA2, GEO, CPTAC, and HPA databases were analyzed to examine both the mRNA and protein expression of SPOCK2 in LUAD. GEPIA2 and the Kaplan-Meier Plotter (KM Plotter) were used to evaluate the prognostic value of SPOCK2 in LUAD patients. TCGA data were examined for a correlation between SPOCK2 expression and clinical characteristics. Gene enrichment analyses were performed to explore the underlying mechanism of SPOCK2 based on LinkedOmics. RegNetwork was used to predict the regulators of SPOCK2. The correlation between SPOCK2 and TIICs, including immune infiltration level and relative proportion was investigated via TIMER. KM Plotter was also used to evaluate the prognostic role of SPOCK2 expression in LUAD with enriched and decreased TIIC subgroups. We found SPOCK2 was significantly downregulated in LUAD compared with that in non-tumor controls and was correlated with clinical parameters. Moreover, a high SPOCK2 expression level predicted better survival. The SPOCK2-associated regulatory network was constructed. SPOCK2 influenced the TIIC infiltration level and relative proportion in LUAD. Furthermore, a high SPOCK2 expression level was associated with a favorable prognosis in enriched CD4 + T cells and macrophage subgroups in LUAD. In conclusion, a high level of SPOCK2 expression predicted favorable prognosis and was significantly correlated with TIICs in LUAD. Therefore, the expression of SPOCK2 may affect the prognosis of LUAD partly due to TIICs.

BACKGROUND:Emerging evidence indicates a regulatory role of long non-coding RNAs (lncRNAs) in the development of gastric cancer (GC), but the mechanisms underlying their function have remained largely unknown. Recent microarray-based expression profiling has led to the identification of a novel differentially expressed lncRNA, LINC00858, in GC. Subsequently, LINC00858 was found to be highly expressed in GC tissues and cells. This study was designed to clarify the functional role of LINC00858 in GC, including its effect on methylation of the WNK2 gene promoter and its downstream MAPK signaling pathway. METHODS:After exogenous over-expression and knockdown of LINC00858 and the addition of a MAPK pathway inhibitor in GC cells, we explored the effects of LINC00858 and the MAPK signaling pathway on GC cell behavior using various in vitro and in vivo assays. RESULTS:LINC00858 was found to negatively regulate WNK2 expression by enhancing its promoter methylation and to activate the MAPK signaling pathway. Moreover, we found that knockdown of LINC00858 or inhibition of the MAPK signaling pathway resulted in decreased GC cell growth, migration and invasion, as well as decreased cell cycle progression, along with increased apoptosis and decreased tumorigenicity. CONCLUSIONS:Together, these findings indicate that silencing of LINC00858 increases WNK2 expression and inhibits the MAPK signaling pathway, thereby inhibiting GC growth and development. Our data highlight LINC00858 as a potential target in GC therapy.

Triple-negative breast cancer has been classified as basal-like immune activated (BLIA), basal-like immune-suppressed (BLIS), and two other subtypes, suggesting potential immune therapeutic targets for basal-like breast cancer (BLBC). 2'-5'-Oligoadenylate synthetases (OASs), identified from differentially expressed genes (DEGs) between BLIA and BLIS breast cancers (GSE76124), are involved in antiviral activity induced by interferons. However, the association between the four OASs and prognosis or tumor-infiltrating immune cells (TIICs) remains unclear. Expression, survival data, and immune correlations for OASs in BLBC were assessed using bioinformatics tools. We found that OASs were highly expressed in BLIA breast cancer. Survival analysis suggested that high transcriptional levels of OASs were associated with better overall survival, relapse-free survival, and distant metastasis-free survival in patients with BLBC. Moreover, the prognostic value of OASs with respect to different clinicopathological factors, and especially according to lymph node metastasis, in patients with BLBC was further assessed. Our findings elucidated the expression, prognostic role, and effect of OASs in TIICs on BLBC, which might promote the development of OAS-targeted immunotherapy for BLBC.

Sirtuin 5 (SIRT5) is a NAD+ -dependent class III protein deacetylase, and its role in prostate cancer has not yet been reported. Therefore, to explore the diagnosis and treatment of prostate cancer, we investigated the effect of SIRT5 on prostate cancer. Sirtuin 5 was assessed by immunohistochemistry in 57 normal and cancerous prostate tissues. We found that the tissue expression levels of SIRT5 in patients with Gleason scores ≥7 were significantly different from those in patients with Gleason scores <7 (P < .05, R > 0). Further, mass spectrometry and pathway screening experiments showed that SIRT5 regulated the activity of the mitogen-activated protein kinase (MAPK) pathway, which in turn modulated the expression of MMP9 and cyclin D1. Being a substrate of SIRT5, acetyl-CoA acetyltransferase 1 (ACAT1) was regulated by SIRT5. SIRT5 also regulated MAPK pathway activity through ACAT1. These results revealed that SIRT5 promoted the activity of the MAPK pathway through ACAT1, increasing the ability of prostate cancer cells to proliferate, migrate and invade. Overall, these results indicate that SIRT5 expression is closely associated with prostate cancer progression. Understanding the underlying mechanism may provide new targets and methods for the diagnosis and treatment of the disease.

The aims of the study were: (1) compare sociodemographic characteristics among active tuberculosis (TB) cases and their household contacts in cold and hot spot transmission areas, and (2) quantify the influence of locality, genotype and potential determinants on the rates of latent tuberculosis infection (LTBI) among household contacts of index TB cases. Parallel case-contact studies were conducted in two geographic areas classified as “cold” and “hot” spots based on TB notification and spatial clustering between January and June 2018 in Guangxi, China, using data from field contact investigations, whole genome sequencing, tuberculin skin tests (TSTs), and chest radiographs. Beijing family strains accounted for 64.6% of Mycobacterium tuberculosis (Mtb) strains transmitted in hot spots, and 50.7% in cold spots (p-value = 0.02). The positive TST rate in hot spot areas was significantly higher than that observed in cold spot areas (p-value < 0.01). Living in hot spots (adjusted odds ratio (aOR) = 1.75, 95%, confidence interval (CI): 1.22, 2.50), Beijing family genotype (aOR = 1.83, 95% CI: 1.19, 2.81), living in the same room with an index case (aOR = 2.29, 95% CI: 1.5, 3.49), travelling time from home to a medical facility (aOR = 4.78, 95% CI: 2.96, 7.72), history of Bacillus Calmette-Guérin vaccination (aOR = 2.02, 95% CI: 1.13 3.62), and delay in diagnosis (aOR = 2.56, 95% CI: 1.13, 5.80) were significantly associated with positive TST results among household contacts of TB cases. The findings of this study confirmed the strong transmissibility of the Beijing genotype family strains and this genotype’s important role in household transmission. We found that an extended traveling time from home to the medical facility was an important socioeconomic factor for Mtb transmission in the family. It is still necessary to improve the medical facility infrastructure and management, especially in areas with a high TB prevalence.

Immune checkpoint inhibitors are among the newest, cutting‐edge methods for the treatment of cancer. Currently, they primarily influence T cell adaptive immunotherapy targeting the PD‐1/PD‐L1 and CTLA‐4/B7 signalling pathways. These inhibitors fight cancer by reactivating the patient's own adaptive immune system, with good results in many cancers. With the discovery of the “Don't Eat Me” molecule, CD47, antibody‐based drugs that target the macrophage‐related innate immunosuppressive signalling pathway, CD47‐SIRPα, have been developed and have achieved stunning results in the laboratory and the clinic, but there remain unexplained instances of tumour immune escape. While investigating the immunological tolerance of cancer to anti‐CD47 antibodies, a second “Don't Eat Me” molecule on tumour cells, beta 2 microglobulin (β2m), a component of MHC class I, was described. Some tumour cells reduce their surface expression of MHC class I to escape T cell recognition. However, other tumour cells highly express β2m complexed with the MHC class I heavy chain to send a “Don't Eat Me” signal by binding to leucocyte immunoglobulin‐like receptor family B, member 1 (LILRB1) on macrophages, leading to a loss of immune surveillance. Investigating the mechanisms underlying this immunosuppressive MHC class I‐LILRB1 signalling axis in tumour‐associated macrophages will be useful in developing therapies to restore macrophage function and control MHC class I signalling in patient tumours. The goal is to promote adaptive immunity while suppressing the innate immune response to tumours. This work will identify new therapeutic targets for the development of pharmaceutical‐based tumour immunotherapy.

Sirtuin 5 (SIRT5), a mitochondrial class III NAD-dependent deacetylase, plays controversial roles in tumorigenesis and chemoresistance. Accordingly, its role in ovarian cancer development and drug resistance is not fully understood. Here, we demonstrate that SIRT5 is increased in ovarian cancer tissues compared to its expression in normal tissues and this predicts a poor response to chemotherapy. SIRT5 levels were also found to be higher in cisplatin-resistant SKOV-3 and CAOV-3 ovarian cancer cells than in cisplatin-sensitive A2780 cells. Furthermore, this protein was revealed to facilitate ovarian cancer cell growth and cisplatin-resistance in vitro. Mechanistically, we show that SIRT5 contributes to cisplatin resistance in ovarian cancer by suppressing cisplatin-induced DNA damage in a reactive oxygen species (ROS)-dependent manner via regulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway.

Guangxi is one of the provinces having the highest reported incidence of tuberculosis (TB) in China. However, spatial and temporal pattern and causation of the situation are still unclear. In order to detect the spatiotemporal pattern of TB and the association with ecological environment factors in Guangxi Zhuang autonomous region, China, We performed a spatiotemporal analysis with prediction using time series analysis, Moran’s I global and local spatial autocorrelation statistics, and space-time scan statistics, to detect temporal and spatial clusters. Spatial panel models were employed to identify the influence factors. The time series analysis shows that the number of reported cases peaked in spring and summer and decreased in autumn and winter with the annual reported incidence of 113.1/100,000 population. Moran’s I global statistics were greater than 0 (0.363 – 0.536) during the study period. The most significant hot spots were mainly located in the central part. The east part exhibited a low-low relation. By spacetime scanning, the clusters identified were similar to that of the local autocorrelation statistics, and were clustered toward the early of 2016. Duration of sunshine, per capita gross domestic product (PGDP), the recovery rate of TB and participation rate of new cooperative medical care insurance in rural areas had a significant negative association with TB. In conclusion, the reported incidence of TB in Guangxi remains high. The main cluster was located in the central part of Guangxi, a region where promoting the productivity, improving TB treatment pathway and strengthening environmental protective measures (increasing sunshine exposure) are urgently needed.

Background: This study aimed to investigate the effects of ambroxol hydrochloride chitosan reduced the degree of peritoneal adhesion.Methods: A total of 120 Sprague-Dawley (SD) rats were experimented, group A: the damaged peritoneal was covered with ambroxol hydrochloride chitosan, group B: chitosan membrane only, group C: nothing. Enzyme-linked immunosorbent assay (ELISA), western blotting, and immunohistochemistry (IHC) were used to observe the expression of TNF-alpha and NF-kappa B p65.Results: TNF-alpha and NF-kappa B p65 in group A significantly decreased in comparison with the controls. IHC showed TNF-alpha and NF-kappa B p65 were significantly down-regulated in group A. Adhesion grade in the treatment group was significantly lower than in controls.Conclusion: Ambroxol hydrochloride chitosan reduced the degree of peritoneal adhesion.