Prognostic and therapeutic significance of XPO1 in T-cell lymphoma.

T-cell lymphoma (TCL) is a highly heterogeneous group of invasive non-Hodgkin lymphoma with adverse prognosis and limited treatment options. The relationship between TCL and Exportin-1 (XPO1), a major nuclear export receptor, has not been established yet. We here investigated the prognostic role and therapeutic implication of XPO1 in TCL. We analyzed XPO1 expression in a cohort of 69 TCL tumors and found that XPO1 was over-expressed in 76.8% of TCL and correlated with decreased progression-free survival (PFS) and overall survival (OS). In vitro treatment of TCL cell lines with KPT-8602, the second-generation selective inhibitor of nuclear export (SINE), inhibited XPO1 expression and showed significant anti-proliferative, cell-cycle arrest and pro-apoptotic efficacy. In mechanism, KPT-8602 restored the localization of cytoplasmic FOXO3A, p27, p21, IκBα and PP2A into the nucleus, leading to AKT and NF-κB deactivation. Our data demonstrate for the first time that XPO1 could be an unfavorable prognostic factor for TCL, and provide a rationale for further investigation of the efficacy of KPT-8602 in TCL patients.

Comparative efficacy and safety of eleven induction chemotherapy regimens for young adult patients with newly diagnosed acute myeloid leukemia: a network meta-analysis.

The optimal induction chemotherapy regimens for young adult patients with newly diagnosed acute myeloid leukemia (AML) are not well-defined since the lack of direct comparisons between emerging treatments. Network meta-analysis (NMA) is a statistical tool to integrate direct and indirect evidence to evaluate the effect of multiple interventions. Thus, we conducted an NMA to systematically assess the efficacy and safety of different inductions for these patients. PubMed, Embase, Cochrane Library, and Web of Science were searched from establishment to 2020-03-11. Randomized controlled trials (RCTs) using different inductions were included. We deemed 11 trials eligible, including 11 inductions with 5052 participants. Relative risk (RR) and 95% confidence intervals (CIs) were calculated. In terms of complete remission (CR) rate, DAC ranked highest and was significantly higher than IA (RR = 1.27, 95% CI (1.09-1.48)) and DA (RR = 1.28, 95% CI (1.13-1.46)) (p < 0.05). The ranking of DA + Pioglitazone was second only to that of DAC, followed by HAA. For early mortality, HAD, HAA, and DA + GO were significantly higher than DA/IA (p < 0.05). DAC and DA + Pioglitazone showed similar early mortality compared to DA/IA (p > 0.05). Regarding incidence of early grade 3-4 infection, no significant differences between interventions were observed. To conclude, among the included 11 induction regimens, DAC was potentially the top choice for young adult patients with newly diagnosed AML, with highest CR rate, low early mortality, and incidence of early infection. DA + Pioglitazone and HAA also showed a superiority over the others to achieve higher CR rate, while caution should be kept in mind due to the higher early mortality of HAA.

Mesenchymal stem cell exosomes promote immunosuppression of regulatory T cells in asthma.

Mesenchymal stem cells (MSCs) and regulatory T cells (Tregs) are both potent immune-modulators. The aberrant proliferation and function of Tregs plays an important role in the development of asthma. Our previous studies have demonstrated the role of MSCs in promoting proliferation and immune-modulating of Tregs, as well as alleviating airway inflammation of asthmatic mice. In the present study, we isolated exosomes secreted by MSCs and investigated their immunomodulation effect on peripheral blood mononuclear cells (PBMCs) of asthmatic patient. We found that MSC exosomes upregulated IL-10 and TGF-ß1 from PBMCs, thus promoting proliferation and immune-suppression capacity of Tregs. Furthermore, antigen presenting cells (APCs) but not CD4+ T cells-dependent pathway was shown to be possible mechanism involved in MSC exosome-mediated regulation. Our data elucidated the key role of exosomes in immune-modulation of MSCs, and suggested the therapeutic potential of MSC exosomes for asthma.

High frequency of GATA2 variants in patients with pulmonary fungal disease without immunocompromised risk factors: a retrospective study.

Background: The global incidence of pulmonary fungal diseases is on the rise. Individuals harboring underlying immunocompromised conditions such as human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), malignant tumors, or those who have undergone organ transplantation, among others, are particularly susceptible to fungal infections. However, in clinical practice, certain patients diagnosed with pulmonary fungal infections exhibit no discernible risk factors for immunosuppression. GATA2, a pivotal transcription factor governing hematopoiesis, is implicated in GATA2 deficiency, predisposing individuals to fungal infections. This study aims to scrutinize GATA2 variants in adult patients afflicted with pulmonary fungal infections devoid of recognized risk factors for immunosuppression. Methods: A cohort of adult patients (aged 18-65 years old, n=22) diagnosed with pulmonary fungal diseases lacking underlying immunosuppression risk factors, treated at Sun Yat-sen Memorial Hospital from January 2016 to December 2021, underwent Sanger sequencing of the GATA2 gene. Results: Among the 22 patients devoid of immunocompromised risk factors and diagnosed with pulmonary fungal diseases, 17 patients (77.3%) exhibited single nucleotide variants (SNVs) within the exons of the GATA2 gene. Notably, exon 3 variants were present in 7 cases (41.2%), exon 4 variants in 10 cases (58.8%), and exon 5 variants in 11 cases (64.7%), emerging as the most prevalent exonic variants within GATA2. Among the 17 patients harboring GATA2 SNVs, a total of 28 SNVs were identified. Of these, eight variants (NM_001145661.2:c.33G>A, NM_001145661.2:c.523C>T, NM_001145661.2:c.77A>G, NM_001145661.2:c.545C>T, NM_001145661.2:c.7G>A, NM_001145661.2:c.1406A>G, NM_001145661.2:c.977A>G, NM_001145661.2:c.742A>C) were identified as missense mutations with the potential to alter the structure and function of the GATA2 protein on the basis of multiple in silico predictive programs interpretation. One nonsense mutation (NM_001145661.2:c.664A>T) was classified as "likely pathogenic" according to 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. Conclusions: GATA2 variants are prevalent among patients afflicted with pulmonary fungal infections in the absence of traditional immunosuppressive risk factors. Further investigations are warranted to elucidate the impact of GATA2 variants on the expression and functionality of the GATA2 protein.

Growth of T-cell lymphoma cells is inhibited by mPGES-1/PGE2 suppression via JAK/STAT, TGF-ß/Smad3 and PI3K/AKT signal pathways.

Background: T-cell lymphoma (TCL) has a very poor prognosis with limited treatment options and novel therapeutic target is urgently needed. Our previous studies have found that suppression of membrane-bound prostaglandin E2 synthase l/prostaglandin E2 (mPGES-1/PGE2) exerted anti-neoplastic effects in leukemia cells by suppressing AKT signal pathway. Here, we aim at evaluating the role and mechanism of mPGES-1/PGE2 signaling in TCL. Methods: Expression of mPGES-1 in TCL cell line Hut78 was analyzed by Western blot and immunofluorescence. CAY10526, a selective mPGES-1 inhibitor, was used to treat Hut 78 cells. Cell viability assays was performed by using cell counting kit-8 (CCK-8). Cell apoptosis rate was examined by flow cytometer. PGE2 synthesis was detected by enzyme immunoassay (EIA). The expression of mPGES-1, cleaved caspase-3, Janus kinase/signal transduction and transcription (JAK/STAT), transforming growth factor-ß (TGF-ß)/Smad3 and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway of Hut 78 cells after exposed to CAY10526 was analyzed by Western blot. Results: mPGES-1 was highly expressed in Hut78 cell compared to normal peripheral blood mono-nuclear cells. CAY10526 inhibited cell proliferation and induced apoptosis in Hut78 cells. These effects may be partially attributed to the activation of the Caspase family and the inhibition of JAK/STAT, TGF-ß/Smad3 and PI3K/AKT signal pathways. Conclusions: Our results suggested that mPGES-1/PGE2 could be a potential therapeutic target for TCL.

Clinical characteristics of Hepatoid adenocarcinoma of the lung: Four case reports and literature review.

PURPOSE: Hepatoid adenocarcinoma of the lung (HAL) is a rare form of lung cancer, which is characterized by its morphologic hepatoid features. The clinical characteristics and prognosis of this rare form of lung cancer remain obscure. METHODS: The clinical courses of four cases of HAL were reported. A literature search was performed up to December 31, 2020, using the electronic databases PubMed and Web of Science. RESULTS: Including the present 4 cases, a total of 42 cases of HAL have been reported in the literature. The median age was 58.5 years old (range, 36-73 years). 36 (85.7%) patients were male. 26 (61.9%) patients had a history of smoking, the median amount of smoking was 40 pack years (range, 8-180). The most common site of the primary tumor was the right upper lobe (22 cases, 52.3%) and the left upper lobe (10 cases, 23.8%). 21 patients (50%) had pretreatment serum AFP levels higher than the upper limit, and 4 patients (9.5%) had normal pretreatment serum AFP levels. Treatment of HAL included surgery, chemotherapy, radiotherapy, tyrosine kinase inhibitors (TKIs), anti-angiogenesis therapy, and anti-PD-1/PD-L1 monoclonal antibody. Overall, the prognosis of HAL was poor, with median overall survival (OS) of 14 months. CONCLUSIONS: HAL is an aggressive tumor, with a poor prognosis and male predominance, which tends to occur in heavy smokers and affects the right upper lobe of the lung.

MSCs exosomal miR-1470 promotes the differentiation of CD4+CD25+FOXP3+ Tregs in asthmatic patients by inducing the expression of P27KIP1.

Exosomes derived from Mesenchymal Stem Cells (MSCs) possesses similar immunomodulatory effect as MSCs. It had been suggested that MSCs exosomes contain higher level of miR-1470 compared to exosomes derived from fibroblast. Here, we show that MSCs exosomal miR-1470 can elevate the proportion of CD4+CD25+FOXP3+ regulatory T cells (Tregs) in asthmatic patients. Moreover, mechanistic studies revealed that miR-1470 can promote the upregulation of P27KIP1 by directly targeting the 3' region of c-Jun mRNA. Furthermore, miR-1470 mimic transfection could significantly upregulate the proportion of CD4+CD25+FOXP3+ Tregs in CD4+ T cells. P27KIP1 knockdown via siRNA silencing significantly inhibited the proportion of CD4+CD25+FOXP3+ Tregs with over-expression of miR-1470, which indicates that miR-1470 induces the differentiation of CD4+CD25+FOXP3+ Tregs through P27KIP1.

Anti-PD-1/PD-L1 antibody versus conventional chemotherapy for previously-treated, advanced non-small-cell lung cancer: a meta-analysis of randomized controlled trials.

BACKGROUND: The anti-PD-1/PD-L1 monoclonal antibody has showed promising results in various cancers via enhancing T cell functions. However, many questions remain in the role and safety in previously-treated, advanced non-small-cell lung cancer (NSCLC). Thus, we conducted a meta-analysis incorporating all available evidences to evaluate the efficacy and safety of anti-PD-1/PD-L1 antibody compared with chemotherapy. METHODS: PubMed, Web of Science and the Cochrane Library database were searched for the studies about the efficacy and safety of anti-PD-1/PD-L1 antibody in previously-treated, progressive NSCLC patients. Only randomized controlled trials (RCTs) comparing anti-PD-1/PD-L1 antibody with conventional chemotherapy in NSCLC were included. Overall survival (OS) in the intention-to-treat population was the primary outcome. The secondary outcomes were: progression-free survival (PFS) in the intention-to-treat population, objective response rate (ORR), the incidence of adverse events, OS and PFS in different PD-L1 expression subgroups. RESULTS: Four trials with a total of 2,174 patients were included. Anti-PD-1/PD-L1 antibody showed a significant benefit to OS in the intention-to-treat population [combined hazard ratio (HR) 0.67; 95% CI: 0.61-0.75, P<0.00001], a 33% reduction in the relative risk of death. PFS also favored anti-PD-1/PD-L1 antibody (HR 0.81, 95% CI: 0.70-0.95, P=0.009). The ORR was significantly higher with anti-PD-1/PD-L1 antibody than those with chemotherapy (RR of nonresponse, 0.92; 95% CI: 0.89-0.95, P<0.00001). Anti-PD-1/PD-L1 antibody was associated with greater efficacy than chemotherapy across the end points of OS and PFS when tumor PD-L1 expression scored ≥1%, ≥5%, and ≥50%, except for tumor PD-L1 expression scored <1%. The group receiving anti-PD-1/PD-L1 antibody had lower rates of treatment-related adverse events of any grade (RR 0.77; 95% CI: 0.73-0.81, P<0.00001) and treatment-related adverse events of grade 3-5 (RR 0.24; 95% CI: 0.14-0.41, P<0.00001). CONCLUSIONS: Anti-PD-1/PD-L1 antibody significantly improved survival compared with chemotherapy in previously-treated, progressive NSCLC patients. Besides, it also had a better safety profile.

CD80 and CD86 knockdown in dendritic cells regulates Th1/Th2 cytokine production in asthmatic mice.

Dendritic cells (DCs) are associated with the activation and differentiation of T helper (Th) cells. Cluster of differentiation (CD)80 and CD86, the co-stimulatory molecules highly expressed in DCs, have are prominent in promoting the differentiation of Th cells toward Th2 cells. However, little is known about the effect of CD80 and CD86 knockdown on Th1/Th2 cytokine production in mature DCs (mDCs). The aim of the present study was to investigate whether small-interfering RNA (siRNA) could suppress the surface expression of CD80 and CD86 in mDCs. The effects of CD80 and CD86 knockdown in mDCs on Th1/Th2 cytokine expression were examined using an asthmatic murine model. DCs were isolated, separated and cultured in vitro. Flow cytometry was used to examine the expression of CD11c, CD80 and CD86 on the DCs. The DCs were transfected with CD80- and CD86-specific siRNA, while non-siRNA and negative siRNA controls were also designed. Then, the mRNA and protein expression levels of CD80 and CD86 were determined by reverse transcription-quantitative polymerase chain reaction and flow cytometry, respectively. The levels of interferon (IFN)-γ and interleukin (IL)-4 produced by T cells co-cultured with mDCs were measured by enzyme-linked immunosorbent assay. Substantial downregulation of CD80 and CD86 mRNA and protein levels were observed in the mDCs following transfection with siRNA. The level of IFN-γ produced by T cells co-cultured with mDCs was significantly increased in the siRNA group, while IL-4 production was significantly decreased. These results show that specific targeting of CD80 and CD86 with siRNA is able to suppress CD80/CD86 expression and consequently regulate Th1/Th2 cytokine levels by increasing IFN-γ production and decreasing IL-4 levels in an asthmatic murine model.