This study aimed to predict the 5-year overall survival (OS) benefit of pola-R-CHP versus R-CHOP in the POLARIX trial based on the 2-year event-free survival (EFS) and progression-free survival (PFS) rates in diffuse large B-cell lymphoma (DLBCL). We identified randomized controlled trials (RCT) published before 31 May 2023. The correlation between the logarithmic (log) hazard ratio (HR) for EFS (HREFS ) or PFS (HRPFS ) and the HR for OS (HROS ) was estimated at the trial-level. Correlation analysis was performed between 2-year PFS or EFS and 5-year OS rates at the treatment arm-level. Linear regression models were used to calculate the 5-year OS of pola-R-CHP and R-CHOP. In the included 20 RCTs, a linear correlation between HREFS (r = 0.765) or HRPFS (r = 0.534) and HROS was observed at the trial- level. Two-year EFS (r = 0.918) or 2-year PFS (r = 0.865) correlated linearly with 5-year OS. Linear regression analysis between 2-year EFS/PFS and 5-year OS gave estimated 5-year OS rates between pola-R-CHP and R-CHOP of 6.4% and 6.3%, respectively. Two-year EFS and PFS are feasible early endpoints in patients with DLBCL treated primarily with immunochemotherapy. The pola-R-CHP regimen is expected to improve 5-year OS.

The present study aimed to investigate the effect of sinomenine hydrochloride (SIN) on cell survival/proliferation in the human hepatoma cell line Huh7, as well as determine the underlying mechanisms. Three different doses of SIN, 140, 280 and 560 µM, were tested. Cellular apoptosis and cell cycle distribution were analyzed by flow cytometry. Western blotting was used to determine protein levels of the apoptosis-associated regulators, cleaved caspase 3, B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax), Bcl-2 homologous antagonist/killer (Bak) and Bcl-extra large (Bcl-xl), as well as the cell cycle-related regulators, p21 and p27. It was observed that the three doses of SIN were able to suppress Huh7 cell survival/proliferation, and efficiently induce cellular apoptosis as well as multiphase cell cycle arrest. Mechanistically, SIN treatment upregulated the levels of the pro-apoptotic regulators, cleaved caspase 3 and Bax, and downregulated the level of anti-apoptotic Bcl-xl. Additionally, SIN treatment also increased the protein levels of p21 and p27, as two regulators functioning to slow cell cycle progression. Taken together, the present studied indicated SIN to be a promising compound for the treatment of hepatocellular carcinoma, based on its apparent effect in modulating cell apoptosis and the cell cycle in Huh7 cells in vitro.

Several prognostic scoring systems have been developed to assess prognosis in myelodysplastic syndrome (MDS). However, currently there are no systems that list gender as a prognostic factor. We queried a National Cancer Institute database to investigate the prognostic influence of gender on the survival of patients with MDS. We first identified 34,681 qualified patients diagnosed with MDS from 2001-2014 in the Surveillance, Epidemiology, and End Results (SEER) database, and then analyzed the characteristics of these patients using chi-squared tests. The Kaplan-Meier method and the multivariate Cox regression model were used to examine whether gender disparity in the survival of patients with MDS existed. We found that male patients had higher incidence rate of MDS (55.3% vs 44.7%, P<0.001) and a significant survival disadvantage (27.6% vs 33.6%, P<0.001) compared to female patients. Moreover, the less favorable survival rate of male MDS patients was associated with the age at diagnosis, race, marital status at diagnosis and the histological subtypes including refractory anemia (RA), refractory cytopenia with multilineage dysplasia (RCMD), myelodysplastic associated with isolated del 5q (MDS 5q-), myelodysplastic/myeloproliferative neoplasm (MDS/MPN) and not otherwise specified (NOS). In conclusion, gender can be considered as an independent prognostic factor for the overall survival of patients with MDS.

Studying the microbial symbionts of eukaryotic hosts has revealed a range of interactions that benefit host biology. Most eukaryotes are also infected by parasites that adversely affect host biology for their own benefit. However, it is largely unclear whether the ability of parasites to develop in hosts also depends on host-associated symbionts, e.g., the gut microbiota. Here, we studied the parasitic wasp Leptopilina boulardi (Lb) and its host Drosophila melanogaster. Results showed that Lb successfully develops in conventional hosts (CN) with a gut microbiota but fails to develop in axenic hosts (AX) without a gut microbiota. We determined that developing Lb larvae consume fat body cells that store lipids. We also determined that much larger amounts of lipid accumulate in fat body cells of parasitized CN hosts than parasitized AX hosts. CN hosts parasitized by Lb exhibited large increases in the abundance of the bacterium Acetobacter pomorum in the gut, but did not affect the abundance of Lactobacillus fructivorans which is another common member of the host gut microbiota. However, AX hosts inoculated with A. pomorum and/or L. fructivorans did not rescue development of Lb. In contrast, AX larvae inoculated with A. pomorum plus other identified gut community members including a Bacillus sp. substantially rescued Lb development. Rescue was further associated with increased lipid accumulation in host fat body cells. Insulin-like peptides increased in brain neurosecretory cells of parasitized CN larvae. Lipid accumulation in the fat body of CN hosts was further associated with reduced Bmm lipase activity mediated by insulin/insulin-like growth factor signaling (IIS). Altogether, our results identify a previously unknown role for the gut microbiota in defining host permissiveness for a parasite. Our findings also identify a new paradigm for parasite manipulation of host metabolism that depends on insulin signaling and the gut microbiota.

Typically, peripheral T-cell lymphoma (PTCLs) prognosis is estimated using overall survival before treatment. However, these estimates cannot show how prognosis evolves with the changing hazard rate over time. Patients (n = 650) with newly diagnosed PTCLs were enrolled retrospectively. After a median follow-up of 5.4 years, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) and NK/T cell lymphoma had initially lower 3-year conditional overall survival (COS3; i.e., the 3-year conditional overall survival was defined as the probability of surviving an additional 3 years) and higher hazards of death (26-44.3%). However, after 2 years, the COS3 increased and the death risk decreased over time, whereas anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma constantly had a lower risk over time (0-19.5%). For patients with complete remission after initial treatment, prognosis varied by histological subtypes, with PTCL, NOS having a negative impact. Our data suggested that the risk stratification using the International Prognostic Index might not accurately predict the COS3 for survivors of PTCLs. The COS3 provided time-dependent prognostic information for PTCLs, representing a possible surrogate prognosis indicator for long-term survivors after systemic chemotherapy.

Neuroinflammation is an important pathological process of neurodegenerative diseases, and microglial contributes to chronic inflammation and neuronal loss in progressive neurodegenerative. Therefore, regulating the inflammatory response of microglia could lead to the discovery of promising treatments for neurodegenerative diseases. In this study, we investigated the effects of the nutmeg plant seed extract, macelignan, on the inflammatory response of microglia and neuronal cell survival. We detected NO and iNOS using the Griess test and Western blotting. We measured phosphoinositide 3 kinase (PI3K)/Akt expression by Western blotting. The release of NO and inflammatory cytokines and the expression of iNOS decreased in a concentration-dependent manner, with an increase in macelignan concentration. PI3K/Akt phosphorylation levels decreased in a dose-dependent manner in lipopolysaccharide (LPS)-activated microglial cells after exposure to macelignan. We also demonstrated that macelignan improved HT22 cell viability, following exposure to a microglial-conditioned medium. Furthermore, macelignan inhibited microglial cell near neurons treated with a hypoxic conditioned medium. Finally, macelignan treatment reduced the expression of p27 and cyclin D1 in neurons cultured in an LPS-activated microglia-conditioned medium. Therefore, these results imply that macelignan can inhibit the inflammatory response of microglia and regulate neuronal survival through the PI3K/Akt pathway.

Clear-cell renal-cell carcinoma (ccRCC) is the most common pathological subtype of renal cell carcinoma (RCC), accounting for about 80% of RCC. In order to find potential prognostic biomarkers in ccRCC, we presented a four-gene signature to evaluate the prognosis of ccRCC. SurvExpress and immunohistochemical (IHC) staining of tissue microarrays were used to analyze the association between the four genes and the prognosis of ccRCC. Data from TCGA dataset revealed a prognostic prompt function of the four genes (PTEN, PIK3C2A, ITPA and BCL3). Further discovery suggested that the four-gene signature predicted survival better than any of the four genes alone. Moreover, IHC staining demonstrated a consistent result with TCGA, indicating that the signature was an independent prognostic factor of survival in ccRCC. Univariate and multivariate Cox proportional hazard regression analysis were conducted to verify the association of clinicopathological variables and the four genes' expression levels with survival. The results further testified that the risk (four-gene signature) was an independent prognostic factors of both Overall Survival (OS) and Disease-free Survival (DFS) (P<0.05). In conclusion, the four-gene signature was correlated with the survival of ccRCC, and therefore, may help to provide significant clinical implications for predicting the prognosis of patients.

DDX3X is a highly conserved DEAD-box RNA helicase that participates in RNA transcription, RNA splicing, and mRNA transport, translation, and nucleo-cytoplasmic transport. It is highly expressed in metaphase II (MII) oocytes and is the predominant DDX3 variant in the ovary and embryo. However, whether it is important in mouse early embryo development remains unknown. In this study, we investigated the function of DDX3X in early embryogenesis by cytoplasmic microinjection with its siRNA in zygotes or single blastomeres of 2-cell embryos. Our results showed that knockdown of Ddx3x in zygote cytoplasm led to dramatically diminished blastocyst formation, reduced cell numbers, and an increase in the number of apoptotic cells in blastocysts. Meanwhile, there was an accumulation of p53 in RNAi blastocysts. In addition, the ratio of cell cycle arrest during 2-cell to 4-cell transition increased following microinjection of Ddx3x siRNA into single blastomeres of 2-cell embryos compared with control. These results suggest that Ddx3x is an essential gene associated with cell survival and cell cycle control in mouse early embryos, and thus plays key roles in normal embryo development.

Extracellular matrix (ECM) integrity in the central nervous system (CNS) is essential for neuronal homeostasis. Signals from the ECM are transmitted to neurons through integrins, a family of cell surface receptors that mediate cell attachment to ECM. We have previously established a causal link between the activation of the matrix metalloproteinase-9 (MMP-9), degradation of laminin in the ECM of retinal ganglion cells (RGCs), and RGC death in a mouse model of retinal ischemia-reperfusion injury (RIRI). Here we investigated the role of laminin-integrin signaling in RGC survival in vitro, and after ischemia in vivo. In purified primary rat RGCs, stimulation of the β1 integrin receptor with laminin, or agonist antibodies enhanced RGC survival in correlation with activation of β1 integrin's major downstream regulator, focal adhesion kinase (FAK). Furthermore, β1 integrin binding and FAK activation were required for RGCs' survival response to laminin. Finally, in vivo after RIRI, we observed an up-regulation of MMP-9, proteolytic degradation of laminin, decreased RGC expression of β1 integrin, FAK and Akt dephosphorylation, and reduced expression of the pro-survival molecule bcl-xL in the period preceding RGC apoptosis. RGC death was prevented, in the context of laminin degradation, by maintaining β1 integrin activation with agonist antibodies. Thus, disruption of homeostatic RGC-laminin interaction and signaling leads to cell death after retinal ischemia, and maintaining integrin activation may be a therapeutic approach to neuroprotection.

Objective: Glioblastoma (GBM) is the most common and fatal primary brain tumor in adults. It is necessary to identify novel and effective biomarkers or risk signatures for GBM patients. Methods: Differentially expressed genes (DEGs) between GBM and low-grade glioma (LGG) in TCGA samples were screened out and weight correlation network analysis (WGCNA) was performed to confirm WHO grade-related genes. Five genes were selected via multivariate Cox proportional hazards regression analysis and were used to construct a risk signature. A nomogram composed of the risk signature and clinical characters (age, radiotherapy, and chemotherapy experience) was established to predict 1, 3, 5-year survival rate for GBM patients. Results: One hundred ninety-four DEGs in blue gene module were found to be positively related to WHO grade via WGCNA. Five genes (DES, RANBP17, CLEC5A, HOXC11, POSTN) were selected to construct a risk signature for GBM via R language. This risk signature was identified to independently predict the outcome of GBM patients, as well as stratified by IDH1 status, MGMT promoter status, and radio-chemotherapy. The nomogram was established which combined the risk signature with clinical factors. The results of c-index, ROC curve and calibration plot revealed the nomogram showing a good accuracy for predicting 1, 3, or 5-year survival of GBM patients. Conclusion: The risk signature with five genes could serve as an independent factor for predicting the prognosis of patients with GBM. Moreover, the nomogram with the risk signature and clinical traits proved to perform better for predicting 1, 3, 5-year survival rate.

Estrogen receptor α (ERα) is a hormone receptor and key driver for over 70% of breast cancers that has been studied for decades as a transcription factor. Unexpectedly, we discover that ERα is a potent non-canonical RNA-binding protein. We show that ERα RNA binding function is uncoupled from its activity to bind DNA and critical for breast cancer progression. Employing genome-wide cross-linking immunoprecipitation (CLIP) sequencing and a functional CRISPRi screen, we find that ERα-associated mRNAs sustain cancer cell fitness and elicit cellular responses to stress. Mechanistically, ERα controls different steps of RNA metabolism. In particular, we demonstrate that ERα RNA binding mediates alternative splicing of XBP1 and translation of the eIF4G2 and MCL1 mRNAs, which facilitates survival upon stress conditions and sustains tamoxifen resistance of cancer cells. ERα is therefore a multifaceted RNA-binding protein, and this activity transforms our knowledge of post-transcriptional regulation underlying cancer development and drug response.

Objectives: This study aimed to explore the predictive value of MRI-based radiomic model for progression-free survival (PFS) in nonmetastatic nasopharyngeal carcinoma (NPC). Methods: A total of 327 nonmetastatic NPC patients [training cohort (n = 230) and validation cohort (n = 97)] were enrolled. The clinical and MRI data were collected. The least absolute shrinkage selection operator (LASSO) and recursive feature elimination (RFE) were used to select radiomic features. Five models [Model 1: clinical data, Model 2: overall stage, Model 3: radiomics, Model 4: radiomics + overall stage, Model 5: radiomics + overall stage + Epstein-Barr virus (EBV) DNA] were constructed. The prognostic performances of these models were evaluated by Harrell's concordance index (C-index). The Kaplan-Meier method was applied for the survival analysis. Results: Model 5 incorporating radiomics, overall stage, and EBV DNA yielded the highest C-indices for predicting PFS in comparison with Model 1, Model 2, Model 3, and Model 4 (training cohorts: 0.805 vs. 0.766 vs. 0.749 vs. 0.641 vs. 0.563, validation cohorts: 0.874 vs. 0.839 vs. 836 vs. 0.689 vs. 0.456). The survival curve showed that the high-risk group yielded a lower PFS than the low-risk group. Conclusions: The model incorporating radiomics, overall stage, and EBV DNA showed better performance for predicting PFS in nonmetastatic NPC patients.

Glioblastoma multiforme (GBM) is a devastating brain tumour without effective treatment. Recent studies have shown that autophagy is a promising therapeutic strategy for GBM. Therefore, it is necessary to identify novel biomarkers associated with autophagy in GBM. In this study, we downloaded autophagy-related genes from Human Autophagy Database (HADb) and Gene Set Enrichment Analysis (GSEA) website. Least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analysis were performed to identify genes for constructing a risk signature. A nomogram was developed by integrating the risk signature with clinicopathological factors. Time-dependent receiver operating characteristic (ROC) curve and calibration plot were used to evaluate the efficiency of the prognostic model. Finally, four autophagy-related genes (DIRAS3, LGALS8, MAPK8 and STAM) were identified and were used for constructing a risk signature, which proved to be an independent risk factor for GBM patients. Furthermore, a nomogram was developed based on the risk signature and clinicopathological factors (IDH1 status, age and history of radiotherapy or chemotherapy). ROC curve and calibration plot suggested the nomogram could accurately predict 1-, 3- and 5-year survival rate of GBM patients. For function analysis, the risk signature was associated with apoptosis, necrosis, immunity, inflammation response and MAPK signalling pathway. In conclusion, the risk signature with 4 autophagy-related genes could serve as an independent prognostic factor for GBM patients. Moreover, we developed a nomogram based on the risk signature and clinical traits which was validated to perform better for predicting 1-, 3- and 5-year survival rate of GBM.

Acute megakaryoblastic leukaemia (AMKL) is characterized by expansion of megakaryoblasts, which are hyper-proliferative cells that fail to undergo differentiation. Insight to the cell-cycle regulation revealed important events in early or late megakaryocytes (MKs) maturation; the cyclin-dependent kinases 4 and 6 (CDK4/6) have been reported to participate in the development of progenitor megakaryocytes, mainly by promoting cell cycle progression and DNA polyploidization. However, it remains unclear whether the continuous proliferation, but not differentiation, of megakaryoblasts is related to an aberrant regulation of CDK4/6 in AMKL. Here, we found that CDK4/6 were up regulated in patients with AMKL, and persistently maintained at a high level during the differentiation of abnormal megakaryocytes in vitro, according to a database and western blot. Additionally, AMKL cells were exceptionally reliant on the cell cycle regulators CDK4 or 6, as blocking their activity using an inhibitor or short hairpin RNA (shRNA) significantly reduced the proliferation of 6133/MPL megakaryocytes, reduced DNA polyploidy, induced apoptosis, decreased the level of phosphorylated retinoblastoma protein (p-Rb), and activation of caspase 3. Additionally, CDK4/6 inhibitors and shRNA reduced the numbers of leukemia cells in the liver and bone marrow (BM), alleviated hepatosplenomegaly, and prolonged the survival of AMKL-transplanted mice. These results suggested that blocking the activity of CDK4/6 may represent an effective approach to control megakaryoblasts in AMKL.

The gastrointestinal (GI) tract is the second most frequent extranasal involvement site for ENKTL. This study aimed to explore the clinicopathological features, treatment models, survival outcomes, and prognosis of gastrointestinal ENKTL (GI-ENKTL).

Background: Here, we establish a prognostic signature based on glycosyltransferase-related genes (GTRGs) for head and neck squamous cell carcinoma (HNSCC) patients. Methods: The prognostic signature of GTRGs was constructed via univariate and multivariate Cox analyses after obtaining the expression patterns of GTRGs from the TCGA. A nomogram based on the signature and clinical parameters was established to predict the survival of each HNSCC patient. Potential mechanisms were explored through gene set enrichment analysis (GSEA) and immune cell infiltration, immune checkpoints, immunotherapy, and tumor mutational burden (TMB) analyses. The expression differences and prognostic efficacy of the signature were verified through the gene expression omnibus (GEO) and several online databases. Results: The prognostic signature was constructed based on five glycosyltransferases (PYGL, ALG3, EXT2, FUT2, and KDELC1) and validated in the GSE65858 dataset. The pathways enriched in the high- and low-risk groups were significantly different. The high-risk group had higher tumor purity; lower infiltration of immune cells, such as CD8+ T cells and Tregs; higher cancer-associated fibroblast (CAF) infiltration; lower immune function; and lower checkpoint expression. The signature can also be applied to distinguish whether patients benefit from immunotherapy. In addition, the high-risk group had a higher TMB and more gene mutations, including those in TP53, CSMD1, CDKN2A, and MUC17. Conclusion: We propose a prognostic signature based on glycosyltransferases for HNSCC patients that may provide potential targets and biomarkers for the precise treatment of HNSCC.

Progressive retinal ganglion cells (RGCs) death that triggered by retinal ischemia reperfusion (IR), leads to irreversible visual impairment and blindness, but our knowledge of post-IR neuronal death and related mechanisms is limited. In this study, we first demonstrated that apart from necroptosis, which occurs before apoptosis, ferroptosis, which is characterized by iron deposition and lipid peroxidation, is involved in the whole course of retinal IR in mice. Correspondingly, all three types of RGCs death were found in retina samples from human glaucoma donors. Further, inhibitors of apoptosis, necroptosis, and ferroptosis (z-VAD-FMK, Necrostatin-1, and Ferrostatin-1, respectively) all exhibited marked RGC protection against IR both in mice and primary cultured RGCs, with Ferrostatin-1 conferring the best therapeutic effect, suggesting ferroptosis plays a more prominent role in the process of RGC death. We also found that activated microglia, Müller cells, immune responses, and intracellular reactive oxygen species accumulation following IR were significantly mitigated after each inhibitor treatment, albeit to varying degrees. Moreover, Ferrostatin-1 in combination with z-VAD-FMK and Necrostatin-1 prevented IR-induced RGC death better than any inhibitor alone. These findings stand to advance our knowledge of the post-IR RGC death cascade and guide future therapy for RGC protection.

Limiting CD4+ T cell responses is important to prevent solid organ transplant rejection. In a mouse model of costimulation blockade-dependent cardiac allograft tolerance, we previously reported that alloreactive CD4+ conventional T cells (Tconvs) develop dysfunction, losing proliferative capacity. In parallel, induction of transplantation tolerance is dependent on the presence of regulatory T cells (Tregs). Whether susceptibility of CD4+ Tconvs to Treg suppression is modulated during tolerance induction is unknown. We found that alloreactive Tconvs from transplant tolerant mice had augmented sensitivity to Treg suppression when compared with memory T cells from rejector mice and expressed a transcriptional profile distinct from these memory T cells, including down-regulated expression of the transcription factor Special AT-rich sequence-binding protein 1 (Satb1). Mechanistically, Satb1 deficiency in CD4+ T cells limited their expression of CD25 and IL-2, and addition of Tregs, which express higher levels of CD25 than Satb1-deficient Tconvs and successfully competed for IL-2, resulted in greater suppression of Satb1-deficient than wild-type Tconvs in vitro. In vivo, Satb1-deficient Tconvs were more susceptible to Treg suppression, resulting in significantly prolonged skin allograft survival. Overall, our study reveals that transplantation tolerance is associated with Tconvs' susceptibility to Treg suppression, via modulated expression of Tconv-intrinsic Satb1. Targeting Satb1 in the context of Treg-sparing immunosuppressive therapies might be exploited to improve transplant outcomes.

Background: D'Amico high-risk prostate cancer (Pca) patients experience poor and heterogeneous oncological outcomes. This heterogeneity highlights a need to extensively explore factors associated with poor outcomes to guide decision-making. Objective: To assess predictors of biochemical recurrence (BCR)-free survival in high-risk patients following radical prostatectomy (RP), and subsequently establish a model predicting outcomes. Methods: We retrospectively identified D'Amico high-risk non-metastatic Pca patients who underwent RP between 2013 and 2019 in our hospital. We collected data including PSA level, clinical stage, biopsy Gleason score (GS), number of D'Amico high-risk factors (RF), the inflammatory status (Neutrophil-to-lymphocyte ratio [NLR], derived NLR [dNLR], platelet-to-lymphocyte ratio [PLR] and LDH). Kaplan-Meier methods were used to analyze BCR-free survival. Univariate and multivariate analyses were performed using Cox proportional hazards model to evaluate the association between clinicopathological parameters and BCR-free survival. Results: The median follow-up time for the 101 patients' cohort was 26 months (range: 3-81 months). The number of RF (1RF vs. ≥2RF), biopsy GS (<8 vs. ≥8), clinical stage (≤cT2c vs. >cT2c), pathological stage, and the presence of adverse pathological features were significant predictors of BCR (P < 0.05). Other parameters including inflammatory status (dNLR, NLR, PLR, and LDH) were not of predictive value. On multivariable analysis, biopsy GS (<8 vs. ≥8; HR 2.439) and clinical stage (≤cT2c vs. >cT2c; HR 3.271) were the independent predictors of BCR. Based on these two independent predictors, patients were stratified into three risk subgroups: favorable (0 risk factor; 47% of patients), intermediate (1 risk factor; 42 %), unfavorable (2 risk factors; 11%). The intermediate and unfavorable subgroups have a significantly shorter median BCR-free survival compared to the favorable subgroup (P < 0.001). Conclusion: Several factors are associated with BCR. Clinical stage (≤cT2c vs. >cT2c) and biopsy GS (<8 vs. ≥8) are the independent predictors of BCR. The stratification of high-risk patients into risk subgroups based on these two predictors shows that the intermediate and unfavorable subgroups have a significantly shorter median BCR-free survival compared to the favorable subgroup. The preoperative stratification model may help urologists and patients during decision-making. In non-metastatic high-risk patients, preoperative inflammatory markers (NLR, dNLR, PLR, and LDH) are not of prognostic value.

Triple negative breast cancer (TNBC) is an aggressive and heterogeneous disease. Nomograms predicting outcomes of TNBC are needed for risk management.