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Abstract Multiple myeloma (MM) is a heterogeneous and incurable tumor characterized by the malignant proliferation of plasma cells. It is necessary to clarify the heterogeneity of MM and identify new theranostic targets. We constructed a single-cell transcriptome profile of 48,293 bone marrow cells from MM patients and health donors (HDs) annotated with 7 continuous B lymphocyte lineages. Through CellChat, we discovered that the communication among B lymphocyte lineages between MM and HDs was disrupted, and unique signaling molecules were observed. Through pseudotime analysis, it was found that the differences between MM and HDs were mainly reflected in plasma cells. These differences are primarily related to various biological processes involving mitochondria. Then, we identified the key subpopulation associated with the malignant proliferation of plasma cells. This group of cells exhibited strong proliferation ability, high CNV scores, high expression of frequently mutated genes, and strong glucose metabolic activity. Furthermore, we demonstrated the therapeutic potential of WNK1 as a target. Our study provides new insights into the development of B cells and the heterogeneity of plasma cells in MM and suggests that WNK1 is a potential therapeutic target for MM.

Abstract The serine/arginine-rich splicing factors (SRSFs) play an important role in regulating the alternative splicing of precursor RNA (pre-RNA). During this procedure, introns are removed from the pre-RNA, while the exons are accurately joined together to produce mature mRNA. In addition, SRSFs also involved in DNA replication and transcription, mRNA stability and nuclear export, and protein translation. It is reported that SRSFs participate in hematopoiesis, development, and other important biological process. They are also associated with the development of several diseases, particularly cancers. While the basic physiological functions and the important roles of SRSFs in solid cancer have been extensively reviewed, a comprehensive summary of their significant functions in normal hematopoiesis and hematopoietic malignancies is currently absent. Hence, this review presents a summary of their roles in normal hematopoiesis and hematopoietic malignancies. Graphical Abstract

Abstract Immune thrombocytopenia (ITP) is an autoimmune disease caused by T-cell dysfunction. Recently, several studies have shown that a disturbed Th17/Treg balance contributes to the development of ITP. MicroRNAs (miRNAs) are small noncoding RNA moleculesthat posttranscriptionally regulate gene expression. Emerging evidences have demonstrated that miRNAs play an important role in regulating the Th17/Treg balance. In the present study, we found that miR-641 was upregulated in ITP patients. In primary T cells, overexpression of miR-641 could cause downregulation of its target genes STIM1 and SATB1, thus inducing a Th17 (upregulated)/Treg (downregulated) imbalance. Inhibition of miR-641 by a miR-641 sponge in primary T cells of ITP patients or by antagomiR-641 in an ITP murine model could cause upregulation of STIM1 and SATB1, thus restoring Th17/Treg homeostasis. These results suggested that the miR-641-STIM/SATB1 axis plays an important role in regulating the Th17/Treg balance in ITP.

Acute myeloid leukemia (AML), a highly heterogeneous myeloid malignancy, remains a challenge in terms of proper risk stratification. In this study, we developed a novel pyroptosis prognostic model based on pyroptosis-related gene pairs, which exhibited excellent prognostic performance across multiple cohorts (N = 1506) and accurately predicted both adult and pediatric AML prognosis. Additionally, we integrated the pyroptosis risk model with other clinical risk factors to construct a highly operational nomogram. Moreover, our findings indicate a significant correlation between elevated pyroptosis risk scores and increased stemness of AML. Using CIBERSORT immune analysis, we found a decreased proportion of resting NK cells and activated mast cells in the high-risk group. Through analyzing the correlation between chemotherapy drug response sensitivity and risk scores, we found that AZD1332 and BPD-0008900 were extremely sensitive in the high-risk group.

The hypoxic microenvironment is an essential characteristic of most malignant tumors. Notably, hypoxia-inducible factor-1 alpha (HIF-1α) is a key regulatory factor of cellular adaptation to hypoxia, and many critical pathways are correlated with the biological activity of organisms via HIF-1α. In the intra-tumoral hypoxic environment, HIF-1α is highly expressed and contributes to the malignant progression of tumors, which in turn results in a poor prognosis in patients. Recently, it has been indicated that HIF-1α involves in various critical processes of life events and tumor development via regulating the expression of HIF-1α target genes, such as cell proliferation and apoptosis, angiogenesis, glucose metabolism, immune response, therapeutic resistance, etc. Apart from solid tumors, accumulating evidence has revealed that HIF-1α is also closely associated with the development and progression of hematological malignancies, such as leukemia, lymphoma, and multiple myeloma. Targeted inhibition of HIF-1α can facilitate an increased sensitivity of patients with malignancies to relevant therapeutic agents. In the review, we elaborated on the basic structure and biological functions of HIF-1α and summarized their current role in various malignancies. It is expected that they will have future potential for targeted therapy.

Objective To investigate the effect of the kinase inhibitor AT9283 on Burkitt lymphoma (BL) cells and elucidate the underlying mechanisms. Methods The effect of AT9283 on the proliferation of BL cell lines was tested using the MTT assay. Apoptosis and cell cycle were measured by flow cytometry. The proteins associated with the cell cycle, apoptosis, and the Warburg effect were detected using Western blotting. Alterations in glycolytic metabolism in terms of glucose intake and lactate concentrations were determined by glucose and lactate assays. Results The current study utilized the GEPIA, the Human Protein Atlas (HAP) database and immunohistochemistry to conduct analyses, which revealed a high expression of Aurora kinases and Warburg effect-related proteins in malignant B-cell lymphoma tissues. AT9283 significantly inhibited the cell proliferation of BL cells and induced G2/M arrest. Additionally, AT9283 induced apoptosis in BL cells and reversed the Warburg effect by increasing glucose uptake and reducing lactate production. Moreover, the protein expression of hexokinase 2, pyruvate kinase M2, and lactate dehydrogenase A was significantly suppressed by AT9283, possibly through the inhibition of c-Myc and HIF-1α protein expression. Conclusion The reversal of the Warburg effect in BL cells and the subsequent inhibition of cell proliferation and induction of apoptosis were observed by targeting Aurora A and Aurora B with AT9283. This finding may present new therapeutic options and targets for BL.

ABSTRACTBackground Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. We aimed to build a ferroptosis-related gene (FRG) prognostic signature to predict the outcome of DLBCLs.Methods Our study retrospectively investigated the mRNA expression level and clinical data of 604 DLBCL patients from three GEO public datasets. We performed Cox regression analysis to extract the FRGs with prognostic values. ConsensusClusterPlus was used to categorize the DLBCL samples according to gene expression. The least absolute shrinkage and selection operator (LASSO) method and univariate Cox regression were implemented to construct the FRG prognostic signature. The association between the FRG model and clinical characteristics was also investigated.Results We identified 19 FRGs with potential prognostic values and classified the patients into clusters 1 and 2. Cluster 1 showed a shorter overall survival (OS) time than cluster 2. The two clusters had different patterns of infiltrating immune cells. LASSO was used to generate a six-gene risk signature (GCLC, LPCAT3, NFE2L2, ABCC1, SLC1A5, and GOT1), based on which a risk score formula and prognostic model were constructed for predicting the OS of DLBCL patients. Kaplan–Meier survival analysis proved that poorer OS was exhibited in the higher-risk patients stratified by the prognostic model in both the training and test cohorts. In addition, both the decision curve and the calibration plots showed that the nomogram had good agreement between the predicted results and actual observations.Conclusions We developed and validated a novel FRG-based prognostic model which could help to predict the outcomes of DLBCL patient.

5-methylcytosine modifications play a significant role in carcinogenesis; however, studies exploring 5-methylcytosine-related genes in diffuse large B-cell lymphoma patients are lacking. In this study, we aimed to understand the potential role and clinical prognostic impact of 5-methylcytosine regulators in diffuse large B-cell lymphoma and identify a prognostic biomarker based on 5-methylcytosine-associated genes. Gene expression profiles and corresponding clinical information of diffuse large B-cell lymphoma patients and normal controls were obtained from The Cancer Genome Atlas, Gene Expression Omnibus, and Genotype-Tissue Expression databases. Diffuse large B-cell lymphoma was divided into three clusters according to the 5-methylcytosine regulators, and differentially expressed genes were screened among the three clusters. Univariate Cox and Lasso-Cox regression analyses were used to screen prognostic genes and construct a prognostic risk model. Kaplan-Meier curve analysis, univariate and multivariate Cox regression analyses, and time-dependent receiver operator characteristic curve analysis were used to evaluate prognostic factors. GSVA was used to enrich potential pathways associated with 5-methylcytosine modification patterns. SsGSEA and CIBERSORT were used to assess immune cell infiltration. Six 5-methylcytosine-related genes (TUBB4A, CD3E, ZNF681, HAP1, IL22RA2, and POSTN) were used to construct a prognostic risk model, which was proved to have a good predictive effect. In addition, univariate and multivariate Cox regression risk scores were independent prognostic factors for diffuse large B-cell lymphoma. Further analysis showed that the 5-methylcytosine risk score was significantly correlated with immune cell infiltration and immune checkpoint of diffuse large B-cell lymphoma. Our study reveals for the first time a potential role for 5-methylcytosine modifications in diffuse large B-cell lymphoma, provides novel insights for future studies on diffuse large B-cell lymphoma, and offers potential prognostic biomarkers and therapeutic targets for patients with diffuse large B-cell lymphoma.

Abstract Purpose Endometriosis (EMS) is confirmed pathophysiologically to be an estrogen-dependent disease, similar to endometrial hyperplasia/cancer and breast cancer. Epidemiological and biological data on endometriosis might explain links between endometriosis and these cancers. We sought to identify the differences in the risk of endometrial cancer and breast cancer between women with and women without endometriosis. Methods We searched PubMed, EMBASE, the Cochrane Library, and four Chinese databases (CNKI, VIP, WanFang, CBM) to identify relevant studies published online between January 2011 and March 2021. In our meta-analysis, we used the Newcastle–Ottawa Scale (NOS) to evaluate the design and quality of all studies, and we calculated the pooled risk ratio (RR) using the random model. The Q test and I2 were used to evaluate the degree of heterogeneity of eligible studies. We used funnel plots and Begg’s and Egger’s tests to assess publication bias. Results Of the 1369 articles, we finally included 14 cohort studies and seven case–control studies. Data from large cohort and case–control studies indicate that women with endometriosis had an increased risk of both endometrial cancer [RR, 1.662; 95% CI, (1.148–2.407)] and breast cancer [RR, 1.082; 95% CI, (1.001–1.169)]. Conclusion Endometriosis can increase the risk of endometrial cancer and breast cancer, and women with endometriosis are recommended to receive routine screening in long-term management.

Abstract AlGaAsSb attracts significant interest for near‐infrared avalanche photodiodes (APD). The authors report a two‐order reduction in the dark current and a six‐time enhancement of gain in random alloy (RA) AlGaAsSb APD that is surface passivated by conformal coating of Al2O3 via atomic layer deposition (ALD). The dark currents of the APDs with 400‐µm diameter (dry etched) at 90% breakdown voltage (0.9 Vbr) are (5.5 ± 0.5) × 10−5 A, (2.1 ± 0.4) × 10−5 A, and (6.2 ± 0.8) × 10−7 A for non‐passivated, Si3N4 passivated, and Al2O3 passivated devices, respectively. The dark current at a gain of 10 for the Al2O3 passivated device is 1 × 10−8 A which is comparable to the reported value for 100‐µm diameter mesa diodes passivated by SU‐8. Maximum gain values of 6, 12, and 35 were obtained for non‐passivated, Si3N4 passivated, and Al2O3 passivated devices, respectively. Moreover, punch‐through capacitance of 8 pF in a spectral response of 450 to 850 nm was obtained. Thus, Al2O3 passivation can be the best solution for antimonide optoelectronic devices.

Abstract Endometrial cancer (EC) is the most common female reproductive tract cancer and its incidence has been continuously increasing in recent years. The underlying mechanisms of EC tumorigenesis remain unclear, and efficient target therapies are lacking, for both of which feasible endometrial cancer animal models are essential but currently limited. Here, an organoid and genome editing‐based strategy to generate primary, orthotopic, and driver‐defined ECs in mice is reported. These models faithfully recapitulate the molecular and pathohistological characteristics of human diseases. The authors names these models and similar models for other cancers as organoid‐initiated precision cancer models (OPCMs). Importantly, this approach can conveniently introduce any driver mutation or a combination of driver mutations. Using these models,it is shown that the mutations in Pik3ca and Pik3r1 cooperate with Pten loss to promote endometrial adenocarcinoma in mice. In contrast, the Kras G12D mutati led to endometrial squamous cell carcinoma. Then, tumor organoids are derived from these mouse EC models and performed high‐throughput drug screening and validation. The results reveal distinct vulnerabilities of ECs with different mutations. Taken together, this study develops a multiplexing approach to model EC in mice and demonstrates its value for understanding the pathology of and exploring the potential treatments for this malignancy.

Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma (PTCL) strongly correlated with worse clinical outcomes. However, the role of characteristic pathway-related genes in patients with AITL (e.g., subtype typing and pathogenesis) remains unknown. In this study, we intended to understand the potential role and prognostic value of characteristic pathways in AITL and identified a model for subtype identification based on pathway-related functional status. Transcriptomic (RNA-seq) data were obtained from the Gene Expression Omnibus database for three sets of tumor tissues from AITL patients. AITL was divided into three clusters based on the pathway profile of patients and the best clustering k = 3, and differentially expressed genes (DEGs) in the three clusters were analyzed. The top 45 important variables associated with characteristic pathways, such as Huntington's disease, VEGF signaling pathway, nucleotide excision repair, ubiquitin-mediated proteolysis, purine metabolism, olfactory transduction, etc., were used to construct a subtype identification model. The model was experimentally validated and proved to possess good predictive efficacy. In addition, pathway-related subtype typing was significantly associated with different immune cell infiltration in AITL. Further analysis revealed that the drug IC50 values predicted also differed markedly among the different subtypes, thus further identifying some subtype-specific drugs. Our study indicates a potential role of characteristic pathways in AITL staging for the first time, provides novel insights for future research targeting AITL, and points to potential therapeutic options for patients with different subtypes of AITL.

Since the avalanche phenomenon was first found in bulk materials, avalanche photodiodes (APDs) have been exclusively investigated. Among the many devices that have been developed, silicon APDs stand out because of their low cost, performance stability, and compatibility with CMOS. However, the increasing industrial needs pose challenges for the fabrication cycle time and fabrication cost. In this work, we proposed an improved fabrication process for ultra-deep mesa-structured silicon APDs for photodetection in the visible and near-infrared wavelengths with improved performance and reduced costs. The improved process reduced the complexity through significantly reduced photolithography steps, e.g., half of the steps of the existing process. Additionally, single ion implantation was performed under low energy (lower than 30 keV) to further reduce the fabrication costs. Based on the improved ultra-concise process, a deep-mesa silicon APD with a 140 V breakdown voltage was obtained. The device exhibited a low capacitance of 500 fF, the measured rise time was 2.7 ns, and the reverse bias voltage was 55 V. Moreover, a high responsivity of 103 A/W@870 nm at 120 V was achieved, as well as a low dark current of 1 nA at punch-through voltage and a maximum gain exceeding 1000.

Abstract Herein, we describe the clinical and hematological features of three genetically related families predisposed to myeloproliferative neoplasms (MPNs). Using whole-exome sequencing, we identified a c.1367delG mutation(p.Arg456fs) in CHST15 (NM_001270764), a gene encoding a type II transmembraneglycoproteinthat acts as a sulfotransferase and participates in the biosynthesis of chondroitin sulfate E, in germline and somatic cells in familial MPN. CHST15defects caused an increased JAK2V617F allele burden and upregulated p-Stat3 activity,leading to an increase in the proliferative and prodifferentiation potential of transgenic HEL cells. We demonstrated that mutant CHST15 is able to coimmmunoprecipitate the JAK2 protein,suggesting the presence of a CHST15-JAK2-Stat3 signaling axis in familial MPN. Gene expression profiling showed that the FREM1, IFI27 and C4B_2 genes are overexpressed in familial MPN, suggesting the activation of an “inflammatory response-extracellular matrix-immune regulation” signaling network in the CHST15 mutation background.We thus concluded that CHST15 is a novel gene that predisposes to familial MPN and increases the probability of disease development or transformation.

Abstract We aimed to comprehensively investigate the proteomic profile and underlying biological function of exosomal proteins associated with B-cell acute lymphoblastic leukemia. Exosomes were isolated from plasma samples collected from five patients with B-ALL and five healthy individuals, and their protein content was quantitatively analyzed by liquid chromatography with tandem mass spectrometry. A total of 342 differentially expressed proteins were identified in patients with B-ALL. The DEPs were mainly associated with protein metabolic processes and protein activity regulation and were significantly enriched in the Notch and autophagy pathways. Furthermore, we found that ADAM17 and ATG3 were upregulated in patients with B-ALL and enriched in the Notch and autophagy pathways, respectively. Further western blot analysis of exosomes collected from additional 18 patients with B-ALL and 10 healthy controls confirmed that both ADAM17 and ATG3 were overexpressed in exosomes derived from patients with B-ALL (p

Tumor-associated macrophages (TAMs) are a dynamic and heterogeneous cell population of the tumor microenvironment (TME) that plays an essential role in tumor formation and progression. Cancer cells have a high metabolic demand for their rapid proliferation, survival, and progression. A comprehensive interpretation of pro-tumoral and antitumoral metabolic changes in TAMs is crucial for comprehending immune evasion mechanisms in cancer. The metabolic reprogramming of TAMs is a novel method for enhancing their antitumor effects. In this review, we provide an overview of the recent research on metabolic alterations of TAMs caused by TME, focusing primarily on glucose, amino acid, and fatty acid metabolism. In addition, this review discusses antitumor immunotherapies that influence the activity of TAMs by limiting their recruitment, triggering their depletion, and re-educate them, as well as metabolic profiles leading to an antitumoral phenotype. We highlighted the metabolic modulational roles of TAMs and their potential to enhance immunotherapy for cancer.

Histiocytic sarcoma (HS) is a rare hematological malignancy with limited treatment options, and it is also prone to complications such as hemophagocytic lymphohistiocytosis (HLH) in the later stages of the disease, leading to difficulties in treatment and poor prognosis. It highlights the importance of developing novel therapeutic agents. Herein, we present a case of a 45-year-old male patient who was diagnosed with PD-L1-positive HS with HLH. The patient was admitted to our hospital with recurrent high fever, multiple skin rashes with pruritus throughout the body and enlarged lymph nodes. Subsequently, pathological biopsy of the lymph nodes revealed high expression of CD163, CD68, S100, Lys and CD34 in the tumor cells and no expression of CD1a and CD207, confirming this rare clinical diagnosis. Concerning the low remission rate by conventional treatment in this disease, the patient was administered with sintilimab (an anti-programmed cell death 1 [anti-PD-1] monoclonal antibody) at 200 mg/d combined with a first-line chemotherapy regimen for one cycle. Further exploration of pathological biopsy by using next-generation gene sequencing led to the use of targeted therapy of chidamide. After one cycle of combination therapy (chidamide+sintilimab, abbreviated as CS), the patient achieved a favorable response. The patient showed remarkable improvement in the general symptoms and laboratory examination results (e.g., elevated indicators of inflammation); even the clinical benefits was not persistent, he survived one more month after his cessation of treatment by himself due to economic difficulty. Our case suggests that PD-1 inhibitor coupled with targeted therapy might constitute a potential therapeutic option for primary HS with HLH.

Background: Polycythemia Vera (PV) is a type of typical Myeloproliferative Neoplasms (MPNs) characterized with excessive erythropoiesis and thrombosis. Anoikis is a special programmed cell death mode induced by the adhesion disorder between cells and extracellular matrix (ECM) or adjacent cells facilitating cancer metastasis. However, few studies have focused on the role of anoikis in PV, especially on the development of PV.Methods: The microarray and RNA-seq results were screened from the Gene Expression Omnibus (GEO) database and the anoikis-related genes (ARGs) were downloaded from Genecards. The functional enrichment analysis of intersecting differentially expressed genes (DEGs) and protein-protein interaction (PPI) network analysis were performed to discover hub genes. The hub genes expression was tested in the training (GSE136335) and validation cohort (GSE145802), and RT-qPCR was performed to verify the gene expression in PV mice.Results: In the training GSE136335, a total of 1,195 DEGs was obtained from Myeloproliferative Neoplasm (MPN) patients compared with controls, among which 58 were anoikis-related DEGs. The significant enrichment of the apoptosis and cell adhesion pathways (i.e., cadherin binding) were shown in functional enrichment analysis. The PPI network was conducted to identify top five hub genes (CASP3, CYCS, HIF1A, IL1B, MCL1). The expression of CASP3 and IL1B were significantly upregulated both in validation cohort and PV mice and downregulated after treatment, suggesting that CASP3 and IL1B could be important indicators for disease surveillance.Conclusion: Our research revealed a relationship between anoikis and PV for the first time by combined analysis of gene level, protein interaction and functional enrichment, allowing novel insights into mechanisms of PV. Moreover, CASP3 and IL1B may become promising indicators of PV development and treatment.

Although classic Hodgkin lymphoma (cHL) is highly curable with current treatment paradigms, therapy fails in 10-25% of patients. This prospective multicenter phase II study attempted to investigate the efficacy and safety of the combination of tislelizumab with gemcitabine and oxaliplatin (T-GemOx) in relapsed or refractory cHL. Participants received six to eight courses of gemcitabine (1 g/m2 on day 1) and oxaliplatin (100 mg/m2 on day 1) combined with tislelizumab (200 mg on day 2) at 21-day intervals, followed by tislelizumab maintenance (every 2 months for 2 years). The main outcome measure was the best complete remission rate. As of August 2022, a total of 30 patients had been consecutively enrolled and given induction therapy. The best overall response rate and complete remission rate were 100% (95% confidence interval [CI]: 88.4-100%) and 96.7% (95% CI: 82.8-99.9%), respectively. The median duration of follow-up after initiation of T-GemOx was 15.8 months. The 12-month progression-free survival rate without autologous stem cell transplant was 96% (95% CI: 74.8-99.4%). There were 122 adverse events recorded, of which 93.4% were grade 1 or 2. Thrombocytopenia (10%) and anemia (6.7%) were the most common grade 3 or 4 adverse events. Overall, T-GemOx demonstrated promising antitumor activity with manageable toxicities as a salvage treatment for relapsed or refractory cHL. A longer follow-up duration is required to determine whether maintenance therapy with tislelizumab rather than transplantation can be curative following such a highly active regimen. This trial was registered with the Chinese Clinical Trials Registry (http://www.chictr.org.cn) on June 1, 2020, identifier ChiCTR2000033441.

Abstract Background Women with advanced-stage high-grade serous ovarian cancer (HGSOC) are likely to have a bad prognosis. Relapses are common in patients even with no evidence of disease after primary treatment. We aimed to identify the prognostic factors for disease recurrence in these patients. Methods A nested case-control study was conducted in a large medical center in Southwest China. The primary outcome was recurrence of disease within 3 years after clinical remission (CR). Cox regression was used to calculate the time to event analysis in different groups. Results Ninety-seven patients were finally included. Fifty-seven patients (58.8%) relapsed within 3 years after CR. Among all the variables, the difference in posttreatment CA-125 level was statistically significant (P

Abstract Disordered chromatin remodeling regulation has emerged as an essential driving factor for cancers. Imitation switch (ISWI) family are evolutionarily conserved ATP-dependent chromatin remodeling complexes, which are essential for cellular survival and function through multiple genetic and epigenetic mechanisms. Omics sequencing and a growing number of basic and clinical studies found that ISWI family members displayed widespread gene expression and genetic status abnormalities in human cancer. Their aberrant expression is closely linked to patient outcome and drug response. Functional or componential alteration in ISWI-containing complexes is critical for tumor initiation and development. Furthermore, ISWI-non-coding RNA regulatory networks and some non-coding RNAs derived from exons of ISWI member genes play important roles in tumor progression. Therefore, unveiling the transcriptional regulation mechanism underlying ISWI family sparked a booming interest in finding ISWI-based therapies in cancer. This review aims at describing the current state-of-the-art in the role of ISWI subunits and complexes in tumorigenesis, tumor progression, immunity and drug response, and presenting deep insight into the physiological and pathological implications of the ISWI transcription machinery in cancers.

Immunotherapies have shown modest benefits in the current clinical trials for ovarian cancer. The tumor microenvironment (TME) in an immunosuppressive phenotype contributes to this “failure” of immunotherapy in ovarian cancer. Many stromal cell types in the TME (e.g., tumor-associated macrophages and fibroblasts) have been identified as having plasticity in pro- and antitumor activities and are responsible for suppressing the antitumor immune response. Thus, the TME is an extremely valuable target for adjuvant interventions to improve the effects of immunotherapy. The current strategies targeting the TME include: 1) eliminating immunosuppressive cells or transforming them into immunostimulatory phenotypes and 2) inhibiting their immunosuppressive or pro-tumor production. Most of the effective agents used in the above strategies are genetic materials (e.g., cDNA, mRNA, or miRNA), proteins, or other small molecules (e.g., peptides), which are limited in their target and instability. Various formulations of drug delivery system (DDS) have been designed to realize the controlled release and targeting delivery of these agents to the tumor sites. Nanoparticles and liposomes are the most frequently exploited materials. Based on current evidence from preclinical and clinical studies, the future of the DDS is promising in cancer immunotherapy since the combination of agents with a DDS has shown increased efficacy and decreased toxicities compared with free agents. In the future, more efforts are needed to further identify the hallmarks and biomarkers in the ovarian TME, which is crucial for the development of more effective, safe, and personalized DDSs.

Abstract Uncontrolled proliferation is the hallmark of cancer cells. Previous studies mainly focused on the role of protein-coding genes in cancer cell proliferation. Emerging evidence showed that long non-coding RNAs (lncRNAs) also play critical roles in cancer cell proliferation and growth. LncRNA KCNQ1OT1 is found to contribute to carcinogenesis, but its role in acute promyelocytic leukemia (APL) is unclear. In this study, by analyzing data from Gene Expression Omnibus, The Cancer Genome Atlas database and our clinical samples, we found that KCNQ1OT1 was selectively highly expressed in APL. Functional assays demonstrated that knockdown of KCNQ1OT1 reduced APL cell proliferation and increased apoptosis. Further evidence showed that KCNQ1OT1 was mainly located in the cytoplasm of APL patient-derived NB4 cells and APL patient bone marrow samples. Mechanistically, KCNQ1OT1 bound to RNA binding protein FUS, and silencing either KCNQ1OT1 or FUS reduced the expression level and stability of MAP3K1 mRNA. Whereas KCNQ1OT1 and FUS did not affect each other. Importantly, knockdown of MAP3K1 impaired APL cell proliferation. Finally, c-Myc transactivated KCNQ1OT1 in APL cells through binding to its promoter while knockdown of c-Myc decreased KCNQ1OT1 expression. Our results not only revealed that c-Myc transactivated KCNQ1OT1 and upregulated KCNQ1OT1 promoted APL cell proliferation, but also demonstrated that KCNQ1OT1 bound to FUS to synergistically stabilize MAP3K1 mRNA, thus facilitating APL cell proliferation. This study established a previously unidentified role of KCNQ1OT1 in the development of APL, and KCNQ1OT1 may serve as a potential therapeutic target for APL.

Abstract Background Prophylactic uterine artery embolization (UAE) combined with subsequent curettage is suggested as an effective and minimally invasive treatment strategy for cesarean scar pregnancy (CSP) with a high bleeding risk. However, the timing of curettage after UAE remains to be studied. Thus, we aimed to identify the optimal time interval to perform curettage after UAE in patients with CSP. Methods We conducted a retrospective cohort study in a large medical center for women and children in Southwest China. CSP patients treated by UAE combined with subsequent curettage were included and grouped by the treatment time interval between these two procedures. The clinical outcomes among arms were compared by univariate and multivariable analysis. Results Our study included 314 CSP patients who received this combination treatment in our department from January 2014 to December 2019. The median time interval between UAE and curettage was 48 h, with a range of 12-168 h among all participants. Thirty-two patients (10.2%) experienced intraoperative hemorrhage (blood loss ≥200 mL). Intrauterine balloon tamponade was used in 17 cases (5.4%). In 14 cases (4.5%), the procedure was converted to laparoscopy (or laparotomy). In the cohort study, patients with longer treatment intervals had more intraoperative blood loss and a higher incidence of complications than those with shorter intervals (P 72 h had an adjusted odds ratio of 3.37 (95% confidence interval: 1.40-8.09). Conclusion We suggest that curettage not be delayed longer than 72 h after UAE in this combined treatment of CSP.

Background: Despite conventional treatment, the prognosis of antiphospholipid syndrome (APS) pregnancy remains poor, and some pregnancies are still complicated by preeclampsia (PE). This study aimed to identify the relationship between conventionally-treated APS and the onset of PE. Methods: Relevant studies published up to April 2021 were searched on the PubMed, Cochrane Library, and Embase databases. Related data were extracted from the included studies, and we performed a meta-analysis. Review Manager 5.4 were used to calculate the pooled odds ratio (OR) and 95% confidence intervals (CIs). Results: This study screened 6 studies, including 1 cohort study and 5 case-control studies. Even after conventional treatment, the rate of PE in APS pregnancy is still significantly higher than in the control group. There was a higher pooled OR in the cohort study (OR: 8.37, 95% CI: 3.42–20.48) than the case-control studies (OR: 2.30, 95% CI: 1.12–4.74) in the subgroup analysis. Conclusions: APS pregnancy increases the risk of PE even after conventional treatment. Routine monitoring and standardized and better treatment methods should be developed to prevent the occurrence of PE.

Abstract Hematopoiesis requires finely tuned regulation of gene expression at each stage of development. The regulation of gene transcription involves not only individual transcription factors (TFs) but also transcription complexes (TCs) composed of transcription factor(s) and multisubunit cofactors. In their normal compositions, TCs orchestrate lineage-specific patterns of gene expression and ensure the production of the correct proportions of individual cell lineages during hematopoiesis. The integration of posttranslational and conformational modifications in the chromatin landscape, nucleosomes, histones and interacting components via the cofactor–TF interplay is critical to optimal TF activity. Mutations or translocations of cofactor genes are expected to alter cofactor–TF interactions, which may be causative for the pathogenesis of various hematologic disorders. Blocking TF oncogenic activity in hematologic disorders through targeting cofactors in aberrant complexes has been an exciting therapeutic strategy. In this review, we summarize the current knowledge regarding the models and functions of cofactor–TF interplay in physiological hematopoiesis and highlight their implications in the etiology of hematological malignancies. This review presents a deep insight into the physiological and pathological implications of transcription machinery in the blood system.

Abstract Background T‐cell acute lymphoblastic leukemia (T‐ALL) is an uncommon and aggressive subtype of acute lymphoblastic leukemia (ALL). In the serum of T‐ALL patients, the activity of lactate dehydrogenase A (LDHA) is increased. We proposed that targeting LDHA may be a potential strategy to improve T‐ALL outcomes. The current study was conducted to investigate the antileukemic effect of LDHA gene‐targeting treatment on T‐ALL and the underlying molecular mechanism. Methods Primary T‐ALL cell lines Jurkat and DU528 were treated with the LDH inhibitor oxamate. MTT, colony formation, apoptosis, and cell cycle assays were performed to investigate the effects of oxamate on T‐ALL cells. Quantitative real‐time PCR (qPCR) and Western blotting analyses were applied to determine the related signaling pathways. A mitochondrial reactive oxygen species (ROS) assay was performed to evaluate ROS production after T‐ALL cells were treated with oxamate. A T‐ALL transgenic zebrafish model with LDHA gene knockdown was established using CRISPR/Cas9 gene‐editing technology, and then TUNEL, Western blotting, and T‐ALL tumor progression analyses were conducted to investigate the effects of LDHA gene knockdown on T‐ALL transgenic zebrafish. Results Oxamate significantly inhibited proliferation and induced apoptosis of Jurkat and DU528 cells. It also arrested Jurkat and DU528 cells in G0/G1 phase and stimulated ROS production (all P

Tumour necrosis factor receptor-associated factor 4 (TRAF4) is a member of the TRAF protein family, a cytoplasmic bridging molecule closely associated with various immune functions. The physiological processes of TRAF4 are mainly involved in embryonic development, cell polarity, cell proliferation, apoptosis, regulation of reactive oxygen species production. TRAF4 is overexpressed in a variety of tumors and regulates the formation and development of a variety of tumors. In this review, we summarize the physiological and pathological regulatory functions of TRAF4 and focus on understanding the biological processes involved in this gene, to provide a reference for further studies on the role of this gene in tumorigenesis and development.

Mesenchymal stem cells (MSCs) participate in the occurrence and development of multiple myeloma. This study is aimed at exploring whether the presence of MSCs affects dexamethasone’s antitumor effects against multiple myeloma. Multiple myeloma cells (OPM-2 and RPMI8226 cells) were cocultured with MSCs with or without dexamethasone. Cell viability was determined by using cell number count, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and colony formation assay, respectively. Cell cycle distribution and cell apoptosis were evaluated by using flow cytometry. The mRNA and protein expressions of target genes were checked by using qRT-PCR and western blotting, respectively. It was found that cell viability of multiple myeloma cells increased in the presence of MSCs. Besides, the presence of MSCs suppressed cell apoptosis induced by dexamethasone via the regulation of BCL-2 (B cell lymphoma 2). The presence of MSCs also affected the effects of dexamethasone on cell cycle distribution. Similarly, LINC00461 overexpression suppressed the inhibition of cell proliferation, suppressed the induction of cell apoptosis, and affected the effects on cell cycle distribution induced by dexamethasone insult. However, LINC00461 knockdown enhanced the inhibitory effects on cell proliferation and the induction of cell apoptosis induced by dexamethasone. In summary, MSCs inhibited the effects of dexamethasone on multiple myeloma and its regulatory effects were associated with LINC00461.

Objectives: Purpose of this narrative review is to comprehensively summarize and compare the methods of human papilloma viruses (HPV) detection to provide a reference for clinical selection. And it also concludes the research progress of preventive HPV vaccines and therapeutic HPV vaccines to provide new ideas for the future development of HPV vaccines. Mechanism: A comprehensive search of published relevant articles was conducted. Multiple database were searched including PubMed, SCOPUS, and Ovid. Searches included the key terms: human papilloma viruses (HPV), HPV infection, epidemiology, HPV vaccine, cervical cancer (CC) screening, detection technology. Findings in Brief: HPV is a sexually transmitted virus and also a common cause of female reproductive tract infections. HPV has been reported to be associated with approximately 5% of human cancers worldwide, among which high-risk HPV (HR-HPV) infection is the most closely related to cervical cancer. The advantages of using HPV testing for cervical cancer screening are the high long-term negative predictive value (NPV), the high sensitivity (90–95%) for cervical intraepithelial neoplasia (CIN) 2 or 3, and the significant reduction in CIN2/3 and cancer in test-negative women over long term follow-up. The current detection of HPV infection is mainly for HPV DNA, RNA and oncoprotein, and vrious methods have their own features. Currently, there is no treatment for an HPV infection, so prevention is the key to cancer reduction. HPV vaccine is an important means to reduce the incidence rate of HPV infection and HPV related cervical cancer. Conclusions: With the development of assay technology, assays with low cost, high versatility and operability will be needed in the future. The HPV vaccine, as a primary prevention measure for cervical cancer, has achieved significant results in preventing HPV infection and reducing the incidence of reproductive tract diseases. In the future, it is expected that the HPV vaccine will make significant breakthroughs in the treatment of current HPV infections and cervical cancer.

Cell death is essential for the normal metabolism of human organisms. Ferroptosis is a unique regulated cell death (RCD) mode characterized by excess accumulation of iron-dependent lipid peroxide and reactive oxygen species (ROS) compared with other well-known programmed cell death modes. It has been currently recognized that ferroptosis plays a rather important role in the occurrence, development, and treatment of traumatic brain injury, stroke, acute kidney injury, liver damage, ischemia–reperfusion injury, tumor, etc. Of note, ferroptosis may be explained by the expression of various molecules and signaling components, among which iron, lipid, and amino acid metabolism are the key regulatory mechanisms of ferroptosis. Meanwhile, tumor cells of hematological malignancies, such as leukemia, lymphoma, and multiple myeloma (MM), are identified to be sensitive to ferroptosis. Targeting potential regulatory factors in the ferroptosis pathway may promote or inhibit the disease progression of these malignancies. In this review, a systematic summary was conducted on the key molecular mechanisms of ferroptosis and the current potential relationships of ferroptosis with leukemia, lymphoma, and MM. It is expected to provide novel potential therapeutic approaches and targets for hematological malignancies.

Abstract Background GTF2I-RARA is a newly identified RARA fusion gene in variant acute promyelocytic leukemia (APL) patients with t(7;17)(q11;q21). Clinical manifestation in the patient showed that it is a sort of ATRA-insensitive oncogene and is different from the classic PML-RARA in terms of therapeutic reaction. Methods To reveal the functional characteristics and regulating mechanism of the GTF2I-RARA fusion gene, we established a GTF2I-RARA-transfected HL60 cell model and examined its sensitivity to ATRA by western blot, MTT assay, flow cytometry, and Wright-Giemsa staining. Coimmunoprecipitation and confocal microscopy were used to examine the binding of GTF2I-RARA and transcriptional corepressors. We also performed ChIP-seq to search for potential target genes. Immunoprecipitation, ubiquitination assay, western blot, luciferase assay, and real-time PCR were used to analyze the effects of RNF8 on RARA. Flow cytometry and Wright-Giemsa staining were used to study the effect of MG132 and ATRA on the GTF2I-RARA-transfected HL60 cell model. Result We confirmed resistance of GTF2I-RARA to ATRA. Compared with PML-RARA, GTF2I-RARA has a higher affinity to HDAC3 under ATRA treatment. Using the ChIP-sequencing approach, we identified 221 GTF2I-RARA binding sites in model cells and found that the RING finger protein 8 (RNF8) is a target gene of GTF2I-RARA. RNF8 participates in disease progression and therapy resistance in APL with the GTF2I-RARA transcript. Elevated RNF8 expression promotes the interaction between RARA and RNF8 and induces RARA Lys-48 linkage ubiquitylation and degradation, resulting in attenuated transcriptional activation of RARA. Conclusion Our results suggest that RNF8 is a key GTF2I-RARA downstream event. Using the combination of MG132 and ATRA to treat GTF2I-RARA-HL60 cells, a synergistic effect leading to GTF2I-RARA-HL60 cell differentiation was confirmed. Taken together, the targeting of RNF8 may be an alternative choice for treatment in variant APL with GTF2I-RARA fusion.

Owing to the recent emergence of drug resistance to Bruton’s tyrosine kinase inhibitors (BTK) in chronic lymphocytic leukemia (CLL) treatment, it is crucial to identify alternative therapeutic targets. Therefore, we aimed to identify therapeutic options for CLL besides BTK. We identified that HIF1A expression was higher in CLL patients than in controls, which may suggest good prognosis. We used a lentiviral knockdown of EGLN1 (encoding hypoxia-inducible factor prolyl hydroxylase [HIF-PH]) and found that the growth of MEC-1 cells slowed in the knockdown group. Treatment of CLL cell lines MEC-1 and HG3 with the HIF-PH inhibitor molidustat showed that molidustat could induce apoptosis in a concentration-dependent manner in CLL cells and had low cytotoxicity at this concentration. CXCR4, HIF1A, SLC2AI, and VEGF, the downstream molecules of the HIF pathway, were upregulated after molidustat treatment. Western blotting results indicated that molidustat increased HIF1A expression in CLL cell lines and cells from CLL patients, and sequencing/quantitative PCR analysis demonstrated that the ribosome biogenesis pathway was inhibited in MEC-1 cells after molidustat treatment. We further identified synergistic cytotoxicity of molidustat in combination with ibrutinib on the MEC-1 and HG3 cell lines at certain concentrations. Therefore, molidustat is a potential therapeutic option for CLL.

The outbreak of SARS-CoV-2 began in December 2019 and rapidly became a pandemic. The present study investigated the significance of lymphopenia on disease severity. A total of 115 patients with confirmed COVID-19 from a tertiary hospital in Changsha, China, were enrolled. Clinical, laboratory, treatment and outcome data were gathered and compared between patients with and without lymphopenia. The median age was 42 years (1-75). Fifty-four patients (47.0%) of the 115 patients had lymphopenia on admission. More patients in the lymphopenia group had hypertension (30.8% vs. 10.0%, P = 0.006) and coronary heart disease (3.6% vs. 0%, P = 0.029) than in the nonlymphopenia group, and more patients with leukopenia (48.1% vs 14.8%, P

Improving the efficiency of photocatalytic water splitting to produce hydrogen is currently a hot topic in research. TiO2 nanosheets are a good carrier of photocatalytic materials and have become attractive materials in the new century because of their high active surface exposure characteristics and special morphology. Considering the advantages and disadvantages of conventional chemical and physical methods that are used for preparing TiO2 nanosheets, an optimized scheme for the preparation of TiO2 nanosheets via hydrothermal calcination was proposed. X-ray powder diffraction (XRD), scanning electron microscopy (SEM), and UV-visible diffuse reflection absorption spectra (DRS) were used to characterize the structure and morphology of the TiO2 nanosheets, and differences in the photocatalytic water splitting hydrogen production activity of the different calcination temperatures were compared. The suitable calcination temperature of the TiO2 nanosheets was 400°C, and the hydrogen production rate was 270 μmol/h, which indicated that the sheet structure was beneficial for improving the photocatalytic water splitting hydrogen production performance of the material. It is hoped that this work will support the regulation of the surface morphology and surface modification of nanomaterials.

Background: The relationship between oral contraceptive (OC) use and breast cancer risk is highly debated. Recent publications support a slight increase in overall breast cancer risk among OC user women, in particular among the current users. Women with inherited BRCA1 (Breast cancer type 1) or BRCA2 (Breast cancer type 2) gene mutations are at increased risk of breast and ovarian cancers, which is often mistakenly attributed to their elevated endogenous estrogen levels. The aim of presented meta-analysis was to assess the effects of OC use on breast cancer risk in BRCA mutation carrier women with minimal bias. Methods: A systematic search strategy was used to identify relevant studies, Stata (version 15) was used for meta-analysis. Results: Individual datasets from 13 studies totaling 20,202 patients were analyzed. The combined results showed no significant increase in risk of breast cancer in BRCA mutation carriers who had ever used oral contraceptive (HR = 1.09, 95% CI: 0.71–1.69 among BRCA1 mutation carriers and HR = 1.19, 95% CI: 0.73–1.95 among BRCA2 mutation carriers, respectively). However, in correlation with long-term (>5 years) OC users, the breast cancer risk was significantly increased in both BRCA1 mutation carriers (HR = 1.39, 95% CI: 1.19–1.60) and BRCA1 mutation carriers (HR = 1.61, 95% CI: 1.25–1.96). Conclusion: The presented results indicate that in BRCA mutation carriers women who have defective liganded activation of estrogen receptors (ERs), the use of synthetic estrogens means an additive factor for ER deregulation further increasing the risk for breast cancer. Long term OC use in BRCA mutation carriers results in a significantly increased risk for breast cancer by exhausting the compensatory genome defending process.

Recent studies have found that administration of stem cells or extracellular vehicles (EVs) derived from stem cells exert neuroprotective effects after transient global ischemia. However, the underlying mechanisms of this effect remain unclear, especially at the level of synaptic functions. In this study, we compared the suppressive effects on cyclooxygenase-2 (COX-2) upregulation by EVs derived from bone marrow mesenchymal stem cells (BMSC-EV), adipose tissue MSC (AdMSC-EV) and serum (serum-EV). Then we examined whether BMSC-EVs could restore functional integrity of synaptic transmission and plasticity. Mice were randomly assigned to four groups: sham, sham with EV treatment, ischemia and ischemia with EV treatment. EVs were administered by intracerebroventricular injection (ICVI). We examined the consequence of transient global ischemia on pre- and post-synaptic functions of the hippocampal CA3-CA1 synapses at basal level, and long-term potentiation (LTP), an activity-dependent form of synaptic plasticity. Then we tested the therapeutic effects of EVs on these synaptic deficits. Meanwhile, Morris water maze (MWM) test was performed to examine the efficacy of EVs in rescuing ischemia-induced impairments in spatial learning and memory. EV treatment significantly restored impaired basal synaptic transmission and synaptic plasticity, and improved spatial learning and memory compared with the control group. In addition, EVs significantly inhibited ischemia-induced pathogenic expression of COX-2 in the hippocampus. EVs exert ameliorating effects on synaptic functions against transient global cerebral ischemia, which may be partly attributed to suppression of COX-2 pathogenic expression.