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In this paper, the microstructure evolution in an Al–Mg–Si alloy during the soaking and cooling of homogenization was investigated. Moreover, the effects of the cooling rate on the hot deformation and subsequent age-hardening behavior were studied. During the soaking, the eutectic Mg2Si is dissolved, the solute segregation is eliminated, and the Fe-bearing phase is refined. During subsequent cooling, no precipitate is formed in the water-quenched sample, while β'' and β-Mg2Si are the predominant phases formed in the air- and furnace-quenched samples, respectively. The experiments agree with the simulated continuous cooling transformation (CCT) curves. The cooling rate in homogenization has a significant effect on the flow stress when the compression is performed at 450 °C. The air-quenched sample exhibits the highest flow stress due to the formation of nanoscale β-Mg2Si particles. The effect of the cooling rate diminishes as the compression temperature increases. At a compression temperature of 500 °C, the water-quenched sample exhibits a slightly higher flow stress due to the precipitation of micrometer-scale β-Mg2Si particles and the Mg and Si solutes retained in the matrix. The compressed samples have nearly similar thermal effects and peak aging hardness increments after compression at 500 °C, indicating that the age-hardening potential of the alloys is equivalent. The same types of precipitates are formed in all compressed samples at peak aging, including the GP zone, β'', β′ and B′, where β'' is the main strengthening phase. The relationship between the precipitation behavior and the increments of hardness, electrical conductivity (EC) was analyzed.

ABSTRACTBackground Plasma cell leukemia (PCL) is a rare and aggressive plasma cell disorder, exhibiting a more unfavorable prognosis than multiple myeloma. PCL is classified into pPCL and sPCL. Recently, the IMWG has recommended new PCL definition criteria, which require the presence of ≥5% circulating plasma cells in peripheral blood smears. Due to its low incidence, research on pPCL and sPCL is limited.Methods We conducted a retrospective study and analyzed clinical and cytogenetic data of pPCL and sPCL patients. Overall survival (OS) and progression-free survival (PFS) were assessed by the Kaplan-Meier method, and survival distributions were compared using the log-rank test.Results This is a small cohort comprising 23 pPCL and 9 sPCL patients. Notably, sPCL patients showed a higher incidence of extramedullary infiltration and a higher percentage of bone marrow plasma cells (p = 0.015 and 0.025, respectively). Although no significant difference was found between the two groups in OS and PFS, a trend emerged suggesting a superior survival outcome for pPCL patients, with a higher cumulative 1-year PFS rate (38.3% vs. 13.3%) and a lower early mortality rate (mortality rate at 3 months: 15% vs. 33%). We also suggested that pPCL patients carrying t(11;14) may have a longer median survival time than individuals with other cytogenetic abnormalities, but this was not confirmed due to the small sample size.Conclusion Our study revealed clinical and cytogenetic features of pPCL and sPCL patients according to the new diagnostic criteria. The findings suggested a generally better prognosis for pPCL than sPCL and the likelihood of t(11;14) translocation acting as a favorable prognostic factor in pPCL. It is important to note that our study had a limited sample size, which may lead to bias. We hope well-designed studies can be conducted to provide more results.

ABSTRACTMyelodysplastic syndromes (MDS) refer to a set of clonal hematopoietic disorders with fusion transcript as disease progression. Breakpoint cluster region/abelson (BCR::ABL) fusion mostly occurs during the progressive phase from MDS to higher stages and acute leukemia transformation. Besides, it is extremely rare reported on the diagnosis of MDS. Here, the first case of transformation of de nove philadelphia (Ph)-positive MDS to chronic myeloid leukemia (CML) with rapid progression to acute myeloid leukemia (AML) was reported. Fluorescence in situ hybridization (FISH) analysis revealed an atypical BCR::ABL positive signal (2R2G1Y) that accounted for 3% at the diagnosis of MDS and increased to 21.4% at information to CML. The result of multiplex reverse transcriptase polymerase chain reaction (RT–PCR) indicated a rearrangement of e19a2 (p230 BCR::ABL). The treatment with 400 mg of imatinib daily at the transformation from MDS to CML led to a hematological response. However, the patient stopped taking imatinib due to the worsening of cytopenias after five weeks of therapy and rapid progression to AML in another two months. The treatment with azacitidine (AZA) and venetoclax (VEN) achieved partial remission (PR). Unfortunately, the patient relapsed six months after PR and died shortly thereafter. In addition, another 16 cases of adult cases that reported MDS with de nove Ph-positive were also reviewed to learn about clinical features and outcomes.

Abstract Background Circular RNAs (circRNAs) are enriched in exosomes and are extremely stable. Exosome-mediated intercellular transfer of specific biologically active circRNA molecules can drive the transformation of the tumor microenvironment and accelerate or inhibit the local spread and multifocal growth of hepatocellular carcinoma (HCC). In this study, we explored in depth about the biological roles of HCC cell-derived exosomes and exosome-transported circRNAs on HCC in vivo and in vitro. Methods Exosomes extracted from HCC cells (Huh7 and HA22T) were characterized using transmission electron microscopy, nanoparticle size tracer analysis, and western blotting. Exosomes were observed for endocytosis using fluorescent labeling. The effects of HCC cell-derived exosomes and the circ_002136 they carried on cell growth, metastasis and apoptosis were determined by CCK-8 assay, transwell assay, flow cytometry analysis and TUNEL staining, respectively. The expressions of circ_002136, miR-19a-3p and RAB1A were detected by quantitative RT-PCR (qRT-PCR). Targeted binding between miR-19a-3p and circ_002136 or RAB1A was predicted and verified by bioinformatics analysis, dual-luciferase reporter and RNA pull-down experiments. The in vivo effect of circ_002136 was determined by constructing a xenograft tumor model. Results The findings revealed that Huh7 and HA22T exosomes conferred enhanced viability as well as invasive ability to recipient HCC cells. Circ_002136 was shown for the first time to be differentially upregulated in HCC tissues and cells and transferred by HCC cell-derived exosomes. More importantly, selective silencing of circ_002136 depleted the malignant biological behaviors of HCC exosome-activated Huh7 and HA22T cells. Depletion of circ_002136 in vivo effectively retarded the growth of HCC xenograft tumors. Furthermore, a well-established circ_002136 ceRNA regulatory network was constructed, namely circ_002136 blocked miR-19a-3p expression, elevated RAB1A expression activity and stimulated HCC development. Finally, high levels of circ_002136 or RAB1A, as well as low levels of miR-19a-3p, negatively affected HCC patient survival. Conclusion The study on circ_002136 provides good data to support our insight into the mechanism of to-be-silenced circRNA as a therapeutic agent in the progression of HCC.

Objectives This review aims to see the progress of several clinically-used monoclonal antibodies in treating ALL patients and how they improved patients' outcomes.Methods We searched Web of Science, Elsevier and PubMed for relevant published studies, and summarized eligible evidence on the management of newly-diagnosed and relapsed or refractory ALL with monoclonal antibodies. Ongoing trials were identified from ClinicalTrials.gov.Results Rituximab, an anti-CD20 monoclonal antibody, prolonged patients' complete remission duration and overall survival when combined with hyper-CVAD regimen. Another anti-CD20 monoclonal antibody, Ofatumumab, was reported to have similar benefits. Blinatumomab allows endogenous CD3-positive cytotoxic T cells to target and eliminate CD19-positive blasts. FDA has approved its efficacy in patients with R/R B-ALL and eliminating minimal residual disease (MRD). It serves as a bridge to eradicate MRD before transplantation, and may also be a new choice for patients unable to undergo transplantation. An anti-CD22 monoclonal antibody named Inotuzumab Ozogamicin showed great improvement in patients' outcome, but its toxicity to liver is also worthy of our attention.Conclusion Monoclonal antibodies are proven to be a promising immunotherapeutic strategy to improve ALL patients' outcome in the long term. There's still a need for individualized treatment with effective and well-tolerated medicines.Trial registration: ClinicalTrials.gov identifier: NCT01363128.Trial registration: ClinicalTrials.gov identifier: NCT01466179.Trial registration: ClinicalTrials.gov identifier: NCT02013167.Trial registration: ClinicalTrials.gov identifier: NCT02000427.Trial registration: ClinicalTrials.gov identifier: NCT01564784.Trial registration: ClinicalTrials.gov identifier: NCT03677596.Trial registration: ClinicalTrials.gov identifier: NCT01363297.Trial registration: ClinicalTrials.gov identifier: NCT02981628.Trial registration: ClinicalTrials.gov identifier: NCT03094611.Trial registration: ClinicalTrials.gov identifier: NCT01371630.Trial registration: ClinicalTrials.gov identifier: NCT04224571.Trial registration: ClinicalTrials.gov identifier: NCT02458014.Trial registration: ClinicalTrials.gov identifier: NCT04546399.Trial registration: ClinicalTrials.gov identifier: NCT02879695.Trial registration: ClinicalTrials.gov identifier: NCT03913559.Trial registration: ClinicalTrials.gov identifier: NCT03441061.Trial registration: ClinicalTrials.gov identifier: NCT03739814.Trial registration: ClinicalTrials.gov identifier: NCT02877303.Trial registration: ClinicalTrials.gov identifier: NCT03698552.Trial registration: ClinicalTrials.gov identifier: NCT04601584.Trial registration: ClinicalTrials.gov identifier: NCT04684147.Trial registration: ClinicalTrials.gov identifier: NCT04681105.

Objectives: To study the effect of TET on the reversal of drug resistance in the bone marrow microenvironment, and to further promote the research on drug reversal.Methods: We established a co-culture system of bone marrow mesenchymal stem cells (BM-MSC) and K562 cell lines, and compared the cell inhibition rate of K562 cells between the co-culture group and K562 singleculture group by daunorubicin (DNR) single-drug intervention with CCK-8 and also compared K562 proliferation in the co-culture group and K562 single-culture group after combined intervention with DNR and TET, then used Western blot and RT-qPCR to verify the expression of P-gp of K562 cells at protein and mRNA levels, confirmed the concentration of DNR in K562 of different experimental groups by HPLC-MS.Results: According to the results of CCK-8, after co-culture with bone marrow mesenchymal stem cells (BM-MSCs), the inhibition rate of DNR on K562 decreased significantly. When TET (1μmol/L) combined with daunorubicin (DNR) treated on the co-culture group, the inhibition rate increased significantly. Then, the results of RT-qPCR and western blot showed a remarkable difference of the expression of P-glycoprotein (P-gp). After co-culture with BM-MSCs, the protein expression of P-gp showed a significant upward trend. After adding TET intervention, the expression of P-gp decreased both in mRNA and protein levels. Also, the DNR concentration in K562 also performed the correspondent trend.Conclusion: The bone marrow microenvironment can promote the MDR of acute leukemia. TET can reverse the MDR mediated by the bone marrow microenvironment by inhibiting the expression of P-glycoprotein.

Recent studies have shown that microtransplant (MST) could improve outcome of patients with elderly acute myeloid leukemia (EAML). To further standardize the MST therapy and improve outcomes in EAML patients, based on analysis of the literature on MST, especially MST with EAML from January 1st, 2011 to November 30th, 2022, the International Microtransplant Interest Group provides recommendations and considerations for MST in the treatment of EAML. Four major issues related to MST for treating EAML were addressed: therapeutic principle of MST (1), candidates for MST (2), induction chemotherapy regimens (3), and post-remission therapy based on MST (4). Others included donor screening, infusion of donor cells, laboratory examinations, and complications of treatment.

Abstract Background Novel fusion genes such as ZNF384, have been identified in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in recent years. Patients harboring ZNF384 rearrangements have a distinctive immunophenotype with weak CD10 and aberrant CD13 and/or CD33 expression. Thus, ZNF384-rearranged ALL is a unique subtype of BCP-ALL. However, research on the prognostic significance of ZNF384 rearrangements has been limited to date, especially in adolescents. Case presentation We described a 17-year-old adolescent who was diagnosed with ALL and had renal involvement as the first manifestation, which was very rare in the existing studies. FISH analysis indicated a rearrangement of ZNF384 according to its probe. The patient had a typical characteristic immunophenotype of ZNF384 rearrangement, with CD10 negativity and CD13 and CD33 positivity. She had an unfavorable prognosis because she responded poorly to chemotherapy and developed a relapse shortly after reaching CR. Conclusion The importance of ZNF384 rearrangements in terms of prognosis remains unclear. We reported an adolescent who was diagnosed with ZNF384-rearranged ALL with renal involvement. She underwent different therapies, but her prognosis remained poor. Since ZNF384 rearrangements may act as a prognostic predictor in children or adolescents, early detection based on its characteristic immunophenotype is of great necessity.

Abstract The application of cells as carriers to encapsulate chemotherapy drugs is of great significance in antitumor therapy. The advantages of reducing systemic toxicity, enhancing targeting and enhancing the penetrability of drugs to tumor cells make it have great potential for clinical application in the future. Many studies and advances have been made in the encapsulation of drugs by using erythrocytes, white blood cells, platelets, immune cells and even tumor cells. The results showed that the antitumor effect of cell encapsulation chemotherapy drugs was better than that of single chemotherapy drugs. In recent years, the application of cell-based vectors in cancer has become diversified. Both chemotherapeutic drugs and photosensitizers can be encapsulated, so as to achieve multiple antitumor effects of chemotherapy, photothermal therapy and photodynamic therapy. A variety of ways of coordinated treatment can produce ideal results even in the face of multidrug-resistant and metastatic tumors. However, it is regrettable that this technology is only used in vitro for the time being. Standard answers have not yet been obtained for the preservation of drug-loaded cells and the safe way of infusion into human body. Therefore, the successful application of drug delivery technology in clinical still faces many challenges in the future. In this paper, we discuss the latest development of different cell-derived drug delivery systems and the challenges it will face in the future.

Abstract Background The third-generation epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have shown significant therapeutic effects on patients with non-small cell lung carcinoma (NSCLC) who carry active EGFR mutations, as well as those who have developed acquired resistance to the first-generation of EGFR-TKIs due to the T790M mutation. However, most patients develop drug resistance after 8–10 months of treatment. Currently, the mechanism has not been well clarified, and new therapeutic strategies are urgently needed. Methods Osimertinib resistant cell lines were established by culturing sensitive cells in chronically increasing doses of osimertinib. The anticancer effect of reagents was examined both in vitro and in vivo using the sulforhodamine B assay and a xenograft mouse model. The molecular signals were detected by western blotting. The combination effect was analyzed using CompuSyn software. Results We found that bromodomain and extra-terminal proteins (BETs) were upregulated in osimertinib resistant (H1975-OR) cells compared with those in the paired parental cells (H1975-P), and that knockdown of BETs significantly inhibited the growth of H1975-OR cells. The BET inhibitor JQ1 also exhibited stronger growth-inhibitory effects on H1975-OR cells and a greater expression of BETs and the downstream effector c-Myc than were observed in H1975-P cells. The histone deacetylase (HDAC) inhibitor trichostatin A (TSA) showed stronger growth suppression in H1975-OR cells than in H1975-P cells, but vorinostat, another HDAC inhibitor, showed equal inhibitory efficacy in both cell types. Consistently, downregulation of BET and c-Myc expression was greater with TSA than with vorinostat. TSA restrained the growth of H1975-OR and H1975-P xenograft tumors. The combination of TSA and JQ1 showed synergistic growth-inhibitory effects in parallel with decreased BET and c-Myc expression in both H1975-OR and H1975-P cells and in xenograft nude mouse models. BETs were not upregulated in osimertinib resistant HCC827 cells compared with parental cells, while TSA and vorinostat exhibited equal inhibitory effects on both cell types. Conclusion Upregulation of BETs contributed to the osimertinib resistance of H1975 cells. TSA downregulated BET expression and enhanced the growth inhibitory effect of JQ1 both in vitro and in vivo. Our findings provided new strategies for the treatment of osimertinib resistance.

Abstract Background Some studies have investigated the prognostic value exhibited by the Prognostic Nutritional Index (PNI) in patients suffering diffuse large B-cell lymphoma (DLBCL), but varying results were obtained. In order to determine the specific prognostic value more accurately, a meta-analysis was conducted in this study. Methods Literatures were searched from the China National Knowledge Infrastructure (CNKI), Wanfang, PubMed, Embase, the Cochrane Library, and Web of Science. Pooled hazard ratio (HR) and the 95% confidence interval (CI) were calculated to assess the association between PNI and the overall survival (OS) and the progression-free survival (PFS) of patients with DLBCL. Results Based on seven studies with a total number of 1311 patients, our meta-analysis revealed that low PNI may meant poor OS (HR = 2.14, 95% CI 1.66–2.75, p

Abstract Background Multiple myeloma (MM) is an incurable hematological tumor, which is closely related to hypoxic bone marrow microenvironment. However, the underlying mechanisms are still far from fully understood. We took integrated bioinformatics analysis with expression profile GSE110113 downloaded from National Center for Biotechnology Information-Gene Expression Omnibus (NCBI-GEO) database, and screened out major histocompatibility complex, class II, DP alpha 1 (HLA-DPA1) as a hub gene related to hypoxia in MM. Methods Differentially expressed genes (DEGs) were filtrated with R package “limma”. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were performed using “clusterProfiler” package in R. Then, protein-protein interaction (PPI) network was established. Hub genes were screened out according to Maximal Clique Centrality (MCC). PrognoScan evaluated all the significant hub genes for survival analysis. ScanGEO was used for visualization of gene expression in different clinical studies. P and Cox p value

Background The five‐year survival rate of lung adenocarcinoma patients (LUAD) is very low,and the methods of predicting survival are a great obstacle for LUAD therapies. Endothelin receptor type B (EDNRB) gene is associated with tumorigenesis. In this study, we aimed to evaluate the predictive value of EDNRB on LUAD. Methods Survival analyses was performed to assess the correlation between EDNRB expression and survival of LUAD patients from the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) datasets. Gene set enrichment analysis (GSEA) was conducted to illustrate possible biological functions of EDNRB. Laboratory methods were used to verify the function of EDNRB in LUAD. Results The TCGA results showed that a low expression of EDNRB was found in LUAD patients which led to poor outcome and worse survival, compared with the high expression in GSEA results which suggested that expression of EDNRB might be associated with regulation of the ERK pathway. Laboratory results suggested that EDNRB could inhibit the proliferation and migration of LUAD H1299 cells. Conclusions EDNRB is a potential prognostic marker for LUAD patients and might exert its functions by regulating the ERK pathway in LUAD.

Abstract It is well acknowledged that allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for numerous malignant blood diseases, which has also been applied to autoimmune diseases for more than a decade. Whereas graft-versus-host disease (GVHD) occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a common serious complication, seriously affecting the efficacy of transplantation. Mesenchymal stem cells (MSCs) derived from a wealth of sources can easily isolate and expand with low immunogenicity. MSCs also have paracrine and immune regulatory functions, leading to a broad application prospect in treatment and tissue engineering. This review focuses on immunoregulatory function of MSCs, factors affecting mesenchymal stem cells to exert immunosuppressive effects, clinical application of MSCs in GVHD and researches on MSC-derived extracellular vesicles (EVs). The latest research progress on MSC in related fields is reviewed as well. The relevant literature from PubMed databases is reviewed in this article.

Abstract Background 5-Fluorouracil (5-FU) has been commonly prescribed for patients with colorectal cancer (CRC), but resistance to 5-FU is one of the main reasons for failure in CRC. Recently, microRNAs (miRNAs) have been established as a means of reversing the dilemma by regulating signaling pathways involved in initiation and progression of CRC. However, how to safely and effectively deliver miRNA to target cells becomes a main challenge. Results In this study, Engineered exosomes were exploited to simultaneously deliver an anticancer drug 5-FU and miR-21 inhibitor oligonucleotide (miR-21i) to Her2 expressing cancer cells. Purified engineered exosomes from the donor cells loaded with 5-FU and miR-21i via electroporation to introduce into 5-FU-resistant colorectal cancer cell line HCT-1165FR. Furthermore, systematic administration of 5-FU and miR-21i loaded exosomes in tumor bearing mice indicated a significantly anti-tumor effect. The results showed that the engineered exosome-based 5-FU and miR-21i co-delivery system could efficiently facilitate cellular uptake and significantly down-regulate miR-21 expression in 5-FU resistant HCT-1165FR cell lines. Consequently, the down-regulation of miR-21 induced cell cycle arrest, reduced tumor proliferation, increased apoptosis and rescued PTEN and hMSH2 expressions, regulatory targets of miR-21. Of particular importance was the significant reduction in tumor growth in a mouse model of colon cancer with systematic administration of the targeting miR-21i. More excitedly, the combinational delivery of miR-21i and 5-FU with the engineered exosomes effectively reverse drug resistance and significantly enhanced the cytotoxicity in 5-FU-resistant colon cancer cells, compared with the single treatment with either miR-21i or 5-FU. Conclusion The strategy for co-delivering the functional small RNA and anticancer drug by exosomes foreshadows a potential approach to reverse the drug resistance in CRC and thus to enhance the efficacy of the cancer treatment.

Hematologic malignancies (HMs) mainly include acute and chronic leukemia, lymphoma, myeloma and other heterogeneous tumors that seriously threaten human life and health. The common effective treatments are radiotherapy, chemotherapy and hematopoietic stem cell transplantation (HSCT), which have limited options and are prone to tumor recurrence and (or) drug resistance. Metformin is the first-line drug for the treatment of type 2 diabetes (T2DM). Recently, studies identified the potential anti-cancer ability of metformin in both T2DM patients and patients that are non-diabetic. The latest epidemiological and preclinical studies suggested a potential benefit of metformin in the prevention and treatment of patients with HM. The mechanism may involve the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway by metformin as well as other AMPK-independent pathways to exert anti-cancer properties. In addition, combining current conventional anti-cancer drugs with metformin may improve the efficacy and reduce adverse drug reactions. Therefore, metformin can also be used as an adjuvant therapeutic agent for HM. This paper highlights the anti-hyperglycemic effects and potential anti-cancer effects of metformin, and also compiles the in vitro and clinical trials of metformin as an anti-cancer and chemosensitizing agent for the treatment of HM. The need for future research on the use of metformin in the treatment of HM is indicated.

The gene changes for diagnosis and prognosis of diffuse large B cell lymphoma (DLBCL) still remain unclear. RAC1 was reported to be asso;ciated with the B cell receptor signal pathway, but its relations with DLBCL have not yet been systematically explored. In this study, we have conducted molecular, bioinformatics and clinical analyses by using publicly available data from The Cancer Genome Atlas (TCGA). Wilcoxon signed-rank test and logistic regression were performed to evaluate the association between RAC1 and clinical features in patients. Kaplan–Meier and Cox regression methods were used to examine the impacts of RAC1 expression level on overall survival, and a nomogram was performed to illustrate the correlation between RAC1 and the risk of DLBCL. Our results revealed that the expression level of RAC1 in DLBCL was higher than that in normal tissues or lymphadenitis. High-level expression of RAC1 was significantly associated with clinical stage, as well as being an independent factor affecting overall survival. RAC1 was negatively correlated with Bruton’s tyrosine kinase (BTK). The association between RAC1 gene expression and the risk of DLBCL was presented in a nomogram. In conclusion, RAC1 expression patterns may be used to predict the development and prognosis of DLBCL.

The WD40 repeat (WDR) domain is one of the most abundant protein interaction domains in the human proteome. More than 360 protein interaction domains have been annotated thus far. The WDR domains mediate interactions with peptide regions of important interaction partners in a variety of biological processes. Proteins with the WDR domain which typically contains a seven-bladed β propeller, are continuously being discovered. They represent a large class of proteins that are likely to play important roles. WD40 repeat domain-containing protein 76 (WDR76) is a member of WDR domain-containing proteins. Although it remains poorly understood, it is potentially involved in DNA damage repair, apoptosis, cell cycle progression, and gene expression regulation. Ongoing research on WDR76 is increasing the knowledge regarding its basic functions and role in different pathophysiological. The study of WDR76 is challenging due to the complexity of its interactions with its partners. In the present review, we summarized the current knowledge regarding WDR76, its physiological functions, the close relationship with human diseases, and potential opportunities for target therapy.

Non-small-cell lung cancer takes up the majority of lung carcinoma-caused deaths. It is reported that targeting PD-1/PD-L1, a well-known immune evasion checkpoint, can eradicate tumor. Checkpoint inhibitors, such as monoclonal antibodies, are actively employed in cancer treatment. Thus, this review aimed to assess the therapeutic and toxic effects of PD-1/PD-L1 inhibitors in treatment of NSCLC. So far, 6 monoclonal antibodies blocking PD-1/PD-L1 interaction are identified and used in clinical trials and randomized controlled trials for NSCLC therapy. These antibody-based therapies for NSCLC were collected by using search engine PubMed, and articles about the assessment of adverse events were collected by using Google search. Route of administration and dosage are critical parameters for efficient immunotherapy. Although antibodies can improve overall survival and are expected to be target-specific, they can cause systemic adverse effects in the host. Targeting certain biomarkers can limit the toxicity of adverse effects of the antibody-mediated therapy. Clinical experts with knowledge of adverse effects (AEs) of checkpoint inhibitors can help manage and reduce mortalities associated with antibody-based therapy of NSCLC.

Abstract Numerous reports have elucidated the important participation of exosomes in the communication between tumor cells and other cancer‐related cells including tumor‐associated macrophages (TAMs) in microenvironment. However, the interchange of exosomes between tumor cells and TAMs in the progression of lung adenocarcinoma (LUAD) remains largely enigmatic. Herein, we discovered that LUAD cells induced the M2 polarization of TAMs and the M2‐polarized macrophages facilitated LUAD cell invasion and migration and tumor metastasis in vivo. In detail, LUAD cells secreted exosomes to transport miR‐19b‐3p into TAMs so that miR‐19b‐3p targeted PTPRD and inhibited the PTPRD‐mediated dephosphorylation of STAT3 in TAMs, leading to STAT3 activation and M2 polarization. Also, the activated STAT3 transcriptionally induced LINC00273 in M2 macrophages and exosomal LINC00273 was transferred into LUAD cells. In LUAD cells, LINC00273 recruited NEDD4 to facilitate LATS2 ubiquitination and degradation, so that the Hippo pathway was inactivated and YAP induced the transcription of RBMX. RBMX bound to miR‐19b‐3p to facilitate the packaging of miR‐19b‐3p into LUAD cell‐derived exosomes. Collectively, our results revealed the mechanism underlying the interactive communication between LUAD cells and TAMs through elucidating the exchange of exosomal miR‐19b‐3p and LINC00273 and proved the prometastatic effect of the interchange between two cells. These discoveries opened a new vision for developing LUAD treatment.

Circulating cancer cells (CTCs) can serve as a non-invasive liquid biopsy and provide opportunities for early cancer diagnosis and evaluation. However, the value of CTCs for diagnosis or prognosis of small pulmonary nodules (SPNs) is unclear. Fifty-three patients diagnosed with SPNs with a diameter less than 30 mm by CT examination were enrolled in the study. The CTC numbers, CT examination features, serum tumor marker concentrations, and histopathological characteristics were analyzed. Centromere probe 8 (CEP8) was used as a marker for CTC identification. The CTC numbers were significantly different in patients with malignant and benign SPNs and with early (0/Ⅰa) and advanced (Ⅰb/Ⅱ/Ⅲ) lung cancer stages. ROC analysis showed that the CTC numbers was effective on malignant SNP diagnosis. The combined use of CTCs and the density features of the nodules determined by CT further improved the overall screening, the diagnostic effectiveness for malignant SNPs, and determination of the pTNM (≤Ia vs.>Ia) stage. The CT morphology revealed that large, single, and solid SPNs were associated with significant CTC numbers and the CTC numbers were correlated with malignant histopathology. Using CEP8 as a marker resulted in detection of more CTC numbers in 22 patient samples triple stained for CEP8, EpCAM, and CKs. The CTCs determined by CEP8-positive staining could serve as potential screening and diagnostic markers for malignant SPNs.

We report the clinical features of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a family setting of 13 people with person-to-person transmission in Yancheng, Jiangsu Province, China.

Over the past decade, screening and identifying novel compounds for their biomedical applications has become an upcoming area of research. Identifying the molecular mechanisms of these compounds has become an integral part of anticancer research. β-elemene, a sesquiterpene, is renowned for its anticancer activity against a variety of cell lines. Recent studies on β-elemene have elucidated that it possesses anti-proliferative effect on cancer cells by creating an apoptotic trigger. Interestingly, it also induces protective autophagy in some cancerous cell lines and is less cytotoxic compared to other widely accepted chemotherapeutic agents. This provides an edge with the perception of limited toxicity to normal cells. This mini-review precisely focuses on the studies performed to identify the mechanism of anticancer activity of β-elemene against cancer cells of multiple origin. In accordance to the evaluation made by the studies mentioned, apoptosis has been identified to be most possible reason behind anticancer activity exerted by β-elemene against a variety of cancer cell lines. Cell cycle arrest and necrosis have been credited to be possible alternate mechanisms for the anticancer effect of β-elemene.

As a good photosensitizer, TiO2 nanomaterials show potential biomedical applications, such as drug carriers or enhancers in photodynamic therapy. In this contribution, novel nanocomposites through the blending of TiO2 nanofibers with the active compound, gambogic acid (GA), were explored, and the results showed that GA could inhibit cancer cell proliferation in a time-dependent and dose-dependent manner, inducing apoptosis and cell cycle arrest at the G0/G1 phase in HepG2 cells. It is evident that after the GA-TiO2 nanocomposites were cultured with the cancer cells, the cooperation effect could effectively enhance the cytotoxicity of GA for HepG2 cells. Meanwhile, if activated by UV irradiation, under the presence of GA-TiO2 nanocomposites, this would lead to significant apoptosis and necrosis for HepG2 cells with a photodynamic therapy (PDT) effect. Associated with the controlled drug-release from these nanocomposites, TiO2 nanofibers could readily cut down the drug consumption in HepG2 cells and reduce the side-effect for the normal cells and tissue, which may be further utilized in the therapeutic alliance for cancer therapy.

Develop and evaluate an electrochemical method to identify healthy individuals, malignant hematopathic patients and solid tumor patients by detecting the leukocytes in whole-blood.A total of 114 individual blood samples obtained from our affiliated hospital in China (June 2015- August 2015) were divided into three groups: healthy individuals (n = 35), hematologic malignancies (n = 41) and solid tumors (n = 38). An electrochemical workstation system was used to measure differential pulse voltammetry due to the different electrochemical behaviors of leukocytes in blood samples. Then, one-way analysis of variance (ANOVA) was applied to analyze the scanning curves and to compare the peak potential and peak current.The scanning curve demonstrated the specific electrochemical behaviors of the blank potassium ferricyanide solution and that mixed with blood samples in different groups. Significant differences in mean peak potentials of mixture and shifts (ΔEp (mV)) were observed of the three groups (P< = 0.001). 106.00±9.00 and 3.14±7.48 for Group healthy individuals, 120.90±11.18 and 18.10±8.81 for Group hematologic malignancies, 136.84±11.53 and 32.89±10.50 for Group solid tumors, respectively. In contrast, there were no significant differences in the peak currents and shifts.The newly developed method to apply the electrochemical workstation system to identify hematologic malignancies and solid tumors with good sensitivity and specificity might be effective, suggesting a potential utility in clinical application.

Jun Wang1, Baoan Chen1, Jian Chen1, Xiaohui Cai1, Guohua Xia2, Ran Liu1, Pingsheng Chen2, Yu Zhang3, Xuemei Wang31Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China 210009; 2Medical School, Southeast University, Nanjing; 3State Key Laboratory of Bioelectronics, Southeast University, Nanjing, China 210009Background: A promising approach to optimize the disposition of daunorubicin-loaded magnetic nanoparticles (DNR-MNPs) was developed to minimize serious side effects of systematic chemotherapy for cancer.Methods: The physical properties of DNR-MNPs were investigated and their effect on leukemia cells in vitro was evaluated by a standard WST-1 cell proliferation assay. Furthermore, cell apoptosis and intracellular accumulation of DNR were determined by FACSCalibur flow cytometry.Results: Our results showed that the majority of MNPs were spherical and their sizes were from 10 to 20 nm. The average hydrodynamic diameter of DNR-MNPs in water was 94 nm. The in vitro release data showed that the DNR-MNPs have excellent sustained release property. Proliferation of K562 cells was inhibited in a dose-dependent manner by DNR in solution (DNR-Sol) or by DNR-MNPs. The IC50 for DNR-MNPs was slightly higher than that for DNR-Sol. DNR-MNPs also induced less apoptosis in K562 cells than did DNR-Sol. Detection of fluorescence intensity of intracellular DNR demonstrated that DNR-MNPs could be taken up by K562 cells and persistently released DNR in cells.Conclusion: Our study suggests that optimized DNR-MNPs formulation possesses sustained drug-release and favorable antitumor properties, which may be used as a conventional dosage form for antitumor therapy.Keywords: daunorubicin, magnetic iron oxide nanoparticles, drug delivery system, target selection, K562 cells

Jun Wang1, Yue Chen1, Baoan Chen1, Jiahua Ding1, Guohua Xia1, Chong Gao1, Jian Cheng1, Nan Jin1, Ying Zhou1, Xiaomao Li1, Meng Tang2, Xue Mei Wang21Department of Hematology, Zhongda Hospital, Clinical Medical School, Southeast University, Nanjing, People’s Republic of China; 1Department of Physics, University of Saarland, D-266041 Saarbruechen, Germany; 2National Key Laboratory of Bioelectronics (Chien-Shiung Wu Laboratory), Southeast University, Nanjing, People’s Republic of ChinaBackground: This study explored the pharmacokinetic parameters and tissue distribution of magnetic iron oxide nanoparticles (Fe3O4 MNPs) in imprinting control region (ICR) mice.Methods: The Fe3O4 MNPs were synthesized by chemical coprecipitation, and their morphology and appearance were observed by transmission electron microscopy. ICR mice were divided into a control group and a Fe3O4 MNP-treated group. Probable target organs in ICR mice were observed, and the pharmacokinetic parameters and biodistribution of Fe3O4 MNPs in tissues were identified using atomic absorption spectrophotometry.Results: Fe3O4 MNPs were spherical with a well distributed particle diameter, and were distributed widely in various target organs and tissues including the heart, liver, spleen, lungs, kidneys, brain, stomach, small intestine, and bone marrow. The majority of Fe3O4 MNPs were distributed to the liver and the spleen. Fe3O4 MNP levels in brain tissue were higher in the Fe3O4 MNP-treated group than in the control group, indicating that Fe3O4 MNPs can penetrate the blood–brain barrier.Conclusion: These results suggest that the distribution of Fe3O4 MNPs was mostly in the liver and spleen, so the curative effect of these compounds could be more pronounced for liver tumors. Furthermore, Fe3O4 MNPs might be used as drug carriers to overcome physiologic barriers.Keywords: magnetic nanoparticles, Fe3O4, tissue distribution, mice

Lijie Liu1, Baoan Chen2, Feixiang Teng1, Lijuan Shi1, Nan Jing2, Li Wang1, Ningna Chen2, Guohua Xia2, Xiaomao Li31Department of Physiology and Pharmacology, Medical School, Southeast University, Nanjing, People’s Republic of China; 2Department of Hematology, Affiliated Zhongda Hospital, Clinical Medical School, Southeast University, Nanjing, People’s Republic of China; 3Department of Physics, University of Saarland, Saarbruechen, GermanyAbstract: While the potential impact of magnetic nanoparticles (MNPs) has been widely explored in almost all medical fields, including cardiology, one question remains; that is whether MNPs interfere with cardiac physiological processes such as the expression and function of ion channels, especially in vivo. KCNQ1 channels are richly expressed in cardiac myocytes and are critical to the repolarization of cardiac myocytes. In this study, we evaluated the effects of Fe3O4-magnetic nanoparticles (MNPs-Fe3O4) on the expression of KCNQ1 in cardiac muscle of mice at rest and at different times following a single bout of swimming (SBS). Firstly, we demonstrated that the expression levels of KCNQ1 channels are significantly up-regulated in mice following a SBS by means of reverse transcription polymerase chain reaction (RT-PCR) and western-blot. After treating mice with normal saline or pure MNPs-Fe3O4 separately, we studied the potential effect of MNPs-Fe3O4 on the expression profile of KCNQ1 in mouse cardiac muscle following a SBS. A SBS increased the transcription of KCNQ1 at 3 hours post exercise (3PE) 164% ± 24% and at 12 hours post exercise (12PE) by 159% ± 23% (P < 0.05), and up-regulated KCNQ1 protein 161% ± 27% at 12PE (P < 0.05) in saline mice. In MNPs-Fe3O4 mice, KCNQ1 mRNA increased by 151% ± 14% and 147% ± 12% at 3 and 12 PE, respectively (P < 0.05). Meanwhile, an increase of 152% ± 14% in KCNQ1 protein was also detected at by 12PE. These results indicated that the administration of MNPs-Fe3O4 did not cause any apparent effects on the expression profile of KCNQ1 in rested or exercised mice cardiac muscle. Our studies suggest a novel path of KCNQ1 current adaptations in the heart during physical exercise and in addition provide some useful information for the biomedical application of MNPs which are imperative to advance nanomedicine.Keywords: KCNQ1, cardiac muscle, magnetic nanoparticles of Fe3O4

Baoan Chen1,*, Yiqiong Liang1,*, Weiwei Wu1, Jian Cheng1, Guohua Xia1, Feng Gao1, Jiahua Ding1, Chong Gao1, Zeye Shao1, Guohong Li1, Wenji Chen1, Wenlin Xu2, Xinchen Sun3, Lijie Liu4, Xiaomao Li5, Xuemei Wang61Department of Hematology; 3Department of Oncology, The Affiliated Zhongda Hospital, Clinical Medical School, Southeast University, Nanjing, People’s Republic of China; 2Department of Hematology, The Affiliated People’s Hospital, Jiangsu University, Zhenjiang, People’s Republic of China; 4Institution of Physiology, Southeast University, Nanjing, People’s Republic of China; 5Department of Physics, University of Saarland, Saarbruechen, Germany; 6State Key Lab of Bioelectronics (Chien-Shiung Wu Laboratory), Southeast University, Nanjing, Peoples Republic of China; *These authors have contributed equally to this workAbstract: Gambogic acid (GA) has a significant anticancer effect on a wide variety of solid tumors. Recently, many nanoparticles have been introduced as drug-delivery systems to enhance the efficiency of anticancer drug delivery. The aim of this study was to investigate the potential benefit of combination therapy with GA and magnetic nanoparticles of Fe3O4 (MNPs-Fe3O4). The proliferation of K562 cells and their cytotoxicity were evaluated by MTT assay. Cell apoptosis was observed and analyzed by microscope and flow cytometry, respectively. Furthermore, realtime polymerase chain reaction and Western blotting analyses were performed to examine gene transcription and protein expression, respectively. The results showed that MNPs-Fe3O4 dramatically enhanced GA-induced cytotoxicity and apoptosis in K562 cells. The typical morphological features of apoptosis treated with GA and MNPs-Fe3O4 were observed under an optical microscope and a fluorescence microscope, respectively. The transcription of caspase-3 and bax gene in the group treated with GA and MNPs-Fe3O4 was higher than that in the GA-alone group or MNPs-Fe3O4-alone group, but the transcription of bcl-2, nuclear factor-κB, and survivin degraded as did the expression of corresponding proteins in K562 cells. Our data suggests a potential clinical application of a combination of GA and MNPs-Fe3O4 in leukemia therapy.Keywords: gambogic acid, magnetic nanoparticles of Fe3O4, traditional Chinese medicine, K562 leukemia cells, apoptosis

Baoan Chen1*, Jian Cheng1*, Mingfang Shen1, Feng Gao1, Wenlin Xu2, et al1Department of Hematology;2Department of Hematology, The Affiliated People’s Hospital, Jiangsu University, Zhenjiang, P.R China, et al *These authors have contributed equally to this work.Abstract: Apoptosis is a common pathway that finally mediated the killing functions of anticancer drugs, which is an important cause of multidrug resistance (MDR). The aim of this study was to investigate the potential benefit of combination therapy with magnetic nanoparticle of Fe3O4 (MNP(Fe3O4)) and 5-bromotetrandrin (BrTet). Analysis of the apoptosis percentage showed that combination of daunorubicin (DNR) with either MNP(Fe3O4) or BrTet exerted a potent cytotoxic effect on K562/A02 cells, while MNP(Fe3O4) and BrTet cotreatment can synergistically enhance DNR-induced apoptosis. Importantly, we confirmed that the distinct synergism effect of that composite on reverse multidrug resistance may owe to the regulation of various proliferative and antiapoptotic gene products, including P53 and caspase-3. Thus our in vitro data strongly suggests a potential clinical application of MNP(Fe3O4) and BrTet combination on CML.Keywords: K562/A02 leukemic cells, multidrug resistance, magnetic nanoparticle of Fe3O4, 5-bromotetrandrine, apoptosis, P53, caspase-3

Baoan Chen1,* Jian Cheng1,* Yanan Wu1, Feng Gao1, Wenlin Xu2, et al 1Department of Hematology;2Department of Hematology, The Affiliated People’s Hospital, Jiangsu University, Zhenjiang, PR China *These authors have contributed equally to this workAbstract: In this paper we establish the xenograft leukemia model with stable multidrug resistance in nude mice and to investigate the reversal effect of 5-bromotetrandrine (5-BrTet) and magnetic nanoparticle of Fe3O4 (MNP-Fe3O4) combined with daunorubicin (DNR) in vivo. Two subclones of K562 and K562/A02 cells were inoculated subcutaneously into the back of athymic nude mice (1 × 107 cells/each) respectively to establish leukemia xenograft models. Drug-resistant and sensitive tumor-bearing nude mice were assigned randomly into five groups which were treated with normal saline; DNR; NP-Fe3O4 combined with DNR; 5-BrTet combined with DNR; 5-BrTet and MNP-Fe3O4 combined with DNR, respectively. The incidence of formation, growth characteristics, weight, and volume of tumors were observed. The histopathologic examination of tumors and organs were detected. For resistant tumors, the protein levels of Bcl-2, and BAX were detected by Western blot. Bcl-2, BAX, and caspase-3 genes were also detected. For K562/A02 cells xenograft tumors, 5-BrTet and MNP-Fe3O4 combined with DNR significantly suppressed growth of tumor. A histopathologic examination of tumors clearly showed necrosis of the tumors. Application of 5-BrTet and MNP-Fe3O4 inhibited the expression of Bcl-2 protein and upregulated the expression of BAX and caspase-3 proteins in K562/A02 cells xenograft tumor. It is concluded that 5-BrTet and MNP-Fe3O4 combined with DNR had a significant tumor-suppressing effect on a MDR leukemia cells xenograft model.Keywords: 5-bromotetrandrine, magnetic nanoparticle of Fe3O4, multidrug-resistance, xenograft model

Baoan Chen1,5, Qian Sun1,5, Xuemei Wang2, Feng Gao1, Yongyuan Dai1, Yan Yin1, Jiahua Ding1, Chong Gao1, Jian Cheng1, Jingyuan Li2, Xinchen Sun1, Ningna Chen1, Wenlin Xu3, Huiling Shen3, Delong Liu41Department of Hematology, Zhongda Hospital, Southeast University, Nanjing, China; 2State Key Lab of Bioelectronics(Chien-Shiung Wu Laboratory), Southeast University, Nanjing 210096, China; 3Department of Hematology, The First People’s Hospital of Zhenjiang, Zhenjiang, China; 4Westchester Medical Center, New York Medical College, NY, USA; 5These authors have contributed equally to this work.Abstract: Drug resistance is a primary hindrance for efficiency of chemotherapy. To investigate whether Fe3O4-magnetic nanoparticles (Fe3O4-MNPs) loaded with adriamycin (ADM) and tetrandrine (Tet) would play a synergetic reverse role in multidrug resistant cell, we prepared the drug-loaded nanoparticles by mechanical absorption polymerization to act with K562 and one of its resistant cell line K562/A02. The survival of cells which were cultured with these conjugates for 48 h was observed by MTT assay. Using cells under the same condition described before, we took use of fluorescence microscope to measure fluorescence intensity of intracellular ADM at an excitation wavelength of 488 nm. P-glycoprotein (P-gp) was analyzed with flow cytometer. The expression of mdr1 mRNA was measured by RT-PCR. The results showed that the growth inhibition efficacy of both the two cells increased with augmenting concentrations of Fe3O4-MNPs which were loaded with drugs. No linear correlation was found between fluorescence intensity of intracellular adriamycin and augmenting concentration of Fe3O4-MNPs. Tet could downregulate the level of mdr-1 gene and decrease the expression of P-gp. Furthermore, Tet polymerized with Fe3O4-MNPs reinforced this downregulation, causing a 100-fold more decrease in mdr1 mRNA level, but did not reduce total P-gp content. Our results suggest that Fe3O4-MNPs loaded with ADM or Tet can enhance the effective accumulation of the drugs in K562/A02. We propose that Fe3O4-MNPs loaded with ADM and Tet probably have synergetic effect on reversal in multidrug resistance.Keywords: magnetic nanoparticles, tetrandrine, adriamycin, multidrug resistance reversal, leukemia K562/A02

A novel technique was developed, that was high throughput simultaneousscreening of multiple resistance protein expression based on a protein array system. Themethod combined the advantage of the specificity of enzyme-linked immunosorbentassays with the sensitivity and high throughput of microspot. In this system, the multipleresistance protein arrays were created by spotting the captured antibodies onto the glassslide. The arrays were then incubated with cell samples of leukemia patients. The boundproteins were recognized by biotin-conjugated antibodies and detected by CCD.Experiments demonstrated that three multiple resistance proteins, including Pgp, MRPand BCRP which are members of the ATP-binding-cassette (ABC) superfamily ofmembrane transporters could be simultaneously detected using this new approach.Research work shows the result is coincident with flow cytometry (FCM) (P>0.01). Itprovided a methodology to develop many high-density protein array systems to detect avariety of proteins. The protein arrays will provide a powerful tool to identify theleukemia cell protein expression and rapidly validate their MDR determination.