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We have previously reported that human endogenous retrovirus-K (HERV-K) envelope (env) protein is a tumorassociated antigen (TAA) for cancer vaccines, and that its antibodies (mAbs) possess antitumor activity against cancer. In this study, a chimeric antigen receptor (CAR) specific for HERV-K env protein (K-CAR) was generated using anti-HERVK mAb. K-CAR T cells from peripheral blood mononuclear cells (PBMCs) of 9 breast cancer (BC) patients and 12 normal donors were able to inhibit growth of, and to exhibit significant cytotoxicity toward, BC cells but not MCF-10A normal breast cells. The antitumor effects in cancer cells were significantly reduced when control T cells were used, or the expression of HERV-K was knocked down by an shRNA. Secretion of multiple cytokines, including IFNg, TNF-α, and IL-2, was significantly enhanced in culture media of BC cells treated with K-CARs. Significantly reduced tumor growth and tumor weight was observed in xenograft models bearing MDA-MB-231 or MDA-MB-435.eB1 BC cells. Importantly, the K-CAR prevented tumor metastasis to other organs. Furthermore, downregulation of HERV-K expression in tumors of mice treated with K-CAR correlated with upregulation of p53 and downregulation of MDM2 and p-ERK. Importantly, the expression of HERV-K env protein in metastatic tumor tissues treated with K-CAR T cells correlated with the expression of Ras. Our results indicate that HERV-K env protein is an oncoprotein and may play an important role in tumorigenesis related to p53 and Ras signaling pathways. Anti-HERV-K treatment, including K-CAR treatment, shows potential for immunotherapy of BC. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy most common in East Asia, Africa and Alaska. Radiotherapy and cisplatin-based chemotherapy are the main treatment options. Unfortunately, disease response to concurrent chemoradiotherapy varies among patients with NPC, and many cases are resistant to cisplatin and radiotherapy. Signal transducer and activator of transcription 3 (Stat3) has been implicated in the development and progression of various solid tumors. In this study, we assessed the activation and expression of Stat3 in NPC cells. We found that Stat3 was activated and could be blocked by the small molecule inhibitor Stattic. The inhibition of Stat3 in NPC cells by Stattic decreased the expression of cyclin D1 in a dose- and time-dependent manner. Thus, Stattic was used to target Stat3 in NPC cell lines. We found that Stattic could inhibit cell viability and proliferation in NPC cells and significantly induced apoptosis. Additionally, Stat3 transfection attenuated, whereas Stat3 knockdown enhanced, the effects of Stattic upon cell viability inhibition and apoptosis induction. Furthermore, Stattic sensitized NPC cells to cisplatin and ionizing radiation (IR) by preventing cell proliferation and inducing apoptosis. Taken together, Stattic inhibit Stat3 and display antitumor effect in NPC, and enhanced chemosensitivity and radiosensitivity in NPC. Therefore, our findings provide the base for more rational approaches to treat NPC in the clinic. [ABSTRACT FROM AUTHOR]

As no unified treatment protocol or evidence yet exists for plasmapheresis without plasma, this study explored the outcomes of using 4% human albumin (ALB) solution as a replacement solution in patients undergoing plasma exchange for multiple myeloma (MM) patients with acute kidney injury (AKI). This study was prospectively registered (ChiCTR2000030640 and NCT05251896). Bortezomib-based chemotherapy plus therapeutic plasmapheresis (TPP) with 4% human ALB solution was assessed for three years in patients with MM aged >18 years, with AKI according to the Kidney Disease Improving Global Outcomes criteria, and without previous renal impairment from other causes. The primary endpoints were changes in renal function over 18 weeks and survival outcomes at 36 months. The secondary endpoints were the incidence of adverse reactions and symptom improvement. Among the 119 patients included in the analysis, 108 experienced renal reactions. The M protein (absolute changes: median −12.12%, interquartile ranges (IQRs) −18.62 to −5.626) and creatine (median −46.91μmol/L, IQR −64.70 to −29.12) levels decreased, whereas the estimated glomerular filtration rate (eGFR) increased (median 20.66mL/(min·1.73 m² ), IQR 16.03–25.29). Regarding patient survival, 68.1% and 35.3% of patients survived for >12 and >36 months, respectively. The three symptoms with the greatest relief were urine foam, poor appetite, and blurred vision. All 11 patients (7.6%) who experienced mild adverse reactions achieved remission. In conclusion, in MM patients with AKI, plasma-free plasmapheresis with 4% human ALB solution and bortezomib-based chemotherapy effectively alleviated light chain damage to kidney function while improving patient quality of life. [ABSTRACT FROM AUTHOR]

Granulocyte colony-stimulating factor (G-CSF) mobilizes regulatory T cells (Tregs) from bone marrow into the peripheral blood, by reducing the expression of stromal cell-derived factor-1a (SDF-1α). However, G-CSF has rarely been studied in acute myeloid leukemia (AML) immunotherapy. The present study performed a Transwell migration assay in vitro to determine the contribution of SDF-1a to the migration of leukemia cells, and the effects of G-CSF were evaluated. The effects of G-CSF on SDF-1a and Tregs in the AML microenvironment were examined, by employing a WEHI-3-grafted BALB/c mouse AML model (AML-M4). It is evident that G-CSF reversed immunosuppression of the AML microenvironment by reducing SDF-1a in bone marrow and elevating Tregs in the peripheral blood in in vivo studies. Furthermore, AML mice treated with vaccines combined with G-CSF achieved a longer survival time than those treated with vaccines without G-CSF, showing the efficiency of the regimen. The present study demonstrates the effects of G-CSF on the mobilization of leukemia cells and Tregs into the peripheral blood. In addition, immunotherapy with G-CSF priming represents a promising therapeutic strategy of targeting the immunosuppression. [ABSTRACT FROM AUTHOR]

A pandemic designated as Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading worldwide. Up to date, there is no efficient biomarker for the timely prediction of the disease progression in patients. To analyze the inflammatory profiles of COVID-19 patients and demonstrate their implications for the illness progression of COVID-19. Retrospective analysis of 3,265 confirmed COVID-19 cases hospitalized between 10 January 2020, and 26 March 2020 in three medical centers in Wuhan, China. Patients were diagnosed as COVID-19 and hospitalized in Leishenshan Hospital, Zhongnan Hospital of Wuhan University and The Seventh Hospital of Wuhan, China. Univariable and multivariable logistic regression models were used to determine the possible risk factors for disease progression. Moreover, cutoff values, the sensitivity and specificity of inflammatory parameters for disease progression were determined by MedCalc Version 19.2.0. Age (95%CI, 1.017 to 1.048; P < 0.001), serum amyloid A protein (SAA) (95%CI, 1.216 to 1.396; P < 0.001) and erythrocyte sedimentation rate (ESR) (95%CI, 1.006 to 1.045; P < 0.001) were likely the risk factors for the disease progression. The Area under the curve (AUC) of SAA for the progression of COVID-19 was 0.923, with the best predictive cutoff value of SAA of 12.4 mg/L, with a sensitivity of 83.9% and a specificity of 97.67%. SAAcontaining parameters are novel promising ones for predicting disease progression in COVID-19. [ABSTRACT FROM AUTHOR]

Monocytic leukemia‑associated antigen‑34 (MLAA‑34) is a novel monocytic leukemia‑associated antigen and a candidate oncogene. The aim of the present study was to investigate the involvement of the MLAA‑34 gene in acute myeloid leukemia (AML). MLAA‑34 expression level, chromosome location, gene copy number and single nucleotide polymorphisms (SNPs) of 40 patients with AML and 5 healthy volunteers were analyzed by reverse transcription‑polymerase chain reaction, fluorescence in situ hybridization and DNA sequencing. The effects of MLAA‑34 mutation on overall survival (OS) and progression‑free survival (PFS) of patients with AML were also analyzed. MLAA‑34 was significantly upregulated in patients with AML when compared with volunteer controls, and this upregulation was associated with a C59T SNP site located in the second exon of MLAA‑34. MLAA‑34 was mapped to 13q14.2 and no translocation was observed in patients with AML. In addition, this SNP site is affinitive to the well‑known molecular markers of AML, including Fms‑like tyrosine kinase 3 and DNA methyltransferase 3A, as well as extramedullary lesions, periphery leukocyte numbers, remission and cytogenetic abnormalities of patients with AML. Patients with AML with MLAA‑34 C59T mutations had significantly shorter OS and PFS times compared with that of patients without C59T mutations. The present findings indicated that the MLAA‑34 C59T mutation was a high‑risk factor for recurrence of AML, and may be a candidate target for AML therapy. [ABSTRACT FROM AUTHOR]

Background The persistence of minimal residual disease (MRD) during therapy is the strongest adverse prognostic factor in acute lymphocytic leukemia (ALL). This study was to identify serum candidate peptides for monitoring MRD in adult ALL.Results A total of 33 peptides in the molecular weight range of 1000-10000 Da were detected using ClinProt system and statistically different between adult patients with ALL and healthy controls. Quick classifier (QC) algorithm was used to obtain a diagnostic model consisting of five peptides that could discriminate patients with ALL from controls with a high sensitivity (100%) and specificity (96.67%). The peptides in the QC model were identified as fibrinogen alpha chain (FGA), glutathione S-transferase P1 (GSTP1), isoform 1 of fibrinogen alpha chain precursor, platelet factor 4 (PF4) by high pressure∕performance liquid chromatography mass spectrometry∕mass spectrometry. Relative intensities of the five peptides were compared among ALL different groups for the potential importance of MRD evaluation in ALL. The peptides with increased relative intensities in newly diagnosed (ND) ALL patients were found to be decreased in their relative intensities after complete remission (CR) of adult ALL. When ALL patients were refractory&relapsed (RR), relative intensities of the peptides were elevated again. Peptides with decreased relative intensities in ND and RR ALL patients were found to be increased in their relative intensities when ALL patients achieved CR. The findings were validated by ELISA and western blot. Further linear regression analyses were performed to eliminate the influence of platelet and white blood cell counts on serum protein contents and indicated that there were no correlations between the contents of all four proteins (PF4, connective tissue active peptideш, FGA and GSTP1) and white blood cell or platelet counts in ALL different groups and healthy control. Conclusions We speculate the five peptides, FGA, isoform 1 of fibrinogen alpha chain precursor, GSTP1, PF4 and connective tissue active peptide шwould be potential biomarkers for forecasting relapse, monitoring MRD and evaluating therapeutic response in adult ALL. [ABSTRACT FROM AUTHOR]