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CAR T cell therapy has shown dramatic clinical success in relapsed or refractory (r/r) B-ALL and other haematological malignancies. However, the loss of specific antigens, cell fratricide, T cell aplasia, and normal T cell separation are challenges in treating T cell leukemia/lymphoma with CAR T therapy. CD99 is a promising antigen to target T-ALL and AML as it is expressed on the majority of T-ALL and AML. Here, we isolated a low-affinity CD99 (12E7) antibody, which specifically recognizes leukemia cells over normal bone marrow cells. T cells transduced with an anti-CD99-specific CAR that contained the 12E7 scFv expanded with minor fratricide, maintained their cytotoxic function and mediated powerful antitumour effects. Subsequently, we conducted a pilot clinical study to evaluate the safety and feasibility of therapy with anti-CD99 CAR T cells in 4 patients with r/r T-LBL (n=1), AML (n=2) or myeloid sarcoma (MS) (n=1). The clinical overall response rate (ORR) was 50% (2/4 patients), and 1 patients (25%) achieved complete remission (CR) for 2 month. Mild cytokine release syndrome (CRS) occurred in 2 patients and the CRS no more than grade 2. Together, our results demonstrate that anti-CD99 CAR T cells specifically recognize and efficiently eliminate CD99+ leukemia cells.

RNA-binding proteins (RBPs) are critical regulators of transcription and translation that are often dysregulated in cancer. Although RBPs are increasingly recognized as being important for normal hematopoiesis and for hematologic malignancies as oncogenes or tumor suppressors, RBPs that are essential for the maintenance and survival of leukemia remain elusive. Here we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival in an N6-methyladenosine (m6A)-dependent manner. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 dramatically induces apoptosis and promotes differentiation coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia cells in vitro and in vivo. Loss of YBX1 has no obvious effect on normal hematopoiesis. Mechanistically, YBX1 interacts with insulin-like growth factor 2 messenger RNA (mRNA)-binding proteins (IGF2BPs) and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency dysregulates the expression of apoptosis-related genes and promotes mRNA decay of MYC and BCL2 in an m6A-dependent manner, which contributes to the defective survival that results from deletion of YBX1. Thus, our findings have uncovered a selective and critical role of YBX1 in maintaining myeloid leukemia survival, which might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.

Background Excessive generation of reactive oxygen species (ROS) in the presence of a defective antioxidant system can induce cellular damage and disrupt normal physiological functions. Several studies have revealed the unfavorable role of ROS in promoting the growth, proliferation, migration, and survival of leukemia cells. In this review study, we summarize the mechanisms of ROS production and its role in leukemogenesis, counteractive effects of antioxidants, and implicate the current ROS-dependent anticancer therapies in acute myeloid leukemia. Body The dysregulation of the redox system is known to play a significant role in the pathogenesis of leukemia. Leukemia cells generate high levels of ROS, which further increases the levels through extra pathways, including mitochondrial deoxyribonucleic mutation, leukemic oncogene activation, increased nicotinamide adenine phosphate hydrogen (NADPH), and cytochrome P450 activities. Aforementioned pathways once activated have shown to promote genomic instability, induce drug resistance to leukemia medical therapy, disease relapse and reduce survival period. The current standard of treatment with chemotherapy employs the pro-oxidant approach to induce apoptosis and promote tumor regression. However, this approach retains several deleterious effects on the subject resulting in degradation of the quality of life. Nevertheless, the addition of an antioxidant as an adjuvant drug to chemotherapy alleviates treatment-related toxicity, increases chemotherapeutic efficacy, and improves survival rates of a patient. Conclusion Acute myeloid leukemia remains a daunting challenge to clinicians. The desire to achieve the maximum benefit of chemotherapy but also improve patient outcomes is investigated. ROS generated through several pathways promotes leukemogenesis, drug resistance, and disease relapse. Chemotherapy, the mainstay of treatment, further upregulates ROS levels. Therefore, the addition of an antioxidant to leukemia medical therapy alleviates toxicity and improves patient outcomes.

Long noncoding RNAs (LncRNAs) are essential epigenetic regulators with critical roles in tumor initiation and malignant progression; however, the mechanism by which aberrantly expressed lncRNA RP11-84E24.3 regulates the pathogenesis of glioma is not fully understood. Here, we investigate the function of lncRNA RP11-84E24.3 in glioma onset and progression as well as identify a molecular pathway regulated by this lncRNA. Differentially expressed lncRNAs related to glioma were identified. The aberrant expression of lncRNA RP11-84E24.3 was verified in samples from patients with glioma as well as glioma cell lines. The role of lncRNA RP11-8424.3 in proliferation, apoptosis, migration, and invasion was assessed using gain- and loss-of function approaches, EdU incorporation, flow cytometry, wound healing and Transwell invasion assays. Western blot analysis was utilized to examine the expression of proteins associated with epithelial-to-mesenchymal transition (EMT). The interaction between lncRNA RP11-84E24.3, TFAP2C and SNAI1 was confirmed using RNA pull-down, ChIP and luciferase reporter assays. LncRNA RP11-84E24.3 was up-regulated in both glioma tissues and cell lines. LncRNA RP11-84E24.3 overexpression enhanced the proliferation, migration and invasion of glioma cells while reducing apoptosis. This was associated with a decrease in E-cadherin expression and an increase in N-cadherin and Vimentin expression. LncRNA RP11-84E24.3 directly targeted TFAP2C protein, resulting in increased SNAI1 expression. Knockdown of TFAP2C or SNAI1 reversed the effects of lncRNA RP11-84E24.3 overexpression, while silencing lncRNA RP11-84E24.3 inhibited tumor formation of glioma cells in vivo. LncRNA RP11-84E24.3 increased SNAI1 expression by forming a complex with TFAP2C protein, promoting EMT in glioma cells and tumor formation.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide and has the ability to damage multiple organs. However, information on serum SARS-CoV-2 nucleic acid (RNAemia) in patients affected by coronavirus disease 2019 (COVID-19) is limited.MethodsPatients who were admitted to Zhongnan Hospital of Wuhan University with laboratory-confirmed COVID-19 were tested for SARS-COV-2 RNA in serum from 28 January 2020 to 9 February 2020. Demographic data, laboratory and radiological findings, comorbidities, and outcomes data were collected and analyzed.ResultsEighty-five patients were included in the analysis. The viral load of throat swabs was significantly higher than of serum samples. The highest detection of SARS-CoV-2 RNA in serum samples was between 11 and 15 days after symptom onset. Analysis to compare patients with and without RNAemia provided evidence that computed tomography and some laboratory biomarkers (total protein, blood urea nitrogen, lactate dehydrogenase, hypersensitive troponin I, and D-dimer) were abnormal and that the extent of these abnormalities was generally higher in patients with RNAemia than in patients without RNAemia. Organ damage (respiratory failure, cardiac damage, renal damage, and coagulopathy) was more common in patients with RNAemia than in patients without RNAemia. Patients with vs without RNAemia had shorter durations from serum testing SARS-CoV-2 RNA. The mortality rate was higher among patients with vs without RNAemia.ConclusionsIn this study, we provide evidence to support that SARS-CoV-2 may have an important role in multiple organ damage. Our evidence suggests that RNAemia has a significant association with higher risk of in-hospital mortality.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause acute respiratory distress syndrome, hypercoagulability, hypertension, and multiorgan dysfunction. Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis. In an analysis of a randomly collected cohort of 124 patients with COVID-19, we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity. By virtual screening of a U.S. FDA approved drug library, we identified an anticoagulation agent dipyridamole (DIP) in silico, which suppressed SARS-CoV-2 replication in vitro. In a proof-of-concept trial involving 31 patients with COVID-19, DIP supplementation was associated with significantly decreased concentrations of D-dimers (P < 0.05), increased lymphocyte and platelet recovery in the circulation, and markedly improved clinical outcomes in comparison to the control patients. In particular, all 8 of the DIP-treated severely ill patients showed remarkable improvement: 7 patients (87.5%) achieved clinical cure and were discharged from the hospitals while the remaining 1 patient (12.5%) was in clinical remission.

The Wilms' tumor 1 (WT1) gene is an important regulatory molecule that plays a vital role in cell growth and development. Initially, knowledge of WT1 was mostly limited to Wilms' tumor. Over the past years, numerous studies have shown that WT1 is aberrant expressed or mutated in hematopoietic malignancies, including acute leukemia (AL), myelodysplastic syndrome (MDS) and chronic myelogenous leukemia (CML). Currently, many studies focus on exploring the role of WT1 in hematopoietic malignancies. Such studies improve the understanding of hematopoietic malignancies, and the collection of data about WT1 expression or mutation in hematopoietic malignancies over the past years can facilitate the risk stratification of hematopoietic malignancies. In this review, we highlight the important role of WT1 in hematopoietic malignancies, discuss its potential clinical applications as a minimal residual disease (MRD) and prognostic biomarker, and evaluate the possible therapy target of WT1 in hematopoietic malignancies.

The novel coronavirus disease 2019 (COVID-19) has become a global health emergency. Early detection and intervention are key factors for improving outcomes in patients with COVID-19. Real-time reverse transcriptase polymerase chain reaction-based molecular assays and antibody for detecting SARS-CoV-2 in respiratory specimens are the current reference standard for COVID-19 diagnosis. Clinical implications of different specimen types for nucleic acid and antibody testing of COVID-19 in Zhongnan hospital of Wuhan University were analyzed. Compared with health groups, tumor patients had higher rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (+/-) immunoglobulin M (IgM) (+) immunoglobulin G (IgG) (+). The rate of SARS-CoV-2 (-) IgM (+) IgG (-) or SARS-CoV-2 (-) IgM (-) IgG (+) in female was significantly higher than that in male. These results can help governments to take screening measures to prevent the COVID-19 pandemic again.

This study aimed to evaluate the existing staging systems for multiple myeloma (MM) in the real world. From January 2010 to June 2019, we retrospectively analyzed 859 newly diagnosed MM patients from two institutions. Clinical data including laboratory findings, imaging examinations and staging system were obtained by reviewing medical records. Survival distributions were estimated using the Kaplan-Meier curve analysis, and Cox proportional hazards model were used to identified risk factors. The overall survival (OS) of eligible patients was 61.0 months. The Revised International Staging System (R-ISS) had a larger receiver operating characteristic curve area (0.603) than both the International Staging System (0.573) and the Durie Salmon staging system (0.567). In the group receiving immunomodulatory agents-based regimens, the median OS was 92.0 months in R-ISS I, 63.0 months in R-ISS II and 18.0 months in R-ISS III (p 0.0001). In the group receiving proteasome inhibitors-based regimens, the median OS was 102.0 months in R-ISS I, 63.0 months in R-ISS II and 22.0 months in R-ISS III (p 0.0001). In different subgroups grouped according to age, hemoglobin (HGB), creatinine, and Ca, R-ISS also had a good stratification effect. Patients in R-ISS II, which accounted for 69.9% of all patients, were further analyzed. Univariate and multivariate Cox analyses revealed that age65 years (p = 0.001), HGB100 g/L (p 0.001), elevated LDH (p = 0.001), and Ca (p = 0.010) were independent predictors of worse prognosis within R-ISS II. To conclusion, R-ISS remains a valuable staging system in the real world of the novel drug era. However, patients classified as R-ISS II still have great heterogeneity.

PurposeWe aimed to compare the clinical characteristics, efficacy and survival of newly diagnosed extramedullary multiple myeloma patients (EMM) between single and multiple sites invasion.MethodsA total of 90 EMM patients were included. The characteristics including gender, age, Durie-Salmon stage, ISS stage, hemoglobin, blood calcium, creatinine, M-protein types, β2-microglobulin, lactate dehydrogenase and so on were analyzed. We compared the overall remission rates (ORR) in patients with single site invasion and multiple sites invasion. Progression free survival (PFS) and overall survival (OS) were also compared.ResultsPatients with multiple sites invasion had higher lactate dehydrogenase than single site invasion (179.0U/L vs. 154.7U/L, P=0.016). The ORR in patients with single site invasion (72.1%) was not significantly higher than multiple sites invasion (68.2%) (P=0.690). In patients with multiple sites invasion, PI-based regimen (78.9% vs. 33.3%, P=0.035) or PI combined with IMiD regimen (84.6% vs. 33.3%, P=0.026) could achieve superior efficacy than routine chemotherapy. Among patients with single site invasion, the COX model analysis showed that proteasome inhibitors combined with immunomodulators could significantly improve the PFS (HR=0.080, 95%CI: 0.007-0.855, P=0.037). Among patients with multiple sites invasion, the associations of RISS 3 with poor PFS (HR=4.081, 95%CI: 1.533-10.865, P=0.005) and OS (HR=13.295, 95%CI: 3.219-54.907, P=0.000) were showed.ConclusionRISS stage 3 was possibly associated with poor survival of extramedullary multiple myeloma patients with multiple sites invasion. We propose a prospective and large-sample study to explore the effects of new drugs and autologous hematopoietic stem cell transplantation on survival of patients at RISS stage 3.

Sensitive and efficient detection of drug-resistant mutations is essential in cancer precision medicine. In treating acute myeloid leukemia (AML), FLT3 gene F691L mutation shows universal resistance to all currently available FLT3 inhibitors. However, there is no particular detection method for FLT3-F691L. Commonly-used first-generation sequencing (FGS) approaches have low sensitivity, and next-generation sequencing (NGS) is time-consuming. Herein, we developed an accurate and sensitive FLT3-F691L diagnostic method by CRISPR detection. Briefly, the FLT3-691 region is amplified by recombinase polymerase amplification (RPA) and detected by L691-crRNA induced Cas12a reaction, and finally the result can be directly observed under a blue lamp or analyzed by a fluorescence reader. Confirmed by the tests on diluted plasmids and 120 AML patient samples, this method can achieve a sensitivity of 0.1% and complete the whole diagnosis process within 40 min. Potentially, this method will play an important role in point-of-care applications and guidance of AML treatment.

Objective Multiple myeloma (MM) patients with bone destruction are difficult to restore, so it is of great clinical significance to further explore the factors affecting MM bone destruction. Methods and results This study retrospectively analyzed 419 cases with MM. Multiple linear regression analysis showed that those MM patients with a higher concentration of Ca2+ in serum, higher positive rate of CD138 immuno-phenotype and advanced in stage with 13q34 deletion in cytogenetics would be more prone to bone destruction, while total bile acid (TBA) and kappa chain isotope negatively correlated with bone destruction in MM patients. The Kaplan-Meier analysis indicated that Ca2+, serum β2-microglobulin (β2-MG), hemoglobin (HGB), creatinine (CREA), uric acid (UA) and age correlated with the survival of bone destruction in MM patients. Cox regression analysis further showed that the independent prognostic factors of β2-MG and CREA had a higher risk for early mortality in bone destruction patients. Moreover, an index was calculated based on β2-MG and globulin (GLB) to white blood cell (WBC) ratio to predict the poor survival of bone destruction patients. Conclusion We provide a novel marker to predict the prognosis of myeloma patients using routine examination method instead of bone marrow aspiration, and provide a reference for clinical evaluation.

The thioredoxin (Trx) system is a major antioxidant system for keeping the intracellular redox state in almost all forms of life, including Trx, Trx reductase (TrxR) and NADPH. It regulates many signaling pathways related to antioxidative action, growth promotion, anti-apoptosis, cell migration, inflammatory modulation, immune function, etc. The oxidative stress has been proved to promote cancer occurrence and the readjustment of Trx system. Considerable results have demonstrated overexpression of Trx in cancer cells, moreover, the overexpression of Trx is closely related to high risk of cancer recurrence and drug resistance. This review focuses on the relationship between Trx system and acute leukemia (AL). The crux of the development of any useful therapy is a knowledge of disease etiology and progression. The potential of thioredoxin system inhibitors as therapeutic agents for acute leukemia is highlighted. Furthermore, targeting Trx as an anti-leukemic strategy is clinically beneficial to AL patients.

Objective: Early identification of coronavirus disease 2019 (COVID-19) patients with worse outcomes may benefit clinical management of patients. We aimed to quantify pneumonia findings on CT at admission to predict progression to critical illness in COVID-19 patients.Methods: This retrospective study included laboratory-confirmed adult patients with COVID-19. All patients underwent a thin-section chest computed tomography (CT) scans showing evidence of pneumonia. CT images with severe moving artifacts were excluded from analysis. Patients' clinical and laboratory data were collected from medical records. Three quantitative CT features of pneumonia lesions were automatically calculated using a care.ai Intelligent Multi-disciplinary Imaging Diagnosis Platform Intelligent Evaluation System of Chest CT for COVID-19, denoting the percentage of pneumonia volume (PPV), ground-glass opacity volume (PGV), and consolidation volume (PCV). According to Chinese COVID-19 guidelines (trial version 7), patients were divided into noncritical and critical groups. Critical illness was defined as a composite of admission to the intensive care unit, respiratory failure requiring mechanical ventilation, shock, or death. The performance of PPV, PGV, and PCV in discrimination of critical illness was assessed. The correlations between PPV and laboratory variables were assessed by Pearson correlation analysis.Results: A total of 140 patients were included, with mean age of 58.6 years, and 85 (60.7%) were male. Thirty-two (22.9%) patients were critical. Using a cutoff value of 22.6%, the PPV had the highest performance in predicting critical illness, with an area under the curve of 0.868, sensitivity of 81.3%, and specificity of 80.6%. The PPV had moderately positive correlation with neutrophil (%) (r = 0.535, p < 0.001), erythrocyte sedimentation rate (r = 0.567, p < 0.001), d-Dimer (r = 0.444, p < 0.001), high-sensitivity C-reactive protein (r = 0.495, p < 0.001), aspartate aminotransferase (r = 0.410, p < 0.001), lactate dehydrogenase (r = 0.644, p < 0.001), and urea nitrogen (r = 0.439, p < 0.001), whereas the PPV had moderately negative correlation with lymphocyte (%) (r = −0.535, p < 0.001).Conclusions: Pneumonia volume quantified on initial CT can non-invasively predict the progression to critical illness in advance, which serve as a prognostic marker of COVID-19.

Acute lymphoblastic leukemia (ALL) is a hematological malignancy characterized by the malignant clonal expansion of lymphoid hematopoietic precursors. It is regulated by various signaling molecules such as cytokines and adhesion molecules in its microenvironment. Chemokines are chemotactic cytokines that regulate migration, positioning and interactions of cells. Many chemokine axes such as CXCL12/CXCR4 and CCL25/CCR9 have been proved to play important roles in leukemia microenvironment and further affect ALL outcomes. In this review, we summarize the chemokines that are involved in ALL progression and elaborate on their roles and mechanisms in leukemia cell proliferation, infiltration, drug resistance and disease relapse. We also discuss the potential of targeting chemokine axes for ALL treatments, since many related inhibitors have shown promising efficacy in preclinical trials, and some of them have entered clinical trials.

Purpose This study was to evaluate existing staging system of multiple myeloma (MM) in the real world. Methods We retrospectively analyzed 886 newly diagnosed MM from two institutions. Results The overall survival (OS) of eligible patients was 61.0 months. R-ISS held a larger receiver operating characteristic curve (ROC) area (0.603) than that of ISS (0.573) and DS staging system (0.567). In the group of immunomodulatory agents-based regimens, the median OS was 92.0 months in R-ISS I, 63.0 months in R-ISS II and 18.0 months in R-ISS III (p65 years (p=0.001), HGBConclusion R-ISS remains a valuable staging system in the real world of new drug era. But patients classified in R-ISS II still have large heterogeneity.

Background Severe cases of coronavirus disease 2019 (COVID-19) among pediatric patients are more common in children less than 1 year of age. Our aim is to address the underlying role of immunity and inflammation conditions among different age groups of pediatric patients. Methods We recruited pediatric patients confirmed of moderate COVID-19 symptoms, admitted to Wuhan Children's Hospital from January 28th to April 1st in 2020. Patients were divided into four age groups (≤ 1, 1–6, 7–10, and 11–15 years). Demographic information, clinical characteristics, laboratory results of lymphocyte subsets test, immune and inflammation related markers were all evaluated. Results Analysis included 217/241 (90.0%) of patients with moderate clinical stage disease. Average recovery time of children more than 6 years old was significantly shorter than of children younger than 6 years (P = 0.001). Reduced neutrophils and increased lymphocytes were significantly most observed among patients under 1 year old (P n = 12, 30.0%, P n = 13, 32.5%, P P P P P P = 0.007), interleukin (IL)-10 (P = 0.011), IL-6 (P = 0.008), lactate dehydrogenase (P P = 0.007). Conclusion The higher rate of severe cases and long course of COVID-19 among children under 1 year old may be due to the lower production of antibodies and serum complements of in this age group.

Shengxuening (SXN) is a Chinese patent medicine with main ingredients (including chlorophyll derivatives and sodium iron chlorophyllin) extracted from silkworm excrement. SXN exhibited efficacy in clinical trials of renal anemia and iron deficiency anemia; however, the specific mechanisms remain unclear. This study found that SXN increased the number of peripheral blood cells and improved the bone marrow morphology in myelosuppressed mouse model, reversed the reduction in body weight and spleen indices, and increased the serum levels of erythropoietin and granulocyte-macrophage colony-stimulating factor. Quantitative real-time PCR array and Western blot analysis showed the enhanced expression of stem cell factor (SCF), JAK2, and STAT3 in the liver. These results suggested that SXN promoted the recovery of hemopoietic function in myelosuppressed models by increasing the secretion of hematopoietic factors and activating the JAK2/STAT3 pathway. Therefore, this medicine may be applied as therapeutic pharmaceutical drug to mitigate myelosuppression.

The inhibitory effect of long intergenic non-coding RNA 00320 (LINC00320) in glioma cell proliferation has been proposed in a recent study. However, the mechanisms by which LINC00320 regulate aquaporin 9 (AQP9) in glioma require further exploration. Hence, this study aims to investigate effects of LINC00320 on tumorigenicity of glioma cells and angiogenesis of microvascular endothelial cells (MVECs). Expression of LINC00320 and AQP9 in glioma tissues and cells was measured by reverse transcription–quantitative polymerase chain reaction and Western blot analysis. The relationship among LINC00320, nuclear factor κB subunit 1 (NFKB1) and AQP9 was examined by RNA immunoprecipitation, dual-luciferase reporter gene, and chromatin immunoprecipitation assays. The participation of LINC00320 and AQP9 in glioma cell proliferation and MVEC angiogenesis was analyzed using gain- and loss-of-function approaches. Finally, a nude mouse orthotopic xenograft model of glioma was established to investigate the effects of LINC00320 and AQP9 on glioma growth in vivo. LINC00320 was under-expressed and AQP9 was over-expressed in glioma tissues. Further mechanistic investigation showed that LINC00320 downregulated AQP9 by inhibiting the recruitment of NFKB1 to the promoter region of AQP9. LINC00320 overexpression or AQP9 silencing inhibited the proliferation of glioma cells and angiogenesis of MVECs. Also, upregulation of LINC00320 restrained tumor growth and angiogenesis in xenograft mice by downregulating AQP9. Taken together, LINC00320 acts as a tumor suppressor in glioma, thus presenting a novel therapeutic target.

The increasing incidence of geriatric patients with multiple myeloma has elevated concerns in clinical practice. While the introduction of novel therapeutic agents has substantially improved outcomes in younger patients with myeloma, poorer outcomes remain in older patients. Managing older patients requires a multidisciplinary team approach to consider factors that may influence both treatment selection and outcomes. Aging is associated with remodeling of vital organs, physiological downregulations of basal metabolism, susceptibility to multiple comorbidities with ultimate frailty, thereby contributing to the underrepresentation and exclusion of very old patients from clinical trials. Therefore, timely confirmation of a precise diagnosis is crucial for prompt initiation of treatment if the desired outcome is to be achieved. Adequate and judicious assessment using comprehensive geriatric assessment tools minimizes toxicities and treatment discontinuation. Initiating treatment with combinational therapy requires knowledge of indications and anticipated outcomes, as well as individualized therapy with appropriate dose-adjustment. Individualized therapy based on good clinical acumen and best practices obverts unwanted polypharmacy, preventing iatrogenic harm. This review will therefore address the approaches and challenges faced in managing myeloma in geriatric patients aged 80 years and older, highlighting recommended therapeutic strategies and future prospective regimens.

The dysregulation of CD3+ CD8+ T lymphocytes, CD16+ CD56+ NK cells, C1q as well as IL-6, along with bacterial coinfection, were important causes of exacerbation of the patients’ condition and death., The outbreak of coronavirus disease 2019 (COVID-19), caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a threat to global health. The mortality rate of severely ill patients in the early stage is 32.5%. The exacerbation of the condition and death of patients are closely associated with inflammatory cytokine storms, which are caused by excessive activation of the immune and complement systems as well as the coinfection of other pathogens. However, the immunological characteristics and the mechanisms underlying inflammatory storms have not been well elucidated. Here, we analyzed the clinical and immunological characteristics of 71 confirmed COVID-19 patients. Based on the National Health Commission of China (NHCC) guidelines, patients were stratified into mild and severe types. We compared the clinical and laboratory data obtained from electronic medical records between the two types. In regard to the hematological parameters, COVID-19 patients showed decreased erythrocyte count, hemoglobin, hematocrit, lymphocyte count, eosinophil count, and complement C1q, whereas neutrophils, C-reactive protein, and procalcitonin were significantly increased, especially in severe cases. We also found that CD3+ CD4+ T lymphocytes, CD3+ CD8+ T lymphocytes, CD19+ B lymphocytes, and CD16+ CD56+ NK cells in the peripheral blood of all patients were decreased. In addition, CD3+ CD8+ T lymphocytes, CD16+ CD56+ NK cells, and complement C1q in severely ill patients decreased more significantly. Additionally, interleukin 6 (IL-6) elevation was particularly prominent in all patients, especially in severe cases. These results suggest that CD3+ CD8+ T lymphocytes, CD16+ CD56+ NK cells, C1q as well as IL-6 may play critical roles in the inflammatory cytokine storm. The dysregulation of these aforementioned immune parameters, along with bacterial coinfection, were the important causes of exacerbation of the patients’ condition and death. This study improves our understanding of the immune dysregulation of COVID-19 and provides potential immunotherapeutic strategies. IMPORTANCE The dysregulation of CD3+ CD8+ T lymphocytes, CD16+ CD56+ NK cells, C1q as well as IL-6, along with bacterial coinfection, were important causes of exacerbation of the patients’ condition and death.

Abnormal coagulation parameters and potential benefits of anticoagulant therapy in general population with novel coronavirus pneumonia (COVID-19) have been reported. However, limited data are available on cancer patients. Coagulation indexes and inflammation parameters in 57 cancer patients with SARS-CoV-2 infection with different severity were retrospectively analyzed. We found that D-dimer levels were increased in 33 patients (57.9%, median: 790 ng/mL). Compared with ordinary type patients, severe and critical ill patients had decreased MPV values (P = 0.006), prolonged PT (median: 13.3 vs. 11.5 vs. 11.4 s, P < 0.001), significant higher D-dimer levels (median: 2,400 vs. 940 vs. 280 ng/mL, P < 0.001), higher PCT levels (median: 0.17 vs. 0.055 vs. 0.045 ng/mL, P = 0.002), higher IL-6 (median: 20.6 vs. 2.3 vs. 3.0 pg/mL, P = 0.040), and decreased PaO2 (median: 68 vs. 84 vs. 96 mm Hg, P < 0.001). Importantly, three patients, one severe and two critical ill type, with increased D-dimer survived after anticoagulant therapy with continuous heparin infusion. Increased D-dimer levels positively correlated with increased PCT levels (r = 0.456, P = 0.002) and IL-6 levels (r = 0.501, P = 0.045). A negative correlation between D-dimer levels and PaO2 levels (r = −0.654, P = 0.021) were also existed. Cancer patients with COVID-19 showed prominent hypercoagulability associated with severe inflammation, anticoagulation therapy might be useful to improve the prognosis and should be immediately used after the onset of hypercoagulability.

Cancer immunotherapy has achieved great success in hematological cancers. However, immune cells are a highly heterogeneous population and can vary highly in clonal expansion, migration and function status, making it difficult to evaluate and predict patient response to immune therapy. Conventional technologies only yield information on the average population information of the treatment, masking the heterogeneity of the individual T cell activation status, the formation of immune synapse, as well as the efficacy of tumor cell killing at the single-cell level. To fully interrogate these single-cell events in detail, herein, we present a microfluidic microwell array device that enables the massive parallel analysis of the immunocyte's heterogeneity upon its interaction pairs with tumor cells at the single-cell level. By precisely controlling the number and ratio of tumor cells and T cells, our technique can interrogate the dynamics of the CD8+ T cell and leukemia cell interaction inside 6400 microfluidic wells simultaneously. We have demonstrated that by investigating the interactions of T cell and tumor cell pairs at the single-cell level using our microfluidic chip, details hidden in bulk investigations, such as heterogeneity in T cell killing capacity, time-dependent killing dynamics, as well as drug treatment-induced dynamic shifts, can be revealed. This method opens up avenues to investigate the efficacy of cancer immunotherapy and resistance at the single-cell level and can explore our understanding of fundamental cancer immunity as well as determine cancer immunotherapy efficacy for personalized therapy.

Jab1 overexpression correlates with poor prognosis in breast cancer patients, suggestting that targeting the aberrant Jab1 signaling in breast cancer could be a promising strategy. In the current study, we investigate the hypothesis that Jab1 positively regulates the DNA repair protein Rad51 and, in turn, the cellular response of breast cancer to chemotherapy with adriamycin and cisplatin. High-throughput mRNA sequencing (RNA-Seq) data from 113 normal and 1109 tumor tissues (obtained from TCGA) were integrated to our analysis to give further support to our findings. We found that Jab1 was overexpressed in adriamycin-resistant breast cancer cell MCF-7R compared with parental MCF-7 cells, and that knockdown of Jab1 expression conferred cellular sensitivity to adriamycin and cisplatin both in vivo and in vitro. By contrast, exogenous Jab1 expression enhanced the resistance of breast cancer cells to adriamycin and cisplatin. Moreover, we discovered that Jab1 positively regulated Rad51 in p53-dependent manner and that overexpression of Rad51 conferred cellular resistance to adriamycin and cisplatin in Jab1-deficient cells. Data from TCGA further validated an correlation between Jab1 and Rad51 in breast cancer, and elevated Jab1 and Rad51 associated with poor survival in breast cancer patients. Our findings indicate that Jab1 association with Rad51 plays an important role in cellular response to chemotherapy in breast cancer.

Background. The outbreak of COVID-19 has attracted the attention of the whole world. Our study aimed to describe illness progression and risk profiles for mortality in non-survivors. Methods. We retrospectively analyzed 155 patients with COVID-19 in Wuhan and focused on 18 non-survivors among them. Briefly, we compared the dynamic profile of biochemical and immune parameters and drew an epidemiological and clinical picture of disease progression from disease onset to death in non-survivors. The survival status of the cohort was indicated by a Kaplan–Meier curve. Results. Of the non-survivors, the median age was 73.5 years, and the proportion of males was 72.2%. Five and 13 patients were hospital-acquired and community-acquired infection of SARS-CoV-2, respectively. The interval between disease onset and diagnosis was 8.5 days (IQR, [4–11]). With the deterioration of disease, most patients experienced consecutive changes in biochemical parameters, including lymphopenia, leukocytosis, thrombocytopenia, hypoproteinemia, as well as elevated D-dimer and procalcitonin. Regarding the immune dysregulation, patients exhibited significantly decreased T lymphocytes in the peripheral blood, including CD3+T, CD3+CD4+Th, and CD3+CD8+Tc cells. By the end of the disease, most patients suffered from severe complications, including ARDS (17/18; 94.4%), acute cardiac injury (10/18; 55.6%), acute kidney injury (7/18; 38.9%), shock (6/18; 33.3%), gastrointestinal bleeding (1/18; 5.6%), as well as perforation of intestine (1/18; 5.6%). All patients died within 45 days after the initial hospital admission with a median survivor time of 13.5 days (IQR, 8–17). Conclusions. Our data show that patients experienced consecutive changes in biochemical and immune parameters with the deterioration of the disease, indicating the necessity of early intervention.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated deaths worldwide. Although recent studies have proposed different biomarkers for HCC progression and therapy resistance, a better understanding of the molecular mechanisms underlying HCC progression and recurrence, as well as the identification of molecular markers with a higher diagnostic accuracy, are necessary for the development of more effective clinical management strategies. Here, we aimed to identify novel players in HCC progression. SPRYD4 mRNA and protein expression analyses were carried out on a normal liver-derived cell line (HL-7702) and four HCC-derived cell lines (HepG2, SMMC7721, Huh-7, BEL-7402) using qRT-PCR and Western blotting, respectively. Cell proliferation Cell Counting Kit-8 (CCK-8) assays, protein expression analyses for apoptosis markers using Western blotting, and Caspase-Glo 3/7 apoptosis assays were carried out on the four HCC-derived cell lines. Expression comparison, functional annotation, gene set enrichment, correlation and survival analyses were carried out on patient data retrieved from the NCBI Gene module, the NCBI GEO database and the TCGA database. Through a meta-analysis we found that the expression of SPRYD4 was downregulated in primary HCC tissues compared to non-tumor tissues. We also found that the expression of SPRYD4 was downregulated in HCC-derived cells compared to normal liver-derived cells. Subsequently, we found that the expression of SPRYD4 was inversely correlated with a gene signature associated with HCC cell proliferation. Exogenous SPRYD4 expression was found to inhibit HCC cell proliferation by inducing apoptotic cell death. We also found that SPRYD4 expression was associated with a good prognosis and that its expression became downregulated when HCCs progressed towards more aggressive stages and higher grades. Finally, we found that SPRYD4 expression may serve as a biomarker for a good overall and relapse-free survival in HCC patients. Our data indicate that a decreased SPRYD4 expression may serve as an independent predictor for a poor prognosis in patients with HCC and that increased SPRYD4 expression may reduce HCC growth and progression through the induction of apoptotic cell death, thereby providing a potential therapeutic target.

Multiple myeloma (MM) is a complex aggressive mature B-cell malignancy. Although with the wide application of chemotherapy drugs, it remains incurable and the vast majority of patients relapse. Natural killer (NK) cells, also known as CD56+CD3− large granular lymphocytes, are cytotoxic innate immune cells against MM without prior sensitization steps. NK cell-based immunotherapy is extensively promising in a wide range of clinical settings. It is worthy of note that some novel drugs such as monoclonal antibodies (mAbs), proteasome inhibitors (PIs), and immunomodulators (IMiDs) directly or indirectly activate NK cells to enhance their antitumor activity, and the combined regimens significantly improve the prognosis of MM patients. In this review, we summarize recent findings that support a role for NK cells in the pathogenesis of MM and outline innovative approaches in the implementation of NK cell-based immunotherapy against MM.

Real-time detection and monitoring of the drug resistance of single cells have important significance in clinical diagnosis and therapy. Traditional methods operate a number of times for each individual concentration, and innovation is required for the design of more simple and efficient manipulation platforms with necessary higher sensitivity. Here, we have developed a novel diffused total internal reflection (TIR) method to perform drug metabolism and cytotoxicity analysis of trapped myeloid leukemia cells. Molm-13 cells, a type of acute myeloid leukemia cell, were chosen and injected into the device and fittingly captured by cell traps. Differing from previous studies, a series of different concentrations of azelaic acid (AZA) drug could be used from 0 mM to 50 mM through convection and diffusion processes in a single chip, with each concentration region featuring 50 cells, with a total of 549 cell trapping units. Thanks to the high sensitivity of the TIR method, only cells with the same drug concentration could be illuminated in the detection process. By adjusting the incident angle, we could exactly detect and monitor the drug resistance of the cells using different drug concentrations and the experimental resolution of the drug concentration was as small as 5 mM. Images of the membrane integrity and morphology of the cells in the bright field were measured and we also monitored the cell viabilities in the dark field over 2 hours. The effects of AZA on the Molm-13 cells were explored in different concentrations at the single cell level. Compared with the results of the traditional MTT assay method, the experimental results are more simple and accurate. A cell death of 5% at an AZA concentration of 5 mM was observed after 30 minutes, while a concentration of 40 mM corresponded to a 98% cell death. The designed method in this study provides a novel toolkit to control and monitor drug resistance at the single cell level more easily with higher sensitivity and we believe it has significant potential application in single cell quality assessment and medicine analysis in clinical practice.

Radioresistance is one of the primary causes responsible for therapeutic failure and recurrence of cancer. It is well documented that reactive oxygen species (ROS) contribute to the initiation and development of gastric cancer (GC), and the levels of ROS are significantly increased in patients with GC accompanied with abnormal expressions of multiple inflammatory factors. It is also well documented that ROS can activate cancer cells and inflammatory cells, stimulating the release of a variety of inflammatory cytokines, which subsequently mediates the tumor microenvironment (TME) and promotes cancer stem cell (CSC) maintenance as well as renewal and epithelial-mesenchymal transition (EMT), ultimately resulting in radioresistance and recurrence of GC.

The abnormalities of blood pressure (BP) nocturnal decline have been found to be predictive for carotid plaque and lacunar infarction in patients with hypertension. In this study, BP dipping patterns in postmenopausal females with hypertension were investigated. The nocturnal decline of systolic BP (SBP) was evaluated using 24-hour ambulatory BP monitoring (ABPM). A total of 163 postmenopausal females were eventually included in our study. The prevalence of reverse-dipper BP pattern was 32.3% in females with menopause age in their 40s and 40% in their 50s. However, after multivariate logistic regression analysis, menopause age was shown to be an independent risk factor for BP reverse dipping (Odds ratio [OR] 1.148; 95%CI 1.020 - 1.292; P = 0.020). Moreover, menopause age was negatively correlated with the decline rate of nocturnal SBP (r = -0.159; P < 0.05) and diastolic BP (r = -0.161; P < 0.05). Our study suggested that the menopause age might serve as a risk factor for reverse-dipper BP pattern in postmenopausal females with hypertension.

Multiple myeloma (MM) is a bone marrow-based malignancy that has a range of consequences resulting from either its direct effects on the bone marrow microenvironment- causing anaemia, more extensive myelosuppression and bone lysis - or its indirect effects on the kidney and other organ systems. Over the past several years, the introduction of autologous stem cell transplantation, immunomodulatory drugs, proteasome inhibitors, histone deacetylase inhibitors, and monoclonal antibodies has substantially improved survival outcomes. However, MM remains biologically heterogeneous with significant variability among patients in terms of clinical features, response to therapy and overall survival (OS). Several prognostic variables can help predict this variability in outcomes ranging from clinical based systems such as the International Staging System (ISS) to more advanced molecular characterizations of the myeloma PCs by cytogenetics and gene expression profiling. However with the advancement in technology utilized for laboratory testing and the emergence of new treatments for MM, there has been an evolution in the significance of these previously defined prognostic markers with time. Assessment of disease activity and depth of response continues to be a moving target in MM. Super-resolution fluorescence imaging is a major breakthrough in the field of optical imaging in this century. Super-resolution fluorescence imaging has been applied to a variety of biological imaging applications, including membrane, cytoskeletal and cytosolic proteins in fixed and living cells. Molecular motions can be quantified. To establish the detection limit and sensitivity threshold of dSTORM and FC, we used serial dilutions of anti-CD38 antibody to detect expression of CD38 on 8226 cells by Super Resolution localization Microscopy and flow cytometry (FC). Design six different antibody concentrations (300ng/ml, 30ng/ml, 10ng/ml, 3ng/ml, 1ng/ml, 0.3ng/ml) to label MM cells with immunofluorescence, and then detect them by flow cytometry. Similarly, design eight different antibody concentrations (1μg/ml, 300ng/ml, 30ng/ml, 10ng/ml, 3ng/ml, 1ng/ml, 0.3ng/ml, 0.1ng/ml), and perform the same treatment, perform immunofluorescence labeling on MM cells, and then perform super-resolution imaging, and calculate the density of CD38 protein on the surface of MM cells of each concentration. Figure 1A detects the ratio of the number of cells to the total number of cells, it can be seen from Figure 1A that when the antibody concentration is not less than 30ng/ml, almost all MM thinners can detect the signal, but when the antibody concentration is less than at 30ng/ml, only a few or no cells can detect the signal. This shows that when the antibody concentration is lower than 30ng/ml, the sensitivity of flow cytometry is no longer sufficient to detect CD38 protein on the surface of MM cells. From Figure 1B, it can be seen that even when the CD38 antibody concentration is 0.3ng/ml, super-resolution imaging can still accurately identify each CD38 antigen molecule on the surface of MM cells, and the statistical CD38 protein density is 8.5864±1.4180/μm2. This shows that the sensitivity of super-resolution is much higher than that of streaming. Disclosures No relevant conflicts of interest to declare.

Objective: Acute monocytic leukemia (AMoL) is the M5 subtype of acute myeloid leukemia (AML) which has the characteristics of high degree of malignancy, prone to extramedullary infiltration, poor efficacy of conventional chemotherapy, easy recurrence and so on. Besides, chemotherapy has large side effects and high cost. Therefore, it is urgent to find natural, non-toxic and cheap drugs for the treatment of acute monocytic leukemia. We evaluated the anti-acute mononuclear leukemia activities of selenium nanoparticles embedded in lentinan in vivo and in vitro, and explored the mechanism of how AMoL cells react to it. It is expected to provide a new method and basis for the treatment of acute mononuclear leukemia. Methods: Utilizing the aggregation and assembly behavior of Lentinus edodes extracted rigid tri-helical β-glucan (Lentinan, LNT) in aqueous solution, cooperative research group prepared Lentinus β-glucan/Selenium nanoparticle complex called LNT-Se by encapsulating selenium nanoparticles (SeNPs) in the cavity of LNT. CCK-8 and flow cytometry were used to detect cytotoxicity, apoptosis rate and cell cycle changes after LNT-Se treatment. Single cell microfluidics chip was used to observe the fluorescence intensity of green fluorescent protein (GFP) of single cell treated by drug. Transmission electron microscopy (TEM) was used to detect ultrastructural changes of THP-1. Coumarin 6 (C6) was used to modify LNT-Se, flow cytometry and confocal microscopy were used to detect drug uptake and primary targeting organelles in AML-M5 cells treated with C6-LNT-Se. The changes of reactive oxygen species (ROS) levels in AML-M5 cells after LNT-Se treatment were detected by flow cytometry. Oxidation-related indexes were further detected, such as malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px). The RNA extracted from untreated and LNT-Se-treated THP-1 cells was sequenced by mRNA-seq. AML-M5 patient-derived tumor xenograft (PDX) leukemia mouse model was established to evaluate the efficacy of LNT-Se in vivo. Serum was collected for detecting liver and kidney functions. Tissue sections were stained by hematoxylin-eosin staining (HE). Specific molecules on the surface of human leukemia cells were detected by immunohistochemistry (IHC) to investigate the efficacy of LNT-Se. Results: SeNPs were successfully embedded into LNT hollow nanotubes and were stably dispersed in water. LNT-Se could significantly inhibit the proliferation of AML-M5 cell lines and had no obvious toxic effect on normal cell lines. LNT-Se could promote the apoptosis of AML-M5 cells and block the cell cycle in the G2/M phase. 50μg/ mL LNT-Se could promote more than 40% apoptosis rate in AML-M5 patient cells, while only about 10% in healthy volunteer cells. At the single cell microfluidic level, the green fluorescence of THP-1 GFP + cells decreased rapidly after 2mg/mL LNT-Se treatment for 2h. After LNT-Se treatment, THP-1 cells showed obvious apoptotic vacuolation, nuclear condensation, chromatin agglutination under TEM. AML-M5 cells could take up C6-LNT-Se and reached the highest uptake at 2h, and C6 fluorescence sites mainly overlapped with lysosomal fluorescence. LNT-Se could decrease intracellular ROS level and MDA content, and increase the activity of GPX in supernatant, but the MDA content and SOD activity in supernatant had no significant changes. Differential gene analysis of transcriptome showed that the first 12 genes were all mitochondrial coding genes. Enrichment analysis showed that TNF, MAPK and NF-κB pathways were up-regulated and oxidative phosphorylation pathways were down-regulated. The experimental results of leukemia PDX animal model showed that the weight loss of mice was slowed down after LNT-Se treatment, and the tumor burden was reduced. Compared with normal mice, there was no significant difference in liver and kidney function after LNT-Se administration, and no pathological changes were observed in viscera. Conclusions: LNT-Se had a good anti-acute mononuclear leukemia effect in vitro and in vivo, and could be absorbed by cells, and the primary target organelle was lysosome. Both in vivo and in vitro experiments suggested that LNT-Se was less toxic. LNT-Se had antioxidant activity and might exert anti-AML-M5 activity through TNF, MAPK and NF-κB pathways. These results indicated that LNT-Se could be used as an effective anti-AML-M5 drug. Disclosures No relevant conflicts of interest to declare.

Background: Multiple myeloma is a hematological malignant disease in which clonal plasma cells proliferate abnormally. NIR-II fluorophores have great application prospects for cancer treatment. Methods: Multiple detection techniques were used to evaluate effect and mechanisms of the novel small-molecule NIR-II fluorophores probe on multiple myeloma cells in vitro experiment. In vivo MM.1S Luc+ B-NSG mouse model was built to assess the role of probe in multiple myeloma treatment. Results: The novel small-molecule NIR-II fluorophores probe shown high affinity with multiple myeloma cells and specific myeloma imaging in vivo. More importantly, the probe could effectively induce tumor death with 808 nm laser irradiation in a dose-dependent manner. Further, Confocal found that the probe was mainly distributed in mitochondria and significantly reduced the mitochondrial membrane potential with laser irradiation. Moreover, Reactive Oxygen Species (ROS) level was notably increased and the up-regulation expression of cleaved poly ADP-ribose polymerase (PARP) was detected after treated with the probe and laser irradiation. Consistent with the previous results, the disease was alleviated obviously in probe laser-treated group. Conclusions: Our work confirm for the first time that the specific imaging and remarkable photodynamic therapy (PDT) effect of a novel NIR-II fluorophores probe to multiple myeloma. It provides the foundation for application of NIR-II fluorophores from solid tumor to non-solid tumor. Disclosures No relevant conflicts of interest to declare.

Objective: As the incidence of tumors increases, more patients need chemotherapy. Patients receiving chemotherapy also inevitably suffer side effects from treatment. Damage to the immune and hematopoietic system causes the failure of therapies. Mesenchymal stem cells have excellent capabilities in immune regulation and hematopoietic support. This study preliminarily explored the safety and effectiveness and of human umbilical cord mesenchymal stem cells (UCMSC) in myelosuppressive patient-derived tumor xenograft (PDX) models of acute myeloid leukemia (AML). Methods: B-NDG mice were used to establish the PDX models. The mice were randomly divided into three groups: AML group, AML+Ara-C group and AML+Ara-C+MSC group. Mice in the AML+Ara-C group and AML+Ara-C+MSC group were injected intraperitoneally with cytarabine (Ara-C) 60mg/kg on day1-day3 to induce myelosuppression. Mice in the AML+Ara-C+MSC group were injected 3×10 6 UCMSC through the tail vein on day4. We observed the changes in peripheral blood, bone marrow signaling pathways, and AML progression in mice. Results: The experiment found that UCMSC rescued the body weight and peripheral blood. We also found that UCMSC could increase the number of bone marrow CD117 + hematopoietic stem/progenitor cells and CD41 + megakaryocytes through flow cytometry. We verified at protein level that the hematopoiesis-related signaling pathway JAK2/STAT3 was up-regulated in AML+Ara-C+MSC group compared with AML+Ara-C group through flow cytometry and immunohistochemistry. At the same time, the infusion of UCMSC after Ara-C had no influence on disease progression. On day15, the proportion of human CD45 + cells in the bone marrow of between AML+Ara-C+MSC group and AML+Ara-C group was similar, and there was no statistical difference (21.96±3.10 vs. 23.04±1.51; P=0.6792). Conclusion: Infusion of exogenous UCMSC after chemotherapy in PDX models could promote the recovery of hematopoiesis without affecting the efficacy of Ara-C. A reasonable UCMSC infusion scheme is potential to be used in the treatment of AML patients and it requires a lot of preclinical exploration in the future. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Cytarabine (Ara-C) was administrated to mice models to induce myelosuppression.

Objective To evaluate the association of 18 F-2'-deoxy 2'-fluorodeoxyglucose (18 F-FDG) PET/CT with clinical parameters in predicting patients with newly diagnosed multiple myeloma (MM). Methods A total of 120 MM patients undergoing 18 F-FDG PET/CT scanning were analyzed in a retrospective cohort study. Results Based on multivariate analysis, β2M, LDH, number of focal lesions (FLs), and SUVmax were significantly correlated with OS. These 4 variables were used to construct a new staging system (NSS) based on the number of risk factors. NSS provided a better discrimination of risk between stages III and II than International staging system (ISS) (P .05). Based on Spearman correlation analysis, the presence of lesions in appendicular skeleton, number of FLs, and SUVmax appeared to indicate advanced stage of MM. ROC curves which showed the combination of β2M with calcium got a specificity of 96.3% for lesions in appendicular skeleton, and LDH alone had 100% specificity in predicting the number of FLs, although the sensitivity was only 50%. Conclusions 18 F-FDG PET/CT in combination with clinical parameters provided an accurate and simple method for risk stratification of patients with newly diagnosed MM.

// Lingling Chen 1,2,* , Chunyan Liu 1,* , Jianfeng Gao 1 , Zhiwen Xie 3 , Lawrence W.C. Chan 4 , Damien J. Keating 5 , Yibin Yang 6 , Jiazhong Sun 7 , Fuling Zhou 8 , Yongchang Wei 9 , Xiuli Men 10 and Sijun Yang 1 1 ABSL-3 Laboratory at the Center for Animal Experiment and Institute of Animal Model for Human Disease, Wuhan University School of Medicine, Wuhan, P. R. China 2 Department of Cell Biology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, P.R. China 3 School of Bioscience and Technology , Weifang Medical University, Weifang Shandong, P.R. China 4 Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hong Kong, Hong Kong 5 Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia 6 Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China 7 Department of Respiratory, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China 8 Department of Hematology and Radiation, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China 9 Department of Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China 10 School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, P.R. China * These authors have contributed equally to this work Correspondence to: Sijun Yang, email: // Keywords : Miro1, mitophagy, insulin resistance, HFD, diabetes, Pathology Section Received : June 26, 2017 Accepted : August 29, 2017 Published : September 16, 2017 Abstract Mitochondrial function is essential to meet metabolic demand of pancreatic beta cells respond to high nutrient stress. Mitophagy is an essential component to normal pancreatic β-cell function and has been associated with β-cell failure in Type 2 diabetes (T2D). Our previous studies have indicated that mitochondrial Rho (Miro) GTPase-mediated mitochondrial dysfunction under high nutrient stress leads to NOD-like receptor 3 (NLRP3)-dependent proinflammatory responses and subsequent insulin resistance. However, the in vivo mechanism by which Miro1 underlies mitophagy has not been identified. Here we show firstly that the expression of Miro is reduced in human T2D and mouse db/db islets and in INS-1 cell line exposed to high glucose and palmitate. β-cell specific ablation of Miro1 (Miro1f/f: Rip-cre mice, or (IKO) under high nutrient stress promotes the development of hyperglycemia. β-cells from IKO mice display an inhibition of mitophagy under oxidative stress and induces mitochondrial dysfunction. Dysfunctional mitophagy in IKO mice is represented by damaged islet beta cell mitochondrial and secretory capacity, unbalanced downstream MKK-JNK signalling without affecting the levels of MEK, ERK or p38 activation and subsequently, impaired insulin secretion signaling via inhibition IRS-AKT-Foxo1 pathway, leading to worsening glucose tolerance in these mice. Thus, these data suggest that Miro1 may be responsible for mitophagy deficiency and β-cell dysfunction in T2D and that strategies target Miro1 in vivo may provide a therapeutic target to enhance β-cell mitochondrial quality and insulin secretion to ameliorate complications associated with T2D.

// Weijie Ma 1, * , Xi Chen 1, * , Lu Ding 2, * , Jianhong Ma 3, * , Wei Jing 4 , Tian Lan 1 , Haseeb Sattar 5 , Yongchang Wei 6 , Fuling Zhou 3 and Yufeng Yuan 1 1 Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China 2 Department of Clinical Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China 3 Department of Gynaecology and Obstetrics, Zhongnan Hospital of Wuhan University, Wuhan, China 4 Department of Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China 5 Department of Clinical Pharmacy, Wuhan Union Hospital, Affiliated Hospital, Tongji Medical College, Huazhong University of Science And Technology, Wuhan, China 6 Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China * These authors have contributed equally to this work Correspondence to: Yufeng Yuan, email: yuanyf1971@whu.edu.cn Keywords: long non-coding RNA, prognosis, survival, clinicopathology, prostate cancer Received: March 06, 2017 Accepted: April 25, 2017 Published: May 07, 2017 ABSTRACT The abnormally expressed LncRNAs played irreplaceable roles in the prognosis of prostate cancer (PCa). Therefore, we conducted this systematic review and meta-analysis to summarize the association between the expression of LncRNAs, prognosis and clinicopathology of PCa. 18 eligible studies were recruited into our analysis, including 18 on prognosis and 9 on clinicopathological features. Results indicated that aberrant expression of LncRNAs was significantly associated with biochemical recurrence-free survival (BCR-FS) (HR = 1.55, 95%CI: 1.01–2.37, P < 0.05), recurrence free survival (RSF) (HR = 3.07, 95%CI: 1.07–8.86, P < 0.05) and progression free survival (PFS) (HR = 2.34, 95%CI: 1.94–2.83, P < 0.001) in PCa patients. LncRNAs expression level was correlated with several vital clinical features, like tumor size (HR = 0.52, 95%CI: 0.28–0.95, P = 0.03), distance metastasis (HR = 4.55, 95%CI: 2.26–9.15, P < 0.0001) and histological grade (HR = 6.23, 95% CI: 3.29–11.82, P < 0.00001). Besides, down-regulation of PCAT14 was associated with the prognosis of PCa [over survival (HR = 0.77, 95%CI: 0.63–0.95, P = 0.01), BCR-FS (HR = 0.61, 95%CI: 0.48–0.79, P = 0.0001), prostate cancer-specific survival (HR = 0.64, 95%CI: 0.48–0.85, P = 0.002) and metastasis-free survival (HR = 0.61, 95%CI: 0.50-0.74, P < 0.00001)]. And, the increased SChLAP1 expression could imply the worse BCR-FS (HR = 2.54, 95%CI: 1.82-3.56, P < 0.00001) and correlate with Gleason score (< 7 vs ≥ 7) (OR = 4.11, 95% CI: 1.94-8.70, P = 0.0002). Conclusively, our present work demonstrated that LncRNAs transcription level might be potential prognostic markers in PCa.

The expression profiles and biological relevance of long non-coding RNA XIST and its activator JPX in hepatocellular carcinoma (HCC) are not well elucidated. We measured JPX and XIST expression levels in HCC, evaluated their clinical significance in HCC progression, and verified their potential as biomarkers for diagnosing HCC.JPX and XIST expression in 68 HCC tissues and adjacent normal tissues were evaluated by quantitative reverse transcription-PCR (qRT-PCR); their association with pathologic features and overall survival was analyzed. Plasma JPX/XIST levels in 42 patients with HCC and 68 healthy controls were measured by qRT-PCR to determine their potential as biomarkers.JPX and XIST levels were significantly decreased in HCC and associated with histological grade and tumor-node-metastasis stage (P0.05). Low JPX and XIST expression resulted in significantly poor overall survival of HCC. Multivariate Cox regression analysis demonstrated that JPX/XIST expression levels were independent prognostic factors for HCC overall survival rates. Moreover, plasma JPX levels in patients were lower than that in controls; JPX yielded an area under the receiver operating characteristic curve of 0.814 and the combination of JPX and AFP possessed a promoted ability for discrimination between HCC patients and controls (AUC 0.905, 72.2% specificity, 97.1% sensitivity).Downregulated JPX and XIST may serve as novel biomarkers of poor prognosis in HCC.

PurposeEarly infection was an important cause of mortality in patients with multiple myeloma (MM). The study aimed to assess factors affecting early infection and identify patients with high risk developing infection. MethodsDuring January 2010 to June 2019, patients with MM were analyzed, retrospectively. The data was divided into training and independent validation cohort. The least absolute shrinkage and selection operator (LASSO) regression model was used for data dimension reduction, feature selection, and model building. ResultsOf 745 confirmed MM patients, 540 eligible cases were included in final analyses. In total, 165 patients (30.6%) suffered infections, while 110 patients (20.4%) occurred early infections during the first 3 months after diagnosis. Bacteria and the respiratory tract were the most common pathogen and localization of infection, respectively. In training cohort, PS≥2, HGB ConclusionWe determined risk factors for early infection and established a predictive model to help clinicians identify patients with high-risk infection. It can help clinicians to determine whether to adjust monitoring and treatment strategies, or apply prophylactic interventions to high-risk patients. Disclosures No relevant conflicts of interest to declare.

Background: Multiple myeloma (MM) is a hematology malignant disease originated from B-cell line and still incurable. Compound Kushen Injection (CKI) as a Traditional Chinese Medicines are promising agents in our previous research for treating cancer. The effect of CKI on multiple myeloma was still unknown. Methods: In vitro experiment, flow cytometry was used to evaluate effect of CKI on multiple myeloma cells. Optofluidic chip was applied to detect effect at single-cell level. And in vivo RPMI-8226 GFP+ B-NSG mouse model was built to assess the role of CKI in multiple myeloma treatment. Results: CKI inhibited MM cells proliferation of and increased its apoptosis rate. And the cell cycle of MM cells was also arrested by CKI treatment. In contrast, CKI has few toxic effects on mesenchymal stem cells (MSCs) and MC3T3 cells. At the single-cell level, MM cells was died in time and dose dependent manner. Transcriptome find that the expression of MYC and TERT in CKI-treated RPMI-8226 cells was significantly down-regulated and confirmed by qRT-PCR and Western blot. Overexpression of TERT can partly reverse the inhibition effect of CKI on RPMI-8226 cells. B-NSG mouse was injected with GFP+ RPMI-8226 cells through caudal vein, and the disease was partially alleviated by decreased tumor burden in the CKI-treated group. Furthermore, it is surprising that in animal models with myeloma bone disease, the bone mass was higher in CKI treatment group than control. Conclusions: CKI inhibits MM cells through the MYC/TERT signaling pathway and improve the quality of life of MM mouse. Our findings provide preclinical evidence to show that CKI could be a promising candidate in human MM therapy. Disclosures No relevant conflicts of interest to declare.

MicroRNAs (miRNAs) can participate in many behaviors of various tumors. Prior studies have reported that miR-15b-5p in different tumors can either promote or inhibit tumor progression. In breast cancer, the role of miR-15b-5p is unclear. The main objective of this paper is to explore miR-15b-5p effects and their mechanisms in breast cancer using both in vitro and in vivo experiments. This study showed that miR-15b-5p expression was upregulated in breast cancer compared with normal breast tissue and was positively correlated with poor overall survival in patients. Knockdown of miR-15b-5p in MCF-7 and MD-MBA-231 breast cancer cells restrained cell growth and invasiveness and induced apoptosis, whereas overexpression of miR-15b-5p achieved the opposite effects. We next revealed a negative correlation between miR-15b-5p and heparanase-2 (HPSE2) expression in breast cancer. Knockdown of miR-15b-5p significantly increased HPSE2 expression at both mRNA and protein levels in breast cancer cells in vitro. The underlying mechanisms of miR-15-5p in breast cancer were investigated using luciferase activity reporter assay and rescue experiments. In addition, miR-15b-5p knockdown significantly inhibited tumor growth in a xenograft model in mice. In summary, we showed that miR-15b-5p promotes breast cancer cell proliferation, migration, and invasion by directly targeting HPSE2. Accordingly, miR-15b-5p may serve both as a tool for prognosis and as a target for therapy of breast cancer patients.

Acute myeloid leukemia (AML) is a difficult therapeutic hematological tumor. It is urgent to find a non-toxic natural drug to treat AML. Herein, the selenium nanoparticles (SeNPs) embedded in nanotubes consisted of triple helix β-(1, 3)-d-glucan (BFP) from the black fungus that were wrapped to form stable inclusion complex BFP-Se, which was self-assembled and exhibited high stability in water. In vitro, the BFP-Se significantly inhibited the proliferation of AML cells and increased the cytotoxicity on AML cells. On single-cell levels, the U937 cells were gradually swelled and lysed with BFP-Se treatment on optofluidics chips. Further, the blood and bone marrow analysis indicated the anti-leukemia effects of BFP-Se in vivo. Moreover, BFP-Se increased the total antioxidant capacity of AML cells and decreased the expression of c-Jun activation domain-binding protein 1 and thioredoxin 1. Our results suggest that this biocompatible polysaccharide nanotube containing Se nanoparticles would provide a novel strategy for AML therapy.

Background: The outbreak of a new coronavirus (2019-nCoV) induced pneumonia (NCP) in the central city of Wuhan in China poses a threat to the public health Thi

Background: Coronavirus disease 2019 (COVID-19) has been widely spread and caused tens of thousands of deaths, mainly in patients with severe COVID-19. Methods: Patients with COVID-19 were retrospectively analyzed. Clinical characteristics were compared, and LASSO regression as well as multivariate analysis were used to screen variables and establish prediction model. Findings: A total of 2529 patients with COVID-19 was retrospectively analyzed, and 452 eligible severe COVID-19 were used for finally analysis. In training cohort, the median age was 66·0 years while it was 73·0 years in non-survivors. Patients aged 60-75 years accounted for the largest proportion of infected populations and mortality toll. Anti-SARS-CoV-2 antibodies were monitored up to 54 days, and IgG levels reached the highest during 20-30 days. About 60.2% of severe patients had complications. Acute myocardial injury was the earliest injured organ, whereas the time from acute kidney injury to death was the shortest. Age, diabetes, coronary heart disease (CHD), percentage of lymphocytes (LYM%), procalcitonin (PCT), serum urea, C reactive protein and D-dimer (DD), were identified associated with mortality by LASSO binary logistic regression. Then multivariate analysis was performed to conclude that old age, CHD, LYM%, PCT and DD remained independent risk factors for mortality. Based on the above variables, a scoring system of COVID-19 (CSS) was established and divided into low-risk and high-risk groups. This model displayed good discrimination (AUC=0·919) and calibration (P =0·264). The complications in low-risk and high-risk groups were significantly different. We also found that the use of corticosteroids in low-risk groups increased hospital stays by 4·5 days (P =0·036) and durations of disease by 7·5 days (P =0 · 012) compared with no corticosteroids. Interpretation: Old age, CHD, LYM%, PCT and DD were independently related to mortality. CSS was useful for predicting in-hospital mortality and complications, and it could help clinicians to identify high-risk patients with poor prognosis. Funding Statement: This work was supported by the Key Project for Anti-2019 novel Coronavirus Pneumonia from the Ministry of Science and Technology, China (grant number 2020YFC0845500). Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: This study was conducted according to the principles of Helsinki and approved by the Ethics Committee of Zhongnan Hospital of Wuhan University (No.2020063).

Aims: Type 2 diabetes (T2D) is associated with pancreatic β-cell dysfunction, manifested by reduced glucose-stimulated insulin secretion (GSIS). The regulator of calcineurin 1 (RCAN1) in islets is an endogenous inhibitor of calcium-activated protein phosphatase. Previous studies have indicated that global RCAN1 overexpression under high nutrient stress is involved in insulin resistance in T2D. However, the specific role and mechanism of this gene's overexpression in pancreatic β-cells have not been thoroughly elucidated to date. Results: In this study, we showed that mice overexpressing islet-specific RCAN1 exhibited a prediabetic phenotype with markedly reduced GSIS under nutrient stress. Overexpression of RCAN1 increased the autophagy-associated DNA methylation level of Beclin-1 suppressing the induction of autophagy, affected the protein kinase B, and downregulated the activation of mammalian target of rapamycin, leading to Miro1-mediated mitophagy deficiency. Furthermore, the exacerbated impairment of autophagy induction and mitophagy flux failures induced β-cell apoptosis, resulting in GSIS impairment, lipid imbalance, and NOD-like receptor 3 proinflammation under high nutrient stress in mice. Innovation: Our present data identify a detrimental effect of RCAN1 overexpression on Miro1-mediated mitophagy deficiency and β-cell dysfunction in high-fat diet-fed RCAN1 overexpressing mice. Conclusion: Our results revealed that strategies targeting RCAN1 in vivo may provide a therapeutic target to enhance β-cell mitophagy quality and may determine the crucial factor in T2D development.

Spinal cord compression (SCC) is a devastating complication of multiple myeloma and has the potential to cause loss of neurological function. The common symptoms of SCC are back pain, motor weakness, and sensory change. Once diagnosed, the patient should be managed as soon as possible to prevent permanent loss of neurological function. Currently, there have been a number of studies describing the mechanism and management experience of SCC in patients with myeloma. The clinical features, diagnostic strategies, and the roles of different therapeutic options are herein reviewed.

High relapse rate of acute myeloid leukemia (AML) is still a crucial problem despite considerable advances in anti-cancer therapies. One crucial cause of relapse is the existence of leukemia stem cells (LSCs) with self-renewal ability, which contribute to repeated treatment resistance and recurrence. Treatments targeting LSCs, especially in combination with existing chemotherapy regimens or hematopoietic stem cell transplantation might help achieve a higher complete remission rate and improve overall survival. Many novel agents of different therapeutic strategies that aim to modulate LSCs self-renewal, proliferation, apoptosis, and differentiation are under investigation. In this review, we summarize the latest advances of different therapies in development based on the biological characteristics of LSCs, with particular attention on natural products, synthetic compounds, antibody therapies, and adoptive cell therapies that promote the LSC eradication. We also explore the causes of AML recurrence and proposed potential strategies with new dimensions for targeting LSCs in the future.