Chronic myeloid leukaemia: Biology and therapy.

Chronic myeloid leukaemia (CML) is caused by BCR::ABL1. Tyrosine kinase-inhibitors (TKIs) are the initial therapy. Several organizations have reported milestones to evaluate response to initial TKI-therapy and suggest when a change of TKI should be considered. Achieving treatment-free remission (TFR) is increasingly recognized as the optimal therapy goal. Which TKI is the best initial therapy for which persons and what depth and duration of molecular remission is needed to achieve TFR are controversial. In this review we discuss these issues and suggest future research directions.

Ginsenoside Rg5 Improves Sleep by Regulating Energy Metabolism in Sleep-Deprived Rats.

Sleep deprivation (SD) has become a universal social problem. There is a causal relationship between SD and energy metabolism disorder. Phytochemicals have been demonstrated to have excellent sleep-promoting effects, and studies have shown that ginsenoside Rg5 (Rg5) exerts sedative and hypnotic effects. The present study aimed to investigate the role of Rg5 in regulating energy metabolism and explore the potential mechanism of improving sleep. Sleep-deprived rats were randomly divided into a control group (Ctrl), SD model group (SD), Rg5 group (GRg5), and melatonin group (MT). Sleep-deprived model rats were generated by housing rats in an SD box for 4 weeks. The Ctrl and SD groups were given equal volumes of saline. The Rg5 groups were given 25[Formula: see text]mg/kg Rg5 or 50[Formula: see text]mg/kg Rg5, and the MT group was given 0.27[Formula: see text]g/kg MT. A Western blot analysis and ELISA were used to detect the metabolic levels, mitochondrial functional proteins, AMPK pathway proteins, clock-related proteins, adenosine receptors, and neurotransmitter receptors. The results showed that Rg5 corrected abnormal glucose and lipid metabolism as well as improved ATP levels. In addition, Rg5 alleviated mitochondrial structural damage and improved the expression of proteins involved in mitochondrial biosynthesis, fission, and fusion. Moreover, Rg5 improved the expression of AMPK/PGC-1/Nrf-1 pathway proteins, regulated mitochondrial biological functions, and affected the rhythm characteristics of circadian clock-related proteins. Further, Rg5 improved the expression of A1R and A[Formula: see text]R as well as regulated the expression levels of GABAA1[Formula: see text] and mGluR5 to improve sleep in SD rats.

Burden of multiple myeloma in China: an analysis of the Global Burden of Disease, Injuries, and Risk Factors Study 2019.

BACKGROUND: There is limited data to comprehensively evaluate the epidemiological characteristics of multiple myeloma (MM) in China; therefore, this study determined the characteristics of the disease burden of MM at national and provincial levels in China. METHODS: The burden of MM, including incidence, mortality, prevalence, and disability-adjusted life years (DALYs), with a 95% uncertainty interval (UI), was determined in China following the general analytical strategy used in the Global Burden of Disease, Injuries, and Risk Factors Study 2019. The trends in the burden of MM from 1990 to 2019 were also evaluated. RESULTS: There were an estimated 347.45 thousand DALYs with an age-standardized DALY rate of 17.05 (95% UI, 12.31-20.77) per 100,000 in 2019. The estimated number of incident case and deaths of MM were 18,793 and 13,421, with age-standardized incidence and mortality rates of 0.93 (95% UI, 0.67-1.15) and 0.67 (95% UI, 0.50-0.82) per 100,000, respectively. The age-specific DALY rates per 100,000 increased to more than 10.00 in the 40 to 44 years age group reaching a peak (93.82) in the 70 to 74 years age group. Males had a higher burden than females, with approximately 1.5- to 2.0-fold sex difference in age-specific DALY rates in all age groups. From 1990 to 2019, the DALYs of MM increased 134%, from 148,479 in 1990 to 347,453 in 2019. CONCLUSION: The burden of MM has doubled over the last three decades, which highlights the need to establish effective disease prevention and control strategies at both the national and provincial levels.

IDH2 regulates U2AF1 expression and hydroxymethylation in MDS patients.

The expression of some genes regulated by their DNA methylation is involved in pathogenesis and disease progression of myelodysplastic syndrome (MDS), which is characterised by abnormal differentiation and development of myeloid cells. Therefore, it is significant for us to work on investigating what factors regulate U2AF1 expression and hydroxymethylation in MDS patients. However, the members of TET protein family can change 5-methylcytosine (5mC) into 5-hydroxymethylcytosine5-methyl cytosine (5hmC). In general, 5mC and 5hmC levels maintain dynamic equilibrium, and their imbalance is associated with the onset and progression of some tumors. In this study, the expression and 5mC and 5hmC levels of U2AF1 gene decreased significantly after the treatment by decitabine in Mutz-1 cells. The decreased degree of 5hmC is far greater than that of 5mC. IDH2 expression decreased significantly followed by U2AF1 5hmC levels. However, the expression of other hydroxymethylation-related genes such as IDH1, TET1 and TET2 also decreased, but the difference did not achieve significance. Compared with IDH2 or U2AF1 wild-type MDS patients, U2AF1 expression and 5hmC level in patients with these two gene mutations were both significantly reduced.

Quercetin Inhibits KBM7R Cell Proliferation through Wnt/ß-Catenin Signaling.

Background: Tyrosine kinase inhibitors could treat chronic myelogenous leukemia (CML) effectively, but they have no effect on patients with T315I mutation. It is necessary to find drugs to overcome the resistance. Quercetin (Qu) is a kind of bioflavonoid with an antitumor effect. In this study, we observed the effect of Qu on proliferation and Wnt/ß-catenin pathway in KBM7R cells, an imatinib-resistant cell with T315I mutation. Methods: The IC50 of Qu was detected by trypan blue staining. The KBM7R cell apoptosis and cycle were detected through the method of flow cytometry (FCM). The expression of the related mRNA and protein was evaluated by means of an RT-PCR assay and western blot in KBM7 (sensitive to IM) and KBM7R cells. Results: These results showed that in the KBM7R cell, the proliferation inhibition effect was increased after 48 h administration with different Qu concentrations. The IC50 to Qu was 241.7 µmol/L. The different doses of Qu (50, 100, and 200 µmol/L) would raise apoptosis and depress the cell cycle at the G1 phase. Dealing with a median Qu concentration (100 µmol/L) for 48 h, the mRNA and the protein level of caspase-3, caspase-8, and caspase-9 along with p21 and p27 raised compared with the control. The median concentration of Qu could inhibit both the mRNA and protein levels of GSK-3ß, ß-catenin, and Lef-1 in the Wnt/ß-catenin signal pathway and also the downstream targets PPAR-δ and cyclin D1 in both KBM7 and KBM7R cells. Conclusions: Our findings suggest that Qu could inhibit proliferation, induce apoptosis, and arrest the cell cycle on IM-resistant KBM7R cells with T315I mutation. And this effect could be related with the inhibition of the Wnt/ß-catenin signal pathway and downstream targets.

Expression and Clinical Value of Eukaryotic Translation Elongation Factor 1A1 (EEF1A1) in Diffuse Large B Cell Lymphoma.

BACKGROUND: The eukaryotic translation elongation factor 1A1 (EEF1A1) participates in protein translation and has been reported to be involved in tumor progression such as hepatocellular carcinoma. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. In the present study, we aimed to detect the expression of EEF1A1 in DLBCL and to analyze its relationship with prognosis. METHODS: We reviewed medical records of DLBCL patients in our hospital and evaluated their expression level of EEF1A1 in tumor tissues using immunohistochemical (IHC) assay. The Chi-square method was used for correlation analysis. The Kaplan-Meier method with Log rank test was used for univariate analysis. Cox proportional hazards model was used for multivariate analysis. Cellular and mice models were introduced to validate its oncogenic role. RESULTS: EEF1A1 expression in tumor cells was higher in certain DLBCL cases. Patients with higher EEF1A1 expression were more likely to have advanced tumor stage and poorer 5-year overall survival (OS) rates. EEF1A1 expression in tumor cells was an independent risk predictor for OS (P < 0.05). Cellular assays demonstrated that EEF1A1-shRNA significantly inhibited lymphoma cell proliferation. The study of xenografts further verified the effect of EEF1A1-shRNA on suppressing tumor growth in vivo. CONCLUSION: EEF1A1 positivity predicts short survival in DLBCL patients. For patients with higher EEF1A1 expression, more strategy such as anti-EEF1A1 antibody treatment should be developed.

MicroRNA-204 Potentiates the Sensitivity of Acute Myeloid Leukemia Cells to Arsenic Trioxide.

Although arsenic trioxide (ATO) is a well-known antileukemic drug used for acute promyelocytic leukemia treatment, the development of ATO resistance is still a big challenge. We previously reported that microRNA-204 (miR-204) was involved in the regulation of acute myeloid leukemia (AML) cell apoptosis, but its role in chemoresistance is poorly understood. In the present study, we showed that miR-204 was significantly increased in AML cells after ATO treatment. Interestingly, the increased miR-204 level that was negatively correlated with ATO induced the decrease in cell viability and baculoviral inhibition of apoptosis protein repeat-containing 6 (BIRC6) expression. Overexpression of miR-204 potentiated ATO-induced AML cell growth inhibition and apoptosis. Furthermore, miR-204 directly targets to the 3'-UTR of BIRC6. Upregulation of miR-204 decreased BIRC6 luciferase activity and expression, which subsequently enhanced the expression of p53. Restoration of BIRC6 markedly reversed the effect of miR-204 on the regulation of AML cell sensitivity to ATO. Taken together, our study demonstrates that miR-204 decreases ATO chemoresistance in AML cells at least partially via promoting BIRC6/p53-mediated apoptosis. miR-204 represents a novel target of ATO, and upregulation of miR-204 may be a useful strategy to improve the efficacy of ATO in AML treatment.

Challenges and Opportunities for High-grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangement (Double-hit Lymphoma).

The most common subtype of non-Hodgkin lymphoma, diffuse large B-cell lymphoma, is cured in approximately two thirds of patients after initial therapy. The remaining one-third of patients who suffer relapse or become refractory have very poor survival outcomes despite salvage chemotherapy with or without stem cell transplantation. A considerable proportion of relapsed or refractory large B cells belong to the WHO subtype known as high-grade B-cell lymphoma with rearrangement of MYC and BCL2 and/or BCL6, also known as double-hit lymphoma (DHL). Most DHL patients present with Ann Arbor's stage III/IV, a comparatively higher rate of extranodal involvement including bone marrow and central nervous system infiltration, high levels of lactate dehydrogenase, and an elevated Ki67 expression in the tumor cells. Newer therapeutic approaches, including targeted therapy against BCL2, MYC, or other associated pathways, are needed. In addition, recent therapies that harness the immune system, such as checkpoint inhibitors and chimeric antigen receptor T-cell therapy, are changing the paradigm of treatment for non-Hodgkin lymphoma and could impact the outcome of DHL.

Dual inhibition of PI3K signaling and histone deacetylation halts proliferation and induces lethality in mantle cell lymphoma.

The dysregulation of PI3K signaling has been implicated as an underlying mechanism associated with resistance to Bruton's tyrosine kinase inhibition by ibrutinib in both chronic lymphocytic leukemia and mantle cell lymphoma (MCL). Ibrutinib resistance has become a major unmet clinical need, and the development of therapeutics to overcome ibrutinib resistance will greatly improve the poor outcomes of ibrutinib-exposed MCL patients. CUDC-907 inhibits both PI3K and HDAC functionality to exert synergistic or additive effects. Therefore, the activity of CUDC-907 was examined in MCL cell lines and patient primary cells, including ibrutinib-resistant MCL cells. The efficacy of CUDC-907 was further examined in an ibrutinib-resistant MCL patient-derived xenograft (PDX) mouse model. The molecular mechanisms by which CUDC-907 dually inhibits PI3K and histone deacetylation were assessed using reverse protein array, immunoblotting, and chromatin immunoprecipitation (ChIP) coupled with sequencing. We showed evidence that CUDC-907 treatment increased histone acetylation in MCL cells. We found that CUDC-907 caused decreased proliferation and increased apoptosis in MCL in vitro and in vivo MCL models. In addition, CUDC-907 was effective in inducing lethality in ibrutinib-resistant MCL cells. Lastly, CUDC-907 treatment increased histone acetylation in MCL cells. Overall, these studies suggest that CUDC-907 may be a promising therapeutic option for relapsed or resistant MCL.

Long-term outcomes and mutation profiling of patients with mantle cell lymphoma (MCL) who discontinued ibrutinib.

Long term outcomes and mutations in patients with mantle cell lymphoma (MCL) who discontinued ibrutinib have not been described. Using deep targeted next generation sequencing, we performed somatic mutation profiling from 15 MCL patients (including 5 patients with paired samples; before and after progression on ibrutinib). We identified 80 patients with MCL who discontinued ibrutinib therapy for various reasons. Median follow-up after ibrutinib discontinuation was 38 months. The median duration on ibrutinib was 7·6 months. Forty-one (51%) patients discontinued ibrutinib due to disease progression/transformation, 20 (25%) for intolerance, 7 (9%) due to patient choice, 5 (6%) for stem cell transplant, 4 (5%) due to second cancers and 3 (4%) other causes. The median survival after ibrutinib was 10 and 6 months for disease progression and transformation, respectively, and 25 months for patients with ibrutinib intolerance. Overall, BTK mutations were observed in 17% patients after progression on ibrutinib. Notably, TP53 alterations were observed after progression in 75% patients. Among the 4 patients with blastoid transformation, 3 (75%) had NSD2 mutations (co-existing with TP53). Ibrutinib-refractory MCL patients had a short survival. Demonstration of TP53 and NSD2 mutations in patients who developed blastoid transformation and ATM and TP53 mutations in patients who progressed, opens the door for future investigations in ibrutinib-refractory MCL.

Spontaneous regression of mantle cell lymphoma: a report of four cases.

BACKGROUND: Spontaneous regression has been reported in some indolent forms of lymphoma. Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm and has a poor prognosis. However, approximately 30% of MCL patients can exhibit indolent clinical behavior. To date, complete spontaneous regression of MCL has not been reported. CASE PRESENTATION: We describe four cases of spontaneous regression of MCL. At the time of presentation, these patients were asymptomatic, with lymph node enlargement and mild to moderate fluorodeoxyglucose (FDG) uptake on FDG-positron emission tomography combined with computed tomography. One of the possible mechanisms of spontaneous regression of the tumor could be due to the host immune response through humoral and cellular immunity, which may have a role in the clearance of tumor cells. CONCLUSIONS: In this report, we support the use of a "wait and watch" strategy for MCL patients with no risk factors and indolent behavior. This strategy helps spare patients from further potentially harmful chemotherapy. In addition, we describe the phenomenon of spontaneous regression in MCL patients who are asymptomatic and have low-volume disease.

Magic year for multiple myeloma therapeutics: Key takeaways from the ASH 2015 annual meeting.

Despite the availability of various anticancer agents, Multiple Myeloma (MM) remains incurable in most cases, along with high relapse rate in the patients treated with these agents. The year 2015 saw major advancements in our battle against multiple myeloma. In 2015, the U.S. Food and Drug Administration (FDA) approved three new therapies for multiple myeloma, namely Ixazomib (an oral proteasome inhibitor), Daratumumab and Elotuzumab (monoclonal antibodies against CD38 and SLAMF7 respectively). The purpose of this review is to provide a detailed analysis of these aforementioned breakthrough therapies and two other newer agents, Filanesib (kinesis spindle inhibitor) and selinexor (SINE inhibitor), presented at the 2015 annual meeting of American Society of Hematology (ASH). We also describe the role of agents targeting PD-1 axis and chimeric antigen receptor T (CAR-T) cells in the treatment of MM.

[Clinical application of the distal island muscle flap of the gastrocnemius muscle for repairing the defects around knee and within the upper 2/3 of lower leg].

OBJECTIVE: To summarize clinical application of the distal island muscle flap of the gastrocnemius muscle for repairing the defects around knee and within the upper 2/3 of lower leg. METHODS: 18 patients with defects around knee and within the upper 2/3 of lower leg, were treated with the distal island muscle flap of the gastrocnemius muscle, including 12 cases with medial muscle head and 6 cases with lateral muscle head. The muscular flaps were covered with meshed split-thickness skin grafts. The wound at donor sites were closed directly. RESULTS: All the skin grafts and muscle flaps survived with superior infection at the wound edge in two cases. The patients were followed up for 8 months to 4.8 years with satisfactory cosmetic and functional results. CONCLUSIONS: The distal island muscle flap of the gastrocnemius muscle has a reliable blood supply, long pedicle and suitable thickness. It is an ideal method for repairing the defects around knee and within the upper 2/3 of lower leg.

[Micro-decompression procedure for lumbar spinal stenosis].

OBJECTIVE: To evaluate clinical result of the micro-decompression procedure for lumbar spinal stenosis. METHODS: From September 2001 to May 2006,87 patients (male 60, female 27) with lumbar spinal stenosis underwent micro-decompression. The age of patients were from 43 to 80 years with an average of 51 years. Among them,2 cases with spinal stenosis occured in L(3,4), 47 in L(4,5), 38 in L5S1. RESULTS: All patients were followed up for 18-48 months with an average of 26 months. The results were excellent in 52 cases, good in 28, poor in 7, according to Macnab of back leg pain standard. The rate of excellent and good was 92%. CONCLUSION: Operative treatment for lumbar spinal stenosis is focused at the areas causing symptomatic neural root compression rather than prophylactic decompression at areas of nonsymptomatic disease. The micro-decompression procedures are more likely to be well tolerated by older patients.