ABSTRACT
BACKGROUND: Immune thrombocytopenia (ITP) is a prevalent autoimmune bleeding disorder, with the primary objective of treatment being the prevention of bleeding. Clinical investigations have indicated that individuals with ITP face an elevated risk of thrombosis, and the occurrence of thromboembolic events in ITP patients can be attributed to a multitude of factors. However, establishing a definitive causal relationship between ITP and thrombosis remains challenging. METHODS: A two-sample Mendelian randomization (MR) study utilizing summary data from FinnGen consortium and UK Biobank was undertaken to investigate the causal association between ITP and thrombosis. The primary analysis employed the inverse-variance weighted (IVW) method, while supplementary analyses were conducted using the MR-Egger, weighted median, and MR-PRESSO approaches. RESULTS: Based on IVW method, there was a statistically significant but small positive correlation between ITP and thrombosis. Specifically, ITP patients exhibited a suggestive positive correlation with myocardial infarction and deep-vein thrombosis. However, our investigation did not identify any causal relationship between ITP and cerebral infarction, arterial embolism, other arterial embolisms, pulmonary embolism, thrombophlebitis, or portal vein thrombosis. Sensitivity analyses further confirmed the accuracy and robustness of these findings. CONCLUSIONS: This study presents empirical support for the causal relationship between ITP and thrombosis. It is important to note that a diminished platelet count does not serve as a preventive measure against thrombus formation. Consequently, when managing a newly diagnosed ITP patient, clinicians need to be aware that there is a slight elevation in the risk of thrombosis during treatment.
ABSTRACT
Recent studies have shown that abnormalmiRNA-378expression is a rule, rather than an exception, in cervical cancer and can be used as a diagnostic and prognostic biomarker to assess tumor initiation. In this study, we developed a general, sensitive strategy for detectingmiRNA-378using catalytic hairpin self-assembly (CHA) combined with gold nanoparticles (AuNP) colorimetry. The presence ofmiRNA-378triggers the repeated self-assembly of two designed hairpin DNAs (H1 and H2) into dsDNA polymers, which leads to changes in the surface plasmon resonance absorption band and the macroscopic color of the AuNP colloids due to the formation of nanoparticle-DNA conjugates. This experimental phenomenon can be observed by ultraviolet-visible spectrometry or even with the naked eye. Using this method,miRNA-378could be quantitatively detected at the picomolar level (as low as 20.7 pM). Compared with traditional methods, such as quantitative polymerase chain reaction and RNA blotting, this strategy has a simple operation, low cost, and high sensitivity and selectivity, and thus, exhibits significant potential for miRNA detection.
Subject(s)
Colorimetry , Gold , Metal Nanoparticles , MicroRNAs , MicroRNAs/genetics , MicroRNAs/analysis , Gold/chemistry , Metal Nanoparticles/chemistry , Humans , Colorimetry/methods , Surface Plasmon Resonance/methods , DNA/chemistry , DNA/genetics , CatalysisABSTRACT
BACKGROUND: Individuals with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs) are at risk of developing venous thromboembolism (VTE), a serious complication. There is no established clinical model for predicting VTE in the Chinese population. We develop a new risk assessment model (RAM) for IMiD-associated VTE in Chinese MM patients. METHODS: We retrospectively selected 1334 consecutive MM patients receiving IMiDs from 16 medical centers in China and classified them randomly into the derivation and validation cohorts. A multivariate Cox regression model was used for analysis. RESULTS: The overall incidence of IMiD-related VTE in Chinese MM patients was 6.1%. Independent predictive factors of VTE (diabetes, ECOG performance status, erythropoietin-stimulating agent use, dexamethasone use, and VTE history or family history of thrombosis) were identified and merged to develop the RAM. The model identified approximately 30% of the patients in each cohort at high risk for VTE. The hazard ratios (HRs) were 6.08 (P < 0.001) and 6.23 (P < 0.001) for the high-risk subcohort and the low-risk subcohort, respectively, within both the derivation and validation cohorts. The RAM achieved satisfactory discrimination with a C statistic of 0.64. The stratification approach of the IMWG guidelines yielded respective HRs of 1.77 (P = 0.053) and 1.81 (P = 0.063). The stratification approach of the SAVED score resulted in HRs of 3.23 (P = 0.248) and 1.65 (P = 0.622), respectively. The IMWG guideline and the SAVED score-based method yielded C statistics of 0.58 and 0.51, respectively. CONCLUSIONS: The new RAM outperformed the IMWG guidelines and the SAVED score and could potentially guide the VTE prophylaxis strategy for Chinese MM patients.
ABSTRACT
The photocatalytic efficiency is commonly restrained by inferior charge separation rate. Herein, the S-scheme MIL-100(Fe)/NH2-MIL-125(Ti) (MN) photo-Fenton catalyst with the built-in electric field (BEF) was successfully constructed by a simple ball-milling technique. As a result, the MN-3 (the mass ratio of MIL-100(Fe) to NH2-MIL-125(Ti) was 3) composite presented the best visible-light-induced photocatalytic ability, in contrast to pure MIL-100(Fe) and NH2-MIL-125(Ti). The reduction efficiency of Cr(VI) almost reached 100% within 35 min of illumination. Moreover, the MN-3 heterojunction also exhibited the highest antibacterial activity, and about 100% E. coli and more than 90% S. aureus were killed within 60 min of illumination. In photo-Fenton system, In the photo-Fenton system, e-, O2â¢- and Fe2+ played vital roles for Cr(VI) reduction, and â¢OH, h+ and O2â¢- and 1O2 were responsible for sterilization. Additionally, 5 cyclic tests and relevant characterizations confirmed the excellent repeatability and stability of the composite. Also, the S-scheme charge transfer process was put forward. This work offers a novel idea for establishing the MOF-on-MOF photo-Fenton catalyst for high-efficiency environmental mitigation.
Subject(s)
Escherichia coli , Staphylococcus aureus , Anti-Bacterial Agents/pharmacology , ChromiumABSTRACT
Flexible transparent electrodes (FTEs) have been widely witnessed in various printable electronic devices, especially those involving light. So far, solution processes have demonstrated increasing advantages in preparing FTEs not only in their mild operation conditions and high-throughput but also in the diversity in micropatterning conductive nanomaterials into networks. For the FTEs, both high transparency and high conductivity are desirable, which therefore create requirements for the conductive network by considering the trade-off relationship between the coverage and the micropatterns of the network. In addition, the conductive networks also affect the flexibility of FTEs due to the deformation during bending/stretching. Consequently, solution processes capable of micropatterning conductive nanomaterials including nanoparticles, nanowires/polymers, and graphene/MXene play a crucial role in determining the performance of FTEs. Here, we reviewed recent research progress on solution-processed FTEs, including the solution processes, the solution-processable conductive nanomaterials and the substrates for making FTEs, and applications of FTEs in flexible electronics. Finally, we proposed several perspective outlooks of the FTEs, which aim at not only the enhanced performance but also the performances in extreme conditions and in integration. We believe that the review would offer inspiration for developing functional FTEs.
ABSTRACT
OBJECTIVES: Corticosteroid is first-line therapy in immune thrombocytopenia. However, nearly 30% of patients appear in steroid-resistance. Our research analyses the relevant indicators of patients and develops a risk prediction model to predict the poor response to steroid-therapy in ITP patients. METHODS: We collected data from 111 ITP patients admitted to Xiamen University Zhongshan Hospital from 2013 to 2019 as the training cohort and 65 ITP patients during 2019-2020 as the external validation cohort. Screening significant factors(P < 0.05) in univariate analysis, and further identified to be independent variables in multivariable logistic regression analysis. Incorporated the significant risk factors in and presented them with a nomogram based on independent risk predictors. The nomogram was assessed by receiver operating characteristics curves and decision curve analysis. RESULTS: We constructed a steroid-resistance prediction model based on the potential predictors including age, serum ferritin and expression of HBsAg. As a result, based on the area under the ROC curves, the training cohort (AUC: 0.718, 95% CI: 0.615-0.821) and the external validation cohort (AUC:0.799,95%CI:0.692-0.905), which displayed good discrimination. The decision curve showed that predicting the steroid-refractory risk in ITP patients using this nomogram with a range of the threshold probability between >16% and <70%. The nomogram appears good performance in predicting steroid-refractory ITP patients. CONCLUSION: Prediction model shows that elder patients with a high level of ferritin and positive expression of HBsAg may appear a high possibility of steroid-resistance. For these patients, TPO-RAs can be considered to help patients to get better treatment effects and develop a better health-related quality of life.
Subject(s)
Purpura, Thrombocytopenic, Idiopathic/drug therapy , Steroids/therapeutic use , Adult , Age Factors , Drug Resistance , Female , Ferritins/blood , Humans , Male , Middle Aged , Nomograms , Purpura, Thrombocytopenic, Idiopathic/blood , ROC Curve , RecurrenceABSTRACT
RATIONALE: Monoclonal gammopathy of undetermined significance (MGUS) is a clinically asymptomatic clonal plasma cell or lymphoplasmacytic proliferative disorder. Recently, some case reports have described the association of pure red cell aplasia (PRCA) with MGUS, even with a relatively low monoclonal immunoglobulin burden. T large granular lymphocyte leukemia (T-LGLL) is a chronic lymphoproliferative disorder characterized by clonal expansion of T large granular lymphocytes, which is rare in China. There are some reports about T-LGL leukemia in patients with B-cell lymphoma; however, it is very rare that T-LGLL coexists with MGUS and clonal B-cell lymphoproliferative disorders (CB-LPD). PATIENT CONCERNS: A 77-year-old man was hospitalized because of anemia. He was diagnosed with MGUS, CB-LPD, and PRCA. During the development of the disease, a group of abnormal T lymphocytes was detected by flow cytometry of peripheral blood. DIAGNOSIS: Combining clinical manifestations with the result of T cell receptor gene rearrangement and immunophenotype, it was consistent with the diagnosis of T large granular lymphocyte leukemia. INTERVENTIONS: The patient was treat with bortezomib and dexamethasone regimen, Rituximab and sirolimus. OUTCOMES: The patient was transfusion independent after therapies. LESSONS: We report a patient with 4 concomitant hematological disorders: T-LGLL, MGUS, CB-LPD, and PRCA, aiming to represent the clinical and flow cytometry characteristics of these concomitant diseases, analyze the mechanism between diseases, and provide a clinical reference.
Subject(s)
Leukemia, Large Granular Lymphocytic/diagnosis , Lymphoproliferative Disorders/diagnosis , Monoclonal Gammopathy of Undetermined Significance/diagnosis , Red-Cell Aplasia, Pure/diagnosis , Aged , Anemia/etiology , Antineoplastic Agents/therapeutic use , Bendamustine Hydrochloride , Bortezomib/therapeutic use , Dexamethasone/therapeutic use , Humans , Leukemia, Large Granular Lymphocytic/complications , Leukemia, Large Granular Lymphocytic/drug therapy , Lymphoproliferative Disorders/complications , Lymphoproliferative Disorders/drug therapy , Male , Monoclonal Gammopathy of Undetermined Significance/complications , Monoclonal Gammopathy of Undetermined Significance/drug therapy , Red-Cell Aplasia, Pure/complications , Red-Cell Aplasia, Pure/drug therapy , Rituximab/therapeutic use , Sirolimus/therapeutic useABSTRACT
BACKGROUND: The development of multiple myeloma (MM) is considered to involve a multistep transformation process, but the role of cytogenetic abnormalities and molecular alterations in determining the cell fate of multiple myeloma (MM) remains unclear. Here, we have analyzed single cell RNA-seq data and bulk gene profiles to reveal a novel signature associated with MM development. METHODS: The scRNA-seq data from GSE118900 was used to profile the transcriptomes of cells from MM patients at different stages. Pseudotemporal ordering of the single cells was performed using Monocle package to feature distinct transcriptomic states of the developing MM cells. The bulk microarray profiles from GSE24080 and GSE9782 were applied to identify a signature associated with MM development. RESULTS: The 597 cells were divided into 7 clusters according to different risk levels. They were initiated mainly from monoclonal gammopathy of undetermined significance (MGUS), newly diagnosed MM (NDMM), or relapsed and/or refractory myeloma (RRMM) with cytogenetically favorable t(11;14), moved towards the cells from smoldering MM (SMM) or NDMM without t(11;14) or t(4;14), and then finally to cells from SMM or RRMM with t(4;14). Based on the markers identified in the late stage, the bulk data was used to develop a 20-gene signature stratifying patients into high and low-risk groups (GSE24080: HR = 3.759, 95% CI 2.746-5.145; GSE9782: HR = 2.612, 95% CI 1.894-3.603), which was better than the previously published gene signatures (EMC92, UAMS70, and UAMS17) and International Staging System. This signature also succeeded in predicting the clinical outcome of patients treated with bortezomib (HR = 2.884, 95% CI 1.994-4.172, P = 1.89e-8). The 20 genes were further verified by quantitative real-time polymerase chain reaction using samples obtained from the patients with MM. CONCLUSION: Our comprehensive analyses offered new insights in MM development, and established a 20-gene signature as an independent biomarker for MM.
ABSTRACT
P53 is an apoptosis marker which is involved in determining nucleus pulposus (NP) cell fate. Little is known about P53 interaction with N-Myc downstream-regulated gene 2 (NDRG2) in intervertebral disc degeneration (IVDD). Here, we studied the role of the P53-NDRG2 axis in IVDD. We found that NDRG2 was expressed in NP tissue obtained from patients with IVDD. The level of NDRG2 was positively related to the severity of IVDD, as determined by Pfirrmann grading. Subsequently, we overexpressed NDRG2 in human NP cells by adenoviral transfection and studied the effects of increased levels of NDRG2 on the viability and apoptosis of these cells. NDRG2 overexpression induced NP cell apoptosis and reduced viability in NP cells obtained from patient with IVDD. We also found that the level of P53 was elevated in NP cells from patients with IVDD and treatment with exogenous P53 upregulated NDRG2 in NP cells. Last, IVDD model was established in P53 knockout mice and the pathological changes in the intervertebral discs and NDRG2 expression were examined. P53 knockout can reduce the damage of NP tissues after IVDD surgery to some extent. Restoration of NDRG2 antagonized the effect of P53 knockout on IVDD. Collectively, this study suggests that elevated P53 in NP cells stimulates apoptosis of the cells by upregulating NDRG2 expression, thereby exacerbating IVDD.
Subject(s)
Gene Expression Regulation , Intervertebral Disc Degeneration/metabolism , Nucleus Pulposus , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Proteins/metabolism , Adult , Animals , Apoptosis , Cell Line , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Nucleus Pulposus/cytology , Nucleus Pulposus/metabolism , Nucleus Pulposus/pathology , Young AdultABSTRACT
RATIONALE: Acute promyelocytic leukemia (APL) is one of the most curable cancers. However, relapse of the disease is a difficult issue in clinical practice and it remains a great challenge that patients have a poor effect of conventional treatment in the clinic. Therefore, new and more effective therapeutic measures are urgently needed. Herein, we report a case of relapsed and refractory APL harboring a RARA-LBD region mutation successfully treated with venetoclax (VEN). PATIENT CONCERNS: A 37-years-old woman was admitted to our hospital with worsening spontaneous gingival bleeding and skin ecchymosis. Physical examination revealed multiple petechiae and ecchymosis in the extremities. DIAGNOSES: The patient was diagnosed with L-type PML-RARα-positive APL, harboring a RARA-LBD region mutation, low-risk, based on bone marrow cytology, immunophenotypic analysis by flow cytometry, karyotype analysis, and molecular analysis. INTERVENTIONS: Complete remission was achieved after the first induction therapy of all-trans retinoic acid (ATRA) combined with arsenic trioxide, but relapse was observed only after 11âmonths. Reinduction with ATRA and arsenic trioxide combined with anthracycline failed. Therefore, we tried to provide a new treatment with the Bcl-2 inhibitor VEN orally (100âmg d1, 200âmg d2 to d18, followed by 300âmg daily continuously). OUTCOMES: Clinical symptoms and laboratory indicators improved rapidly with VEN treatment. A complete hematologic response was achieved with VEN-based therapy. LESSONS: Related drug resistance gene monitoring should be performed canonically in relapsed and refractory APL. Some relapsed and refractory APL that failed to respond to conventional treatment were at risk of death. Bcl-2 inhibitors are expected to be an effective salvage therapy for patients with resistance to ATRA, which is worthy of further discussion.
Subject(s)
Antineoplastic Agents/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Salvage Therapy , Sulfonamides/therapeutic use , Adult , Arsenic Trioxide/therapeutic use , Ecchymosis , Female , Humans , Leukemia, Promyelocytic, Acute/genetics , Mutation/genetics , Proto-Oncogene Proteins c-bcl-2/therapeutic use , Recurrence , Treatment Outcome , Tretinoin/therapeutic useABSTRACT
Self-propelled directional liquid transport (SDLT) has been observed on many natural substrates, serving as an efficient strategy to utilize surrounding liquids for a better habitat to the local environment. Drawing inspiration, various artificial materials capable of SDLT have been developed. However, the liquid transport velocity is normally very low (ca. 3-30 µm/s), which limits its practical applications. Herein, we developed novel pyramid-structured fibers with concave curved surfaces (P-concave curved-fiber, PCCF), which enable the ultrafast SDLT. Specifically, the liquid transport velocity can be up to â¼28.79 mm/s on a dry tri-PCCF, over 50 times faster than that on the surface of Sarracenia trichome (â¼520 µm/s). The velocity is even faster on a wet fiber by two times (â¼47.34 mm/s). Here, the Laplace pressure difference (FL) induced by the tapered structure determines the liquid transport direction. It is proposed that both the capillary rises imparted by the concave curved surfaces and the oriented microridges/valleys and the enhanced FL aroused by the reduced cross-sectional area accelerate the SDLT on surfaces of the PCCFs. Consequently, the PCCF takes a different liquid transport strategy with a convex-shaped advancing meniscus, differing from that on traditional conical fibers. Moreover, the as-developed PCCF is also applicable for underwater ultrafast SDLT of oil. We envision that the result will open a new perspective for fabricating a fibrous system for microfluidic and liquid manipulation.
ABSTRACT
Pyramidal SnO/CeO2 nano-heterojunction photocatalysts were successfully synthesized via a facile hydrothermal method. The structural characterization was investigated by using common characterization tools. The content of SnO affected the morphology and photocatalytic performance of the SnO/CeO2 nano-heterojunctions. With the increase of the SnO content, the morphology of the samples changed from a spherical structure to a pyramidal structure. The photocurrent of the SnO/CeO2 (1:6) sample was about 36 times that of pure CeO2. With SnO/CeO2 (1:6) as the photocatalyst, the degradation rate of tetracycline (TC) was 99% within 140 min under visible light and after five cyclic tests the photocatalytic efficiency of TC remained at 98%, which suggests that the SnO/CeO2 (1:6) nano-heterojunction had a high photocatalytic efficiency and stable photocatalytic performance. These results indicate that SnO/CeO2 (1:6) nano-heterojunction possesses broad prospects for industrial application.
ABSTRACT
RATIONALE: Fusarium is the second most common cause of fungi infections in the immunocompromised patients with the mortality rate over 80%. Early identification and appropriate selection of antifungal drugs is the key to successful treatment. PATIENT CONCERNS: A 31-year-old female was diagnosed with acute lymphocytic leukemia (pro-B ALL). She developed a high fever and presented with typical painful purple nodules with central necrosis formed on the upper and lower limbs during the induction chemotherapy. DIAGNOSIS: Combining clinical manifestations with results of blood culture testing and sequencing methods, it was consistent with the diagnosis of disseminated fusariosis. INTERVENTIONS: The patient was treated with the combination of tigecycline and antifungal agents (Liposomal Amphotericin B and Voriconazole), OUTCOMES:: The skin lesions generally healed with some scar left after treating with antifungal agents for 6 weeks. The final date of follow-up was 1.5 years later, and the patient was alive with no diseases. LESSONS: This case highlights the importance of the typical cutaneous lesions for early diagnosis and proper treatment to decrease the mortality rate of this severe infection. This patient was successfully treated with the combination of tigecycline and antifungal agents, which may be the first clinical confirmation of tigecycline that improved the effectiveness of antifungal agents against fusariosis, but it requires more studies to verify. We reviewed 62 cases from literature and analyzed using logistic regression and recognized the high-risk factor for fusariosis mortality in patients with acute leukemia was non-remission of underlying disease.
Subject(s)
Amphotericin B/therapeutic use , Anti-Bacterial Agents/therapeutic use , Antifungal Agents/therapeutic use , Fusariosis/drug therapy , Tigecycline/therapeutic use , Voriconazole/therapeutic use , Adult , Female , Fusariosis/etiology , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Remission InductionABSTRACT
The present study aimed to evaluate the therapeutic efficacy of dasatinib in a patient with nucleoporin 214-tyrosine protein kinase ABL1 proto-oncogene 1 (NUP214-ABL1)-positive early T-cell precursor-acute lymphoblastic leukemia (ETP-ALL), as well as that of selinexor and dasatinib for NUP214-ABL1-positive ETP-ALL in vitro. ETP leukemia is a form of T-cell ALL (T-ALL) with poor prognosis. The NUP214-ABL1 gene is present in ~6% of T-ALL cases, however the prevalence of NUP214-ABL1 gene expression in ETP-ALL in particular has not yet been verified. The current study reports the rare case of a 29-year-old man with ETP-ALL harboring the NUP214-ABL1 fusion gene, presenting with low-grade fever, stomachache and splenomegaly. The patient was successfully treated with dasatinib and vincristine, idarubicin, cyclophosphamide and prednisone (VICP) chemotherapy. The therapeutic efficacy of selinexor and dasatinib was also evaluated in vitro. Apoptosis was analyzed using Annexin V/propidium iodide staining and flow cytometry, and poly ADP-ribose polymerase (PARP) cleavage was detected using western blot analysis. The results demonstrated that the apoptotic cell population significantly increased following selinexor or dasatinib treatment compared with the control (P<0.05). Furthermore, combined selinexor and dasatinib treatment led to a significant increase in cell apoptosis compared with either treatment alone (P<0.05). The apoptosis results were confirmed by PARP cleavage. Thus, NUP214-ABL1 fusion gene expression should be tested in T-ALL, including ETP-ALL. Dasatinib used in combination with traditional induction chemotherapy may reverse the high induction failure of ETP-ALL with NUP214-ABL1 fusion gene; however, further prospective studies are required to confirm this. Therefore, selinexor with or without dasatinib may serve as a potential salvage therapy in the case of relapse and may be developed as a novel treatment for ETP-ALL with the NUP214-ABL1 fusion gene.
ABSTRACT
Organolead trihalide perovskite materials have been widely used as light absorbers in efficient photovoltaic cells. Solution engineering is a fast and effective method to fabricate perovskite films. Here, we report a fast precipitation of a pin-hole free perovskite film by small molecule-driven directed diffusion engineering. Solvent molecules diffuse easily and quickly by colliding with small molecules, e.g. helium. Fully compact perovskite films and highly efficient perovskite solar cells are achieved, and the devices show remarkable stability of ca. 90% original efficiency after more than 1000 hours of testing. The small molecule driving directed diffusion offers a promising fast precipitation of a perovskite film and highly efficient, stable perovskite solar cells.
ABSTRACT
Mantle cell lymphoma (MCL) remains incurable and new treatments are needed, especially in the relapsed/refractory setting. We therefore investigated the effects of carfilzomib, a novel, long-acting, second-generation proteasome inhibitor, in MCL cells. Eight established MCL cell lines and freshly isolated primary MCL cells were treated with carfilzomib. Cell proliferation was assessed by a 3H-thymidine incorporation assay. Cell apoptosis was evaluated by flow cytometry with annexin V and propidium iodide. Electrophoresis mobility shift (EMSA), Western blot, and luciferase assays were used to analyze NF-κB activation and related signaling proteins. Carfilzomib inhibited growth and induced apoptosis in both established MCL cell lines and freshly isolated primary MCL cells in a dose-dependent manner. In contrast, carfilzomib was less toxic to normal peripheral blood mononuclear cells from healthy individuals. The carfilzomib-induced apoptosis of MCL cells occurred in a caspase-dependent manner through both intrinsic and extrinsic caspase pathways. In addition, carfilzomib inhibited constitutive activation of the NF-κB signaling cascade, both in MCL cell lines and primary MCL cells, by completely blocking the phosphorylation of IκBα. Our results demonstrate that carfilzomib can induce growth arrest and apoptosis in MCL cells and that the mechanism may involve the NF-κB signaling pathway.
Subject(s)
Apoptosis/drug effects , Lymphoma, Mantle-Cell/drug therapy , NF-kappa B/metabolism , Neoplasm Proteins/metabolism , Oligopeptides/pharmacology , Signal Transduction/drug effects , Cell Line, Tumor , Humans , Lymphoma, Mantle-Cell/metabolism , Lymphoma, Mantle-Cell/pathologyABSTRACT
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.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Multiple Myeloma/drug therapy , Proteasome Inhibitors/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/adverse effects , Boron Compounds/adverse effects , Boron Compounds/therapeutic use , Congresses as Topic , Glycine/adverse effects , Glycine/analogs & derivatives , Glycine/therapeutic use , Humans , Hydrazines/adverse effects , Hydrazines/therapeutic use , Molecular Targeted Therapy , Multiple Myeloma/enzymology , Multiple Myeloma/immunology , Multiple Myeloma/pathology , Proteasome Inhibitors/adverse effects , Protein Kinase Inhibitors/adverse effects , Signal Transduction/drug effects , Thiadiazoles/adverse effects , Thiadiazoles/therapeutic use , Treatment Outcome , Triazoles/adverse effects , Triazoles/therapeutic useABSTRACT
The aim of this study was to explore the expression of pituitary tumor-transforming gene (PTTG) in acute lymphoblastic leukemia (ALL) and its relationship with the pathogenesis of ALL, as well as study the difference of the PTTG expression in ALL patients with Ph1 chromosome and without Ph1 chromosome. The mRNA expressions of PTTG in bone marrow from 28 patients with ALL and 28 normal controls were quantitatively detected by real-time quantitative polymerase chain reaction (real-time PCR). The results indicated that the expression of PTTG mRNA was significantly higher in ALL patients (1.9428E5 ± 1.8372E5) than that in normal controls (4.5766E3 ± 1.1817E3) (P < 0.05). The expression of PTTG mRNA was higher in Ph1 chromosome positive patients. The initial expression of PTTG mRNA was lower in patients achieved complete remission than that in patients with non-complete remission. It is concluded that the overexpression of PTTG may be related to the progression and genesis of ALL. Overexpression of PTTG may be intimately related to the progression and genesis of Ph1 chromosome positive ALL. It provides a new ideas to research the pathogenesis and genic target treatment of ALL.
Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Securin/genetics , Adolescent , Adult , Aged , Case-Control Studies , Female , Gene Expression , Gene Expression Regulation, Leukemic , Humans , Male , Middle Aged , Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Young AdultABSTRACT
Overexpression of the cellular nuclear exportin 1, more commonly called chromosomal region maintenance 1 (CRM1), has been associated with malignant progression and mortality. Therefore, activation of nuclear export can play a significant etiologic role in some forms of human neoplasia and serve as a novel target for the treatment of these cancers. Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma that remains incurable. The objective of this study was to investigate the functional significance of CRM1 in MCL by evaluating the therapeutic efficacy of CRM1 inhibition in MCL in vitro and in vivo. Our results showed that CRM1 is highly expressed in MCL cells and is involved in regulating growth and survival mechanisms through the critical nuclear factor-κB survival pathway, which is independent of p53 status. Inhibition of CRM1 by two novel selective inhibitors of nuclear export (SINE), KPT-185 and KPT-276, in MCL cells resulted in significant growth inhibition and apoptosis induction. KPT-185 also induced CRM1 accumulation in the nucleus, resulting in CRM1 degradation by the proteasome. Oral administration of KPT-276 significantly suppressed tumor growth in an MCL-bearing severe combined immunodeficient mouse model, without severe toxicity. Our data suggest that SINE CRM1 antagonists are a potential novel therapy for patients with MCL, particular in relapsed/refractory disease.