Venetoclax combined with decitabine induced tumor lysis syndrome in a young patient with acute myeloid leukemia: a case report and literature review.

Venetoclax, in combination with hypomethylation agents (HMAs), is a novel treatment for leukemia patients with low chemotherapy tolerance. However, it has been reported to be a risk of causing tumor lysis syndrome (TLS) in chronic lymphocytic leukemia (CLL) and elderly acute myeloid leukemia (AML) patients. Here we report a rare case of a young adult AML patient who induced TLS after receiving a combination therapy of venetoclax with decitabine (DEC). A 36-year-old male patient presented with an unexplained fever and was diagnosed with AML-M5a. The patient was first treated with a combination of antibiotics, including voriconazole 300 mg Q12h. After the infection was relieved, he was treated with 100 mg venetoclax in combination with 75 mg/m 2 DEC. However, 12 h after the first treatment, he developed diarrhea, fatigue and other symptoms, and the laboratory results were consistent with the laboratory TLS. The patient stopped chemotherapy immediately, and TLS gradually improved after receiving rehydration, diuresis, dialysis and other treatments. Finally, the patient achieved complete remission. Based on the experience of this case and related studies, we recommend the prevention of TLS should not be limited to elderly patients taking venetoclax, and it is equally important in young patients. And reduce the dosage of venetoclax when using azole antifungal drugs.

Elucidating the distinctive regulatory effects and mechanisms of active compounds in Salvia miltiorrhiza Bunge via network pharmacology: Unveiling their roles in the modulation of platelet activation and thrombus formation.

Salvia miltiorrhiza Bunge. (DS), as an important traditional Chinese medicine (TCM), has a long history of usage for promoting blood circulation and removing blood stasis. Modern studies have shown that the chemical components of DS have many biological activities such as cardiovascular protection, anti-arrhythmia, anti-atherosclerosis, improvement of microcirculation, protection of myocardium, inhibition and removal of platelet aggregation. Nevertheless, the action mechanism of DS as well its active compounds on platelet activation has not been fully uncovered. This study aimed to find out the potential targets and mechanisms of DS in the modulation of platelet activation and thrombosis, using network pharmacology and biological experimental. These compounds with anti-thrombotic activity in DS, cryptotanshinone (CPT), isoeugenol (ISO) and tanshinone IIA (TSA), together with the corresponding targets being Src, Akt and RhoA are screened by network pharmacology. We confirmed that ISO, CPT and TSA dose-dependently inhibited platelet activation in vitro, mainly by inhibiting agonist-induced clot retraction, aggregation and P-selectin and ATP release. The western blot findings indicated that ISO, CPT, and TSA led to reduced levels of p-Akt and p-ERK in activated platelets. Additionally, ISO and TSA were observed to decrease p-cSrc expression while increasing RhoA expression. ISO, CPT, and TSA demonstrated a potential to restrict the advancement of carotid arterial thrombosis in vivo. We confirm that ISO, CPT and TSA are the key anti-thrombotic active compounds in DS. These active compounds exhibit unique inhibitory effects on platelet activation and thrombus formation by modulating the Akt/ERK and cSrc/RhoA signaling pathways.

Nuclear Matrix-associated Protein SMAR1 Attenuated Acute Graft-versus-host Disease by Targeting JAK-STAT Signaling in CD4 + T Cells.

BACKGROUND: Acute graft-versus-host disease (aGVHD) mediated by alloreactive T cells remains a serious and life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). The contribution of the different CD4 + T helper cell subtypes to the pathogenesis and regulation of aGVHD is a central point in current research. The specialized effector subsets of T cells that differentiate from naive T cells into mature cells are closely related to scaffold/matrix-associated region-1-binding protein (SMAR1). However, the role of SMAR1 in aGVHD is unclear. METHODS: Peripheral blood was collected from the patients with or without aGVHD after allo-HCT. The differences in CD4 + T cells transduced with the SMAR1 lentivirus vector and empty vector were analyzed. A humanized aGVHD mouse model was constructed to evaluate the function of SMAR1 in aGVHD. RESULTS: The expression of SMAR1 was significantly reduced in the CD4 + T cells from aGVHD patients and related to the occurrence of aGVHD. SMAR1 overexpression in human CD4 + T cells regulated CD4 + T-cell subsets differentiation and inflammatory cytokines secretion and inhibited the Janus kinase/signal transducer and activator of transcription pathway. Moreover, SMAR1 changed chromatin accessibility landscapes and affected the binding motifs of key transcription factors regulating T cells. Additionally, upregulation of SMAR1 expression in CD4 + T cells improved the survival and pathology in a humanized aGVHD mouse model. CONCLUSIONS: Our results showed that upregulation of SMAR1 regulated the CD4 + T-cell subpopulation and cytokines secretion and improved survival in a humanized aGVHD mouse model by alleviating inflammation. This study provides a promising therapeutic target for aGVHD.

ALKHB5-demethylated lncRNA SNHG15 promotes myeloma tumorigenicity by increasing chromatin accessibility and recruiting H3K36me3 modifier SETD2.

Chromatin instability plays a crucial role in multiple myeloma (MM) relapse and progression, but its mechanism remains obscure. Here, we uncovered that m6A-demethylase ALKBH5 upregulated and stabilized long noncoding RNA (lncRNA) small nucleolar RNA host gene 15 (SNHG15), which was elevated in MM and positively correlated with unfavorable clinical prognosis factors. ALKBH5-SNHG15 axis participated in viability and migration/invasion of myeloma cell lines and MM-xenografted SCID/NOD mice. Mechanically, ALKBH5 promoted the expression of trimethylated histone H3 at lysine 36 (H3K36me3) methyltransferase SETD2 through lncRNA SNHG15-mediated protein stability. ALKBH5-SNHG15 axis increased chromatin accessibility and altered the H3K36me3 enrichment at the gene body, which is responsible for transcription elongation. Our study suggested a novel epigenetically interaction of N6-methyladenosine (m6A) methylation, lncRNA SNHG15, and histone SETD2/H3K36me3 modifications in myeloma progression, indicating that ALKBH5 and lncRNA SNHG15 could serve as potential novel therapeutic targets for MM treatment.NEW & NOTEWORTHY To our knowledge, this study first demonstrated the prognostic significance and biological function of long noncoding RNA (lncRNA) small nucleolar RNA host gene 15 (SNHG15) in multiple myeloma (MM), and indicated a novel revelation on the effect of N6-methyladenosine (m6A)-regulated lncRNA on MM tumorigenicity. Moreover, the novel chromatin-regulatory mechanism of lncRNA by interacting with epigenetic modifiers including m6A demethylase ALKBH5 and H3K36me3 methyltransferase SETD2 in myeloma progression elucidated intricate mechanism of tumor pathogenesis.

Adaptive and blind audio watermarking algorithm based on dither modulation and butterfly optimization algorithm.

How to improve the robustness to resist attacks and how to adaptively match the key parameters of the watermarking algorithm with the performance requirements to achieve the best performance in different applications are two hot issues in the research of audio watermarking algorithms. An adaptive and blind audio watermarking algorithm based on dither modulation and butterfly optimization algorithm (BOA) is proposed. Based on the convolution operation, a stable feature is designed to carry the watermark, which will improve the robustness by means of the stability of this feature to prevent the watermark loss. Blind extraction will be achieved only by comparing the feature value and the quantized value without the original audio. The BOA is used to optimize the key parameters of the algorithm which can be matched with the performance requirements by coding the population and constructing the fitness function. Experimental results confirm that this proposed algorithm can adaptively search for the optimal key parameters that match the performance requirements. Compared with other related algorithms in recent years, it exhibits strong robustness against various signal processing attacks and synchronization attacks.

Comprehensive analysis of prognosis of cuproptosis-related oxidative stress genes in multiple myeloma.

Introduction: Multiple myeloma (MM) is a highly heterogeneous hematologic malignancy. The patients' survival outcomes vary widely. Establishing a more accurate prognostic model is necessary to improve prognostic precision and guide clinical therapy. Methods: We developed an eight-gene model to assess the prognostic outcome of MM patients. Univariate Cox analysis, Least absolute shrinkage and selection operator (LASSO) regression, and multivariate Cox regression analyses were used to identify the significant genes and construct the model. Other independent databases were used to validate the model. Results: The results showed that the overall survival of patients in the high-risk group was signifificantly shorter compared with that of those in the low-risk group. The eight-gene model demonstrated high accuracy and reliability in predicting the prognosis of MM patients. Discussion: Our study provides a novel prognostic model for MM patients based on cuproptosis and oxidative stress. The eight-gene model can provide valid predictions for prognosis and guide personalized clinical treatment. Further studies are needed to validate the clinical utility of the model and explore potential therapeutic targets.

The application of nanopore targeted sequencing in the diagnosis and antimicrobial treatment guidance of bloodstream infection of febrile neutropenia patients with hematologic disease.

Traditional microbiological methodology has limited sensitivity, detection range, and turnaround times in diagnosis of bloodstream infection in Febrile Neutropenia (FN) patients. A more rapid and sensitive detection technology is urgently needed. Here we used the newly developed Nanapore targeted sequencing (NTS) to diagnose the pathogens in blood samples. The diagnostic performance (sensitivity, specificity and turnaround time) of NTS detection of 202 blood samples from FN patients with hematologic disease was evaluated in comparison to blood culture and nested Polymerase Chain Reaction (PCR) followed by sanger sequence. The impact of NTS results on antibiotic treatment modification, the effectivity and mortality of the patients under the guidance of NTS results were assessed. The data showed that NTS had clinical sensitivity of 92.11%, clinical specificity of 78.41% compared with the blood culture and PCR combination. Importantly, the turnaround time for NTS was <24 h for all specimens, and the pre-report time within 6 h in emergency cases was possible in clinical practice. Among 118 NTS positive patients, 98.3% patients' antibiotic regimens were guided according to NTS results. There was no significant difference in effectivity and mortality rate between Antibiotic regimen switched according to NTS group and Antibiotic regimen covering pathogens detected by NTS group. Therefore, NTS could yield a higher sensitivity, specificity and shorter turnaround time for broad-spectrum pathogens identification in blood samples detection compared with traditional tests. It's also a good guidance in clinical targeted antibiotic treatment for FN patients with hematologic disease, thereby emerging as a promising technology for detecting infectious disease.

A Visualized Mortality Prediction Score Model in Hematological Malignancies Patients with Carbapenem-Resistant Organisms Bloodstream Infection.

Background: Bloodstream infection (BSI) due to carbapenem-resistant organisms (CROs) has emerged as a worldwide problem associated with high mortality. This study aimed to evaluate the risk factors associated with mortality in HM patients with CROs BSI and to establish a scoring model for early mortality prediction. Methods: We conducted a retrospective cohort study at our hematological department from January 2018 to December 2021, including all HM patients with CROs BSI. The outcome measured was death within 30-day of BSI onset. Survivor and non-survivor subgroups were compared to identify predictors of mortality. Univariate and multivariate Cox regression analyses were used to identify prognostic risk factors and develop a nomogram. Results: In total, 150 HM patients were included in the study showing an overall 30-day mortality rate of 56%. Klebsiella pneumonia was the dominant episode. Cox regression analysis showed that pre-infection length of stay was >14 days (score 41), Pitt score >4 (score 100), mucositis (score 41), CAR (The ratio of C-reactive protein to albumin) >8.8 (score 57), early definitive therapy (score 44), and long-duration (score 78) were positive independent risk predictors associated with 30-day mortality, all of which were selected into the nomogram. Furthermore, all patients were divided into the high-risk group (≥160 points) or the low-risk group based on the prediction score model. The mortality of the high-risk group was 8 times more than the low-risk group. Kaplan-Meier analysis showed that empirical polymyxin B therapy was associated with a lower 30-day mortality rate, which was identified as a good prognostic factor in the high-risk group. In comparison, empirical carbapenems and tigecycline were poor prognostic factors in a low-risk group. Conclusion: Our score model can accurately predict 30-day mortality in HM patients with CROs BSI. Early administration of CROs-targeted therapy in the high-risk group is strongly recommended to decrease mortality.

Long noncoding RNA LINC01882 ameliorates aGVHD via skewing CD4+ T cell differentiation toward Treg cells.

Acute graft-versus-host disease (aGVHD) is a severe T cell-mediated immune response after allogeneic hematopoietic stem cell transplantation (allo-HSCT), the molecular mechanisms remain to be elucidated and novel treatments are necessary to be developed. In the present study, we found that the expression of long noncoding RNA (lncRNA) LINC01882 decreased significantly in the peripheral blood CD4+ T lymphocytes of patients with aGVHD than non-aGVHD patients. In addition, lncRNA LINC01882 overexpression promoted Treg differentiation but exhibited no effects on Th17 percentages, while its knockdown resulted in opposite effects. Mechanistically, lncRNA LINC01882 could competitively bind with let-7b-5p to prevent the degradation of its target gene smad2, which acts as a promoter in Treg differentiation. Furthermore, the mice cotransplanted with LINC01882-overexpressed CD4+ T cells with PBMCs had a lower histological GVHD score and higher survival rate compared with control mice. In conclusion, our study discloses a novel LINC01882/let-7b-5p/smad2 pathway in the modulation of aGVHD and indicates that lncRNA LINC01882 could be a promising biomarker and therapeutic target for patients with aGVHD.

Isotopically Modified Bioassay Bridges the Bioavailability and Toxicity Risk Assessment of Metals in Bedded Sediments.

The application of bioavailability-based risk assessment for the management of contaminated sediments requires new techniques to rapidly and accurately determine metal bioavailability. Here, we designed a multimetal isotopically modified bioassay to directly measure the bioavailability of different metals by tracing the change in their isotopic composition within organisms following sediment exposure. With a 24 h sediment exposure, the bioassay sensed significant bioavailability of nickel and lead within the sediment and determined that cadmium and copper exhibited low bioavailable concentrations and risk profiles. We further tested whether the metal bioavailability sensed by this new bioassay would predict the toxicity risk of metals by examining the relationship between metal bioavailability and metal toxicity to chironomid larvae emergence. A strong dose-toxicity relationship between nickel bioavailability (nickel assimilation rate) and toxicity (22 days emergence ratio) indicated exposure to bioavailable nickel in the sediment induced toxic effects to the chironomids. Overall, our study demonstrated that the isotopically modified bioassay successfully determined metal bioavailability in sediments within a relatively short period of exposure. Because of its speed of measurement, it may be used at the initial screening stage to rapidly diagnose the bioavailable contamination status of a site.

A Novel Risk Predictive Scoring Model for Predicting Subsequent Infection After Carbapenem-Resistant Gram-Negative Bacteria Colonization in Hematological Malignancy Patients.

Background: This study investigated the high-risk factors associated with the increased vulnerability for subsequent clinical CR-GNB infection in carbapenem-resistant Gram-negative bacteria (CR-GNB)-colonized hematological malignancy (HM) patients and built a statistical model to predict subsequent infection. Method: All adult HM patients with positive rectoanal swabs culture for CR-GNB between January 2018 and June 2020 were prospectively followed to assess for any subsequent CR-GNB infections and to investigate the risk factors and clinical features of subsequent infection. Results: A total of 392 HM patients were enrolled. Of them, 46.7% developed a subsequent clinical CR-GNB infection, with 42 (10.7%) cases of confirmed infection and 141 (36%) cases of clinically diagnosed infection. Klebsiella pneumoniae was the dominant species. The overall mortality rate of patients colonized and infected with CR-GNB was 8.6% and 43.7%. A multivariate analysis showed that remission induction chemotherapy and the duration of agranulocytosis, mucositis, and hypoalbuminemia were significant predictors of subsequent infection after CR-GNB colonization. According to our novel risk-predictive scoring model, the high-risk group were >3 times more likely to develop a subsequent infection in comparison with the low-risk group. Conclusion: Our risk-predictive scoring model can early and accurately predict a subsequent CR-GNB infection in HM patients with CR-GNB colonization. The early administration of CR-GNB-targeted empirical therapy in the high-risk group is strongly recommended to decrease their mortality.

ALKBH5 Promotes Multiple Myeloma Tumorigenicity through inducing m6A-demethylation of SAV1 mRNA and Myeloma Stem Cell Phenotype.

N6-methyladenosine (m6A) is the most prevalent modification to RNA in higher eukaryotes. ALKBH5 is an RNA demethylase that impacts RNA export and metabolism, and its aberrant expression is associated with the generation of tumours. In this study, we found that ALKBH5 was highly expressed in both primary CD138+ plasma cells isolated from multiple myeloma (MM) patients and MM cell lines. Downregulation of ALKBH5 inhibited myeloma cell proliferation, neovascularization, invasion and migration ability, and promoted the apoptosis in vivo and in vitro. MeRIP-seq identified the SAV1 gene as main target gene of ALKBH5. Inhibiting ALKBH5 in MM cells increased SAV1 m6A levels, decreased SAV1 mRNA stability and expression, suppressed the stem cell related HIPPO-pathway signalling and ultimately activates the downstream effector YAP, exerting an anti-myeloma effect. Additionally, MM stem cell phenotype was suppressed in ALKBH5-deficient cells and the expression of pluripotency factors NANOG, SOX2 and OCT4 were also decreased. Altogether, our results suggest that ALKBH5 acts as an oncogene in MM and might serve as an attractive potential biomarker and therapeutic target.

Prognostic Significance of Comprehensive Gene Mutations and Clinical Characteristics in Adult T-Cell Acute Lymphoblastic Leukemia Based on Next-Generation Sequencing.

Background: Adult T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous malignant tumor with poor prognosis. However, accurate prognostic stratification factors are still unclear. Methods: Data from 90 adult T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) patients were collected. The association of gene mutations detected by next-generation sequencing and clinical characteristics with the outcomes of T-ALL/LBL patients were retrospectively analyzed to build three novel risk stratification models through Cox proportional hazards model. Results: Forty-seven mutated genes were identified. Here, 73.3% of patients had at least one mutation, and 36.7% had ≥3 mutations. The genes with higher mutation frequency were NOTCH1, FBXW7, and DNMT3A. The most frequently altered signaling pathways were NOTCH pathway, transcriptional regulation pathway, and DNA methylation pathway. Age (45 years old), platelet (PLT) (50 G/L), actate dehydrogenase (LDH) (600 U/L), response in D19-BMR detection, TP53 and cell cycle signaling pathway alterations, and hematopoietic stem cell transplantation (HSCT) were integrated into a risk stratification model of event-free survival (EFS). Age (45 years old), white blood cell (WBC) count (30 G/L), response in D19-BMR detection, TP53 and cell cycle signaling pathway alterations, and HSCT were integrated into a risk stratification model of overall survival (OS). According to our risk stratification models, the 1-year EFS and OS rates in the low-risk group were significantly higher than those in the high-risk group. Conclusions: Our risk stratification models exhibited good prognostic roles in adult T-ALL/LBL patients and might guide individualized treatment and ultimately improve their outcomes.

Acute Promyelocytic Leukemia Presenting With a Myeloid Sarcoma of the Spine: A Case Report and Literature Review.

Myeloid sarcoma is a rare extramedullary tumor of immature myeloid cells. Certain known acute myeloid leukemia cytogenetic abnormalities, in particular t(8,21), has been associated with a higher incidence. Myeloid sarcoma, which rarely happens in acute promyelocytic leukemias, is more common in recurrent patients after the advent of all-trans retinoic acid (ATRA) and are rare in untreated acute promyelocytic leukemia. We described a case of, to our knowledge, de novo myeloid sarcoma of the spine confirmed as acute promyelocytic leukemia. Myeloid sarcoma is diagnosed by spinal tumor biopsy, and microscopic examination of a bone marrow smear and cytogenetic analysis led to a confirmed diagnosis of acute promyelocytic leukemia.

Emerging roles of long non-coding RNAs in allotransplant rejection.

Allotransplantation has extensively been employed for managing end-stage organ failure and malignant tumors. Acute and chronic post-transplant rejections are major causes of late morbidity and mortality after allotransplantation. However, there are no objective diagnostic criteria and specific therapy for post-transplant rejections. Owing to key advances in high-throughput RNA sequencing techniques, a wealth of studies have disclosed that long noncoding RNA (lncRNA) expression increased or decreased evidently in biopsies, blood, plasma, urine and specific cells of rejecting patients, and the dysregulated lncRNAs affected the cellular functions and differentiation of the immune system. Hence, we present an overview of the functions of lncRNAs expressed in various immune cells related to allotransplant rejection. Moreover, our review explores the regulatory interplay of relevant lncRNAs and recipients with or without allograft rejection after solid organ transplantations or hematopoietic stem cell transplantation, then discuss whether these relevant lncRNAs can be molecular biomarkers for diagnosis and new therapeutic targets in the management of post-transplanted patients.

Application of a Multi-Metal Stable-Isotope-Enriched Bioassay to Assess Changes to Metal Bioavailability in Suspended Sediments.

The direct measurement of particulate contaminant bioavailability is a challenging aspect for the environmental risk assessment of contaminated sites. Here, we demonstrated a multi-metal stable-isotope-enriched bioassay to simultaneously measure the bioavailability of Cd, Cu, and Zn in naturally contaminated sediments following differing periods of resuspension treatment. Freshwater filter-feeding clams were pre-labeled with the isotopes 114Cd, 65Cu, and 68Zn to elevate isotope abundances in their tissues and then exposed to metal-contaminated suspended sediments. The assimilation of sediment-associated metals by clams would decrease the isotope ratios (Cd114/111, Cu65/63, and Zn68/64) in tissues, providing a direct measurement of metal bioavailability. For the sediments tested here, the method revealed bioavailable cadmium and non-bioavailable copper in sediments but was inconclusive for zinc. With a longer resuspension time, the bioavailability of particulate cadmium increased, but that of copper was unaffected. Metal bioavailability predicted using traditional wet-chemical extraction methods was inconsistent with these findings. The study indicated that multi-metal stable-isotope-enriched bioassay provides a new tool for directly assessing metal bioavailability in sediments, and this method is amenable for use in in situ assessments.

Inhibition of the miR-155 and protein prenylation feedback loop alleviated acute graft-versus-host disease through regulating the balance between T helper 17 and Treg cells.

MicroRNA-155(miR-155) and protein prenylation have been reported to participate in acute graft-versus-host disease (aGVHD) through modulating T lymphocyte differentiation, however the mechanism remains elusive. In this study, we found that the expression of miR-155 and protein prenyltransferases in peripheral blood T lymphocytes of aGVHD mice was significantly increased. Suppression of miR-155 by antagomir-155 could remarkably reduce prenyltransferases mRNA and protein expression in T lymphocytes of aGVHD mice. Conversely, prenyltransferase inhibitors significantly reduced the level of miR-155. Inhibition of this feedback loop of miR-155 and protein prenylation in aGVHD mice led to improved survival and lower aGVHD histopathology scores and significantly induced T cell deficient differentiation towards T helper 17 (Th17) cells and titled differentiation towards CD4+CD25hi regulatory T (Treg) cells. Furthermore, the immunoregulatory effects and protection from aGVHD of prenyltransferase inhibitors could be reversed by the addition of miR-155. The dual treatment of prenylation inhibitors and antagomir-155 showed synergistic effects on T polarization and protection from aGVHD. Consistent with the in vivo changes, inhibition of this feedback loop of miR-155 and protein prenylation affected Th17 and Treg cell polarization in vitro. Our data suggest that miR-155 and protein prenylation may constitute a feedback loop that amplifies immune and inflammatory responses in subjects with aGVHD, and they may serve as potential targets for aGVHD prophylaxis and treatment.

Carbonic Anhydrase III Attenuates Hypoxia-Induced Apoptosis and Activates PI3K/Akt/mTOR Pathway in H9c2 Cardiomyocyte Cell Line.

Myocardial ischemia can cause insufficient oxygen and functional damage to myocardial cells. Carbonic anhydrase III (CAIII) has been found to be closely related to the abnormality of cardiomyocytes. To investigate the role of CAIII in the apoptosis of myocytes under hypoxic conditions and facilitate the strategy for treating hypoxia-induced damage, in vitro experiments in H9c2 were employed. The protein expression of CAIII in H9c2 cells after hypoxia or normoxia treatment was determined by western blotting and immunohistochemistry. MTT assay was employed for cells viability measurement and LDH release was monitored. The apoptotic cells were observed using immunofluorescence assay, flow cytometric analysis, and TUNEL assay. CAIII-overexpression or -knockdown cells were constructed to determine the role of CAIII in regulating apoptosis-related proteins caspase-3, Bax, Bcl-2, and anti-apoptosis pathway PI3K/Akt/mTOR. The mRNA levels of CAIII and genes related to CAIII synthesis including REN, IGHM, APOBEC 3F, and SKOR2 were significantly upregulated in hypoxia fetal sheep. The expression of CAIII protein and content of apoptotic H9c2 cells were increased at 1, 3, 6, and 12 h after hypoxia treatment. Overexpression of CAIII significantly upregulated Bcl2 level and downregulated Bax and caspase-3 cleavage levels, while its knockdown led to the contrary results. Overexpressed CAIII promoted the HIF-1α level and activated the PI3K/Akt/mTOR pathway, thereby exerting an inhibitory effect on hypoxia-induced apoptosis. In conclusion, our findings revealed that CAIII could protect cell from hypoxia-apoptosis of H9c2 cells, in which, activated PI3K/Akt/mTOR signaling pathway may be involved.

The role of E255K/V-inclusive mutations in a Philadelphia-positive acute lymphoblastic leukemia with mutation evolution during sequential TKIs therapies: A case report.

RATIONALE: Until recently, the survival rate in patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) was approximately 30%. Tyrosine kinase inhibitors (TKIs), which are a new class of drugs that target BCR-ABL fusion protein, have shown to be effective in treating Ph+ ALL in adults. However, the resistance mechanisms that promote the disease recurrence have altered the initial success of these revolutionary agents. PATIENT CONCERNS: A 71-year-old Chinese female patient who suffered from severe shoulder and back pain for 1 week. DIAGNOSIS: The patient was diagnosed with Ph+ ALL (B-cell) because of the following items. Complete blood count showed extremely abnormal white blood cell count (26.26×109/l), hemoglobin concentration (65 g/l) and platelet count (14×109/l). And because that Bone marrow aspirate showed 72.5% lymphoblasts and 59.30% lymphoblasts were confirmed by flow cytometry (FCM). At mean time, Real-time fluorescent quantitative PCR analysis confirmed that the P190 BCR/ABL fusion gene expression was 5.9%. Karyotype analysis indicated the following: 45, XX, -7, t (922) (q34; q11) [cp3]. INTERVENTIONS: The patient was treated with chemotherapy and different TKIs including imatinib, dasatinib, ponatinib, and bosutinib. OUTCOMES: The patient achieved complete remissions with different TKIs after diagnose but relapsed afterward and died of infection. LESSONS: Multidrug-resistant mutations within the BCR-ABL1 kinase domain are an emerging clinical problem for patients receiving sequential TKIs therapy. Acquisition of E255K/V-inclusive mutations is usually associated with ponatinib resistance, thus it is necessary to screen out new real pan-inhibitor compounds for all BCR/ABL mutations and figure out the potential efficacy of asciminib-based drug combinations in the future.

RNA methylation in hematological malignancies and its interactions with other epigenetic modifications.

Hematological malignancies are a class of malignant neoplasms attributed to abnormal differentiation of hematopoietic stem cells (HSCs). The systemic involvement, poor prognosis, chemotherapy resistance, and recurrence common in hematological malignancies urge researchers to look for novel treatment targets and mechanisms. In recent years, epigenetic abnormalities have been shown to play a vital role in tumorigenesis and progression in hematological malignancies. In addition to DNA methylation and histone modifications, which are most studied, RNA methylation has become increasingly significant. In this review, we elaborate recent advances in the understanding of RNA modification in the pathogenesis, diagnosis and molecular targeted therapies of hematological malignancies and discuss its intricate interactions with other epigenetic modifications, including DNA methylation, histone modifications and noncoding RNAs.