Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia.

OBJECTIVE: In B-cell acute lymphoblastic leukemia (B-ALL), current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50% of cases, underscoring the urgent need for new therapeutic regimens for this patient population. The present study aimed to determine whether HZX-02-059, a novel dual-target inhibitor targeting both phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) and tubulin, is lethal to B-ALL cells and is a potential therapeutic for B-ALL patients. METHODS: Cell proliferation, vacuolization, apoptosis, cell cycle, and in-vivo tumor growth were evaluated. In addition, Genome-wide RNA-sequencing studies were conducted to elucidate the mechanisms of action underlying the anti-leukemia activity of HZX-02-059 in B-ALL. RESULTS: HZX-02-059 was found to inhibit cell proliferation, induce vacuolization, promote apoptosis, block the cell cycle, and reduce in-vivo tumor growth. Downregulation of the p53 pathway and suppression of the phosphoinositide 3-kinase (PI3K)/AKT pathway and the downstream transcription factors c-Myc and NF-κB were responsible for these observations. CONCLUSION: Overall, these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.

Effect of prior lenalidomide or daratumumab exposure on hematopoietic stem cell collection and reconstitution in multiple myeloma.

BACKGROUND: The roles of Lenalidomide (Len) and Daratumumab (Dara) in multiple myeloma treatment are well-established, yet their influences on hematopoietic stem cell harvesting and reconstitution remain disputed. METHODS: We conducted a systematic database review to identify cohort studies or RCTs evaluating the effect of the use of Len or Dara on hematopoietic stem cell collection and peripheral blood count recovery in multiple myeloma patients. Effects on hematopoietic collection or reconstitution were estimated by comparing standardized mean differences (SMD) and mean differences (MD), or median differences. RESULTS: Eighteen relevant studies were identified, summarizing mobilization results. For Len, data from 13 studies were summarized, including total CD34+ cell yield, collection failure rate, and time to neutrophil and platelet engraftment. Results indicated that Len exposure led to decreased stem cell collection [SMD=-0.23, 95% CI (-0.34, -0.12)]. However, collection failure (<2×106) could be mitigated by plerixafor [OR=2.14, 95% CI (0.96, 4.77)]. For Dara, two RCTs and three cohort studies were included, showing that Dara exposure resulted in a reduction in total stem cells even with optimized plerixafor mobilization [SMD=-0.75, 95% CI (-1.26, -0.23)], and delayed platelet engraftment recovery [MD=1.20, 95% CI (0.73, 1.66)]. CONCLUSIONS: Our meta-analysis offers a comprehensive view of Len and Dara's impacts on hematopoietic stem cell collection and reconstitution in multiple myeloma. Len usage could lead to reduced stem cell collection, counteracted by plerixafor mobilization. Dara usage could result in diminished stem cell collection and delayed platelet engraftment.

Anlotinib suppresses the DNA damage response by disrupting SETD1A and inducing p53-dependent apoptosis in Transformed Follicular Lymphoma.

Purpose: The high tumor mutational burden (TMB) of transformed follicular lymphoma (tFL) leads to tumor heterogeneity and poor prognosis in follicular lymphoma, in which endogenous DNA damage and epigenetic modification are the key factors. This study aims to evaluate the efficacy of anlotinib in tFL and to investigate its potential therapeutic mechanism. Methods: Cell viability and apoptosis were tested with CCK-8 and annexin V/PI staining kits, respectively. The tumorigenicity test in mice was utilized to further confirm the efficacy of anlotinib in vivo. Western blotting was utilized to explore the molecular mechanisms. Results: Anlotinib induced G2/M phase arrest in tFL cells, inhibited the proliferation of tFL cells and promoted the apoptosis of tFL cells in a dose-dependent manner. Administration of anlotinib markedly reduced tumor mass and weight in an FL xenograft mouse model. The western blot and immunohistochemistry staining results confirmed that the mechanism by which anlotinib promoted tumor cell apoptosis was DNA damage. Further results showed that anlotinib significantly downregulated the expression of SETD1A, leading to its destruction. Anlotinib administration resulted in a significant dose-dependent increase in the level of p-p53. Furthermore, anlotinib greatly downregulated the antiapoptotic proteins Mcl-1 and in parallel upregulated the proapoptotic element BAX and Bak, accompanied by caspase-3 activation and PARP degradation. Conclusion: Anlotinib has a good proapoptotic effect on tumor cells in vitro and in vivo, and its possible mechanism is related to the inhibition of the DNA damage response by disrupting SETD1A.

Ritanserin suppresses acute myeloid leukemia by inhibiting DGKα to downregulate phospholipase D and the Jak-Stat/MAPK pathway.

Refractory or relapsed (R/R) AML is the most challenging form of AML to treat. Due to frequent genetic mutations, therapy alternatives are limited. Here, we identified the role of ritanserin and its target DGKα in AML. Several AML cell lines and primary patient cells were treated with ritanserin and subjected to cell proliferation, apoptosis and gene analyses with CCK-8 assay, Annexin V/PI assay and Western blotting, respectively. We also evaluated the function of the ritanserin target diacylglycerol kinase alpha (DGKα) in AML by bioinformatics. In vitro experiments have revealed that ritanserin inhibits AML progression in a dose- and time-dependent manner, and it shows an anti-AML effect in xenograft mouse models. We further demonstrated that the expression of DGKα was elevated in AML and correlated with poor survival. Mechanistically, ritanserin negatively regulates SphK1 expression through PLD signaling, also inhibiting the Jak-Stat and MAPK signaling pathways via DGKα. These findings suggest that DGKα may be an available therapeutic target and provide effective preclinical evidence of ritanserin as a promising treatment for AML.

Stratification and therapeutic potential of ELL in cytogenetic normal acute myeloid leukemia.

Optimizing prognostic stratification of patients with cytogenetic normal acute myeloid leukemia (CN-AML), a highly heterogeneous subgroup in AML, appears to be important to improve its treatment and clinical outcome. Here, we report a potential role of ELL, a gene associated with leukemogenesis in AML, in prognostic stratification of CN-AML patients. By analyzing public available databases, we found that ELL was highly expressed in AML patients compared with healthy donors. Kaplan-Meier analysis revealed that ELL expression markedly correlated with short overall survival (OS) of CN-AML patients. In COX multivariable regression analysis, higher ELL expression was an independent prognostic factor for OS in CN-AML. Knockdown of ELL by shRNAs sensitized KG-1α cells to anti-leukemic agents such as idarubicin (IDA) and chidamide (CS055), supporting its role in therapeutic response and outcome in AML. To understand its function in CN-AML, we further analyzed the ELL-driving gene signature. ELL-related genes were particularly enriched in cell adhesion molecules, cell differentiation, pathways in cancer, sequence-specific DNA binding, and extracellular matrix (ECM)-receptor interaction. Analysis of the PPI network identified 25 hub genes, including the stem cell gene BMP4. While BMP4 expression was significantly associated with ELL in CN-AML, knockdown of ELL markedly down-regulated BMP4 expression, suggesting that ELL might function via regulating BMP4 in AML. Together, these observations suggest a novel mechanism underlying pro-leukemogenic role of ELL via BMP4 up-regulation in AML and its potential value to serve as a predictive biomarker for therapeutic response and outcome of CN-AML patients.

Therapeutic inhibition of PPARα-HIF1α-PGK1 signaling targets leukemia stem and progenitor cells in acute myeloid leukemia.

Treatment of acute myeloid leukemia (AML) with chemotherapeutic agents fails to eliminate leukemia stem cells (LSC)，and thus patients remain at high risk for relapse. Therefore, the identification of agents that target LSC is an important consideration for the development of new therapies. Enhanced glycolysis in LSC contributes to the aggressiveness of AML, which is difficult to be targeted. In this study, we showed that targeting peroxisome-proliferator-activated receptor α (PPARα), a ligand-activated transcription factor by chiglitazar provided a promising therapeutic approach. We first identified that chiglitazar reduced cell viability and proliferation of the leukemia stem-like cells population in AML. Treatment with chiglitazar blocked the ubiquitination of PPARα and increased its expression, resulting in the inhibition of glucose metabolism and apoptosis of AML cells. Consistent with its anti-leukemia stem-like cells activity in vitro, chiglitazar treatment in vivo resulted in the significant killing of leukemia stem-like cells as demonstrated in AML patient-derived xenograft (PDX) models. Mechanistically, PPARα overexpression inhibited the expression and promoter activity of PGK1 through blocking HIF1-α interaction on the PGK1 promoter. Thus, we concluded that targeting PPARα may serve as a novel approach for enhancing stem and progenitor cells elimination in AML.

Orelabrutinib and venetoclax synergistically induce cell death in double-hit lymphoma by interfering with the crosstalk between the PI3K/AKT and p38/MAPK signaling.

PURPOSE: Double-hit lymphoma (DHL) is a rare and aggressive mature B-cell malignancy with concurrent MYC and BCL2 rearrangements. When DHL becomes relapsed or refractory, it becomes resistant to the majority of therapeutic approaches and has subpar clinical results. Therefore, innovative therapeutics for this particular patient population are urgently needed. METHODS: Orelabrutinib, a new oral BTK inhibitor, combined with the Bcl-2 inhibitor venetoclax, was used to confirm the antitumor effect of DHL. Cell counting kit-8 and Annexin V-FITC/PI assays were used to examine the interaction of this combined regimen on DHL cell lines and primary lymphoma cells. RNA sequencing, EdU incorporation assay, mitochondrial membrane potential assay, and western blotting were employed to explore the molecule mechanism for the cytotoxicity of orelabrutinib with or without venetoclax against DHL cell lines. RESULTS: In this study, orelabrutinib combined with venetoclax synergistically induced DHL cell death, as evidenced by the inhibition of cell proliferation, the induct of cell cycle arrest, and the promotion of cell apoptosis via the mitochondrial pathway. Orelabrutinib treatment alters genome-wide gene expression in DHL cells. The combined regimen decreases the expression of BTK and Mcl-1, potentially interfering with the activity and crosstalk of PI3K/AKT signaling and p38/MAPK signaling. In addition, the combination of orelabrutinib and venetoclax shows cytotoxic activity in primary B-lymphoma cells. CONCLUSION: In summary, these findings reveal a novel therapy targeting BCR signaling and the Bcl-2 family for DHL patients with a poor prognosis.

Preclinical Evaluation of the Multiple Tyrosine Kinases Inhibitor Anlotinib in Leukemia Stem Cells.

Leukemia stem cells (LSCs) constitute the critical barrier to the cure of acute myeloid leukemia (AML) due to their chemoresistance and immune evasion property. Herein, the role of anlotinib, a multiple tyrosine kinase inhibitor, in killing LSCs and regulating chemoresistance and immune evasion was explored. Anlotinib treatment induced apoptosis of LSC-like cells as well as primary AML LSCs, while sparing the normal mononuclear cells in vitro. Moreover, anlotinib could impair the regeneration capacity of LSCs in the patient-derived leukemia xenograft mouse model. Mechanistically, anlotinib inhibited phosphorylation of c-kit, JAK2/STAT3, and STAT5, and downregulated STAT3 and STAT5 expression. In addition, anlotinib downregulated the anti-apoptotic proteins Bcl-2 and Bcl-xL, and upregulated Bax, thereby enhancing the sensitivity of LSCs to idarubicin in vitro. Intriguingly, anlotinib could also partially rescue the interferon-g production of T cells cocultured with LSCs by downregulating PD-L1 expression. In conclusion, anlotinib showed anti-LSC activity and the potential to enhance the sensitivity to idarubicin and inhibit the immunosuppressive feature of LSCs via JAK2/STAT signaling pathway downregulation in the preclinical study. Our results provided a rational basis for combinatory strategies involving anlotinib and chemotherapy or immunotherapy.

Foreign Object Detection in Railway Images Based on an Efficient Two-Stage Convolutional Neural Network.

Foreign object intrusion is one of the main causes of train accidents that threaten human life and public property. Thus, the real-time detection of foreign objects intruding on the railway is important to prevent the train from colliding with foreign objects. Currently, the detection of railway foreign objects is mainly performed manually, which is prone to negligence and inefficient. In this study, an efficient two-stage framework is proposed for foreign object detection in railway images. In the first stage, a lightweight railway image classification network is established to classify any input railway images into one of two classes: normal or intruded. To enable real-time and accurate classification, we propose an improved inverted residual unit by introducing two improvements to the original inverted residual unit. First, the selective kernel convolution is used to dynamically select kernel size and learn multiscale features from railway images. Second, we employ a lightweight attention mechanism, called the convolutional block attention module, to exploit both spatial and channel-wise relationships between feature maps. In the second stage of our framework, the intruded image is fed to the foreign object detection network to further detect the location and class of the objects in the image. Experimental results confirm that the performance of our classification network is comparable to the widely used baselines, and it obtains outperforming efficiency. Moreover, the performances of the second-stage object detection are satisfying.

Anlotinib exerts potent antileukemic activities in Ph chromosome negative and positive B-cell acute lymphoblastic leukemia via perturbation of PI3K/AKT/mTOR pathway.

OBJECTIVES: Despite advances in the development of novel targeted therapies, the need for B-ALL alternative treatments has not been met. Anlotinib could blunt the proangiogenic activity of VEGFR, PDGFR, and FGFR, and has shown strong antitumor activities across multiple tumors. However, anlotinib cytotoxicity against B-ALL has not ever been evaluated, thus prompting us to initiate this study. METHODS: Expression2Kinases program was used to identify potential treatment targets. Cell viability and apoptosis were determined by CCK-8 and Annexin V/PI staining kit, respectively. qRT-PCR and Western blotting were utilized to investigate the molecular mechanisms. In vivo antileukemia activity of Anlotinib was evaluated in a Ph+ B-ALL patient-Derived Xenograft (PDX) model. RESULTS: Compared with treatment-naive B-ALL cases, RR B-ALL patients had higher activities in the VEGF/VEGFR signaling and the PI3K/AKT/mTOR pathway. Exposure of Ph- and Ph+ B-ALL cells to anlotinib resulted in significant cell viability reduction, apoptosis enhancement, and cell cycle arrest at G2/M phase. Importantly, anlotinib treatment led to remarkably decreased leukemia burdens and extended the survival period in a Ph+ B-ALL PDX model. Blockade of the role of the proangiogenic mediators, comprising VEGFR2, PDGFR-beta, and FGFR3, played a critical role in the cytotoxicity of anlotinib against Ph- and Ph+ B-ALL. Moreover, anlotinib dampened the activity of PI3K/AKT/mTOR pathway that resides in the convergence of the three mentioned proangiogenic signals. CONCLUSION: This work provides impressive preclinical evidence of anlotinib against Ph- and Ph+ B-ALL and raises a rationale for future clinical evaluation of this drug in the management of Ph- and Ph+ B-ALL.

Chidamide and apatinib are therapeutically synergistic in acute myeloid leukemia stem and progenitor cells.

BACKGROUND: Leukemia stem cells (LSCs) are responsible for the initiation and perpetuation of acute myeloid leukemia (AML), and also represent leukemia relapse reservoirs with limited therapeutic approaches. Thus, additional treatment strategies are medical unmet needs to eliminate LSCs. METHODS: Cell counting kit-8 and Annexin-V-FITC/PI assays were used to examine the interaction of chidamide and apatinib on LSC-like cell lines (CD34+CD38- KG1α and Kasumi-1 cells) and primary CD34+ AML cells. AML patient-derived xenografts were established to investigate the in vivo efficacy of the combined regimen. RNA sequencing, Glutamine uptake assay, oxygen consumption assay, and western blotting were employed to explore the molecule mechanism for the cytotoxicity of chidamide with or without apatinib against LSC-like cell lines and/or primary CD34+ AML cells. RESULTS: In this study, chidamide and apatinib were synergisitc to diminish cell viability and induce apoptosis in CD34+CD38- KG1α and Kasumi-1 cells and in CD34+ primary AML cells. Importantly, chidamide combined with apatinib had more powerful in reducing leukemia burden and improving prognosis than single drug alone in an AML PDX model without significant adverse effects. Chidamide cytotoxicity was associated with decreasing glutamine uptake. The therapeutic synergy of chidamide and apatinib correlated with reprogramming of energy metabolic pathways. In addition, inactivating the VEGFR function and reducing the anti-apoptotic ability of the Bcl2 family contributed to the synergism of chidamide and apatinib in CD34+CD38- KG1α cells and CD34+ primary AML cells. CONCLUSION: Chidamide in combination with apatinib might be a promising therapeutic strategy to get rid of the population of AML stem and progenitor cells, and thus provide a potentially curative option in the treatment of patients with AML, although further clinical evaluations are required to substantiate the conclusion.

Therapeutic synergy of Triptolide and MDM2 inhibitor against acute myeloid leukemia through modulation of p53-dependent and -independent pathways.

Dysregulation of MDM2, a p53 negative regulator, frequently occurs in acute myeloid leukemia (AML) and is associated with unfavorable prognoses, rendering the p53-MDM2 axis an attractive target for the development of small-molecule inhibitors. MDM2 antagonists have been intensely developed but only lead to limited clinical activity, suggesting combination with additional drugs is an unmet medical need. In this study, we reported that Triptolide synergized with MDM2 inhibitor Nutlin-3a to suppress cell proliferation and induce mitochondrial-mediated apoptosis in p53 wt AML in vitro and ex vivo. More importantly, Triptolide cooperated with Nutlin-3a to delay tumor growth and abrogate leukemia burden in an AML xenograft model. In addition, we observed that Triptolide and Nutlin-3a were also cooperative in part of p53 deficient cases. Mechanistically, Nutlin-3a upregulated the transcriptional expressions of the p53 downstream targets PUMA and p21, while Triptolide declined the mRNA levels of two anti-apoptotic factors, XIAP and Mcl-1, in p53 wt cells. These effects were more notable when Triptolide and Nutlin-3a were combined. Our results revealed that Triptolide monotherapy exerted its antileukemia effect via both p53-dependent and independent ways, with the latter through perturbation of the MYC-ATF4 axis-mediated ER stress. Collectively, these data suggested that the Triptolide-Nutlin-3a combination might be a novel potential therapeutic intervention for patients with AML and it warrants further clinical evaluations.

Pharmacological targeting PIKfyve and tubulin as an effective treatment strategy for double-hit lymphoma.

Double-hit lymphoma is one of the most aggressive and refractory lymphoma subtypes with recurrent genetic abnormalities of MYC and BCL-2 or BCL6 rearrangement, leading to a poor prognosis in the present clinical practice. Therefore, new therapeutic strategies for eliminating double-hit lymphomas are urgently needed. Here, we reported that HZX-02-059, a novel PIKfyve and tubulin dual-target inhibitor, showed a highly cytotoxic activity against double-hit lymphoma cell lines in vitro and in vivo through a noncanonical caspase-independent cell death, methuosis. Mechanistically, the cytotoxicity triggered by HZX-02-059 was contributed to the PIKfyve/TFEB axis-induced cell death of methuosis, as well as the inhibition of tubulin and mTOR/Myc axis-induced cell cycle arrest. In summary, the present findings suggest that HZX-02-059 represents a good starting point for developing targeted therapeutics against double-hit lymphomas.

Preclinical Studies of Chiauranib Show It Inhibits Transformed Follicular Lymphoma through the VEGFR2/ERK/STAT3 Signaling Pathway.

Transformed follicular lymphoma (t-FL), for which there is no efficient treatment strategy, has a rapid progression, treatment resistance, and poor prognosis, which are the main reasons for FL treatment failure. In this study, we identified a promising therapeutic approach with chiauranib, a novel orally developed multitarget inhibitor targeting VEGFR/Aurora B/CSF-1R. We first determined the cytotoxicity of chiauranib in t-FL cell lines through CCK-8, EdU staining, flow cytometry, and transwell assays. We also determined the killing effect of chiauranib in a xenograft model. More importantly, we identified the underlying mechanism of chiauranib in t-FL tumorigenesis by immunofluorescence and Western blotting. Treatment with chiauranib significantly inhibited cell growth and migration, promoted apoptosis, induced cell cycle arrest in G2/M phase, and resulted in significant killing in vivo. Mechanistically, chiauranib suppresses the phosphorylation level of VEGFR2, which has an anti-t-FL effect by inhibiting the downstream MEK/ERK/STAT3 signaling cascade. In conclusion, chiauranib may be a potential therapy to treat t-FL, since it inhibits tumor growth and migration and induces apoptosis by altering the VEGFR2/ERK/STAT3 signaling pathway.

Preclinical Evaluation of the HDAC Inhibitor Chidamide in Transformed Follicular Lymphoma.

The key factors leading to transformed follicular lymphoma (t-FL) include the aberrations of epigenetic modifiers as early and driving events, especially mutations in the gene encoding for histone acetyltransferase. Therefore, reversal of this phenomenon by histone deacetylase (HDAC) inhibitors is essential for the development of new treatment strategies in t-FL. Several t-FL cell lines were treated with various doses of chidamide and subjected to cell proliferation, apoptosis and cell cycle analyses with CCK-8 assay, Annexin V/PI assay and flow cytometry, respectively. Chidamide dose-dependently inhibited cell proliferation, caused G0/G1 cycle arrest and triggered apoptosis in t-FL cells. In addition, the effects of chidamide on tumor growth were evaluated in vivo in xenograft models. RNA-seq analysis revealed gene expression alterations involving the PI3K-AKT signaling pathway might account for the mechanism underlying the antitumor activity of chidamide as a single agent in t-FL. These findings provide a basis for further clinical exploration of chidamide as a promising treatment for FL.

Simvastatin potentiates the cell-killing activity of imatinib in imatinib-resistant chronic myeloid leukemia cells mainly through PI3K/AKT pathway attenuation and Myc downregulation.

Constitutively activated BCR-ABL kinase is considered the driver event responsible in the initiation and development of chronic myeloid leukemia (CML). The advent of the first BCR-ABL inhibitor imatinib has significantly improved the clinical outcome of CML cases. However, resistance to imatinib occurs in 25-30% of CML patients. Due to the lack of effective therapeutic strategies, novel treatment approaches are urgently required for imatinib-resistant CML. Simvastatin, a well-known HMG-CoA reductase inhibitor that confers tremendous clinical benefits in cardiovascular diseases, has attracted mounting attentions for its potent antitumor effects on multiple tumor types. In this study, we demonstrated that simvastatin monotherapy was effective in diminishing cell viability in both imatinib-sensitive and imatinib-resistant CML cells, including T351I mutated cells, with the latter being less vulnerable to the simvastatin than the former. Notably, we found that simvastatin acted as a robust cytotoxic sensitizer of imatinib to kill imatinib-resistant and T315I mutated CML cells in vitro and in vivo. Mechanistically, the cooperative interaction of simvastatin and imatinib was associated with the inactivation of the PI3K/Akt signaling pathway, which was a classical downstream pro-survival cascade of the BCR-ABL kinase. In addition, this drug combination obviously decreased Myc expression through attenuation of canonical Wnt/ß-catenin signaling and increased H3K27 trimethylation. Taken together, we provide attractive preclinical results for the combinatorial regimen of simvastatin and imatinib against imatinib-resistant and T315I mutated CML cells. This combined regimens warrants further clinical investigations in patients with imatinib-resistant CML.

Therapeutic Interaction of Apatinib and Chidamide in T-Cell Acute Lymphoblastic Leukemia through Interference with Mitochondria Associated Biogenesis and Intrinsic Apoptosis.

T-cell acute lymphoblastic leukemia (T-ALL) shows poor clinical outcome and has limited therapeutic options, indicating that new treatment approaches for this disease are urgently required. Our previous study demonstrated that apatinib, an orally selective VEGFR-2 antagonist, is highly effective in T-ALL. Additionally, chidamide, a histone deacetylase inhibitor, has proven to be cytotoxic against T-ALL in preclinical and clinical settings. However, whether the therapeutic interaction of apatinib and chidamide in T-ALL remains unknown. In this study, apatinib and chidamide acted additively to decrease cell viability and induce apoptosis in T-ALL in vitro. Notably, compared with apatinib or chidamide alone, the combinational regimen was more efficient in abrogating the leukemia burden in the spleen and bone marrow of T-ALL patient-derived xenograft (PDX) models. Mechanistically, the additive antileukemia effect of apatinib and chidamide was associated with suppression of mitochondrial respiration and downregulation of the abundance levels of several rate-limiting enzymes that are involved in the citric acid cycle and oxidative phosphorylation (OXPHOS). In addition, apatinib enhanced the antileukemia effect of chidamide on T-ALL via activation of the mitochondria-mediated apoptosis pathway and impediment of mitochondrial biogenesis. Taken together, the study provides a potential role for apatinib in combination with chidamide in the management of T-ALL and warrants further clinical evaluations of this combination in patients with T-ALL.

CS2164 and Venetoclax Show Synergistic Antitumoral Activities in High Grade B-Cell Lymphomas With MYC and BCL2 Rearrangements.

High-grade B-cell lymphoma with concurrent MYC and BCL2 rearrangements (HGBL-DHL) is a rare, aggressive mature B-cell malignancy with a high likelihood of treatment failure following front-line immunochemotherapies. Patients with HGBL-DHL who develop a relapsed or refractory disease have little effective therapeutic strategies and show very poor clinical outcomes, thus calling for development of novel therapies for this specific patient population. In this study, we investigated the preclinical anti-lymphoma efficacies and potential mechanism of action of a novel treatment approach, combining the BCL2 inhibitor venetoclax with CS2164, a new orally active multitarget inhibitor, in HGBL-DHL models. This combination therapy exhibited a robust synergistic cytotoxicity against HGBL-DHL cells, evidenced by cooperatively inducing loss of cell viability and promoting cell apoptosis. Moreover, coadministration of CS2164 and venetoclax resulted in significant superior suppression of HGBL-DHL cell growth and remarkably abrogated tumor burden in a HGBL-DHL-xenografted mouse model. The synergistic lethality of CS2164 and venetoclax in HGBL-DHL cells was associated with induction of DNA damage and impairment of DNA repair ability. Of importance, the combined treatment almost abolished the expression of both BCL2 and MYC, two hallmark proteins of HGBL-DHL, and substantially blunted the activity of PI3K/AKT/mTOR signaling cascade. In addition, MCL1 and BCL-XL, two well-characterized contributors for venetoclax resistance, were significantly lessened in the presence of CS2164 and venetoclax, thus leading to the accumulation of proapoptotic proteins BAX and PUMA and then initiating the intrinsic apoptosis pathway. Taken together, these findings suggest that the regimen of CS2164 and venetoclax is highly effective to eliminate HGBL-DHL cells in the preclinical setting, warranting further clinical investigations of this regimen for the treatment of unfavorable HGBL-DHL patients.

Mortality trend and predictors of mortality in dysphagic stroke patients postpercutaneous endoscopic gastrostomy.

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) feeding is widely used in stroke patients suffering from persistent dysphagia; however, predicting the risks and benefits of PEG insertion in the individual patient is difficult. The aim of our study was to investigate if candidate risk factors could predict short-term mortality risk in poststroke patients who had PEG tube insertion for persistent dysphagia. METHODS: This was a retrospective study of 3504 consecutive stroke patients admitted to two metropolitan hospitals during the period January 2005 to December 2013 and who also underwent PEG insertion for feeding due to persistent dysphagia. RESULTS: A total of 102 patients were included in the study. There were 22 deaths in 6 months after insertion of PEG tubes and 20 deaths of those occurred within 3 months post PEG. Those who survived beyond 6 months showed significantly lower mean age (75.9 ± 9.0 years vs. 83.0 ± 4.9 years, P < 0.001), a lower mean American Society of Anesthesia (ASA) score (3.04 ± 0.63 vs. 3.64 ± 0.58, P < 0.001) compared to nonsurvivors. In multiple Logistic, age (P = 0.004, odds ratio [OR] = 1.144; 95% confidence interval [CI]: 1.044-1.255); ASA (P = 0.002, OR = 5.065; 95% CI: 1.815-14.133) and albumin level pre-PEG insertion (P = 0.033, OR = 0.869; 95% CI: 0.764-0.988) were the independent determinants of mortality respectively. CONCLUSIONS: We propose that age, ASA score and albumin level pre-PEG insertion to be included as factors to assist in the selection of patients who are likely to survive more than 3 months post PEG insertion.