Regulation Of Bcl-2 Research Articles

COPB2 promotes metastasis and inhibits apoptosis of lung adenocarcinoma cells through functioning as a target of miR-216a-3p

BackgroundLung adenocarcinoma is a non-small cell lung cancer with a high mortality. There is little published data on the role of coatomer protein complex subunit β (COPB2) in lung adenocarcinoma. The current study aimed to explore the effects of COPB2 on lung adenocarcinoma cells.MethodsThe differential expression of COPB2 in normal cells and lung adenocarcinoma cells was detected by quantitative real time-polymerase chain reaction (qRT-PCR) and Western blotting. Then, cell viability assay, flow cytometry and Transwell experiments were performed to study the effects of COPB2 on cell growth, apoptosis, migration and invasion. MiRNA targeting COPB2 was predicted by TargetScan and validated by luciferase assay, qRT-PCR and Western blotting. The effects of miRNA inhibitor on siCOPB2 were analyzed by rescue experiments. Finally, apoptosis and metastatic marker proteins were detected by Western blotting.ResultsCOPB2 was high-expressed in lung adenocarcinoma cells. Silencing COPB2 inhibited cell viability and cell metastasis, and significantly increased apoptosis. MiR-216a-3p was predicted to be able to target COBP2. Rescue experiment showed that miR-216a-3p inhibitor promoted cell viability, migration and invasion, and inhibited apoptosis of lung adenocarcinoma cells, partly reversed the effects of siCOPB2. Moreover, Western blotting showed that siCOPB2 up-regulated expressions of cleaved Caspase-3, Caspase-3, BCL2 associated X (Bax), and E-Cadherin, and down-regulated expressions of BCL2 apoptosis regulator (Bcl-2), N-Cadherin, and Vimentin, and the above effects were also partly reversed by miR-216a-3p inhibitor.ConclusionsHigh-expressed COPB2 promotes metastasis and inhibits apoptosis of lung adenocarcinoma cells through functioning as a target of miR-216a-3p.

Effects and mechanisms of water-soluble Semen cassiae polysaccharide on retinitis pigmentosa in rats

Abstract This study aimed to investigate the effects and mechanisms of water-soluble Semen cassiae polysaccharide (SCP) on retinitis pigmentosa (RP) in rats. One hundred rats were randomly divided into control, model, and 50, 100 and 200 mg/kg SCP groups. The 50, 100 and 200 mg/kg SCP groups were treated with 50, 100 and 200 mg/kg SCP for 5 days, respectively. On the sixth day, the model, and 50, 100 and 200 mg/kg SCP groups were treated with N-nitroso-N-methylurea (MNU). After 12 h and 5 days, the electroretinogram, retinal thickness, apoptosis of retinal photoreceptor cells, and expressions of apoptosis related protein in retina tissue were determined. Results showed that, after 12 h and on 5 days from MNU treatment, compared with model group, the a-wave and b-wave amplitude and retinal thickness in SCP groups were significantly increased, the apoptosis rate of retinal photoreceptor cells was significantly decreased, the Bcl-2 protein expression level in retinal tissue was significantly increased, and the Bax and Caspase-3 protein level were significantly decreased (all P < 0.05). In conclusion, SCP has obvious protective effects on RP in rats. The mechanism may be related to it regulation of Bcl-2, Bax and Caspase-3 protein expression in retina tissue.

Down-regulation of miR-383-5p suppresses apoptosis in oxidative stress rat hepatocytes by targeting Bcl2.

miRNAs are a class of small non-coding RNAs that are involved in various biological processes. In the preliminary work of the laboratory, found that miR-383-5p was down-regulated in the liver tissue of acute cold stress rats and has been shown to be an important regulatory factor in tumour proliferation, but there are very few studies involving the mediation of cold stress in rat liver tissues. Therefore, the purpose of this study was to determine the effect of miR-383-5p on the livers of cold stress rats by simulating the cold stress state of rat liver tissues in vitro using H2 O2 to induce rat hepatocyte oxidative stress. The results showed that MDA content, Caspase 3 and Cyto C protein levels increased significantly; GPx activity and SOD1 protein levels decreased significantly and miR-383-5p expression was significantly down-regulated in rat liver tissues after cold stress. Different concentrations of H2 O2 was added to rat hepatocytes, and the results showed that the expression of miR-383-5p, the ROS level, and the apoptosis rate in rat hepatocytes was increased significantly in a concentration-dependent fashion. Transfection of miR-383-5p inhibitor revealed that the apoptosis rate of rat hepatocytes, and the protein level of apoptosis-related protein Caspase 3 were reduced; the results of the dual-luciferase reporter gene assay showed that miR-383-5p targeted regulation of Bcl2. The results suggested that the expression of miR-383-5p was up-regulated in oxidative stress rat hepatocytes and may aggravate the apoptosis of rat hepatocytes induced by targeting inhibition of Bcl2 translation.

Neonatal Rhesus Macaques Have Distinct Immune Cell Transcriptional Profiles following HIV Envelope Immunization

SUMMARYHIV-1-infected infants develop broadly neutralizing antibodies (bnAbs) more rapidly than adults, suggesting differences in the neonatal versus adult responses to the HIV-1 envelope (Env). Here, trimeric forms of HIV-1 Env immunogens elicit increased gp120-and gp41-specific antibodies more rapidly in neonatal macaques than adult macaques. Transcriptome analyses of neonatal versus adult immune cells after Env vaccination reveal that neonatal macaques have higher levels of the apoptosis regulator BCL2 in T cells and lower levels of the immunosuppressive interleukin-10 (IL-10) receptor alpha (IL10RA) mRNA transcripts in T cells, B cells, natural killer (NK) cells, and monocytes. In addition, immunized neonatal macaques exhibit increased frequencies of activated blood T follicular helper-like (Tfh) cells compared to adults. Thus, neonatal macaques have transcriptome signatures of decreased immunosuppression and apoptosis compared with adult macaques, providing an immune landscape conducive to early-life immunization prior to sexual debut.

Retraction: Downregulation of uPAR and Cathepsin B Induces Apoptosis via Regulation of Bcl-2 and Bax and Inhibition of the PI3K/Akt Pathway in Gliomas.

Retraction: Downregulation of uPAR and Cathepsin B Induces Apoptosis via Regulation of Bcl-2 and Bax and Inhibition of the PI3K/Akt Pathway in Gliomas.

The Opposite Effect of L-kynurenine and Ahr Inhibitor Ch223191 on Apoptotic Protein Expression in Pancreatic Carcinoma Cells (Panc-1).

L-kynurenine, derivate of L-tryptophan, is synthetized by indoleamine 2,3-dioxygenase (IDO). The effects of L-kynurenine depend on its binding to an aryl hydrocarbon receptor (AhR). The aim of this study was to investigate the changes within the apoptotic pathway in PANC-1 cells subjected to L-kynurenine or L-tryptophan considering the production of anti-apoptotic proteins from the IAPs and Bcl-2 family, as well as the regulation of NF-κB signaling. The investigated substances were added alone or in combination with the AhR inhibitor (CH223191) to cultures of PANC-1 cells. Cytoplasmic and nuclear proteins were analyzed by immunoblotting and cells were incubated with the investigated substances to determine cytotoxicity and proliferative effects. Incubation of PANC-1 cells with L-kynurenine or L-tryptophan resulted in the increase in antiapoptotic cIAP-1, cIAP-2, XIAP and Bcl-2 expression and a decrease in pro-apoptotic Bax. These changes were accompanied by the reduction of active caspases -9, -3 and PARP-1. The treatment leads to translocation and enhanced production of nuclear NF-κB p50 and Bcl-3. Incubation of the cells with AhR blocker either alone or together with L-kynurenine or L-tryptophan resulted in the opposite effect, leading to the downregulation of IAPs and Bcl-2, upregulation of Bax and caspases expression. 1) L-kynurenine and its precursor promote anti-apoptotic effects through the modulation of IDOdependent pathway and regulation of IAPs, Bcl-2 and NF-κB family members in pancreatic carcinoma cells 2) inhibition of AhR by CH223191 exerts an apoptosis-promoting effect, and this observation might suggest the potential use of this compound in pancreatic cancer therapy.

MicroRNA-145 suppresses gastric cancer progression by targeting Hu-antigen R.

Hu-antigen R (HuR) is involved in the carcinogenesis and progression of multiple types of cancer. However, its precise role in gastric cancer (GC) and the relevant molecular mechanism remain largely unclear. In the present study, we found that HuR expression level was higher in GC tissues and cell lines than in adjacent normal tissues and normal gastric epithelial cell lines, and this elevated expression was found to have a significant association with lymph node metastasis. Moreover, silencing HuR with RNA interference inhibited cell viability and induced cell apoptosis through the apoptosis-related regulators (Bcl-2 and Bax) in GC cells. In addition, bioinformatic analysis revealed that HuR expression was inversely correlated with miR-145 expression in GC tissue samples, and HuR was identified as a direct target of miR-145 with the dual-luciferase reporter. Enforced expression of miR-145 inhibited the HuR expression at both mRNA and protein levels and induced similar biologic effects of silencing HuR in GC cells. Additionally, we also found that restoration of HuR could eliminate the effects induced by miR-145 in GC cells. Taken together, these findings demonstrate the exact role of the miR-145-HuR axis in the progression of GC and indicate a potential target for GC therapy.

Up-regulation of miR-106a targets LIMK1 and contributes to cognitive impairment induced by isoflurane anesthesia in mice.

Postoperative cognitive dysfunction (POCD) had a great relationship with anesthesia during surgery, and miRNAs have been found involved in anesthesia-induced cognitive impairment. To explore the role and potential mechanism of miR-106a in isoflurane anesthesia-induced cognitive impairment. Adult male mice were treated with isoflurane anesthesia; Morris water maze tests and fear conditioning tests were performed; and expression levels of miR-106a and LIMK1 were determined by quantitative real-time PCR (qRT-PCR) and western blot. Dual luciferase reporter assay was used to determine the binding of miR-106a and 3'UTR of LIMK1. To verify the role of miR-106a, antagomir of miR-106a were intrahippocampally injected. Finally, expression of BCL2 apoptosis regulator (Bcl-2), LIM domain kinase 1 (LIMK1), BCL2-associated X, apoptosis regulator (Bax) and cleaved caspase3 was determined by western blot. In isoflurane anesthesia-treated group (IS), the percentage of target quadrant dwell time was significantly lower and the escape latency was significantly higher than in the control group (sham), and the freezing behavior of IS was significantly less in contextual fear conditioning tests. Expression levels of miR-106a were increased and those of LIMK1 were decreased in response to IS. Dual luciferase reporter assay showed that miR-106a could bind with the 3'UTR of LIMK1. Decreased expression levels of miR-106a improved the cognitive impairment of the mice treated with isoflurane. Intrahippocampally injected antagomir of miR-106a also increased LIMK1 and Bcl-2 levels, decreased the BAX and cleaved caspase3 expression levels in the mice treated with isoflurane. Decrease of LIMK1 expression by miR-106a played an important role in isoflurane anesthesia-induced cognitive impairment.

Design, Synthesis, and Evaluation of Novel 2-Methoxyestradiol Derivatives as Apoptotic Inducers Through an Intrinsic Apoptosis Pathway.

In order to discover novel derivatives in the anti-tumor field, reported anti-tumor pharmacophores (uridine, uracil, and thymine) were combined with 2-methoxyestradiol, which has been characterized as having excellent biological properties in terms of anti-tumor activity. Thus, 20 hybrids were synthesized through etherification at the 17β-OH or 3-phenolic hydroxyl group of 2-methoxyestradiol, and evaluated for their biological activities against the human breast adenocarcinoma MCF-7 cell lines, human breast cancer MDA-MB-231 cell lines, and the normal human liver L-O2 cell lines. As a result, all the uridine derivatives and single-access derivatives of uracil/thymine possessed good anti-proliferative activity against tested tumor cells (half maximal inhibitory concentration values from 3.89 to 19.32 µM), while only one dual-access derivative (21b) of thymine possessed good anti-proliferative activity (half maximal inhibitory concentration ≈ 25 µM). Among them, the uridine derivative 11 and the single-access derivative of uracil 12a possessed good anti-proliferative selectivity against tested tumor cells. Furthermore, basic mechanism studies revealed that hybrids 11 and 12a could induce apoptosis in MCF-7 cells through mitochondrial pathway. These hybrids induced morphological changes in MCF-7 cells, causing mitochondrial depolarization. These two hybrids also had the following effects: arrest of the cell cycle at the G2 phase; up regulation of Apaf-1, Bax, and cytochrome c; down regulation of Bcl-2 and Bcl-xL for both mRNA and protein; and increase of the expression for caspase-8 and -9. Finally, apoptotic effector caspase-3 was increased, which eventually caused nuclear apoptosis at least through an intrinsic pathway in the mitochondria. Additionally, hybrids 11 and 12a could specifically bind to estradiol receptor alpha in a dose-dependent manner.

Role of Bcl-2 on drug resistance in breast cancer polyploidy-induced spindle poisons.

Spindle poisons are chemotherapeutic drugs used in the treatment of malignant tumors; however, numerous patients develop resistance following chemotherapy. The present study aimed to induce polyploidy in breast cancer cells using the spindle poison nocodazole to investigate the mechanism of polyploid-induced tumor resistance. It was revealed that the spindle poison nocodazole induced apoptosis in HCC1806 cells but also induced polyploidy in MDA-MB-231 cells. The drug sensitivities of the polyploid MDA-MB-231 cells to paclitaxel, docetaxel, epirubicin, 5-fluorouracil and oxaliplatin were lower than those of the original tumor cells; however, the polyploid MDA-MB-231 cells were more sensitive to etoposide than the original tumor cells. The expression of F-box and WD repeat domain containing 7 (FBW7) was decreased, while the expression of MCL1 apoptosis regulator BCL2 family member (MCL-1) and Bcl-2 was increased, and caspase-3/9 and Bax were not expressed in MDA-MB-231 cells. The resistance to docetaxel and etoposide was reversed, but the sensitivity of paclitaxel was not changed following Bcl-2 silencing. The formation of polyploidy in tumors may be one of the molecular mechanisms underlying tumor resistance to spindle poisons. Expression of the Bcl-2 family members, for example FBW7 and MCL-1, plays a key role in apoptosis and the cell escape process that forms polyploid cells. However, Bcl-2 silencing has different reversal effects on different anti-tumor drugs, which requires further investigation.

The tripartite interaction of phosphate, autophagy, and αKlotho in health maintenance.

Aging-related organ degeneration is driven by multiple factors including the cell maintenance mechanisms of autophagy, the cytoprotective protein αKlotho, and the lesser known effects of excess phosphate (Pi), or phosphotoxicity. To examine the interplay between Pi, autophagy, and αKlotho, we used the BK/BK mouse (homozygous for mutant Becn1F121A ) with increased autophagic flux, and αKlotho-hypomorphic mouse (kl/kl) with impaired urinary Pi excretion, low autophagy, and premature organ dysfunction. BK/BK mice live longer than WT littermates, and have heightened phosphaturia from downregulation of two key NaPi cotransporters in the kidney. The multi-organ failure in kl/kl mice was rescued in the double-mutant BK/BK;kl/kl mice exhibiting lower plasma Pi, improved weight gain, restored plasma and renal αKlotho levels, decreased pathology of multiple organs, and improved fertility compared to kl/kl mice. The beneficial effects of heightened autophagy from Becn1F121A was abolished by chronic high-Pi diet which also shortened life span in the BK/BK;kl/kl mice. Pi promoted beclin 1 binding to its negative regulator BCL2, which impairs autophagy flux. Pi downregulated αKlotho, which also independently impaired autophagy. In conclusion, Pi, αKlotho, and autophagy interact intricately to affect each other. Both autophagy and αKlotho antagonizes phosphotoxicity. In concert, this tripartite system jointly determines longevity and life span.

MicroRNA-212-3p Attenuates Neuropathic Pain via Targeting Sodium Voltage-gated Channel Alpha Subunit 3 (NaV 1.3).

To explore the role and potential mechanism of miR-212-3p in neuropathic pain regulation. Adult male rats were used to establish chronic constriction injury (CCI) model to mimic the neuropathic pain. Then, paw withdrawal threshold (PWT) and paw withdrawal thermal latency (PWL) were determined. The concentrations of interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were measured with enzyme-linked immune sorbent assay (ELISA) kit and the expression of miR-212-3p was measured by real time quantitative PCR (RTqPCR). Besides, miR-212-3p agomir was intrathecally injected into CCI rats and the expression of key apoptotic proteins was determined by western blot. Furthermore, dual-luciferase reporter assay was used to determine the binding of miR-212-3p and 3' untranslated regions (3'UTR) of NaV1.3 and the expression levels of NaV1.3 were measured by western blot and RT-qPCR. In the CCI group, the PWT and PWL were significantly decreased and IL-1β, IL-6 and TNF-α were increased. miR-212-3p was decreased in response to CCI. The intrathecal injection of miR-212-3p agomir into CCI rats improved the PWT and PWL, decreased the IL-1β, IL-6 and TNF-α, decreased the expression levels of BCL2 associated X, apoptosis regulator (Bax), cleaved caspase-3 and increased the expression levels of BCL2 apoptosis regulator (Bcl-2). The results of dual--luciferase reporter assay showed that miR-212-3p could directly bind with 3'UTR of NaV1.3. The expression of NaV1.3 was up-regulated in CCI rats who were intrathecally injected with miRctrl, whereas it decreased in CCI rats intrathecally injected with miR-212-3p agomir. The expression of miR-212a-3p attenuates neuropathic pain by targeting NaV1.3.

LncRNA DLX6-AS1 Contributes to Epithelial–Mesenchymal Transition and Cisplatin Resistance in Triple-negative Breast Cancer via Modulating Mir-199b-5p/Paxillin Axis

Triple-negative breast cancer (TNBC) is one of the most aggressive cancer types with high recurrence, metastasis, and drug resistance. Recent studies report that long noncoding RNAs (lncRNAs)-mediated competing endogenous RNAs (ceRNA) play an important role in tumorigenesis and drug resistance of TNBC. Although elevated lncRNA DLX6 antisense RNA 1 (DLX6-AS1) has been observed to promote carcinogenesis in various cancers, the role in TNBC remained unclear. In this study, expression levels of DLX6-AS1 were increased in TNBC tissues and cell lines when compared with normal tissues or breast fibroblast cells which were determined by quantitative real-time PCR (RT-qPCR). Then, CCK-8 assay, cell colony formation assay and western blot were performed in CAL-51 cells transfected with siRNAs of DLX6-AS1 or MDA-MB-231 cells transfected with DLX6-AS1 over expression plasmids. Knock down of DLX6-AS1 inhibited cell proliferation, epithelial-mesenchymal transition (EMT), decreased expression levels of BCL2 apoptosis regulator (Bcl-2), Snail family transcriptional repressor 1 (Snail) as well as N-cadherin and decreased expression levels of cleaved caspase-3, γ-catenin as well as E-cadherin, while up regulation of DLX6-AS1 had the opposite effect. Besides, knockdown of DLX6-AS1 in CAL-51 cells or up regulation of DLX6-AS1 in MDA-MB-231 cells also decreased or increased cisplatin resistance of those cells analyzed by MTT assay. Moreover, by using dual luciferase reporter assay, RNA immunoprecipitation and RNA pull down assay, a ceRNA which was consisted by lncRNA DLX6-AS1, microRNA-199b-5p (miR-199b-5p) and paxillin (PXN) was identified. And DLX6-AS1 function through miR-199b-5p/PXN in TNBC cells. Finally, results of xenograft experiments using nude mice showed that DLX6-AS1 regulated cell proliferation, EMT and cisplatin resistance by miR-199b-5p/PXN axis in vivo. In brief, DLX6-AS1 promoted cell proliferation, EMT, and cisplatin resistance through miR-199b-5p/PXN signaling in TNBC in vitro and in vivo.

Влияние мелатонина на экспрессию белков-регуляторов апоптоза Bcl-2 и Bad в фолликулярном аппарате яичников после воздействия высокой температуры

Влияние мелатонина на экспрессию белков-регуляторов апоптоза Bcl-2 и Bad в фолликулярном аппарате яичников после воздействия высокой температуры

CircularRNA abhydrolase domain containing 16A-microRNA-1237-5p-apoptosis associated tyrosine kinase axis regulates the apoptosis of michigan cancer foundation-7 in breast cancer cells

Objective To investigate the circular RNA abhydrolase domain containing 16A (circRNA ABHD16A)-microRNA (miRNA, miR)-1237-5p-Apoptosis associated tyrosine kinase (AATK) axis on apoptosis of breast cancer cell munggan cancer foundation-7 (MCF-7). Methods The correlation between ABHD16A and miR-1237-5p and miR-1237-5p and AATK was analyzed by CSCD and TargetScan online analysis. The luciferase assay was used to detect whether circRNA ABHD16A targets miR-1237-5p and whether miR-1237-5p targets AATK. The expression of apoptotic marker proteins in AATK and breast cancer cells MCF-7 was detected by Western blot after over-expression or knockdown of circRNA ABHD16A. Cell viability of breast cancer cells MCF-7 was analyzed by methyl thiazolyl tetrazolium (MTT) assay; staining by Annexin-V was performed by MTT assay. The level of apoptosis of breast cancer cells MCF-7 was measured. Student’s t-test analyzed two sets of one-way analysis of variance. Results circRNA ABHD16A targets miR-1237-5p; miR-1237-5p targets the 320-326 and 469-475 regions of the AATK 3’ UTR. When overexpressing ABHD16A, AATK expression increased significantly (t=15.295, P<0.01), apoptosis-related protein bcl-2 antagonist/killer 1 (bak), bcl-2 Associated X Apoptosis Regulator (bax) and cleaved Caspase-9 (cleaved-CAS9) expression levels increased significantly (t=7.403, 8.381, 21.583, P<0.01). The expression of bcl-2 Apoptosis Regulator (bcl-2) was significantly decreased (t=6.301, P<0.01), the activity of MCF7 cells was decreased (t=17.392, P<0.01), and the level of apoptosis was increased (t=8.491, P<0.05). When ABHD16A was knocked down, the expression of AATK was significantly decreased (t=9.290, P<0.01), and the expression levels of apoptosis-related proteins bak, bax and cleaved-CAS9 were significantly decreased (t=8.381, 5.296, 11.492, P<0.01), while the expression of bcl-2 increased significantly (t=5.609, P<0.01), the activity level of MCF7 cells increased (t=5.694, P<0.01), and the level of apoptosis decreased (t=13.502, P<0.01). Conclusion circRNA ABHD16A targets miR-1237-5p and increases the expression of AATK and promotes the apoptosis of breast cancer cells MCF-7. Key words: CircularRNA abhydrolase domain containing 16A; MicroRNA-1237-5p; Apoptosis associated tyrosine kinase; Breast cancer; Michigan cancer foundation-7; Cell apoptosis

LncRNA UBE2R2-AS1 Had Anti-Tumor Effects in Non-Small Cell Lung Cancer

Background: The purpose of our work was to discuss anti-tumor effects and mechanisms of lncRNA UBE2R2-AS1 in NSCLC. Methods : lncRNA UBE2R2-AS1 gene level was measured by RT-qPCR in BEAS-2B, A549, H1975, H1650 and HCC827. Dividing A549 and H1650 cells into NC, Vector and UBE2R2-AS1. Measuring the cell proliferation by CCK-8 assay; Using flow cytometer to evaluate cell apoptosis, using transwell and wound healing methods to evaluate invasion and migration abilities. The relative protein expressions were measured by WB assay. Results: UBE2R2-AS1 mRNA expression of A549 and H1650 were the lowest in all cells lines. With UBE2R2-AS1 transfection, the cell proliferation rates were significantly down-regulation with cell apoptosis significantly increasing (P &lt; 0 001). Meanwhile, the invasion cell number and wound healing rates of UBE2R2-AS1 groups were significantly depressed (P &lt; 0 001). Bcl-2, TLR4 and MyD88 proteins expressions were significantly down-regulation and Caspase-3 and Caspase-8 proteins levels were significantly upregulation in UBE2R2-AS1 groups (P &lt; 0 001). Conclusion: UBE2R2-AS1 overexpression had antitumor in NSCLC, the mechanisms might be correlation with regulation Bcl-2, caspase-3, caspase-8, TLR4 and MyD88 protein levels.

Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia Abstract. CLL is an indolent B-cell lymphoma characterized by a leukemic course. It is clinically and biologically very heterogeneous. The disease is preceded by a condition called monoclonal B lymphocytosis (MBL). The treatment of CLL has changed dramatically in recent years. Chemoimmunotherapy is being replaced by new molecularly targeted therapeutic modalities like B cell receptor inhibitors and BCL-2 regulators of programmed cell death. When to initiate therapy and what "new" drug combinations to use in which line of treatment are issues currently addressed in clinical trials.

Blinatumomab and Venetoclax for Minimal Residual Disease Relapse in Acute Lymphoblastic Leukemia

Introduction: The 5-year relative survival in patients aged 15-24 years old is around 57% (Blood 2019; 134: 407-410), with a median survival after relapse of 10 months. No uniform consensus about rescue treatment is available, but those who achieve a complete remission can undergo to an allogeneic transplant if feasible. The use of intense rescue chemotherapy is associated with systemic toxicities and risk of serious infections that can delay an allogeneic transplant. Objective: We describe the combination of two ALL targeted therapies, combining bispecific T-cell engager (BiTE) against CD 19 (Blinatumomab) and selective inhibitor of the B-cell lymphoma 2 (Bcl-2) regulator protein, an antiapoptotic protein (Venetoclax). This combination was developed based in their mechanism of action that offers synergetic effects against ALL cells and the reports of ongoing clinical trials using Venetoclax combinations for ALL, but no with Blinatumomab. Patients and methods: Patients with B cell precursors ALL in minimal residual disease relapse by flow cytometry. Rescue treatment with Blinatumomab and Venetoclax before allogeneic transplant. Results: Two patients treated with LAFAMI-LLA-2002 Protocol (Blood 2009; 114: 4104 and Hematologia 2016; 17: 5137), adapted to young adults with high dose methotrexate at 5 gr/m2 every four months in the maintenance phase, had MDR positivity by FC in the surveillance phase, with normal CBC. One male with 22 years old at the time of relapse, after 60 months of surveillance with 1.9 % of malignant lymphoblasts. One female with 21 years old at the time of relapse, after 25 months of surveillance with 0.2 % of malignant lymphoblasts. Both relapses were confirmed with an additional MRD one week after. Extension studies were performed, including PET-CT, to determinate other affected sites and were negative. Treatment administrated was Blinatumomab at 9 mcg/day continuous IV infusion on days 1-7 and 28 mcg/day on days 8-14 with Venetoclax in a ramp-up phase for 5 weeks. Both patients were in negative MRD after the complete Blinatumomab and continue with Venetoclax while a donor was available. No side effects were observed during and after the treatment. Both patients had a compatible sibling and underwent for allogeneic transplant. At the moment of this report the patients have 11 months and 18 months after transplant with EMR negative and complete donor cells from the bone marrow, with no secondary effects. Conclusion: This is a novel combination with no reports of its use before our communication. Targeted therapies in low leukemic burden is a feasible treatment with no side effects and rapid control of the relapse, allowing the patients to reach an allogeneic transplant as soon as possible avoiding substantial toxicity and risk of infections. No infusion related reaction or cytokine release syndrome were observed due low leukemic burden. More patients need to be included to this combination to demonstrate reproducibility, optimizing time and costs. OffLabel Disclosure: Blinatumomab and Venetoclax combination for acute lymphoblastic leukemia relapse

Four-Year Analysis of Murano Study Confirms Sustained Benefit of Time-Limited Venetoclax-Rituximab (VenR) in Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)

Four-Year Analysis of Murano Study Confirms Sustained Benefit of Time-Limited Venetoclax-Rituximab (VenR) in Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)

Oxidative stress-mediated photoactivation of carbazole inhibits human skin cell physiology.

Prolonged exposure of the earth's surface to the sun's ultraviolet radiation may result in various skin diseases and cataract. Carbazole (CBZ), as a polycyclic-aromatic hydrocarbon (PAH), is blended with a five-member nitrogen-containing ring. It is found in cigarette smoke, coal, eye kohl, tattoo ink, and wood combustion and affects various types of flora and fauna. Our findings suggest that CBZ generates reactive oxygen species (ROS) like through type-I photodynamic reaction and causes phototoxicity in the human keratinocyte cell line (HaCaT), which has been proved by mitochondrial dehydrogenase and neutral red uptake assays. CBZ induces single strand DNA damage. We have investigated the involvement of the apoptotic pattern of cell death and confirmed it by cytochrome C release from mitochondria and caspase-9 activation. Similarly, photo-micronuclei formation was associated to CBZ-induced phototoxicity. The results of this study strongly support that the upregulation of bax, cyto-C, apaf-1, casp-9 and down regulation of bcl2, keap-1, nrf-2, and hmox-1 genes cause apoptopic cell death. Downregulation of antioxidant genes showed a significant amount of ROS generation by photosensitized CBZ. Therefore, the current study will be a step forward to safeguard human beings from sunlight-induced photosensitive CBZ prolonged exposure.