Reverse Drug Research Articles

Advanced nanoparticles that can target therapy and reverse drug resistance may be the dawn of leukemia treatment: A bibliometrics study.

With the development of nanomedicine, more and more nanoparticles are used in the diagnosis and treatment of leukemia. This study aimed to identify author, country, institutional, and journal collaborations and their impacts, assess the knowledge base, identify existing trends, and uncover emerging topics related to leukemia research. 1825 Articles and reviews were obtained from the WoSCC and analyzed by Citespace and Vosviewer. INTERNATIONAL JOURNAL OF NANOMEDICINE is the journal with the highest output. The contribution of FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY is also noteworthy. The three main aspects of research in Nanoparticles-leukemia-related fields included nanoparticles for the diagnosis and treatment of leukemia, related to the type and treatment of leukemia, the specific molecular mechanism, and existing problems of the application of nanoparticles in leukemia. In the future, synthesize nano-drugs that have targeted therapy and chemotherapy resistance according to the mechanism, which may be the dawn of the solution to leukemia. This study offers a comprehensive overview of the Nanoparticles-leukemia-related field using bibliometrics and visual methods for the first time, providing a valuable reference for researchers interested in Nanoparticles-leukemia.

Cuprous oxide-based nanocrystals with combined chemo/chemodynamic therapy to increase tumor drug sensitivity by reducing mitochondria-derived adenosine-triphosphate

Gastrointestinal (GI) tumor is a serious disease with high mortality rates and morbidity rates worldwide. Chemotherapy is a key treatment for GI, however, systematic side effects and inevitable drug resistance complicate the situation. In the process of therapy, P-glycoprotein (P-gp) could remove chemotherapy drugs from cells, thus causing multi-drug resistance. Chemodynamic therapy (CDT) utilizing Fenton chemistry has been used for cancer therapy, along with various combination therapies. The reactive oxygen species produced by CDT could inhibit P-gp’s efflux pump function, which reduce chemoagents excretion and reverse drug resistance. In the present study, we developed novel nanocrystals (Cu2O@Pt NCs) to overcome drug resistance by reducing mitochondria-derived ATP through chemo/CDT in GI cancer. Furthermore, in vivo results in tumor-bearing mice demonstrated that treatment with Cu2O@Pt NCs with CDT and chemotherapy could achieve the most effective antitumor therapeutic effect with the least amounts of adverse effects. As a result, Cu2O@Pt NCs could provide a promising strategy for chemo/CDT-synergistic therapy.

Adagrasib, a KRAS G12C inhibitor, reverses the multidrug resistance mediated by ABCB1 in vitro and in vivo

BackgroundMultidrug resistance (MDR) is a complex phenomenon that frequently leads to chemotherapy failure during cancer treatment. The overexpression of ATP-binding cassette (ABC) transporters represents the major mechanism contributing to MDR. To date, no effective MDR modulator has been applied in clinic. Adagrasib (MRTX849), a specific inhibitor targeting KRAS G12C mutant, is currently under investigation in clinical trials for the treatment of non-small cell lung cancer (NSCLC). This study focused on investigating the circumvention of MDR by MRTX849.MethodsThe cytotoxicity and MDR reversal effect of MRTX849 were assessed by MTT assay. Drug accumulation and drug efflux were evaluated by flow cytometry. The MDR reversal by MRTX849 in vivo was investigated in two ABCB1-overexpressing tumor xenograft models in nude mice. The interaction between MRTX849 and ABCB1 substrate binding sites was studied by the [125I]-IAAP-photoaffinity labeling assay. The vanadate-sensitive ATPase assay was performed to identify whether MRTX849 would change ABCB1 ATPase activity. The effect of MRTX849 on expression of ABCB1 and PI3K/AKT signaling molecules was examined by flow cytometry, Western blot and Quantitative Real-time PCR analyses.ResultsMRTX849 was shown to enhance the anticancer efficacy of ABCB1 substrate drugs in the transporter-overexpressing cells both in vitro and in vivo. The MDR reversal effect was specific against ABCB1 because no similar effect was observed in the parental sensitive cells or in ABCG2-mediated MDR cells. Mechanistically, MRTX849 increased the cellular accumulation of ABCB1 substrates including doxorubicin (Dox) and rhodamine 123 (Rho123) in ABCB1-overexpressing MDR cells by suppressing ABCB1 efflux activity. Additionally, MRTX849 stimulated ABCB1 ATPase activity and competed with [125I]-IAAP for photolabeling of ABCB1 in a concentration-dependent manner. However, MRTX849 did not alter ABCB1 expression or phosphorylation of AKT/ERK at the effective MDR reversal drug concentrations.ConclusionsIn summary, MRTX849 was found to overcome ABCB1-mediated MDR both in vitro and in vivo by specifically attenuating ABCB1 efflux activity in drug-resistant cancer cells. Further studies are warranted to translate the combination of MRTX849 and conventional chemotherapy to clinical application for circumvention of MDR.3A9j1Q87GL5CKdhmy4PpapVideo

Nanoparticles design considerations to co-deliver nucleic acids and anti-cancer drugs for chemoresistance reversal

Chemoresistance and hence the consequent treatment failure is considerably challenging in clinical cancer therapeutics. The understanding of the genetic variations in chemoresistance acquisition encouraged the use of gene modulatory approaches to restore anti-cancer drug efficacy. Many smart nanoparticles are designed and optimized to mediate combinational therapy between nucleic acid and anti-cancer drugs. This review aims to define a rational design of such co-loaded nanocarriers with the aim of chemoresistance reversal at various cellular levels to improve the therapeutic outcome of anticancer treatment. Going through the principles of therapeutics loading, physicochemical characteristics tuning, and different nanocarrier modifications, also looking at combination effectiveness on chemosensitivity restoration. Up to now, these emerging nanocarriers are in development status but are expected to introduce outstanding outcomes.

Solubility determination and thermodynamic model analysis of nevirapine in different organic solvents from 278.15 K to 328.15 K

Nevirapine (NVP) is the first non-nucleoside reverse transcriptase inhibitor drug to be marketed for the treatment of HIV. The solubility of NVP under atmospheric pressure in eleven pure solvents and three mixtures was measured from 278.15 to 323.15 K. XRD and DSC were used to detect the crystal form and stability of NVP in this work. Overall, the solubility of NVP gradually increases as the temperature rises. In addition, under the same temperature conditions, the solubility of NVP increases with the ratio of the positive solvents in binary solvents. In the mixture (DMF + acetonitrile), when the proportion of DMF reaches 0.8, the solubility in the binary solvent is greater than that in pure DMF. The experimental data was fitted by five thermodynamic models (Buchowski-Ksiazaczak λh model, the Modified Apelblat model, Jouyban-Acree model, SUN model, and CNIBS/R-K model). Subsequently, the largest mean square deviation value (RMSD) is only 2.31E-04, which demonstrates that the correlation of the solubility data and the five models is relatively good. Additionally, KAT-LSER model was used to explore the effects of solute–solvent interactions on solubility at 298.15 K. The analysis results indicated that the dipolarity/polarizability (π∗) of pure solvents plays a crucial role in the dissolution of NVP and its proportion of the total solvent effect reaches 30.92 %. This research was explored and developed the important systems (1-propyl alcohol and DMF + acetonitrile) for the industrial crystallization purification of NVP.

Hypoxia induces docetaxel resistance in triple-negative breast cancer via the HIF-1α/miR-494/Survivin signaling pathway

Cytotoxic chemotherapy is the major strategy to prevent and reduce triple-negative breast cancer (TNBC) progression and metastasis. Hypoxia increases chemoresistance and is associated with a poor prognosis for patients with cancer. Based on accumulating evidence, microRNAs (miRNAs) play an important role in acquired drug resistance. However, the role of miRNAs in hypoxia-induced TNBC drug resistance remains to be clarified. Here, we found that hypoxia induced TNBC docetaxel resistance by decreasing the miR-494 level. Modulating miR-494 expression altered the sensitivity of TNBC cells to DTX under hypoxic conditions. Furthermore, we identified Survivin as a direct miR-494 target. Hypoxia upregulated survivin expression. In a clinical study, the HIF-1α/miR-494/Survivin signaling pathway was also active in primary human TNBC, and miR-494 expression negatively correlated with HIF-1α and survivin expression. Finally, in a xenograft model, both miR-494 overexpression and the HIF-1α inhibitor PX-478 increased the sensitivity of TNBC to DTX by suppressing the HIF-1α/miR-494/Survivin signaling pathway in vivo. In conclusion, treatments targeting the HIF-1α/miR-494/Survivin signaling pathway potentially reverse hypoxia-induced drug resistance in TNBC.

Temozolomide hexadecyl ester targeted plga nanoparticles for drug-resistant glioblastoma therapy via intranasal administration

Introduction: Temozolomide (TMZ) is the first-line drug for glioblastoma (GBM), but it is limited in clinical use due to the drug resistance, poor brain targeting, and side effects. Temozolomide hexadecyl ester (TMZ16e), a TMZ derivative with high lipophilicity, membrane permeability, and high anti-glioma properties, has the potential to reverse drug resistance. In this study, anti-ephrin type-A receptor 3 (EphA3) modified TMZ16e loaded nanoparticles (NPs) were prepared for targeted GBM therapy via intranasal administration to deliver TMZ16e to the brain, treat drug-resistant glioma effectively, and reduce peripheral toxicity. Methods: TMZ16e loaded NPs were prepared by emulsion solvent evaporation method followed by modified with anti-EphA3 (anti-EphA3-TMZ16e-NPs). In vitro evaluations were performed by an MTT assay and flow cytometry analysis. The orthotopic nude mice models were used to evaluate the anti-glioma effect in vivo. Additionally, we investigated the anti-drug resistant mechanism by western blot analysis. Results: The particle size of the prepared NPs was less than 200 nm, and the zeta potential of TMZ16e-NPs and anti-EphA3-TMZ16e-NPs were -23.05 ± 1.48 mV and -28.65 ± 1.20mV, respectively, which is suitable for nasal delivery. In vitro studies have shown that anti-EphA3 modification increased the cellular uptake of nanoparticles in T98G cells. The cytotoxicity in the anti-EphA3-TMZ16e-NPs treated group was significantly higher than that of the TMZ16e-NPs, TMZ16e, and TMZ groups (p < 0.01), and the cell cycle was blocked. Western blotting analysis showed that the TMZ16e-loaded NPs were able to effectively downregulate the expression level of O6-methylguanine-deoxyribonucleic acid-methyltransferase (MGMT) protein in T98G cells and reverse drug resistance. In vivo studies showed that the median survival time of tumor-bearing nude mice in the anti-EphA3-TMZ16e-NPs group was extended to 41 days, which was 1.71-fold higher than that of the saline group and the TUNEL staining results of the brain tissue section indicated that the TMZ16e-loaded NPs could elevate apoptosis in T98G cells. Conclusion: In conclusion, the TMZ16e-loaded NPs can be effectively delivered to the brain and targeted to gliomas, exhibiting better anti-glioma activity, indicating they possess great potential in the treatment of drug-resistant glioma.

Improving in vitro continuous cultivation of Plasmodium cynomolgi, a model for P. vivax.

The absence of a routine continuous in vitro cultivation method for Plasmodium vivax, an important globally distributed parasite species causing malaria in humans, has restricted investigations to field and clinical sampling. Such a method has recently been developed for the Berok strain of P. cynomolgi, a parasite of macaques that has long been used as a model for P. vivax, as these two parasites are nearly indistinguishable biologically and are genetically closely related. The availability of the P. cynomolgi Berok in routine continuous culture provides for the first time an opportunity to conduct a plethora of functional studies. However, the initial cultivation protocol proved unsuited for investigations requiring extended cultivation times, such as reverse genetics and drug resistance. Here we have addressed some of the critical obstacles to this, and we propose a set of modifications that help overcome them.

CD13 downregulation mediated by ubenimex inhibits autophagy to overcome 5-FU resistance by disturbing the EMP3/FAK/NF-κB pathway in gastric cancer cells.

BackgroundGastric cancer (GC) is one of the most common malignant tumours in China, but the efficacy of chemotherapy on GC is significantly reduced due to the occurrence of drug resistance. Some studies have shown that the expression level of CD13 is associated with tumour resistance, but whether ubenimex, as a CD13 inhibitor, reverses GC drug resistance and the underlying mechanism remain unclear.MethodsHerein, resistance to 5-fluorouracil (5-FU) was reversed in GC by ubenimex, and the underlying mechanism was determined using Cell Counting Kit-8 (CCK-8) assays, gene chip analysis, high content screening (HCS), transmission electron microscopy, flow cytometry, immunofluorescence and western blot assays.ResultsFlow cytometry, transmission electron microscopy and immunofluorescence analyses indicated that ubenimex, an inhibitor of CD13, regulated the autophagy and apoptosis of SGC7901/5-FU cells by downregulating CD13 expression. In addition, Gene chip analysis and HCS demonstrated that epithelial membrane protein 3 (EMP3)/focal adhesion kinase (FAK) was a putative signalling pathway downstream of CD13. Furthermore, western blot analyses showed that ubenimex not only inhibited EMP3, FAK and nuclear factor-κB (NF-κB) expression but also suppressed GC autophagy and activated apoptosis by targeting CD13. These findings indicated a potential mechanism via the CD13/EMP3/FAK/NF-κB pathway and that the activity of which was restrained.ConclusionsUbenimex affects autophagy and apoptosis to reverse GC cell resistance by targeting the CD13/EMP3/FAK/NF-κB pathway. These results showed that ubenimex is a promising agent that may inhibit GC autophagy to improve chemotherapeutic drug sensitivity and thereby reverse drug resistance.

β-Elemene Promotes Apoptosis Induced by Hyperthermia via Inhibiting HSP70.

Thermotherapy has been presented as a promising strategy to be used as an effective nonsurgical technique for colorectal carcinoma. Although this strategy presents several advantages, including low toxicity and high repeatability, thermotherapy often needs to be combined with other therapies because residual tumor cells that survive hyperthermal treatment often lead to relapse. In this study, we evaluated the effects of β-elemene, which has been proven to have the potential to reverse chemotherapy drug resistance, on promoting the antitumor effects of hyperthermia. β-elemene treatment significantly promoted apoptosis after 2 hours of hyperthermia treatment and blocked cell cycle phases at G1/G0. β-elemene also significantly decreased colony formation and tumor formation abilities after hyperthermia treatment. β-elemene treatment significantly decreased HSP70, but not HSP90 or HSP27, induced by hyperthermia treatment without disturbing HSP70 mRNA. It was also found that β-elemene decreased phosphorylated ERK1/2 induced by hyperthermia. Regain of HSP70 reversed β-elemene-mediated apoptosis, indicating that β-elemene may induce apoptosis by decreasing HSP70. Moreover, β-elemene treatment significantly decreased invasion capacity by decreasing the EMT, which was induced by hyperthermia treatment. Taken together, our results offer a potential strategy for CRC therapy via the combination of hyperthermia and β-elemene.

IGF1 receptor-targeted black TiO2 nanoprobes for MRI-guided synergetic photothermal-chemotherapy in drug resistant pancreatic tumor

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest malignant tumors with features of matrix barrier caused poor drug permeability, and susceptibility to drug resistance. Herein, a PDAC and its stromal cell dual-targeted photothermal-chemotherapy strategy is explored to loosen the matrix and reverse drug resistance. To achieve this goal, black TiO2-Gd nanocomposites were conjugated with insulin like growth factor 1 (IGF1), and loaded with gemcitabine (GEM) to construct bTiO2-Gd-IGF1-GEM nanoprobes. In vitro results show that under 808 nm near-infrared irradiation, killing effect of the nanoprobes on drug-resistant MIA PaCa-2 cell is 3.3 times than that of GEM alone. In vivo experiments indicate the synergetic photothermal-chemotherapy not only loosens fibrous matrix of pancreatic tumor model, but also dramatically inhibits tumor growth, and almost completely eradicates the tumor after 12 days of treatment. In addition, relaxation rate of the nanoprobes is 8.2 times than commercial contrast agent Magnevist, therefore boosts the signal of magnetic resonance imaging in pancreatic tumor. In conclusion, our results reinforce that the prepared nanoprobes are promising to break matrix barrier and overcome drug resistance in PDAC.

Fibroblast growth factor signalling influences homologous recombination-mediated DNA damage repair to promote drug resistance in ovarian cancer

BackgroundOvarian cancer patients frequently develop chemotherapy resistance, limiting treatment options. We have previously shown that individuality in fibroblast growth factor 1 (FGF1) expression influences survival and chemotherapy response.MethodsWe used MTT assays to assess chemosensitivity to cisplatin and carboplatin following shRNA-mediated knockdown or heterologous over-expression of FGF1 (quantified by qRT-PCR and immunoblot analysis), and in combination with the FGFR inhibitors AZD4547 and SU5402, the ATM inhibitor KU55933 and DNA-PK inhibitor NU7026. Immunofluorescence microscopy was used to quantify the FGF1-dependent timecourse of replication protein A (RPA) and γH2AX foci formation.ResultsPharmacological inhibition of FGF signalling reversed drug resistance in immortalised cell lines and in primary cell lines from drug-resistant ovarian cancer patients, while FGF1 over-expression induced resistance. Ataxia telangiectasia mutated (ATM) phosphorylation, but not DNA adduct formation was FGF1 dependent, following cisplatin or carboplatin challenge. Combining platinum drugs with the ATM inhibitor KU55933, but not with the DNA-PK inhibitor NU7026 re-sensitised resistant cells. FGF1 expression influenced the timecourse of damage-induced RPA and γH2AX nuclear foci formation.ConclusionDrug resistance arises from FGF1-mediated differential activation of high-fidelity homologous recombination DNA damage repair. FGFR and ATM inhibitors reverse platinum drug resistance, highlighting novel combination chemotherapy approaches for future clinical trial evaluation.

Study on the implementation of reverse logistics in medicines from health centers in Brazil

The need to implement innovative sustainable production processes is a topic of important social relevance in this current century. Environmental tragedies on different continents have revealed that humanity needs to understand how nature belongs to a system that needs to be balanced in order to maintain its existence. One of the major sustainability challenges globally is the management of solid wastes (SW). The rapid urbanization coupled with the increase in the world population has resulted in a consequential increase in the use of various products and their associated generated wastes. Of such SW that is complicated to manage are medical wastes which are deemed hazardous. Thus, the various industries including the health industry must implement a reverse logistic methodology in the disposal of solid wastes in order to efficiently and effectively manage their wastes. Countries such as Brazil, have incorporated reverse logistics into their National Solid Waste Policy (NSWP) thereby ensuring adequate disposal of various solid wastes and co-responsibility among the generators of various wastes. In this study, the strategies adopted within the scope of the Unified Health System (SUS, in Portuguese) in Brazil related to the reverse logistics of medicines consumed in the health industry were investigated. As a methodology, qualitative research such as literature review and documentary were utilized in order to obtain knowledge about the major information about the health industry in Brazil. The findings and discussions provided in this paper revealed that reverse logistics applied to pharmaceutical products in Brazil is still incipient. Although there is consolidated literature on the subject in national studies, there is a lack of evidence that indicates effective models of reverse drug logistics in the country, in a scenario of growth of 10% per year in the generation of this waste on average in the country. It is concluded that reverse drug logistics in Brazil is in an embryonic process, strengthened by the construction of regulations and laws that may encourage industries to adopt good practices in the production and management of drug wastes, and which, when implemented, can generate a reduction of around 12% in the volume generated per year. • Implement a reverse logistic methodology in the disposal of solid wastes. • Application of reverse logistics in hazardous solid health waste. • Increased generation of healthcare waste due to COVID-19. • Management and management of health waste in Brazil.

Public struggles with naloxone access, acceptance.

It’s easy to go into a pharmacy in Rhode Island and walk out with a supply of the opioid reversal drug naloxone. But not enough people are doing so, says Anita Jacobson, clinical professor at the University of Rhode Island College of Pharmacy. Anita Jacobson “People aren’t taking the initiative to go in and ask for it,” she said. “That’s something they just don’t do. It really has to be almost aggressively marketed to them.” Jacobson does her part to get naloxone where it’s most needed by setting up tables during rural community events and offering the lifesaving reversal agent at no cost to people who stop by. The effort, initially funded through a rural opioid technical assistance grant from the federal Substance Abuse and Mental Health Services Administration, is part of the Community First Responder Program, which Jacobson has led since its launch in late 2019. The program has distributed more than 6,500 naloxone nasal spray kits at “tabling events” and during in-person and virtual education programs. During the program’s events, Jacobson works alongside student pharmacists, nursing students, and others to educate community members about naloxone and teach them how and when to administer it.

Are thyrotropin-releasing hormone (TRH) and analog taltirelin viable reversal agents of opioid-induced respiratory depression?

Opioid‐induced respiratory depression (OIRD) is a potentially life‐threatening complication of opioid consumption. Apart from naloxone, an opioid antagonist that has various disadvantages, a possible reversal strategy is treatment of OIRD with the hypothalamic hormone and neuromodulator thyrotropin‐releasing hormone (TRH). In this review, we performed a search in electronic databases and retrieved 52 papers on the effect of TRH and TRH‐analogs on respiration and their efficacy in the reversal of OIRD in awake and anesthetized mammals, including humans. Animal studies show that TRH and its analog taltirelin stimulate breathing via an effect at the preBötzinger complex, an important respiratory rhythm generator within the brainstem respiratory network. An additional respiratory excitatory effect may be related to TRH’s analeptic effect. In awake and anesthetized rodents, TRH and taltirelin improved morphine‐ and sufentanil‐induced respiratory depression, by causing rapid shallow breathing. This pattern of breathing increases the work of breathing, dead space ventilation, atelectasis, and hypoxia. In awake and anesthetized humans, a continuous infusion of intravenous TRH with doses up to 8 mg, did not reverse sufentanil‐ or remifentanil‐induced respiratory depression. This is related to poor penetration of TRH into the brain compartment but also other causes are discussed. No human data on taltirelin are available. In conclusion, data from animals and human indicate that TRH is not a viable reversal agent of OIRD in awake or anesthetized humans. Further human studies on the efficacy and safety of TRH’s more potent and longer lasting analog taltirelin are needed as this agent seems to be a more promising reversal drug.

Alantolactone-Loaded Pegylated Prodrug Nanocarriers for Synergistic Treatment of Cisplatin-Resistant Ovarian Cancer via Reactivating Mitochondrial Apoptotic Pathway.

Ovarian cancer (OV) seriously damages women's health because of refractory OV and the development of platinum (Pt) resistance. New treatment strategies are urgently needed to deal with the treatment of cisplatin-resistant OV. Here, a reduction-sensitive pegylated Pt(IV) prodrug was synthesized by amidation of methoxy polyethylene glycol amine (PEG750-NH2) with monocarboxylic Pt(IV) prodrug (Pt(IV)-COOH). Then alantolactone (AL) loaded PEG-Pt(IV) nanocarriers (NP(Pt)@AL) were prepared. In the cisplatin-resistant model of OV, cancer cells actively ingest NP(Pt)@AL through endocytosis, and AL and Pt(II) were disintegrated and released under high intracellular reductant condition. The activity of thioredoxin reductase 1 (TrxR1) inhibited by AL and the adducts of Pt(II) with mitochondrial DNA (mDNA) can costimulate reactive oxygen species (ROS) and reactivate the mitochondrial pathway of apoptosis. Meanwhile, Pt(II) binds with nuclear DNA (nDNA) to jointly promote cell apoptosis. Both in vitro and in vivo results demonstrated that NP(Pt)@AL could effectively reverse the drug resistance and displayed excellent synergistic therapeutic efficacy on platinum-resistant OV with high safety. Therefore, reactivation of the mitochondrial pathway of apoptosis would be a potential strategy to improve the therapeutic effect of Pt-based chemotherapy and even reverse drug resistance.

Long-term outcomes in patients with potential reversible causes of bradycardia

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Hyperkalemia and negative chronotropic drugs are well known causes of reversible bradycardia. Their synergic combination may result in BRASH syndrome (Bradycardia, Renal failure, Atrioventricular blockade, Shock, and Hyperkalemia), a consequence of the vicious cycle between bradycardia, renal failure and worsening hyperkalemia, leading ultimately to multiorgan dysfunction. In potentially reversible bradycardia, drug discontinuation or metabolic correction is recommended before permanent pacemaker (PPM) implantation. Objectives To determine the long-term prognosis in patients with potentially reversible symptomatic bradycardia. Methods We retrospectively reviewed 176 patients who presented to the emergency department with symptomatic bradycardia, between January 2015 and August 2016. Patients without any reversible cause of bradycardia were excluded. Participants were stratified into three groups according to the reversible causes of bradycardia: patients with hyperkalemia, with or without acute renal injury (ARI) (group 1); patients taking negative chronotropic drugs, with or without ARI (group 2); patients with BRASH syndrome (combination of hyperkalemia and negative chronotropic drugs, with or without ARI) (group 3). The primary endpoint was PPM implantation after discharge. Secondary endpoints included: bradycardia-related rehospitalization, heart failure (HF) hospitalization, all-cause mortality and a composite of all the previous endpoints. Results A total of 105 patients were included (52.4% female; mean age 79.8±8.6 years). Group 1 was comprised by 15 patients (14.3%), group 2 by 69 patients (65.7%) and group 3 by 21 patients (20%, figure 1). The incidence of each event is presented in figure 2. During a mean follow-up of 3.2±2.1 years, PPM was implanted in 60 patients (57.1%) – 51 during hospital stay (85%) and 9 after discharge (15%). Across all groups, approximately 50% of the patients needed PPM implantation at some point, without significant differences between groups (p=0.508). Group 3 had the lowest need of in-hospital PPM (38.1%) but the highest bradycardia-related readmissions (9.5%). Nevertheless, post-discharge PPM implantation was still higher in group 1 (33.3%), followed by group 3 (22.2%). There were no significant differences in the post-discharge PPM implantation rate between groups (p=0.76). In groups 1 and 3 the composite endpoint (73.3% and 76.2%, respectively) was significantly more frequent than in group 2 (44.9%, p=0.046 and p=0.012, respectively). Conclusions Nearly half of the patients with an episode of reversible bradycardia needed a PPM at some point. Given the advanced age of most patients with bradycardia secondary to metabolic derangement and/or drug toxicity, it is possible that this unveils underlying conduction system disease, which is likely to recur without PPM implantation.

LncRNA CCAT1 enhances chemoresistance in hepatocellular carcinoma by targeting QKI-5

A major reason for treatment failure of cancer is acquisition of drug resistance. The specific mechanisms underlying hepatocellular carcinoma (HCC) chemoresistance need to be fully elucidated. lncRNAs involve in drug resistance in some cancers, however, the exact functions of lncRNA colon cancer-associated transcript 1 (CCAT1) in oxaliplatin resistance in HCC are still unknown. Our study indicated that CCAT1 promoted HCC proliferation and reduced the apoptosis induced by oxaliplatin. Knockout of CCAT1 could increased chemosensitivity in vitro and in vivo. Further study found that QKI-5 was an important mediator and blocking of QKI-5/p38 MAPK signaling pathway could enhance oxaliplatin sensitivity. In conclusions, CCAT1 promoted proliferation and oxaliplatin resistance via QKI-5/p38 MAPK signaling pathway in HCC. Targeting CCAT1 in combination with chemotherapeutics may be a promising alternative to reverse drug resistance in HCC treatment.

Insights into HIV-1 Reverse Transcriptase (RT) Inhibition and Drug Resistance from Thirty Years of Structural Studies.

The enzyme reverse transcriptase (RT) plays a central role in the life cycle of human immunodeficiency virus (HIV), and RT has been an important drug target. Elucidations of the RT structures trapping and detailing the enzyme at various functional and conformational states by X-ray crystallography have been instrumental for understanding RT activities, inhibition, and drug resistance. The structures have contributed to anti-HIV drug development. Currently, two classes of RT inhibitors are in clinical use. These are nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). However, the error-prone viral replication generates variants that frequently develop resistance to the available drugs, thus warranting a continued effort to seek more effective treatment options. RT also provides multiple additional potential druggable sites. Recently, the use of single-particle cryogenic electron microscopy (cryo-EM) enabled obtaining structures of NNRTI-inhibited HIV-1 RT/dsRNA initiation and RT/dsDNA elongation complexes that were unsuccessful by X-ray crystallography. The cryo-EM platform for the structural study of RT has been established to aid drug design. In this article, we review the roles of structural biology in understanding and targeting HIV RT in the past three decades and the recent structural insights of RT, using cryo-EM.

Effect of MiR-155 Knockout Mediated by Dual sgRNAs on Drug Sensitivity of FLT3-ITD+AML

Two sgRNAs transfected FLT3-ITD+AML cell line MV411 with different binding sites were introduced into CRISPR/cas9 to obtain MV411 cells with miR-155 gene knockout. To compare the efficiency of miR-155 gene knockout by single and double sgRNA transfection and their effects on cell phenotypes. The lentiviral vectors were generated containing either single sgRNA or dual sgRNAs and packaged into lentivirus particles. PCR was conducted to measure gene editing efficiency, and miR-155 expression was evaluated by qPCR. CCK-8 assay was used to evaluate the cell proliferation, and calculate drug sensitivity of cells to adriamycin and quizartinib. Annexin V-APC/7-AAD staining was used to label cell apoptosis induced by adriamycin and quizartinib. In the dual sgRNAs transfected cells, a cleavage band could be observed, meaning the success of gene editing. Compared with the single sgRNA transfected MV411 cells, the expression level of mature miR-155-5p was lower in the dual sgRNA transfected cells. And, dual sgRNA transfected MV411 were more sensitive to adriamycin and quizartinib with lower IC50 and higher apoptosis rate. The inhibition rate of miR-155 gene expression transfected by dual sgRNA is higher than that by single sgRNA. Dual sgRNA transfection can inhibit cell proliferation, reverse drug resistance, and induce apoptosis more significantly. Compared with single sgRNA transfection, dual sgRNA transfection is a highly efficient gene editing scheme.