In vivo effects of AZD4547, a novel fibroblast growth factor receptor inhibitor, in a mouse model of endometriosis.

Endometriosis is a chronic disease, characterized by the growth of endometrial-like cells outside the uterine cavity. Due to its complex pathophysiology, a totally resolving cure is yet to be found. The aim of this study was to compare the therapeutic efficacy of AZD4547, a novel fibroblast growth factor receptor inhibitor (FGFRI), with a well-characterized progestin, etonogestrel (ENG) using a validated in vivo mouse model of endometriosis. Endometriosis was induced by transplanting uterine fragments from donor mice in proestrus into the peritoneal cavity of recipient mice, which then developed into cyst-like lesions. AZD4547 and ENG were administered systemically either from the day of endometriosis induction or 2-weeks post-surgery. After 20 days of treatment, the lesions were harvested; their size and weight were measured and analyzed histologically or by qRT-PCR. Stage of estrous cycle was monitored throughout. Compared to vehicle, AZD4547 (25 mg/kg) was most effective in counteracting lesion growth when treating from day of surgery and 2 weeks after; ENG (0.8 mg/kg) was similarly effective in reducing lesion growth but only when administered from day of surgery. Each downregulated FGFR gene expression (p < 0.05). AZD4547 at all doses and ENG (0.008 mg/kg) caused no disturbance to the estrous cycle. ENG at 0.08 and 0.8 mg/kg was associated with partial or complete estrous cycle disruption and hyperemia of the uteri. AZD4547 and ENG both attenuated endometriotic lesion size, but only AZD4547 did not disrupt the estrous cycle, suggesting that targeting of FGFR is worthy of further investigation as a novel treatment for endometriosis.

Ferroptosis and Photodynamic Therapy Synergism: Enhancing Anticancer Treatment.

Photodynamic therapy (PDT) is widely used in cancer treatment; however, several challenges compromise its efficiency. We propose a synergistic action between PDT and ferroptotic cell death. PDT acts as a source of reactive oxygen species for the Fenton reaction, which may reinforce ferroptosis induction and increase PDT efficacy in anticancer therapy.

Dolutegravir and pregnancy outcomes in women on antiretroviral therapy in Brazil: a retrospective national cohort study.

BACKGROUND: Dolutegravir has been widely available in Brazil since 2017. Following the signal that infants born to women with dolutegravir exposure at conception in Botswana had a higher risk of neural tube defects (NTDs), public health leaders initiated a national investigation to evaluate periconception dolutegravir exposure among all pregnant Brazilian women with HIV and its potential association with risk of NTDs, stillbirth, or miscarriage before 22 weeks (also called spontaneous abortion). METHODS: In this retrospective, observational, national, cohort study, we identified all women with pregnancies and possible dolutegravir exposure within 8 weeks of estimated date of conception between Jan 1, 2017, and May 31, 2018, and approximately 3:1 matched pregnant women exposed to efavirenz between Jan 1, 2015, and May 31, 2018, using the Brazilian antiretroviral therapy database. We did detailed chart reviews for identified women. The primary outcomes were NTD and a composite measure of NTD, stillbirth, or miscarriage. NTD incidences were calculated with 95% CI. The composite outcome was examined with logistic regression using propensity score matching weights to balance confounders. FINDINGS: Of 1427 included women, 382 were exposed to dolutegravir within 8 weeks of estimated date of conception. During pregnancy, 183 (48%) of 382 dolutegravir-exposed and 465 (44%) of 1045 efavirenz-exposed women received folic acid supplementation. There were 1452 birth outcomes. There were no NTDs in either dolutegravir-exposed (0, 95% CI 0-0·0010) or efavirenz-exposed groups (0, 95% CI 0-0·0036). There were 23 (6%) stillbirths or miscarriages in 384 dolutegravir-exposed fetuses and 28 (3%) in the 1068 efavirenz-exposed fetuses (p=0·0037). Logistic regression models did not consistently indicate an association between dolutegravir exposure and risk of stillbirths or miscarriages. After study closure, two confirmed NTD outcomes in fetuses with periconception dolutegravir exposure were reported to public health officials. An updated estimate of NTD incidence incorporating these cases and the estimated number of additional dolutegravir-exposed pregnancies between Jan 1, 2015 and Feb 28, 2019, is 0·0018 (95% CI 0·0005-0·0067). INTERPRETATION: Neither dolutegravir nor efavirenz exposure was associated with NTDs in our national cohort; incidence of NTDs is probably well under 1% in dolutegravir-exposed HIV-positive women but still slightly above HIV-uninfected women (0·06%) in Brazil. FUNDING: The Brazilian Ministry of Health and the United States' National Institutes of Health.

Etoposide and olaparib polymer-coated nanoparticles within a bioadhesive sprayable hydrogel for post-surgical localised delivery to brain tumours.

Glioblastoma is a malignant brain tumour with a median survival of 14.6 months from diagnosis. Despite maximal surgical resection and concurrent chemoradiotherapy, reoccurrence is inevitable. To try combating the disease at a stage of low residual tumour burden immediately post-surgery, we propose a localised drug delivery system comprising of a spray device, bioadhesive hydrogel (pectin) and drug nanocrystals coated with polylactic acid-polyethylene glycol (NCPPs), to be administered directly into brain parenchyma adjacent to the surgical cavity. We have repurposed pectin for use within the brain, showing in vitro and in vivo biocompatibility, bio-adhesion to mammalian brain and gelling at physiological brain calcium concentrations. Etoposide and olaparib NCPPs with high drug loading have shown in vitro stability and drug release over 120 h. Pluronic F127 stabilised NCPPs to ensure successful spraying, as determined by dynamic light scattering and transmission electron microscopy. Successful delivery of Cy5-labelled NCPPs was demonstrated in a large ex vivo mammalian brain, with NCPP present in the tissue surrounding the resection cavity. Our data collectively demonstrates the pre-clinical development of a novel localised delivery device based on a sprayable hydrogel containing therapeutic NCPPs, amenable for translation to intracranial surgical resection models for the treatment of malignant brain tumours.

Fasting-mimicking diet and hormone therapy induce breast cancer regression.

Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.

Management of epistaxis in patients on novel oral anticoagulation therapy.

BACKGROUND: Individuals on anticoagulation therapy are at increased risk of bleeding, including epistaxis. There is a lack of available reversal agents for novel oral anticoagulation therapy. OBJECTIVE: This paper reviews the current literature on epistaxis in the context of novel oral anticoagulation use, in order to recommend guidelines on management. METHOD: A comprehensive search of published literature was conducted to identify all relevant articles published up to April 2019. RESULTS: Patients on oral anticoagulation therapy are over-represented in individuals with epistaxis. Those on novel oral anticoagulation therapy were more likely to relapse compared to patients on classic oral anticoagulants or non-anticoagulated patients. Idarucizumab is an effective antidote for bleeding associated with dabigatran use. Recommendations for epistaxis management in patients on novel oral anticoagulation therapy are outlined. CONCLUSION: Clinicians need to be aware of the potential severity of epistaxis and the increased likelihood of recurrence. High-quality studies are required to determine the efficacy and safety of andexanet alfa and ciraparantag, as well as non-specific reversal agents.

Successful use of once-daily high-dose darunavir and dolutegravir in multidrug-resistant HIV.

WHAT IS KNOWN AND OBJECTIVE?: Antiretroviral (ARV) resistance may result during periods of consistently poor adherence. We report the successful use of a novel once-daily (QD) ARV regimen in a patient with multidrug-resistant (MDR) HIV. CASE SUMMARY: Once-daily darunavir 1200 mg/ritonavir 100 mg, dolutegravir and emtricitabine/tenofovir alafenamide was initiated with directly observed therapy. With the assistance of therapeutic drug monitoring, dolutegravir dosing was increased to 150 mg daily. The patient maintained virologic suppression for 18 months. WHAT IS NEW AND CONCLUSIONS?: In this case, QD darunavir/ritonavir achieved similar trough concentrations to twice daily dosing with dolutegravir dose titration necessitated and resulted in HIV virologic control.

Electropharmacological effects of intracellular Ca2+ handling modulator caldaret on the heart assessed in the halothane-anesthetized dogs.

We analyzed how the enhancement of net sarcoplasmic reticulum (SR) Ca2+ uptake may affect cardiac electrophysiological properties in vivo by using caldaret which can decrease SR diastolic Ca2+ leak, enhance SR Ca2+ reuptake and inhibit reverse-mode Na+/Ca2+ exchanger. Caldaret in doses of 0.5, 5 and 50 µg/kg was intravenously administered over 10 min to the halothane-anesthetized beagle dogs (n = 5), attaining pharmacologically active plasma concentration. The low and middle doses of caldaret increased the ventricular contraction, which could be explained by its on-target pharmacological activities. The high dose enhanced the sinus automaticity followed by its suppression in addition to the increase of the total peripheral resistance, which may be unfavorable for treating diastolic heart failure. The low and middle doses enhanced the atrioventricular conduction, which may have some potential for predisposing the atria to the onset of atrial fibrillation via an induction of mitral and/or tricuspid regurgitation. The middle and high doses of caldaret prolonged the ventricular effective refractory period without altering the intraventricular conduction or repolarization period, which may prevent the onset of ventricular arrhythmias. Thus, modulation of intracellular Ca2+ handling by caldaret can induce not only inotropic effect, but also various electrophysiological actions on the in situ heart.

Discovery and optimization of novel piperazines as potent inhibitors of fatty acid synthase (FASN).

The discovery, structure-activity relationships, and optimization of a novel class of fatty acid synthase (FASN) inhibitors is reported. High throughput screening identified a series of substituted piperazines with structural features that enable interactions with many of the potency-driving regions of the FASN KR domain binding site. Derived from this series was FT113, a compound with potent biochemical and cellular activity, which translated into excellent activity in in vivo models.

The preclinical discovery and development of cariprazine for the treatment of schizophrenia.

INTRODUCTION: Cariprazine is approved in the United States and Europe for the treatment of manic or mixed episodes associated with bipolar I disorder and for the treatment of schizophrenia in adult patients. It is typically administered orally once a day (a dose range 1.5 - 6 mg/day), does require titration, and may be given with or without food. It has a half-life of 2 - 4 days with an active metabolite that has a terminal half-life of 2 - 3 weeks. Areas covered: This review article focuses on the preclinical discovery of cariprazine providing details regarding its pharmacological, behavioral, and neurochemical mechanisms and its contribution to clinical therapeutic benefits. This article is based on the available literature with respect to the preclinical and clinical findings and product labels of cariprazine. Expert opinion: Cariprazine shows highest affinity toward D3 receptors, followed by D2, 5-HT2B, and 5-HT1A receptors. It also shows moderate affinity toward σ1, 5-HT2A, and histamine H1 receptors. Long-term administration of cariprazine altered the abundance of dopamine, serotonin, and glutamate receptor subtypes in different brain regions. All these mechanisms of cariprazine may contribute toward its unique preclinical profile and its clinically observed benefits in the treatment of schizophrenia, bipolar mania, and possibly other psychiatric disorders.

Physicochemical, pharmacokinetic, efficacy and toxicity profiling of a potential nitrofuranyl methyl piperazine derivative IIIM-MCD-211 for oral tuberculosis therapy via in-silico-in-vitro-in-vivo approach.

Recent tuberculosis (TB) drug discovery programme involve continuous pursuit for new chemical entity (NCE) which can be not only effective against both susceptible and resistant strains of Mycobacterium tuberculosis (Mtb) but also safe and faster acting with the target, thereby shortening the prolonged TB treatments. We have identified a potential nitrofuranyl methyl piperazine derivative, IIIM-MCD-211 as new antitubercular agent with minimum inhibitory concentration (MIC) value of 0.0072 µM against H37Rv strain. Objective of the present study is to investigate physicochemical, pharmacokinetic, efficacy and toxicity profile using in-silico, in-vitro and in-vivo model in comprehensive manner to assess the likelihood of developing IIIM-MCD-211 as a clinical candidate. Results of computational prediction reveal that compound does not violate Lipinski's, Veber's and Jorgensen's rule linked with drug like properties and oral bioavailability. Experimentally, IIIM-MCD-211 exhibits excellent lipophilicity that is optimal for oral administration. IIIM-MCD-211 displays evidence of P-glycoprotein (P-gp) induction but no inhibition ability in rhodamine cell exclusion assay. IIIM-MCD-211 shows high permeability and plasma protein binding based on parallel artificial membrane permeability assay (PAMPA) and rapid equilibrium dialysis (RED) assay model, respectively. IIIM-MCD-211 has adequate metabolic stability in rat liver microsomes (RLM) and favourable pharmacokinetics with admirable correlation during dose escalation study in Swiss mice. IIIM-MCD-211 has capability to appear into highly perfusable tissues. IIIM-MCD-211 is able to actively prevent progression of TB infection in chronic infection mice model. IIIM-MCD-211 shows no substantial cytotoxicity in HepG2 cell line. In acute toxicity study, significant increase of total white blood cell (WBC) count in treatment group as compared to control group is observed. Overall, amenable preclinical data make IIIM-MCD-211 ideal candidate for further development of oral anti-TB agent.

Prospective study to compare antibiosis versus the association of N-acetylcysteine, D-mannose and Morinda citrifolia fruit extract in preventing urinary tract infections in patients submitted to urodynamic investigation.

BACKGROUND: The abuse of antimicrobical drugs has increased the resistance of microorganisms to treatments, thus to make urinary tract infections (UTIs) more difficult to eradicate. Among natural substances used to prevent UTI, literature has provided preliminary data of the beneficial effects of D-mannose, N-acetylcysteine, and Morinda citrifolia fruit extract, due to their complementary mechanism of action which contributes respectively to limit bacteria adhesion to the urothelium, to destroy bacterial pathogenic biofilm, and to the anti-inflammatory and analgesic activity. The purpose of this study was to compare the administration of an association of D-mannose, N-acetylcysteine (NAC) and Morinda citrifolia extract versus antibiotic therapy in the prophylaxis of UTIs potentially associated with urological mini-invasive diagnostics procedures, in clinical model of the urodynamic investigation. METHODS: 80 patients eligible for urodynamic examination, 42 men and 38 women, have been prospectively enrolled in the study and randomised in two groups (A and B) of 40 individuals. Patients of group A followed antibiotic therapy with Prulifloxacine, by mouth 400 mg/day for 5 days, while patients of the group B followed the association of mannose and NAC therapy, two vials/day for 7 days. Ten days after the urodynamic study, the patients were submitted to urine examination and urine culture. RESULTS: The follow up assessment didn't show statistical significant difference between the two groups regarding the incidence of UTI. CONCLUSIONS: The association of mannose and NAC therapy resulted similar to the antibiotic therapy in preventing UTIs in patients submitted to urodynamic examination. This result leads to consider the possible use of these nutraceutical agents as a good alternative in the prophylaxis of the UTI afterwards urological procedures in urodynamics.

Acute dosing of vortioxetine strengthens event-related brain activity associated with engagement of attention and cognitive functioning in rats.

Studies of the antidepressant vortioxetine have demonstrated beneficial effects on cognitive dysfunction associated with depression. To elucidate how vortioxetine modulates neuronal activity during cognitive processing we investigated the effects of vortioxetine (3 and 10mg/kg) in rats performing an auditory oddball (deviant target) task. We investigated neuronal activity in target vs non-target tone responses in vehicle-treated animals using electroencephalographic (EEG) recordings. Furthermore, we characterized task performance and EEG changes in target tone responses of vortioxetine vs controls. Quantification of event-related potentials (ERPs) was supplemented by analyses of spectral power and inter-trial phase-locking. The assessed brain regions included prelimbic cortex, the hippocampus, and thalamus. As compared to correct rejection of non-target tones, correct target tone responses elicited increased EEG power in all regions. Additionally, neuronal synchronization was increased in vehicle-treated rats during both early and late ERP responses to target tones. This indicates a significant consistency of local phases across trials during high attentional load. During early sensory processing, vortioxetine increased both thalamic and frontal synchronized gamma band activity and EEG power in all brain regions measured. Finally, vortioxetine increased the amplitude of late hippocampal P3-like ERPs, the rodent correlate of the human P300 ERP. These findings suggest differential effects of vortioxetine during early sensory registration and late endogenous processing of auditory discrimination. Strengthened P3-like ERP response may relate to the pro-cognitive profile of vortioxetine in rodents. Further investigations are warranted to explore the mechanism by which vortioxetine increases network synchronization during attentive and cognitive processing.

Neuroprotective strategies for patients with acute myocardial infarction combined with hypoxic ischemic encephalopathy in the ICU.

BACKGROUND: We investigated neuroprotective treatment strategies for patients with acute myocardial infarction (AMI) complicated with hypoxic ischemic encephalopathy (HIE) in the ICU. METHODS: The 83 cases diagnosed with secondary AMI were, for the first time, divided into an observation group (n = 43) and control group (n = 40). All of the patients underwent emergency or elective PCI. Patients in the control group were treated with mannitol to reduce intracranial pressure and cinepazide maleate to improve microcirculation in the brain as well as given a comprehensive treatment with oxygen inhalation, fluid infusion, acid-base imbalance correction and electrolyte disturbance. Patients in the observation group underwent conventional treatment combined with neuroprotective therapeutic strategies. The effects of the different treatment strategies were compared. RESULTS: Consciousness recovery time, reflex recovery time, muscle tension recovery time and duration of ICU stay were significantly shorter in the observation group compared with the control group (P < 0.05). After treatment, the jugular vein oxygen saturation (SjvO2) and blood lactate (JB-LA) levels of both groups were lower than before treatment and the cerebral oxygen utilization rate (O2UC) increased, with a significantly higher increase in the observation group (P < 0.05). After treatment, the activities of daily living (ADL) score was higher for both groups and the neural function defect (NIHS) score was lower. CONCLUSION: The neuroprotective strategies of hypothermia and ganglioside administration assisted with hyperbaric oxygen was effective for treating AMI patients with HIE and may be worth clinical promotion.

Idarucizumab and factor Xa reversal agents: role in hospital guidelines and protocols.

As expected with all antithrombotic agents, there is a risk of bleeding complications in patients receiving direct oral anticoagulants (DOACs) because of the DOAC itself, acute trauma, invasive procedures, or underlying comorbidities. For many bleeding events, a prudent course of action will be to withdraw the DOAC, then "wait and support" the patient, with the expectation that the bleeding event should resolve with time. Likewise, DOAC therapy may be interrupted ahead of a planned procedure, the stopping time being dependent on the agent involved and the patient's renal function. However, urgent reversal of anticoagulation is required in patients with serious or life-threatening bleeding or in those requiring urgent surgery or procedures. Novel specific reversal agents, either under development or recently approved, will need to be incorporated into local anticoagulation reversal protocols. For dabigatran-treated patients, idarucizumab recently has been approved for clinical use in cases of life-threatening or uncontrolled bleeding or when patients require emergency surgery or urgent procedures, both associated with a high risk of bleeding. As clinical experience with individual specific reversal agents grows, their roles in managing major bleeding events in DOAC-treated patients will become better defined. Future research, as well as ongoing use of idarucizumab, should help establish when it is appropriate to re-dose with idarucizumab, coadminister with prothrombin complex concentrates, or re-initiate DOAC after idarucizumab use. Ongoing trials should help identify the appropriate doses and expected durations of effect for andexanet alfa and ciraparantag, which are likely to vary depending on the individual oral anticoagulants.

A single dose of vortioxetine, but not ketamine or fluoxetine, increases plasticity-related gene expression in the rat frontal cortex.

Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that has been shown to induce a rapid antidepressant effect in treatment-resistant patients. Vortioxetine is a multimodal-acting antidepressant that exert its therapeutic activity through serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibition and modulation of several 5-HT receptors. In clinical trials, vortioxetine improves depression symptoms and cognitive dysfunction. Neuroplasticity as well as serotonergic and glutamatergic signaling attain significant roles in depression pathophysiology and antidepressant responses. Here, we investigate the effects of ketamine and vortioxetine on gene expression related to serotonergic and glutamatergic neurotransmission as well as neuroplasticity and compare them to those of the selective serotonin reuptake inhibitor fluoxetine. Rats were injected with fluoxetine (10mg/kg), ketamine (15mg/kg), or vortioxetine (10mg/kg) at 2, 8, 12, or 27h prior to harvesting of the frontal cortex and hippocampus. mRNA levels were measured by real-time quantitative polymerase chain reaction (qPCR). The main finding was that vortioxetine enhanced plasticity-related gene expression (Mtor, Mglur1, Pkcα, Homer3, Spinophilin, and Synapsin3) in the frontal cortex at 8h after a single dose. Ingenuity pathway analysis of this subset of data identified a biological network that was engaged by vortioxetine and is plausibly associated with neuroplasticity. Transcript levels had returned to baseline levels 12h after injection. Only minor effects on gene expression were found for ketamine or fluoxetine. In conclusion, acute vortioxetine, but not fluoxetine or ketamine, transiently increased plasticity-related gene expression in the frontal cortex. These effects may be ascribed to the direct 5-HT receptor activities of vortioxetine.

Palbociclib: A new hope in the treatment of breast cancer.

Breast cancer being one of the common cancers has high morbidity and mortality. Despite the conventional treatment, the burden of the disease increases year after year. There is a need for newer drugs that target the different mechanisms in the pathogenesis. The interaction of cyclins with cyclin dependent kinases (CDKs) plays a major role in the abnormal cell cycle in cancer and it is considered to be an important target. Palbociclib is a CDK inhibitor currently approved for the treatment of breast cancer. The preclinical studies with breast cancer lines were sensitive to palbociclib and the clinical trials phase I, phase II (PALOMA 1), and phase III (PALOMA 2, 3, PENTELOPE, PEARL) showed that the drug was efficacious when combined other conventional drugs for breast cancer. Palbociclib was also been tested in various other germ cell tumors, melanoma, multiple myeloma, glioblastoma multiforme etc., The major adverse effect of the drug includes hematological toxicity mainly neutropenia, gastrointestinal adverse effects.

Cell cycle regulation therapy combined with cytokine blockade enhances antiarthritic effects without increasing immune suppression.

OBJECTIVE: Biological disease-modifying antirheumatic drugs (DMARDs) that inhibit aberrant immune reactions in rheumatoid arthritis (RA) cannot induce complete remission in all patients. Combination therapies using two biological DMARDs have failed to exert additive effects and increased serious infections. We have found that cell cycle inhibition of synovial fibroblasts with cyclin-dependent kinase (CDK) inhibitors ameliorated the disease in animal models of RA without attenuating acquired immunity. The objective of this study was to determine whether a clinically well-tolerated selective CDK 4/6 inhibitor (CDKI), palbociclib, is effective and whether combination with cytokine blockers acts additively without enhancing immune suppression. METHODS: The effects of CDKI on haematopoiesis and physical and behavioural findings in mice were evaluated. Mice with collagen-induced arthritis (CIA) were treated with CDKI, etanercept or anti-interleukin (IL)-6 receptor antibody (MR16-1) alone or with a combination of CDKI with etanercept or MR16-1. Their clinical, histological and radiographic scores, serum anti-(type II collagen (CII)) antibody levels and proliferative responses of lymph node cells to CII were determined. RESULTS: Although CDKI induced marginal myelosuppression, it was well tolerated and ameliorated CIA dose-dependently. The combinations of low-dose CDKI and either tumour necrosis factor-α or IL-6 blocker enhanced the antiarthritic effects additively. The addition of CDKI to either cytokine blocker did not affect the levels of anti-CII antibodies and proliferative responses of lymphocytes to CII. CONCLUSIONS: A clinically well-tolerated CDK4/6 inhibitor exerted antiarthritic effects in this mouse model. By combining therapeutic agents targeting immune reaction and synovial proliferation, we have demonstrated for the first time that two molecular targeting treatments act additively and may not increase immune suppression.

A high-throughput small molecule screen identifies synergism between DNA methylation and Aurora kinase pathways for X reactivation.

X-chromosome inactivation is a mechanism of dosage compensation in which one of the two X chromosomes in female mammals is transcriptionally silenced. Once established, silencing of the inactive X (Xi) is robust and difficult to reverse pharmacologically. However, the Xi is a reservoir of >1,000 functional genes that could be potentially tapped to treat X-linked disease. To identify compounds that could reactivate the Xi, here we screened ∼367,000 small molecules in an automated high-content screen using an Xi-linked GFP reporter in mouse fibroblasts. Given the robust nature of silencing, we sensitized the screen by "priming" cells with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5azadC). Compounds that elicited GFP activity include VX680, MLN8237, and 5azadC, which are known to target the Aurora kinase and DNA methylation pathways. We demonstrate that the combinations of VX680 and 5azadC, as well as MLN8237 and 5azadC, synergistically up-regulate genes on the Xi. Thus, our work identifies a synergism between the DNA methylation and Aurora kinase pathways as being one of interest for possible pharmacological reactivation of the Xi.

American Psychiatric Association - 168th Annual Meeting (May 16-20, 2015 - Toronto, Canada).

The theme of this year's American Psychiatric Association (APA) meeting was 'Psychiatry: integrating body and mind, heart and soul', with special focus given to advances in basic and cognitive neuroscience and how these may contribute to integrated care of mental health and illness. The program featured numerous tracks and subtracks in areas of interest such as addiction psychiatry, child, adolescent and geriatric psychiatry, and psychosomatic medicine.