Significant Increase In Survival Time Research Articles

Anlotinib Inhibiting Mantle Cell Lymphoma Proliferation and Inducing Apoptosis through PI3K/AKT/mTOR Pathway.

This study investigates the inhibitory mechanism of anlotinib on human Mantle Cell Lymphoma (MCL) cells through in vitro and in vivo experiments. In vitro cellular experiments validate the effects of anlotinib on MCL cell proliferation and apoptosis. Moreover, a subcutaneous xenograft nude mice model of Mino MCL cells was established to assess the anti-tumour effect and tumour microenvironment regulation of anlotinib in vivo. The results indicate that MCL cell proliferation was significantly inhibited upon anlotinib exposure. The alterations in the expression of apoptosis-related proteins further confirm that anlotinib can induce apoptosis in MCL cells. Additionally, anlotinib significantly reduced the PI3K/Akt/mTOR phosphorylation level in MCL cells. The administration of a PI3K phosphorylation agonist, 740YP, could reverse the inhibitory effect of anlotinib on MCL. In the xenograft mouse model using Mino MCL cells, anlotinib treatment led to a gradual reduction in body weight and a significant increase in survival time compared to the control group. Additionally, anlotinib attenuated PD-1 expression and elevated inflammatory factors, CD4, and CD8 levels in tumour tissues. Anlotinib effectively inhibits proliferation and induces apoptosis in MCL both in vitro and in vivo. This inhibition is likely linked to suppressing phosphorylation in the PI3K/Akt/mTOR pathway.

The Use of Tetrahydrocannabinol Is Associated with an Increase in Survival Time in Palliative Cancer Patients: A Retrospective Multicenter Cohort Study

Introduction: Tetrahydrocannabinol (THC) is often prescribed for ambulatory palliative patients to improve sleep quality and appetite and to reduce anxiety, stress, and pain. However, it is not known if THC has also an effect on the mortality of these patients. Method: The objective was the impact of THC on mortality of ambulatory palliative patients. For this purpose, data from the palliative treatment documentation from 5 ambulatory palliative care teams in Brandenburg, Germany were used for this analysis. Survival time was calculated for 3 groups of patients: (1) without THC; (2) with THC in a low dosage (≤4.7 mg per day); and (3) THC in higher doses (≥4.7 mg per day). The analysis was done for 2 cohorts of patients. Cohort 1: all patients with a survival time of at least 7 days after inclusion in specialized ambulatory palliative care (SAPC) and cohort 2: a subgroup of patients with a survival time between 7 and 100 days. Kaplan-Meier curves were created, and multivariate analysis was done to investigate the impact of THC on mortality. Results: A total of 9,419 patients with a survival time of at least 7 days after inclusion in SAPC were included in the analysis (cohort 1). 7,085 among them had a survival time between 7 and 100 days (cohort 2). In both cohorts, survival time was significantly prolonged by THC, but only when the daily THC dose was above the median of 4.7 mg. Survival time was 15 days longer in cohort 2 (40 vs. 25 days), when more than 4.7 mg THC were prescribed per day. Conclusion: Use of THC is associated with a significant increase in survival time in ambulatory palliative patients which survive longer than 7 days the initiation of THC prescription and which use of THC >4.7 mg/day.

Biogenic selenium nanoparticles: trace element with promising anti-toxoplasma effect

ABSTRACT Toxoplasmosis is an opportunistic infection caused by the coccidian Toxoplasma gondii which represents a food and water contaminant. The available chemotherapeutic agents for toxoplasmosis are limited and the choice is difficult when considering the side effects. Selenium is an essential trace element. It is naturally found in dietary sources, especially seafood, and cereals. Selenium and selenocompounds showed anti-parasitic effects through antioxidant, immunomodulatory, and anti-inflammatory mechanisms. The present study evaluated the potential efficacy of environmentally benign selenium nanoparticles (SeNPs) against acute toxoplasmosis in a mouse model. SeNPs were fabricated by nanobiofactory Streptomyces fulvissimus and characterized by different analytical techniques including, UV-spectrophotometry, transmission electron microscopy, EDX, and XRD. Swiss albino mice were infected with Toxoplasma RH strain in a dose of 3500 tachyzoites in 100 μl saline to induce acute toxoplasmosis. Mice were divided into five groups. Group I: non-infected, non-treated, group II: infected, non-treated, group III: non-infected, treated with SeNPs, group IV: infected, treated with co-trimoxazole (sulfamethoxazole/trimethoprim) and group V: infected, treated with SeNPs. There was a significant increase in survival time in the SeNPs-treated group and minimum parasite count was observed compared to untreated mice in hepatic and splenic impression smears. Scanning electron microscopy showed tachyzoites deformity with multiple depressions and protrusions, while transmission electron microscopy showed excessive vacuolization and lysis of the cytoplasm, especially in the area around the nucleus and the apical complex, together with irregular cell boundary and poorly demarcated cell organelles. The present study demonstrated that the biologically synthesized SeNPs can be a potential natural anti-Toxoplasma agent in vivo.

ANTIOXIDANT AND ANTIDIABETIC EFFECTS OF VERNONIA AMYGDALINA DEL. ETHANOLIC LEAF EXTRACT ON DROSOPHILA MELANOGASTER

Diabetes mellitus (DM) is a significant global public health concern. Vernonia amygdalina Del. is a medicinal herb reported to have multiple biological activities, including antidiabetic properties. This work investigated the in vitro and in vivo antioxidant and antidiabetic properties of Vernonia amygdalina Del. ethanolic leaf extract (VAE). Total phenolic content (TPC) and total flavonoid (TFC) content of VAE were assessed using Folin-Ciocalteu and aluminum chloride colorimetric methods, respectively. The antioxidant activities of VAE were assessed by the DPPH and FRAP methods. The effects of the VAE on the gustatory, toxicity, body weight, and triglycerides were determined in wild-type Drosophila melanogaster. The results showed that VAE had high levels of TPC (57.45±0.45 mg GAE/g DW), TFC 79.55±0.88 mg QE/g DW), and in vitro antioxidant activities (0.11±0.02 mg/mL).VAE exhibited the in vitro inhibitory activities against α-glucosidase and α-amylase with the IC50 values of 267.69±11.51 µg mL-1 and 331.56±26.47 µg mL-1. Treatment with VAE at 5 and 15 mg/mL did not affect the fruit fly survival, indicating that VAE was not toxic to the insects. In D. melanogaster supplemented with 15 mg/mL VAE, significant increases in survival time after exposure to H2O2 and paraquat were observed. VAE also reduced triglyceride levels in fruit flies fed with a high-sugar diet. These findings suggest that VAE, which is derived from natural sources, possesses antioxidant and antidiabetic properties and may also be used as a potential source of bioactive compounds for managing hyperglycemia.

The extent of mediastinal lymph node dissection correlates with survival of small cell lung cancer patients after resection: a propensity score-matched cohort study analysis.

BackgroundEvidence on the importance of lymph node (LN) dissection during resection for small cell lung cancer (SCLC) is scarce. This study sought to investigate the clinical impact of the extent of lymphadenectomy on the survival of patients with SCLC.MethodsPatients who underwent resection for primary SCLC between 2000 and 2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) cancer registry. The patients were stratified based on the number of LNs dissected (0, 1–3, 4–11, and ≥12) via an X-Tile software analysis, and lung cancer-specific survival (LCSS) and overall survival (OS) were compared between these stratified groups using Kaplan-Meier curves. A propensity score-matched analysis and a Cox regression model were used to adjust for potential confounders.ResultsA total of 1,883 patients with SCLC met our criteria and were enrolled in the study. The LCSS and OS analyses revealed that patients who underwent LN dissection during surgery had longer survival times significantly than patients who did not. Similarly, patients who underwent more extensive LN dissection (≥4 LNs) had longer survival times than those who underwent less extensive LN dissection (1–3 LNs). However, no significant increase in survival time was found for patients who underwent the dissection of ≥12 LNs compared to those who underwent the dissection of 4–11 LNs. These results were confirmed in our propensity-matched and Cox regression analyses.ConclusionsOur study revealed that patient survival after surgical resection for SCLC is associated with the number of dissected LNs, and the number of LNs for dissection ranges from 4 to 11 achieve the best survival outcome.

A novel polymeric peptide delivery platform and association with targeted co-delivery of antigens and STING agonists with antitumor immune response.

2564 Background: Use of tumor antigens for the development of patient-specific cancer vaccines has been a promising therapeutic strategy. However, challenges remain in delivering subunit vaccine components in a coordinated fashion to elicit antitumor immune responses. To overcome these, we developed rationally designed vaccines using a novel nanoplatform called the Protein-Like Polymer (PLP), in reference to its globular structure reminiscent of native proteins, with unique characteristics that allow for sustained/targeted delivery of tumor antigens in conjunction with STING agonists. Methods: PLPs containing a model melanoma antigen were synthesized via ring-opening metathesis polymerization (ROMP) and characterized. A library of compounds were generated with different sidechain linkage chemistries (amide, ester, or disulfide), degrees of polymerization, and inclusion/exclusion of Oligo(ethylene glycol) (OEG) side chains. In vitro uptake and functional assays using gp100-specific T Cells were conducted with fluorescently-labeled and non-labeled polymers respectively. In vivo experiments were done using a B16F10 murine melanoma tumor model over-expressing gp100. Ability of PLPs to co-deliver immunomodulatory compounds was tested by electrostatically coupling a small molecule STING agonist 2’3’ cGAMP which formed stable nanostructures. The optimized construct was also tested in an OVA system to prove generalizability. Results: Conjugating peptide antigens using a cleavable disulfide linkage, which reduces intracellularly in antigen presenting cells (APCs), resulted in increased endosomal localization and efficacy. Incorporating a diluent amount of OEG side chains increased resistance to enzymatic degradation while improving bioactivity and uptake by APCs. In vivo studies using PLPs conjugated with gp100 resulted in significant increases in survival time and reduced tumor burden in B16 melanoma. Increasing the DP, and therefore the density of antigen side chains, improved vaccine efficacy and resistance to proteolysis. Mice treated with STING-PLP complexes showed significantly smaller tumors vs control at day 14 (0.038g vs 0.76g; p < 0.0001) and allowed for subcutaneous administration of 2’3’ cGAMP, which otherwise diffuses rapidly away from the injection site. OVA-PLPs behaved similarly in their cognate system but showed no activity when tested on gp100-specific cells and vice versa demonstrating antigen-specificity. Conclusions: This work validates the potential of PLPs to overcome major limitations in cancer vaccine development. The modularity of the platform allows for complex nano-architectures including systems capable of delivering challenging compounds, ie small molecule STING agonists, subcutaneously through electrostatic coupling. This technology has the potential to revolutionize cancer vaccinology.

Current Trends in Advanced Prostate Cancer Medical Setting

Abstract Treatment of advanced and metastatic prostate carcinoma (PCa) is still challenging and changing in the era of personalised medicine. Combination therapies with docetaxel and new anti-hormonal substances lead to improved OS (overall survival) in a broad group of patients with metastatic hormone sensitive prostate carcinoma (mHSPCa). Addition of docetaxel or an androgen receptor targeting agent (ARTA) with abiraterone plus prednisolone, with apalutamide or with enzalutamide leads to a significant improvement in OS and an increase in the time to transition to castration resistance. The choice of therapy sequence in advanced PCa should be based, among other things, on the side-effect profiles of the substances and patient’s preferences. Within metastatic castration resistant prostate carcinoma (mCRPCa) setting, the therapy with abiraterone, enzalutamide, docetaxel, cabazitaxel and radium-223 is approved and indicated in Europe. Respectively, five substances are available, each of which has led to a significant increase in survival time in phase III studies. The optimal therapy sequence in the mCRPCa stage is still unclear. The current trend in personalised medicine in the next decade in therapy, regarding prostate carcinoma, are poly(ADP)-ribose polymerase (PARP) inhibitors, which are and will be available as an effective therapy option for patients with mutations in DNA repair genes. The most important question is when and how patients should be tested for mutations in DNA repair genes and to which line of therapy will PARP inhibitors belong.

Potent anti-tumor activity of CD45RA-targeting Hm3A4-Ranpirnase against myeloid lineage leukemias

ABSTRACT CD45RA is a specific marker for leukemia stem cell (LSC) sub-populations in acute myeloid leukemia (AML). Ranpirnase (Rap), an amphibian RNase, has been extensively investigated in preclinical and clinical studies for its antitumor activity. Rap could be administered repeatedly to patients without inducing an immune response. Reversible renal toxicity has been reported to be dose-limiting. In this study, we generated a novel immunotoxin targeting LSCs: Hm3A4-Rap, which was composed of Rap and Hm3A4, a human-mouse chimeric antibody against CD45RA. This immunotoxin was generated recombinantly by fusing Rap to Hm3A4 at the Fc terminus and then produced by stably transfecting CHO cells. The immunotoxin was purified using Ni-NTA and then evaluated using RT-PCR, SDS-PAGE, antibody titer assays, competitive inhibition assays, and internalization assays. In addition, the purity, molecular integrity, and affinity to the CD45RA antigen were determined. In vitro studies demonstrated that Hm3A4-Rap could efficiently kill target cells. In vivo studies demonstrated that Hm3A4-Rap had potent anti-leukemia activity, with dosed mice showing a significant increase in survival time compared to control mice (P < 0.01). In summary, our immunotoxin had excellent biological activity suggesting its potential therapeutic value for treating AML patients. Additional preclinical and clinical studies are needed to develop this immunotoxin as a treatment option for patients with leukemia.

Effects of physician visit frequency for Parkinson\u2019s disease treatment on mortality, hospitalization, and costs: a retrospective cohort study

BackgroundThe number of patients with Parkinson’s disease among older adults is rapidly increasing. Such patients mostly take medication and require regular physician visits. However, the effect of physician visit frequency for the treatment for Parkinson’s disease has not been evaluated. This study aimed to evaluate the impact of physician visit frequency for Parkinson’s disease treatment on mortality, healthcare days, and healthcare and long-term care costs among older adults.MethodsThis study employed a retrospective cohort design utilizing claims data from the Fukuoka Prefecture Wide-Area Association of Latter-Stage Elderly Healthcare Insurance and Long-Term Care Insurance. Patients aged ≥75 years who were newly diagnosed with Parkinson’s disease in 2014 were included in this study, following the onset of Parkinson’s disease to March 31, 2019. We calculated the restricted mean survival time to evaluate mortality, focusing on the frequency of physician visits for Parkinson’s disease treatment. Inpatient days, outpatient days, and healthcare and long-term care costs per month were calculated using a generalized linear model.ResultsThere were 2224 participants, with 46.5% mortality among those with a higher frequency of physician visits and 56.4% among those with a lower frequency of physician visits. A higher frequency of physician visits was associated with a significant increase in survival time (1.57 months at 24 months and 5.00 months at 60 months) after the onset of Parkinson’s disease and a decrease in inpatient days and healthcare costs compared to a lower frequency of physician visits.ConclusionsA higher frequency of physician visits was significantly associated with longer survival time, fewer inpatient days, and lower healthcare costs. Caregivers should support patients with Parkinson’s disease to visit physicians regularly for their treatment.

Predictive Value of Temporal Muscle Thickness Measurements on Cranial Magnetic Resonance Images in the Prognosis of Patients With Primary Glioblastoma.

Objective: To investigate the predictive value of prognosis of primary GBM patients using TMT on three-dimensional (3D) MR images of the brain.Methods: Data of 130 patients with primary GBM from the TCGA-GBM database were analyzed retrospectively. TMT was measured on the axial plane by multi-planar reformation (MPR) of T1WI MR images perpendicular to the long axis of the temporal muscle at the level of the orbital roof. The axial MR plane was oriented parallel to the anterior commissure-posterior commissure line. Student's t-test or Mann–Whitney U-test was utilized to determine whether there were significant differences in the TMT and OS between male and female patients. The Pearson correlation analysis was adopted to evaluate the correlation between the age at GBM diagnosis and TMT. All patients were divided into two groups based on their median TMT, and the Kaplan–Meier curve was used to calculate the OS curve. The association between TMT and OS of GBM patients, as well as the multivariate analysis of TMT and other clinical factors affecting the survival time, was evaluated with Cox regression model.Results: TMT was a risk factor for the prognosis of GBM with its hazard ratio (HR) of 0.802 (95% CI 0.698–0.922; P = 0.002; Cox regression model). Grouped by median TMT, the group with above-median TMT demonstrated a significant increase in survival time (15.6 months) compared with the one with below-median TMT (11.2 months) (P < 0.001; log-rank test). In the multivariate survival analysis using a Cox regression model, TMT (HR 0.863; 95% CI 0.748–0.996; P = 0.044), age at the diagnosis of GBM (HR 1.042; 95% CI 1.024–1.060; P < 0.001), and concurrent chemoradiotherapy (HR 0.510; 95% CI 0.336–0.775; P = 0.002) were significantly associated with survival time.Conclusion: TMT as an independent predictor is sensitive to the survival prognosis of primary GBM patients, which has potential to predict the survival time.

Research on the predicting power of the revised Tokuhashi system: how much time can surgery give to patients with short life expectancy?

ObjectThe primary treatment option for symptomatic metastatic spinal tumors is surgery. Prognostic systems are designed to assist in the establishment of the indication and the choice of surgical methodology. The best-known prognostic system is the revised Tokuhashi system, which has a predictive ability of about 60%. In our study, we are attempting to find the reason for its poor predictive ability, despite its proper separation ability.MethodsWe have designed a one-center-based retrospective clinical trial, by which we would like to test the feasibility and the inaccuracy of the revised Tokuhashi system. In our database, there are 329 patients who underwent surgery. Statistical analysis was performed.ResultsA significant increase in survival time was observed in the ‘conservative’ category. Earlier studies reported OS 0.15 at the 180-day control time, in contrast with our 0.38 OS value. The literature suggested supportive care for this category, but in our population, every patient underwent surgery. Our population passes the 0.15 OS value on day 475. We propose an adjustment of the Tokuhashi category scores. We observed significant success in resolving pain. Motor functions were improved or stabilized compared to changes in vegetative dysfunction.ConclusionAccording to our results, the Tokuhashi scoring system makes very conservative predictions and prefers non-surgical palliative or supportive care. Surgical treatment increases the life expectancy of patients in poor condition. We propose modifying the therapeutic options of the revised Tokuhashi system, taking into consideration modern spine surgery techniques.

Epidemiologic and Clinicopathologic Features of Advanced Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide as well as in Egypt where it constitutes a significant public health problem. HCC is the third most common cause of death from cancer and chronic infection with HBV and HCV are the most important precursors for HCC development. Objective: To study the epidemiologic, clinical and pathological features of advanced HCC in clinical oncology and Nuclear medicine department, Suez Canal University hospital. Method: This is a retrospective study done to analyse the clinical, demographic and pathological data of advanced HCC patients that attended clinical oncology and Nuclear Medicine Department, Suez Canal University Hospital in the period between January 2013 and December 2016. Results: Results revealed that mean age of the patients was 60.2 ± 7.69, 71.74% male and 28.26% Female, 91.3% were HCV positive while 6.5% were HBV positive. Liver cirrhosis was in 89.13% of patients. Majority of the patients (78.2%) were child Pugh Score B and 21.7% were child Pugh Score C. 67.39% of patients had diabetes. Portal vein thrombosis was present in 50% of cases. Alpha fetoprotein was elevated >400 in 56.52% of cases. Thirty four patients received treatment in the form of chemotherapy while 12 patients did not receive treatment. There is a highly significant increase in survival time P < 0.001 in treated group compared to untreated group. Median survival time (in months) was five months in the treated group versus one month in the untreated group. Conclusion: HCC is one of the increasing major health problems in both developing and developed countries. The most important risk factor is cirrhosis which is mainly due to HCV infection. Thus, much effort should be put into the field of prevention and treatment of viral hepatitis infections and chronic liver disease. Screening programs should be done to get rid of the problem, and most importantly, there must be an acceptable and effective therapy for HCC.

The administration of acetazolamidum for the symptom prophylaxis of an acute mountain sickness when short-term dislocation from middle mountains to highlands takes place

The development of mountain sickness symptoms is one of the limiting factors of successful physical performance in middle mountains and highlands. Among drugs with established effectiveness for the prophylaxis of an acute mountain sickness carbonic anhydrase inhibitor acetazolamidum is also viewed, but at presence there is no universal approach to this issue and drug dosage regimen for its administration have not been elaborated. Aim. А comprehensive analysis of acetazolamidum being administered in the range of effective doses has been carried out. Methods. During the experiment the effect of acetazolamidum on physical performance and resistance of rats to an acute hypobaric hypoxia when administered in the range of effective doses (20, 40 and 80 mg/kg) was studied. During full-scale approbation the effect of acetazolamidum in various dosages on adaptation processes in the course of a rapid dislocation from middle mountains to highlands (glade Azau-the Elbrus mountain) was assessed. Results. The undertaken study showed that the administration of acetazolamidum to rats beginning from a daily dosage 20 mg/kg, that corresponds to human intake of 250 mg of the drug, promotes significant increase of survival time of rats following acute hypoxic exposure as well as growth of an animal performance ability factor under hypoxia. Conclusion. In the course of full-scale approbation it was established that prophylactic intake of acetazolamidum in examined doses prevents the development of symptoms of an acute mountain sickness when rapid dislocation from middle mountains (2300 m) to highlands (5000 m) takes place in the background of physical activity according to the results of sportsmen’s performance of Lake Louise test. (For citation: Vetryakov OV, Bykov VN, Fateev IV, Khalimov YS. The administration of acetazolamidum for the symptom prophylaxis of an acute mountain sickness when short-term dislocation from middle mountains to highlands takes place. Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(2):42-48. doi: 10.17816/RCF16242-48).

Temporal muscle thickness is an independent prognostic marker in melanoma patients with newly diagnosed brain metastases

ObjectivesThe purpose of this study was to evaluate the prognostic relevance of temporal muscle thickness (TMT) in melanoma patients with newly diagnosed brain metastases.MethodsTMT was retrospectively assessed in 146 melanoma patients with newly diagnosed brain metastases on cranial magnetic resonance images. Chart review was used to retrieve clinical parameters, including disease-specific graded prognostic assessment (DS-GPA) and survival times.ResultsPatients with a TMT > median showed a statistically significant increase in survival time (13 months) compared to patients with a TMT < median (5 months; p < 0.001; log rank test). A Cox regression model revealed that the risk of death was increased by 27.9% with every millimeter reduction in TMT. In the multivariate analysis, TMT (HR 0.724; 95% 0.642–0.816; < 0.001) and DS-GPA (HR 1.214; 95% CI 1.023–1.439; p = 0.026) showed a statistically significant correlation with overall survival.ConclusionTMT is an independent predictor of survival in melanoma patients with brain metastases. This parameter may aid in patient selection for clinical trials or to the choice of different treatment options based on the determination of frail patient populations.

PO-133 Hoxa9 transcription factor: a potential novel therapeutic target in renal cell carcinoma (RCC)

IntroductionDysregulation of mRNA translational control in cancer leads to cell transformation, metabolic reprogramming and angiogenesis. eIF6 is an oncogenic translation factor, which regulates the initiation phase of translation acting on 60S availability in the cytoplasm and controlling active 80S complex formation. eIF6 activation is mTORC1-independent and driven by PKCβ mediated phosphorylation on Ser235. An increment of eIF6 expression is reported in several cancer cell lines and human tumours, due to amplification or overexpression. In mice, eIF6 haploinsufficiency blocks Myc-driven lymphomagenesis. Intriguingly, high levels of PKC and eIF6 are found in T-cell lymphomas. In particular, in Anaplastic Large Cell Lymphoma (ALCL) eIF6 is overexpressed and hyperactivated.Material and methodsHere, we aimed to define the role of eIF6 phosphorylation in NPM-ALK mediated T-cell lymphomagenesis, combining multidisciplinary studies on murine and cellular models. We used a conditional eIF6SAKI mouse model in which Ser235 is replaced by an Ala.Results and discussionsFirst, we addressed the effect of eIF6 mutated protein expression in all tissues: homozygosity is lethal after gastrulation while heterozygous mice are viable but resistant to NPM-ALK driven lymphomagenesis. Then, we investigated the role of Ser235 phosphorylation specifically in T-cell lineage, crossing eIF6SAKI mice with CD4-Cre mice. Physiological T-cell development and subsets composition are not affected by the eIF6 mutated protein. In cancer, eIF6SA/SA CD4-Cre NPM-ALK mice have a significant increase in survival time, compared to wt with a delay in the appearance of lymphoma up to 6 months. Histological analysis and ex vivo cultures confirm the delay in disease development. eIF6SA/SA CD4-Cre NPM-ALK thymocytes are smaller respect to wt counterparts and show a striking senescence-like phenotype in vitro. Similarly, in vitro generated eIF6SA/SA MEFs show a markedly reduced proliferation and increased SA β-gal positivity. This phenotype is completely rescued by transducing eIF6 wild-type, but not by eIF6SA. Currently, we are investigating the molecular mechanisms by which eIF6 phosphorylation affects ALK-induced malignancy and whether it may modulate premature cell senescence, thus establishing an effective barrier to T-cell lymphomagenesis.ConclusionOur work demonstrates for the first time that eIF6 phosphorylation plays an essential role in mammals development, cell homeostasis and is rate-limiting for T-cell lymphomagenesis in vivo.

PO-130 SER235 residue drives eIF6 oncogenic activity in NPM-ALK induced T cell lymphomagenesis

Introduction Dysregulation of mRNA translational control in cancer leads to cell transformation, metabolic reprogramming and angiogenesis. eIF6 is an oncogenic translation factor, which regulates the initiation phase of translation acting on 60S availability in the cytoplasm and controlling active 80S complex formation. eIF6 activation is mTORC1-independent and driven by PKCβ mediated phosphorylation on Ser235. An increment of eIF6 expression is reported in several cancer cell lines and human tumours, due to amplification or overexpression. In mice, eIF6 haploinsufficiency blocks Myc-driven lymphomagenesis. Intriguingly, high levels of PKC and eIF6 are found in T-cell lymphomas. In particular, in Anaplastic Large Cell Lymphoma (ALCL) eIF6 is overexpressed and hyperactivated. Material and methods Here, we aimed to define the role of eIF6 phosphorylation in NPM-ALK mediated T-cell lymphomagenesis, combining multidisciplinary studies on murine and cellular models. We used a conditional eIF6 SA KI mouse model in which Ser235 is replaced by an Ala. Results and discussions First, we addressed the effect of eIF6 mutated protein expression in all tissues: homozygosity is lethal after gastrulation while heterozygous mice are viable but resistant to NPM-ALK driven lymphomagenesis. Then, we investigated the role of Ser235 phosphorylation specifically in T-cell lineage, crossing eIF6 SA KI mice with CD4-Cre mice. Physiological T-cell development and subsets composition are not affected by the eIF6 mutated protein. In cancer, eIF6 SA/SA CD4-Cre NPM-ALK mice have a significant increase in survival time, compared to wt with a delay in the appearance of lymphoma up to 6 months. Histological analysis and ex vivo cultures confirm the delay in disease development. eIF6 SA/SA CD4-Cre NPM-ALK thymocytes are smaller respect to wt counterparts and show a striking senescence-like phenotype in vitro . Similarly, in vitro generated eIF6 SA/SA MEFs show a markedly reduced proliferation and increased SA β-gal positivity. This phenotype is completely rescued by transducing eIF6 wild-type, but not by eIF6 SA . Currently, we are investigating the molecular mechanisms by which eIF6 phosphorylation affects ALK-induced malignancy and whether it may modulate premature cell senescence, thus establishing an effective barrier to T-cell lymphomagenesis. Conclusion Our work demonstrates for the first time that eIF6 phosphorylation plays an essential role in mammals development, cell homeostasis and is rate-limiting for T-cell lymphomagenesis in vivo .

Combination drug treatment prolongs survival of experimentally infected mice with silver-haired bat rabies virus

Rabies is a lethal disease in humans and animals, killing approximately 60,000 people every year. Currently, there is no treatment available, except post-exposure prophylaxis (PEP) that can be administered whenever exposure to a rabid animal took place. Here we describe the beneficial effects of a combination treatment initiated at day 4 post infection, containing anti-viral drugs and immune modulators in infected mice. Combination therapy resulted in significant increase in survival time (P < 0.05) and significantly lowers viral RNA in the brain and spinal cord (P < 0.05). Furthermore, treatment influenced markers of pyroptosis and apoptosis and early inflammatory response as measured by the levels of TNF-α. Morphological lesions were absent in rabies virus infected mice with few signs of inflammation. However, these were not significant between the different groups.

Retrospective evaluation of pimobendan and sildenafil therapy for severe pulmonary hypertension due to lung disease and hypoxia in 28 dogs (2007-2013).

Pulmonary hypertension (PH) is the persistent abnormal increase in pulmonary artery (PA) pressure and in dogs is usually secondary to congenital disease causing pulmonary over circulation, chronic respiratory disease and elevated left atrial pressure. Sildenafil (SF) is a phosphodiesterase (PDE) V inhibitor that causes pulmonary artery (PA) vasodilation by increasing pulmonary vascular concentrations of cyclic guanosine monophosphate which subsequently increases the activity of endogenous nitric oxide. Pimobendan (PB) is a PDE III inhibitor with calcium sensitizing effects thereby exerting positive inotropy and vasodilation. The purpose of this retrospective study was to evaluate the long‐term survival of dogs with severe PH treated with SF and PB compared to SF alone. The use of PB in combination with SF did not result in a statistically significant increase in survival times in dogs with pulmonary hypertension secondary to chronic respiratory disease compared to SF alone.

Improved survival in metastatic breast cancer 1985–2016

PurposeIn the last 25 years new treatment options in breast cancer have evolved. We wanted to determine whether the survival of; patients with metastatic breast cancer have improved during this period. MethodsPatients consecutively diagnosed with disseminated breast cancer 1985–2014 in the County of Kalmar, Sweden, were identified and followed to 2016. Survival was calculated for each successive 5 year interval. Separate analyses were performed for pts with ER and/or PR and HER2 positive tumours resp. ResultsMedian survival of the 784 patients increased successively from 13 to 33 months. Five year survival increased from 10 to 27%. Patients with high grade primary tumours had the shortest post recurrence survival time but their median survival increased significantly by time from 12 to 30 months, 3 year survival from 16 to 38% and 5 year from 5 to 20%. Median survival for patients with grade 2 tumours was 2 years and did not improve. Only 47 patients had grade 1 tumours and their median survival of 4 years did not change.Median survival for HER2 positive patients treated before the introduction of trastuzumab in year 2000 was 14 months and after 2000 29 months, 5 year survival improved from 2 to 31%. ConclusionsSurvival in metastatic breast cancer improved 1985–2016. For the first time a significant increase in survival time for patients with metastasis from fast-growing grade 3 tumours was seen. The most striking improvement was achieved in the HER2 positive subset.

Long-term stability of the HR 8799 planetary system without resonant lock

HR 8799 is a star accompanied by four massive planets on wide orbits. The observed planetary configuration has been shown to be unstable on a timescale much shorter than the estimated age of the system (~ 30 Myr) unless the planets are locked into mean motion resonances. This condition is characterised by small-amplitude libration of one or more resonant angles that stabilise the system by preventing close encounters. We simulate planetary systems similar to the HR 8799 planetary system, exploring the parameter space in separation between the orbits, planetary masses and distance from the Sun to the star. We find systems that look like HR 8799 and remain stable for longer than the estimated age of HR 8799. None of our systems are forced into resonances. We find, with nominal masses and in a narrow range of orbit separations, that 5 of 100 systems match the observations and lifetime. Considering a broad range of orbit separations, we find 12 of 900 similar systems. The systems survive significantly longer because of their slightly increased initial orbit separations compared to assuming circular orbits from the observed positions. A small increase in separation leads to a significant increase in survival time. The low eccentricity the orbits develop from gravitational interaction is enough for the planets to match the observations. With lower masses, but still comfortably within the estimated planet mass uncertainty, we find 18 of 100 matching and long-lived systems in a narrow orbital separation range. In the broad separation range, we find 82 of 900 matching systems. Our results imply that the planets in the HR 8799 system do not have to be in strong mean motion resonances.