scholarly journals P11.06 Non epigenetic effect of vorinostat in glioblastoma cells

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii43-iii43
Author(s):  
T Perez ◽  
R Berges ◽  
H Maccario ◽  
D Braguer ◽  
S Honoré
Keyword(s):  
Side Effects ◽  
Low Dose ◽  
Therapeutic Option ◽  
Hdac Inhibitors ◽  
Time Lapse ◽  
Glioblastoma Cells ◽  
Tumor Cell Death ◽  
Alpha Tubulin ◽  
Cellular Models ◽  
Microtubular Cytoskeleton

Abstract BACKGROUND Glioblastoma multiform (GBM) is the most frequent primitive brain tumor. GBM has a high recurrence and mortality. Histone deacetylase (HDAC) inhibitors have evoked great interest because they are able to change transcriptomic profiles to promote tumor cell death but also show undesirable side effects due to the lack of selectivity.We show new properties of low dose vorinostat, which inhibits cytoplasmic HDAC6 and display interesting non-epigenetics effects, especially on the microtubular cytoskeleton. MATERIAL AND METHODS We used murine (GL261) and human (U87 and GBM6 stem cells) cellular models. The cell proliferation was assessed by MTT tests, the migration by the 24 hours Transwell technic and by wound/healing tests. The expression levels of proteins of interest were assessed by Western Blot. Microtubules dynamics were assessed by time-lapse videomicroscopy. The synergy between drugs was tested by Loewe model. RESULTS Vorinostat inhibited the proliferation and the migration of the three cell lines mentioned above at level below the EC50.Vorinostat induces tubulin acetylation and alpha-tubulin c-terminal detyrosination that signed microtubular stabilization and these effects are independent of histone acetylation (HADC3). Interestingly, vorinostat decreases EB1 expression (a bad prognostic factor in GBM) and decreases microtubule dynamics. Moreover, vorinostat decreases neural markers such as GFAP, beta3-tubulin and CNPase and increases mural markers expression such as SMA/EGFR and PDGFR. Finally, it showed a synergy combined with erlotinib. CONCLUSION Low dose vorinostat, which do not affect histone désacetylase, has antitumor effect on glioblastoma cells by a new mechanism involving microtubule cytoskeleton. Interestingly, combination of low doses vorinostatand erlotinibshowed a strong synergy. Low dose, vorinostat could therefore represent an interesting therapeutic option and fewer side effects and that could be used to increased GBM patient sensitivity to erlotinib.

CONTRACEPTION IN DIABETIC PATIENTS

1974 ◽  
Vol 77 (3_Suppl) ◽  
pp. S87-S94 ◽  
Author(s):  
J. Wiese ◽  
M. Osler
Keyword(s):  
Side Effects ◽  
Contraceptive Method ◽  
Low Dose ◽  
Unplanned Pregnancy ◽  
Intrauterine Device ◽  
Diabetic Patients ◽  
Intrauterine Contraception ◽  
Unwanted Pregnancies ◽  
Unreliable Method ◽  
Retrospective Investigation

ABSTRACT A retrospective investigation was made of contraception in diabetic women delivered in our department in 1969 and 1970. Seventy-nine (69 per cent) answered the questionnaires. About one third had found the contraceptive instruction insufficient. A shift from conventional to intrauterine contraception and sterilization was seen, but nearly 25% of the patients were still using conventional methods, mainly the condom. The patients consider this an unreliable method. Thirty-three patients were using intrauterine contraception. Although 10 of them had bleeding irregularities, all were satisfied with the method. Sterilization had been performed on 17 patients, all of whom were fully satisfied and had experienced no side effects. Four of 11 insulin-requiring diabetics, who have used combined oestrogen-progesterone medication have had difficulties in the regulation of the diabetes. Of 24 unwanted pregnancies 12 occurred since the hospitalization in 1969 and 1970. In diabetic women the contraceptive method should either be sterilization, intrauterine device or low dose progestagens, and only in a few cases conventional. A thorough contraceptive instruction as well as a close control of the diabetic women are of importance in order to avoid unplanned pregnancy. The best way to achieve this is by having an out-patient clinic in connection with the obstetrical department to supervise contraception in all diabetic women in the area.

Efficacy and safety of oral dapsone in acne vulgaris – experience of a tertiary care teaching hospital in central Lahore

2020 ◽  
Vol 14 (2) ◽  
pp. 87-90
Author(s):  
Sadaf Amin Chaudhry ◽  
Nadia Ali Zafar ◽  
Rabia Hayat ◽  
Ayesha Noreen ◽  
Gulnaz Ali ◽  
...  
Keyword(s):  
Side Effects ◽  
Therapeutic Option ◽  
Acne Vulgaris ◽  
Treatment Options ◽  
Tertiary Care ◽  
Poor Response ◽  
Global Assessment Scale ◽  
Severe Acne ◽  
Hematologic Profile

Background: Acne is the eighth most prevalent disease affecting 9.4% of the population worldwide and its prevalence in our country is estimated to be around 5%. Severe inflammatory acne is most likely to leave scars and in order to prevent facial disfigurement due to acne scarring, early treatment is desirable. Various treatment options have been formulated for acne, and are tailored according to the severity of the disease. Numerous clinical trials have been conducted till now, to determine the usefulness and side effect profile of such therapies, making acne treatment a highly studied area in dermatology. Objective of this study is to highlight the fact that oral Dapsone could be used as a cheaper alternate to isotretinoin in recalcitrant severe acne, especially in females where retinoids are sometimes contraindicated. Patients and methods: 51 patients, suffering from severe nodulocystic acne, fulfilling the criteria, were enrolled from the Department of Dermatology, Sir Ganga Ram Hospital, Lahore. All the study patients were given oral Dapsone 50mg for initial two weeks and then 100mg daily for the next 10 weeks along with oral cimetidine and topical clindamycin application twice daily. Investigator Global Assessment Scale (IGAS) was employed to measure effectiveness. The treatment was considered ʽeffectiveʹ if the patient achieves 2 or more than 2-grade improvement or almost clear or clear skin at the end of 12 weeks according to IGAS scale. The lesion counts were also done before the start of therapy (day 1) and at every two weeks follow up for 12 weeks. The change in lesion count observed between the baseline number and that seen at follow up visits was also used to evaluate the effectiveness of oral Dapsone. Safety was analyzed by fortnightly visits of the patients to look for any undesirable side effects and monitoring of the hematologic profile of the patients. Final follow up was done at the end of 16 weeks. Results: The study was conducted on 51 patients, with a ratio of 1:3 for males and females and a mean age of 25.2 years (SD ±5.81). At 12th week, patients had significant reduction in their acne lesions; with 7 patients (13.7%) showing completely clear skin, 17 patients (33.3%) had almost clear skin, 5 patients (9.8%) had 3-grade improvement. Twelve patients (23.5%) had 2-grade improvement from baseline score and only 2 patients (3.9%) had 1-grade improvement from baseline. Based on percentage reduction of lesions, excellent response was seen in 32 patients (62.7%), good response in 9 patients (17.6%), moderate response in 2 patients (3.9%), while no patient showed poor response. Dapsone was discontinued in 8 patients due to derangement of hematologic profile. Conclusion: Oral Dapsone, when given carefully, is a very effective therapeutic option in severe recalcitrant acne, with limited side effects.

scholarly journals Targeting the Regulatory Subunit R2Alpha of Protein Kinase A in Human Glioblastoma through shRNA-Expressing Lentiviral Vectors

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1361
Author(s):  
Maira Zorzan ◽  
Claudia Del Vecchio ◽  
Stefania Vogiatzis ◽  
Elisa Saccon ◽  
Cristina Parolin ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Lentiviral Vectors ◽  
Brain Parenchyma ◽  
Regulatory Subunit ◽  
Glioblastoma Cells ◽  
Cellular Models ◽  
Therapeutic Setting ◽  
Promising Target ◽  
Kinase A

Glioblastoma is the most malignant and most common form of brain tumor, still today associated with a poor 14-months median survival from diagnosis. Protein kinase A, particularly its regulatory subunit R2Alpha, presents a typical intracellular distribution in glioblastoma cells compared to the healthy brain parenchyma and this peculiarity might be exploited in a therapeutic setting. In the present study, a third-generation lentiviral system for delivery of shRNA targeting the regulatory subunit R2Alpha of protein kinase A was developed. Generated lentiviral vectors are able to induce an efficient and stable downregulation of R2Alpha in different cellular models, including non-stem and stem-like glioblastoma cells. In addition, our data suggest a potential correlation between silencing of the regulatory subunit of protein kinase A and reduced viability of tumor cells, apparently due to a reduction in replication rate. Thus, our findings support the role of protein kinase A as a promising target for novel anti-glioma therapies.

scholarly journals Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 925
Author(s):  
Eva-Maria Faulhaber ◽  
Tina Jost ◽  
Julia Symank ◽  
Julian Scheper ◽  
Felix Bürkel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Side Effects ◽  
Ionizing Radiation ◽  
Cell Lines ◽  
Normal Tissue ◽  
Kinase Inhibitors ◽  
Induced Response ◽  
Tumor Control ◽  
Tumor Cell Death

(1) Kinase inhibitors (KI) targeting components of the DNA damage repair pathway are a promising new type of drug. Combining them with ionizing radiation therapy (IR), which is commonly used for treatment of head and neck tumors, could improve tumor control, but could also increase negative side effects on surrounding normal tissue. (2) The effect of KI of the DDR (ATMi: AZD0156; ATRi: VE-822, dual DNA-PKi/mTORi: CC-115) in combination with IR on HPV-positive and HPV-negative HNSCC and healthy skin cells was analyzed. Cell death and cell cycle arrest were determined using flow cytometry. Additionally, clonogenic survival and migration were analyzed. (3) Studied HNSCC cell lines reacted differently to DDRi. An increase in cell death for all of the malignant cells could be observed when combining IR and KI. Healthy fibroblasts were not affected by simultaneous treatment. Migration was partially impaired. Influence on the cell cycle varied between the cell lines and inhibitors; (4) In conclusion, a combination of DDRi with IR could be feasible for patients with HNSCC. Side effects on healthy cells are expected to be limited to normal radiation-induced response. Formation of metastases could be decreased because cell migration is impaired partially. The treatment outcome for HPV-negative tumors tends to be improved by combined treatment.

scholarly journals Oral and Palmitate Paliperidone Long-Acting Injectable Formulations use in Schizophrenia Spectrum Disorders: a retrospective cohort study from the CRUPEP First Episode Psychosis Intervention Program

2021 ◽  
Author(s):  
R Segarra ◽  
M Recio-Barbero ◽  
M Sáenz-Herrero ◽  
O Mentxaka ◽  
J Cabezas-Garduño ◽  
...  
Keyword(s):  
Side Effects ◽  
Retrospective Cohort ◽  
Intervention Program ◽  
Therapeutic Option ◽  
Cohort Analysis ◽  
Clinical Information ◽  
First Episode ◽  
Psychotic Episode ◽  
Schizophrenia Spectrum Disorders ◽  
Long Acting

Abstract Background Long-acting injectable antipsychotics (LAIs) may be a suitable therapeutic option for those patients in earlier stages of psychosis to avoid relapses and disease progression. Despite that, there is a lack of evidence in the literature regarding the use of LAIs in this profile of patients. Methods This is a retrospective cohort analysis to assess the efficacy, tolerability, and pattern of use of palmitate paliperidone long-acting injectable (PPLAI) formulations (1-monthly and 3-monthly) compared to oral paliperidone/risperidone in patients with a non-affective First Psychotic Episode(FEP) over a 12-month follow-up. Relevant sociodemographic and clinical information were assessed as well as main clinical scales: Positive and Negative Syndrome Scale (PANSS), Personal and Social Performance Scale (PSP), and Clinical Global Impression Scale (CGI-I and CGI-S). Results Forty-eight patients, 16 per arm, 20-50 year aged with a FEP were included. Significant improvements were registered for all treatment groups. Despite that, patients receiving PPLAI 1-monthly and PPLAI 3-monthly formulations obtained greater improvements than the oral group in the main domains assessed (p<0.001). We found no statistically significant differences in hospitalizations between groups. Side effects were presented in 24% of patients. A trend towards reducing antipsychotic doses was observed in 43.8% of patients to achieve the minimum effective dose and avoid the occurrence of side effects. Conclusions To our knowledge, this is the first study assessing the use of palmitate paliperidone long-acting formulations versus oral risperidone or paliperidone in FEP. Treatment with PPLAI formulations seems to be an effective therapeutic choice at earlier stages of the disease.

scholarly journals Catheter-directed low-dose fibrinolysis infusion for treat acute intermediate-high risk pulmonary embolism

2021 ◽  
Vol 10 (Supplement_1) ◽  
Author(s):  
MM Martin Cabeza ◽  
MJ Garcia Gonzalez ◽  
P Jorge Perez ◽  
A Sanchez-Grande Flecha ◽  
R Munoz Rodriguez ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Pulmonary Hypertension ◽  
High Risk ◽  
Low Dose ◽  
Therapeutic Option ◽  
Bleeding Complications ◽  
Common Disease ◽  
Effective Treatment Option ◽  
Femoral Access ◽  
Rv Function

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND  Intermediate-high risk  (IHR) Pulmonary Embolism (PE) are a common disease witch could have a high mortality. Anticoagulation remains the first therapeutic option, but Catheter-directed therapies are being investigated as a safe and effective treatment option. PURPOSE To evaluate the safety and efficacy of Catheter-directed low-dose fibrinolysis infusion to treat IHR-PE. METHODS Retrospective analysis of 16 patients IHR-PE treated. After performing Right catheterization (RC) and angiogram, Pigtail catheters were located for intrapulmonary infusion of Alteplase 1mg/h/catheter for 24 h (25-30mg/day). Baseline and clinical characteristics, inicial and evolutive echocardiography, also clinical evaluation and echocardiography 6 months after discharge were evaluated.   RESULTS The majority were women (11) and obese (93.8%), aged 22-74 years with cardiovascular risk factors: 5 hypertension, 3 Dyslipidemia, 2 smokers and 3 severe CKD . At admission 11 patients consulted for dyspnea and 5 for syncope; all were hemodynamic stable. 68.8% presented respiratory failure. All had bilateral PE (angiography) and elevation of Nt-proBNP and troponins. The echocardiographic at admission, and its evolution are shown in Table 1.  The invasive measurement of pulmonary hypertension (PH) reflected greater severity than the estimated by echo:  5 (31.3%) Severe PH, 5 (31.3%) Moderate PH and 2 (12.5%) mild PH. At discharge all presented a decrease in PH and 15 (93.8%) improved RV function. 2 patients suffered bleeding complications (relation with femoral access): 1 not severe, 1 severe without mortality; none suffered intracranial hemorrhage. In the evaluation at 6-months: 13 patients (81.3%) where on functional Class I and without PH, 3 patients (18.8%) where in Class II and with mild-PH. CONCLUSION In short-term follow-up, intrapulmonary low-dose fibrinolysis reduces PA pressures and improves RV function, without an increased bleeding complications, especially if femoral access is avoided. However impact on long-term remains unclear. Table 1: Echocardiography evolution.RV function admissionNormal Function1 (6.3%)Mild Dysfunction9 (56.3%)Moderate Dysfunction6 (37.5%)RV Dilatation admissionDilatation 16 (100%)Not dilatation 0 (0%)PH Degree admissionMild PH6 (37.5%)Moderate PH5 (31.3%)Severe PH5 (31.3%)PH Degree 24h-postNot PH1 (6.3%)Mild PH10 (62.5%)Moderate/severe PH5 (31.3%)Improvement RV 24h-postYes14 (87.5%)Not2 (12.5%)RV function dischargeNormal Function16 (100%)Mild Dysfunction0 (0%)Moderate Dysfunction0 (0%)RV Dilatation dischargeDilatation 5 (31.3%)Not dilatation 11 (68.8%)PH Degree dischargeNot PH 9 (56.3%)Mild PH7 (43.8%)Moderate/severe PH0 (0%)RV Right Ventricular; PH: Pulmonary Hypertension,

scholarly journals Low-dose IL-2 therapy limits the reduction in absolute numbers of circulating regulatory T cells in rheumatoid arthritis

2021 ◽  
Vol 13 ◽  
pp. 1759720X2110113
Author(s):  
Sheng-Xiao Zhang ◽  
Jia Wang ◽  
Cai-Hong Wang ◽  
Rui-Huan Jia ◽  
Ming Yan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Side Effects ◽  
Regulatory T Cells ◽  
Disease Activity ◽  
Immune Tolerance ◽  
Low Dose ◽  
Fold Increase ◽  
Plain Language ◽  
T Subsets

Background: Circulating regulatory T cells (Tregs) are responsible for mediating immune tolerance and maintaining immunological homeostasis. Decreases in Tregs may be involved in the onset of rheumatoid arthritis (RA). Low-dose interleukin-2 (IL-2) has been considered for the treatment of inflammatory diseases mediated by T cells. This study focused on the status of circulating CD4+T subsets and the clinical feasibility of IL-2 therapies in patients with RA. Methods: The subjects included 888 patients with RA and 100 healthy controls (HCs); 233 RA patients received IL-2 treatment with 0.5 million international units (MIU)/day from days 1 through 5. The demographic features, disease activity, and levels of CD4+T cells measured by modified flow cytometry were collected in all RA patients before and after treatment. Results: RA patients had lower absolute Treg counts (but not Th17) compared with HCs, which was associated with disease activity; previously treated RA patients had the fewest circulating Tregs ( p < 0.05). Patients treated with low-dose IL-2 had a three-fold increase in absolute anti-inflammatory Treg counts, as well as a two-fold increase in the other CD4+T subsets. Moreover, post-treatment levels of markers of disease activity in RA patients treated with IL-2 were significantly lower than the baseline values ( p < 0.001), with no apparent side effects. Conclusion: Decreased absolute counts of circulating CD4+T lymphocyte subsets were observed in patients with RA. Circulating Tregs, which mediate immune tolerance, may be involved in the pathogenesis and progression of RA; however, this was ameliorated by low-dose IL-2, without obvious side effects. Plain language summary Low-dose IL-2 treatment for rheumatoid arthritis • Circulating Tregs may be involved in the pathogenesis and progression of RA. • The absolute count of Tregs was significantly correlated with disease activity measures. • Low-dose IL-2 was able to effectively expade Tregs and help for RA patients’ symptoms remission without evaluated side effects.

scholarly journals Low dose Mifepristone (100 mg) for medical termination of pregnancy

2011 ◽  
Vol 3 (1) ◽  
Author(s):  
Shikha Seth ◽  
Arun Nagrath ◽  
Neeru Goel
Keyword(s):  
Side Effects ◽  
Success Rate ◽  
Low Dose ◽  
Medical Abortion ◽  
First Trimester ◽  
Effective Regimen ◽  
Minimal Dose ◽  
Medical Termination ◽  
Gestation Age ◽  
Post Abortion

Background: Abortion is the most common entity in the practice of obstetrics and gynaecology. Different methods and modes have been opted for until now to find an effective regimen with the least complications. We have tried the minimal dose (100 mg) of Mifepristone (PO) instead of the presently recommended 200 mg for medical abortion in early first trimester cases. Objectives: The objective of the study was to determine the efficacy of low dose (100 mg) Mifepristone for medical termination of early pregnancy with oral Misoprostol 800 μg, 24 hours later.Design: A prospective analytical study was conducted on a population of 82 early-pregnant patients who have requested medical abortions.Method: Pregnant women of less than 56 days gestation age from their last menstrual period, requesting medical abortion were selected over a period of 14 months from January 2007 to March 2008. They were given 100 mg Mifepristone orally on Day-1, followed by 800 μg Misoprostol orally 24 hours later on Day-2, keeping the patient in the ward for at least 6 hours. Abortion interval, success rate, post-abortion bleeding and side-effects were noted. Success was defined as complete uterine evacuation without the need for surgical intervention.Results: The total success rate of this minimal dose Mifepristone regimen was 96.25%. Pain and nausea were the predominant side-effects noted. In total 72 (90%) women had completely aborted within 5 hours of taking Misoprostol. Three (3.75%) women only required suction aspiration, hence termed as failed medical abortion. The abortion interval increased with the gestation age. All three failures were of the more-than-42-day gestational age group. The overall mean abortion interval was 4.68 ± 5.32 hours.Conclusion: Mifepristone 100 mg, followed 24 hours later by Misoprostol 800 μg orally, is a safe and effective regimen for medical abortion.

Comparison of the Effects of Low Dose Methylprednisolone and Metoclopramide on Nausea and Vomiting and Respiratory Complications after Adenotonsillectomy

2021 ◽  
Vol 15 (9) ◽  
pp. 2753-2756
Author(s):  
Shahid Adalat Chaudhry ◽  
Madiha Zafar ◽  
Usman Zeeshan ◽  
Mubashar Iqbal ◽  
Arooj Fatima ◽  
...  
Keyword(s):  
Side Effects ◽  
Pain Score ◽  
Low Dose ◽  
Operative Time ◽  
Oral Intake ◽  
Respiratory Complications ◽  
Group I ◽  
Male Patients ◽  
Group Ii ◽  
Mean Time

Objective: The aim of this study is to compare the effects of low dose methylprednisolone and metoclopramide on nausea, vomiting and respiratory complications after adenotonsillectomy. Study Design: Retrospective study Place and Duration: The study was conducted in Divisional Headquarter Teaching Hospital, Mirpur AJK for duration of six months from December 2020 to May 2021. Methods: Total 150 patients of both genders underwent adenotonsillectomy presented in this study. Patients were aged between 3-15 years. Detailed demographics of enrolled cases age, sex and weight were recorded after taking informed written consent. Patients were equally divided into two groups. Group I had 75 patients and received 1 mg/kg IV methylpredinosolone and group II received 0.15 mg/kg metoclopramide among 75 patients. Post-operative effects on PONV were assessed and compared among both groups in terms of oral intake time, vomiting episodes, respiratory complications and side effects. Mean pain score was calculated by VAS. Complete data was analyzed by SPSS 23.0 version. Results: There were 40 (53.3%) females and 35 (46.7%) males in group I with mean age 9.43±1.44 years while in group II 42 (56%) were females and 33 (44%) were male patients with mean age 8.04±3.36 years. Mean weight of the patients in group I was 23.08±4.61 kg and in group II mean body weight was 22.11±6.84 kg. Mean operative time in group I was 27.41±8.53 min and in group II mean time was 28.17±6.34 min. Post-operative frequency of vomiting and nausea was lower in group I 14 (18.7%) and 16 (21.3%) as compared to group II 21 (28%) and 24 (34%). Low pain score was found in group I 1.71±6.11 as compared to group II 3.02±4.09. Time to oral intake was higher in group II 2.98±3.48 hours as compared to group I 1.09±7.51 hours. Rate of respiratory complications and side effects were significantly higher in group II. Conclusion: We concluded in this study that the use of methylpredinosolone was effective among patients those underwent for adenotonsillectomy in terms of post-operative frequency of PONV, pain, respiratory complications and side effects. Except this low dose of methylpredinosolone were effective in earlier tolerance of oral intake. Keywords: Adenotonsillectomy, Metoclopramide, Methylpredinosolone, Oral Intake

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