Breast cancer and oxidative stress

Endocrine and anti-EGFR strategies are used to treat breast cancer. Unfortunately, resistance can be acquired. Deciphering resistance mechanisms remains essential to design treatments for this adverse state. Oxidative stress is the cellular imbalance of pro-oxidants (promoting cell death) and antioxidants (facilitating cell survival and chemotherapy/radiotherapy resistance). However, it remains unexplored whether endocrine or anti-EGFR resistance also associates with altered redox balance. In this project, redox balance was examined using in vitro human resistant breast cancer models TAMR, FASR, X-MCF and NEW DUBS, comparing with responsive w/tMCF7 cells using microarray analysis, PCR, and TAC, ROS, or MTT assays. Pro-oxidant levels increased significantly in all resistant models but this did not impact adversely on growth. Significantly increased antioxidant levels were also observed in all resistant models, perhaps limiting pro-oxidant increases to maintain cell survival. Antioxidants were also significantly induced by antihormones in w/tMCF7 cells that may limit apoptosis with early treatment. Expression of 15 antioxidant genes increased in resistant cells spanning multiple resistant states. While gefitinib challenge revealed many antioxidant genes were EGFR/kinase signalling-regulated in TAMR cells, gefitinib and further signal transduction inhibitors (STIs) indicated total antioxidant capacity was not. Thus, additional genes/signalling probably drive increased antioxidants in resistant cells future deciphering and depletion of antioxidants could feasibly block cell survival in multiple resistant states. Several STIs further increased pro-oxidants in TAMR cells, indicating oxidative stress was also not EGFR/kinase-promoted since STIs also further increased antioxidant capacity, this may again limit pro-oxidant increases and hence apoptotic effect. Importantly, the thesis revealed resistant cells may be particularly sensitive to agents inducing excessive oxidative stress. Redox balance and feasibility of agents influencing redox remains complex. However, new findings and concepts emerging from this thesis are worthy of future exploration for potential treatments for resistance to endocrine/anti-EGFR agents.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Breast cancer and oxidative stress

Endocrine and anti-EGFR strategies are used to treat breast cancer. Unfortunately, resistance can be acquired. Deciphering resistance mechanisms remains essential to design treatments for this adverse state. Oxidative stress is the cellular imbalance of pro-oxidants (promoting cell death) and antioxidants (facilitating cell survival and chemotherapy/radiotherapy resistance). However, it remains unexplored whether endocrine or anti-EGFR resistance also associates with altered redox balance. In this project, redox balance was examined using in vitro human resistant breast cancer models TAMR, FASR, X-MCF and NEW DUBS, comparing with responsive w/tMCF7 cells using microarray analysis, PCR, and TAC, ROS, or MTT assays. Pro-oxidant levels increased significantly in all resistant models but this did not impact adversely on growth. Significantly increased antioxidant levels were also observed in all resistant models, perhaps limiting pro-oxidant increases to maintain cell survival. Antioxidants were also significantly induced by antihormones in w/tMCF7 cells that may limit apoptosis with early treatment. Expression of 15 antioxidant genes increased in resistant cells spanning multiple resistant states. While gefitinib challenge revealed many antioxidant genes were EGFR/kinase signalling-regulated in TAMR cells, gefitinib and further signal transduction inhibitors (STIs) indicated total antioxidant capacity was not. Thus, additional genes/signalling probably drive increased antioxidants in resistant cells future deciphering and depletion of antioxidants could feasibly block cell survival in multiple resistant states. Several STIs further increased pro-oxidants in TAMR cells, indicating oxidative stress was also not EGFR/kinase-promoted since STIs also further increased antioxidant capacity, this may again limit pro-oxidant increases and hence apoptotic effect. Importantly, the thesis revealed resistant cells may be particularly sensitive to agents inducing excessive oxidative stress. Redox balance and feasibility of agents influencing redox remains complex. However, new findings and concepts emerging from this thesis are worthy of future exploration for potential treatments for resistance to endocrine/anti-EGFR agents

Nail as a foreign body in a neonate, an unusual presentation at an unusual age

Children are prone to ingest substances due to their exploratory nature and tendency to put everything in the mouth. Commonly ingested foreign bodies are coins, batteries and buttons. Foreign body ingestion in neonates is a very rare presentation and always needs important consideration as it can be a part of child abuse and can lead to serious life threatening consequence

Association of Serum PSA Levels with Histopathological Pattern of Prostate Lesions

Background: Pathological changes that mainly affect prostate gland are prostatitis, benign prostatic hyperplasia (BPH) and cancerous lesions. Digital rectal examination (DRE), Transrectal Ultrasonography (TUS), and prostate specific antigen (PSA) followed by histopathological examination, are routinely used tests for diagnosis of prostate lesions. The aim of the present study is to determine the role of serum PSA levels in differentially diagnosing the different types of prostate lesions.Material and Methods: This retrospective (observational) study was conducted in Ibn-e-Sina Hospital Multan. Data of 2189 patients who were operated from 2007 to 2017 due to prostatic lesions were included in this analysis. Patients with BPH, prostatitis, prostate carcinoma and Prostatic Intraepithelial Neoplasia (PIN) were grouped according to serum PSA levels (ranging from 0 to >100 ng/ml) into five groups. Frequencies and percentages were calculated for different histopathological findings. Association of PSA levels with different histological patterns was determined with chi-square test with P-value < 0.05 taken as significant difference.Results: Mean age of patients was 62.45+10.64 years. On histopathology, BPH was diagnosed in 1676 (76.56%) patients, prostatitis in 133 (6.07%), carcinoma in 378 (17.26%) and PIN in 02 (0.09%) patients, respectively. Serum PSA levels of 4.01-10 ng/ml were found in 1050 (62.64%) BPH patients and in 59 (44.36%) prostatitis patients. Serum PSA levels of 10.01-20 ng/ml were found in only 40 (2.4%) BPH patients, 47 (35.33%) prostatitis patients, 22 (5.82%) carcinoma patients and in 1 (50.0%) PIN patient. Serum PSA levels of 20.01-100 ng/ml were found in 32 (1.9%) BPH patients, 11 (8.27%) prostatitis patients, 302 (79.89%) carcinoma patients, and in 1 (50.0%) PIN patient. Serum PSA levels of >100 ng/ml were absent in patients with BPH and PIN, and present in 1 (0.75%) prostatitis and 54 (14.28%) carcinoma patients.Conclusion: Benign prostatic hyperplasia was the commonest lesion in our patients (76.56%) with serum PSA levels >10 ng/ml reported in all patients with prostate carcinoma and prostatic intraepithelial neoplasia (PIN) patients

Traumatic Injuries Caused by Fall in the Elderly Referred to the Emergency Department; an Epidemiologic Study

مقدمه: سقوط و صدمات ناشی از آن از مشکلات مهم سالمندان در سراسر جهان محسوب شده و افزایش بار مالی و مراقبتی قابل توجهی را برای سیستم های بهداشتی و درمانی بدنبال دارد. در راستای دستیابی به اطلاعات صحیح جهت برنامه ریزی های پیشگیرانه و یا درمانی دقیق تر، مطالعه حاضر با هدف بررسی اپیدمیولوژیک آسیب های ناشی از سقوط در سالمندان مراجعه کننده به بخش اورژانس طراحی شده است. روش کار: پژوهش حاضر یک مطالعه مقطعی گذشته نگر می باشد که طی سال های 93- 1392 بر روی سالمندان مراجعه کننده بدنبال سقوط به بخش اورژانس، بیمارستان امام رضا، مشهد، ایران، انجام شده است. نمونه گیری به روش سرشماری و شامل تمامی بیماران با سن 60 سال و بالاتر بود. اطلاعات دموگرافیک، ویژگی های حادثه، طول مدت بستری، نوع آسیب و شکستگی، تعداد دفعات مراجعه و پیامد نهایی بیماران با استفاده از آماره توصیفی گزارش گردید. يافته ها: 1033 بیمار با میانگین سنی 07/9 ± 37/73 (دامنه سنی بین60 تا 106سال) در طی مدت دو سال مورد مطالعه قرار گرفتند. از این بین 8/64 درصد زن و بقیه مرد بودند و نسبت جنسی زن به مرد 83/1 بود (5/69 درصد متاهل). میانگین سنی خانم های آسیب دیده (89/8 ± 07/73) تفاوت معنی داری با میانگین سنی مردان آسیب دیده (36/9 ± 92/73) نداشت (156/0=p). بیشتر آسیب دیدگان (6/56 درصد) در گروه سنی 74-60 سال قرار داشتند. وقوع حادثه در فصل تابستان (6/29 درصد) و در ماه شهریور بیشتر از سایر زمان ها بود. متوسط طول مدت بستری 96/6 ± 05/5 روز (دامنه مدت بستری از یک ساعت تا 98 روز) بود. بیشترین تعداد روز بستری به دلیل شکستگی فمور بود. متوسط تعداد مراجعه مجدد در بین زنان (84/0 ± 34/1) و مردان (43/1± 48/1) تفاوت معنی داری نداشت (078/0=p). بررسی مکان های سقوط نشان داد که در 6/73 درصد موارد سقوط از سطح همتراز، 23 درصد سقوط از ارتفاع و 7/2 درصد نیز سقوط اشیاء روی سالمند و بقیه موارد نامشخص بود. 7/65 درصد از زنان سقوط را از سطح همتراز و 9/78 درصد مردان سقوط اشیاء روی سالمند را تجربه نموده بودند (001/0 >p). در بررسی نوع شکستگی به تفکیک جنسیت به ترتیب شکستگی فمور (4/34 درصد)، شکستگی ساعد (34 درصد) و شکستگی شانه (9/8 درصد) در زنان و در مردان به ترتیب شکستگی فمور (3/48 درصد)، شکستگی ساعد (7/13 درصد) و بعد از آن شکستگی ساق (6/10 درصد) شایعترین علل شکستگی بوده اند (001/0 > p). در مجموع 7/2 درصد از موارد سقوط منجر به فوت شده بود. بررسی میانگین سنی بین افراد زنده مانده (97/8 ± 20/73) و فوت شده (50/10 ± 57/97) نشان دهنده تفاوت معنی دار بین این دو گروه بود (001/0 > p). اغلب فوت شدگان در گروه سنی 75-89 سال (50 درصد) و در میان مردان (6/53 درصد) بوده اند. نتيجه گيری: بر اساس یافته های مطالعه حاضر بیشترین موارد سقوط در سالمندان مربوط به خانم های متاهل با متوسط سنی 73 سال، در فصل تابستان (ماه شهریور)، به دنبال سقوط همتراز و بین ساعات 18 -13اتفاق افتاده بود. شایعترین آسیب ناشی از سقوط در سری حاضر شکستگی اندام فوقانی و تحتانی بود و میزان مرگ و میر ناشی از سقوط 7/2 درصد گزارش گردید.Introduction: Falling and its resulting injuries are among the important problems of the elderly all over the world and bring about a considerable rise in financial and care burdens for health care systems. To gain accurate data for prevention or treatment planning, the present study aimed to epidemiologically assess the injuries resulting from falling in elderly patients presenting to emergency department (ED).Methods: The present study is a retrospective cross-sectional study carried out on elderly patients presenting to ED of Imam Reza Hospital, Mashhad, Iran, during 2011 and 2012 following falling. Consecutive sampling was used and patients over the age of 60 were included. Demographic data, accident characteristics, hospitalization duration, type of injury and fracture, frequency of visits and final outcome of the patients were recorded using descriptive statistics. Results: 1033 patients with the mean age of 73.37 ± 9.07 years (range: 60 – 106) were studied during 2 years. 64.8% were female and the female to male ratio was 1.83 (69.5% married). Mean age of the injured women (73.07 ± 8.89) was not significantly different from that of injured men (73.92 ± 9.36) (p = 0.156). Most patients (56.6%) were in the 60-74 years age group. Frequency of accidents was higher in summer (29.6%) and was the highest in September. Mean duration of hospitalization was 5.05 ± 6.96 days (range: 1 hour-98 days). The longest duration of hospitalization was due to femur fraction. Mean frequency of revisits was not significantly different between women (1.34 ± 0.84) and men (1.48 ± 1.43) (p = 0.078). Evaluation of falling locations revealed falling from the same level in 73.6% of cases, falling from a height in 23% of cases, objects falling on the patient in 2.7% of cases and other cases were undefined. 65.7% of females had fallen from the same level and 78.9% of males had experienced falling of objects (p < 0.001). In assessing the type of fracture based on gender, fractures of femur (34.4%), forearm (34%), and shoulder (8.9%) in women and femur (48.3%), forearm (13.7%), and leg (10.6%) in men were the most common types, respectively (p < 0.001). In total, 2.7% of falling cases had led to death. Comparison of mean age between those who survived (73.20 ± 8.97) and those who died (97.57 ± 10.50) showed a significant difference (p < 0.001). Most patients that died were in the 75-89 years age group (50%) and male (53.6%). Conclusion:Based on the results of the present study, the highest frequency of falling in the elderly happened in married women with the mean age of 73 years, in summer (September), following same level falling between 1pm and 6 pm. The most common injury caused by falling in this population was fraction of upper and lower extremities and mortality rate due to falling was 2.7%

Development of an Age-Appropriate Mini Orally Disintegrating Carvedilol Tablet with Paediatric Biopharmaceutical Considerations

Owing to considerable differences observed in anatomy and physiology between paediatric subsets, it has been well established that children respond to drugs differently compared to adults. Furthermore, from a formulation perspective, there is a distinct challenge to develop a dosage form that is capable of safely, accurately, and reliably delivering the dose across the whole paediatric population. Orally disintegrating mini-tablets (ODMT) have widely been considered as an age-appropriate formulation option that possess the ability for adequate dose flexibility, avoids swallowing difficulties, and exhibits superior stability due to its solid state. Within this study, two strengths (0.5 mg and 2 mg) of carvedilol ODMT formulations were developed using an excipient composition and load that is appropriate for paediatric use. The formulations demonstrated adequate mechanical strength (>20 N) and fast disintegration times (<30 s). Dissolution profiles observed were robust and comparable to the marketed conventional tablet formulation across various parts of the gastrointestinal (GI) tract in both the fed and fasted state, signifying appropriate efficacy, quality, and performance. As such, the formulations developed in this study show potential to address the need of an ‘age-appropriate’ formulation of carvedilol, as highlighted by the European Medicines Agency (EMA) Inventory of the Needs for Paediatric Medicine

Response to First Course of Intensified Immunosuppression in Genetically-Stratified Steroid Resistant Nephrotic Syndrome

BACKGROUND AND OBJECTIVES: Intensified immunosuppression in steroid-resistant nephrotic syndrome is broadly applied, with disparate outcomes. This review of patients from the United Kingdom National Study of Nephrotic Syndrome cohort aimed to improve disease stratification by determining, in comprehensively genetically screened patients with steroid-resistant nephrotic syndrome, if there is an association between response to initial intensified immunosuppression and disease progression and/or post-transplant recurrence. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Pediatric patients with steroid-resistant nephrotic syndrome were recruited via the UK National Registry of Rare Kidney Diseases. All patients were whole-genome sequenced, whole-exome sequenced, or steroid-resistant nephrotic syndrome gene-panel sequenced. Complete response or partial response within 6 months of starting intensified immunosuppression was ascertained using laboratory data. Response to intensified immunosuppression and outcomes were analyzed according to genetic testing results, pattern of steroid resistance, and first biopsy findings. RESULTS: Of 271 patients, 178 (92 males, median onset age 4.7 years) received intensified immunosuppression with response available. A total of 4% of patients with monogenic disease showed complete response, compared with 25% of genetic-testing-negative patients (P=0.02). None of the former recurred post-transplantation. In genetic-testing-negative patients, 97% with complete response to first intensified immunosuppression did not progress, whereas 44% of nonresponders developed kidney failure with 73% recurrence post-transplant. Secondary steroid resistance had a higher complete response rate than primary/presumed resistance (43% versus 23%; P=0.001). The highest complete response rate in secondary steroid resistance was to rituximab (64%). Biopsy results showed no correlation with intensified immunosuppression response or outcome. CONCLUSIONS: Patients with monogenic steroid-resistant nephrotic syndrome had a poor therapeutic response and no post-transplant recurrence. In genetic-testing-negative patients, there was an association between response to first intensified immunosuppression and long-term outcome. Patients with complete response rarely progressed to kidney failure, whereas nonresponders had poor kidney survival and a high post-transplant recurrence rate. Patients with secondary steroid resistance were more likely to respond, particularly to rituximab

Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric Use

The rapid onset of action of nifedipine causes a precipitous reduction in blood pressure leading to adverse effects associated with reflex sympathetic nervous system (SNS) activation, including tachycardia and worsening myocardial and cerebrovascular ischemia. As a result, short acting nifedipine preparations are not recommended. However, importantly, there are no modified release preparations of nifedipine authorised for paediatric use, and hence a paucity of clinical studies reporting pharmacokinetics data in paediatrics. Pharmacokinetic parameters may differ significantly between children and adults due to anatomical and physiological differences, often resulting in sub therapeutic and/or toxic plasma concentrations of medication. However, in the field of paediatric pharmacokinetics, the use of pharmacokinetic modelling, particularly physiological-based pharmacokinetics (PBPK), has revolutionised the ability to extrapolate drug pharmacokinetics across age groups, allowing for pragmatic determination of paediatric plasma concentrations to support drug licensing and clinical dosing. In order to pragmatically assess the translation of resultant dissolution profiles to the paediatric populations, virtual clinical trials simulations were conducted. In the context of formulation development, the use of PBPK modelling allowed the determination of optimised formulations that achieved plasma concentrations within the target therapeutic window throughout the dosing strategy. A 5 mg sustained release mini-tablet was successfully developed with the duration of release extending over 24 h and an informed optimised dosing strategy of 450 µg/kg twice daily. The resulting formulation provides flexible dosing opportunities, improves patient adherence by reducing frequent administration burden and enhances patient safety profiles by maintaining efficacious levels of consistent drug plasma levels over a sustained period of time

Association of heat shock protein70-2 (HSP70-2) gene polymorphism with obesity

Peer reviewedPublisher PD