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HER2+ meme kanseri hücrelerinde pan-her inhibitörü dacomitinib'e hücre ölümü cevabının AVEN tarafından düzenlenmesi
Get PDFMeme kanseri kadınlarda en sık görülen kanser tipidir ve geliştirilen yenilikçi tanı ve
tedavi stratejilerine rağmen mortalite oranları halen yüksek seyretmektedir. Bu
durumun en önemli nedenlerinden birisi hastanın tedavisinin başlangıcında varolan ya
da tedavi sırasında ortaya çıkan terapi direncidir. HER reseptör ailesinin üyelerinin
mutasyon ya da amplifikasyon ile aşırı aktif hale gelmesi birçok meme kanseri tipinde
malign değişikliklerin nedenidir. HER2 amplifikasyonu meme kanseri hastalarının
yaklaşık yüzde 20’sinde görülmektedir ve kötü prognozla ilişkilidir. Trastuzumab ve
lapatinib gibi hedeflenmiş terapiler her ne kadar bu tümörlerde etkinlik gösterseler de
terapi direnci önemli bir sorun olarak karşımıza çıkmaktadır. Bu nedenle tüm HER
ailesi üyelerini eşzamanlı olarak hedefleyen panHER inhibitörleri (neratinib,
dacomitinib, afatinib) geliştirilmiştir. Mitokondriyal apoptotik yolak gerek
konvansiyonel gerekse hedeflenmiş terapilerin kanser hücreleri üzerindeki öncelikli
etki yollarındandır. Mitokondriyal apoptotik yolak BCL-2 protein ailesi tarafından
düzenlenir. BAX ve BAK proteinlerinin aktivatör BH3 proteinleri tarafından aktive
edilmesi, mitokondriyal dış membran geçirgenliğinin artışı, sitokrom c’nin sitozole
geçişi ve kaspaz aktivasyonu mitokondriyal apoptotik yolağın ana basamaklarıdır.
AVEN, mitokondriyal apoptoz yolağının ve DNA hasar yanıtının düzenlenmesinde
kritik rol oynayan sitozolik bir proteindir. BCL-xL proteinin anti-apoptotik aktivitesini
destekleyerek ve Apaf-1 proteinin oligomerizasyonunu engelleyerek apoptoz yanıtnı
inhibe etmektedir. Dahası sahip olduğu sinyal dizisi sayesinde nükleusa göç ederek
ATM ve ATR proteinleri ile etkileşime girmekte ve hücre döngüsünün
regülasyonunda rol oynamaktadır. AVEN’in ifadelenmesindeki ve/veya
aktivasyonundaki artış kanserleşme ve ilaç direnciyle ilişkilendirilmektedir. Bu çalışmada amacımız AVEN’ın HER2+ meme kanseri hücrelerinde dacomitinib
tarafından indüklenen hücre ölümü cevabını nasıl etkilediğini ortaya koymaktı. Bu
amaç çerçevesinde HER2+ SKBR3 meme kanseri hücrelerinde AVEN ifadelenmesini
arttırarak ya da azaltarak hücre ölümü cevabını değerlendirdik. AVEN’ın aşırı
ifadelenmesi dacomitinib tarafından indüklenen mitokondriyal hücre ölümü cevabını
azaltırken, RNAi yoluyla sustumu ise hücre ölümü cevabını arttırdı.
Gerçekleştirdiğimiz çalışma literatürde HER2+ meme kanseri hücrelerinde AVEN’ın
panHER baskılanmasına cevaben mitokondriyal hücre ölümünü nasıl etkilediğine dair
ilk bulguları sağlamıştır.
Breast cancer is the most common malignancy in women and the mortality rates are
still high despite the development of novel diagnostic and therapeutic strategies.
Resistance to therapy is among the leading causes of therapy failure, presenting either
initially or emerges druing the course of the therapy. Overactivation of HER family of
receptor kinases due to mutations or amplifications promotes malign transformation in
various breast cancer cases. HER2 amplification is seen in 20% breast cancer patients
and related to poor prognosis. Targeted therapies including trastuzumab and lapatinib
exerted prominent antitumor effect in these breast cancer tumors, but therapy
resistance significantly circumvents their activities. To cope with this issue, several
panHER inhibitors (neratinib, dacomitinib, afatinib) have been developed.
Mitochondrial apoptotic pathway is among the main mechanisms that modulates the
effects of conventional and targeted therapies on cancer cells. BCL-2 proteins regulate
mitochondrial apoptotic pathway. Activation of BAX and BAK by BH3-only proteins
leads to mitochondrial outer membrane permeabilization, translocation of cytochrome
c into cytosol and caspase activation are key steps of mitochondrial apoptotic
signaling.
AVEN is a cytosolic protein which regulates mitochondrial apoptotic pathway and
DNA damage response. AVEN interferes with apoptotic signaling by enhancing the
antiapoptotic activity of BCL-XL and by preventing Apaf-1 oligomerization. In
addition, AVEN translocates to nucleus by means of its nuclear localization signal and
interacts with ATM and ATR. These interactions regulate cell cycle response.
Furthermore, increased AVEN activity or expression have been shown to trigger
tumorigenesis and tumor maintenance. In this study, we aimed to identify how AVEN regulates dacomitinib-induced cell
death response in HER2+ breast cancer cells. To explore these responses, we
overexpressed or silenced AVEN in HER2+ SKBR3 breast cancer cells. AVEN
overexpression led to attenuation of dacomitinib-induced mitochondrial apoptotic
response and RNAi-mediated suppression of AVEN increased dacomitinib-induced
apoptosis. Our results provided first findings in the literature regarding the modulation
of panHER inhibition-induced apoptosis by AVEN
Ketamine dosing for sedation during repeated radiotherapy sessions in children
Get PDFBackground/aim: We report the analysis of ketamine doses needed and the recovery tones in pediatric oncology patients undergoing repeated radiotherapy sessions.
Materials and methods: In a single-blind prospective study design, thirty-three pediatric patients undergoing radiotherapy due to oncologic disorders received 2 mg/kg ketamine and 10 mu g/kg atropine intravenously and the rescue drug to be administered was ketamine at 0.5 mg/kg when the sedation level was inadequate. Total ketamine consumption, additional doses, and recovery time were recorded.
Results: Data of 635 consecutive radiotherapy sessions were evaluated. There was no significant alteration in total ketamine consumption required to complete the radiotherapy periods during consecutive procedures (P > 0.05). However, the recovery times started to decrease by the fourth session (P = 0.02) and continued to decrease onwards during the whole study period (P = 0.001). The mean of the first recovery time was 13.68 +/- 3.99 min, whereas the mean of the last recovery time was 7.66 +/- 6.35 min.
Conclusion: A requirement for an incremental increase in ketamine dose after subsequent administrations was not detected, despite a significant decrease in recovery times being anticipated when ketamine is used repeatedly for sedative purposes in consecutive radiotherapy sessions
Laparoscopic gastrostomy under awake thoracic epidural anesthesia: A successful experience
No full textGeneral anesthesia is the first choice as an anesthesia method particularly for abdominal operations. However, because neuromuscular blockade induced during general anesthesia will increase atelectasis in a patient with pulmonary disease, it will also increase postoperative ventilator dependence, which will be even more apparent in cases of chronic obstructive pulmonary disease (COPD) that pose a risk, particularly for postoperative complications. Herein, thoracic epidural anesthesia (TEA) was found to be a better option for our patient with severe COPD and stage IV lung cancer, as it provided sufficient anesthesia and better postoperative care for laparoscopic gastrostomy
The Feasibility of Sparing the Hippocampus and Hypothalamic -Hypophysial Axis During Whole Brain Radiotherapy: A Dosimetric Study
No full textWe aimed to investigate the feasibility of simultaneously sparing the hippocampus and hypothalamic-hypophysial axis (HHA) during whole brain radiotherapy (WBRT) using helical tomotherapy. Images of totally 12 patients were analyzed. Hippocampi and HHA were delineated according to available guidelines. First, radiotherapy plans were analyzed according to dose constraints of the Radiation Therapy Oncology Group-0933 for 30 Gy (3 Gy/fr). Second, dose constraints were decreased by 1/6 to simulate the 25 Gy prophylactic cranial irradiation practice. The mean D98% and D2% was 25.9 +/- 0.85 Gy and 35.0 +/- 1.32 Gy, and 21.4 +/- 0.40 Gy and 30.5 +/- 1.33 Gy for planning target volumes in the original and modified protocol plans, respectively. The D loo96 and Dmax for the hippocampus was 8.1 +/- 0.47 Gy and 15.7 +/- 0.84 Gy in the original and 7.1 +/- 0.68 Gy and 13.2 +/- 1.08 Gy in the modified protocol, respectively. The mean doses for the hypothalamus and hypophysis was 12.6 +/- 0.76 Gy and 11.4 +/- 1.22 Gy in the original and 10.8 +/- 1.38 Gy and 9.8 +/- 1.50 Gy in the modified plans, respectively. This study demonstrated the feasibility of sparing the hippocampus and HHA simultaneously during WBRT with helical tomotherapy regarding target dose coverage and dose constraints suggested by the literature
The Effect of Extensively Drug-resistant Infections on Mortality in Surgical Intensive Care Patients
No full textObjective: The aim of the study was to assess the outcomes of intensive care unit acquired extensively drug-resistant (XDR) bacterial infections in a surgical patient cohort.
Materials and Methods: The data of patients with XDR bacteria isolated at Baskent University Hospital, Anesthesia and Surgical Intensive Care Unit between January 2016 and December 2016 were reviewed retrospectively. Adult patients over 18 years of age who had undergone surgery within the first 24 hours and who developed intensive care unit infection 48 hours after admission to intensive care unit were included in the study.
Results: All of the 341 patients who admitted to the surgical intensive care unit during the study period were underwent surgery within the first 24 hours. XDR bacterial infections were isolated in 30 out (9%) of these 341 patients. The mean APACHE II score was calculated as 18.5 +/- 5.3, and expected mean mortality rate of 35 +/- 17.1. The mean length of intensive care unit stay was 27.0 +/- 27.4 days, while the mean hospital stay was 49.0 +/- 34.3 days. The hospital mortality rate was found to be 57% (n=7).
Conclusion: As a conclusion of our study, we found that XDR bacterial infections were common (9%) among intensive care surgical patients and their mortality rate was higher than their expected mortality rate according to their APACHE II scores calculated during intensive care unit admission (57% vs. 35%, respectively)
Long-term and Perioperative Outcomes of Laparoscopic and Open Surgery for Rectal Cancer
No full textObjectives: The necessity of comparing oncologic results with the use of minimally invasive surgery in rectal cancer has arisen. The aim of the present study was to evaluate the treatment approach in rectal cancer and to compare the outcomes of laparoscopic and open surgery.
Methods: Patients who underwent surgery for rectal carcinoma between January 2006 and January 2016 in our institution were evaluated. The results were compared between the two groups according to open or laparoscopic surgery. Clinical characteristics, preoperative and postoperative results, pathological examination results, and disease-free survival rates were compared after the surgical procedure.
Results: A total of 121 patients were included in the study. Of the patients, 50 underwent open, and 71 underwent laparoscopic surgery. The median follow-up times were 56.75 months in the open surgery group and 55.2 months in the laparoscopic surgery group. Pathological examination revealed similar numbers of lymph nodes in both groups (p>0.05). The duration of hospital stay was statistically significantly lower in the open surgery group than in the laparoscopic group (p0.05).
Conclusion: There was no significant difference in complication and recurrence between laparoscopic and open surgery for rectal cancer in our study. The duration of hospital stay of patients was statistically significantly lower in the laparoscopic group than in the open surgery group. Laparoscopic or open surgical options could be preferred according to the clinical suitability of the patient, experience of the surgeon, and resources of the center in rectal cancer treatment
Simultaneous determination of copper(II) and zinc(II) via simple acid-base titrimetry using glass pH electrode
No full textThe combination of potentiometric methods with multivariate calibration techniques allows complex mixtures to be analyzed. In this study, a new method was developed and reported for simultaneous determination of copper(II) and zinc(II) cations in a mixture by titrimetric methods. The developed method permits simultaneous cation analysis with low detection limits, just by using a pH electrode. This work has achieved the challenging goal of developing a cost-effective and applicable method that can be applied in most laboratories due to independence of any chemical instruments. Partial least squares 1, one of the multivariate calibration techniques, was used in the analysis of titrimetric data. Copper(II) and zinc(II) were simultaneously determined with approximately 5 ppm detection limits and the developed method was validated by performing the titration with known sample mixtures and a certificated alloy sample
The Impact of the Flipped Classroom Model on Students' Academic Achievement
No full textThe aim of this study is twofold. First, it aims to investigate the impact of the Flipped Classroom (FC) Model on students' academic achievement. Second, it reveals the students' opinions about the model itself. For four weeks, the students in the experimental group were taught in a blended learning context where the FC Model was applied, while the lessons in the control group were carried out through traditional blended learning. Both groups were administered a test before and after the Flipped Classroom sessions. To analyze the data, a two-way ANOVA for Mixed Measures was conducted to compare the means of test scores of each group. The results showed that there were no statistically significant differences between the scores of the two groups. Coming to classes prepared and completing the assignments in class, so that students did not need to do assignments at home, were among the positive aspects of the FC Model. The problems encountered in this model, however, are categorized under three main titles: Motivation, Content, and Learning. At the end of the study, the advantages and disadvantages of the FC Model are identified in accordance with the participants' opinions, and necessary suggestions made
Prospective Observational Study on acute Appendicitis Worldwide (POSAW)
No full textBackground: Acute appendicitis (AA) is the most common surgical disease, and appendectomy is the treatment of choice in the majority of cases. A correct diagnosis is key for decreasing the negative appendectomy rate. The management can become difficult in case of complicated appendicitis. The aim of this study is to describe the worldwide clinical and diagnostic work-up and management of AA in surgical departments.
Methods: This prospective multicenter observational study was performed in 116 worldwide surgical departments from 44 countries over a 6-month period (April 1, 2016-September 30, 2016). All consecutive patients admitted to surgical departments with a clinical diagnosis of AA were included in the study.
Results: A total of 4282 patients were enrolled in the POSAW study, 1928 (45%) women and 2354 (55%) men, with a median age of 29 years. Nine hundred and seven (21.2%) patients underwent an abdominal CT scan, 1856 (43.3%) patients an US, and 285 (6.7%) patients both CT scan and US. A total of 4097 (95.7%) patients underwent surgery; 1809 (42.2%) underwent open appendectomy and 2215 (51.7%) had laparoscopic appendectomy. One hundred eighty-five (4.3%) patients were managed conservatively. Major complications occurred in 199 patients (4.6%). The overall mortality rate was 0.28%.
Conclusions: The results of the present study confirm the clinical value of imaging techniques and prognostic scores. Appendectomy remains the most effective treatment of acute appendicitis. Mortality rate is low
Adli uygulamalar için ses içerik analizi
No full textGünümüzde artan şiddet olayları, adli incelemelerin de önemini artırmıştır. Şiddet
olaylarının ardından gerçekleştirilecek olan adli incelemeler esnasında, erişilebilir
durumda olan bütün işitsel ve görsel veriler oldukça kıymetlidir. Olayın gerçekleştiği
konumun tespit edilmesi, şiddetin türünün belirlenmesi ve benzeri süreçler, adli ses
analizi kapsamında yer almaktadır. Günümüzde çevrimiçi içeriğe erişimin akıllı
cihazlar aracılığıyla konum bağımsız olarak gerçekleştirilebiliyor olması ve sunulan
içeriğin miktarının hızlı bir şekilde artmasıyla; içeriğin otomatik olarak
sınıflandırılmasının önemini artırmıştır. Özellikle çocuk ve gençleri olumsuz olarak
etkileyebilecek içeriğin otomatik olarak tespit edilmesi, içerik miktarının hızlı artışıyla
birlikte önem kazanmıştır. Buna karşılık, sinyal işleme alanında, özellikle de adli ses
analizi kapsamında gerçekleştirilen çalışmaların başarımı, diğer alanlarda kullanılan
makine öğrenmesi yöntemlerinin şiddet sahnesi sınıflandırması alanına
uygulanabileceğini göstermiştir. Bu tez çalışması kapsamında, silah seslerinin ve
video verilerinin şiddet içeren sahnelerinin ses tabanlı sınıflandırılması problemleri ele
alınmıştır. Bu amaçla, makine öğrenmesi metotlarının ve topluluk öğrenmesi
yaklaşımları probleme uygulanmıştır. Yöntemler, performans veri kümeleri üzerinde
karşılaştırmalı olarak incelenmiş ve silah sesleri sınıflandırılması alanında %66,
şiddet sahnesi sınıflandırması alanında %62'ye varan sınıflandırma başarımları elde
edilmiştir.
Nowadays, the increase in violent events has enhanced the importance of forensic
investigations. All accessible auditory and visual data are highly valuable during the
examination to be performed after violent events. Audio forensics analysis contains
determination of location in which violent incident occur and determination of type of
violence. Recently, the location-free and easier access to online content via smart
devices and the increase of content have enhanced the importance of automatical
classification of content. With the rapid growth in the amount of content, it has
become crucial to automatically determine the content that can adversely affect
children and youth. On the other hand, the success of the studies carried out in the
field of signal processing, especially in the context of audio forensic analysis, shows
that the methods of machine learning used in other areas can be applied to the field
of violent scene classification. In this study, we study the problem of gunshot sounds
and violent scene classification. For this purpose, machine learning and ensemble
learning approaches applied to this problem. We examine classification rates of
various machine learning and ensemble learning approaches comperatively and we
achieve classification accuracies of 66% and 62% in audio gunshot classification and
violent scene classification, respectively