ALLOJENEİK HEMATOPOİETİK KÖK HÜCRE NAKLİ YAPILAN HASTALARDA AKUT GRAFT VERSUS HOST HASTALIĞI VE KRONİK GRAFT VERSUS HOST HASTALIĞI’NIN RETROSPEKTİF DEĞERLENDİRİLMESİ

Enfeksiyon proflaksisinde, immünsüpresif stratejilerde, DNA bazlı doku tiplendirmesinde ve destekleyici bakım önlemlerinde kaydedilen gelişmelerle birlikte allojeneik hematopoietik kök hücre nakli (Allo-HKHN) ile önemli oranda hastalık kontrolü ve kür sağlama başarısı sağlanmıştır. Nakil sayılarının artmasına paralel olarak görülen komplikasyonların sayısı ve çeşitliliği de artış göstermektedir. Graft Versus Host Hastalığı (GVHH) da Allo-HKHN sonrasında görülen en ciddi morbidite ve mortalite nedeni olan komplikasyonlardan biridir. Bu gözlemsel çalışmanın amacı; Allo-HKHN yapılan hastalarda nakil sonrası GVHH’nin görülme sıklığı, akut GVHH (aGVHH) ve kronik GVHH (krGVHH) gelişiminde ki risk faktörlerinin belirlenmesi, proflakside kullanılan ilaçların GVHH gelişimi üzerine etkisi, GVHH’nin mortalite ve morbidite üzerine etkisini araştırmaktır. Çalışmada Adnan Menderes Üniversite Hastanesi ve Özel Kent Hastanesi Erişkin Kemik İliği Nakil Merkezlerinden Ocak 2013 ile Mayıs 2019 tarihleri arasında Allo-HKHN yapılan ve yeterli dosya verilerine ulaşılan 162 hasta GVHH açısından geriye dönük olarak değerlendirildi. Hastaların tıbbi değerlendirme ve izlem amaçlı yapılmış olan laboratuvar incelemeleri, patoloji ve epikriz raporları hastane otomasyon sisteminden ve hastanede kayıtlı dosyalarından elde edildi. Hastalara ait tüm bilgiler SPSS for Windows versiyon 19.0 modüllüne girilerek istatistiksel analiz yapıldı. Çoğunluğunu akut lösemilerin oluşturduğu Allo-HKHN yapılan hastaların %54,3’ünde nakil sonrasında GVHH tanısı saptandı. GVHH tipinin ve derecesinin sağkalım sürelerini etkilediği görüldü. Sağkalım süreleri açısından GVHH tipinden en çok etkilen tanı AML idi. CMV-Reaktivasyonunun pozitifliği ile GVHH tipi arasında da anlamlı bir ilişki bulundu. GVHH’den en sık etkilen organ deri olarak saptandı. Enfeksiyon en sık ölüm nedeni olarak saptanırken, GVHH’den ölen hastaları oranı %3,06 idi. Bu çalışma sonucunda GVHH tipi ve derecesi ile CMV-Reaktivasyonunun sağkalımı çok önemli oranda düşürdüğü gösterilmiştir. Ayrıca aGVHH derecesinin de özellikle AML tanılı hastaların sağkalımını ciddi oranda düşürdüğü gösterilmiştir.KABUL ONAY ………..………………………………………………………………..…….. i TEŞEKKÜR ……………………………………………..……………….……………..…..... ii İÇİNDEKİLER ……………………………………….………………………………..…….. iii SİMGELER VE KISALTMALAR DİZİNİ ………………..……………………………......... v ŞEKİLLER DİZİNİ ……………………………………………………………………......... vii RESİMLER DİZİNİ…………………………………………………………...……………. viii TABLOLAR DİZİNİ …………………………………………………………….………...… ix ÖZET …………………………………………………………………………...……….……. x ABSTRACT…………………………………………………………………….…….……... xii 1. GİRİŞ …………..……………………………………………………………..…….……... 1 2. GENEL BİLGİLER …………………………………………………………………...…… 3 2.1. Hematopoietik Kök Hücrelerin Genel Özelliklerine Kısa Bir Bakış …………………….. 3 2.1.1. Hematopoietik Kök Hücre Nakli Çeşitleri ………………………………………...…… 4 2.1.2. Hematopoietik Kök Hücre Naklinin Tarihçesi ………………………………………… 5 2.1.3. Allojeneik Hematopoietik Kök Hücre Nakli Öncesi Verici Seçimi ve HLA ………….. 6 2.1.4. Allojeneik Hematopoietik Kök Hücre Toplanması ……………………………………. 8 2.2. Hazırlama Rejimleri ………..…………………………………………………………… 10 2.2.1. Myeloablatif Hazırlama Rejimleri …………………………………………………… 10 2.2.2. Non-myeloablatif Hazırlama Rejimleri ……………………………………………… 11 2.3. Allojeneik Hematopoietik Kök Hücre Nakli .…………………………………………... 11 2.4. Allojeneik Hematopoietik Kök Hücre Nakli Komplikasyonları ………………………. 12 2.4.1. Graft Versus Host Hastalığı (GVHH) ………………………………………………... 13 2.4.1.1. Akut Graft Versus Host Hastalığı ………………………………………………….. 15 2.4.1.2. Akut Graft Versus Host Hastalığı’nın Patogenezi …………………………………. 17 2.4.1.3. Akut Graft Versus Host Hastalığı’nın Önlenmesi ve Tedavisi …………………….. 17 2.4.1.4. Kronik Graft Versus Host Hastalığı ………………………………………………... 18 2.4.1.5. Kronik Graft Versus Host Hastalığı’nın Patogenezi ……………………………….. 18 2.4.1.6. Kronik Graft Versus Host Hastalığı’nın Önlenmesi ve Tedavisi ………………...... 19 2.4.1.7. Akut ve Kronik GVHH’de Yeni Yaklaşımlar ……………………………………… 20 2.4.1.8. Graft Versus Host Hastalığı’nda Yeni Sınıflandırma Sistemi ....…………………… 22 2.4.2. Enfeksiyonlar ...………………………………………………………………………. 26 vi 2.4.3. Graft Yetmezliği ……………………………………………………………………… 26 2.4.4. Diğer Komplikasyonlar ………………………………………………………………. 27 3. GEREÇ VE YÖNTEM …………………………………………………………………… 28 3.1. Hastalar ……………………………………………………………………….………… 28 3.2. İstatistiksel Analizler ……………………………………………………….…………… 29 4. BULGULAR ………………………………………………………………………..…….. 30 5. TARTIŞMA ………………………………………………………………………………. 42 6. SONUÇLAR VE ÖNERİLER ..…………………………………………………….…….. 46 KAYNAKLAR …………………………………………………………………………….... 48 EKLER ……………………………………………………………………………………… 59 EK 1 – ADÜ Araştırma ve Uygulama Hastanesi Etik Kurul Onayı ………………………. 59 EK 2 – Olgu Rapor Formu …………………………………………………………………… 60 ÖZGEÇMİŞ ...…………………………………………………………………………..…… 6

Magnetotransport study on AllnN/(GaN)/AIN/GaN heterostructures

Cataloged from PDF version of article.We report the effect of a thin GaN (2?nm) interlayer on the magnetotransport properties of AlInN/AlN/GaN-based heterostructures. Two samples were prepared (Sample A: AlInN/AlN/GaN and sample B: AlInN/GaN/AlN/GaN). Van der Pauw and Hall measurements were performed in the 1.9300?K temperature range. While the Hall mobilities were similar at room temperature (RT), sample B had nearly twice as large Hall mobility as sample A at the lowest temperature; 679 and 889?cm2/Vs at RT and 1460 and 3082?cm2/Vs at 1.9?K for samples A and B. At 1.910?K, the longitudinal magnetoresistance was measured up to 9?T, in turn revealing Shubnikovde Haas (SdH) oscillations. The carrier concentration, effective mass and quantum mobility of the two-dimensional electron gas (2DEG) were determined from SdH oscillations. At 1.9?K, the 2DEG concentration of sample B was nearly seven times larger than of sample A (1.67 x 10(13)/cm2 vs. 0.24 x 10(13)/cm2). On the contrary, the quantum mobility was changed adversely nearly three times (sample B 2500?cm2/Vs and sample A 970?cm2/Vs). The increase of the 2DEG concentration was attributed to the existence of the GaN interlayer, which has strengthened the spontaneous polarization difference between the AlInN and GaN layers of the heterostructure. Hence, the stronger electric field at the 2DEG region bent the conduction band profile downwards and consequently the quantum mobility decreased due to the increased interface roughness scattering

Temperament Systems Influence Emotion Induction but not Makam Recognition Performance in Turkish Makam Music

We tested how induced emotions and Turkish makam recognition are influenced by participation in an ear training classes, and if either is influenced by the temperament system employed. The ear training class was attended by 19 music students and was based on the Hicaz makam presented as a between-subjects factor in either unfamiliar Turkish Original Temperament (OT, pitches unequally divided into 24 intervals) or familiar Western Equal Temperament (ET, pitches equally divided into 12 intervals). Before the and after the class, participants listened to 20 music excerpts from five different Turkish makams (in both OT and ET versions). Emotion-induction was assessed via GEMS-25, and participants were also asked to identify the makam that was present in the excerpt. The unfamiliar original temperament was experienced as less vital and more uneasy before the ear training class, and recognition of the Hicaz makam increased after ear training classes (independent of the temperament system employed). Results suggest that unfamiliar temperament systems are experienced as less vital and more uneasy. Furthermore, being exposed to this temperament system for just one hour does not seem to be enough to change participants’ mental representations of it or their emotional responses to it

Developing markets? Understanding the role of markets and development at the intersection of macromarketing and transformative consumer research (TCR)

Situated at the intersection of markets and development, this commentary aims to promote a cross-fertilization of macromarketing and Transformative Consumer Research (TCR) that directs attention to the sociocultural context and situational embeddedness of consumer experience and well-being, while acknowledging complex, systemic interdependencies between markets, marketing, and society. Based on a critical review of the meaning of development and an interrogation of various developmental discourses, the authors develop a conceptual framework that brings together issues of development, well-being, and social inequalities. We suggest that these issues are better understood and addressed when examined via grounded investigations of the role of markets in shaping the management of resources, consumer agency, power inequalities and ethics. The use of markets as units of analysis may lead to further cross-fertilizations of TCR and macromarketing and to more comprehensive theorizing and transformational impact. Two empirical cases are provided to illustrate our framework

Coxiella burnetii Phagocytosis Is Regulated by GTPases of the Rho Family and the RhoA Effectors mDia1 and ROCK

The GTPases belonging to the Rho family control the actin cytoskeleton rearrangements needed for particle internalization during phagocytosis. ROCK and mDia1 are downstream effectors of RhoA, a GTPase involved in that process. Coxiella burnetii, the etiologic agent of Q fever, is internalized by the host´s cells in an actin-dependent manner. Nevertheless, the molecular mechanism involved in this process has been poorly characterized. This work analyzes the role of different GTPases of the Rho family and some downstream effectors in the internalization of C. burnetii by phagocytic and non-phagocytic cells. The internalization of C. burnetii into HeLa and RAW cells was significantly inhibited when the cells were treated with Clostridium difficile Toxin B which irreversibly inactivates members of the Rho family. In addition, the internalization was reduced in HeLa cells that overexpressed the dominant negative mutants of RhoA, Rac1 or Cdc42 or that were knocked down for the Rho GTPases. The pharmacological inhibition or the knocking down of ROCK diminished bacterium internalization. Moreover, C. burnetii was less efficiently internalized in HeLa cells overexpressing mDia1-N1, a dominant negative mutant of mDia1, while the overexpression of the constitutively active mutant mDia1-ΔN3 increased bacteria uptake. Interestingly, when HeLa and RAW cells were infected, RhoA, Rac1 and mDia1 were recruited to membrane cell fractions. Our results suggest that the GTPases of the Rho family play an important role in C. burnetii phagocytosis in both HeLa and RAW cells. Additionally, we present evidence that ROCK and mDia1, which are downstream effectors of RhoA, are involved in that processFil: Salinas Ojeda, Romina Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Ortiz Flores, Rodolfo Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Distel, Jesús Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Aguilera, Milton Osmar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Colombo, Maria Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Beron, Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin

Mitochondrial Priming by CD28

T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that, upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial fatty acid oxidation (FAO), before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation—cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity that is essential for future T cell responses

Neuroendocrine tumors presenting with thyroid gland metastasis: a case series

<p>Abstract</p> <p>Introduction</p> <p>Autopsy series have shown that metastasis to the thyroid gland has occurred in up to 24% of patients who have died of cancer. Neuroendocrine tumors may metastasize to thyroid gland.</p> <p>Case presentations</p> <p>Case 1 was a 17-year-old Turkish woman who was referred from our Endocrinology Department for a thyroidectomy for treatment of neuroendocrine tumor metastasis. She was treated with a bilateral total thyroidectomy. Histopathological examination results were consistent with a neuroendocrine tumor; neoplastic cells showed strong immunoreactivity to chromogranin A and synaptophysin, but the immunohistochemical profile was inconsistent with medullary thyroid carcinoma in that the tumor was negative for calcitonin, carcinoembryonic antigen, and thyroid transcription factor-1.</p> <p>Case 2 was a 54-year-old Turkish woman who presented with a 3-cm nodule on her right thyroid lobe. She had undergone surgery for a right lung mass four years previously. After a right pneumonectomy, thymectomy and lymph node dissection, a typical carcinoid tumor was diagnosed. Under ultrasonographic guidance, fine needle aspiration biopsy of her right thyroid pole nodule was performed and the biopsy was compatible with a neuroendocrine tumor metastasis. She was treated with a bilateral total thyroidectomy. Histopathological examination indicated three nodular lesions, 5 cm and 0.4 cm in diameter in her right lobe and 0.1 cm in diameter in her left lobe. The tumors were consistent with a neuroendocrine phenotype, showing strong immunoreactivity to chromogranin A and synaptophysin.</p> <p>Conclusion</p> <p>Thyroid nodules detected during follow-up of neuroendocrine tumor patients should be thoroughly investigated. A fine needle aspiration biopsy of the thyroid confirms the diagnosis in most cases and leads to appropriate management of those patients and may prevent unnecessary treatment approaches.</p

A new simplified comorbidity score as a prognostic factor in non-small-cell lung cancer patients: description and comparison with the Charlson's index

Treatment of non-small-cell lung cancer (NSCLC) might take into account comorbidities as an important variable. The aim of this study was to generate a new simplified comorbidity score (SCS) and to determine whether or not it improves the possibility of predicting prognosis of NSCLC patients. A two-step methodology was used. Step 1: An SCS was developed and its prognostic value was compared with classical prognostic determinants in the outcome of 735 previously untreated NSCLC patients. Step 2: the SCS reliability as a prognostic determinant was tested in a different population of 136 prospectively accrued NSCLC patients with a formal comparison between SCS and the classical Charlson comorbidity index (CCI). Prognosis was analysed using both univariate and multivariate (Cox model) statistics. The SCS summarised the following variables: tobacco consumption, diabetes mellitus and renal insufficiency (respective weightings 7, 5 and 4), respiratory, neoplastic and cardiovascular comorbidities and alcoholism (weighting=1 for each item). In step 1, aside from classical variables such as age, stage of the disease and performance status, SCS was a statistically significant prognostic variable in univariate analyses. In the Cox model weight loss, stage grouping, performance status and SCS were independent determinants of a poor outcome. There was a trend towards statistical significance for age (P=0.08) and leucocytes count (P=0.06). In Step 2, both SCS and well-known prognostic variables were found as significant determinants in univariate analyses. There was a trend towards a negative prognostic effect for CCI. In multivariate analysis, stage grouping, performance status, histology, leucocytes, lymphocytes, lactate dehydrogenase, CYFRA 21-1 and SCS were independent determinants of a poor prognosis. CCI was removed from the Cox model. In conclusion, the SCS, constructed as an independent prognostic factor in a large NSCLC patient population, is validated in another prospective population and appears more informative than the CCI in predicting NSCLC patient outcome

A constrained analysis of the 40Ca(18O,18F)40K direct charge exchange reaction mechanism at 275 Mev

The40 Ca(18 O,18 F)40 K single charge exchange (SCE) reaction is explored at an incident energy of 275 MeV and analyzed consistently by collecting the elastic scattering and inelastic scattering data under the same experimental conditions. Full quantum-mechanical SCE calculations of the direct mechanism are performed by including microscopic nuclear structure inputs and adopting either a bare optical potential or a coupled channel equivalent polarization potential (CCEP) constrained by the elastic and inelastic data. The direct SCE mechanism describes the magnitude and shape of the angular distributions rather well, thus suggesting the suppression of sequential multi-nucleon transfer processes

Expression of an Epitope-Tagged Virulence Protein in Rickettsia parkeri Using Transposon Insertion

Despite recent advances in our ability to genetically manipulate Rickettsia, little has been done to employ genetic tools to study the expression and localization of Rickettsia virulence proteins. Using a mariner-based Himar1 transposition system, we expressed an epitope-tagged variant of the actin polymerizing protein RickA under the control of its native promoter in Rickettsia parkeri, allowing the detection of RickA using commercially-available antibodies. Native RickA and epitope-tagged RickA exhibited similar levels of expression and were specifically localized to bacteria. To further facilitate protein expression in Rickettsia, we also developed a plasmid for Rickettsia insertion and expression (pRIE), containing a variant Himar1 transposon with enhanced flexibility for gene insertion, and used it to generate R. parkeri strains expressing diverse fluorescent proteins. Expression of epitope-tagged proteins in Rickettsia will expand our ability to assess the regulation and function of important virulence factors