Current Approaches in Chronic Pancreatitis

Chronic pancreatitis is a fibroinflammatory syndrome of the pancreas that results in exocrine and endocrine pancreatic insufficiency and chronic pain. It can be seen in all age groups depending on the etiologic factors. It is believed that alcohol is one of the major etiologic factors of chronic pancreatitis, but it is now recognized that alcohol is responsible for 50% of the cases. Mutations in many genes such as PRSS1, SPINK1, CTRC, CFTR are identified as causative or predisposing factors for CP. Early diagnosis and staging of CP are still a challenge in clinic. Although the chief complaint of patients with CP is abdominal pain, CP can cause many disorders such as diabetes or metabolic bone diseases. The treatment of CP mainly depends on the severity of the disease and morphology of the pancreas. Medical therapy, endoscopy and surgery are all used for the treatment of CP and its complications

Mechanisms of T-Cell Exhaustion in Pancreatic Cancer.

T-cell exhaustion is a phenomenon that represents the dysfunctional state of T cells in chronic infections and cancer and is closely associated with poor prognosis in many cancers. The endogenous T-cell immunity and genetically edited cell therapies (CAR-T) failed to prevent tumor immune evasion. The effector T-cell activity is perturbed by an imbalance between inhibitory and stimulatory signals causing a reprogramming in metabolism and the high levels of multiple inhibitory receptors like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte-activation gene 3 (Lag-3). Despite the efforts to neutralize inhibitory receptors by a single agent or combinatorial immune checkpoint inhibitors to boost effector function, PDAC remains unresponsive to these therapies, suggesting that multiple molecular mechanisms play a role in stimulating the exhaustion state of tumor-infiltrating T cells. Recent studies utilizing transcriptomics, mass cytometry, and epigenomics revealed a critical role of Thymocyte selection-associated high mobility group box protein (TOX) genes and TOX-associated pathways, driving T-cell exhaustion in chronic infection and cancer. Here, we will review recently defined molecular, genetic, and cellular factors that drive T-cell exhaustion in PDAC. We will also discuss the effects of available immune checkpoint inhibitors and the latest clinical trials targeting various molecular factors mediating T-cell exhaustion in PDAC

Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

T-cell exhaustion is a phenomenon that represents the dysfunctional state of T cells in chronic infections and cancer and is closely associated with poor prognosis in many cancers. The endogenous T-cell immunity and genetically edited cell therapies (CAR-T) failed to prevent tumor immune evasion. The effector T-cell activity is perturbed by an imbalance between inhibitory and stimulatory signals causing a reprogramming in metabolism and the high levels of multiple inhibitory receptors like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte-activation gene 3 (Lag-3). Despite the efforts to neutralize inhibitory receptors by a single agent or combinatorial immune checkpoint inhibitors to boost effector function, PDAC remains unresponsive to these therapies, suggesting that multiple molecular mechanisms play a role in stimulating the exhaustion state of tumor-infiltrating T cells. Recent studies utilizing transcriptomics, mass cytometry, and epigenomics revealed a critical role of Thymocyte selection-associated high mobility group box protein (TOX) genes and TOX-associated pathways, driving T-cell exhaustion in chronic infection and cancer. Here, we will review recently defined molecular, genetic, and cellular factors that drive T-cell exhaustion in PDAC. We will also discuss the effects of available immune checkpoint inhibitors and the latest clinical trials targeting various molecular factors mediating T-cell exhaustion in PDAC

Normal ve major depresyonlu hasta populasyonlarında duygusal çelişki çözümlemenin beyindeki fonksiyonel lokalizasyonu ve etken nöroanatomik morfolojik faktörlerin incelenmesi

TÜBİTAK EEEAG01.06.2012Dünya Sağlık Örgütü’nün açıklamalarına göre depresyon dünya çapında 120 milyondan fazla insanı etkisi altına almış olan ve kimi zaman intiharla sonuçlanabilen, dolayısıyla anlaşılması önem arzeden bir hastalıktır. Depresyon hastalarının bilişsel ve emosyonel fonksiyonlarında (ör: çelişki çözümleme, dikkat, motivasyon, ve amaca yönelik işlevler) pek çok davranışsal, metabolik ve beyin aktivasyonu bozuklukları tespit edilmiştir. Bu bozuklukların önemli bir kısmı, prefrontal bölgedeki pek çok anatomik yapı ile direkt bağlantıları olan anterior-singulat kortekste lokalize olmuş durumdadır. Öte yandan, depresyonlu hastaların beyinleri ile normal beyinler yapısal olarak karşılaştırıldığında, hastaların beyinlerinde gözlenen en önemli farklılıklar, prefrontal korteksin ve limbik sistemin karşılıklı olarak bağlantısı olan bölgelerindeki (ör: amygdala, hippocampus, parahippocampal girus, anterior singulat korteks, orbito-frontal korteks) hacimsel azalmalardır. Bu farklılıklar bilinmekle birlikte, günümüzde morfolojik ve fonksiyonel nörogörüntüleme alanında geliştirilmiş en son teknikleri birarada kullanarak depresyondaki yapısal ve işlevsel sorunları aynı anda ele alan çalışma pek azdır. Projemizde nörogörüntülemedeki en son teknikler kullanılarak ve yeni teknikler geliştirilerek önemli bir işlevsel bozukluk olan duygusal-çelişki çözümlemenin depresyonlu hastaların beynindeki lokalizasyonu ve fonksiyonel sorunların oluşmasında etken olabilecek yapısal faktörler incelenmektedir. MR görüntülerinde anterior-singulat korteksin ve alt-bölgelerinin dokusal karakteristiği, T1, longitudinal relaksasyon zamanı üzerinden araştırılmaktadır. Buradaki bulgular, diğer yapısal özellikler olan hacim ve korteks kalınlığı ile ilişkilendirilmektedir. Diğer taraftan Anterior singulat korteks tarafından üstlenilen duygusal çelişki çözümleme işlevi, kendi geliştirdiğimiz bir bilgisayar testi kullanılarak fMR görüntüleme ile araştırılmaktadır. Sağlıklı ve depresyonlu bireylerdeki beyin aktivitesi haritaları istatistiksel yöntemlerle karşılaştırılmaktadır. Çalışmalarımız sonucunda üç temel bulguya ulaşmak mümkün olmuştur: 1. Sağlıklı bireylerde Anterior singulat kortekstte Dorsal, Rostral ve ventral bölgelerde doku farklılıkları mevcuttur 2. Sağlıklı bireylerde çelişki çözümleme işlevi Dorsal ACC, uyaranın duygusal değerlendirmesi Rostral ve Ventral ACC’de odaklanmıştır. 3. Duygusal Çelişki çözümleme 5 testinde, hasta ve sağlıklı bireyler arasında Rostral ACC, Dorsal ACC ve Orbitofrontal kortekste beyin aktivitesi farklılıkları mevcuttur. Depresyonlu hasta sayısı arttırılabilirse, hacimsel ve korteks kalınlığı gibi yapısal farklılıkları da daha detaylı olarak incelememiz mümkün olacaktır.According to the World Health Organization, depression is a debilitating disease affecting some 120 million people worldwide, sometimes even resulting in suicide. Many behavioral, metabolic and brain activation disorders have been found in the cognitive and emotional functions (ex: conflict resolution, attention, motivation, goal-oriented-behavior) of depressive patients. An important fraction of these dysfunctionalities have been localized in the anterior- cingulate cortex, which is connected to a multitude of anatomical structures in the prefrontal lobe. On the other hand, when the brains of depression patients and healthy controls are compared morphologically, major differences in terms of volumetric reductions are found in the patients' brains, mostly in regions in the prefrontal and limbic systems (such as: amygdala, hippocampus, parahippocampal gyrus, anterior cingulate cortex (ACC), orbito-frontal cortex, which are conjoined reciprocally. Although these differences have been reported for a while now, there are very few depression studies which investigate the structural and functional problems at the same time using the most recent technological developments in neuroimaging. In this project, we are investigating the localization of problems in emotional conflict resultion in the depressive patients' brains, as well as the underlying structural factors using existing state-of-the-art techniques as well as new techniques developed by us. Through the newly intended structural technique, the structural charateristics of the anterior-cingulate cortex will be investigated, based on the T1 longitudinal relaxation times. These findings are being correlated with other structural measurements such as volume and cortical thickness. On another front, we are studying the emotional conflict resolution process localized to the anterior cingulate cortex through a new emotional conflict test that we have developed for administration during fMRI. We then investigate the brain activity maps of the healthy and depressed populations through statistical analysis. At the end of our investigations, we were able to reach three principal findings: 1. In the healthy brains, there exist tissue differences in the Dorsal, Rostral and Ventral compartments of the ACC. 2. The conflict resolution process is centered at the Dorsal ACC of healthy 7 population, while evaluation of the emotional stimuli is localized to the Rostral and ventral Areas of ACC. 3. In the emotional conflict resolution test, helathy and depressed populations show acitivity differences at the Rostral, Dorsal ACC as well as Orbitofrontal Cortex. If we are able to increase the scans for depressed population, we will be able to investigate the volume and cortical differences in more detail

Low skeletal muscle mass index is associated with function and nutritional status in residents in a Turkish nursing home

Introduction: To determine the prevalence of low muscle mass (LMM) and the relationship between LMM with functional and nutritional status as defined using the LMM evaluation method of European Working Group on Sarcopenia in Older People (EWGSOP) criteria among male residents in a nursing home

THYROID ABSCESS IN A PATIENT WITH ACUTE LYMPHOBASTIC LEUKEMIA DURING CHEMOTHERAPY INDUCED NEUTROPENIA

Febrile neutropenia is a commonly encountered complication during the treatment of hematological malignancies. Respiratory system, skin, gastrointestinal system and genitourinary system infections are the common causes of febrile neutropenia. The infection of thyroid gland is rarely seen even in neutropenic patients. Here, we describe a patient with acute lymphoblastic leukemia who was treated with intensive chemotherapy and developed suppurative thyroiditis during neutropenic period. It is proposed that prior neutropenia and preceding cellulitis around the thyroid gland, which might be subsequent to oral mucosal damage induced by anticancer drugs, may play a role in the development of gland infection. Thyroid gland infection should be considered a potential complication of aggressive chemotherapy for leukemia

Case report of fatal Mycobacterium tilburgii infection.

There are few reports concerning Mycobacterium tilburgii infection in humans because this bacterium is non-cultivatable. Herein, using new molecular techniques, we report the case of an immunocompromised patient with fatal disseminated lymphadenitis that was caused by M. tilburgii. 26 years old Caucasian HIV negative female patient presented with abdominal pain. Her clinical assessment revealed disseminated lymphadenitis, that was acid fast bacilli positive. Further molecular evaluation showed the causative agent as M. tilburgii. Despite anti mycobacterial therapy and careful management of intervening complications patient died because of an intraabdominal sepsis