Betül Ünal

The divergent roles of growth differentiation factor-15 (GDF-15) in benign and malignant skin pathologies

GDF-15 (Growth Differentiation Factor-15) is a member of the transforming growth factor β (TGF-β) superfamily. GDF-15 is not only involved in cancer development, progression, angiogenesis and metastasis, but also controls stress responses, bone formation, hematopoietic development, adipose tissue function and cardiovascular diseases. GDF-15, which is regulated by p53, has shown antitumorigenic and proapoptotic activities in vivo and in vitro. Also, GDF-15 is involved in skin biology and histamine-induced melanogenesis; it is overexpressed in melanoma cells and is associated with depth of tumor invasion and metastasis. GDF-15 level is increased in patients with systemic sclerosis and is related with the degree of skin sclerosis and intensity of pulmonary fibrosis. In the future, GDF-15 may be a potential target for therapy in benign disorders with skin fibrosis and malignant lesions of the skin.

Neutral Sphingomyelinase Inhibition Alleviates Apoptosis, but not ER Stress, in Liver Ischemia–Reperfusion Injury

Abstract Previous studies have revealed the activation of neutral sphingomyelinase (N-SMase)/ceramide pathway in hepatic tissue following warm liver ischemia reperfusion (IR) injury. Excessive ceramide accumulation is known to potentiate apoptotic stimuli and a link between apoptosis and endoplasmic reticulum (ER) stress has been established in hepatic IR injury. Thus, this study determined the role of selective N-SMase inhibition on ER stress and apoptotic markers in a rat model of liver IR injury. Selective N-SMase inhibitor was administered via intraperitoneal injections. Liver IR injury was created by clamping blood vessels supplying the median and left lateral hepatic lobes for 60 min, followed by 60 min reperfusion. Levels of sphingmyelin and ceramide in liver tissue were determined by an optimized multiple reactions monitoring (MRM) method using ultrafast-liquid chromatography (UFLC) coupled with tandem mass spectrometry (MS/MS). Spingomyelin levels were significantly increased in all IR groups compared with controls. Treatment with a specific N-SMase inhibitor significantly decreased all measured ceramides in IR injury. A significant increase was observed in ER stress markers C/EBP-homologous protein (CHOP) and 78 kDa glucose-regulated protein (GRP78) in IR injury, which was not significantly altered by N-SMase inhibition. Inhibition of N-SMase caused a significant reduction in phospho-NF-kB levels, hepatic TUNEL staining, cytosolic cytochrome c, and caspase-3, -8, and -9 activities which were significantly increased in IR injury. Data herein confirm the role of ceramide in increased apoptotic cell death and highlight the protective effect of N-SMase inhibition in down-regulation of apoptotic stimuli responses occurring in hepatic IR injury.

Gastric collision tumor: Case report of a rare adenocarcinoma and a typical carcinoid tumor

We report a case with features of gastric adenocarcinoma colliding with a typical carcinoid component. A 51-year-old female was admitted to the Department of Internal Medicine with complaints of epigastric pain. On physical examination of the patient there was significant epigastric tenderness and the CA19-9 level was higher than the normal titer value. An upper gastrointestinal endoscopy showed an ulcerated polypoid mass located on the cardiac region of the stomach. Pathological and immunohistochemical findings diagnosed as a collision tumor comprising both adenocarcinoma and carcinoid tumor. Metastasis of adenocarcinoma was found in 7 perigastric lymph nodes, while metastasis of the carcinoid was not detected. The admixture of neoplastic endocrine and nonendocrine cells, have been found infrequently in gastric tumors. The mixed tumors can be further classified into composite tumors that show an admixture of two histological components with histological transitions and collision tumors where the two components are not intermixed In general it is not easy to morphologically distinguish a collision tumor, from composite tumor. Microscopically, hematoxylin and eosin-stained tissue sections from two different areas of the mass revealed two different types of tumor; an intestinal type adenocarcinoma and a carcinoid tumor. We report a case with features of adenocarcinoma colliding with a typical carcinoid component, along with a review of the literature.

Inhibition of neutral sphingomyelinase decreases elevated levels of nitrative and oxidative stress markers in liver ischemia–reperfusion injury

Oxidative stress and excessive nitric oxide production via induction of inducible nitric oxide synthase (NOS)-2 have been shown in the pathogenesis of liver ischemia–reperfusion (IR) injury. Neutral sphingomyelinase (N-SMase)/ceramide pathway can regulate NOS2 expression therefore this study determined the role of selective N-SMase inhibition on nitrative and oxidative stress markers following liver IR injury. Selective N-SMase inhibitor was administered via intraperitoneal injections. Liver IR injury was created by clamping blood vessels supplying the median and left lateral hepatic lobes for 60 min, followed by 60 min reperfusion. Nitrative and oxidative stress markers were determined by evaluating NOS2 expression, protein nitration, nitrite/nitrate levels, 4-hydroxynonenal (HNE) formation, protein carbonyl levels and xanthine oxidase/xanthine dehydrogenase (XO/XDH) activity. Levels of sphingmyelin and ceramide in liver tissue were determined by an optimized multiple reaction monitoring method using ultra-fast liquid chromatography coupled with tandem mass spectrometry (MS/MS). Spingomyelin levels were significantly increased in all IR groups compared to controls. Treatment with a specific N-SMase inhibitor significantly decreased all measured ceramides in IR injury. NOS2 expression, nitrite/nitrate levels and protein nitration were significantly greater in IR injury and decreased with N-SMase inhibition. Treatment with a selective N-SMase inhibitor significantly decreased HNE formation, protein carbonyl levels and the hepatic conversion of XO. Data confirm the role of nitrative and oxidative injury in IR and highlight the protective effect of selective N-SMase inhibition. Future studies evaluating agents blocking N-SMase activity can facilitate the development of treatment strategies to alleviate oxidative injury in liver I/R injury.

S100A8 and S100A9 Positive Cells in Colorectal Carcinoma: Clinicopathological Analysis.

Introduction. In colorectal carcinoma, tumoral tissues infiltrate with various immune/inflammatory cells along their invasive margins and the increased S100A8/A9 expression in these immune cells infiltrating the tumor has recently been demonstrated. We examined S100A8/A9 as a potential therapeutic target in the treatment of colorectal carcinoma. Materials and Methods. The current study included a sample of 80 patients diagnosed with CRC (30 cases with distant metastasis, 30 cases with lymph node metastasis, and 20 cases with no metastasis). Peritumoral and intratumoral S100A8 and S100A9 expressing inflammatory cells were counted in primary tumors and their metastasis and correlated with clinicopathological parameters. Results. The peritumoral and intratumoral S100A8/A9 positive cells showed no correlation with age, gender, or depth of tumor invasion. However higher counts of peritumoral and intratumoral S100A8/A9 positive cells were associated with larger tumor size, higher grade, and the presence of metastasis (P < 0.05). Conclusion. Our study also found significantly higher number of S100A8/A9 positive cells in the tumor microenvironment among patients with large tumor size, high grade, and metastatic disease. Moreover, in our study, we observed that the expression in the tumor metastasis appeared similar to that of primary tumor.

Diagnostic Value of Ultrasound-Guided Fine Needle Aspiration Biopsy in Malignant Thyroid Nodules: Utility for Micronodules

BACKGROUND The diagnostic approach to thyroid nodules involves ultrasound-guided fine needle aspiration biopsy (US-FNAB).We especially aimed to evaluate the contribution and the place of US-FNAB in preoperative evaluation of the malignant cases and draw attention to discordant cases diagnosed with papillary thyroid microcarcinoma (PTMC). MATERIALS AND METHODS A total of 276 cases were retrospectively reviewed who were subsequently diagnosed with a malignancy and who underwent US-FNAB. RESULTS Some 45 were found to have previously undergone the US-FNAB procedure. Of the patients in whom the surgical specimen was diagnosed with a malignancy, 21 (46.7%) were diagnosed as malignant or suspicious for malignancy, and 24 (53.3%) were concluded as benign or insufficient for diagnosis. Patients with the diagnosis of PTMC outnumbering the others was a striking finding (11 cases, 24%). CONCLUSIONS We suggest performing repeat aspiration biopsy considering sampling errors in cases where inconsistency exists between clinical findings and cytological results in thyroid nodules smaller than 10 mm in diameter and with suspicious findings on ultrasonography.

A Rare Complication of Gastric Bypass (Weight Loss) Surgery: Nesidioblastosis

Here, we present the case of a 31-year-old woman patient who underwent distal pancreatectomy with the history of gastric bypass surgery for obesity. The final histopathological diagnosis of the lesion was nesidioblastosis. Nesidioblastosis is the most common cause of organic persistent hyperinsulinemic hypoglycemia in newborns; however, it is rare in adults. In adults, it is difficult to diagnose nesidioblastosis with only clinical findings. The definitive diagnosis of the disease depends on the histopathological examination of pancreatic tissue and the exclusion of insulinoma.

Characterization of Notch Signalling Pathway Members in Normal Prostate, Prostatic Intraepithelial Neoplasia (PIN) and Prostatic Adenocarcinoma

Prostate Cancer (PCa) holds the second place in terms of cancer-related mortality rate among men. The Notch signalling pathway regulates the proliferation and differentiation in embryonic and adult tissues and determines the cell fate. The body of knowledge in the present literature is currently controversial about the effect of the Notch pathway on prostatic cancer. Therefore, the present study aimed to examine the immunolocalization and expression levels of Notch1-4, Jagged1-2, Delta, HES1 and HES5 from among the members of the Notch signalling pathway in tissues of normal, prostatic intraepithelial neoplasia (PIN) and malignant prostate. The current study included a sample of 20 patients with localised prostatic adenocarcinoma, 18 patients with high grade PIN (H-PIN) and 18 normal prostatic tissue. Immunolocalisations of Notch1, 2, 3, 4, Jagged1, 2, Delta, HES1 and HES5 were identified through the immunohistochemical method. The findings of the present study showed that all in-scope members of the Notch signalling pathway were localised in PIN structures to a greater extent than in other tissues and from amongst these members, specifically Notch1, Notch4, Jagged1 and HES1 were at more significant levels. Consequently, the findings of the present study may indicate that the Notch signalling pathway can play a role especially in the formation of PIN structures.

Cytomegalovirus Colitis with Common Variable Immunodeficiency and Crohn’s Disease

Here we present an eleven-year-old male patient who had been diagnosed with common variable immunodeficiency (CVID) three years ago due to recurrent sinopulmonary infections. Two years later he had been diagnosed with Crohns disease (CD) due to diarrhea episodes which were unresponsive to the treatment. Depending on the active gastrointestinal bleeding and perforation he underwent total colectomy. Despite immunoglobulin and antiviral therapies, general condition of patient deteriorated and he died in the postoperative seventh day. Laboratory analysis was seronegative. CMV inclusion containing cells were detected in postmortem biopsies taken from liver, lungs, and lymph nodes.

Echinococcus Multilocularis Infestation in the Head of the Pancreas

Primary hydatid cyst of the pancreas is extremely rare, and occurs at a rate of 0.2-2% [1]. The causative agent is often Echinococcusgranulosus (EG), which accounts for 99% of the cases. The hydatid disease caused by Echinococcusmultilocularis (EM) is less frequent when compared with EG; however, the differentiation from neoplastic lesions poses a challenge [2-5]. We present a patient who underwent surgery with clinical diagnosis of a malignant tumor of the pancreases, and in whom serological tests and pathological examination revealed EM infection.