👤 Hakan Ozturk

The nervous system is increasingly recognized as a dynamic and regulatory component of the tumor microenvironment playing critical roles in cancer initiation, progression, metastasis, and resistance to therapy. Recent evidence in cancer neuroscience have revealed a specialized "neural niche" a microanatomical and functional domain enriched in neural inputs and neuromodulatory signals orchestrated through bidirectional communication between tumor, nervus system and immune cellsCancer cells secrete neurotrophic factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) to attract and remodel peripheral innervation. Infiltrating nerve fibers, in turn, release neurotransmitters (e.g., norepinephrine, acetylcholine) and neuropeptides (e.g., substance P, calcitonin gene-related peptide) that influence not only tumor growth, angiogenesis but also immune cell polarization, T cell exhaustion, dendritic cell maturation and myeloid derived suppressor cell recruitment. This neural-immune crosstalk establishes immune suppressive microenvironment that facilitates tumor immune escape and leading to metastatic progression. Perineural invasion (PNI), a distinct pathological process of tumor dissemination, further exemplifies neuroepithelial integration and correlates with recurrence, pain and poor prognosis across multiple solid tumors. Beyond local interactions, chronic stress and systemic neuroendocrine activation via the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic-adrenal-medullary networks, contribute to tumor-promoting immunosuppression through glucocorticoid signaling and sympathetic responses. In this review, we discuss mechanistically integrated and clinical relevant synthesis of tumor-neuron-immune interactions. We emphasize recent conceptual advances, including autonomic balance, systemic neuroendocrine feedback and therapeutic strategies targeting this axis. These insights establish a framework for future translational research and development of neuromodulatory therapies that complement immunotherapy as well as conventional therapeutics. Show less

Aging in dogs is a multifactorial process involving behavioral, cognitive, immunological, and microbiota-related changes, yet distinguishing healthy from pathological aging remains challenging. This exploratory study aimed to evaluate physiological indicators of health by integrating pain evaluation and cognitive testing in senior companion dogs. Eighteen companion dogs aged ≥8 years underwent standardized behavioral and cognitive evaluations (Mini C-BARQ, DISHAA, object choice test), chronic pain assessment (Helsinki Chronic Pain Index), and quality-of-life (QoL) scoring. Hematological parameters, serum brain-derived neurotrophic factor (BDNF), and Th1/Th2 ratios were measured as physiological indicators, while fecal samples were analyzed via 16S rRNA sequencing for microbiota profiling. All dogs scored above the chronic pain threshold (mean HCPI: 28.72), although caregiver-reported QoL ratings suggested good overall wellbeing. Cognitive testing yielded low average scores on the DISHAA (mean: 9.05), with only one dog showing mild cognitive decline; however, mean performance on the object choice test was low (1.94/5). Mean serum BDNF concentration was 0.154 ng/dL (SD: 0.082) and correlated positively with red blood cell (RBC) count and negatively with MCV, MCH, and MCHC ( These preliminary findings highlight potential interactions between pain, microbiota composition, and immune dysregulation, suggesting their possible utility as candidate indicators for differentiating healthy from pathological aging in dogs. Show less

Insulin resistance is considered the most important key mechanism in the development of nonalcoholic fatty liver disease (NAFLD). Some studies have reported that hyperinsulinemia decreases the hepatic secretion of apolipoprotein (Apo) B. Chronic hyperinsulinemia in NAFLD may be responsible for the accumulation of triglycerides in hepatocytes. We aimed to investigate whether apolipoproteins are related to histological findings in patients with biopsy-proven NAFLD. We also aimed to evaluate the effects of obesity on apolipoproteins and the pathogenesis of NAFLD. In this cross-sectional study, 91 patients with biopsy-proven NAFLD were included. The control group consisted of 39 healthy subjects who had no history of liver disease or alcohol consumption and were matched for age, gender and smoking. Apoliprotein A1 and Apo B were measured via an immunoturbidimetric method with commercially available OSR6142 Apo A1 and OSR6143 Apo B immunoassay kits on an Olympus AU2700 analyzer. Age, gender, and smoking distribution were similar among nonalcoholic steatohepatitis patients, simple steatosis patients, and controls. The differences in the mean Apo A1 and Apo B levels and the Apo B/A1 ratio among non-alcoholic steatosis, simple steatosis, and control subjects did not reach statistical significance. In addition, patients with obese NAFLD had higher steatosis scores than patients with nonobese NAFLD (p<0.05). Apo A1 and B levels and the B/A1 ratio were not associated with histopathological findings in patients with NAFLD. Fibrosis and ApoB1/A were found to be independent risk factors for metabolic associated fatty liver disease. In addition, obesity increases the grade of hepatic steatosis but does not cause lobular inflammation, ballooning or fibrosis. Show less

Koolen-de Vries syndrome (KdVS) is a rare multisystemic disorder caused by a microdeletion on chromosome 17q21.31 including KANSL1 gene or intragenic pathogenic variants in KANSL1 gene. Here, we describe the clinical and genetic spectrum of eight Turkish children with KdVS due to a de novo 17q21.31 deletion, and report on several rare/new conditions. Eight patients from unrelated families aged between 17 months and 19 years enrolled in this study. All patients evaluated by a clinical geneticist, and the clinical diagnosis were confirmed by molecular karyotyping. KdVS patients had some common distinctive facial features. All patients had neuromotor retardation, and speech and language delay. Epilepsy, structural brain anomalies, ocular, ectodermal, and musculoskeletal findings, and friendly personality were remarkable in more than half of the patients. Hypertension, hypothyroidism, celiac disease, and postaxial polydactyly were among the rare/new conditions. Our study contributes to the clinical spectrum of patients with KdVS, while also provide a review by comparing them with previous cohort studies. Show less

Embryonic poly(A)-binding protein (EPAB) is an RNA-binding protein that binds to the poly(A) tails and AU-rich element at the 3' ends of messenger RNA (mRNAs). The main functions of EPAB are to protect stored mRNAs from undergoing deadenylation and subsequent degradation and to be involved in their translational regulation during spermatogenesis, oogenesis, and early embryogenesis. Following the first characterization of Epab in the Xenopus oocytes and early embryos, spatial and temporal expression and potential roles of the Epab gene have been determined in the vertebrate germ cells and early embryos. In this review, we have comprehensively evaluated all studies in this field and discussed the particular functions of EPAB in the spermatogenic cells, oocytes, early embryos, and somatic cells in vertebrates. Show less

Hepatocellular carcinoma (HCC) represents a major form of primary liver cancer in adults. Chronic infections with hepatitis B (HBV) and C (HCV) viruses and alcohol abuse are the major factors leading to HCC. This deadly cancer affects more than 500,000 people worldwide and it is quite resistant to conventional chemo- and radiotherapy. Genetic and epigenetic studies on HCC may help to understand better its mechanisms and provide new tools for early diagnosis and therapy. Recent literature on whole genome analysis of HCC indicated a high number of mutated genes in addition to well-known genes such as TP53, CTNNB1, AXIN1 and CDKN2A, but their frequencies are much lower. Apart from CTNNB1 mutations, most of the other mutations appear to result in loss-of-function. Thus, HCC-associated mutations cannot be easily targeted for therapy. Epigenetic aberrations that appear to occur quite frequently may serve as new targets. Global DNA hypomethylation, promoter methylation, aberrant expression of non-coding RNAs and dysregulated expression of other epigenetic regulatory genes such as EZH2 are the best-known epigenetic abnormalities. Future research in this direction may help to identify novel biomarkers and therapeutic targets for HCC. Show less

Human breast cancer displays nuclear accumulation of beta-catenin and induction of cyclin D1 expression, which suggests that canonical Wnt/beta-catenin signaling is activated. In other cancers, the activation of canonical wnt/beta-catenin signaling is associated with APC, CTNNB1 or AXIN1 mutations. However, these mutations are rare or absent in breast cancer. In search of alternative mechanisms, we performed comprehensive expression analysis of Wnt signaling molecules, including 19 Wnt ligands, ten Frizzled receptors, two co-receptors and four Lef/TCF transcription factors in immortalized normal human mammary epithelial cells (HMEC) and six breast cancer cell lines. HMEC expressed all Frizzled receptors except FZD9 and FZD10. They also expressed LRP5 and LRP6 co-receptors, as well as four Lef/TCF transcription factors. HMEC cells also expressed many Wnt ligands, including WNT1, WNT2B, WNT3, WNT5A, WNT5B, WNT7B, WNT9A, WNT10B and WNT16. Redundant expression of Wnt ligands, Frizzled receptors, co-receptors and Lef/TCF transcription factors was maintained in breast cancer cell lines with some exceptions. The most important changes in cancer cell lines concerned Wnt ligand expression. We noticed that most breast cancer cell lines overexpressed WNT3A, WNT4, WNT6, WNT8B, WNT9A and WNT10B. In contrast, the expression of WNT5A, WNT5B and WNT16 was usually down-regulated. It is noteworthy that all six Wnt ligands that are overexpressed in malignant cell lines are known to signal through the canonical Wnt/beta-catenin signaling pathway, whereas down-regulated WNT5A and WNT5B ligands signal via the non-canonical pathway. The expression of both canonical Wnt ligands and most Frizzled receptors in breast cancer cell lines suggests that canonical Wnt/beta-catenin signaling is activated in these cell lines by an autocrine/paracrine mechanism. In support of this prediction, we observed nuclear beta-catenin accumulation and cyclin D1 induction in breast cancer cell lines, but not in HMEC. These results imply that ligand-dependent canonical Wnt/beta-catenin signaling is active in human breast cancer. Show less

We studied in vitro effects of glycogen synthase kinase 3beta (GSK3beta)-inhibitor lithium on the growth of hepatocellular carcinoma (HCC) cells. Lithium induced strong growth inhibition (> 70%) in 75% (n = 9 of 12) of cell lines, apparently independent from the status of major genes that are mutated in HCC including p53, p16(INK4a), beta-catenin and Axin1. Comparative studies with a growth-sensitive Huh7 and growth-resistant Hep40 cell lines showed that lithium induces growth arrest in Huh7 cells but not in Hep40 cells. Lithium induced the accumulation of N-terminally phosphorylated inactive form of GSK3beta with concomitant increase in beta-catenin and beta-catenin/TCF transcriptional activity in both cell lines. This suggests that lithium-mediated HCC growth inhibition is independent of its well-known stimulatory effect on Wnt-beta-catenin signaling. The main differences between Huh7 and Hep40 responses to lithium treatment were observed at the levels PKB/Akt and cyclin E proteins. Lithium induced depletion of both proteins in growth-sensitive Huh7, but not in growth-resistant Hep40 cells. PKB/Akt and Cyclin E are 2 major proteins that are known to be constitutively active in HCC. The targeting of both proteins with lithium may be the main reason why most HCC cells are responsive to lithium-mediated growth inhibition, independent of their p53, retinoblastoma and Wnt-beta-catenin pathways. The exploration of molecular mechanisms involved in lithium-mediated growth inhibition in relation with PKB/Akt and cyclin E downregulation may provide new insights for therapy of liver tumors. Show less

beta-catenin is involved in both cell-cell interactions and wnt pathway-dependent cell fate determination through its interactions with E-cadherin and TCF/LEF transcription factors, respectively. Cytoplasmic/nuclear levels of beta-catenin are important in regulated transcriptional activation of TCF/LEF target genes. Normally, these levels are kept low by proteosomal degradation of beta-catenin through Axin1- and APC-dependent phosphorylation by CKI and GSK-3beta. Deregulation of beta-catenin degradation results in its aberrant accumulation, often leading to cancer. Accordingly, aberrant accumulation of beta-catenin is observed at high frequency in many cancers. This accumulation correlates with either mutational activation of CTNNB1 (beta-catenin) or mutational inactivation of APC and Axin1 genes in some tumors. However, there are many tumors that display beta-catenin accumulation in the absence of a mutation in these genes. Thus, there must be additional sources for aberrant beta-catenin accumulation in cancer cells. Here, we provide experimental evidence that wild-type beta-catenin accumulates in hepatocellular carcinoma (HCC) cells in association with mutational inactivation of p53 gene. We also show that worldwide p53 and beta-catenin mutation rates are inversely correlated in HCC. These data suggest that inactivation of p53 is an important cause of aberrant accumulation of beta-catenin in cancer cells. Show less