A classical epithelial state drives acute resistance to KRAS inhibition in pancreas cancer.

Intra-tumoral heterogeneity in pancreatic ductal adenocarcinoma (PDAC) is characterized by a balance between basal and classical epithelial cancer cell states, with basal dominance associating with chemoresistance and a dismal prognosis. Targeting oncogenic KRAS, the primary driver of pancreatic cancer, shows early promise in clinical trials but efficacy is limited by acquired resistance. Using genetically engineered mouse models and patient-derived xenografts, we find that basal PDAC cells are highly sensitive to KRAS inhibitors. Employing fluorescent and bioluminescent reporter systems, we longitudinally track cell-state dynamics in vivo and reveal a rapid, KRAS inhibitor-induced enrichment of the classical state. Lineage-tracing identifies these enriched classical PDAC cells to be a reservoir for disease relapse. Genetic ablation of the classical cell-state is synergistic with KRAS inhibition, providing a pre-clinical proof-of-concept for this therapeutic strategy. Our findings motivate combining classical-state directed therapies with KRAS inhibitors to deepen responses and counteract resistance in pancreatic cancer.

Intra-ampullary Papillary Tubular Neoplasm (IAPN): Clinicopathologic Analysis of 72 Cases Highlights the Distinctive Characteristics of a Poorly Recognized Entity.

The guidelines recently recognized the intra-ampullary papillary tubular neoplasm (IAPN) as a distinct tumor entity. However, the data on IAPN and its distinction from other ampullary tumors remain limited. A detailed clinicopathologic analysis of 72 previously unpublished IAPNs was performed. The patients were: male/female=1.8; mean age=67 years (range: 42 to 86 y); mean size=2.3 cm. Gross-microscopic correlation was crucial. From the duodenal perspective, the ampulla was typically raised symmetrically, with a patulous orifice, and was otherwise covered by stretched normal duodenal mucosa. However, in 6 cases, the protrusion of the intra-ampullary tumor to the duodenal surface gave the impression of an "ampullary-duodenal tumor," with the accurate diagnosis of IAPN established only by microscopic correlation illustrating the abrupt ending of the lesion at the edge of the ampulla. Microscopically, the preinvasive component often revealed mixed phenotypes (44.4% predominantly nonintestinal). The invasion was common (94%), typically small (mean=1.2 cm), primarily pancreatobiliary-type (75%), and showed aggressive features (lymphovascular invasion in 66%, perineural invasion in 41%, high budding in 30%). In 6 cases, the preinvasive component was pure intestinal, but the invasive component was pancreatobiliary. LN metastasis was identified in 42% (32% in those with ≤1 cm invasion). The prognosis was significantly better than ampullary-ductal carcinomas (median: 69 vs. 41 months; 3-year: 68% vs. 55%; and 5-year: 51% vs. 35%, P =0.047). In conclusion, unlike ampullary-duodenal carcinomas, IAPNs are often (44.4%) predominantly nonintestinal and commonly (94%) invasive, displaying aggressive features and LN metastasis even when minimally invasive, all of which render them less amenable to ampullectomy. However, their prognosis is still better than that of the "ampullary-ductal" carcinomas, with which IAPNs are currently grouped in CAP protocols (while IAPNs are kindreds of intraductal tumors of the pancreatobiliary tract, the latter represents the ampullary counterpart of pancreatic adenocarcinoma/cholangiocarcinoma).

The effect of sleep disorders on quality of life in patients with epilepsy: A multicenter study from Turkey.

OBJECTIVE: We aimed to investigate sleep disorders in patients with epilepsy (PWE) and to investigate the effects of sleep disorders on quality of life. METHODS: In our multicenter study conducted in Turkey, 1358 PWE were evaluated. The demographic and clinical data of the patients were recorded. The Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), Beck Depression Inventory (BDI), and Quality of Life in Epilepsy Inventory-10 (QOLIE-10) were administered. RESULTS: The mean age of 1358 patients was 35.92 ±â€¯14.11 (range, 18-89) years. Seven hundred fifty-one (55.30 %) were women. Some 12.7 % of the patients had insomnia (ISI > 14), 9.6 % had excessive daytime sleepiness (ESS > 10), 46.5 % had poor sleep quality (PSQI > 5), and 354 patients (26.1 %) had depressive symptoms (BDI > 16). The mean QOLIE-10 score was 22.82 ±â€¯8.14 (10-48). Resistant epilepsy was evaluated as the parameter with the highest risk affecting quality of life Adjusted odds ratio (AOR = 3.714; 95 % confidence interval (CI): [2.440-5.652] < 0.001)). ISI (AOR = 1.184; 95 % CI: [1.128-1.243]; p < 0.001), ESS (AOR = 1.081; 95 % CI: [1.034-1.130]; p < 0.001), PSQI (AOR = 0.928; 95 % CI: [0.867 - 0.994]; p = 0.034), BDI (AOR = 1.106; 95 % CI: [1.084-1.129]; p < 0.001), epilepsy duration (AOR = 1.023; 95 % CI: [1.004-1.041]; p = 0.014), were determined as factors affecting quality of life. SIGNIFICANCE: Sleep disorders are common in PWE and impair their quality of life. Quality of life can be improved by controlling the factors that may cause sleep disorders such as good seizure control, avoiding polypharmacy, and correcting the underlying mood disorders in patients with epilepsy.

Solitary Fibrous Tumor of the Pancreas: Analysis of 9 Cases With Literature Review.

Solitary fibrous tumor (SFT) has been increasingly reported in various anatomic sites. However, it is still extremely rare in the pancreas. Herein, we present the first series of primary pancreatic SFTs. Nine cases of primary pancreatic SFTs were analyzed. The mean age was 60 years (36 to 76 y) with no sex predilection. Six tumors were in the head, 3 were in the tail. On imaging studies, tumors were described as a hypervascular mass, 2 revealed cystic areas, and 3 were favored to be neuroendocrine tumors. On biopsy, 2 cases were diagnosed as atypical spindle cell tumor; one was misdiagnosed as suspicious for sarcoma, and another case as metastatic renal cell carcinoma. Two were diagnosed as low-grade sarcoma and low-grade stromal tumor on frozen sections. Grossly, tumors were well-demarcated with a median size of 4 cm (0.9 to 15 cm). Microscopically, they were composed of ovoid to spindle tumor cells with no significant mitotic activity and were arranged in alternating hypercellular and hypocellular areas. Staghorn-like vessels and entrapped pancreatic parenchyma were also detected within all tumors. Tumor cells revealed diffuse/strong nuclear STAT6 expression in 7 of 8, CD34 in 7 of 9, and bcl-2 in 4 of 4 tested cases. One tested tumor harbored NAB2 - STAT6 fusion. Eight patients with available follow-up data were free of disease at a mean follow-up of 76 months (3 to 189 mo). SFT should be considered in the differential diagnoses of mesenchymal neoplasms of the pancreas. Immunohistochemical nuclear STAT6 expression is a characteristic feature of SFT. Primary pancreatic SFTs seem to have favorable biological behavior in our series.

Latency of epileptic and psychogenic nonepileptic seizures.

BACKGROUND: Due to their semiological similarities, psychogenic nonepileptic seizures (PNESs) can occasionally hardly be differentiated from epileptic seizures (ESs), and long-term video-electroencephalographic monitoring (VEM) is needed for the differential diagnosis. OBJECTIVE: To investigate the time of the first clinical event and its distribution on the days of VEM in ES and PNES patients. METHODS: In total, a consecutive series of 48 PNES and 51 ES patients matched for gender and age were retrospectively and consecutively evaluated. The time distribution of the seizures during the day was noted. Seizure latency was determined as the time in hours from the start of the video-electroencephalographic recording to the first clinical event. RESULTS: The seizure latency was significantly shorter in PNES patients compared to ES patients (p < 0.001). Seventy-two percent of PNES patients and 49.1% of ES patients had their first seizure in the 24 hours of video-EEG recording (p = 0.023). Recording longer than 48 hours was required for 12.5% of PNES patients and 37.3% of ES patients (p = 0.006). While ESs were almost evenly distributed throughout the day, most PNESs occurred during the evening hours (p = 0.011). CONCLUSION: We observed that the PNESs appeared earlier than the ESs in the VEM and were concentrated during daylight hours. Although not strictly reliable, seizure latency can contribute to the differential diagnosis of ES and PNES.

ANTECEDENTES: Debido a sus similitudes semiológicas, las crisis no epilépticas psicógenas (CNEP) en ocasiones apenas se pueden diferenciar de las crisis epilépticas (CE), y se necesita una monitorización video-electroencefalográfica (EEG) prolongada para el diagnóstico diferencial. OBJECTIVO: Investigar el momento del primer evento clínico y su distribución en los días de monitorización video-EEG en pacientes con CE y CNEP. MéTODOS: Se evaluó retrospectivamente a una serie consecutiva de 48 pacientes con CNEP y 51 con ES emparejados por sexo y edad. Se anotó la distribución temporal de las incautaciones durante el día. La latencia de las crisis se determinó como el tiempo en horas desde el inicio de la grabación del video-EEG hasta el primer evento clínico. RESULTADOS: La latencia de las crisis fue significativamente menor en los pacientes con CNEP en comparación con los pacientes con CE (p < 0,001). El 72% de los pacientes con CNEP y el 49,1% de los pacientes con CE tuvieron su primera crisis en las 24 horas de registro del video-EEG (p = 0,023). Se requirió un registro de más de 48 horas para el 12,5% de los pacientes con CNEP y el 37,3% de los pacientes con CE (p = 0,006). Mientras que las CE se distribuyeron casi uniformemente a lo largo del día, la mayoría de las CNEP ocurrieron durante las horas después del anochecer (p = 0,011). CONCLUSIóN: Observamos que las CNEPs aparecieron antes que las CEs en la monitorización video-EEG, y se agruparon durante las horas del día. Aunque no es estrictamente confiable, la latencia de las crisis puede contribuir al diagnóstico diferencial de ES y CNEP.

Latency of epileptic and psychogenic nonepileptic seizures / Latencia de las crisis epilépticas y psicógenas no epilépticas

Abstract Background Due to their semiological similarities, psychogenic nonepileptic seizures (PNESs) can occasionally hardly be differentiated from epileptic seizures (ESs), and long-term video-electroencephalographic monitoring (VEM) is needed for the differential diagnosis. Objective To investigate the time of the first clinical event and its distribution on the days of VEM in ES and PNES patients. Methods In total, a consecutive series of 48 PNES and 51 ES patients matched for gender and age were retrospectively and consecutively evaluated. The time distribution of the seizures during the day was noted. Seizure latency was determined as the time in hours from the start of the video-electroencephalographic recording to the first clinical event. Results The seizure latency was significantly shorter in PNES patients compared to ES patients (p < 0.001). Seventy-two percent of PNES patients and 49.1% of ES patients had their first seizure in the 24 hours of video-EEG recording (p = 0.023). Recording longer than 48 hours was required for 12.5% of PNES patients and 37.3% of ES patients (p = 0.006). While ESs were almost evenly distributed throughout the day, most PNESs occurred during the evening hours (p = 0.011). Conclusion We observed that the PNESs appeared earlier than the ESs in the VEM and were concentrated during daylight hours. Although not strictly reliable, seizure latency can contribute to the differential diagnosis of ES and PNES.

Resumen Antecedentes Debido a sus similitudes semiológicas, las crisis no epilépticas psicógenas (CNEP) en ocasiones apenas se pueden diferenciar de las crisis epilépticas (CE), y se necesita una monitorización video-electroencefalográfica (EEG) prolongada para el diagnóstico diferencial. Objectivo Investigar el momento del primer evento clínico y su distribución en los días de monitorización video-EEG en pacientes con CE y CNEP. Métodos Se evaluó retrospectivamente a una serie consecutiva de 48 pacientes con CNEP y 51 con ES emparejados por sexo y edad. Se anotó la distribución temporal de las incautaciones durante el día. La latencia de las crisis se determinó como el tiempo en horas desde el inicio de la grabación del video-EEG hasta el primer evento clínico. Resultados La latencia de las crisis fue significativamente menor en los pacientes con CNEP en comparación con los pacientes con CE (p < 0,001). El 72% de los pacientes con CNEP y el 49,1% de los pacientes con CE tuvieron su primera crisis en las 24 horas de registro del video-EEG (p = 0,023). Se requirió un registro de más de 48 horas para el 12,5% de los pacientes con CNEP y el 37,3% de los pacientes con CE (p = 0,006). Mientras que las CE se distribuyeron casi uniformemente a lo largo del día, la mayoría de las CNEP ocurrieron durante las horas después del anochecer (p = 0,011). Conclusión Observamos que las CNEPs aparecieron antes que las CEs en la monitorización video-EEG, y se agruparon durante las horas del día. Aunque no es estrictamente confiable, la latencia de las crisis puede contribuir al diagnóstico diferencial de ES y CNEP.

Prevalence of Transmitted Drug Resistance among HIV-1 Patients in the Aegean Region: Results from the Western Part of Turkey.

OBJECTIVES: This study aimed to analyze the antiretroviral drug resistance in antiretroviral treatment-naïve HIV-positive patients in the Aegean Region of Turkey from 2012 to 2019. METHODS: The study included 814 plasma samples from treatment-naïve HIV-positive patients. Drug resistance analysis was performed by Sanger sequencing (SS) between 2012-2017 and by next-generation sequencing sequencing (NGS) between 2018-2019. SS was used to analyze resistance mutations in the protease (PR) and reverse transcriptase (RT) gene regions using a ViroSeq HIV-1 Genotyping System. PCR products were analyzed with an ABI3500 GeneticAnalyzer (Applied Biosystems). The sequencing of the HIV genome in the PR, RT, and integrase gene regions was carried out using MiSeq NGS technology. Drug resistance mutations and subtypes were interpreted using the Stanford University HIV-1 drug resistance database. RESULTS: Transmitted drug resistance (TDR) mutation was detected in 34/814 (4.1 %) samples. Nonnucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI), and protease inhibitor (PI) mutations were identified in 1.4 % (n =12), 2.4 % (n =20), and 0.3 % (n = 3) of samples, respectively. The most common subtypes were B (53.1 %), A (10.9%), CRF29_BF (10.6%), and B + CRF02_AG (8,2%). The most common TDR mutations were E138A (3.4%), T215 revertants (1.7%), M41L (1.5%), and K103N (1.1%). CONCLUSION: Transmitted drug resistance rate in the Aegean Region is compatible with national and regional data. Routine surveillance of resistance mutations may guide the safe and correct selection of initial drug combinations for antiretroviral therapy. The identification of HIV-1 subtypes and recombinant forms in Turkey may contribute to international molecular epidemiological data.

A prodrug of 3-(ferrocenylaminocarbonyloxymethyl)phenol activated by reactive oxygen species in cancer cells.

Hybrid drugs containing ferrocene and phenol residues, whose π systems are not conjugated with each other, exhibit potent anticancer activity as previously reported. Few important open questions are remaining before practical application of these drugs becomes possible. First, their mode of action is not fully clarified. Second, it is not known whether these drugs exhibit cancer cell specificity. Third, due to the presence of the phenol moiety, these drugs can potentially be oxidatively deactivated and eliminated via phase II metabolism when applied in vivo. In this paper we report on synthesis of three prodrugs of aminoferrocene-phenol hybrids, where the phenolic OH group is masked as a boronic acid pinacol ester. We confirmed that the best prodrug in this small series p5 is activated in human ovarian cancer A2780 and Burkitt's lypmphoma BL-2 cells, but remains inactive in representative normal SBLF9 cells. Since p5 does not contain free phenolic OH groups, it will not be metabolized as phenols in vivo. We confirmed that the mechanism of anticancer activity of aminoferrocene-phenol prodrug p5 relies on generation of reactive oxygen species in cells.

Predictive value of 18F-FDG PET/CT indices on extensive residual cancer burden in breast cancer patients treated with neoadjuvant chemotherapy.

AIM: We investigated the correlation between 18F-FDG PET/CT indices and pathological response in breast cancer treated with neoadjuvant chemotherapy (NACT) which was scored with Residual Cancer Burden (RCB) system after surgery. Our aim is to detect extensive residual cancer burden earlier by using PET/CT indices. METHODS: Characteristics of patients were retrieved retrospectively. Baseline maximum Standart Uptake Value (SUVmax), Metabolic Tumor Volume (MTV) and Total Lesion Glycolysis (TLG) indices and reduction rate (RR) between baseline and interim evaluation were calculated with FDG PET/CT scan. All patients were evaluated according to RCB scores after surgery. Pathological responses and PET/CT measurement results were analyzed with demographic and clinical parameters. RESULTS: A total of 95 patients were included in the study. According to pathological responses, the distribution of RCB -0, -1, -2, -3 were 13 (13.7%), 11 (11.6%), 30 (31.6%), 41 (43.2%), respectively. Disease-free survival was significantly lower in the RCB3 group compared to the pathological responder group (p = 0.01). According to multivariate analysis, RR of SUVmax was determined as an independent variable predicting extensive residual cancer burden with an optimal cut-off value of 86% (p < 0.05). CONCLUSIONS: We determined RR of SUVmax as an independent factor for predicting extensive residual tumor burden. We believe that RR of SUVmax is sufficient to predict pathological response in daily practice. In addition, MTV and TLG measurements do not contribute additionally to SUVmax alone and can cause unnecessary labor loss.

Anticancer Aminoferrocene Derivatives Inducing Production of Mitochondrial Reactive Oxygen Species.

Elevated levels of reactive oxygen species (ROS) and deficient mitochondria are two weak points of cancer cells. Their simultaneous targeting is a valid therapeutic strategy to design highly potent anticancer drugs. The remaining challenge is to limit the drug effects to cancer cells without affecting normal ones. We have previously developed three aminoferrocene (AF)-based derivatives, which are activated in the presence of elevated levels of ROS present in cancer cells with formation of electron-rich compounds able to generate ROS and reduce mitochondrial membrane potential (MMP). All of them exhibit important drawbacks including either low efficacy or high unspecific toxicity that prevents their application in vivo up to date. Herein we describe unusual AF-derivatives lacking these drawbacks. These compounds act via an alternative mechanism: they are chemically stable in the presence of ROS, generate mitochondrial ROS in cancer cells, but not normal cells and exhibit anticancer effect in vivo.

Monomethine cyanine probes for visualization of cellular RNA by fluorescence microscopy.

We have studied spectral-luminescent properties of the monomethine cyanine dyes both in their free states and in the presence of either double-stranded deoxyribonucleic acids (dsDNAs) or single-stranded ribonucleic acids (RNAs). The dyes possess low fluorescence intensity in an unbound state, which is increased up to 479 times in the presence of the nucleic acids. In the presence of RNAs, the fluorescence intensity increase was stronger than that observed in the presence of dsDNA. Next, we have performed staining of live and fixed cells by all prepared dyes. The dyes proved to be cell and nuclear membrane permeant. They are photostable and brightly stain RNA-containing organelles in both live and fixed cells. The colocalization confirmed the specific nucleoli staining with anti-Ki-67 antibodies. The RNA digestion experiment has confirmed the selectivity of the dyes toward intracellular RNA. Based on the obtained results, we can conclude that the investigated monomethine cyanine dyes are useful fluorescent probes for the visualization of intracellular RNA and RNA-containing organelles such as nucleoli by using fluorescence microscopy.

Intracellular Amplifiers of Reactive Oxygen Species Affecting Mitochondria as Radiosensitizers.

Radiotherapy (RT) efficacy can be improved by using radiosensitizers, i.e., drugs enhancing the effect of ionizing radiation (IR). One of the side effects of RT includes damage of normal tissue in close proximity to the treated tumor. This problem can be solved by applying cancer specific radiosensitizers. N-Alkylaminoferrocene-based (NAAF) prodrugs produce reactive oxygen species (ROS) in cancer cells, but not in normal cells. Therefore, they can potentially act as cancer specific radiosensitizers. However, early NAAF prodrugs did not exhibit this property. Since functional mitochondria are important for RT resistance, we assumed that NAAF prodrugs affecting mitochondria in parallel with increasing intracellular ROS can potentially exhibit synergy with RT. We applied sequential Cu+-catalyzed alkyne-azide cycloadditions (CuAAC) to obtain a series of NAAF derivatives with the goal of improving anticancer efficacies over already existing compounds. One of the obtained prodrugs (2c) exhibited high anticancer activity with IC50 values in the range of 5-7.1 µM in human ovarian carcinoma, Burkitt's lymphoma, pancreatic carcinoma and T-cell leukemia cells retained moderate water solubility and showed cancer specificity. 2c strongly affects mitochondria of cancer cells, leading to the amplification of mitochondrial and total ROS production and thus causing cell death via necrosis and apoptosis. We observed that 2c acts as a radiosensitizer in human head and neck squamous carcinoma cells. This is the first demonstration of a synergy between the radiotherapy and NAAF-based ROS amplifiers.

Prognostic Role of Immune Markers in Triple Negative Breast Carcinoma.

Tumor immune microenvironment (TIME) is a significant prognostic parameter for triple negative breast carcinomas (TNBC) due to being a target for immunotherapeutic agents and its essential role during the cancer immunoediting process. In this study, CD8, FOXP3, CD163, PD-L1/SP142 and PD-L1/SP263 antibodies were examined in a sample of 51 TNBC cases. Patients who received neoadjuvant therapy were excluded. CD8, FOXP3 and CD163 antibodies were evaluated separately in intratumoral area (ITA) and tumor stroma (TS). PD-L1 status was also examined in tumor cells (TC) and immune cells (IC) using both SP142 and SP263 antibodies. In multivariate Cox regressions, the only antibody that was found to be significantly associated with survival was SP142. SP142-positivity in TC and IC was related to increased overall survival. Higher CD163 expression in ITA and SP263-positivity in IC were associated with younger age. Lymphatic/angioinvasion was more frequent in cases with negative/low CD8 and FOXP3 expressions. Moreover, metastatic axillary lymph node(s) was associated with negative/low FOXP3 expression in TS. CD8, FOXP3, CD163, SP142 and SP263 expressions were positively correlated with each other, except a mild discordance caused by CD163 in ITA. Although PD-L1 status with both SP142 and SP263 antibodies were concordant in the majority of cases, 33.3% and 13.7% of the cases showed SP142-negative/SP263-positive pattern in TC and IC respectively. In conclusion, we suggest that composition, density and localization of the immune cells and the check point molecules are important prognostic parameters in TNBC. Immunohistochemistry can be used as an accessible and less expensive tool to demonstrate TIME.

N-Alkylaminoferrocene-Based Prodrugs Targeting Mitochondria of Cancer Cells.

Intracellular concentration of reactive oxygen species (e.g., H2O2) in cancer cells is elevated over 10-fold as compared to normal cells. This feature has been used by us and several other research groups to design cancer specific prodrugs, for example, N-alkylaminoferrocene (NAAF)-based prodrugs. Further improvement of the efficacy of these prodrugs can be achieved by their targeting to intracellular organelles containing elevated reactive oxygen species (ROS) amounts. For example, we have previously demonstrated that lysosome-targeted NAAF-prodrugs exhibit higher anticancer activity in cell cultures, in primary cells and in vivo (Angew. Chem. Int. Ed. 2017, 56, 15545). Mitochondrion is an organelle, where electrons can leak from the respiratory chain. These electrons can combine with O2, generating O2-• that is followed by dismutation with the formation of H2O2. Thus, ROS can be generated in excess in mitochondria and targeting of ROS-sensitive prodrugs to these organelles could be a sensible possibility for enhancing their efficacy. We have previously reported on NAAF-prodrugs, which after their activation in cells, are accumulated in mitochondria (Angew. Chem. Int. Ed. 2018, 57, 11943). Now we prepared two hybrid NAAF-prodrugs directly accumulated in mitochondria and activated in these organelles. We studied their anticancer activity and mode of action. Based on these data, we concluded that ROS produced by mitochondria is not available in sufficient quantities for activation of the ROS-responsive prodrugs. The reason for this can be efficient scavenging of ROS by antioxidants. Our data are important for the understanding of the mechanism of action of ROS-activatable prodrugs and will facilitate their further development.

Identification of Boronic Acid Derivatives as an Active Form of N-Alkylaminoferrocene-Based Anticancer Prodrugs and Their Radiolabeling with 18F.

N-Alkylaminoferrocene (NAAF)-based prodrugs are activated in the presence of elevated amounts of reactive oxygen species (ROS), which corresponds to cancer specific conditions, with formation of NAAF and p-quinone methide. Both products act synergistically by increasing oxidative stress in cancer cells that causes their death. Though it has already been demonstrated that the best prodrugs of this type retain their antitumor activity in vivo, the effects were found to be substantially weaker than those observed in cell cultures. Moreover, the mechanistic studies of these compounds in vivo are missing. For clarification of these important questions, labeling of the prodrugs with radioactive moieties would be necessary. In this paper, we first observed that the representative NAAF-based prodrugs are hydrolyzed in dilute aqueous solutions to the corresponding arylboronic acids. We confirmed that these products are responsible for ROS amplification and anticancer properties of the parent prodrugs. Next, we developed the efficient synthetic protocol for radiolabeling the hydrolyzed NAAF-based prodrugs by [18F]fluoroglucosylation under the conditions of the copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition and used this protocol to prepare one representative hydrolyzed NAAF-based prodrug radiolabeled with 18F. Finally, we studied the stability of the 18F-labeled compound in human serum in vitro and in rat blood in vivo and obtained preliminary data on its biodistribution in vivo in mice carrying pancreatic (AR42J) and prostate (PC3) tumors by applying PET imaging studies. The compound described in this paper will help to understand in vivo effects (e.g., pharmacokinetics, accumulation in organs, the nature of side effects) of these prodrugs that will strongly contribute to their advancement to clinical trials.

Calcitonin gene related peptide gene polymorphism in migraine patients.

OBJECTIVE: Calcitonin gene related peptide (CGRP), which has a vasodilator effect, is held responsible for neurogenic inflammation and vasodilatation of the cranial vessels in migraine pathophysiology. In this study, we investigated the association between alpha CGRP gene polymorphism (CALCA T-692C) and migraine. MATERIAL AND METHODS: One hundred and thirty-four female migraineurs and 96 healthy female cases were enrolled in the study. The patient group was further subdivided into migraine with and without aura groups. The CALCA T-692C gene polymorphism was identified using polymerase chain reaction (PCR) technique and restriction fragment length polymorphism (RFLP). RESULTS: The genotype and allele frequencies of CALCA T-692C gene polymorphism did not differ between the migraine and control groups. Between the migraine with and without aura subgroups, there was no difference. No association was seen between the CALCA T-692C gene polymorphisms and migraine attack severity and frequency. CONCLUSION: Our study did not show any association between CALCA T-692C gene polymorphism and migraine.

Necrotizing enterocolitis in a newborn following intravenous immunoglobulin treatment for haemolytic disease.

ABO iso-immunization is the most frequent haemolytic disease of the newborn. Treatment depends on the total serum bilirubin level, which may increase very rapidly in the first 48 hours of life in cases of haemolytic disease of the newborn. Phototherapy and, in severe cases, exchange transfusion are used to prevent hyperbilirubinaemic encephalopathy. Intravenous immunoglobulins (IVIG) are used to reduce exchange transfusion. Herein, we present a female newborn who was admitted to the NICU because of ABO immune haemolytic disease. After two courses of 1 g/kg of IVIG infusion, she developed necrotizing enterocolitis (NEC). Administration of IVIG to newborns with significant hyperbilirubinaemia due to ABO haemolytic disease should be cautiously administered and followed for complications.

Endothelial Nitric Oxide Synthase and Angiotensin Converting Enzyme Gene Polymorphisms in Migraine Patients.

INTRODUCTION: In this study, we investigated the association of migraine with the Variable Number of Tandem Repeats (VNTR), repeated as 27 base pair, gene polymorphism in intron 4 of the endothelial nitric oxide synthase (eNOS) and the insertion/deletion of angiotensin converting enzyme (ACE) gene polymorphisms. METHODS: One hundred and five migraine and ninety seven healthy female control subjects were enrolled in the study. The patients were subdivided as migraine with aura and without aura, and the frequency and severity of migraine headaches were recorded. The eNOS VNTR (eNOS 4 a/b) and ACE insertion/deletion gene polymorphisms (ACE I/D) were assessed by polymerase chain reactions. RESULT: The allele and genotype frequencies of eNOS 4 a/b gene polymorphism showed no difference between the migraine and control groups. The genotypic distribution of the ACE I/D gene polymorphism in the migraine group significantly differed from that in the control group. The DD and ID genotype increased the risk of migraine as much as 2.571 (95% CI-1.138-5.811) and 4.453 (95% CI-2.006-9.883) compared to the II genotype. The same increased risk sustained for both genotypes in the migraine with aura subgroup, but only the ID genotype remained as the risk factor in the migraine without aura subgroup (OR-3.750, 95% CI-1.493-9.420). No association of gene polymorphisms with migraine frequency and severity was observed. CONCLUSION: Our findings support the relationship between migraine and the ACE I/D gene polymorphism. However, no association was found between migraine and the eNOS 4 a/b gene polymorphism.

[Incidence of intestinal parasites detected in the Department of Parasitology in Celal Bayar University Hospital between 2006 and 2010]. / Celal Bayar Üniversitesi Hastanesi Parazitoloji Poliklinigi'nde 2006-2010 Yillari Arasinda Saptanan Bagirsak Parazitlerinin Insidansi

OBJECTIVE: Results of 17.711 patien admitted to the Department of Parasitology in Celal Bayar University Hospital for parasitological stool examination between January 2006 and December 2010 were evaluated. METHODS: All stool samples were examined with wet mounts, formalin ethyl acetate concentration and trichrome staining methods. In addition, cellophane tape preparations from 5952 patients were evaluated. RESULTS: Intestinal parasites were detected in 2337 (13.12%) of 17.711 patients who were admitted during a five year period. The highest parasite infected individual ratio (16.69%) was found in 2008. The most frequently identified intestinal parasites were Blastocystis spp. 1353 (7.64%) and Giardia intestinalis 348 (1.96%) in stool samples, with Enterobius vermicularis 253 (4.25%) in cellophane tape preparations. Two or more parasites were detected in 158 (6.76%) of the positive cases. The mean age of persons identified as having a parasite was 21.9. Parasite incidence was 10.7% in females, and 13.6% in males (p < 0.001). The highest ratio was 23.8% in patients who lived in rural areas when all positive cases were evaluated in terms of settlement areas. CONCLUSION: While Blastocystis spp., E. vermicularis and G. intestinalis were the most frequently detected intestinal parasites in our province, intestinal parasites still remain important despite advances in infrastructure in recent years.