Reinvestigation of the internal glycan rearrangement of Lewis a and blood group type H1 epitopes.

Protonated ions of fucose-containing oligosaccharides are prone to undergo internal glycan rearrangement which results in chimeric fragments that obfuscate mass-spectrometric analysis. Lack of accessible tools that would facilitate systematic analysis of glycans in the gas phase limits our understanding of this phenomenon. In this work, we use density functional theory modeling to interpret cryogenic IR spectra of Lewis a and blood group type H1 trisaccharides and to establish whether these trisaccharides undergo the rearrangement during gas-phase analysis. Structurally unconstrained search reveals that none of the parent ions constitute a thermodynamic global minimum. In contrast, predicted collision cross sections and anharmonic IR spectra provide a good match to available experimental data which allowed us to conclude that fucose migration does not occur in these antigens. By comparing the predicted structures with those obtained for Lewis x and blood group type H2 epitopes, we demonstrate that the availability of the mobile proton and a large difference in the relative stability of the parent ions and rearrangement products constitute the prerequisites for the rearrangement reaction.

High-Risk Human Papilloma Virus Genotype Distribution and Correlation with Cervical Cytomorphological Data in Turkish and Immigrant Women in Mersin Province.

Human papilloma virus (HPV) is the most common sexually transmitted viral agent in the world and the most common cause of cervical cancer. HPV prevalence and genotype distribution vary by region and demographic data. In a province in the south of Turkey that constantly receives immigration, we aimed to determine the prevalence of high-risk HPV (HR-HPV) genotypes, evaluate the compatibility between cervical Pap smear cytology results patients and HR-HPVs, and make an up-to-date contribution to the elucidation of epidemiological data. In this single-centre study, a total of 12,641 women aged 18 and over were evaluated retrospectively from January 2019 to July 2022. HPV detection and genotyping were analysed by the PCR method. Bethesda scoring was used for Pap smear cytological evaluation. The overall prevalence of HR-HPV was 12.6% (12.7% in Turkish women, 11.2% in foreign women). Among the typed HPVs that were detected, HPV-16 (31%) was found first, followed by HPV-18 (8%). The prevalence of HR-HPV was higher in women with abnormal cytology (977/1762, 55.4%) than in women with normal cytology (620/10879, 5.7%) (p<0.001). Turkey doesn't yet have a national HPV immunisation program. We think that determining the specific regional frequency of other HR-HPVs separately will be useful in the follow-up of the natural course of the type-specific infection and in vaccine studies in the future.

Determination of hepatitis C virus viremia and genotype distribution in Turkish citizens and immigrants from 2018 to 2022.

Hepatitis C virus (HCV) infection is an important public health problem with potential risk for Turkey. In order to contribute to the epidemiological data, we aimed to investigate the changes in seroprevalence, viremia rates, and genotypes in the last five years in HCV patients in the southern region of Turkey, which has received heavy migration in recent years, according to demographic criteria. In our study, we analyzed the results retrospectively with demographic data. Conducted at a single center, the study involved 259,875 anti-HCV antibody tests administered between January 2018 and July 2022. The study revealed a prevalence of 0.5% for HCV antibody positivity and a viremia prevalence of 0.1%. Among Turkish nationals, the most common genotypes were GT1 (65.1%), while foreign nationals, mainly of Syrian and Ukrainian origin, showed GT4 (52.3%) as the predominant genotype (p<0.001 for both). Although GT2 (7.4% vs. 4.5%) and GT3 (23.3% vs. 13.6%) were relatively higher in Turkish nationals compared to foreign nationals, the difference was not statistically significant (p=0.750 and p=0.154, respectively). This highlights the importance of continuous monitoring and public health efforts to address the potential impact of these demographic shifts on HCV epidemiology in the region.

Decoding the Fucose Migration Product during Mass-Spectrometric analysis of Blood Group Epitopes.

Fucose is a signaling carbohydrate that is attached at the end of glycan processing. It is involved in a range of processes, such as the selectin-dependent leukocyte adhesion or pathogen-receptor interactions. Mass-spectrometric techniques, which are commonly used to determine the structure of glycans, frequently show fucose-containing chimeric fragments that obfuscate the analysis. The rearrangement leading to these fragments-often referred to as fucose migration-has been known for more than 25 years, but the chemical identity of the rearrangement product remains unclear. In this work, we combine ion-mobility spectrometry, radical-directed dissociation mass spectrometry, cryogenic IR spectroscopy of ions, and density-functional theory calculations to deduce the product of the rearrangement in the model trisaccharides Lewis x and blood group H2. The structural search yields the fucose moiety attached to the galactose with an α(1→6) glycosidic bond as the most likely product.

Design, synthesis and anticancer/antiestrogenic activities of novel indole-benzimidazoles.

Indole-benzimidazoles have recently gained attention due to their antiproliferative and antiestrogenic effects. However, their structural similarities and molecular mechanisms shared with selective estrogen receptor modulators (SERMs) have not yet been investigated. In this study, we synthesized novel ethylsulfonyl indole-benzimidazole derivatives by substituting the first (R1) and fifth (R2) positions of benzimidazole and indole groups, respectively. Subsequently, we performed 1H NMR, 13C NMR, and Mass spectral and in silico docking analyses, and anticancer activity screening studies of these novel indole-benzimidazoles. The antiproliferative effects of indole-benzimidazoles were found to be more similar between the estrogen (E2) responsive cell lines MCF-7 and HEPG2 in comparison to the Estrogen Receptor negative (ER-) cell line MDA-MB-231. R1:p-fluorobenzyl group members were selected as lead compounds for their potent anticancer effects and moderate structural affinity to ER. Microarray expression profiling and gene enrichment analyses (GSEA) of the selected compounds (R1:p-fluorobenzyl: 48, 49, 50, 51; R1:3,4-difluorobenzyl: 53) helped determine the similarly modulated cellular signaling pathways among derivatives. Moreover, we identified known compounds that have significantly similar gene signatures to that of 51 via queries performed in LINCS database; and further transcriptomics comparisons were made using public GEO datasets (GSE35428, GSE7765, GSE62673). Our results strongly demonstrate that these novel indole-benzimidazoles can modulate ER target gene expression as well as dioxin-mediated aryl hydrocarbon receptor and amino acid deprivation-mediated integrated stress response signaling in a dose-dependent manner.

Modified Temporalis Muscle Flap for Eyelid Reanimation.

The reanimation of both upper and lower paralytic eyelids requires dynamic procedures for longevity of correction. Temporalis muscle ensures the criteria for reanimation and is used widely as a result. Many modifications were described to improve the success of the classical technique. One of these modifications was reported by the senior author in 1999. Twice as much muscle mass (in thickness) to the upper eyelid than the lower was taken and passed submuscularly 5 to 6 mm away from the limbus and a thinner split was passed subcutaneously beneath the lower cilia. The aim of this study was to present the outcomes of the technique after 38 operations with 37 patients and to describe deep temporalis musculofascial-fatty flap to recover depression of temporalis muscle split donor area. Seventeen lower eyelids were evaluated as mild, 12 were as moderate, and 9 were as severe ectropion. One upper eyelid was evaluated as mild, 14 were as moderate, and 23 were as severe lagophthalmos preoperatively. Mean follow-up time was 28.8 months. Five patients had mild ectropion and 2 patients had mild lagophthalmos postoperatively at last follow-up. Two patients needed medial canthal tendon reinsertion secondary to relaxation of fixation suture at medial canthus. All patients tolerated the procedure and all complaints were resolved without creating a notable cosmetic deformity.

Clinicopathological characteristics and mutation profile of BRAF and NRAS mutation in cutaneous melanomas in the Western Turkish population

Background/aim: Malignant melanoma is the most common cause of death due to skin cancers. The most common mutations in RAFRAS pathway from tumor oncogenes are BRAF and NRAS. In this study, we analyzed the frequency of BRAF and NRAS gene mutations and investigated their association with clinicopathological features of melanomas in the Turkish population. Materials and methods: 65 primary cutaneous melanoma were included in the study. The mutations were evaluated with real-time PCRbased PCR-array through allele-specific amplification, and the results were correlated with various clinicopathological characteristics. Results: 52.3% of the patients were female and 47.7% were male. The mean age of the patients with a mutation was lower than those without mutation. 16 patients had BRAF mutation. 12 patients had NRAS mutation. NRAS mutation was statistically more common in men (P = 0.036). The number of mitoses increased with the increase of the tumor thickness (P = 0.003). There was more mitosis in the presence of ulceration (P = 0.05). A total of 41.7% of NRAS mutations had adjuvant chemotherapy. Conclusion: We found lower mutation rate when compared to regional studies. NRAS mutation was common in men. This is the first study from our region evaluating the prognostic value of clinical stage and necessity of adjuvant treatment with the presence of BRAF and NRAS mutations.

Synthesis and Structure of Novel Phenothiazine Derivatives, and Compound Prioritization via In Silico Target Search and Screening for Cytotoxic and Cholinesterase Modulatory Activities in Liver Cancer Cells and In Vivo in Zebrafish.

Phenothiazines (PTZ) are antipsychotics known to modulate a variety of neurotransmitter activities that include dopaminergic and cholinergic signaling and have been identified as potential anticancer agents in vitro. However, it is important to also test whether a highly cytotoxic, repurposed, or novel PTZ has low toxicity and neuromodulatory activity in vivo using vertebrate model organisms, such as zebrafish. In this study, we synthesized novel phenothiazines and screened them in vitro in liver cancer and in vivo in zebrafish embryos/larvae. The syntheses of several intermediate PTZ 10-yl acyl chlorides were followed by elemental analysis and determination of 1H NMR and 13C NMR mass (ESI+) spectra of a large number of novel PTZ 10-carboxamides. Cytotoxicities of 28 PTZ derivatives (1-28) screened against Hep3B and SkHep1 liver cancer cell lines revealed five intermediate and five novel leads along with trifluoperazine (TFP), prochlorperazine (PCP), and perphenazine, which are relatively more cytotoxic than the basic PTZ core. Overall, the derivatives were more cytotoxic to Hep3B than SkHep1 cells. Moreover, in silico target screening identified cholinesterases as some of the commonest targets of the screened phenothiazines. Interestingly, molecular docking studies with acetylcholinesterase (AChE) and butyrylcholinesterase proteins showed that the most cytotoxic compounds 1, 3, PCP, and TFP behaved similar to Huprin W in their amino acid interactions with the AChE protein. The highly cytotoxic intermediate PTZ derivative 1 exhibited a relatively lower toxicity profile than those of 2 and 3 during the zebrafish development. It also modulated in vivo the cholinesterase activity in a dose-dependent manner while significantly increasing the total cholinesterase activity and/or ACHE mRNA levels, independent of the liver cancer cell type. Our screen also identified novel phenothiazines, i.e., 8 and 10, with significant cytotoxic and cholinesterase modulatory effects in liver cancer cells; yet both compounds had low levels of toxicity in zebrafish. Moreover, they modulated the cholinesterase activity or expression of ACHE in a cancer cell line-specific manner, and compound 10 significantly inhibited the cholinesterase activity in zebrafish. Accordingly, using a successful combination of in silico, in vitro, and in vivo approaches, we identified several lead anticancer and cholinesterase modulatory PTZ derivatives for future research.

Interplay between HIV and Human Pegivirus (HPgV) Load in Co-Infected Patients: Insights from Prevalence and Genotype Analysis.

Human pegivirus (HPgV) is transmitted through sexual or parenteral exposure and is common among patients receiving blood products. HPgV is associated with lower levels of human immunodeficiency virus (HIV) RNA and better survival among HIV-infected patients. This study aimed to investigate the prevalence of HPgV and determine its subtypes in HIV-infected individuals living in Istanbul, which has the highest rate of HIV infection in Türkiye. Total RNA extraction from plasma, cDNA synthesis, and nested PCR were performed for HPgV on plasma samples taken from 351 HIV-1-infected patients. The HPgV viral load was quantified on HPgV-positive samples. HPgV genotyping was performed by sequencing the corresponding amplicons. In the present study, the overall prevalence of HPgV RNA in HIV-infected patients was 27.3%. HPgV subtypes 1, 2a, and 2b were found, with subtype 2a being the most frequent (91.6%). Statistical analysis of HIV-1 viral load on HPgV viral load showed an opposing correlation between HIV-1 and HPgV loads. In conclusion, these data show that HPgV infection is common among HIV-positive individuals in Istanbul, Türkiye. Further comprehensive studies are needed to clarify both the cellular and molecular pathways of these two infections and to provide more information on the effect of HPgV on the course of the disease in HIV-infected individuals.

Crystal-to-Crystal Transition and the Structure Development of Electrospun Poly(ethylene 2,6 naphthalate) (PEN) Nanofibers from Solution.

Poly(ethylene naphthalate) (PEN) nanofiber membranes were prepared using hexafluoroisopropanol (HFIP) as a solvent. Crystallization and conformation of PEN nanofibers were characterized for the first time by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and Raman spectroscopy. SEM micrographs revealed that the size and uniformity of nanofibers depended on the PEN concentration in HFIP solution. DSC results showed that cold crystallization temperature (Tcc) decreased and the crystallinity of PEN nanofibers increased with increasing the concentration of spinning PEN/HFIP solution. FTIR and Raman spectroscopies showed that PEN nanofibers formed metastable ß-crystals during electrospinning due to the fast evaporation of a solvent, while the concentration of spinning solution did not affect the crystal form of as-prepared PEN nanofibers. Upon annealing of PEN nanofiber membranes above 140 °C, metastable ß-crystals were transformed into the thermodynamically most stable α-crystals. Our polarized FTIR spectroscopic studies revealed that no molecular orientation was developed when fibers were collected randomly.

Case Report: Gorham-Stoute Syndrome with Involvement of Majority of Mandible, and Partial Maxillary, Temporal and Zygomatic Bones.

The Gorham-Stout syndrome is a rare condition in which spontaneous, progressive resorption of bone occurs. The diagnosis is based on clinical, radiological and histopathological findings after excluding other etiologies and as a result it is often delayed. We present the case of a 21-year-old male diagnosed with Gorham-Stout syndrome with involvement of the majority of the mandible, partial involvement of right maxillary, temporal and zygomatic bones and discuss its diagnostic and therapeutic features.