Small Warriors of Nature: Novel Red Emissive Chlorophyllin Carbon Dots Harnessing Fenton-Fueled Ferroptosis for In Vitro and In Vivo Cancer Treatment.

The appeal of carbon dots (CDs) has grown recently, due to their established biocompatibility, adjustable photoluminescence properties, and excellent water solubility. For the first time in the literature, copper chlorophyllin-based carbon dots (Chl-D CDs) are successfully synthesized. Chl-D CDs exhibit unique spectroscopic traits and are found to induce a Fenton-like reaction, augmenting photodynamic therapy (PDT) efficacies via ferroptotic and apoptotic pathways. To bolster the therapeutic impact of Chl-D CDs, a widely used cancer drug, temozolomide, is linked to their surface, yielding a synergistic effect with PDT and chemotherapy. Chl-D CDs' biocompatibility in immune cells and in vivo models showed great clinical potential.Proteomic analysis was conducted to understand Chl-D CDs' underlying cancer treatment mechanism. The study underscores the role of reactive oxygen species formation and pointed toward various oxidative stress modulators like aldolase A (ALDOA), aldolase C (ALDOC), aldehyde dehydrogenase 1B1 (ALDH1B1), transaldolase 1 (TALDO1), and transketolase (TKT), offering a deeper understanding of the Chl-D CDs' anticancer activity. Notably, the Chl-D CDs' capacity to trigger a Fenton-like reaction leads to enhanced PDT efficiencies through ferroptotic and apoptotic pathways. Hence, it is firmly believed that the inherent attributes of Chl-CDs can lead to a secure and efficient combined cancer therapy.

An innovative method for the detection of alpha synuclein, a potential biomarker of Parkinson's disease: quartz tuning fork-based mass sensitive immunosensor design.

An innovative biosensing fabrication strategy has been demonstrated for the first time using a quartz tuning fork (QTF) to develop a practical immunosensor for sensitive, selective and practical analysis of alpha synuclein protein (SYN alpha), a potential biomarker of Parkinson's disease. Functionalization of gold-coated QTFs was carried out in 2 steps by forming a self-assembled monolayer with 4-aminothiophenol (4-ATP) and conjugation of gold nanoparticles (AuNPs). The selective determination range for SYN alpha of the developed biosensor system is 1-500 ng mL-1 in accordance with the resonance frequency shifts associated with a limit of detection of 0.098 ng mL-1. The changes in surface morphology and elemental composition were evaluated using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and energy-dispersive X-ray spectroscopy (EDX). The remarkable point of the study is that this QTF based mass sensitive biosensor system can capture the SYN alpha target protein in cerebrospinal fluid (CSF) samples with recoveries ranging from 92% to 104%.

The effect of thoracic trauma scoring system in thoracic trauma patients with rib fracture.

OBJECTIVE: Rib fractures are common in thoracic trauma patients. There are various factors, including flail chest, pulmonary contusion, and accompanying conditions, affecting morbidity and mortality. The study aimed to identify high-risk patients for morbidity and mortality with a scoring system that the authors created. METHODS: Cases over the age of 18 admitted due to trauma and diagnosed with rib fractures between 1 January 2019 and 1 March 2023, were included. Trauma scores were determined by applying the new trauma scoring system. Trauma scores and other variables regarding morbidity and mortality were evaluated. RESULTS: A total of 1023 cases were included in the study. The total trauma scores were higher in bilateral and multiple fractures. In those without respiratory failure, the total score was statistically significantly lower than in the groups with respiratory failure. The total score was significantly higher in those who needed surgery, those who were hospitalized, and those who needed intensive care compared to the non-surgical groups. However, there was no correlation between intensive care unit stay and total score. Trauma mechanism, presence of additional extrathoracic pathology, and thoracic trauma-age score were independent predictors of survival. CONCLUSION: The present study demonstrated that the number of rib fractures and the presence of pulmonary contusion did not have an effect on mortality and morbidity. The presence of extrathoracic pathology and age significantly affect survival.

Clinical features of generalized lipodystrophy in Turkey: A cohort analysis.

AIM: To describe the Turkish generalized lipodystrophy (GL) cohort with the frequency of each complication and the death rate during the period of the follow-up. METHODS: This study reports on 72 patients with GL (47 families) registered at different centres in Turkey that cover all regions of the country. The mean ± SD follow-up was 86 ± 78 months. RESULTS: The Kaplan-Meier estimate of the median time to diagnosis of diabetes and/or prediabetes was 16 years. Hyperglycaemia was not controlled in 37 of 45 patients (82.2%) with diabetes. Hypertriglyceridaemia developed in 65 patients (90.3%). The Kaplan-Meier estimate of the median time to diagnosis of hypertriglyceridaemia was 14 years. Hypertriglyceridaemia was severe (≥ 500 mg/dl) in 38 patients (52.8%). Seven (9.7%) patients suffered from pancreatitis. The Kaplan-Meier estimate of the median time to diagnosis of hepatic steatosis was 15 years. Liver disease progressed to cirrhosis in nine patients (12.5%). Liver disease was more severe in congenital lipodystrophy type 2 (CGL2). Proteinuric chronic kidney disease (CKD) developed in 32 patients (44.4%) and cardiac disease in 23 patients (31.9%). Kaplan-Meier estimates of the median time to diagnosis of CKD and cardiac disease were 25 and 45 years, respectively. Females appeared to have a more severe metabolic disease, with an earlier onset of metabolic abnormalities. Ten patients died during the follow-up period. Causes of death were end-stage renal disease, sepsis (because of recurrent intestinal perforations, coronavirus disease, diabetic foot infection and following coronary artery bypass graft surgery), myocardial infarction, heart failure because of dilated cardiomyopathy, stroke, liver complications and angiosarcoma. CONCLUSIONS: Standard treatment approaches have only a limited impact and do not prevent the development of severe metabolic abnormalities and early onset of organ complications in GL.

Evaluating the conversion degree of interim restorative materials produced by different 3-dimensional printer technologies.

STATEMENT OF PROBLEM: Three-dimensional (3D) printers are a relatively new technology, but the degree of conversion (DC) of the resin specimens produced by using this method is currently unknown. However, the DC of resin interim restorative materials is critical for their biocompatibility and physical properties. PURPOSE: The purpose of this in vitro study was to evaluate the DC of interim restorative materials produced by using different 3D printer technologies and compare them with conventionally manufactured polymethyl methacrylate. MATERIAL AND METHODS: Stereolithography, digital light processing, and liquid crystal display 3D printers were used as experimental groups, and a conventional (C) method was used as the control. Five different 3D printers (DWS Systems, Formlabs [FL], Asiga, Mega, and Vega) were included. The 3D printed specimens were designed in a rectangular prism geometry (10×4×2.5 mm) by using a computer-aided design software program (Materialise 3-matic) and printed with a layer thickness of 50 µm in the horizontal direction (n=15). Fourier transform infrared spectroscopy (FT-IR) spectra were measured in 3 steps: the liquid state of the resins, after washing with 99% isopropanol, and after final polymerization. For the C method, FT-IR spectra were assessed in 2 steps: immediately after mixing the liquid and powder and after polymerization. Statistical analysis of the data was performed with 1-way ANOVA followed by the post hoc Tukey honestly significant difference (HSD) test (α=.05). RESULTS: There was no statistically significant difference in DC values between the 3D printed groups (P>.05). There was a statistically significant difference only between FL and the C in terms of DC (P=.042). CONCLUSIONS: Three-dimensionally printed interim resin materials found comparable results with those of the C group. The DC was not affected by different 3D printing technologies.

Clinical characteristics and the treatment modalities of Graves' orbitopathy in a tertiary referral center in Turkey: changes over two decades.

PURPOSE: To evaluate the changes in demographics, clinical findings, and treatment modalities in Graves' orbitopathy (GO) patients at a tertiary referral center in Turkey over the last two decades. METHODS: The clinical data of 752 GO patients were evaluated retrospectively. Patients were divided into 2 groups according to the first ophthalmic examination date; Group 1(n:344) between January 1998 and December 2007 and Group 2(n:408) between January 2008 and December 2017. RESULTS: The number of nonsmokers was significantly higher in Group 2 (44.0 vs. 26.5%, p < 0.001). The time from the diagnosis of thyroid dysfunction and referral to our center was 32.4 months in Group 1 and 34.8 months in Group 2, (p = 0.166). The most common treatment of hyperthyroidism was antithyroid medications. Radioiodine ablation treatment rate was significantly lower in Group 2 (14.8 vs. 9.1%, p < 0.001). The time between the diagnosis of thyroid disease and orbital involvement was 22.0 vs. 26.6 months in Groups 1 and 2, respectively (p = 0.009). The time elapsed between the diagnosis of orbital disease and referral to our clinic was 21.0 months vs. 22.4 months in Group 1 and 2, respectively (p = 0.068). Orbital disease was most commonly mild, and inactive. Mild and moderate to severe GO and the mean Clinical Activity Score significantly increased, and the rate of sight-threatening disease and orbital decompression surgery significantly decreased in Group 2 (p = 0.042; p < 0.001, respectively). CONCLUSIONS: Mild and inactive orbital disease was the most common form of GO. The severity of GO is declining over the last two decades in Turkey.

A novel SLC35D1 variant causing milder phenotype of Schneckenbecken dysplasia in a large pedigree.

SLC35D1 gene encodes UDP-glucuronic acid/UDP-n-acetylgalactosamine dual transporter protein and transports organic or inorganic molecules across cellular membranes. SLC35D1 gene pathogenic variants causes Schneckenbecken dysplasia (SHNKND) which is a rare lethal autosomal recessive disorder characterized by the snail-like pelvis, flattening of vertebral bodies, short and broad long bones with a dumbbell-like appearance, thoracic hypoplasia. Only six cases with homozygous SLC35D1 variants have been reported to date, and all of these cases were lost in the perinatal period. Here we report different family members with a novel SLC35D1 variant who presented a milder phenotype of SHNKND. The affected patients have common clinical features such as short stature, mild mesomelia, shortening of the lower extremity, genu valgum, and narrow thorax. Exome sequencing of the proband revealed a homozygous missense variant of SLC35D1 gene, c.401 T > C (p. Met134Thr). The affected siblings, their two cousins, and their paternal uncle with a similar phenotype were also homozygous for the variant. This is the first case report of a family with a novel likely pathogenic variant (p. Met134Thr) and mild phenotypic features. It has the largest family with different ages of patients (ages ranged 4-31 years old) reported to date. The present report supports the evidence that the p. Met134Thr variant is responsible for a milder phenotype than previously reported cases with SLC35D1 pathogenic variants.

Graphene Oxide Nanosheets Interact and Interfere with SARS-CoV-2 Surface Proteins and Cell Receptors to Inhibit Infectivity.

Nanotechnology can offer a number of options against coronavirus disease 2019 (COVID-19) acting both extracellularly and intracellularly to the host cells. Here, the aim is to explore graphene oxide (GO), the most studied 2D nanomaterial in biomedical applications, as a nanoscale platform for interaction with SARS-CoV-2. Molecular docking analyses of GO sheets on interaction with three different structures: SARS-CoV-2 viral spike (open state - 6VYB or closed state - 6VXX), ACE2 (1R42), and the ACE2-bound spike complex (6M0J) are performed. GO shows high affinity for the surface of all three structures (6M0J, 6VYB and 6VXX). When binding affinities and involved bonding types are compared, GO interacts more strongly with the spike or ACE2, compared to 6M0J. Infection experiments using infectious viral particles from four different clades as classified by Global Initiative on Sharing all Influenza Data (GISAID), are performed for validation purposes. Thin, biological-grade GO nanoscale (few hundred nanometers in lateral dimension) sheets are able to significantly reduce copies for three different viral clades. This data has demonstrated that GO sheets have the capacity to interact with SARS-CoV-2 surface components and disrupt infectivity even in the presence of any mutations on the viral spike. GO nanosheets are proposed to be further explored as a nanoscale platform for development of antiviral strategies against COVID-19.

House dust mite-derived allergens effect on matrix metalloproteases in airway epithelial cells.

Aim of the Study: Many allergens have protease activities. Although the immunomodulatory effects of these antigens are well known, the effects attributed to their protease activities are not thoroughly investigated. We set out to determine the effects of house dust mite (HDM) allergens with varying protease activities on bronchial epithelial cell functions. Materials and methods: BEAS-2B cells were maintained in ALI-culture and stimulated with Der p1 (cysteine protease), Der p6 (serine protease), and Der p2 (non-protease) with and without specific protease inhibitors or heat denaturation. Cell viability and epithelial permeability were measured with MTT and paracellular flux assay, respectively. The effect of heat denaturation on allergen structure was examined using in silico models. Matrix metalloproteinases (MMPs) were investigated at the transcription (qPCR), protein (ELISA), and functional (zymography) levels. Results: Epithelial permeability increased only after Der p6 but not after Der p1 or Der p2 stimulation. Der p2 increased both MMP-2 and MMP-9 expression, while Der p1 increased only MMP-9 expression. The heat-denatured form of Der p1 unexpectedly increased MMP-9 gene expression, which, through the use of in silico models, was attributed to its ability to change receptor connections by the formation of new electrostatic and hydrogen bonds. IL-8 and GM-CSF production were increased after Der p1 and Der p2 but decreased after Der p6 stimulation. IL-6 decreased after Der p1 but increased following stimulation with Der p6 and heat-denatured Der p2. Conclusion: Allergens in house dust mites are capable of inducing various changes in the epithelial cell functions by virtue of their protease activities.

Ribavirin shows antiviral activity against SARS-CoV-2 and downregulates the activity of TMPRSS2 and the expression of ACE2 in vitro.

Ribavirin is a guanosine analog with broad-spectrum antiviral activity against RNA viruses. Based on this, we aimed to show the anti-SARS-CoV-2 activity of this drug molecule via in vitro, in silico, and molecular techniques. Ribavirin showed antiviral activity in Vero E6 cells following SARS-CoV-2 infection, whereas the drug itself did not show any toxic effect over the concentration range tested. In silico analysis suggested that ribavirin has a broad-spectrum impact on SARS-CoV-2, acting at different viral proteins. According to the detailed molecular techniques, ribavirin was shown to decrease the expression of TMPRSS2 at both mRNA and protein levels 48 h after treatment. The suppressive effect of ribavirin in ACE2 protein expression was shown to be dependent on cell types. Finally, proteolytic activity assays showed that ribavirin also showed an inhibitory effect on the TMPRSS2 enzyme. Based on these results, we hypothesized that ribavirin may inhibit the expression of TMPRSS2 by modulating the formation of inhibitory G-quadruplex structures at the TMPRSS2 promoter. As a conclusion, ribavirin is a potential antiviral drug for the treatment against SARS-CoV-2, and it interferes with the effects of TMPRSS2 and ACE2 expression.

Photocatalytically Active Graphitic Carbon Nitride as an Effective and Safe 2D Material for In Vitro and In Vivo Photodynamic Therapy.

Thanks to its photocatalytic property, graphitic carbon nitride (g-C3 N4 ) is a promising candidate in various applications including nanomedicine. However, studies focusing on the suitability of g-C3 N4 for cancer therapy are very limited and possible underlying molecular mechanisms are unknown. Here, it is demonstrated that photoexcitation of g-C3 N4 can be used effectively in photodynamic therapy, without using any other carrier or additional photosensitizer. Upon light exposure, g-C3 N4 treatment kills cancer cells, without the need of any other nanosystem or chemotherapeutic drug. The material is efficiently taken up by tumor cells in vitro. The transcriptome and proteome of g-C3 N4 and light treated cells show activation in pathways related to both oxidative stress, cell death, and apoptosis which strongly suggests that only when combined with light exposure, g-C3 N4 is able to kill cancer cells. Systemic administration of the mesoporous form results in elimination from urinary bladder without any systemic toxicity. Administration of the material significantly decreases tumor volume when combined with local light treatment. This study paves the way for the future use of not only g-C3 N4 but also other 2D nanomaterials in cancer therapy.

Identification of novel Nrf2/Keap1 pathway mutations in pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a malignancy of lymphoid progenitor cells, characterized by a wide range of biological and clinical heterogeneity. Oxidative stress is a common problem observed in carcinogenesis and it is involved in developing treatment resistance. Nuclear Factor Erythroid-2-Like 2 (Nrf2) transcription factor is the main regulator of antioxidant responses. The levels of reactive oxygen species (ROS) are tightly controlled and regulated by Nrf2 and its suppressor protein Kelch-like ECH-associated protein 1 (Keap1). Recently, many studies have shown that most of the genes in the Nrf2/Keap1/nuclear factor kappa-B (NF-κB)/phosphotyrosine-independent ligand for the Lck SH2 domain Of 62 KDa (p62) pathway show abnormally high mutational variations in cancer. However, variations in the Nrf2/Keap1/NF-κB1/p62 pathway in pediatric ALL have not been thoroughly investigated, yet. Thirty children, who were diagnosed with pediatirc ALL were included in the study. The Nrf2/Keap1/NF-κB1/p62 pathway variants were analyzed by DNA sequencing analysis. The PolyPhen-2 program was used for identifying pathogenic mutations. Our study examined the molecular dynamics (MD) perspectives of the effect of A159T and E121K mutations on protein stability for the first time in the literature by using the GROMACS45 software package utilizing the OPSLAA force field. Of the detected 17 nucleotide changes, 6 were novel. The study predicted the potential pathological effect of two mutations p. A159T and p.E121K in the Keap1 gene. The MD perspectives revealed that the E121K mutant's observed structural behavior accounted for the key role of His-129 and E121K, where E121K exhibited much higher drift compared to His-129. For a future perspective, it would be meaningful to study the protein-small molecule interactions of the Keap1 protein to elaborate on the drug effects in patients carrying these mutations.

Long-term isotretinoin use does not cause parenchymal liver change: Ultrasonographic study in 50 patients.

The effect of isotretinoin on liver enzymes and lipid profile is reported as rare and reversible. However, possible parenchymal liver changes have not been demonstrated so far. The aim of this study was to evaluate the ultrasonography findings of the liver in patients receiving long-term isotretinoin therapy. We examined ultrasonographic findings of the liver together with serum alanin aminotransferase (ALT), aspartate aminotransferase (AST), and total cholesterol and triglyceride levels in 50 consecutive patients who have taken isotretinoin 10-40 mg daily for at least 6 months between January and December 2017. Of 50 patients examined, 40 were female, 10 were male. Mean age of the patients was 24.8 years. Five patients aged between 42 and 62 were found to have Grade 1 hepatosteatosis. Despite a moderate elevation, serum ALT, AST, and total cholesterol and triglyceride levels were in normal range in these five patients. Moreover, one patient had elevated ALT, and one another patient had elevated triglyceride level although both have normal liver ultrasonographic findings. Isotretinoin did not cause parenchymal liver changes as well as serum ALT, AST, and total cholesterol and triglyceride levels in patients who take it 10-40 mg daily for at least 6 months.

Use of adapalene in alopecia areata: Efficacy and safety of mometasone furoate 0.1% cream versus combination of mometasone furoate 0.1% cream and adapalene 0.1% gel in alopecia areata.

Alopecia areata (AA) is an autoimmune disease characterized by non-cicatricial hair loss. No definitive therapy currently exists for AA. To compared the efficacy and safety of the mometasone furoate 0.1% cream alone with the mometasone furoate 0.1% cream plus adapalene 0.1% gel in treatment of AA. Twenty patients with AA and with mean age of 27.4 ± 9.2 years were enrolled. Patches with a diameter of < 5 cm were treated with mometasone furate 0.1% cream (M), and patches with a diameter of ≥5 cm were treated with mometasone furate 0.1% cream plus adapalene 0.1% gel (M + D) for a period of 12 weeks. Hair regrowth was evaluated using a Re-growth score (RGS). Mean RGSs of M + D group were higher than M group for 4th week (2.60 vs. 1.45); 8th week (3.85 vs. 2.40) and 12th week (4.40 vs. 3.30). Mean percentages of hair re-growth in M + D group were statistically higher than M group for 4th (50.2% vs. 23.5%), 8th (78.5% vs. 50.7%), and 12th week (90.5% vs. 71%). Study revealed the efficacy and safety of adapalene and mometasone furoate combination in AA. Adapalene can be used as a new therapeutic modality in AA.

Postpneumonectomy bronchopleural fistula in non-small cell lung cancer patients: incidence, survival, mortality, and treatment analysis.

PURPOSE: Bronchopleural fistula (BPF) is a catastrophic complication after pneumonectomy, still associated with high mortality. We reviewed our recent experience of managing BPF, particularly after right pneumonectomy for non-small cell lung cancer (NSCLC), and analyzed our findings. METHODS: A total of 436 patients underwent pneumonectomy for NSCLC in our department between January 2000 and June 2017. BPF developed during follow-up in 47 of these patients, who are the subjects of this retrospective analysis. RESULTS: The overall incidence of BPF was 10.8% (47/436), being 22.8% (33/145) after right pneumonectomy and 4.8% (14/291) after left pneumonectomy (P = 0.0001). The incidence of BPF in patients with a history of tuberculosis was 33.3% (6/18; P = 0.008). The fistula healed in 48.9% (23/47) of the patients and the rate of mortality caused by the fistula was 19.1% (9/47). CONCLUSIONS: The side of the pneumonectomy and previous tuberculosis were the two most important risk factors independent of the bronchial closure methods. The incidence of BPF was much higher after right pneumonectomy than after left pneumonectomy. The high mortality and morbidity rates show that the treatment of BPF is still not satisfactory.

Soluble Tumor Necrosis Factor (TNF)-Like Weak Inducer of Apoptosis (Tweak) Independently Predicts Subclinical Atherosclerosis in Behcet's Disease.

BACKGROUND: Vasculopathy is a major cause of mortality and morbidity in Behcet's Disease (BD). Subclinical atherosclerosis can even be detected in the early stage of BD. Soluble tumor necrosis factor-like (TNF) weak inducer of apoptosis (TWEAK) is known as a good marker of the inflammation in vascular tree. The aim of this study is to examine the relationship between carotid artery intima-media thickness (cIMT) and serum TWEAK levels in patients with BD. MATERIALS AND METHODS: In line with International BD Study Group criteria, 48 BD, and 30 controls were included in our study. Disease activity was evaluated according to BD current activity form (BDCAF). C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), lipid parameters, serum TWEAK levels, and cIMT were measured. RESULTS: Disease activity score of BD patients was found as 2 (range 0-7). cIMT, serum TWEAK, CRP and ESR levels of BD patients were significantly higher comparing to cIMT (0.62 ± 0.13 mm vs. 0.43 ± 0.09 mm, p < 0.001), serum TWEAK (667.5 ± 130.6 vs. 603.4 ± 89.6 pg/ml, p = 0.015), CRP (3.9 ± 4.3 vs. 1.4 ± 1.0 mg/dl, p < 0.001) and ESR (10.2 ± 10.0 vs. 5.6 ± 3.7 mm/h, p = 0.005) levels of the control group. There was a positive correlation between serum TWEAK level and disease activity (r = 0.251, p = 0.030) and cIMT (r = 0.463, p < 0.001). Our study also revealed an independent correlation between cIMT and serum TWEAK levels (beta = 0.354, p < 0.001). CONCLUSION: Increased serum TWEAK levels can play a part in the development of atherosclerotic heart disease in BD. Due to their liability to atherosclerosis, patients with BD must followed closely.

Reconstruction of Traumatic Composite Tissue Defect of Medial Longitudinal Arch With Free Osteocutaneous Fibular Graft.

A 34-year-old male sustained a crush injury resulting in bone and soft tissue loss along the medial longitudinal arch of his left foot. Specifically, the injury resulted in loss of first metatarsal without injury to the medial cuneiform or proximal phalanx, fracture of the third metatarsal, and a 5-cm × 9-cm soft tissue defect overlying the dorsomedial aspect of the right foot. After debridement and daily wound care, the defect was subsequently reconstructed using a free osteocutaneous fibular graft. Approximately 6 months after reconstructive surgery, the patient returned to his job without pain, and his pedogram showed almost equal weightbearing distribution on both feet.