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In order to establish signaling mechanisms of platelet dysfunction among patients with acute gastroduodenal ulcer bleeding the assessment of agonist-induced platelet aggregation was performed by means of the spectrophotometric method and inhibitory method at the time of hospitalization of patients and the third day after. It has been shown that on the first day of hospitalization the level of collagen- and ADP- induced platelet aggregation was decreased among patients with acute gastroduodenal ulcer bleeding in comparison with the controlgroup. In cases of medium/high level of platelet aggregation, the reverse aggregation graph was recorded that was associated with the risk of recurrent bleeding. On the third day after hospitalization, the rise of ADP-induced platelet aggregation was found on account of PKA becomes a positive regulator of platelet intracellular signaling system. The assessment of induced platelet aggregation among patients with acute gastroduodenal ulcer bleeding compared with the control group allowed to discover a double decreased platelet aggregation to ADP (p=0.004) and 4.5-times decreased platelet aggregation to collagen (p=0.0001). The characteristics of aggregation graphs to ADP have shown partially inverse and inverse platelet aggregation, that was widely spread among patients with medium/high level of platelet aggregation. The previous issue has been associated with reverse and partially reverse aggregation graphs to collagen. Moreover, the highest rate of recurrent bleeding was found among patients with medium/high level of platelet aggregation to collagen (p=0.02) which was featured by a long latency period. The scrutiny also has revealed the correlation between ADP and collagen-induced platelet aggregation (r=0.28; p=0.01), which indicates that platelet disfunction takes place in the intracellular signaling system. On the first day of hospitalization no effect of PK A inhibitor on ADP-induced platelet aggregation was detected (p=0.71). The examination of effect of PK C inhibitor on ADP-induced platelet aggregation also has revealed no effect (p=0.57). In addition to the level of platelet aggregation inhibitors did not influence the characteristics of aggregation graphs. The comparison of ADP- and collagen-induced platelet aggregation in dynamics (on the first and the third days of hospitalization) has shown 2-times growth of platelet aggregation to ADP (p

Edward Barinov,1 Oksana Sulaieva,1 Yuriy Lyakch,2 Vitaliy Guryanov,2 Petr Kondratenko,3 Yevgeniy Radenko3 1Department of Histology, Cytology, and Embryology, 2Department of Medical, Biological Physics, Medical Informatics, and Biostatistics, 3Department of Surgery and Endoscopy, M Gorky Donetsk National Medical University, Donetsk, Ukraine Background: The purpose of this study was to identify factors associated with the risk of unsustainable hemostasis in patients with gastric and duodenal ulcer bleeding by in vitro assessment of platelet reactivity using artificial neural networks. Methods: Patients with gastroduodenal ulcers complicated by bleeding were studied. Platelet aggregation was measured using aggregometry with adenosine diphosphate 5 µM, epinephrine 2.5 µM, 5-hydroxytryptophan 10 µM, collagen 1 µM, and thrombin 0.06 NIH Unit/mL as agonists. Multiple logistic regression was used to evaluate the independent relationship between demographic, clinical, endoscopic, and laboratory data and in vitro assessment of platelet reactivity and local parameters of hemostasis in patients with ulcer bleeding. Results: Analysis of platelet aggregation in patients with gastroduodenal ulcer bleeding allowed the variability of platelet response to different agonists used in effective concentration which induces 50% platelet aggregation (EC50) to be established. The relationship between platelet aggregation and the spatial-temporal characteristics of ulcers complicated by bleeding was demonstrated. Adrenoreactivity of platelets was associated with time elapsed since the start of ulcer bleeding and degree of hemorrhage. The lowest platelet response to collagen and thrombin was detected in patients with active bleeding (P< 0.001) and unsustainable recent bleeding (P < 0.01). Decreased adenosine diphosphate-induced platelet aggregation in patients with ulcer bleeding was correlated with the platelet response to thrombin (r = 0.714, P < 0.001) and collagen (r = 0.584, P < 0.01). Conclusion: Estimation of platelet reactivity in vitro indicates the key mechanisms of failure of hemostasis in patients with ulcer bleeding. In addition to gender, an important determinant of unsustainable hemostasis was a decreased platelet response to thrombin and adenosine diphosphate. Keywords: ulcer, hemostasis, blood platelets

Background. Gastroduodenal ulcer bleeding is one of the main causes of morbidity, mortality and high medical care expenses. It is unclear why regardless of the optimization of antisecretory therapy among the patients with peptic ulcer the frequency of bleeding remains as high. Objective. We suggest that acute bleeding development is related with hyperstimulation of acute inflammatory response due to macrophages dysfunction. Methods. To test this hypothesis we assessed characteristics of inflammatory process in different zones of the gastroduodenal area under acute bleeding in 46 patients. The number and distribution of neutrophils, eosinophils, plasma cells, mast cells, macrophages (CD68+), T- (CD3+) and B-lymphocytes (CD20+) were evaluated. Results. The comparison of morphological changes in ulcer margin and intact gastric mucosa has revealed that the development of ulcer bleeding is associated with acute inflammation. High recruitment of neutrophils in ulcer margin was associated with edema and alteration of covering epithelium. CD68-positive cells prevailed in subepithelial region. However, in the 2nd group number of macrophages (p

Digital pathology (DP) has become a part of the cancer healthcare system, creating additional value for cancer patients. DP implementation in clinical practice provides plenty of benefits but also harbors hidden ethical challenges affecting physician-patient relationships. This paper addresses the ethical obligation to transform the physician-patient relationship for informed and responsible decision-making when using artificial intelligence (AI)-based tools for cancer diagnostics. DP application allows to improve the performance of the Human-AI Team shifting focus from AI challenges towards the Augmented Human Intelligence (AHI) benefits. AHI enhances analytical sensitivity and empowers pathologists to deliver accurate diagnoses and assess predictive biomarkers for further personalized treatment of cancer patients. At the same time, patients' right to know about using AI tools, their accuracy, strengths and limitations, measures for privacy protection, acceptance of privacy concerns and legal protection defines the duty of physicians to provide the relevant information about AHI-based solutions to patients and the community for building transparency, understanding and trust, respecting patients' autonomy and empowering informed decision-making in oncology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Sulaieva, Dudin, Koshyk, Panko and Kobyliak.)

Synovial sarcoma is a relatively common soft tissue tumor characterized by highly specific t(X;18)(p11;q11) translocation resulting in the fusion of SS18 with members of SSX gene family. Typically, detection of SS18 locus rearrangement by fluorescence in situ hybridization or SS18 :: SSX fusion transcripts confirms the diagnosis. More recently, immunohistochemistry (IHC) for SS18-SSX chimeric protein (E9X9V) and C-terminus of SSX (E5A2C) showed high specificity and sensitivity for synovial sarcoma. This study screened a cohort of >1000 soft tissue and melanocytic tumors using IHC and E9X9V and E5A2C antibodies. Three percent (6/212) of synovial sarcomas were either negative for SS18-SSX or had scattered positive tumor cells (n=1). In these cases, targeted RNA next-generation sequencing detected variants of SS18 :: SSX chimeric transcripts. DNA methylation profiles of 2 such tumors matched with synovial sarcoma. A few nonsynovial sarcoma tumors (n=6) revealed either focal SS18-SSX positivity (n=1) or scattered positive tumor cells. However, targeted RNA next-generation sequencing failed to detect SS18 :: SSX transcripts in these cases. The nature of this immunopositivity remains elusive and may require single cell sequencing studies. All synovial sarcomas showed positive SSX IHC. However, a mosaic staining pattern or focal loss of expression was noticed in a few cases. Strong and diffuse SSX immunoreactivity was also seen in epithelioid sclerosing osteosarcoma harboring EWSR1 :: SSX1 fusion, while several sarcomas and melanocytic tumors including cellular blue nevus (5/7, 71%) revealed focal to diffuse, mostly weak to intermediate SSX staining. The SS18-SSX and SSX IHC is a useful tool for synovial sarcoma differential diagnosis, but unusual immunophenotype should trigger molecular genetic testing., Competing Interests: Conflicts of Interest and Source of Funding: Supported as a part of NCI’s intramural research program. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: This study aimed to investigate the incidence of BRAF mutation in cutaneous melanoma in the Ukrainian population with respect to clinical and histopathological data., Materials & Methods: This single-center retrospective cohort study enrolled 299 primary CM with known BRAF status assessed by RT-PCR., Results: The overall BRAF mutation rate was 56.5% in CM and demonstrated a link with the younger age (p < 0.001), anatomical site (p < 0.001) and histological type of CM (p = 0.022). BRAF -positive CM possessed a slightly higher mitotic rate (p = 0.015) and Breslow thickness (p = 0.028) but did not relate to tumor-infiltrating lymphocytes., Conclusion: The high rate of BRAF mutations in CM patients in the Ukrainian cohort was associated with superficial spreading histology, higher depth of invasion and proliferation., Competing Interests: Competing interests disclosure The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties., (© 2023 The Authors.)

Introduction: Estrogens play a considerable role in maintaining bone and articular cartilage homeostasis. Menopause provokes joint disorders due to metabolic syndrome and altered signaling pathways. Phytoestrogen resveratrol was demonstrated to provide chondroprotective and osteoprotective effects. However, the mechanisms of such action of Resveratrol are still being explored., Aim: The study aims to determine the effect of Resveratrol on the joints and its therapeutic mechanism in ovariectomized rats., Material and Methods: The study was carried out on Wistar female rats that were divided into three groups, including control animals; ovariectomized rats (OVX); and the OVX group treated with an intravaginal gel containing Resveratrol (0.5 % 0.1 mL, daily 28 days). Knee joint tissues (articular cartilage, subchondral plate, subchondral bone) were assessed by histomorphometry. The expression of mTOR, PTEN, Caspase 3 and BCL-2 in articular cartilage and subchondral bone were evaluated immunohistochemically., Results: Resveratrol treatment of OVX rats prevented weight gain by 17 % (P < 0.001), demonstrating the systemic effect on metabolic pathways. Although there were no statistically significant differences in the thickness of articular cartilage between groups, OVX rats possessed degenerative changes in chondrocytes, associated with the enhanced expression of mTOR (P < 0.001) and Casp-3 (P = 0.005). Resveratrol decreased mTOR (P = 0.007) and Casp-3 (P = 0.011) expression in chondrocytes, reducing degenerative changes. At the same time, resveratrol attenuated the deterioration of trabecular bone in OVX rats (P = 0.002). This effect was through the up-regulation of BCL-2 (P = 0.018) and down-regulation of Casp-3 expression (P < 0.001)., Conclusions: Intravaginal administration of resveratrol provided systemic effects and ameliorated joint tissue structure and signaling in OVX rats through stimulation of BCL-2 and reduced Casp-3 expression., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The Covid-19 pandemic and ongoing war in Ukraine caused unprecedented disruption in healthcare, including cytopathology activities. This paper elucidates the effect of two consecutive disasters-the COVID-19 pandemic followed by the war-on cytopathology practice in Ukraine through a single-centre retrospective study. Total testing volumes, geographic distribution, and indicators of laboratory operations were assessed during three periods of 3 months each: the first 3 months of the acute phase of the war (March-May 2022, period 1); summer (June-August 2022, period 2); and the fall (September-November 2022, period 3, associated with massive attacks on the energy infrastructure in Ukraine). These data were compared with the corresponding periods in 2020, during the COVID-19 pandemic, and in 2021, the post-lockdown period. The ongoing war in Ukraine has caused a dramatic disruption in routine health maintenance and cytological practice. A net decline in both PAP testing and non-gynaecological pathology was associated with a geographic redistribution of cytopathological testing, and an increase in the rate of abnormal sample reporting. Despite these challenges, cytopathology practice in Ukraine demonstrates resilience, allowing for maintaining the healthcare system and addressing the needs of the civil population during the war. The ongoing war in Ukraine heavily affected cytological practice. The decline in PAP testing during the early period of the war was associated with an increase in the abnormal sample rate. Further study of the war's impact on the cervical pathology rate and the health of the population in the next decades is needed., (© 2023 John Wiley & Sons Ltd.)

Biodegradable Magnesium (Mg) implants are promising alternatives to permanent metallic prosthesis. To improve the biocompatibility and with the aim of degradation control, we provided Plasma Electrolytic Oxidation (PEO) of pure Mg implant in silicate-based solution with NaOH (S1 250 V) and Ca(OH) 2 (S2 300 V). Despite the well-structured surface, S1 250 V implants induced enormous innate immunity reaction with the prevalence of neutrophils (MPO+) and M1-macrophages (CD68+), causing secondary alteration and massive necrosis in the peri-implant area in a week. This reaction was also accompanied by systemic changes in visceral organs affecting animals' survival after seven days of the experiment. In contrast, S2 300 V implantation was associated with focal lymphohistiocytic infiltration and granulation tissue formation, defining a more favorable outcome. This reaction was associated with the prevalence of M2-macrophages (CD163+) and high density of αSMA+ myofibroblasts, implying a resolution of inflammation and effective tissue repair at the site of the implantation. At 30 days, no remnants of S2 300 V implants were found, suggesting complete resorption with minor histological changes in peri-implant tissues. In conclusion, Ca(OH) 2 -contained silicate-based solution allows generating biocompatible coating reducing toxicity and immunogenicity with appropriate degradation properties that make it a promising candidate for medical applications.

Maxillary sinus augmentation is a commonly used procedure for the placement of dental implants. However, the use of natural and synthetic materials in this procedure has resulted in postoperative complications ranging from 12% to 38%. To address this issue, we developed a novel calcium deficient HA/β-TCP bone grafting nanomaterial using a two-step synthesis method with appropriate structural and chemical parameters for sinus lifting applications. We demonstrated that our nanomaterial exhibits high biocompatibility, enhances cell proliferation, and stimulates collagen expression. Furthermore, the degradation of β-TCP in our nanomaterial promotes blood clot formation, which supports cell aggregation and new bone growth. In a clinical trial involving eight cases, we observed the formation of compact bone tissue 8 months after the operation, allowing for the successful installation of dental implants without any early postoperative complications. Our results suggest that our novel bone grafting nanomaterial has the potential to improve the success rate of maxillary sinus augmentation procedures.

Introduction: Research in recent years has shown the potential benefits of fecal microbiota transplantation (FMT) for irritable bowel syndrome (IBS). Acute infectious gastroenteritis is a well-established risk factor for developing such forms of IBS as post-infectious IBS (PI-IBS). However, the effective use of FMT in patients with IP-IBS has not yet been clarified., Aim: The study aimed to conduct a single-center, randomized clinical trial (RCT) to assess FMT's safety, clinical and microbiological efficacy in patients with PI-IBS., Materials and Methods: Patients with PI-IBS were randomized into two groups: I (standard-care, n = 29) were prescribed basic therapy, namely a low FODMAP diet, as well as Otilonium Bromide (1 tablet TID) and a multi-strain probiotic (1 capsule BID) for 1 month; II (FMT group, n = 30), each patient with PI-IBS underwent a single FMT procedure with fresh material by colonoscopy. All patients underwent bacteriological examination of feces for quantitative and qualitative microbiota composition changes. The clinical efficacy of treatment was evaluated according to the dynamics of abdominal symptoms, measured using the IBS-SSS scale, fatigue reduction (FAS scale), and a change in the quality of life (IBS-QoL scale)., Results: FMT was associated with rapid onset of the effect, manifested in a significant difference between IBS-SSS points after 2 weeks of intervention ( p < 0.001). In other time points (after 4 and 12 weeks) IBS-SSS did not differ significantly across both groups. Only after 3 months of treatment did their QoL exceed its initial level, as well value for 2 and 4 weeks, to a significant extent. The change in the ratio of the main microbial phenotypes in the form of an increase in the relative abundance of Firmicutes and Bacteroidetes was recorded in all patients after 4 weeks. It should be noted that these changes were significant but eventually normalized only in the group of PI-IBS patients who underwent FMT. No serious adverse reactions were noted., Conclusion: This comparative study of the results of FMT use in patients with PI-IBS demonstrated its effectiveness compared to traditional pharmacotherapy, as well as a high degree of safety and good tolerability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tkach, Dorofeyev, Kuzenko, Sulaieva, Falalyeyeva and Kobyliak.)

Phytoestrogen resveratrol (R) has been demonstrated to benefit human reproductive health. However, R bioavailability and pharmacokinetics are still problematic under oral supplementation. We used an experimental vaginal gel with R and hyaluronic acid (HA) to improve bioavailability and pharmacokinetic properties. The study aimed to assess the impact of vaginal R-HA gel on the reproductive system in ovariectomized rats. Methods: The study was carried out on Wistar female rats. It investigated the body weight, tail temperature, vaginal pH, estrogen and progesterone blood levels, and immunohistochemical biomarkers (COX2, Casp-3, Bcl-2, and VEGF). Animals were divided into control animals; ovariectomized rats (OVX); and OVX group treated with vaginal 0.5% R-HA gel (0.5%, 0.1 mL, daily 28 days). Results: The R-HA gel’s therapeutic effect was manifested by slowing weight gain by 17% (p < 0.001), less pronounced symptom of fever at the root of the tail by 9% (p < 0.001) and lowering the vaginal pH to 4.4−4.5 compared with OVX rats. The anti-inflammatory effect and the reduction of COX-2 expression in vagina were accompanied by antiapoptotic impact of RA-H on endometrium, associated with the decreased Casp-3 expression (p < 0.001) and elevated Bcl-2 score in endometrial glands (p = 0.01). Together with enhanced VEGF expression in endometrial glands (p < 0.001) and stromal cells (p = 0.007), these changes prevented endometrial atrophy (p < 0.001) after ovariectomy. Thus, this study substantiates the feasibility of developing an innovative topical drug with R and HA for treating hypoestrogenic disorders.

Innovative therapies are urgently needed to combat cancer. Thermal ablation of tumor cells is a promising minimally invasive treatment option. Infrared light can penetrate human tissues and reach superficial malignancies. MXenes are a class of 2D materials that consist of carbides/nitrides of transition metals. The transverse surface plasmons of MXenes allow for efficient light absorption and light-to-heat conversion, making MXenes promising agents for photothermal therapy (PTT). To date, near-infrared (NIR) light lasers have been used in PTT studies explicitly in a continuous mode. We hypothesized that pulsed NIR lasers have certain advantages for the development of tailored PTT treatment targeting tumor cells. The pulsed lasers offer a wide range of controllable parameters, such as power density, duration of pulses, pulse frequency, and so on. Consequently, they can lower the total energy applied and enable the ablation of tumor cells while sparing adjacent healthy tissues. We show for the first time that a pulsed 1064 nm laser could be employed for selective ablation of cells loaded with Ti 3 C 2 T x MXene. We demonstrate both low toxicity and good biocompatibility of this MXene in vitro , as well as a favorable safety profile based on the experiments in vivo . Furthermore, we analyze the interaction of MXene with cells in several cell lines and discuss possible artifacts of commonly used cellular metabolic assays in experiments with MXenes. Overall, these studies provide a basis for the development of efficient and safe protocols for minimally invasive therapies for certain tumors.

Background: Conventionally, breast cancer (BC) prognosis and prediction of response to therapy are based on TNM staging, histological and molecular subtype, as well as genetic alterations. The role of various epigenetic factors has been elucidated in carcinogenesis. However, it is still unknown to what extent miRNAs affect the response to neoadjuvant chemotherapy (NACT). This pilot study is focused on evaluating the role of miR-34a, miR-124a, miR-155, miR-137 and miR-373 in response to NACT., Methods: That was a prospective study enrolling 34 patients with histologically confirmed BC of II-III stages. The median age of patients was 53 (47-59.8) years old, 70.6% of whom were HR-positive. MiRs levels were measured in the primary tumor before and after NACT. The response to therapy was assessed after surgery using the Miller-Payne scoring system. To establish the role of miRs in modulating response to NACT the Cox model was applied for analysis., Results: BC demonstrated a great variability of miRs expression before and after NACT with no strong links to tumor stage and molecular subtype. Only miR-124a and miR-373 demonstrated differential expression between malignant and normal breast tissues before and after therapy though these distinctions did not impact response to NACT. Besides miR-124a and miR-137 levels after NACT were found to be dependent on HR status. While miR-124a levels increased (p = 0.021) in the tumor tissue, the expression of miR-137 was downregulated (p = 0.041) after NACT in HR positive BC., Conclusions: The study revealed differences in miR-124a and miR-373 expression after NACT in primary BC tissues. Although miRs levels did not impact the response to NACT, we found miR-124a and miR-137 levels to be related to hormonal sensitivity of BC., (© 2022. The Author(s).)

In this study, we investigated the relationship between the tumor immune microenvironment (TIME), histological differentiation and hypoxia in patients with muscular-invasive urothelial carcinomas (MIUC) after radical cystectomy. Forty-two cases of pT2-3N0M0 MIUCs underwent clinical, histological and immunohistochemical evaluation by counting CD8+, FOXP3+, CD68+, CD163+ cells and polymorphonuclear leukocytes (PMN) in intra-tumoral and peritumoral areas, assessing PD-L1 and GLUT1 expression for defining the impact of tumor immune contexture on patients' outcomes. Five-year survival rates and overall survival were calculated. Most of the MIUCs demonstrated the immune-desert or immune-excluded TIME, reflecting altered mechanisms of T-cells' activation or traffic into tumors. Tumor immune contexture was closely related to histological differentiation. CD8+ cells were scant in MIUCs with papillary and squamous differentiation, while basal-like or mesenchymal-like histological differentiation was associated with increased density of CD8+ cells. A high rate of PD-L1 expression (47.6%) was not related to immune cell infiltration. M2-macrophages predominated under CD8+ lymphocytes. The abundance of PMN and CD163+ macrophages in MIUCs was associated with high GLUT1 expression. CD8+, CD68+, FOXP3+ cells and PD-L1 status did not affect patients' outcomes, while high CD163+ density and PMN infiltration were associated with the unfavorable outcome of patients with MIUC. These data drive the hypothesis that in MIUC, immune escape mechanisms are shifted towards the role of the innate immunity cells rather than CD8+ lymphocytes' functioning.

Background: In a previous worldwide survey, the authors showed a drastic reduction in the number of cytological specimens processed during the coronavirus disease 2019 "lockdown" period along with an increase in malignancy rates. To assess the continued impact of the pandemic on cytological practices around the world, they undertook a second follow-up worldwide survey collecting data from the post-lockdown period (2020)., Methods: Participants were asked to provide data regarding their cytopathology activity during the first 12 weeks of their respective national post-lockdown period (2020), which ranged from April 4 to October 31. Differences between the post-lockdown period and the corresponding 2019 period were evaluated, and the authors specifically focused on rates of malignant diagnoses., Results: A total of 29 respondents from 17 countries worldwide joined the survey. Overall, a lower number of cytological specimens (n = 236,352) were processed in comparison with the same period in 2019 (n = 321,466) for a relative reduction of 26.5%. The overall malignancy rate showed a statistically significant increase (12,442 [5.26%] vs 12,882 [4.01%]; P < .001) during the same time period. Similar results were obtained if both malignancy and suspicious for malignancy rates were considered together (15,759 [6.58%] vs 16,011 [4.98%]; P < .001)., Conclusions: The data showed a persistent reduction in the cytological specimen volume during the post-lockdown period (2020). However, the relative increase in the cytological workload in the late part of the post-lockdown is a promising finding of a slow return to normality., (© 2022 American Cancer Society.)

Perinatal exposure to starvation is a risk factor for development of severe retinopathy in adult patients with diabetes. However, the underlying mechanisms are not completely understood. In the present study, we shed light on molecular consequences of exposure to short-time glucose starvation on the transcriptome profile of mouse embryonic retinal cells. We found a profound downregulation of genes regulating development of retinal neurons, which was accompanied by reduced expression of genes encoding for glycolytic enzymes and glutamatergic signaling. At the same time, glial and vascular markers were upregulated, mimicking the diabetes-associated increase of angiogenesis-a hallmark of pathogenic features in diabetic retinopathy. Energy deprivation as a consequence of starvation to glucose seems to be compensated by upregulation of genes involved in fatty acid elongation. Results from the present study demonstrate that short-term glucose deprivation during early fetal life differentially alters expression of metabolism- and function-related genes and could have detrimental and lasting effects on gene expression in the retinal neurons, glial cells, and vascular elements and thus potentially disrupting gene regulatory networks essential for the formation of the retinal neurovascular unit. Abnormal developmental programming during retinogenesis may serve as a trigger of reactive gliosis, accelerated neurodegeneration, and increased vascularization, which may promote development of severe retinopathy in patients with diabetes later in life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Özgümüs, Sulaieva, Jain, Artner and Lyssenko.)

Type 1 diabetes is a chronic autoimmune disease requiring insulin treatment for survival. Prolonged duration of type 1 diabetes is associated with increased risk of microvascular complications. Although chronic hyperglycemia and diabetes duration have been considered as the major risk factors for vascular complications, this is not universally seen among all patients. Persons with long-term type 1 diabetes who have remained largely free from vascular complications constitute an ideal group for investigation of natural defense mechanisms against prolonged exposure of diabetes. Transcriptomic signatures obtained from RNA sequencing of the peripheral blood cells were analyzed in non-progressors with more than 30 years of diabetes duration and compared to the patients who progressed to microvascular complications within a shorter duration of diabetes. Analyses revealed that non-progressors demonstrated a reduction in expression of the oxidative phosphorylation (OXPHOS) genes, which were positively correlated with the expression of DNA repair enzymes, namely genes involved in base excision repair (BER) machinery. Reduced expression of OXPHOS and BER genes was linked to decrease in expression of inflammation-related genes, higher glucose disposal rate and reduced measures of hepatic fatty liver. Results from the present study indicate that at transcriptomic level reduction in OXPHOS, DNA repair and inflammation-related genes is linked to better insulin sensitivity and protection against microvascular complications in persons with long-term type 1 diabetes., (© 2021. The Author(s).)

Surgical site infection (SSI) substantially contributes each year to patients' morbidity and mortality, accounting for about 15% of all nosocomial infections. SSI drastically increases the rehab stint and expenses while jeopardizing health outcomes. Besides prevention, the treatment regime relies on an adequate antibiotic therapy. On the other hand, resistant bacterial strains have currently reached up to 34.3% of the total infections, and this percentage grows annually, reducing the efficacy of the common treatment schemes. Thus, new antibacterial strategies are urgently demanded. Here, we demonstrated in rats the effectiveness of non-persistent silver nano-architectures (AgNAs) in infected wound healing together with their synergistic action in combination with chlorhexidine. Besides the in vivo efficacy evaluation, we performed analysis of the bacteriological profile of purulent wound, histological evaluations, and macrophages polarization quantifications to further validate our findings and elucidate the possible mechanisms of AgNAs action on wound healing. These findings open the way for the composition of robust multifunctional nanoplatforms for the translation of safe and efficient topical treatments of SSI.

Background: Various histological types of gastric carcinomas (GCs) differ in terms of their pathogenesis and their preexisting background, both of which could impact the tumor immune microenvironment (TIME). However, the current understanding of the immune contexture of GC is far from complete., Aim: To clarify the tumor-host immune interplay through histopathological features and the tumor immune cycle concept., Methods: In total, 50 GC cases were examined (15 cases of diffuse GC, 31 patients with intestinal-type GC and 4 cases of mucinous GC). The immunophenotype of GC was assessed and classified as immune desert (ID), immune excluded (IE) or inflamed (Inf) according to CD8+ cell count and spatial pattern. In addition, CD68+ and CD163+ macrophages and programmed death-ligand 1 (PD-L1) expression were estimated., Results: We found that GCs with different histological differentiation demonstrated distinct immune contexture. Most intestinal-type GCs had inflamed TIMEs rich in both CD8+ cells and macrophages. In contrast, more aggressive diffuse-type GC more often possessed ID characteristics with few CD8+ lymphocytes but abundant CD68+ macrophages, while mucinous GC had an IE-TIME with a prevalence of CD68+ macrophages and CD8+ lymphocytes in the peritumor stroma. PD-L1 expression prevailed mostly in intestinal-type Inf-GC, with numerous CD163+ cells observed. Therefore, GCs of different histological patterns have specific mechanisms of immune escape. While intestinal-type GC was more often related to PD-L1 expression, diffuse and mucinous GCs possessing more aggressive behavior demonstrated low immunogenicity and a lack of tumor antigen recognition or immune cell recruitment into the tumor clusters., Conclusion: These data help to clarify the links between tumor histogenesis and immunogenicity for a better understanding of GC biology and more tailored patient management., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Presently, persons with diabetes are classified as having type 1 (T1D) or type 2 diabetes (T2D) based on clinical diagnosis. However, adult patients exhibit diverse clinical representations and this makes treatment approaches challenging to personalize. A recent Scandinavian study proposed a novel classification of adult diabetes into five clusters based on disease pathophysiology and risk of vascular complications. The current study aimed to characterize new subgroups of adult diabetes using this strategy in a defined population from northern Ukraine., Methods: We analyzed 2,140 patients with established diabetes from the DOLCE study ( n = 887 with new-onset diabetes and n = 1,253 with long duration). We used the k-means approach to perform clustering analyses using BMI, age at onset of diabetes, HbA 1c , insulin secretion (HOMA2-B), and insulin resistance (HOMA2-IR) indices and glutamic acid decarboxylase antibodies (GADA) levels. Risks of macro- (myocardial infarction or stroke) and microvascular [retinopathy, chronic kidney disease (CKD) and neuropathy] complications and associations of genetic variants with specific clusters were studied using logistic regression adjusted for age, sex, and diabetes duration., Results: Severe autoimmune diabetes (SAID, 11 and 6%) and severe insulin-deficient diabetes (SIDD, 25 and 14%) clusters were twice as prevalent in patients with long-term as compared to those with new-onset diabetes. Patients with long duration in both SAID and SIDD clusters had highest risks of proliferative retinopathy, and elevated risks of CKD. Long-term insulin-resistant obese diabetes 1 (IROD1) subgroup had elevated risks of CKD, while insulin-resistant obese diabetes 2 (IROD2) cluster exhibited the highest HOMA2-B, lowest HbA 1c , and lower prevalence of all microvascular complications as compared to all other clusters. Genetic analyses of IROD2 subgroup identified reduced frequency of the risk alleles in the TCF7L2 gene as compared to all other clusters, cumulatively and individually ( p = 0.0001)., Conclusion: The novel reclassification algorithm of patients with adult diabetes was reproducible in this population from northern Ukraine. It may be beneficial for the patients in the SIDD subgroup to initiate earlier insulin treatment or other anti-diabetic modalities to preserve β-cell function. Long-term diabetes cases with preserved β-cell function and lower risk for microvascular complications represent an interesting subgroup of patients for further investigations of protective mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fedotkina, Sulaieva, Ozgumus, Cherviakova, Khalimon, Svietleisha, Buldenko, Ahlqvist, Asplund, Groop, Nilsson and Lyssenko.)

Background: To the authors' knowledge, the impact of the coronavirus disease 2019 (COVID-19) pandemic on cytopathology practices worldwide has not been investigated formally. In the current study, data from 41 respondents from 23 countries were reported., Methods: Data regarding the activity of each cytopathology laboratory during 4 weeks of COVID-19 lockdown were collected and compared with those obtained during the corresponding period in 2019. The overall number and percentage of exfoliative and fine-needle aspiration cytology samples from each anatomic site were recorded. Differences in the malignancy and suspicious rates between the 2 periods were analyzed using a meta-analytical approach., Results: Overall, the sample volume was lower compared with 2019 (104,319 samples vs 190,225 samples), with an average volume reduction of 45.3% (range, 0.1%-98.0%). The percentage of samples from the cervicovaginal tract, thyroid, and anorectal region was significantly reduced (P < .05). Conversely, the percentage of samples from the urinary tract, serous cavities, breast, lymph nodes, respiratory tract, salivary glands, central nervous system, gastrointestinal tract, pancreas, liver, and biliary tract increased (P < .05). An overall increase of 5.56% (95% CI, 3.77%-7.35%) in the malignancy rate in nongynecological samples during the COVID-19 pandemic was observed. When the suspicious category was included, the overall increase was 6.95% (95% CI, 4.63%-9.27%)., Conclusions: The COVID-19 pandemic resulted in a drastic reduction in the total number of cytology specimens regardless of anatomic site or specimen type. The rate of malignancy increased, reflecting the prioritization of patients with cancer who were considered to be at high risk. Prospective monitoring of the effect of delays in access to health services during the lockdown period is warranted., (© 2020 American Cancer Society.)

Background: Osteoarthritis (OA) is a joint affection, defined by articular cartilage demolition, risks of which rise with age. The aim of this study was to compare the efficacy of chondroitin sulfate (CS) course and multistrain live probiotic (LP) administered alone or in combination on the expression of TLR-2, TLR-4, TNF-α and NF-κB in articular cartilage, subchondral bone and synovial membrane during OA in rats., Methods: OA was induced in male rats by injecting monoiodoacetate (MIA) in right hind knee. Therapeutic groups received 3 mg/kg of chondroprotector (ChP) CS for 28 days and/or 140 mg/kg of LP diet for 14 days. The expression of TLR-2, TLR-4, TNF-α and NF-κB in articular cartilage, subchondral bone and synovial membrane were determined with immunohistochemical staining kits (Thermo Fisher Scientific)., Results: It was established that MIA injection is associated with long-term structural changes in joint tissues that corresponded to OA-like features and associated with activation of pathogen-recognizing molecules and proinflammatory signaling pathways expression. Separate therapy with ChP and probiotics slightly decreased OA score limiting cell death and subchondral bone resorption. However, these changes were not associated with a significant decrease in TLR-2, TLR-4, NF-kB and TNF-α expression. On the other hand, the combination of ChP and LP treatment significantly decreased OA score. This correlated with a decrease in TLR-2, TLR-4, NF-kB and TNF-α expression in chondrocytes and synovial cells., Conclusions: The outcomes of our research prove that ChPs amplify the positive action of LPs in OA attenuation.