Wound Microbiota and Its Impact on Wound Healing.

Wound healing is a complex process influenced by age, systemic conditions, and local factors. The wound microbiota's crucial role in this process is gaining recognition. This concise review outlines wound microbiota impacts on healing, emphasizing distinct phases like hemostasis, inflammation, and cell proliferation. Inflammatory responses, orchestrated by growth factors and cytokines, recruit neutrophils and monocytes to eliminate pathogens and debris. Notably, microbiota alterations relate to changes in wound healing dynamics. Commensal bacteria influence immune responses, keratinocyte growth, and blood vessel development. For instance, Staphylococcus epidermidis aids keratinocyte progression, while Staphylococcus aureus colonization impedes healing. Other bacteria like Group A Streptococcus spp. And Pseudomonas affect wound healing as well. Clinical applications of microbiota-based wound care are promising, with probiotics and specific bacteria like Acinetobacter baumannii aiding tissue repair through molecule secretion. Understanding microbiota influence on wound healing offers therapeutic avenues. Tailored approaches, including probiotics, prebiotics, and antibiotics, can manipulate the microbiota to enhance immune modulation, tissue repair, and inflammation control. Despite progress, critical questions linger. Determining the ideal microbiota composition for optimal wound healing, elucidating precise influence mechanisms, devising effective manipulation strategies, and comprehending the intricate interplay between the microbiota, host, and other factors require further exploration.

From Biomarkers to the Molecular Mechanism of Preeclampsia-A Comprehensive Literature Review.

Preeclampsia (PE) is a prevalent obstetric illness affecting pregnant women worldwide. This comprehensive literature review aims to examine the role of biomarkers and understand the molecular mechanisms underlying PE. The review encompasses studies on biomarkers for predicting, diagnosing, and monitoring PE, focusing on their molecular mechanisms in maternal blood or urine samples. Past research has advanced our understanding of PE pathogenesis, but the etiology remains unclear. Biomarkers such as PlGF, sFlt-1, PP-13, and PAPP-A have shown promise in risk classification and preventive measures, although challenges exist, including low detection rates and discrepancies in predicting different PE subtypes. Future perspectives highlight the importance of larger prospective studies to explore predictive biomarkers and their molecular mechanisms, improving screening efficacy and distinguishing between early-onset and late-onset PE. Biomarker assessments offer reliable and cost-effective screening methods for early detection, prognosis, and monitoring of PE. Early identification of high-risk women enables timely intervention, preventing adverse outcomes. Further research is needed to validate and optimize biomarker models for accurate prediction and diagnosis, ultimately improving maternal and fetal health outcomes.

Renal cancer secretome induces migration of mesenchymal stromal cells.

BACKGROUND: Advanced renal cell carcinoma (RCC) is therapeutically challenging. RCC progression is facilitated by mesenchymal stem/stromal cells (MSCs) that exert remarkable tumor tropism. The specific mechanisms mediating MSCs' migration to RCC remain unknown. Here, we aimed to comprehensively analyze RCC secretome to identify MSCs attractants. METHODS: Conditioned media (CM) were collected from five RCC-derived cell lines (Caki-1, 786-O, A498, KIJ265T and KIJ308T) and non-tumorous control cell line (RPTEC/TERT1) and analyzed using cytokine arrays targeting 274 cytokines in addition to global CM proteomics. MSCs were isolated from bone marrow of patients undergoing standard orthopedic surgeries. RCC CM and the selected recombinant cytokines were used to analyze their influence on MSCs migration and microarray-targeted gene expression. The expression of genes encoding cytokines was evaluated in 100 matched-paired control-RCC tumor samples. RESULTS: When compared with normal cells, CM from advanced RCC cell lines (Caki-1 and KIJ265T) were the strongest stimulators of MSCs migration. Targeted analysis of 274 cytokines and global proteomics of RCC CM revealed decreased DPP4 and EGF, as well as increased AREG, FN1 and MMP1, with consistently altered gene expression in RCC cell lines and tumors. AREG and FN1 stimulated, while DPP4 attenuated MSCs migration. RCC CM induced MSCs' transcriptional reprogramming, stimulating the expression of CD44, PTX3 and RAB27B. RCC cells secreted hyaluronic acid (HA), a CD44 ligand mediating MSCs' homing to the kidney. AREG emerged as an upregulator of MSCs' transcription. CONCLUSIONS: Advanced RCC cells secrete AREG, FN1 and HA to induce MSCs migration, while DPP4 loss prevents its inhibitory effect on MSCs homing. RCC secretome induces MSCs' transcriptional reprograming to facilitate their migration. The identified components of RCC secretome represent potential therapeutic targets.

Evidence of Placental Aging in Late SGA, Fetal Growth Restriction and Stillbirth-A Systematic Review.

During pregnancy, the placenta undergoes a natural aging process, which is considered normal. However, it has been hypothesized that an abnormally accelerated and premature aging of the placenta may contribute to placenta-related health issues. Placental senescence has been linked to several obstetric complications, including abnormal fetal growth, preeclampsia, preterm birth, and stillbirth, with stillbirth being the most challenging. A systematic search was conducted on Pubmed, Embase, and Scopus databases. Twenty-two full-text articles were identified for the final synthesis. Of these, 15 presented original research and 7 presented narrative reviews. There is a paucity of evidence in the literature on the role of placental aging in late small for gestational age (SGA), fetal growth restriction (FGR), and stillbirth. For future research, guidelines for both planning and reporting research must be implemented. The inclusion criteria should include clear differentiation between early and late SGA and FGR. As for stillbirths, only those with no other known cause of stillbirth should be included in the studies. This means excluding stillbirths due to congenital defects, infections, placental abruption, and maternal conditions affecting feto-maternal hemodynamics.

Intravenous immunoglobulins (IVIG) in severe/critical COVID-19 adult patients.

The coronavirus disease 2019 (COVID-19) pandemic has become a huge obstacle to the health system due to the high rate of contagion. It is postulated that intravenous immunoglobulins (IVIG) can lower the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related inflammation and prevent the development of acute respiratory distress syndrome (ARDS). The main advantages of IVIG treatment might be targeting cytokine storm in severe and critical COVID-19 by influences on complement, innate immune cells, effector T-cells, and Tregs. Randomized clinical trials (RCTs) and non-RCTs evaluating the safety and efficacy of IVIG in patients with severe/critical COVID-19 were performed. It seems that early administration of high-dose IVIG (in the acceleration phase of the disease) in severe or especially critical COVID-19 may be an effective therapeutic option, but there are no strong data to use it routinely. The results regarding mortality reduction are inconclusive. Additionally, IVIG treatment carries a risk of complications that should be considered when initiating treatment. However, given the COVID-19 mortality rate and limited therapeutic options, the use of IVIG is worth considering. This review summarizes the development and highlights recent advances in treatment with IVIG of severe/critically ill COVID-19 patients.

Adenoid hypertrophy in children: a narrative review of pathogenesis and clinical relevance.

Adenoids (nasopharyngeal tonsils), being part of Waldeyer's ring, are masses of lymphoid tissues located at the junction of the roof and the posterior wall of the nasopharynx. Adenoids play an important role in the development of the immune system and serve as a defence against infections, being the first organs that come into contact with respiratory and digestive antigens. The causes of adenoid hypertrophy are not fully known. They are most likely associated with aberrant immune reactions, infections, environmental exposures and hormonal or genetic factors. The aim of this review is to summarise the current knowledge of adenoid hypertrophy in children and associated diseases. Adenoid hypertrophy has many clinical manifestations that are frequent in the paediatric population and is accompanied by various comorbidities.

Coordinated reprogramming of renal cancer transcriptome, metabolome and secretome associates with immune tumor infiltration.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. The molecules (proteins, metabolites) secreted by tumors affect their extracellular milieu to support cancer progression. If secreted in amounts detectable in plasma, these molecules can also serve as useful, minimal invasive biomarkers. The knowledge of ccRCC tumor microenvironment is fragmentary. In particular, the links between ccRCC transcriptome and the composition of extracellular milieu are weakly understood. In this study, we hypothesized that ccRCC transcriptome is reprogrammed to support alterations in tumor microenvironment. Therefore, we comprehensively analyzed ccRCC extracellular proteomes and metabolomes as well as transcriptomes of ccRCC cells to find molecules contributing to renal tumor microenvironment. METHODS: Proteomic and metabolomics analysis of conditioned media isolated from normal kidney cells as well as five ccRCC cell lines was performed using mass spectrometry, with the following ELISA validation. Transcriptomic analysis was done using microarray analysis and validated using real-time PCR. Independent transcriptomic and proteomic datasets of ccRCC tumors were used for the analysis of gene and protein expression as well as the level of the immune infiltration. RESULTS: Renal cancer secretome contained 85 proteins detectable in human plasma, consistently altered in all five tested ccRCC cell lines. The top upregulated extracellular proteins included SPARC, STC2, SERPINE1, TGFBI, while downregulated included transferrin and DPP7. The most affected extracellular metabolites were increased 4-hydroxy-proline, succinic acid, cysteine, lactic acid and downregulated glutamine. These changes were associated with altered expression of genes encoding the secreted proteins (SPARC, SERPINE1, STC2, DPP7), membrane transporters (SLC16A4, SLC6A20, ABCA12), and genes involved in protein trafficking and secretion (KIF20A, ANXA3, MIA2, PCSK5, SLC9A3R1, SYTL3, and WNTA7). Analogous expression changes were found in ccRCC tumors. The expression of SPARC predicted the infiltration of ccRCC tumors with endothelial cells. Analysis of the expression of the 85 secretome genes in > 12,000 tumors revealed that SPARC is a PanCancer indicator of cancer-associated fibroblasts' infiltration. CONCLUSIONS: Transcriptomic reprogramming of ccRCC supports the changes in an extracellular milieu which are associated with immune infiltration. The proteins identified in our study represent valuable cancer biomarkers detectable in plasma.

TGF­ß1 affects the renal cancer miRNome and regulates tumor cells proliferation.

TGF­ß1 is a pleiotropic cytokine that can either promote or inhibit cancer development and progression. It was previously found that TGF­ß1 can regulate the expression of several microRNAs (miR or miRNA) involved in the progression of renal cell carcinoma (RCC). Therefore, the present study aimed to analyze the effects of TGF­ß1 on the global RCC miRNome. It was found that TGF­ß1 can regulate a complex network consisting of miRNAs and mRNAs involved in RCC transformation. In particular, TGF­ß1 was revealed to regulate the proliferation of RCC cells while concomitantly modifying the expression of oncogenic regulators, including avian erythroblastosis virus E26 (V­Ets) oncogene homolog­1 (ETS1). In addition, TGF­ß1 was demonstrated to regulate the expression of a number of miRNAs including miR­30c­5p, miR­155­5p, miR­181a­5p and miR­181b­5p. By contrast, TGF­ß1 reciprocally modified the expression of genes encoding TGF­ß1 receptors and SMADs, indicating a novel regulatory feedback mechanism mediated through the miRNAs. These data suggested that ETS1 served different roles in different subtypes of RCC tumors, specifically by functioning as an oncogene in clear cell RCC while as a tumor suppressor in papillary RCC.

piRNAs and PIWI Proteins as Diagnostic and Prognostic Markers of Genitourinary Cancers.

piRNAs (PIWI-interacting RNAs) are small non-coding RNAs capable of regulation of transposon and gene expression. piRNAs utilise multiple mechanisms to affect gene expression, which makes them potentially more powerful regulators than microRNAs. The mechanisms by which piRNAs regulate transposon and gene expression include DNA methylation, histone modifications, and mRNA degradation. Genitourinary cancers (GC) are a large group of neoplasms that differ by their incidence, clinical course, biology, and prognosis for patients. Regardless of the GC type, metastatic disease remains a key therapeutic challenge, largely affecting patients' survival rates. Recent studies indicate that piRNAs could serve as potentially useful biomarkers allowing for early cancer detection and therapeutic interventions at the stage of non-advanced tumour, improving patient's outcomes. Furthermore, studies in prostate cancer show that piRNAs contribute to cancer progression by affecting key oncogenic pathways such as PI3K/AKT. Here, we discuss recent findings on biogenesis, mechanisms of action and the role of piRNAs and the associated PIWI proteins in GC. We also present tools that may be useful for studies on the functioning of piRNAs in cancers.

Cellular and molecular basis of thyroid autoimmunity.

Autoimmune thyroid disease (AITD) is the most common human autoimmune disease. The two major clinical manifestations of AITD are Graves' disease and Hashimoto's thyroiditis (HT). AITD is characterized by lymphocytic infiltration of the thyroid gland, leading either to follicular cell damage, thyroid gland destruction, and development of hypothyroidism (in HT) or thyroid hyperplasia, induced by thyroid antibodies which activate thyrotropin receptor (TSHR) on thyrocytes, leading to hyperthyroidism. The aim of this review is to present up-to-date picture of the molecular and cellular mechanisms that underlie the pathology of AITD. Based on studies involving patients, animal AITD models, and thyroid cell lines, we discuss the key events leading to the loss of immune tolerance to thyroid autoantigens as well as the signaling cascades leading to the destruction of thyroid gland. Special focus is given on the interplay between the environmental and genetic factors, as well as ncRNAs and microbiome contributing to AITD development. In particular, we describe mechanistic models by which SNPs in genes involved in immune regulation and thyroid function, such as CD40, TSHR, FLT3, and PTPN22, underlie AITD predisposition. The clinical significance of novel diagnostic and prognostic biomarkers based on ncRNAs and microbiome composition is also underscored. Finally, we discuss the possible significance of probiotic supplementation on thyroid function in AITD.

Public Interest in Cataract Surgery: Analysis and Implications of Google Trends Data from 14 European Countries.

PURPOSE: Cataract surgery is the most common surgery performed in the European Union (EU) annually. Analysis of Google Trends (GT) data could give European eye care providers useful information regarding interest in cataract surgery and potential barriers making patients unwilling to undergo surgery. METHODS: Data were collected using GT for cataract surgery and the two most related queries, for each of 14 included countries from January 2004 to December 2018. Case volumes were extracted from the Eurostat report for the calendar years 2004-2018. RESULTS: The most related queries analysis demonstrated surgery outcomes, founding issues and understanding of the disease as potential factors for patients considering cataract surgery. Trend analysis showed that the total search volumes for "cataract surgery" gradually increased over the study period. Also, for "cataract", "after cataract surgery", "cataract surgery NHF" rising trends were revealed. Trends found for "cataract surgery price" and "cataract surgery complications" were inconclusive. Univariate linear regression analysis demonstrated statistically significant correlations between average annual search volumes of "cataract surgery" and the annual volume of cataract surgeries performed in included countries, according to Eurostat data (R2 = 0.889, p = <.001). In addition, univariate linear regression analyses revealed similar, statistically significant correlation for each the most related queries. CONCLUSION: To the knowledge of the authors, this is the first and the only analysis of GT data in the ophthalmology literature to date. This study highlights this potentially powerful data set for European eye care providers.

Nucleolar Proteins and Non-Coding RNAs: Roles in Renal Cancer.

Renal cell cancer is the most frequent kidney malignancy. Most RCC cases are classified as clear cell renal cell carcinoma (ccRCC), characterized by high aggressiveness and poor prognosis for patients. ccRCC aggressiveness is defined by classification systems based on changes in morphology of nucleoli, the membraneless substructures of nuclei. The latter act as the sites of ribosome biogenesis as well as the hubs that trap and immobilize proteins, preventing their action in other cellular compartments. Thereby, nucleoli control cellular functioning and homeostasis. Nucleoli are also the sites of activity of multiple noncoding RNAs, including snoRNAs, IGS RNA, and miRNAs. Recent years have brought several remarkable discoveries regarding the role of nucleolar non-coding RNAs, in particular snoRNAs, in ccRCC. The expression of snoRNAs is largely dysregulated in ccRCC tumors. snoRNAs, such as SNHG1, SNHG4 and SNHG12, act as miRNA sponges, leading to aberrant expression of oncogenes and tumor suppressors, and directly contributing to ccRCC development and progression. snoRNAs can also act without affecting miRNA functioning, by altering the expression of key oncogenic proteins such as HIF1A. snoRNAs are also potentially useful biomarkers of ccRCC progression. Here, we comprehensively discuss the role of nucleolar proteins and non-coding RNAs in ccRCC.

Publication Times in Ophthalmology Journals: The Story of Accepted Manuscripts.

INTRODUCTION: The process of scientific publishing changed greatly in the past decades. The authors aimed to get insight into the time required for articles to be accepted and released online in high-impacted ophthalmology journals. METHODS: Comprehensive review of all original articles published by eight ophthalmology journals during a one-year period was performed for 2020 and 2005. Time taken from submission to acceptance and the first online release of the article was abstracted and analyzed. RESULTS: A total of 3110 articles were reviewed. In 2020, the overall median time from submission to acceptance (AT) was 119 days (IQR 83-168) and 30 days (10-71) from acceptance to the first online release of the article (OP). AT increased by 7.3% from 2005 to 2020, whereas OP reduced by 73%. Publications, which the corresponding author was affiliated with US-located institution had shorter both AT and OP in 2005 and 2020. The author's specialty in ophthalmology had an inconclusive impact on AT and OP. Papers with multiple affiliated institutions had shorter AT and OP in both 2005 and 2020; however, these differences were not statistically significant. CONCLUSION: This study demonstrated that increasing pressure on authors, editors, and reviewers to publish articles and journals with high impact factor (IF) significantly influenced publication times in ophthalmology journals. Inflation of research papers was associated with rising AT time. A significant decrease in OP time was potentially explained by the editor's demand to achieve decent journal IF. This article brings to light relative publication times in the ophthalmology scientific journals.

A Comparative Study of Ranibizumab and Aflibercept for Neovascular Age-Related Macular Degeneration: 12-Month Outcomes of Polish Therapeutic Program in Non-Tertiary Institution.

Introduction This single-center study aimed to compare the 12-month treatment outcomes of ranibizumab with that of aflibercept in routine clinical practice. Methods Cohort of patients diagnosed with treatment-naïve neovascular age-related macular degeneration (AMD), treated using either ranibizumab (n = 33 eyes) or aflibercept (n = 44 eyes) monotherapy over a 12-month follow-up period was analyzed. Anonymous data were extracted from the electronic database dedicated to the drug program. Results In the ranibizumab group, there were no statistically significant changes in best-corrected visual acuity (BCVA) (Early Treatment Diabetic Retinopathy Study [ETDRS] letters) and central retina thickness (CRT) (µm), between baseline (67.9 ± 8.6 & 384.9 ± 97.9) and at 12 months (67.9 ± 12.1 & 398.9 ± 127.1; P = 0.372 & P = 0.884, respectively). In the aflibercept, there was an improvement in BCVA and reduction in CRT between baseline (64.2 ± 8.1 & 414.3 ± 97.8) and at 12 months (70.7 ± 7.4 & 342.3 ± 71.6; P < 0.001 & P < 0.001, respectively). There was no difference in BCVA between the two groups at either diagnosis (P = 0.101) or 12 months (P = 0.917). Mean number of injections in the ranibizumab group was significantly lower (4.9 ± 1.5) than in the aflibercept group (6.7 ± 1; P < 0.001). Conclusions  One initial injection of ranibizumab and then pro re nata (PRN) regimen resulted in stabilization of disease progression. Drug selection and treatment scheme could influence twelve-months outcomes. In the aflibercept group, three initial monthly injections and then every two months provided both significant BCVA improvement and CRT reduction at 12 months of treatment.

Fibromyalgia syndrome and the eye-A review.

Fibromyalgia is a chronic, widespread pain syndrome of unclear etiology characterized by fatigue, sleeping problems, cognitive disorders, somatic complaints, and severe pain in parts of the body at the time of physical activity, with no laboratory findings specific to the disease or diagnostic tests. Fibromyalgia can be associated with ocular symptoms (foreign body sensation, irritation) and visual disturbances (blurred vision), coexisting with dry eye syndrome and reduced corneal sensitivity. Cases of scleritis, including the necrotizing form, accompanying fibromyalgia have been reported. Changes in the eye may contribute to the pathogenesis of fibromyalgia. Research shows the choroid to be significantly thinner in patients with fibromyalgia, revealing changes in optic disc perfusion and a decreased retinal nerve fiber layer thickness. There are also thin corneal stromal nerves with diminished sub-basal plexus nerve density. Pathological changes and functional abnormalities of small nerve fibers are observed in patients with fibromyalgia. Corneal confocal bio-microscopy is a new noninvasive method to evaluate small nerve fiber morphology, serving as an alternative for skin biopsies, and reveals new possibilities in diagnostics and finding innovative therapies for this disease. Fibromyalgia remains a challenge for ophthalmologists, and further studies are required to evaluate ocular involvement. It may be that future diagnostic criteria for fibromyalgia will contain ophthalmic examination modalities. Observed ocular changes and their pathomechanisms may constitute new targets for therapy to improve the quality of life of patients with fibromyalgia.

Correction: Kedzierska, H., et al. Decreased Expression of SRSF2 Splicing Factor Inhibits Apoptotic Pathways in Renal Cancer. Int. J. Mol. Sci. 2016, 17, 1598.

The authors wish to make the following corrections to this paper [1]: in Figure 4 the same gelscans were mistakenly pasted to illustrate splicing changes of: i) BIM in KIJ-265T and KIJ308T cells,and ii) MCL-1 in UOK171 and KIJ-265T [...].

TGF-ß and microRNA Interplay in Genitourinary Cancers.

Genitourinary cancers (GCs) include a large group of different types of tumors localizing to the kidney, bladder, prostate, testis, and penis. Despite highly divergent molecular patterns, most GCs share commonly disturbed signaling pathways that involve the activity of TGF-ß (transforming growth factor beta). TGF-ß is a pleiotropic cytokine that regulates key cancer-related molecular and cellular processes, including proliferation, migration, invasion, apoptosis, and chemoresistance. The understanding of the mechanisms of TGF-ß actions in cancer is hindered by the "TGF-ß paradox" in which early stages of cancerogenic process are suppressed by TGF-ß while advanced stages are stimulated by its activity. A growing body of evidence suggests that these paradoxical TGF-ß actions could result from the interplay with microRNAs: Short, non-coding RNAs that regulate gene expression by binding to target transcripts and inducing mRNA degradation or inhibition of translation. Here, we discuss the current knowledge of TGF-ß signaling in GCs. Importantly, TGF-ß signaling and microRNA-mediated regulation of gene expression often act in complicated feedback circuits that involve other crucial regulators of cancer progression (e.g., androgen receptor). Furthermore, recently published in vitro and in vivo studies clearly indicate that the interplay between microRNAs and the TGF-ß signaling pathway offers new potential treatment options for GC patients.

MicroRNA-Mediated Metabolic Reprograming in Renal Cancer.

Metabolic reprogramming is one of the hallmarks of renal cell cancer (RCC). We hypothesized that altered metabolism of RCC cells results from dysregulation of microRNAs targeting metabolically relevant genes. Combined large-scale transcriptomic and metabolic analysis of RCC patients tissue samples revealed a group of microRNAs that contribute to metabolic reprogramming in RCC. miRNAs expressions correlated with their predicted target genes and with gas chromatography-mass spectrometry (GC-MS) metabolome profiles of RCC tumors. Assays performed in RCC-derived cell lines showed that miR-146a-5p and miR-155-5p targeted genes of PPP (the pentose phosphate pathway) (G6PD and TKT), the TCA (tricarboxylic acid cycle) cycle (SUCLG2), and arginine metabolism (GATM), respectively. miR-106b-5p and miR-122-5p regulated the NFAT5 osmoregulatory transcription factor. Altered expressions of G6PD, TKT, SUCLG2, GATM, miR-106b-5p, miR-155-5p, and miR-342-3p correlated with poor survival of RCC patients. miR-106b-5p, miR-146a-5p, and miR-342-3p stimulated proliferation of RCC cells. The analysis involving >6000 patients revealed that miR-34a-5p, miR-106b-5p, miR-146a-5p, and miR-155-5p are PanCancer metabomiRs possibly involved in global regulation of cancer metabolism. In conclusion, we found that microRNAs upregulated in renal cancer contribute to disturbed expression of key genes involved in the regulation of RCC metabolome. miR-146a-5p and miR-155-5p emerge as a key "metabomiRs" that target genes of crucial metabolic pathways (PPP (the pentose phosphate pathway), TCA cycle, and arginine metabolism).