Keratin Research Articles

Validation of Keratin 17 as a Tissue Biomarker in the Diagnosis of Upper Tract Urothelial Carcinoma.

Upper tract urothelial carcinoma (UTUC) has a relatively low incidence but presents significant surveillance and treatment challenges. Therefore, novel biomarkers for the accurate detection of upper tract urothelial tumors are urgently needed. We evaluated the expression of Keratin 17 (KRT17), an oncoprotein implicated in the cell cycle progression of multiple human cancers and previously studied in bladder urothelial carcinoma, by immunohistochemistry in 139 UTUC cases, including noninvasive, invasive papillary urothelial carcinoma and urothelial carcinoma in situ. KRT17 expression pattern (basal/negative vs. nonbasal) and H-score were evaluated. The expression pattern was significantly different in normal (NL) compared to malignant urothelium. Nonbasal KRT17 expression was significantly higher in pTa (p<0.001) and invasive (pTinv) (p=0.0023) urothelial carcinoma compared to NL, and in pTinv compared to pTa (p=0.0391). Sensitivity and specificity for distinguishing benign from malignant tumors were 85% and 82, respectively, with an area under the curve of 0.83 (p <0.001). The KRT17 H-score was significantly higher in pTa and pTinv compared to NL (p < 0.001 and p=0.0035, respectively). Sensitivity and specificity for distinguishing benign from malignant carcinoma were 91% and 69%, respectively, with an AUC of 0.81 (p=0.0010). KRT17 was not associated with tumor site, grade, or stage. In summary, K17 is a sensitive and specific marker of neoplastic upper tract urothelium, and its potential use in routine diagnostics should be explored in larger studies.

Enhanced Antitumor Efficacy of Oncolytic Vaccinia Virus Therapy Through Keratin-Mediated Delivery in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) represents an aggressive subtype characterized by high rates of recurrence and metastasis, necessitating the exploration of alternative treatment strategies. Oncolytic vaccinia virus (OVV) therapy has emerged as a promising approach, selectively infecting and destroying tumor cells. However, its efficacy is often hampered by inadequate viral distribution within the tumor microenvironment. Here, we investigate the potential of keratin (KTN) as a carrier for OVV delivery to enhance viral distribution and antitumor efficacy. In vitro assays revealed that KTN significantly improves OVV stability, leading to increased tumor cell apoptosis and necrosis. Furthermore, KTN effectively inhibits cancer cell migration by suppressing the epithelial-mesenchymal transition (EMT) process and downregulating metastasis-related proteins. These findings are corroborated in a syngeneic TNBC mouse model, where KTN-mediated OVV delivery enhances cytotoxic T cell-mediated antitumor immune responses without compromising the anti-angiogenic effects of the virus. Notably, KTN alone exhibits antitumor effects by suppressing tumor growth and metastasis, underscoring its potential as a standalone therapeutic agent. In conclusion, our study underscores the promise of KTN-mediated OVV delivery as a promising therapeutic strategy for TNBC. By improving viral distribution, suppressing EMT, and enhancing antitumor immunity, this approach holds significant potential for enhancing patient outcomes in TNBC treatment. Further investigation is warranted to explore the broader utility of KTN in various cancer therapy approaches.

Retinol intake and PCOS management: a plasma metabolite and protein analysis via Mendelian randomization and NHANES 2011-2016.

Polycystic Ovary Syndrome (PCOS) represents a complex endocrine disorder characterized by a significant interplay with metabolic dysfunction and obesity. This research endeavors to elucidate the causal dynamics among plasma metabolites, proteins, and PCOS, alongside Body Mass Index (BMI), to pinpoint prospective therapeutic interventions. This investigation employed Mendelian randomization (MR) analyses combined with data derived from the National Health and Nutrition Examination Survey (NHANES) to explore the relationships between 1,400 plasma metabolites and PCOS, factoring in BMI adjustments. Additionally, the study examined the influence of plasma proteins and performed a retrospective cross-sectional analysis focusing on retinol consumption and testosterone levels. MR analyses showed metabolite Glycosyl-N-(2-hydroxynervonoyl)-sphingosine (GNS) and protein Keratin 19 (KRT19) were identified as significant markers in the context of PCOS and BMI adjustments. A Phenome-Wide Association Study (PheWAS) underscored the linkage between KRT19 and BMI, while gene-drug interaction findings demonstrated a connection between KRT19 and retinol. Analysis for NHANES data disclosed a negative correlation between retinol intake and testosterone levels, particularly within normal weight and obese cohorts, suggesting the feasibility of dietary interventions for PCOS management. The study sheds light on the intricate interactions between plasma metabolites, proteins, and PCOS, considering BMI variations, and highlights KRT19 protein as a promising therapeutic target. The outcomes support the integration of retinol consumption into dietary strategies to regulate testosterone levels and potentially alleviate PCOS symptoms, underscoring the necessity for personalized nutritional and therapeutic approaches in the effective management of PCOS.

Upregulation of keratin 15 is required for varicella-zoster virus replication in keratinocytes and is attenuated in the live attenuated vOka vaccine strain

Varicella-zoster virus (VZV) is the etiological agent of chickenpox and shingles, diseases characterised by epidermal virus replication in skin and mucosa and the formation of blisters. We have previously shown that VZV infection has a profound effect on keratinocyte differentiation, altering the normal pattern of epidermal gene expression. In particular, VZV infection reduces expression of suprabasal keratins 1 and 10 and desmosomal proteins, disrupting epidermal structure to promote expression of a blistering phenotype. Here, we extend these findings to show that VZV infection upregulates the expression of keratin 15 (KRT15), a marker expressed by basal epidermal keratinocytes and hair follicles stem cells. We demonstrate that KRT15 is essential for VZV replication in the skin, since downregulation of KRT15 inhibits VZV replication in keratinocytes, while KRT15 exogenous overexpression supports viral replication. Importantly, our data show that VZV upregulation of KRT15 depends on the expression of the VZV immediate early gene ORF62. ORF62 is the only regulatory gene that is mutated in the live attenuated VZV vaccine and contains four of the five fixed mutations present in the VZV Oka vaccine. Our data indicate that the mutated vaccine ORF62 is not capable of upregulating KRT15, suggesting that this may contribute to the vaccine attenuation in skin. Taken together our data present a novel association between VZV and KRT15, which may open a new therapeutic window for a topical targeting of VZV replication in the skin via modulation of KRT15.

Single-cell sequencing analysis revealed that NEAT1 was a potential biomarker and therapeutic target of prostate cancer.

Prostate cancer (PCa) usually manifests atypical symptoms in the early stage, and once symptoms appear, most PCa patients have developed to the advanced stage, failing to undergo radical surgery. In this study, PCa occurrence-related biomarkers were explored based on single-cell RNA sequencing (scRNA-seq) data. scRNA-seq data of prostate normal (Normal), benign prostatic hyperplasia (BPH), and PCa (Tumor) samples were acquired from the Gene Expression Omnibus (GEO). Cellular subsets associated with PCa occurrence were obtained using cell annotation. Additionally, the mRNA expression of nuclear enriched abundant transcript 1 (NEAT1) was detected by quantitative real-time PCR (qRT-PCR). The effects of NEAT1 on cell proliferation and apoptosis were analyzed by 5-ethynyl-2-deoxyuridine (EdU) and flow cytometry. Subsequently, cell-derived xenograft (CDX) models were constructed and divided into the LV-NC and LV-shNEAT1 groups. After the tumor tissues of CDX model mice in each group were extracted, the cell growth and Ki67 expression were observed separately using hematoxylin-eosin (H&E) staining and immunohistochemistry (IHC). Ten cellular subsets were obtained via cell annotation, and significantly differential changes were observed between Basal intermediate and Luminal during the course of BPH to PCa. NEAT1-Luminal was highly recruited in the Tumor group with low stemness and high malignancy scores. Matrix metallopeptidase 7 (MMP7)- keratin 17 (KRT17)-Basal intermediate had high ratios in the Tumor group with low stemness and high malignancy scores. The results of pseudotime analysis revealed that NEAT1-Luminal in the Tumor group were consistently distributed with tumor stage cells. In vitro assays showed that NEAT1 expression was elevated in PCa cells, and NEAT1 knockdown could inhibit cell proliferation and induce apoptosis. CDX assays indicated that silencing NEAT1 could reduce the growth rate of PCa tumor volume in CDX model mice. H&E staining results showed that nuclei of tumor cells were reduced and exhibited lighter color in the LV-shNEAT1 group compared with the LV-NC group. IHC results showed that Ki67 positivity was significantly lower in the LV-shNEAT1 group than in the LV-NC group. NEAT1 expression is increased in PCa, and NEAT1 can be a potential biomarker and therapeutic target for PCa.

Plasmonics-enhanced spikey nanorattle-based biosensor for direct SERS detection of mRNA cancer biomarkers.

We present a plasmonics-enhanced spikey nanorattle-based biosensor for direct surface-enhanced Raman scattering (SERS) detection of mRNA cancer biomarkers. Early detection of cancers such as head and neck squamous cell carcinoma (HNSCC) is critical for improving patient outcomes in regions with limited access totraditional diagnostic methods. Our method targets Keratin 14 (KRT14), a promising diagnostic mRNA biomarker for HNSCC, using a sandwich hybridization approach with magnetic beads and SERS spikey nanorattles (SpNR). We synthesized SpNR with a core-gap-shell structure to enhance SERS signals, achieving a limit of detection of 90 femtomolar. A pilot study using clinical samples demonstrated the efficacy of our biosensor in distinguishing between tissue with positive or negative diagnosis for HNSCC, highlighting its potential for rapid and sensitive cancer diagnostics in low-resource settings. This plasmonic assay offers a promising avenue for portable and high-specificity detection of nucleic acid biomarkers, with implications for early cancer detection and improved patient care, especially in middle and low-resource settings.

Unveiling the impact of cell death-related genes and immune dynamics on drug resistance in lung adenocarcinoma: a risk score model and functional insights

Lung adenocarcinoma (LUAD), characterized by its heterogeneity and complex pathogenesis, is the focus of this study which investigates the association between cell death-related genes and LUAD. Through machine learning, a risk score model was developed using the Coxboost rsf algorithm, demonstrating strong prognostic accuracy in both validation (GSE30219, GSE31210, GSE72094) and training (TCGA-LUAD) datasets with C-indices of 0.93, 0.67, 0.68, and 0.64, respectively. The study reveals that the expression of Keratin 18 (KRT18), a key cytoskeletal protein, varies across LUAD cell lines (DV-90, PC-9, A549) compared to normal bronchial epithelial cells (BEAS-2B), suggesting its potential role in LUAD's pathogenesis. Kaplan–Meier survival curves further validate the model, indicating longer survival in the low-risk group. A comprehensive analysis of gene expression, functional differences, immune infiltration, and mutations underscores significant variations between risk groups, highlighting the high-risk group's immunological dysfunction. This points to a more intricate tumor immune environment and the possibility of alternative therapeutic strategies. The study also delves into drug sensitivity, showing distinct responses between risk groups, underscoring the importance of risk stratification in treatment decisions for LUAD patients. Additionally, it explores KRT18's epigenetic regulation and its correlation with immune cell infiltration and immune regulatory molecules, suggesting KRT18's significant role in the tumor immune landscape. This research not only offers a valuable prognostic tool for LUAD but also illuminates the complex interplay between cell death-related genes, drug sensitivity, and immune infiltration, positioning KRT18 as a potential therapeutic or prognostic target to improve patient outcomes by personalizing LUAD treatment strategies.

Impact of Keratins 8 and 18 Genetic Variants on the Severity of Alcoholic Liver Disease

Alcohol-related liver disease (ALD) affects ∼30% of heavy drinkers and is characterized by liver steatosis, fibrosis, and steatohepatitis. The aggregation of keratins 8 (KRT8) and 18 (KRT18) plays a key role in the formation of Mallory–Denk bodies, a hallmark of ALD. Circulating levels of KRT18 fragments are elevated during ALD, and several KRT8/18 genetic variants have been linked to an increased risk of liver disease. In this study, we explored the relationship between the histologic features of ALD and genetic variants of KRT8/18 in 106 severe patients with ALD from the Hôpitaux Universitaires de Genève. We found a significant over-representation of several KRT8 (rs2070910, rs137898974, rs1065306) and KRT18 (rs17120866, rs1492241) variants located in the noncoding regions of these genes. Increased circulating level of keratins 18 fragments were associated with rs17120866 and alcoholic hepatitis. The combination of several KRT18 variants appeared associated with a poorer prognosis. These results highlight the possible role of KRT18 variants in ALD.

Evaluation of the novel ALK5 inhibitor EW-7197 on therapeutic efficacy in renal fibrosis using a three-dimensional chip model.

EW-7197, a potent oral ALK5 inhibitor, was assessed for its impact on transforming growth factor beta 1 (TGF-β1)-induced fibrosis in a three-dimensional (3D) renal fibrosis-on-a-chip and a mouse model. The evaluation included tubular epithelial-mesenchymal transition, angiogenesis, and inflammatory cytokine expression. In a 3D renal fibrosis-on-a-chip model, three cell types (kidney fibroblasts, human proximal tubular cell line, and human umbilical vein endothelial cells) were cultured and treated with TGF-β1 and EW-7197. Expression of alpha smooth muscle actin (α-SMA) and keratin 8 (KRT-8) was assessed, angiogenesis was observed via confocal microscopy, and cytokine levels were measured using real-time polymerase chain reaction, immunoassay, and enzyme-linked immunosorbent assay. In a cisplatin-induced renal fibrosis mouse model, blood urea nitrogen levels, TGF-β, and Smad 2/3 were determined, and renal fibrosis was assessed with Masson's trichrome stain. The α-SMA expression was significantly lower in the EW-7197 group than in the TGF-β fibrosis group. TGF-β decreased the expression of the epithelial marker KRT-8, an effect that was reversed by EW-7197 and SB431542. In the TGF-β-induced fibrosis model, the length of the thick vessels was reduced, and the diameter of both thick and thin vessels was decreased, but EW-7197 reversed these effects. EW-7197 significantly reduced the messenger RNA expression of TGF-β and increased the levels of vascular endothelial growth factor receptor 2, interleukin (IL)-10, and IL-6. EW-7197 reduced the levels of secretory cytokines TGF-β1, TGF-β3, IL-1β. In the cisplatin-induced renal fibrosis mouse model, EW-7197 reduced renal fibrosis by down-regulating TGF-β signaling. EW-7197 attenuated the TGF-β1-induced fibrotic cellular response in the 3D chip model and animal model. These findings indicate the potential effect of EW-7197 in attenuating renal fibrosis.

Oxidative Stress and Annexin A2 Differential Expression in Free Fatty Acids-Induced Non-Alcoholic Fatty Liver Disease in HepG2 Cells.

Non-alcoholic fatty liver disease (NAFLD) is a rising global burden, affecting one in four adults. Despite the increasing prevalence of NAFLD, the exact cellular and molecular mechanisms remain unclear, and effective therapeutic strategies are still limited. In vitro models of NAFLD are critical to understanding the pathogenesis and searching for effective therapies; thus, we evaluated the effects of free fatty acids (FFAs) on NAFLD hallmarks and their association with the modulation of Annexin A2 (ANXA2) and Keratin 17 (KRT17) in HepG2 cells. Our results show that oleic and palmitic acids can differentially induce intracellular lipid accumulation, cell death, and promote oxidative stress by increasing lipid peroxidation, protein carbonylation, and antioxidant defense depletion. Moreover, a markedly increased expression of inflammatory cytokines demonstrated the activation of inflammation pathways associated with lipotoxicity and oxidative stress. ANXA2 overexpression and KRT17 nuclear translocation were also observed, supporting the role of both molecules in the progression of liver disease. Taken together, these data provide insights into the interplay between ANXA2 and KRT17 in NAFLD, paving the way for understanding molecular mechanisms involved with the disease and developing new therapeutic strategies.

CSF1-dependent macrophage support matrisome and epithelial stress-induced keratin remodeling in Eosinophilic esophagitis

Atopic diseases such as Eosinophilic Esophagitis (EoE) often progress into fibrosis (FS-EoE), compromising organ function with limited targeted treatment options. Mechanistic understanding of FS-EoE progression is confounded by the lack of preclinical models and the heavy focus of research on eosinophils themselves. We found that macrophage accumulation precedes esophageal fibrosis in FS-EoE patients. We developed a FS-EoE model via chronic administration of oxazalone allergen, in a transgenic mouse over-expressing esophageal epithelial hIL-5 (L2-IL5OXA). These mice display striking histopathologic features congruent with that found in FS-EoE patients. Unbiased proteomic analysis, using a unique extracellular-matrix (ECM) focused technique, identified an inflammation-reactive provisional basal lamina membrane signature and this was validated in two independent EoE patient RNA-sequencing/proteomic cohorts, supporting model significance. A wound healing signature was also observed involving hemostasis-associated molecules previously unnoted in EoE. We further identified the ECM glycoprotein, Tenascin-C (TNC), and the stress-responsive keratin-16 (KRT16) as IL-4 and IL-13 responsive mediators, acting as biomarkers of FS-EoE. To mechanistically address how the immune infiltrate shapes FS-EoE progression, we phenotyped the major immune cell subsets that coalesce with fibrosis in both the L2-IL5OXA mice and in FS-EoE patients. We found that macrophage are required for matrisome and cytoskeletal remodeling. Importantly, we show that macrophage accumulation precedes esophageal fibrosis and provide a novel therapeutic target in FS-EoE as their depletion with anti-CSF1 attenuated reactive matrisome and cytoskeletal changes. Thus, macrophage-based treatments and the exploration of TNC and KRT16 as biomarkers may provide novel therapeutic options for patients with fibrostenosis.

Transcriptome-based classification to predict FOLFIRINOX response in a real-world metastatic pancreatic cancer cohort

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at metastatic stage and typically treated with fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX). Few patients benefit from this treatment. Molecular subtypes are prognostic in particularly resectable PDAC and might predict treatment response. This study aims to correlate molecular subtypes in metastatic PDAC with FOLFIRINOX responses using real-world data, providing assistance in counselling patients. We collected 131 RNA-sequenced metastatic biopsies and applied a network-based meta-analysis using published PDAC classifiers. Subsequent survival analysis was performed using the most suitable classifier. For validation, we developed an immunohistochemistry (IHC) classifier using GATA6 and keratin-17 (KRT17), and applied it to 86 formalin-fixed paraffin-embedded samples of advanced PDAC. Lastly, GATA6 knockdown models were generated in PDAC organoids and cell lines. We showed that the PurIST classifier was the most suitable classifier. With this classifier, classical tumors had longer PFS and OS than basal-like tumors (PFS: 216 vs. 78 days, p = 0.0002; OS: 251 vs. 195 days, p = 0.049). The validation cohort showed a similar trend. Importantly, IHC GATA6low patients had significantly shorter survival with FOLFIRINOX (323 vs. 746 days, p = 0.006), but no difference in non-treated patients (61 vs. 54 days, p = 0.925). This suggests that GATA6 H-score predicts therapy response. GATA6 knockdown models did not lead to increased FOLFIRINOX responsiveness. These data suggest a predictive role for subtyping (transcriptomic and GATA6 IHC), though no direct causal relationship was found between GATA6 expression and chemoresistance. GATA6 immunohistochemistry should be seamlessly added to current diagnostics and integrated into upcoming clinical trials.

Effects of pulmonary surfactant combined with noninvasive positive pressure ventilation in neonates with respiratory distress syndrome.

Neonatal respiratory distress syndrome (NRDS) is one of the most common diseases in neonatal intensive care units, with an incidence rate of about 7% among infants. Additionally, it is a leading cause of neonatal death in hospitals in China. The main mechanism of the disease is hypoxemia and hypercapnia caused by lack of surfactant. To explore the effect of pulmonary surfactant (PS) combined with noninvasive positive pressure ventilation on keratin-14 (KRT-14) and endothelin-1 (ET-1) levels in peripheral blood and the effectiveness in treating NRDS. Altogether 137 neonates with respiratory distress syndrome treated in our hospital from April 2019 to July 2021 were included. Of these, 64 control cases were treated with noninvasive positive pressure ventilation and 73 observation cases were treated with PS combined with noninvasive positive pressure ventilation. The expression of KRT-14 and ET-1 in the two groups was compared. The deaths, complications, and PaO2, PaCO2, and PaO2/FiO2 blood gas indexes in the two groups were compared. Receiver operating characteristic curve (ROC) analysis was used to determine the diagnostic value of KRT-14 and ET-1 in the treatment of NRDS. The observation group had a significantly higher effectiveness rate than the control group. There was no significant difference between the two groups in terms of neonatal mortality and adverse reactions, such as bronchial dysplasia, cyanosis, and shortness of breath. After treatment, the levels of PaO2 and PaO2/FiO2 in both groups were significantly higher than before treatment, while the level of PaCO2 was significantly lower. After treatment, the observation group had significantly higher levels of PaO2 and PaO2/FiO2 than the control group, while PaCO2 was notably lower in the observation group. After treatment, the KRT-14 and ET-1 levels in both groups were significantly decreased compared with the pre-treatment levels. The observation group had a reduction of KRT-14 and ET-1 levels than the control group. ROC curve analysis showed that the area under the curve (AUC) of KRT-14 was 0.791, and the AUC of ET-1 was 0.816. Combining PS with noninvasive positive pressure ventilation significantly improved the effectiveness of NRDS therapy. KRT-14 and ET-1 levels may have potential as therapeutic and diagnostic indicators.

Helicobacter pylori upregulates PAD4 expression via stabilising HIF-1α to exacerbate rheumatoid arthritis

ObjectiveHelicobacter pylori infection has been reported to aggravate rheumatoid arthritis (RA), but the relevant mechanism remains unclear. This study aimed to investigate the underlying pathogenic mechanism of H. pylori infection...

Anticancer effects of Erzhimaoling decoction in high-grade serous ovarian cancer in vitro and in vivo

BackgroundHigh-grade serous ovarian cancer (HGSOC) is a common gynecologic malignancy with a poor prognosis. The traditional Chinese medicine formula Erzhimaoling decoction (EZMLD) has anticancer potential. This study aims to elucidate the anticancer effects of EZMLD on HGSOC in vitro and in vivo.Materials and methodsEZMLD-containing serum was prepared from Sprague–Dawley rats for treating SKOV3 ovarian cancer cells at varying concentrations for 24 h and 48 h to determine the IC50. Concentrations of 0%, 5%, and 10% for 24 h were chosen for subsequent in vitro experiments. The roles of METTL3 and METTL14 in SKOV3 cells were explored by overexpressing these genes and combining EZMLD with METTL3/14 knockdown. Investigations focused on cell viability and apoptosis, apoptosis-related protein expression, and KRT8 mRNA m6A modification. For in vivo studies, 36 BALB/c nude mice were divided into six groups involving EZMLD (6.75, 13.5, and 27 g/kg) and METTL3 or METTL14 knockdowns, with daily EZMLD gavage for two weeks.ResultsIn vitro, EZMLD-containing serum had IC50 values of 8.29% at 24 h and 5.95% at 48 h in SKOV3 cells. EZMLD-containing serum decreased SKOV3 cell viability and increased apoptosis. EZMLD upregulated METTL3/14 and FAS-mediated apoptosis proteins, while downregulating Keratin 8 (KRT8). EZMLD increased KRT8 mRNA m6A methylation. METTL3/14 overexpression reduced SKOV3 cell viability and increased apoptosis, while METTL3/14 knockdown mitigated EZMLD's effects. In vivo, EZMLD suppressed SKOV3 xenografts growth, causing significant apoptosis and modulating protein expression.ConclusionsEZMLD has therapeutic potential for ovarian cancer and may be considered for other cancer types. Future research may explore its broader effects beyond cell apoptosis.

Urine biomarkers can predict prostate cancer and PI-RADS score prior to biopsy

Prostate-Specific Antigen (PSA) based screening of prostate cancer (PCa) needs refinement. The aim of this study was the identification of urinary biomarkers to predict the Prostate Imaging—Reporting and Data System (PI-RADS) score and the presence of PCa prior to prostate biopsy. Urine samples from patients with elevated PSA were collected prior to prostate biopsy (cohort = 99). The re-analysis of mass spectrometry data from 45 samples was performed to identify urinary biomarkers to predict the PI-RADS score and the presence of PCa. The most promising candidates, i.e. SPARC-like protein 1 (SPARCL1), Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), Alpha-1-microglobulin/bikunin precursor (AMBP), keratin 13 (KRT13), cluster of differentiation 99 (CD99) and hornerin (HRNR), were quantified by ELISA and validated in an independent cohort of 54 samples. Various biomarker combinations showed the ability to predict the PI-RADS score (AUC = 0.79). In combination with the PI-RADS score, the biomarkers improve the detection of prostate carcinoma-free men (AUC = 0.89) and of those with clinically significant PCa (AUC = 0.93). We have uncovered the potential of urinary biomarkers for a test that allows a more stringent prioritization of mpMRI use and improves the decision criteria for prostate biopsy, minimizing patient burden by decreasing the number of unnecessary prostate biopsies.

High keratin 15 expression reflects favorable prognosis in early cervical cancer patients.

Keratin 15 (KRT15) exhibits inconsistent prognostic roles in different cancers, and its prognostic value in early cervical cancer patients who receive tumor resection remains unknown. This study aimed to assess the relationship of KRT15 expression with prognosis in these patients. Totally, 147 early cervical cancer patients who received tumor resection were reviewed in this retrospective study. KRT15 was detected in formalin-fixed paraffin-embedded tumor tissue by immunohistochemistry (IHC). KRT15 IHC scores were computed by multiplying the percentage of positively stained cells (scored as 0-4) and corresponding staining intensity (scored as 0-3), ranging from 0 to 12. Elevated KRT15 IHC score was linked with moderate to well differentiation (P = 0.005), tumor size ≤ 4cm (P = 0.017), and International Federation of Gynecology and Obstetrics (FIGO) stage Ia/Ib (P < 0.001). KRT15 IHC score was inversely associated with adjuvant radiotherapy (P = 0.025) and adjuvant chemotherapy (P = 0.016). KRT15 IHC score ≥ 1 was linked with increased disease-free survival (DFS) (P = 0.003) and overall survival (OS) (P = 0.049). Meanwhile, KRT15 IHC score ≥ 1 independently predicted increased DFS (hazard ratio = 0.213, P = 0.017), but not OS (P > 0.05). KRT15 IHC score ≥ 3 and KRT15 IHC score ≥ 6 could not predict DFS or OS (all P > 0.05). By subgroup analyses, KRT15 IHC score ≥ 1 forecasted favorable DFS in patients with age > 45years, human papillomavirus-positive, squamous carcinoma, and tumor size ≤ 4cm (all P < 0.05). KRT15 IHC score ≥ 1 and KRT15 IHC score ≥ 3 predicted ascended DFS in patients without adjuvant radiotherapy or adjuvant chemotherapy (all P < 0.05). High KRT15 expression reflects favorable tumor features and longer survival in early cervical cancer patients who receive tumor resection.

NAT10 Promotes Prostate Cancer Growth and Metastasis by Acetylating mRNAs of HMGA1 and KRT8.

N4-acetylcytidine (ac4C) is essential for the development and migration of tumor cells. According to earlier research, N-acetyltransferase 10 (NAT10) can increase messenger RNAs (mRNAs) stability by catalyzing the synthesis of ac4C. However, little is known about NAT10 expression and its role in the acetylation modifications in prostate cancer (PCa). Thus, the biological function of NAT10 in PCa is investigated in this study. Compared to paraneoplastic tissues, the expression of NAT10 is significantly higher in PCa. The NAT10 expression is strongly correlated with the pathological grade, clinical stage, Gleason score, T-stage, and N-stage of PCa. NAT10 has the ability to advance the cell cycle and the epithelial-mesenchymal transition (EMT), both of which raise the malignancy of tumor cells. Mechanistically, NAT10 enhance the stability of high mobility group AT-hook 1 (HMGA1) by acetylating its mRNA, thereby promoting cell cycle progression to improve cell proliferation. In addition, NAT10 improve the stability of Keratin 8 (KRT8) by acetylating its mRNA, which promotes the progression of EMT to improve cell migration. This findings provide a potential prognostic or therapeutic target for PCa.

Variants in the L12 linker domain of KRT10 are causal to atypical epidermolytic ichthyosis.

Epidermolytic ichthyosis (EI) is a type of congenital ichthyosis, characterized by erythema and blistering at birth followed by hyperkeratosis. EI is caused by pathogenic variants in the genes KRT1 and KRT10, encoding the proteins keratin 1 (KRT1) and keratin 10 (KRT10), respectively, and is primarily transmitted by autosomal-dominant inheritance, although recessive inheritance caused by nonsense variants in KRT10 is also described. The keratins form a network of intermediate filaments and are a structural component of the cytoskeleton, giving strength and resilience to the skin. We present three cases of mild EI caused by pathogenic KRT10 variations in the L12 linker domain. To our knowledge, this is the first time L12 linker domain pathogenic variants are identified in KRT10 for EI. The aim of this study was to identify gene variants for patients with EI in KRT1 or KRT10. To establish the pathogenicity of the found variations in KRT10, we evaluated all patients and available family members clinically. Genetic analyses were performed using Sanger sequencing. Vectors containing wild-type or mutated forms of KRT10 were transfected into HaCaT cells and analyzed by high-resolution confocal microscopy. Genetic analysis of KRT10 identified a heterozygous de novo variant c.910G>A p.(Val304Met) in family 1, a familial heterozygous variant c.911T>C p.(Val304Ala) in family 2, and a familial heterozygous variant c.917T>C p.(Met306Thr) in family 3. All identified missense variants were located in the L12 linker domain of KRT10. Invitro study of aggregate formation of the missense variants in KRT10 only showed a very mild and not quantifiable aggregate formation in the KRT10 network, compared with the wild-type sequence. We report three different novel missense variants in the L12 linker domain of KRT10 in patients with an atypical, milder form of EI resembling peeling skin syndrome.

Assessment of the Role of Keratin 18 and High Mobility Group Box 1 Biomarkers for Early Prediction of Drugs and Chemicals Induced Hepatotoxicity A Prospective Study in the Poison Control Center of Ain Shams University Hospitals (PCC-ASUH)

Abstract Background Drug-induced hepatotoxicity represents a major clinical problem worldwide. Hepatotoxicity may be caused by drugs, chemicals used in laboratories and industries or natural products and rodenticides such as metal phosphides. Early identification of hepatotoxicity would facilitate patient- individualized treatment strategies. New biomarkers (HMGB1and K18) used to identify subsequent acute liver injury (ALI) in patients on admission to the hospital. Objectives This study aims to assess the role of keratin 18 and high mobility group box 1 biomarkers in early prediction of drugs and chemicals induced hepatotoxicity for better outcome and to compare these new liver biomarkers with the currently used parameters (ALT &amp; AST) in the early prediction of drugs and chemicals induced hepatotoxicity. Methods This prospective study was conducted on 50 adult patients of both sex presented to the PCC- ASUH with acute intoxication of hepatotoxic drugs or chemicals. For all patients, we measured high mobility group box-1 (HMGB1), keratin-18 (K18), AST and ALT on admission then patients were followed- up for development of liver injury . Subjects were classified into group I (control group), group II (no liver affection) and group III (with liver affection). Receiver operator characteristic (ROC) curve was used to compare sensitivity and specificity to report liver injury versus alanine transaminase (ALT) and aspartate transaminase (AST). Results This study showed that HMGB1 and K18 were much more elevated in patients who developed liver injury in the first hospital presentation when ALT and AST were within normal ranges with a highly significant difference between the hepatotoxic and non-hepatotoxic group. ROC analysis showed that HMGB1 and K18 were more sensitive than ALT and AST and more specific than AST in predicting ALI. Conclusion Elevations in plasma HMGB1, and K18 identified subsequent ALI development in patients on admission to the hospital, soon after drug and chemical overdose, and in patients with ALT and AST in the normal range.