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PANoptosis is a form of inflammatory programmed cell death that is regulated by the PANoptosome. This PANoptosis possesses key characteristics of pyroptosis, apoptosis, and necroptosis, yet cannot be fully explained by any of these cell death modes. The unique nature of this cell death mechanism has garnered significant interest. However, the specific role of PANoptosis-associated features in gastric cancer (GC) is still uncertain. Patients were categorized into different PAN subtypes based on the expression of genes related to the PANoptosome. We conducted a systematic analysis to investigate the variations in prognosis and tumor microenvironment (TME) among these subtypes. Furthermore, we developed a risk score, called PANoptosis-related risk score (PANS), which is constructed from genes associated with the PANoptosis. We comprehensively analyzed the correlation between PANS and GC prognosis, TME, immunotherapy efficacy and chemotherapeutic drug sensitivity. Additionally, we performed in vitro experiments to validate the impact of Keratin 7 (KRT7) on GC. We identified two PAN subtypes (PANcluster A and B). PANoptosome genes were highly expressed in PANcluster A. PANcluster A has the characteristics of favorable prognosis, abundant infiltration of anti-tumor lymphocytes, and sensitivity to immunotherapy, thus it was categorized as an immune-inflammatory type. Meanwhile, our constructed PANS can effectively predict the prognosis and immune efficacy of GC. Patients with low PANS have a good prognosis, and have the characteristics of high tumor mutation load (TMB), high microsatellite instability (MSI), low tumor purity and sensitivity to immunotherapy. In addition, PANS can also identify suitable populations for different chemotherapy drugs. Finally, we confirmed that KRT7 is highly expressed in GC. Knocking down the expression of KRT7 significantly weakens the proliferation and migration abilities of GC cells. The models based on PANoptosis signature help to identify the TME features of GC and can effectively predict the prognosis and immune efficacy of GC. Furthermore, the experimental verification results of KRT7 provide theoretical support for anti-tumor treatment.

Clinical improvement in pigmentation is frequently observed after kidney transplantation. However, the underlying molecular and histological mechanisms remain unclear. We conducted a study to quantify the skin color change using a handheld reflected light colorimeter and to investigate protein expression changes in the skin before and after kidney transplantation. Paired skin biopsies were obtained from three patients who underwent kidney transplantation before and one month after transplantation. Protein expression was analyzed using iTRAQ-based quantitative proteomics. Differentially expressed proteins were identified and visualized using hierarchical clustering and volcano plots. Histopathological evaluation included hematoxylin and eosin (H&E), Masson's trichrome, and immunohistochemical (IHC) staining for keratin (KRT) 7, KRT19, and MelanA. Skin pigmentation of the arms, ankles, and abdomen had significant L-value improvement after kidney transplantation. Proteomic profiling identified 2148 proteins, with six proteins showing significant differential expression after transplantation. Among them, KRT7, KRT19, and prostaglandin D2 synthase (PTGDS) were significantly downregulated, potentially reflecting reduced epithelial stress and systemic inflammation. H&E and Masson's trichrome staining revealed a post-transplantation reduction in dermal pigmentation and collagen content. IHC showed decreased KRT7, KRT19, and MelanA expression after transplantation. Our results suggest that targeting KRT or prostaglandin pathways may offer new treatments for ESRD-related skin symptoms.

This study primarily focuses on the potential sources of autofluorescence, including keratins (KRT) encoded by KRT1 , KRT7 , and KRT8 , to investigate their contributions to the differences in autofluorescence between cancerous tissues and adjacent non-tumor tissues, as well as their potential for real-time diagnosis of RCC. First, the autofluorescence of renal cell carcinoma (RCC) tissues under 488 nm laser excitation was observed and compared with the autofluorescence of neighboring non-tumor tissues. Then, the effect on the autofluorescence intensity was analyzed by knocking down the KRT1/KRT7 gene. In addition, autofluorescence data were collected from 174 pairs of tumor and adjacent non-tumor tissue samples (from 60 RCC patients). Diagnostic performance was evaluated using ROC analysis to determine the threshold value for tumor autofluorescence intensity. Under 488 nm laser excitation, the intensity of green autofluorescence in cancerous tissues of RCC patients was significantly lower than that in non-tumor tissues. Further analysis showed that KRT1 knockdown resulted in a 73% reduction in autofluorescence intensity, suggesting that KRT1 plays a key role in the reduced autofluorescence observed in tumor tissues. In addition, analysis of autofluorescence data from 174 tumor and adjacent non-tumor tissue samples showed an AUC of 0.880 for ROC analysis, a diagnostic sensitivity and specificity of 0.843 and 0.835, respectively, and a threshold value of 27.45 for using tumor autofluorescence intensity. KRT1 is a major contributor to the tumor autofluorescence observed in RCC. An autofluorescence-based diagnostic model facilitates real-time assessment of surgical margins during partial nephrectomy, thereby potentially improving surgical success rates.

The squamous–columnar junction (SCJ) is a boundary consisting of precisely positioned transitional epithelium between the squamous and columnar epithelium. Transitional epithelium is a hotspot for precancerous lesions, and is therefore clinically important; however, the origins and physiological properties of transitional epithelium have not been fully elucidated. Here, by using mouse genetics, lineage tracing, and organoid culture, we examine the development of the SCJ in the mouse stomach, and thus define the unique features of transitional epithelium. We find that two transcription factors, encoded by Sox2 and Gata4 , specify primitive transitional epithelium into squamous and columnar epithelium. The proximal–distal segregation of Sox2 and Gata4 expression establishes the boundary of the unspecified transitional epithelium between committed squamous and columnar epithelium. Mechanistically, Gata4 -mediated expression of the morphogen Fgf10 in the distal stomach and Sox2 -mediated Fgfr2 expression in the proximal stomach induce the intermediate regional activation of MAPK/ERK, which prevents the differentiation of transitional epithelial cells within the SCJ boundary. Our results have implications for tissue regeneration and tumorigenesis, which are related to the SCJ. How boundary regions form in the epithelia of tissues, for example, the squamous–columnar junction is unclear. Here, the authors identify the transcription factors Sox2 and Gata4 as specifying the transitional epithelium in the murine squamous–columnar junction region in the stomach epithelia.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with a dismal prognosis due to distant metastasis. Through an analysis of large RNA sequencing and proteomics datasets, we found that high KRT7 expression in PDAC patients was correlated with liver metastasis and poor survival. A functional investigation revealed that the overexpression of KRT7 promoted liver metastasis but did not affect tumor cell proliferation in vivo or in vitro. Analysis of scRNA-Seq data from 24 PDAC samples revealed a negative correlation between KRT7 expression in PDAC cells and cancer-associated fibroblast (CAF) infiltration, and this was further confirmed in orthotopic tumor model mice injected with KRT7-overexpressing PDAC cells, which led the development of to a prometastatic niche with reduced ECM deposition. Mechanistically, KRT7 in PDAC cells promoted the secretion of FGF2, which inhibited CAF proliferation and ECM-related gene transcription through the Wnt/β-catenin pathway. Moreover, targeting FGF2 decreased liver metastasis in vivo. Our study revealed that KRT7 promotes PDAC liver metastasis by remodeling the extracellular matrix niche through FGF2-fibroblast crosstalk and provides a promising strategy for preventing PDAC liver metastasis.

Colorectal cancer (CRC) is a leading global cause of illness and death. There is a need for identification of better prognostic markers beyond traditional clinical variables like grade and stage. Previous research revealed that abnormal expression of cytokeratin 7 (CK7) and loss of the intestinal-specific Special AT-rich sequence-binding protein 2 (SATB2) are linked to poor CRC prognosis. This study aimed to explore these markers’ prognostic significance alongside two extraintestinal mucins (MUC5AC, MUC6), claudin 18, and MUC4 in 285 CRC cases using immunohistochemistry on tissue microarrays (TMAs). CK7 expression and SATB2-loss were associated with MUC5AC, MUC6, and claudin 18 positivity. These findings suggest a distinct \"non-intestinal\" immunohistochemical profile in CRC, often right-sided, SATB2-low, with atypical expression of CK7 and non-colorectal mucins (MUC5AC, MUC6). Strong MUC4 expression negatively impacted cancer-specific survival (hazard ratio = 2.7, p = 0.044). Genetic analysis via next-generation sequencing (NGS) in CK7 + CRCs and those with high MUC4 expression revealed prevalent mutations in TP53, APC, BRAF, KRAS, PIK3CA, FBXW7, and SMAD4, consistent with known CRC mutation patterns. NGS also identified druggable variants in BRAF, PIK3CA, and KRAS . CK7 + tumors showed intriguingly common (31.6%) BRAF V600E mutations corelating with poor prognosis, compared to the frequency described in the literature and databases. Further research on larger cohorts with a non-colorectal immunophenotype and high MUC4 expression is needed.

Expression of the long non-coding RNA (lncRNA) keratin-7 antisense (KRT7-AS) is downregulated in various types of cancer; however, the impact of KRT7-AS deficiency on tumorigenesis and apoptosis is enigmatic. We aim to explore the influence of KRT7-AS in carcinogenesis and apoptosis. We found that KRT7-AS was deficient in breast and lung cancers, and low levels of KRT7-AS were a poor prognostic factor in breast cancer. Cellular studies showed that silencing of KRT7-AS in lung cancer cells increased oncogenic Keratin-7 levels and enhanced tumorigenesis, but diminished cancer apoptosis of the cancer cells; by contrast, overexpression of KRT7-AS inhibited lung cancer cell tumorigenesis. Additionally, KRT7-AS sensitized cancer cells to the anti-cancer drug cisplatin, consequently enhancing cancer cell apoptosis. In vivo, KRT7-AS overexpression significantly suppressed tumor growth in xenograft mice, while silencing of KRT7-AS promoted tumor growth. Mechanistically, KRT7-AS reduced the levels of oncogenic Keratin-7 and significantly elevated amounts of the key tumor suppressor PTEN in cancer cells through directly binding to PTEN protein via its core nucleic acid motif GGCAAUGGCGG. This inhibited the ubiquitination-proteasomal degradation of PTEN protein, therefore elevating PTEN levels in cancer cells. We also found that KRT7-AS gene transcription was driven by the transcription factor RXRα; intriguingly, the small molecule berberine enhanced KRT7-AS expression, reduced tumorigenesis, and promoted apoptosis of cancer cells. Collectively, KRT7-AS functions as a new tumor suppressor and an apoptosis enhancer in lung and breast cancers, and we unraveled that the RXRα-KRT7-AS-PTEN signaling axis controls carcinogenesis and apoptosis. Our findings highlight a tumor suppressive role of endogenous KRT7-AS in cancers and an important effect the RXRα-KRT7-AS-PTEN axis on control of cancer cell tumorigenesis and apoptosis, and offer a new platform for developing novel therapeutics against cancers.

Loose tumor cells and tumor cell clusters can be recognized in the lumen of intratumoral pulmonary arteries of resected non-small cell lung cancer specimens. It is unclear whether these should be considered tumor-emboli, and as such could predict a worsened prognosis. To investigate the nature and prognostic impact of pulmonary artery intraluminal tumor cells. This multicenter study involved an exploratory pilot study and a validation study from 3 institutions. For the exploratory pilot study, a retrospective pulmonary resection cohort of primary adenocarcinomas, diagnosed between November 2007 and November 2010, were scored for the presence of tumor cells, as well as potentially other cells in the intravascular spaces, using hematoxylin-eosin and cytokeratin 7 (CK7) stains. In the validation part, 2 retrospective cohorts of resected pulmonary adenocarcinomas, between January 2011 and December 2016, were included. Recurrence-free survival (RFS) and overall survival (OS) data were collected. In the pilot study, CK7+ intravascular cells, mainly tumor cells, were present in 23 of 33 patients (69.7%). The 5-year OS for patients with intravascular tumor cells was 61%, compared with 40% for patients without intravascular tumor cells (P = .19). In the validation study, CK7+ intravascular tumor cells were present in 41 of 70 patients (58.6%). The 5-year RFS for patients with intravascular tumor cells was 80.0%, compared with 80.6% in patients without intravascular tumor cells (P = .52). The 5-year OS rates were, respectively, 82.8% and 71.6% (P = .16). Loose tumor cells in pulmonary arterial lumina were found in most non-small cell lung cancer resection specimens and were not associated with a worse RFS or OS. Therefore, most probably they represent an artifact.

We evaluated keratin 7 (K7) hepatocellular expression in 92 patients with common types of acute and chronic cholestatic diseases caused by bile duct obstruction/destruction or parenchymal lesions [acute hepatitis (n=20), mixed/pure cholestasis (n=16), primary biliary cholangitis-PBC (n=35), primary sclerosing cholangitis-PSC (n=10), vanishing bile duct syndrome (n=3), complete large bile duct obstruction due to space-occupying lesions (n=8)]. K7 immunohistochemical hepatocellular expression and ductular reaction (DR) were semi-quantitatively assessed. Results were correlated with liver enzyme serum levels, cholestasis type, histological features, hepatocellular Ki67 labelling index (LI) and HepPar1 expression. Hepatocellular K7 expression was detected in 87% (81/92) cases and in all cholestatic disease types with lowest incidence in pure/mixed cholestasis and highest in incomplete bile duct obstruction (iBDO), reaching 100% in PSC. K7-positive hepatocytes had low Ki67 LI (0-5%) retaining HepPar1 expression, irrespective of disease type. PSC cases had high K7 hepatocellular expression even with intact bile ducts, a feature that may aid differential diagnosis of cholestatic syndromes. K7 hepatocellular expression significantly correlated with cholestasis type, bile duct loss and fibrosis stage. It was higher in milder acute cholestatic hepatitis showing inverse correlation with hepatocyte proliferation and serum transaminase levels. In iBDO, younger age independently correlated with high K7 expression, while serum GGT levels showed a nearly significant correlation. Correlation with DR findings implied that K7-positive hepatocytes may result through metaplasia. In conclusion, K7 hepatocellular expression is a sensitive though non-specific marker of cholestasis. It may represent a cytoprotective reaction of resting hepatocytes in cholestasis of longer duration especially in younger patients.

Most Crohn’s disease-associated small bowel carcinomas (CrD-SBCs) are diagnosed in advanced stage and have poor prognosis. To improve diagnosis and therapy, a better knowledge of tumour precancerous lesions, histotypes and prognostic factors is needed. We investigated histologically and immunohistochemically 52 CrD-SBCs and 51 small bowel carcinomas unrelated to inflammatory disease, together with their tumour-associated mucosa, looking for Crohn-selective changes. Histologic patterns and phenotypic markers potentially predictive of CrD-SBC histogenesis and prognosis were analysed. Cytokeratin 7 or MUC5AC-positive metaplastic changes were found in about half of investigated CrD-SBCs, significantly more frequently than in CrD-unrelated SBCs. They correlated with metaplastic changes of their associated mucosa, while being absent in normal ileal mucosa. Histologic patterns suggestive for progression of some cytokeratin 7 and/or MUC5AC-positive metaplastic lesions into cancer of the same phenotype were also observed. Patient survival analyses showed that tumour cytokeratin 7 or MUC5AC expression and non-cohesive histotype were adverse prognostic factors at univariable analysis, while cytokeratin 7 and non-cohesive histotype were also found to predict worse survival in stage- and age-inclusive multivariable analyses. Besides conventional dysplasia, hyperplasia-like non-conventional lesions were observed in CrD-SBC-associated mucosa, with patterns suggestive for a histogenetic link with adjacent cancer. In conclusion the cytokeratin 7 and/or MUC5AC-positive metaplastic foci and the non-conventional growths may have a role in cancer histogenesis, while tumour cytokeratin 7 and non-cohesive histotype may also predict poor patient survival. Present findings are worth being considered in future prospective histogenetic and clinical studies.