Recruitment of transcription factor ETS1 to activated accessible regions promotes the transcriptional program of cilia genes.

Defects in cilia genes, which are critical for cilia formation and function, can cause complicated ciliopathy syndromes involving multiple organs and tissues; however, the underlying regulatory mechanisms of the networks of cilia genes in ciliopathies remain enigmatic. Herein, we have uncovered the genome-wide redistribution of accessible chromatin regions and extensive alterations of expression of cilia genes during Ellis-van Creveld syndrome (EVC) ciliopathy pathogenesis. Mechanistically, the distinct EVC ciliopathy-activated accessible regions (CAAs) are shown to positively regulate robust changes in flanking cilia genes, which are a key requirement for cilia transcription in response to developmental signals. Moreover, a single transcription factor, ETS1, can be recruited to CAAs, leading to prominent chromatin accessibility reconstruction in EVC ciliopathy patients. In zebrafish, the collapse of CAAs driven by ets1 suppression subsequently causes defective cilia proteins, resulting in body curvature and pericardial oedema. Our results depict a dynamic landscape of chromatin accessibility in EVC ciliopathy patients, and uncover an insightful role for ETS1 in controlling the global transcriptional program of cilia genes by reprogramming the widespread chromatin state.

TEAD4 antagonizes cellular senescence by remodeling chromatin accessibility at enhancer regions.

Dramatic alterations in epigenetic landscapes are known to impact genome accessibility and transcription. Extensive evidence demonstrates that senescent cells undergo significant changes in chromatin structure; however, the mechanisms underlying the crosstalk between epigenetic parameters and gene expression profiles have not been fully elucidated. In the present study, we delineate the genome-wide redistribution of accessible chromatin regions that lead to broad transcriptome effects during senescence. We report that distinct senescence-activated accessibility regions (SAAs) are always distributed in H3K27ac-occupied enhancer regions, where they are responsible for elevated flanking senescence-associated secretory phenotype (SASP) expression and aberrant cellular signaling relevant to SASP secretion. Mechanistically, a single transcription factor, TEAD4, moves away from H3K27ac-labled SAAs to allow for prominent chromatin accessibility reconstruction during senescence. The enhanced SAAs signal driven by TEAD4 suppression subsequently induces a robust increase in the expression of adjacent SASP genes and the secretion of downstream factors, which contribute to the progression of senescence. Our findings illustrate a dynamic landscape of chromatin accessibility following senescence entry, and further reveal an insightful function for TEAD4 in regulating the broad chromatin state that modulates the overall transcriptional program of SASP genes.

Primary malignant melanoma of the gastroesophageal junction with KIT gene exon 11 mutation.

Mucosal melanoma (MM) represents an uncommon form of melanoma. Primary gastrointestinal tract (GIT) melanoma is even rarer. A 70-year-old male visited the Liaoning Cancer Hospital and Institute, China, due to upper abdominal discomfort for the past two months. His endoscopy revealed a prominent, 6-cm ulcerated neoplasm in the gastroesophageal junction (GEJ). Lesion endoscopic biopsy showed diffusely distributed tumour cells. He underwent subtotal gastrectomy with lymph node dissection (LND). Postoperative histopathology revealed a diffuse distribution of tumour cells with numerous tumourinfiltrating lymphocytes (TILs) and pigment granules. Immunohistochemical (IHC) results were positive for both S-100 and HMB-45. Molecular analysis showed KIT gene exon 11 mutations. Although the clinicians emphasised the necessity of systemic chemotherapy and immunotherapy with the patient and his family, the patient did not receive any adjuvant therapy and died 36 months after surgery. Primary malignant melanoma of GEJ should be considered in a differential diagnosis for gastrointestinal malignancies, especially after excluding the source of metastasis through a systemic examination.

The evolution of extremely diverged plastomes in Selaginellaceae (lycophyte) is driven by repeat patterns and the underlying DNA maintenance machinery.

Two factors are proposed to account for the unusual features of organellar genomes: the disruptions of organelle-targeted DNA replication, repair, and recombination (DNA-RRR) systems in the nuclear genome and repetitive elements in organellar genomes. Little is known about how these factors affect organellar genome evolution. The deep-branching vascular plant family Selaginellaceae is known to have a deficient DNA-RRR system and convergently evolved organellar genomes. However, we found that the plastid genome (plastome) of Selaginella sinensis has extremely accelerated substitution rates, a low GC content, pervasive repeat elements, a dynamic network structure, and it lacks direct or inverted repeats. Unexpectedly, its organelle DNA-RRR system is short of a plastid-targeted Recombinase A1 (RecA1) and a mitochondrion-targeted RecA3, in line with other explored Selaginella species. The plastome contains a large collection of short- and medium-sized repeats. Given the absence of RecA1 surveillance, we propose that these repeats trigger illegitimate recombination, accelerated mutation rates, and structural instability. The correlations between repeat quantity and architectural complexity in the Selaginella plastomes support these conclusions. We, therefore, hypothesize that the interplay of the deficient DNA-RRR system and the high repeat content has led to the extraordinary divergence of the S. sinensis plastome. Our study not only sheds new light on the mechanism of plastome divergence by emphasizing the power of cytonuclear integration, but it also reconciles the longstanding contradiction on the effects of DNA-RRR system disruption on genome structure evolution.

USP6-associated neoplasm as a tentative subset of postoperative spindle cell nodule.

AIM: Postoperative spindle cell nodule (PSCN) is a pseudosarcomatous proliferative lesion of unclear molecular genetic origins. METHODS AND RESULTS: We examined seven patients with PSCN, using routine haematoxylin-eosin (H&E) slide preparations and a series of immunostains. The latter targeted keratin, vimentin, α-smooth muscle actin (SMA), anaplastic lymphoma kinase (ALK [D5F3]), and other proteins. Ubiquitin-specific peptidase 6 (USP6) and anaplastic lymphoma kinase (ALK) gene rearrangements were also analysed by fluorescence in situ hybridization (FISH). There were histories of prior surgical intervention (n = 6) or trauma (n = 1) in all seven patients. All lesions were highly cellular and mitotically active spindle cell proliferations, with no cytologic atypia, nuclear pleomorphism, or aberrant mitoses. Immunohistochemical (IHC) staining disclosed focal, weak keratin positivity in two lesions, whereas vimentin (diffuse, strongly positive) and SMA (tram-track pattern) were present in each instance, and ALK (D5F3) was entirely negative. FISH analysis confirmed USP6 gene rearrangements in all seven cases, showing no ALK gene rearrangements. RNA sequencing results showed an MYH9::USP6 gene fusion in only one lesion (No. 6). CONCLUSION: A subset of PSCN is marked by USP6 gene rearrangements, a genetic feature of nodular fasciitis (NF). Given its similarity to NF, a designation as USP6-associated neoplasm (UAN) seems reasonable, signifying a transient clonal neoplastic lesion.

FAP, CD10, and GPR77-labeled CAFs cause neoadjuvant chemotherapy resistance by inducing EMT and CSC in gastric cancer.

OBJECTIVE: A significant proportion of patients can not benefit from neoadjuvant chemotherapy (NCT) due to drug resistance. Cancer-associated fibroblasts (CAFs) influence many biological behaviours of tumors, including chemo-resistance. This study aims to explore whether CAFs expressing FAP, CD10, and GPR77 affect the efficacy of NCT and the prognosis of patients with gastric cancer, and its mechanism. METHODS: One hundred seventy-one patients with locally progressive gastric adenocarcinoma who had undergone NCT and radical surgery were collected. Immunohistochemistry was used to detect the expression of FAP, CD10, and GPR77 in CAFs; the EMT markers (N-cadherin, Snail1, and Twist1) and the CSC markers (ALDH1, CD44, and LGR5) in gastric cancer cells. The χ2 test was used to analyze the relationship between the expression of CAF, EMT, and CSC markers and the clinicopathological factors, as well as the relationship between CAF markers and EMT, and CSC markers. Logistic regression and Cox risk regression were used to analyze the relationship between the expression of CAF, EMT, and CSC markers and TRG grading and OS; Kaplan-Meier analysis was used for survival analysis and plotting the curves. RESULTS: The expression of CAF markers FAP, CD10, and GPR77 was closely associated with that of EMT markers; FAP and CD10 were closely related to CSC markers. In the univariate analysis of pathological response, CAF markers (FAP, CD10, GPR77), EMT markers (N-cadherin, Snail1, Twist1), and CSC markers (ALDH1, LGR5, CD44), were all closely associated with pathological response (all p < 0.05). Only Twist1 was an independent factor affecting pathological response in multifactorial analysis (p = 0.001). In a univariate analysis of OS, expression of FAP and CD10 in CAF, as well as expression of EMT biomarkers (N-cadherin, Snail1), were significant factors influencing patient prognosis (all p < 0.05). Multifactorial analysis revealed N-cadherin (p = 0.032) and Snail1 (p = 0.028), as independent prognostic factors affecting OS. CONCLUSION: FAP, CD10, and GPR77 labeled CAF subgroup may lead to NCT resistance and poor prognosis by inducing EMT and CSC of gastric cancer cells in locally advanced gastric cancer patients.

Correlation of clinicopathological and prognostic characteristics between endometriosis-associated and primary ovarian cancer.

BACKGROUND: The main aim of this study was to establish the clinicopathological and prognostic correlations between endometriosis-associated and non-endometriosis-associated primary ovarian cancer, with a view to providing a reference guide for revision of diagnostic criteria for malignant transformation of endometriosis. METHODS: Clinicopathological and follow-up data of 174 patients with clear cell and endometrial ovarian cancer were retrospectively extracted. Cases were divided into endometriosis-associated and non-endometriosis-associated primary ovarian cancer for comparative analysis of clinicopathological characteristics and prognosis. RESULTS: Average age and post-menopausal rate in the endometriosis-associated ovarian cancer group were lower relative to the primary ovarian cancer group (P < 0.05). Body mass index, age at menopause, operation history, dysmenorrhea, complications, tumor size, tumor side, ascites, CA125, HE4, CA19.9, stage, differentiation, expression of ER, PR, P53, P16, Ki67, MMR, HNF-1ß and Napsin A were not significantly different between the groups (P > 0.05). Furthermore, rates of resistance to platinum chemotherapy, relapse, progression-free survival and overall survival were comparable between the two groups (P > 0.05). CONCLUSION: Endometriosis-associated and primary ovarian cancers of the same pathological type are speculated to be homologous in terms of origin from malignant transformation of endometriosis. It may therefore be necessary to revise the diagnostic criteria for ovarian endometriosis malignancy.

What is new in cancer-associated fibroblast biomarkers?

The tumor microenvironment is one of the important drivers of tumor development. Cancer-associated fibroblasts (CAFs) are a major component of the tumor stroma and actively participate in tumor development, invasion, metastasis, drug resistance, and other biological behaviors. CAFs are a highly heterogeneous group of cells, a reflection of the diversity of their origin, biomarkers, and functions. The diversity of CAF origin determines the complexity of CAF biomarkers, and CAF subpopulations expressing different biomarkers may play contrasting roles in tumor progression. In this review, we provide an overview of these emerging CAF biomarkers and the biological functions that they suggest, which may give a better understanding of the relationship between CAFs and tumor cells and be of great significance for breakthroughs in precision targeted therapy for tumors. Video Abstract.

Efficacy of agomelatine with cognitive behavioral therapy for delayed sleep-wake phase disorder in young adults: A randomized controlled study.

BACKGROUND: Delayed sleep-wake phase disorder (DSWPD) is common and easily misdiagnosed in young people, and to date, there is no evidence-based treatment. PURPOSE: A nonblinded randomized controlled study evaluated the effect of agomelatine therapy (AT) and cognitive behavior therapy (CBT) on DSWPD in young adults. METHODS: Sixty adolescents and young adults (range = 19-24 years, mean = 22 years, 52% female) diagnosed with DSWPD were randomized to receive 4 weeks of agomelatine therapy with or without cognitive behavior therapy. Sleep diaries, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Insomnia Severity Index (ISI), and World Health Organization wellbeing questionnaire (WHO-5) were measured pre-treatment and post-treatment. RESULTS: Agomelatine therapy for 4 weeks shifted the sleep-wake rhythm (p < .001) forward in both groups at the week 4 assessment. There were no significant differences in sleep onset (p = .099) and sleep offset (p = .959) between the CBT group and the no treatment (NT) group at the follow-up visits. However, significant differences were found in sleep duration (p = .002), sleep quality (p=0.005), sleep difficulties (p < .001), daytime sleepiness (p = .001), and wellbeing (p = .007) between groups. CONCLUSIONS: The improvements were received largely through the sleep-promoting effects of agomelatine therapy, and combining with cognitive behavior therapy on maintenance of altered sleep rhythms might be feasible.

JAZF1, YWHAE and BCOR gene translocation in primary extrauterine low-grade and high-grade endometrial stromal sarcomas.

AIMS: JAZF1 translocation is the most common genetic change in low-grade (LG) endometrial stromal sarcoma (ESS), and YWHAE and BCOR translocations are common in high-grade (HG) ESS. Primary extrauterine ESS is rare, and there are limited data on molecular alterations in these tumours. METHODS AND RESULTS: Cases of primary extrauterine ESS, comprising eight LG-ESS cases and five HG-ESS cases were collected. Haematoxylin and eosin and immunohistochemical staining were used to observe the histomorphology and analyse related protein expression. JAZF1, YWHAE and BCOR rearrangements were explored with fluorescence in-situ hybridisation (FISH). In LG-ESS, the tumour cells resembled normal proliferative-phase endometrial stromal cells; CD10, oestrogen receptor and progesterone receptor were expressed in all eight cases. In HG-ESS, the tumour cells had uniform HG round and/or spindle morphology, sometimes with an LG component; CD10 was fully expressed in one case and focally expressed in four cases; BCOR was expressed in all five cases, and cyclin D1 in four of five cases. FISH analysis showed JAZF1 translocation in one of eight LG-ESS cases (12.5%). YWHAE translocation occurred in four of five HG-ESS cases, with a positivity rate of 80%. BCOR translocation was absent in all five cases. CONCLUSIONS: In extrauterine LG-ESS, the rate of JAZF1 rearrangement was significantly lower than in uterine LG-ESS. This result limited the value of JAZF1 translocation for diagnosis. YWHAE rearrangement is a common genetic change in extrauterine HG-ESS. Further studies are required to confirm these findings, especially in LG-ESS.