OBJECTIVE: WHO Grade 3 (G3) meningiomas are rare tumours with limited data to guide management. This retrospective study documents UK management approaches across 14 centres over 11 years.
METHODS: Patients with WHO G3 meningioma between 01/01/2008 and 31/12/2018 were identified. Data were collected on demographics, management strategy, adjuvant radiotherapy, approach in recurrence setting and survival.
RESULTS: 84 patients were identified. 21.4% transformed from lower-grade disease. 96.4% underwent primary surgical resection, with 20.8% having evidence of residual disease on their post-op MRI. 59.3% of patients underwent adjuvant radiotherapy (RT) following surgical resection. Overall median PFS and OS were 12.6 months and 28.2 months, respectively. Median OS in the group who underwent complete surgical resection was 34.9 months, compared to 27.5 months for those who had incomplete resection (HR 0.58, 95% CI 0.27-1.23, p = 0.15). Median OS was 33.1 months for those who underwent adjuvant RT and 14.0 months for those who did not (HR 0.48, 95% CI 0.27-0.84, p = 0.004). Median adjuvant RT dose delivered was 60Gy (range 12Gy-60Gy), 45.8% of adjuvant RT was delivered using IMRT. At disease relapse, 31% underwent salvage surgery and 29.3% underwent salvage RT. Of those treated with salvage RT, 64.7% were re-treats and all were treated with hypofractionated RT.
CONCLUSIONS: Surgery continues to be the preferred primary management strategy. Post-operative MRI within 48 hours is indicated to assess presence of residual disease and guide further surgical options. Adjuvant radiotherapy plays an important part of the management paradigm in these patients with the data supporting an attached survival advantage. Further surgery and re-irradiation is an option in the disease recurrence setting with radiosurgery frequently utilised in this context.

In recent years, dysregulation of the notch pathway has been associated with the development and progression of various cancers. Notch signaling is involved in several cellular processes such as proliferation, differentiation, apoptosis, and angiogenesis, and its abnormal activation can lead to uncontrolled cell growth and tumorigenesis. In various cancers, the Notch pathway has been shown to have both tumor-promoting and tumor-suppressive effects, depending on the context and stage of cancer development. In some cases, activation of the Notch pathway has been shown to promote tumor growth and progression, while in others it has been shown to inhibit tumor growth and induce cell death. The Notch pathway has been found to be particularly important in the development of leukaemia, breast cancer, lung cancer and pancreatic cancer. In leukaemia, the Notch pathway is often activated, which promotes the survival and proliferation of leukaemia cells. In breast cancer, Notch signaling has been implicated in tumor initiation and maintenance of cancer stem cells. In cervical cancer, the Notch signaling pathway has been shown to play a crucial role in the development of the disease. In lung cancer, Notch activation promotes cancer cell proliferation and migration, while in pancreatic cancer, Notch signaling is associated with tumor initiation and resistance to chemotherapy. Understanding the role of the Notch pathway in cancer development and progression may provide new opportunities for the development of targeted therapies for cancer treatment. Several drugs targeting the Notch pathway are currently in preclinical or clinical development and may hold promise for anticancer therapy in the future.

Understanding the anatomy of suprascapular area helps the clinicians and surgeons in management of any disability at the shoulder region. This work aimed to clear the different morphological and morphometrical types of suprascapular notch (SSN). Unknown 120 dry human scapulae of both sides and 60 formalin-embalmed cadaveric upper limbs (40 males and 20 females) were used in the present study. Three main morphological forms of SSN were reported: J, U, and V-shaped. J-shaped notch showed the highest incidence followed by U-shaped then V-shaped one. Morphometrically, type (III) notch was the most prevalent in both dry bones and cadavers, while the incidence of type (II) was the lowest form. Also, the measurements of superior transverse diameter, middle transverse diameter and vertical dimension of the different types of the notch showed no side or sex significant difference. The suprascapular foramen with ossified superior transverse scapular ligament (STSL) was seen in 5.8% of dry bones and 10% of cadaveric specimens. Fan and band-shaped ossified transverse scapular ligaments were reported. Absence of SSN was seen in 10.8% of dry bones, 7.5% of male and 10% of female specimens with left side predominance. V-shaped, absence, and ossified STSL were considered as predisposing factors of suprascapular nerve entrapment syndrome. Knowledge of the morphology and morphometric parameters of SSN is of great clinical significance for anatomists, radiologists, physiotherapists, orthopedics and neurosurgeons to perform good diagnosis and best planning for surgical or arthroscopic interventions within the shoulder region.

OBJECTIVE: It has been suggested that noise exposure can accelerate hearing decline after the noise exposure has ceased. We aimed to assess long-term hearing decline in persons with and without prior occupational noise exposure.
METHODS: We conducted a population-based longitudinal study in Norway using the Trøndelag Health Study (HUNT) from 1996 to 1998 (baseline) and from 2017 to 2019 (follow-up). The sample included 1648 participants with baseline age ≥55 years (42% men, mean age 60 years) and <5 years occupational noise exposure after baseline. We analyzed the association between occupational noise exposure before baseline and mean hearing decline between 1998 and 2018 (20-year decline) at each frequency, adjusted for age, sex, education, and impulse noise exposure before baseline.
RESULTS: Occupational noise exposure before baseline (N = 603) was associated with baseline hearing loss, but not with later accelerated 20-year decline, at any frequency. Noise-exposed persons had less subsequent 20-year decline at 3 kHz than did nonexposed. Restricting the noise-exposed group to persons who also had a baseline Coles notch (hearing thresholds at 3, 4, or 6 kHz of 10 dB or more compared with thresholds at 1 or 2 kHz and 6 or 8 kHz; N = 211), the exposed group showed less 20-year decline at both 3 and 4 kHz, as well as less accelerated 20-year decline at 8 kHz, compared with the nonexposed.
CONCLUSIONS: Our large long-term longitudinal study shows no increased risk of continuing hearing decline after occupational noise exposure has ceased. The finding supports a conclusion that ear damage stops when the noise exposure is ended.

Estrogens induce several regulatory signals in the nervous system that are mainly mediated through estrogen receptors (ERs). ERs are largely expressed in the nervous system, yet the importance of ERs to neural development has only been elucidated over the last decades. Accumulating evidence shows a fundamental role for estrogens in the development of the central and peripheral nervous systems, hence, the contribution of ERs to neural function is now a growing area of research. The conservation of the structure of the ERs and their response to estrogens make the zebrafish an interesting model to dissect the role of estrogens in the nervous system. In this review, we highlight major findings of ER signaling in embryonic zebrafish neural development and compare the similarities and differences to research in rodents. We also discuss how the recent generation of zebrafish ER mutants, coupled with the availability of several transgenic reporter lines, its amenability to pharmacological studies and in vivo live imaging, could help us explore ER function in embryonic neural development.

The mechanism of copper-induced cellular death was newly discovered and termed cuproptosis. Inducing cuproptosis in cancer cells is well anticipated for its curative potential in treating tumor diseases. However, ferredoxin 1 (FDX1), the core regulatory gene in cuproptosis, is rarely studied, and the regulation of FDX1 in tumor biology remains obscure. A comprehensive pan-cancer analysis of FDX1 is needed.
Thirty-three types of tumors were included with paired normal tissues in The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets. The interaction between transcription, protein, phosphorylation, and promoter methylation levels was analyzed. Survival, immune infiltration, single-cell FDX1 expression, FDX1-related tumor mutational burden (TMB), microsatellite instability (MSI), stemness, tumor immune dysfunction and exclusion (TIDE), and immunotherapy-related analyses were performed. FDX1 protein expression was assessed by kidney renal clear cell carcinoma (KIRC) tissue microarray immunohistochemistry. The function of FDX1 in KIRC was further explored by experiments in 786-O cell lines in vitro.
FDX1 is highly expressed in 15 tumor types and lowly expressed in 11 tumor types. The corresponding changes in protein expression, phosphorylation, and promoter methylation level of FDX1 have been described in several tumors. Survival analysis showed that FDX1 was related to favorable or poor overall survival in eight tumors and progression-free survival in nine tumors. Immune infiltration and single-cell analysis indicated the indispensable role of FDX1 expression in macrophages and monocytes. Multiple established immunotherapy cohorts suggested that FDX1 may be a potential predictor of treatment effects for tumor patients. Tissue microarray analysis showed decreased FDX1 expression in KIRC patients\' tumor tissues. Knockdown of FDX1 resulted in the downregulation of cuproptosis in kidney renal clear tumor cells. Mechanistically, the FDX1-associated gene expression signature in KIRC is related to the enrichment of genes involved in the tricarboxylic acid (TCA) cycle, NOTCH pathway, etc. Several NOTCH pathway genes were differentially expressed in the high- and low-FDX1 groups in KIRC.
Our analysis showed that the central regulatory gene of cuproptosis, FDX1, has differential expression and modification levels in various tumors, which is associated with cellular function, immune modulation, and disease prognosis. Thus, FDX1-dependent cuproptosis may serve as a brand-new target in future therapeutic approaches against tumors.

BACKGROUND: Mesenchymal stem cells (MSCs) have been documented as possible candidates for wound healing treatment because their use could reinforce the regenerative capacity of many tissues. Human adipose stem cells (hADSCs) have the advantages of easy access, large quantity and easy operation. They can be fully applied in the treatment of skin wounds.
OBJECTIVE: In this study, we aim to explore the roles and potential mechanisms of hADSCs in cutaneous wound healing.
METHODS: hADSCs were obtained from human subcutaneous fat. Adipocytes and osteocytes differentiated from hADSCs were determined by staining with Oil Red O and alkaline phosphatase (ALP), respectively. We assessed the effects of hADSCs and hADSC conditional medium (CM) on wound healing in an injury model of mice. Then, we investigated the biological effects of hADSCs on human keratinocytes HaCAT cells in vitro.
RESULTS: The results showed that hADSCs could be successfully differentiated into osteogenic and lipogenic cells. hADSCs and hADSCs-CM significantly promote skin wound healing in vivo. hADSCs significantly promoted HaCAT cell proliferation and migration by activating the Notch signaling pathway and activated the AKT signaling pathway by Rps6kb1 kinase in HaCAT cells. In addition, we found that hADSCs-mediated activation of Rps6kb1/AKT signaling was dependent on the Notch signaling pathway.
CONCLUSIONS: We demonstrated that hADSCs can promote skin cell-HaCAT cell proliferation and migration via the Notch pathway, suggesting that hADSCs may provide an alternative therapeutic approach for the treatment of skin injury.

The pathobiology of ascending aorta aneurysms (AAA) onset and progression is not well understood and only partially characterized. AAA are also complicated in case of bicuspid aorta valve (BAV) anatomy. There is emerging evidence about the crucial role of endothelium-related pathways, which show in AAA an altered expression and function. Here, we examined the involvement of ERG-related pathways in the differential progression of disease in aortic tissues from patients having a BAV or tricuspid aorta valve (TAV) with or without AAA. Our findings identified ERG as a novel endothelial-specific regulator of TGF-β-SMAD, Notch, and NO pathways, by modulating a differential fibrotic or calcified AAA progression in BAV and TAV aortas. We provided evidence that calcification is correlated to different ERG expression (as gene and protein), which appears to be under control of Notch signaling. The latter, when increased, associated with an early calcification in aortas with BAV valve and aneurysmatic, was demonstrated to favor the progression versus severe complications, i.e., dissection or rupture. In TAV aneurysmatic aortas, ERG appeared to modulate fibrosis. Therefore, we proposed that ERG may represent a sensitive tissue biomarker to monitor AAA progression and a target to develop therapeutic strategies and influence surgical procedures.

Notch signaling is associated with many human malignancies, including oral squamous cell carcinoma (OSCC). However, the exact function of Notch signaling in OSCC remains unclear. Here, we investigated the effect of Notch signaling inhibition using a γ-secretase inhibitor (DAPT) on OSCC behaviours in vitro. Bioinformatic analysis of public-available gene expression profiles revealed the dysregulation of the Notch signaling pathway in OSCC compared with normal tissues, indicating the role of Notch signaling in OSCC regulation. RNA sequencing analysis of DAPT-treated human OSCC cells revealed the dysregulation of genes related to cell cycle-related pathways. Blocking Notch signaling significantly inhibited cell proliferation. DAPT-induced G0/G1 cell cycle arrest induced cell apoptosis. Furthermore, cell migration and invasion were also reduced in DAPT-treated cells. These findings indicate that Notch signaling activation participates in OSCC regulation by promoting cell growth, cell cycle progression, cell migration, and invasion. These mechanisms could facilitate OSCC progression. These results imply the potential use of Notch signaling inhibitors as a candidate adjuvant treatment in OSCC patients.

OBJECTIVE: To analyze the development status, research hotspots, research frontiers and future development trends of the Notch signaling pathway in cancer through bibliometric analysis.
METHODS: Publications related to the Notch signaling pathway in cancer were obtained from the Web of Science Core Collection (WoSCC), and information was extracted from the articles using Microsoft Excel 2020, CiteSpace V and VOSviewer software for visual analysis.
RESULTS: The country and institution with the most publications are the USA and Harvard University, respectively. PLoS One is the most published journal, and Cancer Research is the most cocited journal. The author with the most published articles was L Miele, and the most cocited author was ZW Wang. The top 3 keywords were activation, differentiation and growth. Metastasis, epithelial-mesenchymal transition (EMT), invasion, target and resistance are the current research hotspots and frontiers in this field.
CONCLUSIONS: Research related to the Notch signaling pathway in cancer is currently booming, and the USA has made the greatest contribution to this field. At present, the research hotspots and research frontiers in this field mainly focus on the regulatory role of the Notch signaling pathway in tumor invasion and metastasis, the regulation of the Notch signaling pathway in tumor progression through EMT, and the participation of the Notch signaling pathway in the regulation of chemotherapy or immunotherapy resistance to tumors.