In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells

Oncogenic signaling in melanocytes results in oncogene-induced senescence (OIS), a stable cell-cycle arrest frequently characterized by a bi- or multinuclear phenotype that is considered as a barrier to cancer progression. However, the long-sustained conviction that senescence is a truly irreversible process has recently been challenged. Still, it is not known whether cells driven into OIS can progress to cancer and thereby pose a potential threat. Here, we show that prolonged expression of the melanoma oncogene N-RAS61K in pigment cells overcomes OIS by triggering the emergence of tumor-initiating mononucleated stem-like cells from senescent cells. This progeny is dedifferentiated, highly proliferative, anoikis-resistant and induces fast growing, metastatic tumors. Our data describe that differentiated cells, which are driven into senescence by an oncogene, use this senescence state as trigger for tumor transformation, giving rise to highly aggressive tumor-initiating cells. These observations provide the first experimental in vitro evidence for the evasion of OIS on the cellular level and ensuing transformation

Effects of antipsychotics with different weight gain liabilities on human in vitro models of adipose tissue differentiation and metabolism

AbstractWeight gain and metabolic abnormalities are serious side effects associated with the use of several second generation antipsychotics (SGA). The adipose tissue has been considered a direct SGA target involved in the development of these adverse effects. Recent studies, mainly using murine cells, have suggested that SGA increase both adipogenesis of preadipocytes and lipid accumulation in mature adipocytes. However, to date there has been little research comparing the effects of antipsychotics with different propensities to induce weight gain on human in vitro models of white adipose tissue neoformation and metabolism. The present study aimed to investigate the effects of antipsychotics either strongly associated with weight gain, such as the SGA clozapine and olanzapine, or not, such as the SGA ziprasidone and the classical antipsychotic haloperidol, on proliferation and adipocyte differentiation of human adipose-derived stem cells (ADSCs) and lipogenesis in human mature adipocytes. Whereas ziprasidone induced elevated levels of cell death during adipogenesis and could not be investigated further, we observed that clozapine, olanzapine and haloperidol had slight stimulatory effects on the transcriptional program of ADSCs adipogenesis. However, the observed changes in adipocyte-specific genes were not accompanied by a significant increase in triglyceride accumulation within differentiated adipocytes. Our data also showed that these three antipsychotics displayed inhibitory effects on the proliferation rates of undifferentiated ADSCs. Regarding mature adipocyte metabolism, we observed that olanzapine slightly inhibited insulin-stimulated lipogenesis at the highest concentration used, and haloperidol exerted the strongest inhibitory effects on both basal and insulin-stimulated lipogenesis. Taken together, our results suggest that a direct and potent effect of clozapine and olanzapine on adipose tissue biology is not an important mechanism by which these SGA induce metabolic disturbances in humans. On the other hand, the haloperidol-mediated downregulation of the lipogenic capacity of human adipose tissue may be a possible mechanism contributing to its lower propensity to induce serious metabolic side effects

Better outcome for parotid versus neck metastasis of head and neck cutaneous squamous cell carcinoma: a new report on reemerging data

Introduction: Regional metastases of cutaneous head and neck squamous cell carcinoma occur in approximately 5 % of cases, being the most important prognostic factor in survival, currently with no distinction between parotid and neck metastasis. Objective: The purpose of this study was to evaluate the prognostic features among patients with head and neck cutaneous squamous cell carcinoma exhibiting regional metastasis. Methods: A retrospective analysis of patients with cutaneous squamous cell carcinoma who underwent parotidectomy and/or neck dissection from 2011 to 2018 at a single institution tertiary center was performed. Patient demographics, clinical, surgical and pathological information, adjuvant treatments, and outcome at last follow-up were collected. Outcomes included disease recurrence and death due to the disease. Prognostic value of clinic pathological features associated with disease-specific survival was obtained. Results: Thirty-eight cases of head and neck cutaneous squamous cell carcinoma with parotid and/or neck metastasis were identified. Overall, 18 (47.3 %) patients showed parotid metastasis alone, 12 (31.5 %) exhibited neck metastasis alone and 8 (21.0 %) had both. A primary tumor in the parotid zone (Hazard Ratio ‒ HR = 5.53; p = 0.02) was associated with improved disease-specific survival. Poorer disease-specific survival was observed in patients with higher primary tumor diameter (HR = 1.54; p = 0.002), higher depth of invasion (HR = 2.89; p = 0.02), invasion beyond the subcutaneous fat (HR = 5.05; p = 0.002), neck metastasis at first presentation (HR = 8.74; p < 0.001), number of positive lymph nodes (HR = 1.25; p = 0.004), and higher TNM stages (HR = 7.13; p = 0.009). Patients presenting with isolated parotid metastasis during all follow-ups had better disease-specific survival than those with neck metastasis or both (HR = 3.12; p = 0.02). Conclusion: Head and neck cutaneous squamous cell carcinoma with parotid lymph node metastasis demonstrated better outcomes than cases with neck metastasis

Factors associated with incomplete surgical margins in basal cell carcinoma of the head and neck

Introduction: Cutaneous basal cell carcinoma recurrence is associated with inadequate surgical margins. The frequency of and the factors associated with compromised or inadequate surgical margins in head and neck basal cell carcinoma varies. Objective: The purpose of this study was to evaluate the clinical and pathological factors associated with inadequate surgical margins in head and neck basal cell carcinoma. Methods: We developed a cross-sectional study comprising all patients who had undergone resection of head and neck basal cell carcinoma from January 2017 to December 2019. Data on age, sex, head and neck topography, histopathological findings, and staging were retrieved and compared. Each tumor was considered an individual case. Compromised and close margins were termed “inadequate” or “incomplete”. Variables that were significantly associated with the presence of incomplete margins were further assessed by logistic regression. Results: In total, 605 tumors from 389 patients were included. Overall, sixteen cases (2.6%) were classified as compromised, 52 (8.5%) as close, and 537 (88.7%) as free margins. Presence of scleroderma (p = 0.005), higher Clark level (p < 0.001), aggressive variants (p < 0.001), invasion beyond the adipose tissue (p < 0.001), higher T stage (p < 0.001), perineural invasion (p = 0.002), primary site (p = 0.04), multifocality (p = 0.01), and tumor diameter (p = 0.02) showed association with inadequate margins. After Logist regression, multifocality, Clark level and depth of invasion were found to be independent risk factors for inadequate margins. Conclusion: Gross clinical examination may be sufficient for determining low prevalence of inadequate surgical margins when treating head and neck basal cell carcinoma in highly experienced oncologic centers. Multifocality, Clark level and depth of invasion were found to be independent risk factors for incomplete margins

Competition between spin and charge polarized states in nanographene ribbons with zigzag edges

Effects of the nearest neighbor Coulomb interaction on nanographene ribbons with zigzag edges are investigated using the extended Hubbard model within the unrestricted Hartree-Fock approximation. The nearest Coulomb interaction stabilizes a novel electronic state with the opposite electric charges separated and localized along both edges, resulting in a finite electric dipole moment pointing from one edge to the other. This charge-polarized state competes with the peculiar spin-polarized state caused by the on-site Coulomb interaction and is stabilized by an external electric field.Comment: 4 pages; 4 figures; accepted for publication in Phys. Rev. B; related Web site: http://staff.aist.go.jp/k.harigaya/index_E.htm

Electrostatic Dust Detection and Removal for ITER

We present some recent results on two innovative applications of microelectronics technology to dust inventory measurement and dust removal in ITER. A novel device to detect the settling of dust particles on a remote surface has been developed in the laboratory. A circuit board with a grid of two interlocking conductive traces with 25 μm spacing is biased to 30 – 50 V. Carbon particles landing on the energized grid create a transient short circuit. The current flowing through the short circuit creates a voltage pulse that is recorded by standard nuclear counting electronics and the total number of counts is related to the mass of dust impinging on the grid. The particles typically vaporize in a few seconds restoring the previous voltage standoff. Experience on NSTX however, showed that in a tokamak environment it was still possible for large particles or fibers to remain on the grid causing a long term short circuit. We report on the development of a gas puff system that uses helium to clear such particles. Experiments with varying nozzle designs, backing pressures, puff durations, and exit flow orientations have given an optimal configuration that effectively removes particles from an area up to 25 cm² with a single nozzle. In a separate experiment we are developing an advanced circuit grid of three interlocking traces that can generate a miniature electrostatic traveling wave for transporting dust to a suitable exit port. We have fabricated such a 3-pole circuit board with 25 micron insulated traces that operates with voltages up to 200 V. Recent results showed motion of dust particles with the application of only 50 V bias voltage. Such a device could potentially remove dust continuously without dedicated interventions and without loss of machine availability for plasma operations

Shapes, contact angles, and line tensions of droplets on cylinders

Using an interface displacement model we calculate the shapes of nanometer-size liquid droplets on homogeneous cylindrical surfaces. We determine effective contact angles and line tensions, the latter defined as excess free energies per unit length associated with the two contact lines at the ends of the droplet. The dependences of these quantities on the cylinder radius and on the volume of the droplets are analyzed.Comment: 26 pages, RevTeX, 10 Figure

An Immunocompetent Mouse Model of HPV16(+) Head and Neck Squamous Cell Carcinoma

The incidence of human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is increasing and implicated in more than 60% of all oropharyngeal carcinomas (OPSCCs). Although whole-genome, transcriptome, and proteome analyses have identified altered signaling pathways in HPV-induced HNSCCs, additional tools are needed to investigate the unique pathobiology of OPSCC. Herein, bioinformatics analyses of human HPV(+) HNSCCs revealed that all tumors express full-length E6 and identified molecular subtypes based on relative E6 and E7 expression levels. To recapitulate the levels, stoichiometric ratios, and anatomic location of E6/E7 expression, we generated a genetically engineered mouse model whereby balanced expression of E6/E7 is directed to the oropharyngeal epithelium. The addition of a mutant PIK3CAE545K allele leads to the rapid development of pre-malignant lesions marked by immune cell accumulation, and a subset of these lesions progress to OPSCC. This mouse provides a faithful immunocompetent model for testing treatments and investigating mechanisms of immunosuppression