Cholesteatoma and family history: An international survey

Objective To explore the relative frequency of a family history of cholesteatoma in patients with known cholesteatoma, and whether bilateral disease or earlier diagnosis is more likely in those with a family history. Associations between cleft lip or palate and bilateral disease and age of diagnosis were also explored. Design An online survey of patients with diagnosed cholesteatoma was conducted between October 2017 and April 2019. Participants The sample consisted of patients recruited from two UK clinics and self‐selected respondents recruited internationally via social media. Main outcome measures Side of cholesteatoma, whether respondents had any family history of cholesteatoma, age of diagnosis and personal or family history of cleft lip or palate were recorded. Results Of 857 respondents, 89 (10.4%) reported a positive family history of cholesteatoma. Respondents with a family history of cholesteatoma were more likely to have bilateral cholesteatoma (P = .001, odds ratio (OR) 2.15, 95% confidence interval (CI) 1.35‐3.43), but there was no difference in the age of diagnosis (P = .23). Those with a history of cleft lip or palate were not more likely to have bilateral disease (P = .051, OR 2.71, CI 1.00‐7.38), and there was no difference in age of diagnosis (P = .11). Conclusion The relatively high proportion of respondents that reported a family history of cholesteatoma offers supporting evidence of heritability in cholesteatoma. The use of social media to recruit respondents to this survey means that the results cannot be generalised to other populations with cholesteatoma. Further population‐based research is suggested to determine the heritability of cholesteatoma

Mitotic stress is an integral part of the oncogene-induced senescence program that promotes multinucleation and cell cycle arrest

Oncogene-induced senescence (OIS) is a tumor suppression mechanism that blocks cell proliferation in response to oncogenic signaling. OIS is frequently accompanied by multinucleation; however, the origin of this is unknown. Here, we show that multinucleate OIS cells originate mostly from failed mitosis. Prior to senescence, mutant H-RasV12 activation in primary human fibroblasts compromised mitosis, concordant with abnormal expression of mitotic genes functionally linked to the observed mitotic spindle and chromatin defects. Simultaneously, H-RasV12 activation enhanced survival of cells with damaged mitoses, culminating in extended mitotic arrest and aberrant exit from mitosis via mitotic slippage. ERK-dependent transcriptional upregulation of Mcl1 was, at least in part, responsible for enhanced survival and slippage of cells with mitotic defects. Importantly, mitotic slippage and oncogene signaling cooperatively induced senescence and key senescence effectors p21 and p16. In summary, activated Ras coordinately triggers mitotic disruption and enhanced cell survival to promote formation of multinucleate senescent cells

Tumor-specific T cells in human Merkel cell carcinomas: a possible role for Tregs and T cell exhaustion in reducing T cell responses

Merkel cell carcinomas (MCC) are rare but highly malignant skin cancers associated with a novel polyomavirus. MCC tumors were infiltrated by T cells, including effector, central memory and regulatory T cells. Infiltrating T cells showed markedly reduced activation as evidenced by reduced expression of CD69 and CD25. Treatment of MCC tumors in vitro with IL-2 and IL-15 led to T cell activation, proliferation, enhanced cytokine production and loss of viable tumor cells from cultures. Expanded tumor-infiltrating lymphocytes showed TCR repertoire skewing and upregulation of CD137. MCC tumors implanted into immunodeficient mice failed to grow unless human T cells in the tumor grafts were depleted with denileukin diftitox, suggesting tumor-specific T cells capable of controlling tumor growth were present in MCC. Both CD4+ and CD8+ FOXP3+ regulatory T cells were frequent in MCC. 50% of non-activated T cells in MCC expressed PD-1, a marker of T-cell exhaustion, and PD-L1 and PD-L2 were expressed by a subset of tumor dendritic cells and macrophages. In summary, we observed tumor-specific T cells with suppressed activity in MCC tumors. Agents that stimulate T cell activity, block Treg function or inhibit PD-1 signaling may be effective in the treatment of this highly malignant skin cancer

Age and Inclusivity in Umm an-Nar Communal Tombs from Southeastern Arabia

Umm an-Nar (2700-2000 BCE) tombs in the United Arab Emirates contained the commingled remains of hundreds of individuals interred across multiple generations. Archaeologists commonly reference tomb demographics as being inclusive of all ages, but this assumption is based on a handful of studies that rarely distinguish age categories beyond “subadult” or “adult.” An undergraduate research training program sought to examine age distributions – and thus inclusivity in tomb membership – in greater detail, with a particular focus on fetal and older adult age categories. A combination of traditional and novel aging techniques were applied to bones from tombs Unar 1 (U1; MNI = 194) and 2 (U2; MNI = 410) at Shimal. Transition Analysis 3 scores for the femur, humerus, and pubic symphysis revealed older age categories not previously recognized in the region, with means ranging from 40.4-47.8 years, contrasting with an average of 31 years produced by Suchey-Brooks. Measurements identified fetuses and perinates in both tombs using the basilar (U1: 5; U2: 10), petrous (U1 left: 29; U2 right: 33), and distal femur (U1 left: 5; U2 left: 11), some as young as 20-22 fetal weeks. MicroCT scans of suspected fetal humeri (U1: 10; U2: 14) revealed a lack of bioerosion, confirming that stillborn infants were permitted access to tombs. These data substantiate the presence of very young and older adults in both tombs, and demonstrate that despite subsistence and environmental changes tied to increasing social stratification during this period, no age group was separated from the larger community in death.https://jagworks.southalabama.edu/present_yr2/1003/thumbnail.jp

Resident Memory T Cells (TRM) Are Abundant in Human Lung: Diversity, Function, and Antigen Specificity

Recent studies have shown that tissue resident memory T cells (TRM) are critical to antiviral host defense in peripheral tissues. This new appreciation of TRM that reside in epithelial tissues and mediate host defense has been studied most extensively in skin: adult human skin contains large numbers of functional TRM that express skin specific markers. Indeed, more than twice as many T cells reside in skin as in peripheral blood. This T cell population has a diverse T cell receptor repertoire, and can produce a broad array of cytokines. More recently, we have begun to examine other epithelial tissues for the presence of resident T cells. In the present study, we asked whether analogous populations of resident T cells could be found in human lung. We were able to demonstrate abundant resident T cells in human lung-more than 10 billion T cells were present. Lung T cells were largely of the effector memory T cell (TEM) phenotype, though small numbers of central memory T cells (TCM) and T regulatory cells (Treg) could be identified. Lung T cells had a diverse T cell receptor repertoire and subsets produced IL-17, IL-4, IFNγ, as well as TNFα. A significant number of lung TRM CD4+Th cells produced more than one cytokine, identifying them as “multifunctional” Th1 type cells. Finally, lung TRM, but not TRM resident to skin or T cells from blood, proliferated in response to influenza virus. This work suggests that normal human lung contains large numbers of TRM cells, and these cells are poised to respond to recall antigens previously encountered through lung mucosa. This population of T cells may contribute to the pathogenesis of asthma and other T cell mediated lung diseases

Patients’ Experiences of a Sarcoma Diagnosis: A Process Mapping Exercise of Diagnostic Pathways

Patients with sarcoma often report prolonged time to diagnosis, which is attributed to the rarity of sarcoma and the low awareness of pre-diagnostic signs and symptoms. Aims: To describe patients’ experiences of pre-diagnostic signs/symptoms and pathways to diagnosis, including where help was sought, and the processes involved. Methods: Mixed methods involving quantitative, qualitative and inductive thematic analyses using novel process mapping of patient journey data, as reported by the patients. We examined the time from symptom onset to first professional presentation (patient interval, PI), first consultation to diagnostic biopsy, first consultation to diagnosis (diagnostic interval) and first presentation to diagnosis (total interval). Results: A total of 87 interviews were conducted over 5 months in 2017. Of these, 78 (40 males/38 females) were included. The sarcoma subtypes were bone (n = 21), soft tissue (n = 41), head and neck (n = 9) and gastro-intestinal (GIST; n = 7). Age at diagnosis was 13–24 (n = 7), 25–39 (n = 23), 40–64 (n = 34) and 65+ (n = 14) years. The median PI was 13 days (1–4971) and similar between sarcoma subtypes, with the exception of GIST (mPI = 2 days, (1–60). The longest mPI (31 days, range 4–762) was for those aged 13–24 years. The median diagnostic interval was 87.5 (range 0–5474 days). A total of 21 patients were misdiagnosed prior to diagnosis and symptoms were commonly attributed to lifestyle factors. Conclusions: Prolonged times to diagnosis were experienced by the majority of patients in our sample. Further research into the evolution of pre-diagnostic sarcoma symptoms is required to inform awareness interventions

Spatially and cell-type resolved quantitative proteomic atlas of healthy human skin

Human skin provides both physical integrity and immunological protection from the external environment using functionally distinct layers, cell types and extracellular matrix. Despite its central role in human health and disease, the constituent proteins of skin have not been systematically characterized. Here, we combine advanced tissue dissection methods, flow cytometry and state-of-the-art proteomics to describe a spatially-resolved quantitative proteomic atlas of human skin. We quantify 10,701 proteins as a function of their spatial location and cellular origin. The resulting protein atlas and our initial data analyses demonstrate the value of proteomics for understanding cell-type diversity within the skin. We describe the quantitative distribution of structural proteins, known and previously undescribed proteins specific to cellular subsets and those with specialized immunological functions such as cytokines and chemokines. We anticipate that this proteomic atlas of human skin will become an essential community resource for basic and translational research (https://skin.science/)

Diagnosing Norms Surrounding Sexual Harassment at a Jordanian University

Sexual harassment (SH) is a form of gender-based violence (GBV) that negatively impacts women’s physical, mental, social, and financial well-being. Although SH is a global phenomenon, it also is a contextualized one, with local and institutional norms influencing the ways in which harassment behavior manifests. As more women attend institutions of higher education in Jordan, these women are at increased risk of experiencing SH in university settings, with potential implications for their health and future employment. Social norms theory, which examines the informal rules governing individual behavior within groups, has been a useful framework for understanding and developing interventions against GBV globally. We sought to apply a social-norms lens to the understanding and prevention of SH at a Jordanian university. To gain a comprehensive and nuanced picture of social norms surrounding SH, we collected qualitative data using three complementary methods: focus group discussions (n = 6) with male and female students (n = 33); key informant interviews with staff and faculty (n = 5); and a public, participatory event to elicit anonymous short responses from students (n = 317). Using this data, we created a codebook incorporating social-norms components and emergent themes. As perceived by participants, SH was unacceptable yet common, characterized as a weak norm primarily because negative sanctioning of harassers was unlikely. Distal norms related to gender and tribal affiliation served to weaken further norms against SH by blaming the victim, preventing reporting, discouraging bystander intervention, and/or protecting the perpetrator. The complexity of the normative environment surrounding SH perpetration will necessitate the use of targeted, parallel approaches to change harmful norms. Strengthening weak norms against SH will require increasing the likelihood of sanctions, by revising university policies and procedures to increase accountability, increasing the acceptability of bystander intervention and reporting, and fostering tribal investment in sanctioning members who harass women. Creating dialogue that emphasizes the harmful nature of SH behaviors and safe spaces to practice positive masculinity also may be an effective strategy to change how male students interact in the presence of peers. Any social norms change intervention will need to consider the various reference groups that dictate and enforce norms surrounding SH