The gut microbiome and cancer immunotherapeutics: A review of emerging data and implications for future gynecologic cancer research.

Investigation of the gynecologic tract microbial milieu has revealed potential new biomarkers. Simultaneously, immunotherapeutics are establishing their place in the treatment of gynecologic malignancies. The interplay between the microbiome, the tumor micro-environment and response to therapy is a burgeoning area of interest. There is evidence to support that microbes, through their genetic make-up, gene products, and metabolites affect human physiology, metabolism, immunity, disease susceptibility, response to pharmacotherapy, and the severity of disease-related side effects. Specifically, the richness and diversity of the gut microbiome appears to affect carcinogenesis, response to immunotherapy, and modulate severity of immune-mediated adverse effects. These effects have best been described in other tumor types and these have shown compelling results. This review summarizes the current understanding and scope of the interplay between the human microbiome, host factors, cancer, and response to treatments. These findings support further exploring whether these associations exist for gynecologic malignancies.

Proinflammatory cytokine TNFα promotes HPV-associated oral carcinogenesis by increasing cancer stemness.

High-risk human papillomaviruses (HPVs) are involved in the development of several human cancers, including oropharyngeal squamous cell carcinomas. However, many studies have demonstrated that HPV alone is not sufficient for the oncogenic transformation of normal human epithelial cells, indicating that additional cofactors are required for the oncogenic conversion of HPV-infected cells. Inasmuch as chronic inflammation is also closely associated with carcinogenesis, we investigated the effect of chronic exposure to tumor necrosis factor α (TNFα), the major proinflammatory cytokine, on oncogenesis in two immortalized oral keratinocyte cell lines, namely, HPV16-immortalized and human telomerase reverse transcriptase (hTERT)-immortalized cells. TNFα treatment led to the acquisition of malignant growth properties in HPV16-immortalized cells, such as (1) calcium resistance, (2) anchorage independence, and (3) increased cell proliferation in vivo. Moreover, TNFα increased the cancer stem cell-like population and stemness phenotype in HPV16-immortalized cells. However, such transforming effects were not observed in hTERT-immortalized cells, suggesting an HPV-specific role in TNFα-promoted oncogenesis. We also generated hTERT-immortalized cells that express HPV16 E6 and E7. Chronic TNFα exposure successfully induced the malignant growth and stemness phenotype in the E6-expressing cells but not in the control and E7-expressing cells. We further demonstrated that HPV16 E6 played a key role in TNFα-induced cancer stemness via suppression of the stemness-inhibiting microRNAs miR-203 and miR-200c. Overexpression of miR-203 and miR-200c suppressed cancer stemness in TNFα-treated HPV16-immortalized cells. Overall, our study suggests that chronic inflammation promotes cancer stemness in HPV-infected cells, thereby promoting HPV-associated oral carcinogenesis.

The Effect of Rhus verniciflua Stokes Extracts on Photo-Aged Mouse Skin.

BACKGROUND: Rhus verniciflua Stokes (RV) has traditionally been used in Korea as an indigenous food (Rhus chicken soup) and as an herbal medicinal plant. While the anticancer, antimicrobial, and anti-inflammatory properties of RV have been actively studied in the medical field, its antioxidant effects in the skin that resist the reactive oxygen species in keratinocytes and fibroblasts is less understood. OBJECTIVE: We designed to evaluate the effects of R. verniciflua Stokes extract (RVE) on the photo-aged skin by an in vitro experiment using human fibroblasts and an in vivo experiment using a photo-aged murine model. METHODS: For the in vitro experiments, human fibroblasts irradiated with ultraviolet (UV) B were treated with RVE or vehicle, and the growth levels and the expression level of type 1 procollagen were compared. For the in vivo experiment, photo-aged mice irradiated with UVB and UVA were administered drinking water with or without RVE, and histological changes and the expression level of type 1 procollagen and matrix metalloprotease (MMP)-13 were compared. RESULTS: In vitro experiments using fibroblasts irradiated with UVB showed that RVE promoted growth and significantly increased the expression of type 1 procollagen as compared to the control group. In the photo-aged mice, RVE increased collagen content in the dermis and promoted the synthesis of type 1 procollagen without any visible decrease in MMP-13 as compared to control group. CONCLUSION: In addition to the previously reported antioxidant effects of RVE, oral intake of RVE effectively inhibited photo-aging in hairless mice by enhancing collagen synthesis.

The Challenge of Universal Eye Health in Latin America: distributive inequality of ophthalmologists in 14 countries.

BACKGROUND: No comprehensive study currently exists on the supply of ophthalmologists across Latin America. We explored sociogeographic inequalities in the availability and distribution of ophthalmologists across 14 Latin American countries. METHODS: The National Ophthalmologic Societies of Argentina, Bolivia, Brazil, Colombia, Costa Rica, Chile, the Dominican Republic, Ecuador, Guatemala, Mexico, Paraguay, Peru, Uruguay and Venezuela provided data on affiliated ophthalmologists by first-order subnational divisions in 2013. Human Development Index (HDI) estimates at the corresponding subnational division were used as equity stratifiers. Distributional inequality of ophthalmologists within each country was assessed by the health concentration index (HCI) and the index of dissimilarity (ID), along with the mean level of ophthalmologists per population. RESULTS: Across all countries studied, there were 5.2 ophthalmologists per 100 000 population on average (95% CI 5.0 to 5.4) in 2013, with a mean HCI of 0.26 (0.16 to 0.37) and a mean relative ID of 22.7% (20.9% to 24.7%). There was wide inequality in ophthalmologist availability between countries, ranging from 1.2 (1.1 to 1.4) in Ecuador to 8.6 (8.5 to 8.8) in Brazil. All countries had positive (ie, pro-rich) HCI values ranging from 0.68 (0.66 to 0.71) in Guatemala to 0.02 (-0.11 to 0.14) in Venezuela. Correspondingly, redistributive potential to achieve equity was closest in Venezuela (ID: 1.5%) and farthest in Guatemala (ID: 60.3%). Benchmarked against regional averages, most countries had a lower availability of ophthalmologists and higher relative inequality. CONCLUSIONS: There is high inequality in the level and distribution of ophthalmologists between and within countries in Latin America, with a disproportionate number concentrated in more developed, socially advantaged areas. More equitable access to ophthalmologists could be achieved by implementing incentivised human resources redistribution programmes and by improving the social determinants of health in underserved areas.

Spontaneous Involution of Congenital Melanocytic Nevus With Halo Phenomenon.

Congenital melanocytic nevus (CMN) is a neural crest-derived hamartoma, which appear at or soon after birth. CMN has a dynamic course and may show variable changes over time, including spontaneous involution. Spontaneous involution of CMN is a rare phenomenon and is often reported in association with halo phenomenon or vitiligo. The mechanism of halo phenomenon is yet to be investigated but is suggested to be a destruction of melanocytes by immune responses of cytotoxic T cells or IgM autoantibodies. Here, the authors report an interesting case of spontaneously regressed medium-sized CMN with halo phenomenon and without vitiligo, which provides evidence that cytotoxic T cells account for the halo formation and pigmentary regression of CMN.

Comparison of hair shaft damage after chemical treatment in Asian, White European, and African hair.

BACKGROUND: Diverse causes of extrinsic damage to the hair shaft have been documented and can be roughly divided into physical and chemical causes. Chemical causes of hair damage include bleaching, hair dyeing, and perming. OBJECTIVES: The goal of this study was to investigate differences in patterns of serial damage in Asian, White European (WE), and African hair after chemical stress imposed by straightening and coloring treatments. METHODS: Hairs were divided into control and treatment groups (straightening, coloring, and a combination of straightening and coloring). At 24 hours after the final treatment, patterns of hair damage were evaluated using transmission electron microscopy (TEM) and lipid TEM. Grades of hair cuticle and cortex damage were evaluated by three dermatologists. RESULTS: In the TEM examination, the cuticle of Asian hair proved to be resistant to damage caused by straightening treatments, whereas the WE hair cuticle and cortex were relatively susceptible to stress imposed by coloring treatments. In the combination treatment of straightening and coloring, African hair emerged as the most resistant to stress. In the lipid TEM examination, no notable differences in cell membrane complex damage were observed among the three groups of hairs. CONCLUSIONS: The present study suggests that WE hair is relatively susceptible and African hair is more resistant to chemical stresses, such as those imposed by straightening and coloring.

Compound loss of muscleblind-like function in myotonic dystrophy.

Myotonic dystrophy (DM) is a multi-systemic disease that impacts cardiac and skeletal muscle as well as the central nervous system (CNS). DM is unusual because it is an RNA-mediated disorder due to the expression of toxic microsatellite expansion RNAs that alter the activities of RNA processing factors, including the muscleblind-like (MBNL) proteins. While these mutant RNAs inhibit MBNL1 splicing activity in heart and skeletal muscles, Mbnl1 knockout mice fail to recapitulate the full-range of DM symptoms in these tissues. Here, we generate mouse Mbnl compound knockouts to test the hypothesis that Mbnl2 functionally compensates for Mbnl1 loss. Although Mbnl1(-/-) ; Mbnl2(-/-) double knockouts (DKOs) are embryonic lethal, Mbnl1(-/-) ; Mbnl2(+/-) mice are viable but develop cardinal features of DM muscle disease including reduced lifespan, heart conduction block, severe myotonia and progressive skeletal muscle weakness. Mbnl2 protein levels are elevated in Mbnl1(-/-) knockouts where Mbnl2 targets Mbnl1-regulated exons. These findings support the hypothesis that compound loss of MBNL function is a critical event in DM pathogenesis and provide novel mouse models to investigate additional pathways disrupted in this RNA-mediated disease.

Reliability of the pattern hair loss classifications: a comparison of the basic and specific and Norwood-Hamilton classifications.

Pattern hair loss (PHL) is the most common form of baldness in both sexes. The Norwood-Hamilton classification is the most commonly used classification worldwide, but it has many limitations. The basic and specific (BASP) classification was introduced as an improvement over the Norwood-Hamilton classification. Previous research was done to estimate the reliability of the Norwood-Hamilton classification and the result was unsatisfactory. However, the reliability of the BASP and Norwood-Hamilton classifications has not yet been compared. Eight dermatological specialists, 17 dermatological residents and 15 general physicians classified PHL in 100 sets of photographs using both the BASP and Norwood-Hamilton classifications. Intergroup reproducibility was evaluated by examining the match rate of the individual data in each group and the match rate between hair specialist and the other examiners. Intragroup repeatability was determined by calculating the match rate between the first and second studies. In terms of intergroup reproducibility of the match rate for individual data in each group, the basic type had the best agreement, the specific type had the second best, and the Norwood-Hamilton classification had the lowest match rate. In comparison, hair specialist and intragroup repeatability showed the same patterns. The BASP classification not only distinguishes all kinds of hair loss patterns, but also has better reproducibility and repeatability than the Norwood-Hamilton classification.

TNFα enhances cancer stem cell-like phenotype via Notch-Hes1 activation in oral squamous cell carcinoma cells.

Cancer stem-like cell (CSC; also known as tumor initiating cell) is defined as a small subpopulation of cancer cells within a tumor and isolated from various primary tumors and cancer cell lines. CSCs are highly tumorigenic and resistant to anticancer treatments. In this study, we found that prolonged exposure to tumor necrosis factor alpha (TNFα), a major proinflammatory cytokine, enhances CSC phenotype of oral squamous cell carcinoma (OSCC) cells, such as an increase in tumor sphere-forming ability, stem cell-associated genes expression, chemo-radioresistance, and tumorigenicity. Moreover, activation of Notch1 signaling was detected in the TNFα-exposed cells, and suppression of Notch1 signaling inhibited CSC phenotype. Furthermore, we demonstrated that inhibition of a Notch downstream target, Hes1, led to suppression of CSC phenotype in the TNFα-exposed cells. We also found that Hes1 expression is commonly upregulated in OSCC lesions compared to precancerous dysplastic lesions, suggesting the possible involvement of Hes1 in OSCC progression and CSC in vivo. In conclusion, inflammatory cytokine exposure may enhance CSC phenotype of OSCC, in part by activating the Notch-Hes1 pathway.

miR-181a shows tumor suppressive effect against oral squamous cell carcinoma cells by downregulating K-ras.

MicroRNAs (miRNAs) are epigenetic regulators of gene expression, and their deregulation plays an important role in human cancer, including oral squamous cell carcinoma (OSCC). Recently, we found that miRNA-181a (miR-181a) was upregulated during replicative senescence of normal human oral keratinocytes. Since senescence is considered as a tumor suppressive mechanism, we thus investigated the expression and biological role of miR-181a in OSCC. We found that miR-181a was frequently downregulated in OSCC. Ectopic expression of miR-181a suppressed proliferation and anchorage independent growth ability of OSCC. Moreover, miR-181a dramatically reduces the growth of OSCC on three dimensional organotypic raft culture. We also identified K-ras as a novel target of miR-181a. miR-181a decreased K-ras protein level as well as the luciferase activity of reporter vectors containing the 3'-untranslated region of K-ras gene. Finally, we defined a minimal regulatory region of miR-181a and found a positive correlation between its promoter activity and the level of miR-181a expression. In conclusion, miR-181a may function as an OSCC suppressor by targeting on K-ras oncogene. Thus, miR-181a should be considered for therapeutic application for OSCC.