Melatonin and Its Role in the Epithelial-to-Mesenchymal Transition (EMT) in Cancer.

The epithelial-to-mesenchymal transition (EMT) is a cell-biological program that occurs during the progression of several physiological processes and that can also take place during pathological situations such as carcinogenesis. The EMT program consists of the sequential activation of a number of intracellular signaling pathways aimed at driving epithelial cells toward the acquisition of a series of intermediate phenotypic states arrayed along the epithelial-mesenchymal axis. These phenotypic features include changes in the motility, conformation, polarity and functionality of cancer cells, ultimately leading cells to stemness, increased invasiveness, chemo- and radioresistance and the formation of cancer metastasis. Amongst the different existing types of the EMT, type 3 is directly involved in carcinogenesis. A type 3 EMT occurs in neoplastic cells that have previously acquired genetic and epigenetic alterations, specifically affecting genes involved in promoting clonal outgrowth and invasion. Markers such as E-cadherin; N-cadherin; vimentin; and transcription factors (TFs) like Twist, Snail and ZEB are considered key molecules in the transition. The EMT process is also regulated by microRNA expression. Many miRNAs have been reported to repress EMT-TFs. Thus, Snail 1 is repressed by miR-29, miR-30a and miR-34a; miR-200b downregulates Slug; and ZEB1 and ZEB2 are repressed by miR-200 and miR-205, respectively. Occasionally, some microRNA target genes act downstream of the EMT master TFs; thus, Twist1 upregulates the levels of miR-10b. Melatonin is an endogenously produced hormone released mainly by the pineal gland. It is widely accepted that melatonin exerts oncostatic actions in a large variety of tumors, inhibiting the initiation, progression and invasion phases of tumorigenesis. The molecular mechanisms underlying these inhibitory actions are complex and involve a great number of processes. In this review, we will focus our attention on the ability of melatonin to regulate some key EMT-related markers, transcription factors and micro-RNAs, summarizing the multiple ways by which this hormone can regulate the EMT. Since melatonin has no known toxic side effects and is also known to help overcome drug resistance, it is a good candidate to be considered as an adjuvant drug to conventional cancer therapies.

Adeno-associated virus type 2 in US children with acute severe hepatitis.

As of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA1,2. Previous studies have found human adenoviruses (HAdVs) in the blood from patients in Europe and the USA3-7, although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing to analyse samples from 16 HAdV-positive cases from 1 October 2021 to 22 May 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus type 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls (P < 0.001) and to 0 of 30 patients with hepatitis of defined aetiology (P < 0.001). In controls, HAdV type 41 was detected in blood from 9 (39.1%) of the 23 patients with acute gastroenteritis (without hepatitis), including 8 of 9 patients with positive stool HAdV testing, but co-infection with AAV2 was observed in only 3 (13.0%) of these 23 patients versus 93% of cases (P < 0.001). Co-infections by Epstein-Barr virus, human herpesvirus 6 and/or enterovirus A71 were also detected in 12 (85.7%) of 14 cases, with higher herpesvirus detection in cases versus controls (P < 0.001). Our findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses.

Vascular anatomy of the breast and its implications in the breast-sharing reconstruction technique.

The most frequently described breast-sharing procedure consists in a pedicled technique where the transferred lower breast pole is based on the lower perforators of the internal mammary (IM) artery. The current article investigates the vascular supply of the breast and its surgical implications in breast-sharing reconstruction. Contrast-enhanced magnetic resonance images of 55 patients (110 breasts) were retrospectively examined. A total of 473 branches of the IM, lateral thoracic (LT) and anterior intercostal (AI) arteries with a diameter greater than 0.5 mm were traced throughout their course in the breast. Distinct connections between the vessels were equally recorded. Although any vessel could vascularise any quadrant in the individual patient, blood supply to the lower quadrants came fundamentally from the AI arteries (76.2% of all the perforators). Lower IM branches (4th-5th) were seen to reach both lower quadrants in only 6.4% of the breasts, whereas LT branches did in 15.5%. In 86.4% of the breasts, at least a distinct AI perforator was seen to perfuse both lower quadrants. Well-defined connections between the IM and the LT arteries were observed in 41.8% of the breasts, always at or above the nipple-areola level. Other connections were far less common. Our study strongly indicates that the breast-sharing technique based on 4th-5th contralateral branches of the IM or LT arteries is unreliable in most patients. Given the unpredictable vascularization pattern in the lower breast pole, a preoperative imaging study is mandatory when the use of the contralateral breast is considered. Due to its accuracy, availability, and anatomical reliability, contrast-enhanced magnetic resonance is the best technique in the preoperative evaluation of the breast-sharing reconstruction.

Development of in vitro and in vivo tools to evaluate the antiangiogenic potential of melatonin to neutralize the angiogenic effects of VEGF and breast cancer cells: CAM assay and 3D endothelial cell spheroids.

Melatonin is a molecule with different antitumor actions in breast cancer and has been described as an inhibitor of vascular endothelial growth factor (VEGF). Despite the recognition of the key role exerted by VEGF in tumor angiogenesis, limitations arise when developing models to test new antiangiogenic molecules. Thus, the aim of this study was to develop rapid, economic, high capacity and easy handling angiogenesis assays to test the antiangiogenic effects of melatonin and demonstrate its most effective dose to neutralize and interfere with the angiogenic sprouting effect induced by VEGF and MCF-7. To perform this, 3D endothelial cell (HUVEC) spheroids and a chicken embryo chorioallantoic membrane (CAM) assay were used. The results showed that VEGF and MCF-7 were able to stimulate the sprouting of the new vessels in 3D endothelial spheroids and the CAM assay, and that melatonin had an inhibitory effect on angiogenesis. Specifically, as the 1 mM pharmacological dose was the only effective dose able to inhibit the formation of ramifications around the alginate in the CAM assay model, this inhibition was shown to occur in a dose-dependent manner. Taken together, these techniques represent novel tools for the development of antiangiogenic molecules such as melatonin, with possible implications for the therapy of breast cancer.

TRIM25 mutation (p.C168*), coding for an E3 ubiquitin ligase, is a cause of early-onset autosomal dominant dementia with amyloid load and parkinsonism.

INTRODUCTION: Patients with familial early-onset dementia (EOD) pose a unique opportunity for gene identification studies. METHODS: We present the phenotype and whole-exome sequencing (WES) study of an autosomal dominant EOD family. Candidate genes were examined in a set of dementia cases and controls (n = 3712). Western blotting was conducted of the wild-type and mutant protein of the final candidate. RESULTS: Age at disease onset was 60 years (range 56 to 63). The phenotype comprised mixed amnestic and behavioral features, and parkinsonism. Cerebrospinal fluid and plasma biomarkers, and a positron emission tomography amyloid study suggested Alzheimer's disease. WES and the segregation pattern pointed to a nonsense mutation in the TRIM25 gene (p.C168*), coding for an E3 ubiquitin ligase, which was absent in the cohorts studied. Protein studies supported a loss-of-function mechanism. DISCUSSION: This study supports a new physiopathological mechanism for brain amyloidosis. Furthermore, it extends the role of E3 ubiquitin ligases dysfunction in the development of neurodegenerative diseases. HIGHLIGHTS: A TRIM25 nonsense mutation (p.C168*) is associated with autosomal dominant early-onset dementia and parkinsonism with biomarkers suggestive of Alzheimer's disease. TRIM25 protein studies support that the mutation exerts its effect through loss of function. TRIM25, an E3 ubiquitin ligase, is known for its role in the innate immune response but this is the first report of association with neurodegeneration. The role of TRIM25 dysfunction in development of amyloidosis and neurodegeneration merits a new line of research.

Cirugía micrográfica de Mohs en carcinomas cutáneos: siete años de experiencia en Uruguay / Mohs micrographic surgery in skin cancer: 7 years' experience in uruguay / Cirurgia micrográfica de Mohs em carcinomas cutáneos: 7 anos de experiência no Uruguai

Introducción: la cirugía micrográfica de Mohs es una técnica para la exéresis de cánceres de piel con la ventaja del examen histológico del 100% de los márgenes quirúrgicos, logrando así la tasa de curación más alta con la máxima preservación de tejido sano circundante. Objetivo: realizar una descripción clínico-epidemiológica de 7 años de experiencia en Uruguay. Método: análisis descriptivo de pacientes operados por un mismo cirujano de Mohs registrando datos clínicos, tumorales y quirúrgicos. Resultados: se estudiaron 641 cirugías. 54,9% fueron realizadas en hombres y 45,1% en mujeres. La edad media fue de 69 años. El 68,2% correspondió a carcinoma basocelular y 31,8% a carcinoma espinocelular. El 79,4% se encontraba en cabeza y cuello. El 87,8% de los tumores fueron primarios y un 11,1% recidivas. El tipo más frecuente de cierre fue el cierre simple con 48,7% seguido de los colgajos con un 31,7%. Conclusiones: la cirugía de Mohs es un procedimiento seguro y eficaz, y nuestros resultados coinciden con lo descrito en centros de referencia internacional. Este trabajo describe 7 años de experiencia en Uruguay de la técnica de CMM, siendo el mayor a nivel nacional.

Introduction: Mohs micrographic surgery is a technique for skin cancer exeresis involving the advantage of 100% of surgical margins histological exam, which leads to highest healing rates with the maximum preservation of the surrounding healthy tissue. Objective: to conduct a clinical and epidemiological description of a 7 years' experience in Uruguay. Method: descriptive analysis of patients operated by the same Mohs surgeon who recorded clinical, tumor and surgical data. Results: 641 surgeries were included in the study. 54.9% of surgeries were performed in men and 45.1% in women. Average age was 69 years old. 68.2% of cases corresponded to basal cell carcinoma and 31.8% to squamous cell carcinoma. 79.4% were located in the head and neck, 87.8% of tumors were primary and 11.1% were cases of relapse. The most frequent type of closure was simple in 48.7% of cases, followed by flaps in 31.7%. Conclusions: Mohs surgery is a safe an effective procedure, and the results of the study agree with what is described in international reference centers. The study describes a 7 years' experience in Uruguay of Mohs micrographic surgery, being it the largest research conducted in Uruguay.

Introdução: a cirurgia micrográfica de Mohs é uma técnica de excisão de cânceres de pele com a vantagem do exame histológico de 100% das margens cirúrgicas, alcançando assim a maior taxa de cura com a máxima preservação do tecido saudável circundante. Objetivo: realizar uma descrição clínico-epidemiológica de 7 anos de experiência no Uruguai. Método: análise descritiva de pacientes operados pelo mesmo cirurgião com experiência na técnica de Mohs registrando dados clínicos, tumorais e cirúrgicos. Resultados: foram estudadas 641 cirurgias. 54,9% foram realizados em homens e 45,1% em mulheres. A média de idade foi de 69 anos. 68,2% corresponderam a carcinoma basocelular e 31,8% a carcinoma espinocelular. 79,4% estavam na cabeça e pescoço. 87,8% dos tumores eram primários e 11,1% recidivas. O tipo de fechamento mais frequente foi o fechamento simples (48,7%) seguido do fechamento com retalhos com (31,7%). Conclusões: a cirurgia de Mohs é um procedimento seguro e eficaz, e nossos resultados coincidem com os descritos em centros de referência internacionais. Este trabalho descreve 7 anos de experiência no Uruguai da técnica CMM, sendo a maior a nível nacional.

Melatonin Modulation of Radiation-Induced Molecular Changes in MCF-7 Human Breast Cancer Cells.

Radiation therapy is an important component of cancer treatment scheduled for cancer patients, although it can cause numerous deleterious effects. The use of adjuvant molecules aims to limit the damage in normal surrounding tissues and enhance the effects of radiation therapy, either killing tumor cells or slowing down their growth. Melatonin, an indoleamine released by the pineal gland, behaves as a radiosensitizer in breast cancer, since it enhances the therapeutic effects of ionizing radiation and mitigates side effects on normal cells. However, the molecular mechanisms through which melatonin modulates the molecular changes triggered by radiotherapy remain mostly unknown. Here, we report that melatonin potentiated the anti-proliferative effect of radiation in MCF-7 cells. Treatment with ionizing radiation induced changes in the expression of many genes. Out of a total of 25 genes altered by radiation, melatonin potentiated changes in 13 of them, whereas the effect was reverted in another 10 cases. Among them, melatonin elevated the levels of PTEN and NME1, and decreased the levels of SNAI2, ERBB2, AKT, SERPINE1, SFN, PLAU, ATM and N3RC1. We also analyzed the expression of several microRNAs and found that melatonin enhanced the effect of radiation on the levels of miR-20a, miR-19a, miR-93, miR-20b and miR-29a. Rather surprisingly, radiation induced miR-17, miR-141 and miR-15a but melatonin treatment prior to radiation counteracted this stimulatory effect. Radiation alone enhanced the expression of the cancer suppressor miR-34a, and melatonin strongly stimulated this effect. Melatonin further enhanced the radiation-mediated inhibition of Akt. Finally, in an in vivo assay, melatonin restrained new vascularization in combination with ionizing radiation. Our results confirm that melatonin blocks many of the undesirable effects of ionizing radiation in MCF-7 cells and enhances changes that lead to optimized treatment results. This article highlights the effectiveness of melatonin as both a radiosensitizer and a radioprotector in breast cancer. Melatonin is an effective adjuvant molecule to radiotherapy, promoting anti-cancer therapeutic effects in cancer treatment. Melatonin modulates molecular pathways altered by radiation, and its use in clinic might lead to improved therapeutic outcomes by enhancing the sensitivity of cancerous cells to radiation and, in general, reversing their resistance toward currently applied therapeutic modalities.

Trigeminal trophic syndrome: An unusual nasal ulceration. A case report and review of the literature.

Trigeminal trophic syndrome is a rare condition characterized by self-inflicted persistent facial ulceration. It is believed to be consequent to central or peripheral insult to trigeminal nerve, which may have taken place even years before the ulcer development. The aggression to the nerve pathway causes dysesthesias in the trigeminal dermatomes that induce a self-mutilating behavior, with repetitive pinching or scratching in order to mitigate the altered sensation. Due to associated skin anesthesia, the patient does not interrupt manipulation of the affected area despite severe skin necrosis. Ulceration typically occurs in the ala nasi and may resemble other more common cutaneous diseases, such as tumors or infections. Given that this condition is not included in our daily clinical practice, the risk is that of a diagnostic delay with devastating functional and esthetic facial consequences. We present the case of a patient with a history of meningioma resection who developed this syndrome and we have reviewed the published literature to provide an update on the etiopathogenesis, diagnosis and treatment of this rare condition.

Safety and tolerability of regadenoson in comparison with adenosine stress cardiovascular magnetic resonance: Data from a multicentre prospective registry.

To assess the feasibility and incidence of immediate complications of stress cardiovascular magnetic resonance (CMR) with regadenoson in comparison with adenosine in a large referral population. This is a large, multicenter, prospective registry of vasodilator stress-CMR in a referral population. We recorded the clinical and demographic data, quality of test, CMR findings, hemodynamic data, and complications. Between January 2016 and July 2019, 2908 patients underwent stress-CMR, 2253 with regadenoson and 655 with adenosine. 25.1% of patients had previously known coronary artery disease (CAD). In 305 patients regadenoson was used due to presence of chronic obstructive pulmonary disease (COPD) or asthma, while in 1948 subjects regadenoson was used as first-line vasodilator. Quality was optimal in 90.0%, suboptimal in 9.5%, and poor in 0.5%. Images were diagnostic in 98.9%. After stress with regadenoson, aminophylline 200 mg was administered intravenously in all patients. No patient died or had severe immediate complications with regadenoson as opposed to 2 severe bronchospasm with adenosine (p = 0.05). 11 patients (0.5%) had non-severe complications with regadenoson and five patients (0.8%) with adenosine (p = n.s.). Only two patients (0.088%) had non-severe bronchospasm after regadenoson administration. All complications were solved in the CMR unit, with no need for further specific care. Factors significantly associated with presence of complications were history of COPD or asthma and detection of inducible ischaemia. Patients had significantly more minor symptoms when adenosine was used (66.0% vs. 18.4%, p < 0.0001). Stress-CMR with regadenoson is feasible, providing diagnostic information in a referral population. Regadenoson had an excellent safety profile and better tolerability than adenosine, with no serious immediate complications and low incidence of non-severe complications. Only inducible ischaemia and previous history of COPD or asthma were associated with complications after regadenoson-CMR. The incidence of minor symptoms was low.

Comparación de las tinciones con hematoxilina y eosina versus azul de toluidina en la evaluación de los carcinomas cutáneos durante la cirugía micrográfica de Mohs / Comparative study of toluidine blue and hematoxylin and eosin staining in evaluating skin-carcinoma during Mohs micrographic surgery / Comparação da coloração de hematoxilina e eosina versus azul de toluidina na avaliação de carcinomas cutâneos durante a cirurgia micrográfica de Mohs

Resumen: Introducción: la cirugía micrográfica de Mohs es una técnica quirúrgica especializada para el tratamiento del cáncer de piel no melanoma. La histopatología cumple un rol fundamental, y la elección de la tinción es un punto de controversia. Objetivos: comparar el rendimiento de las tinciones de hematoxilina y eosina (HyE) versus azul de toluidina (AT) durante la cirugía. Método: estudio observacional, descriptivo y transversal a partir de noviembre de 2017 hasta mayo de 2018. Se incluyeron las láminas empleadas durante la cirugía en el período mencionado. Estas fueron analizadas por el cirujano de Mohs, tres residentes y una dermopatóloga. Se valoró el rendimiento de ambas tinciones, teniendo en cuenta las características celulares y los elementos del estroma. Resultados: se estudiaron 23 tumores (16 carcinomas basocelulares y 7 carcinomas espinocelulares). Al observarse al microscopio óptico tanto con la tinción de AT como con HyE no se encontraron diferencias significativas entre ambos grupos en lo global, sólo en algunas características, especialmente con la HyE. Conclusiones: es el primer trabajo en Uruguay que compara la eficacia de las dos tinciones durante la cirugía micrográfica de Mohs. Como conclusión tanto la tinción de HyE como el AT son muy buenas técnicas para el diagnóstico de carcinomas cutáneos.

Abstract: Introduction: Mohs micrographic surgery is a specialized surgical technique used to treat nonmelanoma carcinoma. Histopathology plays a vital role in the diagnosis of this condition, and the choice staining method is controversial. Objective: to compare results in the use of hematoxylin and eosin (H&E) versus Toluidine blue (TB) staining during surgery. Method: observational, descriptive and transversal study conducted from November, 2017 until May, 2018 of the slides used during surgeries in the selected period. Slides were analysed by the Mohs surgeon, 3 residents and a dermopathologist to evaluate the results of both staining methods, in consideration of cell features and stromal elements. Results: 23 tumors were analysed (16 Basal Cell carcinomas and 7 Squamous Cell Carcinoma). Microscopic observation of slides prepared with Toluidine blue and hematoxylin and eosin stains did not show significant global differences between both groups, except in terms of a few characteristics, in particular with hematoxylin and eosin stains. Conclusions: this was the first study in Uruguay to evaluate the effectiveness of both staining methods during Mohs micrographic surgery, and it concluded that both Toluidine blue and hematoxylin and eosin stains are very good techniques in evaluating skin-cancer.

Resumo: Introdução: a cirurgia micrográfica de Mohs é uma técnica cirúrgica especializada para o tratamento do câncer de pele não melanoma. A histopatologia desempenha um papel fundamental, onde a escolha da coloração é um ponto de controvérsia. Objetivos: comparar o desempenho das colorações de hematoxilina e eosina versus azul de toluidina durante a cirurgia. Método: estudo observacional, descritivo e transversal de novembro de 2017 a maio de 2018. Foram incluídas as lâminas utilizadas durante as cirurgias no referido período. Estas foram analisadas pelo cirurgião especializado na técnica de Mohs, 3 residentes e um dermatopatologista onde foi avaliado o desempenho de ambas as colorações, levando em consideração as características celulares e os elementos do estroma. Resultados: foram estudados 23 tumores (16 carcinomas basocelulares e 7 carcinomas espinocelulares). Quando observados ao microscópio de luz para coloração AT e H&E, não foram encontradas diferenças significativas entre os dois grupos em geral, apenas em algumas características, especialmente com o H&E. Conclusões: é o primeiro estudo no Uruguai que compara a eficácia dos 2 corantes durante a cirurgia micrográfica de Mohs. Em conclusão, tanto a coloração com hematoxilina e eosina quanto com azul de toluidina são técnicas muito boas para o diagnóstico de carcinomas de pele.

Effects of Alcohol Binge Drinking and Oleoylethanolamide Pretreatment in the Gut Microbiota.

Introduction: Chronic alcohol consumption is known to cause gut dysbiosis (changes in microbiota composition and/or function, disruptive of the normal host-microbiota interactions). However, little is known about the changes that alcohol binge drinking induces in the gut microbiota. Here, we have tested the hypothesis that a protocol of alcohol binge drinking, known to induce neuroinflammation in previous studies, also promotes intestinal dysbiosis, and we explored how oleoylethanolamide (OEA, an acylethanolamide proven to counteract alcohol binge drinking-induced neuroinflammation) pretreatment modulates alcohol-induced dysbiosis. Methods: Alcohol binges were forced by gavage three times per day during 4 consecutive days; OEA pretreatment (intraperitoneal or intragastric) was administered before each alcohol gavage. Stool microbiota composition was assessed by next-generation 16S rRNA gene sequencing, prior and after the 4-day alcohol binge protocol. Results: Alcohol binge drinking reduced the richness of the gut microbiota and changed the microbial community, reducing Lactobacillus among other genera. Pretreatment with OEA in the alcohol-administered rats decreased the richness, evenness, and Shannon indices to a greater extent with respect to alcohol alone, also changing the community structure. Microbial interactions in the association network were further decreased following OEA administration in the alcohol group, with respect to the water administration. The synergistic interaction between alcohol binge and OEA was affected by the route of administration of OEA, since oral and i.p. administrations differently changed the community structure. Conclusion: Results suggest that alcohol binge drinking produces a clear dysbiosis in animals; we observed that the well-known protective actions of OEA in the context of alcohol abuse might not be related to OEA-induced changes in alcohol-induced dysbiosis. These are observational results, and thus, further research will be needed for a complete understanding of the biological significance of the observed changes.

Relationships of Gut Microbiota Composition, Short-Chain Fatty Acids and Polyamines with the Pathological Response to Neoadjuvant Radiochemotherapy in Colorectal Cancer Patients.

Emerging evidence has suggested that dysbiosis of the gut microbiota may influence the drug efficacy of colorectal cancer (CRC) patients during cancer treatment by modulating drug metabolism and the host immune response. Moreover, gut microbiota can produce metabolites that may influence tumor proliferation and therapy responsiveness. In this study we have investigated the potential contribution of the gut microbiota and microbial-derived metabolites such as short chain fatty acids and polyamines to neoadjuvant radiochemotherapy (RCT) outcome in CRC patients. First, we established a profile for healthy gut microbiota by comparing the microbial diversity and composition between CRC patients and healthy controls. Second, our metagenomic analysis revealed that the gut microbiota composition of CRC patients was relatively stable over treatment time with neoadjuvant RCT. Nevertheless, treated patients who achieved clinical benefits from RTC (responders, R) had significantly higher microbial diversity and richness compared to non-responder patients (NR). Importantly, the fecal microbiota of the R was enriched in butyrate-producing bacteria and had significantly higher levels of acetic, butyric, isobutyric, and hexanoic acids than NR. In addition, NR patients exhibited higher serum levels of spermine and acetyl polyamines (oncometabolites related to CRC) as well as zonulin (gut permeability marker), and their gut microbiota was abundant in pro-inflammatory species. Finally, we identified a baseline consortium of five bacterial species that could potentially predict CRC treatment outcome. Overall, our results suggest that the gut microbiota may have an important role in the response to cancer therapies in CRC patients.

Gut and Endometrial Microbiome Dysbiosis: A New Emergent Risk Factor for Endometrial Cancer.

Endometrial cancer is one of the most common gynaecological malignancies worldwide. Histologically, two types of endometrial cancer with morphological and molecular differences and also therapeutic implications have been identified. Type I endometrial cancer has an endometrioid morphology and is estrogen-dependent, while Type II appears with non-endometrioid differentiation and follows an estrogen-unrelated pathway. Understanding the molecular biology and genetics of endometrial cancer is crucial for its prognosis and the development of novel therapies for its treatment. However, until now, scant attention has been paid to environmental components like the microbiome. Recently, due to emerging evidence that the uterus is not a sterile cavity, some studies have begun to investigate the composition of the endometrial microbiome and its role in endometrial cancer. In this review, we summarize the current state of this line of investigation, focusing on the relationship between gut and endometrial microbiome and inflammation, estrogen metabolism, and different endometrial cancer therapies.

Melatonin as an Adjuvant to Antiangiogenic Cancer Treatments.

Melatonin is a hormone with different functions, antitumor actions being one of the most studied. Among its antitumor mechanisms is its ability to inhibit angiogenesis. Melatonin shows antiangiogenic effects in several types of tumors. Combination of melatonin and chemotherapeutic agents have a synergistic effect inhibiting angiogenesis. One of the undesirable effects of chemotherapy is the induction of pro-angiogenic factors, whilst the addition of melatonin is able to overcome these undesirable effects. This protective effect of the pineal hormone against angiogenesis might be one of the mechanisms underlying its anticancer effect, explaining, at least in part, why melatonin administration increases the sensitivity of tumors to the inhibitory effects exerted by ordinary chemotherapeutic agents. Melatonin has the ability to turn cancer totally resistant to chemotherapeutic agents into a more sensitive chemotherapy state. Definitely, melatonin regulates the expression and/or activity of many factors involved in angiogenesis which levels are affected (either positively or negatively) by chemotherapeutic agents. In addition, the pineal hormone has been proposed as a radiosensitizer, increasing the oncostatic effects of radiation on tumor cells. This review serves as a synopsis of the interaction between melatonin and angiogenesis, and we will outline some antiangiogenic mechanisms through which melatonin sensitizes cancer cells to treatments, such as radiotherapy or chemotherapy.

A New Paradigm in the Relationship between Melatonin and Breast Cancer: Gut Microbiota Identified as a Potential Regulatory Agent.

In this review we summarize a possible connection between gut microbiota, melatonin production, and breast cancer. An imbalance in gut bacterial population composition (dysbiosis), or changes in the production of melatonin (circadian disruption) alters estrogen levels. On the one hand, this may be due to the bacterial composition of estrobolome, since bacteria with ß-glucuronidase activity favour estrogens in a deconjugated state, which may ultimately lead to pathologies, including breast cancer. On the other hand, it has been shown that these changes in intestinal microbiota stimulate the kynurenine pathway, moving tryptophan away from the melatonergic pathway, thereby reducing circulating melatonin levels. Due to the fact that melatonin has antiestrogenic properties, it affects active and inactive estrogen levels. These changes increase the risk of developing breast cancer. Additionally, melatonin stimulates the differentiation of preadipocytes into adipocytes, which have low estrogen levels due to the fact that adipocytes do not express aromatase. Consequently, melatonin also reduces the risk of breast cancer. However, more studies are needed to determine the relationship between microbiota, melatonin, and breast cancer, in addition to clinical trials to confirm the sensitizing effects of melatonin to chemotherapy and radiotherapy, and its ability to ameliorate or prevent the side effects of these therapies.

Biodiversidad de ofiuroideos (Echinodermata: Ophiuroidea) del talud de la Península de Yucatán, México

Introduction: The Ophiuroidea class is the most diverse of the Phylum Echinodermata, with 2 064 described species, which can be found from intertidal zones to abyssal depths, but the fauna of Yucatan peninsula needs more study. Objective: To describe the diversity of ophiuroids in the Yucatan continental slope. Methods: Information was compiled from four oceanographic surveys carried out in August 2005, June 2007 (BIOREPES 1 and 2: BRP1 and BRP2), April 2011 and August 2014 (COBERPES 2 and 6: CBP2 and CBP6). The specimens were obtained by trawling with a shrimp net in soft substrates and with a skimmer-type trawl dredge at a depth range of 200 to 1 071 m off the states of Yucatán and Quintana Roo, Mexico. Results: We found members of two superorders, five orders, six suborders, five superfamilies, 18 families, 28 genera and 43 species. Conclusions: The northeast zone Yucatan Peninsula has at least 43 species, of which 19 are new records for the area.

Introducción: La clase Ophiuroidea es la más diversa del Phylum Echinodermata, con 2 064 especies descritas, que se pueden encontrar desde zonas intermareales hasta profundidades abisales, pero la fauna de la península de Yucatán necesita más estudio. Objetivo: Describir la diversidad de ofiuroideos en el talud continental de Yucatán. Métodos: Se recopiló información de cuatro estudios oceanográficos llevados a cabo en agosto de 2005, junio de 2007 (BIOREPES 1 y 2: BRP1 y BRP2), abril de 2011 y agosto de 2014 (COBERPES 2 y 6: CBP2 y CBP6). Los especímenes se obtuvieron mediante la pesca de arrastre con una red camaronera en sustratos blandos y con una draga de arrastre tipo skimmer en un rango de profundidad de 200 a 1 071 m frente a los estados de Yucatán y Quintana Roo, México. Resultados: Encontramos miembros de dos superórdenes, cinco órdenes, seis subórdenes, cinco superfamilias, 18 familias, 28 géneros y 43 especies. Conclusiones: La zona noreste de la Península de Yucatán tiene al menos 43 especies, de las cuales 19 son nuevos registros para el área.

Ontogenetic variation of the odontophore of Luidia superba (Asteroidea: Paxillosida) and its taxonomic implications

Introduction: The sea star odontophore is the structure positioned between the paired oral ossicles, with which they articulate through proximal and distal processes. The internal anatomy structures may be used as taxonomic characters for a precise differentiation between species, so it is necessary to describe the structures variation throughout growth. Objective: To describe the odontophore shape and variation of Luidia superba A. H. Clark, 1917 from specimens of the Gulf of California deposited in the Echinoderm National Collection, ICML UNAM. Methods: A total of 735 specimens were examined to describe the external characters, from which 55 selected specimens, within a range of R = 14 mm and R = 210 mm, were dissected to extract the odontophores and analyzed with geometric morphometrics. Results: Scanning electronic microscopy (SEM) images of the odontophores showing the variations in shape throughout growth are presented. Differences in shape between size groups were confirmed with a Canonical Variables Analysis (P < 0.05). Conclusions: There are three main groups in this size ranges where specialization of the stereom can be observed through the ontogenetic series; the variation in shape of the odontophore shown here is a precedent for the use of internal anatomy as new taxonomic characters of identification.

Introducción: El odontóforo es la estructura posicionada entre las placas orales pareadas con las que se articula a través de procesos proximales y distales. Las estructuras de la anatomía interna se pueden usar como caracteres taxonómicos para la diferenciación más precisa entre especies, por lo que es necesario describir la variación de las estructuras a lo largo del crecimiento. Objetivo: Describir la forma y la variación del odontóforo de Luidia superba A. H. Clark, 1917 de ejemplares del Golfo de California depositados en la Colección Nacional de Equinodermos, ICML UNAM. Métodos: Se revisaron un total de 735 ejemplares para describir los caracteres externos y de las cuales se seleccionaron 55 ejemplares, dentro de un intervalo de R = 14 mm a R = 210 mm, de los cuales se extrajeron los odontóforos y fueron analizados utilizando morfometría geométrica. Resultados: Se presentan imágenes de microscopía electrónica de barrido (MEB) de los odontóforos que muestran las variaciones de la forma durante el crecimiento. Se confirmaron diferencias significativas de la forma entre los grupos de tallas mediante un CVA (p< 0.05). Conclusiones: Se observa especialización del estereoma a lo largo de la serie ontogenética; la variación en la forma del odontóforo aquí mostrada es precedente para el uso de estructuras de la anatomía interna como nuevos caracteres de identificación.

Expansion of the genus Massinium (Holothuroidea: Thyonidae) to the American continent and description of a new species / Expansión del género Massinium (Holothuroidea: Thyonidae) al continente americano y descripción de una nueva especie

Introduction: The genus Massinium includes 11 species, most from the Indo Pacific Ocean, and had not previously being reported from the American continent. Objective: To present the new record of the genus Massinium and describe a new species of this genus. Methods: Material collection was done by SCUBA-diving to depths of a maximum of 9 m. Results: Massinium ocumichoensis sp. nov. is described from seven specimens that extends the range of the genus to the American continent (Guerrero, Michoacan and Jalisco, Mexico). The new species lives in sandy-rocky substrata, from 2 to 16 m deep. It is distinguished from its congeneric species by a combination of morphological characters: mid-dorsal slightly bigger pseudobuttons (40-60 μm), and tables in the body wall. A taxonomic key for distinguishing the species of Massinium is provided. Conclusions: The geographic range of the genus Massinium is extended to the Mexican Pacific with M. ocumichoensis sp. nov.

Introducción : El género Massinium incluye 11 especies, la mayoría del Océano Indo-Pacífico, y no se había reportado previamente en el continente americano. Objetivo: Presentar el nuevo registro del género Massinium y describir una nueva especie de este. Métodos: La recolección de material se realizó mediante buceo a una profundidad máxima de 9 m. Resultados: Massinium ocumichoensis sp. nov. se describe a partir de siete ejemplares que extiende el rango de distribución del género al Continente Americano (Guerrero, Michoacán y Jalisco, México). La nueva especie vive en sustratos arenosos-rocosos, de 2 a 16 m de profundidad. Se distingue de sus especies congenéricas por una combinación de caracteres morfológicos: pseudobotones de la zona dorsal media ligeramente más grandes (40-60 μm) y tablas en la pared del cuerpo. Se proporciona una clave taxonómica para distinguir las especies de Massinium. Conclusiones: El rango geográfico del género Massinium se extiende al Pacífico mexicano con M. ocumichoensis sp. nov.

Changing the time intervals between cisplatin cycles alter its ototoxic side effect.

Various methods have been tested and deployed clinically to identify and minimize cisplatin ototoxicity. Upon early identification of hearing loss, one of the possible approaches to reducing future ototoxicity is to increase the gaps or breaks between cycles or doses of cisplatin. However, recent findings about the retention of cisplatin in the cochlea and the potential for its long-term ototoxic effects call into question whether such an approach is effective in reducing hearing loss. The current study was undertaken to determine whether increasing the rest intervals between cycles of cisplatin altered the resulting ototoxicity. CBA/CaJ mice were exposed to a cumulative dose of 48 mg/kg cisplatin delivered in three cycles of 16 mg/kg (4 mg/kg per day for 4 consecutive days). The cycles were separated by either 10, 17, or 87 days to determine if the inter-cycle rest intervals affected resulting ototoxicity. Ototoxicity was measured using auditory brainstem response threshold shifts and hair cell losses. Results indicated that longer intervals between cycles of cisplatin led to lower threshold shifts and outer hair cell lesions. The results support the principle that 'slowing down' cisplatin dosing by increasing rest intervals between doses can reduce the ototoxic side effect. Further testing is needed to optimize the timing and to determine the impact of longer inter-cycle intervals on cisplatin's anti-tumor efficacy.

Margin Reanalysis With 3-Dimensional Micrographic Surgery Technique of Conventional Excision Specimens With Negative Margin Readings.

INTRODUCTION: Mohs micrographic surgery technique allows for complete margin analysis of skin tumors, which explains its lower recurrence rates over conventional surgery. Although it is known that routine processing of excision specimens represents less than 0.5% of the margins, a direct comparison with micrographic technique has not been performed so far. OBJECTIVE: To compare the margins of nonmelanoma skin cancers excised conventionally, processed with serial transverse cross-sectioning ("bread-loafing"), and had negative margin readings, against the margins obtained through micrographic technique from the same tumors. MATERIALS AND METHODS: Retrospective, descriptive, historical cohort study. Inclusion criteria as follows: patients who underwent conventional excision for nonmelanoma skin cancers between 2010 and 2013 in our dermatology department and had negative margin readings. Samples were dewaxed and processed with the 3-dimensional Mohs micrographic technique. RESULTS: One hundred one basal cell carcinomas and 26 squamous cell carcinomas were analyzed. Thirteen positive fragments were obtained, which corresponded to 11 tumors and patients; therefore, 8.7% of patients were given a false negative result in their original study. Lateral margins were more commonly affected (81.8%). There was no clear association between false negative results and histopathologic type or subtype. CONCLUSIONS: Our study is the first of its kind in terms of methodology. The "bread-loafing" technique can incorrectly report the state of the margins of surgical pieces excised by conventional surgery. Mohs' micrographic technique is superior when it comes to evaluating margins and should be regarded as the gold standard.