The Value of CXCL1, CXCL2, CXCL3, and CXCL8 as Potential Prognosis Markers in Cervical Cancer: Evidence of E6/E7 from HPV16 and 18 in Chemokines Regulation.

Cervical cancer (CC) is a serious global health issue, and it is well-known that HPV infection is the main etiological factor that triggers carcinogenesis. In cancer, chemokine ligands and receptors are involved in tumor cell growth, metastasis, leukocyte infiltration, and angiogenesis; however, information on the role played by E6/E7 of HPV16/18 in the modulation of chemokines is very limited. Therefore, this study aimed to determine whether chemokines are differentially expressed in CC-derived cell lines; if E6/E7 oncoproteins from HPV16 and 18 are capable of mediating chemokine expression, what is the expression profile of chemokines in tissues derived from CC and what is their impact on the overall survival of patients with this pathology? For this purpose, RNA sequencing and real-time PCR were performed on SiHa, HeLa, and C33A tumorigenic cell lines, on the non-tumorigenic HaCaT cells, and the E6/E7 HPV-transduced HaCaT cell models. Furthermore, chemokine expression and survival analysis were executed on 304 CC and 22 normal tissue samples from The Cancer Genome Atlas (TCGA) repository. The results demonstrate that CXCL1, CXCL2, CXCL3, and CXCL8 are regulated by E6/E7 of HPV16 and 18, are overexpressed in CC biopsies, and that their higher expression is related to a worse prognostic survival.

The Road to Malignant Cell Transformation after Particulate Matter Exposure: From Oxidative Stress to Genotoxicity.

In cells, oxidative stress is an imbalance between the production/accumulation of oxidants and the ability of the antioxidant system to detoxify these reactive products. Reactive oxygen species (ROS), cause multiple cellular damages through their interaction with biomolecules such as lipids, proteins, and DNA. Genotoxic damage caused by oxidative stress has become relevant since it can lead to mutation and play a central role in malignant transformation. The evidence describes chronic oxidative stress as an important factor implicated in all stages of the multistep carcinogenic process: initiation, promotion, and progression. In recent years, ambient air pollution by particulate matter (PM) has been cataloged as a cancer risk factor, increasing the incidence of different types of tumors. Epidemiological and toxicological evidence shows how PM-induced oxidative stress could mediate multiple events oriented to carcinogenesis, such as proliferative signaling, evasion of growth suppressors, resistance to cell death, induction of angiogenesis, and activation of invasion/metastasis pathways. In this review, we summarize the findings regarding the involvement of oxidative and genotoxic mechanisms generated by PM in malignant cell transformation. We also discuss the importance of new approaches oriented to studying the development of tumors associated with PM with more accuracy, pursuing the goal of weighing the impact of oxidative stress and genotoxicity as one of the main mechanisms associated with its carcinogenic potential.

High frequency of HPV genotypes 59, 66, 52, 51, 39 and 56 in women from Western Mexico.

BACKGROUND: Human papillomavirus infection is an important factor associated with cervical cancer (CC) development. The prevalence and genotype distribution vary greatly worldwide. Examining local epidemiological data constitutes an important step towards the development of vaccines to prevent CC. In this work, we studied the prevalence of HPV genotypes in women from Western Mexico with the COBAS 4800 and/or Linear Array Genotyping Test (LA). METHODS: The samples analysed in this study represent a population from Western Mexico, which includes six different states. Our approach was first to test for HPV in cervical samples from women who attended their health clinic for routine gynaecological studies (open-population, n = 3000) by utilizing COBAS 4800. Afterwards, 300 of the HPV-positive samples were randomly selected to be genotyped with LA; finally, we genotyped samples from women with cervical intraepithelial neoplasia grade 1 (CIN 1, n = 71) and CC (n = 96) with LA. Sociodemographic data of the diverse groups were also compared. RESULTS: The overall HPV prevalence among the open-population of women as determined by COBAS 4800 was 12.1% (n = 364/3000). Among the HPV-positive samples, single infections (SI) with HPV16 were detected in 12.4% (n = 45/364), SI with HPV18 were detected in 1.4%, and infection with at least one of the genotypes included in the high-risk HPV pool was detected in 74.5% of the cases. LA analysis of the samples showed that in addition to HPV genotypes 16 and 18, there was a high prevalence of HPV genotypes 59, 66, 52, 51, 39 and 56 in women from Western Mexico. With respect to the sociodemographic data, we found statistically significant differences in the number of pregnancies, the use of hormonal contraceptives and tobacco intake. CONCLUSIONS: Our data indicate that there is a high prevalence of HPV genotypes which are not covered by the vaccines currently available in Mexico; therefore, it is necessary to include HPVs 59, 66, 51, 39 and 56 in the design of future vaccines to reduce the risk of CC development. It is also essential to emphasize that the use of hormonal contraceptives and tobacco smoking are risk factors for CC development in addition to the presence of HPV.

Detection of Alpha, Beta, Gamma, and Unclassified Human Papillomaviruses in Cervical Cancer Samples From Mexican Women.

Background: Cervical cancer (CC) is associated to high-risk human papillomavirus (HPV) infections, for this reason it is crucial to have sensitive and accurate HPV diagnostic tests. To date, most research is focused on HPVs within the Alphapapillomavirus (α-PVs) genus and little attention has been paid to cervical infections with other HPV genotypes, like those of the Betapapillomavirus (ß-PVs) and Gammapapillomavirus (γ-PVs) genera. The aim of this study was to determine the HPV genotypes from different genera in women with CC using Next-Generation Sequencing (NGS). Methods: The study comprised 48 HPV positive CC samples evaluated with the Linear Array HPV Genotyping test and individually sequenced by 454 NGS using PGMY09/11 and FAP primers. To determine the HPV genotypes present in each sample, the obtained sequences were compared with all HPV L1 gene reference sequences from the Papillomavirus Episteme database (PaVE). Moreover, 50 HPV positive low-grade cervical lesion samples individually genotyped with NGS were also included to determine the genotypes present preferentially in CC patients. Results: Among the 48 CC samples, 68.75% consisted of multiple HPV infections, 51 different genotypes were detected, of which 7 are still unclassified, 28 belong to α-PVs (6, 11, 16, 18, 26, 30, 33, 35, 39, 42, 43, 44, 45, 51, 52, 53, 54, 59, 62, 66, 68, 69, 70, 71, 74, 81, 102, 114), 10 to ß-PVs (5, 12, 21, 37, 38b, 47, 80, 107, 118, 122), and 6 to γ-PVs (101, 103, 123, 135, 147, 214). Among them, HPV16 was the most prevalent genotype (54.2%), followed by HPV18 (16.7%), HPV38b (14.6%), and HPVs 52/62/80 (8.3%). Some genotypes were exclusively found in CC when compared with Cervical Intraepithelial Neoplasia grade 1 (CIN1) samples, such as HPVs 5, 18, 38b, 107, 122, FA39, FA116, mSK_120, and mSK_136. Conclusions: This work demonstrates the great diversity of HPV genotypes detected by combining PGMY and FAP primers with NGS in cervical swabs. The relatively high attribution of ß- and γ- PVs in CC samples suggest their possible role as carcinogenic cofactors, but deeper studies need to be performed to determine if they have transforming properties and the significance of HPV-coinfections.

Cranial nerve 13.

Contrary to popular belief, there are 13 cranial nerves. The thirteenth cranial nerve, commonly referred to as the nervus terminalis or terminal nerve, is a highly conserved multifaceted nerve found just above the olfactory bulbs in humans and most vertebrate species. In most forms its fibers course from the rostral portion of the brain to the olfactory and nasal epithelia. Although there are differing perspectives as to what constitutes this nerve, in most species GnRH-immunoreactive neurons appear to be its defining feature. The involvement of this trophic peptide, as well as the nerve's association with the development of the hypothalamic-pituitary-gonadal axis, suggest a primary role in reproductive development and, in humans, disorders such as Kallmann syndrome. In some species, this enigmatic nerve appears to influence sensory processing, sexual behavior, autonomic and vasomotor control, and pathogenic defense (via secretion of nitric oxide). In this review, we provide a general overview of what is known about this neglected cranial nerve, with the goal of informing neurologists and neuroscientists of its presence and the need for its further study.

E6/E7 and E6* From HPV16 and HPV18 Upregulate IL-6 Expression Independently of p53 in Keratinocytes.

Keratinocyte infection with high-risk human papillomavirus genotypes has been linked to cancer development. In cervix, the alpha HPV16 and HPV18 have been reported as the mayor causative agents of cervical cancer. Oncogenic progression and chronic inflammation are closely related processes, with IL-6 as one of the main pro-inflammatory cytokines involved. However, there are limited studies about the regulation of IL-6 by low and high risk HPVs and the HPV proteins implicated in this modulation. In this work, we report the overexpression of IL-6 in HPV infected cervical cancer derived cell lines (HeLa and SiHa) compared to non-tumorigenic keratinocytes (HaCaT), and in Cervical Intraepithelial Neoplasia grade 1 HPV16 and HPV18 positive cervical samples compared to HPV negative samples without lesions. Moreover, we generated HaCaT keratinocytes that express E5, E6, and E7 from high risk (16 or 18) or low risk (62 and 84) HPVs. E5 proteins do not modify IL-6 expression, while E7 modestly increase it. Interestingly, E6 proteins in HaCaT cells upregulate IL-6 mRNA expression and protein secretion. Indeed, in HaCaT cells that express high risk HPV16E6 or HPV18E6 proteins, only the truncated E6* isoforms were expressed, showing the stronger IL-6 overexpression, while in HaCaT cells that express low risk HPV62 and HPV84 full length E6 proteins, IL-6 was also upregulated but not so drastically. Since HaCaT cells have a mutated p53 form that is not degraded by the introduction of E6 or E6/E7, it seems that E6/E7 regulate IL-6 by an additional mechanism independent of p53. In addition, basal keratinocytes showed a strong expression of IL-6R using immunohistochemistry, suggesting an autocrine mechanism over proliferative cells. Altogether, IL-6 cytokine expression in keratinocytes is upregulated by E6 and E7 proteins from HPVs 16, 18, 62, and 84, especially by high risk HPV16 and HPV18 E6*, which may contribute to promote a pro-inflammatory and highly proliferative microenvironment that can persist over time and lead to cervical tumorigenesis.

Estudio comparativo in-vitro del selldo apical de tres cementos endodónticos / Comparative in-vitro study of apical sealing of three endodontic sealers

Una de las bases del éxito en el tratamiento de endo - doncia es realizar un buen sellado apical mediante la obturación hermética tridimensional del sistema de conductos radiculares. Objetivo: Evaluar si existe diferencia significativa en los resultados alcanzados en el sellado apical según el tipo de cemento utiliza - do Materiales y Métodos: Estudio cuasi-experimental, treinta dientes unirradiculares fueron instrumentados y obturados, se dividieron en tres grupos de diez, grupo I: resina epóxica, grupo II: hidróxido de cal- cio y grupo III: óxido de zinc y eugenol. Cada diente fue sellado coronalmente con ionómero de vidrio y se colocaron en suero fisiológico por 4 días; se im - permeabilizaron con 3 capas de esmalte de uñas sumergiéndolos en tinta china a 37ºC por 48 horas. Se realizó el proceso de diafanización para evaluar el nivel de filtración de la tinta china a nivel apical. El análisis inferencial fue realizado con ANOVA unifac- torial, y la prueba post hoc de Games- Howell para evaluar entre que cementos utilizados existían dife- rencias significativas. Resultados: La media de filtra - ción apical fue: 0.1mm utilizando cementos a base de resina epóxica, 0.4mm con el cemento a base de hidróxido de calcio y 1.5mm con el cemento de óxi- do de zinc y eugenol. La prueba de ANOVA unifac- torial, indica que hay diferencias significativas en la filtración de los dientes, según el cemento utilizado (p < 0.1) Conclusión: El cemento a base de resi- na epóxica presenta mejores propiedades de sella - do apical en comparación a los cementos a base de óxido de zinc y eugenol e hidróxido de calcio...(AU)

Neuroprotective effects of the immunomodulatory drug FK506 in a model of HIV1-gp120 neurotoxicity.

BACKGROUND: HIV-associated neurocognitive disorders (HAND) continue to be a common morbidity associated with chronic HIV infection. It has been shown that HIV proteins (e.g., gp120) released from infected microglial/macrophage cells can cause neuronal damage by triggering inflammation and oxidative stress, activating aberrant kinase pathways, and by disrupting mitochondrial function and biogenesis. Previous studies have shown that FK506, an immunophilin ligand that modulates inflammation and mitochondrial function and inhibits calcineurin, is capable of rescuing the neurodegenerative pathology in models of Parkinson's disease, Alzheimer's disease, and Huntington's disease. In this context, the main objective of this study was to evaluate if FK506 could rescue the neuronal degeneration and mitochondrial alterations in a transgenic (tg) animal model of HIV1-gp120 neurotoxicity. METHODS: GFAP-gp120 tg mice were treated with FK506 and analyzed for neuropathology, behavior, mitochondrial markers, and calcium flux by two-photon microscopy. RESULTS: We found that FK506 reduced the neuronal cell loss and neuro-inflammation in the gp120 tg mice. Moreover, while vehicle-treated gp120 tg mice displayed damaged mitochondria and increased neuro-inflammatory markers, FK506 rescued the morphological mitochondrial alterations and neuro-inflammation while increasing levels of optic atrophy 1 and mitofusin 1. By two-photon microscopy, calcium levels were not affected in the gp120 tg mice and no effects of FK506 were detected. However, at a functional level, FK506 ameliorated the gp120 tg mice hyperactivity in the open field. CONCLUSIONS: Together, these results suggest that FK506 might be potentially neuroprotective in patients with HAND by mitigating inflammation and mitochondrial alterations.

Human papillomavirus detection from human immunodeficiency virus-infected Colombian women's paired urine and cervical samples.

Infection, coinfection and type-specific human papillomavirus (HPV) distribution was evaluated in human immunodeficiency virus (HIV)-positive women from paired cervical and urine samples. Paired cervical and urine samples (n = 204) were taken from HIV-positive women for identifying HPV-DNA presence by using polymerase chain reaction (PCR) with three generic primer sets (GP5+/6+, MY09/11 and pU1M/2R). HPV-positive samples were typed for six high-risk HPV (HR-HPV) (HPV-16, -18, -31, -33, -45 and -58) and two low-risk (LR-HPV) (HPV-6/11) types. Agreement between paired sample results and diagnostic performance was evaluated. HPV infection prevalence was 70.6% in cervical and 63.2% in urine samples. HPV-16 was the most prevalent HPV type in both types of sample (66.7% in cervical samples and 62.0% in urine) followed by HPV-31(47.2%) in cervical samples and HPV-58 (35.7%) in urine samples. There was 55.4% coinfection (infection by more than one type of HPV) in cervical samples and 40.2% in urine samples. Abnormal Papanicolau smears were observed in 25.3% of the women, presenting significant association with HPV-DNA being identified in urine samples. There was poor agreement of cervical and urine sample results in generic and type-specific detection of HPV. Urine samples provided the best diagnosis when taking cytological findings as reference. In conclusion including urine samples could be a good strategy for ensuring adherence to screening programs aimed at reducing the impact of cervical cancer, since this sample is easy to obtain and showed good diagnostic performance.

Javier Brandam y los orígenes del Hospital Psiquiátrico de San Luis / Javier Brandan and the origins of the Psychiatric Hospital of San Luis

El presente trabajo, que constituye el primer relevamiento de fuentes sobre el tema, indaga los orígenes del Hospital Psiquiátrico en San Luis. En primer lugar, se enmarca la creación de la institución, y las razones de la misma en el contexto del movimiento de la higiene mental y del desarrollo de la psiquiatría en el país, aún cuando persistieran vestigios de modelos alienistas de mayor antigüedad. En segundo lugar, se analiza la figura del primer director y organizador de tal institución, Javier Brandam, psiquiatra reconocido a nivel nacional, quien fuera profesor de Psiquiatría en la Universidad de Buenos Aires

Javier Brandam y los orígenes del Hospital Psiquiátrico de San Luis / Javier Brandan and the origins of the Psychiatric Hospital of San Luis

El presente trabajo, que constituye el primer relevamiento de fuentes sobre el tema, indaga los orígenes del Hospital Psiquiátrico en San Luis. En primer lugar, se enmarca la creación de la institución, y las razones de la misma en el contexto del movimiento de la higiene mental y del desarrollo de la psiquiatría en el país, aún cuando persistieran vestigios de modelos alienistas de mayor antig³edad. En segundo lugar, se analiza la figura del primer director y organizador de tal institución, Javier Brandam, psiquiatra reconocido a nivel nacional, quien fuera profesor de Psiquiatría en la Universidad de Buenos Aires

Javier Brandam y las orígenes del Hospital Psiquiatrico de San Luis / Javier Branam and the origins of the Psychiatric Hospital of San Luis

Indaga las origenes del Hospital Psiquiatrico en San Luis. En primer lugar, se emmarca la creación de la institución, y las razones de la misma en el contexto del movimiento de la higiene mental y del desarrollo de la psiquiatria en el país, aun cuando persistieran vestigios de modelos alienistas de mayor antiguedad. En segundo lugar, se analiza la figura del primer director y organizador de tal institución, Javier Bramdam, psiquiatra reconocido a nivel nacional, quien fuera profesor de Psiquiatria en la Universidad de Buenos Aires. (AU)