Kaposi Sarcoma Mimicking a Lingual Lesion in an HIV-Negative Patient: A Case Report.

Tonsillar Kaposi sarcoma is rare, reported in patients with human immunodeficiency virus (HIV) infection. This case report of a tonsillar Kaposi sarcoma (KS) in an HIV-negative male patient, initially misinterpreted as a lingual lesion diagnosed with KS following tonsillectomy, highlights the value of a differential diagnosis in atypical presentations. The case report discusses the etiologic agent of KS, its detection and treatment, and a few case reports about tonsillar KS with no association with AIDS. The case underscores the diagnostic challenge of oropharyngeal lesions, particularly in patients with risk factors but negative HIV status.

Etiology, risk factors, treatments and current status of Alzheimer's disease in Mexico.

Alzheimer's disease is a neurodegenerative disorder whose etiology continues to be discussed, to the point that there are different hypotheses that seek to clarify it, in addition to the fact that, given its multifactorial nature, there are different risk factors associated with its development. As regards diagnosis, advances in molecule detection techniques at femtomolar scales have allowed to distinguish between healthy and diseased subjects at relatively early stages, although there is still much to be done. Aducanumab is a monoclonal antibody targeted against Aß, whose marketing approval by the Food and Drug Administration has been questioned by the international medical community, given the controversial results in clinical trials. Approval of this antibody as a disease-modifying treatment for Alzheimer's disease opens the door to continue using this type of treatments, but with different therapeutic targets, such as, for example, tau protein. Finally, given the population tendency towards longevity, conditions such as Alzheimer's disease are gaining epidemiological importance, which is why it is imperative to analyze and link what is being done in the social, familiar, clinical and research fields and, most importantly, to find those areas of opportunity for the benefit of the patient.

La enfermedad de Alzheimer es un desorden neurodegenerativo cuya etiología aún se discute, al punto de que existen diferentes hipótesis que pretenden esclarecerla; además, dada su naturaleza multifactorial, existen diferentes factores de riesgo asociados a su desarrollo. Respecto al diagnóstico, los avances en las técnicas de detección de moléculas a escalas femtomolares han permitido discernir entre sujetos sanos y enfermos en estadios relativamente tempranos, aunque todavía hay mucho por hacer. Aducanumab es un anticuerpo monoclonal dirigido contra Aß, cuya aprobación por parte de la Food and Drug Administration para comercializarse ha sido cuestionada por la comunidad médica internacional, dados los resultados controversiales en los ensayos clínicos. La aprobación de este anticuerpo como tratamiento modificador de la enfermedad de Alzheimer abre la puerta para seguir utilizando este tipo de tratamientos, pero con blancos terapéuticos diferentes, como, por ejemplo, la proteína tau. Finalmente, dada la tendencia de la población hacia la longevidad, padecimientos como la enfermedad de Alzheimer están tomando importancia epidemiológica, por lo que resulta imperativo analizar y vincular lo que se está haciendo en los ámbitos social, familiar, clínico y de investigación y, sobre todo, encontrar esas áreas de oportunidad en beneficio del paciente.

Etiología, factores de riesgo, tratamientos y situación actual de la enfermedad de Alzheimer en México / Etiology, risk factors, treatments and current status of Alzheimer's disease in Mexico

Resumen La enfermedad de Alzheimer es un desorden neurodegenerativo cuya etiología aún se discute, al punto de que existen diferentes hipótesis que pretenden esclarecerla; además, dada su naturaleza multifactorial, existen diferentes factores de riesgo asociados a su desarrollo. Respecto al diagnóstico, los avances en las técnicas de detección de moléculas a escalas femtomolares han permitido discernir entre sujetos sanos y enfermos en estadios relativamente tempranos, aunque todavía hay mucho por hacer. Aducanumab es un anticuerpo monoclonal dirigido contra Aβ, cuya aprobación por parte de la Food and Drug Administration para comercializarse ha sido cuestionada por la comunidad médica internacional, dados los resultados controversiales en los ensayos clínicos. La aprobación de este anticuerpo como tratamiento modificador de la enfermedad de Alzheimer abre la puerta para seguir utilizando este tipo de tratamientos, pero con blancos terapéuticos diferentes, como, por ejemplo, la proteína tau. Finalmente, dada la tendencia de la población hacia la longevidad, padecimientos como la enfermedad de Alzheimer están tomando importancia epidemiológica, por lo que resulta imperativo analizar y vincular lo que se está haciendo en los ámbitos social, familiar, clínico y de investigación y, sobre todo, encontrar esas áreas de oportunidad en beneficio del paciente.

Abstract Alzheimer's disease is a neurodegenerative disorder whose etiology continues to be discussed, to the point that there are different hypotheses that seek to clarify it, in addition to the fact that, given its multifactorial nature, there are different risk factors associated with its development. As regards diagnosis, advances in molecule detection techniques at femtomolar scales have allowed to distinguish between healthy and diseased subjects at relatively early stages, although there is still much to be done. Aducanumab is a monoclonal antibody targeted against Aβ, whose marketing approval by the Food and Drug Administration has been questioned by the international medical community, given the controversial results in clinical trials. Approval of this antibody as a disease-modifying treatment for Alzheimer's disease opens the door to continue using this type of treatments, but with different therapeutic targets, such as, for example, tau protein. Finally, given the population tendency towards longevity, conditions such as Alzheimer's disease are gaining epidemiological importance, which is why it is imperative to analyze and link what is being done in the social, familiar, clinical and research fields and, most importantly, to find those areas of opportunity for the benefit of the patient.

Autophagy: A Key Regulator of Homeostasis and Disease: An Overview of Molecular Mechanisms and Modulators.

Autophagy is a highly conserved lysosomal degradation pathway active at basal levels in all cells. However, under stress conditions, such as a lack of nutrients or trophic factors, it works as a survival mechanism that allows the generation of metabolic precursors for the proper functioning of the cells until the nutrients are available. Neurons, as post-mitotic cells, depend largely on autophagy to maintain cell homeostasis to get rid of damaged and/or old organelles and misfolded or aggregated proteins. Therefore, the dysfunction of this process contributes to the pathologies of many human diseases. Furthermore, autophagy is highly active during differentiation and development. In this review, we describe the current knowledge of the different pathways, molecular mechanisms, factors that induce it, and the regulation of mammalian autophagy. We also discuss its relevant role in development and disease. Finally, here we summarize several investigations demonstrating that autophagic abnormalities have been considered the underlying reasons for many human diseases, including liver disease, cardiovascular, cerebrovascular diseases, neurodegenerative diseases, neoplastic diseases, cancers, and, more recently, infectious diseases, such as SARS-CoV-2 caused COVID-19 disease.

Biomarker Candidates for Alzheimer's Disease Unraveled through In Silico Differential Gene Expression Analysis.

Alzheimer's disease (AD) is neurodegeneration that accounts for 60-70% of dementia cases. Symptoms begin with mild memory difficulties and evolve towards cognitive impairment. The underlying risk factors remain primarily unclear for this heterogeneous disorder. Bioinformatics is a relevant research tool that allows for identifying several pathways related to AD. Open-access databases of RNA microarrays from the peripheral blood and brain of AD patients were analyzed after background correction and data normalization; the Limma package was used for differential expression analysis (DEA) through statistical R programming language. Data were corrected with the Benjamini and Hochberg approach, and genes with p-values equal to or less than 0.05 were considered to be significant. The direction of the change in gene expression was determined by its variation in the log2-fold change between healthy controls and patients. We performed the functional enrichment analysis of GO using goana and topGO-Limma. The functional enrichment analysis of DEGs showed upregulated (UR) pathways: behavior, nervous systems process, postsynapses, enzyme binding; downregulated (DR) were cellular component organization, RNA metabolic process, and signal transduction. Lastly, the intersection of DEGs in the three databases showed eight shared genes between brain and blood, with potential use as AD biomarkers for blood tests.

Analyzing Olfactory Neuron Precursors Non-Invasively Isolated through NADH FLIM as a Potential Tool to Study Oxidative Stress in Alzheimer's Disease.

Among all the proposed pathogenic mechanisms to understand the etiology of Alzheimer's disease (AD), increased oxidative stress seems to be a robust and early disease feature where many of those hypotheses converge. However, despite the significant lines of evidence accumulated, an effective diagnosis and treatment of AD are not yet available. This limitation might be partially explained by the use of cellular and animal models that recapitulate partial aspects of the disease and do not account for the particular biology of patients. As such, cultures of patient-derived cells of peripheral origin may provide a convenient solution for this problem. Peripheral cells of neuronal lineage such as olfactory neuronal precursors (ONPs) can be easily cultured through non-invasive isolation, reproducing AD-related oxidative stress. Interestingly, the autofluorescence of key metabolic cofactors such as reduced nicotinamide adenine dinucleotide (NADH) can be highly correlated with the oxidative state and antioxidant capacity of cells in a non-destructive and label-free manner. In particular, imaging NADH through fluorescence lifetime imaging microscopy (FLIM) has greatly improved the sensitivity in detecting oxidative shifts with minimal intervention to cell physiology. Here, we discuss the translational potential of analyzing patient-derived ONPs non-invasively isolated through NADH FLIM to reveal AD-related oxidative stress. We believe this approach may potentially accelerate the discovery of effective antioxidant therapies and contribute to early diagnosis and personalized monitoring of this devastating disease.

Expression of Pregnancy Specific ß-1 Glycoprotein 1 in Cervical Cancer Cells.

BACKGROUND: Cervical Cancer (CC) is a worldwide public health concern associated with genetic alterations, among these the gain of the 19q chromosome harboring the Pregnancy Specific Glycoproteins (PSG) gene family. These proteins play a critical role in pregnancy, with participation in immunotolerance, angiogenesis, and invasion processes, which are also observed in carcinogenesis. The aim of this study was to determine the molecular alterations of PSG1 and its relationship with CC. METHODS: PSG1 Copy Number Variation (CNV) was evaluated in 31 CC and eight normal cervical tissues by qPCR. PSG1 expression was correlated with HPV detection and IL-10 and TGF-ß expression in CC samples. Finally, PSG1 protein expression was evaluated by immunofluorescence in CC cell lines, by immunohistochemistry in a tissue microarray, and by immunoblotting in the sera of women with normal cervix, pre-invasive lesions, and CC. RESULTS: PSG1 showed a gain of 25.6% in CNV and gene expression in CC. There was a lack of PSG1 expression in normal cervical epithelium and positive immunostaining in 57% of CC tissues, while all CC cell lines expressed PSG1. Finally, PSG1 was immunodetected in 90% of pre-invasive lesions and in all CC serum samples, but not in healthy women. PSG1 expression correlates with the expression of IL-10 and TGF-ß in CC tissues, but not with the presence of HPV. CONCLUSION: These data show evidence of the differential expression of PSG1 in CC that could explain its participation in tumor-biology and immunotolerance mechanisms. Further, its immunodetection could provide early detection of this cancer.

Krüppel-Like Factor 10 participates in cervical cancer immunoediting through transcriptional regulation of Pregnancy-Specific Beta-1 Glycoproteins.

Cervical cancer (CC) is associated with alterations in immune system balance, which is primarily due to a shift from Th1 to Th2 and the unbalance of Th17/Treg cells. Using in silico DNA copy number analysis, we have demonstrated that ~20% of CC samples exhibit gain of 8q22.3 and 19q13.31; the regions of the genome that encodes the KLF10 and PSG genes, respectively. Gene expression studies demonstrated that there were no alterations in KLF10 mRNA expression, whilst the PSG2 and -5 genes were up-regulated by 1.76 and 3.97-fold respectively in CC compared to normal tissue controls. siRNA and ChIP experiments in SiHa cells have demonstrated that KLF10 participates in immune response through regulation of IL6, IL25 and PSG2 and PSG5 genes. Using cervical tissues from KLF10-/- mice, we have identified down-regulation of PSG17, -21 and -23 and IL11. These results suggest that KLF10 may regulate immune system response genes in cervical cancer among other functions. KLF10 and PSG copy number variations and alterations in mRNA expression levels could represent novel molecular markers in CC.

The KISS1 gene overexpression as a potential molecular marker for cervical cancer cells.

BACKGROUND: Similarities between the pathologic progression of cancer and the physiologic process of placentation have been recognized for many years proposing that both present similar mechanisms and processes. Cervical cancer (CC) is one of the most frequent neoplasia among Mexican women turning it into an important health problem. OBJECTIVE: The aim of this study was to determine the degree of the involvement of pregnancy related genes and in cancer progression by in-silico analysis and validated in CC samples. RESULTS: The data mining analysis resulted in the identification of genes expressed in term placenta, first trimester placenta and normal cervical tissues. Finally, we selected KISS1 for the involvement of pregnancy related gene and also in cancer process. In order to explore KISS1 in CC, we analyzed Copy Number Variation (CNV) and gene expression using microarray experiments. KISS1 showed 20% genomic gain in 1q32.1 on CC samples. Furthermore, microarray analysis showed KISS1 as up-regulated genes. Results were validated showing an overexpression of 85% of KISS1 in CC samples. CONCLUSIONS: Data suggest KISS1 as a great candidate for CC molecular markers or as a therapeutic target for CC. Also, HPV presence does not seem to alter the KISS1 expression in CC.

Soluble Factors from Human Olfactory Neural Stem/Progenitor Cells Influence the Fate Decisions of Hippocampal Neural Precursor Cells.

Neurogenesis plays a significant role during adulthood, and the observation that neural stem cells reside in the central nervous system and the olfactory epithelium has attracted attention due to their importance in neuronal regeneration. In addition, soluble factors (SFs) release by neural stem cells may modulate the neurogenic process. Thus, in this study, we identified the SFs released by olfactory human neural stem/progenitor cells (hNS/PCs-OE). These cells express Ki67, nestin, and ßIII-tubulin, indicating their neural lineage. The hNS/PCs-OE also express PSD95 and tau proteins during proliferation, but increased levels are observed after differentiation. Thus, we evaluated the effects of SFs from hNS/PCs-OE on the viability, proliferation, and differentiation potential of adult murine hippocampal neural precursor cells (AHPCs). SFs from hNS/PCs-OE maintain cells in the precursor and proliferative stages and mainly promote the astrocytic differentiation of AHPCs. These effects involved the activation, as measured by phosphorylation, of several proteins (Erk1/2; Akt/PRAS40/GSK3ß and JAK/STAT) involved in key events of the neurogenic process. Moreover, according to the results from the antibody-based microarray approach, among the soluble factors, hNS/PCs-OE produce interleukin-6 (IL-6) and neurotrophin 4 (NT4). However, residual epidermal growth factor (EGF) was also detected. These proteins partially reproduced the effects of SFs from hNS/PCs-OE on AHPCs, and the mechanism underlying these effects is mediated by Src proteins, which have been implicated in EGF-induced transactivation of TrkB receptor. The results of the present study suggest the potential use of SFs from hNS/PCs-OE in controlling the differentiation potential of AHPCs. Thus, the potential clinical relevance of hNS/PCs-OE is worth pursuing.

Interferon epsilon mRNA expression could represent a potential molecular marker in cervical cancer.

The effects of the immune system response in the malignant transformation process have been described. Molecules such as interferons are involved in such process. Interferons are small single-chained glycoproteins, involved in the first line of defense against pathogens such as viruses, bacteria, and parasites. Interferon epsilon (IFNε) is located in the 9p21.3 cytogenetic region, transcribes into a single exon mRNA. Contrary to other family members, IFNε exerts low antiviral activity. In the present work molecular alterations such as copy number variation (CNV) and expression were analyzed by available microarrays and fifty-nine cervical tissues ranging from normal to cancer and three cell lines were assessed for IFNε expression by RT-PCR, immunohistochemistry, and immunocytofluorescence. No significant CNV alterations were observed. Positive immunosignal was primarily present in the proliferative basal strata cells in the normal tissue, whereas in cervical cancer, all epithelial transformed cells were positive. The cell lines analyzed were HPV16, -18, and negative, all three cell-lines were positive for cytoplasmic protein presence. Interestingly, at the mRNA level, increased band intensity was observed, as the lesions were higher, and IFNε up-regulation in CC (P=0.0001) is reported here. Our results suggest that up-regulation is present as an independent event from single or multiple HPV infection (P=0.90). In conclusion, we suggest that IFNε mRNA up-regulation could represent a potential molecular marker in CC. Expression of IFNε might not be related to HPV infection or CNV, which could have an important role in cellular homeostasis and could influence immune related events in cervical carcinogenesis.

Krüppel Like Factors Family Expression in Cervical Cancer Cells.

BACKGROUND AND AIMS: Krüppel Like Factors (KLF) refers to a family of seventeen members of transcription factors. Involved in several cellular processes. As other cancer types, Cervical Cancer (CC) presents molecular deregulations in transcription factors, but especially Human Papilloma Virus (HPV) sequences. Here in this work we analyzed the mRNA expression of all KLF family members in CC-derived cell lines and CC tissues. METHODS: The cell lines used were HeLa, INBL, RoVa, C4-I, Ms751, ViPa, CaLo, SiHa, CaSki, C33a and ViBo and the non-tumorigenic HaCaT. mRNA expression was analyzed by means of expression microarray and RT-PCR, and KLF5 protein by immunofluorescence. RESULTS: The cell lines were grouped according to HPV genotype as HPV16, HPV18 positive or HPV negative cells. Heterogeneous expression was observed among the cell lines. Despite the heterogeneous expression profile, KLF3, -5, -12, -15 and -16 transcripts were present in all cell lines, KLF4 and -10 which were not expressed in CaSki; KLF11 and 13 were not expressed by Vipa and C4-I, and KLF7 was not expressed by C4-I and Rova. The CC tissue analysis shows expression of most of the KLF members, such as KLF5. KLF5 immunosignal was positive in the three cell lines analyzed. CONCLUSIONS: We suggest that KLF expression could not be related to HPV presence/genotype, at least at transcriptional level, and the expression of KLF family members may be necessary in the biology of the CC cells.

The role of tau oligomers in the onset of Alzheimer's disease neuropathology.

Most neurodegenerative diseases are characterized by the presence of protein aggregates. Alzheimer's disease (AD) is the most common cause of dementia in people over age 60. One of the histopathological hallmarks of AD is the presence of tau protein aggregates. Historically, it has been thought that paired helical filaments (PHFs) were the toxic form of tau that assembled to form neurofibrillary tangles (NFTs), but recently there has been evidence that tau oligomers, which form before PHFs and NFTs, could be the structures mediating neurodegeneration even before the fibrillary tau is deposited. Here, we discuss the recent advances in tau oligomer research, their implications on AD and other tauopathies, the mechanisms of tau turnover by the principal protein clearance systems (the proteasome and autophagy), and the potential use of tau oligomers as drug targets for the development of new therapeutic approaches.

Las zonas neurogénicas en el adulto y su relación con las enfermedades neuropsiquiátricas / Neurogenic regions in the adult: Relationship with the neuropsychiatric disorders

Neuropsychiatric diseases (NPD) are characterized by changes in brain plasticity involving alterations in the morphology and functionality of neurons. However, affectations of the neuronal development (neurogenesis) in the adult brain are also shown. The neurogenic process is widely regulated by different factors such as genes, microenvironment, hormones, neurotransmitters, environmental cues and, also, nutrition. Thus, alterations in these factors negatively impact the neuronal development. Several studies performed in humans have revealed alterations of neurogenesis in NPD. However, most of the knowledge derives from studies done in animal models of NPD. The evidences from animal models are controversial, thus the use of human-induced pluripotent stem cells as a model of NPD has marked a way to study alterations in the neuronal development. Recently, the use of another cellular model for studying NPD has been proposed. Multipotent stem cells derived from olfactory epithelium (MOESCs) are a good candidate. However, evidences are scarce and deeper studies are necessary to know if there is or not a correlation of alterations in neuronal development in the OE with the changes observed in the brain; or if the MOESCs can mimic alterations shown in NPD that could let to get more knowledge about the factors promoting these diseases. Thus, in this review we discuss basic information about adult neurogenesis under physiological and non-physiological conditions in the hippocampus, olfactory bulb and olfactory epithelium.

Las enfermedades neuropsiquiátricas (ENP) se caracterizan por cambios en la plasticidad cerebral que incluyen la pérdida neuronal en regiones específicas en el encéfalo, cambios en la transmisión sináptica originada por alteraciones en los contactos sinápticos y también por la expresión de genes. Además, otro proceso que forma parte de la plasticidad cerebral y que también se encuentra afectado en las ENP es la generación de nuevas neuronas (neurogénesis). El proceso neurogénico en el adulto es regulado de manera fina por diversos factores como los aspectos genéticos, celulares, el microambiente, los elementos neuroquímicos, los ambientales y los nutricionales. Las alteraciones de estos factores impactan en el desarrollo y en la función de las nuevas neuronas. Algunos estudios realizados en humanos han revelado las alteraciones en la neurogénesis en algunos ENP. Sin embargo los mayores avances logrados han utilizado modelos animales de ENP. En algunos casos estas evidencias son controvertidas y recientemente se han tratado de aclarar utilizando cultivos de células madre pluripotenciales-inducibles humanas como modelos de ENP. Otro modelo que se ha propuesto para estudiar las alteraciones en el desarrollo neuronal en las ENP son las células madre multipotenciales del epitelio olfatorio (CMPEO). Sin embargo las evidencias obtenidas con las CMPEO son escasas y resulta necesario demostrar si existe o no un correlato con las alteraciones que ocurren en el desarrollo neuronal a nivel central en las ENP, o bien si las CMPEO pueden mostrar las alteraciones observadas en las ENP que permitan obtener información acerca de los factores que promueven estas enfermedades. Por lo tanto en esta revisión se incluyen aspectos básicos de la neurogénesis e información relevante de las alteraciones de este proceso en las tres regiones neurogénicas en el adulto: el hipocampo, el bulbo olfatorio y el epitelio olfatorio.