Role of collagen and immunostaining for TGF-β in the clinical andmicroscopic findings of pyogenic granuloma and peripheral ossifying fibroma

Background: Collagen is a component of Pyogenic Granuloma (PG) and Peripheral Ossifying Fibroma (POF) and performs different functions in these lesions. The objective of this study is to evaluate the role of collagen and immunostaining for Transforming Growth Factor beta (TGF-β) in the clinical and microscopic findings of PG and POF. Material and Methods: PG (n=20) and POF (n=20) were selected for clinical evaluation (sex, age, localization, size and evolution time) and microscopic analysis (picrosirius red staining for collagen analysis and immunohistochemistry for TGF-β) performed in the superficial and deep areas of the two lesions. ANOVA/Bonferroni and t-test, Pearson correlation and χ2 were used to compare the sites and parameters analyzed (p<0.05, GraphPad Prism 5.0). Results: The depth of PG presented the highest amount of collagen (p<0.001), and its surface showed the lowest amount of type 1 collagen (yellow-red strong birefringence). Type 1 collagen gradually increased in depth of PG, surface and depth of POF (p<0.001). The number of TGF-β+ cells was lower on the surface of PG compared with the depth of PG and the two areas of POF (p<0.001). Sex and localization did not affect these parameters, but the profile of collagen and immunostaining for TGF-β suffered from modifications by the time of evolution and the size of the lesion. Conclusions: Although PG and POF are reactive gingival lesions, the expression of TGF-β and its role in collagen showed different biological behaviors in these lesions, suggesting different biological origins for its components. (AU)

Bodas de plata: 25 años de la primera demostración del efecto directo del fósforo en la célula paratiroidea / Silver jubilee: 25 years of the first demonstration of the direct effect of phosphate on the parathyroid cell

Aunque el fósforo es un elemento indispensable para la vida, en la naturaleza no se encuentra en estado nativo sino combinado en forma de fosfatos inorgánicos (PO43−), con niveles plasmáticos estrechamente regulados que se asocian a efectos deletéreos y mortalidad cuando estos se encuentran fuera de la normalidad. El interés creciente sobre el acúmulo de PO43− en la fisiopatología humana se originó en el papel que se le atribuyó en la patogenia del hiperparatiroidismo secundario a la enfermedad renal crónica. En este artículo revisamos los mecanismos por los cuales se justificaba dicho efecto y conmemoramos la importante contribución de un grupo español liderado por el Dr. M. Rodríguez, ahora hace justo 25 años, cuando demostraron por primera vez el efecto directo del PO43− sobre la regulación de la síntesis y secreción de hormona paratiroidea (manteniendo la integridad estructural de las glándulas paratiroides en su nuevo modelo experimental. Además de demostrar la importancia del ácido araquidónico (AA) y la vía de la fosfolipasa A2-AA como mediadora de respuestas en la glándula paratiroidea, estos hallazgos fueron predecesores de la reciente descripción del importante papel del PO43− sobre la actividad del receptor-sensor de calcio y alimentaron asimismo diversas líneas de investigación sobre la importancia de la sobrecarga de PO43−, no solo en la fisiopatología del hiperparatiroidismo secundario sino también en su papel patogénico sistémico. (AU)

Although phosphorus is an essential element for life, it is not found in nature in its native state but rather combined in the form of inorganic phosphates (PO43−), with tightly regulated plasma levels that are associated with deleterious effects and mortality when these are out of bounds. The growing interest in the accumulation of PO43− in human pathophysiology originated in its attributed role in the pathogenesis of secondary hyperparathyroidism in chronic kidney disease. In this article, we review the mechanisms by which this effect was justified and we commemorate the important contribution of a Spanish group led by Dr. M. Rodríguez, just 25 years ago, when they first demonstrated the direct effect of PO43− on the regulation of the synthesis and secretion of parathyroid hormone by maintaining the structural integrity of the parathyroid glands in their original experimental model. In addition to demonstrating the importance of arachidonic acid (AA) and the phospholipase A2-AA pathway as a mediator of parathyroid gland response, these findings were predecessors of the recent description of the important role of PO43− on the activity of the calcium sensor-receptor, and also fueled various lines of research on the importance of PO43− overload not only for the pathophysiology of secondary hyperparathyroidism but also of its systemic pathogenic role. (AU)

The peri- and intratumoral immune cell infiltrate and PD-L1 status in invasive squamous cell carcinomas of the penis

IntroductionPenile carcinomas are rare tumors throughout Europe. Therefore, little attention is drawn to this disease. That makes it important to study tumor-associated key metrics and relate these to known data on penile neoplasias.Materials and methodsA cohort of 60 well-defined penile invasive carcinomas with known human papillomavirus (HPV) infection status was investigated. Data on tumor type, grading and staging were recorded. Additionally, data on the peri- and intratumoral immune cell infiltrate in a semiquanititave manner applying an HE stain were assessed.ResultsOur study showed a significant correlation of immune cell infiltrate and pT stage with overall survival. Therefore, in a subset of tumors, PD-L1 staining was applied. For tumor proportion score (TPS), 26 of 30 samples (87%) were scored >0%. For the immune cell score (IC), 28 of 30 samples (93%) were defined as >0% and for CPS, 29 of 30 samples (97%) scored >0. PD-L1 expression was not associated with overall survival.ConclusionPD-L1 is expressed in penile carcinomas, providing a rationale for targeted therapy with checkpoint inhibitors. We were able to show that immune reaction appears to be prognostically relevant. These data enhance the need for further studies on the immune cell infiltrate in penile neoplasias and show that PD-L1 expression is existent in our cohort, which may be a potential target for checkpoint inhibitor therapy.

Ferroptosis: an iron-dependent cell death form linking metabolism, diseases, immune cell and targeted therapy / Ferroptosis: una forma de muerte celular dependiente de hierro que vincula el metabolismo, las enfermedades, las células inmunitarias y la terapia dirigida

Compared with the traditional forms of cell death—apoptosis, necrosis and autophagy, ferroptosis is a novel form of iron-dependent programmed cell death forms which is different from the above traditional forms of cell death. Brent R Stockwell, a Professor of Columbia University, firstly proposed that this from of cell death was named ferroptosis in 2012. The main characteristics of ferroptosis is increasing iron loading and driving a lot of lipid peroxide generated and ultimately lead to cell death. In this paper, the mechanism of ferroptosis, relationship between ferroptosis and common diseases and immune state of body are reviewed, and the inhibitors and inducers related to ferroptosis that have been found are summarized to provide medicine exploration targeted of ferroptosis and reference for the research in the future.

The inverse paradigm and the ancestral cell of IDH-wildtype glioblastoma

Rethinking IDH-wildtype glioblastoma through its unique features can help researchers find innovative and effective treatments. It is currently emerging that, after decades of therapeutic impasse, some traditional concepts regarding IDH-wildtype glioblastoma need to be supplemented and updated to overcome therapeutic resistance. Indeed, multiple clinical aspects and recent indirect and direct experimental data are providing evidence that the supratentorial brain parenchyma becomes entirely and quiescently micro-infiltrated long before primary tumor bulk growth. Furthermore, they are indicating that the known micro-infiltration that occurs during the IDH-wildtype glioblastoma growth and evolution is not at the origin of distant relapses. It follows that the ubiquitous supratentorial brain parenchyma micro-infiltration as a source for the development of widespread distant recurrences is actually due to the silent stage that precedes tumor growth rather than to the latter. All this implies that, in addition to the heterogeneity of the primary bulk, there is a second crucial cause of therapeutic resistance that has never hitherto been identified and challenged. In this regard, the ancestral founder cancer stem cell (CSC) appears as the key cell that can link the two causes of resistance.

Isolated cancer stem cells from human liver cancer: morphological and functional characteristics in primary culture

BackgroundPrimary liver cancer cells (PLCs) could more directly simulate the human tumor microenvironment. Compared with liver cancer cell lines, PLCs could reflect the human situation. As in previous studies, tumor stem cells were a small number of cancer cells in the microenvironment and considered to be one of the origins of liver cancer. This study aimed to screen stem cells in PLCs, analyze their biological characteristics, propose the possibility that liver cancer originated from stem cells.MethodsLiver cancer tissues of 17 patients were taken from the Affiliated Hospital of Guangdong Medical College, and PLCs were isolated by tissue slice method. The proliferation, tumor formation in nude mice, stem protein expression of PLCs were observed. C-kit+ liver cancer cells were screened and their biological characteristics were analyzed.ResultsPLCs could be stably passaged. Transmission electron microscopy indicated that the nucleus was irregular, there were many mitochondria, and the endoplasmic reticulum was irregularly distributed. PLCs could express E-Cadherin, Oct-4, β-Catenin, Sox2, CD326, C-kit, GPC3, Nanog. The proliferation curve of PLCs and Hep3B cells were similar, and they all could form tumors in nude mice. Flow-sorted C-kit+ PLCs, as well as C-kit+ Hep3B cells could highly express Bmi1, Sox2, Oct4, Notch1, Nanog, C-kit, β-Catenin, Smo, Nestin, ABCG2, ABCB1. And they also could clone and form tumors in vivo. But C-kit+ PLCs were more sensitive to chemotherapy drugs than C-kit+ liver cancer cell lines.ConclusionC-kit+ PLCs had the characteristics of tumor stem cells and were more sensitive to chemotherapy drugs.

Examination of cytological smears and cell blocks of pleural fluid: Complementary diagnostic value for malignant effusions / Examen del frotis citológico y bloque celular del líquido pleural: valor diagnóstico complementario en los derrames malignos

Objectives. To evaluate the independent usefulness of pleural fluid smear and cell block (CB) preparations for the diagnosis of malignant effusions. Patients and methods. A total of 632 cytological smears and 554 CBs from 414 consecutive patients with malignant effusions were retrospectively evaluated. Results. The diagnostic yield of a first specimen was 44% regardless of whether a smear or CB cytologic examination was performed. The use of subsequent separated specimens increased the identification of malignancy to 56%. Overall, 11% of samples found to be negative by cytologic smears showed malignant cells on CBs, whereas 15% of negative CBs were reported as positive on smear slides. Pleural fluid specimens with low red and/or white blood cell counts more frequently resulted in the generation of suboptimal CB preparations. Conclusions. If CBs and smears are prepared and examined, the percentage of positive diagnoses will be greater than if only one method is used (AU)

Objetivos. Evaluar la utilidad independiente de frotis y bloques celulares (BC) del líquido pleural para diagnosticar derrames malignos. Pacientes y métodos. Se evaluaron retrospectivamente un total de 632 frotis citológicos y 554 BC de 414 pacientes consecutivos con derrame pleural maligno. Resultados. La sensibilidad diagnóstica de una primera muestra fue del 44%, tanto en frotis como en BC. El análisis de muestras separadas ulteriores aumentó al 56% la identificación de derrames malignos. Globalmente, el 11% de muestras negativas mediante frotis mostraron células malignas en los BC, mientras que el 15% de BC negativos resultaron positivos en el estudio del frotis. Los líquidos pleurales con recuentos bajos de hematíes o leucocitos produjeron con mayor frecuencia BC insuficientes para diagnóstico. Conclusiones. Si se evalúan frotis y BC, el porcentaje de resultados positivos es superior que si se emplean estas técnicas de forma aislada (AU)

An adult case of systemic Epstein-Barr virus-positive T-cell lymphoproliferative disorder with severe hepatic dysfunction and megalosplenia

Epstein-Barr virus-positive T/NK-cell lymphoproliferative disorder (EBV+T/NK-LPD) is a continuous spectrum of diseases that share a common feature observed in T cells and NK cells: Excessive lymphoid proliferation. This disease is rare in adults and predominantly affects children with high mortality. Herein, we present a case of EBV+T-LPD that occurred in an adult with clinical manifestations of hepatic dysfunction and megalosplenia. The patient received a splenectomy at a local hospital for the treatment of megalosplenia. Before surgery, she exhibited mild hepatomegaly and normal liver function. However, after the operation, abdominal computed tomography (CT) showed obvious hepatomegaly and severely damaged liver function. After a final diagnosis of EBV+TLPD at our hospital, the patient received combination therapy with antiviral and immunosuppressive agents. At the 4-month follow-up visit, hepatic function was normal and the size of the liver decreased. Because this patient presented with hepatomegaly before the splenectomy and because hepatic dysfunction rapidly progressed after surgery, an early diagnosis of EBV+T-LPD was crucial. Splenectomy may be recommended before liver involvement to reduce negative postoperative effects on the liver (AU)

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Sirolimus, una opción terapéutica en la linfangioleiomiomatosis / No disponible

La linfangioleiomiomatosis (LAM) es una enfermedad rara que se caracteriza por la proliferación anormal de células musculares lisas atípicas (células LAM) que condicionan la destrucción del parénquima pulmonar con formación de quistes. A pesar de que el trasplante pulmonar se considera la única opción terapéutica cuando la enfermedad progresa, ensayos clínicos recientes muestran que el tratamiento con sirolimus, fármaco inhibidor de mTOR (mammalian target of rapamycin), puede tener un efecto beneficioso sobre la función pulmonar y la reducción del tamaño de los angiomiolipomas renales que se asocian a la LAM. Presentamos el caso de una mujer de 20 años, diagnosticada de linfangioleiomiomatosis asociada a esclerosis tuberosa, en tratamiento con sirolimus

Lymphangioleiomyomatosis (LAM) is a rare disease that affects young females in their reproductive years. It is characterized by proliferation of abnormal smooth muscle-like cells (LAM cells) leading to progressive cystic destruction of the lung. Even though lung transplantation is considered the only treatment for severe LAM, some recent trials of sirolimus (mTOR inhibitor) showed that there was an improvement in lung function and a reduction in the size of renal angiomyolipomas. We report the case of a twenty years old woman with LAM associated to the tuberous sclerosis complex, who is being treated with sirolimus

Cell Anatomy: still alive

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Epigenetics and atherosclerosis

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Factores de riesgo emergentes / Emergent risk factors

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Citocinas inflamatorias y factores de reparaci¨®n en los m¨²sculos intercostales de pacientes con EPOC grave / Inflammatory Cytokines and Repair Factors in the Intercostal Muscles of Patients With Severe COPD

Introducci¨®nLas acciones locales de las citocinas en los m¨²sculos de los pacientes con enfermedad pulmonar obstructiva cr¨®nica (EPOC) se hallan sometidas a debate. El objetivo del presente estudio ha sido analizar las relaciones entre su expresi¨®n y la activaci¨®n gen¨¦tica de programas de reparaci¨®n muscular.Pacientes y m¨¦todosSe incluy¨® en el estudio a 25 pacientes con EPOC grave en situaci¨®n estable. Se les realiz¨® una biopsia del m¨²sculo intercostal externo, donde se evaluaron los signos de lesi¨®n muscular (morfometr¨ªa), la infiltraci¨®n de c¨¦lulas inflamatorias (inmunohistoqu¨ªmica) y la expresi¨®n de genes seleccionados (t¨¦cnica de reacci¨®n en cadena de la polimerasa en tiempo real) correspondientes a las propias citocinas ¡ªfactor de necrosis tumoral alfa (TNF-¦Á) y sus receptores 1 y 2 (TNFR1 y TNFR2), e interleucinas-1¦Â, 6 y 10¡ª, un marcador panleucocitario (CD18) y mol¨¦culas clave en las v¨ªas de reparaci¨®n-miog¨¦nesis (Pax7, M-Caderina y Mio-D).ResultadosLa expresi¨®n de TNFR2 se relacion¨® directamente con la funci¨®n muscular inspiratoria (representada por la presi¨®n inspiratoria m¨¢xima sostenible; r=0,496, p<0,05), mientras que la expresi¨®n de CD18 se relacion¨® inversamente con ella (r=−0,462, p<0,05). Por otra parte, la expresi¨®n de los 2 receptores del TNF-¦Á se relacion¨® directamente con la de las mol¨¦culas clave de las v¨ªas de reparaci¨®n analizadas (TNFR1 con Pax7, r=0,650, y M-Caderina, r=0,678, ambas con p<0,001; TNFR2 con Pax7, r=0,395, M-Caderina, r=0,409, y Mio-D, r=0,418, con p<0,05 en todas).ConclusionesLa expresi¨®n de los receptores del TNF-¦Á guarda una estrecha relaci¨®n tanto con la activaci¨®n de los programas de miog¨¦nesis como con la propia funci¨®n muscular inspiratoria. Este hecho refuerza nuestra hip¨®tesis de que algunas citocinas locales participan en la reparaci¨®n de los m¨²sculos respiratorios en los pacientes con EPOC(AU)

ObjectiveThere is disagreement regarding the local action of cytokines in the respiratory muscles of patients with chronic obstructive pulmonary disease (COPD). The objective of this study was to analyze the relationships between cytokine expression and genetic activation of the mechanisms of muscle repair.Patients and methodsTwenty-five patients with severe COPD and in stable condition were enrolled in the study. We performed a biopsy of the external intercostal muscle of the patients and analyzed the specimen for signs of muscle lesion (morphometry), infiltration of inflammatory cells (immunohistochemistry), and expression of selected genes (real-time polymerase chain reaction technique) corresponding to the cytokines (tumor necrosis factor ¦Á [TNF-¦Á] and its type 1 and 2 receptors [TNFR1 and TNFR2], and interleukin [IL] 1¦Â, IL-6, and IL-10), a pan-leukocyte marker (CD18), and key molecules in the repair-myogenesis pathways (Pax7, M-cadherin, and MyoD).ResultsExpression of TNFR2 is directly related to inspiratory muscle function (represented by maximum sustainable inspiratory pressure; r=0.496; P<.05), whereas expression of CD18 is inversely related (r=0.462; P<.05). Moreover, expression of the 2 TNF-¦Á receptors was directly related to that of the key molecules of the repair pathways analyzed (TNFR1 to Pax7 [r=0.650; P<.001] and M-cadherin [r=0.678; P<.001]; TNFR2 to Pax7 [r=0.395; P<.05], M-cadherin [r=0.409; P<.05], and MyoD [r=0.418; P<.05]).ConclusionsExpression of TNF-¦Á receptors bears a close relationship both to activation of the myogenesis programs and to inspiratory muscle function. This reinforces our hypothesis that some local cytokines take part in the repair of respiratory muscles in patients with COPD(AU)

Immunophenotypic profile of T cells in common variable immunodeficiency: is there an association with different clinical findings?

Background: A system based on the B-cell phenotype has recently been proposed to classify patients suffering from common variable immunodeficiency (CVID). Immunophenotypic T-cell abnormalities have also been correlated with clinical findings, although they have never been used in classification strategies. Objective: To simultaneously assess T and B-cell subset abnormalities in CVID patients and their relationship with clinical findings. To identify potential immunophenotypic T-cell abnormalities that could be further evaluated in multicenter studies. Patients and Methods: Peripheral blood lymphocytes from 21 CVID patients and 21 healthy donors were stained for T and B-cell subsets, analyzed by flow cytometry, and correlated with clinical characteristics. Results: Patients classified as MB0 (CD19/CD27+ < 11 %) showed higher percentages of CD4/CD45RA— (87 % vs 67 %, p = 0.028) and lower percentages of CD8/CD45RA+CCR7+ (10 % vs 26 %, p = 0.028) and CD4/CD25+ T-cells (36 % vs 62 %, p = 0.034) than MB2 patients. Even though our cohort was small, we observed a higher prevalence of distinct clinical complications of CVID in patients with B and T-cell abnormalities. Nonmalignant lymphoproliferative disorders and IgG hypercatabolism were more frequently observed in MB0 patients. A higher prevalence of splenomegaly was observed among CVID patients with increased levels of CD4/CD45RA—, activated CD4/CD38+DR+, CD8/DR+, and CD8/CD38+ T-cells, as well as in those with lower percentages of CD4/CD45RA+CCR7+ and CD4/CD25+ T-cells. Lymphoproliferative disorders were more prevalent among CVID patients with higher CD4/CD45RA— percentages. Conclusion: The study of T-cell subsets warrants further evaluation as a potential tool to better identify CVID patients with distinct clinical profiles (AU)

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Una aproximación farmacológica al tratamiento de la acondroplasia / A pharmacological appoach to achondroplasia treatment

La acondroplasia es una patología caracterizada por una mutación en el receptorpara el factor de crecimiento de fibroblastos de tipo 3 (FGFR3). Esta alteracióncausa la patología que conocemos habitualmente con el nombre de enanismo congénitoy que se manifiesta con individuos de talla baja con diversos problemasmúsculo-esqueléticos. La aplicación de nucleótidos y dinucleótidos ha permitidoobservar que las células acondroplásicas pueden fenomenológicamente comportarsecomo células normales, en especial cuando son tratadas con el dinucleótidoAp4A. Este compuesto reestablece los niveles de calcio en los condrocitos acondroplásicos,permitiendo que se comporten como células absolutamente normales enlo que respecta a este ion. Por otro lado, también este dinucleótido permite que elreceptor de FGFR3, que no se internaliza y degrada con normalidad, pueda pasara ser degradado por las vías proteosomales y lisosomales, como sucede en lascélulas normales, haciendo que el receptor motivo de la patología desaparezca de las membranas de los condrocitos acondroplásicos. Por último, hemos podidocomprobar cómo el derivado del piridoxalfosfato, el PPADS, presenta propiedadesextraordinarias al reducir prácticamente a cero los niveles de fosforilación de lasproteínas ERK, que son anormalmente elevadas por el receptor FGFR3 acondroplásicoy que originan la patología. En resumen, se plantean una serie de nuevasestrategias encaminadas al tratamiento de la acondroplasia por medio de estrategiasde tipo farmacológico en claro contrate con las estrategias actuales de tipoquirúrgico

Achondroplasia is a pathology due to a mutation in the receptor for thefibroblast growth factor type 3 (FGFR3). This alteration produces problems inindividuals’ stature as well as other muscle-skeletal problems. The application ofnucleotides and dinucleotides permit achondroplasic cells (chondrocytes) torecover, aparently, from this pathology. In particular, the application of thedinucleotide Ap4A, permits to restore the correct calcium levels in achondroplasiccell. Moreover, this dinucleotide permits the right degradation of the FGFR3receptor, which does not downregulate properly in achondropasic chondrocytes,by facilitating the proteosomal and lysosomal pathways alter the dinucleotideapplication. Also we have discovered that the pyridoxal phosphate derivative PPADScan dramatically reduce the activation of ERK casacade which is abnormalyelevated by the achondroplasic FGFR3 receptor raising the pathology. In summary,we wish to introduce a series of new pharmacological strategies for the treatmentof achondroplasia in clear contrast with the current surgery ones

Virus del papiloma humano. Aspectos virológicos e inmunitarios / Human papilloma virus. Virological and immune features

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Tumour cells resistance in cancer therapy

Resistance to chemotherapeutic drugs presents a big caveat for cancer treatment. In this review we will describe the molecular mechanisms involved in chemoresistance, discussing the mechanisms of resistance related to tumour microenvironment, as well as their intracellular mechanisms. Chemoresistance can also appear as a consequence to treatments with new anticancer drugs. In this sense, we will exemplify this type of resistance discussing mechanisms of action of epidermal growth factor receptor (EGFR) inhibitors. We conclude that the main problem of chemoresistance is due to its pleiotropic and multifactorial nature(AU)

Tumor metabolism: new opportunities for cancer therapy

Mammalian cells depend on extracellular input for the regulation of growth, proliferation and survival. Cancer cells evade these requirements, and are able to take up nutrients in a cell-autonomous fashion, which allows continuous growth and proliferation. To fulfill the high bioenergetic demands imposed by transformation, tumors must develop alternative mechanisms of energy production. Accordingly, the biochemical signature of cancer cells involves a shift to aerobic glycolysis, also known as the "Warburg effect". This property of cancer cells has resulted of great utility in modern medicine for detection of early tumors by positron-emission scanning. Nonetheless, the underlying mechanisms and contribution of the Warburg effect to the malignant phenotype have remained obscure. Thanks to recent advances in cancer research, we are beginning to understand the link between cancer genetics and the abnormal use of glucose by tumors. A new scenario is thus emerging, in which bioenergetics would contribute to and sustain malignant transformation. These findings are not only important for a better understanding of tumorigenesis; tumor reliance on glycolysis can be exploited in the search for novel, more potent therapeutic approaches to cancer treatment (AU)