Administration of intestinal mesenchymal stromal cells reduces colitis-associated cancer in C57BL/6J mice modulating the immune response and gut dysbiosis.

BACKGROUND: Patients with inflammatory bowel disease (IBD) have a higher risk of developing colitis-associated colorectal cancer (CAC) with poor prognosis. IBD etiology remains undefined but involves environmental factors, genetic predisposition, microbiota imbalance (dysbiosis) and mucosal immune defects. Mesenchymal stromal cell (MSC) injections have shown good efficacy in reducing intestinal inflammation in animal and human studies. However, their effect on tumor growth in CAC and their capacity to restore gut dysbiosis are not clear. METHODS: The outcome of systemic administrations of in vitro expanded human intestinal MSCs (iMSCs) on tumor growth in vivo was evaluated using the AOM/DSS model of CAC in C57BL/6J mice. Innate and adaptive immune responses in blood, mesenteric lymph nodes (MLNs) and colonic tissue were analyzed by flow cytometry. Intestinal microbiota composition was evaluated by 16S rRNA amplicon sequencing. RESULTS: iMSCs significantly inhibited colitis and intestinal tumor development, reducing IL-6 and COX-2 expression, and IL-6/STAT3 and PI3K/Akt signaling. iMSCs decreased colonic immune cell infiltration, and partly restored intestinal monocyte homing and differentiation. iMSC administration increased the numbers of Tregs and IFN-γ+CD8+ T cells in the MLNs while decreasing the IL-4+Th2 response. It also ameliorated intestinal dysbiosis in CAC mice, increasing diversity and Bacillota/Bacteroidota ratio, as well as Akkermansia abundance, while reducing Alistipes and Turicibacter, genera associated with inflammation. CONCLUSION: Administration of iMSCs protects against CAC, ameliorating colitis and partially reverting intestinal dysbiosis, supporting the use of MSCs for the treatment of IBD.

Tigecycline reduces tumorigenesis in colorectal cancer via inhibition of cell proliferation and modulation of immune response.

BACKGROUND: and Purpose: Colorectal cancer (CRC) is one of the cancers with the highest incidence in which APC gene mutations occur in almost 80% of patients. This mutation leads to ß-catenin aberrant accumulation and an uncontrolled proliferation. Apoptosis evasion, changes in the immune response and microbiota composition are also events that arise in CRC. Tetracyclines are drugs with proven antibiotic and immunomodulatory properties that have shown cytotoxic activity against different tumor cell lines. EXPERIMENTAL APPROACH: The effect of tigecycline was evaluated in vitro in HCT116 cells and in vivo in a colitis-associated colorectal cancer (CAC) murine model. 5-fluorouracil was assayed as positive control in both studies. KEY RESULTS: Tigecycline showed an antiproliferative activity targeting the Wnt/ß-catenin pathway and downregulating STAT3. Moreover, tigecycline induced apoptosis through extrinsic, intrinsic and endoplasmic reticulum pathways converging on an increase of CASP7 levels. Furthermore, tigecycline modulated the immune response in CAC, reducing the cancer-associated inflammation through downregulation of cytokines expression. Additionally, tigecycline favored the cytotoxic activity of cytotoxic T lymphocytes (CTLs), one of the main immune defenses against tumor cells. Lastly, the antibiotic reestablished the gut dysbiosis in CAC mice increasing the abundance of bacterial genera and species, such as Akkermansia and Parabacteroides distasonis, that act as protectors against tumor development. These findings resulted in a reduction of the number of tumors and an amelioration of the tumorigenesis process in CAC. CONCLUSION AND IMPLICATIONS: Tigecycline exerts a beneficial effect against CRC supporting the use of this antibiotic for the treatment of this disease.

Food Consumption and Metabolic Risks in Young University Students.

The purpose of this study was to analyze the association between components of the diet, metabolic risks, and the serum concentrations of adiponectin and interleukin-6 (IL-6). With prior informed consent, an analytical cross-sectional study was carried out with 72 students in their first year of university. The subjects had a mean age of 19.2 ± 1.0 years and body mass index of 23.38 ± 4.2, and they were mainly women (80.6%). Sociodemographic, anthropometric, and dietary data and metabolic risk factors were evaluated, and biochemical parameters and adipocytokines were also considered. The data were analyzed using means, ranges, and correlations, as well as principal components. In general, the protein, fat, and sodium intake were higher than the international dietary recommendations, and deficiencies in vitamins B5 and E, potassium, phosphorus, selenium, and zinc were observed. The most frequently observed metabolic risks were insulin resistance and hypoalphalipoproteinemia. IL-6 was positively correlated with lipid and protein intake. Adiponectin showed a positive correlation with high-density lipoprotein and a negative correlation with insulin, weight, and waist, while the adiponectin pattern was similar to that of vitamins E and A, which decreased with increasing intake of calories, macronutrients, and sodium. In general, a hypercaloric diet that was high in protein, fat, and sodium and deficient in vitamins, mainly fat-soluble, was associated with a lower concentration of adiponectin and a higher concentration of IL-6, which favor the presence of metabolic risks, including insulin resistance. Intervention studies are required to evaluate the dietary intake of metabolic markers in young people without comorbidities, which will lay the foundation for implementing prevention strategies.

In Vivo Imaging and Tracking of Technetium-99m Labeled Bone Marrow Mesenchymal Stem Cells in Equine Tendinopathy.

Recent advances in the application of bone marrow mesenchymal stem cells (BMMSC) for the treatment of tendon and ligament injuries in the horse suggest improved outcome measures in both experimental and clinical studies. Although the BMMSC are implanted into the tendon lesion in large numbers (usually 10 - 20 million cells), only a relatively small number survive (<10%) although these can persist for up to 5 months after implantation. This appears to be a common observation in other species where BMMSC have been implanted into other tissues and it is important to understand when this loss occurs, how many survive the initial implantation process and whether the cells are cleared into other organs. Tracking the fate of the cells can be achieved by radiolabeling the BMMSC prior to implantation which allows non-invasive in vivo imaging of cell location and quantification of cell numbers. This protocol describes a cell labeling procedure that uses Technetium-99m (Tc-99m), and tracking of these cells following implantation into injured flexor tendons in horses. Tc-99m is a short-lived (t1/2 of 6.01 hr) isotope that emits gamma rays and can be internalized by cells in the presence of the lipophilic compound hexamethylpropyleneamine oxime (HMPAO). These properties make it ideal for use in nuclear medicine clinics for the diagnosis of many different diseases. The fate of the labeled cells can be followed in the short term (up to 36 hr) by gamma scintigraphy to quantify both the number of cells retained in the lesion and distribution of the cells into lungs, thyroid and other organs. This technique is adapted from the labeling of blood leukocytes and could be utilized to image implanted BMMSC in other organs.

Histologic study of a human immature permanent premolar with chronic apical abscess after revascularization/revitalization.

INTRODUCTION: Histologic studies of teeth from animal models of revascularization/revitalization are available; however, specimens from human studies are lacking. The nature of tissues formed in the canal of human revascularized/revitalized teeth was not well established. METHODS: An immature mandibular premolar with infected necrotic pulp and a chronic apical abscess was treated with revascularization/revitalization procedures. At both the 18-month and 2-year follow-up visits, radiographic examination showed complete resolution of the periapical lesion, narrowing of the root apex without root lengthening, and minimal thickening of the canal walls. The revascularized/revitalized tooth was removed because of orthodontic treatment and processed for histologic examination. RESULTS: The large canal space of revascularized/revitalized tooth was not empty and filled with fibrous connective tissue. The apical closure was caused by cementum deposition without dentin. Some cementum-like tissue was formed on the canal dentin walls. Inflammatory cells were observed in the coronal and middle third of revascularized/revitalized tissue. CONCLUSIONS: In the present case, the tissue formed in the canal of a human revascularized/revitalized tooth was soft connective tissue similar to that in the periodontal ligament and cementum-like or bone-like hard tissue, which is comparable with the histology observed in the canals of teeth from animal models of revascularization/revitalization.

A novel IFITM5 mutation in severe atypical osteogenesis imperfecta type VI impairs osteoblast production of pigment epithelium-derived factor.

Osteogenesis imperfecta (OI) types V and VI are caused, respectively, by a unique dominant mutation in IFITM5, encoding BRIL, a transmembrane ifitm-like protein most strongly expressed in the skeletal system, and recessive null mutations in SERPINF1, encoding pigment epithelium-derived factor (PEDF). We identified a 25-year-old woman with severe OI whose dermal fibroblasts and cultured osteoblasts displayed minimal secretion of PEDF, but whose serum PEDF level was in the normal range. SERPINF1 sequences were normal despite bone histomorphometry consistent with type VI OI and elevated childhood serum alkaline phosphatase. We performed exome sequencing on the proband, both parents, and an unaffected sibling. IFITM5 emerged as the candidate gene from bioinformatics analysis, and was corroborated by membership in a murine bone co-expression network module containing all currently known OI genes. The de novo IFITM5 mutation was confirmed in one allele of the proband, resulting in a p.S40L substitution in the intracellular domain of BRIL but was absent in unaffected family members. IFITM5 expression was normal in proband fibroblasts and osteoblasts, and BRIL protein level was similar to control in differentiated proband osteoblasts on Western blot and in permeabilized mutant osteoblasts by microscopy. In contrast, SERPINF1 expression was decreased in proband osteoblasts; PEDF was barely detectable in conditioned media of proband cells. Expression and secretion of type I collagen was similarly decreased in proband osteoblasts; the expression pattern of several osteoblast markers largely overlapped reported values from cells with a primary PEDF defect. In contrast, osteoblasts from a typical case of type V OI, with an activating mutation at the 5'-terminus of BRIL, have increased SERPINF1 expression and PEDF secretion during osteoblast differentiation. Together, these data suggest that BRIL and PEDF have a relationship that connects the genes for types V and VI OI and their roles in bone mineralization.

Distribution of injected technetium(99m)-labeled mesenchymal stem cells in horses with naturally occurring tendinopathy.

This study aimed to investigate immediate cell survival and distribution following different administration routes of mesenchymal stem cells (MSCs) into naturally occurring tendon injuries. Ten million MSCs, labeled with technetium-99m hexamethylpropyleneamine oxime, were implanted into 13 horses with naturally occurring tendon or ligament injuries intra-lesionally, intravenously and by regional perfusion, and traced for up to 48 h using planar gamma scintigraphy. Labeling efficiencies varied between 1.8% and 18.5% (mean 9.3%). Cells were retained in the damaged area after intra-lesional administration but only 24% of cells were still present within the tendon after 24 h. After intravenous injection, cells largely distributed to the lung fields, with no detectable cells in the tendon lesions. Significant labeling of the tendon lesions was observed in 11/12 horses following regional perfusion but at a lower level to intra-lesional injection. The highest cell numbers were retained after intra-lesional injection, although with considerable cell loss, while regional perfusion may be a viable alternative for MSC delivery. Cells did not "home" to damaged tendon in large numbers after intravenous administration. Cells were detected in the lungs most frequently after intravascular administration, although with no adverse effects. Low cell retention has important implications for designing effective clinical therapies for human clinical use.

Tabaco y salud oral en estudiantes de la Universidad de Santiago de Compostela / Oral health and tobacco in students at Santiago de Compostela University

Objetivo. Describir los hábitos de salud oral y consumo de tabaco en los estudiantes de la Universidad de Santiago de Compostela. Material y métodos. Estudio transversal en estudiantes universitarios mediante encuesta sobre hábitos de salud oral y tabaco, exploración de la cavidad oral y determinación de monóxido de carbono (CO) en aire espirado. Resultados. Se realizaron 1279 encuestas, el 27´5% a hombres y el 72´5% a mujeres. La media de edad fue de 21´4 años. Nueve de cada diez sujetos dice que se lava los dientes después de cada comida y el 8 de cada diez que le dedica más de un minuto a su higiene oral en cada cepillado. El número medio de cepillos dentales utilizados en un año fue superior a 3. Prácticamente el 100% de los encuestados ha acudido alguna vez al dentista por diferentes motivos. Se realizaron 342 exploraciones bucodentales, en las que se halló un índice CAOD superior a 3 y un índice de restauración próximo al 70%. Con respecto al hábito de fumar, el 32´4% dice que fuma en la actualidad, con una media de 11´15 cigarrillos al día. La edad media de inicio de consumo fue a los 16 años. No se observaron diferencias estadísticamente significativas en ninguna de las variables estudiadas entre fumadores y no fumadores excepto en las tinciones dentarias y en la cantidad de pasta utilizada. La media de CO en aire espirado fue de 12,6 en los fumadores. Conclusiones. En los universitarios hay un elevado grado de concienciación sobre hábitos de salud oral y consumo de tabaco, mayor que en la población general de esa edad. No se observan diferencias en los hábitos ni en el estado de salud oral entre fumadores y no fumadores (AU)

Objective. The aim of this study was to describe the habits related to oral health and to determine the patterns of tobacco smoking among students at the University of Santiago de Compostela. Material and Methods. Advanced students in dentistry carried out a survey on habits and an examination of the oral cavity of their peers. They also determined CO concentration in exhaled air. Results. The questionnaires were answered by 1279 students, 27.5% of which were male and 72.5% female. The mean age of the sample was 21.4 years. Among respondents, 90% washed their teeth after eating, above 80% spent more than 1 minute in their oral hygiene and used an average of more than 3 toothbrushes per year. Nearly 100% of the sample visited the dentist. We performed 342 examinations which resulted in a DMF rate of 3.71 and a restoration rate of 70.8%; 32.4% of the population smoked an average of 11.5 cigarettes per day. The most frequent starting age of the habit was 16 years-old. No significant differences were found between smokers and non smokers for most of the studied variables with the exceptions of the presence of discolored teeth, the amount of toothpaste used for brushing teeth and the subjective perception of oral health. The average value of expired CO in smokers was 12.6. Conclusions. Among students of our university there is a high degree of awareness concerning oral health. Tobacco smoking habit is less frequent than in the general population in the same age range. There were no differences between smokers and non smokers for oral health and oral health habits (AU)

Tabaco y salud oral en estudiantes de la Universidad de Santiago de Compostela / Oral health and tobacco in students at Santiago de Compostela University

Objetivo. Describir los hábitos de salud oral y consumo de tabaco en los estudiantes de la Universidad de Santiago de Compostela. Material y métodos. Estudio transversal en estudiantes universitarios mediante encuesta sobre hábitos de salud oral y tabaco, exploración de la cavidad oral y determinación de monóxido de carbono (CO) en aire espirado. Resultados. Se realizaron 1279 encuestas, el 27´5% a hombres y el 72´5% a mujeres. La media de edad fue de 21´4 años. Nueve de cada diez sujetos dice que se lava los dientes después de cada comida y el 8 de cada diez que le dedica más de un minuto a su higiene oral en cada cepillado. El número medio de cepillos dentales utilizados en un año fue superior a 3. Prácticamente el 100% de los encuestados ha acudido alguna vez al dentista por diferentes motivos. Se realizaron 342 exploraciones bucodentales, en las que se halló un índice CAOD superior a 3 y un índice de restauración próximo al 70%. Con respecto al hábito de fumar, el 32´4% dice que fuma en la actualidad, con una media de 11´15 cigarrillos al día. La edad media de inicio de consumo fue a los 16 años. No se observaron diferencias estadísticamente significativas en ninguna de las variables estudiadas entre fumadores y no fumadores excepto en las tinciones dentarias y en la cantidad de pasta utilizada. La media de CO en aire espirado fue de 12,6 en los fumadores. Conclusiones. En los universitarios hay un elevado grado de concienciación sobre hábitos de salud oral y consumo de tabaco, mayor que en la población general de esa edad. No se observan diferencias en los hábitos ni en el estado de salud oral entre fumadores y no fumadores

Objective. The aim of this study was to describe the habits related to oral health and to determine the patterns of tobacco smoking among students at the University of Santiago de Compostela. Material and Methods. Advanced students in dentistry carried out a survey on habits and an examination of the oral cavity of their peers. They also determined CO concentration in exhaled air. Results. The questionnaires were answered by 1279 students, 27.5% of which were male and 72.5% female. The mean age of the sample was 21.4 years. Among respondents, 90% washed their teeth after eating, above 80% spent more than 1 minute in their oral hygiene and used an average of more than 3 toothbrushes per year. Nearly 100% of the sample visited the dentist. We performed 342 examinations which resulted in a DMF rate of 3.71 and a restoration rate of 70.8%; 32.4% of the population smoked an average of 11.5 cigarettes per day. The most frequent starting age of the habit was 16 years-old. No significant differences were found between smokers and non smokers for most of the studied variables with the exceptions of the presence of discolored teeth, the amount of toothpaste used for brushing teeth and the subjective perception of oral health. The average value of expired CO in smokers was 12.6. Conclusions. Among students of our university there is a high degree of awareness concerning oral health. Tobacco smoking habit is less frequent than in the general population in the same age range. There were no differences between smokers and non smokers for oral health and oral health habits

Indicadores nutricionales y curva de crecimiento postnatal para recién nacidos de muy bajo peso / Nutritional indicators and postnatal growth curve in very low birth weight newborn infants

Se estudiaron 100 recién nacidos de muy bajo peso (RNMBP) sobrevivientes, nacidos entre 1986-89 en el Hospital Edgardo Rebagliati Martins, IPSS, Lima-Perú, alimentados con leche materna y fórmula para prematuros suplementada con 1,000 UI de vitamina D, en los cuales se evaluaron ocho indicadores nutricionales. Estudiando la relación variable peso al nacimiento y tres variables dependientes (Indicadores Nutricionales): día de máxima pérdida de peso, número de días para recuperar el peso al nacimiento, y número de días para alcanzar 2,000 g; y con el uso del análisis de Regresión Múltiple se confeccionó una Curva de Crecimiento intrahospitalario. Se encontró que la ganancia de peso (g/día) era similar entre los niños de nuestro estudio y el reportado en estudios efectuados en países desarrollados a paratir de los 1,350 g. Los indicadores nutricionales son excelentes parámetros para estudiar el patrón evolutivo nutricional por ser fáciles de reproducir, confiables y accesibles al uso diario en las nurserías.