How the Cervical Microbiota Contributes to Cervical Cancer Risk in Sub-Saharan Africa

Despite ongoing efforts, sub-Saharan Africa faces a higher cervical cancer burden than anywhere else in the world. Besides HPV infection, definitive factors of cervical cancer are still unclear. Particular states of the cervicovaginal microbiota and viral infections are associated with increased cervical cancer risk. Notably, HIV infection, which is prevalent in sub-Saharan Africa, greatly increases risk of cervicovaginal dysbiosis and cervical cancer. To better understand and address cervical cancer in sub-Saharan Africa, a better knowledge of the regional cervicovaginal microbiome is required This review establishes current knowledge of HPV, HIV, cervicovaginal infections, and the cervicovaginal microbiota in sub-Saharan Africa. Because population statistics are not available for the region, estimates are derived from smaller cohort studies. Microbiota associated with cervical inflammation have been found to be especially prevalent in sub-Saharan Africa, and to associate with increased cervical cancer risk. In addition to high prevalence and diversity of HIV and HPV, intracellular bacterial infections such as Chlamydia, Gonorrhea, and Mycoplasma hominis are much more common than in regions with a low burden of cervical cancer. This suggests the prevalence of cervical cancer in sub-Saharan Africa may be partially attributed to increased cervical inflammation resulting from higher likelihood of cervical infection and/or microbial dysbiosis

How the Cervical Microbiota Contributes to Cervical Cancer Risk in Sub-Saharan Africa

Despite ongoing efforts, sub-Saharan Africa faces a higher cervical cancer burden than anywhere else in the world. Besides HPV infection, definitive factors of cervical cancer are still unclear. Particular states of the cervicovaginal microbiota and viral infections are associated with increased cervical cancer risk. Notably, HIV infection, which is prevalent in sub-Saharan Africa, greatly increases risk of cervicovaginal dysbiosis and cervical cancer. To better understand and address cervical cancer in sub-Saharan Africa, a better knowledge of the regional cervicovaginal microbiome is required This review establishes current knowledge of HPV, HIV, cervicovaginal infections, and the cervicovaginal microbiota in sub-Saharan Africa. Because population statistics are not available for the region, estimates are derived from smaller cohort studies. Microbiota associated with cervical inflammation have been found to be especially prevalent in sub-Saharan Africa, and to associate with increased cervical cancer risk. In addition to high prevalence and diversity of HIV and HPV, intracellular bacterial infections such as Chlamydia, Gonorrhea, and Mycoplasma hominis are much more common than in regions with a low burden of cervical cancer. This suggests the prevalence of cervical cancer in sub-Saharan Africa may be partially attributed to increased cervical inflammation resulting from higher likelihood of cervical infection and/or microbial dysbiosis

Mycoplasma Co-Infection Is Associated with Cervical Cancer Risk

Tanzania faces one of the highest cervical cancer burdens in the world. Recent work has suggested that the bacterial family Mycoplasmataceae is associated with higher levels of human papillomavirus (HPV), human immunodeficiency virus (HIV), and pre-cancerous cervical lesions. Mycoplasmataceae infection in Tanzania is not well understood, especially when considering the differences between sexually transmitted species of Mycoplasmataceae. To establish the prevalence of common Mycoplasmataceae cervical infections and evaluate their relationship with risk factors for cervical cancer, 1160 Tanzanian women responded to an epidemiological questionnaire and were tested for HIV, HPV, cervical lesions, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma spp., and Lactobacillus iners. A subset of 134 women were used for 16s metagenomic sequencing of cervical DNA to establish the relative abundance of Mycoplasmataceae and Lactobacillus present. PCR detection of bacteria at the cervix found Ureaplasma spp. in 51.4% of women, M. hominis in 34%, M. genitalium in 2.3%, and L. iners in 75.6%. M. hominis and M. genitalium infection were significantly more prevalent among women with HPV and HIV. M. hominis prevalence was similar despite severity of cervical lesions; however, abundance of M. hominis increased significantly in women with cervical lesions. These results emphasize the importance of understanding the relationship between M. hominis and HPV-related cervical pathogenesis

Transcription factors in the pathogenesis of pulmonary arterial hypertension—Current knowledge and therapeutic potential

Pulmonary arterial hypertension (PAH) is a disease characterized by elevated pulmonary vascular resistance and pulmonary artery pressure. Mortality remains high in severe cases despite significant advances in management and pharmacotherapy. Since currently approved PAH therapies are unable to significantly reverse pathological vessel remodeling, novel disease-modifying, targeted therapeutics are needed. Pathogenetically, PAH is characterized by vessel wall cell dysfunction with consecutive remodeling of the pulmonary vasculature and the right heart. Transcription factors (TFs) regulate the process of transcribing DNA into RNA and, in the pulmonary circulation, control the response of pulmonary vascular cells to macro- and microenvironmental stimuli. Often, TFs form complex protein interaction networks with other TFs or co-factors to allow for fine-tuning of gene expression. Therefore, identification of the underlying molecular mechanisms of TF (dys-)function is essential to develop tailored modulation strategies in PAH. This current review provides a compendium-style overview of TFs and TF complexes associated with PAH pathogenesis and highlights their potential as targets for vasculoregenerative or reverse remodeling therapies

Publikumsinklusion beim "Freitag": Fallstudienbericht aus dem DFG-Projekt "Die (Wieder-)Entdeckung des Publikums"

Der Bericht stellt Ergebnisse einer Fallstudie beim Freitag und bei freitag.de vor, die im Rahmen eines Forschungsprojekts zur Rolle von Publikumsbeteiligung im professionellen, redaktionell organisierten Journalismus in Deutschland durchgeführt wurde. Auf Grundlage eines theoretisch-analytischen Modells, das Partizipation als Zusammenspiel von Inklusionsleistungen und Inklusionserwartungen auf Seiten des Journalismus und des Publikums versteht, werden Befunde aus qualitativen Interviews mit Redaktionsmitgliedern (n = 6) und Lesern bzw. Nutzern unterschiedlichen Aktivitätsgrads (n = 6) sowie aus standardisierten Befragungen von Redaktionsmitgliedern (n = 10) sowie von Nutzern von freitag.de (n = 344) vorgestellt. Auf journalistischer Seite kann so nachgezeichnet werden, dass für die vergleichsweise kleine Redaktion des Freitag Formen der Publikumsbeteiligung eine wichtige Rolle für das redaktionelle Selbstverständnis als "Debattenmedium" spielen und als Teil des "Markenkerns" betrachtet werden. Das Publikum wird vor allem als "Community" adressiert, die auf freitag.de eigene Nutzer-Blogs betreiben kann. Diese dienen regelmäßig als Ressource, aus der Beiträge zur Publikation auf der Website und z. T. auch in der Printausgabe ausgewählt werden. Deutlich wird, dass diese weitreichende Form der Publikumsbeteiligung auch auf gewisse publizistisch-ökonomische Zwänge zurückgeht: Die Beiträge aus dem Publikum werden gebraucht, allein um einen gewissen Angebotsumfang zu garantieren. Auf Publikumsseite lässt sich außerdem zeigen, dass der Freitag ein vergleichsweise aktives, durchaus auch kommentierfreudiges Publikum hat, das besonderen Wert auf Quellentransparenz und Möglichkeiten der Anschlusskommunikation (auch untereinander) legt und vom Freitag vor allem auch eine kritische und meinungsbetonte Haltung erwartet. Der Abgleich beider Seiten erlaubt es zudem, Aussagen über das Inklusionslevel und die Inklusionsdistanz zu treffen: Das Inklusionslevel ist insgesamt als hoch zu bezeichnen, da der Freitag neben den Standardelementen der Publikumsbeteiligung (wie Kommentarbereiche unter Online-Artikeln) mit einigem redaktionellen Aufwand eine Community pflegt. In diese bringt sich zwar nur eine Minderheit des Publikums aktiv und auch nur ein "harter Kern" regelmäßig in Form von selbstverfassten Beiträgen ein. Allerdings trägt zu einem ausgeglichenen Inklusionslevel bei, dass der hohe redaktionsseitige Aufwand (z. T.) dadurch aufgewogen erscheint, dass diese Inhalte regelmäßig und substanziell für die Erweiterung der Inhalte der Website gebraucht und ggf. auch im Printprodukt publiziert werden. Die Inklusionsdistanz fällt im Hinblick auf die unter diesem Konzept subsumierten Dimensionen uneinheitlich aus: Es liegt weitgehende Übereinstimmung zwischen der vom Publikum erwarteten und der redaktionsseitig angestrebten journalistischen Rolle vor: Zu den beidseitig als am wichtigsten eingeschätzten Aufgaben gehören diejenigen, welche einen kritisch-kontrollierenden (und politisch links stehenden) Journalismus charakterisieren. Allerdings wird Publikumsbeteiligung in ihrer Wichtigkeit für das Publikum von den befragten Redaktionsmitgliedern z. T. sehr deutlich überschätzt; demgegenüber unterschätzen sie stark die Bedeutung, die Quellentransparenz für ihr Publikum hat. Als deutlich wichtiger als die befragten Publikumsmitglieder schätzen sie auch Beteiligungsmotive von aktiven Nutzerinnen und Nutzern ein, die in Richtung "Austausch und Vernetzung innerhalb der Community" gehen. Diese scheinen jedoch vor allem für die besonders aktiven Nutzer relevant. Insgesamt wird deutlich: Das redaktionsseitig erklärte strategische Ziel "die Grenzen zwischen Redaktion und Community so weit wie möglich abzusenken" (DF_Leit §18) erscheint durch die weitreichenden Beteiligungsmöglichkeiten zwar prinzipiell erreicht, allerdings möchte nur ein (geringer) Teil der Nutzer diese Grenze auch überschreiten bzw. aufgehoben wissen

Selective Bispecific T Cell Recruiting Antibody and Antitumor Activity of Adoptive T Cell Transfer

Background: One bottleneck for adoptive T cell therapy (ACT) is recruitment of T cells into tumors. We hypothesized that combining tumor-specific T cells, modified with a marker antigen and a bispecific antibody (BiAb) that selectively recognizes transduced T cells and tumor cells would improve T cell recruitment to tumors and enhance therapeutic efficacy. Methods: SV40 T antigen-specific T cells from T cell receptor (TCR)-I-transgenic mice were transduced with a truncated human epidermal growth factor receptor (EGFR) as a marker protein. Targeting and killing by combined ACT and anti-EGFR-anti-EpCAM BiAb therapy was analyzed in C57Bl/6 mice (n = six to 12 per group) carrying subcutaneous tumors of the murine gastric cancer cell line GC8 (SV40+ and EpCAM+). Anti-EGFR x anti-c-Met BiAb was used for targeting of human tumor-specific T cells to c-Met+ human tumor cell lines. Differences between experimental conditions were analyzed using the Student's t test, and differences in tumor growth with two-way analysis of variance. Overall survival was analyzed by log-rank test. All statistical tests were two-sided. Results: The BiAb linked EGFR-transduced T cells to tumor cells and enhanced tumor cell lysis. In vivo, the combination of ACT and Biab produced increased T cell infiltration of tumors, retarded tumor growth, and prolonged survival compared with ACT with a control antibody (median survival 95 vs 75 days, P < .001). In human cells, this strategy enhanced recruitment of human EGFR-transduced T cells to immobilized c-Met and recognition of tyrosinase+ melanoma cells by TCR-, as well as of CEA+ colon cancer cells by chimeric antigen receptor (CAR)-modified T cells. Conclusions: BiAb recruitment of tumor-specific T cells transduced with a marker antigen to tumor cells may enhance efficacy of AC

Elevated serum IL-10 is associated with severity of neonatal encephalopathy and adverse early childhood outcomes

BACKGROUND: Neonatal encephalopathy (NE) contributes substantially to child mortality and disability globally. We compared cytokine profiles in term Ugandan neonates with and without NE, with and without perinatal infection or inflammation and identified biomarkers predicting neonatal and early childhood outcomes. METHODS: In this exploratory biomarker study, serum IL-1α, IL-6, IL-8, IL-10, TNFα, and VEGF (<12 h) were compared between NE and non-NE infants with and without perinatal infection/inflammation. Neonatal (severity of NE, mortality) and early childhood (death or neurodevelopmental impairment to 2.5 years) outcomes were assessed. Predictors of outcomes were explored with multivariable linear and logistic regression and receiver-operating characteristic analyses. RESULTS: Cytokine assays on 159 NE and 157 non-NE infants were performed; data on early childhood outcomes were available for 150 and 129, respectively. NE infants had higher IL-10 (p < 0.001), higher IL-6 (p < 0.017), and lower VEGF (p < 0.001) levels. Moderate and severe NE was associated with higher IL-10 levels compared to non-NE infants (p < 0.001). Elevated IL-1α was associated with perinatal infection/inflammation (p = 0.013). Among NE infants, IL-10 predicted neonatal mortality (p = 0.01) and adverse early childhood outcome (adjusted OR 2.28, 95% CI 1.35-3.86, p = 0.002). CONCLUSIONS: Our findings support a potential role for IL-10 as a biomarker for adverse outcomes after neonatal encephalopathy. IMPACT: Neonatal encephalopathy is a common cause of child death and disability globally. Inflammatory cytokines are potential biomarkers of encephalopathy severity and outcome. In this Ugandan health facility-based cohort, neonatal encephalopathy was associated with elevated serum IL-10 and IL-6, and reduced VEGF at birth. Elevated serum IL-10 within 12 h after birth predicted severity of neonatal encephalopathy, neonatal mortality, and adverse early childhood developmental outcomes, independent of perinatal infection or inflammation, and provides evidence to the contribution of the inflammatory processes. Our findings support a role for IL-10 as a biomarker for adverse outcomes after neonatal encephalopathy in a sub-Saharan African cohort

Metabolic effects of exercise in patients with type IV hyperlipoproteinemia

Metabolic responses to 30 minutes of submaximal exercise were investigated in 11 healthy control subjects and 6 patients with type IV hyperlipoproteinemia (endogenous or essential hypertriglyceridemia). All subjects were male and ranged in age from 35 to 55 years. Before exercise they fasted overnight for at least 12 hours.The relative work performed, judged by the levels in heart rate and cardiac output on exercise, was comparable in the two groups, and the effects of exercise were qualitatively similar. Plasma glucose and triglyceride levels showed little change. Plasma concentration of cholesterol increased at the end of exercise by approximately 13 percent above control values compared to a concomitant increase in hematocrit of 3 percent. Plasma free fatty acid levels fell as exercise started and then returned to normal valves at the end of the 30 minutes of exercise; they then increased markedly after exercise but returned subsequently to control levels after 45 minutes.In response to muscular exercise, therefore, both control subjects and patients with type IV hyperlipoproteinemia significantly increase plasma cholesterol concentration. Subjects with hyperlipoproteinemia appear to mobilize free fatty acids in a normal manner for energy purposes, and the excess release of free fatty acids during exercise is apparently not derived from the abundantly circulating triglycerides; the latter were not altered by submaximal exercise.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32754/1/0000123.pd