An assessment of the level of knowledge of secondary school students from the State of Pernambuco, Brazil, regarding Human Papillomavirus (HPV) and prophylactic vaccinations/ Uma avaliação do nível de conhecimento de estudantes do ensino médio do estado de Pernambuco, Brasil, sobre o Papilomavírus Humano (HPV) e as vacinas profiláticas

The aim of this study was to assess the knowledge of high school students about HPV and their awareness that a vaccine is available as prophylactic treatment. Nine hundred and eighty-six students were surveyed—the gender distribution being 61.5% female and 38.5% male. Of those surveyed, 67.1% said they had heard of HPV, but only 53.3% of those familiar with the virus knew a prophylactic treatment was available. Female students knew more about HPV than did their male counterparts (71.6% v. 60%), consequently fewer males knew of the vaccine (58.3% v. 50.7%). The students’ acceptance of the HPV vaccine as prophylactic treatment was correlated with both prior knowledge of the virus and the vaccine. Therefore, the study concluded that it is necessary to increase public awareness about HPV and with the availability of a the vaccine as preventative treatment. That is important due to a great level of resistance to vaccination in several states of Brazil. This study highlights the need for new public health policies.

Ad5/3 is able to avoid neutralization by binding to erythrocytes and lymphocytes

Oncolytic adenoviruses are promising cancer therapeutic agents. Clinical data have shown adenoviruses' ability to transduce tumors after systemic delivery in human cancer patients, despite antibodies. In the present work, we have focused on the interaction of a chimeric adenovirus Ad5/3 with human lymphocytes and human erythrocytes. Ad5/3 binding with human lymphocytes and erythrocytes was observed to occur in a reversible manner, which allowed viral transduction of tumors, and oncolytic potency of Ad5/3 in vitro and in vivo,with or without neutralizing antibodies. Immunodeficient mice bearing xenograft tumors showed enhanced tumor transduction following systemic administration, when Ad5/3 virus was bound to lymphocytes or erythrocytes (P <0.05). In conclusion, our findings reveal that chimeric Ad5/3 adenovirus reaches non-injected tumors in the presence of neutralizing antibodies: it occurs through reversible binding to lymphocytes and erythrocytes.Peer reviewe

Oncolytic Adenovirus Type 3 Coding for CD40L Facilitates Dendritic Cell Therapy of Prostate Cancer in Humanized Mice and Patient Samples

Dendritic cell (DC)-based vaccines have shown some degree of success for the treatment of prostate cancer (PC). However, the highly immunosuppressive tumor microenvironment leads to DC dysfunction, which has limited the effectiveness of these vaccines. We hypothesized that use of a fully serotype 3 oncolytic adenovirus (Ad3-hTERT-CMV-hCD40L; TILT-234) could stimulate DCs in the prostate tumor microenvironment by expressing CD40L. Activated DCs would then activate cytotoxic T cells against the tumor, resulting in therapeutic immune responses. Oncolytic cell killing due to cancer cell-specific virus replication adds to antitumor effects but also enhances the immunological effect by releasing tumor epitopes for sampling by DC, in the presence of danger signals. In this study, we evaluated the companion effect of Ad3-hTERT-CMV-hCD40L and DC-therapy in a humanized mouse model and PC histocultures. Treatment with Ad3-hTERT-CMV-hCD40L and DC resulted in enhanced antitumor responses in vivo. Treatment of established histocultures with Ad3-hTERT-CMV-hCD40L induced DC maturation and notable increase in proinflammatory cytokines. In conclusion, Ad3-hTERT-CMV-hCD40L is able to modulate an immunosuppressive prostate tumor microenvironment and improve the effectiveness of DC vaccination in PC models and patient histocultures, setting the stage for clinical translation.Peer reviewe

Constitutively active GSK3 beta as a means to bolster dendritic cell functionality in the face of tumor-mediated immune suppression

In patients with cancer, the functionality of Dendritic Cells (DC) is hampered by high levels of tumor-derived suppressive cytokines, which interfere with DC development and maturation. Poor DC development can limit the efficacy of immune checkpoint blockade and in vivo vaccination approaches. Interference in intracellular signaling cascades downstream from the receptors of major tumor-associated suppressive cytokines like IL-10 and IL-6, might improve DC development and activation, and thus enhance immunotherapy efficacy. We performed exploratory functional screens on arrays consisting of >1000 human kinase peptide substrates to identify pathways involved in DC development and its inhibition by IL-10 or IL-6. The resulting alterations in phosphorylation of the kinome substrate profile pointed to glycogen-synthase kinase-3 beta (GSK3 beta) as a pivotal kinase in both DC development and suppression. GSK3 beta inhibition blocked human DC differentiation in vitro, which was accompanied by decreased levels of IL-12p70 secretion, and a reduced capacity for T cell priming. More importantly, adenoviral transduction of monocytes with a constitutively active form of GSK3 beta induced resistance to the suppressive effects of IL-10 and melanoma-derived supernatants alike, resulting in improved DC development, accompanied by up-regulation of co-stimulatory markers, an increase in CD83 expression levels in mature DC, and diminished release of IL-10. Moreover, adenovirus-mediated intratumoral manipulation of this pathway in an in vivo melanoma model resulted in DC activation and recruitment, and in improved immune surveillance and tumor control. We propose the induction of constitutive GSK3 beta activity as a novel therapeutic means to bolster DC functionality in the tumor microenvironment.Peer reviewe

Oncolytic adenovirus ORCA-010 activates pro-inflammatory myeloid cells and facilitates T cell recruitment and activation by PD-1 blockade in melanoma

Immune checkpoint inhibitors have advanced the treatment of melanoma. Nevertheless, a majority of patients are resistant, or develop resistance, to immune checkpoint blockade, which may be related to prevailing immune suppression by myeloid regulatory cells in the tumor microenvironment (TME). ORCA-010 is a novel oncolytic adenovirus that selectively replicates in, and lyses, cancer cells. We previously showed that ORCA-010 can activate melanoma-exposed conventional dendritic cells (cDCs). To study the effect of ORCA-010 on melanoma-conditioned macrophage development, we used an in vitro co-culture model of human monocytes with melanoma cell lines. We observed a selective survival and polarization of monocytes into M2-like macrophages (CD14+CD80-CD163+) in co-cultures with cell lines that expressed macrophage colony-stimulating factor. Oncolysis of these melanoma cell lines, effected by ORCA-010, activated the resulting macrophages and converted them to a more proinflammatory state, evidenced by higher levels of PD-L1, CD80, and CD86 and an enhanced capacity to prime allogenic T cells and induce a type-1 T cell response. To assess the effect of ORCA-010 on myeloid subset distribution and activation in vivo, ORCA-010 was intratumorally injected and tested for T cell activation and recruitment in the human adenovirus nonpermissive B16-OVA mouse melanoma model. While systemic PD-1 blockade in this model in itself did not modulate myeloid or T cell subset distribution and activation, when it was preceded by i.t. injection of ORCA-010, this induced an increased rate and activation state of CD8α+ cDC1, both in the TME and in the spleen. Observed increased rates of activated CD8+ T cells, expressing CD69 and PD-1, were related to both increased CD8α+ cDC1 rates and M1/M2 shifts in tumor and spleen. In conclusion, the myeloid modulatory properties of ORCA-010 in melanoma, resulting in recruitment and activation of T cells, could enhance the antitumor efficacy of PD-1 blockade

Gastroprotective and ulcer healing effects of essential oil of Hyptis martiusii Benth. (Lamiaceae).

Hyptis martiusii Benth. is an aromatic plant found in abundance in northeastern Brazil that is used in ethnomedicine to treat gastric disorders. The aim of this study was to elucidate the mechanisms of action involved in the gastroprotection of the essential oil of Hyptis martiusii (EOHM) and to evaluate its healing capacity. Wistar rats were exposed to different protocols and subsequently were treated with 1% Tween-80 aqueous solution (negative control), pantoprazole, carbenoxolone, N-acetylcysteine (depending on the specificity of each model) or EOHM. The antisecretory activity (basal or stimulated) was determined using the pyloric ligature method. The gastroprotective action of nitric oxide and sulphydryl groups (-SH groups), as well as the quantification of adherent mucus and the levels of malondialdehyde and -SH groups in gastric mucosa, were evaluated using ethanol-induced gastric ulcer model. The healing ability was evaluated using the acetic acid-induced gastric ulcer model and histological and immunohistochemical analysis (HE, PAS and PCNA). EOHM (400 mg/kg) reduced the volume and acidity of gastric secretion stimulated by histamine and pentagastrin. The gastroprotective effect of EOHM involves the participation of endogenous sulfhydryl groups. EOHM increased mucus production (54.8%), reduced levels of MDA (72.5%) and prevented the depletion of -SH groups (73.8%) in the gastric mucosa. The treatment with EOHM reduced in 70.3% the gastric lesion area, promoting significant regeneration of the gastric mucosa, as confirmed by histological analysis and analysis of proliferating cell nuclear antigen. The results show that gastroprotective effect of EOHM is mediated by cytoprotective and antioxidant mechanisms and by their antisecretory activity, and suggest that the essential oil of Hyptis martiusii is a promising candidate for the treatment of gastric ulcers

Chemical constituents of essential oil of leaves of <i>Hyptis martiusii</i> Benth.

<p>Chemical constituents of essential oil of leaves of <i>Hyptis martiusii</i> Benth.</p

Effect of the essential oil of <i>Hyptis martiusii</i> (EOHM) on the macroscopical appearance of the gastric mucosa in rats after the induction of gastric lesions by ethanol (70%, 0.5 mL/100 g, p.o).

<p>The non-injured control group (A) received no treatment. (B) injured control (1% Tween-80 aqueous solution), (C) pantoprazole (40 mg/kg), (D) N-acetylcysteine (750 mg/kg) or (E) EOHM (400 mg/kg).</p

Histological study and immunohistochemical analysis for PCNA (proliferating cell nuclear antigen) of gastric mucosa of rats treated with 1% Tween-80 aqueous solution (control), pantoprazole (40 mg/kg) and essential oil of <i>Hyptis martiusii</i> (EOHM, 400 mg/kg) for 14 days after injury induced by 30% acetic acid.

<p>The filled arrow indicates the absence of the epithelial layer (ulcer area internal) and the dashed arrow indicates epithelial layer remaining (ulcer edge). Haematoxylin/eosin (HE) and Periodic Acid–Schiff staining (PAS), magnification, 40×. Microphotographs depict PCNA immunoreactivity in the groups, magnification, 200× (control) and 500× (pantoprazole or EOHM).</p