Tumor Cell-Surface Binding of Immune Stimulating Polymeric Glyco-Adjuvant via Cysteine-Reactive Pyridyl Disulfide Promotes Antitumor Immunity.

Immune stimulating agents like Toll-like receptor 7 (TLR7) agonists induce potent antitumor immunity but are limited in their therapeutic window due to off-target immune activation. Here, we developed a polymeric delivery platform that binds excess unpaired cysteines on tumor cell surfaces and debris to adjuvant tumor neoantigens as an in situ vaccine. The metabolic and enzymatic dysregulation in the tumor microenvironment produces these exofacial free thiols, which can undergo efficient disulfide exchange with thiol-reactive pyridyl disulfide moieties upon intratumoral injection. These functional monomers are incorporated into a copolymer with pendant mannose groups and TLR7 agonists to target both antigen and adjuvant to antigen presenting cells. When tethered in the tumor, the polymeric glyco-adjuvant induces a robust antitumor response and prolongs survival of tumor-bearing mice, including in checkpoint-resistant B16F10 melanoma. The construct additionally reduces systemic toxicity associated with clinically relevant small molecule TLR7 agonists.

Pro-lymphangiogenic VEGFR-3 signaling modulates memory T cell responses in allergic airway inflammation.

In allergic airway inflammation, VEGFR-3-mediated lymphangiogenesis occurs in humans and mouse models, yet its immunological roles, particularly in adaptive immunity, are poorly understood. Here, we explored how pro-lymphangiogenic signaling affects the allergic response to house dust mite (HDM). In the acute inflammatory phase, the lungs of mice treated with blocking antibodies against VEGFR-3 (mF4-31C1) displayed less inflammation overall, with dramatically reduced innate and T-cell numbers and reduced inflammatory chemokine levels. However, when inflammation was allowed to resolve and memory recall was induced 2 months later, mice treated with mF4-31C1 as well as VEGF-C/-D knockout models showed exacerbated type 2 memory response to HDM, with increased Th2 cells, eosinophils, type 2 chemokines, and pathological inflammation scores. This was associated with lower CCL21 and decreased TRegs in the lymph nodes. Together, our data imply that VEGFR-3 activation in allergic airways helps to both initiate the acute inflammatory response and regulate the adaptive (memory) response, possibly in part by shifting the TReg/Th2 balance. This introduces new immunomodulatory roles for pro-lymphangiogenic VEGFR-3 signaling in allergic airway inflammation and suggests that airway lymphatics may be a novel target for treating allergic responses.

A new species of Hisonotus (Siluriformes: Otothyrinae) from the upper rio Paraná and rio São Francisco basins, Brazil.

A new species of Hisonotus is described from the upper rio Paraná and rio São Francisco basins. The new species is distinguished from congeners by (1) completely exposed abdomen with no development of dermal plates (with the exception of extremely small platelets present near the urogenital pore in some specimens) and the combination of the following characters: (2) lack of a conspicuous tuft of enlarged odontodes on posterior tip of parieto-supraoccipital; (3) rectangular dorsal-fin spinelet; (4) complete mid-lateral plate series; (5) higher number of vertebrae, 29-30; (6) dark brown coloration on caudal fin with one pair of circular hyaline colored regions at center of both lobes; (7) absence of broad light stripes on dorsolateral surface of head; (8) odontodes not forming longitudinally aligned rows on head and trunk; and (9) apex of teeth yellowish in color.

Combination of ensiling and fungal delignification as effective wheat straw pretreatment.

BACKGROUND: Utilization of lignocellulosic feedstocks for bioenergy production in developing countries demands competitive but low-tech conversion routes. White-rot fungi (WRF) inoculation and ensiling are two methods previously investigated for low-tech pretreatment of biomasses such as wheat straw (WS). This study was undertaken to assess whether a combination of forced ensiling with Lactobacillus buchneri and WRF treatment using a low cellulase fungus, Ceriporiopsis subvermispora, could produce a relevant pretreatment effect on WS for bioethanol and biogas production. RESULTS: A combination of the ensiling and WRF treatment induced efficient pretreatment of WS by reducing lignin content and increasing enzymatic sugar release, thereby enabling an ethanol yield of 66 % of the theoretical max on the WS glucan, i.e. a yield comparable to yields obtained with high-tech, large-scale pretreatment methods. The pretreatment effect was reached with only a minor total solids loss of 5 % by weight mainly caused by the fungal metabolism. The combination of the biopretreatments did not improve the methane potential of the WS, but improved the initial biogas production rate significantly. CONCLUSION: The combination of the L. buchneri ensiling and C. subvermispora WRF treatment provided a significant improvement in the pretreatment effect on WS. This combined biopretreatment produced particularly promising results for ethanol production.

Comparative radiographic and histological analyses of periapical lesion development.

OBJECTIVE: The present study evaluated the dynamics of the development of periapical lesions. STUDY DESIGN: Root canals from dogs' teeth were exposed to the oral environment, and then sealed for 7 days (Group A), 15 days (Group B), 30 days (Group C), and 60 days (Group D). After each experimental period, radiographs were taken to detect periapical bone resorption. In addition, histological sections from the periapical region were prepared. The radiographic and histological results were analyzed by ANOVA and Tukey's, Wilcoxon, and Pearson's tests. Significance level was set at 5%. RESULTS: Lesions were radiographically visible at 15 and 30 days, and had similar size at these periods (P > .05). At 60 days, lesions were larger than in the other periods (P < .05). Bone resorption was detected histologically at 7 days. The greatest values of bone resorption were observed at the 30- and 60-day periods (P < .05). The results of the methods of evaluation were similar only at the 30-day period. There was no correlation between the radiographic and histological results. CONCLUSIONS: Periapical radiography did not provide detection of periapical lesion in its initial stages. The periapical lesions became more evident radiographically when the bone resorption area increased.

Evaluation of the radiopacity of calcium hydroxide- and glass-ionomer-based root canal sealers.

AIM: To evaluate the radiopacity of calcium hydroxide-based root canal sealers (Acroseal, Sealapex and Sealer 26), a glass-ionomer-based sealer (Activ GP Sealer) and a zinc oxide and eugenol-based sealer (Intrafill). METHODOLOGY: Five disc-shaped specimens (10 x 1 mm) were fabricated from each material, according to the International Organization for Standardization (ISO) 6876/2001 standard. After setting of the materials, radiographs were taken using occlusal films and a graduated aluminum step-wedge varying from 2 to 16 mm in thickness. The dental X-ray unit (GE1000) was set at 50 Kvp, 10 mA, 18 pulses s(-1) and distance of 33.5 cm. The radiographs were digitized and the radiopacity compared with that of the aluminum step-wedge, using WIXWIN-2000 software (Gendex). Data (mm Al) were submitted to ANOVA and Tukey test. RESULTS: Intrafill was the most radiopaque material (7.67 mm Al) followed by Sealer 26 (6.33 mm Al), Sealapex (6.05 mm Al) and Acroseal (4.03 mm Al). Activ GP was the least radiopaque material (1.95 mm Al, P < 0.05). CONCLUSIONS: The sealers evaluated in this study had different radiopacities. However, except for the glass-ionomer-based sealer, all materials had radiopacity values above the minimum recommended by the ISO standard.