The tumor microenvironment confers profound resistance to anti-cancer immunotherapy. By targeting LIGHT, a member of the TNF superfamily of cytokines, to tumor vessels via a vascular targeting peptide (VTP), we developed a reagent with the dual ability to modulate the angiogenic vasculature and to induce tertiary lymphoid structures (TLSs). LIGHT-VTP triggered the influx of endogenous T cells into autochthonous or syngeneic tumors, which are resistant to immunotherapy. LIGHT-VTP in combination with checkpoint inhibition generated a large number of intratumoral effector and memory T cells with ensuing survival benefits, while the addition of anti-tumor vaccination achieved maximal therapeutic efficacy. Thus, the combination treatments stimulated the trafficking of pre-existing endogenous effector T cells as well as their intratumoral activation and were more successful than current immunotherapies, which fail due to tumor-intrinsic resistance mechanisms.
The surface of the oral plaque bacterium Streptococcus cristatus is decorated with a lateral tuft of fibrils. The fibrillar tuft functions in the adhesion of S. cristatus to heterologous bacterial species in the plaque biofilm. The tuft typically consists of a densely packed fringe of shorter fibrils 238 ± 19 nm long with longer, less abundant fibrils 403 ± 66 nm long projecting through the fringe of short fibrils. The two types of fibrils in the tufts of S. cristatus have been refractory to biochemical separation, complicating their characterization. A hexadecane partition assay was used to enrich for subpopulations of S. cristatus CR311 (type strain NCTC 12479) having distinct fibrillar morphotypes. Negative staining in the TEM revealed that cells of a hydrophobic subpopulation of S. cristatus (CR311var1) carried only the long fibrils (395 ± 32 nm). A hydrophilic subpopulation of S. cristatus (CR311var3) consisted of mixed morphotypes having no fibrils or remnant short fibrils (223 ± 49 nm). No long fibrils were observed on any cells in the CR311var3 subpopulation. The CR311var3 morphotype, unlike the wild-type strain and CR311var1, was not able to form corncobs with either Corynebacterium matruchotii or Fusobacterium nucleatum. Variant CR311var3 did not express the novel gene srpA, which encodes a high molecular weight (321,882 Da) serine-rich protein, SrpA. The SrpA protein contains two extensive repeat motifs of 17 and 71 amino acids and a gram-positive cell wall anchor consensus sequence (LPNTG). The unusual properties of SrpA most closely resemble those of Fap1, the fimbrial-associated adhesin protein of Streptococcus parasanguis. The association of long fibrils, high surface hydrophobicity, ability to form corncob formations, and expression of the srpA gene suggest that SrpA is a long fibril protein in S. cristatus. Keywordscorncobs; fibrils; SrpA; Streptococcus cristatus; tuftsThe surfaces of oral streptococci control the adhesive interactions that determine the specific ecologic niche of these bacteria within the oral cavity. It is believed that many of these interactions are associated with appendages that decorate the bacterial surface. Two classes of these structures, fibrils and fimbriae, have been described on different streptococcal species (11). The majority of the streptococci carry short fibrils (40-400 nm), which are thin Copyright clumped structures that may be peritrichous or localized in tufts (8). A few streptococcal strains carry peritrichous fimbriae, with a width of 3-5 nm, which are longer (1-3 μm) and more flexible than fibrils.The structure and function of one peritrichous fibril component on Streptococcus gordonii DL1 has been studied by McNab et al. (17), who showed that the sparse, peritrichous fibrils (61 nm long) are encoded by the cshA gene (18). The CshA polypeptide (259 kDa) contains 2508 amino acid residues and is apparently not glycosylated. The protein comprises a 41-residue amino-terminal signal sequence, a nonrepetitive region, and an extensive 101 amino ac...
BackgroundMicroscopic evaluation of urine is inconsistently performed in veterinary clinics. The IDEXX SediVue Dx® Urine Sediment Analyzer (SediVue) recently was introduced for automated analysis of canine and feline urine and may facilitate performance of urinalyses in practice.ObjectiveCompare the performance of the SediVue with manual microscopy for detecting clinically relevant numbers of cells and 2 crystal types.SamplesFive‐hundred thirty urine samples (82% canine, 18% feline).MethodsFor SediVue analysis (software versions [SW] 1.0.0.0 and 1.0.1.3), uncentrifuged urine was pipetted into a cartridge. Images were captured and processed using a convolutional neural network algorithm. For manual microscopy, urine was centrifuged to obtain sediment. To determine sensitivity and specificity of the SediVue compared with manual microscopy, thresholds were set at ≥5/high power field (hpf) for red blood cells (RBC) and white blood cells (WBC) and ≥1/hpf for squamous epithelial cells (sqEPI), non‐squamous epithelial cells (nsEPI), struvite crystals (STR), and calcium oxalate dihydrate crystals (CaOx Di).ResultsThe sensitivity of the SediVue (SW1.0.1.3) was 85%‐90% for the detection of RBC, WBC, and STR; 75% for CaOx Di; 71% for nsEPI; and 33% for sqEPI. Specificity was 99% for sqEPI and CaOx Di; 87%‐90% for RBC, WBC, and nsEPI; and 84% for STR. Compared to SW1.0.0.0, SW1.0.1.3 had increased sensitivity but decreased specificity. Performance was similar for canine versus feline and fresh versus stored urine samples.Conclusions and Clinical ImportanceThe SediVue exhibits good agreement with manual microscopy for the detection of most formed elements evaluated, but improvement is needed for epithelial cells.
Objective—To examine associations between CSF biomarkers, initial neurologic dysfunction, and long-term ambulatory outcome in dogs with acute intervertebral disk herniation (IVDH). Design—Prospective clinical study. Animals—54 dogs with acute thoracolumbar IVDH and 16 clinically normal dogs. Procedures—For each dog, variables, including CSF myelin basic protein (MBP), lactate, calcium, glucose, and total protein concentrations; nucleated cell count; and creatine kinase (CK) and aspartate aminotransferase activities, were measured. For dogs with thoracolumbar IVDH, initial neurologic function was characterized by use of a modified Frankel score (MFS; determined on a scale of 0 to 5, where 0 represented paraplegia with no deep nociception and 5 represented paraspinal hyperesthesia only). Long-term follow-up was assessed. Results—Among dogs with thoracolumbar IVDH, those with CSF CK activity ≤ 38 U/L had a 35-fold increase in the odds of long-term ambulation, compared with the odds in dogs with CSF CK activity > 38 U/L, adjusting for neurologic functioning at the evaluation. The CSF lactate, calcium, and glucose concentrations and aspartate aminotransferase activity were not predictive of long-term ambulatory outcome. Data analysis revealed that long-term functional recovery was > 98% for affected dogs, regardless of their initial MFS, when CSF CK activity was ≤ 38 U/L and MBP concentration was ≤ 3 ng/mL. Conclusions and Clinical Relevance—In dogs with acute thoracolumbar IVDH, CSF CK activity and MBP concentration appeared to be prognostic indicators and, along with initial MFS, can be used to predict long-term ambulatory outcome.
Background: Release of myelin basic protein (MBP) into the cerebrospinal fluid (CSF) is associated with active demyelination and correlates with outcome in various neurological diseases.Hypothesis/Objectives: To describe associations among CSF MBP concentration, initial neurological dysfunction, and long-term ambulatory outcome in dogs with acute thoracolumbar intervertebral disk herniation (IVDH).Animals: Five hundred and seventy-four dogs with acute thoracolumbar IVDH and 16 clinically normal dogs. Methods: Prospective case series clinical study. Signalment, initial neurological dysfunction as determined by a modified Frankel score (MFS), and ambulatory outcome at 43-month follow-up were recorded. Cisternal CSF MBP concentration was determined by an ELISA. Associations were estimated between CSF MBP concentration and various clinical parameters.Results: Dogs with thoracolumbar IVDH that did not ambulate at follow-up had a higher CSF MBP concentration (median, 3.56 ng/mL; range, 0.59-51.2 ng/mL) compared with control dogs (median, 2.22 ng/mL; range, 0-3.82 ng/mL) (P 5 .032). A CSF MBP concentration of !3 ng/mL had a sensitivity of 78% and specificity of 76% to predict an unsuccessful outcome based on receiver-operating characteristics curve analysis (area under the curve 50.688, P 5 .079). Affected dogs with a CSF MBP concentration !3 ng/mL had 0.09 times the odds of ambulation at follow-up compared with affected dogs with CSF MBP concentration o3 ng/mL when adjusted for initial MFS (95% confidence interval 0.01-0.66, P 5 .018).Conclusions and Clinical Importance: These results would suggest that CSF MBP concentration may be useful as an independent prognostic indicator in dogs with thoracolumbar IVDH.
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