The present study examined the effects of a visual-based biofeedback training on improving balance challenges in autism spectrum disorder (ASD). Twenty-nine youth with ASD (7–17 years) completed an ...intensive 6-week biofeedback-based videogame balance training. Participants exhibited training-related balance improvements that significantly accounted for postural-sway improvements outside of training. Participants perceived the training as beneficial and enjoyable. Significant moderators of training included milder stereotyped and ritualistic behaviors and better starting balance. Neither IQ nor BMI moderated training. These results suggest that biofeedback-based balance training is associated with balance improvements in youth with ASD, most robustly in those with less severe repetitive behaviors and better starting balance. The training was perceived as motivating, further suggesting its efficacy and likelihood of use.
Checkpoint inhibitors and T-cell therapies have highlighted the critical role of T cells in anti-cancer immunity. However, limitations associated with these treatments drive the need for alternative ...approaches. Here, we engineer red blood cells into artificial antigen-presenting cells (aAPCs) presenting a peptide bound to the major histocompatibility complex I, the costimulatory ligand 4-1BBL, and interleukin (IL)-12. This leads to robust, antigen-specific T-cell expansion, memory formation, additional immune activation, tumor control, and antigen spreading in tumor models in vivo. The presence of 4-1BBL and IL-12 induces minimal toxicities due to restriction to the vasculature and spleen. The allogeneic aAPC, RTX-321, comprised of human leukocyte antigen-A*02:01 presenting the human papilloma virus (HPV) peptide HPV16 E7
, 4-1BBL, and IL-12 on the surface, activates HPV-specific T cells and promotes effector function in vitro. Thus, RTX-321 is a potential 'off-the-shelf' in vivo cellular immunotherapy for treating HPV + cancers, including cervical and head/neck cancers.
Adnectins are targeted biologics derived from the tenth type III domain of human fibronectin (10Fn3), a member of the immunoglobulin superfamily. Target-specific binders are selected from libraries ...generated by diversifying the three 10Fn3 loops that are analogous to the complementarity determining regions of antibodies. The crystal structures of two Adnectins were determined, each in complex with its therapeutic target, EGFR or IL-23. Both Adnectins bind different epitopes than those bound by known monoclonal antibodies. Molecular modeling suggests that some of these epitopes might not be accessible to antibodies because of the size and concave shape of the antibody combining site. In addition to interactions from the Adnectin diversified loops, residues from the N terminus and/or the β strands interact with the target proteins in both complexes. Alanine-scanning mutagenesis confirmed the calculated binding energies of these β strand interactions, indicating that these nonloop residues can expand the available binding footprint.
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► Adnectins interact with targets using multiple binding modes ► Residues outside of the diversified loops can interact with ligand ► Some fixed scaffold residues contribute to the binding energy ► Adnectins can interact with epitopes that may be inaccessible to antibodies
•Youth with ASD may have balance difficulties when standing on unsteady surfaces.•However, there was substantial variability in postural sway within the ASD group.•IQ accounted for variability within ...the ASD group but not within the control group.•IQ may be an important fact for postural stability on unsteady surfaces in ASD.
Postural stability difficulties are commonly reported in people on the autism spectrum. However, it is unclear whether unsteady surfaces may exacerbate postural stability difficulties in children and adolescents with autism spectrum disorder (ASD). Understanding balance on unsteady surfaces is important because uneven surfaces are commonly encountered in daily life.
Twenty-one youth on the autism spectrum and 16 youth with typical development (ages 6–16 years, IQ ≥ 79) stood on both a fixed and unsteady (tiltable) platform, and center of pressure was measured.
The group with ASD exhibited differentially more postural sway on the unsteady surface compared to the group with typical development. However, there was substantial variability within the ASD group. Follow-up analyses suggested that much of the variability in postural sway in the ASD group was accounted for by IQ.
Clinically, these findings suggest that not all individuals with ASD struggle more with postural stability on unsteady surfaces. Instead children and adolescents with ASD and below-average IQ may have particular difficulty on unsteady surfaces and may require accommodations. Further, these findings lay the groundwork for future research to investigate the underlying mechanisms of poorer balance across the autism spectrum.
Recombinant agonists that activate co-stimulatory and cytokine receptors have shown limited clinical anticancer utility, potentially due to narrow therapeutic windows, the need for coordinated ...activation of co-stimulatory and cytokine pathways and the failure of agonistic antibodies to recapitulate signaling by endogenous ligands. RTX-240 is a genetically engineered red blood cell expressing 4-1BBL and IL-15/IL-15Rα fusion (IL-15TP). RTX-240 is designed to potently and simultaneously stimulate the 4-1BB and IL-15 pathways, thereby activating and expanding T cells and NK cells, while potentially offering an improved safety profile through restricted biodistribution. We assessed the ability of RTX-240 to expand and activate T cells and NK cells and evaluated the in vivo efficacy, pharmacodynamics and tolerability using murine models. Treatment of PBMCs with RTX-240 induced T cell and NK cell activation and proliferation. In vivo studies using mRBC-240, a mouse surrogate for RTX-240, revealed biodistribution predominantly to the red pulp of the spleen, leading to CD8 + T cell and NK cell expansion. mRBC-240 was efficacious in a B16-F10 melanoma model and led to increased NK cell infiltration into the lungs. mRBC-240 significantly inhibited CT26 tumor growth, in association with an increase in tumor-infiltrating proliferating and cytotoxic CD8 + T cells. mRBC-240 was tolerated and showed no evidence of hepatic injury at the highest feasible dose, compared with a 4-1BB agonistic antibody. RTX-240 promotes T cell and NK cell activity in preclinical models and shows efficacy and an improved safety profile. Based on these data, RTX-240 is now being evaluated in a clinical trial.
Pulmonary arterial hypertension (PAH) is often difficult to diagnose and challenging to treat. Untreated, it is characterized by a progressive increase in pulmonary vascular resistance leading to ...right ventricular failure and death. The past decade has seen remarkable improvements in therapy, driven largely by the conduct of randomized controlled trials. Still, the selection of most appropriate therapy is complex, and requires familiarity with the disease process, evidence from treatment trials, complicated drug delivery systems, dosing regimens, side effects, and complications. This chapter will provide evidence-based treatment recommendations for physicians involved in the care of these complex patients. Due to the complexity of the diagnostic evaluation required, and the treatment options available, it is strongly recommended that consideration be given to referral of patients with PAH to a specialized center.
Quality of life in acoustic neuroma patients McLaughlin, Eamon J; Bigelow, Douglas C; Lee, John Y K ...
Otology & neurotology,
2015-April, Letnik:
36, Številka:
4
Journal Article
Recenzirano
To examine the differences in quality of life for vestibular schwannoma patients undergoing conservative management, gamma knife, and surgery.
Vestibular schwannoma patients without a diagnosis of ...NF2.
Vestibular schwannoma treatment or conservative management.
Penn Acoustic Neuroma Quality of Life (PANQOL) survey scores (0-100).
One hundred eighty-six patients (98 conservative, 49 gamma knife, 39 surgery) were included. Mean patient age (years) of the surgery group (49 ± 14) was significantly younger than both the conservative (58 ± 13) and gamma knife group (59 ± 12) (p < 0.001). Mean follow-up time was 2.6 years.Tumor size (mm) was found to be significantly different between the conservative (8 ± 4.8), gamma knife (18 ± 5.9), and surgery (22 ± 8.3) groups (p < 0.001). Speech recognition threshold and speech discrimination percentage were significantly better for the conservative group compared to the gamma knife or surgery groups (p < 0.001).The hearing domain scores seemed better for the conservative group (62 ± 26) when compared to the surgery group (47 ± 25). The general and total domain scores were similar for all treatment groups, whereas the quality-of-life scores for gamma knife and surgery were similar.
Although surgery groups' significantly larger tumors and worse hearing were apparent in specific PANQOL domains, all patients achieved a similar general level of quality of life.
Biological function of the
BCR-ABL oncogene is dependent on its activated tyrosine kinase. Mutations that inactivate the SRC homology 2 (SH2) domain, the GRB2-binding site in BCR, orthe major ...autophosphorylation site of the kinase domain selectively disrupt downstream signaling but not tyrosine kinase activity. Despite a loss of fibroblast transformation activity, all three mutants retain the ability to render hematopoietic cell lines growth factor independent and transform primary bone marrow cells in vitro. In vivo tests of malignant potential reveal a most critical role for signals dependent on the BCR-ABL SH2 domain. The efficiency of both fibroblast and hematopoietic transformation by BCR-ABL is strongly affected by increased dosage of the SHC adapter protein, which can connect tyrosine kinase signals to RAS. The
BCR-ABL oncogene activates multiple alternative pathways to RAS for hematopoietic transformation.
Background: In late 2006, the seaside community in Esperance, Western Australia, was alerted to thousands of native bird species dying. The source of the lead was thought to derive from the handling ...of Pb carbonate concentrate from the Magellan mine through the port of Esperance, begun in July 2005. Concern was expressed for the impact of this process on the community. Objective: This study was designed to evaluate the source of Pb in blood of a random sample of the community using Pb isotope ratios. Methods: The cohort comprised 49 children (48 < 5 years of age) along with 18 adults (> 20 years of age) with a bias toward higher blood lead (PbB) values to facilitate source identification. Results: Mean PbB level of the children was 7.5 micrograms/dL (range, 1.5-25.7 micrograms/dL; n = 49; geometric mean, 6.6 micrograms/dL), with four children whose PbB was > 12 micrograms/dL. The isotopic data for blood samples lay around two distinct arrays. The blood of all children analyzed for Pb isotopes contained a contribution of Pb from the Magellan mine, which for young children ranged from 27% up to 93% (mean, 64%; median, 71%). Subtraction of the ore component gave a mean background PbB of 2.3 micrograms/dL. Several children whose PbB was > 9 micrograms/dL and most of the older subjects have complex sources of Pb. Conclusions: The death of the birds acted as a sentinel event; otherwise, the exposure of the community, arising from such a toxic form of Pb, could have been tragic. Isotopic data and mineralogic and particle size analyses indicate that, apart from the recognized pathway of Pb exposure by hand-to-mouth activity in children, the inhalation pathway could have been a significant contributor to PbB for some of the very young children and in some parents.
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