Biodegradable lipophilic polymeric mRNA nanoparticles for ligand-free targeting of splenic dendritic cells for cancer vaccination.

Nanoparticle (NP)-based mRNA cancer vaccines hold great promise to realize personalized cancer treatments. To advance this technology requires delivery formulations for efficient intracellular delivery to antigen-presenting cells. We developed a class of bioreducible lipophilic poly(beta-amino ester) nanocarriers with quadpolymer architecture. The platform is agnostic to the mRNA sequence, with one-step self-assembly allowing for delivery of multiple antigen-encoding mRNAs as well as codelivery of nucleic acid-based adjuvants. We examined structure-function relationships for NP-mediated mRNA delivery to dendritic cells (DCs) and identified that a lipid subunit of the polymer structure was critical. Following intravenous administration, the engineered NP design facilitated targeted delivery to the spleen and preferential transfection of DCs without the need for surface functionalization with targeting ligands. Treatment with engineered NPs codelivering antigen-encoding mRNA and toll-like receptor agonist adjuvants led to robust antigen-specific CD8+ T cell responses, resulting in efficient antitumor therapy in in vivo models of murine melanoma and colon adenocarcinoma.

Nanoparticles for generating antigen-specific T cells for immunotherapy.

T cell therapy shows promise as an immunotherapy in both immunostimulatory and immunosuppressive applications. However, the forms of T cell-based therapy that are currently in the clinic, such as adoptive cell transfer and vaccines, are limited by cost, time-to-treatment, and patient variability. Nanoparticles offer a modular, universal platform to improve the efficacy of various T cell therapies as nanoparticle properties can be easily modified for enhanced cell targeting, organ targeting, and cell internalization. Nanoparticles can enhance or even replace endogenous cells during each step of generating an antigen-specific T cell response - from antigen presentation and T cell activation to T cell maintenance. In this review, we discuss the unique applications of nanoparticles for antigen-specific T cell therapy, focusing on nanoparticles as vaccines (to activate endogenous antigen presenting cells (APCs)), as artificial Antigen Presenting Cells (aAPCs, to directly activate T cells), and as drug delivery vehicles (to support activated T cells).

A Novel Peptide Prevents Enterotoxin- and Inflammation-Induced Intestinal Fluid Secretion by Stimulating Sodium-Hydrogen Exchanger 3 Activity.

BACKGROUND & AIMS: Acute diarrheal diseases are the second most common cause of infant mortality in developing countries. This is contributed to by lack of effective drug therapy that shortens the duration or lessens the volume of diarrhea. The epithelial brush border sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) accounts for a major component of intestinal Na+ absorption and is inhibited in most diarrheas. Because increased intestinal Na+ absorption can rehydrate patients with diarrhea, NHE3 has been suggested as a potential druggable target for drug therapy for diarrhea. METHODS: A peptide (sodium-hydrogen exchanger 3 stimulatory peptide [N3SP]) was synthesized to mimic the part of the NHE3 C-terminus that forms a multiprotein complex that inhibits NHE3 activity. The effect of N3SP on NHE3 activity was evaluated in NHE3-transfected fibroblasts null for other plasma membrane NHEs, a human colon cancer cell line that models intestinal absorptive enterocytes (Caco-2/BBe), human enteroids, and mouse intestine in vitro and in vivo. N3SP was delivered into cells via a hydrophobic fluorescent maleimide or nanoparticles. RESULTS: N3SP uptake stimulated NHE3 activity at nmol/L concentrations under basal conditions and partially reversed the reduced NHE3 activity caused by elevated adenosine 3',5'-cyclic monophosphate, guanosine 3',5'-cyclic monophosphate, and Ca2+ in cell lines and in in vitro mouse intestine. N3SP also stimulated intestinal fluid absorption in the mouse small intestine in vivo and prevented cholera toxin-, Escherichia coli heat-stable enterotoxin-, and cluster of differentiation 3 inflammation-induced fluid secretion in a live mouse intestinal loop model. CONCLUSIONS: These findings suggest pharmacologic stimulation of NHE3 activity as an efficacious approach for the treatment of moderate/severe diarrheal diseases.

The relationship of rate and pause features to the communicative participation of people living with ALS.

INTRODUCTION/AIMS: Many people living with amyotrophic lateral sclerosis (PALS) report restrictions in their day-to-day communication (communicative participation). However, little is known about which speech features contribute to these restrictions. This study evaluated the effects of common speech symptoms in PALS (reduced overall speaking rate, slowed articulation rate, and increased pausing) on communicative participation restrictions. METHODS: Participants completed surveys (the Communicative Participation Item Bank-short form; the self-entry version of the ALS Functional Rating Scale-Revised) and recorded themselves reading the Bamboo Passage aloud using a smartphone app. Rate and pause measures were extracted from the recordings. The association of various demographic, clinical, self-reported, and acoustic speech features with communicative participation was evaluated with bivariate correlations. The contribution of salient rate and pause measures to communicative participation was assessed using multiple linear regression. RESULTS: Fifty seven people living with ALS participated in the study (mean age = 61.1 years). Acoustic and self-report measures of speech and bulbar function were moderately to highly associated with communicative participation (Spearman rho coefficients ranged from rs = 0.48 to rs = 0.77). A regression model including participant age, sex, articulation rate, and percent pause time accounted for 57% of the variance of communicative participation ratings. DISCUSSION: Even though PALS with slowed articulation rate and increased pausing may convey their message clearly, these speech features predict communicative participation restrictions. The identification of quantitative speech features, such as articulation rate and percent pause time, is critical to facilitating early and targeted intervention and for monitoring bulbar decline in ALS.

Role of articulatory motor networks in perceptual categorization of speech signals: a 7T fMRI study.

Speech and language processing involve complex interactions between cortical areas necessary for articulatory movements and auditory perception and a range of areas through which these are connected and interact. Despite their fundamental importance, the precise mechanisms underlying these processes are not fully elucidated. We measured BOLD signals from normal hearing participants using high-field 7 Tesla fMRI with 1-mm isotropic voxel resolution. The subjects performed 2 speech perception tasks (discrimination and classification) and a speech production task during the scan. By employing univariate and multivariate pattern analyses, we identified the neural signatures associated with speech production and perception. The left precentral, premotor, and inferior frontal cortex regions showed significant activations that correlated with phoneme category variability during perceptual discrimination tasks. In addition, the perceived sound categories could be decoded from signals in a region of interest defined based on activation related to production task. The results support the hypothesis that articulatory motor networks in the left hemisphere, typically associated with speech production, may also play a critical role in the perceptual categorization of syllables. The study provides valuable insights into the intricate neural mechanisms that underlie speech processing.

The association between longitudinal declines in speech sound accuracy and speech intelligibility in speakers with amyotrophic lateral sclerosis.

The purpose of this study was to examine how neurodegeneration secondary to amyotrophic lateral sclerosis (ALS) impacts speech sound accuracy over time and how speech sound accuracy, in turn, is related to speech intelligibility. Twenty-one participants with ALS read the Bamboo Passage over multiple data collection sessions across several months. Phonemic and orthographic transcriptions were completed for all speech samples. The percentage of phonemes accurately produced was calculated across each phoneme, sound class (i.e. consonants versus vowels), and distinctive feature (i.e. features involved in Manner of Articulation, Place of Articulation, Laryngeal Voicing, Tongue Height, and Tongue Advancement). Intelligibility was determined by calculating the percentage of words correctly transcribed orthographically by naive listeners. Linear mixed effects models were conducted to assess the decline of each distinctive feature over time and its impact on intelligibility. The results demonstrated that overall phonemic production accuracy had a nonlinear relationship with speech intelligibility and that a subset of features (i.e. those dependent on precise lingual and labial constriction and/or extensive lingual and labial movement) were more important for intelligibility and were more impacted over time than other features. Furthermore, findings revealed that consonants were more strongly associated with intelligibility than vowels, but consonants did not significantly differ from vowels in their decline over time. These findings have the potential to (1) strengthen mechanistic understanding of the physiological constraints imposed by neuronal degeneration on speech production and (2) inform the timing and selection of treatment and assessment targets for individuals with ALS.

In situ genetic engineering of tumors for long-lasting and systemic immunotherapy.

Cancer immunotherapy has been the subject of extensive research, but highly effective and broadly applicable methods remain elusive. Moreover, a general approach to engender endogenous patient-specific cellular therapy, without the need for a priori knowledge of tumor antigen, ex vivo cellular manipulation, or cellular manufacture, could dramatically reduce costs and broaden accessibility. Here, we describe a biotechnology based on synthetic, biodegradable nanoparticles that can genetically reprogram cancer cells and their microenvironment in situ so that the cancer cells can act as tumor-associated antigen-presenting cells (tAPCs) by inducing coexpression of a costimulatory molecule (4-1BBL) and immunostimulatory cytokine (IL-12). In B16-F10 melanoma and MC38 colorectal carcinoma mouse models, reprogramming nanoparticles in combination with checkpoint blockade significantly reduced tumor growth over time and, in some cases, cleared the tumor, leading to long-term survivors that were then resistant to the formation of new tumors upon rechallenge at a distant site. In vitro and in vivo analyses confirmed that locally delivered tAPC-reprogramming nanoparticles led to a significant cell-mediated cytotoxic immune response with systemic effects. The systemic tumor-specific and cell-mediated immunotherapy response was achieved without requiring a priori knowledge of tumor-expressed antigens and reflects the translational potential of this nanomedicine.

The Current Proposed Total Hip Arthroplasty Surgical Planning Guidelines Based on Classification of Spine Stiffness May be Flawed Due to Incorrect Assumptions.

BACKGROUND: The available classifications and preoperative planning tools for total hip arthroplasty assume that: 1) there is no variation in the sagittal pelvic tilt (SPT) if the radiographs are repeated, and 2) there is no significant change in the postoperative SPT postoperatively. We hypothesized that there would be significant differences in postoperative SPT tilt as measured by the sacral slope, thus rendering the current classifications and tools flawed. METHODS: This study was a multicenter, retrospective analysis of preoperative and postoperative (1.5-6 months) full-body imaging of 237 primary total hip arthroplasty (standing and sitting positions). Patients were categorized as 1) stiff spine (standing sacral slope sitting sacral slope < 10°) and 2) normal spine (standing sacral slope-sitting sacral slope ≥ 10°). Results were compared using the paired t-test. The posthoc power analysis showed a power of 0.99. RESULTS: The difference in mean standing and sitting sacral slope between the preoperative and postoperative measurements was 1°. However, in standing position, this difference was more than 10° in 14.4% of patients. In the sitting position, this difference was more than 10° in 34.2% of patients and more than 20° in 9.8% of patients. Postoperatively, 32.5% of patients switched groups based on the classification, which rendered the preoperative planning suggested by the current classifications flawed. CONCLUSION: Current preoperative planning and classifications are based on a single acquisition of preoperative radiographs without the incorporation of possible postoperative changes in SPT. Validated classifications and planning tools should incorporate repeated measurements to determine the mean and variance in SPT and consider the significant postoperative changes in SPT.

Tongue and Lip Acceleration as a Measure of Speech Decline in Amyotrophic Lateral Sclerosis.

PURPOSE: The goal of this study was to examine the efficacy of acceleration-based articulatory measures in characterizing the decline in speech motor control due to amyotrophic lateral sclerosis (ALS). METHOD: Electromagnetic articulography was used to record tongue and lip movements during the production of 20 phrases. Data were collected from 50 individuals diagnosed with ALS. Articulatory kinematic variability was measured using the spatiotemporal index of both instantaneous acceleration and speed signals. Linear regression models were used to analyze the relationship between variability measures and intelligible speaking rate (a clinical measure of disease progression). A machine learning algorithm (support vector regression, SVR) was used to assess whether acceleration or speed features (e.g., mean, median, maximum) showed better performance at predicting speech severity in patients with ALS. RESULTS: As intelligible speaking rate declined, the variability of acceleration of tongue and lip movement patterns significantly increased (p < 0.001). The variability of speed and vertical displacement did not significantly predict speech performance measures. Additionally, based on R2 and root mean square error (RMSE) values, the SVR model was able to predict speech severity more accurately from acceleration features (R2 = 0.601, RMSE = 38.453) and displacement features (R2 = 0.218, RMSE = 52.700) than from speed features (R2 = 0.554, RMSE = 40.772). CONCLUSION: Results from these models highlight differences in speech motor control in participants with ALS. The variability in acceleration of tongue and lip movements increases as speech performance declines, potentially reflecting physiological deviations due to the progression of ALS. Our findings suggest that acceleration is a more sensitive indicator of speech deterioration due to ALS than displacement and speed and may contribute to improved algorithm designs for monitoring disease progression from speech signals.

Review of methods for conducting speech research with minimally verbal individuals with autism spectrum disorder.

The purpose of this paper was to review best-practice methods of collecting and analyzing speech production data from minimally verbal autistic speakers. Data on speech production data in minimally verbal individuals are valuable for a variety of purposes, including phenotyping, clinical assessment, and treatment monitoring. Both perceptual ("by ear") and acoustic analyses of speech can reveal subtle improvements as a result of therapy that may not be apparent when correct/incorrect judgments are used. Key considerations for collecting and analyzing speech production data from this population are reviewed. The definition of "minimally verbal" that is chosen will vary depending on the specific hypotheses investigated, as will the stimuli to be collected and the task(s) used to elicit them. Perceptual judgments are ecologically valid but subject to known sources of bias; therefore, training and reliability procedures for perceptual analyses are addressed, including guidelines on how to select vocalizations for inclusion or exclusion. Factors to consider when recording and acoustically analyzing speech are also briefly discussed. In summary, the tasks, stimuli, training methods, analysis type(s), and level of detail that yield the most reliable data to answer the question should be selected. It is possible to obtain rich high-quality data even from speakers with very little speech output. This information is useful not only for research but also for clinical decision-making and progress monitoring.

The efficacy of acoustic-based articulatory phenotyping for characterizing and classifying four divergent neurodegenerative diseases using sequential motion rates.

Despite the impacts of neurodegeneration on speech function, little is known about how to comprehensively characterize the resulting speech abnormalities using a set of objective measures. Quantitative phenotyping of speech motor impairments may have important implications for identifying clinical syndromes and their underlying etiologies, monitoring disease progression over time, and improving treatment efficacy. The goal of this research was to investigate the validity and classification accuracy of comprehensive acoustic-based articulatory phenotypes in speakers with distinct neurodegenerative diseases. Articulatory phenotypes were characterized based on acoustic features that were selected to represent five components of motor performance: Coordination, Consistency, Speed, Precision, and Rate. The phenotypes were first used to characterize the articulatory abnormalities across four progressive neurologic diseases known to have divergent speech motor deficits: amyotrophic lateral sclerosis (ALS), progressive ataxia (PA), Parkinson's disease (PD), and the nonfluent variant of primary progressive aphasia and progressive apraxia of speech (nfPPA + PAOS). We then examined the efficacy of articulatory phenotyping for disease classification. Acoustic analyses were conducted on audio recordings of 217 participants (i.e., 46 ALS, 52 PA, 60 PD, 20 nfPPA + PAOS, and 39 controls) during a sequential speech task. Results revealed evidence of distinct articulatory phenotypes for the four clinical groups and that the phenotypes demonstrated strong classification accuracy for all groups except ALS. Our results highlight the phenotypic variability present across neurodegenerative diseases, which, in turn, may inform (1) the differential diagnosis of neurological diseases and (2) the development of sensitive outcome measures for monitoring disease progression or assessing treatment efficacy.

Effects of low-frequency repetitive transcranial magnetic stimulation in adductor laryngeal dystonia: a safety, feasibility, and pilot study.

PURPOSE: The effects of neuromodulation are virtually unexplored in adductor laryngeal dystonia (AdLD), a disorder characterized by involuntary contraction of intrinsic laryngeal muscles. Recent findings indicated that intracortical inhibition is reduced in people with AdLD. Low-frequency repetitive transcranial magnetic stimulation (rTMS) induces prolonged intracortical inhibition, but the effects in AdLD are unexplored. This pilot and feasibility study aimed to examine the safety, feasibility, and effects of a single session 1 Hz rTMS over the laryngeal motor cortex (LMC) in people with AdLD and healthy individuals. METHODS: The stimulation location was individualized and determined through TMS-evoked responses in the thyroarytenoid muscles using fine-wire electrodes. 1200 pulses of 1 Hz rTMS were delivered to the left LMC in two groups: Control (n = 6) and AdLD (n = 7). Tolerance, adverse effects, intracortical inhibition, and voice recordings were collected immediately before and after rTMS. Voice quality was assessed with acoustic-based and auditory-perceptual measures. RESULTS: All participants tolerated the procedures, with no unexpected adverse events or worsening of symptoms. No significant effects on intracortical inhibition were observed. In the AdLD group, there was a large-effect size after rTMS in vocal perturbation measures and a small-effect size in decreased phonatory breaks. CONCLUSIONS: One rTMS session over the LMC is safe and feasible, and demonstrated trends of beneficial effects on voice quality and phonatory function in AdLD. These preliminary findings support further investigation to assess clinical benefits in a future randomized sham-controlled trial. CLINICALTRIALS.GOV: NCT02957942, registered on November 8, 2016.

Mimicking biological functionality with polymers for biomedical applications.

The vast opportunities for biomaterials design and functionality enabled by mimicking nature continue to stretch the limits of imagination. As both biological understanding and engineering capabilities develop, more sophisticated biomedical materials can be synthesized that have multifaceted chemical, biological and physical characteristics designed to achieve specific therapeutic goals. Mimicry is being used in the design of polymers for biomedical applications that are required locally in tissues, systemically throughout the body, and at the interface with tissues.

Summary accuracy feedback and the left digit effect in number line estimation.

A robust left digit effect arises in number line estimation such that adults' estimates for numerals with different hundreds place digits but nearly identical magnitudes are systematically different from one another (e.g., 299 is placed too far to the left of 302). In two experiments, we investigate whether brief feedback interventions designed to increase task effort can reduce or eliminate the left digit effect in a self-paced 0-1,000 number line estimation task. Participants were assigned to complete three blocks of 120 trials each where the middle block contained feedback or no feedback. Feedback was in the form of summary accuracy scores (Experiment 1; N = 153) or competitive (summary) accuracy scores (Experiment 2; N = 145). In both experiments, planned analyses revealed large left digit effects in all blocks regardless of feedback condition. Feedback did not lead to a reduction in the left digit effect in either experiment, but improvements in overall accuracy were observed. We conclude that there are no changes in the left digit effect resulting from either summary accuracy feedback or competitive accuracy feedback. Also reported are exploratory analyses of trial characteristics (e.g., whether 299 is presented before or after 302) and the left digit effect.

Size-Controlled and Shelf-Stable DNA Particles for Production of Lentiviral Vectors.

Polyelectrolyte complex particles assembled from plasmid DNA (pDNA) and poly(ethylenimine) (PEI) have been widely used to produce lentiviral vectors (LVVs) for gene therapy. The current batch-mode preparation for pDNA/PEI particles presents limited reproducibility in large-scale LVV manufacturing processes, leading to challenges in tightly controlling particle stability, transfection outcomes, and LVV production yield. Here we identified the size of pDNA/PEI particles as a key determinant for a high transfection efficiency with an optimal size of 400-500 nm, due to a cellular-uptake-related mechanism. We developed a kinetics-based approach to assemble size-controlled and shelf-stable particles using preassembled nanoparticles as building blocks and demonstrated production scalability on a scale of at least 100 mL. The preservation of colloidal stability and transfection efficiency was benchmarked against particles generated using an industry standard protocol. This particle manufacturing method effectively streamlines the viral manufacturing process and improves the production quality and consistency.

Photocrosslinked Bioreducible Polymeric Nanoparticles for Enhanced Systemic siRNA Delivery as Cancer Therapy.

Clinical translation of polymer-based nanocarriers for systemic delivery of RNA has been limited due to poor colloidal stability in the blood stream and intracellular delivery of the RNA to the cytosol. To address these limitations, this study reports a new strategy incorporating photocrosslinking of bioreducible nanoparticles for improved stability extracellularly and rapid release of RNA intracellularly. In this design, the polymeric nanocarriers contain ester bonds for hydrolytic degradation and disulfide bonds for environmentally triggered small interfering RNA (siRNA) release in the cytosol. These photocrosslinked bioreducible nanoparticles (XbNPs) have a shielded surface charge, reduced adsorption of serum proteins, and enable superior siRNA-mediated knockdown in both glioma and melanoma cells in high-serum conditions compared to non-crosslinked formulations. Mechanistically, XbNPs promote cellular uptake and the presence of secondary and tertiary amines enables efficient endosomal escape. Following systemic administration, XbNPs facilitate targeting of cancer cells and tissue-mediated siRNA delivery beyond the liver, unlike conventional nanoparticle-based delivery. These attributes of XbNPs facilitate robust siRNA-mediated knockdown in vivo in melanoma tumors colonized in the lungs following systemic administration. Thus, biodegradable polymeric nanoparticles, via photocrosslinking, demonstrate extended colloidal stability and efficient delivery of RNA therapeutics under physiological conditions, and thereby potentially advance systemic delivery technologies for nucleic acid-based therapeutics.

The effects of continuous oromotor activity on speech motor learning: speech biomechanics and neurophysiologic correlates.

Sustained limb motor activity has been used as a therapeutic tool for improving rehabilitation outcomes and is thought to be mediated by neuroplastic changes associated with activity-induced cortical excitability. Although prior research has reported enhancing effects of continuous chewing and swallowing activity on learning, the potential beneficial effects of sustained oromotor activity on speech improvements is not well-documented. This exploratory study was designed to examine the effects of continuous oromotor activity on subsequent speech learning. Twenty neurologically healthy young adults engaged in periods of continuous chewing and speech after which they completed a novel speech motor learning task. The motor learning task was designed to elicit improvements in accuracy and efficiency of speech performance across repetitions of eight-syllable nonwords. In addition, transcranial magnetic stimulation was used to measure the cortical silent period (cSP) of the lip motor cortex before and after the periods of continuous oromotor behaviors. All repetitions of the nonword task were recorded acoustically and kinematically using a three-dimensional motion capture system. Productions were analyzed for accuracy and duration, as well as lip movement distance and speed. A control condition estimated baseline improvement rates in speech performance. Results revealed improved speech performance following 10 min of chewing. In contrast, speech performance following 10 min of continuous speech was degraded. There was no change in the cSP as a result of either oromotor activity. The clinical implications of these findings are discussed in the context of speech rehabilitation and neuromodulation.

Biomechanical Biomarkers of Tongue Impairment During Swallowing in Persons Diagnosed with Amyotrophic Lateral Sclerosis.

BACKGROUND: The impact of tongue dysfunction on deglutition in persons diagnosed with amyotrophic lateral sclerosis (ALS) is not well understood. This information is needed to improve our understanding of the mechanisms of swallowing impairment, for identifying risk factors of dysphagia, and for establishing impairment-specific treatments aimed at slowing the loss of swallow function. OBJECTIVES: The goals of this study were to determine the relation between biomechanical measures of oral tongue movements using electromagnetic articulography (EMA) and measures of swallow physiology, swallow safety and efficiency, and self-reported swallowing function. METHODS: Participants were diagnosed with ALS by a neurologist following the El Escorial Criteria from the World Federation of Neurology. Twelve participants underwent (1) EMA to derive biomechanical measures of the tongue, (2) videofluoroscopic evaluation to measure swallow physiology, safety, and efficiency, and (3) maximal tongue strength testing using the Iowa Oral Pressure Instrument (IOPI). Participants completed self-reported functional assessments. Spearman's rank correlations assessed for associations between lingual biomechanics and swallowing physiology, swallow safety and efficiency, and self-reported bulbar function. RESULTS: Results demonstrated strong associations between biomechanical and swallowing physiology, swallow safety, and self-reported measures. Notably, swallowing safety during thin liquid intake was associated with tongue speed (r = - 0.7, p < 0.05) and range of motion (r = - 0.71, p < 0.05), and swallowing safety during puree intake was associated with tongue strength (r = - 0.69, p < 0.05). CONCLUSIONS: Our findings underscore the importance of tongue movements on swallowing physiology and safety, help improve our understanding of mechanisms of swallowing impairment, and highlight a potential clinical tool to index bulbar impairment.

Speech intelligibility loss due to amyotrophic lateral sclerosis: the effect of tongue movement reduction on vowel and consonant acoustic features.

The purpose of this study was to identify aspects of impaired tongue motor performance that limit the ability to produce distinct speech sounds and contribute to reduced speech intelligibility in individuals with dysarthria secondary to amyotrophic lateral sclerosis (ALS). We analyzed simultaneously recorded tongue kinematic and acoustic data from 22 subjects during three target words (cat, dog, and took). The subjects included 11 participants with ALS and 11 healthy controls from the X-ray microbeam dysarthria database (Westbury, 1994). Novel measures were derived based on the range and speed of relative movement between two quasi-independent regions of the tongue - blade and dorsum - to characterize the global pattern of tongue dynamics. These "whole tongue" measures, along with the range and speed of single tongue regions, were compared across words, groups (ALS vs. control), and measure types (whole tongue vs. tongue blade vs. tongue dorsum). Reduced range and speed of both global and regional tongue movements were found in participants with ALS relative to healthy controls, reflecting impaired tongue motor performance in ALS. The extent of impairment, however, varied across words and measure types. Compared with the regional tongue measures, the whole tongue measures showed more consistent disease-related changes across the target words and were more robust predictors of speech intelligibility. Furthermore, these whole tongue measures were correlated with various word-specific acoustic features associated with intelligibility decline in ALS, suggesting that impaired tongue movement likely contributes to reduced phonetic distinctiveness of both vowels and consonants that underlie speech intelligibility decline in ALS.

Nonviral polymeric nanoparticles for gene therapy in pediatric CNS malignancies.

Together, medulloblastoma (MB) and atypical teratoid/rhabdoid tumors (AT/RT) represent two of the most prevalent pediatric brain malignancies. Current treatment involves radiation, which has high risks of developmental sequelae for patients under the age of three. New safer and more effective treatment modalities are needed. Cancer gene therapy is a promising alternative, but there are challenges with using viruses in pediatric patients. We developed a library of poly(beta-amino ester) (PBAE) nanoparticles and evaluated their efficacy for plasmid delivery of a suicide gene therapy to pediatric brain cancer models-specifically herpes simplex virus type I thymidine kinase (HSVtk), which results in controlled apoptosis of transfected cells. In vivo, PBAE-HSVtk treated groups had a greater median overall survival in mice implanted with AT/RT (P = 0.0083 vs. control) and MB (P < 0.0001 vs. control). Our data provide proof of principle for using biodegradable PBAE nanoparticles as a safe and effective nanomedicine for treating pediatric CNS malignancies.