A multi-institutional phase I study of acetazolamide with temozolomide in adults with newly diagnosed MGMT-methylated malignant glioma.

Background: A significant unmet need exists for the treatment of glioblastoma, IDH-wildtype (GBM). Preclinical work shows that acetazolamide sensitizes GBM to temozolomide (TMZ) by overcoming TMZ resistance due to BCL-3-dependent upregulation of carbonic anhydrase. Acetazolamide is Food and Drug Administration-approved for the treatment of altitude sickness. Drug repurposing enables the application of drugs to diseases beyond initial indications. This multi-institutional, open-label, phase I trial examined a combination of acetazolamide and TMZ in patients with MGMT promoter-methylated high-grade glioma. Methods: A total of 24 patients (GBM, IDH-wildtype = 22; Grade 4 astrocytoma, IDH-mutant = 1; Grade 3 astrocytoma, IDH-mutant = 1) were accrued over 17 months. All patients received oral acetazolamide (250 mg BID for 7 days increased to 500 mg BID for Days 8-21 of each 28-day cycle) during the adjuvant phase of TMZ for up to 6 cycles. Results: No patient had a dose-limiting toxicity. Adverse events were consistent with known sequelae of acetazolamide and TMZ. In the 23 WHO Grade 4 patients, the median overall survival (OS) was 30.1 months and the median progression-free survival was 16.0 months. The 2-year OS was 60.9%. In total 37% of the study population had high BCL-3 staining and trended toward shorter OS (17.2 months vs N.R., P = .06). Conclusions: The addition of acetazolamide is safe and tolerable in GBM patients receiving standard TMZ. Survival results compare favorably to historical data from randomized trials in patients with MGMT promoter-methylated GBM and support examination of acetazolamide in a randomized trial. BCL-3 expression is a potential biomarker for prognosis in GBM or for patients more likely to benefit from TMZ.

Surgical Outcomes and EEG Prognostic Factors After Stereotactic Laser Amygdalohippocampectomy for Mesial Temporal Lobe Epilepsy.

Objective: To assess the seizure outcomes of stereotactic laser amygdalohippocampectomy (SLAH) in consecutive patients with mesial temporal lobe epilepsy (mTLE) in a single center and identify scalp EEG and imaging factors in the presurgical evaluation that correlate with post-surgical seizure recurrence. Methods: We retrospectively reviewed the medical and EEG records of 30 patients with drug-resistant mTLE who underwent SLAH and had at least 1 year of follow-up. Surgical outcomes were classified using the Engel scale. Univariate hazard ratios were used to evaluate the risk factors associated with seizure recurrence after SLAH. Results: The overall Engel class I outcome after SLAH was 13/30 (43%), with a mean postoperative follow-up of 48.9 ± 17.6 months. Scalp EEG findings of interictal regional slow activity (IRSA) on the side of surgery (HR = 4.05, p = 0.005) and non-lateralizing or contra-lateralizing seizure onset (HR = 4.31, p = 0.006) were negatively correlated with postsurgical seizure freedom. Scalp EEG with either one of the above features strongly predicted seizure recurrence after surgery (HR = 7.13, p < 0.001) with 100% sensitivity and 71% specificity. Significance: Understanding the factors associated with good or poor surgical outcomes can help choose the best candidates for SLAH. Of the variables assessed, scalp EEG findings were the most clearly associated with seizure outcomes after SLAH.

The Role of CoLab and GAITS in Enabling the RADx Tech Program.

The RADxSM Tech initiative required a massive mobilization of the biomedical community. It was chartered with the extremely ambitious goal of rapidly developing and deploying innovative tests to detect people infected with the SARS-CoV-2 virus. It needed to do so at a scale and with urgency to get the country back to daily activities such as school and work as soon as possible. It required forming and supporting a diversity of teams with members from around the country and beyond. These teams collaborated in complex workflows that needed to be carefully monitored and tracked. This paper describes the key elements of the secure, web-based infrastructure that was configured to enable the efficient and effective operation of RADx Tech's key processes and address its unique and urgent challenges. One such challenge was to manage the flow of applications through a multi-stage, interactive selection process (using the CoLab platform) and another was to support and facilitate the progress of projects selected for support and funding through an accelerated commercialization program (using the GAITS platform).

Airway Volume Simulation in Virtual Mandibular Distraction: A Cohort Study.

BACKGROUND: The authors investigated the accuracy of virtual surgical planning in predicting airway volume changes after mandibular distraction in patients with Pierre Robin sequence and associated tongue-based airway obstruction. METHODS: The authors completed a single-institution retrospective review of patients for whom virtual surgical planning was used during mandibular distraction osteogenesis for treatment of tongue-based airway obstruction. Preoperative airway volume, virtual surgical planning-predicted airway volume, and postoperative airway volume were calculated from three-dimensional computed tomographic scans using industry software. A blinded institutional radiologist also calculated pre- and post-operative airway volumes. Pre- and post-operative polysomnography was used to titrate the endpoint of mandibular lengthening. RESULTS: Eleven patients were included in the study. Mean apnea-hypopnea index (5.42 ± 4.53 versus 44.96 ± 20.57; p < 0.001) and mean nadir oxygen saturation (70.3 ± 9.72 percent versus 82.9 ± 9.62 percent; p = 0.003) improved with mandibular distraction. There was moderate correlation between predicted and actual mandibular distraction lengths (R = 0.65; p = 0.003). There was a strong correlation between predicted and industry-calculated actual post-distraction airway volume (R = 0.99; p < 0.001). There was no significant correlation between actual mandibular distraction length and industry-calculated actual post-distraction airway volume for the entire cohort (R = 0.05; p = 0.49), but correlation approached significance by institutional calculations. No significant correlation existed between industry and institutional-calculated percentage change in post-distraction airway volume (R = 0.06; p = 0.57). CONCLUSIONS: Predictive airway volume calculation may be an effective adjunct to determine anatomic endpoint of mandibular distraction but small sample size, operator and software variability, and patient airway morphology may confound firm conclusions. Further studies are warranted.

Gle1 Regulates RNA Binding of the DEAD-Box Helicase Ded1 in Its Complex Role in Translation Initiation.

DEAD-box proteins (DBPs) are required in gene expression to facilitate changes to ribonucleoprotein complexes, but the cellular mechanisms and regulation of DBPs are not fully defined. Gle1 is a multifunctional regulator of DBPs with roles in mRNA export and translation. In translation, Gle1 modulates Ded1, a DBP required for initiation. However, DED1 overexpression causes defects, suggesting that Ded1 can promote or repress translation in different contexts. Here we show that GLE1 expression suppresses the repressive effects of DED1 in vivo and Gle1 counteracts Ded1 in translation assays in vitro Furthermore, both Ded1 and Gle1 affect the assembly of preinitiation complexes. Through mutation analysis and binding assays, we show that Gle1 inhibits Ded1 by reducing its affinity for RNA. Our results are consistent with a model wherein active Ded1 promotes translation but inactive or excess Ded1 leads to translation repression. Gle1 can inhibit either role of Ded1, positioning it as a gatekeeper to optimize Ded1 activity to the appropriate level for translation. This study suggests a paradigm for finely controlling the activity of DEAD-box proteins to optimize their function in RNA-based processes. It also positions the versatile regulator Gle1 as a potential node for the coordination of different steps of gene expression.

CNS hemangioblastomatosis in a patient without von Hippel-Lindau disease.

We report on a case of disseminated CNS hemangioblastoma, also referred to as hemangioblastomatosis, involving the supratentorial compartment and the entire spine. The patient presented with new onset headache, gait difficulties and memory deficits many years following resection of a hemangioblastoma from the cerebellum. The patient's family history was negative for von Hippel-Lindau (VHL) disease, and his personal history was negative for any additional VHL-defining lesions. Imaging revealed extensive dural caking and nodularity both supratentorially and in the spine, along with scattered parenchymal tumors showing a more typical appearance for hemangioblastoma. Biopsy of the dural thickening revealed histologic features compatible with hemangioblastoma. Genetic testing for VHL was eventually completed, and no evidence of a germline VHL mutation was detected.

Diagnostic Challenge: Sequential Unilateral Cranial Neuropathies Due to Perineural Spread of Carcinoma.

An 86-year old man developed sequential dysfunction of trigeminal (V1), facial, abducens, trigeminal (v2), oculomotor, and hypoglossal cranial nerves on the right over 20 months. Magnetic resonance imaging (MRI) showed a lesion in the right cavernous sinus. Although there was clinical suspicion that this was related to perineural spread of an extracranial tumour, a primary lesion was not discovered. Stereotactic biopsies of the intracranial lesion were non-diagnostic, and the patient succumbed to his tumour following a period of rapid growth. Postmortem examination showed the intracranial lesion to be a carcinoma with squamous features. This case highlights the challenges of diagnosis of intracranial perineural spread and the potential for transformation from indolent to aggressive tumour behaviour.

Healthcare Commercialization Programs: Improving the Efficiency of Translating Healthcare Innovations From Academia Into Practice.

Academic investigators are generating a plethora of insights and technologies that have the potential to significantly improve patient care. However, to address the imperative to improve the quality, cost and access to care with ever more constrained funding, the efficiency and the consistency with which they are translated into cost effective products and/or services need to improve. Healthcare commercialization programs (HCPs) are described and proposed as an option that institutions can add to their portfolio to improve translational research. In helping teams translate specific healthcare innovations into practice, HCPs expand the skillset of investigators and enhance an institution's innovation capacity. Lessons learned are shared from configuring and delivering HCPs, which build on the fundamentals of the National Science Foundation's Innovation Corps program, to address the unique challenges in supporting healthcare innovations and innovators.

National Institute of Biomedical Imaging and Bioengineering Point-of-Care Technology Research Network: Advancing Precision Medicine.

To advance the development of point-of-care technology (POCT), the National Institute of Biomedical Imaging and Bioengineering established the POCT Research Network (POCTRN), comprised of Centers that emphasize multidisciplinary partnerships and close facilitation to move technologies from an early stage of development into clinical testing and patient use. This paper describes the POCTRN and the three currently funded Centers as examples of academic-based organizations that support collaborations across disciplines, institutions, and geographic regions to successfully drive innovative solutions from concept to patient care.

Attending to Race (or Gender) Does Not Increase Race (or Gender) Aftereffects.

Recent research has shown that attention can influence the strength of face aftereffects. For example, attending to changes in facial features increases the strength of identity and figural aftereffects relative to passive viewing (Rhodes et al., 2011). Here, we ask whether attending to a specific social dimension of a face (such as race or gender) influences the strength of face aftereffects along that dimension. Across three experiments, participants completed many single-shot face adaptation trials. In each trial, participants observed a computer-generated adapting face for 5 s while instructed to focus on either the race or gender of that adapting face. Adapting faces were either Asian and female or Caucasian and male. In Experiment 1, all trials included an intermediate question (IQ) following each adaptation period, soliciting a rating of the adapting face on the attended dimension (e.g., race). In Experiment 2, only half of the trials included this IQ, and in Experiment 3 only a quarter of the trials did. In all three experiments, participants were subsequently presented with a race- and gender-neutral face and asked to rate it on either the attended dimension (e.g., race, attention-congruent trials) or the unattended dimension (e.g., gender, attention-incongruent trials) using a seven-point scale. Overall, participants showed significant aftereffects in all conditions, manifesting as (i) higher Asian ratings of the neutral faces following Caucasian vs. Asian adapting faces and (ii) higher female ratings of neutral faces following male vs. female adapting faces. Intriguingly, although reaction times were shorter during attention-congruent vs. attention-incongruent trials, aftereffects were not stronger along attention-congruent than attention-incongruent dimensions. Our results suggest that attending to a facial dimension such as race or gender does not result in increased adaptation to that dimension.

CAPriCORN: Chicago Area Patient-Centered Outcomes Research Network.

The Chicago Area Patient-Centered Outcomes Research Network (CAPriCORN) represents an unprecedented collaboration across diverse healthcare institutions including private, county, and state hospitals and health systems, a consortium of Federally Qualified Health Centers, and two Department of Veterans Affairs hospitals. CAPriCORN builds on the strengths of our institutions to develop a cross-cutting infrastructure for sustainable and patient-centered comparative effectiveness research in Chicago. Unique aspects include collaboration with the University HealthSystem Consortium to aggregate data across sites, a centralized communication center to integrate patient recruitment with the data infrastructure, and a centralized institutional review board to ensure a strong and efficient human subject protection program. With coordination by the Chicago Community Trust and the Illinois Medical District Commission, CAPriCORN will model how healthcare institutions can overcome barriers of data integration, marketplace competition, and care fragmentation to develop, test, and implement strategies to improve care for diverse populations and reduce health disparities.

Multidetector CT of temporal bone fractures.

Temporal bone fracture is a relatively common finding among trauma patients. Before the development of high-resolution multidetector computed tomography (MDCT) imaging, fractures of the skull base and temporal bone were a challenge to diagnose clinically. With current imaging technology, most such fractures are easily detected, and the challenge now lies in predicting the severity of injury and possible complications. In this review, we discuss the detection and classification of temporal bone fractures, their distinction from pseudofractures, and the role of imaging in establishing prognosis, particularly with respect to complications.

Targeted delivery to single cells in precisely controlled microenvironments.

The heterogeneous nature of cells can be an issue for in vitro analysis of cell function due to cell type differences within a population. Observations are most often averaged and dependent on the homogeneity or lack thereof for most cell types. Patterning of features at the sub-cellular scale (< 10 µm) allows for single cell manipulation. Additionally, the ability to pattern multiple materials simultaneously with nanoscale precision enables facile fabrication of multiplexed cellular microenvironment arrays. Here we use this ability to deliver different materials to single or few cells within hundreds of microns of each other on the same substrate. Calcein AM, Calcein Red AM and quantum dots are delivered to live single or few cells. This allows for exposing limited cell numbers to many well defined conditions, thus opening the possibility of single cell based assays.

Stem cell-derived extracellular matrix enables survival and multilineage differentiation within superporous hydrogels.

Hydrophilic poly(ethylene glycol) diacrylate (PEGDA) hydrogel surfaces resist protein adsorption and are generally thought to be unsuitable for anchorage-dependent cells to adhere. Intriguingly, our previous findings revealed that PEGDA superporous hydrogel scaffolds (SPHs) allow anchorage of bone marrow derived human mesenchymal stem cells (hMSCs) and support their long-term survival. Therefore, we hypothesized that the physicochemical characteristics of the scaffold impart properties that could foster cellular responses. We examined if hMSCs alter their microenvironment to allow cell attachment by synthesizing their own extracellular matrix (ECM) proteins. Immunofluorescence staining revealed extensive expression of collagen type I, collagen type IV, laminin, and fibronectin within hMSC-seeded SPHs by the end of the third week. Whether cultured in serum-free or serum-supplemented medium, hMSC ECM protein gene expression patterns exhibited no substantial changes. The presence of serum proteins is required for initial anchorage of hMSCs within the SPHs but not for the hMSC survival after 24 h. In contrast to 2D expansion on tissue culture plastic (TCP), hMSCs cultured within SPHs proliferate similarly in the presence or absence of serum. To test whether hMSCs retain their undifferentiated state within the SPHs, cell-seeded constructs were cultured for 3 weeks in stem cell maintenance medium and the expression of hMSC-specific cell surface markers were evaluated by flow cytometry. CD105, CD90, CD73, and CD44 were present to a similar extent in the SPH and in 2D monolayer culture. We further demonstrated multilineage potential of hMSCs grown in the PEGDA SPHs, whereby differentiation into osteoblasts, chondrocytes, and adipocytes could be induced. The present study demonstrates the potential of hMSCs to alter the "blank" PEGDA environment to a milieu conducive to cell growth and multilineage differentiation by secreting adhesive ECM proteins within the porous network of the SPH scaffolds.

Subcellular scaled multiplexed protein patterns for single cell cocultures.

Tip-based direct protein printing is a relatively new technique that is useful for controlling the cellular microenvironment with subcellular resolution. Coculture studies have been useful for mimicking the in vivo environment and studying effects on stem or progenitor cell function. However, there are many experimental variables that cannot be properly controlled and may lead to confounding results. Here we demonstrate a technique that allows spatial control of multiple cell types at single cell levels on a substrate. Specifically, 3T3 fibroblasts and C2C12 myoblasts and their respective binding dynamics with fibronectin and laminin demonstrate the single cell coculture concept.

Facts, attitudes, and health reasoning about HIV and AIDS: explaining the education effect on condom use among adults in sub-Saharan Africa.

In contrast to earlier in the HIV/AIDS pandemic, net of other demographic factors, formal education acts as a preventative factor in sub-Saharan Africa. Despite this trend, there has been almost no research on the causal mechanisms behind the widely reported education effect. Consistent with the education effect, structural equation modeling of the influence of education attainment on condom use with Demographic Health Survey data from nine sub-Saharan Africa nations collected between 2003 and 2005 finds that net of control variables, there is a robust, positive influence of education on condom use among sexually risky adults. Information-transfer and attitude change, the two most commonly assumed educational influences on the use of condoms, are tested, and although education attainment increases acquisition of basic facts and the inculcation of positive attitudes about HIV/AIDS, these factors have only weak influence on condom use. Given this, a new hypothesis about education's enhancement of health reasoning is developed from neuro-developmental and decision-making research. Modeling finds that education robustly influences health reasoning ability and this factor mediates a significant proportion of the education effect on condom use. The results raise concern about the enormous effort by NGOs in the region to use mainly fact- and attitude-based educational programs to reduce future HIV infections. Future research on the causal mechanisms behind the association between education and HIV/AIDS prevention should focus how on schooling enhances the cognitive skills needed for health reasoning.

Migration and proliferation of human mesenchymal stem cells is stimulated by different regions of the mechano-growth factor prohormone.

Stem cell function is thought to be tightly regulated by growth factor concentration in the confines of the microenvironmental niche. Therefore, the response of human mesenchymal stem cells (hMSCs) was studied in culture with mechano-growth factor (MGF), an isoform of IGF-1 known to be expressed in the heart following injury. Chemotactic migration of hMSCs increased in response to a peptide analog corresponding to the E-domain region of the MGF prohormone, which was greater than the IGF-1 polypeptide after 20 h of culture. Compared to control without growth factor, migration was significantly less with a scrambled peptide (p=0.025) or a peptide harboring a serine to alanine substitution near the carboxy end (p=0.002). The IGF-1 polypeptide increased proliferation of small (5-9 µm) but not large (>13 µm) hMSCs, whereas the E-domain peptide (MGF-E) had no effect on proliferation. Thus, there are complex biological responses of hMSCs to the prehormone of IGF with respect to migration and proliferation. Since neonatal myocytes but not hMSCs express MGF when strained cyclically at 20%, overloading of the heart may trigger immigration of stem cells. It seems possible that regions of the IGF prohormone may act differentially, or in a combinatorial manner, to benefit cardiac tissue recovery after injury.

Stem cell therapy for cardiac repair.

Heart regeneration via stem cell therapy could improve the functional outcome for millions of patients. A goal of cardiac stem cell research is to foster the engraftment of new, beating cardiac cells into the ischemic region of the heart after a myocardial infarction. The key elements of cell therapy for myocardial repair reviewed here are the source of cells and the mechanisms by which these cells improve cardiac function. Injection of stem cells into the heart of animals ignited the field by showing some functional cardiac improvement. Unfortunately, few injected cells are retained in the heart or become a new, beating myocardium, and clinical trials have shown moderate improvement of human heart function. The causes of the minimal functional improvement are still unknown, but blood vessel formation (angiogenesis) or secretion of growth factors or cytokines are likely candidates. Cells appropriate for human therapy might be mesenchymal stem and progenitor cells from bone marrow or the heart itself. A more controversial cell source, embryonic stem cells, have a nearly unlimited self-renewal potential and can differentiate into beating cardiac myocytes. However, all of these cell sources and the mechanisms of improvement need further research, with the differentiation of stem cells into functional cardiac cells a difficult but most beneficial hurdle to leap.