Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer's Disease.

Background: Varoglutamstat is a first-in-class, small molecule being investigated as a treatment for early Alzheimer's disease (AD). It is an inhibitor of glutaminyl cyclase (QC), the enzyme that post-translationally modifies amyloid-ß (Aß) peptides into a toxic form of pyroglutamate Aß (pGlu-Aß) and iso-QC which post-translationally modifies cytokine monocyte chemoattractant protein-1 (CCL2) into neuroinflammatory pGlu-CCL2. Early phase clinical trials identified dose margins for safety and tolerability of varoglutamstat and biomarker data supporting its potential for clinical efficacy in early AD. Objective: Present the scientific rationale of varoglutamstat in the treatment of early AD and the methodology of the VIVA-MIND (NCT03919162) trial, which uses a seamless phase 2A-2B design. Our review also includes other pharmacologic approaches to pGlu-Aß. Methods: Phase 2A of the VIVA-MIND trial will determine the highest dose of varoglutamstat that is safe and well tolerated with sufficient plasma exposure and a calculated target occupancy. Continuous safety evaluation using a pre-defined safety stopping boundary will help determine the highest tolerated dose that will carry forward into phase 2B. An interim futility analysis of cognitive function and electroencephalogram changes will be conducted to inform the decision of whether to proceed with phase 2B. Phase 2B will assess the efficacy and longer-term safety of the optimal selected phase 2A dose through 72 weeks of treatment. Conclusions: Varoglutamstat provides a unique dual mechanism of action addressing multiple pathogenic contributors to the disease cascade. VIVA-MIND provides a novel and efficient trial design to establish its optimal dosing, safety, tolerability, and efficacy in early AD.

Efficacy and safety of different polymyxin-containing regimens for the treatment of pneumonia caused by multidrug-resistant gram-negative bacteria: a systematic review and network meta-analysis.

BACKGROUND: The optimal administration of polymyxins for treating multidrug-resistant gram-negative bacterial (MDR-GNB) pneumonia remains unclear. This study aimed to systematically assess the efficacy and safety of three polymyxin-containing regimens by conducting a comprehensive network meta-analysis. METHODS: We comprehensively searched nine databases. Overall mortality was the primary outcome, whereas the secondary outcomes encompassed microbial eradication rate, clinical success, acute kidney injury, and incidence of bronchospasm. Extracted study data were analyzed by pairwise and network meta-analyses. Version 2 of the Cochrane risk-of-bias tool and the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) assessment tool were used to assess the risk of bias in randomized trials and cohort studies, respectively. RESULTS: This study included 19 observational studies and 3 randomized controlled trials (RCTs), encompassing 3318 patients. Six studies with high risk of bias were excluded from the primary analysis. In the pairwise meta-analysis, compared to the intravenous (IV) polymyxin-containing regimen, the intravenous plus inhaled (IV + IH) polymyxin-containing regimen showed a significant decrease in overall mortality, while no statistically significant difference was found in the inhaled (IH) polymyxin-containing regimen. The network meta-analysis indicated that the IV + IH polymyxin-containing regimen had significantly lower overall mortality (OR 0.67; 95% confidence interval [CI] 0.50-0.88), higher clinical success rate (OR 1.90; 95% CI 1.20-3.00), better microbial eradication rate (OR 2.70; 95% CI 1.90-3.90) than the IV polymyxin-containing regimen, and significantly better microbial eradication rate when compared with the IH polymyxin-containing regimen (OR 2.30; 95% CI 1.30-4.20). Furthermore, compared with IV + IH and IV polymyxin-containing regimens, the IH polymyxin-containing regimen showed a significant reduction in acute kidney injury. CONCLUSIONS: Our study indicates that among the three administration regimens, the IV + IH polymyxin-containing regimen may be the most effective for treating MDR-GNB pneumonia, with a significantly lower overall mortality compared to the IV regimen and a considerably higher microbial eradication rate compared to the IH regimen. The IH regimen may be considered superior to the IV regimen due to its substantially lower incidence of acute kidney injury, even though the reduction in overall mortality was not significant.

Illness perception and intimate relationships in patients with cervical cancer: the mediating role of dyadic coping.

BACKGROUND AND OBJECTIVES: A good intimate relationship (IR) can relieve the psychological distress of patients with cervical cancer and promote a sense of well-being during stressful times. Researchers have found that IR is related to illness perception (IP) and dyadic coping (DC). Therefore, this study aimed to (1) describe the IR of patients with cervical cancer, (2) identify the relationships and pathways among IP, DC and IR in patients with cervical cancer and (3) explore the mediating role of DC between IP and IR in cervical cancer patients. METHODS: A total of 175 patients with cervical cancer were recruited at a tertiary hospital in China from September 2021 to January 2023. The data were collected through a general demographic and disease-related information questionnaire, the Locke-Wallace Marriage Adjustment Test, the Revised Illness Perception Questionnaire of Cervical Cancer and the Dyadic Coping Inventory. RESULTS: The mean score for intimate relationships was 107.78 (SD = 23.99, range 30-154). Pearson's correlation analysis revealed that intimate relationships were positively correlated with IP (personal control) and DC (stress communication, supportive DC, delegated DC and common DC) and were negatively correlated with IP (consequence, timeline acute/chronic, timeline cyclical and emotional representation) and negative DC. As for the results of the structural equation model, DC fully mediated the influencing effects of both positive and negative IP on IR. CONCLUSIONS: The level of IR of patients with cervical cancer in China should be improved. DC has a significant mediating effect on the link between the IP and IR.

Flexible sensors with zero Poisson's ratio.

Flexible sensors have been developed for the perception of various stimuli. However, complex deformation, usually resulting from forces or strains from multi-axes, can be challenging to measure due to the lack of independent perception of multiaxial stimuli. Herein, flexible sensors based on the metamaterial membrane with zero Poisson's ratio (ZPR) are proposed to achieve independent detection of biaxial stimuli. By deliberately designing the geometric dimensions and arrangement parameters of elements, the Poisson's ratio of an elastomer membrane can be modulated from negative to positive, and the ZPR membrane can maintain a constant transverse dimension under longitudinal stimuli. Due to the accurate monitoring of grasping force by ZPR sensors that are insensitive to curvatures of contact surfaces, rigid robotic manipulators can be guided to safely grasp deformable objects. Meanwhile, the ZPR sensor can also precisely distinguish different states of manipulators. When ZPR sensors are attached to a thermal-actuation soft robot, they can accurately detect the moving distance and direction. This work presents a new strategy for independent biaxial stimuli perception through the design of mechanical metamaterials, and may inspire the future development of advanced flexible sensors for healthcare, human-machine interfaces and robotic tactile sensing.

Cortical activity in patients with high-functioning ischemic stroke during the Purdue Pegboard Test: insights into bimanual coordinated fine motor skills with functional near-infrared spectroscopy.

After stroke, even high-functioning individuals may experience compromised bimanual coordination and fine motor dexterity, leading to reduced functional independence. Bilateral arm training has been proposed as a promising intervention to address these deficits. However, the neural basis of the impairment of functional fine motor skills and their relationship to bimanual coordination performance in stroke patients remains unclear, limiting the development of more targeted interventions. To address this gap, our study employed functional near-infrared spectroscopy to investigate cortical responses in patients after stroke as they perform functional tasks that engage fine motor control and coordination. Twenty-four high-functioning patients with ischemic stroke (7 women, 17 men; mean age 64.75 ± 10.84 years) participated in this cross-sectional observational study and completed four subtasks from the Purdue Pegboard Test, which measures unimanual and bimanual finger and hand dexterity. We found significant bilateral activation of the sensorimotor cortices during all Purdue Pegboard Test subtasks, with bimanual tasks inducing higher cortical activation than the assembly subtask. Importantly, patients with better bimanual coordination exhibited lower cortical activation during the other three Purdue Pegboard Test subtasks. Notably, the observed neural response patterns varied depending on the specific subtask. In the unaffected hand task, the differences were primarily observed in the ipsilesional hemisphere. In contrast, the bilateral sensorimotor cortices and the contralesional hemisphere played a more prominent role in the bimanual task and assembly task, respectively. While significant correlations were found between cortical activation and unimanual tasks, no significant correlations were observed with bimanual tasks. This study provides insights into the neural basis of bimanual coordination and fine motor skills in high-functioning patients after stroke, highlighting task-dependent neural responses. The findings also suggest that patients who exhibit better bimanual performance demonstrate more efficient cortical activation. Therefore, incorporating bilateral arm training in post-stroke rehabilitation is important for better outcomes. The combination of functional near-infrared spectroscopy with functional motor paradigms is valuable for assessing skills and developing targeted interventions in stroke rehabilitation.

On-skin biosensors for noninvasive monitoring of postoperative free flaps and replanted digits.

Severe soft tissue defects and amputated digits are clinically common injuries. Primary treatments include surgical free flap transfer and digit replantation, but these can fail because of vascular compromise. Postoperative monitoring is therefore crucial for timely detection of vessel obstruction and survival of replanted digits and free flaps. However, current postoperative clinical monitoring methods are labor intensive and highly dependent on the experience of nurses and surgeons. Here, we developed on-skin biosensors for noninvasive and wireless postoperative monitoring based on pulse oximetry. The on-skin biosensor was made of polydimethylsiloxane with gradient cross-linking to create a self-adhesive and mechanically robust substrate that interfaces with skin. The substrate was shown to exhibit appropriate adhesion on one side for both high-fidelity measurements of the sensor and low risk of peeling injury to delicate tissues. The other side demonstrated mechanical integrity to facilitate flexible hybrid integration of the sensor. Validation studies using a model of vascular obstruction in rats demonstrated the effectiveness of the sensor in vivo. Clinical studies indicated that the on-skin biosensor was accurate and more responsive than current clinical monitoring methods in identifying microvascular conditions. Comparisons with existing monitoring techniques, including laser Doppler flowmetry and micro-lightguide spectrophotometry, further verified the sensor's accuracy and ability to identify both arterial and venous insufficiency. These findings suggest that this on-skin biosensor may improve postoperative outcomes in free flap and replanted digit surgeries by providing sensitive and unbiased data directly from the surgical site that can be remotely monitored.

Larger cerebral cortex is genetically correlated with greater frontal area and dorsal thickness.

Human cortical expansion has occurred non-uniformly across the brain. We assessed the genetic architecture of cortical global expansion and regionalization by comparing two sets of genome-wide association studies of 24 cortical regions with and without adjustment for global measures (i.e., total surface area, mean cortical thickness) using a genetically informed parcellation in 32,488 adults. We found 393 and 756 significant loci with and without adjusting for globals, respectively, where 8% and 45% loci were associated with more than one region. Results from analyses without adjustment for globals recovered loci associated with global measures. Genetic factors that contribute to total surface area of the cortex particularly expand anterior/frontal regions, whereas those contributing to thicker cortex predominantly increase dorsal/frontal-parietal thickness. Interactome-based analyses revealed significant genetic overlap of global and dorsolateral prefrontal modules, enriched for neurodevelopmental and immune system pathways. Consideration of global measures is important in understanding the genetic variants underlying cortical morphology.

A simple genetic stratification method for lower cost, more expedient clinical trials in early Alzheimer's disease: A preliminary study of tau PET and cognitive outcomes.

INTRODUCTION: Identifying individuals who are most likely to accumulate tau and exhibit cognitive decline is critical for Alzheimer's disease (AD) clinical trials. METHODS: Participants (N = 235) who were cognitively normal or with mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative were stratified by a cutoff on the polygenic hazard score (PHS) at 65th percentile (above as high-risk group and below as low-risk group). We evaluated the associations between the PHS risk groups and tau positron emission tomography and cognitive decline, respectively. Power analyses estimated the sample size needed for clinical trials to detect differences in tau accumulation or cognitive change. RESULTS: The high-risk group showed faster tau accumulation and cognitive decline. Clinical trials using the high-risk group would require a fraction of the sample size as trials without this inclusion criterion. DISCUSSION: Incorporating a PHS inclusion criterion represents a low-cost and accessible way to identify potential participants for AD clinical trials.

Effectiveness and Success Factors of Bilateral Arm Training After Stroke: A Systematic Review and Meta-Analysis.

Bilateral arm training (BAT) presents as a promising approach in upper extremity (UE) rehabilitation after a stroke as it may facilitate neuroplasticity. However, the effectiveness of BAT is inconclusive, and no systematic reviews and meta-analyses have investigated the impact of different factors on the outcomes of BAT. This systematic review and meta-analysis aimed to (1) compare the effects of bilateral arm training (BAT) with unilateral arm training (UAT) and conventional therapy (CT) on the upper limb (UL) motor impairments and functional performance post-stroke, and (2) investigate the different contributing factors that may influence the success of BAT. A comprehensive literature search was performed in five databases. Randomized control trials (RCTs) that met inclusion criteria were selected and assessed for methodological qualities. Data relating to outcome measures, characteristics of participants (stroke chronicity and severity), and features of intervention (type of BAT and dose) were extracted for meta-analysis. With 25 RCTs meeting the inclusion criteria, BAT demonstrated significantly greater improvements in motor impairments as measured by Fugl-Meyer Assessment of Upper Extremity (FMA-UE) than CT (MD = 3.94, p = < 0.001), but not in functional performance as measured by the pooled outcomes of Action Research Arm Test (ARAT), Box and Block Test (BBT), and the time component of Motor Function Test (WMFT-time) (SMD = 0.28, p = 0.313). The superior motor impairment effects of BAT were associated with recruiting mildly impaired individuals in the chronic phase of stroke (MD = 6.71, p < 0.001), and applying a higher dose of intervention (MD = 6.52, p < 0.001). Subgroup analysis showed that bilateral functional task training (BFTT) improves both motor impairments (MD = 7.84, p < 0.001) and functional performance (SMD = 1.02, p = 0.049). No significant differences were detected between BAT and UAT for motor impairment (MD = -0.90, p = 0.681) or functional performance (SMD = -0.09, p = 0.457). Thus, our meta-analysis indicates that BAT may be more beneficial than CT in addressing post-stroke UL motor impairment, particularly in the chronic phase with mild UL paresis. The success of BAT may be dose-dependent, and higher doses of intervention may be required. BFTT appears to be a valuable form of BAT that could be integrated into stroke rehabilitation programs. BAT and UAT are generally equivalent in improving UL motor impairments and functional performance.

Advances in electrical impedance tomography-based brain imaging.

Novel advances in the field of brain imaging have enabled the unprecedented clinical application of various imaging modalities to facilitate disease diagnosis and treatment. Electrical impedance tomography (EIT) is a functional imaging technique that measures the transfer impedances between electrodes on the body surface to estimate the spatial distribution of electrical properties of tissues. EIT offers many advantages over other neuroimaging technologies, which has led to its potential clinical use. This qualitative review provides an overview of the basic principles, algorithms, and system composition of EIT. Recent advances in the field of EIT are discussed in the context of epilepsy, stroke, brain injuries and edema, and other brain diseases. Further, we summarize factors limiting the development of brain EIT and highlight prospects for the field. In epilepsy imaging, there have been advances in EIT imaging depth, from cortical to subcortical regions. In stroke research, a bedside EIT stroke monitoring system has been developed for clinical practice, and data support the role of EIT in multi-modal imaging for diagnosing stroke. Additionally, EIT has been applied to monitor the changes in brain water content associated with cerebral edema, enabling the early identification of brain edema and the evaluation of mannitol dehydration. However, anatomically realistic geometry, inhomogeneity, cranium completeness, anisotropy and skull type, etc., must be considered to improve the accuracy of EIT modeling. Thus, the further establishment of EIT as a mature and routine diagnostic technique will necessitate the accumulation of more supporting evidence.

Monitoring the delicate operations of surgical robots via ultra-sensitive ionic electronic skin.

The arrival of surgical robots in high-end medical equipment is a landmark, and the realization of tactile sensation a major challenge in this important cutting-edge research field. Aiming to address this issue, we present ultra-sensitive ionic electronic skin in the form of flexible capacitive pressure sensors, which incorporate multistage bionic microstructures in ion gels for the purpose of monitoring the delicate operations of surgical robots. Significantly, the ionic skin exhibits an ultra-high sensitivity of 9484.3 kPa-1 (<15 kPa), and the sensitivity remains higher than 235 kPa-1 in the wide range of 15-155 kPa. The device has also achieved a detection limit as low as 0.12 Pa or, equivalently, 0.31 mg, fast response within 24 ms, and high robustness (loading/unloading for 5000 cycles without fatigue). The sensor facilitates the challenging task of tele-operated robotic threading, which exceeds the human tactile perception limit when threading a needle. We have also confirmed that ionic skin can be used in robot-assisted invasive surgery, such as incision/resection of tissues and suturing of wounds, providing tactile information to surgeons to improve operation success rates. The flexible ionic skin is capable of conforming to the various shapes of robotic manipulators, thus has great promise for applications in robotic dexterous manipulation, prosthetics and human-machine interfaces.

Impact of potential modifications to Alzheimer's disease clinical trials in response to disruption by COVID-19: a simulation study.

BACKGROUND: The COVID-19 pandemic disrupted Alzheimer disease randomized clinical trials (RCTs), forcing investigators to make changes in the conduct of such trials while endeavoring to maintain their validity. Changing ongoing RCTs carries risks for biases and threats to validity. To understand the impact of exigent modifications due to COVID-19, we examined several scenarios in symptomatic and disease modification trials that could be made. METHODS: We identified both symptomatic and disease modification Alzheimer disease RCTs as exemplars of those that would be affected by the pandemic and considered the types of changes that sponsors could make to each. We modeled three scenarios for each of the types of trials using existing datasets, adjusting enrollment, follow-ups, and dropouts to examine the potential effects COVID-19-related changes. Simulations were performed that accounted for completion and dropout patterns using linear mixed effects models, modeling time as continuous and categorical. The statistical power of the scenarios was determined. RESULTS: Truncating both symptomatic and disease modification trials led to underpowered trials. By contrast, adapting the trials by extending the treatment period, temporarily stopping treatment, delaying outcomes assessments, and performing remote assessment allowed for increased statistical power nearly to the level originally planned. DISCUSSION: These analyses support the idea that disrupted trials under common scenarios are better continued and extended even in the face of dropouts, treatment disruptions, missing outcomes, and other exigencies and that adaptations can be made that maintain the trials' validity. We suggest some adaptive methods to do this noting that some changes become under-powered to detect the original effect sizes and expected outcomes. These analyses provide insight to better plan trials that are resilient to unexpected changes to the medical, social, and political milieu.

The effect of Subthalamic nucleus deep brain stimulation on verb and noun naming in Turkish-Speaking Parkinson's disease patients.

Parkinson's disease (PD) is associated with an action language deficit. Subthalamic nucleus deep brain stimulation (STN DBS) deteriorates verbal fluency, but may improve verb naming more than nouns in PD. We investigated effects of grammatical class (verb vs noun), action content (action vs non-action) of words and unilateral, bilateral or no stimulation on naming. Nouns were named more accurately and faster by controls and PD participants; however the noun-verb difference was higher for PD participants. Language, executive and visuospatial function deficits in PD accounted for this difference between PD group and controls. Noun-verb difference was accounted by differences in imageability, familiarity and complexity of the stimuli. Non-action words were named more accurately than action words in the overall sample. Stimulation conditions did not have an effect on naming. This study in Turkish-speaking participants show an action language deficit due to underlying cognitive deficits without an STN DBS effect in PD.

Enriching the design of Alzheimer's disease clinical trials: Application of the polygenic hazard score and composite outcome measures.

INTRODUCTION: Selecting individuals at high risk of Alzheimer's disease (AD) dementia and using the most sensitive outcome measures are important aspects of trial design. METHODS: We divided participants from Alzheimer's Disease Neuroimaging Initiative at the 50th percentile of the predicted absolute risk of the polygenic hazard score (PHS). Outcome measures were the Alzheimer's Disease Assessment Schedule-Cognitive Subscale (ADAS-Cog), ADNI-Mem, Clinical Dementia Rating-Sum of Boxes (CDR SB), and Cognitive Function Composite 2 (CFC2). In addition to modeling, we use a power analysis compare numbers needed with each technique. RESULTS: Data from 188 cognitively normal and 319 mild cognitively impaired (MCI) participants were analyzed. Using the ADAS-Cog to estimate sample sizes, without stratification over 24 months, would require 930 participants with MCI, while using the CFC2 and restricting participants to those in the upper 50th percentile would require only 284 participants. DISCUSSION: Combining stratification by PHS and selection of a sensitive combined outcome measure in a cohort of patients with MCI can allow trial design that is more efficient, potentially less burdensome on participants, and more cost effective.

Oligogenic Effects of 16p11.2 Copy-Number Variation on Craniofacial Development.

A copy-number variant (CNV) of 16p11.2 encompassing 30 genes is associated with developmental and psychiatric disorders, head size, and body mass. The genetic mechanisms that underlie these associations are not understood. To determine the influence of 16p11.2 genes on development, we investigated the effects of CNV on craniofacial structure in humans and model organisms. We show that deletion and duplication of 16p11.2 have "mirror" effects on specific craniofacial features that are conserved between human and rodent models of the CNV. By testing dosage effects of individual genes on the shape of the mandible in zebrafish, we identify seven genes with significant effects individually and find evidence for others when genes were tested in combination. The craniofacial phenotypes of 16p11.2 CNVs represent a model for studying the effects of genes on development, and our results suggest that the associated facial gestalts are attributable to the combined effects of multiple genes.

Cognitive heterogeneity in probable Alzheimer disease: Clinical and neuropathologic features.

OBJECTIVE: To identify heterogeneity in cognitive profiles of patients with probable Alzheimer disease (AD) who have mild to moderate dementia and satisfy inclusion and exclusion criteria for a typical AD clinical trial, and to determine whether cognitive profiles are systematically related to the clinical course and neuropathologic features of the disease. METHODS: Neuropsychological test data from patients with mild to moderate probable AD (n = 4,711) were obtained from the National Alzheimer's Coordinating Center. Inclusion and exclusion criteria usually used in AD clinical trials were applied. Principal component analysis and model-based clustering were used to identify cognitive profiles in a subset of patients with autopsy-verified AD (n = 800) and validated in the overall (nonautopsy) sample and an independent cohort with similar test data. Relationships between cognitive profile, clinical characteristics, and rate of decline were examined with mixed-effects models. RESULTS: In the autopsy-confirmed sample, 79.6% of patients had a typical AD cognitive profile (greater impairment of episodic memory than other cognitive functions), and 20.4% had an atypical profile (comparable impairment across cognitive domains). Similar results were obtained in the overall (typical 79.8%, atypical 20.2%) and validation (typical 71.8%, atypical 28.2%) samples. Atypicality was associated with younger age, male sex, lower probability of APOE ε4, less severe global dementia, higher depression scores, lower Braak stage at autopsy, and slower cognitive decline. CONCLUSION: We can reliably identify distinct cognitive profiles among patients with clinically diagnosed probable AD that are associated with tangle pathology and with different rates of decline. This may have implications for clinical trials in AD, especially therapies targeting tau.

Effects of a Comprehensive Performance Improvement Strategy on Postoperative Adverse Events in Head and Neck Surgery.

OBJECTIVES: We aimed to demonstrate the efficacy of a multifaceted performance improvement regimen to reduce the incidence of adverse events following a spectrum of head and neck surgical procedures. METHODS: We conducted a chart review of patients who underwent a head and neck procedure between January 1, 2013, and October 30, 2015, at our institution, including 392 patients (450 procedures) before the quality improvement regimen was implemented (October 1, 2013) and 942 patients (1136 procedures) after implementation. Multivariate statistical models were used to investigate the association of clinical parameters and the intervention with postoperative adverse event rate. RESULTS: The incidence of adverse events decreased from 12.9% to 7.2% (95% CI, 2.46%-9.38%) after the intervention. Male sex (adjusted odds ratio [ORadj] = 1.57; 95% CI, 1.06-2.31) and the intervention (ORadj = 0.51; 95% CI, 0.35-0.74) were predictive of overall adverse event incidence by univariate and multivariate analyses. Although patient comorbid status, quantified with the Charlson Comorbidity Index, was not found to affect overall adverse event risk, each 1-point increase in index score was associated with a 17% relative increase (ORadj = 1.17; 95% CI, 1.03-1.33) in the odds of a high-grade adverse event. DISCUSSION: Comprehensive performance improvement programs can improve perioperative adverse event risk in head and neck surgery. Patient comorbid status and sex are considerations during assessment of the likelihood of high-grade and overall adverse event risk, respectively. IMPLICATIONS FOR PRACTICE: Given the cost of surgical complications, a comprehensive approach to perioperative risk mitigation is warranted.

Integrated Analysis of Exosomal Protein Biomarkers on Alternating Current Electrokinetic Chips Enables Rapid Detection of Pancreatic Cancer in Patient Blood.

Pancreatic ductal adenocarcinoma (PDAC) typically has nonspecific symptoms and is often found too late to treat. Because diagnosis of PDAC involves complex, invasive, and expensive procedures, screening populations at increased risk will depend on developing rapid, sensitive, specific, and cost-effective tests. Exosomes, which are nanoscale vesicles shed into blood from tumors, have come into focus as valuable entities for noninvasive liquid biopsy diagnostics. However, rapid capture and analysis of exosomes with their protein and other biomarkers have proven difficult. Here, we present a simple method integrating capture and analysis of exosomes and other extracellular vesicles directly from whole blood, plasma, or serum onto an AC electrokinetic microarray chip. In this process, no pretreatment or dilution of sample is required, nor is it necessary to use capture antibodies or other affinity techniques. Subsequent on-chip immunofluorescence analysis permits specific identification and quantification of target biomarkers within as little as 30 min total time. In this initial validation study, the biomarkers glypican-1 and CD63 were found to reflect the presence of PDAC and thus were used to develop a bivariate model for detecting PDAC. Twenty PDAC patient samples could be distinguished from 11 healthy subjects with 99% sensitivity and 82% specificity. In a smaller group of colon cancer patient samples, elevated glypican-1 was observed for metastatic but not for nonmetastatic disease. The speed and simplicity of ACE exosome capture and on-chip biomarker detection, combined with the ability to use whole blood, will enable seamless "sample-to-answer" liquid biopsy screening and improve early stage cancer diagnostics.

Oral Vitamin D Rapidly Attenuates Inflammation from Sunburn: An Interventional Study.

The diverse immunomodulatory effects of vitamin D are increasingly being recognized. However, the ability of oral vitamin D to modulate acute inflammation in vivo has not been established in humans. In a double-blinded, placebo-controlled interventional trial, 20 healthy adults were randomized to receive either placebo or a high dose of vitamin D3 (cholecalciferol) one hour after experimental sunburn induced by an erythemogenic dose of UVR. Compared with placebo, participants receiving vitamin D3 (200,000 international units) demonstrated reduced expression of proinflammatory mediators tumor necrosis factor-α (P = 0.04) and inducible nitric oxide synthase (P = 0.02) in skin biopsy specimens 48 hours after experimental sunburn. A blinded, unsupervised hierarchical clustering of participants based on global gene expression profiles revealed that participants with significantly higher serum vitamin D3 levels after treatment (P = 0.007) demonstrated increased skin expression of the anti-inflammatory mediator arginase-1 (P = 0.005), and a sustained reduction in skin redness (P = 0.02), correlating with significant expression of genes related to skin barrier repair. In contrast, participants with lower serum vitamin D3 levels had significant expression of proinflammatory genes. Together the data may have broad implications for the immunotherapeutic properties of vitamin D in skin homeostasis, and implicate arginase-1 upregulation as a previously unreported mechanism by which vitamin D exerts anti-inflammatory effects in humans.

Naringenin prevents TGF-ß1 secretion from breast cancer and suppresses pulmonary metastasis by inhibiting PKC activation.

BACKGROUND: Targeting the TGF-ß1 pathway for breast cancer metastasis therapy has become an attractive strategy. We have previously demonstrated that naringenin significantly reduced TGF-ß1 levels in bleomycin-induced lung fibrosis and effectively prevented pulmonary metastases of tumors. This raised the question of whether naringenin can block TGF-ß1 secretion from breast cancer cells and inhibit their pulmonary metastasis. METHODS: We transduced a lentiviral vector encoding the mouse Tgf-ß1 gene into mouse breast carcinoma (4T1-Luc2) cells and inoculated the transformant cells (4T1/TGF-ß1) into the fourth primary fat pat of Balb/c mice. Pulmonary metastases derived from the primary tumors were monitored using bioluminescent imaging. Spleens, lungs and serum (n = 18-20 per treatment group) were analyzed for immune cell activity and TGF-ß1 level. The mechanism whereby naringenin decreases TGF-ß1 secretion from breast cancer cells was investigated at different levels, including Tgf-ß1 transcription, mRNA stability, translation, and extracellular release. RESULTS: In contrast to the null-vector control (4T1/RFP) tumors, extensive pulmonary metastases derived from 4T1/TGF-ß1 tumors were observed. Administration of the TGF-ß1 blocking antibody 1D11 or naringenin showed an inhibition of pulmonary metastasis for both 4T1/TGF-ß1 tumors and 4T1/RFP tumors, resulting in increased survival of the mice. Compared with 4T1/RFP bearing mice, systemic immunosuppression in 4T1/TGF-ß1 bearing mice was observed, represented by a higher proportion of regulatory T cells and myeloid-derived suppressor cells and a lower proportion of activated T cells and INFγ expression in CD8(+) T cells. These metrics were improved by administration of 1D11 or naringenin. However, compared with 1D11, which neutralized secreted TGF-ß1 but did not affect intracellular TGF-ß1 levels, naringenin reduced the secretion of TGF-ß1 from the cells, leading to an accumulation of intracellular TGF-ß1. Further experiments revealed that naringenin had no effect on Tgf-ß1 transcription, mRNA decay or protein translation, but prevented TGF-ß1 transport from the trans-Golgi network by inhibiting PKC activity. CONCLUSIONS: Naringenin blocks TGF-ß1 trafficking from the trans-Golgi network by suppressing PKC activity, resulting in a reduction of TGF-ß1 secretion from breast cancer cells. This finding suggests that naringenin may be an attractive therapeutic candidate for TGF-ß1 related diseases.