Disrupting Six/Eya Signalling as New Therapy for Lung Fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most common type of interstitial lung disease, with a median survival of 2-4 years from the time of diagnosis [1]. It is estimated that the prevalence of IPF in the US is approximately 10-60 cases per 100,000 people, with limited pharmacological therapies available [2, 3]. IPF is a chronic, progressive disease characterized by alveolar injury, increased extracellular matrix (ECM) deposition and resultant alveolar destruction. Macroscopically, this leads to poor lung compliance, impaired trans-alveolocapillary membrane gas exchange and ultimately, end-stage respiratory failure, necessitating lung transplantation [2, 4, 5]. Several non-genetic risk factors, such as male sex, older age, and smoking, increase the risk of developing IPF [4, 6]. More recently, several genetic risk factors for IPF have also been discovered, including a single-nucleotide polymorphism (rs35705950) in the promoter region of MUC5B [7-9], which codes for an essential protein for airway clearance and innate immune response, along with genes associated with telomere maintenance, such as telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT) [1, 10].

Mapping state-sponsored information operations with multi-view modularity clustering.

This paper presents a new computational framework for mapping state-sponsored information operations into distinct strategic units. Utilizing a novel method called multi-view modularity clustering (MVMC), we identify groups of accounts engaged in distinct narrative and network information maneuvers. We then present an analytical pipeline to holistically determine their coordinated and complementary roles within the broader digital campaign. Applying our proposed methodology to disclosed Chinese state-sponsored accounts on Twitter, we discover an overarching operation to protect and manage Chinese international reputation by attacking individual adversaries (Guo Wengui) and collective threats (Hong Kong protestors), while also projecting national strength during global crisis (the COVID-19 pandemic). Psycholinguistic tools quantify variation in narrative maneuvers employing hateful and negative language against critics in contrast to communitarian and positive language to bolster national solidarity. Network analytics further distinguish how groups of accounts used network maneuvers to act as balanced operators, organized masqueraders, and egalitarian echo-chambers. Collectively, this work breaks methodological ground on the interdisciplinary application of unsupervised and multi-view methods for characterizing not just digital campaigns in particular, but also coordinated activity more generally. Moreover, our findings contribute substantive empirical insights around how state-sponsored information operations combine narrative and network maneuvers to achieve interlocking strategic objectives. This bears both theoretical and policy implications for platform regulation and understanding the evolving geopolitical significance of cyberspace.

Pharmacologic Intervention with CMX-2043 for the Acute Treatment of Neurotrauma and Traumatic Brain Injury (TBI)

The initial phases of the study began late in the third quarter, having been delayed by the closing of the Kilbaugh lab for approx. six months due to Covid-19 pandemic. However, during the fourth quarter it was decided that the dose levels to be evaluated in this dose response/PK study should be increased on a mg/kg basis. The reason we have decided to increase the dose level is that earlier in 2020 we requested CRL to perform a single-dose, maximum tolerated dose study (the MTD study) to confirm the dose levels we had originally envisioned for the repeat-dose tox study. (This MTD study was not originally thought to be necessary, was not planned as a part of the Award, and, consistent with the fixed-price nature of the Award, was paid for 100% by Ischemix.) The result of the MTD study was that no toxicity was seen at levels up to and including 320 mg/kg. Therefore we have decided to increase the amount of drug to be administered in higher dose groups of the dose response/PK study to accommodate a potentially higher efficacious dose in later human studies than was originally anticipated.

Novel Class of Galectin 1 Inhibitors for Prostate Cancer Therapy

The overall goal of this award is to find ways to prolong the efficacy of cabazitaxel chemotherapy in patients with castration resistant prostate cancer (CRPC) who have previously been treated with and developed resistance to Abiraterone Acetate (ABI) or enzalutamide (ENZ). In months 1-12 of this award, we aimed to determine whether a novel galectin-1 (Gal-1) inhibitor, S-LLS30 developed by the applicant, prevents ABI/ENZ resistance and/or sensitizes the cells to cabazitaxel (Major task 1). We have shown that indeed S-LLS30 sensitizes CRPC cells to ENZ and strongly affected cells expressing Gal-1. The experiments with cabazitaxel are continuing despite prolonged operational shutdown at the University due to COVID-19 restrictions. We have also started to investigate the role of Gal-1 nuclear localization, and its binding partners Gemin4 and HSP90 in this process (Major task 2, subtask 1). It appears that Gemin4 plays a substantial role in Gal-1 activity in this context but the role of HSP90 is unclear. Finally, we conducted preliminary experiments to evaluate the toxicity of S-LLS30 and determine the maximum tolerated dose (Major task 3, subtask 1). S-LLS30 was deemed to be of limited toxicity and very well tolerated in mice up to 30 mg/Kg doses. S-LLS30 is a viable potential drug candidate to overcome resistance to ABI/ENZ in models of CRPC.

MADLx: Setting Foundations to Measure ROI Protocol/Recommendations Report: DI-MISC-80711A Bold Quest 20.2

The Coalition Capability Demonstration and Assessment series, known as Bold Quest, fosters Joint and Coalition resource pooling, collaborative data collection, and data analysis to inform capability development on a Joint and Coalition scale. The Advanced Distributed Learning (ADL) Initiatives Maturing ADL in Exercises (MADLx) project participated in Bold Quest 20.2 held in October 2020 at Camp Atterbury, Indiana. The exercise sponsor, Joint Chiefs of Staff J-6 (Command, Control Communications, and Computers/Cyber), agreed to allow participants to receive pre-event online training focused on the Android Tactical Assault Kit (ATAK), a suite of software to provide geospatial information for warfighter collaboration. After the exercise, participant performance data was shared with the MADLx team for analysis. This report provides the results and findings and includes impacts on exercise performance due to COVID-19 pandemic circumstances. It documents the ADL contributions to the exercise, the planning process and implementation protocol ("how to"), lessons learned, and recommendations.

Ridge count thresholding to uncover coordinated networks during onset of the Covid-19 pandemic.

In order to combat information operations (IO) and disinformation campaigns, one must look at the behaviors of the accounts pushing specific narratives and stories through social media, not at the content itself. In this work, we present a new process for extracting tweet storms and uncovering networks of accounts that are working in a coordinated fashion using ridge count thresholding (RCT). To do this, we started with a dataset of 60 million individual tweets from the early weeks of the Covid-19 pandemic. Coherent topics are extracted from this data by testing three different preprocessing pipelines and applying Orthogonal Nonnegative Matrix Factorization (ONMF). The most effective preprocessing pipeline used hashtag preclustering to downselect the total dataset to the 7 million tweets that included the top hashtags. Each topic identified by ONMF is described by a topic-tweet signal, crafted using the time stamp included in each tweet's metadata. These signals were broken down into tweet storms using RCT, which is calculated from the Dynamic Wavelet Fingerprint transform of each topic-tweet signal. Each tweet storm described a time of increased activity around a topic. Tweet storms identified in this way each represent some behavior in the underlying network. In total, we identified 39,817 total tweet storms that included about 2 million unique tweets. These tweet storms were used to identify networks of accounts that commonly co-occur within tweet storms to isolate those communities most responsible for driving narratives and pushing stories through social media. Through this process, we were able to identify 22 unique networks of accounts that were densely connected based on RCT tweet storm identification. Many of the identified networks exhibit obvious inauthentic behaviors that are potentially a part of an IO campaign.

Finding Metabolomic Signatures in Pregnancy that Predict Breast Cancer: 60-Year Prospective Study in the Child Health and Development Studies Pregnancy Cohort

We propose to study 2nd and 3rd trimester archival serum samples of women in the Child Health and Development Studies (CHDS) pregnancy cohort who subsequently developed breast cancer, compared to 2nd and 3rd trimester archival serum samples from women who did not develop breast cancer, to identify predictive gestational biomarkers which could lead to new approaches to prevent breast cancer. For this, we will apply powerful high-resolution metabolomics (HRM) with advanced computational tools to identify chemicals and biochemical metabolic networks in pregnancy which are linked to subsequent breast cancer occurrence. There were minor delays caused by staff and offices transitioning to remote work due to the COVID-19 pandemic. We still accomplished all major tasks specified in the first year (obtaining all human subjects approvals, sample selection, preparation and order of archived pregnancy serum for delivery to Site 2).

Effect of Mecp2 Mutation on Cortical Projections Revealed by Correlated Single-Cell Transcriptomics and Projectomics

Rett Syndrome is caused by mutations in Mecp2, which result in a constellation of language, cognitive, motor, and autonomic deficits later in life. Although changes in long-range neuronal connectivity likely underlie the behavioral defects in Rett syndrome, it is unclear how long-range axonal projections are disrupted. Here we develop and apply high-throughput single-cell techniques to identify cell type-specific changes in projections in Mecp2 animals. We identified two subtypes of cortical projection neurons with potential changes in long-range projections, including the corticothalamic neurons and L6b neurons. Our results provide candidate cell types for future in depth studies on the long-range circuitry changes associated with Mecp2 mutation. Furthermore, our approach is generally applicable to other brain areas and disease models to reveal cell type-specific changes in projections that are difficult to detect using conventional methods.

Probiotic (VSL#3) for Gulf War Illness

The overall objective of the study is to determine whether probiotic VisbiomeTM will improve 1) Intestinal symptoms of Irritable Bowel Syndrome and 2) Non-intestinal symptoms (fatigue, joint pain, insomnia, general stiffness and headache) associated with IBS. All these symptoms are part of the Gulf War illness. We screened our first participant in September 2013. Overall, we have screened 101 and enrolled 62 Gulf War Veterans. We have stopped enrolling patients in this study. The stool samples analysis ongoing as well the statistical data analysis.

Trauma-Informed Guilt Reduction (TrIGR) Intervention

Posttraumatic guilt and shame are common among Veterans and have been implicated in the development and maintenance of posttraumatic distress and a range of adverse outcomes, including posttraumatic stress disorder (PTSD), depression and suicidality, and alcohol/substance use disorders. There is a pressing need for effective treatments targeting transdiagnostic mechanisms such as guilt. We developed Trauma Informed Guilt Reduction (TrIGR) therapy as a therapeutic tool to help Veterans accurately appraise deployment-related guilt and to re-identify and re-engage with their values. The overall objective of this study is to examine the efficacy of TrIGR in reducing deployment-related guilt. The overarching hypothesis is that TrIGR will reduce guilt, shame, and related distress, and these improvements will be significantly greater than in the comparison condition, Supportive Care Therapy (SCT). The study is a Stage 2 randomized, controlled trial of TrIGR compared to SCT. Recruitment of participants takes place at two VA Medical Centers (San Diego, CA and Providence, RI). 150 OEF/OIF Veterans will be randomized to TrIGR or SCT (at least 75 in San Diego). All eligible participants complete an in-person baseline assessment, receive 6 sessions of TrIGR or SCT in individual format, complete brief bi-weekly self-report measures during treatment, and complete follow-up assessments immediately post-treatment, and 3- and 6-months later.

More Resiliency in the Rehabilitation of Active Duty Service Members

The purpose of our prospective cohort study is to address important knowledge gaps on resiliency in the rehabilitation of adults with lower-extremity injuries. Specific aims are to develop and test a resiliency instrument that is relevant to active duty military Service Members. The proposed project will leverage the infrastructure of the Maximizing Outpatient Rehabilitation Effectiveness (MORE) study that is currently being conducted at Brooke Army Medical Center. The first year of the project focused on selecting items from three well-established resiliency instruments that have been validated in civilian populations. Interviews and focus groups were conducted in up to 28 active duty military Service Members. A pre-test of the MORE resiliency instrument in 60 Service Members was conducted which finalized the instrument. Currently, we are testing the MORE resiliency instrument in 310 Service Members to determine reliability and construct and predictive validity of the instrument in active duty Service Members with lower-extremity injury. This project has HRPO approval and has enrolled 77 out of the 310 participants for the testing cohort phase of the project.

IM ABLE Study: A Cross-Sector, Multisite Initiative to Advance Care for Warriors and Veterans Following Neuromusculoskeletal Injury of the Lower Limb

An estimated 20,000 military service members sustained extremity injury in the recent wars in Iraq and Afghanistan. This high number of limb injured Service Personnel catalyzed advancements in lower limb bracing technology and a focus on therapy to maximize utilization of these devices. This is a considerable problem in the Veteran and private sectors as well. It is presently unclear whether these newer (i.e. advanced) braces improve comfort and function in those with limb injury compared to bracing options formerly in use. The cost of newer devices and the associated fabrication time is rapidly climbing and some reimbursors are not paying for these newer devices. For instance, a conventional ankle-foot-orthosis has a reimbursable cost of approximately $1400. Alternatively, newer advanced bracing systems such as the Intrepid Dynamic Exoskeletal Orthosis (IDEO), are approximately twice the cost of conventional devices to fabricate. Reimbursement costs are not yet widely agreed upon, if accepted at all. If the devices truly improve function and comfort, then the initial high costs of provision may be justified. The primary objective of this clinical trial is to determine if different types of leg/foot braces will improve comfort and function in persons who have sustained injury affecting their lower limb.

Bone Regeneration Device for Compromised Wounds

This device will promote bone regeneration in compromised wounds. It addresses the critical limiting factors in repair: low osteo/chondro-progenitors, low vascular supply, and a fibrotic immune response. Our hypothesis that controlled prolonged delivery of the immunomodulatory and chondrogenic cytokines will promote bone regeneration in both comminuted fractures and critically sized bone void defects compared to no cytokine delivery. We also hypothesize that the hydrogel component will promote bone regeneration in both models via formation of a larger cartilaginous callus-like tissue. The device is designed to be applied via two different modalities depending on the nature of the bone injury: an Injectable Hydrogel device and an Implantable Hydrogel Infused Scaffold device. The injectable hydrogel is used to treat comminuted fractures and small bone deficits while the implantable hydrogel infused scaffold is used to treat large bone deficits. We will test the injectable device in a bi-lateral simulated comminuted fractures of the fibulas while the implantable device in bi-lateral fibular segmental defects in swine. The Specific Aims are: 1. Manufacture the bone regeneration devices;2. Assess the immunomodulatory effect and potential for endochondral ossification at 1 month post-surgery;3. Assess the functional bone healing response after 5 months post-surgery(bone formation and strength, revascularization and reinnervation).

Addressing Post-Intensive Care Syndrome Among Survivors of Acute Lung Injury

APICS-01 seeks to address clinical and operational knowledge gap for acute lung injury (ALI) survivors by defining patterns of unmet needs, resource utilization, readmissions, and long-term functional outcomes among ICU survivors. We will employ a prospective, multi-center, observational study of outcomes and healthcare utilization among 200 ALI survivors which are directly relevant to a military population. In the first year of award, APICS-01 secured all approvals, finalized all study materials, and initiated enrollment ahead of schedule. Enrollment is currently at 64 (ahead of a projected 50 at this point). Analysis of data will not occur until after enrollment is closed. Findings to date are of a highly effective multicenter collaborative performing a high-quality clinical study ahead of schedule. The screening activities are functioning well, the eligibility criteria are working well, and the enrollment curves are solid.

Effects of Exercise on Glymphatic Functioning and Neurobehavioral Correlates in Parkinson's Disease

This study is designed to measure the change in patients diagnosed with Parkinson's disease (PD) before, during and after a 12-week exercise program. The focus of this study is the glymphatic system. The glymphatic system is a recently discovered novel waste clearance pathway, in patients with Parkinson's Disease (PD). The glymphatic system acts as a waste-clearance system in the brain of vertebrate animals. The glymphatic system has been proposed in which new clearance pathways involving communication between paravascular spaces, interstitial fluid, and ultimately meningeal and dural lymphatic vessels exists, and we have provided evidence that this system may be dysfunctional in patients with Parkinson's disease with cognitive disorders. Early research suggest glymphatic function increases following exercise, this response is believed to clear beta-amyloid in the brain and may mediate the neurobehavioral response to exercise in PD. This study will use cognitive exams, neurological exams as well as specialized imaging to record data points and evaluate the glymphatic function after exercise.

Prazosin for Prophylaxis of Chronic Post-Traumatic Headaches in OEF/OIF/OND Service Members and Veterans with Mild TBI

Headaches following combat-related mild traumatic brain injury (mTBI) are common, can be refractory to standard therapies, and may persist and worsen to become a debilitating chronic pain syndrome. The purpose of the proposed study is to evaluate the centrally acting alpha-1 adrenoreceptor antagonist drug prazosin as a prophylactic treatment for chronic posttraumatic headache. The impetus for this study comes from a large open-label case series in Iraq and Afghanistan Veterans with mTBI and posttraumatic headaches and data from a placebo-controlled trial evaluating use of prazosin for PTSD in Iraq and Afghanistan active-duty Service Members that found beneficial effect of prazosin for decreasing the frequency and severity of headaches, in addition to decreasing PTSD-related symptoms and improving the quality of sleep. The objectives of this study will be accomplished by conducting a randomized placebo-controlled double blind trial of prazosin vs placebo in 160 Iraq/Afghanistan active-duty Service Members and Veterans with persistent PTHAs.

Practice of Acceptance, Awareness, and Compassion in Caregiving (PAACC)

Caregiving for individuals with Alzheimers disease and related dementias (ADRD) and Traumatic Brain Injury-related dementia has been associated with increased risk of both psychiatric morbidity and mortality, including higher risks of depression, anxiety, poor quality of life, and even early mortality. Although there are several beneficial interventions for caregivers of persons with AD, interventions that can help build skills to recognize and manage stress as well as enhance compassion in caregivers are urgently needed. The purpose of this study is to evaluate the effectiveness of proposed intervention, Practice of Acceptance, Awareness, and Compassion in Caregiving (PAACC) that integrates mindfulness training with caregiving skills training. Several studies have shown effectiveness of mindfulness in decreasing caregiver burden in caregivers of individuals with cognitive deficits, but most of them did not provide caregiving skills training with mindfulness. Our study hypothesis is that intervention such as PAACC which combines education, skill building, and mindfulness practices will enhance caregiving skills and will reduce caregiver stress as well as increase quality of life of the care recipient. The objective of the study will be accomplished by conducting a randomized control trial to test effectiveness of PAACC and compare it with existing cognitive behavior-based intervention called Resources for Enhancing Alzheimers Caregiver Health (REACH).