The Mycobacterium tuberculosis MmpL3 inhibitor MSU-43085 is active in a mouse model of infection.

IMPORTANCE: MmpL3 is a protein that is required for the survival of bacteria that cause tuberculosis (TB) and nontuberculous mycobacterial (NTM) infections. This report describes the discovery and characterization of a new small molecule, MSU-43085, that targets MmpL3 and is a potent inhibitor of Mycobacterium tuberculosis (Mtb) and M. abscessus survival. MSU-43085 is shown to be orally bioavailable and efficacious in an acute model of Mtb infection. However, the analog is inactive against Mtb in chronically infected mice. Pharmacokinetic and metabolite identification studies identified in vivo metabolism of MSU-43085, leading to a short half-life in treated mice. These proof-of-concept studies will guide further development of the MSU-43085 series for the treatment of TB or NTM infections.

Lumbar multifidus muscle ultrasound imaging: Is handheld technology reliable?

BACKGROUND: Advancement in ultrasound imaging technology has led to the development of handheld devices that are more accessible to physical therapists due to decreased cost, reduced size, and improved ease of use relative to current established units. Physical therapists use ultrasound imaging of the lumbar multifidus muscle (LMM) to assist in rehabilitation of patients with lumbar pathology. OBJECTIVES: To identify the inter-device reliability of measuring the LMM thickness during a sustained contraction when comparing handheld (Butterfly iQ+) and established (SonoSite M-Turbo) ultrasound units. A secondary purpose was to determine the reliability of a student physical therapist using both devices. DESIGN: A reliability measurement study METHOD: A blinded examiner identified the LMM at the L4 vertebral level and measured the thickness of the contracted muscle utilizing both the handheld and established ultrasound devices. ICC values were calculated to determine the inter-device and intra-rater reliability. RESULTS: The study included 42 healthy participants, 30 females and 12 males, with a mean age of 38.5 years. The inter-device reliability during a sustained LMM contraction was excellent (ICC = 0.92, 95% CI: 0.87-0.94) and the intra-rater reliability was good for both the handheld (ICC = 0.85, 95% CI: 0.73-0.92) and established (ICC = 0.89, 95% CI: 0.82-0.93) ultrasound units. CONCLUSION: Results support the use of handheld ultrasound by physical therapists and students to measure the LMM thickness. Future studies could investigate the reliability of handheld ultrasound in a variety of musculoskeletal and pathological structures important to PT practice.

Barriers and facilitators to the inclusion of deaf people in clinical trials.

BACKGROUND/AIMS: This article discusses the barriers that prevent deaf people from participating in clinical trials and offers recommendations to overcome these barriers and ensure equal access to study participation. METHODS: Between April and May 2022, we conducted six focus groups with 20 deaf adults who use American Sign Language, all of whom had previous experience as research study participants. Focus group prompts queried community awareness of clinical trial opportunities, barriers and facilitators to deaf people's participation in clinical trials, and recommended resources to improve clinical trial access. This qualitative focus group data is supplemented by survey data gathered from 40 principal investigators and clinical research coordinators between November 2021 and December 2021. The survey queried researchers' prior experiences with enrolling deaf participants in clinical trials and strategies they endorse for enrollment of deaf participants in future clinical trials. RESULTS: Focus group participants unanimously agreed that, compared to the general hearing population, deaf sign language users lack equivalent access to clinical trial participation. Reported barriers included lack of awareness of clinical trial opportunities, mistrust of hearing researchers, and refusal by clinical trial staff to provide accessible communication (e.g. denial of requests for sign language interpreters). Survey data from 40 principal investigators and clinical research coordinators corroborated these barriers. For example, only 2 out of 40 survey respondents had ever enrolled a deaf person in a clinical trial. Respondents indicated that the most helpful strategies for including deaf sign language users in future clinical trials would be assistance with making recruitment information accessible to deaf sign language users and assistance in identifying qualified interpreters to hire to help facilitate the informed consent process. CONCLUSION: The lack of communication accessibility is the most common factor preventing deaf sign language users from participating in clinical trials. This article provides recommendations for hearing researchers to improve deaf people's access to clinical trials moving forward, drawing from mixed-methods data.

The microbiome of an outpatient rehabilitation clinic and predictors of contamination: A pilot study.

BACKGROUND: Understanding sources of microbial contamination in outpatient rehabilitation (REHAB) clinics is important to patients and healthcare providers. PURPOSE: The purpose of this study was to characterize the microbiome of an outpatient REHAB clinic and examine relationships between clinic factors and contamination. METHODS: Forty commonly contacted surfaces in an outpatient REHAB clinic were observed for frequency of contact and swiped using environmental sample collection kits. Surfaces were categorized based on frequency of contact and cleaning and surface type. Total bacterial and fungal load was assessed using primer sets specific for the 16S rRNA and ITS genes, respectively. Bacterial samples were sequenced using the Illumina system and analyzed using Illumina-utils, Minimum Entropy Decomposition, QIIME2 (for alpha and beta diversity), LEfSe and ANCOM-BC for taxonomic differential abundance and ADONIS to test for differences in beta diversity (p<0.05). RESULTS: Porous surfaces had more bacterial DNA compared to non-porous surfaces (median non-porous = 0.0016ng/µL, 95%CI = 0.0077-0.00024ng/µL, N = 15; porous = 0.0084 ng/µL, 95%CI = 0.0046-0.019 ng/µL, N = 18. p = 0.0066,DNA. Samples clustered by type of surface with non-porous surfaces further differentiated by those contacted by hand versus foot. ADONIS two-way ANOVA showed that the interaction of porosity and contact frequency (but neither alone) had a significant effect on 16S communities (F = 1.7234, R2 = 0.0609, p = 0.032). DISCUSSION: Porosity of surfaces and the way they are contacted may play an underestimated, but important role in microbial contamination. Additional research involving a broader range of clinics is required to confirm results. Results suggest that surface and contact-specific cleaning and hygiene measures may be needed for optimal sanitization in outpatient REHAB clinics.

The Triterpenoid CDDO-Methyl Ester Redirects Macrophage Polarization and Reduces Lung Tumor Burden in a Nrf2-Dependent Manner.

The NRF2/KEAP1 pathway protects healthy cells from malignant transformation and maintains cellular homeostasis. Up to 30% of human lung tumors gain constitutive NRF2 activity which contributes to cancer cell survival and chemoresistance, but the effects of NRF2 activation in immune cells within the tumor microenvironment are underexplored. Macrophages can promote cancer progression or regression depending on context, and NRF2 activation affects macrophage activity. The NRF2 activator CDDO-Methyl ester (CDDO-Me or bardoxolone methyl) reprogrammed Nrf2 wild-type (WT) tumor-educated bone marrow-derived macrophages (TE-BMDMs) from a tumor-promoting to a tumor-inhibiting phenotype, marked by an increase in M1 markers TNFα, IL-6, and MHC-II and a decrease in the tumor-promoting factors VEGF, CCL2, and CD206. No changes were observed in Nrf2 knockout (KO) TE-BMDMs. CDDO-Me decreased tumor burden (p < 0.001) and improved pathological grade (p < 0.05) in WT but not Nrf2 KO A/J mice. Tumor burden in Nrf2 KO mice was 4.6-fold higher (p < 0.001) than in WT mice, irrespective of treatment. CDDO-Me increased the number of lung-infiltrating macrophages in WT mice but lowered CD206 expression in these cells (p < 0.0001). In summary, Nrf2 KO exacerbates lung tumorigenesis in A/J mice, and CDDO-Me promotes an Nrf2-dependent, anti-cancer macrophage phenotype.

The challenge of neuropsychological assessment of visual/visuo-spatial memory: A critical, historical review, and lessons for the present and future.

A proliferation of tests exists for the assessment of auditory-verbal memory processes. However, from a clinical practice perspective, the situation is less clear when it comes to the ready availability of reliable and valid tests for the evaluation of visual/visuo-spatial memory processes. While, at face value, there appear to be a wide range of available tests of visual/visuo-spatial memory, utilizing different types of materials and assessment strategies, a number of criticisms have been, and arguably should be, leveled at the majority of these tests. The criticisms that have been directed toward what are typically considered to be visual/visuo-spatial memory tests, such as (1) the potential for verbal mediation, (2) over-abstraction of stimuli, (3) the requirement of a drawing response, and (4) the lack of sensitivity to unilateral brain lesions, mean that, in reality, the number of readily available valid tests of visual/visuo-spatial memory is, at best, limited. This article offers a critical, historical review on the existing measures and resources for the neuropsychological assessment of visual/visuo-spatial memory, and it showcases some examples of newer tests that have aimed to overcome the challenges of assessing these important aspects of memory. The article also identifies new trends and examples of how technological advances such as virtual reality may add value to overcome previous obstacles to assessment, thereby offering professionals more reliable, accurate means to evaluate visual/visuo-spatial memory in clinical practice.

Risk and Dignity in Requesting Signed Language Interpreter Accommodations.

Requesting accommodations such as signed language interpreters in health-care settings is an activity that can present risk to the deaf patient. By providing space for considerations of risk-taking for particular kinds of experiences that are not universally shared, such as interpreter-mediated experiences, the notion of the dignity of risk can be expanded. The author uses two examples of signed language interpreting in health-care settings to demonstrate how the dignity of risk emerges. This is followed by an analysis of the concept of epistemic injustice as applied to insider knowledge of the deaf community and the potential harms to one's dignity resulting from this asymmetry of knowledge. The essay concludes with an evaluation of concerns about dignity and risk for deaf individuals.

The RXR Agonist MSU42011 Is Effective for the Treatment of Preclinical HER2+ Breast Cancer and Kras-Driven Lung Cancer.

(1) Background: Notwithstanding numerous therapeutic advances, 176,000 deaths from breast and lung cancers will occur in the United States in 2021 alone. The tumor microenvironment and its modulation by drugs have gained increasing attention and relevance, especially with the introduction of immunotherapy as a standard of care in clinical practice. Retinoid X receptors (RXRs) are members of the nuclear receptor superfamily and upon ligand binding, function as transcription factors to modulate multiple cell functions. Bexarotene, the only FDA-approved RXR agonist, is still used to treat cutaneous T-cell lymphoma. (2) Methods: To test the immunomodulatory and anti-tumor effects of MSU42011, a new RXR agonist, we used two different immunocompetent murine models (MMTV-Neu mice, a HER2 positive model of breast cancer and the A/J mouse model, in which vinyl carbamate is used to initiate lung tumorigenesis) and an immunodeficient xenograft lung cancer model. (3) Results: Treatment of established tumors in immunocompetent models of HER2-positive breast cancer and Kras-driven lung cancer with MSU42011 significantly decreased the tumor burden and increased the ratio of CD8/CD4, CD25 T cells, which correlates with enhanced anti-tumor efficacy. Moreover, the combination of MSU42011 and immunotherapy (anti-PDL1 and anti-PD1 antibodies) significantly (p < 0.05) reduced tumor size vs. individual treatments. However, MSU42011 was ineffective in an athymic human A549 lung cancer xenograft model, supporting an immunomodulatory mechanism of action. (4) Conclusions: Collectively, these data suggest that the RXR agonist MSU42011 can be used to modulate the tumor microenvironment in breast and lung cancer.

The effect of visceral manipulation on Diastasis Recti Abdominis (DRA): A case series.

BACKGROUND: Diastasis recti abdominis (DRA) is a condition that affects many postpartum and older women, often due to pregnancy-related issues and heavy lifting. Published research on nonsurgical DRA treatment has primarily focused on exercise to correct or prevent this dysfunction. A survey of women's health physical therapists identified that visceral manipulation and other interventions are utilized to treat DRA. No literature exists to identify the specifics of visceral manipulation or its effect on DRA. STUDY DESIGN: This case series is a retrospective chart review of three female patients with DRA who received visceral manipulation. CASE DESCRIPTION: The ages of the patients were 33, 37, 39 years old and all were positive for DRA based on inter-rectus distance (IRD) described as greater than two finger-width measurements at one of three measurement sites. Patients presented with chief complaints of low back pain, abdominal pain, and vulvar burning and itching. All women were gravida two and para two. Each patient received at least four treatments of visceral manipulation (VM). OUTCOMES: VM decreased the IRD, decreased numeric pain rating scores, and improved functional activities in three women with DRA. Improvements were also seen in bladder and bowel symptoms. DISCUSSION: Four treatments of visceral manipulation appear to be effective in decreasing DRA measurements in three women. DRA measurements improved to two finger-widths or less above, at, and below the umbilicus. The changes remained stable for six to sixteen months.

Neurotrophic Factors Secreted by Induced Pluripotent Stem Cell-Derived Retinal Progenitors Promote Retinal Survival and Preservation in an Adult Porcine Neuroretina Model.

Purpose: Paracrine factors released by pluripotent stem cells have shown great potential as therapeutic agents in regenerative medicine. The purpose of this study was to characterize trophic factor secretion of retinal progenitor cells (RPCs) derived from human induced pluripotent stem cells (iPSCs) and to assess its impact on retinal survival ex vivo. Methods: RPCs were generated from human 3D1 iPSCs following previously established protocols with modifications. Conditioned medium (CM) was harvested from iPSC-derived retinal progenitors and analyzed for trophic factor composition through multiplex enzyme-linked immunosorbent assay. Retina-preserving capability of the collected CM was examined using a degenerative porcine neuroretina model. Viability of the CM-treated retina explants was evaluated using the resazurin-based PrestoBlue reagent, whereas the lactate dehydrogenase (LDH) assay was used to assess retinal cytotoxicity. Retina explants were also analyzed morphologically through immunohistochemistry for glial cell activation and apoptosis. Results: We have successfully generated and characterized iPSC-derived RPCs that secreted an array of neuroprotective factors, including osteopontin, hepatocyte growth factor, stromal cell-derived factor 1, and insulin-like growth factor-1. Retina explants cultured in CM derived from iPSC-RPCs (iPSC-RPC-CM) showed better preservation of the retinal microarchitecture and fewer terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)+ nuclei, and reduced reactive gliosis. Furthermore, we saw a reduction in extracellular LDH levels in CM-treated retina explants, which also exhibited higher metabolic activity than the untreated controls. Conclusions: iPSC-derived RPCs secrete many trophic factors that have been shown to promote neuroprotection, tissue repair, and regeneration in the retina. Overall, we have demonstrated the neuroprotective effects of iPSC-RPC-CM through a degenerative neuroretina model ex vivo.

Features and psychometric properties of the Montreal Cognitive Assessment: Review and proposal of a process-based approach version (MoCA-PA).

The current study presents a rapid review of the psychometric features of the standard Montreal Cognitive Assessment (MoCA), and the proposal for a modified version of the test, informed by the methodology of the Boston Process Approach to neuropsychological assessment. In order to aid the process of identification of the primary underlying neurocognitive mechanism responsible for defective test performance, the MoCA-Process-Based Approach (MoCA-PA) adds complementary or satellite test conditions in some of its subtests, includes "new" qualitative indices to capture the cognitive processes involved in each cognitive task, and incorporates new qualitative classifications of error subtypes. It provides concurrent assessment of multiple cognitive processes within each task, without significantly increasing administration time or placing significant additional burden upon the respondent. We present preliminary results obtained from an initial sample of 45 community-dwelling older adults attending a University program for seniors. Results suggest the usefulness of additional indices in providing additional information on cognitive deterioration that may be overlooked with the only consideration of quantitative scores. Future research will aim to collect normative data for different clinical populations using the newly developed indices in order to determine the validity and clinical utility of the relatively novel qualitative process-based methods used in the MoCA-PA.

Traumatic brain injury epidemiology and rehabilitation in Ireland: a protocol paper.

Background: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. In Ireland, a dearth of research means that we neither know the number of people affected by TBI, nor have the required data to improve neuro-rehabilitation services. This is a study protocol to examine the epidemiology and pathways through rehabilitation for a cohort of TBI survivors in the Republic of Ireland. Aims:  1. To document the epidemiological data of TBIs in Ireland. 2. To explore the pathway of TBI survivors through rehabilitation/health services. 3. To document the experiences of those providing care for TBI survivors in Ireland Methods: This is a quantitative cohort study. Existing routine datasets will be used to report epidemiological data. Participants with moderate or severe TBI will be recruited through two brain injury service providers, two acute hospitals that provide neurosurgical services, and the National Rehabilitation Hospital. Participants with TBI will be surveyed on two separate occasions, to explore their use of health and rehabilitation services. Those providing care or support to TBI survivors will be surveyed, on one occasion. Additionally, data from the medical records of TBI survivors will be extracted to capture key information about their TBI, such as mechanism of injury, severity, hospitalisation and follow-up. TBI survivors' use of health care will be followed prospectively for six months. Expected outcomes: The epidemiological data of TBI in Ireland will be documented. Data on survivors' experiences of how rehabilitation services are accessed, and any barriers encountered with rehabilitation/health services will be reported. The experiences of those providing care or support for TBI survivors will be captured. It is expected that the outcomes of the study will support advocacy efforts toward the redevelopment of neuro-rehabilitation services in the Republic of Ireland.

The novel rexinoid MSU-42011 is effective for the treatment of preclinical Kras-driven lung cancer.

Effective drugs are needed for lung cancer, as this disease remains the leading cause of cancer-related deaths. Rexinoids are promising drug candidates for cancer therapy because of their ability to modulate genes involved in inflammation, cell proliferation or differentiation, and apoptosis through activation of the retinoid X receptor (RXR). The only currently FDA-approved rexinoid, bexarotene, is ineffective as a single agent for treating epithelial cancers and induces hypertriglyceridemia. Here, we used a previously validated screening paradigm to evaluate 23 novel rexinoids for biomarkers related to efficacy and safety. These biomarkers include suppression of inducible nitric oxide synthase (iNOS) and induction of sterol regulatory element-binding protein (SREBP). Because of its potent iNOS suppression, low SREBP induction, and activation of RXR, MSU-42011 was selected as our lead compound. We next used MSU-42011 to treat established tumors in a clinically relevant Kras-driven mouse model of lung cancer. KRAS is one of the most common driver mutations in human lung cancer and correlates with aggressive disease progression and poor patient prognosis. Ultrasound imaging was used to detect and monitor tumor development and growth over time in the lungs of the A/J mice. MSU-42011 markedly decreased the tumor number, size, and histopathology of lung tumors compared to the control and bexarotene groups. Histological sections of lung tumors in mice treated with MSU-42011 exhibited reduced cell density and fewer actively proliferating cells compared to the control and bexarotene-treated tumors. Although bexarotene significantly (p < 0.01) elevated plasma triglycerides and cholesterol, treatment with MSU-42011 did not increase these biomarkers, demonstrating a more favorable toxicity profile in vivo. The combination of MSU-42011 and carboplatin and paclitaxel reduced macrophages in the lung and increased activation markers of CD8+T cells compared to the control groups. Our results validate our screening paradigm for in vitro testing of novel rexinoids and demonstrate the potential for MSU-42011 to be developed for the treatment of KRAS-driven lung cancer.

Disability, Ethics, and Health Care in the COVID-19 Pandemic.

This article considers key ethical, legal, and medical dilemmas arising for people with disabilities in the COVID-19 pandemic. We highlight the limited application of existing frameworks of emergency planning with and for people with disabilities in the COVID-19 pandemic, explore key concerns and issues affecting the health care of people with disabilities (i.e., access to information and clinician-patient communication, nondiscrimination and reasonable accommodations, and rationing of medical goods), and indicate possible solutions. Finally, we suggest clinical and public health policy measures to ensure that people with disabilities are included in the planning of future pandemic-related efforts.The devastation evoked by the COVID-19 pandemic raises challenging dilemmas in bioethics. It also speaks to social justice issues that have plagued historically marginalized communities in the United States.Responses to the pandemic must be bound by legal standards, principles of distributive justice, and societal norms of protecting vulnerable populations-core commitments of public health-to ensure that inequities are not exacerbated, and should provide a pathway for improvements to ensure equitable access and treatment in the future.

An Unusual Salmonella Enteritidis Strain Carrying a Modified Virulence Plasmid Lacking the prot6e Gene Represents a Geographically Widely Distributed Lineage.

This study identifies a strain of Salmonella enterica subspecies enterica serovar Enteritidis that harbors a highly unusual virulence plasmid. During the characterisation of a group of S. Enteritidis isolates, 10 isolates recovered from Canadian duck production facilities, of which seven were phage type 9b and three were closely related atypical phage types, failed detection by a PCR targeting the prot6e gene, a marker located on the virulence plasmid often employed for identification of this serovar. Comparison to prot6e+ isolates by several standard genetic typing tools, further revealed their distinctive genomic makeup. Both short read and long read whole genome sequencing were completed on six of these isolates. In addition to loss of the prot6e gene, the virulence plasmid of each isolate was found to be exceptionally large (86.5 Kb) due to a 28 Kb insertion of S. Typhimurium plasmid sequence that encodes multiple genes of the incF operon. Interrogation of the chromosome sequence data of these isolates using a SNP-based typing tool and MLST both indicated their close genetic relatedness. One additional isolate carrying this plasmid was identified in an in-house collection of S. Enteritidis isolates. Finally, the identification of this unusual plasmid sequence in additional isolates submitted to public repositories of Salmonella sequence data was explored. All these analyses indicated that a very distinctive but rarely reported strain of S. Enteritidis was widely distributed across North America and the United Kingdom with one additional report involving a case from Brazil. With increased use of genetic methods for Salmonella identification, the loss of the prot6e sequence may confound correct identification of this serovar while also potentially altering the mode of transmission to humans given the gene's role in facilitating propagation of this bacterium in eggs. Accordingly, this strain may present certain challenges with respect to public health investigations. Our studies also suggest this strain is often associated with duck hosts thereby providing a possible mechanism by which this strain has spread over an extensive geographical area.

Disability Rights as a Necessary Framework for Crisis Standards of Care and the Future of Health Care.

In this essay, we suggest practical ways to shift the framing of crisis standards of care toward disability justice. We elaborate on the vision statement provided in the 2010 Institute of Medicine (National Academy of Medicine) "Summary of Guidance for Establishing Crisis Standards of Care for Use in Disaster Situations," which emphasizes fairness; equitable processes; community and provider engagement, education, and communication; and the rule of law. We argue that interpreting these elements through disability justice entails a commitment to both distributive and recognitive justice. The disability rights movement's demand "Nothing about us, without us" requires substantive inclusion of disabled people in decision-making related to their interests, including in crisis planning before, during, and after a pandemic like Covid-19.

Marrying Past and Present Neuropsychology: Is the Future of the Process-Based Approach Technology-Based?

A cognitive assessment strategy that is not limited to examining a set of summary test scores may be more helpful for early detection of emergent illness such as Alzheimer's disease (AD) and may permit a better understanding of cognitive functions and dysfunctions in those with AD and other dementia disorders. A revisit of the work already undertaken by Kaplan and colleagues using the Boston Process-Approach provides a solid basis for identifying new opportunities to capture data on neurocognitive processes, test-taking strategies and response styles. Thus, this critical review will combine traditional process-based assessment strategies with support provided or offered by newer technologies that have the potential to add value to data collection and interpretation. There is now considerable interest in neuropsychological test administration using computer/digital technology, both in research and in clinical settings. To add value, any computerized version of an existing cognitive test should respect the administration procedure for which normative data were obtained, should be time-saving in terms of scoring and interpretation, and should, we argue, facilitate gathering information about the processes and strategies followed in test completion. This article will offer an overview of the steps needed when implementing computerization of neuropsychological tests using a Process-Based Approach (PBA) to these technology-based adaptations and will discuss further developments in this area by linking it to future technological developments that may be possible in the area of neuropsychological assessment. Additionally, an overview of neuropsychological tests that may benefit from computerization will be presented, together with suggestions on the specific processes, strategies and features that may be captured with the aid of such computerization. Finally, hypotheses on how virtual reality could be an asset for the future of the PBA to neuropsychological assessment will also be discussed.

Detection of Retinal Fibrosis in a Rabbit Model of Penetrating Eye Injury.

INTRODUCTION: To establish a rabbit model of posterior penetrating eye injury as a platform to test potential therapeutics. MATERIALS AND METHODS: Anesthetized rabbits received posterior penetrating eye injury in one eye, whereas contralateral eyes were maintained as uninjured controls. Rabbits were randomized into two experimental groups. Group A was euthanized on Day 14 postinjury to determine retinal fibrosis at an early phase of disease progression. Group B was euthanized on Day 28 postinjury to examine retinal fibrosis at a late phase of disease progression. We examined animals on postinjury Days 7, 14, 21, and 28 with indirect ophthalmoscope and fundus photography. After euthanasia, eyes were processed for histology and immunofluorescence labeling of fibrotic proteins α-smooth muscle actin and collagen I. RESULTS: Early fibrosis was detected by Day 14, as indicated by indirect ophthalmoscopy and fundus imaging. Fibrotic membranes were visible at sites of injury. Immunofluorescence analysis detected α-smooth muscle actin and collagen I within the fibrotic membranes. CONCLUSIONS: These data show that ocular fibrosis can be detected within 14 days after initial injury, with more severe fibrosis detected at 28 days postinjury. These results will be used to determine the optimal time points for later studies designed to test treatment strategies.

The Bromodomain Inhibitor, INCB057643, Targets Both Cancer Cells and the Tumor Microenvironment in Two Preclinical Models of Pancreatic Cancer.

In pancreatic cancer the tumor microenvironment (TME) can account for up to 90% of the tumor mass. The TME drives essential functions in disease progression, invasion and metastasis. Tumor cells can use epigenetic modulation to evade immune recognition and shape the TME toward an immunosuppressive phenotype. Bromodomain inhibitors are a class of drugs that target BET (bromodomain and extra-terminal) proteins, impairing their ability to bind to acetylated lysines and therefore interfering with transcriptional initiation and elongation. INCB057643 is a new generation, orally bioavailable BET inhibitor that was developed for treating patients with advanced malignancies. KrasG12D/+; Trp53R172H/+; Pdx-1-Cre (KPC) mice mimic human disease, with similar progression and incidence of metastasis. Treatment of established tumors in KPC mice with INCB057643 increased survival by an average of 55 days, compared to the control group. Moreover, INCB057643 reduced metastatic burden in these mice. KPC mice treated with INCB057643, starting at 4 weeks of age, showed beneficial changes in immune cell populations in the pancreas and liver. Similarly, INCB057643 modified immune cell populations in the pancreas of KrasG12D/+; Pdx-1-Cre (KC) mice with pancreatitis, an inflammatory process known to promote pancreatic cancer progression. The data presented here suggest that the bromodomain inhibitor INCB057643 modulates the TME, reducing disease burden in two mouse models of pancreatic cancer. Furthermore, this work suggests that BRD4 may play a role in establishing the TME in the liver, a primary metastatic site for pancreatic cancer.

5-HT does not lower blood pressure in the 5-HT7 knockout rat.

The fall in mean arterial pressure (MAP) after 24 h of 5-HT infusion is associated with a dilation of the portal vein (PV) and abdominal inferior vena cava (Ab IVC); all events were blocked by the selective 5-HT7 receptor antagonist SB269970. Few studies have investigated the contribution of the 5-HT7 receptor in long-term cardiovascular control, and this requires an understanding of the chronic activation of the receptor. Using the newly created 5-HT7 receptor knockout (KO) rat, we presently test the hypothesis that continuous activation of the 5-HT7 receptor by 5-HT is necessary for the chronic (1 wk) depressor response and splanchnic venodilation. We also address if the 5-HT7 receptor contributes to endogenous cardiovascular regulation. Conscious MAP (radiotelemeter), splanchnic vessel diameter (ultrasound), and cardiac function (echocardiogram) were measured in ambulatory rats during multiday 5-HT infusion (25 µg·kg-1·min-1 via minipump) and after pump removal. 5-HT infusion reduced MAP and caused splanchnic venodilation of wild-type (WT) but not KO rats at any time point. The efficacy of 5-HT-induced contraction was elevated in the isolated abdominal inferior vena cava from the KO compared with WT rats, supporting loss of a relaxant receptor. Similarly, the efficacy of 5-HT causing an acute pressor response to higher doses of 5-HT in vivo was also increased in the KO vs. WT rat. Our work supports a novel mechanism for the cardiovascular effects of 5-HT, activation of 5-HT7 receptors mediating venodilation in the splanchnic circulation, which could prove useful in the treatment of cardiovascular disease.