Results of the Phase 1 Open-Label Safety Study of Umbilical Cord Lining Mesenchymal Stromal/Stem Cells (Corlicyte®) to Heal Chronic Diabetic Foot Ulcers.

BACKGROUND: Mesenchymal stromal/stem cells (MSCs) play a critical role in wound healing. Corlicyte® is an MSC product derived from allogeneic umbilical cord tissue donated under an institutional review board-approved protocol and processed in accordance with section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act. This open-label phase 1 trial was performed under a United States Food and Drug Administration Investigational New Drug Application to establish the safety and tolerability of Corlicyte® in patients with diabetes and chronic diabetic foot ulcer (DFU). METHODS: Escalating doses were applied topically twice a week for up to 8 weeks after ulcer debridement, wound photography, and measurement. Subjects were followed for 4 weeks after the treatment phase. Adverse events were assessed at every visit. RESULTS: Nine subjects in 2 dosing cohorts completed the trial. No subjects experienced a serious adverse reaction to Corlicyte® or the development of anti-human leukocyte antigen (HLA) antibodies. Sixty percentage of subjects in the lower dose cohort experienced ulcer closure by Day 70 of follow-up, while the mean ulcer size was reduced by 54-67% in the other subjects. CONCLUSIONS: Topical administration of Corlicyte®, a novel biologic therapy consisting of allogeneic umbilical cord lining MSCs, appeared safe and tolerable and resulted in a significant decrease in ulcer area, demonstrating its potential as a therapy for healing of chronic DFU.

Orbital Compartment Syndrome in Severe Burns: Predictive Factors, Timing, and Complications of Intervention.

PURPOSE: Severe burn patients require high-volume fluid resuscitation, which increases risk for orbital compartment syndrome (OCS). We aimed to understand surgeons' practice patterns and to examine risk factors for OCS, timing of lateral canthotomy and cantholysis (LCC), and complications of intervention. METHODS: A survey of American Society of Ophthalmic Plastic and Reconstructive Surgery and North American Society of Academic Orbital Surgeons' practice patterns in burn patients was undertaken. In addition, a retrospective analysis was conducted of 107 patients with burns greater than 20% total body surface area at 1 institution from January 1, 2009, to June 1, 2018. Patients with Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis, frostbite, or no ophthalmologic consultation were excluded. Risk factors for OCS, timing of LCC, and complications of the intervention were examined. RESULTS: In the survey, 37 of 54 respondents had treated burn patients, of which 29 followed no protocol. Threshold intraocular pressure for intervention varied widely, and nearly all reported having seen complications from LCC in burn patients. For the retrospective analysis, 107 patients met criteria, of which 22 (20.6%) required LCC. Renal failure, inhalation injury, eyelid burns, higher total body surface area, elevated lactate, increased number of escharotomies, and greater total fluid required were significantly associated with the clinical decision that the patient was at risk for OCS requiring LCC. Fluid resuscitation in excess of the Ivy Index (250 ml/kg) increased odds of LCC 8.6 times. Average time of LCC was 15.8 hours after burn. LCC patients experienced higher rates of complications including eyelid retraction, exposure keratopathy, and corneal ulceration. CONCLUSIONS: Severe burn patients should be monitored closely by an ophthalmologist during the first 48 hours for signs of OCS. Further studies should aim to recommend protocols guiding evaluation and intervention.

The Trial Innovation Network Liaison Team: building a national clinical and translational community of practice.

In 2016, the National Center for Advancing Translational Science launched the Trial Innovation Network (TIN) to address barriers to efficient and informative multicenter trials. The TIN provides a national platform, working in partnership with 60+ Clinical and Translational Science Award (CTSA) hubs across the country to support the design and conduct of successful multicenter trials. A dedicated Hub Liaison Team (HLT) was established within each CTSA to facilitate connection between the hubs and the newly launched Trial and Recruitment Innovation Centers. Each HLT serves as an expert intermediary, connecting CTSA Hub investigators with TIN support, and connecting TIN research teams with potential multicenter trial site investigators. The cross-consortium Liaison Team network was developed during the first TIN funding cycle, and it is now a mature national network at the cutting edge of team science in clinical and translational research. The CTSA-based HLT structures and the external network structure have been developed in collaborative and iterative ways, with methods for shared learning and continuous process improvement. In this paper, we review the structure, function, and development of the Liaison Team network, discuss lessons learned during the first TIN funding cycle, and outline a path toward further network maturity.

Assessment of a Mobile Health iPhone App for Semiautomated Self-management of Chronic Recurrent Medical Conditions Using an N-of-1 Trial Framework: Feasibility Pilot Study.

BACKGROUND: Management of chronic recurrent medical conditions (CRMCs), such as migraine headaches, chronic pain, and anxiety/depression, remains a major challenge for modern providers. Our team has developed an edge-based, semiautomated mobile health (mHealth) technology called iMTracker that employs the N-of-1 trial approach to allow self-management of CRMCs. OBJECTIVE: This study examines the patterns of adoption, identifies CRMCs that users selected for self-application, and explores barriers to use of the iMTracker app. METHODS: This is a feasibility pilot study with internet-based recruitment that ran from May 15, 2019, to December 23, 2020. We recruited 180 patients to pilot test the iMTracker app for user-selected CRMCs for a 3-month period. Patients were administered surveys before and after the study. RESULTS: We found reasonable usage rates: a total of 73/103 (70.9%) patients who were not lost to follow-up reported the full 3-month use of the app. Most users chose to use the iMTracker app to self-manage chronic pain (other than headaches; 80/212, 37.7%), followed by headaches in 36/212 (17.0%) and mental health (anxiety and depression) in 27/212 (12.8%). The recurrence rate of CRMCs was at least weekly in over 93% (169/180) of patients, with 36.1% (65/180) of CRMCs recurring multiple times in a day, 41.7% (75/180) daily, and 16.1% (29/180) weekly. We found that the main barriers to use were the design and technical function of the app, but that use of the app resulted in an improvement in confidence in the efficiency and safety/privacy of this approach. CONCLUSIONS: The iMTracker app provides a feasible platform for the N-of-1 trial approach to self-management of CRMCs, although internet-based recruitment provided limited follow-up, suggesting that in-person evaluation may be needed. The rate of CRMC recurrence was high enough to allow the N-of-1 trial assessment for most traits.

Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions.

Prophylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.

Prostate Cancer Central Nervous System Metastasis in a Contemporary Cohort.

INTRODUCTION: Central nervous system (CNS) metastasis from prostate cancer (PCA) is a rare event, but one with significant prognostic impact for those affected. There are limited data on its impact in contemporary cohorts treated with modern agents. PATIENTS AND METHODS: A retrospective institutional review was performed to characterize the occurrence/outcome of PCA CNS metastasis on all cases of PCA from 2011 to 2017. A manual chart review was performed to confirm PCA CNS metastases in all cases identified through a diagnostic code screening of the health data. RESULTS: A total of 6596 cases of PCA were identified, with 29 (20 dural and 9 intraparenchymal) confirmed cases of CNS metastases from PCA. The median survival from the time of diagnosis of CNS metastasis was 2.6 months (95% confidence interval, 2.04-10.78 months) and 5.41 months (95% confidence interval, 3.03 months to not reached) for dural and parenchymal metastases, respectively. Among those who developed CNS metastases, approximately 79% of patients had prior exposure to abiraterone and/or enzalutamide, of whom 50% had ≥ 6 months of exposure. Four (0.07%) of the 5841 patients developed CNS metastases prior to the initiation of therapy or on androgen deprivation therapy alone. In contrast, 24 (8.6%) of the 279 patients with 2 or more lines of medical therapy developed CNS metastases. CONCLUSIONS: Our analysis highlights the continued poor prognosis of parenchymal and dural CNS metastases from PCA. CNS metastases in PCA remain a rare event with a 0.4% incidence in this series, but this incidence is considerably increased in patients who receive medical therapy beyond first-line androgen deprivation therapy.

Caenorhabditis elegans ABCRNAi transporters interact genetically with rde-2 and mut-7.

RNA interference (RNAi) mechanisms are conserved and consist of an interrelated network of activities that not only respond to exogenous dsRNA, but also perform endogenous functions required in the fine tuning of gene expression and in maintaining genome integrity. Not surprisingly, RNAi functions have widespread influences on cellular function and organismal development. Previously, we observed a reduced capacity to mount an RNAi response in nine Caenorhabditis elegans mutants that are defective in ABC transporter genes (ABC(RNAi) mutants). Here, we report an exhaustive study of mutants, collectively defective in 49 different ABC transporter genes, that allowed for the categorization of one additional transporter into the ABC(RNAi) gene class. Genetic complementation tests reveal functions for ABC(RNAi) transporters in the mut-7/rde-2 branch of the RNAi pathway. These second-site noncomplementation interactions suggest that ABC(RNAi) proteins and MUT-7/RDE-2 function together in parallel pathways and/or as multiprotein complexes. Like mut-7 and rde-2, some ABC(RNAi) mutants display transposon silencing defects. Finally, our analyses reveal a genetic interaction network of ABC(RNAi) gene function with respect to this part of the RNAi pathway. From our results, we speculate that the coordinated activities of ABC(RNAi) transporters, through their effects on endogenous RNAi-related mechanisms, ultimately affect chromosome function and integrity.

ATP-binding cassette transporters are required for efficient RNA interference in Caenorhabditis elegans.

RNA interference (RNAi) is a conserved gene-silencing phenomenon that can be triggered by delivery of double-stranded RNA (dsRNA) to cells and is a widely exploited technology in analyses of gene function. Although a number of proteins that facilitate RNAi have been identified, current descriptions of RNAi and interrelated mechanisms are far from complete. Here, we report that the Caenorhabditis elegans gene haf-6 is required for efficient RNAi. HAF-6 is a member of the ATP-binding cassette (ABC) transporter gene superfamily. ABC transporters use ATP to translocate small molecule substrates across the membranes in which they reside, often against a steep concentration gradient. Collectively, ABC transporters are involved in a variety of activities, including protective or barrier mechanisms that export drugs or toxins from cells, organellar biogenesis, and mechanisms that protect against viral infection. HAF-6 is expressed predominantly in the intestine and germline and is localized to intracellular reticular organelles. We further demonstrate that eight additional ABC genes from diverse subfamilies are each required for efficient RNAi in C. elegans. Thus, the ability to mount a robust RNAi response to dsRNA depends upon the deployment of two ancient systems that respond to environmental assaults: RNAi mechanisms and membrane transport systems that use ABC proteins.

Synteny perturbations between wheat homoeologous chromosomes caused by locus duplications and deletions correlate with recombination rates.

Loci detected by Southern blot hybridization of 3,977 expressed sequence tag unigenes were mapped into 159 chromosome bins delineated by breakpoints of a series of overlapping deletions. These data were used to assess synteny levels along homoeologous chromosomes of the wheat A, B, and D genomes, in relation to both bin position on the centromere-telomere axis and the gradient of recombination rates along chromosome arms. Synteny level decreased with the distance of a chromosome region from the centromere. It also decreased with an increase in recombination rates along the average chromosome arm. There were twice as many unique loci in the B genome than in the A and D genomes, and synteny levels between the B genome chromosomes and the A and D genome homoeologues were lower than those between the A and D genome homoeologues. These differences among the wheat genomes were attributed to differences in the mating systems of wheat diploid ancestors. Synteny perturbations were characterized in 31 paralogous sets of loci with perturbed synteny. Both insertions and deletions of loci were detected and both preferentially occurred in high recombination regions of chromosomes.

Comparative DNA sequence analysis of wheat and rice genomes.

The use of DNA sequence-based comparative genomics for evolutionary studies and for transferring information from model species to crop species has revolutionized molecular genetics and crop improvement strategies. This study compared 4485 expressed sequence tags (ESTs) that were physically mapped in wheat chromosome bins, to the public rice genome sequence data from 2251 ordered BAC/PAC clones using BLAST. A rice genome view of homologous wheat genome locations based on comparative sequence analysis revealed numerous chromosomal rearrangements that will significantly complicate the use of rice as a model for cross-species transfer of information in nonconserved regions.

The organization and rate of evolution of wheat genomes are correlated with recombination rates along chromosome arms.

Genes detected by wheat expressed sequence tags (ESTs) were mapped into chromosome bins delineated by breakpoints of 159 overlapping deletions. These data were used to assess the organizational and evolutionary aspects of wheat genomes. Relative gene density and recombination rate increased with the relative distance of a bin from the centromere. Single-gene loci present once in the wheat genomes were found predominantly in the proximal, low-recombination regions, while multigene loci tended to be more frequent in distal, high-recombination regions. One-quarter of all gene motifs within wheat genomes were represented by two or more duplicated loci (paralogous sets). For 40 such sets, ancestral loci and loci derived from them by duplication were identified. Loci derived by duplication were most frequently located in distal, high-recombination chromosome regions whereas ancestral loci were most frequently located proximal to them. It is suggested that recombination has played a central role in the evolution of wheat genome structure and that gradients of recombination rates along chromosome arms promote more rapid rates of genome evolution in distal, high-recombination regions than in proximal, low-recombination regions.

Molecular characterization of a set of wheat deletion stocks for use in chromosome bin mapping of ESTs.

The objective of this study was molecular characterization of a set of deletion stocks and other aneuploids for use in chromosome bin mapping of ESTs in wheat. Wheat aneuploid stocks including 21 nullisomic-tetrasomic (NT), 24 ditelosomic (Dt), and 101 deletion (del) lines were screened with 526 EST clones. A total of 1,951 loci were detected by 493 informative EST clones and tagged 150 of the 159 deletion intervals or chromosome bins. Previously described deletion lines del1AS-4, del6AL-2, del6BS-6, and del7DS-6 were found to have normal chromosome constitution. The short arm deletion in del3AS-3 may be translocated from an unknown chromosome as this stock is nullisomic for the 3AS arm. Thirty-five new deletions were detected in 26 lines. Most of the new deletions occurred in terminal regions of chromosomes and probably resulted from the loss of very small terminal fragments that were difficult to detect cytologically. Eleven chromosome aberrations were also detected in two NT and five Dt lines. Overall, the chromosome bin map provides a resolution of around 28 Mb for an anchor map of a basic set of seven chromosomes of the Triticeae. Any target gene can be allocated to a specific 28-Mb bin and associated ESTs, anchored to the other Triticeae/grass maps including rice and, therefore, amenable to molecular cloning by comparative and wheat-based positional cloning methods.