Myositis Ossificans Traumatica of Bilateral Sternocleidomastoid Muscles After Chiropractor Adjustment: A Case Report.

A woman in her 20s with a past medical history of surgical debulking of a right neck mass presented to the hospital for persistent and worsening right shoulder pain. The shoulder pain was associated with trismus and back and neck pain. A CT scan of the neck with contrast revealed post-surgical changes with increased heterotopic ossification throughout the surgical site extending to the supraclavicular soft tissues and the left sternocleidomastoid muscle, suggesting muscle ossification. A biopsy was performed, and the patient was diagnosed with myositis ossificans (MO). Initial treatment began with the administration of steroids and analgesics. She was scheduled for a follow-up with orthopedics, rheumatology, and genetics, but she was lost for follow-up. MO is a very rare medical condition usually associated with trauma, and in our patient, the symptoms started after a chiropractic adjustment.

Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage.

INTRODUCTION: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages. METHODS: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. RESULTS: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. DISCUSSION: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. HIGHLIGHTS: Mutation position influences Aß burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aß burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.

Comparing Tau PET Visual Interpretation with Tau PET Quantification, Cerebrospinal Fluid Biomarkers, and Longitudinal Clinical Assessment.

BACKGROUND: 18F-flortaucipir PET received FDA approval to visualize aggregated neurofibrillary tangles (NFTs) in brains of adult patients with cognitive impairment being evaluated for Alzheimer's disease (AD). However, manufacturer's guidelines for visual interpretation of 18F-flortaucipir PET differ from how 18F-flortaucipir PET has been measured in research settings using standardized uptake value ratios (SUVRs). How visual interpretation relates to 18F-flortaucipir PET SUVR, cerebrospinal fluid (CSF) biomarkers, or longitudinal clinical assessment is not well understood. OBJECTIVE: We compare various diagnostic methods in participants enrolled in longitudinal observational studies of aging and memory (n = 189, 23 were cognitively impaired). METHODS: Participants had tau PET, Aß PET, MRI, and clinical and cognitive evaluation within 18 months (n = 189); the majority (n = 144) also underwent lumbar puncture. Two radiologists followed manufacturer's guidelines for 18F-flortaucipir PET visual interpretation. RESULTS: Visual interpretation had high agreement with SUVR (98.4%)and moderate agreement with CSF p-tau181 (86.1%). Two participants demonstrated 18F-flortaucipir uptake from meningiomas. Visual interpretation could not predict follow-up clinical assessment in 9.52% of cases. CONCLUSION: Visual interpretation was highly consistent with SUVR (discordant participants had hemorrhagic infarcts or occipital-predominant AD NFT deposition) and moderately consistent with CSF p-tau181 (discordant participants had AD pathophysiology not detectable on tau PET). However, close association between AD NFT deposition and clinical onset in group-level studies does not necessarily hold at the individual level, with discrepancies arising from atypical AD, vascular dementia, or frontotemporal dementia. A better understanding of relationships across imaging, CSF biomarkers, and clinical assessment is needed to provide appropriate diagnoses for these individuals.

Obstructing Sigmoid Volvulus: An Unusual Complication in a Pediatric Patient With Ulcerative Colitis.

Acute colonic dilation in pediatric patients with ulcerative colitis (UC) raises a concern for toxic megacolon, but other rare conditions such as sigmoid volvulus may present in a similar manner. We report a rare case of a teenager with UC without prior surgery who developed an obstructing sigmoid volvulus managed with endoscopic detorsion and decompression. Colonic inflammation in patients with UC may result in a volvulus in the absence of other predisposing factors and should be considered in the differential diagnosis of patients with UC who present with obstructive symptoms with an atypical presentation.

Development of membrane-active peptide therapeutics in oncology.

Membrane-active peptides play an essential role in many living organisms and their immune systems and counter many infectious diseases. Many have dual or multiple mechanisms and can synergize with other molecules, like peptides, proteins, and small molecules. Although membrane-active peptides have been intensively studied in the past decades and more than 3500 sequences have been identified, only a few received approvals from the US Food and Drug Administration. In this review, we investigated all the peptide therapeutics that have entered the market or were subjected to preclinical and clinical studies to understand how they succeeded. With technological advancement (e.g., chemical modifications and pharmaceutical formulations) and a better understanding of the mechanism of action and the potential targets, we found at least five membrane-active peptide drugs that have entered preclinical/clinical phases and show promising results for cancer treatment. We summarized our findings in this review and provided insights into membrane-active anticancer peptide therapeutics.

APOE ε4 genotype, amyloid-ß, and sex interact to predict tau in regions of high APOE mRNA expression.

The apolipoprotein E (APOE) ε4 allele is strongly linked with cerebral ß-amyloidosis, but its relationship with tauopathy is less established. We investigated the relationship between APOE ε4 carrier status, regional amyloid-ß (Aß), magnetic resonance imaging (MRI) volumetrics, tau positron emission tomography (PET), APOE messenger RNA (mRNA) expression maps, and cerebrospinal fluid phosphorylated tau (CSF ptau181). Three hundred fifty participants underwent imaging, and 270 had ptau181. We used computational models to evaluate the main effect of APOE ε4 carrier status on regional neuroimaging values and then the interaction of ε4 status and global Aß on regional tau PET and brain volumes as well as CSF ptau181. Separately, we also examined the additional interactive influence of sex. We found that, for the same degree of Aß burden, APOE ε4 carriers showed greater tau PET signal relative to noncarriers in temporal regions, but no interaction was present for MRI volumes or CSF ptau181. This potentiation of tau aggregation irrespective of sex occurred in brain regions with high APOE mRNA expression, suggesting local vulnerabilities to tauopathy. There were greater effects of APOE genotype in females, although the interactive sex effects did not strongly mirror mRNA expression. Pathology is not homogeneously expressed throughout the brain but mirrors underlying biological patterns such as gene expression.

Synthetic molecular evolution of antimicrobial peptides.

As we learn more about how peptide structure and activity are related, we anticipate that antimicrobial peptides will be engineered to have strong potency and distinct functions and that synthetic peptides will have new biomedical applications, such as treatments for emerging infectious diseases. As a result of the enormous number of possible amino acid sequences and the low-throughput nature of antimicrobial peptide assays, computational tools for peptide design and optimization are needed for direct experimentation toward obtaining functional sequences. Recent developments in computational tools have improved peptide design, saving labor, reagents, costs, and time. At the same time, improvements in peptide synthesis and experimental platforms continue to reduce the cost and increase the throughput of peptide-drug screening. In this review, we discuss the current methods of peptide design and engineering, including in silico methods and peptide synthesis and screening, and highlight areas of potential improvement.

Aldafermin in patients with non-alcoholic steatohepatitis (ALPINE 2/3): a randomised, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, and injury, and is associated with an increased risk of liver transplantation and death. NASH affects more than 16 million people in the USA, and there is no approved therapy. The aim of this study was to evaluate the safety and efficacy of aldafermin, an engineered analogue of the gut hormone fibroblast growth factor 19 (FGF19). METHODS: In this randomised, double-blind, placebo-controlled, phase 2b study (ALPINE 2/3) in patients with biopsy-confirmed NASH and stage 2 or 3 fibrosis, we randomly assigned patients stratified by fibrosis stage in a 1:1:1:1 ratio to receive placebo, aldafermin 0·3 mg, 1·0 mg, or 3·0 mg once daily for 24 weeks at 30 study sites in the USA. Patients, investigators, the funder, and all other staff, were masked to treatment assignment throughout the study. The primary endpoint was an improvement in liver fibrosis of at least one stage with no worsening of NASH at week 24. Analyses were done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT03912532, and has been completed. FINDINGS: Between May 16, 2019, and Sept 4, 2020, 786 patients were screened, of whom 171 were randomly assigned to a treatment group and included in the intention-to-treat population: 43 in the 0·3 mg aldafermin group, 42 in the 1·0 mg group, 43 in the 3·0 mg group, and 43 in the placebo group. In total, 145 (85%) of patients completed treatment. At week 24, among patients with biopsies at both baseline and week 24, was seven (19%) of 36 patients in the placebo group, 11 (31%) of 36 in the 0·3 mg aldafermin group (difference 90% CI 12% [-9 to 33]; p=0·11), five (15%) of 34 patients in the 1·0 mg group (difference -5% [-24 to 13]; p=0·80), and 11 (30%) of 37 patients in the 3·0 mg group (difference 10% [-9 to 30]; p=0·12) had an improvement in liver fibrosis of at least one stage with no worsening of NASH, without meeting the prespecified significance for dose response (p=0·55). Adverse events were mostly mild or moderate in severity. Diarrhoea occurred in six (14%) of 43 patients in the placebo group, three (7%) of 43 patients in the 0·3 mg aldafermin group, five (12%) of 41 patients in the 1·0 mg group, and ten (23%) of 43 patients in the 3·0 mg group. Incidences of serious adverse events and discontinuations owing to adverse events were similar between groups. INTERPRETATION: Aldafermin was generally well tolerated but did not produce a significant dose response on fibrosis improvement of at least one stage with no worsening of NASH, despite positive effects on a number of secondary endpoints. The findings of this trial may have implications for the design of future NASH trials. FUNDING: NGM Biopharmaceuticals.

Integrated Design of a Membrane-Lytic Peptide-Based Intravenous Nanotherapeutic Suppresses Triple-Negative Breast Cancer.

Membrane-lytic peptides offer broad synthetic flexibilities and design potential to the arsenal of anticancer therapeutics, which can be limited by cytotoxicity to noncancerous cells and induction of drug resistance via stress-induced mutagenesis. Despite continued research efforts on membrane-perforating peptides for antimicrobial applications, success in anticancer peptide therapeutics remains elusive given the muted distinction between cancerous and normal cell membranes and the challenge of peptide degradation and neutralization upon intravenous delivery. Using triple-negative breast cancer as a model, the authors report the development of a new class of anticancer peptides. Through function-conserving mutations, the authors achieved cancer cell selective membrane perforation, with leads exhibiting a 200-fold selectivity over non-cancerogenic cells and superior cytotoxicity over doxorubicin against breast cancer tumorspheres. Upon continuous exposure to the anticancer peptides at growth-arresting concentrations, cancer cells do not exhibit resistance phenotype, frequently observed under chemotherapeutic treatment. The authors further demonstrate efficient encapsulation of the anticancer peptides in 20 nm polymeric nanocarriers, which possess high tolerability and lead to effective tumor growth inhibition in a mouse model of MDA-MB-231 triple-negative breast cancer. This work demonstrates a multidisciplinary approach for enabling translationally relevant membrane-lytic peptides in oncology, opening up a vast chemical repertoire to the arms race against cancer.

Predicting Membrane-Active Peptide Dynamics in Fluidic Lipid Membranes.

Understanding the interactions between peptides and lipid membranes could not only accelerate the development of antimicrobial peptides as treatments for infections but also be applied to finding targeted therapies for cancer and other diseases. However, designing biophysical experiments to study molecular interactions between flexible peptides and fluidic lipid membranes has been an ongoing challenge. Recently, with hardware advances, algorithm improvements, and more accurate parameterizations (i.e., force fields), all-atom molecular dynamics (MD) simulations have been used as a "computational microscope" to investigate the molecular interactions and mechanisms of membrane-active peptides in cell membranes (Chen et al., Curr Opin Struct Biol 61:160-166, 2020; Ulmschneider and Ulmschneider, Acc Chem Res 51(5):1106-1116, 2018; Dror et al., Annu Rev Biophys 41:429-452, 2012). In this chapter, we describe how to utilize MD simulations to predict and study peptide dynamics and how to validate the simulations by circular dichroism, intrinsic fluorescent probe, membrane leakage assay, electrical impedance, and isothermal titration calorimetry. Experimentally validated MD simulations open a new route towards peptide design starting from sequence and structure and leading to desirable functions.

Intracranial internal carotid artery calcification is not predictive of future cognitive decline.

BACKGROUND: Intracranial internal carotid artery (ICA) calcification is a common incidental finding in non-contrast head CT. We evaluated the predictive value of ICAC (ICAC) for future risk of cognitive decline and compared the results with conventional imaging biomarkers of dementia. METHODS: In a retrospective observational cohort, we included 230 participants with a PET-CT scan within 18 months of a baseline clinical assessment and longitudinal imaging assessments. Intracranial ICAC was quantified on baseline CT scans using the Agatson calcium score, and the association between baseline ICA calcium scores and the risk of conversion from a CDR of zero in baseline to a persistent CDR > 0 at any follow-up visit, as well as longitudinal changes in cognitive scores, were evaluated through linear and mixed regression models. We also evaluated the association of conventional imaging biomarkers of dementia with longitudinal changes in cognitive scores and a potential indirect effect of ICAC on cognition through these biomarkers. RESULTS: Baseline ICA calcium score could not distinguish participants who converted to CDR > 0. ICA calcium score was also unable to predict longitudinal changes in cognitive scores, imaging biomarkers of small vessel disease such as white matter hyperintensities (WMH) volume, or AD such as hippocampal volume, AD cortical signature thickness, and amyloid burden. Severity of intracranial ICAC increased with age and in men. Higher WMH volume and amyloid burden as well as lower hippocampal volume and AD cortical signature thickness at baseline predicted lower Mini-Mental State Exam scores at longitudinal follow-up. Baseline ICAC was indirectly associated with longitudinal cognitive decline, fully mediated through WMH volume. CONCLUSIONS: In elderly and preclinical AD populations, atherosclerosis of large intracranial vessels as demonstrated through ICAC is not directly associated with a future risk of cognitive impairment, or progression of imaging biomarkers of AD or small vessel disease.

Evaluating the Neutralizing Ability of a CpG-Adjuvanted S-2P Subunit Vaccine Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants of Concern.

BACKGROUND: Variants of concern (VoCs) have the potential to diminish the neutralizing capacity of antibodies elicited by vaccines. MVC-COV1901 is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine consisting of recombinant prefusion stabilized spike protein S-2P adjuvanted with CpG 1018 and aluminum hydroxide. We explored the effectiveness of MVC-COV1901 against the VoCs. METHODS: Serum samples were taken from rats and phase 1 clinical trial human subjects immunized with a low, medium, or high dose of MVC-COV1901. The neutralizing titers of serum antibodies were assayed with pseudoviruses coated with the SARS-CoV-2 spike protein of the wild-type (WT), D614G, Alpha, or Beta variants. RESULTS: Rats vaccinated twice with vaccine containing high doses of antigen retained high levels of neutralization activity against the Beta variant, albeit with a slight reduction compared to WT. After the third dose, neutralizing titers against the Beta variant were noticeably enhanced regardless of the amount of antigen used for immunization. In humans, vaccinated phase 1 subjects still showed appreciable neutralization abilities against the D614G, Alpha, and Beta variants, although neutralizing titers were significantly reduced against the Beta variant. CONCLUSIONS: Two doses of MVC-COV1901 were able to elicit neutralizing antibodies against SARS-CoV-2 variants with an overall tendency of inducing higher immune response at a higher dose level. The neutralizing titers to the Beta variant in rats and humans were lower than those for WT and the Alpha variant. An additional third dose in rats was able to partially compensate for the reduction in neutralization against the Beta variant. We have demonstrated that immunization with MVC-COV1901 was effective against VoCs.

Safety and immunogenicity of CpG 1018 and aluminium hydroxide-adjuvanted SARS-CoV-2 S-2P protein vaccine MVC-COV1901: interim results of a large-scale, double-blind, randomised, placebo-controlled phase 2 trial in Taiwan.

BACKGROUND: MVC-COV1901, a recombinant protein vaccine containing pre-fusion-stabilised spike protein S-2P adjuvanted with CpG 1018 and aluminium hydroxide, has been shown to be well tolerated with a good safety profile in healthy adults aged 20-49 years in a phase 1 trial, and provided a good cellular and humoral immune responses. We present the interim safety, tolerability, and immunogenicity results of a phase 2 clinical trial of the MVC-COV1901 vaccine in Taiwan. METHODS: This is a large-scale, double-blind, randomised, placebo-controlled phase 2 trial done at ten medical centres and one regional hospital in Taiwan. Individuals aged 20 years or older who were generally healthy or had stable pre-existing medical conditions were eligible for enrolment. Exclusion criteria included (but were not limited to) travel overseas within 14 days of screening, intention to travel overseas within 6 months of the screening visit, and the absence of prespecified medical conditions, including immunosuppressive illness, a history of autoimmune disease, malignancy with risk to recur, a bleeding disorder, uncontrolled HIV infection, uncontrolled hepatitis B and C virus infections, SARS-CoV-1 or SARS-CoV-2 infections, an allergy to any vaccine, or a serious medical condition that could interfere with the study. Study participants were randomly assigned (6:1) to receive two doses of either MVC-COV1901 or placebo, administered via intramuscular injection on day 1 and day 29. MVC-COV1901 contained 15 µg of S-2P protein adjuvanted with 750 µg CpG 1018 and 375 µg aluminium hydroxide in a 0·5 mL aqueous solution, and the placebo contained the same volume of saline. Randomisation was done centrally by use of an interactive web response system, stratified by age (≥20 to <65 years and ≥65 years). Participants and investigators were masked to group assignment. The primary outcomes were to evaluate the safety, tolerability, and immunogenicity of MVC-COV1901 from day 1 (the day of the first dose) to day 57 (28 days after the second dose). Safety was assessed in all participants who received at least one dose. Immunogenicity was assessed by measuring geometric mean titres (GMTs) and seroconversion rates of neutralising antibody and antigen-specific IgG in the per-protocol population. This study is registered with ClinicalTrials.gov, NCT04695652. FINDINGS: Of 4173 individuals screened between Dec 30, 2020, and April 2, 2021, 3854 were enrolled and randomly assigned: 3304 to the MVC-COV1901 group and 550 to the placebo group. A total of 3844 participants (3295 in the MVC-COV1901 group and 549 in the placebo group) were included in the safety analysis set, and 1053 participants (903 and 150) had received both doses and were included in the per-protocol immunogenicity analysis set. From the start of this phase 2 trial to the time of interim analysis, no vaccine-related serious adverse events were recorded. The most common solicited adverse events in all study participants were pain at the injection site (2346 [71·2%] of 3295 in the MVC-COV1901 group and 128 [23·3%] of 549 in the placebo group), and malaise or fatigue (1186 [36·0%] and 163 [29·7%]). Fever was rarely reported (23 [0·7%] and two [0·4%]). At 28 days after the second dose of MVC-COV1901, the wild-type SARS-CoV-2 neutralising antibody GMT was 662·3 (95% CI 628·7-697·8; 408·5 IU/mL), the GMT ratio (geometric mean fold increase in titres at day 57 vs baseline) was 163·2 (155·0-171·9), and the seroconversion rate was 99·8% (95% CI 99·2-100·0). INTERPRETATION: MVC-COV1901 has a good safety profile and elicits promising immunogenicity responses. These data support MVC-COV1901 to enter phase 3 efficacy trials. FUNDING: Medigen Vaccine Biologics and Taiwan Centres for Disease Control, Ministry of Health and Welfare.

Chromosome-scale assembly and evolution of the tetraploid Salvia splendens (Lamiaceae) genome.

Polyploidization plays a key role in plant evolution, but the forces driving the fate of homoeologs in polyploid genomes, i.e., paralogs resulting from a whole-genome duplication (WGD) event, remain to be elucidated. Here, we present a chromosome-scale genome assembly of tetraploid scarlet sage (Salvia splendens), one of the most diverse ornamental plants. We found evidence for three WGD events following an older WGD event shared by most eudicots (the γ event). A comprehensive, spatiotemporal, genome-wide analysis of homoeologs from the most recent WGD unveiled expression asymmetries, which could be associated with genomic rearrangements, transposable element proximity discrepancies, coding sequence variation, selection pressure, and transcription factor binding site differences. The observed differences between homoeologs may reflect the first step toward sub- and/or neofunctionalization. This assembly provides a powerful tool for understanding WGD and gene and genome evolution and is useful in developing functional genomics and genetic engineering strategies for scarlet sage and other Lamiaceae species.

Safety and immunogenicity of a Recombinant Stabilized Prefusion SARS-CoV-2 Spike Protein Vaccine (MVC-COV1901) Adjuvanted with CpG 1018 and Aluminum Hydroxide in healthy adults: A Phase 1, dose-escalation study.

BACKGROUND: This was a phase 1, dose-escalation open-label trial to evaluate the safety and immunogenicity of MVC-COV1901, a SARS-CoV-2 S-2P protein vaccine adjuvanted with aluminum hydroxide and CpG 1018. METHODS: Between September 28 and November 13 2020, 77 participants were screened. Of these, 45 healthy adults from 20 to 49 years of age were to be administered two doses of MVC-COV1901 in doses of 5 µg, 15 µg, or 25 µg of spike protein at 28 days apart. There were 15 participants in each dose group; all were followed for 28 days after the second dose at the time of the interim analysis. Adverse events and laboratory data were recorded for the safety evaluation. Blood samples were collected for humoral, and cellular immune response at various time points. Trial Registration: ClinicalTrials.gov NCT04487210. FINDINGS: Solicited adverse events were mostly mild and similar. No subject experienced fever. After the second dose, the geometric mean titers (GMTs) for SARS-CoV-2 spike-specific immunoglobulin G were 7178.2, 7746.1, 11,220.6 in the 5 µg, 15 µg, and 25 µg dose groups, respectively. The neutralizing activity were detected in both methods. (Day 43 GMTs, 538.5, 993.1, and 1905.8 for pseudovirus; and 33.3, 76.3, and 167.4 for wild-type virus). The cellular immune response induced by MVC-COV1901 demonstrated substantially higher numbers of IFN-γ- producing cells, suggesting a Th1-skewed immune response. INTERPRETATION: The MVC-COV1901 vaccine was well tolerated and elicited robust immune responses and is suitable for further development. FUNDING: Medigen Vaccine Biologics Corporation.

Tuning of a Membrane-Perforating Antimicrobial Peptide to Selectively Target Membranes of Different Lipid Composition.

The use of designed antimicrobial peptides as drugs has been impeded by the absence of simple sequence-structure-function relationships and design rules. The likely cause is that many of these peptides permeabilize membranes via highly disordered, heterogeneous mechanisms, forming aggregates without well-defined tertiary or secondary structure. We suggest that the combination of high-throughput library screening with atomistic computer simulations can successfully address this challenge by tuning a previously developed general pore-forming peptide into a selective pore-former for different lipid types. A library of 2916 peptides was designed based on the LDKA template. The library peptides were synthesized and screened using a high-throughput orthogonal vesicle leakage assay. Dyes of different sizes were entrapped inside vesicles with varying lipid composition to simultaneously screen for both pore size and affinity for negatively charged and neutral lipid membranes. From this screen, nine different LDKA variants that have unique activity were selected, sequenced, synthesized, and characterized. Despite the minor sequence changes, each of these peptides has unique functional properties, forming either small or large pores and being selective for either neutral or anionic lipid bilayers. Long-scale, unbiased atomistic molecular dynamics (MD) simulations directly reveal that rather than rigid, well-defined pores, these peptides can form a large repertoire of functional dynamic and heterogeneous aggregates, strongly affected by single mutations. Predicting the propensity to aggregate and assemble in a given environment from sequence alone holds the key to functional prediction of membrane permeabilization.

Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies.

PURPOSE: In preclinical studies, the lysine-specific histone demethylase 1A (LSD1) inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of myeloid blasts in non-acute promyelocytic leukemia acute myeloid leukemia (AML). We conducted a phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS). PATIENTS AND METHODS: Seventeen patients were treated with ATRA and TCP (three dose levels: 10 mg twice daily, 20 mg twice daily, and 30 mg twice daily). RESULTS: ATRA-TCP had an acceptable safety profile. The MTD of TCP was 20 mg twice daily. Best responses included one morphologic leukemia-free state, one marrow complete remission with hematologic improvement, two stable disease with hematologic improvement, and two stable disease. By intention to treat, the overall response rate was 23.5% and clinical benefit rate was 35.3%. Gene expression profiling of patient blasts showed that responding patients had a more quiescent CD34+ cell phenotype at baseline, including decreased MYC and RARA expression, compared with nonresponders that exhibited a more proliferative CD34+ phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid-target genes in responders but not nonresponders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response. CONCLUSIONS: These data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of patients with MDS and AML.

Association of differentially expressed R-gene candidates with leaf spot resistance in peanut (Arachis hypogaea L.).

Early leaf spot (ELS) and late leaf spot (LLS) are major fungal diseases of peanut that can severely reduce yield and quality. Development of acceptable genetic resistance has been difficult due to a strong environmental component and many major and minor QTLs. Resistance genes (R-genes) are an important component of plant immune system and have been identified in peanut. Association of specific R-genes to leaf spot resistance will provide molecular targets for marker-assisted breeding strategies. In this study, advanced breeding lines from different pedigrees were evaluated for leaf spot resistance and 76 candidate R-genes expression study was applied to susceptible and resistant lines. Thirty-six R-genes were differentially expressed and significantly correlated with resistant lines, of which a majority are receptor like kinases (RLKs) and receptor like proteins (RLPs) that sense the presence of pathogen at the cell surface and initiate protection response. The largest group was receptor-like cytoplasmic kinases (RLCKs) VII that are involved in pattern-triggered kinase signaling resulting in the production reactive oxygen species (ROS). Four R-genes were homologous to TMV resistant protein N which has shown to confer resistance against tobacco mosaic virus (TMV). When mapped to peanut genomes, 36 R-genes were represented in most chromosomes except for A09 and B09. Low levels of gene-expression in resistant lines suggest expression is tightly controlled to balance the cost of R-gene expression to plant productively. Identification and association of R-genes involved in leaf spot resistance will facilitate genetic selection of leaf spot resistant lines with good agronomic traits.

Correction to: Gallbladder Adenomyomatosis in an Infant.

[This corrects the article DOI: 10.14309/crj.0000000000000433.].