Reduction In Lesion Size Research Articles

Human pluripotent stem cell-derived ectomesenchymal stromal cells promote more robust functional recovery than umbilical cord-derived mesenchymal stromal cells after hypoxic-ischaemic brain damage.

Aims: Hypoxic-ischaemic encephalopathy (HIE) is one of the most serious complications in neonates and infants. Mesenchymal stromal cell (MSC)-based therapy is emerging as a promising treatment avenue for HIE. However, despite its enormous potential, the clinical application of MSCs is limited by cell heterogeneity, low isolation efficiency and unpredictable effectiveness. In this study, we examined the therapeutic effects and underlying mechanisms of human pluripotent stem cell-derived ectomesenchymal stromal cells (hPSC-EMSCs) in a rat model of HIE.Methods: hPSC-EMSCs were induced from either human embryonic stem cells or induced pluripotent stem cells. Stem cells or the conditioned medium (CM) derived from stem cells were delivered intracranially or intranasally to neonatal rats with HIE. Human umbilical cord-derived MSCs (hUC-MSCs) were used as the therapeutic comparison control and phosphate-buffered saline (PBS) was used as a negative control. Lesion size, apoptosis, neurogenesis, astrogliosis and microgliosis were evaluated. The rotarod test and Morris water maze were used to determine brain functional recovery. The PC-12 cell line, rat primary cortical neurons and neural progenitor cells were used to evaluate neurite outgrowth and the neuroprotective and neurogenesis effects of hPSC-EMSCs/hUC-MSCs. RNA-seq and enzyme-linked immunosorbent assays were used to determine the secretory factors that were differentially expressed between hPSC-EMSCs and hUC-MSCs. The activation and suppression of extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) were characterised using western blotting and immunofluorescent staining.Results: hPSC-EMSCs showed a higher neuroprotective potential than hUC-MSCs, as demonstrated by a more significant reduction in lesion size and apoptosis in the rat brain following hypoxia-ischaemia (HI). Compared with PBS treatment, hPSC-EMSCs promoted endogenous neurogenesis and alleviated astrogliosis and microgliosis. hPSC-EMSCs were more effective than hUC-MSCs. hPSC-EMSCs achieved a greater recovery of brain function than hUC-MSCs and PBS in rats with HIE. CM derived from hPSC-EMSCs had neuroprotective and neurorestorative effects in vitro through anti-apoptotic and neurite outgrowth- and neurogenesis-promoting effects. Direct comparisons between hPSC-EMSCs and hUC-MSCs revealed the significant enrichment of a group of secretory factors in hPSC-EMSCs, including nerve growth factor (NGF), platelet-derived growth factor-AA and transforming growth factor-β2, which are involved in neurogenesis, synaptic transmission and neurotransmitter transport, respectively. Mechanistically, the CM derived from hPSC-EMSCs was found to potentiate NGF-induced neurite outgrowth and the neuronal differentiation of NPCs via the ERK/CREB pathway. Suppression of ERK or CREB abolished CM-potentiated neuritogenesis and neuronal differentiation. Finally, intranasal delivery of the CM derived from hPSC-EMSCs significantly reduced brain lesion size, promoted endogenous neurogenesis, mitigated inflammatory responses and improved functional recovery in rats with HIE.Conclusion: hPSC-EMSCs promote functional recovery after HI through multifaceted neuromodulatory activities via paracrine/trophic mechanisms. We propose the use of hPSC-EMSCs for the treatment of HIE, as they offer an excellent unlimited cellular source of MSCs.

Comparison of clinical indices and therapeutic effect of a mucoadhesive system containing Melissa 1% and triamcinolone 0.1% on lichenoid reactions.

Background:Lichenoid reaction (LR) is a relatively common mucocutaneous disease with an unknown etiology. Since the cause of the LRs is unknown, many drugs have been studied to palliate the symptoms. Previous studies reported that corticosteroids are often effective in the management of several oral inflammatory diseases. The aim of the present study was to compare the effect of Melissa gel and triamcinolone 0.1% paste on clinical indices of oral LRs.Materials and Methods:In this randomized clinical trial, sixty patients with erosive oral LRs were randomly divided into two groups, and each group was treated with Melissa gel or triamcinolone acetonide 0.1% paste, three times a day, for 4 weeks. The recovery rate and severity of pain and burning sensation were assessed after 2 and 4 weeks. Finally, the obtained data were analyzed using SPSS software (version 20, IBM Corp., Armonk, NY, USA) and repeated measures ANCOVA, Mann–Whitney test, Chi-square test, paired t-test, and survival analysis.(α = 0.05).Results:The Visual Analog Scale scores for recovery rate, pain, and burning mouth sensation and objective scoring for oral lichen planus were significantly improved at 2 and 4 weeks in both the groups. However, the pain intensity decreased significantly in the Melissa group, as compared to the triamcinolone 1% group.Conclusion:In general, we showed that Melissa gel has a better effect than triamcinolone on pain intensity. Although Melissa gel is effective in reducing lesion size, triamcinolone significantly showed better results.

Nutritional Supplementation Reduces Lesion Size and Neuroinflammation in a Sex-Dependent Manner in a Mouse Model of Perinatal Hypoxic-Ischemic Brain Injury.

Perinatal hypoxia-ischemia (HI) is a major cause of neonatal brain injury, leading to long-term neurological impairments. Medical nutrition can be rapidly implemented in the clinic, making it a viable intervention to improve neurodevelopment after injury. The omega-3 (n-3) fatty acids docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3), uridine monophosphate (UMP) and choline have previously been shown in rodents to synergistically enhance brain phospholipids, synaptic components and cognitive performance. The objective of this study was to test the efficacy of an experimental diet containing DHA, EPA, UMP, choline, iodide, zinc, and vitamin B12 in a mouse model of perinatal HI. Male and female C57Bl/6 mice received the experimental diet or an isocaloric control diet from birth. Hypoxic ischemic encephalopathy was induced on postnatal day 9 by ligation of the right common carotid artery and systemic hypoxia. To assess the effects of the experimental diet on long-term motor and cognitive outcome, mice were subjected to a behavioral test battery. Lesion size, neuroinflammation, brain fatty acids and phospholipids were analyzed at 15 weeks after HI. The experimental diet reduced lesion size and neuroinflammation specifically in males. In both sexes, brain n-3 fatty acids were increased after receiving the experimental diet. The experimental diet also improved novel object recognition, but no significant effects on motor performance were observed. Current data indicates that early life nutritional supplementation with a combination of DHA, EPA, UMP, choline, iodide, zinc, and vitamin B12 may provide neuroprotection after perinatal HI.

Knockdown hsa_circ_0063526 inhibits endometriosis progression via regulating the miR-141-5p / EMT axis and downregulating estrogen receptors.

Endometriosis can cause severe social burdens. Abnormal circular RNA levels have been found to lead to changes of related gene expression, thereby mediating the occurrence and development of a series of diseases, including endometriosis. The role of circRNA in endometriosis is still in its infancy. This study will explore the role of circRNA hsa_circ_0063526 with microRNA-141-5p in the development of endometriosis. The expression levels of genes were detected by RT-qPCR. Transwell, wound-healing, and EdU assays were performed on the End1 / E6E7 cell line from the endometriosis patient. PCR and immunohistochemistry were used to detect the expression of candidate regulatory genes in ectopic lesions in an endometriosis mice model. The expression level of hsa_circ_0063526 in ectopic tissue of endometriosis patients was significantly higher than control (P<0.05), The expression levels of hsa_circ_0063526 and miRNA-141-5P in ectopic tissue of endometriosis were negatively correlated (P<0.05). Knockdown of hsa_circ_0063526 inhibited the invasion, migration, and proliferation ability of End1 / E6E7 cell; the inhibition of microRNA-141-5p rescued this inhibition (P <0.05). In vivo experiments showed that miR-141-5p and si-hsa_circ_0063526 treatment reduced lesion size and regulated endometriosis genes. Our data suggest that hsa_circ_0063526 and miR-141-5p are possible biomarkers and therapeutic targets for endometriosis.

Macrophage LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Is Required for the Effect of CD47 Blockade on Efferocytosis and Atherogenesis-Brief Report.

Antibody blockade of the "do not eat me" signal CD47 (cluster of differentiation 47) enhances efferocytosis and reduces lesion size and necrotic core formation in murine atherosclerosis. TNF (Tumor necrosis factor)-α expression directly enhances CD47 expression, and elevated TNF-α is observed in the absence of the proefferocytosis receptor LRP1 (low-density lipoprotein receptor-related protein 1), a regulator of atherogenesis and inflammation. Thus, we tested the hypothesis that CD47 blockade requires the presence of macrophage LRP1 to enhance efferocytosis, temper TNF-α-dependent inflammation, and limit atherosclerosis. Approach and Results: Mice lacking systemic apoE (apoE-/-), alone or in combination with the loss of macrophage LRP1 (double knockout), were fed a Western-type diet for 12 weeks while receiving anti-CD47 antibody (anti-CD47) or IgG every other day. In apoE-/- mice, treatment with anti-CD47 reduced lesion size by 25.4%, decreased necrotic core area by 34.5%, and decreased the ratio of free:macrophage-associated apoptotic bodies by 47.6% compared with IgG controls (P<0.05), confirming previous reports. Double knockout mice treated with anti-CD47 showed no differences in lesion size, necrotic core area, or the ratio of free:macrophage-associated apoptotic bodies compared with IgG controls. In vitro efferocytosis was 30% higher when apoE-/- phagocytes were incubated with anti-CD47 compared with IgG controls (P<0.05); however, anti-CD47 had no effect on efferocytosis in double knockout phagocytes. Analyses of mRNA and protein showed increased CD47 expression in anti-inflammatory IL (interleukin)-4 treated LRP1-/- macrophages compared with wild type, but no differences were observed in inflammatory lipopolysaccharide-treated macrophages. The proefferocytosis receptor LRP1 in macrophages is necessary for anti-CD47 blockade to enhance efferocytosis, limit atherogenesis, and decrease necrotic core formation in the apoE-/- model of atherosclerosis.

Effectiveness and safety of 0.5% timolol solution in the treatment of pyogenic granuloma: A randomized, double-blind and placebo-controlled study.

Introduction Pyogenic granulomas are benign vascular lesions of the skin and mucosa which are often a source of concern because of their recurrent bleeding even with minimal trauma. Current treatment for pyogenic granuloma is ablative; no medical therapy is standardized to date. Timolol, due to its vasoconstrictive effect, vascular growth factor inhibition and apoptosis promotion properties, is a potential therapeutic option. Objectives: To assess the effectiveness and safety of topical timolol in the treatment of pyogenic granulomas. Methods A two-centre, double-blind and placebo-controlled trial (Registration CTRI/2019/04/018581) was conducted. Patients of either sex were recruited with pyogenic granuloma lesions of less than eight weeks duration. Topical treatment with 0.5% timolol or matching glycerin placebo was continued for six weeks. Changes in color, size, bleeding tendency, physicians' and patients' global assessments and adverse events were assessed. Results Forty subjects were randomized between the two groups which were comparable in age, sex, duration of illness and baseline lesion size.Significant improvement was noted with timolol, with color change from first follow-up onwards and lesion size reduction from second follow-up onward. Patients' assessment of bleeding tendency also showed imrovement from the second visit onward. Between-group comparison showed significant difference with respect to percentage reduction in size (timolol 40.9%, placebo 3.4%; P = 0.002). Rescue treatment (electrosurgery) was required in five patients on placebo and in one in the timolol group (P = 0.182). Complete resolution occurred in 2 (10%) patients with timolol and in no patients on placebo (P = 0.231). Limitations: We observed effects of treatment for only six weeks. Conclusion Topical timolol may be a treatment option for early pyogenic granulomas but complete resolution is unlikely in six weeks. Studies of longer duration are required to assess resolution and recurrence rates.

NEK6 is an injury-responsive kinase cooperating with STAT3 in regulation of reactive astrogliosis.

In response to brain injury, resident astrocytes become reactive and play dynamic roles in neural repair and regeneration. The signaling pathways underlying such reactive astrogliosis remain largely unclear. We here show that NEK6, a NIMA-related serine/threonine protein kinase, is rapidly induced following pathological stimulations and plays critical roles in reactive astrogliosis. Enhanced NEK6 expression promotes reactive astrogliosis and exacerbates brain lesions; and conversely, NEK6 downregulation dampens injury-induced astrocyte reactivity and reduces lesion size. Mechanistically, NEK6 associates with and phosphorylates STAT3. Kinase activity of NEK6 is required for induction of GFAP and PCNA, markers of reactive astrogliosis. Interestingly, NEK6 is also localized in the nucleus and binds to STAT3-responsive genomic elements in astrocytes. These results indicate that NEK6 constitutes a molecular target for the regulation of reactive astrogliosis.

Rationale and design of the Diet Restriction and Exercise-induced Adaptations in Metastatic breast cancer (DREAM) study: a 2-arm, parallel-group, phase II, randomized control trial of a short-term, calorie-restricted, and ketogenic diet plus exercise during intravenous chemotherapy versus usual care

BackgroundAn underlying cause of solid tumor resistance to chemotherapy treatment is diminished tumor blood supply, which leads to a hypoxic microenvironment, dependence on anaerobic energy metabolism, and impaired delivery of intravenous treatments. Preclinical data suggest that dietary strategies of caloric restriction and low-carbohydrate intake can inhibit glycolysis, while acute exercise can transiently enhance blood flow to the tumor and reduce hypoxia. The Diet Restriction and Exercise-induced Adaptations in Metastatic Breast Cancer (DREAM) study will compare the effects of a short-term, 50% calorie-restricted and ketogenic diet combined with aerobic exercise performed during intravenous chemotherapy treatment to usual care on changes in tumor burden, treatment side effects, and quality of life.MethodsFifty patients with measurable metastases and primary breast cancer starting a new line of intravenous chemotherapy will be randomly assigned to usual care or the combined diet and exercise intervention. Participants assigned to the intervention group will be provided with food consisting of 50% of measured calorie needs with 80% of calories from fat and ≤ 10% from carbohydrates for 48–72 h prior to each chemotherapy treatment and will perform 30–60 min of moderate-intensity cycle ergometer exercise during each chemotherapy infusion, for up to six treatment cycles. The diet and exercise durations will be adapted for each chemotherapy protocol. Tumor burden will be assessed by change in target lesion size using axial computed tomography (primary outcome) and magnetic resonance imaging (MRI)-derived apparent diffusion coefficient (secondary outcome) after up to six treatments. Tertiary outcomes will include quantitative MRI markers of treatment toxicity to the heart, thigh skeletal muscle, and liver, and patient-reported symptoms and quality of life. Exploratory outcome measures include progression-free and overall survival.DiscussionThe DREAM study will test a novel, short-term diet and exercise intervention that is targeted to mechanisms of tumor resistance to chemotherapy. A reduction in lesion size is likely to translate to improved cancer outcomes including disease progression and overall survival. Furthermore, a lifestyle intervention may empower patients with metastatic breast cancer by actively engaging them to play a key role in their treatment.Trial registrationClinicalTrials.gov, NCT03795493, registered 7 January, 2019.

Quercetin promotes locomotor function recovery and axonal regeneration through induction of autophagy after spinal cord injury.

Quercetin (Que), one of the flavonoids, exerts numerous actions on the central nervous system. However, the roles and underlying mechanism of Que in locomotor function recovery and axonal regeneration following spinal cord injury (SCI) have not been fully elucidated. A rat model of spinal cord injury (SCI) was established at T10 using the modified Allen's method. The results in our study indicated that Basso, Beattie and Bresnahan (BBB) locomotor scores were significantly higher after Que treatment. Additionally, Que administration cut down the latency of somatosensory evoked potentials (SEP) and motor evoked potentials (MEP), increased the amplitude of MEP and SEP following SCI. Hematoxylin-eosin (HE) staining demonstrated that Que administration reduced lesion size and cavity formation. Biotinylated dextran amine (BDA) anterograde tracing revealed that BDA positive fibres were increased by Que following SCI. Immunofluorescence staining revealed that Que elevated 5-hydroxytryptamine (5-HT) positive nerve fibres and neurofilament-200 (NF-200) positive neurons, reduced glial fibrillary acidic protein (GFAP) positive astrocytes. In addition, Que inhibited GFAP expression, increased both NeuN and NF-200 expression and facilitated the spinal cord energy metabolism. Moreover, Que increased 18 F-FDG uptake in a time-dependent manner. Furthermore, Que increased Beclin 1 and LC3 II expression, blocked the phosphorylation of Akt, mTOR and p70S6K. 3-methyladenine (3-MA) partly abolished the neuro-protective roles of Que following SCI. Taken together, our study suggested that Que might promote locomotor function recovery, axonal regeneration and energy metabolism through induction of autophagy via Akt/mTOR/p70S6K pathway.

Three-dimensional changes in cystic lesions of the mandible after marsupialization

ObjectivesCysts of the mandible are common and are often found clinically in oral surgery. Marsupialization for relatively large cystic lesions may be performed to reduce the size of the lesion and to obtain a histopathological diagnosis. For cystic lesions of the mandible, the effect of marsupialization has many advantages, such as a reduction in lesion size, the avoidance of mental nerve palsy, and preservation of the teeth. It is still unclear whether there is a difference in the reduction rate based on patient age and pathology (dentigerous cyst, odontogenic keratocyst, radicular cyst, ameloblastoma (unicystic type)) and initial size of the lesion. MethodsThe subjects included 55 patients with cystic lesions with a major axis of 3 cm or greater (16 dentigerous cysts, 20 odontogenic keratocysts, 7 radicular cysts, and 12 ameloblastoma) who underwent treatment at our department. Using simulation software (ProPlanCMF®), the volume of the lesion was extracted from the CT data before and after the marsupialization, and the three-dimensional reduction rate before and after marsupialization was calculated. ResultsNo significant difference was observed between the subgroups in terms of histopathological diagnosis, patient age or size of lesion. Although the effect of marsupialization on cystic lesions with a major axis of 3 cm or more showed a significant difference between 3.0 months and 4.5 months, the difference was not significant between 4.5 months and 6.0 months. ConclusionsAn indication for the enucleation timing after marsupialization is 4.5 months when the rate of decrease after fenestration slows down.

Digital Subtraction Angiography-Guided Foam Sclerotherapy with Polidocanol for Treating Superficial Venous Malformation.

Objective: This study aims to describe the angiographic imaging characteristics of superficial venous malformations and evaluate the treatment effectiveness of digital subtraction angiography (DSA)-guided foam sclerotherapy with polidocanol.Materials and Methods: This prospective study was conducted in 18 patients with venous malformation treated by DSA-guided sclerotherapy. Treatment outcomes were evaluated based on pain improvement and reduction in lesion size on magnetic resonance imaging (MRI) 6-months posttreatment.Results: A total 21 lesions and 46 sclerotherapy sessions were analyzed. MRI findings presented 8/21 lesions (38.1%) with excellent response, 9/21 (42.9%) with good response, and 3/21 (14.3%) with average response, while one patient (4.8%) showed no response. All patients experienced pain. A significant reduction (p<0.01) was observed in the pre- to posttreatment pain score (5.45 and 0.64, respectively). Over a follow-up period of 1–4 years, three out of four patients (75%) in the retrospective cohort experienced recurrence; one patient had an increased lesion size and pain score, while the other two patients only showed an increased lesion size. No severe complications were seen.Conclusion: DSA-guided sclerotherapy with polidocanol is a safe and effective procedure for reducing lesion size and pain in symptomatic patients with superficial venous malformations.

516MO Phase I/II study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with solid tumor malignancies

Eprenetapopt is a small molecule that stabilizes the active form of p53 and increases oxidative stress, resulting in tumor cell apoptosis and ferroptosis and alterations in the tumor microenvironment including immune modulation. In preclinical models, eprenetapopt in combination with anti-PD1 therapy significantly improved tumor growth control and survival. We report preliminary safety and efficacy data from the phase 1/2 study of eprenetapopt and pembrolizumab. A safety lead-in with a 3+3 dose de-escalation design for patients (pts) with advanced solid tumors with known tumor TP53 mutation status (mutant and WT are included) is followed by expansion cohorts in pts with NSCLC (prior anti-PD1/PDL1 required), gastric/GEJ (GC) and urothelial cancer (UC) (GC and UC were anti-PD-1/PD-L1 therapy naïve). Primary objective is to establish safety and maximum tolerated dose (MTD) of the combination. Primary endpoints include dose-limiting toxicities (DLTs) and adverse events (AEs). As of April 7, 2021, 20 pts have been enrolled in the study (6 in the safety cohort and 14 in the expansion cohorts: 2 GC, 2 UC, 10 NSCLC) with 18 pts having at least one TP53 mutation. Pts received a median of 4 prior lines of therapy; all pts had ECOG PS≤ 2. No DLTs were reported in the safety cohorts. The dose of eprenetapopt of 4.5 g/day IV D1-4 and pembrolizumab 200mg IV D3 Q3W was established as the RP2D. The most common (>4pts) AEs included nausea (7), abdominal pain (5), fatigue (5), dizziness (5), decreased appetite (5). Treatment-related AEs (all grades) (>2pts) included nausea (6), vomiting (4), fatigue (4), dizziness (4), and decreased appetite (3). The majority of advanced grade AEs and SAEs were unrelated and associated with disease progression. There were no treatment discontinuations due to AEs. Two pts with TP53 mutant NSCLC who received prior anti-PD-1/PD-L1 therapy demonstrated reductions in target lesion size of 27% and 8.2%, respectively, at the first disease assessment. The combination of eprenetapopt and pembrolizumab is safe and tolerable. Early signals of anti-tumor activity are observed. The expansion cohorts of the trial continue to enroll.

A new avirulence gene of Leptosphaeria maculans, AvrLm14, identifies a resistance source in American broccoli (Brassica oleracea) genotypes.

In many cultivated crops, sources of resistance to diseases are sparse and rely on introgression from wild relatives. Agricultural crops often are allopolyploids resulting from interspecific crosses between related species, which are sources of diversity for resistance genes. This is the case for Brassica napus (oilseed rape, canola), an interspecific hybrid between Brassica rapa (turnip) and Brassica oleracea (cabbage). B. napus has a narrow genetic basis and few effective resistance genes against stem canker (blackleg) disease, caused by the fungus Leptosphaeria maculans, are currently available. B. rapa diversity has proven to be a valuable source of resistance (Rlm, LepR) genes, while B. oleracea genotypes were mostly considered susceptible. Here we identified a new resistance source in B. oleracea genotypes from America, potentially effective against French L. maculans isolates under both controlled and field conditions. Genetic analysis of fungal avirulence and subsequent cloning and validation identified a new avirulence gene termed AvrLm14 and suggested a typical gene‐for‐gene interaction between AvrLm14 and the postulated Rlm14 gene. AvrLm14 shares all the usual characteristics of L. maculans avirulence genes: it is hosted in a genomic region enriched in transposable elements and heterochromatin marks H3K9me3, its expression is repressed during vegetative growth but shows a strong overexpression 5–9 days following cotyledon infection, and it encodes a small secreted protein enriched in cysteine residues with few matches in databases. Similar to the previously cloned AvrLm10‐A, AvrLm14 contributes to reduce lesion size on susceptible cotyledons, pointing to a complex interplay between effectors promoting or reducing lesion development.

Intramuscular Boosting with hIFN-Alpha 2b Enhances BCGphipps-Induced Protection in a Murine Model of Leprosy

Host immunity to Mycobacterium leprae encompasses a spectrum of mechanisms that range from cellular immunity-driven protection to damage associated with humoral immunity as in type-2 leprosy reactions. Although type I interferons (IFNs) participate in eliminating intracellular pathogens, their contribution to the production of antibodies and CD3+ FOXP3+ regulatory T cells (Tregs) in BCG vaccine-mediated protection in leprosy is unknown. BCGphipps (BCGph) priming followed by intramuscular hIFN-α 2b boost significantly reduced lesion size and Mycobacterium lepraemurium growth in the skin. T follicular regulatory cells (TFR), a subset of Tregs induced by immunization or infection, reside in the germinal centers (GCs) and modulate antibody production. We found impaired Treg induction and improved GCs in draining lymph nodes of BCGph primed and hIFN-α 2b boosted mice. Moreover, these mice elicited significant amounts of IL-4 and IL-10 in serum. Thus, our results support the adjuvant properties of hIFN-α 2b in the context of BCGph priming to enhance protective immunity against skin leprosy.

PFKFB3 gene deletion in endothelial cells inhibits intraplaque angiogenesis and lesion formation in a murine model of venous bypass grafting

Vein grafting is a frequently used surgical intervention for cardiac revascularization. However, vein grafts display regions with intraplaque (IP) angiogenesis, which promotes atherogenesis and formation of unstable plaques. Graft neovessels are mainly composed of endothelial cells (ECs) that largely depend on glycolysis for migration and proliferation. In the present study, we aimed to investigate whether loss of the glycolytic flux enzyme phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) in ECs inhibits IP angiogenesis and as such prevents unstable plaque formation. To this end, apolipoprotein E deficient (ApoE−/−) mice were backcrossed to a previously generated PFKFB3fl/fl Cdh5iCre mouse strain. Animals were injected with either corn oil (ApoE−/−PFKFB3fl/fl) or tamoxifen (ApoE−/−PFKFB3ECKO), and were fed a western-type diet for 4 weeks prior to vein grafting. Hereafter, mice received a western diet for an additional 28 days and were then sacrificed for graft assessment. Size and thickness of vein graft lesions decreased by 35 and 32%, respectively, in ApoE−/−PFKFB3ECKO mice compared to controls, while stenosis diminished by 23%. Moreover, vein graft lesions in ApoE−/−PFKFB3ECKO mice showed a significant reduction in macrophage infiltration (29%), number of neovessels (62%), and hemorrhages (86%). EC-specific PFKFB3 deletion did not show obvious adverse effects or changes in general metabolism. Interestingly, RT-PCR showed an increased M2 macrophage signature in vein grafts from ApoE−/−PFKFB3ECKO mice. Altogether, EC-specific PFKFB3 gene deletion leads to a significant reduction in lesion size, IP angiogenesis, and hemorrhagic complications in vein grafts. This study demonstrates that inhibition of endothelial glycolysis is a promising therapeutic strategy to slow down plaque progression.

Pathogen and drought stress affect cell wall and phytohormone signaling to shape host responses in a sorghum COMT bmr12 mutant

BackgroundAs effects of global climate change intensify, the interaction of biotic and abiotic stresses increasingly threatens current agricultural practices. The secondary cell wall is a vanguard of resistance to these stresses. Fusarium thapsinum (Fusarium stalk rot) and Macrophomina phaseolina (charcoal rot) cause internal damage to the stalks of the drought tolerant C4 grass, sorghum (Sorghum bicolor (L.) Moench), resulting in reduced transpiration, reduced photosynthesis, and increased lodging, severely reducing yields. Drought can magnify these losses. Two null alleles in monolignol biosynthesis of sorghum (brown midrib 6-ref, bmr6-ref; cinnamyl alcohol dehydrogenase, CAD; and bmr12-ref; caffeic acid O-methyltransferase, COMT) were used to investigate the interaction of water limitation with F. thapsinum or M. phaseolina infection.ResultsThe bmr12 plants inoculated with either of these pathogens had increased levels of salicylic acid (SA) and jasmonic acid (JA) across both watering conditions and significantly reduced lesion sizes under water limitation compared to adequate watering, which suggested that drought may prime induction of pathogen resistance. RNA-Seq analysis revealed coexpressed genes associated with pathogen infection. The defense response included phytohormone signal transduction pathways, primary and secondary cell wall biosynthetic genes, and genes encoding components of the spliceosome and proteasome.ConclusionAlterations in the composition of the secondary cell wall affect immunity by influencing phenolic composition and phytohormone signaling, leading to the action of defense pathways. Some of these pathways appear to be activated or enhanced by drought. Secondary metabolite biosynthesis and modification in SA and JA signal transduction may be involved in priming a stronger defense response in water-limited bmr12 plants.

LB779 Comparison of outcomes for intravenous and intralesional administration of sodium thiosulfate for treatment of Calciphylaxis

Calciphylaxis is a vasculopathy characterized by calcium deposition in cutaneous vessels resulting in skin ulceration. Sodium thiosulfate (STS) has been used to treat calciphyaxis and can be administered via intravenous (IV) or intralesional (IL) injection. Retrospective chart review of patients treated for calciphylaxis at a tertiary hospital was conducted. Skin lesions were followed for at least two years following STS treatment initiation for three outcomes: 1) clinical improvement defined by reduction in lesion size or halted progression of purpura; 2) resolution of disease activity characterized by resolution of purpura; and 3) healing of ulcers.

Giant Perianal Condyloma Successfully Treated with Podophyllin at 25% in Solid Petrolatum

Abstract Purpose Giant perianal condyloma (GPC) is a rare condition. The effective treatment is a multidisciplinary challenge; topical treatments are usually ineffective, and surgical resection has significant morbidity. Podophyllin at 25% in solid petrolatum (25%PSP) can be an effective treatment option for GPC. The aim of the present study was to assess its response and tolerability. Methods This retrospective, single-center case series evaluated the clinical response of 14 patients with GPC treated with 25%PSP in a public hospital in Buenos Aires between December 2015 and December 2019. After obtaining a full history and performing a physical exam, the lesions were measured and photographed. Biopsies were performed to exclude malignancy, as well as exams to rule out pregnancy. Podophyllin at 25% in solid petrolatum was administered topically in cases of GPC and washed off by the patients at home after 4 hours. The patients underwent at least 4 weekly visits, which included interval history, photodocumentation of the lesions, and provider-applied 25%PSP. The response rate was assessed by comparing measurements and the overall decrease in volume of the GPC based on photos from the first and last sessions. Adverse outcomes were noted. Results In total, 10 men, 3 women, and 1 transgender woman with GPC unresponsive to prior treatments and a mean age of 34.5 years were included. A total of 12 patients were immunosuppressed. All the perianal lesions were circumferential and measured between 8 cm and 20 cm. Overall, 7 patients had genital condyloma outside of the anus and perianus; the histology showed low-grade squamous intraepithelial lesions in all cases. While on treatment, 7 patients reported dermatitis, and 71% of the patients had ≥ 75% reduction in lesion size. Conclusions Podophyllin at 25% in solid petrolatum is an effective, well-tolerated topical treatment option for GPC.

Mycobacterial Cell Wall Stimulant in the Treatment of Squamous Cell Carcinoma: A Case Series Regarding Treatment in Equine, Bovine and Caprine Patients.

Squamous cell carcinoma (SCC) is a common dermatological neoplasia found in large animal species. Treatment options, such as surgery and cryotherapy may be difficult or not feasible. Alternative therapies, such as immunomodulating drugs, can potentially be used for companion large animals. The hypothesis of the following retrospective study is: following multiple intravenous and intralesional injections of a mycobacterial cell wall stimulant (MCW) regression of SCC in equine, bovine and caprine patients will be observed. In this observational-retrospective case series, patients included are 2 bovine, 2 caprine and 3 equine patients. The medical records at two different teaching veterinary hospitals were searched for cases with a positive histopathological diagnosis of squamous cell carcinoma that were subsequently treated with MCW, as either the sole therapy, or in conjunction with other therapies. Seven cases were included in this retrospective study. The median duration of therapy was 56.5 days, with 3 of the 7 patients being euthanized. Significant complications were seen in 3/7 patients. Repeated injections of a MCW may lead to reduction in lesion size of SCC in some cases, but long-term resolution is unlikely and the risk of significant complications is high; due to limited sample size and the variety in species, it is difficult to conclude if MCW is an effective therapy for SCC.

Measurement of the active toxoplasma retinochoroiditis lesion size during the disease course with swept-source optical coherence tomography angiography: A retrospective image analysis.

To measure the lesion size reduction in eyes with active toxoplasma retinochoroiditis during the disease course with swept-source optical coherence tomography angiography (SS-OCTA). We retrospectively analysed the chorioretinal lesion size in a group of 14 eyes with a single active toxoplasma retinochoroiditis lesion. SS-OCTA was performed at the baseline and follow-up in all eyes. The 6 × 6mm choriocapillaris slab images were evaluated with image analysis (MATLAB). The number of black and white pixels in a 1500-µm-diameter circle centred on each active lesion was counted at the time of baseline examination and at the first follow-up visit when the chorioretinal scar formation was noticed. Fourteen eyes with a single active toxoplasmosis retinochoroiditis lesion were included. Ten patients were female and three were male. The mean age was 29.1 ± 14.9years. Active lesions were at the macula in five eyes, at the periphery in six eyes and juxtapapillary in three eyes. At the initial examination, the lesion area was observed as an area with a decreased flow signal on SS-OCTA. There was the perilesional capillary disruption in superficial and deep capillary plexi together with a diffuse capillary network attenuation and non-detectable flow signal zones in the choriocapillaris slabs. In addition to sulfamethoxazole-trimethoprim and azithromycin combination, oral corticosteroids were only co-administered in five (35%) eyes with macular involvement. The chorioretinal scar formation was observed in 4 to 16weeks. At the time of inactivity, the original lesion was diminished in size when compared to its baseline in all study eyes (p = 0.001) with a mean black pixel reduction percentage of 21.8%. The reduction was 15.4% in eyes with macular lesion, 31.6% with peripheral lesions and 18.1% with juxtapapillary lesions (p = 0.001, p = 0.032, p = 0.028, p = 0.043, respectively). Visual acuity was correlated with black pixel reduction percentage in eyes with macular lesion (r = 0.56, p < 0.001). Healing of the active toxoplasma retinochoroiditis lesion size could be monitored with an OCTA-based image analysis technique. Interestingly, the reduction in the lesion size was lesser in the macular lesions than the peripheral and juxtapapillary lesions following the treatment and this might contribute to the poorer visual outcomes observed in eyes with macular lesions.