Senescence on Dental Pulp Cells: Effects on Morphology, Migration, Proliferation, and Immune Response.

INTRODUCTION: Evidence indicates that senescence can affect essential dental pulp functions, such as defense capacity and repair, consequently affecting the successes of conservative endodontic treatments. This study aims to evaluate the effects of senescence on the morphology, migration, proliferation, and immune response of human dental pulp cells. METHODS: Cells were treated with doxorubicin to induce senescence, confirmed by ß-galactosidase staining. Morphological changes, cellular proliferation, and migration were evaluated by scanning electron microscopy, trypan blue cells, and the scratch method, respectively. Modifications in the immune response were evaluated by measuring the genes for pro-inflammatory cytokines tumor necrosis factor alpha and interleukin (IL)-6 and anti-inflammatory cytokines transforming growth factor beta 1 and IL-10 using the real time polymerase chain reaction assay. RESULTS: An increase in cell size and a decrease in the number of extensions were observed in senescent cells. A reduction in the proliferative and migratory capacity was also found in senescent cells. In addition, there was an increase in the gene expression of inflammatory cytokines tumor necrosis factor alpha and IL-6 and a decrease in the gene expression of IL-10 and transforming growth factor beta-1, suggesting an exacerbated inflammatory situation associated with immunosuppression. CONCLUSIONS: Cellular senescence is possibly a condition that affects prognoses of conservative endodontic treatments, as it affects primordial cellular functions related to this treatment.

The Role of Omega-3 in Attenuating Cardiac Remodeling and Heart Failure through the Oxidative Stress and Inflammation Pathways.

Cardiac remodeling is defined as molecular, cellular, and interstitial changes that manifest clinically as alterations in the size, shape, and function of the heart. Despite the pharmacological approaches, cardiac remodeling-related mortality rates remain high. Therefore, other therapeutic options are being increasingly studied. This review highlights the role of omega-3 as an adjunctive therapy to attenuate cardiac remodeling, with an emphasis on its antioxidant and anti-inflammatory actions.

Organizing pneumonia and COVID-19.

Organizing pneumonia (OP) is an interstitial lung disease, and can be cryptogenic, if no cause is identified, or secondary to several conditions. COVID-19-induced persistent inflammation can be associated with interstitial lung disease. We present a review of literature of OP and COVID-19-induced OP with an illustrative case. A 38-year-old man was admitted with COVID-19 that required mechanical ventilation for 56 days. Initial chest computed tomography (CT) revealed diffuse bilateral ground-glass opacities in the lungs with consolidation areas involving 75 % of the parenchyma. After weaning from MV, the patient still required oxygen supplementation. A new chest CT scan also showed extensive diffuse areas of consolidation and ground-glass opacity. OP was hypothesized and 40 mg/day prednisone initiated and continued for six months with resolution of lung functional and image abnormalities. Organizing pneumonia should be included in the differential diagnosis of COVID-19 patients with respiratory symptoms after partial pulmonary recovery.

Host defense peptides combined with MTA extract increase the repair in dental pulp cells: in vitro and ex vivo study.

Host Defense Peptides (HDPs) have, in previous studies, been demonstrating antimicrobial, anti-inflammatory, and immunomodulatory capacity, important factors in the repair process. Knowing these characteristics, this article aims to evaluate the potential of HDPs IDR1018 and DJK-6 associated with MTA extract in the repair process of human pulp cells. Antibacterial activity of HDPs, MTA and HDPs combined with MTA in Streptococcus mutans planktonic bacteria and antibiofilm activity was evaluated. Cell toxicity was assayed with MTT and cell morphology was observed by scanning electron microscopy (SEM). Proliferation and migration of pulp cells were evaluated by trypan blue and wound healing assay. Inflammatory and mineralization related genes were evaluated by qPCR (IL-6, TNFRSF, DSPP, TGF-ß). Alkaline phosphatase, phosphate quantification and alizarin red staining were also verified. The assays were performed in technical and biological triplicate (n = 9). Results were submitted for the calculation of the mean and standard deviation. Then, normality verification by Kolmogorov Smirnov test, analyzing one-way ANOVA. Analyses were considered at a 95% significance level, with a p-value < 0.05. Our study demonstrated that HDPs combined with MTA were able to reduce biofilms performed in 24 h and biofilm performed over 7 days S. mutans biofilm (p < 0.05). IDR1018 and MTA, as well as their combination, down-regulated IL-6 expression (p < 0.05). Tested materials were not cytotoxic to pulp cells. IDR1018 induced high cell proliferation and combined with MTA induced high cellular migration rates in 48 h (p < 0.05). Furthermore, the combination of IDR1018 and MTA also induced high expression levels of DSPP, ALP activity, and the production of calcification nodules. So, IDR-1018 and its combination with MTA could assist in pulp-dentine complex repair process in vitro.

Oxidative Stress as a Therapeutic Target of Cardiac Remodeling.

Cardiac remodeling is defined as a group of molecular, cellular, and interstitial changes that clinically manifest as changes in the heart's size, mass, geometry, and function after different stimuli. It is important to emphasize that remodeling plays a pathophysiological role in the onset and progression of ventricular dysfunction and subsequent heart failure. Therefore, strategies to mitigate this process are critical. Different factors, including neurohormonal activation, can regulate the remodeling process and increase cell death, alterations in contractile and regulatory proteins, alterations in energy metabolism, changes in genomics, inflammation, changes in calcium transit, metalloproteases activation, fibrosis, alterations in matricellular proteins, and changes in left ventricular geometry, among other mechanisms. More recently, the role of reactive oxygen species and oxidative stress as modulators of remodeling has been gaining attention. Therefore, this review assesses the role of oxidative stress as a therapeutic target of cardiac remodeling.

Role of Nutrients and Foods in Attenuation of Cardiac Remodeling through Oxidative Stress Pathways.

Cardiac remodeling is defined as a group of molecular, cellular, and interstitial changes that manifest clinically as changes in the heart's size, mass, geometry, and function after different injuries. Importantly, remodeling is associated with increased risk of ventricular dysfunction and heart failure. Therefore, strategies to attenuate this process are critical. Reactive oxygen species and oxidative stress play critical roles in remodeling. Importantly, antioxidative dietary compounds potentially have protective properties against remodeling. Therefore, this review evaluates the role of nutrients and food as modulators of cardiac remodeling.

SERRATUS ANTERIOR MUSCLE FLAP FOR RECONSTRUCTION OF EXTREMITY INJURIES.

Objective: To report the use of the serratus anterior free tissue transfer in the treatment of traumatic injuries. Methods: Twenty-six free flaps or serratus pedicled flaps were performed for reconstruction of traumatic extremity injuries. Results: Complete flap survival was recorded in 20 limbs and 3 patients had circulatory complications. Even with the review of vascular anastomoses, partial flap necrosis could not be prevented and required a skin graft after debridement in the necrotic area. Another flap also required reexploration as a result of heavy congestion due to impaired venous return. Superficial wound infection was found in three patients and treated with conservative measures. Regarding the donor area, seroma formation was found in 8 cases; drainage was necessary in 2, and the others were resolved spontaneously. In 2, bruises formed and were later drained. In 1 limb there was long thoracic nerve injury and scapular winging. Conclusion: According to this study, the serratus anterior muscle flap is an excellent tool for treating small complex lesions in the extremities. Level of Evidence IV; Case series .

Objetivo: Relatar o uso da transferência de retalho livre do serrátil anterior no tratamento de lesões traumáticas. Métodos: Vinte e seis retalhos livres ou pediculados do serrátil anterior foram realizados para reconstrução de lesões traumáticas de extremidades. Resultados: A sobrevida completa do retalho foi registrada em 20 membros e 3 pacientes tiveram complicações circulatórias. Mesmo com a revisão das anastomoses vasculares, a necrose parcial do retalho não pôde ser prevenida e exigiu enxerto de pele após desbridamento da área necrótica. Outro retalho também necessitou reexploração em decorrência de forte congestão por dificuldade de retorno venoso. Infecção de ferida superficial foi encontrada em três pacientes, tratados com medidas conservadoras. Em relação à área doadora, a formação de seroma foi encontrada em 8 casos; em 2 foi necessária drenagem e os demais foram resolvidos espontaneamente. Em 2 houve formação de hematomas, que foram drenados. Em um membro havia lesão longa do nervo torácico e deformidade do tipo escapula alada. Conclusão: De acordo com este estudo, o retalho do músculo serrátil anterior é uma excelente ferramenta para o tratamento de lesões complexas e pouco extensas nas extremidades. Nível de Evidência IV; Série de casos .

A Review of Current Clinical Concepts in the Pathophysiology, Etiology, Diagnosis, and Management of Hypercalcemia.

Calcium is the most abundant extracellular cation in the body, and it is responsible for structural and enzymatic functions. Calcium homeostasis is regulated by 3 factors: calcitonin, vitamin D, and parathyroid hormone (PTH). Hypercalcemia is defined by a serum calcium concentration >10.5 mg/dL, and it is classified into mild, moderate, and severe, depending on calcium values. Most cases are caused by primary hyperparathyroidism and malignancies. Various mechanisms are involved in the pathophysiology of hypercalcemia, such as excessive PTH production, production of parathyroid hormone-related protein (PTHrp), bone metastasis, extrarenal activation of vitamin D, and ectopic PTH secretion. The initial approach is similar in most cases, but a definitive treatment depends on etiology, that is why etiological investigation is mandatory in all cases. The majority of patients are asymptomatic and diagnosed during routine exams; only a small percentage of patients present with severe manifestations which can affect neurological, muscular, gastrointestinal, renal, and cardiovascular systems. Clinical manifestations are related to calcium levels, with higher values leading to more pronounced symptoms. Critically ill patients should receive treatment as soon as diagnosis is made. Initial treatment involves vigorous intravenous hydration and drugs to reduce bone resorption such as bisphosphonates and, more recently, denosumab, in refractory cases; also, corticosteroids and calcitonin can be used in specific cases. This review aims to provide a clinical update on current concepts of the pathophysiology of calcium homeostasis, epidemiology, screening, clinical presentation, diagnosis, and management of hypercalcemia.

Tessier 3 and 4 Clefts and Choanal Atresia: An Unusual Association?

INTRODUCTION: Craniofacial clefts are rare congenital anomalies that might involve both soft tissue and skeletal components. The association of Tessier cleft number 3 and 4 with choanal atresia appears to be unusual and only few clinical cases have been reported in published literature. OBJECTIVES: Report a series of 13 cases of choanal atresia in patients with Tessier numbers 3 or 4 clefts and the literature review on this topic. METHODS: A literature review was undertaken via PUBMED database before April 2020 addressing the association between Tessier numbers 3 or 4 clefts and choanal atresia. Retrospective chart review of patients diagnosed with both comorbidities at a tertiary hospital expertised in craniofacial anomalies. RESULTS: Literature review yielded 10 studies describing the relationship between choanal atresia and Tessier 3 and 4 facial clefts. We identified 98 patients diagnosed with medial oro-ocular facial clefts (Tessier 3 and 4) and 119 with choanal atresia at our institution over a 20 years time period. Altogether, 13 individuals were diagnosed with both malformations, 3 patients with number 3 cleft, and 10 patients with number 4 cleft. It represents 13.26% of the cases. CONCLUSION: This study highlights the features of Tessier 3 and 4 facial clefts associated with choanal atresia. Although the publications regarding this association are very scarce, the authors present the largest series of cases of Tessier number 3 and 4 clefts with choanal atresia showing that association between these conditions could be not so unusual.

Post-Cardiac Arrest: Mechanisms, Management, and Future Perspectives.

Cardiac arrest is an important public health issue, with a survival rate of approximately 15 to 22%. A great proportion of these deaths occur after resuscitation due to post-cardiac arrest syndrome, which is characterized by the ischemia-reperfusion injury that affects the role body. Understanding physiopathology is mandatory to discover new treatment strategies and obtain better results. Besides improvements in cardiopulmonary resuscitation maneuvers, the great increase in survival rates observed in recent decades is due to new approaches to post-cardiac arrest care. In this review, we will discuss physiopathology, etiologies, and post-resuscitation care, emphasizing targeted temperature management, early coronary angiography, and rehabilitation.

Serratus anterior muscle flap for reconstruction of extremity injuries / Retalho do músculo serrátil anterior para reconstrução de lesões em extremidades

ABSTRACT Objective: To report the use of the serratus anterior free tissue transfer in the treatment of traumatic injuries. Methods: Twenty-six free flaps or serratus pedicled flaps were performed for reconstruction of traumatic extremity injuries. Results: Complete flap survival was recorded in 20 limbs and 3 patients had circulatory complications. Even with the review of vascular anastomoses, partial flap necrosis could not be prevented and required a skin graft after debridement in the necrotic area. Another flap also required reexploration as a result of heavy congestion due to impaired venous return. Superficial wound infection was found in three patients and treated with conservative measures. Regarding the donor area, seroma formation was found in 8 cases; drainage was necessary in 2, and the others were resolved spontaneously. In 2, bruises formed and were later drained. In 1 limb there was long thoracic nerve injury and scapular winging. Conclusion: According to this study, the serratus anterior muscle flap is an excellent tool for treating small complex lesions in the extremities. Level of Evidence IV; Case series .

RESUMO Objetivo: Relatar o uso da transferência de retalho livre do serrátil anterior no tratamento de lesões traumáticas. Métodos: Vinte e seis retalhos livres ou pediculados do serrátil anterior foram realizados para reconstrução de lesões traumáticas de extremidades. Resultados: A sobrevida completa do retalho foi registrada em 20 membros e 3 pacientes tiveram complicações circulatórias. Mesmo com a revisão das anastomoses vasculares, a necrose parcial do retalho não pôde ser prevenida e exigiu enxerto de pele após desbridamento da área necrótica. Outro retalho também necessitou reexploração em decorrência de forte congestão por dificuldade de retorno venoso. Infecção de ferida superficial foi encontrada em três pacientes, tratados com medidas conservadoras. Em relação à área doadora, a formação de seroma foi encontrada em 8 casos; em 2 foi necessária drenagem e os demais foram resolvidos espontaneamente. Em 2 houve formação de hematomas, que foram drenados. Em um membro havia lesão longa do nervo torácico e deformidade do tipo escapula alada. Conclusão: De acordo com este estudo, o retalho do músculo serrátil anterior é uma excelente ferramenta para o tratamento de lesões complexas e pouco extensas nas extremidades. Nível de Evidência IV; Série de casos .

Gout Storm.

BACKGROUND Gout is a chronic disease characterized by deposition of monosodium urate crystals, typically manifesting as arthritis. Clinical presentation of gout usually results from activation of local inflammatory response. Despite being one of the oldest diseases in the world, gout pathophysiology is incompletely understood and clinical features are still surprising. Recent reports describe unusual manifestations including atypical joints involvement, tenosynovitis, panniculitis, and multinodular inguinal swelling. Another atypical feature is the acute polyarticular gout with severe systemic inflammatory response. CASE REPORT We report the case of a 55-year-old man presenting with fever, tachycardia, cauda equina syndrome, left-knee arthritis, and systemic inflammatory manifestations. Lumbar spine magnetic resonance imaging showed a 4.0×1.3×2.2 cm calcified mass inside the vertebral canal at the L4-L5 level, causing stenosis of the dural space and intervertebral foramen. Clinical diagnoses were septic knee arthritis and lumbar spine meningioma. Despite antibiotic therapy and left-knee surgical drainage, fever and increased C-reactive protein persisted, and arthritis developed in the elbows and right knee. As cultures were negatives, we then diagnosed gout flare in the affected joints accompanied by a severe systemic inflammatory reaction. A few days after starting colchicine and anti-inflammatory drugs, symptoms and inflammatory markers subsided. It was such a severe attack that we called it a "gout storm". CONCLUSIONS The report highlights the difficulty in diagnosing acute polyarticular gout affecting atypical joints, particularly when faced with a severe systemic inflammatory reaction.

Concentrated MTA Repair HP reduced biofilm and can cause reparative action at a distance.

AIM: To evaluate in vitro whether MTA Repair HP can induce repair processes at a distance, including its effects on biofilm, cell viability, migration, production of TGF-ß, phosphate and ALP, evaluated through MTA diluted extracts. METHODOLOGY: Initially, antibacterial tests were performed with the bacterium Streptococcus mutans (ATCC 25175) in the presence of MTA extracts (dilutions of 1:1, 1:2 and 1:4). Growth inhibition assay by microdilution in broth, antibiofilm plate assay of young biofilm and antibiofilm assay in confocal microscopy of mature biofilm were carried out. Then, pulp cells were stimulated in the presence of several MTA dilutions, and cell viability (MTT assay), proliferation and migration capacity (scratch assay) were evaluated. To evaluate the capacity of 1:1, 1:2 and 1:4 dilutions of MTA Repair HP to promote the production of important agents of odontogenic differentiation and mineralization, ALP activity, TGF-ß secretion and phosphate quantification were measured. Statistical differences were verified using one-way and two-way anova and Tukey's post-tests. RESULTS: The test dilutions of MTA Repair HP did not inhibit planktonic S. mutans growth but were able to reduce young and mature S. mutans biofilm (p < 0.001). In addition, none of the MTA Repair HP dilutions was cytotoxic for pulp cells. The 1:2 and 1:4 dilutions of MTA Repair HP induced migration and proliferation of pulp cells (p < 0.05). ALP activity and TGF-ß secretion were independent of the tested dilution (p < 0.001). Diluted 1:4 MTA Repair HP produced less phosphate than the more concentrated 1:1 and 1:2 MTA dilutions (p < 0.001). CONCLUSIONS: Undiluted MTA Repair HP reduced S. mutans biofilm, when compared to 1:2 and 1:4 MTA dilutions. Furthermore, none of the tested dilutions was cytotoxic to pulp cells. MTA Repair HP promoted cell migration and proliferation at a distance, assessed through the dilution of the MTA. Even from a distance, MTA Repair HP has the ability to participate in some events related to repair, such as migration, proliferation and TGF production.

Transcriptional profile in rat muscle: down-regulation networks in acute strenuous exercise.

BACKGROUND: Physical exercise is a health promotion factor regulating gene expression and causing changes in phenotype, varying according to exercise type and intensity. Acute strenuous exercise in sedentary individuals appears to induce different transcriptional networks in response to stress caused by exercise. The objective of this research was to investigate the transcriptional profile of strenuous experimental exercise. METHODOLOGY: RNA-Seq was performed with Rattus norvegicus soleus muscle, submitted to strenuous physical exercise on a treadmill with an initial velocity of 0.5 km/h and increments of 0.2 km/h at every 3 min until animal exhaustion. Twenty four hours post-physical exercise, RNA-seq protocols were performed with coverage of 30 million reads per sample, 100 pb read length, paired-end, with a list of counts totaling 12816 genes. RESULTS: Eighty differentially expressed genes (61 down-regulated and 19 up-regulated) were obtained. Reactome and KEGG database searches revealed the most significant pathways, for down-regulated gene set, were: PI3K-Akt signaling pathway, RAF-MAP kinase, P2Y receptors and Signaling by Erbb2. Results suggest PI3K-AKT pathway inactivation by Hbegf, Fgf1 and Fgr3 receptor regulation, leading to inhibition of cell proliferation and increased apoptosis. Cell signaling transcription networks were found in transcriptome. Results suggest some metabolic pathways which indicate the conditioning situation of strenuous exercise induced genes encoding apoptotic and autophagy factors, indicating cellular stress. CONCLUSION: Down-regulated networks showed cell transduction and signaling pathways, with possible inhibition of cellular proliferation and cell degeneration. These findings reveal transitory and dynamic process in cell signaling transcription networks in skeletal muscle after acute strenuous exercise.

IL-4 absence triggers distinct pathways in apical periodontitis development.

Dental pulp is a specialized tissue able to respond to infectious processes. Nevertheless, infection progress and root canal colonization trigger an immune-inflammatory response in tooth-surrounding tissues, leading to apical periodontitis and bone tissue destruction, further contributing to tooth loss. In order to shed some light on the effects of IL-4 on periradicular pathology development modulation, microtomographic, histological and proteomic analyses were performed using 60 mice, 30 wild type and 30 IL-4-/-. For that, 5 animals were used for microtomographic and histological analysis, and another 5 for proteomic analysis for 0, 7 and 21 days with/without pulp exposure. The periapical lesions were established in WT and IL-4-/- mice without statistical differences in their volume, and the value of p < 0.05 was adopted as significant in microtomographic and histological analyses. Regarding histological analysis, IL-4-/- mice show aggravation of pulp inflammation compared to WT. By using proteomic analysis, we have identified 32 proteins with increased abundance and 218 proteins with decreased abundance in WT animals after 21 days of pulp exposure, compared to IL-4-/- animals. However, IL-4-/- mice demonstrated faster development of apical periodontitis. These animals developed a compensatory mechanism to overcome IL-4 absence, putatively based on the identification of upregulated proteins related to immune system signaling pathways. Significance: IL-4 might play a protective role in diseases involving bone destruction and its activity may contribute to host protection, mainly due to its antiosteoclastogenic action.

The use of host defense peptides in root canal therapy in rats.

OBJECTIVES: In order to evaluate host defense peptides (HDPs) HHC-10 and synoeca-MP activity in in vitro osteoclastogenesis process and in vivo induced apical periodontitis, testing the effect of molecules in the inflammatory response and in apical periodontitis size/volume after root canal treatment. MATERIALS AND METHODS: In vitro osteoclastogenesis was assessed on bone marrow cell cultures extracted from mice, while in vivo endodontic treatment involved rats treated with Ca(OH)2 or HDPs. In vitro osteoclasts were subjected to TRAP staining, and in vivo samples were evaluated by radiographic and tomographic exams, as well as histologic analysis. RESULTS: None of the substances downregulated the in vitro osteoclastogenesis. Nevertheless, all treatments affected the average of apical periodontitis size in rats, although only teeth treated with HDPs demonstrated lower levels of the inflammatory process. These results demonstrated the in vivo potential of HDPs. Radiographic analysis suggested that HHC-10 and synoeca-MP-treated animals presented a similar lesion size than Ca(OH)2-treated animals after 7-day of endodontic treatment. However, tomography analysis demonstrated smaller lesion volume in synoeca-MP-treated animals than HHC-10 and Ca(OH)2-treated animals, after 7 days. CONCLUSIONS: These molecules demonstrated an auxiliary effect in endodontic treatment that might be related to its immunomodulatory ability, broad-spectrum antimicrobial activity, and possible induction of tissue repair at low concentrations. These results can encourage further investigations on the specific mechanisms of action in animal models to clarify the commercial applicability of these biomolecules for endodontic treatment. CLINICAL SIGNIFICANCE: HDPs have the potential to be adjuvant substances in endodontic therapy due to its potential to reduce inflammation in apical periodontitis.

Plate of ribs: single institution's matched comparison of patients managed operatively and non-operatively for rib fractures.

BACKGROUND: Rib fractures are associated with significant morbidity and mortality in polytraumatized patients. There is considerable variability in the management (operative vs. non-operative) and timing of operative intervention. Although Eastern Association for the Surgery of Trauma (EAST) guidelines recommend early operative intervention in patients with flail chest, there are no strong recommendations regarding operative fixation in patients with a non-flail chest rib fracture pattern. METHODS: We reviewed our Trauma Quality Improvement Program database for patients aged 18 to 99 who underwent operative intervention of ribs from January 2016 to July 2019. We examined hospital length of stay (LOS), intensive care unit (ICU) LOS, ventilator days, Injury Severity Score, age, discharge disposition and packed red blood cell transfusions. Similarly, we collected data from patients aged 18 to 99 who had one or more rib fractures in this time frame. We compared results in a 4:1 ratio of patients managed non-operatively to patients managed operatively. The patient groups were matched based on age, number of rib fractures and presence of bilateral rib fractures. RESULTS: Between January 2016 and July 2019, 33 of 4189 total patients diagnosed with rib fractures underwent operative fixation; the matched non-operative group consisted of 132 patients. The statistically significant differences included presence of bilateral rib fractures, displaced rib fractures and flail chest segments. The median ICU days were longer in the operative group (6.0 vs. 3.5 days). A subgroup analysis of patients without flail segments demonstrated a significant presence of displaced rib fractures.Our single-institution matched comparison of outcomes in operative intervention versus Non-operative Management (NOM) of rib fractures found an increased median number of ICU days. Patients who underwent operative intervention often stayed in the ICU preoperatively and postoperatively for aggressive pulmonary hygiene and pain control, suggesting observer bias. The increased incidence of displaced rib fractures and the presence of a flail segment in the operative group demonstrate congruence with EAST guidelines. A subgroup analysis of patients without flail segment did not demonstrate differences in outcomes nor shoulder girdle injury characteristics. LEVEL OF EVIDENCE: This article presents level III evidence that can be used by other clinicians to analyze eligibility for patients to undergo surgical stabilization of rib fracture (SSRF) and to provide counterarguments for performing SSRF in a heterogenous group of patients.

neoANT-HILL: an integrated tool for identification of potential neoantigens.

BACKGROUND: Cancer neoantigens have attracted great interest in immunotherapy due to their capacity to elicit antitumoral responses. These molecules arise from somatic mutations in cancer cells, resulting in alterations on the original protein. Neoantigens identification remains a challenging task due largely to a high rate of false-positives. RESULTS: We have developed an efficient and automated pipeline for the identification of potential neoantigens. neoANT-HILL integrates several immunogenomic analyses to improve neoantigen detection from Next Generation Sequence (NGS) data. The pipeline has been compiled in a pre-built Docker image such that minimal computational background is required for download and setup. NeoANT-HILL was applied in The Cancer Genome Atlas (TCGA) melanoma dataset and found several putative neoantigens including ones derived from the recurrent RAC1:P29S and SERPINB3:E250K mutations. neoANT-HILL was also used to identify potential neoantigens in RNA-Seq data with a high sensitivity and specificity. CONCLUSION: neoANT-HILL is a user-friendly tool with a graphical interface that performs neoantigens prediction efficiently. neoANT-HILL is able to process multiple samples, provides several binding predictors, enables quantification of tumor-infiltrating immune cells and considers RNA-Seq data for identifying potential neoantigens. The software is available through github at https://github.com/neoanthill/neoANT-HILL.

Acidities under the Perspective of Energy Decomposition Analysis.

The rationalization of acid/base behavior is a central concern for chemistry and related fields. In this work, we describe an alternative approach toward the understanding of gas phase acidities based on the localized molecular orbital energy decomposition analysis (LMOEDA) method. Upon partitioning the molecules (and the corresponding anions) over the X-OH (or X-O-) bond, we have observed a perfect correlation between the interaction energy of the two fragments and the acidity, as given by the energy difference between the anion and the neutral molecule. On the basis of this correlation, acidities could be interpreted according to the energy components provided by LMOEDA, namely, electrostatic, exchange repulsion, polarization, and dispersion. For example, alkyl groups increase the gas phase acidities of alcohols mainly due to electrostatic and polarization interactions. Carboxylic acids are stronger acids than alcohols through the ability of oxygen to stabilize the extra charge formed in the anion (electrostatic interactions) and also through a decrease of exchange repulsions between the two fragments. Polarization interaction (orbital relaxation) also plays an important role. Electrostatic and polarization interactions dominate the enhanced acidity of sulfuric acid over ethanol. Electrostatic and polarization interactions are also responsible for the higher acidity of sulfuric over boric acid. The anomalous behavior of formic acid compared to acetic, propionic, and butyric acids is also explained. The examples worked in this report evince the still unexplored potential of energy decomposition to the comprehension of acid/base phenomena.

Hospital Characteristics Affect Consent and Conversion Rates for Potential Organ Donors.

Consent and conversion rates of potential organ donors in the United States need to be maximized to match the number of individuals awaiting organ donation. Studies to date have not focused on characteristics of centers with better outcomes. We performed an 8-year (2006-2014) retrospective study of our local organ procurement organization database. We categorized hospitals in our region as academic centers versus nonacademic centers, trauma centers versus nontrauma centers, and large (≥400 beds) centers versus small (<400 beds) centers. We also compared trauma centers with Level I designation to all other centers. Primary outcomes included consent and conversion rates for potential organ donors. There were 22,732 referrals to our organ procurement organization that resulted in 1,057 eligible deaths. When comparing academic to nonacademic hospitals, academic hospitals had higher consent (71% vs 59%, P < 0.0001) and conversion (73% vs 64%, P = 0.008) rates. Level I trauma centers had better consent and conversion rates when compared to all other hospitals, 73 versus 55 per cent and 76 versus 61 per cent respectively, P < 0.0001 for both. The small, academic, trauma centers had the highest consent and conversion rates, 77 and 78 per cent, respectively, P < 0.0001 for both. Hospital characteristics such as academic involvement, Level I trauma designation, and size impact consent and conversion rates for potential organ donors. Small (<400 bed), academic, trauma centers have the highest consent rates and conversion rates. Factors for success in these institutions should be examined and applied to assist in improving donor rates across all types of hospitals.