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1.
Front Immunol ; 11: 554301, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193322

RESUMO

The mechanisms that underlie various inflammation paradoxes, metabolically healthy obesity, and increased inflammations after inflammatory cytokine blockades and deficiencies remain poorly determined. We performed an extensive -omics database mining, determined the expressions of 1367 innate immune regulators in 18 microarrays after deficiencies of 15 proinflammatory cytokines/regulators and eight microarray datasets of patients receiving Mab therapies, and made a set of significant findings: 1) proinflammatory cytokines/regulators suppress the expressions of innate immune regulators; 2) upregulations of innate immune regulators in the deficiencies of IFNγ/IFNγR1, IL-17A, STAT3 and miR155 are more than that after deficiencies of TNFα, IL-1ß, IL-6, IL-18, STAT1, NF-kB, and miR221; 3) IFNγ, IFNγR and IL-17RA inhibit 10, 59 and 39 proinflammatory cytokine/regulator pathways, respectively; in contrast, TNFα, IL-6 and IL-18 each inhibits only four to five pathways; 4) The IFNγ-promoted and -suppressed innate immune regulators have four shared pathways; the IFNγR1-promoted and -suppressed innate immune regulators have 11 shared pathways; and the miR155-promoted and -suppressed innate immune regulators have 13 shared pathways, suggesting negative-feedback mechanisms in their conserved regulatory pathways for innate immune regulators; 5) Deficiencies of proinflammatory cytokine/regulator-suppressed, promoted programs share signaling pathways and increase the likelihood of developing 11 diseases including cardiovascular disease; 6) There are the shared innate immune regulators and pathways between deficiency of TNFα in mice and anti-TNF therapy in clinical patients; 7) Mechanistically, up-regulated reactive oxygen species regulators such as myeloperoxidase caused by suppression of proinflammatory cytokines/regulators can drive the upregulation of suppressed innate immune regulators. Our findings have provided novel insights on various inflammation paradoxes and proinflammatory cytokines regulation of innate immune regulators; and may re-shape new therapeutic strategies for cardiovascular disease and other inflammatory diseases.

2.
World J Gastrointest Oncol ; 12(11): 1311-1324, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33250963

RESUMO

BACKGROUND: Colorectal cancer (CRC) is an important disease worldwide, accounting for the second highest number of cancer-related deaths and the third highest number of new cancer cases. The blood test is a simple and minimally invasive diagnostic test. However, there is currently no blood test that can accurately diagnose CRC. AIM: To develop a comprehensive, spontaneous, minimally invasive, label-free, blood-based CRC screening technique based on Raman spectroscopy. METHODS: We used Raman spectra recorded using 184 serum samples obtained from patients undergoing colonoscopies. Patients with malignant tumor histories as well as those with cancers in organs other than the large intestine were excluded. Consequently, the specific diseases of 184 patients were CRC (12), rectal neuroendocrine tumor (2), colorectal adenoma (68), colorectal hyperplastic polyp (18), and others (84). We used the 1064-nm wavelength laser for excitation. The power of the laser was set to 200 mW. RESULTS: Use of the recorded Raman spectra as training data allowed the construction of a boosted tree CRC prediction model based on machine learning. Therefore, the generalized R 2 values for CRC, adenomas, hyperplastic polyps, and neuroendocrine tumors were 0.9982, 0.9630, 0.9962, and 0.9986, respectively. CONCLUSION: For machine learning using Raman spectral data, a highly accurate CRC prediction model with a high R 2 value was constructed. We are currently planning studies to demonstrate the accuracy of this model with a large amount of additional data.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33098856

RESUMO

BACKGROUND: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks. OBJECTIVE: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial). METHODS: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period. RESULTS: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred. CONCLUSION: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day.

4.
Front Pharmacol ; 11: 1291, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973520

RESUMO

Objective: Current prevention and/or treatment options for respiratory syncytial virus (RSV) infections are limited as no vaccine is available. Prophylaxis with palivizumab is very expensive and requires multiple intramuscular injections over the RSV season. Here we present proof-of-concept data using nebulized palivizumab delivery as a promising new approach for the prevention or treatment of severe RSV infections, documenting both aerosol characteristics and pulmonary deposition patterns in the lungs of lambs. Design: Prospective animal study. Setting: Biosecurity Control Level 2-designated large animal research facility at the Murdoch Children's Research Institute, Melbourne, Australia. Subjects: Four weaned Border-Leicester/Suffolk lambs at 5 months of age. Interventions: Four lambs were administered aerosolized palivizumab conjugated to Tc-99m, under gaseous anesthesia, using either the commercially available AeroNeb Go® or the investigational HYDRA device, placed in-line with the inspiratory limb of a breathing circuit. Lambs were scanned in a single-photon emission computed tomography (SPECT/CT) scanner in the supine position during the administration procedure. Measurements and Main Results: Both the HYDRA and AeroNeb Go® produced palivizumab aerosols in the 1-5 µm range with similar median (geometric standard deviation and range) aerosol droplet diameters for the HYDRA device (1.84 ± 1.40 µm, range = 0.54-5.41µm) and the AeroNeb Go® (3.07 ± 1.56 µm, range = 0.86-10 µm). Aerosolized palivizumab was delivered to the lungs at 88.79-94.13% of the total aerosolized amount for all lambs, with a small proportion localized to either the trachea or stomach. No difference between devices were found. Pulmonary deposition ranged from 6.57 to 9.25% of the total dose of palivizumab loaded in the devices, mostly in the central right lung. Conclusions: Aerosolized palivizumab deposition patterns were similar in all lambs, suggesting a promising approach in the control of severe RSV lung infections.

5.
Redox Biol ; : 101696, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32950427

RESUMO

Reactive oxygen species (ROS) are critical for the progression of cardiovascular diseases, inflammations and tumors. However, the mechanisms of how ROS sense metabolic stress, regulate metabolic pathways and initiate proliferation, inflammation and cell death responses remain poorly characterized. In this analytic review, we concluded that: 1) Based on different features and functions, eleven types of ROS can be classified into seven functional groups: metabolic stress-sensing, chemical connecting, organelle communication, stress branch-out, inflammasome-activating, dual functions and triple functions ROS. 2) Among the ROS generation systems, mitochondria consume the most amount of oxygen; and nine types of ROS are generated; thus, mitochondrial ROS systems serve as the central hub for connecting ROS with inflammasome activation, trained immunity and immunometabolic pathways. 3) Increased nuclear ROS production significantly promotes cell death in comparison to that in other organelles. Nuclear ROS systems serve as a convergent hub and decision-makers to connect unbearable and alarming metabolic stresses to inflammation and cell death. 4) Balanced ROS levels indicate physiological homeostasis of various metabolic processes in subcellular organelles and cytosol, while imbalanced ROS levels present alarms for pathological organelle stresses in metabolic processes. Based on these analyses, we propose a working model that ROS systems are a new integrated network for sensing homeostasis and alarming stress in metabolic processes in various subcellular organelles. Our model provides novel insights on the roles of the ROS systems in bridging metabolic stress to inflammation, cell death and tumorigenesis; and provide novel therapeutic targets for treating those diseases. (Word count: 246).

6.
J Allergy Clin Immunol ; 146(4): 863-874, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32659313

RESUMO

BACKGROUND: The PEPITES (Peanut EPIT Efficacy and Safety) trial, a 12-month randomized controlled study of children with peanut allergy and 4 to 11 years old, previously reported the safety and efficacy of epicutaneous immunotherapy (EPIT) for peanut allergy (250 µg, daily epicutaneous peanut protein; DBV712 250 µg). OBJECTIVE: We sought to assess interim safety and efficacy of an additional 2 years of EPIT from the ongoing (5-year treatment) PEOPLE (PEPITES Open-Label Extension) study. METHODS: Subjects who completed PEPITES were offered enrollment in PEOPLE. Following an additional 2 years of daily DBV712 250 µg, subjects who had received DBV712 250 µg in PEPITES underwent month-36 double-blind, placebo-controlled food challenge with an optional month-38 sustained unresponsiveness assessment. RESULTS: Of 213 eligible subjects who had received DBV712 250 µg in PEPITES, 198 (93%) entered PEOPLE, of whom 141 (71%) had assessable double-blind, placebo-controlled food challenge at month 36. At month 36, 51.8% of subjects (73 of 141) reached an eliciting dose of ≥1000 mg, compared with 40.4% (57 of 141) at month 12; 75.9% (107 of 141) demonstrated increased eliciting dose compared with baseline; and 13.5% (19 of 141) tolerated the full double-blind, placebo-controlled food challenge of 5444 mg. Median cumulative reactive dose increased from 144 to 944 mg. Eighteen subjects underwent an optional sustained unresponsiveness assessment; 14 of those (77.8%) maintained an eliciting dose of ≥1000 mg at month 38. Local patch-site skin reactions were common but decreased over time. There was no treatment-related epinephrine use in years 2 or 3. Compliance was high (96.9%), and withdrawals due to treatment-related adverse events were low (1%). CONCLUSIONS: These results demonstrate that daily EPIT treatment for peanut allergy beyond 1 year leads to continued response from a well-tolerated, simple-to-use regimen.

7.
Age Ageing ; 2020 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-32556149

RESUMO

BACKGROUND: multimorbidity contributes to a large portion of the disease burden in low- and middle-income countries. However, limited research has been undertaken in China. This study has investigated the prevalence of multimorbidity and the associations of multimorbidity with activities of daily living (ADL), instrumental activities of daily living (IADL) and depression in China. METHODS: the study participants included 10,055 adults aged 45 years and older from three rounds of the China Health and Retirement Longitudinal Study 2011-2015. Random-effects logistic regression models were used to examine the association of multimorbidity with ADL limitation, IADL limitation and mental disease. RESULTS: the prevalence of multimorbidity amongst adults in China aged 45 years and older was 62.1% in 2015. The prevalence of multimorbidity was increased with older age, among women, in a higher socio-economic group and in the most deprived regions. Multimorbidity is associated with an increased likelihood of experiencing ADL limitation (adjusted odds ratio [AOR] = 5.738, 95% confidence intervals (CI) = 5.733, 5.744) and IADL limitation (AOR = 2.590, 95% CI = 2.588, 2.592) and depression (AOR = 3.352, 95% CI = 3.350, 3.354). Rural-urban disparities in functional difficulties and depression were also found amongst patients with multimorbidity. CONCLUSIONS: the burden of multimorbidity is high in China, particularly amongst the older population. Multimorbidity is associated with higher levels of functional limitations and depression. China healthcare reforms should introduce integrated care models and patient-centred healthcare delivery. The increasing need for reorientation of healthcare resources considering the distribution of multimorbidity and its adverse effect requires more attention from health policymakers in China and other developing countries.

8.
J Natl Cancer Inst ; 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32427313

RESUMO

BACKGROUND: The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies. METHODS: Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer. RESULTS: Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval [CI] = 10.43 to >100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer. CONCLUSIONS: The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing.

9.
Ann Allergy Asthma Immunol ; 125(3): 334-340.e1, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32445670

RESUMO

BACKGROUND: Patients aged 65 years and older with hereditary angioedema (HAE) owing to C1-inhibitor (C1-INH) deficiency may have an altered response to treatment and are at higher risk for treatment-related adverse events (AEs) because of comorbidities and polypharmacy. OBJECTIVE: To investigate the safety and efficacy of subcutaneous C1 esterase inhibitor (C1-INH) in patients aged 65 years and older treated in an open-label extension of a phase 3 trial. METHODS: Eligible patients (≥4 attacks for more than 2 consecutive months) were randomized to receive twice-weekly subcutaneous C1-INH with a dosage of 40 IU/kg or 60 IU/kg for 52 to 140 weeks. Safety end points and efficacy outcomes were evaluated for patients aged 65 years and above and younger than 65 years. RESULTS: Of the 126 patients treated, 10 were 65 years and older (mean age [range], 68 [65-72 years]). A total of 8 of 10 patients had multiple comorbidities, and 6 of these 10 patients were taking more than 5 non-HAE-related drugs concomitantly. AEs occurring in more than 1 patient included injection site bruising (n = 2, related), injection site pain (n = 2, related), urinary tract infection (n = 2, unrelated), and diarrhea (n = 2, unrelated). No thromboembolic events or cases of anaphylaxis were reported. Two patients aged 65 years and older experienced unrelated serious AEs (dehydration and hypokalemia in 1 and pneumonia and an HAE attack leading to hospitalization in another). A total of 6 of 9 evaluable patients were responders, with a greater than or equal to 50% reduction in HAE attacks vs prestudy; 6 of 10 patients had less than 1 attack over 4 weeks and 3 were attack-free (median attack rate, 0.52 attacks per month). CONCLUSION: Subcutaneous C1-INH was well-tolerated and effective in the management of HAE in patients aged 65 years and older with multiple comorbid conditions and polypharmacy.


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Proteína Inibidora do Complemento C1/efeitos adversos , Proteína Inibidora do Complemento C1/uso terapêutico , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
10.
Arterioscler Thromb Vasc Biol ; 40(6): e138-e152, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32459541

RESUMO

In addition to the roles of endothelial cells (ECs) in physiological processes, ECs actively participate in both innate and adaptive immune responses. We previously reported that, in comparison to macrophages, a prototypic innate immune cell type, ECs have many innate immune functions that macrophages carry out, including cytokine secretion, phagocytic function, antigen presentation, pathogen-associated molecular patterns-, and danger-associated molecular patterns-sensing, proinflammatory, immune-enhancing, anti-inflammatory, immunosuppression, migration, heterogeneity, and plasticity. In this highlight, we introduce recent advances published in both ATVB and many other journals: (1) several significant characters classify ECs as novel immune cells not only in infections and allograft transplantation but also in metabolic diseases; (2) several new receptor systems including conditional danger-associated molecular pattern receptors, nonpattern receptors, and homeostasis associated molecular patterns receptors contribute to innate immune functions of ECs; (3) immunometabolism and innate immune memory determine the innate immune functions of ECs; (4) a great induction of the immune checkpoint receptors in ECs during inflammations suggests the immune tolerogenic functions of ECs; and (5) association of immune checkpoint inhibitors with cardiovascular adverse events and cardio-oncology indicates the potential contributions of ECs as innate immune cells.


Assuntos
Células Endoteliais/imunologia , Imunidade Inata/imunologia , Apresentação do Antígeno , Arteriosclerose/imunologia , Sistema Cardiovascular/imunologia , Citocinas/metabolismo , Humanos , Tolerância Imunológica , Memória Imunológica , Inflamação/imunologia , Macrófagos/imunologia , Obesidade Abdominal , Receptores Citoplasmáticos e Nucleares , Transdução de Sinais , Trombose/imunologia
11.
J Allergy Clin Immunol Pract ; 8(7): 2372-2378.e5, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32272284

RESUMO

BACKGROUND: Omalizumab shows greater clinical benefit with 300 mg dose than with the 150 mg dose. OBJECTIVE: To determine outcomes postwithdrawal, relapse, and re-treatment in omalizumab responders, and from stepping up to 300 mg after insufficient symptom control with 150 mg. METHODS: This was a prospective, randomized (3:4), open-label, noncomparator study (clinicaltrials.gov: NCT02161562). A total of 314 adult patients with chronic spontaneous urticaria and symptomatic on H1-antihistamines were enrolled between August 1, 2014, and November 6, 2015. Patients received 150 mg/300 mg omalizumab, every 4 weeks for 24 weeks. Omalizumab 150 mg dose could be stepped up to 300 mg between week 8 and week 24, if the 7-day sum of the daily Urticaria Activity Score (UAS7) was more than 6. If patients relapsed after treatment withdrawal at week 24, they could be re-treated with the same dose on which omalizumab was started. Patients on 300 mg could extend treatment by 12 weeks if they did not achieve symptom control on 300 mg in the initial dosing phase. The primary end point was the proportion of well-controlled patients who relapsed postwithdrawal, and achieved symptom control at the end of re-treatment. Symptom control was assessed using UAS7 (UAS7 ≤ 6 = well controlled). RESULTS: Overall, 115 of 314 patients had adequate symptom control at week 24 (end of the initial dosing period) and 56 were re-treated after relapse postwithdrawal; 87.8% (95% CI, 78.6%-96.9%) regained symptomatic control (UAS7 ≤ 6). Most (141 of 178) patients initially treated with 150 mg required step-up to 300 mg, which resulted in a 9.5-point (95% CI, 7.6-11.3) improvement in UAS7 over the mean change observed initially on 150 mg. CONCLUSIONS: Step-up to 300 mg helps a greater proportion of patients achieve symptom control, and re-treatment with omalizumab is as effective as initial therapy.

12.
Redox Biol ; 34: 101460, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32179051

RESUMO

BACKGROUND: The molecular mechanisms underlying chronic kidney disease (CKD) transition to end-stage renal disease (ESRD) and CKD acceleration of cardiovascular and other tissue inflammations remain poorly determined. METHODS: We conducted a comprehensive data analyses on 7 microarray datasets in peripheral blood mononuclear cells (PBMCs) from patients with CKD and ESRD from NCBI-GEO databases, where we examined the expressions of 2641 secretome genes (SG). RESULTS: 1) 86.7% middle class (molecular weight >500 Daltons) uremic toxins (UTs) were encoded by SGs; 2) Upregulation of SGs in PBMCs in patients with ESRD (121 SGs) were significantly higher than that of CKD (44 SGs); 3) Transcriptomic analyses of PBMC secretome had advantages to identify more comprehensive secretome than conventional secretomic analyses; 4) ESRD-induced SGs had strong proinflammatory pathways; 5) Proinflammatory cytokines-based UTs such as IL-1ß and IL-18 promoted ESRD modulation of SGs; 6) ESRD-upregulated co-stimulation receptors CD48 and CD58 increased secretomic upregulation in the PBMCs, which were magnified enormously in tissues; 7) M1-, and M2-macrophage polarization signals contributed to ESRD- and CKD-upregulated SGs; 8) ESRD- and CKD-upregulated SGs contained senescence-promoting regulators by upregulating proinflammatory IGFBP7 and downregulating anti-inflammatory TGF-ß1 and telomere stabilizer SERPINE1/PAI-1; 9) ROS pathways played bigger roles in mediating ESRD-upregulated SGs (11.6%) than that in CKD-upregulated SGs (6.8%), and half of ESRD-upregulated SGs were ROS-independent. CONCLUSIONS: Our analysis suggests novel secretomic upregulation in PBMCs of patients with CKD and ESRD, act synergistically with uremic toxins, to promote inflammation and potential disease progression. Our findings have provided novel insights on PBMC secretome upregulation to promote disease progression and may lead to the identification of new therapeutic targets for novel regimens for CKD, ESRD and their accelerated cardiovascular disease, other inflammations and cancers. (Total words: 279).

13.
Oncogene ; 39(18): 3650-3665, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32132651

RESUMO

The BRAFV600E mutation occurs in more than 50% of cutaneous melanomas, and results in the constitutive activation of the mitogen-activated protein kinases (MAPK) pathway. MAP kinase-interacting serine/threonine-protein kinase 1 and 2 (MNK1/2) are downstream effectors of the activated MAPK pathway, and important molecular targets in invasive and metastatic cancer. Despite the well-known role of MNK1 in regulating mRNA translation, little is known concerning the impact of its aberrant activation on gene transcription. Here, we show that changes in the activity, or abundance, of MNK1 result in changes in the expression of pro-oncogenic and pro-invasive genes. Among the MNK1-upregulated genes, we identify Angiopoietin-like 4 (ANGPTL4), which in turn promotes an invasive phenotype via its ability to induce the expression of matrix metalloproteinases (MMPs). Using a pharmacologic inhibitor of MNK1/2, SEL201, we demonstrate that BRAFV600E-mutated cutaneous melanoma cells are reliant on MNK1/2 for invasion and lung metastasis.


Assuntos
Proteína 4 Semelhante a Angiopoietina/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/genética , Melanoma/tratamento farmacológico , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Xenoenxertos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Melanoma/genética , Melanoma/patologia , Camundongos , Mutação/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Transcriptoma/genética
14.
BMJ Case Rep ; 13(2)2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32071124

RESUMO

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide with an estimated 17.5 million deaths annually, according to the World Health Organization (WHO). CVD prevention efforts have the potential to prevent the majority of these deaths by supporting guideline-directed medical therapy (GDMT) and lifestyle modification. Mobile health (mHealth) has the potential to address this gap, but has limited evaluation in clinical studies to date. We present the case of a middle-aged patient of low socioeconomic status, with multiple comorbidities, and no prior smartphone experience, who suffered an acute myocardial infarction (MI) and was given the Corrie intervention while hospitalised. The patient demonstrated improvement in lifestyle modification, adherence to GDMT and post-MI recovery through 2.4 years follow-up. This case supports (1) the potential of mHealth interventions to enhance patient experience and outcomes, (2) intuitive design for adoption and improvement in end user experience and (3) the capability of mHealth to reach and empower underserved patients.


Assuntos
Aplicativos Móveis , Monitorização Fisiológica/instrumentação , Infarto do Miocárdio/terapia , Prevenção Secundária/instrumentação , Telemedicina , Doenças Cardiovasculares/prevenção & controle , Feminino , Humanos , Pessoa de Meia-Idade , Smartphone , Sobreviventes
15.
J Arthroplasty ; 35(6): 1489-1496.e4, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32081500

RESUMO

BACKGROUND: Bundled payment initiatives were introduced to reduce costs and improve quality of care. Cemented vs cementless femoral fixation is a modifiable variable that may influence the cost and quality of care. New bundled payment data from the Centers for Medicare and Medicaid Services allowed us to study the influence of femoral fixation strategy on (1) 90-day costs; (2) readmission rates; (3) reoperation rates; (4) length of stay (LOS); and (5) discharge disposition for Medicare patients undergoing total hip arthroplasty. METHODS: We retrospectively studied 1671 primary total hip arthroplasty Medicare cases, comparing 359 patients who received cemented femoral fixation to 1312 patients who received cementless fixation. Centers for Medicare and Medicaid Services cost data as well as clinical data were reviewed. Demographic differences were present between the 2 cohorts. Statistical analyses were performed, including multiple regression models to adjust for baseline differences. RESULTS: Controlling for cohort differences, cemented patients were significantly more likely to be discharged home compared to cementless patients. Cemented patients also demonstrated trends toward lower costs, lower readmission rates, and shorter LOS compared to cementless patients. All reoperations within the early postoperative period occurred in patients managed with cementless femoral fixation. CONCLUSION: Among Medicare patients, cemented femoral fixation outperformed cementless fixation with respect to discharge disposition and also trended toward superiority with regards to LOS, readmission, cost of care, and reoperation. Cemented femoral fixation remains relevant and useful despite the rising popularity of cementless fixation.

16.
Int J Mol Sci ; 21(4)2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093223

RESUMO

Steroidogenic Factor 1 (SF-1/NR5A1), an orphan nuclear receptor, is important for sexual differentiation and the development of multiple endocrine organs, as well as cell proliferation in cancer cells. Activating transcription factor 3 (ATF3) is a transcriptional repressor, and its expression is rapidly induced by DNA damage and oncogenic stimuli. Since both NR5A1 and ATF3 can regulate and cooperate with several transcription factors, we hypothesized that NR5A1 may interact with ATF3 and plays a functional role in cancer development. First, we found that NR5A1 physically interacts with ATF3. We further demonstrated that ATF3 expression is up-regulated by NR5A1. Moreover, the promoter activity of the ATF3 is activated by NR5A1 in a dose-dependent manner in several cell lines. By mapping the ATF3 promoter as well as the site-directed mutagenesis analysis, we provide evidence that NR5A1 response elements (-695 bp and -665 bp) are required for ATF3 expression by NR5A1. It is well known that the transcriptional activities of NR5A1 are modulated by post-translational modifications, such as small ubiquitin-related modifier (SUMO) modification and phosphorylation. Notably, we found that both SUMOylation and phosphorylation of NR5A1 play roles, at least in part, for NR5A1-mediated ATF3 expression. Overall, our results provide the first evidence of a novel relationship between NR5A1 and ATF3.


Assuntos
Fator 3 Ativador da Transcrição/biossíntese , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Fator Esteroidogênico 1/metabolismo , Transcrição Genética , Fator 3 Ativador da Transcrição/genética , Células Hep G2 , Humanos , Células MCF-7 , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/patologia , Fosforilação/genética , Elementos de Resposta , Fator Esteroidogênico 1/genética , Sumoilação/genética
17.
Carcinogenesis ; 41(10): 1432-1443, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31957805

RESUMO

A key challenge in the implementation of anti-metastatics as cancer therapies is the multi-modal nature of cell migration, which allows tumour cells to evade the targeted inhibition of specific cell motility pathways. The nuclear factor-kappaB (NF-κB) co-factor B-cell lymphoma 3 (Bcl-3) has been implicated in breast cancer cell migration and metastasis, yet it remains to be determined exactly which cell motility pathways are controlled by Bcl-3 and whether migrating tumour cells are able to evade Bcl-3 intervention. Addressing these questions and the mechanism underpinning Bcl-3's role in this process would help determine its potential as a therapeutic target. Here we identify Bcl-3 as an upstream regulator of the two principal forms of breast cancer cell motility, involving collective and single-cell migration. This was found to be mediated by the master regulator Cdc42 through binding of the NF-κB transcription factor p50 to the Cdc42 promoter. Notably, Bcl-3 depletion inhibited both stable and transitory motility phenotypes in breast cancer cells with no evidence of migratory adaptation. Overexpression of Bcl-3 enhanced migration and increased metastatic tumour burden of breast cancer cells in vivo, whereas overexpression of a mutant Bcl-3 protein, which is unable to bind p50, suppressed cell migration and metastatic tumour burden suggesting that disruption of Bcl-3/NF-κB complexes is sufficient to inhibit metastasis. These findings identify a novel role for Bcl-3 in intrinsic and adaptive multi-modal cell migration mediated by its direct regulation of the Rho GTPase Cdc42 and identify the upstream Bcl-3:p50 transcription complex as a potential therapeutic target for metastatic disease.

18.
J Biomech ; 100: 109590, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31902608

RESUMO

Flow-diverting (FD) stents are one of three common modes of treating intracranial aneurysms, yet knowledge of their effect on haemodynamics is incomplete. We used particle image velocimetry (PIV) to measure spatially-varying velocity of blood-analogue fluid within a patient-specific aneurysm model, and compared the observed flow behaviour to predictions from a computational fluid dynamics (CFD) model. In PIV experiments we characterised the flow on multiple cross-sections for three different arterial flowrates (150, 250, 400 mL/min) after deployment of a commercially-available FD stent. Our flow-diverting (FD) stent model for CFD simulation was constructed using a permeability adapted from the literature. Aneurysmal haemodynamics without the FD stent treatment provided good similarities between CFD and PIV results, and the results with a Silk stent treatment also provided acceptable concordances, thereby validating the use of CFD as a convenient and flexible tool for investigating intra-aneurysmal flow dynamics after FD stent treatment. Furthermore, for the first time, the porous-medium FD model stent was validated to be both efficient and effective to predict the flow-diversion effects of a FD stent treatment with a patient-specific intracranial aneurysm. Through the qualitative and quantitative comparison of CFD predictions against the experimental outcomes, this study gives confidence for future studies on aneurysmal haemodynamics and FD stent treatment effects to use CFD simulation.

19.
Redox Biol ; 28: 101322, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31605963

RESUMO

Homocysteine-Methionine (HM) cycle produces universal methyl group donor S-adenosylmethione (SAM), methyltransferase inhibitor S-adenosylhomocysteine (SAH) and homocysteine (Hcy). Hyperhomocysteinemia (HHcy) is established as an independent risk factor for cardiovascular disease (CVD) and other degenerative disease. We selected 115 genes in the extended HM cycle (31 metabolic enzymes and 84 methyltransferases), examined their protein subcellular location/partner protein, investigated their mRNA levels and mapped their corresponding histone methylation status in 35 disease conditions via mining a set of public databases and intensive literature research. We have 6 major findings. 1) All HM metabolic enzymes are located only in the cytosol except for cystathionine-ß-synthase (CBS), which was identified in both cytosol and nucleus. 2) Eight disease conditions encountered only histone hypomethylation on 8 histone residues (H3R2/K4/R8/K9/K27/K36/K79 and H4R3). Nine disease conditions had only histone hypermethylation on 8 histone residues (H3R2/K4/K9/K27/K36/K79 and H4R3/K20). 3) We classified 9 disease types with differential HM cycle expression pattern. Eleven disease conditions presented most 4 HM cycle pathway suppression. 4) Three disease conditions had all 4 HM cycle pathway suppression and only histone hypomethylation on H3R2/K4/R8/K9/K36 and H4R3. 5) Eleven HM cycle metabolic enzymes interact with 955 proteins. 6) Five paired HM cycle proteins interact with each other. We conclude that HM cycle is a key metabolic sensor system which mediates receptor-independent metabolism-associated danger signal recognition and modulates SAM/SAH-dependent methylation in disease conditions and that hypomethylation on frequently modified histone residues is a key mechanism for metabolic disorders, autoimmune disease and CVD. We propose that HM metabolism takes place in the cytosol, that nuclear methylation equilibration requires a nuclear-cytosol transfer of SAM/SAH/Hcy, and that Hcy clearance is essential for genetic protection.


Assuntos
Redes Reguladoras de Genes , Homocisteína/metabolismo , Hiper-Homocisteinemia/metabolismo , Metionina/metabolismo , Citosol/metabolismo , Histonas/metabolismo , Humanos , Hiper-Homocisteinemia/genética , Metilação , Mapas de Interação de Proteínas , Transporte Proteico
20.
J Allergy Clin Immunol Pract ; 8(1): 310-317.e3, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31238160

RESUMO

BACKGROUND: Patients with hereditary angioedema (HAE) present to the emergency department (ED), where their symptoms are often incorrectly attributed to common allergic and gastrointestinal conditions, resulting in major delays in diagnosis and treatment. OBJECTIVE: To develop a rapid triage HAE (Hereditary AngioEdema Rapid Triage [HAE-RT]) tool for ED settings. METHODS: A mixed-methods approach was used in 3 phases: Phase 1: A literature review on the current management of patients with HAE in the ED. Phase 2: A Delphi study with HAE specialists (N = 9) and Patient Advocacy Group Members (N = 3) to reach consensus on the predictor variables (PVs) to be included in the HAE-RT tool. Phase 3: A retrospective chart review to assess the performance of the PVs for HAE. RESULTS: The literature review informed the final list of PVs included in the HAE-RT prototype. Nine experts participated in the Delphi study. Of 8 identified HAE-specific PVs, 3 reached consensus: (1) absence of urticaria, (2) recurrent abdominal pain/swelling, and (3) lack of response to allergic-directed therapy. The retrospective study included 107 patients (N = 66 with HAE; N = 41 non-HAE). Patients with HAE were more likely to have a family history of HAE (71%; P < .0001), previous recurrent angioedema (96%; P < .002), and previous recurrent abdominal pain (77%; P < .0001), and only 6% responded to allergy treatments (P < .0001). The HAE-RT tool had 98% sensitivity and specificity. CONCLUSIONS: Expert consensus led to the identification and prioritization of variables that when incorporated into an HAE-RT tool were associated with a high level of sensitivity and specificity when applied to known patients.

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