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BACKGROUND: People with disability (PWD) face challenges accessing healthcare. Websites are a public-facing resource that can help PWD determine if a hospital can accommodate their needs, yet few studies have described whether hospital websites contain adequate accommodation information. OBJECTIVE: To characterize the extent to which information about disability accommodations is available on US hospital websites. METHODS: We manually reviewed hospital websites using a structured extraction form. We used the Centers for Medicare and Medicaid Services' Hospital General Information Data set to identify a stratified random sample of 600 nonspecialty hospitals in the United States. We excluded hospitals that shared a website with a previously reviewed hospital for a final sample of 445. We recorded (1) content about specific disability accommodations (in 11 predetermined categories); (2) descriptions of hospital policy mentioning disability; and (3) the point of contact to obtain more information about accommodations. RESULTS: About two-thirds (65.6%) of sampled hospitals were acute care hospitals (vs 34.4% critical access); 53.5% had 26-299 beds. Overall, 73.7% websites had information about accommodations; of these, 36.3% had information solely within hospital policies. Of the 47.0% websites with accommodation information beyond hospital policies, the mean number of accommodations listed (excluding policy statements) was 2.37 (of 11 possible). Hospitals with 300+ beds had higher odds of listing any nonpolicy accommodations than those with 1-26 beds (odds ratio = 2.768, p = .02). Less than half (40.5%) hospitals listed a contact person. CONCLUSIONS: Information about disability accommodations is sparse on hospital websites. Comprehensive and actionable communication about accommodations is needed to better protect PWD's rights to accessible healthcare.
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BACKGROUND: Malnutrition in hospitalized patients is associated increased length of stay, cost, readmission, and death. No recent studies have examined trends in prevalence or outcomes of hospitalized patients with a diagnosis of malnutrition. OBJECTIVES: To study the prevalence of malnutrition diagnostic codes and associated hospital outcomes in the United States between 2016 and 2019. METHODS: We conducted a retrospective trends study to identify use of malnutrition codes in hospitalizations in the National Inpatient Sample between 2016 and 2019. We used direct standardization by logistic regression to adjust outcomes of percutaneous gastrostomy tube placement, mechanical ventilation, and death for age, Gagne comorbidity score, and sex. We then used linear regression to test for trends over time by malnutrition type. RESULTS: Across all hospitalizations, codes for diagnoses of non-severe malnutrition and severe malnutrition were present in 3.7% and 4.1% of hospitalizations, respectively. Codes for any malnutrition increased over time, from 6.6% in 2016 to 8.6% in 2018 (p = .03). Codes for severe malnutrition increased from 3.3% to 4.7% (p = .01). Among hospitalizations with coded severe malnutrition diagnoses, there was a statistically significant decrease in adjusted rate of death over time (-0.54% per year, p = .03) which was not seen in hospitalizations without coded malnutrition diagnoses. CONCLUSIONS: Use of malnutrition diagnosis codes increased significantly from 2016 to 2019. During this time, mortality among hospitalizations with a diagnosis code for severe malnutrition decreased. Though the increased prevalence of malnutrition codes may represent a change in the clinical characteristics of hospitalized patients, the decline in mortality suggests some of the increase may be due to lower threshold for coding and assignment of the diagnosis to less ill patients.
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PURPOSE: Our objectives were to compare overall survival (OS) and pulmonary relapse between patients with metastatic Ewing sarcoma (EWS) at diagnosis who achieve rapid complete response (RCR) and those with residual pulmonary nodules after induction chemotherapy (non-RCR). PATIENTS AND METHODS: This retrospective cohort study included children under 20 years with metastatic EWS treated from 2007 to 2020 at 19 institutions in the Pediatric Surgical Oncology Research Collaborative. Chi-square tests were conducted for differences among groups. Kaplan-Meier curves were generated for OS and pulmonary relapse. RESULTS: Among 148 patients with metastatic EWS at diagnosis, 61 (41.2%) achieved RCR. Five-year OS was 71.2% for patients who achieved RCR, and 50.2% for those without RCR (p = .04), and in multivariable regression among patients with isolated pulmonary metastases, RCR (hazards ratio [HR] 0.42; 95% confidence interval [CI]: 0.17-0.99) and whole lung irradiation (WLI) (HR 0.35; 95% CI: 0.16-0.77) were associated with improved survival. Pulmonary relapse occurred in 57 (37%) patients, including 18 (29%) in the RCR and 36 (41%) in the non-RCR groups (p = .14). Five-year pulmonary relapse rates did not significantly differ based on RCR (33.0%) versus non-RCR (47.0%, p = .13), or WLI (38.8%) versus no WLI (46.0%, p = .32). DISCUSSION: Patients with EWS who had isolated pulmonary metastases at diagnosis had improved OS if they achieved RCR and received WLI, despite having no significant differences in rates of pulmonary relapse.
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Neoplasias Ósseas , Neoplasias Pulmonares , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/mortalidade , Sarcoma de Ewing/terapia , Sarcoma de Ewing/patologia , Feminino , Masculino , Criança , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/secundário , Estudos Retrospectivos , Adolescente , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/terapia , Neoplasias Ósseas/secundário , Neoplasias Ósseas/patologia , Pré-Escolar , Taxa de Sobrevida , Prognóstico , Seguimentos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto Jovem , Indução de Remissão , Lactente , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Quimioterapia de InduçãoRESUMO
BACKGROUND: Recent evidence showing that computer-assisted total knee arthroplasty (TKA) is associated with better outcomes compared with conventional TKA for patients with end-stage knee osteoarthritis has not been included in economic evaluations of computer-assisted TKA, which are needed to support coverage decisions. This study evaluated the cost-effectiveness of computer-assisted TKA from a payer's perspective, incorporating recent evidence. METHODS: We compared computer-assisted TKA with conventional TKA with regard to costs (in 2022 U.S. dollars) and quality-adjusted life-years (QALYs) using Markov models for elderly patients (≥65 years of age) and patients who were not elderly (55 to 64 years of age). Costs and QALYs were estimated in the lifetime for elderly patients and in the short term for patients who were not elderly, under a bundled payment program and a Fee-for-Service program. Transition probabilities, costs, and QALYs were retrieved from the literature, a national knee arthroplasty registry, and the National Center for Health Statistics. Threshold and probabilistic sensitivity analyses were conducted to examine the robustness of key estimates used in the base-case analysis. Using projected estimates of TKA utilization, the total cost savings of performing computer-assisted TKA rather than conventional TKA were estimated. RESULTS: Compared with conventional TKA, computer-assisted TKA was associated with higher QALYs and lower costs for both elderly patients and patients who were not elderly, regardless of payment programs, making computer-assisted TKA a favorable treatment option. Widespread adoption of computer-assisted TKA in all U.S. patients would result in an estimated total cost saving of $1 billion for payers. CONCLUSIONS: Compared with conventional TKA, computer-assisted TKA reduces costs to payers while providing favorable outcomes. Payers may consider providing additional payment incentives to providers for performing computer-assisted TKA, to achieve outcome improvement and cost control by facilitating widespread adoption of computer-assisted TKA. LEVEL OF EVIDENCE: Economic and Decision Analysis Level II. See Instructions for Authors for a complete description of levels of evidence.
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BACKGROUND: Evidence of higher hospital volume being associated with improved outcomes for patients undergoing total knee replacement (TKR) is mostly based on arbitrary distribution-based thresholds. OBJECTIVE: We aimed to define outcome-based volume thresholds using data from a national database. METHODS: We used the MedPAR Limited Data Set inpatient data from 2010-2015 to identify patients who had undergone primary TKR. Surgical and TKR specific complications occurring within the index hospitalization and all-cause readmission within 90 days were considered adverse events. We derived an average annual TKR case volume for each hospital and applied the stratum-specific likelihood ratio method to determine volume categories indicative of a similar likelihood of 90-day post-operative complications. Hierarchical multivariable logistic regression with a random intercept for hospital nested within study year and adjusted for patient and hospital characteristics was performed to determine if these volume thresholds were still associated with the odds of 90-day readmission for complications after adjustment. RESULTS: SSLR analysis yielded 4 hospital volume categories based on the likelihood of 90-day postoperative complications: 1-31 (low), 32-127 (medium), 128-248 (high), and 429+ (very high) TKRs performed per year. The results of the hierarchical multivariable logistic regression showed significantly increased odds of 90-day complications at lower volume categories. Sensitivity analyses confirmed our main findings. CONCLUSIONS: This study is the first to provide national-level volume categories that are evidence-based. Publicizing these thresholds may enhance quality measures available to patients, providers, and payors.
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Artroplastia do Joelho , Humanos , Hospitalização , Complicações Pós-Operatórias/epidemiologia , Hospitais , Bases de Dados FactuaisRESUMO
Introduction: Laparoscopic cholecystectomy (LC) during index hospitalization for gallstone pancreatitis is standard in adult populations. The objective of this study was to evaluate trends in use of LC and endoscopic retrograde cholangiopancreatography (ERCP) for children with gallstone pancreatitis. Materials and Methods: This retrospective cohort study used the Kids' Inpatient Database, spanning 2000-2019, to identify patients aged 18 years or younger with a principal diagnosis of gallstone pancreatitis. The Mann-Kendall trend test was used to assess trends over time. Results: Gallstone pancreatitis occurred in 5028 patients. The rate of LC during index hospitalization ranged from 55.4% to 63.8% (P = .76). Trends demonstrate that LC occurred on average hospital day 4.6 in 2000 and decreased to 3.4 in 2019 (P < .01). Among those undergoing LC, average length of stay (LOS) decreased from 6.8 days in 2000 to 5.1 days in 2019 (P < .01). The rate of ERCP alone decreased from 24.8% in 2000 to 14.0% in 2019 (P = .23). For those undergoing ERCP, average hospital day of ERCP decreased from 3.3 in 2000 to 2.3 in 2019 (P = .07). The rate of undergoing both an ERCP and LC decreased from 19.0% in 2000 to 8.5% in 2019 (P = .13). For patients who underwent either LC or ERCP, average LOS decreased from 7.0 days in 2000 to 5.1 days in 2019 (P < .01). For patients who did not undergo a procedure, average LOS decreased from 5.7 days in 2000 to 4.0 days in 2019 (P = .13). Conclusion: The proportion of LC performed during index hospitalizations for children with gallstone pancreatitis has been stable for two decades. However, trends indicate that interventions are occurring earlier, and LOS is becoming shorter.
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Colecistectomia Laparoscópica , Cálculos Biliares , Pancreatite , Adulto , Humanos , Criança , Cálculos Biliares/complicações , Cálculos Biliares/cirurgia , Estudos Retrospectivos , Colangiopancreatografia Retrógrada Endoscópica/métodos , Colecistectomia Laparoscópica/métodos , Pancreatite/etiologia , Pancreatite/cirurgiaRESUMO
BACKGROUND: Clostridioides Difficile Infection (CDI) is a serious antibiotic related complication that has been reported among children undergoing treatment of appendicitis. CDI likelihood amongst different empiric antibiotic regimens for appendicitis remains unclear but likely has important implications for antibiotic stewardship. METHODS: A retrospective cohort study of the Pediatric Health Information System was used to examine patients ages 1 through 18 who received operative management of acute appendicitis. Common empiric antibiotic regimens 1) Ceftriaxone & Metronidazole (CM) 2) Piperacillin & Tazobactam (PT) and 3) Cefoxitin were compared. Study outcomes were CDI within 28 days post-appendectomy and 30-day post-appendectomy percutaneous drainage procedures. Subset analyses were repeated to only include hospitals that standardized empiric antibiotic choice. RESULTS: Of 105,911 patients, 220 (0.21 %) developed CDI. CDI was more common in patients that received CM (CM 0.29 % vs PT 0.15 % vs Cefoxitin 0.18 %; P < 0.01). On adjusted analysis, PT was associated with a lower likelihood of CDI (OR, 0.48; 95%CI, 0.31-0.74) compared to CM which was consistent in hospitals with standardized antibiotic choice. Exposure to more unique antibiotic regimens (OR, 1.70; 95 % CI, 1.50-1.93) and higher total antibiotic days (OR, 1.17; 95 % CI 1.13-1.21) were associated with an increased likelihood of CDI. There was no significant difference in the likelihood of post-appendectomy percutaneous drainage between antibiotic regimens. CONCLUSIONS: CDI is rare following appendectomy for pediatric appendicitis. While PT was associated with statistically lower rates of CDI compared to CM, antibiotic stewardship efforts to avoid mixed regimens and decrease overall antibiotic exposure warrant exploration. LEVEL OF EVIDENCE: Level III.
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Apendicite , Infecções por Clostridium , Humanos , Criança , Antibacterianos/uso terapêutico , Cefoxitina , Estudos Retrospectivos , Apendicite/tratamento farmacológico , Apendicite/cirurgia , Resultado do Tratamento , Metronidazol/uso terapêutico , Ceftriaxona/efeitos adversos , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/epidemiologia , Infecções por Clostridium/etiologia , Combinação Piperacilina e TazobactamRESUMO
Although specific environmental chemical exposures, including flame retardants, are known risk factors for neurodevelopmental disorders (NDDs), direct experimental evidence linking specific chemicals to NDDs is limited. Studies focusing on the mechanisms by which the social processing systems are vulnerable to chemical exposure are underrepresented in the literature, even though social impairments are defining characteristics of many NDDs. We have repeatedly demonstrated that exposure to Firemaster 550 (FM 550), a prevalent flame retardant mixture used in foam-based furniture and infant products, can adversely impact a variety of behavioral endpoints. Our recent work in prairie voles (Microtus ochrogaster), a prosocial animal model, demonstrated that perinatal exposure to FM 550 sex specifically impacts socioemotional behavior. Here, we utilized a factor analysis approach on a battery of behavioral data from our prior study to extract underlying factors that potentially explain patterns within the FM 550 behavior data. This approach identified which aspects of the behavioral battery are most robust and informative, an outcome critical for future study designs. Pearson's correlation identified behavioral endpoints associated with distance and stranger interactions that were highly correlated across 5 behavioral tests. Using these behavioral endpoints, exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) extracted 2 factors that could explain the data: Activity (distance traveled endpoints) and Sociability (time spent with a novel conspecific). Exposure to FM 550 significantly decreased Activity and decreased Sociability. This factor analysis approach to behavioral data offers the advantages of modeling numerous measured variables and simplifying the data set by presenting the data in terms of common, overarching factors in terms of behavioral function.
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Retardadores de Chama , Organofosfatos , Animais , Gravidez , Feminino , Humanos , Comportamento Animal , Exposição Ambiental/análise , Comportamento Social , Retardadores de Chama/farmacologiaRESUMO
OBJECTIVE: To evaluate the impact of prophylactic antibiotics on early infectious complications after central venous access device (VAD) placement in children with cancer. SUMMARY OF BACKGROUND DATA: Despite the frequency of VAD procedures in children, the effectiveness of prophylactic antibiotics for reducing infectious complications is unknown. METHODS: This was a retrospective cohort study of children with cancer undergoing central VAD placement identified in the Pediatric Health Information System database between 2017-2021. The primary outcome was the rate of early infectious complications (composite surgical site infections, central line-associated bloodstream infections, and bacteremia). Multivariable logistic regression was used to evaluate factors associated with early infection, and heterogeneity of treatment effect of prophylactic antibiotics was compared across subgroups. RESULTS: 9,216 patients were included (6,058 ports and 3,158 tunneled lines). Prophylactic antibiotics were associated with lower early infectious complications overall (1.3% vs. 2.4%; OR 0.55 [95% C.I. 0.39-0.79], P<0.001), an effect demonstrated for tunneled lines (OR 0.59, 95% C.I.: 0.41-0.84) but not ports (OR 3.01, 95% C.I.: 0.66-13.78). On multivariate analysis, prophylactic antibiotics (OR 0.67, 95% C.I.: 0.45-0.97) and solid tumors (OR 0.38, 95% C.I.: 0.22-0.64) were associated with reduced odds of early infections, while tunneled lines (OR 20.78, 95% C.I.: 9.83-43.93) and acute myelogenous leukemia (OR 2.37, 95% C.I.: 1.58-3.57) had increased odds. CONCLUSIONS: Prophylactic antibiotics are associated with reduced early infectious complications after central VAD placement overall. Despite recommendations from multiple national organizations against prophylactic antibiotics, these findings suggest a benefit in children with malignancy undergoing tunneled line placement.
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INTRODUCTION: Our aim was to describe practices in multimodal pain management at US children's hospitals and evaluate the association between non-opioid pain management strategies and pediatric patient-reported outcomes (PROs). METHODS: Data were collected as part of the 18-hospital ENhanced Recovery In CHildren Undergoing Surgery (ENRICH-US) clinical trial. Non-opioid pain management strategies included use of preoperative and postoperative non-opioid analgesics, regional anesthetic blocks, and a biobehavioral intervention. PROs included perioperative nervousness, pain-related functional disability, health-related quality of life (HRQoL). Associations were analyzed using multinomial logistic regression models. RESULTS: Among 186 patients, 62 (33%) received preoperative analgesics, 186 (100%) postoperative analgesics, 81 (44%) regional anesthetic block, and 135 (73%) used a biobehavioral intervention. Patients were less likely to report worsened as compared to stable nervousness following regional anesthetic block (relative risk ratio [RRR]:0.31, 95% confidence interval [CI]:0.11-0.85), use of a biobehavioral technique (RRR:0.26, 95% CI:0.10-0.70), and both in combination (RRR:0.08, 95% CI:0.02-0.34). There were no associations of non-opioid pain control modalities with pain-related functional disability or HRQoL. CONCLUSION: Use of postoperative non-opioid analgesics have been largely adopted, while preoperative non-opioid analgesics and regional anesthetic blocks are used less frequently. Regional anesthetic blocks and biobehavioral interventions may mitigate postoperative nervousness in children. LEVEL OF EVIDENCE: III.
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Analgésicos não Narcóticos , Manejo da Dor , Humanos , Criança , Manejo da Dor/métodos , Qualidade de Vida , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Analgésicos Opioides/uso terapêutico , Anestésicos Locais , Analgésicos/uso terapêuticoRESUMO
Autologous chondrocytes (C cells) are effective sources of cell therapy for engineering cartilage tissue to repair chondral defects, such as degenerative arthritis. The expansion of cells with C cell characteristics has become a major challenge due to inadequate donor sites and poor proliferation of mature C cells. The perichondrial progenitor cells (P cells) from the cambium layer of the perichondrium possessed significantly higher mesenchymal stem cell markers than C cells. In the transwell co-culture system, P cells increased the passaging capacity of C cells from P6 to P9, and the cell number increased 128 times. This system increased the percentage of Alcian blue-positive C cells from 40% in P6 to 62% in P9, contributing about 198 times more Alcian blue-positive C cells than the control group. C cells co-cultured with P cells also exhibited higher proliferation than C cells cultured with P cell-conditioned medium. Similar results were obtained in nude mice that were subcutaneously implanted with C cells, P cells or a mixture of the two cell types, in which the presence of both cells enhanced neocartilage formation in vivo. In aggregate, P cells enhanced the proliferation of C cells in a dose-dependent manner and prolonged the longevity of mature C cells for clinical applications.
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An appropriate animal wound model is urgently needed to assess wound dressings, cell therapies, and pharmaceutical agents. Minipig was selected owing to similarities with humans in body size, weight, and physiological status. Different wound sizes (0.07-100 cm2) were created at varying distances but fail to adequately distinguish the efficacy of various interventions. We aimed to resolve potential drawbacks by developing a systematic wound healing system. No significant variations in dorsal wound closure and contraction were observed within the thoracolumbar region between boundaries of both armpits and the paravertebral region above rib tips; therefore, Lanyu pigs appear suitable for constructing a reliable dorsal wound array. Blood flow signals interfered with inter-wound distances Ë 4 cm; a distance > 4 cm is therefore recommended. Wound sizes ≥ 4 cm × 4 cm allowed optimal differentiation of interventions. Partial- (0.23 cm) and full-thickness (0.6 cm) wounds showed complete re-epithelialization on days 13 and 18 and strongest blood flow signals at days 4 and 11, respectively. Given histological and tensile strength assessments, tissue healing resembling normal skin was observed at least after 6 months. We established some golden standards for minimum wound size and distance between adjacent wounds for effectively differentiating interventions in considering 3R principles.
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Modelos Animais , Porco Miniatura , Cicatrização , Animais , Feminino , SuínosRESUMO
BACKGROUND: The roots of Codonopsis pilosula (Franch.) Nannf. have been used in traditional Chinese medicine for treating cardiovascular disease. In the current study, we aimed to discover herbal extracts from C. pilosula that are capable of improving cardiac function of infarcted hearts to develop a potential therapeutic approach. METHODS: A mouse embryonic stem (ES) cell-based model with an enhanced green fluorescent protein (eGFP) reporter driven by a cardiomyocyte-specific promoter, the α-myosin heavy chain, was constructed to evaluate the cardiogenic activity of herbal extracts. Then, herbal extracts from C. pilosula with cardiogenic activity based on an increase in eGFP expression during ES cell differentiation were further tested in a rat myocardial infarction model with left anterior descending artery (LAD) ligation. Cardiac function assessments were performed using echocardiography, 1, 3, and 6 weeks post LAD ligation. RESULTS: The herbal extract 417W from C. pilosula was capable of enhancing cardiogenic differentiation in mouse ES cells in vitro. Echocardiography results in the LAD-ligated rat model revealed significant improvements in the infarcted hearts at least 6 weeks after 417W treatment that were determined based on left ventricle fractional shortening (FS), fractional area contraction (FAC), and ejection fraction (EF). CONCLUSIONS: The herbal extract 417W can enhance the cardiogenic differentiation of ES cells and improve the cardiac function of infarcted hearts.
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The Comprehensive, Computable NanoString Diagnostic gene panel (C2Dx) is a promising solution to address the need for a molecular pathological research and diagnostic tool for precision oncology utilizing small volume tumor specimens. We translate subtyping-related gene expression patterns of Non-Small Cell Lung Cancer (NSCLC) derived from public transcriptomic data which establish a highly robust and accurate subtyping system. The C2Dx demonstrates supreme performance on the NanoString platform using microgram-level FNA samples and has excellent portability to frozen tissues and RNA-Seq transcriptomic data. This workflow shows great potential for research and the clinical practice of cancer molecular diagnosis.
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AIMS: Arginine depleting enzymes are found effective to treat arginine-auxotrophic cancers and therapy-resistant malignancies, alone or in combination with cytotoxic agents or immune checkpoint inhibitors. We aim to select and validate a long-lasting, safe and effective PEGylated and cobalt-chelated arginase conjugated at the selective cysteine residue as a therapeutic agent against cancers. MAIN METHODS: Exploring pharmacokinetic and pharmacodynamic properties of the three arginase conjugates with different PEG modality (20 kDa linear as A20L, 20 kDa branched as A20Y, and 40 kDa branched as A40Y) by cell-based and animal studies. KEY FINDINGS: Arginase conjugates showed comparable systemic half-lives, about 20 h in rats and mice. The extended half-life of PEGylated arginase was concurrent with the integrity of conjugates of which PEG and protein moieties remain attached in bloodstream for 72 h after drug administration. Arginase modified with a linear 20 kDa PEG (A20L) was chosen as the lead candidate (PT01). In vitro assays confirmed the very potent cytotoxicity of PT01 against cancer cell lines of breast, prostate, and pancreas origin. In MIA PaCa-2 pancreatic and PC-3 prostate tumor xenograft models, weekly infusion of the PT01 at 5 and 10 mg/kg induced significant tumor growth inhibition of 44-67%. All mice experienced dose-dependent but rapidly reversible weight loss following each weekly dose, suggesting tolerable toxicity. SIGNIFICANCE: These non-clinical data support PT01 as the lead candidate for clinical development that may benefit cancer patients by providing an alternative cytotoxic mechanism.
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Antineoplásicos/síntese química , Arginase/síntese química , Arginina/deficiência , Engenharia Química/métodos , Desenho de Fármacos , Polietilenoglicóis/síntese química , Animais , Antineoplásicos/administração & dosagem , Arginase/administração & dosagem , Arginina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/administração & dosagem , Isoenzimas/síntese química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Polietilenoglicóis/administração & dosagem , Estrutura Secundária de Proteína , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Highly expressed in cancer 1 (Hec1) plays an essential role in mitosis and is correlated with cancer formation, progression, and survival. Phosphorylation of Hec1 by Nek2 kinase is essential for its mitotic function, thus any disruption of Hec1/Nek2 protein-protein interaction has potential for cancer therapy. We have developed T-1101 tosylate (9j tosylate, 9j formerly known as TAI-95), optimized from 4-aryl-N-pyridinylcarbonyl-2-aminothiazole of scaffold 9 by introducing various C-4' substituents to enhance potency and water solubility, as a first-in-class oral clinical candidate for Hec1 inhibition with potential for cancer therapy. T-1101 has good oral absorption, along with potent in vitro antiproliferative activity (IC50: 14.8-21.5 nM). It can achieve high concentrations in Huh-7 and MDA-MB-231 tumor tissues, and showed promise in antitumor activity in mice bearing human tumor xenografts of liver cancer (Huh-7), as well as of breast cancer (BT474, MDA-MB-231, and MCF7) with oral administration. Oral co-administration of T-1101 halved the dose of sorafenib (25 mg/kg to 12.5 mg/kg) required to exhibit comparable in vivo activity towards Huh-7 xenografts. Cellular events resulting from Hec1/Nek2 inhibition with T-1101 treatment include Nek2 degradation, chromosomal misalignment, and apoptotic cell death. A combination of T-1101 with either of doxorubicin, paclitaxel, and topotecan in select cancer cells also resulted in synergistic effects. Inactivity of T-1101 on non-cancerous cells, a panel of kinases, and hERG demonstrates cancer specificity, target specificity, and cardiac safety, respectively. Subsequent salt screening showed that T-1101 tosylate has good oral AUC (62.5 µM·h), bioavailability (F = 77.4%), and thermal stability. T-1101 tosylate is currently in phase I clinical trials as an orally administered drug for cancer therapy.
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Antineoplásicos/farmacologia , Proteínas do Citoesqueleto/antagonistas & inibidores , Descoberta de Drogas , Quinases Relacionadas a NIMA/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas do Citoesqueleto/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células K562 , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos SCID , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinases Relacionadas a NIMA/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
BACKGROUND AND OBJECTIVES: Hyaluronan preserves the proliferation and differentiation potential of mesenchymal stem cells. Supplementation of low-concentration hyaluronan (SHA) in stem cells culture medium increases its proliferative rate, whereas coated-surface hyaluronan (CHA) maintains cells in a slow-proliferating mode. We have previously demonstrated that in CHA, the metabolic proliferative state of stem cells was influenced by upregulating mitochondrial biogenesis and function. However, the effect of SHA on stem cells' energetic status remains unknown. In this study, we demonstrate the effect that low-concentration SHA at 0.001 mg/ml (SHA0.001) and high-concentration SHA at 5 mg/ml (SHA5) exert on stem cells' mitochondrial function compared with CHA and noncoated tissue culture surface (control). METHODS AND RESULTS: Fast-proliferating human placenta-derived mesenchymal stem cells (PDMSCs) cultured on SHA0.001 exhibited reduced mitochondrial mass, lower mitochondrial DNA copy number, and lower oxygen consumption rate compared with slow-proliferating PDMSCs cultured on CHA at 5.0 (CHA5) or 30 µg/cm2 (CHA30). The reduced mitochondrial biogenesis observed in SHA0.001 was accompanied by a 2-fold increased ATP content and lactate production, suggesting that hyaluronan-induced fast-proliferating PDMSCs may rely less on mitochondrial function as an energy source and induce a mitochondrial functional switch to glycolysis. CONCLUSIONS: PDMSCs cultured on both CHA and SHA exhibited a reduction in reactive oxygen species levels. The results from this study clarify our understandings on the effect of hyaluronan on stem cells and provide important insights into the effect of distinct supplementation methods used during cell therapies.
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Latin America is a fast-growing region that currently faces unique challenges in the treatment of all forms of diabetes mellitus. The burden of this disease will be even greater in the coming years due, in part, to the large proportion of young adults living in urban areas and engaging in unhealthy lifestyles. Unfortunately, the national health systems in Latin-American countries are unprepared and urgently need to reorganize their health care services to achieve diabetic therapeutic goals. Stem cell research is attracting increasing attention as a promising and fast-growing field in Latin America. As future healthcare systems will include the development of regenerative medicine through stem cell research, Latin America is urged to issue a call-to-action on stem cell research. Increased efforts are required in studies focused on stem cells for the treatment of diabetes. In this review, we aim to inform physicians, researchers, patients and funding sources about the advances in stem cell research for possible future applications in diabetes mellitus. Emerging studies are demonstrating the potential of stem cells for ß cell differentiation and pancreatic regeneration. The major economic burden implicated in patients with diabetes complications suggests that stem cell research may relieve diabetic complications. Closer attention should be paid to stem cell research in the future as an alternative treatment for diabetes mellitus.
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Freshwater shrimps are the most common crustaceans kept in an aquarium. This study was a survey seeking parasites infecting cultured freshwater atyid shrimps at aquarium stores in Tainan, Taiwan. We observed that atyid shrimps were infested with Vorticella and Scutariella. Scutariella is a common shrimp parasite; thus, we focused on Vorticella infection in the atyid shrimps. Vorticella aequilata-like pop TW, a freshwater peritrich ciliate, was isolated from the atyid shrimps. The morphological characteristics were investigated using live observations. Specimens from the population showed identical arrangement of the infraciliature and identical ITS1-5.8SITS2 region sequences. The zooids are bell-shaped, 40-58⯵m wide and 47-70⯵m in long in vivo. The food vacuole is variable in shape and is located in the middle of the cell. ITS1-5.8S-ITS2 sequences of Vorticella aequilata-like pop TW did not match any available sequences in GenBank. Phylogenetically, Vorticella aequilata-like pop TW clusters with the other Vorticella within the family Vorticellidae and nests with Vorticella aequilata in the subclade. Above all, the morphological characteristics and molecular analyses show that the investigated Vorticella is a Vorticella aequilata-like species. The phylogenetic analyses of ciliates based on the ITS1-5.8S-ITS2 sequences reveal that the Vorticella genus consists of Vorticella morphospecies and that taxonomic revision of the genus is needed. Morphometric criteria and molecular analysis were used to describe and identify the Vorticella specie and this study presents the first molecular identification analysis of the Vorticella species in the cultured atyid shrimps in Tainan, Taiwan.
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In order to develop and commercialize for the regenerative medicinal products, smart biomaterials with biocompatibility must be needed. In this chapter, we introduce collagen and hyaluronic acid (HA) as extracellular matrix as well as deal with the molecular mechanism as microenvironment, mechanistic effects, and gene expression. Application of collagen and HA have been reviewed in the area of orthopedics, orthopedics, ophthalmology, dermatology and plastic surgery. Finally, the ongoing and commercial products of collagen and HA for regenerative medicine have been introduced.