Tiratricol, a thyroid hormone metabolite, has potent inhibitory activity against human dihydroorotate dehydrogenase.

Human dihydroorotate dehydrogenase (hDHODH) is a promising drug target for many diseases including autoimmune diseases, cancer, and viral infection. To develop more novel and potent hDHODH inhibitors, we screened our in-house library of old drugs. We found that tiratricol (3,3',5-triiodothyroacetic acid), a thyroid hormone metabolite, has potent hDHODH inhibitory activity (IC50 : 0.754 ± 0.126 µM), and its precursor tetrac (3,3',5,5'-tetraiodothyroacetic acid) also shows a certain inhibitory activity against hDHODH (IC50 : 11.960 ± 1.453 µM). Enzyme kinetic analysis shows that tiratricol and tetrac are noncompetitive inhibitors versus CoQ0 , which is different from the positive control A771726. ThermoFMN assay, molecular docking and site-directed mutagenesis all indicate that tiratricol and tetrac interact with more key residues of hDHODH than A771726, especially some hydrophobic residues in Subsite 1. In conclusion, our experiment results indicate a potential new use for the old drug, tiratricol, and provide a novel chemical scaffold for the design of hDHODH inhibitors.

Effect of Cr on Microstructure and Properties of WVTaTiCrx Refractory High-Entropy Alloy Laser Cladding.

WVTaTiCrx (x = 0, 0.25, 0.5, 0.75, 1) refractory high-entropy alloy coatings were prepared on a 42-CrMo steel plate using laser cladding. The purpose of this work is to investigate the effect of the Cr content on the microstructure and properties of the WVTaTiCrx coating. The morphologies and phase compositions of five coatings with different Cr contents were comparatively observed. In addition, the hardness and high-temperature oxidation resistance of the coatings were also analyzed. As a result, with the increase in Cr, the coating grains were more refined. All the coating is mainly composed of the BCC solid-solution phase, which promotes the precipitation of the Laves phase with the increase in Cr. The addition of Cr greatly improves the hardness, high-temperature oxidation resistance and corrosion resistance of the coating. The WVTaTiCr (Cr1) exhibited superior mechanical properties, especially in terms of its exceptional hardness, high-temperature oxidation resistance and outstanding corrosion resistance. The average hardness of the WVTaTiCr alloy coating reaches 627.36 HV. After 50 h of high-temperature oxidation, the oxide weight of WVTaTiCr increases by 5.12 mg/cm2, and the oxidation rate is 0.1 mg/(cm2·h). In 3.5 wt% NaCl solution, the corrosion potential of WVTaTiCr is -0.3198 V, and the corrosion rate is 0.161 mm/a.

Could meeting the standards of the National Accreditation Program for Rectal Cancer in the National Cancer Database improve patient outcomes?

AIM: The National Accreditation Program for Rectal Cancer (NAPRC) was developed to improve rectal cancer patient outcomes in the United States. The NAPRC consists of a set of process and outcome measures that hospitals must meet in order to be accredited. We aimed to assess the potential of the NAPRC by determining whether achievement of the process measures correlates with improved survival. METHODS: The National Cancer Database was used to identify patients undergoing curative proctectomy for non-metastatic rectal cancer from 2010 to 2014. NAPRC process measures identified in the National Cancer Database included clinical staging completion, treatment starting <60 days from diagnosis, carcinoembryonic antigen level measured prior to treatment, tumour regression grading and margin assessment. RESULTS: There were 48 669 patients identified with a mean age of 62 ± 12.9 years and 61.3% of patients were men. The process measure completed most often was assessment of proximal and distal margins (98.4%) and the measure completed least often was the serum carcinoembryonic antigen level prior to treatment (63.8%). All six process measures were completed in 23.6% of patients. After controlling for age, gender, comorbidities, annual facility resection volume, race and pathological stage, completion of all process measures was associated with a statistically significant mortality decrease (Cox hazard ratio 0.88, 95% CI 0.81-0.94, P < 0.001). CONCLUSION: Participating institutions provided complete datasets for all six process measures in less than a quarter of patients. Compliance with all process measures was associated with a significant mortality reduction. Improved adoption of NAPRC process measures could therefore result in improved survival rates for rectal cancer in the United States.

Drug repurposing of ilepcimide that ameliorates experimental autoimmune encephalomyelitis via restricting inflammatory response and oxidative stress.

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS) that remains incurable. Herein, we demonstrated that ilepcimide (Antiepilepsirine), an antiepileptic drug used for decades, protects mice from experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Our studies found that ilepcimide treatment effectively ameliorates demyelination, blood-brain barrier leakage and infiltration of CD4+ and CD8+ T cells in EAE mice. On the one hand, ilepcimide can inhibit dihydroorotate dehydrogenase (DHODH), an important therapeutic target for MS. Computer molecular docking, thermal shift and fluorescence quenching assay demonstrated the directly interaction between ilepcimide and DHODH. Accordingly, ilepcimide observably repressed T cell proliferation in mixed lymphocyte reaction (MLR) assay and concanavalin A (Con-A) model in a DHODH-dependent manner. On the other hand, ilepcimide exhibited neuroprotective effect possibly through activating NRF2 antioxidant pathway in mouse neural crest-derived Neuro2a cells. Collectively, our findings have revealed the therapeutic potential of ilepcimide in EAE mouse model via restricting inflammatory response and oxidative stress, offering a potential opportunity for repurposing existing drug ilepcimide for MS therapy.

How Far Is Too Far? Cost-Effectiveness Analysis of Regionalized Rectal Cancer Surgery.

BACKGROUND: Regionalized rectal cancer surgery may decrease postoperative and long-term cancer-related mortality. However, the regionalization of care may be an undue burden on patients. OBJECTIVE: This study aimed to assess the cost-effectiveness of regionalized rectal cancer surgery. DESIGN: Tree-based decision analysis. PATIENTS: Patients with stage II/III rectal cancer anatomically suitable for low anterior resection were included. SETTING: Rectal cancer surgery performed at a high-volume regional center rather than the closest hospital available. MAIN OUTCOME MEASURES: Incremental costs ($) and effectiveness (quality-adjusted life year) reflected a societal perspective and were time-discounted at 3%. Costs and benefits were combined to produce the incremental cost-effectiveness ratio ($ per quality-adjusted life year). Multivariable probabilistic sensitivity analysis modeled uncertainty in probabilities, costs, and effectiveness. RESULTS: Regionalized surgery economically dominated local surgery. Regionalized rectal cancer surgery was both less expensive on average ($50,406 versus $65,430 in present-day costs) and produced better long-term outcomes (10.36 versus 9.51 quality-adjusted life years). The total costs and inconvenience of traveling to a regional high-volume center would need to exceed $15,024 per patient to achieve economic breakeven alone or $112,476 per patient to satisfy conventional cost-effectiveness standards. These results were robust on sensitivity analysis and maintained in 94.6% of scenario testing. LIMITATIONS: Decision analysis models are limited to policy level rather than individualized decision-making. CONCLUSIONS: Regionalized rectal cancer surgery improves clinical outcomes and reduces total societal costs compared to local surgical care. Prescriptive measures and patient inducements may be needed to expand the role of regionalized surgery for rectal cancer. See Video Abstract at http://links.lww.com/DCR/C83 . QU TAN LEJOS ES DEMASIADO LEJOS ANLISIS DE COSTOEFECTIVIDAD DE LA CIRUGA DE CNCER DE RECTO REGIONALIZADO: ANTECEDENTES:La cirugía de cáncer de recto regionalizado puede disminuir la mortalidad posoperatoria y a largo plazo relacionada con el cáncer. Sin embargo, la regionalización de la atención puede ser una carga indebida para los pacientes.OBJETIVO:Evaluar la rentabilidad de la cirugía oncológica de recto regionalizada.DISEÑO:Análisis de decisiones basado en árboles.PACIENTES:Pacientes con cáncer de recto en estadio II/III anatómicamente aptos para resección anterior baja.AJUSTE:Cirugía de cáncer rectal realizada en un centro regional de alto volumen en lugar del hospital más cercano disponible.PRINCIPALES MEDIDAS DE RESULTADO:Los costos incrementales ($) y la efectividad (años de vida ajustados por calidad) reflejaron una perspectiva social y se descontaron en el tiempo al 3%. Los costos y los beneficios se combinaron para producir la relación costo-efectividad incremental ($ por año de vida ajustado por calidad). El análisis de sensibilidad probabilístico multivariable modeló la incertidumbre en las probabilidades, los costos y la efectividad.RESULTADOS:La cirugía regionalizada predominó económicamente la cirugía local. La cirugía de cáncer de recto regionalizado fue menos costosa en promedio ($50 406 versus $65 430 en costos actuales) y produjo mejores resultados a largo plazo (10,36 versus 9,51 años de vida ajustados por calidad). Los costos totales y la inconveniencia de viajar a un centro regional de alto volumen necesitarían superar los $15,024 por paciente para alcanzar el punto de equilibrio económico o $112,476 por paciente para satisfacer los estándares convencionales de rentabilidad. Estos resultados fueron sólidos en el análisis de sensibilidad y se mantuvieron en el 94,6% de las pruebas de escenarios.LIMITACIONES:Los modelos de análisis de decisiones se limitan al nivel de políticas en lugar de la toma de decisiones individualizada.CONCLUSIONES:La cirugía de cáncer de recto regionalizada mejora los resultados clínicos y reduce los costos sociales totales en comparación con la atención quirúrgica local. Es posible que se necesiten medidas prescriptivas e incentivos para los pacientes a fin de ampliar el papel de la cirugía regionalizada para el cáncer de recto. Consulte Video Resumen en http://links.lww.com/DCR/C83 . (Traducción- Dr. Francisco M. Abarca-Rendon ).

Impact of Total Neoadjuvant Therapy on Postoperative Outcomes After Proctectomy for Rectal Cancer.

BACKGROUND: Total neoadjuvant therapy is an alternative to neoadjuvant chemoradiation alone for rectal cancer and has the benefits of more completion of planned therapy, increased downstaging, earlier treatment of micrometastases, and assessment of chemosensitivity; however, it may increase surgical complications, especially with increased radiation-to-surgery interval. OBJECTIVE: The study aimed to determine the impact of total neoadjuvant therapy on postoperative complications compared with neoadjuvant chemoradiation alone. DESIGN: Retrospective cohort study. SETTINGS: Single tertiary referral center. PATIENTS: The patient included was a stage II/III rectal cancer patient who underwent total neoadjuvant therapy or long-course neoadjuvant chemoradiation followed by surgical resection from 2018-2020. MAIN OUTCOME MEASURES: The main outcome measures included severe postoperative complications (Clavien-Dindo grade ≥3). RESULTS: Of 181 patients, 86 (47.5%) underwent total neoadjuvant therapy and 95 (52.5%) underwent neoadjuvant chemoradiation. There was no difference in severe postoperative complications or any complications. There was also no difference in the rate of complete total mesorectal excision or negative circumferential margin. Total neoadjuvant therapy had a mean operative time of 355.5 minutes and estimated blood loss of 263.6 mL compared with 326.7 minutes and 297.5 mL in the neoadjuvant chemoradiation group. Total neoadjuvant therapy patients had a lower mean lymph node yield than neoadjuvant chemoradiation patients. On multivariable analysis, total neoadjuvant therapy was associated with increased operative time (OR, 1.19; p < 0.001) and estimated blood loss (OR, 1.22; p < 0.001) and decreased lymph node yield (OR, 0.67; p < 0.001). There was no difference in severe complications or any complications. LIMITATIONS: Selection bias uncontrolled by modeling. CONCLUSIONS: We found no difference in risk of postoperative complications between patients who received total neoadjuvant therapy vs neoadjuvant chemoradiation. Total neoadjuvant therapy patients had longer operations and greater estimated blood loss. This may be a reflection of increased operative difficulty because of increased radiation-to-surgery interval and/or the effects of chemotherapy; however, the absolute differences were small and, therefore, should be interpreted cautiously. See Video Abstract at http://links.lww.com/DCR/C44 . IMPACTO DE LA TERAPIA NEOADYUVANTE TOTAL EN LOS RESULTADOS POSOPERATORIOS DESPUS DE UNA PROCTECTOMA POR CNCER DE RECTO: ANTECEDENTES:La terapia neoadyuvante total es una alternativa a la quimiorradiación neoadyuvante sola para el cáncer de recto y tiene los beneficios de una mayor finalización de la terapia planificada, mayor reducción del estadiage, tratamiento más temprano de las micrometástasis y evaluación de la quimiosensibilidad; sin embargo, puede aumentar las complicaciones quirúrgicas, especialmente con un mayor intervalo entre la radiación y la cirugía.OBJETIVO:Determinar el impacto de la terapia neoadyuvante total sobre las complicaciones posoperatorias en comparación con la quimiorradiación neoadyuvante sola.DISEÑO:Estudio de cohorte retrospectivo.ENTORNO CLINICO:Centro único de referencia terciario.PACIENTES:Paciente con cáncer de recto en estadio II/III que se sometieron a terapia neoadyuvante total o quimiorradiación neoadyuvante de larga duración seguida de resección quirúrgica entre 2018 y 2020.PRINCIPALES MEDIDAS DE RESULTADO:Complicaciones postoperatorias graves (grado de Clavien-Dindo ≥3).RESULTADOS:De 181 pacientes, 86 (47,5%) se sometieron a terapia neoadyuvante total y 95 (52,5%) se sometieron a quimiorradioterapia neoadyuvante. No hubo diferencia en las complicaciones postoperatorias graves o cualquier otra complicación. Tampoco hubo diferencia en la tasa de escisión mesorrectal total completa o margen circunferencial negativo. La terapia neoadyuvante total tuvo un tiempo operatorio promedio de 355,5 minutos y una pérdida de sangre estimada de 263,6 ml en comparación con 326,7 minutos y 297,5 ml en el grupo de quimiorradiación neoadyuvante. Los pacientes con terapia neoadyuvante total tuvieron una media de ganglios linfáticos más bajo en comparación con los pacientes con quimiorradioterapia neoadyuvante. En el análisis multivariable, la terapia neoadyuvante total se asoció con un mayor tiempo operatorio (OR = 1,19, p < 0,001) y pérdida de sangre estimada (OR = 1,22, p < 0,001) y menor cantidad los ganglios linfáticos (OR = 0,67, p < 0,001). No hubo diferencia en las complicaciones graves o cualquier complicación.LIMITACIONES:Sesgo de selección no controlado por modelado.CONCLUSIONES:No encontramos diferencias en el riesgo de complicaciones postoperatorias entre los pacientes que recibieron terapia neoadyuvante total versus quimiorradiación neoadyuvante. Los pacientes con terapia neoadyuvante total tuvieron operaciones más prolongadas y una mayor pérdida de sangre estimada. Esto puede ser un reflejo de una mayor dificultad quirúrgica como resultado de un mayor intervalo entre la radiación y la cirugía y/o los efectos de la quimioterapia; sin embargo, las diferencias absolutas fueron pequeñas y, por lo tanto, deben interpretarse con cautela. Consulte Video Resumen en http://links.lww.com/DCR/C44 . (Traducción- Dr. Francisco M. Abarca-Rendon ).

Is robotic utilization associated with increased minimally invasive colorectal surgery rates? Surgeon-level evidence.

BACKGROUND: It is unclear whether robotic utilization has increased overall minimally invasive colorectal surgery rates or if robotics is being adopted instead of laparoscopy. The goal was to evaluate whether increasing robotic surgery utilization is associated with increased rates of overall colorectal minimally invasive surgery. METHODS: The Statewide Planning and Research Cooperative System (New York) was used to identify patients undergoing elective colectomy or proctectomy from 2009 to 2015. Individual surgeons were categorized as having increasing or non-increasing robotic utilization (IRU or non-IRU, respectively) based on the annual increase in the proportion of robotic surgery performed. The odds of surgical approach across the study period were evaluated with multinomial regression. RESULTS: Among 72,813 resections from 2009 to 2015, minimally invasive-surgery increased (47-61%, p < 0.0001). For colectomy, overall minimally invasive-surgery rates increased (54-66%, p < 0.0001), laparoscopic remained stable (53-54%), and robotics increased (1-12%). For proctectomy, overall minimally invasive-surgery rates increased (22-43%, p < 0.0001), laparoscopic remained stable (20-21%), and robotics increased (2-22%). Over the study period, 2487 surgeons performed colectomies. Among 156 surgeons with IRU for colectomies, robotics increased (2-29%), while laparoscopy decreased (67-44%), and open surgery decreased (31-27%). Overall, surgeons with IRU performed minimally invasive colectomies 73% of the time in 2015 versus 69% in 2009. Over the study period, 1131 surgeons performed proctectomies. Among 94 surgeons with IRU for proctectomies, robotics increased (3-42%), while laparoscopy decreased (25-15%), and open surgery decreased (73-44%). Overall, surgeons with IRU performed minimally invasive proctectomy 56% of the time in 2015 versus 27% in 2009. Patients in the latter study period had 57% greater odds of undergoing robotic surgery. CONCLUSIONS: Overall, minimally invasive colorectal resections increased from 2009 to 2015 largely due to increasing robotic utilization, particularly for proctectomies.

What patient factors and Patient-Reported Outcomes Measurement Information System domains are associated with worse pain coping in pediatric orthopaedic patients in the United States?

We sought to better understand the relationship between Patient-Reported Outcomes Measurement Information System (PROMIS) mobility, pain interference (PI) and depressive symptoms scores, as well as determine what patient factors and PROMIS domains were associated with worse pain coping (PROMIS PI), in a pediatric orthopaedic population. Between 27 August 2015 and 30 April 2019, new pediatric orthopaedic patients 18 years or younger (or their guardians as a proxy) were asked to complete PROMIS mobility, PI and depressive symptoms domains at an academic medical center pediatric orthopaedic clinic. Pearson correlation coefficients (r) were calculated between each PROMIS domain. Linear multivariate regression analysis was used to determine patient characteristics and PROMIS domains associated with presenting PROMIS PI scores. There was a strong-moderate correlation between PROMIS mobility and PI (r = -0.66, P < 0.001), while the correlation between PROMIS mobility and depressive symptoms was moderate-poor (r = -0.38, P < 0.001). There was a moderate correlation between PROMIS depressive symptoms and PI (r = 0.54, P < 0.001). In multivariate linear regression analysis, female gender (ß = 0.82, P < 0.001), self-reported black race (ß = 0.94, P < 0.001), Medicaid insurance (ß = 0.82, P < 0.001) and worsening depressive symptoms (ß = 0.33, P < 0.001) were associated with worse pain coping mechanisms, while increasing mobility (ß = -0.47, P < 0.001) was associated with better pain coping mechanisms. Poor mobility and worse depressive symptoms are associated with worse pain coping mechanisms. Additionally, Medicaid insurance status, black race and female gender are also associated with worse physical limitations secondary to pain.