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Fungi have historically been the source of numerous important medicinal compounds, but full exploitation of their genetic potential for drug development has been hampered in traditional discovery paradigms. Here we describe a radically different approach, top-down drug discovery (TD3), starting with a massive digital search through a database of over 100,000 fully genomicized fungi to identify loci encoding molecules with a predetermined human target. We exemplify TD3 by the selection of cyclin-dependent kinases (CDKs) as targets and the discovery of two molecules, 1 and 2, which inhibit therapeutically important human CDKs. 1 and 2 exhibit a remarkable mechanism, forming a site-selective covalent bond to the CDK active site Lys. We explored the structure-activity relationship via semi- and total synthesis, generating an analog, 43, with improved kinase selectivity, bioavailability, and efficacy. This work highlights the power of TD3 to identify mechanistically and structurally novel molecules for the development of new medicines.
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Quinases Ciclina-Dependentes , Descoberta de Drogas , Inibidores de Proteínas Quinases , Humanos , Relação Estrutura-Atividade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Animais , Genômica/métodos , Modelos MolecularesRESUMO
PURPOSE: To evaluate efficacy and safety of beta-3 adrenergic agonists in adults with neurogenic lower urinary tract dysfunction. MATERIALS AND METHODS: According to a protocol (CRD42022350079), we searched multiple data sources for published and unpublished randomized controlled trials (RCTs) up to 2nd August 2022. Two review authors independently screened studies and abstracted data from the included studies. We performed statistical analyses by using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We used GRADE guidance to rate the certainty of evidence (CoE). RESULTS: We found data to inform two comparisons: beta-3 adrenergic agonists versus placebo (4 RCTs) and anticholinergics (2 RCTs). Only mirabegron was used for intervention in all included studies. Compared to placebo, beta-3 adrenergic agonists may have a clinically unimportant effect on urinary symptoms score (mean difference [MD] -2.50, 95% confidence interval [CI] -4.78 to -0.22; I²=92%; 2 RCTs; 192 participants; low CoE) based on minimal clinically important difference of 3. We are very uncertain of the effects of beta-3 adrenergic agonists on quality of life (MD 10.86, 95% CI 1.21 to 20.50; I²=41%; 2 RCTs; 98 participants; very low CoE). Beta-3 adrenergic agonists may result in little to no difference in major adverse events (cardiovascular adverse events) (risk ratio 0.57, 95% CI 0.14 to 2.37; I²=0%; 4 RCTs; 310 participants; low CoE). Compared to anticholinergics, no study reported urinary symptom scores and quality of life. There were no major adverse events (cardiovascular adverse events) in either study group (1 study; 60 participants; very low CoE). CONCLUSIONS: Compared to placebo, beta-3 adrenergic agonists may have similar effects on urinary symptom scores and major adverse events. There were uncertainties about their effects on quality of life. Compared to anticholinergics, we are either very uncertain or have no evidence about urinary symptom scores, quality of life, and major adverse events.
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Agonistas de Receptores Adrenérgicos beta 3 , Bexiga Urinaria Neurogênica , Humanos , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 3/efeitos adversos , Bexiga Urinaria Neurogênica/tratamento farmacológico , Resultado do Tratamento , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Kidney ischemia and reperfusion injury (IRI) is a significant contributor to acute kidney injury (AKI), characterized by tubular injury and kidney dysfunction. Salvador family WW domain containing protein 1 (SAV1) is a key component of the Hippo pathway and plays a crucial role in the regulation of organ size and tissue regeneration. However, whether SAV1 plays a role in kidney IRI is not investigated. In this study, we investigated the role of SAV1 in kidney injury and regeneration following IRI. A proximal tubule-specific knockout of SAV1 in kidneys (SAV1ptKO) was generated, and wild-type and SAV1ptKO mice underwent kidney IRI or sham operation. Plasma creatinine and blood urea nitrogen were measured to assess kidney function. Histological studies, including periodic acid-Schiff staining and immunohistochemistry, were conducted to assess tubular injury, SAV1 expression, and cell proliferation. Western blot analysis was employed to assess the Hippo pathway-related and proliferation-related proteins. SAV1 exhibited faint expression in the proximal tubules and was predominantly expressed in the connecting tubule to the collecting duct. At 48 h after IRI, SAV1ptKO mice continued to exhibit severe kidney dysfunction, compared to attenuated kidney dysfunction in wild-type mice. Consistent with the functional data, severe tubular damage induced by kidney IRI in the cortex was significantly decreased in wild-type mice at 48 h after IRI but not in SAV1ptKO mice. Furthermore, 48 h after IRI, the number of Ki67-positive cells in the cortex was significantly higher in wild-type mice than SAV1ptKO mice. After IRI, activation and expression of Hippo pathway-related proteins were enhanced, with no significant differences observed between wild-type and SAV1ptKO mice. Notably, at 48 h after IRI, protein kinase B activation (AKT) was significantly enhanced in SAV1ptKO mice compared to wild-type mice. This study demonstrates that SAV1 deficiency in the kidney proximal tubule worsens the injury and delays kidney regeneration after IRI, potentially through the overactivation of AKT.
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Injúria Renal Aguda , Proteínas de Ciclo Celular , Túbulos Renais Proximais , Traumatismo por Reperfusão , Animais , Masculino , Camundongos , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proliferação de Células , Modelos Animais de Doenças , Via de Sinalização Hippo , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/genética , Transdução de SinaisRESUMO
STUDY OBJECTIVES: Sleep disruption is prevalent and persistent among children who experience maltreatment/interpersonal trauma. Weighted blankets have gained popularity in recent years as a potential non-pharmacological intervention for improving sleep in various populations, but their efficacy has not been examined among maltreated children. The current study used a randomized, within-subjects, crossover design to examine whether the use of a weighted blanket improves objective and/or subjective indices of sleep among 30 children, ages 6 to 15 years (M = 9.7, SD = 2.9) adopted from foster care. METHODS: Participants used a weighted blanket for two weeks and their usual blanket for two weeks in a counterbalanced order. Sleep outcomes were measured using actigraphy and subjective sleep diaries. RESULTS: No differences in actigraphy-based or subjective estimates of total sleep time, sleep onset latency, wake after sleep onset, or sleep quality ratings were found based on blanket type. Child age, biological sex, timing of participation (school year versus summer months), and maltreatment/trauma history did not impact outcomes. CONCLUSIONS: Although we did not find evidence that weighted blankets improve sleep among children with a history of maltreatment/interpersonal trauma, additional well-controlled studies using larger samples of children are needed.
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PURPOSE: The purpose of this study was to investigate autophagy in an extruded disc and to compare this activity with the activity in the remaining disc after lumbar disc herniation in the same patient. METHODS: In total, 12 patients (females 4, males 8) with the extruded type of lumbar disc herniation (LDH) were surgically treated. Their mean age was 54.3 ± 15.8 years (range: 29 ~ 78 years). The mean interval from the occurrence of symptoms to the operation was 9.8 ± 9.4 weeks (range: 2 ~ 24 weeks). The extruded discs were excised, and the remaining disc material removed, to prevent recurrence of herniation. Immediately after specimen collection, all tissues were stored at -70 °C prior to analysis. Autophagy was assessed immunohistochemically and via Western blotting for Atg5, Atg7, Atg12, Atg12L1, and Beclin-1. And the relationship between autophagy and apoptosis was investigated by correlation analysis of caspase-3 with autophagy proteins. RESULTS: The expression levels of autophagic markers were significantly increased in the extruded discs compared to the remaining discs within the same patients. The mean expression levels of Atg5, Atg7, Atg12, and Beclin-1 in extruded discs were statistically significantly higher than those in the remaining discs (P < 0.01, P < 0.001, P < 0.01, and P < 0.001 respectively). CONCLUSIONS: The autophagic pathway was more active in extruded disc material than in remaining disc material within the same patient. This may explain spontaneous resorption of the extruded disc after LDH.
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Deslocamento do Disco Intervertebral , Masculino , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Deslocamento do Disco Intervertebral/cirurgia , Proteína Beclina-1 , Vértebras Lombares/cirurgia , Discotomia , AutofagiaRESUMO
Chronic subdural hematoma (cSDH) is one of the most common types of intracranial hemorrhages, particularly in the elderly. Despite extensive research regarding cSDH diagnosis and treatment, there is conflicting data on predictors of postoperative mortality (POM). We conducted a large retrospective review of patients who underwent a cSDH evacuation at a single urban institution between 2015 and 2022. Data were collected from the electronic medical record on prior comorbidities, anticoagulation use, mental status on presentation, preoperative labs, and preoperative/postoperative imaging parameters. Univariate and multivariate analyses were conducted to analyze predictors of mortality. Mortality during admission for this cohort was 6.1%. Univariate analysis showed the mortality rate was higher in those presenting with a history of dialysis. In addition, those who presented with altered mental status, were intubated, and lower GCS scores had higher rates of POM. Usage of Coumadin was correlated with higher rates of POM. Examination of preoperative labs showed that patients who presented with anemia or thrombocytopenia had higher POM. Imaging data showed that cSDH volume and greatest dimension were correlated with higher rates of POM. Finally, patients that were not extubated postoperatively had higher rates of POM. Multivariate analysis showed that only altered mental status and being not being extubated postoperatively were correlated with a higher risk of mortality. In summation, we demonstrated that altered mental status and failure to extubate were independent predictors or mortality in cSDH evacuation. Interestingly, patient age was not a significant predictor of mortality.
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Craniotomia , Hematoma Subdural Crônico , Humanos , Idoso , Craniotomia/métodos , Hematoma Subdural Crônico/cirurgia , Hematoma Subdural Crônico/epidemiologia , Estudos Retrospectivos , Comorbidade , Drenagem/métodos , Resultado do TratamentoRESUMO
PURPOSE: To analyze malignancy of computed tomography (CT) and magnetic resonance imaging (MRI) results in the same renal mass. MATERIALS AND METHODS: We retrospectively reviewed 1,216 patients who underwent partial nephrectomy from January 2017 to December 2021 in our institute. Patients who had both CT and MRI reports prior to surgery were included. We compared the diagnostic accuracy between the CT and the MRI. The patients were divided into two groups according to the consistency of reports: the 'Consistent group' and the 'Inconsistent group'. The Inconsistent group was further divided into two subgroups. Group 1 is the case that showed benign findings on CT but malignancy on MRI. Group 2 is the cases of malignancy on CT but benign on MRI. RESULTS: 410 patients were identified. Benign lesion was identified in 68 cases (16.6%). The sensitivity, specificity and diagnostic accuracy of MRI was 91.2%, 36.8%, and 82.2% respectively, whereas that of CT was 84.8%, 41.2%, and 77.6% respectively. Consistent group were 335 cases (81.7%) and inconsistent group were 75 cases (18.3%). The mean mass size was significantly smaller in the inconsistent group compared to the consistent group (consistent group vs. inconsistent group: 2.31±0.84 cm vs.1.84±0.75 cm, p<0.001). Also, the Group 1 had higher odds of malignancy compared to Group 2 in the renal mass size 2-4 cm (odds ratio, 5.62 [1.02-30.90]). CONCLUSIONS: Smaller mass size affects the discrepancy of CT and MRI reports. In addition, MRI showed better diagnostic performance in mismatch cases in the small renal masses.
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Imageamento por Ressonância Magnética , Tomografia Computadorizada por Raios X , Humanos , Estudos Retrospectivos , NefrectomiaRESUMO
PURPOSE: Ureteral strictures are a common complication after kidney transplantation. Open reconstruction is preferred for long-segment ureteral strictures that cannot be resolved endoscopically; however, it is known to have the potential to fail. We report 2 successful cases of robotic reconstruction surgery of a transplant ureter using the native ureter with the aid of intraoperative Indocyanine green (ICG). MATERIALS AND METHODS: Patients were placed in semi-lateral position. Using Da Vinci Xi, the transplant ureter was dissected, and the stricture site was identified. End-to-side anastomosis of the native ureter to the transplant ureter was performed. ICG was utilized to identify the course of the transplant ureter and confirm the vascularity of the native ureter. RESULTS: Case 1: A 55-year-old female underwent renal transplantation at another hospital. She had recurrent febrile urinary tract infections (UTIs) and a ureteral stricture requiring percutaneous nephrostomy (PCN). The PCN and ureteral stent were removed successfully after surgery. The patient had only 1 febrile UTI episode after surgery. Case 2: A 56-year-old female underwent renal transplantation at another hospital. She had acute pyelonephritis 1-month post-transplantation, and a long-segment ureteral stricture was identified. She developed a UTI with anastomosis site leakage in the early postoperative period, which resolved with conservative treatment. The PCN and ureteral stent were removed 6 weeks after surgery. CONCLUSIONS: Robotic surgery for managing long-segment ureteral stricture after kidney transplantation is safe and feasible. The use of ICG during surgery to identify the ureter course and its viability can improve the success.
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Procedimentos Cirúrgicos Robóticos , Ureter , Feminino , Humanos , Pessoa de Meia-Idade , Ureter/cirurgia , Constrição Patológica/etiologia , Constrição Patológica/cirurgia , Verde de Indocianina , Rim , Fístula Anastomótica , Febre , República da CoreiaRESUMO
Aristolochic acid (AA) is notorious for inducing nephrotoxicity, but the influence of sex on AA-induced kidney injury was not clear. This study sought to investigate sex differences in kidney dysfunction and tubular injury induced by AA. Male and female mice were bilaterally orchiectomized and ovariectomized, respectively. Fourteen days after gonadectomy, the mice were intraperitoneally injected with AA (10 mg/kg body weight/day) daily for 2 days and sacrificed 7 days after the first injection. Body weight, kidney function, and tubular structure were assessed. When compared between male and female non-gonadectomized mice, AA-induced body weight loss was greater in male mice than in female mice. Functional and structural damages in male kidneys were markedly induced by AA injection, but kidneys in AA-injected female mice showed no or mild damages. Ovariectomy had no effect on AA-induced nephrotoxic acute kidney injury in female mice. However, orchiectomy significantly reduced body weight loss, kidney dysfunction, and tubular injury in AA-induced nephrotoxicity in male mice. This study has demonstrated that testis causes AA-induced nephrotoxic acute kidney injury.
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Injúria Renal Aguda , Ácidos Aristolóquicos , Camundongos , Feminino , Masculino , Animais , Testículo , Rim , Ácidos Aristolóquicos/toxicidade , Injúria Renal Aguda/induzido quimicamente , Peso Corporal , Redução de PesoRESUMO
Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites with biological effects, including antiapoptotic, anti-inflammatory, and antifibrotic functions. Soluble epoxide hydrolase (sEH)-mediated hydrolysis of EETs to dihydroxyeicosatrienoic acids (DHETs) attenuates these effects. Recent studies have demonstrated that inhibition of sEH prevents renal tubulointerstitial fibrosis and inflammation in the chronic kidney disease model. Given the pathophysiological role of the EET pathway in chronic kidney disease, we investigated if administration of EET regioisomers and/or sEH inhibition will promote antifibrotic and renoprotective effects in renal fibrosis following unilateral ureteral obstruction (UUO). EETs administration abolished tubulointerstitial fibrogenesis, as demonstrated by reduced fibroblast activation and collagen deposition after UUO. The inflammatory response was prevented as demonstrated by decreased neutrophil and macrophage infiltration and expression of cytokines in EET-administered UUO kidneys. EET administration and/or sEH inhibition significantly reduced M1 macrophage markers, whereas M2 macrophage markers were highly upregulated. Furthermore, UUO-induced oxidative stress, tubular injury, and apoptosis were all downregulated following EET administration. Combined EET administration and sEH inhibition, however, had no additive effect in attenuating inflammation and renal interstitial fibrogenesis after UUO. Taken together, our findings provide a mechanistic understanding of how EETs prevent kidney fibrogenesis during obstructive nephropathy and suggest EET treatment as a potential therapeutic strategy to treat fibrotic diseases.NEW & NOTEWORTHY Epoxyeicosatrienoic acids (EETs) are cytochrome P-450-dependent antihypertensive and anti-inflammatory derivatives of arachidonic acid, which are highly abundant in the kidney and considered renoprotective. We found that EET administration and/or soluble epoxide hydrolase inhibition significantly attenuates oxidative stress, renal cell death, inflammation, macrophage differentiation, and fibrogenesis following unilateral ureteral obstruction. Our findings provide a mechanistic understanding of how EETs prevent kidney fibrogenesis during obstructive nephropathy and suggest that EET treatment may be a potential therapeutic strategy to treat fibrotic diseases.
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Insuficiência Renal Crônica , Obstrução Ureteral , Humanos , Epóxido Hidrolases , Obstrução Ureteral/complicações , Obstrução Ureteral/tratamento farmacológico , Rim/metabolismo , Eicosanoides/metabolismo , Inflamação , Ácidos Araquidônicos , Ácido 8,11,14-EicosatrienoicoRESUMO
OBJECTIVE: The disparity of problems, impairments, and disorders among children in foster care is well-documented and spans virtually every domain of functioning. Sleep, however, has received minimal attention among this vulnerable group, which is concerning given the multitude of ways sleep affects children's development, health, and behavior. METHODS: A total of 485 foster caregivers from across the United States completed a survey including quantitative items and qualitative, open-ended questions about sleep and related health and behavior for one child (M = 6.4 years, SD = 2.2; range 4-11 years) currently in their care. RESULTS: Overall, caregivers reported developmentally appropriate child sleep and wake times; however, difficulty falling asleep (avg. 46 min per night) and staying asleep (avg. 34 min awake overnight) were common. Additionally, a high prevalence of sleep-related problems was reported including moving to someone else's bed during the night (85.8%), nightmares (51.2%), sleep terrors (26.4%), snoring (32.8%), bedwetting (31.6%), and teeth grinding (21.8%). Qualitative responses indicated emotional and behavioral challenges at bedtime, particularly elevated fear, and anxiety. CONCLUSIONS: Findings are consistent with previous work finding significant health disparities among children placed in foster care. Results highlight a need for trauma-informed, behavioral sleep interventions for this pediatric population which might serve to reduce other health disparities.
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Distúrbios do Início e da Manutenção do Sono , Transtornos do Sono-Vigília , Criança , Humanos , Cuidadores/psicologia , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/psicologia , Sono , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Surgical pain management is a critical component in the success of bariatric procedures. With the opioid epidemic, there have been increased efforts to decrease opioid use. In 2019, the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program developed the BSTOP protocol, a multimodal perioperative pain management regimen to minimize opioid use. The objective of this study is to evaluate the effectiveness of the BSTOP protocol on patients' need for opioid medications during their perioperative care. METHODS: This is a single-institution prospective cohort study on patients who underwent bariatric surgery from 10/2019 to 5/2021. Data was collected on morphine equivalent dose of opioids during different stages of inpatient and outpatient care. BSTOP was implemented on 7/2020. Primary outcomes were total inpatient and outpatient opioid use as well as hospital length of hospital stay (LOS). Gabapentin was removed from the protocol between 10/20/2020 and 12/31/2020 due to side effects; it was re-implemented on 1/1/2021 due to observed spikes in opioid use during its absence. RESULTS: 1264 patients who had bariatric surgery between 10/2019 and 5/2021 were included in the study, with 409 patients before (pre-BSTOP) and 855 patients after BSTOP implementation. There was a 36% reduction in total inpatient opiate use and a 57% reduction in total outpatient opiate use. LOS also significantly decreased, from 1.53 to 1.28 days. 179 patients received BSTOP without gabapentin. These patients used more opioids in the post-anesthesia care unit and on the inpatient floors compared to pre-BSTOP and BSTOP with gabapentin patients. With total inpatient and outpatient opioid use, patients on BSTOP without gabapentin used fewer opioids than those pre-BSTOP. However, those on BSTOP without gabapentin used more opioids than those with gabapentin. CONCLUSION: The BSTOP protocol significantly reduced inpatient and outpatient opioid use as well as LOS. Gabapentin is a crucial component of the BSTOP protocol.
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Cirurgia Bariátrica , Transtornos Relacionados ao Uso de Opioides , Humanos , Analgésicos Opioides/uso terapêutico , Gabapentina/uso terapêutico , Estudos Prospectivos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Dor Pós-Operatória/epidemiologia , Cirurgia Bariátrica/efeitos adversos , Morfina/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/etiologia , Prescrições , Estudos RetrospectivosRESUMO
Cisplatin is a potent chemotherapeutic used for the treatment of many types of cancer, but it has nephrotoxic side effects leading to acute kidney injury and subsequently chronic kidney disease (CKD). Previous work has focused on acute kidney tubular injury induced by cisplatin, whereas the chronic sequelae post-injury has not been well-explored. In the present study, we established a kidney fibroblast model of CKD induced by repeated administration of cisplatin (RAC) as a clinically relevant model. In NRK-49F rat kidney fibroblasts, RAC upregulated α-smooth muscle actin (α-SMA) and fibronectin proteins, suggesting that RAC induces kidney fibroblast-to-myofibroblast transformation. RAC also enhanced cell size, including the cell attachment surface area, nuclear area, and cell volume. Furthermore, RAC induced p21 expression and senescence-associated ß-galactosidase activity, suggesting that kidney fibroblasts exposed to RAC develop a senescent phenotype. Inhibition of p21 reduced cellular senescence, hypertrophy, and myofibroblast transformation induced by RAC. Intriguingly, after RAC, kidney fibroblasts were arrested at the G2/M phase. Repeated treatment with paclitaxel as an inducer of G2/M arrest upregulated p21, α-SMA, and fibronectin in the kidney fibroblasts. Taken together, these data suggest that RAC transforms kidney fibroblasts into myofibroblasts through G2/M arrest and cellular senescence.
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Cisplatino , Insuficiência Renal Crônica , Ratos , Animais , Cisplatino/farmacologia , Cisplatino/metabolismo , Fibronectinas/metabolismo , Apoptose , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular , Senescência Celular , Fibroblastos/metabolismo , Rim/metabolismo , Insuficiência Renal Crônica/metabolismoRESUMO
Sleep patterns affect children's socioemotional functioning in ways that may predict long-term social problems. However, precise mechanisms through which these effects occur remain unexplored and thus unknown. Building on findings in adults, the current study examined whether changes in children's facial expressions of emotion after sleep restriction predict social problems concurrently and/or longitudinally. At time 1, 37 children (mean = 9.08 years, SD = 1.3) completed in-lab emotional assessments both when rested and after two nights of sleep restriction. Participants' parents provided reports of their child's social problems at time 1 and approximately 2 years later (time 2; mean = 11.26 years, SD = 1.6). Children who exhibited less positive facial expressions in response to positive images after sleep restriction evidenced greater social problems longitudinally, even when controlling for earlier social problems. Results suggest that inadequate sleep may undermine children's social functioning via alterations in emotional expression which may become more salient with age.
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[This corrects the article DOI: 10.1007/s42761-021-00078-2.].
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BACKGROUND: Kidney ischemia reperfusion injury (IRI) is characterized by tubular cell death. DNA double-strand breaks is one of the major sources of tubular cell death induced by IRI. 2-Mercaptoethanol (2-ME) is protective against DNA double-strand breaks derived from calf thymus and bovine embryo. Here, we sought to determine whether treatment with 2-ME attenuated DNA double-strand breaks, resulting in reduced kidney dysfunction and structural damage in IRI. METHODS: Kidney IRI or sham-operation in mice was carried out. The mice were treated with 2-ME, Ras-selective lethal 3, or vehicle. Kidney function, tubular injury, DNA damage, antioxidant enzyme expression, and DNA damage response (DDR) kinases activation were assessed. RESULTS: Treatment with 2-ME significantly attenuated kidney dysfunction, tubular injury, and DNA double-strand breaks after IRI. Among DDR kinases, IRI induced phosphorylation of ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR), but IRI reduced phosphorylation of other DDR kinases including ataxia telangiectasia and Rad3 related, checkpoint kinase 1 (Chk1), Chk2, and Chinese hamster cells 1 (XRCC1). Treatment with 2-ME enhanced phosphorylation of ATM and ATM-mediated effector kinases in IRI-subjected kidneys, suggesting that 2-ME activates ATM-mediated DDR signaling pathway. Furthermore, 2-ME dramatically upregulated glutathione peroxidase 4 (GPX4) in IRI-subjected kidneys. Inhibition of GPX4 augmented adverse IRI consequences including kidney dysfunction, tubular injury, DNA double-strand breaks, and inactivation of ATM-mediated DDR signaling pathway after IRI in 2-ME-treated kidneys. CONCLUSIONS: We have demonstrated that exogenous 2-ME protects against DNA double-strand breaks after kidney IRI through GPX4 upregulation and ATM activation.
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Ataxia Telangiectasia , Traumatismo por Reperfusão , Bovinos , Animais , Camundongos , Quinase 1 do Ponto de Checagem/genética , Quinase 1 do Ponto de Checagem/metabolismo , Mercaptoetanol/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima , Ataxia Telangiectasia/metabolismo , Antioxidantes/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Dano ao DNA , Fosforilação , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/metabolismo , Rim/metabolismo , DNA/metabolismo , Isquemia/metabolismo , Proteínas de Ciclo Celular/genéticaRESUMO
Purpose: To compare surgical outcomes between robot-assisted laparoendoscopic single-site (R-LESS) surgery using the da Vinci Si or Xi system and the da Vinci SP system for partial nephrectomy. Materials and Methods: From 2008 to 2020, 66 partial nephrectomies were performed using a single-site robotic approach: 44 used the da Vinci Xi or Si system (R-LESS group) and 22 used the da Vinci SP system (SP group). After 1:1 propensity score matching, surgical outcomes were compared between groups. Results: Median patient age was 51.5 years. Median tumor size was 2.1 cm and was not significantly different between groups. Median operation time was longer in the R-LESS group (R-LESS vs SP: 180 vs 155 minutes, p = 0.034), but median warm ischemic time was comparable between groups. Estimated blood loss was higher in the R-LESS group (R-LESS vs SP: 215 vs 20 mL, p < 0.001). Median operation time was significantly shorter in the SP group in patients with moderate- to high-complexity tumors (R-LESS vs SP: 200 vs 172 minutes, p = 0.035). Rates of trifecta achievement were similar between groups (63.6% in both groups, p = 1.00). Conclusions: R-LESS and da Vinci SP methods are both feasible approaches for single-site incision robotic partial nephrectomy. The da Vinci SP platform allows "true" single-site surgery without additional ports and provides a wider working space. It was associated with better performance than R-LESS partial nephrectomy. In complex tumors, operation time was shorter with SP partial nephrectomy than with R-LESS partial nephrectomy, suggesting that the SP method is especially advantageous for managing complex renal tumors.
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Neoplasias Renais , Procedimentos Cirúrgicos Robóticos , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Pessoa de Meia-Idade , Nefrectomia/métodos , Pontuação de Propensão , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/métodos , Resultado do Tratamento , Isquemia QuenteRESUMO
Clear cell renal cell carcinoma (ccRCC) alters metabolic signals frequently, leading to mitochondrial dysfunction, such as increase of glycolysis and accumulation of lipid. Sirtuin3 (SIRT3) is a key factor for the regulation of both mitochondrial integrity and function. SIRT3 is downregulated and contributes in both cancer development and progression in ccRCC. The aim of this study is to investigate SIRT3-regulated mitochondrial biogenesis in ccRCC. SIRT3 overexpression alone reduced glucose uptake rate and enhanced membrane potential in mitochondria. ccRCC with overexpressed SIRT3 further improved the lethal effects when combined with anticancer drugs (Resveratrol, Everolimus and Temsirolimus). Cell viability was markedly decreased in a dose-dependent manner when treated with resveratrol or mTOR inhibitors in SIRT3 overexpressing ccRCC. In conclusion, SIRT3 improved mitochondrial functions in ccRCC through metabolic reprogramming. Mitochondrial reprogramming by SIRT3 regulation improves the sensitivity to anticancer drugs. The combination of SIRT3 and resveratrol functioned synergistically lethal effect in ccRCC.
Assuntos
Antineoplásicos , Carcinoma de Células Renais , Neoplasias Renais , Sirtuína 3 , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Resistência a Medicamentos , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Mitocôndrias/metabolismo , Resveratrol/metabolismo , Resveratrol/farmacologia , Sirtuína 3/genética , Sirtuína 3/metabolismoRESUMO
OBJECTIVE: Evidence of poor sleep health among children in foster care continues to mount, but information about whether and how sleep problems are addressed is unavailable. The goal of this study was to begin to fill these significant knowledge gaps. METHODS: Four hundred eighty-five foster caregivers from across the United States completed a survey focused on the sleep health of one child, 4 to 11 years ( M = 6.4; SD = 2.2) currently in their care. Caregivers provided quantitative and qualitative responses to questions regarding training, information, and services received in relation to their child's sleep. Caregivers also reported on the factors and strategies they perceived as most important for helping children in their care sleep well. RESULTS: Only 13% of caregivers reported receiving any information/education about sleep from agencies or case workers, whereas 55% had sought help from a health provider related to their child's sleep. Nearly half of all caregivers (46%) reported giving their child melatonin. Caregivers reported that a bedtime routine/consistency, reassurance of safety/love, and a calming environment were most important for helping their child sleep well. A recurrent theme in qualitative responses was a need to mitigate child fear/anxiety at night. CONCLUSION: Children in foster care face a range of risk factors that increase the likelihood of poor/insufficient sleep, but these findings suggest this critical aspect of health requires greater clinical and research attention. As these data were collected during the initial months of the COVID-19 pandemic, replication studies are necessary.
Assuntos
COVID-19 , Melatonina , Transtornos do Sono-Vigília , Cuidadores , Criança , Humanos , Pandemias , Transtornos do Sono-Vigília/epidemiologiaRESUMO
Anesthesia for pituitary surgery is tailored to each individual patient and the type of tumor they have. Anesthetic considerations include difficult airways, hormonal and electrolyte abnormalities, cardiac abnormalities, the potential for catastrophic hemorrhage, and the importance of a smooth extubation. The anesthesiologist is able to assist the surgeons by keeping the patient motionless and lowering the blood pressure to minimize surgical bleeding. Postoperative nausea and vomiting are also of greater importance than usual, as the Valsalva movements associated with retching could cause bleeding and disruption of the surgical site.