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We have investigated the gas-phase fragmentation reactions of 11 synthetic 4-aryl-3,4-dihydrocoumarins by electrospray ionization tandem mass spectrometry (ESI-MS/MS) on a quadrupole-time-of flight (Q-TOF) hybrid mass spectrometer. We have also estimated thermochemical data for the protonated coumarins (precursor ion A) and product ion structures by computational chemistry at a B3LYP level of theory to establish the ion structures and to rationalize the fragmentation pathways. The most abundant ions in the product ion spectra of coumarins 1-11 resulted from C8H8O2, CO2, C4H4O3, C8H10O3, C8H8O2, and CH3OH eliminations through retro-Diels-Alder (RDA) reactions, remote hydrogen rearrangements (ß-eliminations), and ß-lactone ring contraction. Although the investigated coumarins shared most of the fragmentation pathways, formation of a benzylic product ion and its corresponding tropylium ion was diagnostic of the substituents at ring C. The thermochemical data revealed that the nature and position of the substituents at ring C played a key role in the formation of this product ion and determined its relative intensity in the product ion spectrum. The results of this study contribute to knowledge of the gas-phase ion chemistry of this important class of organic compounds.
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Chagas disease is a neglected tropical disease that affects more than 8 million people. Although there are therapies against this disease, the search for new drugs is important because the current treatments show limited effectiveness and high toxicity. In this work, eighteen dihydrobenzofuran-type neolignans (DBNs) and two benzofuran-type neolignans (BNs) were synthesized and evaluated against amastigote forms of two Trypanosoma cruzi strains. The in vitro cytotoxicity and hemolytic activity of the most active compounds were also evaluated and their relationships with T. cruzi tubulin DBNs were investigated by an in silico approach. Four DBNs demonstrated activity against the T. cruzi Tulahuen lac-Z strain (IC50 from 7.96 to 21.12 µM), and DBN 1 exhibited the highest activity against the amastigote forms of the T. cruzi Y strain (IC50 3.26 µM). Compounds 1-4 showed CC50 values higher than antitrypanosomal activities, except for DBN 3. All DBNs with antitrypanosomal activity demonstrated CH50 higher than 100 µM. The in silico results indicated that DBNs 1, 2, and 4 are capable of destabilizing the dynamics of the tubulin-microtubule from the vinca site. These compounds displayed promising in vitro activity against T. cruzi, especially compound 1, and can be considered molecular prototypes for the development of new antiparasitic drugs.
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BACKGROUND: Previous studies have reported healthcare disparities in the Texas-Mexico border population. Our aim was to evaluate treatment utilization and oncologic outcomes of colon cancer patients in this vulnerable population. METHODS: Patients with localized and regional colon cancer (CC) were identified in the Texas Cancer Registry (1995-2016). Clinicopathological data, hospital factors, receipt of optimal treatment, and overall survival (OS) were compared between Texas-Mexico Border (TMB) and the Non-Texas-Mexico Border (NTMB) cohorts. Multivariable analysis was performed to identify risk factors associated with decreased survival. RESULTS: We identified 43,557 patients with localized/regional CC (9% TMB and 91% NTMB). TMB patients were more likely to be Hispanic (73% versus 13%), less likely to have private insurance (13% versus 21%), were more often treated at safety net hospitals (82% versus 22%) and less likely at ACS-CoC accredited hospitals (32% versus 57%). TMB patients were more likely to receive suboptimal treatment (21% versus 16%) and had a lower median OS for localized (8.58 versus 9.58 y) and regional colon cancer (5.75 versus 6.18 y, all P < 0.001). In multivariable analysis, TMB status was not associated with worse OS. Factors associated with worse survival included receipt of suboptimal treatment, Medicare/insured status, and treatment in safety net and non-accredited ACS-CoC hospitals (all P < 0.001) CONCLUSIONS: While TMB CC patients had worse OS, TMB status itself was not found to be a risk factor for decreased survival. This survival disparity is likely associated with higher rate of suboptimal treatment, Medicare/Uninsured status, and decreased access to ACS-CoC accredited hospitals.
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Neoplasias do Colo , Medicare , Idoso , Neoplasias do Colo/terapia , Disparidades em Assistência à Saúde , Humanos , México , Texas/epidemiologia , Estados UnidosRESUMO
OBJECTIVES: This study aims to present the outcomes of our decade-long experience of robotic pancreatoduodenectomy and provide insights into successful program implementation. BACKGROUND: Despite significant improvement in mortality over the past 30 years, morbidity following open pancreatoduodenectomy remains high. We implemented a minimally invasive pancreatic surgery program based on the robotic platform as one potential method of improving outcomes for this operation. METHODS: A retrospective review of a prospectively maintained institutional database was performed to identify patients who underwent robotic pancreatoduodenectomy (RPD) between 2008 and 2017 at the University of Pittsburgh. RESULTS: In total, 500 consecutive RPDs were included. Operative time, conversion to open, blood loss, and clinically relevant postoperative pancreatic fistula improved early in the experience and have remained low despite increasing complexity of case selection as reflected by increasing number of patients with pancreatic cancer, vascular resections, and higher Charlson Comorbidity scores (all P<0.05). Operating room time plateaued after 240 cases at a median time of 391 minutes (interquartile rang 340-477). Major complications (Clavien >2) occurred in less than 24%, clinically relevant postoperative pancreatic fistula in 7.8%, 30- and 90-day mortality were 1.4% and 3.1% respectively, and median length of stay was 8 days. Outcomes were not impacted by integration of trainees or expansion of selection criteria. CONCLUSIONS: Structured implementation of robotic pancreatoduodenectomy can be associated with excellent outcomes. In the largest series of RPD, we establish benchmarks for the surgical community to consider when adopting this approach.
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Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/estatística & dados numéricos , Procedimentos Cirúrgicos Robóticos/estatística & dados numéricos , Idoso , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
RATIONALE: Although dihydrobenzofuran neolignans (DBNs) display a wide diversity of biological activities, the identification of their in vivo metabolites using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) remains a challenge to be overcome. Recently, ESI-MS/MS data of protonated DBNs have been reported, but they were shown to be limited due to the scarcity of diagnostic ions. METHODS: The gas-phase fragmentation pathways of a series of biologically active synthetic benzofuran neolignans (BNs) and DBNs were elucidated by means of negative ESI accurate-mass tandem and sequential mass spectrometry, and thermochemical data estimated using computational chemistry and the B3LYP/6-31+G(d,p) model. RESULTS: Deprotonated DBNs produced more diagnostic product ions than the corresponding protonated molecules. Moreover, a series of odd-electron product ions (radical anions) were detected, which has not been reported for protonated DBNs. Direct C2 H3 O2 ⢠elimination from the precursor ion (deprotonated molecule) only occurred for the BNs and can help to distinguish these compounds from the DBNs. The mechanism through which the [M - H - CH3 OH]- ion is formed is strongly dependent on specific structural features. CONCLUSIONS: The negative ion mode provides much more information than the positive ion mode (at least one diagnostic product ion was detected for all the analyzed compounds) and does not require the use of additives to produce the precursor ions (deprotonated molecules).
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Asthma is a chronic inflammatory disease that represents high hospitalizations and deaths in world. Copaiba oil (CO) is popularly used for relieving asthma symptoms and has already been shown to be effective in many inflammation models. This study aimed to investigate the immunomodulatory relationship of CO in ovalbumin (OVA)-induced allergic asthma. The composition of CO sample analyzed by GC and GC-MS and the toxicity test was performed in mice at doses of 50 or 100 mg/kg (by gavage). After, the experimental model of allergic asthma was induced with OVA and mice were orally treated with CO in two pre-established doses. The inflammatory infiltrate was evaluated in bronchoalveolar lavage fluid (BALF), while cytokines (IL-4, IL-5, IL-17, IFN-γ, TNF-α), IgE antibody and nitric oxide (NO) production was evaluated in BALF and lung homogenate (LH) of mice, together with the histology and histomorphometry of the lung tissue. CO significantly attenuated the number of inflammatory cells in BALF, suppressing NO production and reducing the response mediated by TH2 and TH17 (T helper) cells in both BALF and LH. Histopathological and histomorphometric analysis confirmed that CO significantly reduced the numbers of inflammatory infiltrate in the lung tissue, including in the parenchyma area. Our results indicate that CO has an effective in vivo antiasthmatic effect.
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Anti-Inflamatórios/administração & dosagem , Asma/tratamento farmacológico , Fabaceae/química , Óleos Voláteis/administração & dosagem , Óleos de Plantas/administração & dosagem , Administração Oral , Animais , Anti-Inflamatórios/toxicidade , Asma/sangue , Asma/imunologia , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Camundongos , Óxido Nítrico/metabolismo , Óleos Voláteis/toxicidade , Ovalbumina/imunologia , Óleos de Plantas/toxicidade , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Testes de Toxicidade AgudaRESUMO
Objectives: Cutaneous leishmaniasis is a neglected disease, associated with high morbidity, which is partially due to the toxicity of available therapies. The pentavalent antimonial derivatives intralesional infiltration has proven to be as effective as the intravenous drug-based therapy, however, there is a lack of robust safety data.Methods: Phase II, uncontrolled, unicenter clinical trial to assess the safety profile of a standardized meglumine antimionate intralesional therapy, based on weekly infiltrations.Results: Fifty-three patients were studied, predominantly men (60%) and young adults (43.7 ± 17.1 years). Overall, 86.9% of the patients had at least one clinical adverse event. Local events were the most frequent (83%), followed by systemic ones (47.3%). Fourteen participants (26%) presented biochemical abnormalities. In all cases, laboratorial alterations were classified as mild and treatment discontinuation was not required. Differently, the two hypersensitivity (3.8%) reactions observed led to permanent treatment interruption. QTc interval prolongation was recorded in 14 patients (25.5%). The following risk associations to adverse events were identified in the multiple analysis: hypertension with systemic clinical events and smoking with QT interval prolongation.Expert commentary: In general, MA-IL was well tolerated and although associated with local and systemic adverse events, there was a low risk of high intensity or severe complications.
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Antiprotozoários/administração & dosagem , Leishmaniose Cutânea/tratamento farmacológico , Antimoniato de Meglumina/administração & dosagem , Adulto , Antiprotozoários/efeitos adversos , Hipersensibilidade a Drogas/etiologia , Feminino , Humanos , Injeções Intralesionais , Masculino , Antimoniato de Meglumina/efeitos adversos , Pessoa de Meia-Idade , RiscoRESUMO
OBJECTIVE: To determine the impact of enhanced recovery after surgery (ERAS) pathway implementation on outcomes, and cost of robotic and open pancreatoduodenectomy. BACKGROUND: ERAS pathways have shown benefit in open pancreatoduodenectomy (OPD). The impact of ERAS on robotic pancreatoduodenectomy (RPD) is unknown. METHODS: Retrospective review of consecutive RPD and OPDs in the pre-ERAS (July, 2014-July, 2015) and ERAS (July, 2015-July, 2016) period. Univariate and multivariate logistic regression was used to determine impact of ERAS and operative approach alone, or in combination (pre-ERASâ+âOPD, pre-ERASâ+âRPD, ERASâ+âOPD, ERASâ+âRPD) on length of hospital stay (LOS) and overall cost. RESULTS: In all, 254 consecutive pancreatoduodenectomies (RPD 62%, OPD 38%) were analyzed (median age 67, 47% female). ERAS patients had shorter LOS (6 vs 8 days; P = 0.004) and decreased overall cost (USD 20,362 vs 24,277; P = 0.001) compared with non-ERAS patients, whereas RPD was associated with decreased LOS (7 vs 8 days; P = 0.0001) and similar cost compared with OPD. On multivariable analysis (MVA), RPD was predictive of shorter LOS [odds ratio (OR) 0.33, confidence interval (CI) 0.16-0.67, P = 0.002), whereas ERAS was protective against high cost (OR 0.57, CI 0.33-0.97, P = 0.037). On MVA, when combining operative approach with ERAS pathway use, a combined ERASâ+âRPD approach was associated with reduced LOS and optimal cost compared with other combinations (pre-ERASâ+âOPD, pre-ERASâ+âRPD, ERASâ+âOPD). CONCLUSION: ERAS implementation is independently associated with cost savings for pancreatoduodenectomy. A combination of ERAS and robotic approach synergistically decreases hospital stay and overall cost compared with other strategies.
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Recuperação Pós-Cirúrgica Melhorada , Custos de Cuidados de Saúde , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/economia , Procedimentos Cirúrgicos Robóticos/economia , Idoso , Procedimentos Clínicos/economia , Feminino , Humanos , Tempo de Internação/economia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
AIMS: To determine the prevalence and potential risk factors for diabetic peripheral neuropathy with a loss of protective sensation in Barbados. METHODS: A representative population sample aged > 25 years with previously diagnosed diabetes or a fasting blood glucose ≥ 7 mmol/l or HbA1c ≥ 48 mmol/mol (6.5%) was tested by 10 g monofilament at four plantar sites per foot and a 28 Hz tuning fork and neurothesiometer at the hallux. Data were adjusted to the age structure of people with diabetes in Barbados. Multivariable logistic regression assessed associations with peripheral neuropathy with a loss of protective sensation. RESULTS: Of 236 participants [74% response rate, 33% men, 91% black, median age 58.6 years, mean BMI 30.1 kg/m2 , mean HbA1c 54 mmol/mol (7.1%)], 51% had previously diagnosed diabetes. Foot examination demonstrated that 25.8% (95% CI 20.2 to 31.5) had at least one insensate site with monofilament testing, 14.8% (95% CI 10.2 to 19.4) had an abnormal tuning fork test and 10.9% (95% CI 6.9 to 14.9) had a vibration perception threshold > 25 V. Peripheral neuropathy with a loss of protective sensation prevalence was 28.5% (95% CI 22.7 to 34.4) as indicated by monofilament with ≥ 1 insensate site and/or vibration perception threshold > 25 V. With previously diagnosed diabetes the prevalence was 36.4% (95% CI 27.7 to 45.2) with 98.4% of cases identified by monofilament testing. Increasing age, previously diagnosed diabetes, male sex and abdominal obesity were independently associated with peripheral neuropathy with a loss of protective sensation. CONCLUSIONS: Over a third of people with previously diagnosed diabetes had evidence of peripheral neuropathy with a loss of protective sensation. Monofilament testing alone may be adequate to rule out peripheral neuropathy with a loss of protective sensation. Monofilament and neurothesiometer stimuli are reproducible but dependent on participant response.
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Neuropatias Diabéticas/epidemiologia , Transtornos de Sensação/etiologia , Tato , Adulto , África/etnologia , Idoso , Idoso de 80 Anos ou mais , Barbados/epidemiologia , Glicemia/análise , Estudos Transversais , Diabetes Mellitus/sangue , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/fisiopatologia , Pé Diabético/diagnóstico , Pé Diabético/fisiopatologia , Neuropatias Diabéticas/complicações , Feminino , Pé/inervação , Hemoglobinas Glicadas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Transtornos de Sensação/epidemiologiaRESUMO
INTRODUCTION: The safety, efficacy, and learning curve for robotic pancreatoduodenecomy has been reported; however, the outcomes and learning curve of robotic pancreatoduodenecomy with vascular resections remain unknown. Our aim was to evaluate the outcomes of robotic pancreatoduodenecomy with vascular resections compared with robotic pancreatoduodenecomy without vascular resection and to identify the learning curve and benchmarks for improved performance during robotic pancreatoduodenecomy with vascular resections. METHODS: A retrospective review of consecutive patients who underwent robotic pancreatoduodenecomy with vascular resections and robotic pancreatoduodenecomy between 2011 and 2017. Patients were analyzed consecutively, and a cumulative sum analysis was performed to detect improvements in performance over time. RESULTS: Of 380 consecutive robotic pancreatoduodenecomy patients, 50 (13%) underwent robotic pancreatoduodenecomy with vascular resections. Compared with robotic pancreatoduodenecomy, robotic pancreatoduodenecomy with vascular resections were more likely to have had pancreatic adenocarcinoma (84% vs 42%) and had received neoadjuvant therapy (35% vs 65%, P < .01). Robotic pancreatoduodenecomy with vascular resections operative time revealed a steady, significant decrease (Rho = -0.38, p = .006) with marked initial improvement after the first 8 cases and maturation of the learning curve after 35 cases. A significant decrease in duration of the hospital stay was observed throughout the experience (Rho = -0.528, P < .0001), whereas margin status, pancreatic fistula, major morbidity, and mortality remained constant and comparable to robotic pancreatoduodenecomy alone. CONCLUSION: Robotic pancreatoduodenectomy with vascular resections is safe and feasible. For surgeons who have surpassed the learning curve of robotic pancreatoduodenectomy, it appears that improvements in performance of robotic pancreatoduodenecomy with vascular resections can be observed after 35 cases.
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Adenocarcinoma/cirurgia , Curva de Aprendizado , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Procedimentos Cirúrgicos Vasculares/métodos , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Terapia Combinada , Bases de Dados Factuais , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Avaliação de Resultados em Cuidados de Saúde , Pâncreas/irrigação sanguínea , Pâncreas/cirurgia , Fístula Pancreática/etiologia , Fístula Pancreática/fisiopatologia , Fístula Pancreática/cirurgia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia/efeitos adversos , Pancreaticoduodenectomia/mortalidade , Segurança do Paciente/estatística & dados numéricos , Seleção de Pacientes , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/fisiopatologia , Prognóstico , Estudos Retrospectivos , Medição de Risco , Procedimentos Cirúrgicos Robóticos/mortalidade , Análise de Sobrevida , Resultado do Tratamento , Estados UnidosRESUMO
We have investigated gas-phase fragmentation reactions of protonated benzofuran neolignans (BNs) and dihydrobenzofuran neolignans (DBNs) by accurate-mass electrospray ionization tandem and multiple-stage (MSn ) mass spectrometry combined with thermochemical data estimated by Computational Chemistry. Most of the protonated compounds fragment into product ions B ([M + H-MeOH]+ ), C ([B-MeOH]+ ), D ([C-CO]+ ), and E ([D-CO]+ ) upon collision-induced dissociation (CID). However, we identified a series of diagnostic ions and associated them with specific structural features. In the case of compounds displaying an acetoxy group at C-4, product ion C produces diagnostic ions K ([C-C2 H2 O]+ ), L ([K-CO]+ ), and P ([L-CO]+ ). Formation of product ions H ([D-H2 O]+ ) and M ([H-CO]+ ) is associated with the hydroxyl group at C-3 and C-3', whereas product ions N ([D-MeOH]+ ) and O ([N-MeOH]+ ) indicate a methoxyl group at the same positions. Finally, product ions F ([A-C2 H2 O]+ ), Q ([A-C3 H6 O2 ]+ ), I ([A-C6 H6 O]+ ), and J ([I-MeOH]+ ) for DBNs and product ion G ([B-C2 H2 O]+ ) for BNs diagnose a saturated bond between C-7' and C-8'. We used these structure-fragmentation relationships in combination with deuterium exchange experiments, MSn data, and Computational Chemistry to elucidate the gas-phase fragmentation pathways of these compounds. These results could help to elucidate DBN and BN metabolites in in vivo and in vitro studies on the basis of electrospray ionization ESI-CID-MS/MS data only.
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Copaifera (Leguminoseae) species produce a commercially interesting oleoresin that displays several biological activities, including antimicrobial and anti-inflammatory properties. Labdane-type diterpenes are the main chemical constituents of these oleoresins, and copalic acid is the only compound that has been detected in all Copaifera oleoresins. In this study, we investigate some aspects of the gas-phase fragmentation reactions involved in the formation of the product ions from the deprotonated compounds (-)-ent-copalic acid (1), (-)-ent-3ß-hydroxy-copalic acid (2), (-)-ent-3ß-acetoxy-copalic acid (3), and (-)-ent-agathic acid (4) by electrospray ionization tandem mass spectrometry (ESI-MS/MS) and multiple stage mass spectrometry (MSn ). Our results reveal that the product ion with m/z 99 is common to all the analyzed compounds, whereas the product ion with m/z 217 is diagnostic for compounds 2 and 3. Moreover, only compound 4 undergoes CO2 (44 u) and acetic acid (60 u) elimination from the precursor ion. Thermochemical data obtained by computational chemistry at the B3LYP/6-31G(d) level of theory support the proposed ion structures. These data helped us to identify these compounds in a crude commercial Copaifera langsdorffii oleoresin by selective multiple reaction monitoring (MRM). Finally, a precursor ion scan (PIS) strategy aided screening of labdane-type acid diterpenes other than 1 to 4 in the same Copaifera oleoresin sample and led us to propose the structures of 8,17-dihydro-ent-agathic acid (5) and 3-keto-ent-copalic acid (6), which have not been previously reported in Copaifera oleoresins.
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Diterpenos/análise , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Antibacterianos/análise , Bálsamos/análise , Cromatografia Líquida de Alta Pressão , Fabaceae/química , Modelos Moleculares , Estrutura Molecular , Extratos Vegetais/químicaRESUMO
We have evaluated the antischistosomal activity of synthetic dihydrobenzofuran neolignans (DBNs) derived from (±)-trans-dehydrodicoumaric acid dimethyl ester (1) and (±)-trans-dehydrodiferulic acid dimethyl ester (2) against adult Schistosoma mansoni worms in vitro. Compound 4 ((±)-trans-4-O-acetyldehydrodiferulic acid dimethyl ester) displayed the most promising activity; at 200 µm, it kills 100 ± 0% of worms after 24 h, which resembles the result achieved with praziquantel (positive control) at 1.56 µm. The hydrogenation of the double bond between C7' and C8', the introduction of an additional methyl group at C3', and a double bond between C7 and C8 decreased the schistosomicidal activity of DBNs. On the other hand, the presence of the acetoxy group at C4 played an interesting role in this activity. These results demonstrated the interesting schistosomicidal potential of DBNs, which could be further exploited.
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Lignanas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomicidas/farmacologia , Animais , Relação Dose-Resposta a Droga , Lignanas/síntese química , Lignanas/química , Estrutura Molecular , Esquistossomicidas/síntese química , Esquistossomicidas/químicaRESUMO
Background: Postoperative ambulation is encouraged to promote timely recovery but is rarely monitored objectively or examined as a predictor of clinical outcomes, despite growing availability of wearable devices that allow passive quantification and remote real-time monitoring of the number of steps taken during recovery. Purpose: To determine whether the number of steps taken during inpatient recovery predicts 30- and 60-day readmission risk after metastatic cancer surgery. Methods: Patients diagnosed with metastatic peritoneal cancer and scheduled for surgical resection were enrolled in this observational cohort study at their preoperative clinic visit. Fitbits were placed on patients' wrists upon transfer from the ICU following surgery and worn for the duration of their inpatient stay. Information about hospital readmission was extracted from electronic medical records. Results: Seventy-one patients participated in the study (mean age = 57.14, range = 31-80 years; 42% female; 51% diagnosed with appendiceal cancer). Mean steps per day were calculated for each participant over the entire inpatient recovery period (mean stay = 12.12 days, 4-37 days). Readmission within 30 and 60 days was medically indicated for 34% and 39% of patients, respectively. After statistically adjusting for age, body mass index, comorbidity, and length of postoperative stay, higher mean steps per day predicted lower 30-day and 60-day readmission risk. Conclusions: Higher Fitbit step counts during inpatient recovery predicted lower risk of 30- and 60-day readmission after surgery for metastatic peritoneal cancer. Results suggest that passively monitoring perioperative ambulation may identify patients at risk for readmission and highlight opportunities for behavioral intervention.
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Pacientes Internados/estatística & dados numéricos , Readmissão do Paciente/estatística & dados numéricos , Neoplasias Peritoneais/cirurgia , Caminhada/estatística & dados numéricos , Dispositivos Eletrônicos Vestíveis , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Peritoneais/secundário , Período Pós-OperatórioRESUMO
We investigate the chemical composition and the in vitro antileishmanial and cytotoxic activities of the essential oils extracted from the leaves of Ocotea dispersa (Nees) Mez (OD-EO) and Ocotea odorifera (Vell) Rohwer (OO-EO). On the basis of GC-FID and GC-MS, α-eudesmol (20.9%), valencene (10.2%), δ-elemene (9.3%) and isospathulenol (7.3%) are the major constituents of OD-EO, whereas safrole (36.3%), γ-cadinene (6.6%), camphor (6.5%) and α-copaene (6.0%) are the main constituents of OO-EO. Both OD-EO and OO-EO display significant activity against the promastigote forms of Leishmania amazonensis, with IC50 values of 4.67 ± 0.95 and 11.67 ± 2.16 µg/mL, respectively. The 50% cytotoxic concentration (CC50) of OD-EO and OO-EO to mouse peritoneal macrophages is 26.77 ± 4.06 and 49.52 ± 1.04 µg/mL, respectively. This is the first report on the chemical composition of the essential oil extracted from the leaves of O. dispersa. Our results suggest that OD-EO and OO-EO are a promising source of new antileishmanial agents.
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Ocotea/química , Óleos Voláteis/química , Animais , Morte Celular/efeitos dos fármacos , Lauraceae/química , Leishmania/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Óleos Voláteis/farmacologia , Extratos Vegetais/química , Folhas de Planta/química , Sesquiterpenos Policíclicos , SesquiterpenosRESUMO
Although some progress has been made in recent years with the development of more effective chemotherapy regimens, new treatment approaches are needed to improve outcomes for patients with pancreatic adenocarcinoma. The cellular process of autophagy, a cell survival mechanism that allows cancer cells to survive the hazardous conditions of the tumor microenvironment and treatment, has emerged as a viable target in pancreatic cancer. We review the mechanism of autophagy, its role in pancreatic carcinogenesis, the preclinical and clinical evidence supporting targeting autophagy in patients with pancreatic adenocarcinoma, and areas of future investigation that hold promise for improving this treatment approach.
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Adenocarcinoma/patologia , Autofagia/fisiologia , Neoplasias Pancreáticas/patologia , Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias PancreáticasRESUMO
BACKGROUND: Various strategies to decrease postoperative pancreatic fistula after a distal pancreatectomy have proved unsuccessful. Because narcotics can cause spasm of the sphincter of Oddi and thereby increase pressure within the pancreatic duct stump, we hypothesized that increased narcotic use would be associated with increased occurrence of clinically relevant postoperative pancreatic fistula after distal pancreatectomy. METHODS: Retrospective analysis of consecutive distal pancreatectomies (2011-2016) was performed. Postoperative narcotic use was calculated in morphine equivalents. Postoperative pancreatic fistula was graded according to the International Study Group on Pancreatic Surgery. Perioperative variables were evaluated using multivariate logistic regression with clinically relevant postoperative pancreatic fistula as the dependent outcome. RESULTS: In the study, 310 distal pancreatectomies were analyzed (61% robotic, 20% open, 19% laparoscopic). Average age was 62 (53% female), and median total dose of morphine equivalents was 424 mg (interquartile range 242-768). Clinically relevant postoperative pancreatic fistula occurred in 21.6%. Clinically relevant postoperative pancreatic fistula and not clinically relevant postoperative pancreatic fistula cohorts were similar in most demographics and operative variables, but clinically relevant postoperative pancreatic fistula patients had fewer stapled transections (80 vs 90%, P=.025), less pancreatic cancers (11 vs 35%, P<.001), and greater median total morphine equivalents (577 vs 403 mg, P < .009). On univariate analysis, clinically relevant postoperative pancreatic fistula was associated with body mass index, nonstapled transection, suture ligation of the PD, a nonpancreatic cancer pathology, prophylactic octreotide, and total morphine equivalents >424 (cohort median). On multivariate analysis, only pancreatic cancer pathology was protective against a clinically relevant postoperative pancreatic fistula (odds ratio 0.24, confidence interval, 0.10-0.50, P=.001), while increasing total morphine equivalents were predictive of a clinically relevant postoperative pancreatic fistula (odds ratio 1.13, confidence interval, 1.01-1.27, P=.035) with a 13% increased risk for every approximate ≈100 mg increase in total morphine equivalents. CONCLUSION: In this retrospective analysis, postoperative narcotic use was associated with the development of clinically relevant postoperative pancreatic fistula after distal pancreatectomy. Limiting narcotic use may be one of the few available mitigating strategies against the development of a clinically relevant postoperative pancreatic fistula after distal pancreatectomy.
Assuntos
Entorpecentes/uso terapêutico , Pancreatectomia/efeitos adversos , Fístula Pancreática/etiologia , Neoplasias Pancreáticas/cirurgia , Complicações Pós-Operatórias/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
We investigated the gas-phase fragmentation reactions of a series of 2-aroylbenzofuran derivatives by electrospray ionization tandem mass spectrometry (ESI-MS/MS). The most intense fragment ions were the acylium ions m/z 105 and [M+H-C6 H6 ]+ , which originated directly from the precursor ion as a result of 2 competitive hydrogen rearrangements. Eliminations of CO and CO2 from [M+H-C6 H6 ]+ were also common fragmentation processes to all the analyzed compounds. In addition, eliminations of the radicals â¢Br and â¢Cl were diagnostic for halogen atoms at aromatic ring A, whereas eliminations of â¢CH3 and CH2 O were useful to identify the methoxyl group attached to this same ring. We used thermochemical data, obtained at the B3LYP/6-31+G(d) level of theory, to rationalize the fragmentation pathways and to elucidate the formation of E, which involved simultaneous elimination of 2 CO molecules from B.
RESUMO
We have investigated the chemical composition and the antibacterial activity of the essential oil of Dysphania ambrosioides (L.) Mosyakin & Clemants (Chenopodiaceae) (DA-EO) against a representative panel of cariogenic bacteria. We have also assessed the in vitro schistosomicidal effects of DA-EO on Schistosoma mansoni and its cytotoxicity to GM07492-A cells in vitro. Gas chromatography (GC) and gas chromatography-mass spectrometry (GC/MS) revealed that the monoterpenes cis-piperitone oxide (35.2%), p-cymene (14.5%), isoascaridole (14.1%), and α-terpinene (11.6%) were identified by as the major constituents of DA-EO. DA-EO displayed weak activity against Streptococcus sobrinus and Enterococcus faecalis (minimum inhibitory concentration (MIC) = 1000 µg/ml). On the other hand, DA-EO at 25 and 12.5 µg/ml presented remarkable schistosomicidal action in vitro and killed 100% of adult worm pairs within 24 and 72 h, respectively. The LC50 values of DA-EO were 6.50 ± 0.38, 3.66 ± 1.06, and 3.65 ± 0.76 µg/ml at 24, 48, and 72 h, respectively. However, DA-EO at concentrations higher than 312.5 µg/ml significantly reduced the viability of GM07492-A cells (IC50 = 207.1 ± 4.4 µg/ml). The selectivity index showed that DA-EO was 31.8 times more toxic to the adult S. mansoni worms than GM07492-A cells. Taken together, these results demonstrate the promising schistosomicidal potential of the essential oil of Dysphania ambrosioides.