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Aminopyrrolnitrin (APRN), a natural halogenated phenylpyrrole derivative (HPD), has strong antifungal and antiparasitic activities. Additionally, it showed 2.8-fold increased photostability compared to pyrrolnitrin, a commercially available HPD with antimicrobial activity. For microbial production of APRN, we first engineered anthranilate phosphoribosyltransferase encoded by trpD from Corynebacterium glutamicum, resulting in a TrpDA162D mutation that exhibits feedback-resistant against L-tryptophan and higher substrate affinity compared to wild-type TrpD. Plasmid-borne expression of trpDA162D in C. glutamicum TP851 strain with two copies of trpDA162D in the genome led to the production of 3.1 g/L L-tryptophan in flask culture. Subsequent step for L-tryptophan chlorination into 7-chloro-L-tryptophan was achieved by introducing diverse sources of genes encoding tryptophan 7-halogenase (PrnA or RebH) and flavin reductase (Fre, PrnF, or RebF). The combined expression of prnA from Serratia grimesii or Serratia plymuthica with flavin reductase gene from Escherichia coli, Pseudomonas fluorescens, or Lechevalieria aerocolonigenes yielded higher production of 7-chloro-L-tryptophan in comparison to other sets of two-component systems. In the next step, production of putative monodechloroaminopyrrolnitrin (MDAP) from 7-chloro-L-tryptophan was achieved through the expression of prnB encoding MDAP synthase from S. plymuthica or P. fluorescens. Finally, an artificial APRN biosynthetic pathway was constructed by simultaneously expressing genes coding for tryptophan 7-halogenase, flavin reductase, MDAP synthase, and MDAP halogenase (PrnC) from different microbial sources within the L-tryptophan-producing TP851 strain. As prnC from S. grimesii or S. plymuthica was introduced into the host strain, which carried plasmids expressing prnA from S. plymuthica, fre from E. coli, and prnB from S. plymuthica, APN3639 and APN3638 accumulated 29.5 mg/L and 28.1 mg/L of APRN in the culture broth. This study represents the first report on the fermentative APRN production by metabolically engineered C. glutamicum.
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Corynebacterium glutamicum , Engenharia Metabólica , Corynebacterium glutamicum/metabolismo , Corynebacterium glutamicum/genética , Engenharia Metabólica/métodos , Pirrolnitrina/biossíntese , Pirrolnitrina/metabolismo , Fermentação , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Triptofano/biossíntese , Triptofano/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , OxirredutasesRESUMO
Patients with ovarian cancer have a high risk of developing thrombosis. We aimed to investigate pre and post operative biomarkers associated with thrombosis including deep vein thrombosis and pulmonary thromboembolism in patients treated for ovarian cancer. We collected pre and post operative blood samples from 133 patients undergoing surgery for ovarian cancer between December 2021 and August 2022. The measured parameters were white blood cell count, hemoglobin, platelets, monocytes, serum glucose, CA125, D-dimer, fibrinogen, prothrombin time, activated partial thromboplastin time, fibrinogen degradation products, antithrombin III, protein C, protein S, plasminogen, plasminogen activator inhibitor 1, homocysteine, N-terminal pro-brain natriuretic peptide, interleukin 6, thrombopoietin, soluble P-selectin and granulocyte stimulating factor. Body mass index of patients were collected. Differences between patients who developed thrombosis and those without were compared with Wilcoxon rank-sum test and we analyzed the continuous variables using logistic regression. Twenty-one (15.8%) patients developed thrombosis ranging from 6 to 146 days (median 15 days) after surgery. Pre operative values of homocysteine (p = 0.033) and IL-6 (p = 0.043) were significantly increased and post operative aPTT (p = 0.022) was prolonged and plasminogen (p = 0.041) was decreased in patients with thrombosis. It is important to find novel biomarkers for thrombosis to carefully manage patients who are prone to develop thrombosis despite preventive measures were applied.
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Neoplasias Ovarianas , Trombose , Humanos , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrinogênio/metabolismo , Trombose/etiologia , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/cirurgia , Plasminogênio , Biomarcadores , HomocisteínaRESUMO
We evaluated the metabolic effects of gastrectomies and endoscopic submucosal dissections (ESDs) in early gastric cancer (EGC) patients with type 2 diabetes mellitus (T2DM). Forty-one EGC patients with T2DM undergoing gastrectomy or ESD were prospectively evaluated. Metabolic parameters in the patients who underwent gastrectomy with and without a duodenal bypass (groups 1 and 2, n = 24 and n = 5, respectively) were compared with those in patients who underwent ESD (control, n = 12). After 1 year, the proportions of improved/equivocal/worsened glycemic control were 62.5%/29.2%/8.3% in group 1, 40.0%/60.0%/0.0% in group 2, and 16.7%/50.0%/33.3% in the controls, respectively (p = 0.046). The multivariable ordered logistic regression analysis results showed that both groups had better 1-year glycemic control. Groups 1 and 2 showed a significant reduction in postprandial glucose (-97.9 and -67.8 mg/dL), body mass index (-2.1 and -2.3 kg/m2), and glycosylated hemoglobin (group 1 only, -0.5% point) (all p < 0.05). Furthermore, improvements in group 1 were more prominent when preoperative leptin levels were high (p for interaction < 0.05). Metabolic improvements in both groups were also observed for insulin resistance, leptin, plasminogen activator inhibitor-1, and resistin. Gastrectomy improved glycemic control and various metabolic parameters in EGC patients with T2DM. Patients with high leptin levels may experience greater metabolic benefits from gastrectomy with duodenal bypass.
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PURPOSE: Cardiotoxicities are adverse effects often reported in chemotherapy-treated breast cancer patients. This study evaluated the potential risk factors and cumulative incidence of doxorubicin-induced cardiotoxicity in Korean breast cancer patients. METHODS: We retrospectively analyzed the data of 613 breast cancer patients who underwent a multigated acquisition (MUGA) scan or echocardiography prior to chemotherapy and at least one post-chemotherapy follow-up MUGA scan/echocardiography between 2007 and 2016 at National Cancer Center, Korea. The Cox proportional hazards models were used to evaluate cardiotoxicity risks. Competing risks analyses were performed to estimate cumulative incidence of cardiotoxicity. RESULTS: Risk factors associated with cardiotoxicity within 2 years of doxorubicin administration included age [adjusted hazard ratio (aHR) = 1.02, 95% confidence interval (CI) 1.00-1.04; p = 0.05], metastasis (aHR = 2.66; 95% CI 1.36-5.20; p < 0.01), and concomitant trastuzumab (aHR = 4.08; 95% CI 2.31-7.21; p < 0.01). The cumulative incidence of patients with cardiotoxicity was 6.1% at 2 years (without substantial change from about 9 months)and 20.2% at 2 years (without substantial change from about 15 months) after initiation of doxorubicin-containing therapy without and with trastuzumab, respectively. CONCLUSIONS: Susceptibility to chemotherapy-induced cardiotoxicity within 2 years of doxorubicin initiation in breast cancer patients was elevated with old age, metastasis, and concomitant trastuzumab. Regular imaging monitoring at least up to 9 months after doxorubicin initiation in patients treated without concomitant trastuzumab, and 15 months in patients treated with concomitant trastuzumab, is needed for early detection of chemotherapy-induced cardiotoxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/terapia , Cardiotoxicidade/epidemiologia , Doxorrubicina/efeitos adversos , Trastuzumab/efeitos adversos , Adulto , Idoso , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/etiologia , Quimiorradioterapia Adjuvante/efeitos adversos , Quimiorradioterapia Adjuvante/métodos , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Relação Dose-Resposta a Droga , Ecocardiografia , Feminino , Seguimentos , Humanos , Incidência , Mastectomia , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
We report a phase I pharmacological study of an oral formulation of CKD-516, a vascular-disrupting agent, in patients with refractory solid tumors. Twenty-seven patients (16 in the dose-escalation cohort and 11 in the expansion cohort) received a single daily dose (5-25 mg) of CKD-516 five days per week. Nausea (67%) and diarrhea (63%) were the most common treatment-related adverse events. The recommended phase II dose of oral CKD-516 was 20 mg/d (15 mg/d with a body surface area (BSA) <1.65 m2 ). Notably, S-516 half-lives in patients receiving 15-20 mg CKD-516/d significantly differed between patients with and without splenomegaly that is suggestive of portal hypertension associated with liver cirrhosis (6.1 vs 4.6 hours, respectively). Of 11 patients without splenomegaly who completed at least one cycle of a daily CKD-516 dose of either 15 or 20 mg, only one patient (9.1%) suffered from any dose-limiting toxicity. We conclude that a daily oral dose of 15 or 20 mg CKD-516 five days per week could be tolerable in patients without liver cirrhosis.
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Antineoplásicos/farmacocinética , Benzofenonas/farmacocinética , Neoplasias/metabolismo , Valina/análogos & derivados , Administração Oral , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Benzofenonas/efeitos adversos , Benzofenonas/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Resultado do Tratamento , Valina/efeitos adversos , Valina/sangue , Valina/farmacocinética , Adulto JovemRESUMO
PURPOSE: We investigated the effect of gastrectomy on blood pressure (BP) in early gastric cancer survivors with hypertension and whether well-controlled BP was due solely to surgery-induced weight loss. METHODS: The study enrolled 66 early gastric cancer patients with hypertension, undergoing endoscopic submucosal dissection (ESD), or gastrectomy. Blood analyses, 24-h ambulatory BP monitoring, brachial ankle pulse wave velocity (baPWV), and echocardiography were measured prior to, 3 months after, and 1 year after ESD or gastrectomy. The primary endpoint was remission of hypertension at 1 year. RESULTS: The remission rate of hypertension was significantly higher in the gastrectomy group than in the ESD group (p = 0.006). Those with remission of hypertension had a significant weight loss (p < 0.001), decrease in body mass index (p < 0.001), 24-h total systolic BP (p = 0.047), baPWV (p = 0.042), triglycerides (p = 0.049) and apolipoprotein B/apolipoprotein A1 (p = 0.004), and an increase in high-density lipoprotein cholesterol (p < 0.001) at 1 year. Upon multivariate logistic regression analysis, gastrectomy [odds ratio (OR) = 7.77, 95% confidence interval (CI) = 2.05-35.89], diuretic use (OR = 3.76, 95% CI = 1.14-13.98), and lower 24-h total diastolic BP before treatment (OR = 0.90, 95% CI = 0.82-0.96) were predictive of remission of hypertension after adjusting for percent weight. CONCLUSIONS: In early gastric cancer survivors with hypertension, gastrectomy resulted in better BP control than did ESD, which may be due to the gastrectomy itself, beyond weight loss. Therefore, it should be remembered that the adequate reduction of antihypertensives may be necessary in early gastric cancer survivors after gastrectomy.
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Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/fisiologia , Gastrectomia/efeitos adversos , Hipertensão/etiologia , Neoplasias Gástricas/cirurgia , Redução de Peso/fisiologia , Idoso , Anti-Hipertensivos/farmacologia , Sobreviventes de Câncer , Feminino , Gastrectomia/métodos , Humanos , Hipertensão/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologiaRESUMO
AIM: To evaluate the effect of gastrectomy on diabetes mellitus (DM) and hypertension (HTN) in non-obese gastric cancer patients. METHODS: A total of 100000 patients, diagnosed with either type 2 DM or HTN, were randomly selected from the 2004 Korean National Health Insurance System claims. Among them, 360 diabetes and 351 hypertensive patients with gastric cancer who had been regularly treated without chemotherapy from January 2005 to December 2010 were selected. They were divided into three groups according to their treatment methods: total gastrectomy (TG), subtotal gastrectomy (STG) and endoscopic resection (ER). RESULTS: The drug discontinuation rate of anti-diabetic and anti-hypertensive agents after gastric cancer treatment was 9.7% and 11.1% respectively. DM appeared to be improved more frequently (22.8%) and earlier (mean±SE 28.6±1.8 mo) in TG group than in the two other groups [improved in 9.5% of ER group (37.4±1.1 mo) and 6.4% of STG group (47.0±0.8 mo)]. The proportion of patients treated with multiple drugs decreased more notably in TG group compared to others (P=0.001 in DM, and P=0.035 in HTN). In TG group, adjusted hazard ratio for the improvement of DM was 2.87 (95%CI: 1.15-7.17) in a multi-variate analysis and better control of DM was observed with survival analysis (P<0.001). CONCLUSION: TG was found to decrease the need for anti-diabetic medications which can be reflective of improved glycemic control, to a greater extent than either ER or STG in non-obese diabetic patients.
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Anti-Hipertensivos/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Gastrectomia , Hipertensão/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Neoplasias Gástricas/cirurgia , Idoso , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Distribuição de Qui-Quadrado , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/mortalidade , Quimioterapia Combinada , Feminino , Gastrectomia/efeitos adversos , Gastrectomia/métodos , Gastrectomia/mortalidade , Gastroscopia , Humanos , Hipertensão/diagnóstico , Hipertensão/mortalidade , Hipertensão/fisiopatologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Recuperação de Função Fisiológica , República da Coreia/epidemiologia , Estudos Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidade , Fatores de Tempo , Resultado do TratamentoRESUMO
PURPOSE: This study was conducted to evaluate the efficacy and safety of sunitinib in patients with relapsed or refractory small cell lung cancer (SCLC). PATIENTS AND METHODS: Eligibility included histologic or cytologic diagnosis of SCLC, ECOG PS of 0-2, cancer progression following one or two prior chemotherapy or chemo-radiotherapy (CRT) and adequate organ functions. Treatment regimen consisted of a 6-week cycle of sunitinib given as 50mg p.o. daily for 4 weeks followed by 2 weeks off. The primary end point was objective response rate (ORR). RESULTS: From March 2008 to October 2010, 25 patients were enrolled and 24 received treatment. The median age was 64.5 years; 22 patients (92%) were male. Eight patients (33%) displayed sensitive relapse. Seven patients (29%) received CRT and fifteen patients (63%) had received one prior chemotherapy. A median of 1 cycle (range 1-4) of sunitinib was administered, and 23 patients were evaluable for response. Two patients displayed partial response, and seven patients presented stable disease with a ORR of 9% (95% CI, 1-28%). The median progression-free (PFS) and overall survivals were 1.4 months (95% CI, 1.1-1.7) and 5.6 months (95% CI, 3.5-7.7), respectively. The common grade 3 or 4 toxicities included thrombocytopenia (63%), asthenia (29%) and neutropenia (25%). CONCLUSIONS: Although tumor response was noted in 2 patients, the median PFS was short and most patients were unable to tolerate the treatment. At the current dose schedule, sunitinib does not appear to warrant further evaluation.
Assuntos
Antineoplásicos/uso terapêutico , Indóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Pirróis/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Idoso , Antineoplásicos/efeitos adversos , Astenia/induzido quimicamente , Intervalo Livre de Doença , Feminino , Humanos , Indóis/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Pirróis/efeitos adversos , Sunitinibe , Trombocitopenia/induzido quimicamente , Resultado do TratamentoRESUMO
Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare, malignancy-related complication that causes marked pulmonary hypertension, right heart failure, and death. We report on a patient with locally advanced breast cancer whose course was complicated by fatal PTTM based on clinical and laboratory findings.
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BACKGROUND/AIMS: Metabolic syndrome is an emerging risk factor for cardiovascular disease. This study investigated the prevalence of metabolic syndrome among psychiatric patients in order to identify the dominant factors of metabolic syndrome. METHODS: We enrolled 225 patients who had been admitted to a chronic psychiatric hospital from October 2005 to February 2006. The prevalence of metabolic syndrome was assessed based on the Adult Treatment Panel (ATP)-III with the new criterion of waist circumference in the Asia-Pacific Region. RESULTS: The study population was relatively young (41.1 +/- 8.8 years) and obese (waist in men, 91.3 +/- 9.2 cm; waist in women, 84.1 +/- 8.8 cm). Sixty percent of patients met the waist criterion of metabolic syndrome and 56% met the low high density lipoprotein (HDL) criterion. The mean serum triglycerides were high (170.0 +/- 119.7 mg/dL) and 46% of patients met the triglyceride criterion. In contrast, less than 10% of patients showed impaired fasting glucose or high blood pressure (5%, 9%, respectively). The overall prevalence of metabolic syndrome was 34.2% by applying ATP-III criteria (40% in men and 20% in women, respectively). No specific anti-psychotic drugs were related to significant increase in the incidence of metabolic syndrome. CONCLUSIONS: Abdominal obesity and dyslipidemia (low HDL and high triglycerides) were dominant contributing factors of metabolic syndrome among psychiatric patients, and the affected age groups were relatively young. These findings indicate that active and early screening, including triglycerides, HDL, and waist measurement, are absolutely essential to managing metabolic syndrome in psychiatric patients.
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Dislipidemias/epidemiologia , Transtornos Mentais/epidemiologia , Síndrome Metabólica/epidemiologia , Obesidade Abdominal/epidemiologia , Adulto , Antipsicóticos/uso terapêutico , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Hipertensão/epidemiologia , Masculino , Transtornos Mentais/tratamento farmacológico , Pessoa de Meia-Idade , Prevalência , República da Coreia/epidemiologia , Fatores de Risco , Triglicerídeos/sangue , Adulto JovemRESUMO
PURPOSE: We evaluated clinical outcomes after drainage for malignant pericardial effusion with imminent or overt tamponade. MATERIALS AND METHODS: Between August 2001 and June 2007, 100 patients underwent pericardiocentesis for malignant pericardial effusion. Adequate follow-up information on the recurrence of pericardial effusion and survival status was available for 98 patients. RESULTS: Recurrence of effusion occurred in 30 patients (31%), all of whom were diagnosed with adenocarcinoma. Multivariate analysis indicated that adenocarcinoma of the lung (hazard ratio [HR], 6.6; 95% confidence interval [CI], 1.9 to 22.3; p=0.003) and progressive disease despite chemotherapy (HR, 4.3; 95% CI, 1.6 to 12.0; p=0.005) were independent predictors of recurrence. Survival rates three months after pericardiocentesis differed significantly with the type of primary cancer; the rates were 73%, 18%, 90% and 30% in patients with adenocarcinoma of the lung, squamous cell carcinoma of the lung, breast cancer and other cancers, respectively. CONCLUSION: Recurrence and survival of patients with malignant pericardial effusion are dependent on the type of primary cancer and response to chemotherapy. Patients with adenocarcinoma of the lung may be good candidates for surgical drainage to avoid repeated pericardiocentesis, but pericardiocentesis is considered effective as palliative management in patients with other cancers.
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BACKGROUND AND OBJECTIVES: Poor R-wave progression (PRWP) is a common electrocardiographic diagnosis. However, the diagnostic usefulness of PRWP for coronary artery disease (CAD) and the plausible explanation for subjects with normal heart function are unclear. SUBJECTS AND METHODS: We included 20,739 subjects who had routine medical examinations and applied the commonly used criteria (R-waves in V3 or V4 =2 mm) and the Marquette criteria in the current study. Subjects with PRWP by the Marquette criteria, but with no evidence of specific causes, were identified. Healthy age- and gender-matched controls were selected randomly for comparing cardiothoracic ratios. RESULTS: The commonly used criteria in practice were met by 372 of the 20,739 subjects (1.8%). The Marquette criteria were met by 96 subjects (0.5%), and 82 of who agreed to medical evaluation. Five subjects had known CAD and only one subject was shown to have a silent myocardial infarction by additional testing. Therefore, the positive predictive value of PRWP for CAD was 7.3% (6/82) based on the Marquette criteria. As compared with the control group, the subjects with PRWP had a significantly low cardiothoracic ratio (0.425 vs. 0.445, p<0.05), especially among the male group (0.454 vs. 0.407, p=0.02). CONCLUSION: The positive predictive value of PRWP for CAD in the general population is so low that additional tests for diagnosis may be unreasonable. In addition, a low cardiothoracic ratio could be a plausible explanation of PRWP in subjects without any identifiable cause.