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1.
Anticancer Res ; 40(1): 299-304, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892580

RESUMO

BACKGROUND/AIM: To clarify whether renal dysfunction affects the incidence of adverse events associated with oxaliplatin, the present study was designed to investigate the relationship between creatinine clearance (Ccr) and the incidence of oxaliplatin-related adverse events. PATIENTS AND METHODS: A total of 287 CRC patients who received the first cycle of oxaliplatin-based chemotherapy were eligible. Adverse events, including nausea, vomiting, neutropenia and thrombocytopenia, were graded, and the relationship between Ccr and the incidence of adverse events was examined using multivariable logistic regression analysis. RESULTS: A multivariable analysis indicated that the incidence of grade ≥2 nausea increased, while the incidence of other adverse events tended to be higher, as the Ccr decreased. Particularly, renal dysfunction (Ccr <60 ml/min) was a significant risk factor for grade ≥2 nausea (p=0.042). CONCLUSION: Care should be taken to avoid adverse events associated with oxaliplatin in patients with renal dysfunction.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Rim/fisiopatologia , Oxaliplatina/efeitos adversos , Oxaliplatina/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Creatinina/metabolismo , Feminino , Humanos , Incidência , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Fatores de Risco , Adulto Jovem
2.
Gynecol Oncol ; 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31926638

RESUMO

PURPOSE: The aim of this study was to investigate the efficacy and safety of prophylactic administration of 5 mg olanzapine (OLZ) combined with neurokinin 1 receptor antagonist (NK1RA), 5-hydroxytryptamine type-3 receptor antagonist (5-HT3RA), and dexamethasone (DEX) to prevent nausea and vomiting in carboplatin (CBDCA) combination therapy for patients with gynecological cancer. METHODS: We conducted a single-arm, multi-institution, phase II study. Gynecological cancer patients scheduled to receive AUC ≥4 mg/mL/min CBDCA were enrolled. All patients received 5 mg OLZ (once daily after supper on days 1-4) combined with NK1RA, 5-HT3RA, and DEX. The primary end point was complete response (CR; no emesis and rescue therapy) during overall phase (120 h after the start of carboplatin administration). RESULTS: Between May 2018 and June 2019, 60 patients were enrolled from 3 institutions in Japan. A total of 57 patients who met the criteria were included in the efficacy and safety analysis. The CR rate for the overall phase was 78.9%. Acute (0-24 h) and delayed phases (24-120 h) were 96.5% and 80.7%, respectively. Somnolence was observed in 73.7% patients. However, somnolence of grade 2 or higher was observed in only 3.5% of cases. There were no grade 3 or 4 toxicities associated with OLZ. CONCLUSIONS: Preventive use of OLZ combined with standard triplet therapy had promising activity with manageable safety, suggesting that this combination could be an effective standard treatment option for patients with AUC ≥4 mg/mL/min CBDCA combination therapy.

3.
J Phys Condens Matter ; 32(5): 055401, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31600736

RESUMO

A SnI4 molecule lowers its symmetry from T d to [Formula: see text] on the liquid-liquid transition. Because it is possible to lower the molecular symmetry without violating the crystalline symmetry, it is worth examining whether the deformation occurs in the crystalline phase field. Extended x-ray absorption fine structure (EXAFS) measurements on the crystalline state were carried out to investigate the change in the environment around a Sn atom at high pressures and temperatures. We could not find clear evidence on the symmetry change of molecules even close to the melting points, where the melting curve becomes abnormally flat against pressure. Indeed, no inconsistency was found when we assumed that the coordination number of a Sn atom remains unchanged in the temperature and pressure range examined. The situation remains true when the system entered the high-pressure crystalline phase on compression. We can propose a consistent scenario as to the structural change on the phase transformation. The incompressibility of a SnI4 molecule could be suitably quantified. The procedure enabled us to conclude the molecule is more than an order of magnitude incompressible than the lattice.

4.
Int J Clin Pract ; : e13464, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31830345

RESUMO

BACKGROUND: The increasing cost of anticancer drugs is now being recognised as a global problem, and measures against drug wastage are among the most important cost containment strategies for anticancer drugs. OBJECTIVE: When blood examination results or changes to a patient's condition necessitate dose reduction or discontinuation of anticancer drugs after their preparation, the compounded anticancer drugs are discarded. To reduce anticancer drug wastage after preparation, we developed a protocol that set the eligibility, start of treatment, dose reduction and discontinuation criteria for injectable anticancer drugs and assessed the effect of pharmacists' checks of these criteria based on the present protocol prior to preparation of injectable anticancer drugs. METHOD: Observations before and after introduction of the protocol were conducted at Gifu University Hospital. We recorded the number, type and cost of anticancer drugs discarded after preparation and the reason for discarding these drugs in our dedicated database. RESULTS: Checking the criteria for anticancer drug administration before preparation significantly reduced the rate at which anticancer drugs within a chemotherapy cycle were discarded after preparation compared with that prior to the protocol's introduction (0.367% [18/4909] vs 0.032% [2/6248], P < .001). Additionally, the total cost of anticancer drugs discarded after preparation was reduced from JPY 2 041 786 (USD 18 562) to JPY 398 414 (USD 3622). CONCLUSION: Pharmacists' checks of the eligibility, start of treatment, dose reduction and discontinuation criteria for anticancer drugs based on the present protocol prior to preparation of injectable anticancer drugs was useful for reducing drug wastage after preparation.

5.
Shock ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31764619

RESUMO

Myocardial injury in sepsis may be caused by a burst of several inflammatory mediators, leading to vascular endothelial injuries. However, the contribution of neutrophil elastase (NE) to myocardial injury in sepsis is still unknown. We aimed to evaluate whether endotoxaemia-induced myocardial injury is associated with NE. Lipopolysaccharide (LPS) was injected intraperitoneally at a dose of 20 mg/kg into granulocyte-colony-stimulating-factor knockout mice (G-CSF-KO), which have few neutrophils, and littermate control mice. The survival rate of G-CSF-KO mice 48 h after LPS injection was significantly greater than that of control mice. The serum level of troponin I in G-CSF-KO mice was significantly lower than that in control mice. In addition, the concentration of inflammatory cytokine interleukin-6 (IL-6) was significantly decreased 6 and 12 h after LPS administration compared with that in control mice. Ultrastructural analysis revealed that vascular endothelial structures and the endothelial glycocalyx in G-CSF-KO mice were clearly preserved. Next, mice were injected with 0.2 mg/kg sivelestat (an NE inhibitor) after LPS administration. The survival rate was significantly higher and the serum level of troponin I was lower in sivelestat-injected mice than in control mice, respectively. Furthermore, IL-6 levels were significantly decreased 6 and 12 h after LPS administration compared with those in control mice. Vascular endothelial structures and the endothelial glycocalyx in sivelestat-treated mice were clearly preserved at the ultrastructural level. In conclusion, NE is significantly associated with myocardial injury in endotoxaemia. Inhibition of NE may be a useful tool for the management of endotoxaemia. (245 words; 250 word limit).

6.
Oncologist ; 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748337

RESUMO

OBJECTIVE: TAS-102 is effective for treating patients with metastatic colorectal cancer (mCRC). This study determined whether combining bevacizumab (Bmab) with TAS-102 improves clinical outcomes in refractory mCRC. PATIENTS AND METHODS: We retrospectively analyzed data from Japanese patients with refractory mCRC who received TAS-102 (35 mg/m2, twice a day) with (T-B group) or without Bmab (TAS-102 monotherapy; T group) between July 2014 and December 2018. The primary endpoint was median overall survival (OS), and secondary endpoints were median time to treatment failure, overall response rate, and the incidence of adverse events. Clinical outcomes were compared using propensity score matched analysis. RESULTS: Data from 57 patients were analyzed (T-B group: 21 patients, T group: 36 patients). Median OS was significantly longer in the T-B group than the T group (14.4 months vs. 4.5 months, p < .001). Cox proportional hazard analysis showed that combination therapy with Bmab was significantly correlated with OS. Propensity score matched analysis confirmed that the median OS was significantly longer in the T-B group than the T group (14.4 months vs. 6.1 months, p = .006) and that there was a significant correlation between Bmab and OS. The incidence of hypertension (grade ≥2) as an adverse event was significantly higher in the T-B group than the T group (23.8% vs. 0.0%, p = .005), whereas other adverse events were comparable between the two groups. CONCLUSION: Treatment with Bmab in combination with TAS-102 is significantly associated with improved clinical outcomes in patients with mCRC refractory to standard therapies. IMPLICATIONS FOR PRACTICE: Combining bevacizumab (Bmab) with TAS-102 significantly improved overall survival and several prognostic indicators in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies, with manageable toxicities. Treatment with Bmab in combination with TAS-102 is significantly associated with improved clinical outcomes in patients with mCRC.

7.
Cancer Chemother Pharmacol ; 84(5): 1097-1105, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31502115

RESUMO

PURPOSE: Ifosfamide is extensively used to treat several malignant conditions. Administration of ifosfamide can cause encephalopathy and other neurotoxic effects. The aim of this study was to obtain novel information on the onset profiles of ifosfamide-induced encephalopathy (IIE) considering other associated clinical factors using the US Food and Drug Administration Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report (JADER) databases. METHODS: We analyzed the reports of encephalopathy between 2004 and 2018 from the FAERS and JADER databases. To define IIE, we used the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms and standardized queries. The reporting odds ratios (ROR) at 95% confidence interval (CI) was used to detect the signal for IIE and adjusted for covariates using a multivariate logistic regression technique. We evaluated the time-to-onset profile of IIE and used the association rule mining technique to discover undetected associations, such as potential risk factors. RESULTS: In the FAERS database, the ROR (CI) for encephalopathy (preferred term, PT) and encephalopathy (standardized MedDRA queries, SMQ) was 56.58 (51.69-61.93) and 1.57 (1.48-1.67), respectively. In the JADER database, the ROR (95% CI) for encephalopathy (PT) and encephalopathy (SMQ) was 13.54 (9.91-18.50) and 1.24 (1.01-1.53), respectively. The multivariate logistic regression analysis showed a significant contribution in IIE signal in the ≥ 60 year group (p = 0.00094; vs. < 60 year group) and ≥ 2000 mg/m2 dosage group (p = 0.00045; vs. < 2000 mg/m2 dosage group). The association rules of {ifosfamide, aprepitant} → {encephalopathy (SMQ)} demonstrated high lift values. The average dose of ifosfamide in patients with encephalopathy (PT) and without encephalopathy (PT) was 2022.8 ± 592.8 (mean ± standard deviation) and 1568.5 ± 703.2 mg/m2, respectively (p < 0.05). Encephalopathy within the first 7 days of ifosfamide administration was 94.1% for encephalopathy (PT) and 87.7% for encephalopathy (SMQ), respectively. CONCLUSIONS: The present analysis demonstrated that the incidence of encephalopathy with ifosfamide should be closely monitored for a short onset (within 7 days). The patients who are administered a high dose of ifosfamide or co-administrated aprepitant should be carefully monitored for the development of encephalopathy.

8.
Cancer Chemother Pharmacol ; 84(5): 987-992, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31482225

RESUMO

BACKGROUND/AIM: Sunitinib is used for the treatment of metastatic renal cell carcinoma (mRCC). Asian patients, including Japanese, tend not to tolerate long-term sunitinib therapy of 50 mg p.o. once daily for 4 weeks, followed by 2 week off treatment due to severe adverse events at this dosage level. The aim of this retrospective study was to investigate the optimal dose of sunitinib for long-term continuation in Asian patients with mRCC. PATIENTS AND METHODS: The study cases were 50 patients with mRCC who were treated with sunitinib between June 2008 and December 2017. Risk analysis for "unacceptable" adverse events (depending on the physician, ranging from grade 2 to ≥ grade 3) leading to discontinuation of sunitinib was determined by time-dependent Cox proportional hazard regression analysis. RESULTS: A total of 54 unacceptable adverse events leading to discontinuation occurred. Multivariable analysis indicated that a sunitinib dose of ≤ 37.5 mg/day significantly reduced the risk of discontinuation due to adverse events in comparison with 50 mg/day [hazard ratio (HR) 0.08, 95% confidence interval (CI) 0.03-0.21, p < 0.001). The progression-free survival (PFS) with a sunitinib dose ≤ 37.5 mg/day was longer than that associated with a dose of 50 mg/day, albeit not to a statistically significant degree (120 days for ≤ 37.5 mg/day vs 41 days for 50 mg/day, HR 0.39, 95% CI 0.10-1.44, p = 0.157). CONCLUSION: Our findings suggest that the optimal dose of sunitinib for Asian, including Japanese, patients with mRCC is ≤ 37.5 mg/day.

9.
J Clin Pharm Ther ; 44(6): 888-894, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31373043

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Patients who receive hematopoietic stem cell transplantation (HSCT) are usually administered a calcineurin inhibitor. Because vancomycin is associated with an increased incidence of nephrotoxicity, neutropenic patients receiving HSCT are considered a high-risk population for nephrotoxicity with vancomycin. We retrospectively compared the efficacy and safety of vancomycin and teicoplanin in febrile neutropenic patients receiving HSCT. METHODS: A single-centre, retrospective cohort study was conducted at the 614-bed Gifu University Hospital in Japan. Patients who received HSCT and were administered vancomycin or teicoplanin by injection for febrile neutropenia from 1 January 2012 to 31 August 2017 were enrolled. Time to attain an effective trough concentration, clinical efficacy and adverse events were compared between the two groups. RESULTS: Time to attain an effective trough concentration of over 10 µg/mL tended to be shorter in the teicoplanin group than in the vancomycin group (median 3, 95% confidence interval [CI] 2.4-3.6 days vs median 6, 95% CI 1.5-10.5 days; hazard ratio [HR] 0.4, 95% CI 0.15-1.06; P = .066). The rate of clinical failure was lower in the teicoplanin group than in the vancomycin group (18.8% vs 53.8%, P = .113). In addition, the overall incidence of nephrotoxicity was significantly lower in the teicoplanin group (0% vs 46.2%, P = .004). WHAT IS NEW AND CONCLUSION: Our findings suggest that administration of teicoplanin may lead to early attainment of the effective concentration with a lower rate of clinical failure and incidence of nephrotoxicity compared to vancomycin in febrile neutropenic patients receiving HSCT.

10.
J Clin Med ; 8(9)2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31462009

RESUMO

Endothelial disorders are related to various diseases. An initial endothelial injury is characterized by endothelial glycocalyx injury. We aimed to evaluate endothelial glycocalyx injury by measuring serum syndecan-1 concentrations in patients during comprehensive medical examinations. A single-center, prospective, observational study was conducted at Asahi University Hospital. The participants enrolled in this study were 1313 patients who underwent comprehensive medical examinations at Asahi University Hospital from January 2018 to June 2018. One patient undergoing hemodialysis was excluded from the study. At enrollment, blood samples were obtained, and study personnel collected demographic and clinical data. No treatments or exposures were conducted except for standard medical examinations and blood sample collection. Laboratory data were obtained by the collection of blood samples at the time of study enrolment. According to nonlinear regression, the concentrations of serum syndecan-1 were significantly related to age (p = 0.016), aspartic aminotransferase concentration (AST, p = 0.020), blood urea nitrogen concentration (BUN, p = 0.013), triglyceride concentration (p < 0.001), and hematocrit (p = 0.006). These relationships were independent associations. Endothelial glycocalyx injury, which is reflected by serum syndecan-1 concentrations, is related to age, hematocrit, AST concentration, BUN concentration, and triglyceride concentration.

11.
Zoonoses Public Health ; 66(8): 936-942, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31464049

RESUMO

Bergeyella zoohelcum causes rare but severe human clinical diseases, which mostly arise from animal bites. Notably, Bergeyella infections can also occur in older people after prolonged exposure to dogs or cats without biting. We detected B. zoohelcum in oral cavities of therapy dogs in close contact with older people residing in nursing homes. Twenty-two bacterial isolates were identified as B. zoohelcum by using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) and 16S rRNA gene sequencing. Our results showed that MALDI-TOF MS is an effective tool for rapid identification of rarely isolated, difficult-to-identify microorganisms, such as B. zoohelcum, derived from not only human clinical samples but also animal samples. To our knowledge, this is the first report on detection of B. zoohelcum from therapy dogs. We have provided information on dog-assisted therapy to improve the relationship between humans and animals in ageing societies, particularly for preventive healthcare of older people living in nursing care facilities.

12.
Lung Cancer ; 134: 1-6, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31319966

RESUMO

OBJECTIVES: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) represent the first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer. Afatinib is a second-generation EGFR-TKI with excellent therapeutic effects. However, severe diarrhea and skin disorders are observed at high frequencies, often leading to treatment interruption because of low quality of life (QOL). The relationship between individual variations and the onset of these side effects remains to be elucidated. This study aimed to reveal the association among these side effects, pharmacokinetics, and related genetic polymorphisms. MATERIALS AND METHODS: In total, 33 patients were recruited between July 2014 and June 2017. Afatinib plasma concentrations were measured at day 9 when the concentrations reached a steady state (early phase) and when the prescription dose was stable for more than 1 month (stable phase). We analyzed single nucleotide polymorphisms in the genes ATP-binding cassette sub-family B member 1 (ABCB1), ABCG2, and flavin-containing monooxygenase 3. RESULTS: The incidences of both diarrhea and acneiform eruption were greater than 80%. Afatinib plasma concentration and the severity of diarrhea in the early phase were correlated. Pharmacokinetics-related genetic polymorphisms influenced the severity of diarrhea. Particularly, the afatinib plasma concentration was higher and diarrhea was more severe in patients carrying the A allele of ABCG2 C421A. Onset of side effects, genetic polymorphisms, and diarrhea in the maintenance phase or acneiform eruption in the early or maintenance phases were not correlated. The severity of diarrhea is influenced by drug plasma concentrations in the early phase and genetic polymorphisms related to afatinib pharmacokinetics. CONCLUSION: Particular genetic polymorphisms can be screened before afatinib administration and the dose adapted to individual patients can be controlled, leading to reduced side effects, improved QOL, and better patient compliance to maintain the therapeutic effects.

13.
BMJ Open ; 9(7): e028056, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31278102

RESUMO

INTRODUCTION: Adding neurokinin-1 receptor antagonist (NK1RA) to 5-hydroxytryptamine-3 receptor antagonist and dexamethasone (DEX) improved carboplatin (CBDCA)-induced chemotherapy-induced nausea and vomiting (CINV) in patients with thoracic cancer. NK1RAs with high-drug cost are raising medical expenses. Olanzapine (OLZ) is less expensive and can be expected to have an excellent effect on CINV. This phase II trial aimed at evaluating the efficacy and safety of 5 mg OLZ plus granisetron (GRN) and DEX in CBDCA combination therapy with area under curve (AUC) ≥5 mg/mL/min for the prevention of nausea and vomiting in patients with thoracic cancer. METHODS AND ANALYSIS: This is an open-label, single-arm, multicentre, phase II trial. Patients who receive CBDCA-based therapies (AUC ≥5) and have never been administered moderate to high emetogenic chemotherapy will be enrolled. All patients will receive a combination of GRN, DEX and OLZ. The primary endpoint is complete response (CR) rate, defined as the absence of emetic episodes and no use of rescue medication for 120 hours after the initiation of CBDCA. Forty-eight patients are required based on our hypothesis that this regimen can improve CR rate from 65% (null hypothesis) to 80% (alternative hypothesis) with a one-sided type I error of 0.1 and a power of 0.8. We set the target sample size at 50 considering dropouts. ETHICS AND DISSEMINATION: The study protocol was approved by the institutional review board at each of the participating centres. Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: UMIN000031267.

14.
Diabetol Int ; 10(3): 188-197, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31275785

RESUMO

Aims: A number of epidemiologic surveys have demonstrated that improving lifestyle habits, providing patient education, and regular screening of patients for early diabetic symptoms and complications through multidisciplinary collaboration are crucial for the management of diabetes. Methods: To evaluate the Diabetes Coordination Notebook and the Diabetes Regional Coordination Path in management of diabetes, 217 community pharmacies conducted a survey by questionnaire in Gifu Prefecture, Japan. Results: A reply to the questionnaire was obtained from 27,016 individuals, of whom 5,572 claimed to have diabetes or prediabetes. The rate of usage of the Diabetes Coordination Notebook and the Diabetes Regional Coordination Path was 40% and 7%, respectively. Interestingly, patients using the Diabetes Regional Coordination Path more frequently visited an ophthalmic clinic (p < 0.001) and a dental clinic (p < 0.05) than those not using it. Furthermore, multivariate logistic regression analysis revealed that use of the Diabetes Regional Coordination Path was the only factor associated with control of HbA1c < 7.0% (OR: 0.613, 95% CI: 0.395-0.951, p = 0.029). Conclusions: The usage of the Diabetes Regional Coordination Path together with the Diabetes Coordination Notebook is associated not only with regular visits to both an ophthalmic clinic and a dental clinic but also with the maintenance of appropriate HbA1c.

15.
Med Oncol ; 36(7): 63, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31161433

RESUMO

Irinotecan is effective for the treatment of metastatic colorectal cancer (mCRC) and advanced pancreatic cancer (aPC). However, these treatments are often limited due to the incidence of severe neutropenia. We identified risk factors for severe neutropenia in patients with mCRC or aPC, receiving irinotecan-based chemotherapy regimens. The study selected 104 patients (mCRC: 53 and aPC: 51) who received irinotecan-based chemotherapy between January 2014 and May 2018 and who were included in the present study. The initial dose of irinotecan was 150 mg/m2 in all patients, and patients with a lower initial dose of irinotecan were excluded. Severe neutropenia (grade ≥ 3) occurred in 56 patients (53.8%). Multivariable Cox proportional hazards analysis indicated that modified FOLFIRINOX (mFOLFIRINOX) and serum total bilirubin (T-Bil) were significant risk factors for severe neutropenia. Moreover, with receiver-operating characteristic (ROC) curve analysis, the cutoff for T-Bil was found to be 0.7 mg/dL. Among patients treated with mFOLFIRINOX therapy, the incidence of severe neutropenia was significantly higher in patients with high level of T-Bil (> 0.7 mg/dL) than in those without it (93.8% vs 55.0%, P = 0.006). A chemotherapy regimen (modified FOLFIRINOX therapy) and T-Bil > 0.7 mg/dL were significant risk factors for severe neutropenia in patients receiving 150 mg/m2 irinotecan.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bilirrubina/sangue , Irinotecano/efeitos adversos , Neutropenia/sangue , Neutropenia/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Incidência , Irinotecano/administração & dosagem , Irinotecano/uso terapêutico , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxaliplatina/efeitos adversos , Oxaliplatina/uso terapêutico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco
16.
PLoS One ; 14(6): e0217944, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31170247

RESUMO

Anti-prion protein (PrP) monoclonal antibody 132, which recognizes mouse PrP amino acids 119-127, enables us to reliably detect abnormal isoform prion protein (PrPSc) in cells or frozen tissue sections by immunofluorescence assay, although treatment with guanidinium salts is a prerequisite. Despite the benefit of this mAb, the mechanism of PrPSc-specific detection remains unclear. Therefore, to address this mechanism, we analyzed the reactivities of mono- and bivalent mAb 132 to recombinant mouse PrP (rMoPrP) by enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR). In ELISA, binding of the monovalent form was significantly weaker than that of the bivalent form, indicating that bivalent binding confers a higher binding stability to mAb 132. Compared with other anti-PrP mAbs tested, the reactivity of bivalent mAb 132 was easily affected by a decrease in antigen concentration. The binding kinetics of mAb 132 assessed by SPR were consistent with the results of ELISA. The dissociation constant of the monovalent form was approximately 260 times higher than that of the bivalent form, suggesting that monovalent binding is less stable than bivalent binding. Furthermore, the amount of mAb 132 that bound to rMoPrP decreased if the antigen density was too low to allow bivalent binding. If two cellular PrP (PrPC) are close enough to allow bivalent binding, mAb 132 binds to PrPC. These results indicate that weak monovalent binding to monomeric PrPC diminishes PrPC signals to background level, whereas after exposure of the epitope, mAb 132 binds stably to oligomeric PrPSc in a bivalent manner.

17.
J Infect Chemother ; 25(10): 801-805, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31047782

RESUMO

Caspofungin (CPFG) is an echinocandin antifungal agent that inhibits the synthesis of ß-1, 3-D-glucan, a critical component of the cell wall of target fungi. Several clinical studies have confirmed the efficacy and safety of CPFG in patients with febrile neutropenia (FN); however, there are no reports available in Japanese patients with FN. Therefore, we investigated the therapeutic efficacy and pharmacokinetics of CPFG as an empirical therapy in a Japanese hospital. Twenty-four Japanese patients, who were diagnosed with FN at Gifu University Hospital from February 2014 to August 2017, were enrolled. Blood samples were collected at the end of CPFG dosing (0.5 h after the infusion) on day 1 and immediately prior to the next infusion on days 2, 3, and 4. The concentration of CPFG in plasma was measured by high-performance liquid chromatography. The efficacy was assessed by five of the component endpoints, and safety was monitored according to the Common Terminology Criteria for Adverse Events. CPFG showed an excellent effect against FN (75%, 18/24), without any serious hepatic or renal toxicity. Regarding the pharmacokinetics, the plasma concentration of CPFG was significantly correlated with body weight; although, no correlation was observed between the plasma concentration of CPFG and the other factors investigated, such as gender or laboratory results. These results suggest the high efficacy, safety, and tolerability of CPFG as an empirical antifungal therapy for Japanese patients with FN.


Assuntos
Antifúngicos/uso terapêutico , Caspofungina/uso terapêutico , Neutropenia Febril/tratamento farmacológico , Adulto , Idoso , Antifúngicos/farmacocinética , Peso Corporal , Caspofungina/farmacocinética , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Neutropenia Febril/sangue , Feminino , Humanos , Infusões Intravenosas , Japão , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Resultado do Tratamento , Adulto Jovem
18.
Neuron ; 102(6): 1199-1210.e6, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31078368

RESUMO

Long-term synaptic plasticity requires a mechanism that converts short Ca2+ pulses into persistent biochemical signaling to maintain changes in the synaptic structure and function. Here, we present a novel mechanism of a positive feedback loop, formed by a reciprocally activating kinase-effector complex (RAKEC) in dendritic spines, enabling the persistence and confinement of a molecular memory. We found that stimulation of a single spine causes the rapid formation of a RAKEC consisting of CaMKII and Tiam1, a Rac-GEF. This interaction is mediated by a pseudo-autoinhibitory domain on Tiam1, which is homologous to the CaMKII autoinhibitory domain itself. Therefore, Tiam1 binding results in constitutive CaMKII activation, which in turn persistently phosphorylates Tiam1. Phosphorylated Tiam1 promotes stable actin-polymerization through Rac1, thereby maintaining the structure of the spine during LTP. The RAKEC can store biochemical information in small subcellular compartments, thus potentially serving as a general mechanism for prolonged and compartmentalized signaling.

19.
Sci Rep ; 9(1): 7420, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092856

RESUMO

Several igneous activities occur on the surface of the Earth, including island arcs, mid-ocean ridges and hot spots. Based on geophysical observations, melting phenomena in the interior also occur at the asthenosphere's top and the upper mantle's bottom. Additionally, a seismological low-velocity anomaly was observed at the top of the lower mantle that may result from mantle melting due to dehydration decomposition of ringwoodite to bridgmanite and ferropericlase with a downward flow. However, the corresponding high-pressure experimental data are too poor to understand the melting phenomena under the lower mantle condition. Herein, we conducted hydrous peridotite melting experiments at pressures from 23.5 to 26 GPa and at temperatures from 1300 to 1600 °C for demonstrating the melt composition and the gravitational stability of magma at the top of the lower mantle. The melt had a SiO2-poor and MgO-rich composition, which is completely different than that of dry peridotite melting experiments. Compared with the seismological lower mantle, the experimental melt is gravitationally lighter; thus, a similar melt could be observed as seismological low-velocity zone at the lower mantle's top. The generated magma plays as a filter of down-welling mantle and can contribute to a formation of a silicate perovskitic lower mantle.

20.
J Vet Med Sci ; 81(6): 846-850, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-30982806

RESUMO

Atypical bovine spongiform encephalopathy (BSE), first identified in 2004, poses a threat due to the potential to spread the disease to cattle and other animals, including humans. Here, we estimated prion titers in various tissues of cattle infected with atypical BSE using a real-time quaking-induced conversion assay that detects amyloid seeding activity of a disease-specific prion protein, PrPSc, a major component of prions. PrPSc was detected both in and outside of nerve tissues, and some of the peripheral nerve tissues contained relatively high prion titers. Low titers of prions were also observed in masseter, jejunum, and adrenal glands. Quantitative data on prion infectivity in tissues of atypical BSE-affected cattle is useful to assess the risk of atypical BSE.


Assuntos
Encefalopatia Espongiforme Bovina , Immunoblotting/veterinária , Proteínas Priônicas/isolamento & purificação , Animais , Bovinos , Immunoblotting/métodos , Nervos Periféricos , Proteínas Priônicas/metabolismo , Príons/isolamento & purificação , Príons/patogenicidade , Distribuição Tecidual
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