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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.
Dev Biol ; 458(2): 237-245, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31758944

RESUMO

Congenital heart diseases (CHDs) involving the outflow tract (OFT), such as persistent truncus arteriosus (PTA), lead to mortality and morbidity with implications not only in the heart, but also in the pulmonary vasculature. The mechanisms of pulmonary artery (PA) development and the etiologies underlying PA disorders associated with CHD remain poorly understood partly because of a specific marker for PA development is nonexistent. The three subtypes of inositol 1,4,5-trisphosphate receptors (IP3R1, 2, and 3) are intracellular Ca2+ channels that are essential for many tissues and organs. We discovered that IP3R2 was expressed in the vasculature and heart during development using transgenic mice, in which a LacZ marker gene was knocked into the IP3R2 locus. Whole-mount and section LacZ staining showed that IP3R2-LacZ-positive cells were detectable exclusively in the smooth muscle cells, or tunica media, of PA, merging into αSMA-positive cells during development. Furthermore, our analyses suggested that IP3R2-LacZ positive PA smooth muscle layers gradually elongate from the central PA to the peripheral PAs from E13.5 to E18.5, supporting the distal angiogenesis theory for the development of PA, whereas IP3R2-LacZ was rarely expressed in smooth muscle cells in the pulmonary trunk. Crossing IP3R-LacZ mice with mice hypomorphic for Tbx1 alleles revealed that PTA of Tbx1 mutants may result from agenesis or hypoplasia of the pulmonary trunk; thus, the left and right central to peripheral PAs connect directly to the dorsal side of the truncus arteriosus in these mutants. Additionally, we found hypercellular interstitial mesenchyme and delayed maturation of the lung endoderm in the Tbx1 mutant lungs. Our study identifies IP3R2 as a novel marker for clear visualization of PA during development and can be utilized for studying cardiopulmonary development and disease.

3.
World J Surg Oncol ; 17(1): 197, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31771590

RESUMO

BACKGROUND: In Japan, the majority of gastrointestinal tract neuroendocrine tumors (NETs) have been reported to originate from the rectum, and appendiceal NETs are relatively rare. Preoperative diagnosis is very difficult and it is diagnosed after appendectomy. Pediatric appendiceal NET is a disease with a good prognosis. However, in rare cases, lymph node metastasis could occur and additional resection is required. CASE PRESENTATION: A 10-year-old boy complained of right lower quadrant abdominal pain and underwent an appendectomy under a diagnosis of acute appendicitis in previous hospital. The final diagnosis was appendiceal NET, so he was referred to our department for additional resection. The tumor was found in the base of the appendix and invasively reached the subserosal layer with obvious vascular invasion. His Ki-67 index was 1 to 2%, so we classified it as appendiceal NET G1 according to the WHO 2015 classification. We considered the possibility of a tumor remnant or lymph node metastasis, so we performed single-incision laparoscopy with D3 lymph node dissection. The pathological diagnosis revealed no tumor remnant but metastasis to one lymph node. He was discharged on the 9th postoperative day. There has been no recurrence at 3 years and 7 months after surgery. CONCLUSION: When the tumor size is 10-20 mm, the frequency of lymph node metastasis in some reports is variable, and there is no consensus yet on the indications for additional resection. However, there are definitely a certain number of cases with lymph node metastasis that require additional resection. In the present patient, long-term survival can be obtained by additional resection. At present, factors such as the presence of vascular or lymph node invasion and the malignancy grade and tumor's location must be considered on a case-by-case basis. Although the incidence rate of appendiceal NET is rare, the diagnosis can be made only during postoperative pathological examination; thus, reliable histopathological examination is required.

4.
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.

5.
World J Surg Oncol ; 17(1): 178, 2019 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-31677643

RESUMO

BACKGROUND: In recent years, laparoscopic surgery has been widely used for rectal cancer. In laparoscopic rectal surgery, a double-stapling technique (DST) anastomosis using a stapling device is considered a relatively difficult procedure. Postoperative anastomotic leakage (AL) is a major complication related to patients' quality of life and prognosis. METHODS: This study was a retrospective, single-institution study of 101 rectal cancer patients who underwent laparoscopic low anterior resection (LAR) with DST anastomosis (excluding simultaneous resection of other organs and construction of protective diverting stoma) between February 2008 and November 2017 at the Gifu University Graduate School of Medicine. This study aimed to identify risk and early predictive factors of AL. RESULTS: Among 101 patients, symptomatic AL occurred in 13 patients (12.9%), of whom 10 were male and 3 were female. Their median BMI was 22.7 kg/m2 (range, 17.9-26.4 kg/m2). Among the pre- and intraoperative factors, AL was significantly associated with tumor location (lower rectum), distance from the anal verge (< 6 cm), intraoperative blood loss (≥ 50 ml), and the number of linear staples (≥ 2) in univariate analysis. In multivariate analysis, only intraoperative blood loss (≥ 50 ml, odds ratio [OR] 4.59; 95% confidence interval [CI] 1.04-19.52; p = 0.045) was identified as an independent risk factor for AL. Among the postoperative factors, AL was significantly associated with tachycardia-POD1 (≥ 100 bpm), CRP-POD3 (≥ 15 mg/dl), fever on postoperative day (fever-POD) 3 (≥ 38 °C), and first defecation day after surgery (< POD3) in univariate analysis. In multivariate analysis, fever-POD3 (≥ 38 °C, OR 30.97; 95% CI 4.68-311.22; p = 0.0003) and first defecation day after surgery (< POD3, OR 5.82; 95% CI 1.34-31.30; p = 0.019) were identified as early predictive factors for AL. CONCLUSION: In this study, intraoperative blood loss was an indicator of difficulty in a transection and anastomosing procedure, and fever-POD3 and early first defecation day after surgery were independent early predictive factors for AL. Careful surgery using an appropriate technique and standardized procedures with minimal bleeding and careful postoperative management paying attention to fever and defecation may prevent the onset and severity of AL.

6.
Dev Cogn Neurosci ; 39: 100701, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31513977

RESUMO

Language development and the capacity for communication in infants are predominantly supported by their mothers, beginning when infants are still in utero. Although a mother's speech should thus have a significant impact on her neonate's brain, neurocognitive evidence for this hypothesis remains elusive. The present study examined 37 neonates using near-infrared spectroscopy and observed the interactions between multiple cortical regions while neonates heard speech spoken by their mothers or by strangers. We analyzed the functional connectivity between regions whose response-activation patterns differed between the two types of speakers. We found that when hearing their mothers' speech, functional connectivity was enhanced in both the neonatal left and right frontotemporal networks. On the left it was enhanced between the inferior/middle frontal gyrus and the temporal cortex, while on the right it was enhanced between the frontal pole and temporal cortex. In particular, the frontal pole was more strongly connected to the left supramarginal area when hearing speech from mothers. These enhanced frontotemporal networks connect areas that are associated with language (left) and voice processing (right) at later stages of development. We suggest that these roles are initially fostered by maternal speech.

7.
Mol Clin Oncol ; 11(4): 390-396, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31475067

RESUMO

The combination regimen of TAS-102, a novel oral nucleoside antitumor agent containing trifluridine and tipiracil hydrochloride, with bevacizumab (C-TASK FORCE), a selective monoclonal antibody inhibitor of vascular endothelial growth factor-A, as salvage-line therapy for metastatic colorectal cancer (mCRC) was established based on its high clinical effectiveness. The aim of the present study was to evaluate the prognostic accuracy of the modified Glasgow Prognostic Score (mGPS) in patients receiving TAS-102 plus bevacizumab. The study included 17 patients (12 men and 5 women, mean age 60.4±13.4 years) with unresectable mCRC who were confirmed to have wild-type or mutant RAS genes. The patients received salvage-line treatment with TAS-102 plus bevacizumab at the Surgical Oncology Department of Gifu University School of Medicine between March 2016 and August 2018. The study population was heavily pretreated; the majority of the patients (71%) had received ≥4 prior regimens and, in addition to fluoropyrimidine, irinotecan and oxaliplatin, all had received bevacizumab (100%) and either cetuximab or panitumumab (47%). The RAS status was wild-type in 9 (53%) and mutant in 8 (47%) patients. The primary tumor locations included the right-sided colon in 5 patients (29%; cecum in 2 and transverse colon in 3 cases) and left-sided colorectum in 12 patients [71%; sigmoid colon in 4, rectosigmoid (Rs) in 4, and rectum above/below the peritoneal reflection (Ra/b) in 4 cases]. Metastatic sites included the liver in 15 (88%), lung in 13 (76%), lymph nodes in 7 (41%), and peritoneal dissemination in 5 (24%) patients. The number of metastatic sites was 1 in 3 (18%) and >2 in 14 (82%) patients. Their first staging imaging scans (after 2 cycles of therapy) were available for review in all 17 patients. At first evaluation, 5 (29%) patients had progressive disease (PD), 12 (71%) had stable disease, and none had a partial response to TAS-102 plus bevacizumab. The median overall survival (OS) of 14.1 months and progression-free survival (PFS) of 6.8 months were comparable to the 11.2 and 5.6 months, respectively, in the C-TASK FORCE study. Upon considering three groups, namely mGPS 0, mGPS 1 and mGPS 2, the median PFS times were significantly different (mGPS 0 vs. mGPS 2, P=0.02; and mGPS 1 vs. mGPS 2, P=0.06). The median PFS times in the mGPS 0, 1 and 2 groups were 12.1, 4.8 and 2.3 months, respectively. Median OS was also significantly different (mGPS 0 vs. mGPS 2, P=0.01; and mGPS 1 vs. mGPS 2, P=0.04). The median OS times in the mGPS 0, 1 and 2 groups were 14.0, not reached, and 2 months, respectively. The present study demonstrated the efficacy and safety of the TAS-102 plus bevacizumab combination as salvage-line treatment. This combination therapy (the TAS-102 plus bevacizumab) has obtained valid results with PFS OS as well as C-TASK.FORCE study. The results of the present study also confirmed the prognostic accuracy of mGPS in salvage-line treatment of patients with mCRC.

8.
Mult Scler Relat Disord ; 34: 150-157, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31295724

RESUMO

BACKGROUND: Although relatively rare among pediatric patients, acquired demyelinating syndromes of the central nervous system (ADS) is a potentially disabling condition that warrants hospitalization and long-term follow-up. As such, a better understanding of the epidemiology and hospital utilization for this condition could provide critical information for health care planning and resource allocation. OBJECTIVE: To evaluate the trends of hospital utilization and resource use associated with pediatric ADS in the US. METHOD: We conducted a serial cross-sectional trend analysis with complex sampling and weighting using nationally representative hospital discharge records, from the Kids´ Inpatient Database (KID), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality coded with International Classification of Diseases (Healthcare Cost and Utilization Project (HCUP) 2018), Ninth Revision (ICD-9-CM) for the years 2003, 2006, 2009, and 2012. We also conducted a cross-sectional study for the KID2016 dataset coded with ICD10-CM to estimate the pediatric ADS-related hospital utilization for the year. EXCLUDING TRANSFERRING DISCHARGES: we evaluated the discharge records for those aged 0 to 19 years diagnosed with any of ADS of central nervous systems including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), transverse myelitis (TM) and demyelinating disease not specified (DDNS). For the trend analysis, we used variance-weighted regression and Poisson regression for the annual hospitalization rate, total hospital charges and hospital days associated with the ADS hospitalizations for the year 2003 to 2012. RESULTS: We estimated a total of 1,292 ADS-related hospitalizations (95%CI: 1127-1,458) in 2003, 2104 hospitalizations (95%CI: 1823-2385) in 2006, 2851 hospitalizations (95%CI: 2499-3203) in 2009, and 3501 hospitalizations (95%CI: 3058-3945) in 2012 among those aged 19 years or younger with diagnoses of ADS. There was an increase in the proportion of the inpatient hospital cost attributed to ADS from 0.06% in 2003 to 0.20% in 2012. The annual hospitalization rates relative to pediatric ADS were 1.59/100,000 (95%CI: 1.51-1.68) in 2003 and 4.21/100,000 (95%CI: 4.07-4.35) in 2012. In the cross-sectional analysis for the year 2016 coded by ICD10-CM, the number of pediatric ADS related hospitalizations were 4,568, constituting 0.30% of the total pediatric hospitalization cost. The annual hospitalization rate for the year 2016 was estimated to be 5.51/100,000. CONCLUSION: Hospital utilization by pediatric patients with ADS increased during the period 2003 through 2012. The cross-sectional analysis for the year 2016 indicated that the trend could be ongoing, although the direct comparison was not feasible due to the changes in the coding system of the dataset from ICD9-CM to ICD10-CM. Although relatively rare, pediatric ADS warrant long-term follow-ups and hospitalizations, impacting the developmental trajectory of the affected children and the lives of their family members. Th potentially increasing trend of pediatric ADS hospital utilization should be acknowledged when allocating and planning future resources and supporting programs.

9.
Br J Cancer ; 121(3): 222-229, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31285591

RESUMO

BACKGROUND: Chemotherapy with biologics followed by liver surgery improves the resection rate and survival of patients with colorectal liver metastasis (CRLM). However, no prospective study has compared the outcomes of chemotherapy with bevacizumab (BEV) versus cetuximab (CET). METHODS: The ATOM study is the first randomised trial comparing BEV and CET for initially unresectable CRLM. Patients were randomly assigned in a 1:1 ratio to receive mFOLFOX6 plus either BEV or CET. The primary endpoint was progression-free survival (PFS). RESULTS: Between May 2013 and April 2016, 122 patients were enrolled. Median PFS was 11.5 months (95% CI 9.2-13.3 months) in the BEV group and 14.8 months (95% CI 9.7-17.3 months) in the CET group (hazard ratio 0.803; P = 0.33). Patients with a smaller-number but larger-sized metastases did better in the CET group. In the BEV and CET groups, the response rates were 68.4% and 84.7% and the resection rates were 56.1% and 49.2%, respectively. CONCLUSION: Although CET achieved a better response rate than BEV for patients with a small number of large liver metastases, both biologics had similar efficacy regarding liver resection and acceptable safety profiles. To achieve optimal PFS, biologics should be selected in accordance with patient conditions. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (number NCT01836653), and UMIN Clinical Trials Registry (UMIN-CTR number UMIN000010209).

10.
Mol Clin Oncol ; 11(2): 189-191, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31281655

RESUMO

Development of diabetic ketoacidosis (DKA) caused by fulminant type 1 diabetes (FT1D) during administration of uracil-tegafur (UFT) with leucovorin (LV) as adjuvant chemotherapy is extremely rare. Here, we report a case of DKA caused by FT1D during administration of UFT with LV as adjuvant chemotherapy for colon cancer. A woman in her 60s was transferred to the emergency medical center of our hospital with complaints of impaired consciousness and vomiting. She had undergone left hemicolectomy and D3 lymph node dissection for transverse colon cancer 8 months earlier. She was provided UFT with LV as adjuvant chemotherapy. Laboratory analysis revealed hyperglycemia, high anion gap metabolic acidosis and urinary ketones. She was diagnosed with DKA and was started on intravenous infusion of fluid and continuous subcutaneous insulin injections. Following admission, she was examined and diagnosed with FT1D. The present case describes an extremely rare case of DKA caused by FT1D during adjuvant chemotherapy with UFT + LV for colon cancer.

11.
Asian J Endosc Surg ; 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332934

RESUMO

An intractable fistula caused by idiopathic esophageal rupture is a rare but severe condition. In the present case, a 69-year-old man had been treated conservatively at another hospital for esophageal rupture but had developed an abscess in the left thoracic cavity due to an intractable fistula at the rupture site. He was referred to our hospital for treatment 19 months after the esophageal rupture. On admission, the intractable fistula was found to be continuous with an abscess in the left thoracic cavity. Preoperative continuous enteral nutrition was administered to improve the patient's nutritional status, and drainage was performed to reduce the size of the abscess. Then, to minimize the invasion of the intractable fistula, thoracoscopic subtotal esophagectomy was performed via a right thoracic cavity approach 20 months after the esophageal rupture. Preoperative management and thoracoscopic surgery via an opposite chest cavity approach was found to be safe and feasible for the intractable fistula caused by idiopathic esophageal rupture.

12.
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
13.
Vaccine ; 37(30): 4047-4054, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31186191

RESUMO

OBJECTIVES: We assessed the vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) by vaccine dose in children aged 6 months to 12 years for whom two doses are recommended in Japan to ascertain the appropriate vaccine doses. METHODS: VE was assessed according to a test-negative case-control design based on rapid influenza diagnostic test (RIDT) results. Children aged 6 months to 12 years with a fever ≥38 °C who had received an RIDT in outpatient clinics of 24 hospitals were enrolled for all five seasons since 2013/14. VE by vaccine dose (none vs. once or twice, and once vs. twice) was analyzed. RESULTS: In the dose analysis, 20,033 children were enrolled. Both one- and two-dose regimens significantly reduced cases in preventing any influenza, influenza A, and influenza B, but there was no significant difference in adjusted VE between one- and two-dose regimens overall (adjusted OR, 0.560 [95% CI, 0.505-0.621], 0.550 [95% CI, 0.516-0.586]), 0.549 [95% CI, 0.517-0.583], and 1.014 [95% CI, 0.907-1.135], for none vs. once, none vs. twice, none vs. once or twice, and once vs. twice for any influenza, respectively). Both one- and two-dose regimens significantly reduced cases with any influenza and influenza A every season. Also, both regimens significantly reduced cases of any influenza, influenza A, and influenza B among children aged 1-12 years, especially among those aged 1-5 years. In the 2013/14, 2015/16, and 2016/17 seasons, however, only the two-dose regimen was significantly effective in preventing influenza B. Both one- and two-dose regimens significantly reduced cases involving hospitalization due to any influenza and influenza A. CONCLUSIONS: Both one- and two-doses regimens of IIV were effective in preventing influenza for children aged 6 months to 12 years. The two-dose regimen was more effective against influenza B in some seasons.

14.
Am J Med Genet A ; 179(8): 1609-1614, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31140736

RESUMO

Subsets of mitochondrial transfer RNA (tRNA) contain the N6 -isopentenyladenosine (i6 A) or 2-methylthio-N6 -isopentenyladenosine (ms2 i6 A) modification at position A37, which is adjacent to an anticodon. These modifications are essential for efficient protein translation in mitochondria and contribute to energy metabolism. The first step in i6 A and ms2 i6 A modifications is catalyzed by tRNA isopentenyltransferase, which is encoded by the TRIT1 gene. Herein, we report a girl with a developmental delay, frequent episodes of seizures induced by febrile illness, and myoclonic epilepsy who had compound heterozygous missense mutations in TRIT1. A mass spectrometry analysis of RNA nucleoside obtained from the subject's peripheral blood and urine showed a marked decrease in both i6 A and ms2 i6 A modifications. These results suggest that the mitochondrial disorder was caused by defective tRNA isopentenylation arising from a loss-of-function mutation in TRIT1. Furthermore, the present observations suggest that noninvasive biochemical analysis using peripheral blood and urine samples are sufficient for the diagnosis of TRIT1-related disorders, making muscle biopsy for the direct measurement of oxidative phosphorylation unnecessary. Such biochemical analyses before the start of antiepileptic medications would be beneficial to avoid hepatotoxicity in patients with possible mitochondrial disorders.

15.
Palliat Support Care ; 17(6): 738-740, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31104649

RESUMO

OBJECTIVE: Thiamine deficiency (TD) is recognized in various kinds of disease with associated loss of appetite including cancer. However, it has not been recognized to date in bereaved partners after spousal loss from cancer. METHOD: From a series of bereaved partners who lost a spouse to cancer, we report on those who developed TD after bereavement. RESULT: Case 1 was a 57-year-old woman who sought consultation at our "bereavement clinic." Her husband had been diagnosed with pancreatic cancer one year earlier and had died one month previously. At the first visit, she was observed to suffer depression, anxiety, and decreased appetite. Neurological, blood, and biochemical examinations did not reveal any noteworthy findings. She was diagnosed with uncomplicated bereavement. Detailed examination revealed that her appetite had been markedly decreased for approximately five weeks. The diagnosis of TD was supported by her abnormally low serum thiamine level. Case 2 was a bereaved 73-year-old male who had lost his wife to hypopharyngeal cancer one month previously after a five-year illness. He had shown a lack of energy for the month preceding his wife's death, but because there was no improvement after her death, his family recommended he seek consultation at our "bereavement clinic." He was suffering from major depressive disorder. Detailed examination revealed that his appetite had been decreased for more than two weeks. Again, the diagnosis of TD was supported by his abnormally low serum thiamine level. SIGNIFICANCE OF RESULTS: These reports demonstrate that there is a possibility that bereaved could develop TD after the loss of a loved one. TD should be considered whenever there is a loss of appetite lasting for more than 2 weeks, and medical staff should pay careful attention to the physical condition of the bereaved to prevent complications because of TD.

16.
Front Neural Circuits ; 13: 29, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31133819

RESUMO

Recent improvements in correlative light and electron microscopy (CLEM) technology have led to dramatic improvements in the ability to observe tissues and cells. Fluorescence labeling has been used to visualize the localization of molecules of interest through immunostaining or genetic modification strategies for the identification of the molecular signatures of biological specimens. Newer technologies such as tissue clearing have expanded the field of observation available for fluorescence labeling; however, the area of correlative observation available for electron microscopy (EM) remains restricted. In this study, we developed a large-area CLEM imaging procedure to show specific molecular localization in large-scale EM sections of mouse and marmoset brain. Target molecules were labeled with antibodies and sequentially visualized in cryostat sections using fluorescence and gold particles. Fluorescence images were obtained by light microscopy immediately after antibody staining. Immunostained sections were postfixed for EM, and silver-enhanced sections were dehydrated in a graded ethanol series and embedded in resin. Ultrathin sections for EM were prepared from fully polymerized resin blocks, collected on silicon wafers, and observed by multibeam scanning electron microscopy (SEM). Multibeam SEM has made rapid, large-area observation at high resolution possible, paving the way for the analysis of detailed structures using the CLEM approach. Here, we describe detailed methods for large-area CLEM in various tissues of both rodents and primates.


Assuntos
Encéfalo/ultraestrutura , Microscopia Eletrônica de Varredura/métodos , Neuroimagem/métodos , Animais , Callithrix , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência/métodos
17.
Mol Clin Oncol ; 10(6): 571-574, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31031973

RESUMO

The combination of cetuximab (CTX) and chemotherapy, such as FOLFOX or FOLFIRI, is currently the standard treatment for metastatic colorectal cancer (mCRC). Zoledronic acid (ZOL) is used in patients with bone metastasis. We herein report our experience with the case of a 58-year-old male patient with metastatic rectal cancer who was treated with ZOL + CTX as third-line therapy, and in whom this combination appeared to be effective. Although the patient developed bone metastasis and cardiac tamponade due to the recurrence of rectal cancer, he survived for approximately 10 months after the initiation of ZOL and CTX treatment.

18.
Palliat Support Care ; 17(5): 611-613, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30696506

RESUMO

OBJECTIVE: Thiamine deficiency (TD) is recognized in various kinds of disease with associated loss of appetite including cancer; however, TD has not been recognized in the family caregivers of cancer patients to date. METHOD: From a series of cancer patient caregivers, we reported an aged family caregiver who developed TD while caring for the cancer patient. RESULT: The caregiver was a 90-year-old male. He had been accompanying his wife, who was diagnosed with colon cancer 4 years previously, on hospital visits as the primary caregiver, but because of psychological issues, he was recommended to visit the psycho-oncology department's "caregiver's clinic" for a consultation. Detailed examination revealed that his appetite had been only about 50% of usual from about one year before, and he had lost 12 kg in weight in one year. The diagnosis of TD was supported by his abnormally low serum thiamine level. SIGNIFICANCE OF THE RESULTS: This report demonstrates that there is a possibility that care providers could develop TD from the burdens associated with caregiving. TD should be considered whenever there is a loss of appetite lasting for more than 2 weeks, and medical staff should pay careful attention to the physical condition of care providers to prevent complications resulting from TD.

19.
Heart Vessels ; 34(4): 724-734, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30460575

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive disease associated with vasoconstriction and remodeling. Intracellular Ca2+ signaling regulates the contraction of pulmonary arteries and the proliferation of pulmonary arterial smooth muscle cells (PASMCs); however, it is not clear which molecules related to Ca2+ signaling contribute to the progression of PAH. In this study, we found the specific expression of type 2 inositol 1,4,5-trisphosphate receptor (IP3R2), which is an intracellular Ca2+ release channel, on the sarco/endoplasmic reticulum in mouse PASMCs, and demonstrated its inhibitory role in the progression of PAH using a chronic hypoxia-induced PAH mouse model. After chronic hypoxia exposure, IP3R2-/- mice exhibited the significant aggravation of PAH, as determined by echocardiography and right ventricular hypertrophy, with significantly greater medial wall thickness by immunohistochemistry than that of wild-type mice. In IP3R2-/- murine PASMCs with chronic hypoxia, a TUNEL assay revealed the significant suppression of apoptosis, whereas there was no significant change in proliferation. Thapsigargin-induced store-operated Ca2+ entry (SOCE) was significantly enhanced in IP3R2-/- PASMCs in both normoxia and hypoxia based on in vitro fluorescent Ca2+ imaging. Furthermore, the enhancement of SOCE in IP3R2-/- PASMCs was remarkably suppressed by the addition of DPB162-AE, an inhibitor of the stromal-interacting molecule (STIM)-Orai complex which is about 100 times more potent than 2-APB. Our results indicate that IP3R2 may inhibit the progression of PAH by promoting apoptosis and inhibiting SOCE via the STIM-Orai pathway in PASMCs. These findings suggest a previously undetermined role of IP3R in the development of PAH and may contribute to the development of targeted therapies.


Assuntos
Apoptose , Cálcio/metabolismo , Hipertensão Pulmonar/fisiopatologia , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Músculo Liso Vascular/metabolismo , Artéria Pulmonar/fisiopatologia , Animais , Sinalização do Cálcio , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/patologia , Artéria Pulmonar/patologia , Vasoconstrição
20.
Cancer Chemother Pharmacol ; 83(1): 123-129, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30377777

RESUMO

PURPOSE: Irinotecan is effective for metastatic colorectal cancer (mCRC). SN-38 is an active metabolite of irinotecan, which is formed by carboxylesterase and inactivated by UDP-glucuronyltransferase (UGT) 1A1. The UGT enzyme activity is reduced in patients with homozygous mutation in UGT1A1 genes (*6/*6, *28/*28 and *6/*28); thus dose reduction is required for prevention of severe adverse events associated with irinotecan. The present study was designed to investigate the relationship between UGT1A1 polymorphisms and the incidence of adverse events or the therapeutic effect in mCRC patients who received irinotecan. METHODS: Sixty-three mCRC patients who received irinotecan during January 2014 and May 2018 were the subjects of this study. The incidence of adverse events, including diarrhea and neutropenia, and the therapeutic effect of irinotecan were compared among homozygous group, heterozygous group and wild-type group. The initial dose of irinotecan was 150 mg/m2 in the heterozygous group and wild-type group, while the dose was reduced by 20% (120 mg/m2) in the homozygous group. RESULTS: The UGT1A1 polymorphisms occurred in 15.9%, 33.3%, and 50.8% for homozygous group, heterozygous group, and wild-type group, respectively. The average dose of irinotecan during overall cycles was not significantly different among three groups, despite the reduction of initial dose in homozygous group. There were no significant differences in the incidence rates of adverse events, tumor response, or time to treatment failure among three groups. CONCLUSION: The present study demonstrated that dose reduction by 20% ensured safety and efficacy of irinotecan in mCRC patients with homozygous mutation in UGT1A1 genes.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glucuronosiltransferase/genética , Irinotecano/administração & dosagem , Polimorfismo Genético , Inibidores da Topoisomerase I/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Genótipo , Homozigoto , Humanos , Irinotecano/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Inibidores da Topoisomerase I/sangue
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