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231.
Triple-negative breast cancer (TNBC) has a poorer prognosis than other breast cancer subtypes; therefore, identifying markers of early recurrence is important. The present study aimed to establish a liquid biopsy protocol for droplet digital PCR-based detection of frequently mutated genes in patients with TNBC. Tumor DNA from 36 patients with TNBC who relapsed within 2 years after surgical resection was retrospectively analyzed. Somatic mutational profiles were evaluated using targeted sequencing to identify frequently mutated genes and genes associated with molecularly targeted therapies. The association between genetic alterations and associated protein phosphorylation was investigated using immunohistochemical analysis. Recurrent hot spot mutations in the plasma were monitored over time. Mutation-specific probes were used to successfully detect mutations in the blood samples of patients who were positive for PIK3CA H1047R and AKT1 E17K mutations. Somatic mutations in AKT1 (14.9%) and PIK3CA (25.5%) were frequently identified in the data. Robust phosphorylation of AKT and S6RP was more common in tumors with PIK3CA H1047R and AKT1 E17K mutational background than in tumors with wild-type PIK3CA and AKT1. In conclusion, the present study evaluated a high-sensitivity detection system for frequently mutated genes that was also applicable for cell-free DNA. The PI3K/AKT pathway was revealed to be activated in patients harboring PIK3CA H1047R and AKT1 E17K mutations; therefore, the PI3K/AKT pathway may be a promising candidate for targeted therapy in these patients.  相似文献   
232.
Macrophages, particularly M1 macrophages, produce proinflammatory cytokines and contribute to the degenerative process in injured intervertebral discs (IVDs). We previously showed that macrophages in both intact and injured IVDs increased following IVD injury. Resident macrophages and macrophages recruited from the peripheral blood have distinct roles in tissue. However, it remains to be determined whether increased macrophages derive from resident or recruited macrophages. We investigated the origin of M1 macrophages in injured IVDs using green fluorescent protein (GFP) transgenic bone marrow chimeric mice. The M1 macrophage marker, CD86, increased in both disc-derived resident macrophages and bone marrow-derived macrophages (BMMs) after lipopolysaccharide/interferon γ stimulation in vitro. Following IVD injury, the proportion of cells positive for the CD86 ligand, the F4/80 antigen, and the surface glycoprotein CD11b (CD86+ CD11b+ F4/80+) significantly increased in GFP+ populations at days 3, 7, and 14. In contrast, CD86+ CD11b+ F4/80+ cells in GFP− populations significantly increased on day 3, and thereafter decreased on days 7 and 14. The proportion of CD86+ CD11b+ F4/80+ cells in the GFP+ populations was significantly higher than that in the GFP− populations at days 1, 3, 7, and 14. Monocyte chemoattractant protein-1 expression in disc-derived macrophages, but not in BMMs, increased following interleukin-1β stimulation. Our results suggest M1 macrophages following IVD injury originate from recruited macrophages. Resident macrophages may behave differently in IVD injury. The role of resident macrophages needs to be clarified. Further investigation is needed.  相似文献   
233.
The relationship between morphological changes in Pseudomonas aeruginosa following antibiotic treatment of experimental infection in mice, susceptibility to phagocytosis, and release of endotoxin was studied. The intraperitoneal administration of P. aeruginosa with imipenem or ceftazidime into mice induced morphological changes in the cells 2 h after injection. Round P. aeruginosa cells with imipenem treatment became susceptible to phagocytosis by peritoneal cells, whereas long filamentous cells with ceftazidime treatment were hardly phagocytized by peritoneal cells. The morphological changes also affected the plasma endotoxin level in the circulation.  相似文献   
234.
We previously reported that an intravenous injection of specified bacterial lipopolysaccharides (LPS) induced anaphylactoid shock in muramyldipeptide (MDP)-primed mice of various strains, including LPS-resistant C3H/HeJ, accompanied with occasional mortality of mice within 1 h. Prior to shock, rapid accumulation of blood platelets into the lungs and liver followed by degradation of the platelets and tissue destruction were observed. In this report we present the following evidence suggesting that complement activation by LPS is responsible for the anaphylactoid reaction. In C5-deficient DBA/2 mice, the platelet degradation and anaphylactoid reactions did not occur following injection of Prevotella intermedia LPS, although transient platelet accumulation into the lungs and liver was observed. Anti-complement agents K-76 COOH (C5 inhibitor) and cobra venom factor (C5 consumer) protected MDP-primed C3H/HeJ mice from mortality in the anaphylactoid reaction induced by P. intermedia and Salmonella typhimurium LPS, respectively. K-76 COOH also inhibited platelet degradation, but not accumulation, induced by P. intermedia LPS in C3H/HeN mice. LPS specimens carrying mannose-homopolymer (MHP) prepared from wild-type Klebsiella 03 and Escherichia coli 08 and 09 and recombinant E. coli 08 and 09 strains, which have been reported to markedly activate the human complement system probably through the lectin pathway, induced anaphylactoid reactions in MDP-primed C3H/HeJ mice. In contrast, LPS from R-mutant of Klebsiella 03 and the parental strain of the recombinant E. coli strains, which lacked MHP, did not induce anaphylactoid reaction. Based on these findings together with those of our previous studies, we postulated the following mechanism for the anaphylactoid reaction: strong complement activation by specified LPS preparations induced degradation of platelets which have accumulated in the lungs and liver, resulting in acute inflammation accompanied with severe tissue destruction, especially in the lungs, which in turn leads to anaphylactoid reaction. However, the mechanism of platelet accumulation induced by LPS is not yet clear.  相似文献   
235.
To characterize the incidences and outcomes of late acute (LA) and chronic graft-versus-host disease (GVHD) in East Asians according to the 2014 National Institutes of Health criteria, we retrospectively analyzed 506 consecutive Japanese patients who had a first allogeneic hematopoietic cell transplantation (HCT) at our center between 2006 and 2013. According to manifestations at onset 91 patients (60%) had LA GVHD and 60 (40%) had chronic GVHD. The cumulative incidences of LA and chronic GVHD were 20% and 17%, respectively, at 48 months after HCT. The involved sites at the onset of LA GVHD included the skin (71%), gut (13%), and liver (8%). The cumulative incidences of relapse, nonrelapse mortality (NRM), transition to chronic GVHD, and discontinued systemic treatment were 11%, 6%, 22%, and 46%, respectively, at 48 months after onset of LA GVHD. Cox models showed that prior acute GVHD was associated with NRM, and HCT from a female donor to a male patient, myeloablative conditioning, and low Karnofsky performance status were associated with a longer duration of systemic treatment after LA GVHD. The most frequently involved sites at the onset of chronic GVHD included the mouth (83%), liver (75%), skin (69%), and eyes (62%). Cox models showed that use of antithymocyte globulin in conditioning regimens was associated with a higher risk of discontinued systemic treatment after the onset of chronic GVHD. The cumulative incidences of relapse, NRM, and discontinued systemic treatment were 16%, 11%, and 41%, respectively, at 48 months after the onset of chronic GVHD. Our results suggested several potential differences between Japanese patients and those of other ethnicities. A direct comparison is needed to formally investigate ethnic differences.  相似文献   
236.
237.
Background Pharmacists have been involved in promoting the proper and safe use of antimicrobial drugs in our institution since 2010. Setting Kochi Medical School Hospital, Japan. Objective To design and evaluate a plan of administration of meropenem (MEPM) based on its pharmacokinetics and pharmacodynamics, drug sensitivity, bacterial cultures, patient condition and renal function. Method A total of 547 patients admitted between April 2010 and March 2013 with serious infections who were successfully treated with MEPM for three or more days were analysed. Patients were initially divided into two groups according to renal function: group A consisted of patients with mild renal dysfunction [creatinine clearance (CLcr) > 50 mL/min] while group B consisted of patients with moderate to severe renal dysfunction (CLcr ≤ 50 mL/min). These groups were then subdivided into two groups according to the implementation of pharmacist intervention. Main outcome measures Daily dose, frequency of administration, dose interval, duration of therapy, adverse events and cost reduction. Results In the non-intervention subgroup within group A, the daily dose was 1,000 mg/day, the frequency of administration was 1.8 ± 0.6 times/day, and the duration of therapy was 9.4 ± 5.4 days. In the intervention subgroup within group A, the daily dose was 1,500 mg/day, the administration frequency was 2.5 ± 0.6 times/day, and the duration of therapy was 7.4 ± 3.7 days. Although the dose was higher (P < 0.05) and the duration of therapy was an average of 2 days shorter (P < 0.05) in the intervention subgroup, there was no significant difference in the rate of adverse events between the two subgroups. In group B, there were no significant differences between the two subgroups in the daily dose, administration frequency, or duration of therapy. However, liver dysfunction was significantly more common in the non-intervention subgroup than in the intervention subgroup (P < 0.05). The total reduction in drug cost in the intervention groups was estimated to be US$17,490 over 3 years. Conclusion Pharmacist intervention was associated with a shorter duration of therapy, lower drug costs, and decreased adverse effect. We believe that our intervention is beneficial in terms of effectiveness and safety, and supports proper antimicrobial use.  相似文献   
238.

Purpose

Multidrug and toxin extrusion proteins (MATEs) are multispecific organic cation transporters mediating the efflux of various cationic drugs into the urine. The present study aimed at identifying endogenous compounds in human plasma and urine specimens as biomarkers to evaluate drug interactions involving MATEs in the kidney without administration of their exogenous probe drugs.

Methods

An untargeted metabolomic analysis was performed using urine and plasma samples from healthy volunteers and mice treated with or without the potent MATE inhibitor, pyrimethamine. Plasma and urinary concentrations of candidate markers were measured using liquid chromatography-mass spectrometry. Transport activities were determined in MATE- or OCT2-expressing HEK293 cells. The deuterium-labeled compounds of candidates were administered to mice for pharmacokinetics study.

Results

Urinary excretion of eleven compounds including thiamine and carnitine was significantly lower in the pyrimethamine-treatment group in humans and mice, whereas no endogenous compound was noticeably accumulated in the plasma. The renal clearance of thiamine and carnitine was decreased by 70%–84% and 90%–94% (p?<?0.05), respectively, in human. The specific uptake of thiamine was observed in MATE1-, MATE2-K- or OCT2-expressing HEK293 cells with Km of 3.5?±?1.0, 3.9?±?0.8 and 59.9?±?6.7 μM, respectively. The renal clearance of carnitine-d 3 was decreased by 62% in mice treated with pyrimethamine.

Conclusions

Our findings indicate that MATEs account for the efflux of thiamine and perhaps carnitine as well as drugs into the urine. The urinary excretion of thiamine is useful to detect drug interaction involving MATEs in the kidney.  相似文献   
239.
Objective: Spontaneous movements at 2 months of corrected age in preterm infants with intellectual disability (ID) were investigated by assessing individual motor elements separated from movements involving the entire body. Methods: Video recordings of 20 preterm infants with ID (16 males, 4 females; median gestational age 26 weeks; median birth weight 810 g) were analyzed and were compared with those of 21 normal preterm infants (8 males, 13 females; median gestational age 30 weeks; median birth weight 1216 g). Results: In the preterm infants with ID at 2 months corrected age, startle response, lateral decumbent position, predominant shoulder rotation, and maintaining hip adduction were more frequently observed and hand sucking, maintaining shoulder abduction, to-and-fro shoulder abduction, to-and-fro elbow flexion, isolated hip adduction, to-and-fro hip abduction, and leg lift were less frequently seen than in the normal preterm infants (Fisher’s exact test, p < 0.05). Conclusion: Abnormal spontaneous movements at 2 months of age in preterm infants with ID result from persistent immature movements and non-emergence of mature movements.  相似文献   
240.
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