Aims
Primary central nervous system lymphoma (PCNSL) manifest aggressive clinical behaviour and have poor prognosis. Although constitutive activation of the nuclear factor‐κB (NF‐κB) pathway has been ...documented, knowledge about the genetic alterations leading to the impairment of the NF‐κB pathway in PCNSLs is still limited. This study was aimed to unravel the underlying genetic profiles of PCNSL.
Methods
We conducted the systematic sequencing of 21 genes relevant to the NF‐κB signalling network for 71 PCNSLs as well as the pyrosequencing of CD79B and MYD88 mutation hotspots in a further 35 PCNSLs and 46 glioblastomas (GBMs) for validation.
Results
The results showed that 68 out of 71 PCNSLs had mutations in the NF‐κB gene network, most commonly affecting CD79B (83%), MYD88 (76%), TBL1XR1 (23%), PRDM1 (20%) and CREBBP1 (20%). These mutations, particularly CD79B and MYD88, frequently coincided within each tumour in various combinations, simultaneously affecting diverse pathways within the network. No GBMs had hotspot mutation of CD79B Y196 and MYD88 L265.
Conclusions
The prevalence of CD79B and MYD88 mutations in PCNSLs was considerably higher than reported in systemic diffuse large B‐cell lymphomas. This observation could reflect the paucity of antigen stimuli from the immune system in the central nervous system (CNS) and the necessity to substitute them by the constitutive activation of CD79B and MYD88 that would initiate the signalling cascades. These hotspot mutations may serve as a genetic hallmark for PCNSL serving as a genetic marker for diagnose and potential targets for molecular therapy.
Mutations involving the NF‐κB gene network are common and have a unique profile in primary central nervous system lymphomas.
Coronary artery calcification is an index of the severity of atherosclerotic vascular disease, and may predict future adverse cardiovascular events in uremic patients undergoing hemodialysis (HD). HD ...patients are exposed to oxidative stress, and show high plasma levels of advanced glycation end products (AGEs). The association between oxidative stress, AGEs, established cardiovascular risk factors, and coronary artery calcification score (CACS) was studied in 225 HD patients (123 male, 102 female patients). CACS was measured by using multi-detector row computed tomography. Age, systolic blood pressure, calcium, calcium × phosphate, malondialdehyde, lipid peroxides, and pentosidine were significantly and positively correlated with CACS. Duration on HD tended to be positively correlated with CACS. From the independent variables included in the forward stepwise multiple linear regression analysis, only age, systolic blood pressure, lipid peroxides, calcium, and pentosidine were independently associated with CACS. The odds ratios for past history of coronary artery disease and the presence of diabetes mellitus for high CACS (≥100) were 6.25 (95% confidence interval; 1.83–21.4) and 2.03 (95% confidence interval; 1.02–4.05), respectively. The plasma pentosidine was significantly and positively correlated with indoxyl sulfate. In conclusion, in addition to such traditional cardiovascular risk factors as past history, diabetes mellitus, aging, systolic blood pressure and calcium overload, oxidative stress (lipid peroxides), and AGE (pentosidine) are associated with extensive coronary artery calcification in HD patients. Lipid peroxidation and glycoxidation may be involved in the pathogenesis of coronary artery calcification.
In advanced gastric cancer (AGC), most clinical trials are designed on the basis of protein expression or gene amplification of specific genes. Recently, next-generation sequencing (NGS) allowed us ...to comprehensively profile the tumor gene status. This study aimed to elucidate the profiling between gene alterations and protein expression in AGC to aid in future clinical trials on AGC.
Formalin-fixed, paraffin-embedded tumor samples from 121 stage III/IV gastric cancer patients were examined for protein expression of tyrosine kinase receptors (RTKs; ERBB2, EGFR, c-MET, and FGFR2) using immunohistochemistry (IHC). Furthermore, 409 cancer-related genes were sequenced to detect mutations and copy number variations using NGS.
Most ERBB2 overexpression (IHC 3+) cases (80.0%) had ERBB2 amplification and did not have other RTK amplification or oncogene mutations. However, one-fourth of MET overexpression cases (25.0%) had ERBB2 alterations. EGFR and FGFR2 overexpression cases had ERBB2 alterations or other gene alterations such as KRAS or PIK3CA. On the other hand, most of the four RTK amplification cases (88.2%) were mutually exclusive with each amplification. However, RTK amplification did not simply correlate with protein overexpression, whereas cases with RTK high-level amplification had protein overexpression and rarely showed other co-existing gene alterations.
AGC involves a complicated arrangement of protein expression and gene alterations. Comprehensive analyses of NGS and IHC will be necessary to design the optimal therapy for treating the appropriate population of patients in future clinical trials.
The objectives of this study were as follows: 1) to compare the metabolic activities of endogenous compounds and their effects on dopamine formation and hydroxylation of steroid hormones, mediated by ...human cytochrome P450 (CYP), including CYP2C9.1 and CYP2C19, as well as the variants CYP2C9.2 (Arg144Cys) and CYP2C9.3 (Ile359Leu); and 2) to assess the effects of steroid hormones on the activities of CYP2C9.1, CYP2C9.2, and CYP2C19 to estimate the contribution of the CYP2C subfamily to metabolism and drug-drug interactions of endogenous compounds. Dopamine formation from
-tyramine and 6β- and 21- (for progesterone) hydroxylation of testosterone, cortisol, and progesterone by CYP2C9 variants, CYP2C19, CYP2D6, and CYP3A4 were determined using HPLC. The effects of steroid hormones such as testosterone, cortisol, and progesterone on tolbutamide methyl hydroxylation mediated by CYP2C subfamily members were investigated. Only CYP2D6 catalyzed dopamine formation. The 6β-hydroxylation activities of testosterone, cortisol, and progesterone catalyzed by CYP2C9 variants and CYP2D6 were less than 5% of those by CYP3A4. Although cortisol did not inhibit tolbutamide methyl hydroxylation catalyzed by CYP2C9.1, CYP2C9.2, or CYP2C19 and testosterone did not inhibit CYP2C19 activity, the reactions catalyzed by CY2C9.1 and CYP2C9.2 were inhibited by testosterone. The inhibition of progesterone by CYP2C19 was stronger than that by CYP2C9.1 and CYP2C9.2. CYP2C9.1 and CYP2C19 noncompetitively and competitively inhibited tolbutamide methyl hydroxylation with inhibition constants of 43.2 μM and 1.03 μM, respectively. Clinical interactions among endogenous compounds would vary within the CYP2C subfamily, although the contribution of the CYP2C subfamily may be of minor importance for dopamine formation and the detoxification (6β-hydroxylation) of endogenous steroid hormones.
Summary
Background: Antimicrobial stewardship has not always prevailed in a wide variety of medical institutions in Japan.
Methods: The infection control team was involved in the review of ...individual use of antibiotics in all inpatients (6348 and 6507 patients/year during the first and second annual interventions, respectively) receiving intravenous antibiotics, according to the published guidelines, consultation with physicians before prescription of antimicrobial agents and organisation of education programme on infection control for all medical staff. The outcomes of extensive implementation of antimicrobial stewardship were evaluated from the standpoint of antimicrobial use density, treatment duration, duration of hospital stay, occurrence of antimicrobial‐resistant bacteria and medical expenses.
Results: Prolonged use of antibiotics over 2 weeks was significantly reduced after active implementation of antimicrobial stewardship (2.9% vs. 5.2%, p < 0.001). Significant reduction in the antimicrobial consumption was observed in the second‐generation cephalosporins (p = 0.03), carbapenems (p = 0.003), aminoglycosides (p < 0.001), leading to a reduction in the cost of antibiotics by 11.7%. The appearance of methicillin‐resistant Staphylococcus aureus and the proportion of Serratia marcescens to Gram‐negative bacteria decreased significantly from 47.6% to 39.5% (p = 0.026) and from 3.7% to 2.0% (p = 0.026), respectively. Moreover, the mean hospital stay was shortened by 2.9 days after active implementation of antimicrobial stewardship.
Conclusion: Extensive implementation of antimicrobial stewardship led to a decrease in the inappropriate use of antibiotics, saving in medical expenses, reduction in the development of antimicrobial resistance and shortening of hospital stay.
Corynebacterium simulans was first reported in 2000. Although it is a member of the normal skin flora, some cases of C. simulans infection have been reported. Other Corynebacterium spp. rarely cause ...chronic pyogenic spondylitis, and pyogenic spondylitis caused by C. simulans has not been reported at all. Here we report a case of acute pyogenic spondylitis due to C. simulans. A 78-year-old man with diabetes mellitus visited our hospital with a 3-day history of lower back pain and fever. Blood culture revealed C. simulans and magnetic resonance images of lumbar vertebrae showed pyogenic spondylitis. He recovered after treatment by vancomycin for 9 weeks and was discharged home. No recurrence has been observed for half a year. This is likely the first reported case of pyogenic spondylitis by C. simulans. In general, Corynebacterium spp. cause chronic pyogenic spondylitis, but this case showed an acute course.
Tumor-suppressor genes on chromosome X can be inactivated by a single hit, any of the point mutations, chromosomal loss and aberrant DNA methylation. As aberrant DNA methylation can be induced ...frequently, we here aimed to identify a tumor-suppressor gene on chromosome X inactivated by promoter DNA methylation. Of 69 genes on chromosome X upregulated by treatment of a gastric cancer cell line with a DNA-demethylating agent, 5-aza-2'-deoxycytidine, 11 genes had low or no expression in the cell line and abundant expression in normal gastric mucosae. Among them, FHL1 was frequently methylation-silenced in gastric and colon cancer cell lines, and methylated in primary gastric (21/80) and colon (5/50) cancers. Knockdown of the endogenous FHL1 in two cell lines by two kinds of shRNAs significantly increased cell growth in vitro and sizes of xenografts in nude mice. Expression of exogenous FHL1 in a non-expressing cell line significantly reduced its migration, invasion and growth. Notably, a somatic mutation (G642T; Lys214Asn) was identified in one of 144 colon cancer specimens, and the mutant FHL1 was shown to lack its inhibitory effects on migration, invasion and growth. FHL1 methylation was associated with Helicobacter pylori infection and accumulated in normal-appearing gastric mucosae of gastric cancer patients. These data showed that FHL1 is a methylation-silenced tumor-suppressor gene on chromosome X in gastrointestinal cancers, and that its silencing contributes to the formation of an epigenetic field for cancerization.
Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes, as demonstrated by its capacity of neuroprotection. It is ...present at higher levels in human blood (200-500 µM) than in other mammals, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences. Here we identify the long-hypothesized urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate-anion exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.
Background
Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder characterized by abdominal pain and abnormal bowel habits, both of which are exacerbated by psychological ...stress. The translocator protein 18kDa (TSPO) is a marker of reactive gliosis in a number of central nervous system (CNS) diseases and responsible for many cellular functions, including neurosteroidogenesis. Although it has been reported that psychological stress disturbs neurosteroids levels, the pathophysiological relevance of TSPO in IBS is poorly understood.
Methods
We examined the effects of a TSPO antagonist, ONO‐2952, on stress‐induced stool abnormality and abdominal pain in rats, and on anxiety‐related behavior induced by cholecystokinin.
Key Results
Oral administration of ONO‐2952 attenuated stress‐induced defecation and rectal hyperalgesia in rats with an efficacy equivalent to that of a 5‐HT3 receptor antagonist. In addition, ONO‐2952 suppressed cholecystokinin‐induced anxiety‐like behavior with an efficacy equivalent to that of psychotropic drugs. On the other hand, ONO‐2952 did not affect spontaneous defecation, gastrointestinal transit, visceral nociceptive threshold, and neurosteroid production in non‐stressed rats even at a dose 10 times higher than its effective dose in the stress models.
Conclusions and Inferences
These results suggest that TSPO antagonism results in antistress action, and that ONO‐2952 is a promising candidate for IBS without side effects associated with current treatment.
Although the pathophysiology of IBS is unknown, dysfunction of the CNS has been implicated. ONO‐2952, an orally available TSPO antagonist, attenuates IBS‐like symptoms in rodents stress models with no impact in non‐stressed rats. These results suggest that central antagonism of TSPO is a promising option for the treatment of IBS without side effects associated with existing medications.
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