Characterization of genetically modified mice for phosphoglycerate mutase, a vitally-essential enzyme in glycolysis

Models de ratolí; Glucòlisi; Diabetis mellitusModelos de ratón; Glucólisis; Diabetes mellitusMouse models; Glycolysis; Diabetes mellitusGlycolytic metabolism is closely involved in physiological homeostasis and pathophysiological states. Among glycolytic enzymes, phosphoglycerate mutase (PGAM) has been reported to exert certain physiological role in vitro, whereas its impact on glucose metabolism in vivo remains unclear. Here, we report the characterization of Pgam1 knockout mice. We observed that homozygous knockout mice of Pgam1 were embryonic lethal. Although we previously reported that both PGAM-1 and -2 affect global glycolytic profile of cancers in vitro, in vivo glucose parameters were less affected both in the heterozygous knockout of Pgam1 and in Pgam2 transgenic mice. Thus, the impact of PGAM on in vivo glucose metabolism is rather complex than expected before.This work was supported in part by grants from the Japan Society for the Promotion of Science (Grants No. 26310103 to HK and No. 15K19283 to HK), and by the Japan Agency for Medical Research and Development (AMED), Core Research for Evolutional Science and Technology (CREST JP17gm0610002h0306 to HK). HK; Hiroshi Kondoh

Essential role of autoactivation circuitry on Aurora B-mediated H2AX-pS121 in mitosis

Shimada, M., Goshima, T., Matsuo, H. et al. Essential role of autoactivation circuitry on Aurora B-mediated H2AX-pS121 in mitosis. Nat Commun 7, 12059 (2016). https://doi.org/10.1038/ncomms1205

Comprehensive Dipeptide Analysis Revealed Cancer-Specific Profile in the Liver of Patients with Hepatocellular Carcinoma and Hepatitis

As the physical properties and functionality of dipeptides differ from those of amino acids, they have attracted attention in metabolomics; however, their functions in vivo have not been clarified in detail. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and its major cause is chronic hepatitis. This study was conducted to explore tumor-specific dipeptide characteristics by performing comprehensive dipeptide analysis in the tumor and surrounding nontumor tissue of patients with HCC. Dipeptides were analyzed by liquid chromatography tandem mass spectrometry and capillary electrophoresis tandem mass spectrometry. Principal component analysis using 236 detected dipeptides showed differences in the dipeptide profiles between nontumor and tumor tissues; however, no clear difference was observed in etiological comparison. In addition, the N- and C-terminal amino acid compositions of the detected dipeptides significantly differed, suggesting the substrate specificity of enzyme proteins, such as peptidase. Furthermore, hepatitis-derived HCC may show a characteristic dipeptide profile even before tumor formation. These results provide insight into HCC pathogenesis and may help identify novel biomarkers for diagnosis

Muscle mass, quality, and strength; physical function and activity; and metabolic status in cachectic patients with head and neck cancer

Background & aims: Cancer cachexia is commonly associated with poor prognosis in patients with head and neck cancer (HNC). However, its pathophysiology and treatment are not well established. The current study aimed to assess the muscle mass/quality/strength, physical function and activity, resting energy expenditure (REE), and respiratory quotient (RQ) in cachectic patients with HNC. Methods: This prospective cross-sectional study analyzed 64 patients with HNC. Body composition was measured via direct segmental multifrequency bioelectrical impedance analysis, and muscle quality was assessed using echo intensity on ultrasonography images. Muscle strength was investigated utilizing handgrip strength and isometric knee extension force (IKEF). Physical function was evaluated using the 10-mwalking speed test and the five times sit-to-stand (5-STS) test. Physical activity was examined using a wearable triaxial accelerometer. REE and RQ were measured via indirect calorimetry. These parameters were compared between the cachectic and noncachectic groups. Results: In total, 23 (36%) patients were diagnosed with cachexia. The cachectic group had a significantly lower muscle mass than the noncachectic group. Nevertheless, there was no significant difference in terms of fat between the two groups. The cachectic group had a higher quadriceps echo intensity and a lower handgrip strength and IKEF than the noncachectic group. Moreover, they had a significantly slower normal and maximum walking speed and 5 STS speed. The number of steps, total activity time, and time of activity (<3 Mets) did not significantly differ between the two groups. The cachectic group had a shorter time of activity (≥3 Mets) than the noncachectic group. Furthermore, the cachectic group had a significantly higher REE/body weight and REE/fat free mass and a significantly lower RQ than the noncachectic group. Conclusions: The cachectic group had a lower muscle mass/quality/strength and physical function and activity and a higher REE than the noncachectic group. Thus, REE and physical activity should be evaluated to determine energy requirements. The RQ was lower in the cachectic group than that in the noncachectic group, indicating changes in energy substrate. Further studies must be conducted to examine effective nutritional and exercise interventions for patients with cancer cachexia

Infectious cerebral thromboembolism in a patient with lung cancer during long-term administration of gefitinib: a case report

Introduction　Gefitinib is a molecularly targeted drug for oral administration, a selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). It is effective for patients with lung cancer who have EGFR mutation and enables long-term survival of patients with advanced disease.Case presentation　An 84-year-old Asian female with lung cancer (adenocarcinoma, cT4N3M1b stage IV PUL BRA OSS ADR) was treated by gefitinib for two years. The primary tumor was markedly reduced, and bone metastasis had almost disappeared. However, the patient became unconsciousness with general edema and died two days after falling unconsciousness. In the autopsy, it was diagnosed as infectious cerebral thromboembolism due to infectious endocarditis. The cause of death was cardiac tamponade.Conclusions　While long-term survival can be expected in patients with advanced lung cancer by molecular-targeted agents, cautious management is warranted for complications, the same as for the primary disease

The efficacy of magnesium in preventing renal dysfunction due to high-dose cisplatin for treatment of thoracic tumor

Objective: Cisplatin is well known for producing severe adverse events, including renal dysfunction. To prevent renal dysfunctioncaused by cisplatin, routine magnesium supplementation is recommended. However, few reports exist about the efficacy ofmagnesium in preventing renal dysfunction. Therefore, the purpose of this study was to retrospectively survey the efficacy ofmagnesium in preventing renal dysfunction after administration of cisplatin.Methods: We evaluated patients who received first-line cisplatin-based chemotherapy from May 2008 to June 2013.Results: Data from 146 patients and a total of 394 treatments was analyzed. Elevation of serum creatinine was detected in 77 /394 treatments (19.5%). Statistical significance was found between prevention of elevation of serum creatinine and magnesiumsupplementation. The other significant parameters were serum creatinine and eGFR levels before treatment and patient age. Inmultivariate analysis, magnesium and eGFR before treatment were statistically significant.Conclusions: The study results suggest that magnesium supplementation might reduce nephrotoxicity caused by cisplatin. TheeGFR level before treatment might be an important factor associated with nephrotoxicity after cisplatin administration

Cdk1-mediated DIAPH1 phosphorylation maintains metaphase cortical tension and inactivates the spindle assembly checkpoint at anaphase

Animal cells undergo rapid rounding during mitosis, ensuring proper chromosome segregation, during which an outward rounding force abruptly increases upon prometaphase entry and is maintained at a constant level during metaphase. Initial cortical tension is generated by the actomyosin system to which both myosin motors and actin network architecture contribute. However, how cortical tension is maintained and its physiological significance remain unknown. We demonstrate here that Cdk1-mediated phosphorylation of DIAPH1 stably maintains cortical tension after rounding and inactivates the spindle assembly checkpoint (SAC). Cdk1 phosphorylates DIAPH1, preventing profilin1 binding to maintain cortical tension. Mutation of DIAPH1 phosphorylation sites promotes cortical F-actin accumulation, increases cortical tension, and delays anaphase onset due to SAC activation. Measurement of the intra-kinetochore length suggests that Cdk1-mediated cortex relaxation is indispensable for kinetochore stretching. We thus uncovered a previously unknown mechanism by which Cdk1 coordinates cortical tension maintenance and SAC inactivation at anaphase onset

Severe esophagitis directly induced by accumulation of crizotinib-residue at the esophageal mucosa proven with polarizing microscope examination

Crizotinib demonstrates dramatic effects for the patients with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase gene (ALK) fusion or c-ros oncogene 1 (ROS-1) fusion-positive lung cancer, with some characteristic toxicities. Although several studies reported that serious esophagitis was induced by crizotinib, the detailed mechanisms and ways to ameliorate the esophagitis have not been clarified. In this report, we report two cases with lung cancer who had been treated with crizotinib and developed severe esophagitis. Polarizing microscope examination clearly revealed that the accumulation of crizotinib-residue in the esophageal biopsy samples at the second anatomical narrowing of the esophagus in both cases. Since it seemed that the accumulation of crizotinib-residue in the esophageal mucosa directly caused the esophageal inflammation, we recommended taking crizotinib with a large amount of water (more than 200 ml) and to stay sitting upright for 30 minutes after intake. After that, the esophagitis gradually improved and the patients could continue taking crizotinib without dose reduction or withdrawal. Our experiences suggest that this crizotinib-induced esophagitis could be easily prevented by proper administration of crizotinib