Genetic alterations of phosphoinositide 3-kinase subunit genes in human glioblastomas

Genetic alterations of PI3K (phosphoinositide 3-kinase) subunits have been documented in a number of tumor types, with increased PI3K activity linked to gene amplification and mutation of catalytic subunits, as well as mutations of regulatory subunits. Among high grade gliomas, activation of the PI3K-AKT signaling pathway through loss of PTEN function is common. We therefore investigated whether genetic alteration of class IA PI3Ks might provide a mechanism for deregulation of this pathway in glioblastomas. We studied a series of glioblastomas with FISH to assess copy number of catalytic subunits (PIK3CA and PIK3CD) and with PCR-SSCP to screen for somatic mutations of conserved regions of both catalytic and regulatory subunits. FISH revealed frequent balanced copy number increases of both PIK3CA and PIK3CD, and one case showed an extra copy limited to PIK3CA. One glioblastoma exhibited a 9-bp deletion that encompassed the exon-intron junction of exon 12 of PIK3R1, documenting for the first time a mutation within a PI3K regulatory subunit in human glioblastoma. This deletion would be predicted to yield a truncated protein that lacks the inhibitory domain, resulting in increased PI3K activity. Furthermore, the case with selected PIK3CA copy number gain and the case with a truncating PIK3R1 mutation both featured AKT activation without PTEN mutation. These results suggest that genetic alterations of class IA PI3K subunit genes can occasionally play a role in human glioblastoma by activating the PI3K-AKT signaling pathway independently of PTEN mutation.     

REACTIVITY OF LYMPHOCYTE SUBPOPULATIONS IN HUMAN MIXED LYMPHOCYTE CULTURE

Loss of antigenicity in the mixed lymphocyte culture (MLC) reaction of lymphocytes precultured at 22°C for 7–10 days was accompanied by a decrease in bone-marrow-derived lymphocytes (B cells) from 22 ± 1% to 13 ± 1%, and an increase in thymus-derived lymphocytes (T cells) from 65 ± 2% to 83 ± 1% (P < 0.001). Depletion of B cells from a fresh lymphocyte suspension by either antihuman immunoglobulin-coated column fractionation or by sheep red blood cell (SRBC) rosette formation resulted in a significant reduction of the cell's ability to stimulate in MLC (P < 0.001). Coating of lymphocytes with rabbit antihuman brain serum abrogated their ability to respond but not the ability to stimulate in MLC.     

Kampo medicines Rikkunshito and Hangeshashinto prevent cisplatin-induced intestinal mucosal injury in rats

Background/PurposeWe examined the effects and mechanisms of rikkunshito (RKT) and hangeshashinto (HST) on cisplatin-induced mucosal injuries in the rat small bowel.MethodsJuvenile rats were divided into 6 groups: sham control, cisplatin injection without kampo medicines, and cisplatin injection with oral administration of low and high doses of RKT (1000 mg/kg and 2000 mg/kg) and HST (500 mg/kg and 1000 mg/kg). Fecal condition, intestinal morphological changes, enterocyte proliferation, and enterocyte apoptosis were assessed.ResultsDiarrhea and atrophy of ileal villi observed in the cisplatin group were significantly improved in all kampo groups. Injury scores of the jejunum were significantly lower with RKT (2000 mg/kg) and HST (500 and 1000 mg/kg) than with cisplatin, and those of the ileum were significantly lower with HST (500 and 1000 mg/kg) than with cisplatin. Enterocyte proliferation of the jejunum was significantly increased with RKT (2000 mg/kg) and HST (500 mg/kg) compared with cisplatin, and those of the ileum were significantly increased in all kampo groups compared with the cisplatin group. Jejunal and ileal apoptosis following cisplatin administration was significantly inhibited by HST.ConclusionsRKT and HST prevented cisplatin-induced intestinal mucosal injury with increasing proliferation of intestinal epithelial cells. HST also attenuated cisplatin-induced crypt cell apoptosis.     

Therapeutic effects of the combined androgen blockade therapy versus luteinizing hormone-releasing hormone analog monotherapy in patients with hormone naïve metastatic prostate cancer: a multi-institutional comparative analysis

BackgroundThe clinical benefit of the combined androgen blockade (CAB) therapy over luteinizing hormone-releasing hormone analog (LH-RHa) monotherapy for hormone naïve metastatic prostate cancer (mHNPC) is unclear. Therefore, we retrospectively compare the effectiveness of CAB with the LH-RHa monotherapy on the prognosis of Japanese patients with mHNPC.MethodsWe retrospectively evaluated the prognosis of 517 patients diagnosed with mHNPC between August 2001 and May 2017. The patients’ data were obtained from the Michinoku Urological Cancer Research Group database and Hirosaki University-related hospitals. Patients were divided into the CAB and LH-RHa monotherapy groups based on primary androgen deprivation therapy (ADT). Overall survival (OS), cancer-specific survival (CSS), and castrate-resistant prostate cancer-free survival (CRPC-FS) were compared between the two groups using the Kaplan-Meier curve analysis. Inverse probability of treatment weighting (IPTW)-adjusted Cox hazard proportional analyses was performed to investigate the effect of primary ADT on oncological outcomes.ResultsThe median age was 73 years old. The numbers of patients in the CAB and LH-RHa monotherapy groups were 447 and 70, respectively. The Kaplan-Meier curve analysis showed no significant differences in either 5-year OS (56.7% vs. 52.5%, P=0.277), CSS (61.1% vs. 56.4%, P=0.400), and CRPC-FS (33.1% vs. 31.1%, P=0.529) between the groups. IPTW-adjusted multivariate Cox hazard proportional analyses showed no significant differences in OS, CSS, and CRPC-FS between the two groups.ConclusionsNo significant differences in oncological outcomes were observed between the CAB and LH-RHa monotherapy groups in patients with mHNPC.     

Urinaryα 1 as an index of proximal tubular function in early infancy

Urinary ₁-microglobulin (U-A₁M) was measured in healthy term infants on days 1, 4, 7, 14, 28, 90 and 180 of life. U-A₁M was high until day 14 and declined thereafter. It was significantly correlated with urinary ₂-microglobulin (U-B₂M) throughout the study, but not with serum A₁M on days 1 or 7. Similar to U-B₂M, U-A₁M in the clinically stable term infants with intrauterine growth retardation (n=4–7) was not elevated on days 1–7. In the sick infants who needed immediate resuscitatio at birth (n=4–8), U-A₁M as well as U-B₂M was high on days 1–7 and then decreased to normal levels, suggesting that U-A₁M can be used as a sensitive marker of acute proximal tubular damage and its recovery. These observations indicate that U-A₁M is a useful index of proximal tubular function in early infancy.     

Personal exposure to nitrogen dioxide from indoor heaters and cooking stoves

The personal exposure to NO₂ generated from various heaters and cooking stoves were studied, using 85 university students. The students attached NO₂ filter badges to their chests or collars and wrote down the period of time for heating and cooking for 1 week. Types of heaters and smoking habits were described through a questionnaire. The urinary hydroxyproline/creatinine ratio (HOP/C) was examined as a biomarker for health effects. The outdoor NO₂ concentration during the study period was 13.5–13.7 g/m³. Smoking and the usage of electric heaters did not affect the exposure to NO₂. Exposure increased according to the length of time kerosene heaters or oil fan heaters were used. The NO₂ concentration during the heating by a kerosene heater and an oil fan heater was calculated to be 219 and 474 g/m³, respectively. The correlation between the period of cooking and personal exposure was also observed. The NO₂ levels during cooking were calculated to be 290 g/m³. Using these calculated values of NO₂ concentration, it is possible to presume the personal exposure levels from the length of time heaters and cooking stoves are used even if the subjects do not attach the filter badges. Neither smoking nor exposure to NO₂ were associated with the increase of urinary HOP/C.     

New lidocaine ester derivatives with a prolonged anesthetic effect

In order to find a new long acting local anesthetic, methyl, ethyl, and butyl ester derivatives of lidocaine were synthesized in our laboratory. The topical anesthetic activity was studied with the effects on corneal reflex in rabbits, and the duration of action with those on the action potential of rabbit vagus nerve was studied in vitro. All drugs showed adequate topical anesthetic activities. The onset time to induce a complete blockage of the action potential in the excised vagus nerve was 97.1 +/- 6.3 s for lidocaine, 289.3 +/- 29.0 s for methyl ester, 186.3 +/- 18.4 s for ethyl ester, and 85.3 +/- 9.0 s for butyl ester. The mean duration of action, which was assessed as the time to recover from the complete block to 30% of control amplitude in a drug-free medium, was 32.5 +/- 3.1 min for lidocaine, 39.9 +/- 11.3 min for methyl ester, 68.2 +/- 4.2 min for ethyl ester, and 108.7 +/- 12.3 min for butyl ester. The differences in the duration of action between the ester derivatives and the original lidocaine were all statistically significant. The duration of action of all drugs studied paralleled with their protein binding capacities. These findings indicate the possibility that the ester derivatives studied, especially butyl ester, can be used as a long acting local anesthetic.