Relation of protein kinase A and protein kinase C to signaling pathways of hematopoietic factors in leukemia cell lines

In terms of growth, differentiation, and signaling pathways of hematopoietic factors, the effects of protein kinase C (PKC) activator, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and protein kinase A(PKA) activator, dibutyryl cyclic adenosine monophosphate (dbcAMP) were examined in vitro using three factor-responsive myeloid leukemia cell lines. TPA suppressed the growth of OCI/AML-1 and OCI/AML-5 cells but stimulated the proliferation of OCI/AML-4 cells. TPA differentiated OCI/AML-4 and OCI/AML-5 cells to macrophage-like cells. dbcAMP suppressed the growth of the three without differentiation. The stimulation of TPA induced tyrosine phosphorylation of some proteins in OCI/AML-4 and OCI/AML-5 cells. Their molecular weights were the same as those phosphorylated by hematopoietic factors. The patterns of phosphorylated proteins were different between the two. TPA induced the phosphorylation of MAP kinase, but not that of JAK2 protein in three cell lines. The stimulation of dbcAMP did not induce tyrosine phosphorylation in three cell lines. Overnight exposure of TPA inhibited the tyrosine phosphorylation induced by hematopoietic factors, although that of dbcAMP did not. We suggest a close relation of PKC to signaling pathways of hematopoietic factors, however, the ways of relation were diverse among the cell lines and the clear mechanism explaining its effects on growth and differentiation was not elucidated.     

Basiparallel cut by pneumoencephalotomography and cerebellar atrophy

Summary The basiparallel cut is a nearly horizontal slice of the posterior fossa used in air study and the structures are observed on a plane parallel to the clivus. Total shrinkage of the cerebellum, with or without fourth ventricle dilatation, was found in cases of olivopontocerebellar atrophy, some intoxications, and a few senile subjects. Some atrophy of paleocerebellar portions was seen in Holmes-type degeneration. Another pattern was symmetric shrinkage of neocerebellar lobules and relatively specific for the cases of multiple system atrophy such as progressive supranuclear palsy, striatonigral degeneration, Marie's ataxia, etc. Loss of the superior cerebellar peduncle was clearly demonstrated in this view.     

Prevalence of nocturia among Japanese adults

The prevalence of nocturia among Japanese community-dwelling adults was associated with insomnia, taking into account other correlates of insomnia.     

Correlation of prostate-specific antigen before prostate cancer detection and clinicopathologic features: evaluation of mass screening populations

OBJECTIVES: Although prostate-specific antigen (PSA) has become the reference standard for prostate cancer diagnosis, few reports have examined the long-term changes in PSA values before the diagnosis of prostate cancer in a large number of subjects. We investigated serial PSA levels and related values before prostate cancer diagnosis in a mass screening population and analyzed the values in an attempt to discover some values useful in clinical diagnostic science. METHODS: We performed mass screening for prostate cancer in 9671 subjects from 1986 to 1998. The initial screening method was measurement of prostatic acid phosphatase from 1986 to 1991 and measurement of PSA from 1992 to 1998. As a result, 303 cases of prostate cancer were diagnosed. For all the cases diagnosed before 1991, we measured the serum PSA value in preserved frozen serum. RESULTS: The prostate cancer detection rate was 3.1% among all subjects observed during the 13-year period. By measurement of the PSA level using frozen serum during the pre-PSA era, we found that 62% of patients demonstrated a PSA abnormality for more than 1 year (average 2.8) before prostate cancer diagnosis. Prostate cancer that was diagnosed within 1 year after a PSA value became abnormal was not associated with bone metastasis. Concerning the relationship between PSA velocity (PSAV) and clinical stage, the proportion of Stage B cancer was 86% in the subjects whose PSAV level before diagnosis was 0.18 ng/mL/yr or less and it was only 29% in those with PSAV levels of 4.5 ng/mL/yr or more. Only 3 (3.5%) of 86 patients with prostate cancer with PSAV levels of 4.4 ng/mL/yr or less had bone metastasis, and 2 of those 3 patients had poorly differentiated adenocarcinoma. CONCLUSIONS: Although a total of 62% of patients had an abnormal PSA level more than 1 year before prostate cancer diagnosis, no patients with prostate cancer who were diagnosed within 1 year after the PSA level became abnormal had bone metastasis. Among patients who have undergone mass screening twice or more, a clinically useful indicator of the lack of bone metastasis would be a period between the detection of PSA levels of 4.1 ng/mL or more but not more than 10 ng/mL and prostate cancer diagnosis of less than 1 year and a diagnosis of well or moderately differentiated adenocarcinoma or a PSAV of 4.4 ng/mL/yr or less and a cancer diagnosis of well or moderately differentiated adenocarcinoma.     

A case of left renal cell carcinoma in a young male adult with left varicocele

A 25-year-old man presented to our hospital with the chief complaint of left-sided painless scrotal swelling. Varicocele was diagnosed and high ligation was performed. Two months later, he noticed asymptomatic gross hematuria. Transabdominal ultrasonography and abdominal computed tomographic scanning showed a left renal tumor measuring more than 10 cm in diameter. Radical nephrectomy (thoraco-abdominal approach) was performed and pathological diagnosis was granular cell carcinoma (G2, pT2, INF alpha, pNX, pMX). He then received intramuscular injections of interferon-alpha 3 million units on three days per week. The frequency of renal cell carcinoma was reported to be about 1-3% for individuals in the 20s in the recent Japanese literature, and renal cell carcinoma in a young man with left varicocele is very rare.     

Microvascular decompression for cochlear symptoms

OBJECT: The object of this study was to evaluate the efficacy of a new neurovascular decompression technique in relieving symptoms of cochlear nerve dysfunction. METHODS: Nineteen patients with slowly progressive hearing loss, low-frequency fluctuating hearing loss, and high-pitched tinnitus due to neurovascular compression (NVC) of the eighth cranial nerve in a triangular space between the seventh and eighth cranial nerves (the VII-VIII triangle) of the cerebellopontine angle (CPA) were treated using a new technique for microvascular decompression that was developed by anatomical study in 24 cadaver specimens of the CPA. In 12 of 19 patients the anterior inferior cerebellar artery (AICA) was observed to cause compression in the VII-VIII triangle and this vessel was easily mobilized medially for placement of a silicone sponge or Teflon cushion between the compressing artery and nerve. Postoperatively, hearing loss of 20 dB or more that was present in 11 of the 19 patients with NVC improved by more than 5 dB in seven (64%), including the patient with the most severe hearing loss. Of 18 patients presenting with tinnitus preoperatively, eight (44%) had no tinnitus and an additional nine (for a total of 94%) had good improvement in tinnitus after surgery and at long-term follow up. CONCLUSIONS: The microvascular decompression technique described is highly successful in treating symptoms due to direct or indirect compression of the cochlear nerve, with minimal risk of complications. Recordings of auditory brainstem responses confirmed the clinical diagnosis of NVC of the eighth cranial nerve and correlated with clinical results after microvascular decompression of the cochlear nerve.     

Identification of Ki23819, a highly potent inhibitor of kinase activity of mutant FLT3 receptor tyrosine kinase.

Constitutively active internal tandem duplication (ITD) in the juxtamembrane domain of Fms-like tyrosine kinase 3 (FLT3), a type III receptor tyrosine kinase, is the most common molecular defect associated with acute myeloid leukemia. Its presence confers a poor outcome in patients with acute myeloid leukemia who receive conventional chemotherapy. FLT3-ITD has therefore been considered to be an attractive molecular target for a novel therapeutic modality. We describe here the identification and characterization of Ki23819 as a novel FLT3 inhibitor. Ki23819 suppressed proliferation and induced apoptosis of FLT3-ITD-expressing human leukemia cell lines. The growth-inhibitory effect of Ki23819 on MV4-11 cells was superior to that of SU11248, another FLT3 inhibitor (IC(50)<1 vs 3-10 nM). Ki23819 inhibited the autophosphorylation of FLT3-ITD more efficiently than that of wild-type FLT3. FLT3-ITD-dependent activation of the downstream signaling proteins ERK and STAT5 was also inhibited within similar concentration ranges. Thus, Ki23819 is a potent in vitro inhibitor of FLT3.     

Colorectal Cancer Screening Program in Songjiang district,Shanghai between 2015 and 2017: Evaluation of participation rate and the associated factor

Little is known about the participation rate of newly implemented colorectal cancer (CRC) screening programs in China. Our goals were to identify factors associated with nonparticipation for CRC screening in Songjiang District, Shanghai.We analyzed individuals included in an observational cohort study from 4 towns (Xin Qiao, She Shan, Mao Gang, and Zhong Shan) in Songjiang District. The participation rate was calculated for the CRC screening program based on a fecal immunochemical test and a risk assessment questionnaire between 2015 and 2017 inclusive.Of the 27,130 individuals eligible for inclusion in this study, 20,863 (76.9%) participated in CRC screening at least once during 2015 and 2017. The factors linked with nonparticipation were; being male (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.82–0.93, P < .01), unmarried (OR 0.71, 95% CI 0.64–0.80, P < .01), having a high education level (middle school, OR 0.82, 95% CI 0.74–0.90, P < .01, high school or above, OR 0.64, 95% CI 0.57–0.73, P < .01), absence of chronic disease (OR 0.90, 95% CI 0.85–0.96, P < .01), and living in 2 out of the 4 towns covered (Xin Qiao, OR 0.72, 95% CI 0.66–0.78, P < .01, Zhong Shan, OR 0.29, 95% CI 0.26–0.31, P < .01).The current study revealed several associated factors with nonparticipation for the CRC screening in Songjiang district. These findings will help identify target populations that require an individualized approach to increase the participation rate.     

Cetuximab delivery and antitumor effects are enhanced by mild hyperthermia in a xenograft mouse model of pancreatic cancer

Even with current promising antitumor antibodies, their antitumor effects on stroma‐rich solid cancers have been insufficient. We used mild hyperthermia with the intent of improving drug delivery by breaking the stromal barrier. Here, we provide preclinical evidence of cetuximab + mild hyperthermia therapy. We used four in vivo pancreatic cancer xenograft mouse models with different stroma amounts (scarce, MIAPaCa‐2; moderate, BxPC‐3; and abundant, Capan‐1 and Ope‐xeno). Cetuximab (1 mg/kg) was given systemically, and the mouse leg tumors were concurrently heated using a water bath method for 30 min at three different temperatures, 25°C (control), 37°C (intra‐abdominal organ level), or 41°C (mild hyperthermia) (n = 4, each group). The evaluated variables were the antitumor effects, represented by tumor volume, and in vivo cetuximab accumulation, indirectly quantified by the immunohistochemical fluorescence intensity value/cell using antibodies against human IgG Fc. At 25°C, the antitumor effects were sufficient, with a cetuximab accumulation value (florescence intensity/cell) of 1632, in the MIAPaCa‐2 model, moderate (1063) in the BxPC‐3 model, and negative in the Capan‐1 and Ope‐xeno models (760, 461). By applying 37°C or 41°C heat, antitumor effects were enhanced shown in decreased tumor volumes. These enhanced effects were accompanied by boosted cetuximab accumulation, which increased by 2.8‐fold (2980, 3015) in the BxPC‐3 model, 2.5‐ or 4.8‐fold (1881, 3615) in the Capan‐1 model, and 3.2‐ or 4.2‐fold (1469, 1922) in the Ope‐xeno model, respectively. Cetuximab was effective in treating even stroma‐rich and k‐ras mutant pancreatic cancer mouse models when the drug delivery was improved by combination with mild hyperthermia.     

The positron emission tomography with F18 17beta-estradiol has the potential to benefit diagnosis and treatment of endometrial cancer

BACKGROUND: The positron emission tomography (PET) with F18 17beta-estradiol (FES) has good imaging for assessment of estrogen receptor in breast cancer. CASE: We report on a 30-year-old woman who desired to preserve her fertility with well-differentiated endometrial adenocarcinoma. Before hormone treatment was started, FES-PET showed increased uptake of endometrium, magnetic resonance imaging (MRI) showed thickness and F-18 fluorodeoxyglucose (FDG)-PET showed increased uptake. FES-PET after 3 months showed remaining FES uptake, but there were no abnormal findings on MRI and FDG-PET. Hysteroscopy showed remaining adenocarcinoma. After additional treatment, FES-PET showed a therapeutic response, and hysteroscopy showed no abnormal finding. CONCLUSIONS: To our knowledge, this is the first report that FES-PET has the potential to provide more useful information than did FDG-PET about the hormone therapy.