Correlation between mutated genes and forearm deformity in patients with multiple osteochondroma

BackgroundsExostosin-1 (EXT1) and exostosin-2 (EXT2) cause multiple osteochondromas (MO). In this study, we investigated the correlation between forearm deformity and mutant EXTs in Japanese families with MO.MethodsWe evaluated 112 patients in 71 families with MO. Genomic DNA was isolated from peripheral blood leucocytes. Of these, 28 patients were selected and underwent radiography for their forearms since they had gross forearm deformities. We measured the radial articular angle (RAA), ulna variance (UV), carpal slip (CS), and percentage of radial bowing (%RB) to compare between patients with mutant EXT1 or EXT2 and those with missense or other mutations using Student's t-test.ResultsTwenty-two (78.6%) and 6 (11.4%) out of 28 patients had mutations in EXT1 and EXT2, respectively. Nine (32.1%) and 19 (67.9%) of the 28 patients had missense and other mutations, respectively. The mean age of patients with EXT1 and EXT2 were 25.9 ± 20.3 and 33.5 ± 25.4 years, respectively and those with missense mutation and other mutations were 28.7 ± 27.0 and 24.6 ± 17.0 years, respectively. There were no significant differences in RAA, UV, and RB between patients harbouring mutant EXT1 or EXT2 (RAA, 40.1 ± 8.7 and 31.5 ± 13.9°; UV, ?2.7 ± 5.7 and ?3.1 ± 3.7 mm; %RB, 8.6 ± 1.5 and 8.3 ± 2.0%). CS was significantly greater in patients with mutant EXT1 than that in those with mutant EXT2 (EXT1, 44.1 ± 16.8%; EXT2, 18.6 ± 14.0%). There were no significant differences in RAA, UV, CS and %RB between patients with missense and other mutations.ConclusionsPatients with mutant EXT1 displayed greater CS than patients with mutant EXT2, indicating that patients with MO harbouring EXT1 mutations sustain more severe ulnar drift deformities than those with EXT2 mutations.     

A digest of the Evidence-Based Clinical Practice Guideline for Nephrotic Syndrome 2020

Clinical and Experimental Nephrology -     

Occurrence of diffuse amyloid deposits in the presubicular parvopyramidal layer in Alzheimer's disease

Summary Silver staining by a modified Bielschowsky's technique and immunostaining for -amyloid protein BAP have revealed the occurrence of diffuse amyloid deposits bilaterally in the presubiculum in each of fourteen Alzheimer's disease cases examined. Observations on serial blocks show these deposits to be localized in the parvopyramidal layer of the presubiculum proper and the transsubiculum. They are also observed in the cellular islands within the molecular layer of the subiculum but not in the parasubiculum. These amyloid deposits are not accompanied by neurofibrillary tangles, neuropil threads, or the aggregated microglial reaction which is characteristically associated with classic senile plaques. Convergence of input from limbic and cortical areas might play a significant role in the formation of these diffuse amyloid deposits.Supported by grants from the MRC of Canada, the Alzheimer's Society of B.C., the American Health Assistance Foundation and the McLean Foundation     

CD98 regulates the phosphorylation of HER2 and a bispecific anti-HER2/CD98 antibody inhibits the growth signal of human breast cancer cells

Human epidermal growth factor receptor (HER) family proteins are currently major targets of therapeutic monoclonal antibodies against various epithelial cancers. However, the resistance of cancer cells to HER family-targeted therapies, which may be caused by cancer heterogeneity and persistent HER phosphorylation, often reduces overall therapeutic effects. We herein showed that a newly discovered molecular complex between CD98 and HER2 affected HER function and cancer cell growth. The immunoprecipitation of the HER2 or HER3 protein from lysates of SKBR3 breast cancer (BrCa) cells revealed the HER2-CD98 or HER3-CD98 complex. The knockdown of CD98 by small interfering RNAs inhibited the phosphorylation of HER2 in SKBR3 cells. A bispecific antibody (BsAb) that recognized the HER2 and CD98 proteins was constructed from a humanized anti-HER2 (SER4) IgG and an anti-CD98 (HBJ127) single chain variable fragment, and this BsAb significantly inhibited the cell growth of SKBR3 cells. Prior to the inhibition of AKT phosphorylation, BsAb inhibited the phosphorylation of HER2, however, significant inhibition of HER2 phosphorylation was not observed in anti-HER2 pertuzumab, trastuzumab, SER4 or anti-CD98 HBJ127 in SKBR3 cells. The dual targeting of HER2 and CD98 has potential as a new therapeutic strategy for BrCa.     

Effects of acetylcholine, carbachol, and mannitol on rabbit corneal endothelial function as assessed by corneal deturgescence

Background: Anterior chamber miotic solutions are widely used in ophthalmic surgery to induce pupillary contraction. We investigated whether the acetylcholine, carbachol, or mannitol present in perfusing solutions can affect corneal endothelial function. Methods: Freshly dissected deepithelized rabbit corneas were mounted in a Dikstein-Maurice chamber at 36 °C. The endothelial sides were perfused with six solutions: (A) 55 mM (1%) acetylcholine Cl plus modified balanced salts; (B) control for A, with acetylcholine Cl replaced by sucrose; (C) 0.55 mM (0.01%) carbachol Cl plus balanced salts; (D) balanced salts solution (BS; control for C); (E) 3% mannitol plus modified balanced salts; and (F) modified balanced salts (control for E, with mannitol replaced by sucrose). Corneal thickness was followed for 3 h in each experiment. The effect of solution E did not differ from that of solution F. Results: The carbachol-containing solution produced a small increase in corneal thickness compared to the control solution, while the acetylcholine-containing solution resulted in corneal thickness lower than that in control preparations. Conclusion: From these data, acetylcholine is harmless to the endothelium, and may actually stimulate its fluid pump mechanism. Carbachol, on the other hand, appears to have a detrimental effect.     

Risk factors for breast cancer: A case-control study of screen-detected breast cancer in Miyagi Prefecture, Japan

We examined the associations between reproductive factors and the risk of breast cancer on the basis of information from a total of 201,363 breast cancer screening program participants in Miyagi Prefecture, Japan, during 1987-1991. A case-control study method was applied on analysis. Data on 204 breast cancer cases identified and 810 screening year-, age- and screening area-matched normal controls were extracted. After adjustment for potential confounders, a trend of decreasing risk of breast cancer with increasing number of parity was observed (p for trend=0.03). Among parous women, lactation for the last child decreased the risk of breast cancer (odds ratio (OR) = 0.61, 95% confidence interval (95% CI) 0.39–0.94). These findings were consistent with those in clinical breast cancer reported previously. When cases were divided into two age groups, younger ( 49 y.o.) and older (50 y.o. ), family history of breast cancer among mother and sisters (OR=3.51, 95% CI 1.05–11.80), and lactation for the last child (OR=0.46, 95% CI 0.25–0.84) were associated with younger age breast cancer, whereas number of parity was associated with older age breast cancer (p for trend=0.03). The results by age group suggest that different mechanisms may exist in breast cancer developing at early and late onsets.     

Inhibition of nociceptin-induced allodynia in conscious mice by prostaglandin D2

1. We recently showed that intrathecal administration of nociceptin induced allodynia by innocuous tactile stimuli and hyperalgesia by noxious thermal stimuli in conscious mice. In the present study, we examined the effect of prostaglandins on nociceptin-induced allodynia and hyperalgesia.
2. Prostaglandin D₂ (PGD₂) blocked the allodynia induced by nociceptin in a dose-dependent manner with an IC₅₀ of 26 ng kg⁻¹, but did not affect the nociceptin-induced hyperalgesia at doses up to 500 ng kg⁻¹. BW 245C (an agonist for PGD (DP) receptor) blocked the allodynia with an IC₅₀ of 83 ng kg⁻¹.
3. The blockade of nociceptin-induced allodynia by PGD₂ was reversed by the potent and selective DP-receptor antagonist BW A868C in a dose-dependent manner with an ED₅₀ of 42.8 ng kg⁻¹.
4. Glycine (500 ng kg⁻¹) almost completely blocked the nociceptin-induced allodynia. A synergistic effect on the inhibition of nociceptin-evoked allodynia was observed between glycine and PGD₂ at below effective doses.
5. Dibutyryl cyclic AMP, but not dibutyryl cyclic GMP, blocked the nociceptin-induced allodynia with an IC₅₀ of 2.9 μg kg⁻¹.
6. PGE₂, PGF_2α, butaprost (an EP₂ agonist) and cicaprost (a PGI receptor agonist) did not affect the nociceptin-induced allodynia.
7. These results demonstrate that PGD₂ inhibits the nociceptin-evoked allodynia through DP receptors in the spinal cord and that glycine may be involved in this inhibition.

     

Growth suppression of non-small cell lung carcinoma cells by the introduction of the p16(INK4A) gene

The p16(INK4A) gene is frequently inactivated in nonsmall cell lung carcinoma (NSCLC) by either mutations, deletions or DNA methylations. To assess the biological significance of p16(INK4A) inactivation in the development of NSCLC, full-length p16(INK4A) cDNA was introduced into NSCLC cell lines, A549 and H322, in which p16(INK4A) was homozygously deleted. NSCLC cells transfected with the p16(INK4A) expression vector formed colonies in 20-68% of those with a control vector, and exogenous p16(INK4A) protein was expressed in 4 of 68 A549-derived clones and none of 29 H322-derived clones, respectively. A549-derived clones which stably expressed the exogenous p16(INK4A) gene showed significant decrease in growth rate in vitro and tumorigenicity in vivo in proportion to the level of p16(INK4A) expression. Furthermore, the cell cycle of these cells significantly delayed with accumulation of cells in G1 phase. Micro-injection of p16(INK4A) expression vector also revealed that p16(INK4A) blocked S phase entry in both A549 and H322 cells. These results suggest that the restoration of the p16(INK4A) function suppresses the growth of NSCLC cells by induction of G1 arrest in the cells. Therefore, inactivation of p16(INK4A) may play an important role in the enhancement of unregulated NSCLC growth in vivo.