Identification of factors contributing to phenotypic divergence via quantitative image analyses of autosomal recessive woolly hair/hypotrichosis with homozygous c.736T>A LIPH mutation.

BACKGROUND: Autosomal recessive woolly hair/hypotrichosis (ARWH/H) is caused by mutations in LIPH. Homozygotes for the LIPH c.736T>A (p.C246S) mutation, the most prevalent genotype in Japanese patients, present varying degrees of hair loss; however, determinants of this phenotypic diversity remain elusive. OBJECTIVES: To establish methodologies for quantitative assessment of clinical severity and provide a detailed characterization to elucidate the factors contributing to phenotypic divergence. METHODS: Digital image analyses were conducted to convert clinical severities into numerical values. Eight patients with ARWH/H were classified into three groups (mild, severe, very severe), based on severity scores. Dermoscopic images were collected and assessed for total hair numbers and hair thickness for intergroup comparisons. RESULTS: The image analysis detected a difference in hair thickness but not in total hair numbers, between mild and severe cases. A marked decrease in total hair number was noted in an atypical very severe case. Histopathologically, a patient with a mild case demonstrated hair miniaturization and a high telogen/anagen ratio without a decrease in total hair count, endorsing dermoscopic observations. Two children demonstrated spontaneous improvement without an increase in total hair numbers, and two adults responded well to topical minoxidil with increased total hair numbers and hair thickness. CONCLUSIONS: The difference in the frequency of underdeveloped hairs may be a major factor contributing to the clinical diversity of hair sparseness in LIPH c.736T>A homozygotes with ARWH/H. Hence, pharmacological modification to thicken existing fine hairs may provide a therapeutic strategy.

Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas.

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.

Effective treatment by glycolic acid peeling for cutaneous manifestation of familial generalized acanthosis nigricans caused by FGFR3 mutation.

BACKGROUND: Acanthosis nigricans (AN) can occur as a cutaneous manifestation of genetic diseases, one of which is associated with activating mutations of the fibroblast growth factor receptor 3 gene (FGFR3). OBJECTIVE: We explored familial AN patients with FGFR3 mutations and examined the effectiveness of glycolic acid (GA) peeling in improving their skin manifestations. METHODS: Sanger sequencing was performed for the genomic DNA extracted from leucocytes of the family members involving familial AN. GA peeling was carried out for the two patients of familial AN once every 2 weeks. RESULTS: Heterozygous c.1949A>C (p.K650T) mutation in FGFR3 was identified for the affected family members examined, whereas the wild-type sequence was found for two unaffected individuals. Hyperpigmentation and coarseness of the skin were improved by GA peeling at regular intervals with few adverse effects. CONCLUSION: We diagnosed our cases as familial generalized AN caused by heterozygous c.1949A>C (p.K650T) mutation of FGFR3. We propose that GA peeling is a useful and safe therapeutic option to treat familial AN.

Cholesterol 25-hydroxylase is a metabolic switch to constrain T cell-mediated inflammation in the skin.

Interleukin-27 (IL-27) is an immunoregulatory cytokine whose essential function is to limit immune responses. We found that the gene encoding cholesterol 25-hydroxylase (Ch25h) was induced in CD4+ T cells by IL-27, enhanced by transforming growth factor­ß (TGF-ß), and antagonized by T-bet. Ch25h catalyzes cholesterol to generate 25-hydroxycholesterol (25OHC), which was subsequently released to the cellular milieu, functioning as a modulator of T cell response. Extracellular 25OHC suppressed cholesterol biosynthesis in T cells, inhibited cell growth, and induced nutrient deprivation cell death without releasing high-mobility group box 1 (HMGB1). This growth inhibitory effect was specific to actively proliferating cells with high cholesterol demand and was reversed when extracellular cholesterol was replenished. Ch25h-expressing CD4+ T cells that received IL-27 and TGF-ß signals became refractory to 25OHC-mediated growth inhibition in vitro. Nonetheless, IL-27­treated T cells negatively affected viability of bystander cells in a paracrine manner, but only if the bystander cells were in the early phases of activation. In mouse models of skin inflammation due to autoreactive T cells or chemically induced hypersensitivity, genetic deletion of Ch25h or Il27ra led to worse outcomes. Thus, Ch25h is an immunoregulatory metabolic switch induced by IL-27 and dampens excess bystander T effector expansion in tissues through its metabolite derivative, 25OHC. This study reveals regulation of cholesterol metabolism as a modality for controlling tissue inflammation and thus represents a mechanism underlying T cell immunoregulatory functions.

Is response rate increment obtained by molecular targeted agents related to survival benefit in the phase III trials of advanced cancer?

BACKGROUND: It remains unclear whether response rate (RR) is related to survival benefit in phase III trials of advanced cancer treated with molecular targeted agents (MTA) in combination with standard therapies. MATERIALS AND METHODS: We carried out a systematic search of PubMed for randomized phase III trials of four solid tumors examining the efficacy of MTA when added to a standard therapy. We examined whether there were any associations between RR increment obtained by the addition of targeted agents (DeltaRR) and survival benefit in phase III trials. RESULTS: We identified 26 phase III trials of MTA with a total of 21 156 patients and 29 experimental arms of MTA. Studies which showed significant survival benefit had higher DeltaRR compared with those which did not show significant benefit. In the receiver operating characteristic curve analysis, using a 7% gain as threshold value for DeltaRR allowed assessment of survival benefit with high sensitivity and specificity. There were also significant relationships between DeltaRR and hazard ratios for overall survival and progression-free survival in the linear regression analysis. CONCLUSION: RR increment obtained by the addition of MTA to a standard therapy may be useful to predict survival benefit in clinical phase III trials of advanced cancer.

Race, ethnicity, sex and temporal differences in Barrett's oesophagus diagnosis: a large community-based study, 1994-2006.

OBJECTIVE: To evaluate the demographics and incidence of Barrett's oesophagus diagnosis using community-based data. DESIGN: Observational study. SETTING: Kaiser Permanente, Northern California healthcare membership, 1994-2006. PATIENTS: Members with an electronic diagnosis of Barrett's oesophagus. MAIN OUTCOME MEASURES: Incidence and prevalence of a new Barrett's oesophagus diagnosis by race, sex, age and calendar year. RESULTS: 4205 persons met the study definition for a diagnosis of Barrett's oesophagus. The annual incidence in 2006 was highest among non-Hispanic whites (39/100,000 race-specific member-years, 95% confidence interval (95% CI) 35 to 43), with lower rates among Hispanics (22/100,000, 95% CI 16 to 29), Asians (16/100,000, 95% CI 11 to 22), and blacks (6/100,000, 95% CI 2 to 12). The annual incidence was higher among men than women (31 vs 17/100,000, respectively, year 2006; p<0.01). The incidence increased with age from 2 per 100,000 for persons aged 21-30 years, to a peak of 31 per 100,000 member-years for persons aged 61-70 years (year 2006). There was no increase in the incidence of new diagnoses until the last two observation years, which coincided with changes in data collection methods and may be due to bias. The overall prevalence among active members increased almost linearly to 131/100,000 member-years by 2006. CONCLUSIONS: The demographic distributions of Barrett's oesophagus differ markedly by race, age and sex and were comparable to those for oesophageal adenocarcinoma. Thus, demographic disparities in oesophageal adenocarcinoma risk may arise partly from the risk of having Barrett's oesophagus, rather than from differing risks of progression from Barrett's oesophagus to cancer. There has been an almost linear increase in the prevalence of diagnosed disease.

Centriolar satellites: molecular characterization, ATP-dependent movement toward centrioles and possible involvement in ciliogenesis.

We identified Xenopus pericentriolar material-1 (PCM-1), which had been reported to constitute pericentriolar material, cloned its cDNA, and generated a specific pAb against this molecule. Immunolabeling revealed that PCM-1 was not a pericentriolar material protein, but a specific component of centriolar satellites, morphologically characterized as electron-dense granules, approximately 70-100 nm in diameter, scattered around centrosomes. Using a GFP fusion protein with PCM-1, we found that PCM-1-containing centriolar satellites moved along microtubules toward their minus ends, i.e., toward centrosomes, in live cells, as well as in vitro reconstituted asters. These findings defined centriolar satellites at the molecular level, and explained their pericentriolar localization. Next, to understand the relationship between centriolar satellites and centriolar replication, we examined the expression and subcellular localization of PCM-1 in ciliated epithelial cells during ciliogenesis. When ciliogenesis was induced in mouse nasal respiratory epithelial cells, PCM-1 immunofluorescence was markedly elevated at the apical cytoplasm. At the electron microscopic level, anti-PCM-1 pAb exclusively labeled fibrous granules, but not deuterosomes, both of which have been suggested to play central roles in centriolar replication in ciliogenesis. These findings suggested that centriolar satellites and fibrous granules are identical novel nonmembranous organelles containing PCM-1, which may play some important role(s) in centriolar replication.

Disposal of Nuclear Wastes: At an increased but still modest cost, more options can be explored and the outlook can be improved.

For the present and the foreseeable future the following options appear to be either usable or worth further exploration: mausolea; disposal in mines of various sorts, and perhaps in ice; in situ melt; and further chemical separations. The options are interdependent. It is too early to assess disposal in space, and disposal in the oceans remains unsafe for lack of adequate knowledge. Table 3 is a summary of the main ideas for which we have worked out (sometimes uncertain) costs. For the short term, ultimate disposal in deep mines is the best-developed plan. However, the related concept of in situ melt has significant advantages and should be realistically appraised. Further chemical separation with subsequent recycling of the actinides in a LMFBR should be investigated and implemented, for it would be universally beneficial; on the other hand, additional removal of strontium and cesium does not seem attractive. Thus, for the near future we make the following recommendations: 1) Provide temporary storage facilities to ensure that the projected commercial high-level wastes do not become a public hazard. The AEC adopts this view, and has stated an intention to construct such facilities. But because of the capriciousness of man and nature, a workable ultimate disposal scheme must be developed soon. 2) Fund other ultimate disposal schemes at the same rate as the salt mine project-say $1 million a year or more-to sharpen the technological issues, so that a decision can be reached in the next few years. The schemes should include (i) in situ melt, and the variation with a central repository; (ii) burial in mines other than salt mines (including Antarctic rocks and permanent ice); (iii) further chemical separation of actinides and recycling actinides in a LMFBR. 3) Maintain liaison with the developing space shuttle technology to insure that no opportunity is lost. The AEC has a commitment to hold safety foremost in its waste management program, but budget considerations and management priorities have downgraded the program. Past funding levels and management emphasis have yet to produce, after a decade and a half, one operational long-term storage facility-a sign of both commendable caution and inadequate work. If nuclear power is to resolve our energy needs in the coming decades, its benefits should not be delayed for lack of a viable management program for high-level wastes.

Very-long-period seismic signals and caldera formation at Miyake Island, Japan.

Over a period of roughly 40 days, starting on 8 July 2000, a caldera structure 1.7 kilometers in diameter developed by means of gradual depression and expansion of the summit crater at Miyake Island, Japan. At the same time, very-long-period (VLP) seismic signals were observed once or twice a day. Source mechanism analyses of the VLP signals show that the moment tensor solutions are smooth step functions over a time scale of 50 seconds, with dominant volumetric change components. We developed a model to explain the caldera and the VLP signals, in which a vertical piston of solid materials in the conduit is intermittently sucked into the magma chamber by lateral magma outflow. This model offers potential for making quantitative estimations of the characteristic physical properties of magma systems.

Incidence of Carboplatin-related hypersensitivity reactions in Japanese patients with gynecologic malignancies.

Carboplatin is one of the most commonly used and well-tolerated agents for gynecologic malignancies. The rate of hypersensitivity reactions (HSRs) in the overall population of patients receiving carboplatin has been reported to increase after multiple doses of the agent. We retrospectively analyzed the incidence, clinical features, management, or outcome of carboplatin-related HSRs in 113 Japanese patients with gynecologic malignancies and the possibility of rechallenge with the drug. We intravenously administered carboplatin after paclitaxel or docetaxel. Mild HSRs are resolved by temporary interruption of carboplatin infusion, an additional antihistamine, and/or a corticosteroid. If HSRs arose, carboplatin was diluted, not exceeding 1 mg/mL, and slowly infused over 2 hours in subsequent cycles. Ten patients experienced carboplatin HSRs, with an overall incidence of 8.85%. The first HSR episode was mild in all cases. When retreated with carboplatin, 4 exhibited severe HSRs. More than 9 cycles and/or more than 5000 mg of carboplatin administration significantly increased the incidence of HSRs. In particular, carboplatin treatment beyond 15 cycles and/or 8000 mg increased the risk of severe HSRs (P < 0.0001). The incidence of HSRs in the ovarian carcinoma group was significantly greater than that in the uterine carcinoma group (P = 0.0046). Careful attention should be paid to HSRs during carboplatin treatment beyond 9 cycles and/or 5000 mg. The rate of severe HSRs greatly increases beyond 15 cycles and/or 8000 mg. Further studies are needed to identify potential risk factors that may contribute to the development of carboplatin HSRs and to decrease the risk of reactions.

Helicobacter pylori infection and the risk of Barrett's oesophagus: a community-based study.

OBJECTIVE: Gastric colonisation with the Helicobacter pylori bacterium is a proposed protective factor against oesophageal adenocarcinoma, but its point of action is unknown. Its associations with Barrett's oesophagus, a metaplastic change that is a probable early event in the carcinogenesis of oesophageal adenocarcinoma, were evaluated METHODS: A case-control study was carried out in the Kaiser Permanente Northern California population, a large health services delivery organisation. Persons with a new Barrett's oesophagus diagnosis (cases) were matched to subjects with gastro-oesophageal reflux disease (GORD) without Barrett's oesophagus and to population controls. Subjects completed direct in-person interviews and antibody testing for H pylori and its CagA (cytotoxin-associated gene product A) protein. RESULTS: Serological data were available on 318 Barrett's oesophagus cases, 312 GORD patients and 299 population controls. Patients with Barrett's oesophagus were substantially less likely to have antibodies for H pylori (OR = 0.42, 95% CI 0.26 to 0.70) than population controls; this inverse association was stronger among those with lower body mass indexes (BMIs < 25, OR = 0.03, 95% CI 0.00 to 0.20) and those with CagA+ strains (OR = 0.08, 95% CI 0.02 to 0.35). The associations were diminished after adjustment for GORD symptoms. The H pylori status was not an independent risk factor for Barrett's oesophagus compared with the GORD controls. CONCLUSIONS: Helicobacter pylori infection and CagA+ status were inversely associated with a new diagnosis of Barrett's oesophagus. The findings are consistent with the hypothesis that H pylori colonisation protects against Barrett's oesophagus and that the association may be at least partially mediated through GORD.

Ag Nanoparticles/α-Ag2WO4 Composite Formed by Electron Beam and Femtosecond Irradiation as Potent Antifungal and Antitumor Agents.

The ability to manipulate the structure and function of promising systems via external stimuli is emerging with the development of reconfigurable and programmable multifunctional materials. Increasing antifungal and antitumor activity requires novel, effective treatments to be diligently sought. In this work, the synthesis, characterization, and in vitro biological screening of pure α-Ag2WO4, irradiated with electrons and with non-focused and focused femtosecond laser beams are reported. We demonstrate, for the first time, that Ag nanoparticles/α-Ag2WO4 composite displays potent antifungal and antitumor activity. This composite had an extreme low inhibition concentration against Candida albicans, cause the modulation of α-Ag2WO4 perform the fungicidal activity more efficient. For tumor activity, it was found that the composite showed a high selectivity against the cancer cells (MB49), thus depleting the populations of cancer cells by necrosis and apoptosis, without the healthy cells (BALB/3T3) being affected.