G-protein β3 subunit gene (GNB3) variant in causation of essential hypertension

Essential hypertensives display enhanced signal transduction through pertussis toxin-sensitive G proteins. The T allele of a C825T variant in exon 10 of the G protein β3 subunit gene (GNB3) induces formation of a splice variant (Gβ3-s) with enhanced activity. The T allele of GNB3 was shown recently to be associated with hypertension in unselected German patients (frequency=0.31 versus 0.25 in control). To confirm and extend this finding in a different setting, we performed an association study in Australian white hypertensives. This involved an extensively examined cohort of 110 hypertensives, each of whom were the offspring of 2 hypertensive parents, and 189 normotensives whose parents were both normotensive beyond age 50 years. Genotyping was performed by polymerase chain reaction and digestion with BseDI, which either cut (C allele) or did not cut (T allele) the 268-bp polymerase chain reaction product. T allele frequency in the hypertensive group was 0.43 compared with 0.25 in the normotensive group (χ2=22; P=0.00002; odds ratio=2.3; 95% CI=1.7 to 3.3). The T allele tracked with higher pretreatment blood pressure: diastolic=105±7, 109±16, and 128±28 mm Hg (mean±SD) for CC, CT, and 7T, respectively (P=0.001 by 1-way ANOVA). Blood pressures were higher in female hypertensives with a T allele (P=0.006 for systolic and 0.0003 for diastolic by ANOVA) than they were in male hypertensives. In conclusion, the present study of a group with strong family history supports a role for a genetically determined, physiologically active splice variant of the G protein β3 subunit gene in the causation of essential hypertension.

Temperature sensitivity in Indigenous Australians

"To the Editor: Indigenous people face challenges that may make them more sensitive to extreme temperatures. These include poor health, inadequate infrastructure, and poverty.1 Few studies have examined the effects of extreme temperatures on Indigenous people2 or have considered the possible role of body mass in sensitivity to extreme temperatures..."

Hyperopic defocus and diurnal changes in human choroid and axial length

Purpose To investigate the influence of monocular hyperopic defocus on the normal diurnal rhythms in axial length and choroidal thickness of young adults. Methods A series of axial length and choroidal thickness measurements (collected at ~3 hourly intervals, with the first measurement at ~9 am and the final measurement at ~9 pm) were obtained for 15 emmetropic young adults over three consecutive days. The natural diurnal rhythms (Day 1, no defocus), diurnal rhythms with monocular hyperopic defocus (Day 2, – 2.00 DS spectacle lens over the right eye), and the recovery from any defocus induced changes (Day 3, no defocus) in diurnal rhythms were examined. Results Both axial length and choroidal thickness underwent significant diurnal changes on each of the three measurement days (p<0.0001). The introduction of monocular hyperopic defocus resulted in significant changes in the diurnal variations observed in both parameters (p<0.05). A significant (p<0.001) increase in the mean amplitude (peak to trough) of change in axial length (mean increase, 0.016 ± 0.005 mm) and choroidal thickness (mean increase, 0.011 ± 0.003 mm) was observed on day 2 with hyperopic defocus compared to the two ‘no defocus’ days (days 1 and 3). At the second measurement (mean time 12:10 pm) on the day with hyperopic defocus, the eye was significantly longer by 0.012 ± 0.002 mm compared to the other two days (p<0.05). No significant difference was observed in the average timing of the daily peaks in axial length (mean peak time 12:12 pm) and choroidal thickness (21:02 pm) over the three days. Conclusions The introduction of monocular hyperopic defocus resulted in a significant increase in the amplitude of the diurnal change in axial length and choroidal thickness that returned to normal the following day after removal of the blur stimulus.

Self-management of chemotherapy-related nausea and vomiting : a cross-sectional survey of Chinese cancer patients

BACKGROUND Chemotherapy-induced nausea and vomiting (CINV) remain prevalent among cancer patients despite pharmacological advances in CINV therapy. Patients can initiate nonpharmacologic strategies, which potentially play an important role as adjuncts to pharmacological agents in alleviating CINV. Some studies have explored nausea and vomiting self-management (NVSM) behaviors among patients in Western settings; however, little is known about the NVSM behaviors of patients in China. OBJECTIVES This study examines NVSM behaviors of Chinese cancer patients. METHODS A cross-sectional survey was conducted in a specialist cancer hospital in southeast China. RESULTS A sample of 255 cancer patients was recruited. A mean of 8.56 (±3.15) NVSM behaviors was reported. Most NVSM behaviors were rated as moderately effective and were implemented with moderate self-efficacy. Higher distress levels, better functional status, previous similar symptom experiences, receiving chemotherapy as an inpatient, and greater support from multiple levels were related to greater engagement in NVSM; higher self-efficacy levels pertaining to NVSM behaviors were associated with reports of more relief from specific NVSM behaviors. CONCLUSIONS A range of NVSM strategies was initiated by Chinese cancer patients and provided some relief. A range of individual, health status, and environmental factors influenced engagement with and relief from NVSM behaviors. IMPLICATIONS FOR PRACTICE To enhance Chinese patients' NVSM, patients should be supported to engage in behaviors including taking antiemetics, modifying their diet, using psychological strategies, and creating a pleasant environment. The findings highlight the importance of enhancing patients' self-efficacy in NVSM, alleviating symptom distress, and improving social support to achieve better outcomes.

Peripheral refraction patterns out to large field angles

Purpose To investigate hyperopic shifts and the oblique (or 45-degree/135-degree) component of astigmatism at large angles in the horizontal visual field using the Hartmann-Shack technique. Methods The adult participants consisted of 6 hypermetropes, 13 emmetropes and 11 myopes. Measurements were made with a modified COAS-HD Hartmann-Shack aberrometer across T60 degrees along the horizontal visual field in 5-degree steps. Eyes were dilated with 1% cyclopentolate. Peripheral refraction was estimated as mean spherical (or spherical equivalent) refraction, with/against the rule of astigmatism and oblique astigmatism components, and as horizontal and vertical refraction components based on 3-mm major diameter elliptical pupils. Results Thirty percent of eyes showed a pattern that was a combination of type IV and type I patterns of Rempt et al. (Rempt F, Hoogerheide J, Hoogenboom WP. Peripheral retinoscopy and the skiagram. Ophthalmologica 1971;162:1Y10), which shows the characteristics of type IV (relative hypermetropia along the vertical meridian and relative myopia along the horizontal meridian) out to an angle of between 40 and 50 degrees before behaving like type I (both meridians show relative hypermetropia). We classified this pattern as type IV/I. Seven of 13 emmetropes had this pattern. As a group, there was no significant variation of the oblique component of astigmatism with angle, but about one-half of the eyes showed significant positive slopes (more positive or less negative values in the nasal field than in the temporal field) and one-fourth showed significant negative slopes. Conclusions It is often considered that a pattern of relative peripheral hypermetropia predisposes to the development of myopia. In this context, the finding of a considerable portion of emmetropes with the IV/I pattern suggests that it is unlikely that refraction at visual field angles beyond 40 degrees from fixation contributes to myopia development.

Visual performance with lenses correcting peripheral refractive errors

Purpose To design and manufacture lenses to correct peripheral refraction along the horizontal meridian and to determine whether these resulted in noticeable improvements in visual performance. Method Subjective refraction of a low myope was determined on the basis of best peripheral detection acuity along the horizontal visual field out to ±30° for both horizontal and vertical gratings. Subjective refraction was compared to objective refractions using a COAS-HD aberrometer. Special lenses were made to correct peripheral refraction, based on designs optimized with and without smoothing across a 3 mm diameter square aperture. Grating detection was retested with these lenses. Contrast thresholds of 1.25’ spots were determined across the field for the conditions of best correction, on-axis correction, and the special lenses. Results The participant had high relative peripheral hyperopia, particularly in the temporal visual field (maximum 2.9 D). There were differences > 0.5D between subjective and objective refractions at a few field angles. On-axis correction reduced peripheral detection acuity and increased peripheral contrast threshold in the peripheral visual field, relative to the best correction, by up to 0.4 and 0.5 log units, respectively. The special lenses restored most of the peripheral vision, although not all at angles to ±10°, and with the lens optimized with aperture-smoothing possibly giving better vision than the lens optimized without aperture-smoothing at some angles. Conclusion It is possible to design and manufacture lenses to give near optimum peripheral visual performance to at least ±30° along one visual field meridian. The benefit of such lenses is likely to be manifest only if a subject has a considerable relative peripheral refraction, for example of the order of 2 D.

Children’s accommodation during reading of Chinese and English texts

Purpose: Inaccurate accommodation during nearwork and subsequent accommodative hysteresis may influence myopia development. Myopia is highly prevalent in Singapore; an untested theory is that Chinese children are prone to these accommodation characteristics. We measured the accuracy of accommodation responses during and nearwork-induced transient myopia (NITM) after periods spent reading Chinese and English texts. Methods: Refractions of 40 emmetropic and 43 myopic children were measured with a free-space autorefractor for four reading tasks of 10-minute durations: Chinese (SimSun, 10.5 points) and English (Times New Roman, 12 points) texts at 25 cm and 33 cm. Accuracy was obtained by subtracting accommodation response from accommodation demand. Nearwork-induced transient myopia was obtained by subtracting pretask distance refraction from posttask refraction, and regression was determined as the time for the posttask refraction to return to pretask levels. Results: There were significant, but small, effects of text type (Chinese, 0.97 ± 0.32 diopters [D] vs. English, 1.00 ± 0.37 D; F1,1230 = 7.24, p = 0.007) and reading distance (33 cm, 1.01 ± 0.30 D vs. 25 cm, 0.97 ± 0.39 D; F1,1230 = 7.74, p = 0.005) on accommodation accuracy across all participants. Accuracy was similar for emmetropic and myopic children across all reading tasks. Neither text type nor reading distance had significant effects on NITM or its regression. Myopes had greater NITM (by 0.07 D) (F1,81 = 5.05, p = 0.03) that took longer (by 50s) (F1,81 = 31.08, p < 0.01) to dissipate. Conclusions: Reading Chinese text caused smaller accommodative lags than reading English text, but the small differences were not clinically significant. Myopic children had significantly greater NITM and longer regression than emmetropic children for both texts. Whether differences in NITM are a cause or consequence of myopia cannot be answered from this study.

Phase II clinical trial of first or second-line treatment with bortezomib in patients with malignant pleural mesothelioma

Based on promising preclinical efficacy of bortezomib in mesothelioma, a single-arm phase II trial (Ireland Cooperative Oncology Research Group 05-10 study), with Simon's two-stage design, was undertaken to assess efficacy of bortezomib monotherapy in the first-line (poor performance status) and second-line settings. The Bcl-2 homology domain 3-only protein Noxa has been implicated as a key inducer of apoptosis by bortezomib. Thus, in a biomarker research substudy, we hypothesized that deficiency in Noxa expression might correlate with resistance. In the second-line setting, 23 patients were enrolled. Partial response was confirmed in one patient (4.8%) who received four cycles of bortezomib. One patient had stable disease; however, progression occurred in the majority of patients within the first two cycles. Median progression-free survival and overall survival were 2.1 and 5.8 months, respectively. In the first-line setting, ten patients were accrued, and there was no evidence of objective response. In the tumor analysis, expression of Noxa was seen in all biopsies. Bortezomib monotherapy exhibits insufficient activity to warrant further investigation in unselected patients with mesothelioma. © 2012 by the International Association for the Study of Lung.

In arrayed ranks array technology in the study of mesothelioma steven

Mesothelioma is a rare malignancy arising from mesothelial cells lining the pleura and peritoneum. Advances in modern technology have allowed the development of array based approaches to the study of disease allowing researchers the opportunity to study many genes or proteins in a high-throughput fashion. This review describes the current knowledge surrounding array based approaches with respect to mesothelioma research. © 2009 by the International Association for the Study of Lung Cancer.

Potential role of bcl-2 as a suppressor of tumour angiogenesis in non- small-cell lung cancer

It has been reported that genes regulating apoptosis may play a role in tumoral angiogenesis. This study examined the relationship between tumour vascularization, a measure of tumour angiogenesis, and bcl-2 and p53 expression in operable non-small-cell lung cancer (NSCLC). The relationship between bcl-2, p53 and tumour vascularization and epidermal-growth-factor- receptor(EGFR) and c-erbB-2 expression was also studied. Tissue sections from resected tumour specimens of 107 NSCLC patients were evaluated immunohistochemically for vascular grade and bcl-2, p53, EGFR and c-erbB-2 expression. bcl-2 expression was found in 20/107 (19%) cases and was associated with squamous-cell histology (p = 0.03). A strong inverse relationship was found between bcl-2 expression and vascular grade (p = 0.005). All c-erbB-2-positive cases were negative for bcl-2 expression (p = 0.01). Overall no association was found between c-erbB-2 expression and vascular grade. However, in bcl-2-negative cases positive c-erbB-2 expression correlated with low angiogenesis (p = 0.05). No relationship was found between p53 and EGFR expression and bcl-2, c-erbB-2 or vascular grade. The improved prognosis reported in bcl-2-positive NSCLC may be related to low tumour vascularization. The results suggest that the anti-apoptotic gene bcl- 2 plays a role in regulating tumour angiogenesis. Since normal lung epithelium expresses bcl-2, a sequence of tumour progression involving loss of bcl-2, then activation of c-erbB-2 or increase in tumour vascularization is proposed.

Phase III trial comparing paclitaxel poliglumex (CT-2103, PPX) in combination with carboplatin versus standard paclitaxel and carboplatin in the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer

INTRODUCTION: Performance status (PS) 2 patients with non-small cell lung cancer (NSCLC) experience more toxicity, lower response rates, and shorter survival times than healthier patients treated with standard chemotherapy. Paclitaxel poliglumex (PPX), a macromolecule drug conjugate of paclitaxel and polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel and may lead to increased concentrations in tumors due to enhanced vascular permeability. METHODS: Chemotherapy-naive PS 2 patients with advanced NSCLC were randomized to receive carboplatin (area under the curve = 6) and either PPX (210 mg/m/10 min without routine steroid premedication) or paclitaxel (225 mg/m/3 h with standard premedication) every 3 weeks. The primary end point was overall survival. RESULTS: A total of 400 patients were enrolled. Alopecia, arthralgias/myalgias, and cardiac events were significantly less frequent with PPX/carboplatin, whereas grade ≥3 neutropenia and grade 3 neuropathy showed a trend of worsening. There was no significant difference in the incidence of hypersensitivity reactions despite the absence of routine premedication in the PPX arm. Overall survival was similar between treatment arms (hazard ratio, 0.97; log rank p = 0.769). Median and 1-year survival rates were 7.9 months and 31%, for PPX versus 8 months and 31% for paclitaxel. Disease control rates were 64% and 69% for PPX and paclitaxel, respectively. Time to progression was similar: 3.9 months for PPX/carboplatin versus 4.6 months for paclitaxel/carboplatin (p = 0.210). CONCLUSION: PPX/carboplatin failed to provide superior survival compared with paclitaxel/carboplatin in the first-line treatment of PS 2 patients with NSCLC, but the results with respect to progression-free survival and overall survival were comparable and the PPX regimen was more convenient. © 2008International Association for the Study of Lung Cancer.

Single-agent versus combination chemotherapy in patients with advanced non-small cell lung cancer and a performance status of 2 : prognostic factors and treatment selection based on two large randomized clinical trials

Purpose: Data from two randomized phase III trials were analyzed to evaluate prognostic factors and treatment selection in the first-line management of advanced non-small cell lung cancer patients with performance status (PS) 2. Patients and Methods: Patients randomized to combination chemotherapy (carboplatin and paclitaxel) in one trial and single-agent therapy (gemcitabine or vinorelbine) in the second were included in these analyses. Both studies had identical eligibility criteria and were conducted simultaneously. Comparison of efficacy and safety was performed between the two cohorts. A regression analysis identified prognostic factors and subgroups of patients that may benefit from combination or single-agent therapy. Results: Two hundred one patients were treated with combination and 190 with single-agent therapy. Objective responses were 37 and 15%, respectively. Median time to progression was 4.6 months in the combination arm and 3.5 months in the single-agent arm (p < 0.001). Median survival imes were 8.0 and 6.6 months, and 1-year survival rates were 31 and 26%, respectively. Albumin <3.5 g, extrathoracic metastases, lactate dehydrogenase ≥200 IU, and 2 comorbid conditions predicted outcome. Patients with 0-2 risk factors had similar outcomes independent of treatment, whereas patients with 3-4 factors had a nonsignificant improvement in median survival with combination chemotherapy. Conclusion: Our results show that PS2 non-small cell lung cancer patients are a heterogeneous group who have significantly different outcomes. Patients treated with first-line combination chemotherapy had a higher response and longer time to progression, whereas overall survival did not appear significantly different. A prognostic model may be helpful in selecting PS 2 patients for either treatment strategy. © 2009 by the International Association for the Study of Lung Cancer.

Gene expression analysis of diagnostic biopsies predicts pathological response to neoadjuvant chemoradiotherapy of esophageal cancer

OBJECTIVE: This study explored gene expression differences in predicting response to chemoradiotherapy in esophageal cancer. PURPOSE:: A major pathological response to neoadjuvant chemoradiation is observed in about 40% of esophageal cancer patients and is associated with favorable outcomes. However, patients with tumors of similar histology, differentiation, and stage can have vastly different responses to the same neoadjuvant therapy. This dichotomy may be due to differences in the molecular genetic environment of the tumor cells. BACKGROUND DATA: Diagnostic biopsies were obtained from a training cohort of esophageal cancer patients (13), and extracted RNA was hybridized to genome expression microarrays. The resulting gene expression data was verified by qRT-PCR. In a larger, independent validation cohort (27), we examined differential gene expression by qRT-PCR. The ability of differentially-regulated genes to predict response to therapy was assessed in a multivariate leave-one-out cross-validation model. RESULTS: Although 411 genes were differentially expressed between normal and tumor tissue, only 103 genes were altered between responder and non-responder tumor; and 67 genes differentially expressed >2-fold. These included genes previously reported in esophageal cancer and a number of novel genes. In the validation cohort, 8 of 12 selected genes were significantly different between the response groups. In the predictive model, 5 of 8 genes could predict response to therapy with 95% accuracy in a subset (74%) of patients. CONCLUSIONS: This study has identified a gene microarray pattern and a set of genes associated with response to neoadjuvant chemoradiation in esophageal cancer. The potential of these genes as biomarkers of response to treatment warrants further investigation. Copyright © 2009 by Lippincott Williams & Wilkins.

Thymidylate synthase expression and outcome of patients receiving pemetrexed for advanced nonsquamous non-small-cell lung cancer in a prospective blinded assessment phase II clinical trial

INTRODUCTION In retrospective analyses of patients with nonsquamous non-small-cell lung cancer treated with pemetrexed, low thymidylate synthase (TS) expression is associated with better clinical outcomes. This phase II study explored this association prospectively at the protein and mRNA-expression level. METHODS Treatment-naive patients with nonsquamous non-small-cell lung cancer (stage IIIB/IV) had four cycles of first-line chemotherapy with pemetrexed/cisplatin. Nonprogressing patients continued on pemetrexed maintenance until progression or maximum tolerability. TS expression (nucleus/cytoplasm/total) was assessed in diagnostic tissue samples by immunohistochemistry (IHC; H-scores), and quantitative reverse-transcriptase polymerase chain reaction. Cox regression was used to assess the association between H-scores and progression-free/overall survival (PFS/OS) distribution estimated by the Kaplan-Meier method. Maximal χ analysis identified optimal cutpoints between low TS- and high TS-expression groups, yielding maximal associations with PFS/OS. RESULTS The study enrolled 70 patients; of these 43 (61.4%) started maintenance treatment. In 60 patients with valid H-scores, median (m) PFS was 5.5 (95% confidence interval [CI], 3.9-6.9) months, mOS was 9.6 (95% CI, 7.3-15.7) months. Higher nuclear TS expression was significantly associated with shorter PFS and OS (primary analysis IHC, PFS: p < 0.0001; hazard ratio per 1-unit increase: 1.015; 95%CI, 1.008-1.021). At the optimal cutpoint of nuclear H-score (70), mPFS in the low TS- versus high TS-expression groups was 7.1 (5.7-8.3) versus 2.6 (1.3-4.1) months (p = 0.0015; hazard ratio = 0.28; 95%CI, 0.16-0.52; n = 40/20). Trends were similar for cytoplasm H-scores, quantitative reverse-transcriptase polymerase chain reaction and other clinical endpoints (OS, response, and disease control). CONCLUSIONS The primary endpoint was met; low TS expression was associated with longer PFS. Further randomized studies are needed to explore nuclear TS IHC expression as a potential biomarker of clinical outcomes for pemetrexed treatment in larger patient cohorts. © 2013 by the International Association for the Study of Lung Cancer.