Use of Antihypertensive Drugs and Risk of Malignant Melanoma: A Meta-analysis of Observational Studies

Introduction Several antihypertensive drugs are photosensitizing and may promote the development of malignant melanoma (MM), but evidence remains inconsistent. We sought to quantify the association between use of antihypertensive drugs and MM risk. Methods We systematically searched PubMed, Embase, and CENTRAL from inception to August 17, 2017 to identify observational studies that reported the MM risk associated with the use of antihypertensive drugs. A random-effects meta-analysis was used to estimate the odds ratio (OR) with 95% confidence interval (CI). Results Overall, we included eight observational studies (two cohort studies and six case–control studies). Compared with non-use, use of diuretics (OR 1.10; 95% CI 1.03–1.17) or β-adrenergic blocking agents (OR 1.19; 95% CI 1.04–1.37) was significantly associated with increased risk of MM. The use of angiotensin-converting enzyme inhibitors (OR 1.08; 95% CI 0.95–1.23), angiotensin II receptor blockers (OR 1.12; 95% CI 0.95–1.31), and calcium channel blockers (OR 1.12; 95% CI 0.72–1.74) was not significantly associated with increased risk of MM. Conclusions Current evidence from observational studies suggests that use of diuretics or β-adrenergic blocking agents may be associated with increased risk of MM. Further large well-conducted prospective studies are required to confirm our findings

Phosphodiesterase type 5 inhibitors and risk of melanoma: A meta-analysis

Background The association between phosphodiesterase type 5 (PDE5) inhibitors and melanoma risk is controversial. Objective We quantify the association between use of PDE5 inhibitors and melanoma. Methods We systematically searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov for studies that were conducted up to July 13, 2016, and evaluated the association between PDE5 inhibitors and skin cancer. Random effects meta-analyses were used to calculate the adjusted odds ratio (OR) with the 95% confidence interval (CI). Results Five observational studies were included. Compared with PDE5 inhibitor nonuse, PDE5 inhibitor use was slightly but significantly associated with an increased risk for development of melanoma (OR, 1.12; 95% CI, 1.03-1.21) and basal cell carcinoma (OR, 1.14; 95% CI, 1.09-1.19) but not squamous cell carcinoma. For melanoma risk, none of the prespecified factors (dose of PDE5 inhibitor, study design, and study region) significantly affected the results (P > .05). Our sensitivity analysis confirmed the stability of the results. Limitations We included only observational studies, which had some heterogeneities and inconsistent controlling for potential confounders. Conclusions Use of PDE5 inhibitors may be associated with a slightly increased risk for development of melanoma and basal cell carcinoma but not squamous cell carcinoma. However, further large well-conducted prospective studies with adequate adjustment for potential confounders are required for confirmation

Use of antihypertensive drugs and risk of keratinocyte carcinoma: A meta‐analysis of observational studies

Purpose Current epidemiologic evidence on the association between antihypertensive drugs and keratinocyte carcinoma (KC) risk is inconsistent. We sought to quantify this association by meta‐analysis of observational studies. Methods We systematically reviewed observational studies published through August 2016 and reported the KC risk (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]) associated with antihypertensive drugs, including diuretics, angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta‐adrenergic blocking agents (β‐blockers), and calcium channel blockers (CCBs). Random‐effects meta‐analysis was used to estimate the odds ratio (OR) with 95% confidence interval (CI). Results Ten eligible studies were included. Compared with nonuse, diuretic use was significantly associated with increased risk of both BCC (OR, 1.10; 95% CI, 1.01‐1.20) and SCC (OR, 1.40; 95% CI, 1.19‐1.66). Use of β‐blockers or CCBs was associated with increased risk of BCC (but not SCC); the OR with β‐blockers was 1.09 (95% CI, 1.04‐1.15) and with CCBs was 1.15 (95% CI, 1.09‐1.21). Use of ACE inhibitors or ARBs was associated with decreased risk of both BCC (OR, 0.53; 95% CI, 0.39‐0.71) and SCC (OR, 0.58; 95% CI, 0.42‐0.80) in high‐risk individuals. Conclusions Current evidence indicates that use of diuretics might be associated with increased risk of KC, while ACE inhibitors or ARBs might be associated with decreased risk in high‐risk individuals. β‐blockers or CCBs might be positively associated with BCC risk. Further postmarketing surveillance studies and investigations to clarify the possible underlying mechanisms are warranted

Pioglitazone and bladder cancer risk: a systematic review and meta-analysis

Current evidence about the association between pioglitazone and bladder cancer risk remains conflict. We aimed to assess the risk of bladder cancer associated with the use of pioglitazone and identify modifiers that affect the results. We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to 25 August 2016 for randomized controlled trials (RCTs) and observational studies that evaluated the association between pioglitazone and bladder cancer risk. Conventional and cumulative meta-analyses were used to calculate the odds ratio (OR) with 95% confidence interval (CI). A restricted spline regression analysis was used to examine the dose-response relationship with a generalized least-squares trend test. We included two RCTs involving 9114 patients and 20 observational studies (n = 4,846,088 individuals). An increased risk of bladder cancer in patients treated with pioglitazone versus placebo was noted from RCTs (OR, 1.84; 95%CI, 0.99 to 3.42). In observational studies, the increased risk of bladder cancer was slight but significant among ever-users of pioglitazone versus never-users (OR, 1.13; 95%CI, 1.03 to 1.25), which appeared to be both time- (P = 0.003) and dose-dependent (P = 0.05). In addition, we observed the association differed by region of studies (Europe, United States, or Asia) or source of funding (sponsored by industry or not). Current evidence suggests that pioglitazone may increase the risk of bladder cancer, possibly in a dose- and time-dependent manner. Patients with long-term and high-dose exposure to pioglitazone should be monitored regularly for signs of bladder cancer

Novel NAC Transcription Factor TaNAC67 Confers Enhanced Multi-Abiotic Stress Tolerances in <i>Arabidopsis</i>

<div><p>Abiotic stresses are major environmental factors that affect agricultural productivity worldwide. NAC transcription factors play pivotal roles in abiotic stress signaling in plants. As a staple crop, wheat production is severely constrained by abiotic stresses whereas only a few NAC transcription factors have been characterized functionally. To promote the application of NAC genes in wheat improvement by biotechnology, a novel NAC gene designated <i>TaNAC67</i> was characterized in common wheat. To determine its role, transgenic <i>Arabidopsis</i> overexpressing <i>TaNAC67-GFP</i> controlled by the CaMV-35S promoter was generated and subjected to various abiotic stresses for morphological and physiological assays. Gene expression showed that <i>TaNAC67</i> was involved in response to drought, salt, cold and ABA treatments. Localization assays revealed that TaNAC67 localized in the nucleus. Morphological analysis indicated the transgenics had enhanced tolerances to drought, salt and freezing stresses, simultaneously supported by enhanced expression of multiple abiotic stress responsive genes and improved physiological traits, including strengthened cell membrane stability, retention of higher chlorophyll contents and Na⁺ efflux rates, improved photosynthetic potential, and enhanced water retention capability. Overexpression of <i>TaNAC67</i> resulted in pronounced enhanced tolerances to drought, salt and freezing stresses, therefore it has potential for utilization in transgenic breeding to improve abiotic stress tolerance in crops.</p></div

Chromosome location of <i>TaNAC67</i>.

<p>A. Genomic origin of <i>TaNAC67</i> among 20 accessions of wheat and related species. B. Three <i>TaNAC67</i> genes were identified in the A, B and D genomes of hexaploid wheat. AA, <i>T</i>. <i>urartu</i>; SS, <i>Ae</i>. <i>speltoides</i>; DD, <i>Ae</i>. <i>tauschii</i>; AABB, <i>T</i>. <i>diccocoides</i>; AABBDD, <i>T</i>. <i>aestvium</i>; M, 200 bp DNA ladder. C. Chromosome location of <i>TaNAC67</i> genes using 41 nulli-tetrasomic (NT) lines of Chinese Spring. Different <i>TaNAC67</i> genes were missing in each of the NT lines for homoeologous group 6. NT, nulli-tetrasomic line; M, 200 bp DNA ladder. Arrow, pointing at the missing bands in corresponding NT lines.</p

<i>TaNAC67</i> transgenics have higher K⁺ and Na⁺ ion efflux rates than WT.

<p>A. The transgenics had a higher K⁺ ion efflux rate than WT plants after a 30 min NaCl shock. <i>Arabidopsis</i> seedlings were pre-incubated in buffer (0.5 mM KCl, 0.1 mM MgCl₂, 0.1 mM CaCl₂, 0.2 mM Na₂SO₄, and 0.3 mM MES, pH 6.0) for 30 min and assayed in the same buffer containing 100 mM NaCl at pH 6.0. Five plants were measured for each line. Values are means ± SE. B. <i>TaNAC67</i> transgenics had higher Na⁺ ion efflux rates after treatment with 100 mM NaCl. <i>Arabidopsis</i> seedlings were pretreated on MS medium with 100 mM NaCl for 24 h, and then subjected to measurement of Na⁺ ion flux rates. Five plants were measured for each line, and the values are means ± SE.</p

Transgenic <i>TaNAC67 Arabidopsis</i> has enhanced tolerance to drought, salt and freezing stresses.

<p>Phenotypes of six <i>TaNAC67</i> transgenics and WT and GFP controls following drought stress (A), salt stress (B), and freezing stress (C). D, survival rates of transgenic lines under different abiotic stresses. For drought and salinity stress, 11 plants were grown for each line in one treatment, and triplication occurred in three separate plates. For freezing stress, normally pot-cultured transgenic seedlings at 4 weeks were divided into three parts, and each part was stressed at −8±1°C for 1.5 h; 20 plants (5 pots) of each line were used for an experiment. L1-6, six transgenic lines; BF, buffer line. *, ** significantly different at <i>P</i> = 0.05, 0.01, respectively. Values are means ± SE.</p

<i>Cis</i>-acting regulatory elements identified in the promoter region of <i>TaNAC67</i> involved in response to biotic and abiotic stimuli.

<p><i>Cis</i>-acting regulatory elements identified in the promoter region of <i>TaNAC67</i> involved in response to biotic and abiotic stimuli.</p

Sequence alignment of TaNAC67 and NACs in various plant species.

<p>A. Amino acid alignment of TaNAC67 and other NAC family members from selected plant species. The numbers on the left indicate amino acid position. Shared amino acid residues are in black background. Gaps, indicated by dashed lines are introduced for optimal alignment. The region underlined indicates the conserved NAC-domain. ▴, conserved amino acid motif (AA sequences in red rectangles). Alignments were performed using the Megalign program of DNAStar. B. Phylogenetic tree of TaNAC67 and NAC members from other plant species. Abbreviations: At, <i>Arabidopsis thaliana</i>; Bd, <i>Brachypodium distachyon</i>; Eg, <i>Elaeis guineensis</i>; Gm, <i>Glycine max</i>; Hv, <i>Hordeum vulgare</i>; Os, <i>Oryza sativa</i>; Sb, <i>Sorghum bicolor</i>; Sl, <i>Solanum lycopersicum</i>; Vv, <i>Vitis vinifera</i>; Zm, <i>Zea mays</i>. The phylogenetic tree was constructed with the PHYLIP 3.69 package, and the bootstrap values are in percent.</p