Associations of intensity, duration, cumulative dose, and age at start of smoking, with thyroid cancer in Chinese males: A hospital-based case-control study in Zhejiang Province.

INTRODUCTION: There has been considerable research on the association between smoking status and thyroid cancer risk in males, yet the findings are inconsistent. In this study, we investigated the associations of intensity, duration, cumulative dose, and age at start of smoking, with thyroid cancer in Chinese males. METHODS: From a 1:1 matched case-control study conducted between 2015 and 2017 in Zhejiang Province, China, 676 pairs of male subjects were included in the analysis. The associations between smoking characteristics and thyroid cancer were evaluated in logistic regression models by odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Compared with never smokers, the former smokers were 0.096 times (95% CI: 0.012-0.778) less likely to have thyroid cancer. The significant inverse association was not observed in current smokers (OR=0.333; 95% CI: 0.084-1.322). Among both former and current smokers, higher smoking intensity (>10 cigarettes/day), duration (>15 years), and cumulative dose of smoking (>10 packyears) were significantly associated with reduced occurrence of thyroid cancer. CONCLUSIONS: Our findings indicate that former smoking is inversely associated with thyroid cancer occurrence in Chinese males. The reduction in the occurrence of thyroid cancer was also confirmed for both former and current smokers with higher smoking intensity, duration, and cumulative dose.

Proteomic biomarkers for lung cancer progression.

AIM: Lung adenocarcinoma (LUAD) and lung squamous-cell carcinoma (LUSC) are two major subtypes of lung cancer and constitute about 70% of all the lung cancer cases. The patient's lifespan and living quality will be significantly improved if they are diagnosed at an early stage and adequately treated. METHODS & RESULTS: This study comprehensively screened the proteomic dataset of both LUAD and LUSC, and proposed classification models for the progression stages of LUAD and LUSC with accuracies 86.51 and 89.47%, respectively. DISCUSSION & CONCLUSION: A comparative analysis was also carried out on related transcriptomic datasets, which indicates that the proposed biomarkers provide discerning power for accurate stage prediction, and will be improved when larger-scale proteomic quantitative technologies become available.

Dysplasia features of myelodysplastic syndrome in ethnically Chinese people.

OBJECTIVE: It was our aim to study the diagnostic significances of various dysplasia characteristics in myelodysplastic syndrome (MDS). METHODS: We analyzed 160 cases of primary MDS and a control group including 28 cases of paroxysmal nocturnal hemoglobinuria (PNH), 104 cases of idiopathic thrombocytopenic purpura (ITP), 53 cases of non-severe aplastic anemia (NSAA), 40 cases of megaloblastic anemia and 50 cases of infectious and autoimmune diseases. Peripheral blood smears and bone marrow morphology were reviewed. RESULTS: There was no significant difference in the occurrence rates of a variety of dysplasias in three lineages among MDS, megaloblastic anemia and PNH; however, changes in qualities and quantities in three lineages between NSAA and MDS were significantly different. ITP and MDS showed statistical differences in multiple changes in myeloid and erythroid cells. Significant differences also existed in multiple changes in erythroid series and megakaryocytes between infectious and autoimmune diseases and MDS. Morphological abnormalities highly related with MDS included multinucleated erythroblasts, ringed sideroblasts, poikilocytosis and gigantocytes, pseudo-Pelger neutrophils, ring-shaped nucleus, and micromegakaryocytes. CONCLUSIONS: It is difficult to discriminate megaloblastic anemia and PNH from MDS by means of cell morphology. Different dysplasias of MDS have specific diagnostic values.

[Surface stress analysis of distal extension removable partial denture retained with two types of semi-precision attachments].

OBJECTIVE: The aims of this study are to analyze the surface stress of the periodontal supporting bone of the bilateral distol extension removable partial denture which is retained by using intra-coronal or extra-coronal semi-precision attachment, and to characterize the biomechanics of these two designs by using a strain gauge. METHODS: A fresh human mandible specimen with 76|67 missing and six bilateral partial removable denture retained with six semi-precision attachments were made, including three attachments with intra-coronal studs and three attachments with extra-coronal vertical bars. A total of six 45 degrees rosette strain gauges were bonded at six prepared points on the surface of the mandible to measure the surface stress, including the middle point between 76 of the buccal edentulous alveolar crest area under the denture base verge(point 1), the distal buccal cervix of 5 (point 2), the buccal apical area of 5 (point 3), the buccal middle area of 34 roots (point 4, 5), the lingual middle area of 5 root (point 6). The static loads of 14N, 28N and 42N were applied vertically, buccally 45 degrees, lingually 45 degrees at the middle point of the 6|6 occlusal surface. The micro-strain was recorded, and the maximal/minimal principle stresses were calculated for each RPD and each point. The stress characteristics of these two types of attachments were compared and analyzed. RESULTS: In most situations, the stress of these two semi-precision attachments showed significant differences. The vertical load: The stress values of these intra-coronal and extra-coronal attachments at points 1, 2, 3, 4, 6 differed significantly(P < 0.05), including points 1, 2, (sigma intra < sigma extra) and points 3, 4, 6(sigma intra > sigma extra). Buccal loads: The stress values of these intra-coronal and extra-coronal attachments at points 1, 2, 3, 4, 5 differed significantly(P < 0.05), including points 1, 2(sigma intra < sigma extra) and points 3, 4, 5(sigma intra > sigma extra). Lingual loads: The stress values of these intra-coronal and extra-coronal attachments at points 2, 3, 4, 6 differed significantly (P < 0.05, sigma intra > sigma extra). The intra-coronal attachment generally produced higher stress at the site of the alveolar bone around the abutment than the extra-coronal attachment, but extra-coronal attachment produced higher stress at the edentulous alveolar crest and the distal cervical alveolar bone of the distal abutment than the intra-coronal attachment. CONCLUSION: The intra-coronal attachment is suggested to be applied in some cases that the periodontal condition of distal abutment was good, and the extra-coronal attachment is suggested to be used in some cases that the condition of the edentulous alveolar crest is fairly good, while the periodontal condition of the distal abutment was relatively weak.

Synthesis of 2',3'-dideoxy-2'-trifluoromethylnucleosides from alpha-trifluoromethyl-alpha,beta-unsaturated ester.

The treatment of alpha-bromo-alpha,beta-unsaturated esters 2 with FSO(2)CF(2)CO(2)Me and CuI in DMF/HMPA constitutes a new synthetic scheme for the preparation of alpha-trifluoromethyl-alpha, beta-unsaturated esters 3. The trifluoromethylation of (Z)/(E)-ethyl 3-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-bromo-2-propenoate (2e), which is derived from 1-(R)-glyceraldehyde acetonide, yields the key intermediate alpha-trifluoromethyl-alpha,beta-unsaturated esters 3e. This is transformed into anomeric acetates 8a and 8b and is used for the synthesis of a number of 2', 3'-dideoxy-2'-trifluoromethylnucleosides.

Pulmonary angiotensin-converting enzyme (ACE) binding and inhibition in humans. A positron emission tomography study.

Angiotensin-converting enzyme (ACE) inhibition attenuates pulmonary hypertension and delays the development of pulmonary vascular remodeling in animal models. Thus, ACE inhibition might be a useful treatment for primary pulmonary hypertension (PPH). To determine the dose of ACE inhibitor required to specifically block pulmonary ACE in humans, we measured the combined forward rate constant (CFRC) for [(18)F]-fluorocaptopril, which is proportional to the mass of ACE in the lung, using positron emission tomography (PET). In five normal subjects, CFRC was measured twice, 1 wk apart, to assess measurement reproducibility. The CFRC was 0.151 +/- 0.067 for the first measurement and 0.140 +/- 0.060 for the second measurement (p = not significant [NS]). In five normals, CFRC decreased on average 84%, from 0.177 +/- 0.053/s to 0.028 +/- 0.017/s (p < 0.05), after 1 wk ingestion of 5 mg enalapril orally once a day (the scans were performed 24 h after the last medication). Similarly, in five patients with PPH, CFRC decreased on average 76%, from 0.052 +/- 0. 020/s to 0.012 +/- 0.003 (p < 0.01), after 1 wk enalapril, despite much lower baseline values. We conclude that the total mass of pulmonary ACE appears to be significantly reduced in PPH and that only low doses of ACE inhibitors may be needed to block the effects of ACE on vascular remodeling in PPH.

Lutetium texaphyrin (Lu-Tex): a potential new agent for ocular fundus angiography and photodynamic therapy.

PURPOSE: To investigate the suitability of lutetium texaphyrin (lu-tex) as a fluorescence imaging agent in the delineation of retinal vascular and choroidal vascular diseases. The utilization of an efficient fluorescent molecule that is also a photosensitizer represents a unique opportunity to couple diagnosis and therapy. METHODS: Fundus fluorescence angiography comparing lu-tex (motexafin lutetium, Optrin, Pharmacyclics Inc, Sunnyvale, California) with the conventional angiographic dyes, sodium fluorescein, and indocynanine green (ICG), was performed on the eyes of normal and laser-injured New Zealand white rabbits. Plasma pharmacokinetic data and plasma protein binding were assessed in addition to light microscopy of the retina in both imaged and laser-injured eyes. RESULTS: Normal retinal and choroidal vasculature was well delineated by lu-tex angiography. Experimentally induced choroidal and retinal vascular lesions were enhanced by lu-tex and demonstrated different staining patterns than fluorescein or ICG, particularly at the margins of the lesions. Lu-tex cleared rapidly from the plasma, with 39.7% bound to the high-density lipoprotein (HDL) fraction while 15.8% was bound to the low-density lipoprotein (LDL) fraction. No evidence of retinal toxicity after dye administration was observed by either ophthalmoscopy and fundus photography or by light microscopy. CONCLUSION: Lu-tex angiography is a potentially valuable method for retinal vascular and choroidal vascular evaluation, and it has advantages over fluorescein and ICG angiography. The same agent could conceivably be used for both the identification of abnormal vasculature and subsequent photodynamic treatment.

Pulmonary and cardiac beta-adrenoceptor density in vivo in asthmatic subjects.

To examine whether there is a primary deficit in beta-adrenoceptor density in asthma, pulmonary and cardiac beta-receptor density was determined in vivo with positron emission tomography (PET) in 10 male asthmatic subjects (36 +/- 8 yr of age) and compared with that in 30 age-matched normal male subjects (36 +/- 8 yr of age). Pulmonary beta-receptor density was 10.3 +/- 1.8 pmol/g tissue for the asthmatic group and 10.9 +/- 1.9 for the normal group. Cardiac beta-receptor density was 9.1 +/- 3.3 pmol/g for the asthmatic group and 8.8 +/- 2.3 pmol/g for the normal group. There was no difference in either pulmonary or cardiac beta-receptor density between the two groups. In addition, an inverse relationship was observed between FEV1 % predicted and pulmonary beta-receptor density in asthmatic subjects. In conclusion, beta-receptor numbers are normal in untreated asthmatic subjects.

Effect of long-term beta2-agonist dosing on human cardiac beta-adrenoceptor expression in vivo: comparison with changes in lung and mononuclear leukocyte beta-receptors.

BACKGROUND: Tachyphylaxis to the cardiac effects of beta-adrenoceptor stimulation after long-term beta2-agonist administration is well recognized, but the influence on global cardiac beta-adrenoceptor density has not been previously investigated in vivo. Positron emission tomography (PET) has made possible the noninvasive quantification of regional receptor density. This study assesses the effect of long-term beta2-agonist dosing on cardiac beta-adrenoceptors. METHODS AND RESULTS: Beta-adrenoceptors in the hearts of 29 healthy male subjects aged 35 +/- 8 years were imaged and quantified in vivo by means of PET and compared with the receptor density in the same subjects' lung tissue. Mononuclear leukocyte (MNL) beta-receptor density was determined in vitro by means of a radioligand binding assay. Beta-receptor density was 8.41 +/- 2.03 pmol/gm tissue in heart, 10.81 +/- 1.91 pmol/gm tissue in lung, and 38.0 +/- 17.5 fmol/mg protein on MNLs. There was a weak relationship between cardiac and pulmonary beta-receptor densities (r = 0.45, p < 0.02) but not between cardiac and MNL receptor density. In seven subjects, the measurements were repeated after 2 weeks of albuterol treatment (4 mg orally twice daily and 200 microg inhaled four times daily in the first week, with doubling of the dose during the second week). After the albuterol treatment, beta-receptor density fell on average by 19% (p < 0.05) in the heart compared with 22% (p < 0.05) in the lung and 42% (p < 0.05) in MNLs. Correlations were found between the percentage changes in receptor density in heart and lung (r = 0.98, p < 0.001) and in heart and MNLs (r = 0.99, p < 0.002). CONCLUSIONS: Two weeks of high-dose albuterol results in equivalent downregulation of beta-receptors in vivo, both in the lung and in the heart.

In vivo quantification of human pulmonary beta-adrenoceptors: effect of beta-agonist therapy.

In human subjects, chronic beta2-agonist dosing reduces mononuclear leukocyte (MNL) beta-adrenoceptor numbers. The aim of this study was to investigate whether this downregulation also occurs in the lung. Seven healthy male subjects were treated for 2 wk with oral (up to 16 mg/d) and inhaled (up to 1.6 mg/d) albuterol (salbutamol in Europe). Pulmonary maximal beta-adrenoceptor binding capacity (Bmax) was determined in vivo using positron emission tomography (PET) and the beta-receptor antagonist ligand, 11C-labeled CGP-12177, before and after the 2-wk chronic dosing. MNL Bmax was also measured, using a radioligand binding assay and 3H-labeled CGP-12177. Bronchodilator responses to the beta2-agonist were determined after each PET scan by measuring the change in specific airway conductance (SGaw) after increasing doses of inhaled albuterol. Pulmonary and MNL Bmax fell by 22% +/- 14% (p < 0.05) and 42% +/- 19% (p < 0.05) respectively. The changes in pulmonary and MNL Bmax were correlated (r = 0.9, p < 0.05). There was also a reduction in the bronchodilator response to inhaled albuterol. In a further six subjects, pulmonary and MNL Bmax did not change during an acute infusion of albuterol (2 to 4 microg/kg/h). The reduction in pulmonary beta-adrenoceptor numbers after chronic albuterol dosing may be predictable from the changes observed in circulating MNL cells.

In vivo quantification of human pulmonary beta-adrenoceptor density using PET: comparison with in vitro radioligand binding.

UNLABELLED: A new method has recently been developed to quantify pulmonary beta-adrenergic receptors in vivo using PET. This study used in vitro radioligand binding assay (RLBA) as the gold standard to validate in vivo PET measurements. METHODS: Five male patients with lung cancer aged 57 yr (range 42-67 yr) were studied. PET scanning was performed the day before thoracotomy to determine regional pulmonary beta-receptor density. RLBA was carried out on cell membranes prepared from specimens of lung tissue obtained at the thoracotomy to measure beta-receptor density in vitro. In both cases, the hydrophilic nonselective beta-antagonist radioligand (S)-CGP-12177 was used. For PET studies, this was labeled with 11C and for RLBA with 3H. RESULTS: In the PET study, beta-receptor density (Bmax) was 9.43 +/- 1.32 pmole g-1 tissue. In the RLBA study, Bmax was 99.0 +/- 15.5 fmole mg-1 protein, equivalent to 9.90 +/- 1.55 pmole mg-1 tissue. These values are in good agreement with previously reported in vitro measurements on human lung membranes using 125I-iodocyanopindolol. A correlation was found between beta-adrenergic density obtained using PET and beta-adrenergic density obtained using RLBA (r = 0.92; p < 0.05). CONCLUSION: The results support the use of PET as a new method for imaging and the way for studies of physiological and pharmacological regulation of beta-adrenergic receptors through noninvasive serial measurements.

Reduced beta adrenoceptor density in vivo in human lung tumours: a preliminary study with positron emission tomography.

BACKGROUND: Reduced beta adrenergic receptor density in tumours has been reported in previous in vitro studies. The aim of the present study was to assess whether this occurs in vivo. METHODS: Pulmonary beta adrenoceptors were imaged and quantified in vivo using positron emission tomography (PET) and the beta antagonist radioligand (S)-[11C]CGP-12177 in five men with lung tumours of mean age 58 years (range 42-68). The histology of the tumours was squamous cell carcinoma in two cases, adenocarcinoma in one, carcinoid tumour in one, and large cell carcinoma in one. The regional blood volume and extravascular tissue density were also measured using PET. Regions of interest were drawn for both non-tumour and tumour lung tissue. RESULTS: The mean (SD) blood volume was 0.142 (0.025) ml/ml in tumour regions and 0.108 (0.010) ml/ml in normal lung regions--a difference of 31%. Mean (SD) extravascular tissue density was 0.653 (0.133) g/ml in tumour regions, substantially higher than in normal lung regions (0.157 (0.021) g/ml). On the contrary, beta receptor density was 5.1 (1.8) pmol/g in tumour regions, lower than the value of 9.9 (1.6) pmol/g found in adjacent normal lung--a difference of 48%. CONCLUSIONS: In vivo beta adrenoceptor density is reduced in human lung tumours.

Gadolinium(III) texaphyrin: a tumor selective radiation sensitizer that is detectable by MRI.

Gadolinium(III) texaphyrin (Gd-tex2+) is representative of a new class of radiation sensitizers detectable by magnetic resonance imaging (MRI). This porphyrin-like complex has a high electron affinity [E1/2 (red.) approximately = -0.08 V versus normal hydrogen electrode] and forms a long-lived pi-radical cation upon exposure to hydrated electrons, reducing ketyl radicals, or superoxide ions. Consistent with these chemical findings, Gd-tex2+ was found to be an efficient radiation sensitizer in studies carried out with HT29 cells in in vitro as well as in in vivo single and multifraction irradiation studies with a murine mammary carcinoma model. Selective localization of Gd-tex2+ in tumors was confirmed by MRI scanning.

Gadolinium zeolite as an oral contrast agent for magnetic resonance imaging.

The purpose of this study was to evaluate efficacy and safety of a gadolinium (Gd) zeolite suspension as an oral MRI contrast agent. Serial dilutions of GADO-LITE Oral Suspension 1,2-300 micrograms of Gd(III)/mL) were prepared. MRI (T1 and T2 weighted) of standards and dogs (precontrast and postcontrast) were performed. Toxicity and Gd absorption were also assessed. Subsequently, 30 normal male adult volunteers were divided into six groups of five subjects each. Gd zeolite po suspension was administered before and after MRI in volumes and concentrations ranging from 250 to 1500 mL; 6 to 60 micrograms of Gd+3/mL. The images were rated (efficacy score) by a blinded reader. Vital signs, blood chemistries and urinalysis were recorded. Gadolite Oral Suspension produced excellent enhancement of the dog gastrointestinal (GI) tract. No toxicity or absorption of Gd was observed in dogs receiving doses up to 4 times the anticipated human dose daily for 14 consecutive days. In clinical trials, Gd zeolite significantly improved the efficacy scores for all groups and all pulsing sequences (all P values < .05). Efficacy scores and signal intensities generally increased with concentration and volume. No Gd was detected in blood or urine specimens. No significant adverse events were reported. Gd zeolite is a promising contrast medium for enhancement of the GI tract in MRI.

Dynamics of tumor imaging with Gd-DTPA-polyethylene glycol polymers: dependence on molecular weight.

Macromolecular contrast media offer potential advantages over freely diffusible agents in magnetic resonance (MR) imaging outside the central nervous system. To identify an optimum molecular weight for macromolecular contrast media, the authors studied a novel macromolecular contrast agent, gadolinium diethylenetriaminepentaacetic acid polyethylene glycol (DTPA-PEG), synthesized in seven polymer (average) molecular weights ranging from 10 to 83 kd. Twenty-eight rabbits bearing V2 carcinoma in thighs underwent T1-weighted spin-echo imaging before injection and 5-60 minutes and 24 hours after injection of the Gd-DTPA-PEG polymers or Gd-DTPA at a gadolinium dose of 0.1 mmol/kg. Tumor region-of-interest measurements were obtained at each time point to determine contrast enhancement dynamics. Blood-pool enhancement dynamics were observed for the Gd-DTPA-PEG polymers larger than 20 kd. Polymers smaller than 20 kd displayed dynamics similar to those of the freely diffusible agent Gd-DTPA. Above the 20 kd threshold, tumor enhancement was more rapid for smaller polymers. The authors conclude that the 21.9-kd Gd-DTPA-PEG polymer is best suited for clinical MR imaging.

Preclinical evaluation of gadolinium (III) texaphyrin complex. A new paramagnetic contrast agent for magnetic resonance imaging.

RATIONALE AND OBJECTIVES: Gadolinium III texaphyrin (Gd[III] texaphyrin) complex, a new magnetic resonance imaging contrast (MRI) agent, was evaluated. METHODS: In vitro relaxivity (1.5 T) and stability studies (5% dextrose) were conducted. Subchronic toxicity (8 males, 8 females; 2-20 mumol Gd(III) texaphyrin complex/kg body weight; 3 times per week for 3 weeks). Biodistribution and excretion studies were conducted in Sprague-Dawley rats; MRI studies were conducted in normal and tumor-bearing rats and rabbits. RESULTS: Relaxivity values were as follows: r1 = 19 (mumol/L.sec)-1 and r2 = 22 (mumol/L.sec)-1. The 21-day subchronic toxicity study revealed no abnormalities. The compound is stable. Biodistribution demonstrated liver uptake. Magnetic resonance imaging in normal (n = 34) and tumor-bearing (n = 4) rats and normal (n = 8) and tumor-bearing (n = 19) rabbits revealed: significant (P < .05) contrast enhancement of liver and kidney after 1-17 mumol/kg of Gd(III) texaphyrin complex. Gadolinium (III) texaphyrin complex (2.5 mumol/kg) produced significant contrast enhancement of liver carcinomas in rabbits (n = 8). Thigh V2 carcinomas (n = 22) had selective (P < .05) enhancement, 5 mumol/kg. In rat fibrosarcomas (n = 4), 17 mumol Gd(III) texaphyrin complex produced significant enhancement up to 24 hours. CONCLUSIONS: Gadolinium (III) texaphyrin complex appears to be an effective and safe MRI contrast agent.

In vivo quantification of pulmonary beta-adrenoceptor density in humans with (S)-[11C]CGP-12177 and PET.

The in vivo regional distribution of pulmonary beta-adrenoceptors was imaged and quantified in humans with the hydrophilic beta-adrenoceptor antagonist (S)-CGP-12177 labeled with carbon-11 [(S)-[11C]CGP-12177] and positron emission tomography (PET). Six normal male volunteers and eight patients with hypertrophic cardiomyopathy were studied. PET scanning consisted of transmission (tissue density), C15O (blood volume), and (S)-[11C]CGP-12177 (beta-adrenoceptor) emission scans. High-specific-activity (S)-[11C]-CGP-12177 (7.1 +/- 2.0 micrograms, 6.5 +/- 2.1 GBq/mumol) was given intravenously followed by a low-specific-activity (S)-[11C]CGP-12177 injection (34.0 +/- 4.8 micrograms, 2.3 +/- 0.8 GBq/mumol). Binding capacity (Bmax) was calculated in each region of interest as picomoles per gram by normalizing it to the local extravascular tissue density. In normal subjects, average Bmax for all regions of interest was 14.8 +/- 1.6 (SD) pmol/g, which is similar to previously reported in vitro values. In both groups there were no differences in beta-adrenoceptor density between peripheral and central regions nor between right and left lungs. In patients with hypertrophic cardiomyopathy, extravascular tissue density was 24% higher than in normal subjects; Bmax per milliliter thoracic volume was correspondingly higher but was not different from that in normal subjects when expressed per gram tissue (15.8 +/- 2.6 pmol/g). These data suggest that in vivo beta-adrenoceptor density may be quantifiable in humans with the use of PET. This should offer a means to study physiological regulation through repeat measurements.