Citations

Fifteen percent of lung cancer cases occur in never-smokers and show characteristics that are molecularly and clinically distinct from those in smokers. Epidermal growth factor receptor ( EGFR ) gene mutations, which are correlated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs), are more frequent in never-smoker lung cancers. In this study, microRNA (miRNA) expression profiling of 28 cases of never-smoker lung cancer identified aberrantly expressed miRNAs, which were much fewer than in lung cancers of smokers and included miRNAs previously identified (e.g., up-regulated miR-21) and unidentified (e.g., down-regulated miR-138) in those smoker cases. The changes in expression of some of these miRNAs, including miR-21, were more remarkable in cases with EGFR mutations than in those without these mutations. A significant correlation between phosphorylated-EGFR ( p -EGFR) and miR-21 levels in lung carcinoma cell lines and the suppression of miR-21 by an EGFR-TKI, AG1478, suggest that the EGFR signaling is a pathway positively regulating miR-21 expression. In the never-smoker–derived lung adenocarcinoma cell line H3255 with mutant EGFR and high levels of p -EGFR and miR-21, antisense inhibition of miR-21 enhanced AG1478-induced apoptosis. In a never-smoker–derived adenocarcinoma cell line H441 with wild-type EGFR , the antisense miR-21 not only showed the additive effect with AG1478 but also induced apoptosis by itself. These results suggest that aberrantly increased expression of miR-21, which is enhanced further by the activated EGFR signaling pathway, plays a significant role in lung carcinogenesis in never-smokers, as well as in smokers, and is a potential therapeutic target in both EGFR -mutant and wild-type cases.

Abstract Recent studies have demonstrated an important role for circulating serotonin in regulating bone mass in rodents. In addition, patients treated with selective serotonin reuptake inhibitors (SSRIs) have reduced areal bone mineral density (aBMD). However, the potential physiologic role of serotonin in regulating bone mass in humans remains unclear. Thus we measured serum serotonin levels in a population-based sample of 275 women and related these to total-body and spine aBMD assessed by dual-energy X-ray absorptiometry, femur neck total and trabecular volumetric BMD (vBMD) and vertebral trabecular vBMD assessed by quantitative computed tomography (QCT), and bone microstructural parameters at the distal radius assessed by high-resolution peripheral QCT (HRpQCT). Serotonin levels were inversely associated with body and spine aBMD (age-adjusted R = −0.17 and −0.16, P < .01, respectively) and with femur neck total and trabecular vBMD (age-adjusted R = −0.17 and −0.25, P < .01 and < .001, respectively) but not lumbar spine vBMD. Bone volume/tissue volume, trabecular number, and trabecular thickness at the radius were inversely associated with serotonin levels (age-adjusted R = −0.16, −0.16, and −0.14, P < .05, respectively). Serotonin levels also were inversely associated with body mass index (BMI; age-adjusted R = −0.23, P < .001). Multivariable models showed that serotonin levels remained significant negative predictors of femur neck total and trabecular vBMD, as well as trabecular thickness at the radius, after adjusting for age and BMI. Collectively, our data provide support for a physiologic role for circulating serotonin in regulating bone mass in humans. © 2010 American Society for Bone and Mineral Research

Abstract Background: Enzymatic creatinine assays are routinely used in clinical laboratories to provide more accurate estimated glomerular filtration rates and to avoid a perceived lack of analytical specificity associated with picrate (Jaffe) methods. Negative interferences with the enzymatic creatinine assay, which we noted in several patients on dopamine or dobutamine, prompted our further investigation into interference of catecholamines with enzymatic methods. Methods: Spiked solutions of dopamine, dobutamine, epinephrine, and norepinephrine were added to pooled sera at catecholamine concentrations consistent with clinically relevant dosing. Creatinine was measured enzymatically on the Roche P-Modular, Ortho Clinical Diagnostics Vitros 350, and Abbott i-STAT. Jaffe methods were performed on the Roche P-Modular and Siemens Dimension RxL. In 10 patients receiving dopamine and/or dobutamine via a venous or arterial line we evaluated and compared the extent of in vivo creatinine interference in paired serum samples obtained by venipuncture and from indwelling catheters. Results: All catecholamines caused significant negative interference with the Roche enzymatic creatinine assay, most pronounced for dopamine and dobutamine. The Vitros enzymatic assay demonstrated slight negative interferences, and i-STAT enzymatic and Jaffe methods were unaffected by the presence of catecholamines. Significant (P < 0.001) differences in creatinine concentrations by Roche enzymatic vs Jaffe methods were observed in venipuncture specimens compared with arterial or venous catheter specimens, suggesting dopamine and dobutamine reversibly adhere to the catheter lumen. Conclusions: Negative interferences were pronounced for Roche enzymatic results in blood samples obtained from indwelling catheters, a phenomenon not observed in peripheral draws. Physicians and laboratorians should be alert to the possibility of a falsely low creatinine result and reevaluate questionable samples using a method unaffected by catecholamines.

The mechanisms by which aging progressively depletes testosterone (Te) availability in the male are unknown. Accordingly, the objective was to estimate brain gonadotropin-releasing hormone (GnRH) outflow (release and action), which cannot be observed directly, on the basis of downstream effects on pituitary luteinizing hormone (LH) secretion. LH, in turn, feeds forward on (stimulates) gonadal Te secretion, which then feeds back on (inhibits) GnRH-driven LH secretion. LH and Te concentrations were measured repetitively (every 10 min) over 18 h during graded pharmacological blockade of endogenous GnRH outflow in 24 healthy 20- to 72-yr-old men. Data were analyzed using a new age-dependent regression model of GnRH-LH-Te interactions to estimate pulsatile LH secretion and elimination, GnRH outflow, LH feedforward, and Te feedback. By incorporating regression on age within the dose-response model, we show that aging erodes all three primary forward and reverse pathways linking the brain, pituitary gland, and testes. Aging is associated with concomitant deficits in GnRH → LH feedforward, LH → Te feedforward, and Te → GnRH/LH feedback. The analytical formalism should be generalizable to other ensemble regulatory systems, such as those that control growth, reproduction, stress adaptations, and glucose metabolism.

The purpose of this study was to assess tendon metabolism and suture pull-out strength after simple tendon suture in a tissue culture model. One hundred and twelve flexor digitorum profundus tendons from 28 dogs were cultured for 7, 14, or 21 days with or without a static tensile load. In both groups increased levels of matrix metalloproteinase (MMP) mRNA was noted. Suture pull-out strength did not decrease during tissue culture. While the presence of a static load had no effect on the pull-out strength, it did affect MMP mRNA expression. This tissue culture model could be useful in studying the effect of factors on the tendon-suture interface.

Recent experimental and clinical studies suggested that apart from playing an essential role in blood pressure homeostasis, aldosterone is involved in the pathophysiology of cardiovascular and renal diseases by inducing structural changes in the heart, kidney, and vessel wall. The interindividual variation of aldosterone response to antihypertensive treatment is considerable, and is at least partially explained by genetic variation. In this study, we investigated aldosterone response to two antihypertensive drugs—a thiazide diuretic and an angiotensin receptor blocker (ARB). Genetic variations in 50 candidate genes were tested for association with aldosterone response in four independent samples: African American (AA) responders to a diuretic ( n = 289), AA responders to an ARB ( n = 252), European American (EA) responders to a diuretic ( n = 295) and EA responders to an ARB ( n = 300). Linear regression was used to test the association with inclusion of age, sex, and body mass index as covariates. The results indicated the existence of one or more variants in the kininogen gene (KNG) that influence interindividual variation in aldosterone response. The significant association was replicated in three of four studied groups. The single nucleotide polymorphism rs4686799 was associated in AA and EA responders to the diuretic ( P = 0.04 and P = 0.07, respectively), and rs5030062 and rs698078 were significantly associated in EA responders to the diuretic ( P = 0.05 and P = 0.01) and EA responders to the ARB ( P = 0.04 and P = 0.02). Although the clinical implication of KNG gene variation to antihypertensive drug response is yet to be determined, this novel candidate locus provides important new insights into drug response physiology.

Objective: To describe a case of acquired Fanconi syndrome after treatment with capecitabine, irinotecan, and bevacizumab. Case Summary: A 77-year-old female with metastatic colon cancer presented with vomiting and diarrhea. The patient had been diagnosed with stage IIIC (T3, N2, M0) colon cancer 18 months earlier and was initially treated with FOLFOX6 (regimen of oxaliplatin, fluorouracil, and leucovorin) after her hemicolectomy. She was switched to a capecitabine/oxaliplatin regimen after 4 cycles due to central access problems. She did well until 10 months after her cancer diagnosis, when metastasis was discovered. She was started on reduced doses of capecitabine, irinotecan, and bevacizumab. After her eleventh cycle, she presented to the hospital with the above symptoms. Laboratory test results showed hypokalemia, hypocalcemia, hypophosphatemia, and hypouricemia. The patient had not been started on any new medications other than chemotherapy for over 1 year. The electrolyte derangements were new, since the patient had laboratory values checked every 3 weeks. Despite daily intravenous replacements, the electrolyte abnormalities persisted. Laboratory evaluations demonstrated the presence of euglycemic glucosuria and a high fractional excretion of phosphorus in the setting of hypophosphatemia. Fanconi syndrome was confirmed by demonstration of aminoaciduria. Discussion: Fanconi syndrome is a disorder characterized by proximal tubular dysfunction resulting in electrolyte wasting. In the acquired form, medications and multiple myeloma are the most common causes. Based on the Naranjo probability scale, a drug was the probable cause of Fanconi syndrome in our patient. However, because multiple drugs were involved, it was not possible to determine which one was the culprit. Conclusions: This is the first case of Fanconi syndrome reported after the administration of capecitabine, irinotecan, and bevacizumab. More studies are needed to confirm this association.