Can radiomics help to predict skeletal muscle response to chemotherapy in stage IV non-small cell lung cancer?

BACKGROUND: Muscle depletion negatively impacts treatment efficacy and survival rates in cancer. Prevention and timely treatment of muscle loss require prediction of patients at risk. We aimed to investigate the potential of skeletal muscle radiomic features to predict future muscle loss. METHODS: A total of 116 patients with stage IV non-small cell lung cancer included in a randomised controlled trial (NCT01171170) studying the effect of nitroglycerin added to paclitaxel-carboplatin-bevacizumab were enrolled. In this post hoc analysis, muscle cross-sectional area and radiomic features were extracted from computed tomography images obtained before initiation of chemotherapy and shortly after administration of the second cycle. For internal cross-validation, the cohort was randomly split in a training set and validation set 100 times. We used least absolute shrinkage and selection operator method to select features that were most significantly associated with muscle loss and an area under the curve (AUC) for model performance. RESULTS: Sixty-nine patients (59%) exhibited loss of skeletal muscle. One hundred ninety-three features were used to construct a prediction model for muscle loss. The average AUC was 0.49 (95% confidence interval [CI]: 0.36, 0.62). Differences in intensity and texture radiomic features over time were seen between patients with and without muscle loss. CONCLUSIONS: The present study shows that skeletal muscle radiomics did not predict future muscle loss during chemotherapy in non-small cell lung cancer. Differences in radiomic features over time might reflect myosteatosis. Future imaging analysis combined with muscle tissue analysis in patients and in experimental models is needed to unravel the biological processes linked to the radiomic features.

The prognostic value of early onset, CT derived loss of muscle and adipose tissue during chemotherapy in metastatic non-small cell lung cancer.

OBJECTIVES: To evaluate the relationship between early changes in muscle and adipose tissue during chemotherapy and overall survival (OS) in stage IV non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: In this post-hoc analysis of the first line NVALT12 trial (NCT01171170) in stage IV NSCLC, skeletal muscle (SM), radiation attenuation (RA), subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were assessed at the third lumbar level on CT-images obtained before initiation of chemotherapy and shortly after administration of the second cycle. The contribution of changes in different body compartments to overall survival was assessed. RESULTS: CT scans of 111 patients were included. Analysis of body composition changes between the baseline and the follow-up scan, revealed that overall SM cross sectional area (CSA), radiation attenuation and SAT CSA decreased respectively by -1.2 ± 2.9 cm2/m2 (p < 0.001), -0.7 ± 3.3 HU (p = 0.026) and -1.9 ± 8.7 cm2/m2 (p = 0.026), while no significant changes in VAT tissue were observed. Longitudinally, median OS was significantly shorter among patients losing SM compared to patients with preserved SM (9.4 versus 14.2 months; HR 1.9, 95% CI: 1.23, 2.79, p = 0.003). Multivariate analyses showed that proportional loss of muscle mass was associated with poor OS (HR 0.949, 95% CI: 0.915, 0.985, p = 0.006) independent from important clinical prognostic factors including WHO-PS, gender, age and Charlson comorbidity index. CONCLUSION: Early loss of SM during first line chemotherapy is a poor prognostic factor in stage IV NSCLC patients. Future studies have to reveal whether early supportive intervention guided by initial CT muscle response to chemotherapy can influence the wasting process and related mortality risk.

miR-151a induces partial EMT by regulating E-cadherin in NSCLC cells.

miR-151a and its host gene, focal adhesion kinase, FAK, are located in a region of chromosome 8q that is frequently amplified in solid tumors, including lung cancer. Lung cancer is the leading cause of cancer deaths worldwide and metastasis remains the major challenge in battling lung cancer mortality. Here, we demonstrate that miR-151a is overexpressed in non-small cell lung cancer (NSCLC) patient specimens, as compared to healthy lung. In addition, miR-151a overexpression promotes proliferation, epithelial-to-mesenchymal transition (EMT) and induces tumor cell migration and invasion of NSCLC cells. Blocking miR-151a expression using anti-miR-151a approaches significantly reduced NCSLC cell proliferative and motility potential. Furthermore, we determined that miR-151a significantly regulates E-cadherin expression. Finally, functional rescue experiments determined that overexpression of E-cadherin in miR-151a NSCLC cell lines potently repressed miR-151a-induced partial EMT and cell migration of NSCLC cells. In conclusion, our findings suggest that miR-151a functions as an oncomiR in NSCLC by targeting E-cadherin mRNA and inducing proliferation, migration and partial EMT.

[Persistently elevated hepatic transaminases: a patient with late-onset Pompe disease]. / Persisterende verhoging van transaminasewaarden.

BACKGROUND: Pompe disease is a rare hereditary glycogen storage disease. Disease progression can be delayed by enzyme replacement therapy, which makes early identification important. Sometimes, the clinical presentation can be atypical, which may result in late recognition. CASE DESCRIPTION: A 23-year-old male presented with mild fatigue and persistently elevated liver transaminase levels. Biochemical, metabolic, viral, autoimmune, and toxicological examination, augmented with imaging and liver biopsy, initially did not result in a diagnosis. During follow-up, alongside the known liver test abnormalities, increased CK levels were observed. A muscle biopsy demonstrated abnormal glycogen accumulation, indicative of Pompe disease. CONCLUSION: Persistently elevated levels of transaminases are not limited to liver pathology. In patients with this phenomenon, one should also consider extrahepatic causes.

Gas chromatography: an investigative tool in multiple allergies to essential oils.

Essential or fragrant oils are volatile odourous mixtures of organic chemical compounds that are widely used in aromatherapy and in the perfume industry. Because of their frequent use, allergy to essential oils is being increasingly recognized. We report 2 cases of multiple allergies to essential oils in professional aromatherapists. Gas chromatography/mass spectrometry was used to analyse the oils in order to identify a common allergen responsible for the contact dermatitis. In both the cases, alpha- and beta-pinene were found to be the most common constituent in the oils and thus appeared to be key allergens. alpha-pinene was confirmed as an allergen on repeat patch testing with pure alpha-pinene in both cases. 12 controls tested were negative for the same. Gas chromatography-mass spectrometry was found to be an extremely useful tool that could be utilized in investigating multiple allergies to essential oils.

Dialysis cells for controlled DNA: drug binding studies.

An efficient small volume accurate dialysis system has been designed, built and tested for proflavine binding to DNA based upon the side by side design used in the Franz diffusion cell. In a typical experiment 3 cm3 of DNA solution is added to one side and 3 cm3 of ligand to the other with a dialysis membrane between the two sides of 1 cm in diameter, thereby minimizing the area of dialysis membrane that the solutions are in contact with.

DNA structure control by polycationic species: polyamine, cobalt ammines, and di-metallo transition metal chelates.

Many polycationic species bind to DNA and induce structural changes. The work reported here is the first phase of a program whose long-term aim is to create a class of simple and inexpensive sequence-selective compounds that will enable enhanced DNA structure control for a wide range of applications. Three classes of molecule have been included in this work: the polyamine spermine (charge: 4(+)) and spermidine (charge: 3(+)) (which are known to induce a wide range of DNA conformational changes but whose binding modes are still not well understood); cobalt (III) amine transition metal complexes as potential polyamine mimics and [Fe(H(2)O)(6)](3+); and the first member of a new class of di-metallo tris-chelated cylinders of helical structure (charge 4(+)). Temperature-dependent absorption, circular dichroism, linear dichroism, gel electrophoresis, and molecular modeling data are presented. The cobalt amines prove to be effective polyamine mimics, although their binding appears to be restricted to backbone and major groove. All the ligands stabilize the DNA, but the 4(+) di-iron tris-chelate does so comparatively weakly and seems to have a preference for single-stranded DNA. All the molecules studied bend the DNA, with the di-iron tris-chelate having a particularly dramatic effect even at very low drug load.

Efferent neurons and specialization of abdominal segments in grasshoppers.

A specialized behavior, oviposition, is produced by the eighth and ninth abdominal segments of female grasshoppers. To begin to understand how these segments produce the behavior, which is not displayed by males or pregenital regions of the abdomen in females, the structure and function of efferent neurons in abdominal ganglia of both sexes were examined. In females, the eighth and ninth segments are specialized differently for oviposition: 20 ovipositor motor neurons were found in the eighth segment, and 26 were found in the ninth segment. Males had fewer motor neurons in their eighth segment, but the same number in the ninth segment, which is the only genital segment in males. However, the axons of several of the ninth segmental male motor neurons traveled to the periphery in the genital nerve, which is only found in males. In both sexes, pregenital ganglia had the most motor neurons, but these neurons, for the most part, had morphologies that strongly resembled those of genital segments. Efferent modulatory neuron numbers were not sexually dimorphic in the segments examined, except that males had a greater number in their ninth segment. Experimental methods that activate oviposition were found to also activate a rhythmical motor pattern in pregenital abdominal segments of both sexes. In females, the pattern was phase-coupled to oviposition, but persisted after the connections with the terminal abdominal ganglion were severed. The preponderance of similarities among efferent neurons and elicited motor activity suggests a common pattern of neural circuitry in the behaviorally diverse abdominal segments of grasshoppers.

Spectroscopic studies of 9-hydroxyellipticine binding to DNA.

The binding of 9-hydroxyellipticine to calf thymus DNA, poly[d(A-T)]2, and poly[d(G-C)]2 has been studied in detail by means of CD, linear dichroism, resonance light scattering, and molecular dynamics. The transition moment polarizations of 9-hydroxyellipticine were determined in polyvinyl alcohol stretched film. Spectroscopic solution studies of the DNA/drug complex are combined with theoretical CD calculations using the final 50 ps of a series of molecular dynamics simulations as input. The spectroscopic data shows 9-hydroxyellipticine to adopt two main binding modes, one intercalative and the other a stacked binding mode involving the formation of drug oligomers in the DNA major groove. Analysis of the intercalated binding mode in poly[d(A-T)]2 suggests the 9-hydroxyellipticine hydroxyl group lies in the minor groove and hydrogen bonds to water with the pyridine ring protruding into the major groove. The stacked binding mode was examined using resonance light scattering and it was concluded that the drug was forming small oligomer stacks rather than extended aggregates. Reduced linear dichroism measurements suggested a binding geometry that precluded a minor groove binding mode where the plane of the drug makes a 45 degrees angle with the plane of the bases. Thus it was concluded that the drug stacks in the major groove. No obvious differences in the mode of binding of 9-hydroxyellipticine were observed between different DNA sequences; however, the stacked binding mode appeared to be more favorable for calf thymus DNA and poly[d(G-C)]2 than for poly[d(A-T)]2, an observation that could be explained by the slightly greater steric hindrance of the poly[d(A-T)]2 major groove. A strong concentration dependence was observed for the two binding modes where intercalation is favored at very low drug load, with stacking interactions becoming more prominent as the drug concentration is increased. Even at DNA: drug mixing ratios of 70:1 the stacked binding mode was still important for GC-rich DNAs.

DNA-binding studies of XSPTSPSZ, derivatives of the intercalating heptad repeat of RNA polymerase II.

The synthesis, solution conformation, and interaction with DNA of three 8-residue peptides structurally related to the heptad repeat unit found at the C-terminus of RNA polymerase II are reported. Peptides QQ, XQ, and PQ are derived from the parent sequence YSPTSPSY (peptide YY), which was reported to bind to DNA by bisintercalation [M. Suzuki (1990) Nature, Vol. 344, pp. 562-565], and contain either a 2-quinolyl (Q), 2-quinoxolyl (X), or 5-phenanthrolyl (P) group in place of the aromatic side chains of the N- and C-terminal tyrosine residues present in the parent sequence. The combined results of linear dichroism and induced CD measurements of peptides QQ, XQ, and PQ with calf thymus DNA are consistent with weak binding of the peptides to DNA in a preferred orientation in which the chromophores are intercalated. Small increases in the melting temperatures of poly[d(A-T)2] are also consistent with the peptides interacting with DNA. While enzymatic footprinting with DNase I showed no protection from cleavage by the enzyme, chemical footprinting with fotemustine showed that the peptides modify the reactivity of the major groove, presumably via minor groove binding. Peptide QQ inhibited fotemustine alkylation significantly more than either XQ or PQ, and slightly more than YY. In aqueous solution, nmr experiments on QQ, XQ, and PQ show a significant population of a conformation in which Ser2-Pro3-Thr4-Ser5 form both type I and type II beta-turn conformations in equilibrium with open chain conformations. Nuclear magnetic resonance titration experiments of PQ with (GCGTACGC)2 showed small changes in chemical shifts, consistent with the formation of a weak nonspecific complex. Analogous experiments, using peptides QQ and XQ with (GCGTACGC)2, and peptide YY with (CGTACG)2, showed no evidence for the interaction of the peptides with these oligonucleotides. These results show that peptides of general structure XSPTSPSZ are weak nonspecific DNA binders that differ significantly from previously characterized S(T)PXX DNA-binding motifs that are generally AT-selective minor groove binders.

Employee stress and health complaints in jobs with and without electronic performance monitoring.

Current applications of electronic performance monitoring based on job design theories that consider worker performance rather than stress issues are likely to generate unsatisfying and stressful jobs (Smith et al, 1986). This study examines critical job design elements that could influence worker stress responses in an electronic monitoring context. A questionnaire survey of employees in telecommunications companies representative of each region in the United States examined job stress in directory assistance, service representative and clerical jobs with specific emphasis on the influence of electronic monitoring of job performance, satisfaction and employee health. Useable surveys were received from 745 employees representing seven operating companies and AT & T; a response rate of about 25%. The results of this survey indicated that employees who had their performance electronically monitored perceived their working conditions as more stressful, and reported higher levels of job boredom, psychological tension, anxiety, depression, anger, health complaints and fatigue. It is postulated that these effects may be related to changes in job design due to electronic performance monitoring.

Hormonal regulation of the metabolism of carcinogens in renal tissue of BALB/c mice.

The role of androgens in the regulation of carcinogen metabolism in the renal tissue of BALB/c mice was investigated. Kidney microsomal enzyme preparations from mature and immature animals were used in mutagenic studies using the Ames test. Androgen receptors (cytosolic and nuclear) were also evaluated. The results show that the microsomal enzymes from mature males had greater potential to biotransform dimethylnitrosamine than did the microsomal enzymes from mature females or immature animals. Testosterone treatment of mature females or immature animals resulted in a significant increase in the mutagenic ability of their renal microsomal enzymes. Androgen receptors were detected in kidney cytosols of mature and immature animals (both males and females); however, nuclear androgen receptors were detected only in the mature males. Testosterone treatment resulted in a significant accumulation of nuclear androgen receptors in the kidneys of mature females and immature animals. The relationships among mutagenic activity, androgen receptors, the levels of N-demethylase (an enzyme responsible for conversion of dimethylnitrosamine to its active metabolite), dietary fat, and the carcinogen metabolism are discussed.