Inhibition of HSP90 in Driver Oncogene-Defined Lung Adenocarcinoma Cell Lines: Key Proteins Underpinning Therapeutic Efficacy.

The use of 90 kDa heat shock protein (HSP90) inhibition as a therapy in lung adenocarcinoma remains limited due to moderate drug efficacy, the emergence of drug resistance, and early tumor recurrence. The main objective of this research is to maximize treatment efficacy in lung adenocarcinoma by identifying key proteins underlying HSP90 inhibition according to molecular background, and to search for potential biomarkers of response to this therapeutic strategy. Inhibition of the HSP90 chaperone was evaluated in different lung adenocarcinoma cell lines representing the most relevant molecular alterations (EGFR mutations, KRAS mutations, or EML4-ALK translocation) and wild-type genes found in each tumor subtype. The proteomic technique iTRAQ was used to identify proteomic profiles and determine which biological pathways are involved in the response to HSP90 inhibition in lung adenocarcinoma. We corroborated the greater efficacy of HSP90 inhibition in EGFR mutated or EML4-ALK translocated cell lines. We identified proteins specifically and significantly deregulated after HSP90 inhibition for each molecular alteration. Two proteins, ADI1 and RRP1, showed independently deregulated molecular patterns. Functional annotation of the altered proteins suggested that apoptosis was the only pathway affected by HSP90 inhibition across all molecular subgroups. The expression of ADI1 and RRP1 could be used to monitor the correct inhibition of HSP90 in lung adenocarcinoma. In addition, proteins such as ASS1, ITCH, or UBE2L3 involved in pathways related to the inhibition of a particular molecular background could be used as potential response biomarkers, thereby improving the efficacy of this therapeutic approach to combat lung adenocarcinoma.

Identification of Predictive Biomarkers of Response to HSP90 Inhibitors in Lung Adenocarcinoma.

Heat shock protein 90 (HSP90) plays an essential role in lung adenocarcinoma, acting as a key chaperone involved in the correct functioning of numerous highly relevant protein drivers of this disease. To this end, HSP90 inhibitors have emerged as promising therapeutic strategies, even though responses to them have been limited to date. Given the need to maximize treatment efficacy, the objective of this study was to use isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic techniques to identify proteins in human lung adenocarcinoma cell lines whose basal abundances were correlated with response to HSP90 inhibitors (geldanamycin and radicicol derivatives). From the protein profiles identified according to response, the relationship between lactate dehydrogenase B (LDHB) and DNA topoisomerase 1 (TOP1) with respect to sensitivity and resistance, respectively, to geldanamycin derivatives is noteworthy. Likewise, rhotekin (RTKN) and decaprenyl diphosphate synthase subunit 2 (PDSS2) were correlated with sensitivity and resistance to radicicol derivatives. We also identified a relationship between resistance to HSP90 inhibition and the p53 pathway by glucose deprivation. In contrast, arginine biosynthesis was correlated with sensitivity to HSP90 inhibitors. Further study of these outcomes could enable the development of strategies to improve the clinical efficacy of HSP90 inhibition in patients with lung adenocarcinoma.

Comparison of Mechanical and Structural Properties of Nickel-titanium Alloy with Titanium-molybdenum Alloy and Titanium-niobium Alloy as Potential Metals for Endodontic Files.

Introduction: The objective of this study was to compare the mechanical and structural properties of the nickel-titanium (Ni-Ti) alloy already used in endodontics with titanium-molybdenum (Ti-Mo) and titanium-niobium (Ti-Nb) alloys to determine if these can be suggested in the manufacture of endodontic files. Methods and Materials: Orthodontic wires made of the different alloys were used. The previously mentioned alloys were characterized by energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD) and torsion tests. Cyclic fatigue tests were performed on a simulated canal with a curvature of 86° to 375 rpm. The fractured surfaces of the wires were observed by means of scanning electron microscopy (SEM). A Kruskal-Wallis test and U Mann Whitney test were used to determine significant differences in cyclic fatigue between groups. Results: In the mechanical tests, similar values of torsion were found for the three alloys. In XRD, the Ti-Nb showed less structural changes. In the cyclic fatigue test, Ti-Nb was found to be significantly more resistant with respect to Ni-Ti and Ti-Mo. Conclusion: Based on our in vitro study, Ti-Nb is suggested as a possible alloy for the manufacture of rotary files due to its impressive properties.

FGFR1 and FGFR4 oncogenicity depends on n-cadherin and their co-expression may predict FGFR-targeted therapy efficacy.

BACKGROUND: Fibroblast growth factor receptor (FGFR)1 and FGFR4 have been associated with tumorigenesis in a variety of tumour types. As a therapeutic approach, their inhibition has been attempted in different types of malignancies, including lung cancer, and was initially focused on FGFR1-amplified tumours, though with limited success. METHODS: In vitro and in vivo functional assessments of the oncogenic potential of downregulated/overexpressed genes in isogenic cell lines were performed, as well as inhibitor efficacy tests in vitro and in vivo in patient-derived xenografts (PDXs). mRNA was extracted from FFPE non-small cell lung cancer samples to determine the prognostic potential of the genes under study. FINDINGS: We provide in vitro and in vivo evidence showing that expression of the adhesion molecule N-cadherin is key for the oncogenic role of FGFR1/4 in non-small cell lung cancer. According to this, assessment of the expression of genes in different lung cancer patient cohorts showed that FGFR1 or FGFR4 expression alone showed no prognostic potential, and that only co-expression of FGFR1 and/or FGFR4 with N-cadherin inferred a poorer outcome. Treatment of high-FGFR1 and/or FGFR4-expressing lung cancer cell lines and patient-derived xenografts with selective FGFR inhibitors showed high efficacy, but only in models with high FGFR1/4 and N-cadherin expression. INTERPRETATION: Our data show that the determination of the expression of FGFR1 or FGFR4 alone is not sufficient to predict anti-FGFR therapy efficacy; complementary determination of N-cadherin expression may further optimise patient selection for this therapeutic strategy.

Blood Predictive Biomarkers for Patients With Non-small-cell Lung Cancer Associated With Clinical Response to Nivolumab.

BACKGROUND: Immunotherapy is a promising cancer treatment, but surrogate biomarkers of clinical efficacy have not been fully validated. The aim of this work was to evaluate several biomarkers as predictors of response to nivolumab monotherapy in patients with non-small-cell lung cancer. PATIENTS AND METHODS: Blood samples was collected at baseline, at 2 months after treatment start, and at disease progression. Lactate dehydrogenase level (LDH), neutrophils, and leukocyte values were obtained from medical record. Interleukin (IL)-8, IL-11, and kynurenine/tryptophan levels were determined by enzyme-linked immunosorbent assay. Total protein was extracted from circulating CD8+ T cells, and BCL-2 interacting mediator of cell death (BIM) protein expression tested by western blotting. RESULTS: Baseline LDH levels were significantly higher in non-responder patients than in those who responded (P = .045). The increase in indoleamine 2,3 dioxygenase activity was related to progression of disease, mainly in patients who did not respond to nivolumab treatment (P = .001). Increased levels of circulating IL-8 were observed in initially responding patients at time of progression, and it was related to lower overall survival (hazard ratio, 7.49; P = .025). A highest expression of BIM in circulating CD8+ T cells could be related to clinical benefit. The Student t test and Mann-Whitney U test were used to compare groups for continuous variables. Time to events was estimated using the Kaplan-Meier method, and compared by the log-rank test. CONCLUSIONS: Changes in plasma LDH and IL-8, indoleamine 2,3 dioxygenase activity, and BIM expression in CD8+ T cells could be used to monitor and predict clinical benefit from nivolumab treatment in these patients.

Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry.

Heat shock protein 90 (HSP90) is an important chaperone in lung adenocarcinoma, with relevant protein drivers such as EGFR (epidermal growth factor receptor) and EML4-ALK (echinoderm microtubule-associated protein-like protein4 fused to anaplastic lymphoma kinase) depending on it for their correct function, therefore HSP90 inhibitors show promise as potential treatments for lung adenocarcinoma. To study responses to its inhibition, HSP90 was pharmacologically interrupted by geldanamycin and resorcinol derivatives or with combined inhibition of HSP90 plus HSP70 in lung adenocarcinoma cell lines. Two-dimensional electrophoresis was performed to identify proteomic profiles associated with inhibition which will help to understand the biological basis for the responses. HSP90 inhibition resulted in altered protein profiles that differed according the treatment condition studied. Results revealed 254 differentially expressed proteins after treatments, among which, eukaryotic translation initiation factor3 subunit I (eIF3i) and citrate synthase demonstrated their potential role as response biomarkers. The differentially expressed proteins also enabled signalling pathways involved in responses to be identified; these included apoptosis, serine-glycine biosynthesis and tricarboxylic acid cycle. The proteomic profiles identified here contribute to an improved understanding of HSP90 inhibition and open possibilities for the detection of potential response biomarkers which will be essential to maximize treatment efficacy in lung adenocarcinoma.

Corrigendum to "Proteomic-Based Approaches for the Study of Cytokines in Lung Cancer".

[This corrects the article DOI: 10.1155/2016/2138627.].

Proteomic-Based Approaches for the Study of Cytokines in Lung Cancer.

Proteomic techniques are currently used to understand the biology of different human diseases, including studies of the cell signaling pathways implicated in cancer progression, which is important in knowing the roles of different proteins in tumor development. Due to its poor prognosis, proteomic approaches are focused on the identification of new biomarkers for the early diagnosis, prognosis, and targeted treatment of lung cancer. Cytokines are proteins involved in inflammatory processes and have been proposed as lung cancer biomarkers and therapeutic targets because it has been reported that some cytokines play important roles in tumor development, invasion, and metastasis. In this review, we aim to summarize the different proteomic techniques used to discover new lung cancer biomarkers and therapeutic targets. Several cytokines have been identified as important players in lung cancer using these techniques. We underline the most important cytokines that are useful as biomarkers and therapeutic targets. We also summarize some of the therapeutic strategies targeted for these cytokines in lung cancer.

Atresia bronquial: Reporte de dos casos en población adulta / Bronchial Atresia. Report of Two Cases in Adults

La atresia bronquial (AB) es una anomalía congénita poco frecuente y de etiología desconocida. Se caracteriza por la falla en el desarrollo de una porción de un bronquio con acumulación de secreciones bronquiales y atrapamiento aéreo distal a la lesión. El conocimiento de esta patología permite su incorporación dentro de los diagnósticos diferenciales de masas pulmonares.

Bronchial atresia (BA) is an uncommon congenital anomaly of unknown etiology. It is characterized by the failure to develop a portion of the bronchus with accumulation of bronchial secretions and air trapping distal to the lesion. The knowledge of this pathology can be taken into account within the differential diagnosis of lung masses.

Validity and reliability of the 13C-methionine breath test for the detection of moderate hyperhomocysteinemia in Mexican adults.

BACKGROUND: Hyperhomocysteinemia (Hhcy) is considered an independent risk factor for vascular diseases and, more recently, for dementia. The methionine loading test (MLT) is useful for diagnosing additional subjects with moderate Hhcy. However, it is a complex and time-consuming procedure. A noninvasive test for the diagnosis of moderate Hhcy is desirable. METHODS: The study protocol consisted of three consecutive visits. During the first visit, we performed an MLT to characterize the Hhcy status of 75 healthy adult subjects. For the breath test protocol, we selected a subsample and assigned to the control group 17 subjects with fasting and post-loading homocysteine (Hcy) ≤12 and <42.3 µmol/L, respectively, and to the Hhcy group 16 subjects with fasting Hcy ≤12 and >42.3 µmol/L after loading. Selected subjects were requested to have a second visit to perform a breath test within 1-4 weeks following the MLT test and received an oral dose of 2.5 mg/kg of 1-13C-methionine dissolved in water. Breath samples were collected at basal, 20, 40, 60, 80, 100 and 120 min (test 1). The same procedure was repeated within 1 week (test 2). RESULTS: MLT was useful for diagnosing almost twice the number of individuals with Hhcy (24%) in comparison with the fasting determination alone (13.3%). The 13C-methionine breath test reported a sensitivity of 81.3% and a specificity of 64.7% against the MLT. The coefficient of variation between breath test 1 and breath test 2 was 9.0±5.4%. CONCLUSIONS: The 13C-methionine breath test is a valid and reliable method for identifying subjects with moderate Hhcy.