Metal dyshomeostasis based biomarkers for lung cancer diagnosis using human biofluids

Lung cancer (LC) is one of the most common causes of cancer-related deaths in the world and it is well known that trace elements play important roles in the carcinogenic process activating and inhibiting enzymatic reactions and metalloproteins, in which they usually participate as cofactors. A cross-sectional study was conducted on 48 lung cancer patients and 39 controls (56 men and 31 women), aged 44-76 years between March 2011 and June 2012. Eleven elements have been included in the study: V, Cr, Mn, Fe, Co, Cu, Zn, Se, Mo, Cd, and Pb, some of them considered toxic (V, Cd, Cr and Pb), while others are essential (Co, Mo, Se, Fe and Zn), and they have been analyzed by ICP-QQQ-MS in serum, urine and for the first time in bronchoalveolar lavage fluid (BALF). In order to understand the involvement of metals in this process, an analytical metallomic approach based on non-denaturing precipitation of proteins (NDPP) has been optimized for the fractionation of high molecular mass (HMM) and low molecular mass (LMM) metal species, in order to distinguish between metal species that affect the biological activity and toxicological potential of the elements. In this work, the NDPP followed by the analysis of metals by ICP-QQQ-MS has been applied for the first time to serum, urine and BALF samples from lung cancer patients and controls in order to get metal-size molecule profiles (MSMP), which can be used as metal-based biomarkers of altered metabolic processes such as oxidative stress and homeostasis. In this sense, we have demonstrated that several metals are good biomarkers when they are related to labile complexes, complexed with low molecular mass ligands, or in the form of metalloproteins (i.e. V and Cr in HMM and Cu in LMM), which has been described for the first time. On the other hand, metal dyshomeostasis biomarkers are proposed using metal ratios and correlations. Finally, the ratios between elements were shown to be important biomarkers for lung cancer in serum (V/Mn, V/Pb, V/Zn, Cr/Pb), urine (Cr/Cd, Mn/Cd, V/Cd, Co/Cd, Cd/Pb) and BALF (V/Cu), which reflects the dyshomeostasis of metals in lung cancer. In this sense, several metals are correlated to others suggesting also the existence of an interconnected homeostasis in lung cancer.The authors thank the Spanish Ministry of Economy and Competitiveness (CTM2015-67902-C2-1-P) and Regional Ministry of Economy, Innovation, Science and Employment (Andalusian Government. P12-FQM-0442). B. Callejon-Leblic thanks the Ministerio de Educacion for a predoctoral scholarship FPU13/03615. Finally, the authors are grateful to FEDER (European Community) (UNHU13-1E-1611 and UNHU15-CE-3140)

The metallome of lung cancer and its potential use as biomarker

Carcinogenesis is a very complex process in which metals have been found to be critically involved. In this sense, a disturbed redox status and metal dyshomeostasis take place during the onset and progression of cancer, and it is well-known that trace elements participate in the activation or inhibition of enzymatic reactions and metalloproteins, in which they usually participate as cofactors. Until now, the role of metals in cancer have been studied as an effect, establishing that cancer onset and progression affects the disturbance of the natural chemical form of the essential elements in the metabolism. However, it has also been studied as a cause, giving insights related to the high exposure of metals giving a place to the carcinogenic process. On the other hand, the chemical species of the metal or metallobiomolecule is very important, since it finally affects the biological activity or the toxicological potential of the element and their mobility across different biological compartments. Moreover, the importance of metal homeostasis and metals interactions in biology has also been demonstrated, and the ratios between some elements were found to be different in cancer patients; however, the interplay of elements is rarely reported. This review focuses on the critical role of metals in lung cancer, which is one of the most insidious forms of cancer, with special attention to the analytical approaches and pitfalls to extract metals and their species from tissues and biofluids, determining the ratios of metals, obtaining classification profiles, and finally defining the metallome of lung cancer.This research was funded by the projects CTM2015-67902-C-1-P from the Spanish Ministry of Economy and Competitiveness, and P12-FQM-0442 from the Regional Ministry of Economy, Innovation, Science and Employment (Andalusian Government, Spain). Projects Neumosur (8/2012 and 9/2015) and SEPAR (124/2012 and 091/2016). Belén Callejón Leblic thanks the Ministry of Education, Culture and Sport for a predoctoral scholarship. Finally, authors are grateful to FEDER (European Community) for financial support, grants number UNHU13-1E-1611 and UNHU15-CE-3140

Non invasive moisture measurement in agricultural fiel using a rolling spherical robot

Irrigation management in large crop fields is a very important practice. Since the farm management costs and the crop results are directly connected with the environmental moisture, water control optimization is a critical factor for agricultural practices, as well as for the planet sustainability. Usually, the crop humidity is measured through the water stress index (WSI), using imagery acquired from satellites or airplanes. Nevertheless, these tools have a significant cost, lack from availability, and dependability from the weather. Other alternative is to recover to ground tools, such as ground vehicles and even static base stations. However, they have an outstanding impact in the farming process, since they can damage the cultivation and require more human effort. As a possible solution to these issues, a rolling ground robot have been designed and developed, enabling non-invasive measurements within crop fields. This paper addresses the spherical robot system applied to intra-crop moisture measurements. Furthermore, some experiments were carried out in an early stage corn field in order to build a geo-referenced WSI map

Metallomic Signatures of Lung Cancer and Chronic Obstructive Pulmonary Disease

Lung cancer (LC) is the leading cause of cancer deaths, and chronic obstructive pulmonary disease (COPD) can increase LC risk. Metallomics may provide insights into both of these tobaccorelated diseases and their shared etiology. We conducted an observational study of 191 human serum samples, including those of healthy controls, LC patients, COPD patients, and patients with both COPD and LC.We found 18 elements (V, Al, As, Mn, Co, Cu, Zn, Cd, Se,W, Mo, Sb, Pb, Tl, Cr, Mg, Ni, and U) in these samples. In addition, we evaluated the elemental profiles of COPD cases of varying severity. The ratios and associations between the elements were also studied as possible signatures of the diseases. COPD severity and LC have a significant impact on the elemental composition of human serum. The severity of COPD was found to reduce the serum concentrations of As, Cd, and Tl and increased the serum concentrations of Mn and Sb compared with healthy control samples, while LC was found to increase Al, As, Mn, and Pb concentrations. This study provides new insights into the effects of LC and COPD on the human serum elemental profile that will pave the way for the potential use of elements as biomarkers for diagnosis and prognosis. It also sheds light on the potential link between the two diseases, i.e., the evolution of COPD to LC.This work has been supported by the project "Heteroatom-tagged proteomics and metabolomics to study lung cancer. Influence of gut microbiota” (Ref.: PY20_00366) (Project of Excellence, Regional Ministry of Economy, Knowledge, Business and University, Andalusia, Spain). The authors are also grateful for grants 651/2018 and 115/2020 from the Spanish Society of Pneumology and Surgery (SEPAR) and grant 08/2018 from the Association of Pneumology and Thoracic Surgery (Neumosur), which were used to facilitate recruitment at the hospitals and biobank registration. The authors also thank Instituto de Salud Carlos III (AES16/01783) and wish to express their gratitude for the unrestricted funding from the Menarini Group and AstraZeneca

Biomechanical evaluation of oversized drilling technique on primary implant stability measured by insertion torque and resonance frequency analysis

Background: This study evaluated the influence of implant site preparation depth on primary stability measured by insertion torque and resonance frequency analysis (RFA). Material and Methods: Thirty-two implant sites were prepared in eight veal rib blocks. Sixteen sites were prepared using the conventional drilling sequence recommended by the manufacturer to a working depth of 10mm. The remaining 16 sites were prepared using an oversize drilling technique (overpreparation) to a working depth of 12mm. Bone density was determined using cone beam computerized tomography (CBCT). The implants were placed and primary stability was measured by two methods: insertion torque (Ncm), and RFA (implant stability quotient [ISQ]). Results: The highest torque values were achieved by the conventional drilling technique (10mm). The ANOVA test confirmed that there was a significant correlation between torque and drilling depth (p<0.05). However, no statistically significant differences were obtained between ISQ values at 10 or 12 mm drilling depths (p>0.05) at either measurement direction (cortical and medullar). No statistical relation between torque and ISQ values was identified, or between bone density and primary stability (p>0.05). Conclusions: Vertical overpreparation of the implant bed will obtain lower insertion torque values, but does not produce statistically significant differences in ISQ values

Trypanosoma cruzi macrophage infectivity potentiator has a rotamase core and a highly exposed α-helix

The macrophage infectivity potentiator protein from Trypanosoma cruzi (TcMIP) is a major virulence factor secreted by the etiological agent of Chagas' disease. It is functionally involved in host cell invasion. We have determined the three-dimensional crystal structure of TcMIP at 1.7 Å resolution. The monomeric protein displays a peptidyl-prolyl cis-trans isomerase (PPlase) core, encompassing the characteristic rotamase hydrophobic active site, thus explaining the strong inhibition of TcMIP by the immunosuppressant FK506 and related drugs. In TcMIP, the twisted β-sheet of the core is extended by an extra β-strand, preceded by a long, exposed N-terminal α-helix, which might be a target recognition element. An invasion assay shows that the MIP protein from Legionella pneumophila (LpMIP), which has an equivalent N-terminal α-helix, can substitute for TcMIP. An additional exposed α-helix, this one unique to TcMIP, is located in the C-terminus of the protein. The high-resolution structure reported here opens the possibility for the design of new inhibitory drugs that might be useful for the clinical treatment of American trypanosomiasis.This work was supported by grants from Ministerio de Educación y Cultura (PB98-1631 and 2FD97-0518), CSIC and Generalitat de Catalunya (CERBA and 1999SGR188) to M.C., grant PB98-0479 to A.G. and by grant BIO2000-1659 to F.X.G.-R. P.J.B.P. and S.M.-R. acknowledge postdoctoral fellowships from FCT (Portugal). Data collection at DESY was supported by EC grants ERBFMGECT980134 and HPRI-CT-1999-00017 to EMBL-HamburgPeer Reviewe

Characteristics and Management of Patients with Refractory or Unexplained Chronic Cough in Outpatient Hospital Clinics in Spain : A Retrospective Multicenter Study

Purpose: Chronic cough (cough that persists for ≥ 8 weeks) can cause a range of physical symptoms and psychosocial effects that significantly impair patients' quality of life. Refractory chronic cough (RCC) and unexplained chronic cough (UCC) are challenging to diagnose and manage, with substantial economic implications for healthcare systems. Methods: This retrospective multicenter non-interventional study aimed to characterize the profile and health resource consumption of patients with RCC or UCC who attended outpatient clinics at Spanish hospitals. Data were collected from medical records of patients with RCC or UCC for up to 3 years before study inclusion. Results: The patient cohort (n = 196) was representative of the chronic cough population (77.6% female, mean age 58.5 years). Two-thirds of patients (n = 126) had RCC. The most frequently visited doctors were pulmonologists (93.4% of patients) and primary care physicians (78.6%), with a mean of 5 visits per patient over three years' observation. The most common diagnostic tests were chest x-ray (83.7%) and spirometry with bronchodilation (77.0%). The most commonly prescribed treatments were proton pump inhibitors (79.6%) and respiratory medications (87.8%). Antibiotics were prescribed empirically to 56 (28.6%) patients. Differences between RCC or UCC groups related mainly to approaches used to manage cough-associated conditions (gastroesophageal reflux disease, asthma) in patients with RCC. Conclusion: RCC and UCC are responsible for high health resource utilization in Spanish hospitals. Specific treatments targeting the pathological processes driving chronic cough may provide opportunities to reduce the associated burden for patients and healthcare systems

The effect of farming environment on asthma; time dependent or universal?

Funding Information: MJA holds investigator-initiated grants from Pfizer and Boehringer-Ingelheim for unrelated research. He has undertaken an unrelated consultancy for and received assistance with conference attendance from Sanofi. He has also received a speaker’s fee from GSK. The other authors have no conflicts of interest to declare that are relevant for the content of this article. Funding Information: The ECRHS/RHINE/RHINESSA study was supported by grants from The Faculty of Health, Aarhus University, Denmark (Project No. 240008), The Wood Dust Foundation (Project No. 444508795), The Danish Lung Association, the Swedish Heart and Lung Foundation, the Swedish Association Against Asthma and Allergy, the Swedish Association against Heart and Lung Disease, the Swedish Council for Working Life and Social Research, The Bror Hjerpstedt Foundation, The Vårdal Foundation for Health Care and Allergic Research, The Norwegian Research Council (Grant Nos. 214123, 230827/F20, 228174 and 135773/330), The Norwegian Asthma and Allergy Association, HelseVest Norway (Grant No. 911 631), The Icelandic Research Council, The University of Iceland Research Fund, The Icelandic GP’s Research Fund, The Estonian Science Foundation (Grant No. 4350), The Estonian Research Council (Grant No. PUT562), Melbourne University, National Health & Medical Research Council of Australia, SEPAR Spain, Sociedad Española de Neumologia y Cirugía Toracica Spain and Horizon2020 PHC1 (Grant No. 633212). For further information about funding sources, please consult www.rhinessa.net . Vivi Schlünssen and Cecilie Svanes are members of the COST BM1201 network. Publisher Copyright: © 2022, Springer Nature B.V.The increasing prevalence of asthma is linked to westernization and urbanization. Farm environments have been associated with a lower risk of asthma development. However, this may not be universal, as the association differs across birth cohorts and farming methods. The aim of this study was to investigate the associations of farm upbringing with asthma in different generations and at different times in history. The study population consisted of three generations: 13,868 subjects participating in the ECRHS in 2010, their 9,638 parents, and their 8,885 offspring participating in RHINESSA in 2013. Information on place of upbringing and self-reported ever asthma was provided via questionnaires. Logistic regression was performed including subgroup analysis stratified by generation and birthyear into ten-year-intervals. The prevalence of asthma increased from 8% among grandparents to 13% among parents and to 18% among offspring. An overall analysis showed an inverse association of farm upbringing on the risk of asthma (OR = 0.64; 95%CI 0.55–0.74). Subgroup analysis stratified into ten-year-intervals showed a tendency towards a more pronounced inverse association between growing up on a farm and asthma among subjects born in the 1940s (0.74; 0.48–1.12), 1950s (0.70; 0.54–0.90) and 1960s (0.70; 0.52–0.93). For subjects born in 1970 and thereafter this association appeared less consistent. While growing up on a farm was associated with a reduced risk of developing asthma in participants born between 1945–1999, this was mainly driven by generations born from 1945 to 1973.Peer reviewe

High Mitochondrial DNA Stability in B-Cell Chronic Lymphocytic Leukemia

BACKGROUND: Chronic Lymphocytic Leukemia (CLL) leads to progressive accumulation of lymphocytes in the blood, bone marrow, and lymphatic tissues. Previous findings have suggested that the mtDNA could play an important role in CLL. METHODOLOGY/PRINCIPAL FINDINGS: The mitochondrial DNA (mtDNA) control-region was analyzed in lymphocyte cell DNA extracts and compared with their granulocyte counterpart extract of 146 patients suffering from B-Cell CLL; B-CLL (all recruited from the Basque country). Major efforts were undertaken to rule out methodological artefacts that would render a high false positive rate for mtDNA instabilities and thus lead to erroneous interpretation of sequence instabilities. Only twenty instabilities were finally confirmed, most of them affecting the homopolymeric stretch located in the second hypervariable segment (HVS-II) around position 310, which is well known to constitute an extreme mutational hotspot of length polymorphism, as these mutations are frequently observed in the general human population. A critical revision of the findings in previous studies indicates a lack of proper methodological standards, which eventually led to an overinterpretation of the role of the mtDNA in CLL tumorigenesis. CONCLUSIONS/SIGNIFICANCE: Our results suggest that mtDNA instability is not the primary causal factor in B-CLL. A secondary role of mtDNA mutations cannot be fully ruled out under the hypothesis that the progressive accumulation of mtDNA instabilities could finally contribute to the tumoral process. Recommendations are given that would help to minimize erroneous interpretation of sequencing results in mtDNA studies in tumorigenesis