MET Signaling Pathways, Resistance Mechanisms, and Opportunities for Target Therapies.

The MET gene, known as MET proto-oncogene receptor tyrosine kinase, was first identified to induce tumor cell migration, invasion, and proliferation/survival through canonical RAS-CDC42-PAK-Rho kinase, RAS-MAPK, PI3K-AKT-mTOR, and ß-catenin signaling pathways, and its driver mutations, such as MET gene amplification (METamp) and the exon 14 skipping alterations (METex14), activate cell transformation, cancer progression, and worse patient prognosis, principally in lung cancer through the overactivation of their own oncogenic and MET parallel signaling pathways. Because of this, MET driver alterations have become of interest in lung adenocarcinomas since the FDA approval of target therapies for METamp and METex14 in 2020. However, after using MET target therapies, tumor cells develop adaptative changes, favoring tumor resistance to drugs, the main current challenge to precision medicine. Here, we review a link between the resistance mechanism and MET signaling pathways, which is not only limited to MET. The resistance impacts MET parallel tyrosine kinase receptors and signals shared hubs. Therefore, this information could be relevant in the patient's mutational profile evaluation before the first target therapy prescription and follow-up to reduce the risk of drug resistance. However, to develop a resistance mechanism to a MET inhibitor, patients must have access to the drugs. For instance, none of the FDA approved MET inhibitors are registered as such in Chile and other developing countries. Constant cross-feeding between basic and clinical research will thus be required to meet future challenges imposed by the acquired resistance to targeted therapies.

[The impact of novel drugs on the survival of patients with multiple myeloma in two chilean centers]. / Mieloma múltiple en Chile. Uso de drogas noveles en dos centros nacionales.

BACKGROUND: The incorporation of novel drugs, such as proteasome inhibitors and immunomodulators, improved considerably the survival of patients with multiple myeloma. AIM: To evaluate the effect on survival of proteasome inhibitors and immunomodulators in patients with multiple myeloma in two national hospitals. MATERIAL AND METHODS: Review of clinical records from two hospitals of Santiago. Epidemiological, clinical, laboratory and therapeutic data was obtained from 144 patients with multiple myeloma diagnosed between 2002 and 2016. RESULTS: Information was retrieved from 78 patients at one center and from 66 at the other center. The mean age at diagnosis was 58 and 62 years, the proportion of males was 53% and 52%, and presentation at stage III was 34% and 46%, respectively. The use of novel drugs, mainly bortezomib, was 90% in one of the centers and 3% in the other one. The use of autologous stem-cell transplantation was 47% and 3% respectively. The median overall survival of patients from the centers with and without access to novel drugs was 117 and 71 months respectively (p < 0.05). The five-year overall survival was 93 and 43% respectively (p < 0.05). CONCLUSIONS: The use of novel drugs, especially bortezomib, and autologous stem-cell transplantation significantly improved the survival of multiple myeloma patients treated in national hospitals. It is necessary to include them as a first line treatment.

A bibliometric analysis of tropical mangrove forest land use change from 2010 to 2020.

Mangrove land use changes of varied intensities have long been a problem in tropical mangrove forests. This has resulted in various degrees of mangrove land use modification, which catch many interests in the region for research. The research provided here is a bibliometric analysis of scholarly articles published around the world in various publication document types on changes in land use of tropical mangrove forests based on remote sensing and Geographical Information System (GIS). Scientific data analysis was undertaken by using bibliometric approaches on 6,574 papers extracted from the Scopus databases between 2010 and 2020. The findings revealed that the number of publications continuously climbed from under 400 to an average of 50-60 per year till 2019. The data showed that the mangrove forest modifications study gained traction when the highest number of citations, 9,236 in 2015, were observed. We can also notice that the overall number of citations fluctuated a lot during the first five years (2010-2015) but increased from 2013 to 2015. The findings demonstrate how remote sensing satellites have aided vegetation and land study in recent years. The findings also revealed that the analysis tools of Land Use Change, Vegetation Index, Mangrove, Tropical Country, Remote Sensing, and Tropical contributed to scientific knowledge of current issues of mangrove land use change in the tropical region. The authors' keywords, Remote Sensing in particular, supplied roughly 43%, Normalized Difference Vegetation Index (13%), Vegetation Index (9%), and other keywords contributed less than 7%. The growth pattern of the keywords "MODIS" and "Landsat" implies that both will stay important over the next five years, according to an analysis of the type of satellite used in land use assessment. Meanwhile, papers pertaining to policy on land use change, food security, and forest resources were evaluated in order to highlight policy and academic research findings on the topics. The application of the Normalized Difference Vegetation Index, which is a very relevant tool that can be used in monitoring land use changes and assessing vegetation status because it is a desirable technique in measuring plant health and vigour, can help fill the research gaps presented in this study. This review can help with the development of better mangrove land use change approaches in tropical mangroves and around the world using satellite remote sensing and GIS.

Atrial Function Assessed by Speckle Tracking Echocardiography Is a Good Predictor of Postoperative Atrial Fibrillation in Elderly Patients.

OBJECTIVE: Advanced age is an independent predictor of postoperative atrial fibrillation (POAF) in patients undergoing coronary artery bypass surgery. We evaluated whether left atrial (LA) dysfunction assessed by strain contributes to identifying elderly patients prone to POAF. METHODS: Case-control study of 70 subjects undergoing coronary artery bypass surgery. Clinical and laboratory characteristics were recorded at baseline and 72 hours after surgery. Echocardiography was performed during the preoperative period; LA dimensions and deformation by strain (systolic wave [LASs]) as well as strain rate (systolic wave [LASRs] and atrial contraction wave [LASRa]) were assessed. RESULTS: Postoperative atrial fibrillation occurred in 38.5% of patients within the first 72 hours after surgery (28.5% of the younger vs. 48.6% of the older group). Baseline and postoperative inflammatory markers as well as total surgical and aortic clamp time were similar between groups. LA function was markedly impaired in subjects with POAF. Age correlated with LASs, LASRs, and LASRa. These associations remained consistent when subjects 75 years or older were considered separately. Both LASs and LASRa for patients with or without POAF, respectively, were significantly impaired in elderly subjects with POAF. Multivariate analysis provided further evidence that both LASs and age are independent predictors for POAF. CONCLUSION: Age-related changes in atrial function preceding atrial dilation are evident only upon LA strain analysis. LA strain impairment is an independent predictor of POAF irrespective of age and may serve as a surrogate marker for biological processes involved in establishing the substrate for POAF.

Capability of integrated MODIS imagery and ALOS for oil palm, rubber and forest areas mapping in tropical forest regions.

Various classification methods have been applied for low resolution of the entire Earth's surface from recorded satellite images, but insufficient study has determined which method, for which satellite data, is economically viable for tropical forest land use mapping. This study employed Iterative Self Organizing Data Analysis Techniques (ISODATA) and K-Means classification techniques to classified Moderate Resolution Imaging Spectroradiometer (MODIS) Surface Reflectance satellite image into forests, oil palm groves, rubber plantations, mixed horticulture, mixed oil palm and rubber and mixed forest and rubber. Even though frequent cloud cover has been a challenge for mapping tropical forests, our MODIS land use classification map found that 2008 ISODATA-1 performed well with overall accuracy of 94%, with the highest Producer's Accuracy of Forest with 86%, and were consistent with MODIS Land Cover 2008 (MOD12Q1), respectively. The MODIS land use classification was able to distinguish young oil palm groves from open areas, rubber and mature oil palm plantations, on the Advanced Land Observing Satellite (ALOS) map, whereas rubber was more easily distinguished from an open area than from mixed rubber and forest. This study provides insight on the potential for integrating regional databases and temporal MODIS data, in order to map land use in tropical forest regions.

[Mechanical thrombolysis of the basilar artery. Report of one case]. / Trombolisis mecánica de tronco basilar con Solitaire FR®: caso clínico.

We report a 40 year-old male presenting in the emergency room with headache, vertigo and left hemiparesis. A magnetic resonante imaging reported a left cerebellar infarction with occlusion of the basilar artery and a dissection of the right vertebral artery. The patient experienced a clinical deterioration with the appearance of a right hemiparesis. Therefore a brain angiography was performed along with a mechanical thrombolysis using a Solitaire FR® revascularization device. A thrombus located in the distal third of the artery was eliminated obtaining a complete perfusión of the artery. The patient had a satisfactory evolution.

[Infective endocarditis caused by Listeria monocytogenes: review of the literature and a case report]. / Endocarditis infecciosa por Listeria monocytogenes: revisión de la literatura a partir de un caso clínico.

Infective endocarditis caused by Listeria monocytogenesis an extremely rare but usually aggressive disease. We have seen in recent years an increase in age of onset of this disease and a predilection for patients with valvular disease, especially prosthetic valve. The treatment of choice is ampicillin, which is combined with gentamicin for synergy. It is known that even with treatment the mortality is very high and higher than in other types of bacterial endocarditis. With optimal therapy, that is medical-surgical, mortality has declined significantly in recent years. We presents a review of the literature and a clinical case of a patient with a febrile syndrome diagnosed as a infective endocarditis caused by L. monocytogenestreated medically with successful outcome to date.

Acquired Secondary HER2 Mutations Enhance HER2/MAPK Signaling and Promote Resistance to HER2 Kinase Inhibition in Breast Cancer.

HER2 mutations drive the growth of a subset of breast cancers and are targeted with HER2 tyrosine kinase inhibitors (TKI) such as neratinib. However, acquired resistance is common and limits the durability of clinical responses. Most HER2-mutant breast cancers progressing on neratinib-based therapy acquire secondary mutations in HER2. It is unknown whether these secondary HER2 mutations, other than the HER2T798I gatekeeper mutation, are causal to neratinib resistance. Herein, we show that secondary acquired HER2T862A and HER2L755S mutations promote resistance to HER2 TKIs via enhanced HER2 activation and impaired neratinib binding. While cells expressing each acquired HER2 mutation alone were sensitive to neratinib, expression of acquired double mutations enhanced HER2 signaling and reduced neratinib sensitivity. Computational structural modeling suggested that secondary HER2 mutations stabilize the HER2 active state and reduce neratinib binding affinity. Cells expressing double HER2 mutations exhibited resistance to most HER2 TKIs but retained sensitivity to mobocertinib and poziotinib. Double-mutant cells showed enhanced MEK/ERK signaling, which was blocked by combined inhibition of HER2 and MEK. Together, these findings reveal the driver function of secondary HER2 mutations in resistance to HER2 inhibition and provide a potential treatment strategy to overcome acquired resistance to HER2 TKIs in HER2-mutant breast cancer. SIGNIFICANCE: HER2-mutant breast cancers acquire secondary HER2 mutations that drive resistance to HER2 tyrosine kinase inhibitors, which can be overcome by combined inhibition of HER2 and MEK.

Effects of aquaculture waste feeds and antibiotics on marine benthic ecosystems in the Mediterranean Sea.

Intensive aquaculture is an important source of organic waste and antibiotics into the marine environment. Yet, their impacts on benthic marine ecosystems are poorly understood. Here, we investigated the ecological impacts of fish feed waste alone and in combination with three different antibiotics (i.e., oxytetracycline, florfenicol and flumequine) in benthic ecosystems of the Mediterranean Sea by performing a field experiment. We assessed the fate of the antibiotics in the sediment and their accumulation in wild fauna after two weeks of exposure. Moreover, we investigated the impact of the feed waste alone and in combination with the antibiotics on sediment physico-chemical properties, on benthic invertebrates, as well as on the microbiota and resistome of the sampled sediments. One week after the last antibiotic application, average oxytetracycline and flumequine concentrations in the sediment were <1% and 15% of the applied dose, respectively, while florfenicol was not detected. Flumequine concentrations in wild invertebrates reached 3 µg g-1, while concentrations of oxytetracycline were about an order of magnitude lower, and florfenicol was not detected. Feed waste, with and without antibiotics, increased the concentration of fine particulate matter, affected the pH and redox conditions, and significantly reduced the biodiversity and abundance of benthic invertebrates. Feed waste also had a significant influence on the structure of sediment microbial communities, while specific effects related to the different antibiotics ranged from insignificant to mild. The presence of antibiotics significantly influenced the normalized abundance of the measured antibiotic resistance genes. Florfenicol and oxytetracycline contributed to an increase of genes conferring resistance to macrolides, tetracyclines, aminoglycosides and chloramphenicol, while flumequine had a less clear impact on the sediment resistome. This study demonstrates that feed waste from aquaculture farms can rapidly alter the habitat and biodiversity of Mediterranean benthic ecosystems, while antibiotic residual concentrations can contribute to the enrichment of bacterial genes resistant to antibiotic classes that are of high relevance for human medicine.

Effect of temperature on biogeochemistry of marine organic-enriched systems: implications in a global warming scenario.

Coastal biogeochemical cycles are expected to be affected by global warming. By means of a mesocosm experiment, the effect of increased water temperature on the biogeochemical cycles of coastal sediments affected by organic-matter enrichment was tested, focusing on the carbon, sulfur, and iron cycles. Nereis diversicolor was used as a model species to simulate macrofaunal bioirrigation activity in natural sediments. Although bioirrigation rates of N. diversicolor were not temperature dependent, temperature did have a major effect on the sediment metabolism. Under organic-enrichment conditions, the increase in sediment metabolism was greater than expected and occurred through the enhancement of anaerobic metabolic pathway rates, mainly sulfate reduction. There was a twofold increase in sediment metabolism and the accumulation of reduced sulfur. The increase in the benthic metabolism was maintained by the supply of electron acceptors through bioirrigation and as a result of the availability of iron in the sediment. As long as the sediment buffering capacity toward sulfides is not surpassed, an increase in temperature might promote the recovery of organic-enriched sediments by decreasing the time for mineralization of excess organic matter.

[Risk factors for a high carotid intima media thickness among healthy adults]. / Hipertensión arterial: el factor de riesgo más importante para grosor íntima-media carotídeo elevado y placa carotídea en adultos de Santiago.

BACKGROUND: Carotid intima media thickness (CIMT) is a marker of cardiovascular damage that can be modified by traditional risk factors. AIM: To determine attributable risk factors for a high CIMT among healthy adults. MATERIAL AND METHODS: A sample of 1270 individuals (636 males and 634 females) aged 44 ± 11 years, was studied. Blood pressure, weight, height, lipid profile and blood glucose were measured in all. CIMT and the presence of atherosclerotic plaques were determined by carotid ultrasound. Standard criteria were used to define hypertension, dyslipidemia and diabetes. RESULTS: Mean CIMT in the sample studied was 0.62 ± 0.01 mm and percentile 75 was 0.67. The most important risk factor for a CIMT over percentile 75 and the presence of atherosclerotic plaques was hypertension with attributable risks of 54 and 57%, respectively. CONCLUSIONS: In this sample, the main risk factor for a high CIMT was hypertension.

Central catheter-associated deep vein thrombosis in cancer: clinical course, prophylaxis, treatment.

The adequate handling of central venous catheters is a key element in the management of patients with cancer. Catheter-associated deep vein thrombosis is frequently observed in patients with malignant diseases; however, despite being a common complication among these patients, objective information concerning its epidemiology, clinical course, prophylaxis and treatment strategies is very limited. The reported incidence of catheter-related thrombosis (CRT) is highly variable, depending on symptomatic events, or if patients are screened for asymptomatic thrombosis. Several factors have been identified as potential predisposing factors for CRT, both technical and pathological aspects. The anticoagulant of choice is still unclear; while low-molecular-weight heparin is most commonly used, recent studies assessing the role of direct oral anticoagulants in the treatment of CRT show promise as an alternative, but the evidence remains insufficient and the decision must be made on a case-by-case basis.

Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity.

Activating mutations in HER2 (ERBB2) drive the growth of a subset of breast and other cancers and tend to co-occur with HER3 (ERBB3) missense mutations. The HER2 tyrosine kinase inhibitor neratinib has shown clinical activity against HER2-mutant tumors. To characterize the role of HER3 mutations in HER2-mutant tumors, we integrate computational structural modeling with biochemical and cell biological analyses. Computational modeling predicts that the frequent HER3E928G kinase domain mutation enhances the affinity of HER2/HER3 and reduces binding of HER2 to its inhibitor neratinib. Co-expression of mutant HER2/HER3 enhances HER2/HER3 co-immunoprecipitation and ligand-independent activation of HER2/HER3 and PI3K/AKT, resulting in enhanced growth, invasiveness, and resistance to HER2-targeted therapies, which can be reversed by combined treatment with PI3Kα inhibitors. Our results provide a mechanistic rationale for the evolutionary selection of co-occurring HER2/HER3 mutations and the recent clinical observations that HER3 mutations are associated with a poor response to neratinib in HER2-mutant cancers.

Heat wave intensity can vary the cumulative effects of multiple environmental stressors on Posidonia oceanica seedlings.

Climate change is introducing new stressors into already stressed ecosystems. Among these, extreme events such as heat waves play a crucial role in determining the structure of ecosystems. We tested single and combined effects of overgrazing, burial and heat waves on the seedlings of the habitat-forming species Posidonia oceanica. At current heat wave temperatures, overgrazing in isolation had more deleterious effects than seed burial, and effects were synergistic and additive when both factors co-occurred. The combined effect of overgrazing and seed burial with current heat waves could hamper P. oceanica seedling development, with similar or even higher levels than the sole effect of heat waves in the near future (29 °C). The effects of overgrazing and seed burial are expected to be overridden if heat waves temperatures exceed 29 °C. These results suggest that co-occurring environmental stressors, in combination with current heat waves, could compromise the sexual recruitment of this seagrass.

Anthropo-niche characterization of Mediterranean cephalopods with trace elements and isotopic niches.

Human pressure leaves a mark on coastal ecosystems that can be used to study the ecology of marine species. This study compared the trace elements (TEs) composition and isotopic niche metrics of the squid Loligo vulgaris, the cuttlefish Sepia officinalis and the octopus Octopus vulgaris in the western Mediterranean Sea. The results revealed that anthropogenic pressure clearly affected coastal waters and the habitat use of these three cephalopods. Anthropogenic pressure in coastal areas, measured by the LUSI index, correlated with the TEs composition of cephalopods. The DistLM analysis showed that Cr and Zn were strong predictor variables of the LUSI matrix on all three cephalopod species. In this study, isotopic niche, combined with the CAP analysis of TEs, were plotted in a bivariate manner, which could refer to an "anthropo-niche". We provide a useful heuristic scheme for analyzing the interplay among coastal influence, trophic level, and the TEs from environment.

A versatile oblique plane microscope for large-scale and high-resolution imaging of subcellular dynamics.

We present an oblique plane microscope (OPM) that uses a bespoke glass-tipped tertiary objective to improve the resolution, field of view, and usability over previous variants. Owing to its high numerical aperture optics, this microscope achieves lateral and axial resolutions that are comparable to the square illumination mode of lattice light-sheet microscopy, but in a user friendly and versatile format. Given this performance, we demonstrate high-resolution imaging of clathrin-mediated endocytosis, vimentin, the endoplasmic reticulum, membrane dynamics, and Natural Killer-mediated cytotoxicity. Furthermore, we image biological phenomena that would be otherwise challenging or impossible to perform in a traditional light-sheet microscope geometry, including cell migration through confined spaces within a microfluidic device, subcellular photoactivation of Rac1, diffusion of cytoplasmic rheological tracers at a volumetric rate of 14 Hz, and large field of view imaging of neurons, developing embryos, and centimeter-scale tissue sections.

Integrative ecotoxicological assessment of sediment in Portmán Bay (southeast Spain).

Portmán Bay, southeast Spain, contains the most seriously metal-contaminated sediments of the Mediterranean Sea. From 1958 to 1991, approximately 50 million tons of mine tailings were dumped into the bay, completely filling up the bay and dispersing over an extensive area of the continental platform and continental slope. The objective of our study was to characterize the nature and extent of metal contamination and the responses of natural communities to it and to assess the toxicity of the sediment deposits 10 years after mining had ceased. We studied the physical and chemical characteristics of the sediments and toxicity (of the porewater and sediment-water interface) using two sea urchin species (Arbacia lixula and Paracentrotus lividus). Metal bioavailability and patterns of macroinvertebrate community composition along the contamination gradient were also studied. Univariate and multivariate analyses showed positive correlation between the sediment metal concentrations associated to the all biological effects (sea urchins toxicity tests and benthic indices). The effects of sediment contamination on the benthic community structure are visible among sampling stations.

Is Cytoreductive Nephrectomy Still a Standard of Care in Metastatic Renal Cell Carcinoma?

Cytoreductive nephrectomy has been an integral part of management in metastatic renal cell carcinoma for patients with good performance status, based on the benefit shown by prospective trials in the interferon era and retrospective trials in the targeted therapies era. Clinical Trial to Assess the Importance of Nephrectomy (CARMENA), the first prospective phase III trial comparing a targeted agent alone (sunitinib) versus nephrectomy plus sunitinib, has been recently published, showing non-inferiority for the nephrectomy-sparing arm. In this article, we discuss the impact of nephrectomy including its immune-mediated effects, surgical morbidity and mortality, and the clinical data supporting the indications of nephrectomy in order to analyze the CARMENA trial in context, with the aim to identify optimal strategies for different patient populations in the metastatic setting.

Carbon and nitrogen stable isotopes and metal concentration in food webs from a mining-impacted coastal lagoon.

Two food webs from the Mar Menor coastal lagoon, differing in the distance from the desert-stream through which mining wastes were discharged, were examined by reference to essential (Zn and Cu) and non-essential (Pb and Cd) metal concentrations and stable isotopes content (C and N). The partial extraction technique applied, which reflects the availability of metals to organisms after sediment ingestion, showed higher bioavailable metal concentrations in sediments from the station influenced by the mining discharges, in agreement with the higher metal concentrations observed in organisms, which in many cases exceeded the regulatory limits established in Spanish legislation concerning seafood. Spatial differences in essential metal concentrations in the fauna suggest that several organisms are exposed to metal levels above their regulation capacity. Differences in isotopic composition were found between both food webs, the wadi-influenced station showing higher delta(15)N values and lower delta(13)C levels, due to the discharge of urban waste waters and by the entrance of freshwater and allochthonous marsh plants. The linear-regressions between trophic levels (as indicated by delta(15)N) and the metal content indicated that biomagnification does not occur. In the case of invertebrates, since the "handle strategy" of the species and the physiological requirements of the organisms, among other factors, determine the final concentration of a specific element, no clear relationships between trophic level and the metal content are to be expected. For their part, fish communities did not show clear patterns in the case of any of the analyzed metals, probably because most fish species have similar metal requirements, and because biological factors also intervened. Finally, since the study deals with metals, assumptions concerning trophic transfer factors calculation may not be suitable since the metal burden originates not only from the prey but also from adsorption over the body surfaces and seawater ingestion.

Toxicity Studies of Polynuclear Aromatic Hydrocarbons (PAHs) on European Amphipods.

ABSTRACT The effect of phenanthrene, fluoranthene, and pyrene in dimethyl sulfoxide on the amphipods Gammarus aequicauda, Gammarus locusta, and Corophium multisetosum was tested in a static exposure in sea water. The 48-h lethal concentration (LC(50)) of phenanthrene was 173.85 mug/L for G. aequicauda, 147.64 mug/L for G. locusta, and 215.20 mug/L for C. multisetosum. The 48-h LC(50) of fluoranthene was 49.99 mug/L for G. aequicauda, 42.71 mug/L for G. locusta, and 2.85 mug/L for C. multisetosum. The 48-h LC(50) of pyrene was 73.49 mug/L for G. aequicauda, 60.78 mug/L for G. locusta, and 25.29 mug/L for C. multisetosum. Together with their wide distribution along European coasts, the evidence of toxicity on the tested PAH compounds in these amphipods make these species appropriate candidates for evaluating oil-contaminated sediments in Europe.