MET exon 14 skipping mutations in non-small-cell lung cancer: real-world data from the Italian biomarker ATLAS database.

BACKGROUND: Mesenchymal-epithelial transition (MET) exon 14 (METex14) skipping mutation is a rare alteration in non-small-cell lung cancer (NSCLC), occurring in about 3%-4% of cases. Here we report disease and patient characteristics, and efficacy and tolerability of MET inhibitors among advanced METex14 NSCLC patients from the Italian real-world registry ATLAS. MATERIALS AND METHODS: Clinical-pathological and molecular data, and treatment efficacy/tolerability outcomes were retrospectively collected from the ATLAS registry. RESULTS: From July 2020 to July 2023 a total of 146 METex14 advanced NSCLC patients were included across 27 Italian centers. Median age was 74 years, and most patients were male (52%), with an Eastern Cooperative Oncology Group performance status < 2 (72%) and adenocarcinoma subtype (83%). One hundred and twenty-five out of 146 (86%) patients received at least one line of systemic anticancer therapy. Fifty-six (38%) were treated with capmatinib and 34 (23%) with tepotinib. 29% and 52% of them received targeted treatment in the first and second line, respectively. In the cohort of patients treated with MET inhibitors, the response rate (RR) was 37% (33% in previously treated patients and 46% in treatment-naïve) with a disease control rate of 62%. With a median follow-up of 10.8 months, progression-free survival was 6.6 months [95% confidence interval (CI) 4.3-8.3 months] and overall survival was 10.7 months (95% CI 7.2-19.3 months). In patients with measurable brain metastases (17 cases), the intracranial RR was 41%. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 12% of patients with grade 3 peripheral edema in 7% of cases. A fatal adverse reaction occurred in one patient due to pneumonitis. TRAEs-related dose reduction and discontinuation were reported in 6% and 8% of cases, respectively. CONCLUSION: Capmatinib and tepotinib represent an effective treatment option in NSCLC patients with METex14. Real-world efficacy outcomes are worse than those reported in prospective clinical trials. Their activity is more pronounced in the treatment-naïve population, suggesting that this is the right setting in the management of patients with METex14.

Activity of osimeRTInib in non-small-cell lung Cancer with UNcommon epidermal growth factor receptor mutations: retrospective Observational multicenter study (ARTICUNO).

BACKGROUND: Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted. PATIENTS AND METHODS: The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method. RESULTS: Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy. CONCLUSION: The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.

Malignant pleural mesothelioma: from the bench to the bedside.

Optimal management of malignant pleural mesothelioma (MPM), which is mainly based on patient characteristics and clinical stage, is not clearly defined yet, although detailed, practical guidelines for these patients have been proposed by some scientific societies. Translational research, in the field of this disease, is currently in progress and different molecular oncogenic pathways leading to the growth and progression of MPM have been characterized with recent pharmaceutical developments. However, further in-depth analysis still needs to be done for a more advanced deciphering of the step-by-step process leading from early increased mesothelial cell proliferation to invasive mesothelioma, from which we are expecting the development of definitively effective therapy. Thus, this review is an overview of the recent advances in the biology of MPM and their potential therapeutic applications in the field of MPM diagnosis and treatment.

Ancient DNA of Guinea Pigs (Cavia spp.) Indicates a Probable New Center of Domestication and Pathways of Global Distribution.

Guinea pigs (Cavia spp.) have a long association with humans. From as early as 10,000 years ago they were a wild food source. Later, domesticated Cavia porcellus were dispersed well beyond their native range through pre-Columbian exchange networks and, more recently, widely across the globe. Here we present 46 complete mitogenomes of archaeological guinea pigs from sites in Peru, Bolivia, Colombia, the Caribbean, Belgium and the United States to elucidate their evolutionary history, origins and paths of dispersal. Our results indicate an independent centre of domestication of Cavia in the eastern Colombian Highlands. We identify a Peruvian origin for the initial introduction of domesticated guinea pigs (Cavia porcellus) beyond South America into the Caribbean. We also demonstrate that Peru was the probable source of the earliest known guinea pigs transported, as part of the exotic pet trade, to both Europe and the southeastern United States. Finally, we identify a modern reintroduction of guinea pigs to Puerto Rico, where local inhabitants use them for food. This research demonstrates that the natural and cultural history of guinea pigs is more complex than previously known and has implications for other studies regarding regional to global-scale studies of mammal domestication, translocation, and distribution.

Author Correction: Ancient DNA of Guinea Pigs (Cavia spp.) Indicates a Probable New Center of Domestication and Pathways of Global Distribution.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Selection of variables for on-line monitoring, diagnosis, and control of anaerobic digestion processes.

This work aims to systematize the study of indicators for two types of wastewaters: carbohydrate-based and protein-based synthetic wastewaters. Characterization of steady states and dynamic response analysis against disturbances were carried out using both a factorial discriminant analysis (FDA) and a phenomenological analysis, respectively. This research seeks reconciling both sets of indicators in order to optimize resources and provide a minimal cost in instrumentation for its implementation at industrial scale. According to the results of this research, the best indicators for the two types of wastewaters, considering both process steady states and organic load perturbations are: Biogas flow rate or Methane flow rate, and Hydrogen concentration in the biogas; Volatile fatty acids and Partial alkalinity in the liquid phase.

Comparison of Application Methods of Systemic Fungicides to Suppress Branch Cankers in Clementine Trees Caused by Phytophthora citrophthora.

Since 2002, considerable losses of Clementine trees (Citrus clementina) have been observed in Spain due to Phytophthora branch canker of citrus caused by Phytophthora citrophthora. Due to the low efficiency of the available cultural and genetic control measures, application of fungicides is required for economic management of the disease. Fosetyl-Al, metalaxyl, and its enantiomer mefenoxam are the only systemic fungicides registered for control of Phytophthora diseases in Spain. However, their efficacy has not been tested against Phytophthora branch canker. Greenhouse and field experiments were conducted for 3 years in Spain to evaluate the ability of these fungicides and application methods to reduce lesion expansion. Nevertheless, with the inoculation technique used, it was not possible to evaluate the protective activity of fungicides, which can play an important role in their performance under field conditions. None of the fungicide treatments inhibited lesion expansion when applications were made on a curative basis. The residual effect was better on young than on mature trees. Paint treatments were generally more effective in reducing lesion expansion that drip chemigation or foliar sprays. However, this application method is laborious and becomes uneconomical in Spain. Trunk and branch sprays as well as long-term programs of foliar sprays or drip chemigation for control of spring and autumn infections are proposed as targets for future research.

An approach for the application of the Ecological Footprint as environmental indicator in the textile sector.

The Ecological Footprint (EF) is a recent concept which has widely been used as an indicator of environmental sustainability applied to individual lifestyles, regions, nations or even the world. Recently, its application to enterprises has been proposed. In the present study, a textile tailoring plant has been analysed. The overall purpose of this study was to develop a tool useful for evaluating the environmental impact evolution due to the performance of the plant, as well as for comparing the environmental behaviour of different tailoring processes. Therefore, the selected data were those from the manufacturing work. Data were divided in three main categories: energy, resources and waste. The principal contribution to the final EF (expressed in hectares of land) was the resources category, mainly due to the high value associated to the cloth. The consumed energy was the second contributor, while the waste category remained in third place. The final outcomes were divided by the production rates to obtain a comparable relative index, easy to be interpreted by the different stakeholders. This is of special importance for a Company involved in Corporate Social Responsibility and thus meant to have a general communication strategy.

Characterization of anaerobic granular sludge developed in UASB reactors that treat ethanol, carbohydrates and hydrolyzed protein based wastewaters.

In this work, granules developed from UASB reactors that treat different types of wastewaters (ethanol, carbohydrates and protein-based synthetic wastewaters) were studied. Granule parameters (size distribution; density; settlement characteristics; elemental composition; acidogenic and methanogenic activities) were analyzed along with micro-organisms identified by FISH to better understand granule behavior and its formation process. Micro-organisms distributions in anaerobic granules are highly dependent on the type of treated wastewater. Granules developed in a UASB reactor that treats wastewater with a high content of carbohydrates presented high acidogenic bacteria colonization. Members of Methanosaetaceae were the dominant methanogens in the studied granules, and Methanobacteriales appear to be co-dominant in the granules developed with carbohydrates and protein-based wastewaters.

Integration of equalisation tanks within control strategies for anaerobic reactors. Validation based on ADM1 simulations.

The combination of equalisation tanks and anaerobic digesters represents a typical design scenario within the treatment of industrial wastewaters. In this context, if the hydraulic capacity of the equalisation tanks is effectively handled, significant improvements in the performance of anaerobic digesters can be achieved in terms of process stability and biogas production. This paper presents a rule-based control strategy for anaerobic reactors with the objective of maximising in the long-term the net production of biogas. The control algorithm combines real-time information about the state of the anaerobic digester with on-line measurements about the wastewater volume of the equalisation tank in order to set permanently the appropriate production of biogas. Such a strategy guarantees a continuous influent flow so that emptying and overflowing episodes in the equalisation tank can be prevented. Aiming at a further full-scale implementation, only reliable and cost-effective on-line instrumentation has been considered within the control architecture. The performance of the proposed control approach has been validated for an anaerobic hybrid configuration (AHR) by simulation using the IWA ADM1 model.

Integrated pollution prevention and control for heavy ceramic industry in Galicia (NW Spain).

The heavy ceramic industry (building materials and refractory products manufacture) is an important source of pollutants to the environment. For this reason these industrial sub-sectors are included in prevention and control pollution policies, specifically those of the European Union. The IPPC Directive pays particular attention to the mineral industries, not least to the ceramic industry (epigraph 3.5, Annex I). In this paper, a methodology which is being applied to support IPPC installations and the competent administrative authority in Galicia (NW Spain) is presented. For that, the Galician heavy ceramic industry is analysed, as also are the ways to study the Best Available Techniques (BAT) with a view to establishing the emission limit values (ELV) for each specific case. Hence, a technological state of the art has been carried out for both sub-sectors, from the point of view of implementation of the IPPC in Galicia. Following this, the processes are described briefly and an analysis of the consumption and emission levels of the main pollutants is made. An inventory that includes the best environmental practices and the preventive and abatement candidate techniques as BAT was elaborated for both considered sub-sectors. An information data sheet for each candidate BAT is presented as a method to help both the industries and the competent authority to identify a candidate technique of the inventory as BAT. Three illustrative examples of the application of this procedure are presented for different emissions to environmental media for Galician installations.

Winery effluent treatment at an anaerobic hybrid USBF pilot plant under normal and abnormal operation.

A 1.1 m3 hybrid USBF fully instrumented pilot plant has been used for the treatment of diluted wine for four years. In this work, the performance of the wastewater treatment plant (WWTP) during start up and operation (normal operation and overload experiments) is shown. A complete description of the treatment process behaviour (gas and liquid phase composition and anaerobic sludge characteristics) is given by on-line and off-line monitoring of 28 process variables. The results presented here demonstrate the reliability of this technology for the treatment of wastewater from seasonal processes, such as winery wastewaters, during a long period of time (four years). Furthermore, the USBF reactor presented very short start up periods after short and long shut down of the WWTP and rapidly turned back to normal operation after suffering a complete destabilization due to organic overload. Both effluent and biogas were of good quality. Dissolved organic carbon concentration in the effluent was always lower than 100 mg DOC l(-1) under normal operation, while methane concentration in the biogas was in the range 70-74%, making it suitable for energy recovering.

Selection of variables using factorial discriminant analysis for the state identification of an anaerobic UASB-UAF hybrid pilot plant, fed with winery effluents.

Anaerobic wastewater treatment has become a widely used method for wastewater depuration, and has been applied in a wide range of situations, from urban wastewater to highly toxic industrial wastewater. Particularly it has been successfully applied to the treatment of the beverage industries effluents. To avoid the destabilization of the system a monitoring diagnosis and control system of the depuration processes is necessary. The cost of this system is an important issue, that depends on the number of parameters that must be controlled for an adequate performance of a wastewater plant control system. This work shows how the classic statistical classification techniques can be applied to determine the number variables that must be monitored to achieve an adequate performance of anaerobic UASB-UAF hybrid Pilot Plant monitoring and control system. The obtained results had not been unique, so different combinations of variables can be selected for a good wastewater treatment process control. Economic or technical criteria may be considered to determine the final variables set in each particular situation.

Characterization, management and treatment of wastewater from white wine production.

During a 16 months period, the characteristics of the wastewaters generated in a Rias Baixas winery (Spain) producing white wine were determined: The characterization study showed that white wine wastewater had an average CODt and TSS values of 7.3 and 5.2 kg/m3, respectively being the ratio wastewater/wine produced of about 1.6-2.0 L/L and the ratio between load pollution and produced wine of 9.7 kg(CODt)/m3(WINE). A strategy for the management of wastes and wastewaters allowed for an important reduction of a 55% of wastewater generation to be achieved. In order to select a suitable technology for the treatment of wastewaters two configurations were tested at pilot scale: i) An Anaerobic Filter (AF) of 430 L followed by an activated sludge unit of 510 L and: ii) one activated sludge unit of 510 L. The results showed that the anaerobic/aerobic configuration was more flexible as it adapted quickly to the different loads and flows produced during the different phases through the year. Besides it allowed higher COD removals (98.5-99.2%) to be achieved and proved to permit a quicker re-start up after starvation periods.

MANAGEMENT OF ENDOCRINE DISEASE: Risk of overtreatment in patients with adrenal insufficiency: current and emerging aspects.

The effects of long-term replacement therapy of adrenal insufficiency (AI) are still a matter of controversy. In fact, the established glucocorticoid replacement regimens do not completely reproduce the endogenous hormonal production and the monitoring of AI treatment may be a challenge for the lack of reliable clinical and biochemical markers. Consequently, several AI patients are frequently exposed to relative glucocorticoid excess potentially leading to develop chronic complications, such as diabetes mellitus, dyslipidemia, hypertension and fragility fractures with consequent impaired QoL and increased mortality risk. This review deals with the pathophysiological and clinical aspects concerning the over-replacement therapy of primary and secondary AI.

Daily activity rhythms and the stress-related response in the wedge sole (Dicologoglossa cuneata Moreau, 1881).

To gain further insights on the wedge sole (Dicologoglossa cuneata Moreau, 1881) physiology and behavior, we evaluated its daily feeding and locomotor activity rhythms and compared three different feeding strategies: self-feeding (SF), diurnal feeding schedule (DS) and nocturnal feeding schedule (NS). 450 fish divided into three groups (three replicates each), were kept during 65days. SF had free access to self-feeders whereas DS and NS were fed four times a day. Physiological stress parameters as plasma cortisol, glucose, lactate, proteins and triglycerides were determined. Under the SF setting, the 91% of feeding demands occurred during the dark phase. Furthermore, locomotor activity was also higher during the scotophase (64% of the total activity). Significantly higher values for specific growth rate (SGR) and feed efficiency rate (FER) were observed in NS (0.49 and 0.48%day-1, respectively); whereas SF consumed much less food than the rest and presented a high mortality rate (46%). Plasma cortisol levels were dramatically increased in SF and DS compared to NS (21.8±6.1, 65.8±30.3 and 0.3±0.1ngmL-1, respectively). In summary, the wedge sole appears as a species with nocturnal locomotor and feeding behaviors and NS as the most appropriate feeding strategy. These new findings appear as key information for both the preservation of natural stocks of this species and its rearing.

Granulation in high-load denitrifying upflow sludge bed (USB) pulsed reactors.

In this work, the effect of the application of a pulse system to anoxic upflow sludge bed (USB) denitrifying reactors for enhancing sludge granulation was studied. In all, three 0.8 L reactors (two operated with flow pulsation, P1 with effluent recycling and P2 without recycling, and one without pulsation and effluent recycling, no pulsation (NP)) were fed with a mixture of NaNO3 and glucose and inoculated with methanogenic granular sludge. The organic loading rate (OLR) and the nitrogen loading rate (NLR) were progressively increased and, at the end of the experiment, extremely high values were obtained (67.5 kgCOD/m3d and 11.25 kgN-NO3-/m3 d). Ammonia and nitrite accumulation in reactor NP were important in the maturation stage, decreasing the denitrification efficiency to 90%, while in reactor P1 only low nitrite values were obtained in the last few days of the experiment. In reactor P2, nitrogen removal was 100% most of the time. Several operational problems (flotation and the subsequent wash out of biomass) appeared in the NP reactor when working at high denitrifying loading rates, while in reactors P1 and P2 there were no notable problems, mainly due to the good characteristics of the sludge developed and the efficient degasification produced by the pulsing flow. The sludge formed in the NP reactor presented a flocculent structure and a total disintegration of the initial methanogenic granules occurred, while a small-sized granular biomass with a high specific density was developed in the pulsed reactors due to the shear stress produced.

A hydrogen-based variable-gain controller for anaerobic digestion processes.

An easy-to-implement controller based on gas phase measurements for anaerobic digestion processes was developed. The controller is based on the indirect control of COD in the effluent by means of controlling the hydrogen concentration in the biogas. The fast response of hydrogen under destabilizations, such as those caused by overloads, guarantees an early actuation on the system before it destabilizes. The controller is designed such that it brings the anaerobic digestion process to maximum capacity by pushing it to maximum methane production as long as hydrogen remains low. Experiments have been conducted to test the controller under organic over- and underload situations and promising performance was achieved. Further experiments must be carried out to validate the controller under a wider spectrum of situations to enable its robust industrial application.

[Episodic hypertension in postural orthostatic tachycardia syndrome]. / Hipertensión arterial episódica asociada al síndrome de taquicardia postural ortostática.

We report the case of a 17-year-old woman who presented to the emergency department on several occasions due to palpitations, tachycardia, syncope, short spells of dizziness and light-headedness with complete spontaneous recovery, and hypertension. The patient had been evaluated by several specialists, and multiple complementary examinations had revealed no abnormalities that could explain the symptoms. Due to suspicion of orthostatic intolerance or postural orthostatic tachycardia syndrome with hypertension, the patient underwent a 60-degree tilt table test, which confirmed the diagnosis. The patient was successfully treated with bisoprolol. The physiopathological mechanisms, diagnosis, and treatment of this syndrome are reviewed.