Dual challenge inside the womb: a case report of concomitant fetal atrio-ventricular block associated with maternal anti-SSA antibodies and fetal tachyarrhythmia diagnosed as Wolff-Parkinson-White syndrome after birth.

Fetal autoimmune atrioventricular block (AVB) is a rare but potentially life-threatening condition. It results from the passage of maternal anti-SSA/Ro or Anti SSB/La auto-antibodies into the fetal circulation, leading to inflammation and fibrosis of the AV node and often to irreversible damage. Besides AVB, these antibodies can also cause cardiomyopathies, but there is no evidence linking them to tachyarrhythmias. We present the case of a patient with significant risk factors for fetal AVB: a prior history of hydrops fetalis, high anti-SSA/Ro antibody levels and hypothyroidism. In this case, the use of dexamethasone and intravenous immunoglobulin may have contributed to reversing the first-degree atrioventricular block detected at 19 weeks of gestation. Additionally, at 21 weeks, the fetus developed a tachyarrhythmia that needed treatment with flecainide. Soon after the birth, the newborn underwent ECG Holter and Wolff-Parkinson-White Syndrome (WPWS) was diagnosed. To our knowledge, the coexistence of fetal AVB and WPWS has never been described.

Sand smelt larvae's resilience to hypoxia and implications for thermal tolerance.

Deoxygenation is a growing threat to marine ecosystems, with an increase in the frequency, extent and intensity of hypoxia events in recent decades. These phenomena will pose various challenges to marine species, as it affects their survival, growth, body condition, metabolism and ability to handle other environmental stressors, such as temperature. Early life stages are particularly vulnerable to these changes. Thus, it is crucial to understand how these initial phases will respond to hypoxia to predict the impacts on marine populations and ecosystems. In this work, we aimed to evaluate the effect of oxygen (O2) availability on fitness related traits (mortality, growth and body condition), metabolism (Routine metabolic rates [RMR]) and thermal tolerance (CTmax), in early stages of Atherina presbyter, exposed for two weeks, to two O2 levels: normoxia (6.5-7.2 mg L-1) and hypoxia (2-2.5 mg L-1), through an experiment setup. Our findings showed that while low oxygen levels did not negatively impact mortality, total length, weight, or body condition (Fulton K), the larvae undergo metabolic depression when exposed to hypoxia, as an energy conservation mechanism. Furthermore, CTmax suffered a significant reduction in low O2 availability, due to the inability of the circulatory and respiratory systems to fulfill energy demands. These outcomes suggest that although early life stages of Atherina presbyter can survive under low oxygen environments, they are less capable of dealing with sudden increases in temperature when oxygen is scarce.

Integrated behavioural and physiological responses of sand smelt larvae to the effects of warming and hypoxia as combined stressors.

Forecasts indicate that rising temperatures towards the future and the expansion of dead zones will change environmental suitability for fish early stages. Therefore, we assessed the chronic effects of warming (26 °C), hypoxia (<2-2.5 mg L-1) or their combination on mortality rate, growth, behaviour, energy metabolism and oxidative stress using Atherina presbyter larvae as a model species. There were no differences between the treatments in terms of mortality rate. The combination of warming and hypoxia induced faster loss of body mass (+22.7%). Warming, hypoxia or their combination enhanced boldness (+14.7-25.4%), but decreased exploration (-95%-121%), increased the time in frozen state (+60.6-80.5%) and depleted swimming speed (-45.6-50.5%). Moreover, routine metabolic rate was depleted under hypoxia or under the combination of warming and hypoxia (-56.6 and 57.2%, respectively). Under hypoxia, increased catalase activity (+56.3%) indicates some level of antioxidant defence capacity, although increased DNA damage (+25.2%) has also been observed. Larvae also exhibited a great capacity to maintain the anaerobic metabolism stable in all situations, but the aerobic metabolism is enhanced (+19.3%) when exposed to the combination of both stressors. The integrative approach showed that changes in most target responses can be explained physiologically by oxidative stress responses. Increased oxidative damages (lipid peroxidation and DNA damage) and increased interaction between antioxidant enzymes (superoxide dismutase and catalase) are associated to increased time in frozen state and decreased swimming activity, growth rates and boldness. Under all stressful situations, larvae reduced energy-consuming behaviours (e.g. depleted exploration and swimming activity) likely to stabilize or compensate for the aerobic and anaerobic metabolisms. Despite being an active small pelagic fish, we concluded that the sensitive larval phase exhibited complex coping strategies to physiologically acclimate under thermal and hypoxic stress via behavioural responses.

Economic and Accessible Portable Homemade Magnetic Hyperthermia System: Influence of the Shape, Characteristics and Type of Nanoparticles in Its Effectiveness.

Currently, one of the main causes of death in the world is cancer; therefore, it is urgent to obtain a precocious diagnosis, as well as boost research and development of new potential treatments, which should be more efficient and much less invasive for the patient. Magnetic hyperthermia (MH) is an emerging cancer therapy using nanoparticles, which has proved to be effective when combined with chemotherapy, radiotherapy and/or surgery, or even by itself, depending on the type and location of the tumor's cells. This article presents the results obtained by using a previously developed economic homemade hyperthermia device with different types of magnetite nanoparticles, with sizes ranging between 12 ± 5 and 36 ± 11 nm and presenting different shapes (spherical and cubic particles). These magnetic nanoparticles (MNPs) were synthesized by three different methods (co-precipitation, solvothermal and hydrothermal processes), with their final form being naked, or possessing different kinds of covering layers (polyethylene glycol (PEG) or citric acid (CA)). The parameters used to characterize the heating by magnetic hyperthermia, namely the Specific Absorption Rate (SAR) and the intrinsic loss power (ILP), have been obtained by two different methods. Among other results, these experiments allowed for the determination of which synthesized MNPs showed the best performance concerning hyperthermia. From the results, it may be concluded that, as expected, the shape of MNPs is an important factor, as well as the time that the MNPs can remain suspended in solution (which is directly related to the concentration and covering layer of the MNPs). The MNPs that gave the best results in terms of the SAR were the cubic particles covered with PEG, while in terms of total heating the spherical particles covered with citric acid proved to be better.

Early life stage mechanisms of an active fish species to cope with ocean warming and hypoxia as interacting stressors.

Ocean's characteristics are rapidly changing, modifying environmental suitability for early life stages of fish. We assessed whether the chronic effects of warming (24 °C) and hypoxia (<2-2.5 mg L-1) will be amplified by the combination of these stressors on mortality, growth, behaviour, metabolism and oxidative stress of early stages of the white seabream Diplodus sargus. Combined warming and hypoxia synergistically increased larval mortality by >51%. Warming induced faster growth in length and slower gains in weight when compared to other treatments. Boldness and exploration were not directly affected, but swimming activity increased under all test treatments. Under the combination of warming and hypoxia, routine metabolic rate (RMR) significantly decreases when compared to other treatments and shows a negative thermal dependence. Superoxide dismutase and catalase activities increased under warming and were maintained similar to control levels under hypoxia or under combined stressors. Under hypoxia, the enzymatic activities were not enough to prevent oxidative damages as lipid peroxidation and DNA damage increased above control levels. Hypoxia reduced electron transport system activity (cellular respiration) and isocitrate dehydrogenase activity (aerobic metabolism) below control levels. However, lactate dehydrogenase activity (anaerobic metabolism) did not differ among treatments. A Redundancy Analysis showed that ∼99% of the variability in mortality, growth, behaviour and RMR among treatments can be explained by molecular responses. Mortality and growth are highly influenced by oxidative stress and energy metabolism, exhibiting a positive relationship with reactive oxygen species and a negative relationship with aerobic metabolism, regardless of treatment. Under hypoxic condition, RMR, boldness and swimming activity have a positive relationship with anaerobic metabolism regardless of temperature. Thus, seabreams may use anaerobic reliance to counterbalance the effects of the stressors on RMR, activity and growth. The outcomes suggests that early life stages of white seabream overcame the single and combined effects of hypoxia and warming.

Application of Nanoparticles in Cancer Treatment: A Concise Review.

Timely diagnosis and appropriate antitumoral treatments remain of utmost importance, since cancer remains a leading cause of death worldwide. Within this context, nanotechnology offers specific benefits in terms of cancer therapy by reducing its adverse effects and guiding drugs to selectively target cancer cells. In this comprehensive review, we have summarized the most relevant novel outcomes in the range of 2010-2023, covering the design and application of nanosystems for cancer therapy. We have established the general requirements for nanoparticles to be used in drug delivery and strategies for their uptake in tumor microenvironment and vasculature, including the reticuloendothelial system uptake and surface functionalization with protein corona. After a brief review of the classes of nanovectors, we have covered different classes of nanoparticles used in cancer therapies. First, the advances in the encapsulation of drugs (such as paclitaxel and fisetin) into nanoliposomes and nanoemulsions are described, as well as their relevance in current clinical trials. Then, polymeric nanoparticles are presented, namely the ones comprising poly lactic-co-glycolic acid, polyethylene glycol (and PEG dilemma) and dendrimers. The relevance of quantum dots in bioimaging is also covered, namely the systems with zinc sulfide and indium phosphide. Afterwards, we have reviewed gold nanoparticles (spheres and anisotropic) and their application in plasmon-induced photothermal therapy. The clinical relevance of iron oxide nanoparticles, such as magnetite and maghemite, has been analyzed in different fields, namely for magnetic resonance imaging, immunotherapy, hyperthermia, and drug delivery. Lastly, we have covered the recent advances in the systems using carbon nanomaterials, namely graphene oxide, carbon nanotubes, fullerenes, and carbon dots. Finally, we have compared the strategies of passive and active targeting of nanoparticles and their relevance in cancer theranostics. This review aims to be a (nano)mark on the ongoing journey towards realizing the remarkable potential of different nanoparticles in the realm of cancer therapeutics.

Secukinumab-induced systemic lupus erythematosus in psoriatic arthritis.

CASE REPORT: A 68-year-old male treated with secukinumab for psoriatic arthritis suspended treatment for three months due to COVID pandemic. Upon secukinumab reintroduction, anorexia and weight loss ensued and four months later he had an abrupt onset of low-grade fever, fatigue, flu-like symptoms, dyspnoea and widespread inflammatory arthralgias. Laboratory investigations showed de novo anaemia, leukopenia, lymphopenia, cytocholestasis, elevated acute phase reactants, C3 complement consumption, proteinuria (1630mg/24h), active urine sediment, positive antinuclear (1:1280) and anti-double-stranded DNA (212.3 IU/mL) antibodies. Chest imaging showed peripheral pulmonary embolism, lobar pneumonia, and a small bilateral pleural effusion. Drug-induced lupus erythematosus (DILE) was suspected, and the patient was hospitalised. Secukinumab was discontinued and treatment with enoxaparin, antibiotics, enalapril, hydroxychloroquine and prednisolone 0.5mg/kg qd was started. Clinical and laboratorial remission ensued after one month except for proteinuria (decreased to 653mg/24h). Proliferative lupus nephritis was assumed and mycophenolate mofetil was introduced, with sustained complete remission over a 33-month follow-up. DISCUSSION: This is the second reported case of systemic secukinumab-associated DILE, and the first with renal involvement. Clinical and laboratory features of DILE are reviewed and compared with previously described cases.

Frequent Parasitism of Apis mellifera by Trypanosomatids in Geographically Isolated Areas with Restricted Beekeeping Movements.

Trypanosomatids form a group of high prevalence protozoa that parasitise honey bees, with Lotmaria passim as the predominant species worldwide. However, the knowledge about the ecology of trypanosomatids in isolated areas is limited. The Portuguese archipelagos of Madeira and Azores provide an interesting setting to investigate these parasites because of their geographic isolation, and because they harbour honey bee populations devoid of two major enemies: Varroa destructor and Nosema ceranae. Hence, a total of 661 honey bee colonies from Madeira and the Azores were analysed using different molecular techniques, through which we found a high prevalence of trypanosomatids despite the isolation of these islands. L. passim was the predominant species and, in most colonies, was the only one found, even on islands free of V. destructor and/or N. ceranae with severe restrictions on colony movements to prevent the spread of them. However, islands with V. destructor had a significantly higher prevalence of L. passim and, conversely, islands with N. ceranae did not shown any significant correlation with the trypanosomatid. Crithidia bombi was detected in Madeira and on three islands of the Azores, almost always coincident with L. passim. By contrast, Crithidia mellificae was not detected in any sample. A high-throughput sequencing analysis distinguished two main haplotypes of L. passim, which accounted for 98% of the total sequence reads. This work suggests that L. passim and C. bombi are parasites that have been associated with honey bees predating the spread of V. destructor and N. ceranae.

Severe infections in Portuguese patients with rheumatoid arthritis under biologic treatment - a multicenter, nationwide study (SIPPRA-B Study).

INTRODUCTION: Despite years of experience with biological disease modifying anti-rheumatic drugs (bDMARD) in rheumatoid arthritis (RA), little is known about differences in infectious risk among bDMARDs. The aim of this study was to assess the incidence and type of infections in RA patients on bDMARDs and to determine possible predictors. METHODS: A retrospective multicenter cohort study that included patients registered in the Rheumatic Diseases Portuguese Registry (Reuma.pt) with RA, and exposed to at least one bDMARD until April 2021. RA patients under bDMARD and with at least one episode of severe infection (SI), defined as infection that requires hospitalization, use of parenteral antibiotics or that resulted in death, were compared to patients with no report of SI. Demographic and clinical data at baseline and at the time of each SI were collected to establish comparisons between different groups of bDMARDs. Comparisons between different bDMARDs were assessed and logistic regression was performed to identify predictors of SI. RESULTS: We included 3394 patients, 2833 (83.5%) female, with a mean age at RA diagnosis of 45.5±13.7 years. SI was diagnosed in 142 of the 3394 patients evaluated (4.2%), totaling 151 episodes of SI. At baseline, patients with SI had a significantly higher proportion of prior orthopedic surgery, asthma, interstitial lung disease, chronic kidney disease and corticosteroid use, higher mean age and longer median disease duration at first bDMARD. Nine patients died (6.0%). Ninety-two SI (60.9%) occurred with the first bDMARD, the majority leading to discontinuation of the bDMARD within 6 months (n=75, 49.7%), while 65 (43.0%) restarted the same bDMARD and 11 (7.3%) switched to another bDMARD (6 of them to a different mechanism of action). In the multivariate analysis, we found that chronic kidney disease, asthma, infliximab, corticosteroid use, interstitial lung disease, previous orthopedic surgery, higher Health Assessment Questionnaire and DAS284V-ESR are independent predictors of SI. CONCLUSION: This study described the incidence and types of SI among Portuguese RA patients on biologics, identifying several predictors of SI, both globally and with different bDMARDs. Physicians should be aware of the real-word infectious risk in RA patients on bDMARDs when making treatment decisions.

Colonisation Patterns of Nosema ceranae in the Azores Archipelago.

Nosema ceranae is a highly prevalent pathogen of Apis mellifera, which is distributed worldwide. However, there may still exist isolated areas that remain free of N. ceranae. Herein, we used molecular tools to survey the Azores to detect N. ceranae and unravel its colonisation patterns. To that end, we sampled 474 colonies from eight islands in 2014/2015 and 91 from four islands in 2020. The findings revealed that N. ceranae was not only present but also the dominant species in the Azores. In 2014/2015, N. apis was rare and N. ceranae prevalence varied between 2.7% in São Jorge and 50.7% in Pico. In 2020, N. ceranae prevalence increased significantly (p < 0.001) in Terceira and São Jorge also showing higher infection levels. The spatiotemporal patterns suggest that N. ceranae colonised the archipelago recently, and it rapidly spread across other islands, where at least two independent introductions might have occurred. Flores and Santa Maria have escaped the N. ceranae invasion, and it is remarkable that Santa Maria is also free of Varroa destructor, which makes it one of the last places in Europe where the honey bee remains naive to these two major biotic stressors.

Effects of exposure to elevated temperature and different food levels on the escape response and metabolism of early life stages of white seabream, Diplodus sargus.

Recent literature suggests that anthropogenic stressors can disrupt ecologically relevant behaviours in fish, such as the ability to escape from predators. Disruption of these behaviours at critical life history transitions, such as the transition from the pelagic environment to the juvenile/adult habitat, may have even greater repercussions. The literature suggests that an increase in temperature can affect fish escape response, as well as metabolism; however, few studies have focused on the acute sensitivity responses and the potential for acclimation through developmental plasticity. Here, we aimed at evaluating the acute and long-term effects of exposure to warming conditions on the escape response and routine metabolic rate (RMR) of early life stages of the white seabream, Diplodus sargus. Additionally, as food availability may modulate the response to warming, we further tested the effects of long-term exposure to high temperature and food shortage, as individual and interacting drivers, on escape response and RMR. Temperature treatments were adjusted to ambient temperature (19°C) and a high temperature (22°C). Feeding treatments were established as high ration and low ration (50% of high ration). Escape response and RMR were measured after the high temperature was reached (acute exposure) and after 4 weeks (prolonged exposure). Acute warming had a significant effect on escape response and generated an upward trend in RMR. In the long term, however, there seems to be an acclimation of the escape response and RMR. Food shortage, interacting with high temperature, led to an increase in latency response and a significant reduction in RMR. The current study provides relevant experimental data on fishes' behavioural and physiological responses to the combined effects of multiple stressors. This knowledge can be incorporated in recruitment models, thereby contributing to fine-tuning of models required for fisheries management and species conservation.

Favism: A Case Report.

Favism is an acute hemolytic syndrome that occurs in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency following the ingestion of fava beans. Diagnosis can be challenging because the severity of hemolytic anemia varies among this patient population. Furthermore, the severity of hemolytic episodes can vary in the same patient. The diagnosis of G6PD deficiency and patient education pertaining to safe and unsafe medications and foods are crucial to prevent the reoccurrence of hemolytic episodes. Here, we report the case of a man admitted to our hospital with an acute hemolytic episode. At the time of admission, we were unaware that he had ingested fava beans and only discovered that he had G6PD deficiency while performing complementary studies during the hemolytic crisis to determine its etiology.

Importância do debriefing na prática simulada em saúde para militares / Importance of debriefing in simulated health practice for military personnel

Estima-se que cerca de 90% das mortes em combate ocorrem antes da chegada das vítimas a uma Instalação de apoio Sanitário, sendo que a sobrevivência das vítimas é drasticamente dependente da primeira abordagem no local. Em Teatro de Operações, é muito provável que o elemento mais próximo de eventuais vítimas em combate seja um militar não profissional de saúde. Desta forma, considera-se que a pedra basilar consiste em dotar todos os militares de recursos e competências para a primeira assistência no terreno, seja a si próprio ou aos seus camaradas, pelo que o foco de atenção irá incidir sobre a formação em saúde para os militares, a serem projetados para um Teatro de Operações, com recurso ao debriefing após cenários clínicos simulados. O presente estudo tem como objetivo avaliar a influência do debriefing, após os cenários clínicos simulados, no desenvolvimento do conhecimento e desempenho clínico dos militares. Utilizou-se uma abordagem quantitativa do tipo experimental, antes e após, com um grupo controlo. Cada formação em Tactical Combat Casualty Care teve uma duração média de 8 horas. A amostra do estudo foi constituída por 104 indivíduos, militares a integrar uma Força Nacional Destacada, com uma média de idades de 28,90 anos e desvio padrão=8,035 anos. Como instrumentos de colheita de dados foram utilizados uma grelha de avaliação/observação do desempenho clínico e um teste de avaliação de conhecimentos teóricos. Em termos de resultados, observou-se que o debriefing foi eficaz para melhorar o desempenho prático dos militares, pois houve médias significativamente superiores nas avaliações práticas finais no grupo experimental em comparação com o grupo controlo. Por outro lado, o debriefing não teve influência no desenvolvimento dos conhecimentos teóricos dos militares na abordagem à vítima em ambiente tático/operacional. Este estudo mostrou ainda que o curso ministrado teve um impacto positivo no desenvolvimento da aprendizagem dos militares. Os resultados obtidos justificam a implementação e disseminação do debriefing na simulação realística na instituição militar, permitindo que os formandos reflitam sobre a experiência clínica, maximizando a aprendizagem.

Differential tissue accumulation in the invasive Manila clam, Ruditapes philippinarum, under two environmentally relevant lanthanum concentrations.

Among the environmental emerging concern rare earth elements, lanthanum (La) is one of the most common and reactive. Lanthanum is widely used in numerous modern technologies and applications, and its intense usage results in increasing discharges into the environment, with potentially deleterious consequences to earthlings. Therefore, we exposed the important food resource and powerful monitoring tool Manila clam to two environmentally relevant concentrations of La (0.3 µg L-1 and 0.9 µg L-1) for 6 days, through water, to assess the bioaccumulation pattern in the gills, digestive gland, and remaining body. The La bioaccumulation was measured after 1 (T1), 2 (T2), and 6 (T6) days of exposure. Lanthanum was bioaccumulated after 2 days, and the levels increased in all tissues in a dose-dependent manner. When exposed to 0.3 µg L-1, the enrichment factor pattern was gills > body > digestive gland. However, when exposed to 0.9 µg L-1, the pattern appears to change to gills > digestive gland > body. Tissue portioning appears to be linked with exposed concentration: In higher exposure levels, digestive gland seems to gain importance, probably associated with detoxification mechanisms. Here, we describe for the first time La bioaccumulation in these different tissues in a bivalve species. Future studies dealing with the bioaccumulation and availability of La should connect them with additional water parameters (such as temperature, pH, and major cations).

Impaired antioxidant defenses and DNA damage in the European glass eel (Anguilla anguilla) exposed to ocean warming and acidification.

The European eel (Anguilla anguilla) has attracted scientific inquiry for centuries due to its singular biological traits. Within the European Union, glass eel fisheries have declined sharply since 1980, from up to 2000 t (t) to 62.2 t in 2018, placing wild populations under higher risk of extinction. Among the major causes of glass eels collapse, climate change has become a growing worldwide issue, specifically ocean warming and acidification, but, to our knowledge, data on physiological and biochemical responses of glass eels to these stressors is limited. Within this context, we selected some representative biomarkers [e.g. glutathione peroxidase (GPx), catalase (CAT), total antioxidant capacity (TAC), heat shock proteins (HSP70), ubiquitin (Ub) and DNA damage] to study physiological responses of the European glass eel under distinct laboratory-climate change scenarios, such as increased water temperature (+ 4 °C) and pH reduction (- 0.4 units), for 12 weeks. Overall, the antioxidant enzymatic machinery was impaired, both in the muscle and viscera, manifested by significant changes in CAT, GPx and TAC. Heat shock response varied differently between tissues, increasing with temperature in the muscle, but not in the viscera, and decreasing in both tissues under acidification. The inability of HSP to maintain functional protein conformation was responsible for boosting the production of Ub, particularly under warming and acidification, as sole stressors. The overproduction of reactive oxygen species (ROS), either elicited by warming - due to increased metabolic demand - or acidification - through H+ interaction with O2-, generating H2O2 - overwhelmed defense mechanisms, causing oxidative stress and consequently leading to protein and DNA damage. Our results emphasize the vulnerability of eels' early life stages to climate change, with potential cascading consequences to adult stocks.

Complications of Biliary Drainage in Patients with Malignant Biliary Obstruction.

PURPOSE: Biliary tract obstruction in cancer patients is usually associated with a poor prognosis. The obstruction may cause distressing symptoms, such as pruritus. As this situation occurs mostly in advanced cancer, the primary objective of the treatment is in many cases symptom control and not prolonging life. However, some patients can be candidates for chemotherapy. To see the outcomes of stenting insertion in patients of our oncology center. METHODS: A retrospective study of patients who have undergone this procedure between 1 October 2011 and 31 December 2018 was carried out. RESULTS: Insertion of a biliary stent was performed in 171 patients. The most common diagnoses were gastric and colorectal cancers, each with 42 (24%), followed by pancreatic (34 (20%)) and biliary tract cancer (25 (14%)). Most stents (155 (91%)) were placed percutaneously. Complications were seen in 91 (53%) patients and the most common was cholangitis in 48 (53%) patients, and the median survival was 75.5 days (3-1246). A total of 168 (98%) patients were referred to palliative care. In a multivariable analysis, the ECOG performance status was associated with survival, with the ECOG 0, 1, and 2 associated with better survival and peritoneal metastases associated with lower survival. CONCLUSIONS: For many patients with advanced cancers, it may not be clear if the benefits of palliative biliary stents outweigh the risks. Therefore, the problem should be discussed with the patients and their families, making clear the goals of care and the potential benefits and risks that can be expected.

Development of autoimmune diabetes with severe diabetic ketoacidosis and immune-related thyroiditis secondary to durvalumab: a case report.

Immune-mediated endocrinopathies are among the most frequent immune-related adverse events (irAEs) with immune checkpoint inhibitors (ICIs) targeting programmed death-ligand 1 (PD-L1)/PD-1. However, the development of auto-immune diabetes is an uncommon event during PD(L)-1 blockade, either as monotherapy or in combination therapy. Here we report a case of a 75-year-old male with a mediastinal recurrence from a stage IA squamous cell carcinoma of the lung previously treated with stereotactic body radiotherapy (SBRT) who early developed a severe diabetic ketoacidosis (DKA) caused by new-onset auto-immune diabetes, with positive glutamic acid decarboxylase (GAD65) autoantibodies, during durvalumab consolidation therapy after concurrent chemoradiation. The patient had no personal or family history of diabetes or auto-immune diseases and was admitted after the second cycle of durvalumab to the intensive care unit (ICU) with severe DKA. During his hospitalization, insulin and fluid therapy were started and the patient had a favorable clinical course. Durvalumab treatment was interrupted and thyroiditis was verified during follow-up, without anti-thyroid antibodies, that progressed to subsequent hypothyroidism with need of thyroid hormone replacement therapy. This case highlights the rare irAE of autoimmune type 1 diabetes during anti-PD(L)-1 therapy, which can be life-threatening and requires adequate patient education and prompt medical treatment within a multidisciplinary team, including endocrinology and emergency medicine. Besides its low incidence, this case show how irAE must be taken in account about decision of ICI treatment, especially in curative setting, as they can be potentially fatal and impair overall survival. Furthermore, as reported in the present case, multiple endocrine irAEs can occur in the same patient either simultaneously or sequentially, suggesting that active surveillance is needed in those who develop endocrinopathies as a result of ICI treatment. Immune-mediated endocrinopathies are generally irreversible and cause life-long morbidity, which must be taken into consideration when deciding on further lines of treatment.

Warming enhances lanthanum accumulation and toxicity promoting cellular damage in glass eels (Anguilla anguilla).

Cumulative and continuing human emissions of greenhouse gases to the atmosphere are causing ocean warming. Rising temperature is a major threat to aquatic organisms and may affect physiological responses, such as acid-base balance, often compromising species fitness and survival. It is also expected that warming may influence the availability and toxicological effects of pollutants, including Rare Earth Elements. These are contaminants of environmental emerging concern with great economic interest. This group comprises yttrium, scandium and lanthanides, being Lanthanum (La) one of the most common. The European eel (Anguilla anguilla) is critically endangered and constitutes a delicacy in South East Asia and Europe, being subject to an increasing demand on a global scale. Considering the vulnerability of early life stages to contaminants, we exposed glass eels to 1.5 µg L-1 of La for five days, plus five days of depuration, under a present-day temperature and warming scenarios (△T = +4 °C). The aim of this study was to assess the bioaccumulation, elimination and specific biochemical enzymatic endpoints in glass eels (Anguilla anguilla) tissues, under warming and La. Overall, our results showed that the accumulation and toxicity of La were enhanced with increasing temperature. The accumulation was higher in the viscera, followed by the head, and ultimately the body. Elimination was less effective under warming. Exposure to La did not impact acetylcholinesterase activity. Moreover, lipid peroxidation peaked after five days under the combined exposure of La and warming. The expression of heat shock proteins was majorly suppressed in glass eels exposed to La, at both tested temperatures. This result suggests that, when exposed to La, glass eels were unable to efficiently prevent cellular damage, with a particularly dramatic setup in a near-future scenario. Further studies are needed towards a better understanding of the effects of lanthanum in a changing world.

YB-1 variant and androgen receptor axis-targeted agents in metastatic castration-resistant prostate cancer patients.

Aim: To evaluate the influence of YB-1 rs10493112 variant as a genetic marker for response to second-generation androgen receptor axis-target agents. Methods: A hospital-based cohort study of 78 patients with metastatic castration-resistant prostate cancer was conducted. Genotyping was performed by TaqMan® allelic discrimination technology. Main results: In abiraterone-treated and high-risk patients, YB-1 rs10493112 AA genotype carriers showed lower progression-free survival than C allele genotype patients (4 vs 17 months; p = 0.009). For carriers of AA genotype, multivariate Cox regression analysis revealed a fivefold increased risk of progression (p = 0.035). Conclusion: The study findings suggest that, for metastatic and castration-resistant prostate cancer patients, this polymorphism might be a putative marker for the clinical outcome.

New Targets in Lung Cancer (Excluding EGFR, ALK, ROS1).

PURPOSE OF REVIEW: Over the last two decades, the identification of targetable oncogene drivers has revolutionized the therapeutic landscape of non-small cell lung cancer (NSCLC). The extraordinary progresses made in molecular biology prompted the identification of several rare molecularly defined subgroups. In this review, we will focus on the novel and emerging actionable oncogenic drivers in NSCLC. RECENT FINDINGS: Recently, novel oncogene drivers emerged as promising therapeutic targets besides the well-established EGFR mutations, and ALK/ROS1 rearrangements, considerably expanding the list of potential exploitable genetic aberrations. However, the therapeutic algorithm in these patients is far less defined. The identification of uncommon oncogene drivers is reshaping the diagnostic and therapeutic approach to NSCLC. The introduction of novel highly selective inhibitors is expanding the use of targeted therapies to rare and ultra-rare subsets of patients, further increasing the therapeutic armamentarium of advanced NSCLC.