Efficacy of administration sequence: Sacituzumab Govitecan and Trastuzumab Deruxtecan in HER2-low metastatic breast cancer.

BACKGROUND: Current guidelines recommend that patients with HER2-low metastatic breast cancer (MBC) receive sequentially two antibody-drug conjugates (ADCs): Sacituzumab Govitecan (SG) and Trastuzumab Deruxtecan (T-DXd), despite a similar payload. However, the effectiveness of one after another is unknown. METHODS: ADC-Low is a multicentre, retrospective study evaluating the efficacy of SG and T-DXd, one after another, with or without intermediary lines of chemotherapy, in patients with HER2-low MBC. RESULTS: One hundred and seventy-nine patients were included: the majority with HR-negative tumours received SG first (ADC1) (n = 100/108) while most with HR-positive tumours received T-DXd first (n = 56/71). Median progression-free survival 2 was short: 2.7 months (95% CI: 2.4-3.3) in the whole population, respectively, 3.1 (95% CI: 2.6-3.6) and 2.2 months (95% CI: 1.9-2.7) for patients receiving T-DXd or SG second (ADC2). Intermediary lines of chemotherapy between ADC1 and ADC2 had no impact. Primary resistance to ADC2 occurred in 54.4% of patients. Certain patients showed initial response to ADC2. CONCLUSIONS: Clinical benefit of sequentially administered SG and T-DXd is limited for most patients. Nevertheless, a subset of patients might benefit-on the short term-from a second ADC. Additional studies are needed to identify patients who could benefit from two ADCs with similar payloads.

Predictive accuracy of time series models applied to economic data: the European countries retail trade.

Modeling and accurately forecasting trend and seasonal patterns of a time series is a crucial activity in economics. The main propose of this study is to evaluate and compare the performance of three traditional forecasting methods, namely the ARIMA models and their extensions, the classical decomposition time series associated with multiple linear regression models with correlated errors, and the Holt-Winters method. These methodologies are applied to retail time series from seven different European countries that present strong trend and seasonal fluctuations. In general, the results indicate that all the forecasting models somehow follow the seasonal pattern exhibited in the data. Based on mean squared error (MSE), root mean squared error (RMSE), mean absolute percentage error (MAPE), mean absolute scaled error (MASE) and U-Theil statistic, the results demonstrate the superiority of the ARIMA model over the other two forecasting approaches. Holt-Winters method also produces accurate forecasts, so it is considered a viable alternative to ARIMA. The performance of the forecasting methods in terms of coverage rates matches the results for accuracy measures.

Incidence and outcome of brain and/or leptomeningeal metastases in HER2-low metastatic breast cancer in the French ESME cohort.

BACKGROUND: Breast cancer (BC) is the second most common cancer that metastasizes to the brain. Particularly up to half of patients with human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (mBC) may develop brain metastases over the course of the disease. Nevertheless, little is known about the prevalence and the outcome of brain and leptomeningeal metastases (BLMM) in HER2-low BC. We compared the cumulative incidence of BLMM and associated outcomes among patients with HER2-low, HER2-negative (HER2-) and HER2+ mBC. PATIENTS AND METHODS: This cohort study was conducted from the Epidemiological Strategy and Medical Economics (ESME) mBC database and included patients treated for mBC between 2012 and 2020 across 18 French comprehensive cancer centers and with known HER2 and hormone receptor (HR) status. The cumulative incidence of BLMM after metastatic diagnosis was estimated using a competing risk methodology with death defined as a competing event. RESULTS: 19 585 patients were included with 6118 (31.2%), 9943 (50.8%) and 3524 (18.0%) being HER2-low, HER2- and HER2+ mBC, respectively. After a median follow-up of 48.6 months [95% confidence interval (CI) 47.7-49.3 months], BLMM were reported in 4727 patients: 1192 (25.2%) were diagnosed with BLMM at first metastatic diagnosis and 3535 (74.8%) after metastatic diagnosis. Multivariable analysis adjusted for age, histological grade, metastases-free interval and HR status showed that the risk of BLMM at metastatic diagnosis was similar in patients with HER2- compared to HER2-low mBC [odds ratio (OR) (95% CI) 1.00 (0.86-1.17)] and higher in those with HER2+ compared to HER2-low [OR (95% CI) 2.23 (1.87-2.66)]. Similar results were found after metastatic diagnosis; the risk of BLMM was similar in HER2- compared to HER2-low [subdistribution hazard ratio (sHR) (95% CI) 1.07 (0.98-1.16)] and higher in the HER2+ group [sHR (95% CI) 1.56 (1.41-1.73)]. CONCLUSIONS: The prevalence and evolution of BLMM in HER2-low mBC are similar to those in patients with HER2- tumors. In contrast to patients with HER2+ mBC, the prognosis of BLMM remains dismal in this population.

IMpassion132 double-blind randomised phase III trial of chemotherapy with or without atezolizumab for early relapsing unresectable locally advanced or metastatic triple-negative breast cancer.

BACKGROUND: Immune checkpoint inhibitors improve the efficacy of first-line chemotherapy for patients with programmed death-ligand 1 (PD-L1)-positive unresectable locally advanced/metastatic triple-negative breast cancer (aTNBC), but randomised data in rapidly relapsing aTNBC are scarce. PATIENTS AND METHODS: IMpassion132 (NCT03371017) enrolled patients with aTNBC relapsing <12 months after last chemotherapy dose (anthracycline and taxane required) or surgery for early TNBC. PD-L1 status was centrally assessed using SP142 before randomisation. Initially patients were enrolled irrespective of PD-L1 status. From August 2019, enrolment was restricted to PD-L1-positive (tumour immune cell ≥1%) aTNBC. Patients were randomised 1:1 to placebo or atezolizumab 1200 mg every 21 days with investigator-selected chemotherapy until disease progression or unacceptable toxicity. Stratification factors were chemotherapy regimen (carboplatin plus gemcitabine or capecitabine monotherapy), visceral (lung and/or liver) metastases and (initially) PD-L1 status. The primary endpoint was overall survival (OS), tested hierarchically in patients with PD-L1-positive tumours and then, if positive, in the modified intent-to-treat (mITT) population (all-comer patients randomised pre-August 2019). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. RESULTS: Among 354 patients with rapidly relapsing PD-L1-positive aTNBC, 68% had a disease-free interval of <6 months and 73% received carboplatin/gemcitabine. The OS hazard ratio was 0.93 (95% confidence interval 0.73-1.20, P = 0.59; median 11.2 months with placebo versus 12.1 months with atezolizumab). mITT and subgroup results were consistent. Median PFS was 4 months across treatment arms and populations. ORRs were 28% with placebo versus 40% with atezolizumab. Adverse events (predominantly haematological) were similar between arms and as expected with atezolizumab plus carboplatin/gemcitabine or capecitabine following recent chemotherapy exposure. CONCLUSIONS: OS, which is dismal in patients with TNBC relapsing within <12 months, was not improved by adding atezolizumab to chemotherapy. A biology-based definition of intrinsic resistance to immunotherapy in aTNBC is urgently needed to develop novel therapies for these patients in next-generation clinical trials.

Myocardial native T1 mapping at 3T cardiac magnetic resonance-closing the full-vendor reporting cycle of normal values.

AIM: Cardiac magnetic resonance is currently an indispensable tool in the diagnosis of cardiac pathologies, with mapping techniques being one of the most recent advances in this area. T1 mapping is a robust tool that uses the T1 magnetic relaxation time as a quantitative marker of myocardial tissue composition. However, multiple T1 mapping sequences are used, and data comparing them, especially on different vendors, is limited. This study aims to determine the T1 relaxation values in the cardiac muscle of healthy individuals using GE's Discovery 3T scanner, allowing the use of the T1 mapping technique in patients on a sustained basis. MATERIAL AND METHODS: Thirty-one healthy volunteers were submitted to T1 mapping at 3T magnetic resonance imaging (MRI) equipment, with 3 being excluded from the analysis (54% women; mean age: 39.2 ± 13.9 years). The MOLLI 5(3)3 sequence was used, acquiring one short axis slice at midventricular level. Native T1 values were presented as means (± standard deviation), and t-student independent samples tests evaluated gender differences in T1 values. RESULTS: The results show an average global native T1 value of 1193 ± 39 ms, with women's values being statistically higher than men (1211 ± 40 vs 1173 ± 27 ms, respectively, p<0.006). Gender remained the only determinant of native T1 times on a multiple linear regression model that included age, ejection fraction, and T2 status. CONCLUSION: This study has established one of the few native T1 values for a 3T GE Discovery scanner that are on par with those already reported by other vendors for a similar sequence, closing the circle in full-vendor reporting.

Temperature influence on the sensitivity of Artemia franciscana to globally used pesticides - Oxyfluorfen and copper.

Climate change further the world's human population increase is a mainstream political issue, and it's critical to search for solutions to produce enough food to feed everyone. Pesticides and fertilizers have been used as an easy solution to prevent pests and increase food production. Nevertheless, their overuse has dangerous effects on the ecosystems and communities. Oxyfluorfen (Oxy) and copper (Cu) based formulations are used as pesticides and widely applied on agricultural fields for crop protection. However, they have shown negative effects on non-target species. So, this work proposes to: a)determine the lethal concentration of Oxy and Cu to the zooplankton, Artemia franciscana, at different temperatures (15 °C, 20 °C and 25 °C); b)understand the biochemical impacts of these chemicals at the different temperatures scenarios, on A. franciscana and c)evaluate the impact of the climate changes, particularly the temperature increase, on this species sensitivity to the tested pesticides. Acute and sub-lethal bioassays with Oxy and Cu were performed at different temperatures to determine the lethal concentration of each chemical and to understand the effects of the compounds at different temperatures on the biochemical profiles of A. franciscana. Results showed an increase in chemicals toxicity with the temperature, and Oxy was revealed to be more noxious to A. franciscana than Cu; at a biochemical level, significant differences were observed among temperatures, with the biggest differences between the organisms exposed to 15 °C and 25 °C. Overall, a decrease in fatty acids (FA) and sugars was observed with the increase in Cu and oxyfluorfen concentrations. Different trends were observed with temperature increase, with FA increase in the organisms exposed to Cu and the opposite was observed in the ones exposed to oxyfluorfen. Sugar content decreases in the organisms exposed to oxyfluorfen with temperature increase and showed a non-linear behaviour in the ones exposed to Control and Cu treatments.

Transabdominal preperitoneal (TAPP) repair for emergency groin hernia: a systematic review.

PURPOSE: Laparoscopic groin hernia repair has evolved and gained popularity and laparoscopic transabdominal preperitoneal (TAPP) procedure provides an opportunity to evaluate the peritoneal cavity and both inguinal areas without the need for additional dissection. There is still a paucity of evidence to support TAPP repair in the emergency setting. In this systematic review, we aim to evaluate the feasibility and safety of TAPP repair for incarcerated and strangulated groin hernias. METHODS: PRISMA guidelines were followed for literature search and established inclusion and exclusion criteria were applied. Data were extracted and analyzed for the outcomes of interest. RESULTS: Overall, 8 studies were included in the review, comprising 316 patients. Patients characteristics and outcomes were limitedly reported. Only 3 cases of conversion to open approach were reported and 2 recurrences were diagnosed. Postoperative complications are inconsistently reported but mostly refer to minor complications. There were no mortality cases. Visceral resections were performed in 25 cases due to ischemia, mostly extracorporeally. CONCLUSION: Laparoscopy is a game changer and TAPP approach is a feasible, safe, and effective technique for the emergent repair of groin hernias. Further studies and prospective randomized data are needed to establish its role in the emergent groin hernia management.

Nuchal Translucency and Congenital Heart Defects.

Nuchal translucency comprises a temporary accumulation of fluid in the subcutaneous tissue on the back of a fetus's neck, which accompanies the crown-rump length and is observed through an ultrasound performed between 11 and 13 weeks + 6 days gestation. Nuchal translucency is considered to be above normal when values are higher than the 95th/99th percentile or equal to or higher than 2.5/3.5 mm. The first connection between increased nuchal translucency and the presence of congenital heart defects is described in the study of Hyett et al., who observed that they are directly proportional. Since that time, several studies have been conducted to understand if nuchal translucency measurements can be used for congenital heart defect screening in euploid fetuses. However, there is great variability in the estimated nuchal translucency cutoff values for congenital heart defect detection. The purpose of this review was to understand how increased nuchal translucency values and congenital heart defects are related and to identify which of these defects are more frequently associated with an increase in these values.

Brazilian dentist's knowledge of minimum intervention dentistry for caries management: application of a developed knowledge scale (MIDDeC-KS) and evaluation of its psychometric properties.

AIM: To assess the knowledge of Brazilian dentists about Minimum Intervention (MI) using a Minimum Intervention Dentistry to Dental Caries-Knowledge Scale (MIDDeC-KS) and evaluate its psychometric properties. MATERIALS AND METHODS: An online scale was developed to evaluate dentists' knowledge about MI. The higher the score, the greater the knowledge and vice versa. A preliminary study was carried out with 143 dentists to validate the MIDDeC-KS. For psychometric properties analysis, convergent and discriminant validity, test-retest reliability, and internal consistency of the instrument were assessed. After validation, MIDDeC-KS was applied to a representative sample of Brazilian dentists. T test for independent samples, Chi-square, and/or ANOVA one-way tests were applied. RESULTS: The MIDDeC-KS convergent (Spearman's = 0.48) and discriminant (P = 0.001) validity and reliability (ICC = 0.85, α = 0.72 and ω = 0.74) were proved. The participants (n = 637) obtained an overall mean score of 7.4 ± 2.5. The sample was mainly composed of females (P < 0.01), who graduated over 10 years prior (P = 0.02), from public colleges (P < 0.01), and most were pediatric dentists (38.2%). The highest and lowest scores were reached by pediatric dentists (9.2 ± 1.6) and bucomaxillofacial professionals (3.1 ± 2.1), respectively. Brazilian dentists demonstrated more knowledge about diet, biofilm, and topical fluoride control (84.3%), while the Hall technique (31.9%), resin infiltrant (47.6%), and chemical mechanical caries removal (48.4%) were the least known MI techniques. CONCLUSION: Brazilian dentists demonstrated more knowledge about preventive measures and less about more recent protocols, such as the Hall technique, resin infiltrant, and chemical mechanical caries tissue removal. Sufficient psychometric evidence of the MIDDeC-KS was found. CLINICAL RELEVANCE: Identify dentist's knowledge about MI.

Enzymatic activity of bone markers on Lithobates catesbeianus (Shaw, 1802) growth during the ossification process

Abstract In order to better understand the ossification processes in anurans our study was carried out on tadpoles and adults of Lithobates catesbeianus. In this sense, we characterized the kinetic properties of alkaline phosphatase with p-nitrophenylphosphatase (pNPP) and pyrophosphate (PPi) and evaluated the activities of tartrate-resistant acid phosphatase and acid phosphatase. The enzyme extracts were obtained from tadpoles and adult femurs, which were divided into epiphysis and diaphysis. After homogenization, the samples were submitted to differential centrifugation to obtain cell membranes and, further, to phospholipase C (PIPLC) treatment, to remove membrane-bound proteins anchored by phosphatidylinositol. The average of specific activity for pNPP hydrolysis (at pH 10.5) by alkaline phosphatase released by phosphatidylinositol-specific phospholipase C (PIPLC) from Bacillus cereus among different bone regions at different animal ages was 1,142.57 U.mg-1, while for PPi hydrolysis (at pH 8.0), it was 1,433.82 U.mg-1. Among the compounds tested for enzymatic activity, the one that influenced the most was EDTA, with approximately 67% of inhibition for pNPPase activity and 77% for PPase activity. In the case of kinetic parameters, the enzyme showed a Michaelian behavior for pNPP and PPi hydrolysis. The Km value was around 0.6mM for pNPPase activity and ranged from 0.01 to 0.11mM for PPase activity, indicating that the enzyme has a higher affinity for this substrate. The study of pNPP and PPi hydrolysis by the enzyme revealed that the optimum pH of actuation for pNPP was 10.5, while for PPi, which is considered the true substrate of alkaline phosphatase, was 8.0, close to the physiological value. The results show that regardless of the ossification type that occurs, the same enzyme or isoenzymes act on the different bone regions and different life stages of anurans. The similarity of the results of studies with other vertebrates shows that anurans can be considered excellent animal models for the study of biological calcification.

Resumo Para melhor compreender o processo de ossificação em anuros, nosso estudo foi conduzido em girinos e adultos de Lithobates catesbeianus. Nesse sentido, as propriedades cinéticas da fosfatase alcalina com p-nitrofenilfosfato (pNPP) e pirofosfato (PPi) foram caracterizadas, e as atividades enzimáticas das fosfatases ácida e ácida tartarato resistente foram avaliadas. Os extratos enzimáticos foram obtidos de fêmur de girinos e adultos, divididos em epífise e diáfise. Após a homogeneização as amostras foram submetidas à centrifugação diferencial para obter membrana celular e, em seguida, ao tratamento com fosfolipase C (PIPLC), para remover as proteínas de membrana ancoradas por fosfatidilinositol. A média da atividade específica da fosfatase alcalina, liberada pela PIPLC de Bacillus cereus, para a hidrólise de pNPP (pH 10,5) nas diferentes regiões do fêmur e idades dos animais foi de 1.142,57 U.mg-1, enquanto para a hidrólise do PPi (pH 8,0) foi de 1.433,82 U.mg-1. Entre os compostos testados para a atividade enzimática, o de maior influência foi o EDTA, inibindo aproximadamente 67% e 77% das atividades de pNPPase e PPase, respectivamente. Quanto aos parâmetros cinéticos, a enzima apresentou comportamento Michaeliano para a hidrólise dos dois substratos. O valor de Km foi de 0,6 mM para a atividade de pNPPase e variou de 0,01 a 0,11 para a atividade de PPase, indicando uma maior afinidade por esse substrato. O estudo da hidrólise de pNPP e PPi revelou que o pH ótimo aparente de atuação foi de 10,5 para o pNPP e 8,0 para o PPi, próximo ao fisiológico, sendo que esse é considerado o substrato natural da fosfatase alcalina. Os resultados demonstram que, apesar do tipo de ossificação que ocorre, a mesma enzima ou isoenzimas, atuam nos diferentes locais do osso e estágios de vida dos anuros. A similaridade dos estudos com os realizados com outros vertebrados apontam que os anuros podem ser considerados excelentes modelos animais para o estudo da calcificação biológica.

Enzymatic activity of bone markers on Lithobates catesbeianus (Shaw, 1802) growth during the ossification process / Atividade enzimática de marcadores ósseos no crescimento de Lithobates catesbeianus (Shaw, 1802) durante o processo de ossificação

Abstract In order to better understand the ossification processes in anurans our study was carried out on tadpoles and adults of Lithobates catesbeianus. In this sense, we characterized the kinetic properties of alkaline phosphatase with p-nitrophenylphosphatase (pNPP) and pyrophosphate (PPi) and evaluated the activities of tartrate-resistant acid phosphatase and acid phosphatase. The enzyme extracts were obtained from tadpoles and adult femurs, which were divided into epiphysis and diaphysis. After homogenization, the samples were submitted to differential centrifugation to obtain cell membranes and, further, to phospholipase C (PIPLC) treatment, to remove membrane-bound proteins anchored by phosphatidylinositol. The average of specific activity for pNPP hydrolysis (at pH 10.5) by alkaline phosphatase released by phosphatidylinositol-specific phospholipase C (PIPLC) from Bacillus cereus among different bone regions at different animal ages was 1,142.57 U.mg-1, while for PPi hydrolysis (at pH 8.0), it was 1,433.82 U.mg-1. Among the compounds tested for enzymatic activity, the one that influenced the most was EDTA, with approximately 67% of inhibition for pNPPase activity and 77% for PPase activity. In the case of kinetic parameters, the enzyme showed a "Michaelian" behavior for pNPP and PPi hydrolysis. The Km value was around 0.6mM for pNPPase activity and ranged from 0.01 to 0.11mM for PPase activity, indicating that the enzyme has a higher affinity for this substrate. The study of pNPP and PPi hydrolysis by the enzyme revealed that the optimum pH of actuation for pNPP was 10.5, while for PPi, which is considered the true substrate of alkaline phosphatase, was 8.0, close to the physiological value. The results show that regardless of the ossification type that occurs, the same enzyme or isoenzymes act on the different bone regions and different life stages of anurans. The similarity of the results of studies with other vertebrates shows that anurans can be considered excellent animal models for the study of biological calcification.

Resumo Para melhor compreender o processo de ossificação em anuros, nosso estudo foi conduzido em girinos e adultos de Lithobates catesbeianus. Nesse sentido, as propriedades cinéticas da fosfatase alcalina com p-nitrofenilfosfato (pNPP) e pirofosfato (PPi) foram caracterizadas, e as atividades enzimáticas das fosfatases ácida e ácida tartarato resistente foram avaliadas. Os extratos enzimáticos foram obtidos de fêmur de girinos e adultos, divididos em epífise e diáfise. Após a homogeneização as amostras foram submetidas à centrifugação diferencial para obter membrana celular e, em seguida, ao tratamento com fosfolipase C (PIPLC), para remover as proteínas de membrana ancoradas por fosfatidilinositol. A média da atividade específica da fosfatase alcalina, liberada pela PIPLC de Bacillus cereus, para a hidrólise de pNPP (pH 10,5) nas diferentes regiões do fêmur e idades dos animais foi de 1.142,57 U.mg-1, enquanto para a hidrólise do PPi (pH 8,0) foi de 1.433,82 U.mg-1. Entre os compostos testados para a atividade enzimática, o de maior influência foi o EDTA, inibindo aproximadamente 67% e 77% das atividades de pNPPase e PPase, respectivamente. Quanto aos parâmetros cinéticos, a enzima apresentou comportamento Michaeliano para a hidrólise dos dois substratos. O valor de Km foi de 0,6 mM para a atividade de pNPPase e variou de 0,01 a 0,11 para a atividade de PPase, indicando uma maior afinidade por esse substrato. O estudo da hidrólise de pNPP e PPi revelou que o pH ótimo aparente de atuação foi de 10,5 para o pNPP e 8,0 para o PPi, próximo ao fisiológico, sendo que esse é considerado o substrato natural da fosfatase alcalina. Os resultados demonstram que, apesar do tipo de ossificação que ocorre, a mesma enzima ou isoenzimas, atuam nos diferentes locais do osso e estágios de vida dos anuros. A similaridade dos estudos com os realizados com outros vertebrados apontam que os anuros podem ser considerados excelentes modelos animais para o estudo da calcificação biológica.

Efficacy of levamisole, ivermectin and moxidectin against Capillaria spp. in European hedgehogs (Erinaceus europaeus).

This randomised study aimed to assess and compare the efficacy of treatment protocols containing levamisole, ivermectin, or moxidectin against Capillaria spp. in naturally infected European hedgehogs (Erinaceus europaeus) presented to a British wildlife rehabilitation centre. Faecal analysis, consisting of wet mount and flotation, was performed for 229 hedgehogs weighing ≥200g. Animals testing positive for Capillaria spp. (81%), excluding pregnant females, were randomly allocated a treatment protocol. Initially, hedgehogs (n = 50) received one of six 'pilot' protocols, whereas the remaining animals (n = 97) received one of three 'main' protocols. Faecal analysis was repeated on day 8 and day 12 after treatment initiation. Efficacy of each treatment was assessed based on Capillaria reduction rate (CRR), weight gain, presence of respiratory clinical signs, and outcome. Pilot protocols containing only moxidectin had a significantly lower CRR (≥28.1%) compared to those with levamisole or ivermectin (≥86.6%), whereas the main protocols containing levamisole had a significantly higher CRR (≥93.0%) compared to those containing only ivermectin (≥69.3%). Clinical parameters did not differ significantly between treatments, but animals with respiratory clinical signs at the end of the trial were significantly more likely to have lower CRR and test positive for Crenosoma striatum. C. striatum often appeared refractory to treatment, and managing these infections requires additional anthelmintic therapy. Based on the formulations and dosages trialled, moxidectin is not recommended for treating capillariosis in European hedgehogs, whereas levamisole given orally for two consecutive days at 25-35 mg/kg is suggested as the treatment of choice.

Key processes required for the different stages of fungal carnivory by a nematode-trapping fungus.

Nutritional deprivation triggers a switch from a saprotrophic to predatory lifestyle in soil-dwelling nematode-trapping fungi (NTF). In particular, the NTF Arthrobotrys oligospora secretes food and sex cues to lure nematodes to its mycelium and is triggered to develop specialized trapping devices. Captured nematodes are then invaded and digested by the fungus, thus serving as a food source. In this study, we examined the transcriptomic response of A. oligospora across the stages of sensing, trap development, and digestion upon exposure to the model nematode Caenorhabditis elegans. A. oligospora enacts a dynamic transcriptomic response, especially of protein secretion-related genes, in the presence of prey. Two-thirds of the predicted secretome of A. oligospora was up-regulated in the presence of C. elegans at all time points examined, and among these secreted proteins, 38.5% are predicted to be effector proteins. Furthermore, functional studies disrupting the t-SNARE protein Sso2 resulted in impaired ability to capture nematodes. Additionally, genes of the DUF3129 family, which are expanded in the genomes of several NTF, were highly up-regulated upon nematode exposure. We observed the accumulation of highly expressed DUF3129 proteins in trap cells, leading us to name members of this gene family as Trap Enriched Proteins (TEPs). Gene deletion of the most highly expressed TEP gene, TEP1, impairs the function of traps and prevents the fungus from capturing prey efficiently. In late stages of predation, we observed up-regulation of a variety of proteases, including metalloproteases. Following penetration of nematodes, these metalloproteases facilitate hyphal growth required for colonization of prey. These findings provide insights into the biology of the predatory lifestyle switch in a carnivorous fungus and provide frameworks for other fungal-nematode predator-prey systems.

Efficacy of front-line treatment for hormone receptor-positive HER2-negative metastatic breast cancer with germline BRCA1/2 mutation.

BACKGROUND: Efficacy of endocrine therapy in HR+/HER2- metastatic breast cancer could differ depending on the presence of BRCA1/2 germline mutation. METHODS: The ESME metastatic breast cancer platform (NCT03275311) is a French real world database. Multivariable models including a time-varying approach and landmark analyses assessed the association between time-dependent gBRCA status (categorised as gBRCAm, gBRCAwt (wild type), and untested), overall survival (OS), and first-line progression-free survival (PFS1). RESULTS: A total of 170 patients were gBRCAm carriers, 676 gBRCAwt, and 12,930 were untested at baseline. In the multivariable analysis, gBRCAm carriers overall had a lower OS compared to gBRCAwt (adjusted HR [95% CI] 1.26 [1.03-1.55]). gBRCAm patients treated with front-line endocrine therapy had lower adjusted OS (adjusted HR [95% CI] = 1.54 [1.03-2.32]) and PFS1 (adjusted HR [95% CI] 1.58 [1.17-2.12]) compared to gBRCAwt patients. However, for patients who received frontline chemotherapy, neither OS nor PFS1 differed between gBRCAm carriers and the other groups (HR versus gBRCAwt for OS: 1.12 [0.88-1.41], p = 0.350; PFS1: 1.09 [0.90-1.31], p = 0.379). CONCLUSION: In this large cohort of HR+/HER2- MBC patients treated in a pre-CDK4/6 inhibitors era, gBRCAm status was associated with a lower OS and lower PFS following first-line endocrine therapy, but not following first-line chemotherapy.

Efficiency of Invisalign First® to promote expansion movement in mixed dentition: a retrospective study and systematic review.

Aim: The present study aimed: i) to retrospectively evaluate the expansion movement predicted by the Clincheck® software and the achieved expansion using Invisalign First® in children needing maxillary expansion to correct malocclusions; and ii) to critically compare these clinical results with the outcomes obtained for maxillary expansion using conventional removable and cemented expanders. Material and Methods: The 3D digital models of the dental arches of 24 children undergoing orthodontic treatment exclusively with Invisalign First® aligners between 2018 and 2021 were sequentially selected for this study. Three digital models were analysed: pre-treatment (P0), the Clincheck®-predicted tooth positions (P1), and post-treatment (P2) models. The maxillary dental arch width and expansion efficiency were measured andcalculated. An in-depth review of the available literature on maxillary expansion was performed following PRISMA guidelines. Results: Invisalign First® was able to achieve a total effectiveness of maxillary expansion of 62.6%, compared to the predicted movement. Similarly, the total effectiveness of mandibular expansion was 61.6%. Conclusions: Our data shows that Invisalign First® system can increase the arch width with maxillary expansion effectiveness, providing similar results to those achieved with conventional removable appliances. However, neither Invisalign First® aligners nor conventional removable expanders are as much efficient as cemented-retained appliances.

COVID-19 vaccines effectiveness against symptomatic disease and severe outcomes, 2021-2022: a test-negative case-control study.

OBJECTIVES: This study evaluated the effectiveness of COVID-19 vaccines in preventing symptomatic and severe disease. STUDY DESIGN: This was an observational test-negative case-control study. METHODS: Study participants were adults with at least one symptom included in the World Health Organization COVID-19 definition who sought health care in a public emergency department between 1 November 2021 and 2 March 2022 (corresponding with the fifth pandemic wave in Portugal dominated by the Omicron variant). This study used multivariable logistic regression models to estimate and compare the odds ratio of vaccination between test-positive cases and test-negative controls to calculate the absolute and relative vaccine effectiveness. RESULTS: The study included 1059 individuals (522 cases and 537 controls) with a median age of 56 years and 58% were women. Compared with the effectiveness of the primary vaccination scheme that had been completed ≥180 days earlier, the relative effectiveness against symptomatic infection of a booster administered between 14 and 132 days earlier was 71% (95% confidence interval [CI]: 57%, 81%; P < 0.001). The effectiveness of the primary series against symptomatic infection peaked at 85% (95% CI: 56%, 95%) between 14 and 90 days after the last inoculation and decreased to 34% (95% CI: -43%, 50%) after ≥180 days. CONCLUSIONS: Despite the known immunological evasion characteristics of the Omicron variant, results from this study show that vaccine effectiveness increases after booster administration. COVID-19 vaccine effectiveness decreases to less than 50% between 3 and 6 months after completion of the primary cycle; therefore, this would be an appropriate time to administer a booster to restore immunity.

How I treat endocrine-dependent metastatic breast cancer.

Estrogen receptor-positive (ER+)/HER2-negative (HER2-), the so-called luminal-type breast cancer, is the most frequent subset, accounting for around 70% of all breast cancer cases. Endocrine therapy (ET) combined with cyclin-dependent kinases (CDK) 4/6 inhibitors is the standard first option in the management of advanced luminal breast cancer independently of disease extension. Classically, patients undergo multiple lines of ET ± targeted treatments until endocrine resistance occurs and palliative chemotherapy is proposed. Understanding endocrine resistance mechanisms and development of novel ET options is one of the main challenges in current clinical research. Another area of utmost interest is the improvement of post-endocrine therapeutic approaches. Among others, the development of antibody-drug conjugates (ADCs) is very promising, and some of these drugs will probably soon become a part of the therapeutic arsenal against this incurable disease. This review paper provides an overview of currently available treatment options in ER+/HER2- metastatic breast cancer and extensively discusses new approaches in late clinical development.