The role of CDK4/6 inhibitors in early breast cancer

The use of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) has proven to be a successful strategy in the treatment of advanced hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC), leading to a strong interest in their possible role in the treatment of early luminal BC. In this review we collect the most relevant and recent information on the use of CDK4/6i for the treatment of early BC in the neoadjuvant and adjuvant settings. Specifically, we evaluate the results of the large phase 3 adjuvant trials recently released, which have yielded apparently divergent results. We also examine the relevance of biomarkers as response predictive factors for CDI4/6i, the combination between radiotherapy and CDK4/6i, and provide a critical discussion on the evidence that we have so far and future directions of the role of these drugs in the treatment of early BC

The Molecular Biology of Vestibular Schwannomas and Its Association with Hearing Loss: A Review

Hearing loss is the most common symptom in patients with vestibular schwannoma (VS). In the past, compressive mechanisms caused by the tumoral mass and its growth have been regarded as the most likely causes of the hearing loss associated with VS. Interestingly, new evidence proposes molecular mechanisms as an explanation for such hearing loss. Among the molecular mechanisms proposed are methylation of TP73, negative expression of cyclin D1, expression of B7-H1, increased expression of the platelet-derived growth factor A, underexpression of PEX5L, RAD54B, and PSMAL, and overexpression of CEA. Many molecular mechanisms are involved in vestibular schwannoma development; we review some of these mechanisms with special emphasis on hearing loss associated with vestibular schwannoma

Influence of Implantable Hearing Aids and Neuroprosthesison Music Perception

The identification and discrimination of timbre are essential features of music perception. One dominating parameter within the multidimensional timbre space is the spectral shape of complex sounds. As hearing loss interferes with the perception and enjoyment of music, we approach the individual timbre discrimination skills in individuals with severe to profound hearing loss using a cochlear implant (CI) and normal hearing individuals using a bone-anchored hearing aid (Baha). With a recent developed behavioral test relying on synthetically sounds forming a spectral continuum, the timbre difference was changed adaptively to measure the individual just noticeable difference (JND) in a forced-choice paradigm. To explore the differences in timbre perception abilities caused by the hearing mode, the sound stimuli were varied in their fundamental frequency, thus generating different spectra which are not completely covered by a CI or Baha system. The resulting JNDs demonstrate differences in timbre perception between normal hearing individuals, Baha users, and CI users. Beside the physiological reasons, also technical limitations appear as the main contributing factors

Neuroprotective activity of macroalgal fucofuroeckols against amyloid beta peptide-induced cell death and oxidative stress

Published online 14 April 2022Phlorotannins are polyphenolic compounds predominantly found in brown seaweeds tentatively identifiedas having neuroprotective bioactivity; however, the effects of individual constituent phlorotannins againstamyloidbneurotoxicity, the main hallmark neurotoxic protein in Alzheimer’s disease (AD), is yet to befully characterised. In this study, four phlorotannins, namely eckol, dieckol, phlorofucofuroeckol-A(PFFA) and 974-A sourced from the brown seaweed Ecklonia species were assessed for their ability to protect against the toxic effects of H2O2, lipid peroxidation via tert-butyl hydroperoxide (t-BHP) andAb1–42in neuronal PC12 cells. All compounds significantly scavenged reactive oxygen species (ROS).However, only PFFA and 974-A protected PC12 cells from oxidative stress-evoked neurotoxicity, providing significant increases in cell viability in response to both cytosolic (H2O2)and lipid peroxidation-evoked (t-BHP) cell stress. None of the phlorotannins tested inhibited Ab1–42aggregate morphology,which suggested that their neuroprotective activity was unrelated to direct interactions with Ab1–42pro-tein. Our results indicate that while all phlorotannins tested exhibited ROS scavenging activity, only fucofuroeckol-type phlorotannins such as PFFA and 974-A afforded broader neuroprotective activity in response to both oxidative stress and amyloid beta exposure. The additional amyloid-protective capacity of fucofuroeckols reveals the potential importance of the benzofuran moiety in neuroprotection and further studies are encouraged to investigate the chemico-biological basis of this distinction in the search for neuroprotective therapies in dementia and other neurodegenerative conditions.Srijan Shrestha, Jae Sue Choi, Wei Zhang, Scott D. Smi

Modelação versus medição do estado hídrico do solo. Estudo numa cultura de milho no Vale do Sorraia

Mestrado em Engenharia Agronómica - Instituto Superior de AgronomiaA cultura do milho é hoje a cultura arvense de maior expressão em Portugal, tanto para a produção de silagem como de grão. No entanto, esta área tem vindo a diminuir e em 2016 era apenas de cerca de 120 mil hectares de área cultivada. A escassez de água, um problema que se tem vindo a agravar, torna importante tirar um melhor partido da rega, otimizando a quantidade água utlizada. Nesse sentido, é necessário dar mais atenção aos parâmetros da rega para saber com precisão adequada quando regar e qual a quantidade de água a utilizar. O objetivo deste trabalho foi estimar o teor de água no solo para a cultura do milho, com base num modelo simples do balanço hídrico, em que se determina a variação de armazenamento de água, comparando-o com as medições de teor de água do solo recorrendo ao método gravimétrico, para dessa forma ajuizar da adequação dos coeficientes usados na estimativa da evapotranspiração real, um dado de entrada no modelo. Essas medições foram realizadas na Estação Experimental António Teixeira no Vale do Sorraia, numa área regada por pivot. Também nesta Estação, estavam instaladas 4 sondas capacitivas, de empresas diferentes, que registavam o teor de água no solo e apresentavam a sua evolução sazonal, que foi possível analisar qualitativamente. O cálculo da evapotranspiração cultural foi feito com base na evapotranspiração de referência, obtida através da estação meteorológica do IPMA existente na estação experimental, e no coeficiente cultural, que se ajustou para o estudo em questão. Observou-se que a cultura não esteve em stress hídrico. Da comparação dos resultados pode-se concluir que existe um bom ajuste entre o estado hídrico do solo observado e o estimado pelo modeloN/

The good and the bad of T cell cross-reactivity: challenges and opportunities for novel therapeutics in autoimmunity and cancer

T cells are main actors of the immune system with an essential role in protection against pathogens and cancer. The molecular key event involved in this absolutely central task is the interaction of membrane-bound specific T cell receptors with peptide-MHC complexes which initiates T cell priming, activation and recall, and thus controls a range of downstream functions. While textbooks teach us that the repertoire of mature T cells is highly diverse, it is clear that this diversity cannot possibly cover all potential foreign peptides that might be encountered during life. TCR cross-reactivity, i.e. the ability of a single TCR to recognise different peptides, offers the best solution to this biological challenge. Reports have shown that indeed, TCR cross-reactivity is surprisingly high. Hence, the T cell dilemma is the following: be as specific as possible to target foreign danger and spare self, while being able to react to a large spectrum of body-threatening situations. This has major consequences for both autoimmune diseases and cancer, and significant implications for the development of T cell-based therapies. In this review, we will present essential experimental evidence of T cell cross-reactivity, implications for two opposite immune conditions, i.e. autoimmunity vs cancer, and how this can be differently exploited for immunotherapy approaches. Finally, we will discuss the tools available for predicting cross-reactivity and how improvements in this field might boost translational approaches

Ensayo clínico hospitalario: homeopatía en las otitis secretoras infantiles

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Cirugía. Fecha de lectura: 17 de febrero, 201

Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial

Background In animal models of breast cancer, resistance to continuous use of letrozole can be reversed by withdrawal and reintroduction of letrozole. We therefore hypothesised that extended intermittent use of adjuvant letrozole would improve breast cancer outcome compared with continuous use of letrozole in postmenopausal women. Methods We did the multicentre, open-label, randomised, parallel, phase 3 SOLE trial in 240 centres (academic, primary, secondary, and tertiary care centres) in 22 countries. We enrolled postmenopausal women of any age with hormone receptor-positive, lymph node-positive, and operable breast cancer for which they had undergone local treatment (surgery with or without radiotherapy) and had completed 4\u20136 years of adjuvant endocrine therapy. They had to be clinically free of breast cancer at enrolment and without evidence of recurrent disease at any time before randomisation. We randomly assigned women (1:1) to treatment groups of either continuous use of letrozole (2\ub75 mg/day orally for 5 years) or intermittent use of letrozole (2\ub75 mg/day orally for 9 months followed by a 3-month break in years 1\u20134 and then 2\ub75 mg/day during all 12 months of year 5). Randomisation was done by principal investigators or designee at respective centres through the internet-based system of the International Breast Cancer Study Group, was stratified by type of previous endocrine therapy (aromatase inhibitors only vs selective oestrogen receptor modulators only vs both therapies), and used permuted block sizes of four and institutional balancing. No one was masked to treatment assignment. The primary endpoint was disease-free survival, analysed by the intention-to-treat principle using a stratified log-rank test. All patients in the intention-to-treat population who initiated protocol treatment during their period of trial participation were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00553410, and EudraCT, number 2007-001370-88; and long-term follow-up of patients is ongoing. Findings Between Dec 5, 2007, and Oct 8, 2012, 4884 women were enrolled and randomised after exclusion of patients at a non-adherent centre, found to have inadequate documentation of informed consent, immediately withdrew consent, or randomly assigned to intervention groups in error. 4851 women comprised the intention-to-treat population that compared extended intermittent letrozole use (n=2425) with continuous letrozole use (n=2426). After a median follow-up of 60 months (IQR 53\u201372), disease-free survival was 85\ub78% (95% CI 84\ub72\u201387\ub72) in the intermittent letrozole group compared with 87\ub75% (86\ub70\u201388\ub78) in the continuous letrozole group (hazard ratio 1\ub708, 95% CI 0\ub793\u20131\ub726; p=0\ub731). Adverse events were reported as expected and were similar between the two groups. The most common grade 3\u20135 adverse events were hypertension (584 [24%] of 2417 in the intermittent letrozole group vs 517 [21%] of 2411 in the continuous letrozole group) and arthralgia (136 [6%] vs 151 [6%]). 54 patients (24 [1%] in the intermittent letrozole group and 30 [1%] in the continuous letrozole group) had grade 3\u20135 CNS cerebrovascular ischaemia, 16 (nine [<1%] vs seven [<1%]) had grade 3\u20135 CNS haemorrhage, and 40 (19 [1%] vs 21 [1%]) had grade 3\u20135 cardiac ischaemia. In total, 23 (<1%) of 4851 patients died while on trial treatment (13 [<1%] of 2417 patients in the intermittent letrozole group vs ten [<1%] of 2411 in the continuous letrozole group). Interpretation In postmenopausal women with hormone receptor-positive breast cancer, extended use of intermittent letrozole did not improve disease-free survival compared with continuous use of letrozole. An alternative schedule of extended adjuvant endocrine therapy with letrozole, including intermittent administration, might be feasible and the results of the SOLE trial support the safety of temporary treatment breaks in selected patients who might require them