CDK9 inhibition as an effective therapy for small cell lung cancer.

Treatment-naïve small cell lung cancer (SCLC) is typically susceptible to standard-of-care chemotherapy consisting of cisplatin and etoposide recently combined with PD-L1 inhibitors. Yet, in most cases, SCLC patients develop resistance to first-line therapy and alternative therapies are urgently required to overcome this resistance. In this study, we tested the efficacy of dinaciclib, an FDA-orphan drug and inhibitor of the cyclin-dependent kinase (CDK) 9, among other CDKs, in SCLC. Furthermore, we report on a newly developed, highly specific CDK9 inhibitor, VC-1, with tumour-killing activity in SCLC. CDK9 inhibition displayed high killing potential in a panel of mouse and human SCLC cell lines. Mechanistically, CDK9 inhibition led to a reduction in MCL-1 and cFLIP anti-apoptotic proteins and killed cells, almost exclusively, by intrinsic apoptosis. While CDK9 inhibition did not synergise with chemotherapy, it displayed high efficacy in chemotherapy-resistant cells. In vivo, CDK9 inhibition effectively reduced tumour growth and improved survival in both autochthonous and syngeneic SCLC models. Together, this study shows that CDK9 inhibition is a promising therapeutic agent against SCLC and could be applied to chemo-refractory or resistant SCLC.

Why is pet (cat/dog) allergen immunotherapy (AIT) such a controversial topic? Current perspectives and future directions.

Summary: Dogs and cats are the most common pets worldwide. In Italy, the prevalence of allergic sensitization to cats and dogs is 16% and 9% respectively. The limited standardization of allergenic extracts, especially for dogs, emphasizes the importance of Component Resolved Diagnosis (CRD) for accurate diagnosis and subsequent prescription of allergen immunotherapy (AIT). However, this low standardization is the main factor contributing to the unsatisfactory clinical efficacy of traditional AIT, AIT with modified allergens, and intralymphatic allergen-specific immunotherapy (ILAIT). Emerging immunological approaches, particularly for controlling the primary cat allergen, show promise but are hindered by high costs (e.g., use of anti-Fel d 1 monoclonal antibodies in humans) or by exclusively targeting Fel d 1 produced by one's own animal (e.g., immunizing cats to induce neutralizing antibodies against Fel d 1 or including an egg product with anti Fel d 1 IgY antibodies in feline diet). Further studies are imperative for standardizing pet allergens, enhancing the efficacy of various AIT modalities, and exploring other immunological approaches, to optimize the relationship between pets and their owners and prevent distressing "forced removals".

What could the role of can f 5 allergen be in dog-sensitized patients in "Real Life"?

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Can pet keeping be considered the only criterion of exposure to cat/dog allergens in the first year of life?

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Is allergic sensitization to Siberian Hamster preventable in high-risk individuals who are already sensitized or exposed to furry animals?

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Is generalized reaction after exposure to big cats at the circus really unpredictable in highly cat-allergic individuals?

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When should the skin prick tests not be performed?

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Cypress pollen: an unexpected major sensitizing agent in different regions of Italy

Objectives: In this multicenter survey, we assessed the impact of sensitization to cypress in atopic patients in Italy and determined whether cypress pollen concentration changed over time. Methods: Allergists were required to collect the results of 100-200 consecutive skin prick tests (SPTs) performed during 2012. Seasonal symptoms were also recorded, as were airborne cypress pollen concentrations (data from the Italian Aerobiology Association) in 1998- 2000 and 2010-2012. Results: We examined 2258 atopic outpatients (56% females; age, 2-84 years) sensitized to at least 1 of the aeroallergens tested (Dermatophagoides species, grass, pellitory, olive, cypress, birch, Alternaria tenuis, and dog and cat dander). We found that 62.9%, 16.1%, and 32.7% of patients living in central, northern, and southern Italy, respectively, were sensitized to cypress (P<.0001). The cypress pollen concentration peak was delayed from February to March in 1998-2000 and 2010-2012 in all 3 regions, with a shift in pollination towards spring. Patients who were monosensitized to cypress reported mainly rhinitis (90.7%-97.6%) and conjunctivitis (38.1%-100%). In polysensitized patients, the prevalence of rhinitis, conjunctivitis, and asthma increased progressively (P<.0001) from southern to northern Italy. The same trend was observed for the prevalence of reported winter symptoms typical of cypress allergy (28%-65%). Conclusions: Today, cypress pollen is the most frequent sensitizing aeroallergen (assessed by SPT) in several areas of central Italy. Variations in the timing of the cypress pollination period may have favored this increased sensitization. Rhinitis and conjunctivitis are the predominant symptoms. The clinical impact of this allergy was poor in southern Italy and increased in central areas before reaching its peak in northern regions (AU)

Antecedentes: Se trata de una encuesta multicéntrica realizada en Italia para evaluar el impacto de la sensibilización a polen de ciprés en sujetos atópicos y establecer si la concentración de este polen en el aire ha cambiado a lo largo del tiempo. Métodos: El estudio fue realizado por alergólogos que recopilaron 100-200 sujetos consecutivos con pruebas cutáneas positivas (Prick) realizadas en 2012. Se recogieron los síntomas estacionales, junto con la concentración de polen de ciprés (obtenida por la asociación italiana de aerobiología) en 1998-2000 y 2010-2012. Resultados: En cuanto a los resultados obtenidos fueron examinados 2258 pacientes atópicos (56% mujeres; edad 2-84), sensibilizados frente al menos uno de los aeroalérgenos testados (Dermatophagoides, gramíneas, parietaria, olivo, cipres, abedul, Alternaria tenuis y epitelio de gato). El 62.9%, 16.1% y 32.7% de los pacientes que vivían en el centro, norte y sur de Italia, respectivamente, mostraron sensibilización a polen de ciprés (p<0.0001). Observamos un pico de concentración de polen de ciprés de febrero a marzo en los años 1998-2000 y 2010-2012, en todas las áreas. Los pacientes monosensibilizados a ciprés mostraron de forma prevalente rinitis (90.7-97.6%) y conjuntivitis (38.1-100%). La prevalencia de rinitis, conjuntivitis y asma se incrementa progresivamente (p<0.0001) del sur hacia el norte de Italia en los sujetos polisensibilizados. La misma tendencia se observó en los síntomas invernales típicos de la alergia al ciprés. Conclusiones: En conclusión, actualmente el polen de ciprés es el aeroalérgeno sensibilizante más frecuente (según resultados de prueba cutánea) en varias áreas de Italia central. Las variaciones del periodo de polinización pueden favorecer el incremento observado en la sensibilización a este polen. Los síntomas predominantes son rinitis y conjuntivitis. El impacto clínico de esta alergia es pobre en áreas del sur de Italia, siendo alto en las áreas del norte (AU)

Has Sensitization to Cockroach Allergens Changed During the Last 17 Years in the Urban Atopic Population Living In Naples (Southern Italy)?

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Are new pets really responsible for development of new allergies?

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Clinical study on Alternaria spores sensitization

Background: sensitization to fungi spores is often associated with sensitization to other allergens and so it is difficult to estabilish the exact cause of illness. Objective: the aim of the study was to evaluate a group of patients monosensitized to Alternaria and to establish the prevalence, periodicity and clinical profile of this kind of sensitization. Methods: 37 subjects who were monosensitized to Alternaria (prick-test positive), according to a previous epidemiological study were evaluated. Clinical symptoms and the period of their occurrence were taken into consideration as well as immunological parameters (RAST). Results: 20 patients (over 50%) included in the study proved to be affected by asthma associated with other allergic symptoms and 22 patients (60%) presented perennial symptoms. The RAST carried out on 34 monosensitized subjects proved positive in 11 and negative in 23. Conclusions: Alternaria sensitization is characterized by a perennial periodicity with severe respiratory symptoms (asthma) which occur primarily in children. Prick test is preferable to and more reliable than RAST as a diagnostic test (AU)

Introducción: la sensibilización a esporas de hongos se asocia frecuentemente con la sensibilización a otros alergenos, con lo que es difícil establecer la causa exacta de la enfermedad. Objetivo: la finalidad del estudio fue evaluar a grupos de pacientes monosensibilizados a Alternaria y establecer la prevalencia, periodicidad y perfil clínico de esta clase de sensibilización. Métodos: se estudiaron 37 pacientes monosensibilizados a Alternaria (prick test positivo) seleccionados en un estudio epidemiológico previo. También se consideraron los síntomas clínicos y su frecuencia, así como algunos parámetros inmunológicos (RAST). Resultado: 20 pacientes (por encima del 50 por ciento) padecían asma asociada con otros síntomas alérgicos y 22 pacientes (60 por ciento) presentaban síntomas perennes. El RAST llevado a cabo en 34 pacientes monosensibilizados, fue positivo en 11 y negativo en 23. Conclusiones: la sensibilización a Alternaria se caracterizó por ser perenne, cursar con síntomas respiratorios graves (asma) y tener lugar principalmente en niños. Es preferible y más fiable como test diagnóstico el test cutáneo que el RAST. (AU)