A Druggable FOXA1-Glucocorticoid Receptor Transcriptional Axis Drives Tumor Growth in a Subset of Non-Small Cell Lung Cancer.

The FOXA1 pioneer factor is an essential mediator of steroid receptor function in multiple hormone-dependent cancers, including breast and prostate cancers, enabling nuclear receptors such as estrogen receptor (ER) and androgen receptor (AR) to activate lineage-specific growth programs. FOXA1 is also highly expressed in non-small cell lung cancer (NSCLC), but whether and how it regulates tumor growth in this context is not known. Analyzing data from loss-of-function screens, we identified a subset of NSCLC tumor lines where proliferation is FOXA1 dependent. Using rapid immunoprecipitation and mass spectrometry of endogenous protein, we identified chromatin-localized interactions between FOXA1 and glucocorticoid receptor (GR) in these tumor cells. Knockdown of GR inhibited proliferation of FOXA1-dependent, but not FOXA1-independent NSCLC cells. In these FOXA1-dependent models, FOXA1 and GR cooperate to regulate gene targets involved in EGF signaling and G1-S cell-cycle progression. To investigate the therapeutic potential for targeting this complex, we examined the effects of highly selective inhibitors of the GR ligand-binding pocket and found that GR antagonism with ORIC-101 suppressed FOXA1/GR target expression, activation of EGF signaling, entry into the S-phase, and attendant proliferation in vitro and in vivo. Taken together, our findings point to a subset of NSCLCs harboring a dependence on the FOXA1/GR growth program and provide rationale for its therapeutic targeting. Significance: NSCLC is the leading cause of cancer deaths worldwide. There is a need to identify novel druggable dependencies. We identify a subset of NSCLCs dependent on FOXA1-GR and sensitive to GR antagonism.

[Vaccinal prophylaxis against tetanus and hepatitis B: difficulties in application of law and actual status of workers' protection in Lombardy among workers of building sector]. / La profilassi vaccinale antitetanica ed antiepatite B: problematiche applicative della norma e state attuale della copertura tra i lavoratori del Comparto Edile in Lombardia.

Vaccinal prophylaxis is a preventive action which is compulsory, if available and useful for health protection of workers exposed to biological work risk. Definition andrealization of compulsory vaccinal campaigns is assigned by law to Occupational Health Doctor. We report a research carried out in 135 firms of building sector on 2158 workers exposed to biological work risk and concerning their vaccinal status against Tetanus and Hepatitis B. We found that only in a part of firms a plan of vaccination has been activated among workers exposed to biological work risk and, if activated, these plans frequently were partial and incomplete. Vaccinal protections among workers therefore resulted insufficient especially among foreigners workers and among workers active in first aid and emergency work teams. We think that a more active role of Occupational Health Doctors in promotion and realization of vaccinal campaigns is necessary for medico-legal and scientific reasons.

[Foreigner workers in Lombardy. Occupational, relational and cultural problems at work places]. / I lavoratori stranieri in Lombardia. Problematiche occupazionali, relazionali e culturali ai posti di lavoro.

Our research included 1359 foreigner citizens actually working in Lombardy. To better evaluate the eventual presence of relational, cultural and work related problems in their daily work experience we used a specific questionnaire, directly filled in by Occupational Doctors during occupational medical surveillance enforced by law, composed by different items concerning occupational and relational single worker's life. We evidenced that foreigner workers' population changed significantly in these last years loosing the characteristics of an homogeneous group. A foreigner workers' complete socio cultural integration in our country and specifically in working environments seems far to be really achieved.