Rohdepoe1806
αKlotho is a type 1 transmembrane anti-aging protein. αKlotho-deficient mice have premature aging phenotypes and an imbalance of ion homeostasis including Ca2+ and phosphate. Soluble αKlotho is known to regulate multiple ion channels and growth factor-mediated phosphoinositide-3-kinase (PI3K) signaling. Store-operated Ca2+ entry (SOCE) mediated by pore-forming subunit Orai1 and ER Ca2+ sensor STIM1 is a ubiquitous Ca2+ influx mechanism and has been implicated in multiple diseases. However, it is currently unknown whether soluble αKlotho regulates Orai1-mediated SOCE via PI3K-dependent signaling. Among the Klotho family, αKlotho downregulates SOCE while βKlotho or γKlotho does not affect SOCE. Soluble αKlotho suppresses serum-stimulated SOCE and Ca2+ release-activated Ca2+ (CRAC) channel currents. Serum increases the cell-surface abundance of Orai1 via stimulating vesicular exocytosis of the channel. The serum-stimulated SOCE and cell-surface abundance of Orai1 are inhibited by the preincubation of αKlotho protein or PI3K inhibitors. Moreover, the inhibition of SOCE and cell-surface abundance of Orai1 by pretreatment of brefeldin A or tetanus toxin or PI3K inhibitors prevents further inhibition by αKlotho. Functionally, we further show that soluble αKlotho ameliorates serum-stimulated SOCE and cell migration in breast and lung cancer cells. These results demonstrate that soluble αKlotho downregulates SOCE by inhibiting PI3K-driven vesicular exocytosis of the Orai1 channel and contributes to the suppression of SOCE-mediated tumor cell migration.TGF-β1 is a major mediator of airway tissue remodelling during atopic asthma and affects tight junctions (TJs) of airway epithelia. However, its impact on TJs of ciliated epithelia is sparsely investigated. Herein we elaborated effects of TGF-β1 on TJs of primary human bronchial epithelial cells. We demonstrate that TGF-β1 activates TGF-β1 receptors TGFBR1 and TGFBR2 resulting in ALK5-mediated phosphorylation of SMAD2. We observed that TGFBR1 and -R2 localize specifically on motile cilia. TGF-β1 activated accumulation of phosphorylated SMAD2 (pSMAD2-C) at centrioles of motile cilia and at cell nuclei. This triggered an increase in paracellular permeability via cellular redistribution of claudin 3 (CLDN3) from TJs into cell nuclei followed by disruption of epithelial integrity and formation of epithelial lesions. Only ciliated cells express TGF-β1 receptors; however, nuclear accumulations of pSMAD2-C and CLDN3 redistribution were observed with similar time course in ciliated and non-ciliated cells. In summary, we demonstrate a role of motile cilia in TGF-β1 sensing and showed that TGF-β1 disturbs TJ permeability of conductive airway epithelia by redistributing CLDN3 from TJs into cell nuclei. We conclude that the observed effects contribute to loss of epithelial integrity during atopic asthma.
Advances in cancer treatment have led to longer cancer-free periods and overall survival. This study aimed to understand patients' experiences of transitioning out of a state of believing to be cancer free into incurable recurrence with advanced disease.
Using constructivist grounded theory with in-depth interviews patients (n = 15) with solid tumors from a major US cancer center participated. Theoretical sampling enabled concepts to be developed until theme saturation. Constant comparative analysis used initial and focused coding to develop themes and concepts to describe this specific period from extended time cancer free and transition to advanced incurable disease.
Three interrelated concepts were identified reluctant acceptance, seeking survival through continuous treatment, and hope in the face of an uncertain future. A conceptual model of the experience was developed encompassing anger and sadness, at initial recurrence, to reluctant acceptance, and, finally, a cycle of seeking continuous treatment to prolong life leading to a sense of hope in the face of an uncertain future.
The cycle between treatment and hope creates a state of personal equilibrium, which provides insights into the importance of treatment for this population. This study provides direction for future research to understand the expectations of people experiencing advanced cancer recurrence.
Many cancer survivors live with advanced cancer. Assessing their needs as they transition from survivor with no disease to survivor with advanced disease requires a new conceptualization of the experience which recognizes expectations and priorities for care of this patient group.
Many cancer survivors live with advanced cancer. Assessing their needs as they transition from survivor with no disease to survivor with advanced disease requires a new conceptualization of the experience which recognizes expectations and priorities for care of this patient group.
Being a parent alongside a cancer diagnosis presents unique challenges. It is unclear to what degree parenting considerations feature in routine care and how doctors approach treatment decision discussions.
To explore doctor perspectives regarding patients with cancer who have dependent children.
Focus groups and interviews conducted to ascertain doctor views. Responses were audio-recorded, transcribed and thematically analysed.
Twenty-eight doctors participated medical oncology (7), haematology (10), palliative care (8), and psycho-oncology (3). Participants observed cancer impacted upon parenting across several domains psycho-social, practical, and family implications. Having dependent children was perceived to influence the patient experience and decision-making by patients and clinicians. Participants identified this cohort as emotionally demanding to care for with a range of psychological effects identified for doctors, particularly in highly challenging circumstances (single-parent and non-English speaking families, scenarios involving communication difficulties).
Participants recognised the presence of dependent children to profoundly influence the experience of being both a parent and a patient with cancer. Identifying patients with parental responsibilities was noted as relevant for management at diagnosis through to death. CC-930 in vivo Greater understanding of doctors' experiences providing care for this cohort may inform the development of resources to assist doctors and their patients.
Participants recognised the presence of dependent children to profoundly influence the experience of being both a parent and a patient with cancer. Identifying patients with parental responsibilities was noted as relevant for management at diagnosis through to death. Greater understanding of doctors' experiences providing care for this cohort may inform the development of resources to assist doctors and their patients.
