Objective Informal caregivers of people with lung cancer often experience a substantial care burden and associated negative consequences due to the often‐contracted course of the disease. The objective of this review was to systematically examine the evidence on the factors associated with lung cancer caregiver distress. Methods Five databases (MEDLINE, CINAHL, EMBASE, PsychINFO and Web of Science) were searched for studies investigating factors associated with distress amongst caregivers of people with lung cancer. Empirical studies published up to July 2020 were included if they measured distress using a valid and reliable measure and examined its association with at least one other factor, with a sample of 50 or more caregivers. Results Thirty publications describing 27 studies (16 cross‐sectional; 6 prospective; 8 intervention) involving 3744 caregivers (primarily spouse or adult child) were included. A narrative synthesis of the findings is presented due to heterogeneity in study design, variables measured and analyses conducted. Patient variables associated with greater distress included: stage of cancer and quality of spousal relationship. Caregiver variables associated with higher distress included: social support, coping strategies and self‐efficacy. Conclusions Several variables were associated with distress amongst lung cancer caregivers. Understanding these variables could inform the development of interventions that will enable caregivers to care effectively while maintaining their own well‐being. Screening for distress among caregivers may identify those caregivers who would benefit from early intervention.

Steroid hormones are synthesized through enzymatic reactions using cholesterol as the substrate. In steroidogenic cells, the required cholesterol for steroidogenesis can be obtained from blood circulation or synthesized de novo from acetate. One of the key enzymes that control cholesterol synthesis is 24-dehydrocholesterol reductase (encoded by DHCR24). In humans and rats, DHCR24 is highly expressed in the adrenal gland, especially in the zona fasciculata. We recently reported that DHCR24 was expressed in the mouse adrenal gland’s inner cortex and also found that thyroid hormone treatment significantly upregulated the expression of Dhcr24 in the mouse adrenal gland. In the present study, we showed the cellular expression of DHCR24 in mouse adrenal glands in early postnatal stages. We found that the expression pattern of DHCR24 was similar to the X-zone marker gene 20αHSD in most developmental stages. This finding indicates that most steroidogenic adrenocortical cells in the mouse adrenal gland do not synthesize cholesterol locally. Unlike the 20αHSD-positive X-zone regresses during pregnancy, some DHCR24-positive cells remain present in parous females. Conditional knockout mice showed that the removal of Dhcr24 in steroidogenic cells did not affect the overall development of the adrenal gland or the secretion of corticosterone under acute stress. Whether DHCR24 plays a role in conditions where a continuous high amount of corticosterone production is needed requires further investigation.

In the adrenal gland, stem and progenitor cells reside in the capsule and the outer part of the cortex, respectively. The newly formed cortical cells from stem/progenitor cells move inward to the corticomedullary boundary during development. Throughout this developmental process, adrenocortical cells express specific marker genes at different stages which lead to concentric zones of the adrenal cortex (zonation). In mice, the majority of the functional cortex are definitive zones whereas cortical cells in the corticomedullary boundary form the X-zone, which is considered the aged cell population in the cortex and undergoes regression over time. Disruption of signaling pathways such as Wnt, Hedgehog and TGF-beta can cause abnormalities of the developmental process of the adrenal cortex, which may lead to malfunction or malignancy of the adrenal gland. The role of Notch, another key signaling pathway, in adrenal development has not yet been fully studied. Notch signaling pathway involves a variety of gene regulatory mechanisms that control cell proliferation, differentiation, and apoptosis. Although key molecules in Notch signaling pathways are expressed both in the adrenal cortex and in the medulla, the inhibition of canonical Notch signaling only leads to minor/limited effects on the function or the structure of the adrenal gland. We confirmed these observations using Sf1-Cre mediated tissue-specific knockout mouse model that lacks Hes1, one of the most common Notch target genes, in cortical cells in the adrenal gland. Immunostaining with proliferation markers (PCNA & Ki67) and marker genes of different cell populations in the adrenal gland (e.g., β-catenin, 20αHSD, tyrosine hydroxylase) showed normal zonation and proliferation patterns. The unaffected adrenal glands in Hes1 conditional knockout mice suggests Notch signaling is not a dominant developmental pathway in the adrenal cortex. Next, to study how overactivation of Notch signaling affects adrenocortical cells, we used Sf1-Cre mice to overexpress Notch intracellular domain (NICD) in cortical cells in the adrenal gland. The over-expression of NICD in the adrenal cortex disrupted adrenal cortex zonation and led to a small, disorganized adrenal. These Sf1-Cre mediated NICD over-overexpressed adrenals had scattered and disorganized medulla irregularly distributed in the margin of the gland. Immunostaining showed clusters of 3βHSD low-expressing cells underneath the capsule partially surrounding the 3βHSD high-expressing cortex. Moreover, X-zone cells (labeled by 20αHSD) were significantly reduced in NICD over-overexpressed adrenals in two weeks old male and female mice. Our data suggest that overactivation of Notch signaling in the adrenal cortex not only disrupts the development of the definitive cortical zones but also affects the aging and the differentiation of fetal cortical cells in mice.