The built environment and cancer survivorship: A scoping review.

BACKGROUND: There are more than 32 million cancer survivors worldwide. The built environment is one of the contextual factors that may influence cancer survivorship. However, studies investigating the interdisciplinary field of the built environment and cancer survivorship are lacking. OBJECTIVE: To conduct a systematic review of the existing literature regarding the relationship between the built environment and cancer survivorship, identify any knowledge gaps, and recommend future research directions. METHODS: A systematic literature search was performed by searching OVID Medline, Embase, CINAHL, and Web of Science Core Collection. RESULTS: Of 4235 unique records identified, 26 studies met eligibility criteria. Neighborhood walkability and greenness were the most examined built environment characteristics among the included studies. Walkability was found to be associated with various cancer survivorship experience, including increased levels of physical activity, lowered body mass index, and improved quality of life. The association between greenness and cancer survivorship outcomes were inconsistent across the included studies. Additionally, studies have reported the relationship between light and noise pollution and sleep among cancer survivors. Regarding blue space, in one qualitative study, breast cancer survivors brought up the healing properties of water. CONCLUSION: Our scoping review demonstrated a breadth of current cancer survivorship research in the field of neighborhood walkability and greenness, but fewer studies detailing other aspects of the built environment as defined by this review, such as light pollution, noise pollution, and blue space. We identified future research directions for those interested in this interdisciplinary field, which can provide insights for urban planners and policy makers on how to best leverage the built environment to promote the health and wellbeing of cancer survivors.

Marital Status, Living Arrangement, and Survival among Individuals with Advanced Prostate Cancer in the International Registry for Men with Advanced Prostate Cancer.

BACKGROUND: Studies have shown improved survival among individuals with cancer with higher levels of social support. Few studies have investigated social support and overall survival (OS) in individuals with advanced prostate cancer in an international cohort. We investigated the associations of marital status and living arrangements with OS among individuals with advanced prostate cancer in the International Registry for Men with Advanced Prostate Cancer (IRONMAN). METHODS: IRONMAN is enrolling participants diagnosed with advanced prostate cancer (metastatic hormone-sensitive prostate cancer, mHSPC; castration-resistant prostate cancer, CRPC) from 16 countries. Participants in this analysis were recruited between July 2017 and January 2023. Adjusting for demographics and tumor characteristics, the associations were estimated using Cox regression and stratified by disease state (mHSPC, CRPC), age (<70, ≥70 years), and continent of enrollment (North America, Europe, Other). RESULTS: We included 2,119 participants with advanced prostate cancer, of whom 427 died during up to 5 years of follow-up (median 6 months). Two-thirds had mHSPC. Most were married/in a civil partnership (79%) and 6% were widowed. Very few married participants were living alone (1%), while most unmarried participants were living alone (70%). Married participants had better OS than unmarried participants [adjusted HR: 1.44; 95% confidence interval (CI): 1.02-2.02]. Widowed participants had the worst survival compared with married individuals (adjusted HR: 1.89; 95% CI: 1.22-2.94). CONCLUSIONS: Among those with advanced prostate cancer, unmarried and widowed participants had worse OS compared with married participants. IMPACT: This research highlighted the importance of social support in OS within this vulnerable population.

Increased expression of SSEA-4 on TKI-resistant non-small cell lung cancer with EGFR-T790M mutation.

Non-small cell lung cancer (NSCLC), a major life-threatening disease accounting for 85% of all lung cancer cases, has been treated with tyrosine kinase inhibitors (TKIs), but often resulted in drug resistance, and approximately 60% of TKI-resistant cases are due to acquired secondary (epithelial growth factor receptor) EGFR-T790M mutation. To identify alternative targets for TKI-resistant NSCLC with EGFR-T790M mutation, we found that the three globo-series glycosphingolipids are increasingly expressed on this type of NSCLC cell lines, and among them, the increase of stage-specific embryonic antigen-4 (SSEA-4) expression is the most significant. Compared to TKI-sensitive cell lines, SSEA-4 and the key enzyme ß3GalT5 responsible for the synthesis of SSEA3 are more expressed in TKI-resistant NSCLC cell lines with EGFR-T790M mutation, and the expression levels strongly correlate with poor survival in patients with EGFR mutation. In addition, we demonstrated that a SSEA-4 targeted monoclonal antibody, especially the homogeneous glycoform with well-defined Fc glycan designed to improve effective functions, is highly effective against this subpopulation of NSCLC in cell-based and animal studies. These findings provide a direction for the prediction of tumor recurrence and treatment of TKI-resistant NSCLC with EGFR-T790M mutation.

Monoclonal enolase-1 blocking antibody ameliorates pulmonary inflammation and fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic fatal disease with limited therapeutic options. The infiltration of monocytes and fibroblasts into the injured lungs is implicated in IPF. Enolase-1 (ENO1) is a cytosolic glycolytic enzyme which could translocate onto the cell surface and act as a plasminogen receptor to facilitate cell migration via plasmin activation. Our proprietary ENO1 antibody, HL217, was screened for its specific binding to ENO1 and significant inhibition of cell migration and plasmin activation (patent: US9382331B2). METHODS: In this study, effects of HL217 were evaluated in vivo and in vitro for treating lung fibrosis. RESULTS: Elevated ENO1 expression was found in fibrotic lungs in human and in bleomycin-treated mice. In the mouse model, HL217 reduced bleomycin-induced lung fibrosis, inflammation, body weight loss, lung weight gain, TGF-ß upregulation in bronchial alveolar lavage fluid (BALF), and collagen deposition in lung. Moreover, HL217 reduced the migration of peripheral blood mononuclear cells (PBMC) and the recruitment of myeloid cells into the lungs. In vitro, HL217 significantly reduced cell-associated plasmin activation and cytokines secretion from primary human PBMC and endothelial cells. In primary human lung fibroblasts, HL217 also reduced cell migration and collagen secretion. CONCLUSIONS: These findings suggest multi-faceted roles of cell surface ENO1 and a potential therapeutic approach for pulmonary fibrosis.

Impact of age, race, and family history on COVID-19-related changes in breast cancer screening among the Boston mammography cohort study.

PURPOSE: We studied women enrolled in the Boston Mammography Cohort Study to investigate whether subgroups defined by age, race, or family history of breast cancer experienced differences in the incidence of screening or diagnostic imaging rates during the COVID-19 lockdown and had slower rebound in the incidence of these rates during reopening. METHODS: We compared the incidence of monthly breast cancer screening and diagnostic imaging rates over during the pre-COVID-19 (January 2019-February 2020), lockdown (March-May 2020), and reopening periods (June-December 2020), and tested for differences in the monthly incidence within the same period by age (< 50 vs ≥ 50), race (White vs non-White), and first-degree family history of breast cancer (yes vs no). RESULTS: Overall, we observed a decline in breast cancer screening and diagnostic imaging rates over the three time periods (pre-COVID-19, lockdown, and reopening). The monthly incidence of breast cancer screening rates for women age ≥ 50 was 5% higher (p = 0.005) in the pre-COVID-19 period (January 2019-February 2020) but was 19% lower in the reopening phase (June-December 2020) than that of women aged < 50 (p < 0.001). White participants had 36% higher monthly incidence of breast cancer diagnostic imaging rates than non-White participants (p = 0.018). CONCLUSION: The rebound in screening was lower in women age ≥ 50 and lower in non-White women for diagnostic imaging. Careful attention must be paid as the COVID-19 recovery continues to ensure equitable resumption of care.

Suboptimal Outcomes and Retreatment Rate of Patients With Crohn's Disease After Forced Discontinuation of Biologics: A Nationwide Population-Based Study.

Taiwan's National Health Insurance (NHI) program forced discontinuation of biologic use in Crohn's disease (CD) after a limited treatment duration, regardless of disease activity. This study investigated the retreatment rate and suboptimal outcomes (i.e., CD-related surgeries, hospitalizations, emergency room visits, and oral steroid flare-ups) after forced discontinuation. This retrospective cohort study was conducted using data from the NHI Database. Patients who received ≥40 weeks of biologic treatment followed by a forced discontinuation were included. The time of biologic retreatment and the cumulative incidence of suboptimal outcomes after the forced discontinuation as well as related risk factors were analyzed. Included were 215 patients (68% male). At the beginning of biologic therapy, the mean age (±SD) was 35.7 (±13.5) years, and the disease duration was 4.46 (±3.52) years. The median (interquartile range) biologic treatment duration was 57.86 (50.3-83.3) weeks. Within the first year after forced discontinuation, 67% of patients (n = 144) were retreated with a second course of biologics, and 53% of patients (n = 114) experienced at least one suboptimal outcome. The independent risk factors associated with the occurrence of suboptimal outcomes were CD-related emergency room visits and hospitalizations during biologic therapy (hazard ratio: 2.49; 95% confidence interval: 1.59-3.89). More than two-thirds of patients with CD required biological retreatment within 1 year after a forced discontinuation. The substantial proportion of patients with poor disease outcomes highlights the need to continue the biologic.

Sustained-Release and pH-Adjusted Alginate Microspheres-Encapsulated Doxorubicin Inhibit the Viabilities in Hepatocellular Carcinoma-Derived Cells.

The objective of this study aimed to develop biodegradable calcium alginate microspheres carrying doxorubicin (Dox) at the micrometer-scale for sustained release and the capacity of pH regulatory for transarterial chemoembolization. Ultrasonic atomization and CaCl2 cross-linking technologies were used to prepare the microspheres. A 4-by-5 experiment was first designed to identify imperative parameters. The concentration of CaCl2 and the flow rate of the pump were found to be critical to generate microspheres with a constant volume median diameter (~39 µm) across five groups with different alginate: NaHCO3 ratios using each corresponding flow rate. In each group, the encapsulation efficiency was positively correlated to the Dox-loading %. Fourier-transform infrared spectroscopy showed that NaHCO3 and Dox were step-by-step incorporated into the calcium alginate microspheres successfully. Microspheres containing alginate: NaHCO3 = 1 exhibited rough and porous surfaces, high Young's modulus, and hardness. In each group with the same alginate: NaHCO3 ratio, the swelling rates of microspheres were higher in PBS containing 10% FBS compared to those in PBS alone. Microspheres with relatively high NaHCO3 concentrations in PBS containing 10% FBS maintained better physiological pH and higher accumulated Dox release ratios. In two distinct hepatocellular carcinoma-derived cell lines, treatments with microspheres carrying Dox demonstrated that the cell viabilities decreased in groups with relatively high NaHCO3 ratios in time- and dose-dependent manners. Our results suggested that biodegradable alginate microspheres containing relatively high NaHCO3 concentrations improved the cytotoxicity effects in vitro.

High glycosyltransferase 8 domain containing two protein levels contribute to poor prognosis in urothelial carcinoma.

OBJECTIVE: To examine the expression levels of the glycosyltransferase 8 domain containing protein 2 and its clinical implications in urothelial carcinoma patients. METHODS: Data mining, immunohistochemistry together with H-score calculation was carried out to evaluate the glycosyltransferase 8 domain containing protein 2 levels on tissue specimens from urothelial carcinoma patients, retrospectively. Correlations between glycosyltransferase 8 domain containing protein 2 H-score and imperative clinicopathological factors were measured. The indication of glycosyltransferase 8 domain containing protein 2 level on disease-specific and metastasis-free survivals were next analyzed. RESULTS: In upper tract urothelial carcinomas (n = 340) and bladder urothelial carcinomas (n = 295), 170 (50%) and 148 (50%) patients, respectively, were identified to have high glycosyltransferase 8 domain containing protein 2 expression. The glycosyltransferase 8 domain containing protein 2 levels were correlated to several clinicopathological characteristics and patient survival. Upregulation of the glycosyltransferase 8 domain containing protein 2 was correlated to primary tumor (P < 0.001), nodal metastasis (P < 0.001), histological grade (P < 0.001), vascular invasion (P < 0.001), perineural invasion (P < 0.05) and mitotic rate (P < 0.001). High glycosyltransferase 8 domain containing protein 2 levels independently predicted poor disease-specific survival (P = 0.049) and metastasis-free survival (P = 0.008) in upper tract urothelial carcinoma and urinary bladder urothelial carcinoma, respectively. Gene Ontology enrichment analysis additionally showed that multiple biological processes were enriched including "ECM organization" (Gene Ontology:0030198), "extracellular structure organization" (Gene Ontology:0043062), "biological adhesion" (Gene Ontology:0022610), "cell adhesion" (Gene Ontology:0007155), "collagen fibril organization" (Gene Ontology:0030199) and "vasculature development" (Gene Ontology:0001944). CONCLUSIONS: The present findings suggest that upregulation of the glycosyltransferase 8 domain containing protein 2 is an independent and disadvantageous prognosticator in urothelial carcinoma. High glycosyltransferase 8 domain containing protein 2 level might play a crucial role in progression of urothelial carcinoma.

High G protein subunit beta 4 protein level is correlated to poor prognosis of urothelial carcinoma.

Data mining on a public domain detected eight potential transcripts which were upregulated in advanced UBUCs, suggesting that they may take part in UC development or/and progression. Retrospectively, immunohistochemistry along with H-score recording was carried out to evaluate the GNB4 protein levels on tissues from UC patients. Correlations between GNB4 H-score and imperative clinicopathological factors, as well as the implication of GNB4 protein level on disease-specific and metastasis-free survivals were assessed. In UTUCs (n = 340) and UBUCs (n = 295), 170 (50.0%) and 148 (50.0%) cases, respectively, were identified to be of high GNB4 expression. The GNB4 protein levels were correlated to numerous clinicopathological features and patients' survivals. Upregulation of the GNB4 protein was significantly associated with primary tumor, nodal metastasis, histological grade, vascular invasion and mitotic rate. High GNB4 protein levels independently and significantly predicted poor disease-specific and metastasis-free in UTUC and UBUC, respectively. Ingenuity pathway analysis furthermore showed that multiple signaling pathways were enriched including 'Communication between Innate and Adaptive Immune Cells' and 'NFκB Signaling'. Our findings demonstrated that the upregulation of the GNB4 protein is an independent unfavorable prognosticator in UC. High GNB4 gene expression plays an important role in UC progression.

Alfalfa (Medicago sativa L.) MsCML46 gene encoding calmodulin-like protein confers tolerance to abiotic stress in tobacco.

KEY MESSAGE: MsCML46 enhances tolerance to abiotic stresses through alleviating osmotic stress and oxidative damage by regulating the expression of stress-related genes to optimize osmolytes levels and antioxidant enzyme activity in transgenic tobacco. Abiotic stresses are major environmental factors that constraint crop productivity worldwide. Various stimuli regulate intracellular calcium levels and calcium-mediated signal transduction, and cellular responses. Ca2+ signals are perceived by different Ca2+ receptors. Calmodulin-like protein (CML) is one of the best-characterized Ca2+ sensors which shares sequence similarity with highly conserved calmodulin (CaM) ubiquitously expressed in plants. Currently, the molecular and physiological functions of CMLs are largely unknown. In this study, the MsCML46 was characterized in alfalfa (Medicago sativa cv. Zhaodong) under freezing stress. Results showed that MsCML46 was localized to the cytoplasm of Arabidopsis, and its expression was strongly elevated by cold, drought, salt, saline-alkali, and ABA treatments. Overexpressing MsCML46 in tobacco enhanced tolerance to freezing, drought, and salt stresses as evidenced by improved contents of osmotic regulatory solutes and antioxidant enzyme activity but decreased reactive oxygen species (ROS) accumulation. Furthermore, cold, drought, and salt stresses increased the expression of stress-related genes in transgenic tobacco. MsCML46 binds free Ca2+ to promote signal transduction and maintain higher K+/Na+ ratio. In this way, it protects intracellular homeostasis under sodium ion toxicity. These results suggest that MsCML46 plays a crucial role in resisting abiotic stresses and can be exploited in genetic engineering for crops.

Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition.

Epidermal growth factor receptor (EGFR) is a heavily glycosylated transmembrane receptor tyrosine kinase. Upon EGF-binding, EGFR undergoes conformational changes to dimerize, resulting in kinase activation and autophosphorylation and downstream signaling. Tyrosine kinase inhibitors (TKIs) have been used to treat lung cancer by inhibiting EGFR phosphorylation. Previously, we demonstrated that EGFR sialylation suppresses its dimerization and phosphorylation. In this report, we further investigated the effect of sialylation on the phosphorylation profile of EGFR in TKI-sensitive and TKI-resistant cells. Sialylation was induced in cancer progression to inhibit the association of EGFR with EGF and the subsequent autophosphorylation. In the absence of EGF the TKI-resistant EGFR mutant (L858R/T790M) had a higher degree of sialylation and phosphorylation at Y1068, Y1086, and Y1173 than the TKI-sensitive EGFR. In addition, although sialylation in the TKI-resistant mutants suppresses EGFR tyrosine phosphorylation, with the most significant effect on the Y1173 site, the sialylation effect is not strong enough to stop cancer progression by inhibiting the phosphorylation of these three sites. These findings were supported further by the observation that the L858R/T790M EGFR mutant, when treated with sialidase or sialyltransferase inhibitor, showed an increase in tyrosine phosphorylation, and the sensitivity of the corresponding resistant lung cancer cells to gefitinib was reduced by desialylation and was enhanced by sialylation.