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Non-small-cell lung cancer (NSCLC) is a typical inflammation-associated cancer, and lung adenocarcinoma (LUAD) is the most common pathological subtype. Epidermal growth factor (EGF) receptor (EGFR) mutations are the most common driver mutations of LUAD, and they have been identified as important therapeutic targets by EGFR-tyrosine kinase inhibitors (TKIs). The proinflammatory cytokine, interleukin (IL)-17A, and IL-17A-producing cells were reported to be elevated in the tumor microenvironment and peripheral blood of NSCLC patients and to be correlated with tumor progression and poor prognoses. However, the pathophysiological role of IL-17A in NSCLC remains unclear, although some studies suggested its involvement in cancer cell invasion and metastasis. Herein, we observed that expressions of IL-17A and its receptor, IL-17 receptor C (IL-17RC), were elevated in LUAD tissues and were correlated with poor survival in different lung cancer cohorts. In LUAD cells with mutant EGFR, the IL-17A/IL-17RC axis was shown to enhance phosphorylation of EGFR and Met, thereby promoting proliferation and resistance to EGFR-TKIs such as afatinib. In LUAD cells with wild-type (WT) EGFR, we found that the IL-17A/IL-17RC axis enhanced EGF-induced EGFR activation and cell proliferation through causing impairment of EGF-induced EGFR lysosomal degradation. Collectively, our results indicated diverse impacts of the IL-17A/IL-17RC axis on EGFR activation in LUAD cells with WT and mutant EGFR and suggested that developing therapeutic strategies against IL-17A/IL-17RC would be valuable for LUAD treatment.

Purpose:Induction cisplatin and gemcitabine chemotherapy is a standard treatment for locally advanced nasopharyngeal carcinoma (NPC). Inhibition of VEGF axis has been shown to promote maturation of microvasculature and improve perfusion. We conducted a four-arm study to assess the effect of two doses of either sunitinib or bevacizumab with chemotherapy in NPC.Patients and Methods:Patients with treatment-naïve locally advanced NPC were treated with three cycles of 3-weekly cisplatin and gemcitabine preceded by 1 week of anti-VEGF therapy for each cycle, followed by standard concurrent chemoradiation: arm A patients received 7 days of 12.5 mg/day sunitinib; arm B 7 days of 25 mg/day sunitinib; arm C bevacizumab 7.5 mg/kg infusion; arm D bevacizumab 2.5 mg/kg infusion. Patients with metastatic NPC were treated with up to six cycles of similar treatment without concurrent chemoradiation.Results:Complete metabolic response (mCR) by whole body 18FDG PET was highest in arm C (significant difference in four groups Fisher exact test P = 0.001; type 1 error = 0.05), with 42% mCR (95% confidence interval, 18–67) and 3-year relapse-free survival of 88% in patients with locally advanced NPC. Significant increase in pericyte coverage signifying microvascular maturation and increased immune cell infiltration was observed in posttreatment tumor biopsies in Arm C. Myelosuppression was more profound in sunitinib containing arms, and tolerability was established in arm C where hypertension was the most significant toxicity.Conclusions:Bevacizumab 7.5 mg/kg with cisplatin and gemcitabine was well tolerated. Promising tumor response was observed and supported mechanistically by positive effects on tumor perfusion and immune cell trafficking into the tumor.

Figure S1- Study schema Figure S2 - Example of complete metabolic response after 3 cycles of induction therapy in a representative Arm C patient treated with bevacizumab at 7.5mg/kg in combination with cisplatin and gemcitabine. Figure S3- Relapse free survival (RFS) in months by study arms of patients with locally advanced disease who underwent concurrent chemoradiation after induction chemotherapy. Figure S4 - Relapse free survival in months by metabolic response to induction therapy. Figure S5 - (A) Spaghetti Plot of EBV viral load at baseline (BL), C2D1 and C3D1; (B)Circulating VEGF levels in plasma samples collected at BL, C1D1, C2D1 and end of induction therapy, EOT. Figure 6a- Figure S6 - Induction of mature blood vessel in the NPC tumour microenvironment 7 days following initiation of sunitinib and bevacizumab exposure. Figure S6b - Quantification of blood vessel densities Figure S7- Immune cell infiltration in the NPC tumour microenvironment 7 days following initiation of sunitinib or bevacizumab exposure

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Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) has been reported to play an oncogenic role in certain cancer types; however, the role of SPOCK1 in the progression of clear cell renal cell carcinoma (ccRCC) remains elusive. Here, higher SPOCK1 transcript and protein levels were observed in ccRCC tissues compared to normal tissues and correlated with advanced clinical stages, larger tumor sizes, and lymph node and distal metastases. Knockdown and overexpression of SPOCK1 in ccRCC cells led to decreased and increased cell clonogenic and migratory/invasive abilities in vitro as well as lower and higher tumor growth and invasion in vivo, respectively. Mechanistically, the gene set enrichment analysis (GSEA) database was used to identify the gene set of epithelial-to-mesenchymal transition (EMT) pathways enriched in ccRCC samples with high SPOCK1 expression. Further mechanistic investigations revealed that SPOCK1 triggered the Snail/Slug–matrix metalloproteinase (MMP)-2 axis to promote EMT and cell motility. Clinical ccRCC samples revealed SPOCK1 to be an independent prognostic factor for overall survival (OS), and positive correlations of SPOCK1 with MMP-2 and mesenchymal-related gene expression levels were found. We observed that patients with SPOCK1high/MMP2high tumors had the shortest OS times compared to others. In conclusion, our findings reveal that SPOCK1 can serve as a useful biomarker for predicting ccRCC progression and prognosis, and as a promising target for treating ccRCC.

This letter presents a shoe-integrated fall detection system that is based on seven time-of-flight (ToF) range sensors to identify falls on different terrains. The ToF range sensors, which measure the real-time distance between the sensors and the ground surface, can be used to detect simultaneously the variation of the gait cycle and the geometry of the terrain. Using the statistical features of the ToF range signals and an error-correcting output codes-based model, 17 experimental activities, executed by nine participants, are classified into three classes—activities of daily life, near falls, and falls. The experimental F1-scores for these three classes are 100, 98.17, and 99.07%, respectively. The arrangement of ToF range sensors is simplified to develop a compact shoe-integrated system architecture for fall detection.

IntroductionMany regions in the world are using the population health approach and require a means to measure the health of their population of interest. Population health frameworks provide a theoretical grounding for conceptualization of population health and therefore a logical basis for selection of indicators. The aim of this scoping review was to provide an overview and summary of the characteristics of existing population health frameworks that have been used to conceptualize the measurement of population health.MethodsWe used the Population, Concept and Context (PCC) framework to define eligibility criteria of frameworks. We were interested in frameworks applicable for general populations, that contained components of measurement of health with or without its antecedents and applied at the population level or used a population health approach. Eligible reports of eligible frameworks should include at least domains and subdomains, purpose, or indicators. We searched 5 databases (Pubmed, EMBASE, Web of Science, NYAM Grey Literature Report, and OpenGrey), governmental and organizational sites on Google and websites of selected organizations using keywords from the PCC framework. Characteristics of the frameworks were summarized descriptively and narratively.ResultsForty-eight frameworks were included. The majority originated from the US (42%), Canada (23%) and Europe (23%). Apart from 1 framework developed for rural populations and 2 for indigenous populations, the rest were for general urban populations. The numbers of domains, subdomains and indicators were highly variable. Health status and social determinants of health were the most common domains across all frameworks. Different frameworks had different priorities and therefore focus on different domains.ConclusionKey domains common across frameworks other than health status were social determinants of health, health behaviours and healthcare system performance. The results in this review serve as a useful resource for governments and healthcare organizations for informing their population health measurement efforts.

Summary The family is an important contributor to the cultural conditions that support health. Current challenges in family health promotion interventions include programme design that is not always guided by theory and change mechanisms. Multifaceted programmes also make it hard to examine what works for whom, given different family roles and the range of lifestyle behaviour and mechanisms examined within diverse conceptual frameworks and cultures. We performed a scoping review on the heterogeneous literature to map and categorize the models and mechanisms by which a family may promote health behaviours among its members. We searched five electronic databases and grey literature up to 2020. Publications were included if they examined health-promoting behaviours, influences at the family level, and outlined the behavioural mechanisms involved. Two hundred and forty studies were identified. Ecological systems theory, social cognitive theory, family systems theory and the theory of planned behaviour were the frameworks most widely used in explaining either study context and/or mechanism. The most frequently studied family mechanisms involved aspects of family support, supervision and modelling, while some studies also included individual-level mechanisms. Majority of the studies investigated parental influence on the child, while few studies assessed the elderly family member as a recipient or actor of the influences. Studies on African, Asian and Middle Eastern populations were also in the minority, highlighting room for further research. Improving the understanding of context and behavioural mechanisms for family health promotion will aid the development of public health policy and chronic disease prevention programmes, complementing efforts targeted at individuals.

BackgroundThe Family Health Climate (FHC) is a family environment attribute postulated to influence the health behaviors of family members. It can be measured by domain scales for physical activity (FHC-PA) and nutrition (FHC-NU), which have been validated and used to identify health climate patterns in families in Western populations. To extend the use of the scales to Asian settings, this study aimed to adapt and validate the instruments for use in the multi-ethnic population of Singapore, accounting for language and cultural differences.MethodsIn Part A (n = 40) to adapt the scales for the Singapore population, we performed cognitive interviews, face validity testing and pre-testing of the instruments (n = 40). Besides English, the scales were translated into Chinese and Malay. In Part B (n = 400), we performed exploratory and confirmatory factor analyses respectively on two random samples. We also tested for item discriminant validity, internal consistency reliability, construct validity, and measurement invariance.ResultsThe findings from the cognitive interviews in Part A led to scale adaptations to accommodate cultural and linguistic factors. In Part B, EFA on Sample I resulted in a three-factor model for the PA scale (accounting for 71.2% variance) and a four-factor model for the NU scale (accounting for 72.8% variance). CFA on Sample II indicated acceptable model fits: FHC-PA: χ2 = 192.29, df = 101, p < 0.001, χ2/df = 1.90; SRMR = 0.049; RMSEA = 0.067; CFI = 0.969; TLI = 0.963; FHC-NU: χ2 = 170.46, df = 98, p < 0.001, χ2/df = 1.74; SRMR = 0.036; RMSEA = 0.061; CFI = 0.967; TLI = 0.960. The scores of family members demonstrated significant agreement on the FHC-PA (Sg) [ICC(2, 2) = 0.77] and FHC-NU (Sg) [ICC(2, 2) = 0.75] scales. Findings suggest good evidence for item discriminant validity, internal consistency reliability, construct validity, and measurement invariance. Short versions of the scales were also developed.ConclusionWe adapted, translated and validated the scales for assessing the health climate of families in Singapore, including the development of short versions. The results showed good psychometric properties and the constructs had significant relationships with health behaviors and routines. Improving our understanding of family influences on individual health behavior will be important in developing multi-level strategies for health promotion and chronic disease prevention.

The tumorous niche may drive the plasticity of heterogeneity and cancer stemness, leading to drug resistance and metastasis, which is the main reason of treatment failure in most cancer patients. The aim of this study was to establish a tumor microenvironment (TME)-based screening to identify drugs that can specifically target cancer stem cells (CSCs) and cancer-associated fibroblasts (CAFs) in the TME. Methods: Lung cancer patient-derived cancer cell and CAFs were utilized to mimic the TME and reproduce the stemness properties of CSCs in vitro and develop a high-throughput drug screening platform with phenotypical parameters. Limiting dilution assay, sphere-forming and ALDH activity assay were utilized to measure the cancer stemness characteristics. In vivo patient-derived xenograft (PDX) models and single-cell RNA sequencing were used to evaluate the mechanisms of the compounds in CSCs and CAFs. Results: The TME-based drug screening platform could comprehensively evaluate the response of cancer cells, CSCs and CAFs to different treatments. Among the 1,524 compounds tested, several drugs were identified to have anti-CAFs, anticancer and anti-CSCs activities. Aloe-emodin and digoxin both show anticancer and anti-CSCs activity in vitro and in vivo, which was further confirmed in the lung cancer PDX model. The combination of digoxin and chemotherapy improved therapeutic efficacy. The single-cell transcriptomics analysis revealed that digoxin could suppress the CSCs subpopulation in CAFs-cocultured cancer cells and cytokine production in CAFs. Conclusions: The TME-based drug screening platform provides a tool to identify and repurpose compounds targeting cancer cells, CSCs and CAFs, which may accelerate drug development and therapeutic application for lung cancer patients.