Loeys-Dietz and Shprintzen-Goldberg syndromes: analysis of TGF-ß-opathies with craniofacial manifestations using an innovative multimodality method.

BACKGROUND: Elevated transforming growth factor-beta (TGF-ß) signalling has been implicated in the pathogenesis of Loeys-Dietz syndrome (LDS) and Shprintzen-Goldberg syndrome (SGS). In this study, we provide a qualitative and quantitative analysis of the craniofacial and functional features among the LDS subtypes and SGS. METHODS: We explore the variability within and across a cohort of 44 patients through deep clinical phenotyping, three-dimensional (3D) facial photo surface analysis, cephalometric and geometric morphometric analyses of cone-beam CT scans. RESULTS: The most common craniofacial features detected in this cohort include mandibular retrognathism (84%), flat midface projection (84%), abnormal eye shape (73%), low-set ears (73%), abnormal nose (66%) and lip shape (64%), hypertelorism (41%) and a relatively high prevalence of nystagmus/strabismus (43%), temporomandibular joint disorders (38%) and obstructive sleep apnoea (23%). 3D cephalometric analysis demonstrated an increased cranial base angle with shortened anterior cranial base and underdevelopment of the maxilla and mandible, with evidence of a reduced pharyngeal airway in 55% of those analysed. Geometric morphometric analysis confirmed that the greatest craniofacial shape variation was among patients with LDS type 2, with distinct clustering of patients with SGS. CONCLUSIONS: This comprehensive phenotypic approach identifies developmental abnormalities that segregate to mutation variants along the TGF-ß signalling pathway, with a particularly severe phenotype associated with TGFBR2 and SKI mutations. Multimodality assessment of craniofacial anomalies objectively reveals the impact of mutations of the TGF-ß pathway with perturbations associated with the cranium and cranial base with severe downstream effects on the orbit, maxilla and mandible with the resultant clinical phenotypes.

Growing old in China in socioeconomic and epidemiological context: systematic review of social care policy for older people.

BACKGROUND: From 2020 to 2050, China's population aged ≥65 years old is estimated to more than double from 172 million (12·0%) to 366 million (26·0%). Some 10 million have Alzheimer's disease and related dementias, to approach 40 million by 2050. Critically, the population is ageing fast while China is still a middle-income country. METHODS: Using official and population-level statistics, we summarise China's demographic and epidemiological trends relevant to ageing and health from 1970 to present, before examining key determinants of China's improving population health in a socioecological framework. We then explore how China is responding to the care needs of its older population by carrying out a systematic review to answer the question: 'what are the key policy challenges to China achieving an equitable nationwide long-term care system for older people?'. Databases were screened for records published between 1st June 2020 and 1st June 2022 in Mandarin Chinese or English, reflecting our focus on evidence published since introduction of China's second long-term care insurance pilot phase in 2020. RESULTS: Rapid economic development and improved access to education has led to widescale internal migration. Changing fertility policies and household structures also pose considerable challenges to the traditional family care model. To deal with increasing need, China has piloted 49 alternative long-term care insurance systems. Our findings from 42 studies (n = 16 in Mandarin) highlight significant challenges in the provision of quality and quantity of care which suits the preference of users, varying eligibility for long-term care insurance and an inequitable distribution of cost burden. Key recommendations include increasing salaries to attract and retain staff, introduction of mandatory financial contributions from employees and a unified standard of disability with regular assessment. Strengthening support for family caregivers and improving smart old age care capacity can also support preferences to age at home. CONCLUSIONS: China has yet to establish a sustainable funding mechanism, standardised eligibility criteria and a high-quality service delivery system. Its long-term care insurance pilot studies provide useful lessons for other middle-income countries facing similar challenges in terms of meeting the long-term care needs of their rapidly growing older populations.

Ablation of insulin receptor substrates 1 and 2 suppresses Kras-driven lung tumorigenesis.

Non-small-cell lung cancer (NSCLC) is a leading cause of cancer death worldwide, with 25% of cases harboring oncogenic Kirsten rat sarcoma (KRAS). Although KRAS direct binding to and activation of PI3K is required for KRAS-driven lung tumorigenesis, the contribution of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) in the context of mutant KRAS remains controversial. Here, we provide genetic evidence that lung-specific dual ablation of insulin receptor substrates 1/2 (Irs1/Irs2), which mediate insulin and IGF1 signaling, strongly suppresses tumor initiation and dramatically extends the survival of a mouse model of lung cancer with Kras activation and p53 loss. Mice with Irs1/Irs2 loss eventually succumb to tumor burden, with tumor cells displaying suppressed Akt activation and strikingly diminished intracellular levels of essential amino acids. Acute loss of IRS1/IRS2 or inhibition of IR/IGF1R in KRAS-mutant human NSCLC cells decreases the uptake and lowers the intracellular levels of amino acids, while enhancing basal autophagy and sensitivity to autophagy and proteasome inhibitors. These findings demonstrate that insulin/IGF1 signaling is required for KRAS-mutant lung cancer initiation, and identify decreased amino acid levels as a metabolic vulnerability in tumor cells with IR/IGF1R inhibition. Consequently, combinatorial targeting of IR/IGF1R with autophagy or proteasome inhibitors may represent an effective therapeutic strategy in KRAS-mutant NSCLC.

Modifier locus mapping of a transgenic F2 mouse population identifies CCDC115 as a novel aggressive prostate cancer modifier gene in humans.

BACKGROUND: It is well known that development of prostate cancer (PC) can be attributed to somatic mutations of the genome, acquired within proto-oncogenes or tumor-suppressor genes. What is less well understood is how germline variation contributes to disease aggressiveness in PC patients. To map germline modifiers of aggressive neuroendocrine PC, we generated a genetically diverse F2 intercross population using the transgenic TRAMP mouse model and the wild-derived WSB/EiJ (WSB) strain. The relevance of germline modifiers of aggressive PC identified in these mice was extensively correlated in human PC datasets and functionally validated in cell lines. RESULTS: Aggressive PC traits were quantified in a population of 30 week old (TRAMP x WSB) F2 mice (n = 307). Correlation of germline genotype with aggressive disease phenotype revealed seven modifier loci that were significantly associated with aggressive disease. RNA-seq were analyzed using cis-eQTL and trait correlation analyses to identify candidate genes within each of these loci. Analysis of 92 (TRAMP x WSB) F2 prostates revealed 25 candidate genes that harbored both a significant cis-eQTL and mRNA expression correlations with an aggressive PC trait. We further delineated these candidate genes based on their clinical relevance, by interrogating human PC GWAS and PC tumor gene expression datasets. We identified four genes (CCDC115, DNAJC10, RNF149, and STYXL1), which encompassed all of the following characteristics: 1) one or more germline variants associated with aggressive PC traits; 2) differential mRNA levels associated with aggressive PC traits; and 3) differential mRNA expression between normal and tumor tissue. Functional validation studies of these four genes using the human LNCaP prostate adenocarcinoma cell line revealed ectopic overexpression of CCDC115 can significantly impede cell growth in vitro and tumor growth in vivo. Furthermore, CCDC115 human prostate tumor expression was associated with better survival outcomes. CONCLUSION: We have demonstrated how modifier locus mapping in mouse models of PC, coupled with in silico analyses of human PC datasets, can reveal novel germline modifier genes of aggressive PC. We have also characterized CCDC115 as being associated with less aggressive PC in humans, placing it as a potential prognostic marker of aggressive PC.

Disparities Associated With Inpatient Palliative Care Utilization by Patients With Metastatic Gynecologic Cancers: A Study of 3337 Women.

OBJECTIVE: To determine the factors associated with inpatient palliative care (PC) use in patients with metastatic gynecologic cancer. METHODS: Data were obtained from the Nationwide Inpatient Sample (NIS) for patients with metastatic cervical, uterine, and ovarian cancers. Chi-square and multivariate models were used for statistical analyses. RESULTS: Of 67 947 inpatients with metastatic gynecologic cancer, 3337 (5%) utilized PC (median age: 63 years, range: 18-102 years). For the entire cohort, the majority was white (59%) and the remainder was black (10%), Hispanic (8%), and Asian (3%). Sixty-one percent had ovarian, 25% uterine, and 14% cervical cancers. Forty-four percent had Medicare, 37% private insurance, 12% Medicaid, and 3% were uninsured. Fifty-three percent of patients were treated at teaching hospitals, while 33% were treated at nonteaching hospitals. In multivariate analysis, the use of PC was associated with older age (≥63, median; odds ratio [OR] = 1.52, 95% confidence interval [CI]: 1.36-1.70; P < .0001) and black race (OR = 1.22, CI: 1.08-1.39; P < .01). Compared to patients with ovarian cancer, patients with uterine (OR = 1.63, CI: 1.46-1.83; P < .0001) and cervical (OR = 1.14, CI: 1.104-1.25; P < .01) cancer had higher rates of PC utilization. The proportion of patients receiving PC increased from 2% in 2005 to 10% in 2011. In a subset analysis of the 4517 patients who died during hospitalization, only 1056 (23%) patients received PC. CONCLUSION: Patients who were older, black, or had uterine and cervical cancers were more likely to use PC. Although the overall use of PC has increased, less than one-quarter of patients who died in the hospital used PC services during their final hospital admission.

Prostate cancer susceptibility gene HIST1H1A is a modulator of androgen receptor signaling and epithelial to mesenchymal transition.

In 2018, approximately 165,000 new prostate cancer (PC) cases will be diagnosed, and over 29,000 men will succumb to PC in the U.S. alone. The means of assessing outcome in the clinic are inaccurate, and there is a pressing need to more precisely identify men at risk of aggressive PC. We previously identified HIST1H1A as a susceptibility gene for aggressive PC. HIST1H1A encodes H1.1, a member of the linker histone family that is involved in chromatin organization and compaction. To understand the molecular basis of aggressive PC, we have characterized how germline variation modulates susceptibility to neuroendocrine differentiation, which is a form of aggressive PC. Immunohistochemistry studies revealed that HIST1H1A is over-expressed in normal human prostate tissue compared to prostate adenocarcinoma. Functional characterization of HIST1H1A in prostate LNCaP cells indicated that HIST1HA over-expression increased cell growth, as well as the expression of neuroendocrine and epithelial-to-mesenchymal markers in vitro. Assay for Transposase-Accessible Chromatin (ATAC-seq), which is used to assess chromatin compaction and thus the transcriptional availability of individual genomic regions, demonstrated that H1.1 plays a prominent role in modulating Wnt signaling pathway genes, which are implicated in prostate tumorigenesis. These results demonstrate that HIST1H1A is a modulator of aggressive PC susceptibility.

Starved epithelial cells uptake extracellular matrix for survival.

Extracellular matrix adhesion is required for normal epithelial cell survival, nutrient uptake and metabolism. This requirement can be overcome by oncogene activation. Interestingly, inhibition of PI3K/mTOR leads to apoptosis of matrix-detached, but not matrix-attached cancer cells, suggesting that matrix-attached cells use alternate mechanisms to maintain nutrient supplies. Here we demonstrate that under conditions of dietary restriction or growth factor starvation, where PI3K/mTOR signalling is decreased, matrix-attached human mammary epithelial cells upregulate and internalize ß4-integrin along with its matrix substrate, laminin. Endocytosed laminin localizes to lysosomes, results in increased intracellular levels of essential amino acids and enhanced mTORC1 signalling, preventing cell death. Moreover, we show that starved human fibroblasts secrete matrix proteins that maintain the growth of starved mammary epithelial cells contingent upon epithelial cell ß4-integrin expression. Our study identifies a crosstalk between stromal fibroblasts and epithelial cells under starvation that could be exploited therapeutically to target tumours resistant to PI3K/mTOR inhibition.

Evaluation of complex integrated care programmes: the approach in North West London.

BACKGROUND: Several local attempts to introduce integrated care in the English National Health Service have been tried, with limited success. The Northwest London Integrated Care Pilot attempts to improve the quality of care of the elderly and people with diabetes by providing a novel integration process across primary, secondary and social care organisations. It involves predictive risk modelling, care planning, multidisciplinary management of complex cases and an information technology tool to support information sharing. This paper sets out the evaluation approach adopted to measure its effect. STUDY DESIGN: We present a mixed methods evaluation methodology. It includes a quantitative approach measuring changes in service utilization, costs, clinical outcomes and quality of care using routine primary and secondary data sources. It also contains a qualitative component, involving observations, interviews and focus groups with patients and professionals, to understand participant experiences and to understand the pilot within the national policy context. THEORY AND DISCUSSION: This study considers the complexity of evaluating a large, multi-organisational intervention in a changing healthcare economy. We locate the evaluation within the theory of evaluation of complex interventions. We present the specific challenges faced by evaluating an intervention of this sort, and the responses made to mitigate against them. CONCLUSIONS: We hope this broad, dynamic and responsive evaluation will allow us to clarify the contribution of the pilot, and provide a potential model for evaluation of other similar interventions. Because of the priority given to the integrated agenda by governments internationally, the need to develop and improve strong evaluation methodologies remains strikingly important.

Pten-null tumors cohabiting the same lung display differential AKT activation and sensitivity to dietary restriction.

PTEN loss is considered a biomarker for activated phosphoinositide 3-kinase (PI3K)/AKT, a pathway frequently mutated in cancer, and was recently shown to confer resistance to dietary restriction. Here, we show that Pten loss is not sufficient to drive AKT activation and resistance to dietary restriction in tumors with low growth factor receptor levels. We describe a murine Pten-null Kras-driven lung cancer model that harbors both dietary restriction-resistant, higher-grade, bronchiolar tumors with high AKT activity, and dietary restriction-sensitive, lower-grade, alveolar tumors with low AKT activity. We find that this phenotype is cell autonomous and that normal bronchiolar cells express higher levels of insulin-like growth factor-I receptor (IGF-IR) and of ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5), an endoplasmic reticulum enzyme known to modulate growth factor receptor levels. Suppression of ENTPD5 is sufficient to decrease IGF-IR levels and sensitize bronchiolar tumor cells to serum in vitro and to dietary restriction in vivo. Furthermore, we find that a significant percentage of human non-small cell lung carcinomas (NSCLC) have low AKT activity despite PTEN loss.

Integrated care pilot in north-west London: a mixed methods evaluation.

INTRODUCTION: This paper provides the results of a year-long evaluation of a large-scale integrated care pilot in north-west London. The pilot aimed to integrate care across primary, acute, community, mental health and social care for people with diabetes and/or those aged 75+ through care planning, multidisciplinary case reviews, information sharing and project management support. METHODS: The evaluation team conducted qualitative studies of change at organisational, clinician and patient levels (using interviews, focus groups and a survey); and quantitative analysis of change in service use and patient-level clinical outcomes (using patient-level datasets and a matched control study). RESULTS: The pilot had successfully engaged provider organisations, created a shared strategic vision and established governance structures. However, the engagement of clinicians was variable and there was no evidence to date of significant reductions in emergency admissions. There was some evidence of changes in care processes. CONCLUSION: Although the pilot has demonstrated the beginnings of large-scale change, it remains in the early stages and faces significant challenges as it seeks to become sustainable for the longer term. It is critical that National Health Service managers and clinicians have realistic expectations of what can be achieved in a relatively short period of time.

Feasibility and effectiveness of a pilot health promotion program for adults with type 2 diabetes: lessons learned.

PURPOSE: The purpose of this pilot study was to assess the feasibility and effectiveness of an intense health promotion program in older adults with diabetes. The program combined individually prescribed and supervised exercise with nutrition and education programs on glycemic control and aerobic fitness. METHODS: Various recruitment and retention strategies were analyzed for effectiveness. Out of 28 potential subjects assessed for eligibility, 6 subjects with type 2 diabetes (2 male and 4 female; all white; age, 60.2 +/- 4.7 years) participated in the 10-week intervention. Aerobic and resistance exercise was performed on alternate days (3-4 days per week), with individualized nutrition counseling and diabetes health education sessions once weekly. The primary outcome measures were aerobic fitness and glycemic control (A1C), and secondary outcome measures included body mass index (BMI), self-efficacy, and symptoms of neuropathy. Changes in outcomes were assessed using descriptive statistics and paired t test analysis (alpha = .05). RESULTS: Following the intervention, subjects had improvements that approached significance in A1C and pain, with significant improvements in self-efficacy. CONCLUSIONS: A systematic approach to analysis of feasibility revealed issues with recruitment and retention that would need to be addressed for future studies or clinical implementation of this program. However, for the subset of subjects who did complete the intervention, adherence was excellent, and satisfaction with the program was confirmed by exit interview comments. Following participation in this pilot health promotion program, subjects had meaningful improvements in glycemic control, pain, and self-efficacy.