Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer.

Glutamine synthetase (GS) activity is conserved from prokaryotes to humans, where the ATP-dependent production of glutamine from glutamate and ammonia is essential for neurotransmission and ammonia detoxification. Here, we show that mammalian GS uses glutamate and methylamine to produce a methylated glutamine analog, N5-methylglutamine. Untargeted metabolomics revealed that liver-specific GS deletion and its pharmacological inhibition in mice suppress hepatic and circulating levels of N5-methylglutamine. This alternative activity of GS was confirmed in human recombinant enzyme and cells, where a pathogenic mutation in the active site (R324C) promoted the synthesis of N5-methylglutamine over glutamine. N5-methylglutamine is detected in the circulation, and its levels are sustained by the microbiome, as demonstrated by using germ-free mice. Finally, we show that urine levels of N5-methylglutamine correlate with tumor burden and GS expression in a ß-catenin-driven model of liver cancer, highlighting the translational potential of this uncharacterized metabolite.

The Health-Seeking Behavior among Malaysian Adults in Urban and Rural Areas Who Reported Sickness: Findings from the National Health and Morbidity Survey (NHMS) 2019.

Understanding care-seeking behavior among urban and rural populations can help to support the planning and implementation of appropriate measures to improve health in the community. This study aims to determine the factors associated with the health-seeking behavior among Malaysian adults in urban and rural areas who reported sickness. This study used data of Malaysian adults aged 18 years and over from the National Health and Morbidity Survey 2019; a cross-sectional, national household survey that targeted all non-institutionalized residents in Malaysia. Respondent's characteristics and health-seeking behavior were described using complex sample descriptive statistics. Multivariable logistic regression analysis was conducted to examine the association between potential factors (sociodemographic characteristics, enabling, and health need) and health-seeking behaviors (seeking treatment from healthcare practitioners and self-medication). A total of 10,484 respondents, estimated to represent 18.9 million Malaysian adults aged 18 years and over, were included in the analysis. Prevalence of seeking treatment from healthcare practitioners and self-medication among Malaysian adults with self-reported sickness were 57.3% and 23.3%, respectively. Self-reported sickness among both the urban and rural populations who rated their health as poor to very poor was more likely to seek treatment than those who rated good to excellent. However, among the urban population, those who rated their health as poor to very poor were less likely to self-medicate. Among the urban population, government employees were more likely to seek treatment, and being without formal education significantly increased the likelihood to self-medicate. Among the rural population, those with at least one long-term condition were more likely to seek treatment than those with none. Understanding the factors which influence health-seeking behavior among the urban and rural population could close the gaps in healthcare utilization among the population in Malaysia.

Applying Discrete Event Simulation to Reduce Patient Wait Times and Crowding: The Case of a Specialist Outpatient Clinic with Dual Practice System.

Long wait times and crowding are major issues affecting outpatient service delivery, but it is unclear how these affect patients in dual practice settings. This study aims to evaluate the effects of changing consultation start time and patient arrival on wait times and crowding in an outpatient clinic with a dual practice system. A discrete event simulation (DES) model was developed based on real-world data from an Obstetrics and Gynaecology (O&G) clinic in a public hospital. Data on patient flow, resource availability, and time taken for registration and clinic processes for public and private patients were sourced from stakeholder discussion and time-motion study (TMS), while arrival times were sourced from the hospital's information system database. Probability distributions were used to fit these input data in the model. Scenario analyses involved configurations on consultation start time/staggered patient arrival. The median registration and clinic turnaround times (TT) were significantly different between public and private patients (p < 0.01). Public patients have longer wait times than private patients in this study's dual practice setting. Scenario analyses showed that early consultation start time that matches patient arrival time and staggered arrival could reduce the overall TT for public and private patients by 40% and 21%, respectively. Similarly, the number of patients waiting at the clinic per hour could be reduced by 10-21% during clinic peak hours. Matching consultation start time with staggered patient arrival can potentially reduce wait times and crowding, especially for public patients, without incurring additional resource needs and help narrow the wait time gap between public and private patients. Healthcare managers and policymakers can consider simulation approaches for the monitoring and improvement of healthcare operational efficiency to meet rising healthcare demand and costs.

A 5-FU Precursor Designed to Evade Anabolic and Catabolic Drug Pathways and Activated by Pd Chemistry In Vitro and In Vivo.

5-Fluorouracil (5-FU) is an antineoplastic antimetabolite that is widely administered to cancer patients by bolus injection, especially to those suffering from colorectal and pancreatic cancer. Because of its suboptimal route of administration and dose-limiting toxicities, diverse 5-FU prodrugs have been developed to confer oral bioavailability and increase the safety profile of 5-FU chemotherapy regimens. Our contribution to this goal is presented herein with the development of a novel palladium-activated prodrug designed to evade the metabolic machinery responsible for 5-FU anabolic activation and catabolic processing. The new prodrug is completely innocuous to cells and highly resistant to metabolization by primary hepatocytes and liver S9 fractions (the main metabolic route for 5-FU degradation), whereas it is rapidly converted into 5-FU in the presence of a palladium (Pd) source. In vivo pharmokinetic analysis shows the prodrug is rapidly and completely absorbed after oral administration and exhibits a longer half-life than 5-FU. In vivo efficacy studies in a xenograft colon cancer model served to prove, for the first time, that orally administered prodrugs can be locally converted to active drugs by intratumorally inserted Pd implants.

Determinants of community pharmacy utilisation among the adult population in Malaysia: findings from the National Health and Morbidity Survey 2019.

BACKGROUND: Community pharmacies provide alternatives for medication procurement and other basic and minor health-related services in addition to mainstream hospitals and primary healthcare services. This study aimed to determine the characteristics of community pharmacy users and associated factors for community pharmacy utilisation in Malaysia. METHODS: Secondary data analysis was performed using data from the National Health and Morbidity Survey 2019, a nationwide cross-sectional household survey that used a two-stage stratified random sampling design. Adults aged 18 years and over were included in the analysis. Respondents who reported visiting the community pharmacy for health purposes two weeks prior to the study were considered as users. Complex sample descriptive statistics were used to describe the respondents' characteristics. Logistic regression analyses were employed to determine factors associated with community pharmacy utilisation. RESULTS: Of the 11,155 respondents interviewed, 10.3 % reported community pharmacy utilisation for health purposes. Females (OR = 1.41, 95 % CI = 1.14, 1.73), those with tertiary education (OR = 2.03, 95 % CI = 1.26, 3.29), urban dwellers (OR = 1.42, 95 % CI = 1.13, 1.79), and those with self-reported health problems (OR = 7.62, 95 % CI = 6.05, 9.59) were more likely to utilise the community pharmacy. CONCLUSIONS: Demographic and socioeconomic factors were important determinants of community pharmacy utilisation in Malaysia with sex, age, education level, locality, and self-reported health problems as the associated factors. These findings serve as evidence for policy interventions, crucial for improvements in accessibility to healthcare services.

Factors associated with informal caregiving and its effects on health, work, and social activities of adult informal caregivers in Malaysia: findings from the National Health and Morbidity Survey 2019.

BACKGROUND: The increase in the elderly population, chronic and degenerative diseases, as well as accidents at work and on the road in Malaysia would result in an increased demand for informal care. This paper aimed to determine the associated factors of informal caregiving and its effects on health, work and social activities of adult informal caregivers in Malaysia. METHODS: The data from the 2019 National Health and Morbidity Survey (NHMS), a nationwide cross-sectional survey with a two-stage stratified random sampling design, was used in this research. The study included respondents who were 18 years and older (n = 11,674). Data were obtained via face-to-face interviews using validated questionnaires. Descriptive and complex sample logistic regression analyses were employed as appropriate. RESULTS: 5.7% of the adult population were informal caregivers. Provision of informal care were significantly associated with the female sex (OR = 1.52, 95% CI [1.21, 1.92]), those aged 36-59 years (OR = 1.61, 95% CI [1.15, 2.25]), and those who reported illness in the past 2 weeks (OR = 1.79, 95% CI [1.38, 2.33]). The risk of having their health affected were associated with female caregivers (OR = 3.63, 95% CI [1.73, 7.61]), those who received training (OR = 2.10, 95% CI [1.10, 4.00]) and those who provided care for 2 years or more (OR = 1.91, 95% CI [1.08, 3.37]). The factors associated with the effects on work were ethnicity, received training and had no assistance to provide the care. In terms of effect on social activities, female caregivers (OR = 1.96, 95% CI [1.04, 3.69]) and caregivers who received training were more likely (OR = 2.19, 95% CI [1.22, 3.93]) to have their social activities affected. CONCLUSION: Our study revealed that sex, age, and self-reported illness were factors associated with being an informal caregiver in Malaysia. Informal caregivers faced effects on their health, work, and social activities which may be detrimental to their well-being. This understanding is crucial for planning support for caregivers.

Implications of Dual Practice on Cataract Surgery Waiting Time and Rescheduling: The Case of Malaysia.

BACKGROUND: Dual practice was implemented in selected Ministry of Health Malaysia hospitals to reduce brain drain and provide an alternative for patients willing to pay higher user fees to seek prompt treatment from the specialist of their choice. This study aimed to assess the implications of dual practice on waiting time and rescheduling for cataract surgery. METHODS: A retrospective study was conducted in a referral hospital. Inpatient medical records of patients who underwent cataract procedures were used to study the waiting times to surgery and rescheduling between private and public groups. RESULTS: Private patients had a considerably shorter waiting time for cataract surgery, seven times shorter compared to public patients where all surgeries were conducted after hours on weekdays or weekends. Additionally, 14.9% of public patients experienced surgery rescheduling, while all private patients had their surgeries as planned. The main reason for surgery rescheduling was the medical factor, primarily due to uncontrolled blood pressure and upper respiratory tract infection. CONCLUSION: Private service provision utilizing out-of-office hours slots for cataract surgery optimizes public hospital resources, allowing shorter waiting times and providing an alternative to meet healthcare needs.

The impacts of caregiving intensity on informal caregivers in Malaysia: findings from a national survey.

BACKGROUND: Provision of informal care may adversely affect health, daily and social activities of the informal caregivers, but few studies have examined these effects in relation to caregiving intensity. This study examined the predictive factors associated with the effects of caregiving roles on health, daily and social activities of informal caregivers, accounting for caregiving intensity. METHODS: Data of adults aged 18 years and over from the National Health and Morbidity Survey 2019 were used. Respondent's demographic, socioeconomic, health, and caregiving-related characteristics were described using complex samples analysis. Logistic regression analysis was performed to examine the factors affecting health, daily and social activities of caregivers, accounting for caregiving intensity. RESULTS: Five point one percent of adults in Malaysia provided informal care. High intensity caregivers were more likely to be actively employed and provided longer duration of care compared with low intensity caregivers. For low intensity caregiving, females, those aged 35-59 years, and those with long-term condition were more likely to have negative effects on health. Daily activities of non-Malays were more likely to be affected, while no factor was found significantly associated with effect on social activities. For high intensity caregiving, caregivers aged 60 and over, those received training and those without assistance were more likely to have negative effects on health. Daily activities of those without assistance were more likely to be affected. Social activities of non-Malays, those received training and those providing care for 2 years or more were more likely to be affected. CONCLUSIONS: Our study indicates that both low- and high-intensity caregivers have common features, with the exception of employment status and care duration. Caregiving, regardless of intensity, has a significant impact on caregivers. In order to reduce the negative consequences of caregiving responsibilities, all caregivers need assistance from the community and government, that is customised to their needs. By addressing the factors contributing to the negative effects of caregiving, a continuation of informal caregiving can be sustained through policies supporting the growing demand for informal care necessitated by an ageing population and higher life expectancy in Malaysia.

Redesigning a Healthcare Demand Questionnaire for National Population Survey: Experience of a Developing Country.

Since its inception in 1986, the contents of the National Health and Morbidity Survey (NHMS) have been periodically updated to support emerging health data needs for evidence-based policy and program development. In 2018, the healthcare demand questionnaire was redesigned to capture diverse and changing population demand for healthcare services and their utilization pattern. This paper describes the methods and processes undertaken in redesigning the questionnaire. We aim to highlight the systematic and inclusive approach, enabling all potential evidence users to be involved, indirectly encouraging research evidence uptake for policy and program planning. We applied a systematic approach of comprehensive literature search for national-level population survey instruments implemented globally and translated non-English tools to English. The development phases were iterative, conducted in parallel with active stakeholder engagements. Here, we detailed the processes in the planning and exploratory phase as well as a qualitative assessment of the questionnaire. We included instruments from 45 countries. The majority were from the Organisation for Economic Co-operation and Development (OECD) countries and focused on perceived health, health-related behavior, and healthcare use. Thirty-four stakeholders from 14 areas of expertise were involved. Stakeholders identified additional content areas required, such as chronic pain, alternative use of healthcare services (community pharmacy, home-visit, and private medical laboratory), family doctor, and informal caregiving. The questionnaire, redesigned based on existing literature with concordant involvement and iterative feedback from stakeholders, improved the choice of health topics through the identification of new topics and modification of existing questions to better meet future evidence needs on health problems, strategy, and program planning towards strengthening the nation's health systems.

Demographic and socioeconomic inequalities in oral healthcare utilisation in Malaysia: evidence from a national survey.

BACKGROUND: Throughout the years, oral healthcare utilisation in Malaysia has been low despite various efforts by the Ministry of Health Malaysia for improvement. This study aimed to determine the prevalence of oral healthcare utilisation and identify factors associated with oral healthcare utilisation among adults in Malaysia. METHODS: Secondary data analysis of adults aged 18 years and over from the National Health and Morbidity Survey 2019 was conducted in this study. Characteristics of respondents and those who utilised oral healthcare were described using complex sample descriptive statistics. Logistic regression analysis was performed to examine the association between the dependent and independent variables. Dependent variable was oral healthcare utilisation in the last 12 months. Independent variables were demographic and socioeconomic factors (predisposing, enabling and need characteristics) based on Andersen's Behavioural Model. RESULTS: A total of 11,308 respondents, estimated to represent 21.7 million adults aged 18 years and over in Malaysia were included in the analysis. Prevalence of oral healthcare utilisation in the last 12 months was 13.2%. Demographic factors of sex, age, marital status, and socioeconomic factors of education level and occupation as well as health belief such as medical check-up were significantly related to oral healthcare utilisation. Enabling factor of household income quintile had significant association with oral healthcare utilisation. Inequalities were observed; females (OR = 1.57, 95% CI = 1.25, 1.96), younger adults (OR = 1.64, 95% CI = 1.15, 2.33), those who were married (OR = 1.65, 95% CI = 1.23, 2.22), those with higher education (OR = 2.21, 95% CI = 1.23, 3.99), those who had medical check-up in the last 12 months (OR = 1.86, 95% CI = 1.53, 2.25) and those with higher income (OR = 1.43, 95% CI = 1.04, 1.96) were more likely to utilise oral healthcare. CONCLUSION: Understanding factors associated with utilisation of oral healthcare could help in formulating effective interventions to improve oral healthcare utilisation. Demographic and socioeconomic factors are strong determinants of oral healthcare utilisation in Malaysia. Appropriate interventions to strengthen the existing programmes aimed to promote regular and timely oral health check-ups are needed to improve oral healthcare utilisation.

Activation of ß-Catenin Cooperates with Loss of Pten to Drive AR-Independent Castration-Resistant Prostate Cancer.

Inhibition of the androgen receptor (AR) is the main strategy to treat advanced prostate cancers. AR-independent treatment-resistant prostate cancer is a major unresolved clinical problem. Patients with prostate cancer with alterations in canonical WNT pathway genes, which lead to ß-catenin activation, are refractory to AR-targeted therapies. Here, using clinically relevant murine prostate cancer models, we investigated the significance of ß-catenin activation in prostate cancer progression and treatment resistance. ß-Catenin activation, independent of the cell of origin, cooperated with Pten loss to drive AR-independent castration-resistant prostate cancer. Prostate tumors with ß-catenin activation relied on the noncanonical WNT ligand WNT5a for sustained growth. WNT5a repressed AR expression and maintained the expression of c-Myc, an oncogenic effector of ß-catenin activation, by mediating nuclear localization of NFκBp65 and ß-catenin. Overall, WNT/ß-catenin and AR signaling are reciprocally inhibited. Therefore, inhibiting WNT/ß-catenin signaling by limiting WNT secretion in concert with AR inhibition may be useful for treating prostate cancers with alterations in WNT pathway genes. SIGNIFICANCE: Targeting of both AR and WNT/ß-catenin signaling may be required to treat prostate cancers that exhibit alterations of the WNT pathway.

Research funding impact and priority setting - advancing universal access and quality healthcare research in Malaysia.

BACKGROUND: Health Research Priority Setting (HRPS) in the Ministry of Health (MOH) Malaysia was initiated more than a decade ago to drive effort toward research for informed decision and policy-making. This study assessed the impact of funded prioritised research and identified research gaps to inform future priority setting initiatives for universal access and quality healthcare in Malaysia. METHODS: Research impact of universal access and quality healthcare projects funded by the National Institutes of Health Malaysia were assessed based on the modified Payback Framework, addressing categories of informing policy, knowledge production, and benefits to health and health sector. For the HRPS process, the Child Health and Nutrition Research Initiative methodology was adapted and adopted, with the incorporation of stakeholder values using weights and monetary allocation survey. Workshop discussions and interviews with stakeholders and research groups were conducted to identify research gaps, with the use of conceptual frameworks to guide the search. RESULTS: Seventeen ongoing and 50 completed projects were identified for research funding impact analysis. Overall, research fund allocation differed from stakeholders' expectation. For research impact, 48 out of 50 completed projects (96.0%) contributed to some form of policy-making efforts. Almost all completed projects resulted in outputs that contributed to knowledge production and were expected to lead to health and health sector benefits. The HRPS process led to the identification of research priority areas that stemmed from ongoing and new issues identified for universal access and quality healthcare. CONCLUSION: The concerted efforts of evaluation of research funding impact, prioritisation, dissemination and policy-maker involvement were valuable for optimal health research resource utilisation in a resource constrained developing country. Embedding impact evaluation into a priority setting process and funding research based on national needs could facilitate health research investment to reach its potential.

Analysis of Nkx3.1:Cre-driven Erk5 deletion reveals a profound spinal deformity which is linked to increased osteoclast activity.

Extracellular signal-regulated protein kinase 5 (ERK5) has been implicated during development and carcinogenesis. Nkx3.1-mediated Cre expression is a useful strategy to genetically manipulate the mouse prostate. While grossly normal at birth, we observed an unexpected phenotype of spinal protrusion in Nkx3.1:Cre;Erk5 fl/fl (Erk5 fl/fl) mice by ~6-8 weeks of age. X-ray, histological and micro CT (µCT) analyses showed that 100% of male and female Erk5 fl/fl mice had a severely deformed curved thoracic spine, with an associated loss of trabecular bone volume. Although sex-specific differences were observed, histomorphometry measurements revealed that both bone resorption and bone formation parameters were increased in male Erk5 fl/fl mice compared to wild type (WT) littermates. Osteopenia occurs where the rate of bone resorption exceeds that of bone formation, so we investigated the role of the osteoclast compartment. We found that treatment of RANKL-stimulated primary bone marrow-derived macrophage (BMDM) cultures with small molecule ERK5 pathway inhibitors increased osteoclast numbers. Furthermore, osteoclast numbers and expression of osteoclast marker genes were increased in parallel with reduced Erk5 expression in cultures generated from Erk5 fl/fl mice compared to WT mice. Collectively, these results reveal a novel role for Erk5 during bone maturation and homeostasis in vivo.

Increased T-cell Infiltration Elicited by Erk5 Deletion in a Pten-Deficient Mouse Model of Prostate Carcinogenesis.

Prostate cancer does not appear to respond to immune checkpoint therapies where T-cell infiltration may be a key limiting factor. Here, we report evidence that ablating the growth regulatory kinase Erk5 can increase T-cell infiltration in an established Pten-deficient mouse model of human prostate cancer. Mice that were doubly mutant in prostate tissue for Pten and Erk5 (prostate DKO) exhibited a markedly increased median survival with reduced tumor size and proliferation compared with control Pten-mutant mice, the latter of which exhibited increased Erk5 mRNA expression. A comparative transcriptomic analysis revealed upregulation in prostate DKO mice of the chemokines Ccl5 and Cxcl10, two potent chemoattractants for T lymphocytes. Consistent with this effect, we observed a relative increase in a predominantly CD4+ T-cell infiltrate in the prostate epithelial and stroma of tumors from DKO mice. Collectively, our results offer a preclinical proof of concept for ERK5 as a target to enhance T-cell infiltrates in prostate cancer, with possible implications for leveraging immune therapy in this disease. Cancer Res; 77(12); 3158-68. ©2017 AACR.

Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids.

In the adenoma-carcinoma sequence, it is proposed that intestinal polyps evolve through a set of defined mutations toward metastatic colorectal cancer (CRC). Here, we dissect this adenoma-carcinoma sequence in vivo by using an orthotopic organoid transplantation model of human colon organoids engineered to harbor different CRC mutation combinations. We demonstrate that sequential accumulation of oncogenic mutations in Wnt, EGFR, P53, and TGF-ß signaling pathways facilitates efficient tumor growth, migration, and metastatic colonization. We show that reconstitution of specific niche signals can restore metastatic growth potential of tumor cells lacking one of the oncogenic mutations. Our findings imply that the ability to metastasize-i.e., to colonize distant sites-is the direct consequence of the loss of dependency on specific niche signals.

Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer.

Prostate cancer (CaP) is the most common adult male cancer in the developed world. The paucity of biomarkers to predict prostate tumor biology makes it important to identify key pathways that confer poor prognosis and guide potential targeted therapy. Using a murine forward mutagenesis screen in a Pten-null background, we identified peroxisome proliferator-activated receptor gamma (Pparg), encoding a ligand-activated transcription factor, as a promoter of metastatic CaP through activation of lipid signaling pathways, including up-regulation of lipid synthesis enzymes [fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), ATP citrate lyase (ACLY)]. Importantly, inhibition of PPARG suppressed tumor growth in vivo, with down-regulation of the lipid synthesis program. We show that elevated levels of PPARG strongly correlate with elevation of FASN in human CaP and that high levels of PPARG/FASN and PI3K/pAKT pathway activation confer a poor prognosis. These data suggest that CaP patients could be stratified in terms of PPARG/FASN and PTEN levels to identify patients with aggressive CaP who may respond favorably to PPARG/FASN inhibition.

An EphB-Abl signaling pathway is associated with intestinal tumor initiation and growth.

EphB receptors regulate the proliferation and positioning of intestinal stem and progenitor cells. In addition, they can act as tumor promoters for adenoma development but suppress progression to invasive carcinoma. We used imatinib to abrogate Abl kinase activity in Apc(Min/+) mice and in mice with LGR5(+) stem cells that were genetically engineered to develop adenomatous polyposis coli. Imatinib treatment inhibited the tumor-promoting effects of EphB signaling without attenuating EphB-mediated tumor suppression, demonstrating a role for EphB signaling in the initiation of intestinal tumors. The imatinib treatment regimen extended the life span of Apc(Min/+) mice and reduced cell proliferation in cultured slices of adenomas from patients with familial adenomatous polyposis. These findings connect the EphB signaling pathway to the regulation of intestinal adenoma initiation via Abl kinase. Our findings may have clinical implications for pharmacological therapy against adenoma formation and cancer progression in patients predisposed to develop colorectal cancer.

Gelsolin induces colorectal tumor cell invasion via modulation of the urokinase-type plasminogen activator cascade.

Gelsolin is a cytoskeletal protein which participates in actin filament dynamics and promotes cell motility and plasticity. Although initially regarded as a tumor suppressor, gelsolin expression in certain tumors correlates with poor prognosis and therapy-resistance. In vitro, gelsolin has anti-apoptotic and pro-migratory functions and is critical for invasion of some types of tumor cells. We found that gelsolin was highly expressed at tumor borders infiltrating into adjacent liver tissues, as examined by immunohistochemistry. Although gelsolin contributes to lamellipodia formation in migrating cells, the mechanisms by which it induces tumor invasion are unclear. Gelsolin's influence on the invasive activity of colorectal cancer cells was investigated using overexpression and small interfering RNA knockdown. We show that gelsolin is required for invasion of colorectal cancer cells through matrigel. Microarray analysis and quantitative PCR indicate that gelsolin overexpression induces the upregulation of invasion-promoting genes in colorectal cancer cells, including the matrix-degrading urokinase-type plasminogen activator (uPA). Conversely, gelsolin knockdown reduces uPA levels, as well as uPA secretion. The enhanced invasiveness of gelsolin-overexpressing cells was attenuated by treatment with function-blocking antibodies to either uPA or its receptor uPAR, indicating that uPA/uPAR activity is crucial for gelsolin-dependent invasion. In summary, our data reveals novel functions of gelsolin in colorectal tumor cell invasion through its modulation of the uPA/uPAR cascade, with potentially important roles in colorectal tumor dissemination to metastatic sites.

A new tumour suppressor enters the network of intestinal progenitor cell homeostasis.

In this issue of The EMBO Journal, Wilson et al (2012) elegantly discovered an important new axis for intestinal homeostasis and cancer, using an RNAi screen to enhance the RAS-induced multivulva (MUV) phenotype in Caenorhabditis elegans.

C/EBP alpha knock-in hepatocytes exhibit increased albumin secretion and urea production.

The CCAAT/enhancer-binding protein alpha (C/EBP alpha) is essential for maintaining the differentiated state of hepatocytes in vivo. C/EBP alpha activates albumin transcription and coordinates the expression of multiple ornithine cycle enzymes involved in urea production. We have examined the effects of the C/EBP alpha knock-in gene on the mRNA and protein expression of genes involved in liver-specific functions, such as albumin and urea production. Albumin mRNA and protein levels are higher in knock-in hepatocytes compared with wild-type hepatocytes. mRNA levels for the ornithine cycle enzymes, namely arginase, carbamylphosphate synthetase 1, and ornithine transcarbamylase, also increase. Albumin secretion and urea production are sustained at higher levels in culture in knock-in hepatocytes. We have previously established that C/EBP alpha induces early liver glycogen storage in C/EBP alpha knock-in mice. Our present observations underline the importance of C/EBP alpha in liver metabolism and suggest that the induction of C/EBP alpha expression enhances hepatocyte function.