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Inter-patient and intra-tumour heterogeneity (ITH) have prompted the need for a more personalised approach to cancer therapy. Although patient-derived xenograft (PDX) models can generate drug response specific to patients, they are not sustainable in terms of cost and time and have limited scalability. Tumour Organ-on-Chip (OoC) models are in vitro alternatives that can recapitulate some aspects of the 3D tumour microenvironment and can be scaled up for drug screening. While many tumour OoC systems have been developed to date, there have been limited validation studies to ascertain whether drug responses obtained from tumour OoCs are comparable to those predicted from patient-derived xenograft (PDX) models. In this study, we established a multiplexed tumour OoC device, that consists of an 8 × 4 array (32-plex) of culture chamber coupled to a concentration gradient generator. The device enabled perfusion culture of primary PDX-derived tumour spheroids to obtain dose-dependent response of 5 distinct standard-of-care (SOC) chemotherapeutic drugs for 3 colorectal cancer (CRC) patients. The in vitro efficacies of the chemotherapeutic drugs were rank-ordered for individual patients and compared to the in vivo efficacy obtained from matched PDX models. We show that quantitative correlation analysis between the drug efficacies predicted via the microfluidic perfusion culture is predictive of response in animal PDX models. This is a first study showing a comparative framework to quantitatively correlate the drug response predictions made by a microfluidic tumour organ-on-chip (OoC) model with that of PDX animal models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ong, Chia, Wong, Zhang, Chua, Loo, Chua, Chua, Tan, Hentze, Tan, DasGupta and Toh.)

The consensus molecular subtype (CMS) classification of colorectal cancer is based on bulk transcriptomics. The underlying epithelial cell diversity remains unclear. We analyzed 373,058 single-cell transcriptomes from 63 patients, focusing on 49,155 epithelial cells. We identified a pervasive genetic and transcriptomic dichotomy of malignant cells, based on distinct gene expression, DNA copy number and gene regulatory network. We recapitulated these subtypes in bulk transcriptomes from 3,614 patients. The two intrinsic subtypes, iCMS2 and iCMS3, refine CMS. iCMS3 comprises microsatellite unstable (MSI-H) cancers and one-third of microsatellite-stable (MSS) tumors. iCMS3 MSS cancers are transcriptomically more similar to MSI-H cancers than to other MSS cancers. CMS4 cancers had either iCMS2 or iCMS3 epithelium; the latter had the worst prognosis. We defined the intrinsic epithelial axis of colorectal cancer and propose a refined 'IMF' classification with five subtypes, combining intrinsic epithelial subtype (I), microsatellite instability status (M) and fibrosis (F)., (© 2022. The Author(s).)

Metastatic colonization is the primary cause of death from colorectal cancer (CRC). We employed genome-scale in vivo short hairpin RNA (shRNA) screening and validation to identify 26 promoters of CRC liver colonization. Among these genes, we identified a cluster that contains multiple targetable genes, including ITPR3, which promoted liver-metastatic colonization and elicited similar downstream gene expression programs. ITPR3 is a caffeine-sensitive inositol 1,4,5-triphosphate (IP3) receptor that releases calcium from the endoplasmic reticulum and enhanced metastatic colonization by inducing expression of RELB, a transcription factor that is associated with non-canonical NF-κB signaling. Genetic, cell biological, pharmacologic, and clinical association studies revealed that ITPR3 and RELB drive CRC colony formation by promoting cell survival upon substratum detachment or hypoxic exposure. RELB was sufficient to drive colonization downstream of ITPR3. Our findings implicate the ITPR3/calcium/RELB axis in CRC metastatic colony formation and uncover multiple clinico-pathologically associated targetable proteins as drivers of CRC metastatic colonization., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: This cross-sectional observational study summarized the baseline characteristics of subjects who underwent COVID-19 molecular testing in a private medical centre located in the state of Selangor in Malaysia between 1 Oct 2020 and 31 Jan 2021. We compared the baseline characteristics between subjects who were tested positive and negative of SARS-CoV-2 infection, and identified risk factors which may be predictive of SARS-CoV-2 positivity., Methods and Findings: A total of 36603 subjects who were tested for COVID-19 infection via molecular assays at Sunway Medical Centre between Oct 1, 2020 and Jan 31, 2021, and consented to participate in this observation study were included for analysis. Descriptive statistics was used to summarize the study cohort, whereas logistic regression analysis was used to identify risk factors associated with SARS-CoV-2 positivity. Among the reasons listed for COVID-19 screening were those who needed clearance for travelling, clearance to return to work, or clearance prior to hospital admission. They accounted for 67.7% of tested subjects, followed by the self-referred group (27.3%). Most of the confirmed cases were asymptomatic (62.6%), had no travel history (99.6%), and had neither exposure to SARS-CoV-2 confirmed cases (61.9%) nor exposure to patients under investigation (82.7%) and disease clusters (89.2%). Those who presented with loss of smell or taste (OR: 26.91; 95% CI: 14.81-48.92, p<0.001), fever (OR:3.97; 95% CI: 2.54-6.20, p<0.001), running nose (OR: 1.75; 95% CI:1.10-2.79, p = 0.019) or other symptoms (OR: 5.63; 95% CI:1.68-18.91, p = 0.005) were significantly associated with SARS-CoV-2 positivity in the multivariate logistic regression analysis., Conclusion: Our study showed that majority of patients seeking COVID-19 testing in a private healthcare setting were mainly asymptomatic with low epidemiological risk. Consequently, the average positivity rate was 1.2% compared to the national cumulative positivity rate of 4.65%. Consistent with other studies, we found that loss of smell or taste, fever and running nose were associated with SARS-CoV-2 positivity. We believe that strengthening the capacity of private health institutions is important in the national battle against the COVID-19 pandemic, emphasizing the importance of public-private partnership to improve the quality of clinical care., Competing Interests: The authors have declared that no competing interests exist.

Colorectal cancer (CRC) is a leading cause of cancer mortality. Creatine metabolism was previously shown to critically regulate colon cancer progression. We report that RGX-202, an oral small-molecule SLC6A8 transporter inhibitor, robustly inhibits creatine import in vitro and in vivo, reduces intracellular phosphocreatine and ATP levels, and induces tumor apoptosis. RGX-202 suppressed CRC growth across KRAS wild-type and KRAS mutant xenograft, syngeneic, and patient-derived xenograft (PDX) tumors. Antitumor efficacy correlated with tumoral expression of creatine kinase B. Combining RGX-202 with 5-fluorouracil or the DHODH inhibitor leflunomide caused regressions of multiple colorectal xenograft and PDX tumors of distinct mutational backgrounds. RGX-202 also perturbed creatine metabolism in patients with metastatic CRC in a phase 1 trial, mirroring pharmacodynamic effects on creatine metabolism observed in mice. This is, to our knowledge, the first demonstration of preclinical and human pharmacodynamic activity for creatine metabolism targeting in oncology, thus revealing a critical therapeutic target.

Drug resistance is a major obstacle to the treatment of most human tumors. In this study, we find that dual-specificity phosphatase 16 (DUSP16) regulates resistance to chemotherapy in nasopharyngeal carcinoma, colorectal cancer, gastric and breast cancer. Cancer cells expressing higher DUSP16 are intrinsically more resistant to chemotherapy-induced cell death than cells with lower DUSP16 expression. Overexpression of DUSP16 in cancer cells leads to increased resistance to cell death upon chemotherapy treatment. In contrast, knockdown of DUSP16 in cancer cells increases their sensitivity to treatment. Mechanistically, DUSP16 inhibits JNK and p38 activation, thereby reducing BAX accumulation in mitochondria to reduce apoptosis. Analysis of patient survival in head & neck cancer and breast cancer patient cohorts supports DUSP16 as a marker for sensitivity to chemotherapy and therapeutic outcome. This study therefore identifies DUSP16 as a prognostic marker for the efficacy of chemotherapy, and as a therapeutic target for overcoming chemoresistance in cancer.

Colorectal cancer (CRC) is a major cause of human death. Mortality is primarily due to metastatic organ colonization, with the liver being the main organ affected. We modeled metastatic CRC (mCRC) liver colonization using patient-derived primary and metastatic tumor xenografts (PDX). Such PDX modeling predicted patient survival outcomes. In vivo selection of multiple PDXs for enhanced metastatic colonization capacity upregulated the gluconeogenic enzyme PCK1, which enhanced liver metastatic growth by driving pyrimidine nucleotide biosynthesis under hypoxia. Consistently, highly metastatic tumors upregulated multiple pyrimidine biosynthesis intermediary metabolites. Therapeutic inhibition of the pyrimidine biosynthetic enzyme DHODH with leflunomide substantially impaired CRC liver metastatic colonization and hypoxic growth. Our findings provide a potential mechanistic basis for the epidemiologic association of anti-gluconeogenic drugs with improved CRC metastasis outcomes, reveal the exploitation of a gluconeogenesis enzyme for pyrimidine biosynthesis under hypoxia, and implicate DHODH and PCK1 as metabolic therapeutic targets in CRC metastatic progression., Competing Interests: NY, EW, AN, ML, HG, YJ, PP, LS, TK, JL, Ed, ST No competing interests declared, (© 2019, Yamaguchi et al.)

Despite abundant data supporting c-Src as a metastasis-promoting oncogene, activating mutations of c-Src are rare. This suggests that trans-interacting proteins may have a critical role in regulating c-Src activation. Here, we first report the discovery of Src homology 3 (SH3) domain-binding glutamic acid-rich-like protein (SH3BGRL), a novel c-Src activator in mice. Ectopic expression of murine SH3BGRL (mSH3BGRL) strongly promoted both tumor cell invasion and lung metastasis. Molecularly, mSH3BGRL specifically bound the inactive form of c-Src phosphorylated at Tyr527, promoting Tyr416 phosphorylation of c-Src and subsequent FAK-mediated activation of ERK and AKT signaling pathways. Targeting endogenous c-Src alone was sufficient to abolish mSH3BGRL-induced cancer metastasis in vivo. Unexpectedly, human SH3BGRL (hSH3BGRL) in turn suppressed tumorigenesis and metastasis in nature. We attempted site-specific reversion of hSH3BGRL amino-acid sequence to mSH3BGRL and found V108A substitution sufficient to restore SH3BGRL function as a c-Src activator and metastasis promoter. Notably, the somatic mutation R76C of hSH3BGRL can similarly act as hSH3BGRL-V108A and mSH3BGRL in tumorigenesis and metastasis. Our results uncover an evolutionarily controversial role of SH3BGRL in driving tumor metastasis through c-Src activation, and suggests that hSH3BGRL mutation status could be relevant to cancer diagnosis and therapy.

The investigation of the interface between psychological constructs, compulsive consumption of alcohol and pathological gambling is an important avenue for development of future initiatives in social marketing or prevention programs. This cross-cultural study attempts to bridge the gap in literature by providing an evaluation of the predictive ability of psychological variables such as gambling urge, gambling-related erroneous cognitions and comorbid alcohol consumption on pathological gambling behaviour and its impact on overall quality of life indicators. Participants consist of 445 Macao and Australian young adults (Mean age = 23 years). Results indicate that probable pathological gamblers as compared with non-gamblers reported significantly lower quality of life in all domains-physical health, psychological well-being, social relationships and environment. Adults who drank more alcohol and have stronger erroneous cognitions evidenced higher pathological gambling behavior. Our research model fits both cohorts and interestingly, erroneous gambling-related cognitions serve as a full mediator for the predictive relationship between gambling urge and pathological gambling in the Macao sample, but serve as a partial mediator in the Australian sample. Targeting erroneous cognitions in future social marketing or preventive campaigns should demonstrate to be an important strategy in reducing the effects of urge to gamble among at-risk individuals. Further implications for the industry, marketing and governmental strategies are discussed.

Currently, cognitive behavioral therapies appear to be one of the most studied treatments for gambling problems and studies show it is effective in treating gambling problems. However, cognitive behavior models have not been widely tested using statistical means. Thus, the aim of this study was to test the validity of the pathways postulated in the cognitive behavioral theory of gambling behavior using structural equation modeling (AMOS 20). Several questionnaires assessing a range of gambling specific variables (e.g., gambling urges, cognitions and behaviors) and gambling correlates (e.g., psychological states, and coping styles) were distributed to 969 participants from the community. Results showed that negative psychological states (i.e., depression, anxiety and stress) only directly predicted gambling behavior, whereas gambling urges predicted gambling behavior directly as well as indirectly via gambling cognitions. Avoidance coping predicted gambling behavior only indirectly via gambling cognitions. Negative psychological states were significantly related to gambling cognitions as well as avoidance coping. In addition, significant gender differences were also found. The results provided confirmation for the validity of the pathways postulated in the cognitive behavioral theory of gambling behavior. It also highlighted the importance of gender differences in conceptualizing gambling behavior.

Colorectal cancer metastasis to the liver is a major cause of cancer-related death; however, the genes and pathways that govern this metastatic colonization event remain poorly characterized. Here, using a large-scale in vivo RNAi screen, we identified liver and red blood cell pyruvate kinase (PKLR) as a driver of metastatic liver colonization. PKLR expression was increased in liver metastases as well as in primary colorectal tumors of patients with metastatic disease. Evaluation of a murine liver colonization model revealed that PKLR promotes cell survival in the tumor core during conditions of high cell density and oxygen deprivation by increasing glutathione, the primary endogenous antioxidant. PKLR negatively regulated the glycolytic activity of PKM2, the major pyruvate kinase isoenzyme known to regulate cellular glutathione levels. Glutathione is critical for metastasis, and we determined that the rate-limiting enzyme of glutathione synthesis, GCLC, becomes overexpressed in patient liver metastases, promotes cell survival under hypoxic and cell-dense conditions, and mediates metastatic liver colonization. RNAi-mediated inhibition of glutathione synthesis impaired survival of multiple colon cancer cell lines, and pharmacological targeting of this metabolic pathway reduced colonization in a primary patient-derived xenograft model. Our findings highlight the impact of metabolic reprogramming within the niche as metastases progress and suggest clinical potential for targeting this pathway in colorectal cancer.

Problem gambling and sleep difficulty threaten health. Using the basis of self-regulatory theory, potential mechanisms for these problems were investigated. Fifty-nine treatment-seeking gamblers completed the Pittsburgh Sleep Quality Index (sleep difficulty), the Sleep Hygiene Index (negative sleep habits), the Problem Gambling Severity Index and measures of self-regulatory capacity and arousability with data entered into regression analyses. Results supported the relationship between problem gambling and greater sleep difficulty (β = .18, t = 3.22, p < .01). Self-regulatory capacity mediated the relationship between problem gambling and sleep difficulty (R (2) change = .15, F(2, 57) = 12.14, β = -.45, t = -3.45, p < .001) as well as between problem gambling and negative sleep habits; R (2) change = .17, F(2, 57) = 13.57, β = -.28, t = -3.76, p < .001. Arousability predicted sleep difficulty (β = .15, t = 3.07, p < .01) and negative sleep habits (β = .40, t = 5.40, p < .01) but showed no relationship with problem gambling (r = .09, ns). Self-regulatory capacity represents an important mediator of the relationship between problem gambling and sleep-related behaviour and if targeted could reduce behavioural threats to health.

Colorectal cancer primarily metastasizes to the liver and globally kills over 600,000 people annually. By functionally screening 661 microRNAs (miRNAs) in parallel during liver colonization, we have identified miR-551a and miR-483 as robust endogenous suppressors of liver colonization and metastasis. These miRNAs convergently target creatine kinase, brain-type (CKB), which phosphorylates the metabolite creatine, to generate phosphocreatine. CKB is released into the extracellular space by metastatic cells encountering hepatic hypoxia and catalyzes production of phosphocreatine, which is imported through the SLC6A8 transporter and used to generate ATP—fueling metastatic survival. Combinatorial therapeutic viral delivery of miR-551a and miR-483-5p through single-dose adeno-associated viral (AAV) delivery significantly suppressed colon cancer metastasis, as did CKB inhibition with a small-molecule inhibitor. Importantly, human liver metastases express higher CKB and SLC6A8 levels and reduced miR-551a/miR-483 levels relative to primary tumors. We identify the extracellular space as an important compartment for malignant energetic catalysis and therapeutic targeting., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The majority of prevention and intervention research in problem gambling (PG) has focused on identifying negative risk factors. However, not all at-risk individuals go on to develop anticipated disorders and many thrive in spite of them. In healthcare settings, PG and other disorders are typically conceptualized from the biomedical perspective that frame disorders as something negative residing within the individual and reduction in negativity is seen as success. Indeed, this problem-focused conceptualization may be adequate in many cases as reducing PG behaviour is undoubtedly an important outcome, but the focus on negativity alone is too narrow to capture the complexity of human behaviour. Hence, this study attempts to bridge the gap in literature by providing an evaluation of the predictive ability of the positive dispositions on problem gambling severity, gambling-related cognitions, and gambling urges. The positive psychological dispositions examined were curiosity, gratitude, hope, personal growth initiative, and mindfulness. Participants consisted of 801 Taiwanese Chinese students and community individuals (Mean age = 25.36 years). Higher levels of gratitude and hope have been found to predict lower PG, gambling-related cognitions, or gambling urges. Meanwhile, higher mindfulness predicted lower PG, but only among Chinese males. However, lower personal growth initiative predicted lower PG, gambling-related cognitions, and gambling urges. These analyses have small to medium effect sizes with significant predictions. Findings of this study have essential implications in understanding and treating Chinese problem gamblers. These positive dispositions should be addressed by mental health professionals in preventative and treatment programs among Chinese individuals. Further implications and suggestions for future research are discussed.

The purpose of this study was to examine the psychometric properties of the Chinese 9-item Problem Gambling Severity Index (PGSI) derived from the 31-item Canadian Problem Gambling Index (CPGI) originally developed by Ferris and Wynne (2001). Exploratory factor analysis (EFA; n = 386; Group A data) and confirmatory factor analysis (CFA; n = 387; Group B data) on the Chinese student and community data (Mean age = 25.36 years) showed that a unifactorial model fitted the data with good reliability score (Cronbach's alpha = 0.77). The concurrent validity of the PGSI-C was good in terms of the Chinese data matching the expected correlation between PGSI-C and other variables or scales such as SOGS, gambling frequency, gambling urge, gambling cognitions, depression, anxiety, and stress. The scale also reported good discriminant and predictive validity. In sum, the PGSI-C has good psychometric properties and can be used among Chinese communities to identify at-risk problem gamblers. Implications and suggestions for future research are discussed.

Overexpression of phosphatase of regenerating liver (PRL)-3 is associated with the progression of diverse human cancers. We show that the overexpression of PRL-3 protein is not directly associated with its transcript levels, indicating the existence of an underlying posttranscriptional regulation. The 5' untranslanted region (UTR) of PRL-3 mRNA possesses triple GCCCAG motifs capable of suppressing mRNA translation through interaction with PolyC-RNA-binding protein 1 (PCBP1), which retards PRL-3 mRNA transcript incorporation into polyribosomes. Overexpression of PCBP1 inhibits PRL-3 expression and inactivates AKT, whereas knockdown of PCBP1 causes upregulation of PRL-3 protein levels, activation of AKT, and promotion of tumorigenesis. An inverse correlation between protein levels of PRL-3 and PCBP1 in human primary cancers supports the clinical relevance., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Despite being a significant issue, there has been a lack of systematic reviews on gambling and problem gambling (PG) among the Chinese. Thus, this paper attempts to fill this theoretical gap. A literature search of social sciences databases (from 1840 to now) yielded 25 articles with a total sample of 12,848 Chinese community participants and 3397 clinical participants. The major findings were: (1) Social gambling is widespread among Chinese communities as it is a preferred form of entertainment. (2) Prevalence estimates for PG have increased over the years and currently ranged from 2.5% to 4.0%. (3) Chinese problem gamblers consistently have difficulty admitting their issue and seeking professional help for fear of losing respect. (4) Theories, assessments, and interventions developed in the West are currently used to explain and treat PG among the Chinese. There is an urgent need for theory-based interventions specifically tailored for Chinese problem gamblers. (5) Cultural differences exist in patterns of gambling when compared with Western samples; however, evidence is inconsistent. Methodological considerations in this area of research are highlighted and suggestions for further investigation are also included. (6) Much of gambling research has focused on identifying risk factors and at-risk individuals. It is essential to balance this knowledge with a focus on fundamental character strengths, which act as protective factors and motivate one to refrain from gambling.

Catecholamines (dopamine, norepinephrine, and epinephrine) are all synthesized from a common pathway in which tyrosine hydroxylase (TH) is the rate-limiting enzyme. Dopamine is the main neurotransmitter present in dopaminergic neurons of the ventral midbrain, where dysfunction of these neurons can lead to Parkinson's disease and schizophrenia. Neuronal PAS domain protein 1 (NPAS1) was identified as one of the genes up-regulated during dopaminergic MN9D cell differentiation. We found that there was a corresponding decrease in TH level during MN9D differentiation. Overexpression and siRNA experiments revealed that NPAS1, in concert with ARNT, negatively regulates the expression of TH and that this regulation is mediated by a direct binding of NPAS1 on the TH promoter. Expression studies also confirmed a decrease in TH level in the ventral midbrain during mouse development, concomitant with an increase in NPAS1 level. These results suggest that NPAS1 plays a novel and important role in regulating TH level of dopaminergic neurons in the ventral midbrain during development., (Copyright (c) 2007 Wiley-Liss, Inc.)

Neuronal PAS domain protein 1 (NPAS1), a basic helix-loop-helix-PAS transcription factor expressed in the central nervous system, has been suggested to be involved in neuronal differentiation. However, relatively little is known about the molecular mechanism underlying the role of NPAS1 during development. In this study we set out to characterize the different domains within NPAS1. We showed that the nuclear localization of NPAS1 is dependent on the presence of ARNT. In addition, the transcriptional potential of ARNT is not required for this localization. In the absence of ARNT, NPAS1 is excluded from the nucleus, and this exclusion is due to the presence of a nuclear export signal within the N terminus of NPAS1. The interaction between NPAS1 and ARNT is via their N termini. We found no transactivation domain within NPAS1; instead, we mapped out at least three repression domains within NPAS1, suggesting that NPAS1 acts as a repressor. Furthermore, our experiments showed that NPAS1 is able to repress the transactivation functions of ARNT and ARNT2. We suggest that NPAS1 is guided into the nucleus by ARNT via the ARNT nuclear localization signal, and NPAS1 can override the activation function of adjacent transcription factors, providing a mechanism by which NPAS1 may inhibit transcription.

An exhaustive search of the literature on the growth of mold on fiberglass insulation materials was conducted. Because of the paucity of published material, both peer-reviewed and non-peer-reviewed articles were included. The literature indicates that fiberglass can serve as a support matrix for the collection of debris which, when moist, have the capability of supporting the growth of mold. Further, binding and paper-based moisture barriers from fiberglass resins are also capable of supporting the growth of mold when moist.

The aim of the present study was to investigate the influence of a 25-min time interval between the first and the last reading of a series of six, on systolic (SBP) and Phase V diastolic (DBP) blood pressure and its implications for prevalence rates of hypertension. Readings were taken from 5999 persons (2889 men and 3110 women) by two observers using a Hawksley random-zero sphygmomanometer. The first reading was taken 5 min after entering the examining room. The study showed a considerable fall in mean SBP (men, 10.3 mmHg; women, 10.4 mmHg) and hardly a difference in mean DBP (men, 0.8 mmHg; women, 0.1 mmHg) between the first and sixth reading. The fall in SBP was independent of observer and sex and hardly correlated with age or Quetelet's index. The study also showed the implications for the classification of hypertension. Prevalence rates of isolated systolic hypertension dropped remarkably (men, 4.0 to 0.5%; women, 0.9 to 0.1%) between both readings while prevalence rates of severe, moderate and mild diastolic hypertension were nearly similar for the first and sixth reading.