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.
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•miR-551a and miR-483-5p suppress colon cancer metastasis by targeting CKB•CKB promote metastatic survival by modulating intra- and extracellular energetics•miRNAs and CKB can be therapeutically targeted by AAV and small molecule delivery
The tumor microenvironment is a rich source of metabolic substrates that could be utilized by cancer cells. Colon cancer cells secrete a kinase that acts extracellularly to generate one such metabolite, phosphocreatinine, that directly fuels tumor growth and metastasis to the liver.
Tuning in to Kids (TIK) is a parenting program that focuses on emotion coaching and is evidenced to be effective in Western populations. This study used a randomized controlled trial to examine the ...intervention effects of TIK on Chinese parents of low to middle socioeconomic status in Hong Kong. One hundred four parents (99 mothers and five fathers; Mage in years = 37.92) of preschoolers aged 3-6 years were randomly assigned to the experimental (n = 54) or waitlist control group (n = 50). Parent and child outcomes were assessed at baseline (Time 1), immediately after the 6-week intervention (Time 2), and 6 weeks postintervention (Time 3), using the Alabama Parenting Questionnaire, Coping with Children's Negative Emotions Scale, Parenting Stress Index-Short Form, and Emotion Regulation Checklist. The experimental group reported significant reductions in punitive parenting and parenting stress at Time 2, and these effects were maintained at Time 3. Delayed improvements in parents' use of expressive encouragement and children's emotion lability/negativity were observed at Time 3 in the experimental group. The immediate intervention effects were replicated in the waitlist control group at Time 3 after they attended the training. This study represented one of the few randomized controlled trials of TIK conducted in a non-Western sample. Our results corroborated the findings of prior studies of TIK and provided preliminary support for its effectiveness across different cultural contexts.
High expressed emotion (EE) in a patient's family is a known risk factor of relapse in schizophrenia. The three components of high EE – criticism, hostility and emotional over-involvement – were ...developed through a data-driven approach and a focus on overt abrasive behaviours. The influence of covert abrasive behaviours has not been explored.
This study aims to explore both overt and covert abrasive behaviours through semi-structured interviews conducted with 22 people with schizophrenia, who were recruited through iterative purposive sampling.
Thematic analysis suggests that participants' experiences of overt abrasive behaviours resonate with the three-factor structure of high EE, except “emotional over-involvement” is renamed to “over-involvement” to focus on behaviours and embrace different levels or types of emotional reactions. Regarding covert abrasive behaviours, two domains are proposed: disassociation and apathy, which focus on family members' disengaging actions and indifferent attitudes respectively. While both overt and covert abrasive behaviours cause psychological distresses and behavioural reactions on the participants, their precise impacts are not entirely the same.
People with schizophrenia experience both overt and covert abrasive behaviours with family members. The findings of this study may expand the conceptualization of high EE, enhance its content validity, and provide an extended conceptual framework for developing more comprehensive measures.
Schizophrenia; Relapse; Expressed emotions; Covert abrasive behaviours; Ostracism; Psychiatry; Diagnostics; Psychology; Mental health; Psychological disorders; Interpersonal relations; Psychometrics; Well-being
Lynch syndrome is an autosomal dominant condition caused by pathogenic mutations in the DNA mismatch repair (MMR) genes. Although commonly associated with clinical features such as intellectual ...disability and congenital anomalies, contiguous gene deletions may also result in cancer predisposition syndromes. We report on a 52-year-old male with Lynch syndrome caused by deletion of chromosome 2p16.3-p21. The patient had intellectual disability and presented with a prostatic adenocarcinoma with an incidentally identified synchronous sigmoid adenocarcinoma that exhibited deficient MMR with an absence of MSH2 and MSH6 protein expression. Family history was unrevealing. Physical exam revealed short stature, brachycephaly with a narrow forehead and short philtrum, brachydactyly of the hands, palmar transverse crease, broad and small feet with hyperpigmentation of the soles. The patient underwent total colectomy with ileorectal anastomosis for a pT3N1 sigmoid adenocarcinoma. Germline genetic testing of the
MSH2, MSH6
, and
EPCAM
genes revealed full gene deletions. SNP-array based DNA copy number analysis identified a deletion of 4.8 Mb at 2p16.3-p21. In addition to the three Lynch syndrome associated genes, the deleted chromosomal section encompassed genes including
NRXN1, CRIPT, CALM2, FBXO11, LHCGR, MCFD2, TTC7A, EPAS1, PRKCE
, and 15 others. Contiguous gene deletions have been described in other inherited cancer predisposition syndromes, such as Familial Adenomatous Polyposis. Our report and review of the literature suggests that contiguous gene deletion within the 2p16-p21 chromosomal region is a rare cause of Lynch syndrome, but presents with distinct phenotypic features, highlighting the need for recognition and awareness of this syndromic entity.
With increased prevalence of obesity, the number of inflammatory bowel disease (IBD) patients suffering from morbid obesity has raised. It is not clear yet if bariatric surgery is a safe and ...effective option in this population.
Our systematic review aims to summarize the available literature on the safety and efficacy of bariatric surgery in morbidly obese patients with IBD.
University hospital, Iran.
A PubMed/MEDLINE search was performed to identify studies reporting the outcome of morbidly obese IBD patients. Postoperative outcome of IBD patients after bariatric surgery were pooled for early and late complications, change of IBD status, and medication alteration.
A total of 7 studies reported post-bariatric surgery outcomes of 43 morbidly obese IBD patients (31 females, 11 males) with an age ranging from 30 to 64 years and a body mass index from 35.7 to 71 kg/m
. Of these, 25 suffered Crohn's disease (CD) (58.2%) and 18 were ulcerative colitis (UC) patients (41.8%). The small bowel was the most common involved gastrointestinal segment in 27.3% of patients. CD patients more commonly underwent sleeve gastrectomy (72%), while UC patients similarly underwent sleeve gastrectomy and Roux-en-Y gastric bypass (44.4%). After a follow-up of 8 to 77 months, IBD patients lost up to 71.4%±5.9% of excess weight and 14.3 kg/m
±5.7 kg/m
of body mass index. There were 9 early (21.4%) and 10 late (23.8%) postoperative complications related to the bariatric procedure. IBD remitted in 20 patients (47.6%), improved in 2 patients (4.8%), but exacerbated in 7 patients (16.7%).
Although available data on morbidly obese patients with IBD is scarce, bariatric surgery seems to be a safe and effective option for these patients with no added morbidity or mortality. Further studies are necessary to confirm this data.
During COVID-19 pandemic, people experienced lockdown and associated distress. As face-to-face intervention was unfeasible, an 8-week Strength-based Online Community Intervention (SOCI) was developed ...and evaluated with a quasi-experimental design in Hubei Province, China from February to April 2020. Participants (N = 150) self-elected to join either the SOCI group or a casual discussion control group. Pre-/post-measures on post-traumatic stress, positive and negative affect, resilience, and spirituality were taken. Multivariate ANOVA revealed a significant combined effect with a medium effect size (partial eta squared = 0.11). Specifically, significant group × time interaction effects were revealed for resilience, spirituality, and positive affect.
A new analytical procedure is developed using a strong complexing agent, 1,10‐phenanthroline (Phen), for direct UV detection of Zn, Mn, Cu, Co, Cd, and Fe at νg/L concentrations in environmental ...water samples. The metal chelates formed showed different electrophoretic mobilities and solved the comigration problem for capillary electrophoresis (CE) separation of free metal ions. To obtain stable metal‐Phen chelates during the capillary zone electrophoresis (CZE) run, both pre‐column and on‐column complexation are required and threefold excess of Phen over metal ions should be added to the sample. The optimized background electrolyte (BGE) consists of 30 mM hydroxylamine hydrochloride and 0.1% methanol at pH 3.6. Under hydrodynamic sampling, CE run at + 20 kV in 65 cm×0.05 mm ID fused‐silica column with detection at 265 nm, baseline separation, satisfactory working ranges (10 νg/L to 5.5 mg/L), sensitive detection limits (1–3 νg/L), good repeatability for migration times (relative standard deviation, RSD 0.36–0.81%, n = 5), peak area (RSD 3.2–4.2%, n = 5) and peak height (RSD 3.2–4.5%, n = 5) were obtained for the metal cations investigated. The reliability of the method was established by parallel determination using the inductively coupled plasma‐atomic emission spectrometry (ICP‐AES) method giving results within statistical variation. The procedure developed is shown to provide a quick, sensitive, precise, and economic method for simultaneous determination of metal cations that can form stable chelates with Phen.
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.
Growing evidence indicates that family-based mind-body therapy programs (FMBTs) act as an important alternative for attention-deficit/hyperactivity disorder (ADHD) treatment in the youth with minimal ...side-effects. Moreover, FMBTs contribute to improving the family functioning of those affected by ADHD. To summarize and analyze the benefits and mechanisms, an extensive literature search of the EBSCOhost, PubMed, Web of Science, and Scopus databases was conducted to identify eligible studies. Fifteen studies published between 2010–2023 were reviewed. The included FMBTs were implemented with 850 children/adolescents and 996 parents/caregivers, of whom 201 parent couples attended the programs together with their children. All included FMBTs adopted mindfulness/meditation as the core practice to enhance the participants’ mental focus and attention, and were designed for long-term engagement, with six including parent–child joint session(s). Positive changes were observed in both children and adolescents, including improvements in ADHD symptoms, behavioral problems, executive function, and school performance. Additionally, parents experienced positive changes in ADHD traits/symptoms, mental health, and parenting behaviors. Furthermore, FMBTs were found to enhance family functioning by delivering mindful strategies to family, restoring psychological capacity and interpersonal skills in family members, and improving parent–child relationships. The reviewed FMBTs demonstrated high levels of feasibility and participant satisfaction. The factors and issues potentially influencing the effectiveness and feasibility of FMBTs are also discussed. The findings indicate that FMBT holds promise as an ADHD treatment option in home settings. Future efforts may focus on optimizing the design of FMBTs to better address the diverse needs of families in varying circumstances.
To meet the need for a new and validated analytical method for simultaneous determination of inorganic and organic acid anions in beverage drinks, a capillary zone electrophoresis (CZE) procedure had ...been developed based on a new background electrolyte (BGE) system containing 3 mmol/L 1,3,5‐benzenetricarboxylic acid (BTA), 15 mmol/L tris(hydroxymethyl)aminomethane and 1.5 mmol/L tetraethylenepentamine (TEPA) at pH 8.4. Baseline separation of anions commonly found in beverage drinks could be achieved in less than 14 min with indirect UV detection at 240 nm. Comigration problems for hydroxycarboxylic acids could be solved using TEPA as BGE additive. The results indicate excellent repeatability for migration time (RSD, 0.27–0.67%, n = 5) and good precision for both peak height (RSD, 3.2–4.2%, n = 5) and peak area (RSD, 3.1–4.5%, n = 5). Under the optimized conditions and using corrected peak area for quantitation, an excellent linear dynamic range (with correlation coefficient > 0.997 in a concentration range from 0.005 to 2.0 mmol/L) and low detection limit (1–4 μmol/L) were obtained for all the anions investigated. The applicability and reliability of the CE procedure developed were established by parallel method determination using established ion chromatography procedure for the analysis of inorganic and organic acid anions in orange juice and wine samples. Our CZE procedure provided a sensitive and economic technique for simultaneous determination of inorganic and organic acid anions in orange juice, red and white wine samples.
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