Health-state utility of patients with HER2-positive breast cancer in Vietnam: A multicenter cross-sectional study.

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer may have poor prognoses and short overall and disease-free survival. Most previous studies focused on assessing the quality of life and health-state utility of the general population of breast cancer patients. The number of studies for HER2-positive breast cancer patients is negligible. This study investigated the health-state utility and its associated factors among Vietnamese patients with HER2-positive breast cancer. METHODS: We conducted face-to-face interviews with 301 HER2-positive breast cancer patients to collect data. Their health-state utility was measured via the EQ-5D-5L instrument. The Mann-Whitney U and Kruskal-Wallis tests were employed to compare the differences in utility scores between two groups and among three groups or more, respectively. Factors associated with patients' heath-state utility were identified via Tobit regression models. RESULTS: Pain/discomfort (56.1%) and anxiety/depression (39.5%) were the two issues that patients suffered from the most, especially among metastatic breast cancer patients. The severity of distress (depression, anxiety, and stress) in patients was relatively mild. Of 301 patients, their average utility score was 0.86±0.17 (range: 0.03-1.00), and the average EQ-visual analogue scale (VAS) score was 69.12±12.60 (range: 30-100). These figures were 0.79±0.21 and 65.20±13.20 for 102 metastatic breast cancer patients, significantly lower than those of 199 non-metastatic cancer patients (0.89±0.13 and 71.13±11.78) (p<0.001), respectively. Lower health-state utility scores were significantly associated with older age (p = 0.002), lower education level (p = 0.006), lower monthly income (p = 0.036), metastatic cancer (p = 0.001), lower EQ-VAS score (p<0.001), and more severe level of distress (p<0.001). CONCLUSIONS: Our findings showed a significant decrement in utility scores among metastatic breast cancer patients. Patients' health-state utility differed by their demographic characteristics (age, education level, and income) and clinical characteristics (stage of cancer and distress). Their utility scores may support further cost-effectiveness analysis in Vietnam.

Key lifestyles and health outcomes across 16 prevalent chronic diseases: A network analysis of an international observational study.

Background: Central and bridge nodes can drive significant overall improvements within their respective networks. We aimed to identify them in 16 prevalent chronic diseases during the coronavirus disease 2019 (COVID-19) pandemic to guide effective intervention strategies and appropriate resource allocation for most significant holistic lifestyle and health improvements. Methods: We surveyed 16 512 adults from July 2020 to August 2021 in 30 territories. Participants self-reported their medical histories and the perceived impact of COVID-19 on 18 lifestyle factors and 13 health outcomes. For each disease subgroup, we generated lifestyle, health outcome, and bridge networks. Variables with the highest centrality indices in each were identified central or bridge. We validated these networks using nonparametric and case-dropping subset bootstrapping and confirmed central and bridge variables' significantly higher indices through a centrality difference test. Findings: Among the 48 networks, 44 were validated (all correlation-stability coefficients >0.25). Six central lifestyle factors were identified: less consumption of snacks (for the chronic disease: anxiety), less sugary drinks (cancer, gastric ulcer, hypertension, insomnia, and pre-diabetes), less smoking tobacco (chronic obstructive pulmonary disease), frequency of exercise (depression and fatty liver disease), duration of exercise (irritable bowel syndrome), and overall amount of exercise (autoimmune disease, diabetes, eczema, heart attack, and high cholesterol). Two central health outcomes emerged: less emotional distress (chronic obstructive pulmonary disease, eczema, fatty liver disease, gastric ulcer, heart attack, high cholesterol, hypertension, insomnia, and pre-diabetes) and quality of life (anxiety, autoimmune disease, cancer, depression, diabetes, and irritable bowel syndrome). Four bridge lifestyles were identified: consumption of fruits and vegetables (diabetes, high cholesterol, hypertension, and insomnia), less duration of sitting (eczema, fatty liver disease, and heart attack), frequency of exercise (autoimmune disease, depression, and heart attack), and overall amount of exercise (anxiety, gastric ulcer, and insomnia). The centrality difference test showed the central and bridge variables had significantly higher centrality indices than others in their networks (P < 0.05). Conclusion: To effectively manage chronic diseases during the COVID-19 pandemic, enhanced interventions and optimised resource allocation toward central lifestyle factors, health outcomes, and bridge lifestyles are paramount. The key variables shared across chronic diseases emphasise the importance of coordinated intervention strategies.

A Comprehensive Evaluation of Dioxins and Furans Occurrence in River Sediments from a Secondary Steel Recycling Craft Village in Northern Vietnam.

This first study investigated the presence of dioxins and furans in river sediments around a craft village in Vietnam, focusing on Secondary Steel Recycling. Sediment samples were collected from various locations along the riverbed near the Da Hoi Secondary Steel Recycling village in Bac Ninh province. The analysis was conducted using a HRGC/HRMS-DFS device, detecting a total of 17 dioxin/furan isomers in all samples, with an average total concentration of 288.86 ng/kg d.w. The concentrations of dioxin/furan congeners showed minimal variation among sediment samples, ranging from 253.9 to 344.2 ng/kg d.w. The predominant compounds in the dioxin group were OCDD, while in the furan group, they were 1,2,3,4,6,7,8-HpCDF and OCDF. The chlorine content in the molecule appeared to be closely related to the concentration of dioxins and their percentage distribution. However, the levels of furan isomers did not vary significantly. The distribution of these compounds was not dependent on the flow direction, as they were mainly found in solid waste and are not water-soluble. Although the hepta and octa congeners had high concentrations, when converted to TEQ values, the tetra and penta groups (for dioxins) and the penta and hexa groups (for furans) contributed more to toxicity. Furthermore, the source of dioxins in sediments at Da Hoi does not only originate from steel recycling production activities but also from other combustion sites. The average total toxicity was 10.92 ng TEQ/kg d.w, ranging from 4.99 to 17.88 ng TEQ/kg d.w, which did not exceed the threshold specified in QCVN 43:2017/BTNMT, the National Technical Regulation on Sediment Quality. Nonetheless, these levels are still concerning. The presence of these toxic substances not only impacts aquatic organisms in the sampled water environment but also poses potential health risks to residents living nearby.

Neurokinin-2 receptor negatively modulates substance P responses by forming complex with Neurokinin-1 receptor.

BACKGROUND: Tachykinins and their cognate receptors, neurokinin receptors (NKs) including NK1, NK2, and NK3 play vital roles in regulating various physiological processes including neurotransmission, nociception, inflammation, smooth muscle contractility, and stimulation of endocrine and exocrine gland secretion. Their abnormal expression has been reported to be associated with neurological disorders, inflammation, and cancer. Even though NKs are expressed in the same cells with their expression being inversely correlated in some conditions, there is no direct evidence to prove their interaction. Understanding the functional crosstalk between NKs in mediated downstream signaling and cellular responses may elucidate the roles of each receptor in pathophysiology. RESULTS: In this study, we showed that NKs were co-expressed in some cells. However, different from NK3, which only forms homodimerization, we demonstrated a direct interaction between NK1 and NK2 at the protein level using co-immunoprecipitation and NanoBiT-based protein interaction analysis. Through heterodimerization, NK2 downregulated substance P-stimulated NK1 signals, such as intracellular Ca2+ mobilization and ERK phosphorylation, by enhancing ß-arrestin recruitment, even at the ligand concentration that could not activate NK2 itself or in the presence of NK1 specific antagonist, aprepitant. In A549 cells with receptors deleted and reconstituted, NK2 exerted a negative effect on substance P/NK1-mediated cell migration. CONCLUSION: Our study has provided the first direct evidence of an interaction between NK1 and NK2, which highlights the functional relevance of their heterodimerization in cellular responses. Our findings demonstrated that through dimerization, NK2 exerts negative effects on downstream signaling and cellular response mediated by NK1. Moreover, this study has significant implications for understanding the complexity of GPCR dimerization and its effect on downstream signaling and cellular responses. Given the important roles of tachykinins and NKs in pathophysiology, these insights may provide clues for developing NKs-targeting drugs.

Global impacts of COVID-19 on lifestyles and health and preparation preferences: An international survey of 30 countries.

Background: The health area being greatest impacted by coronavirus disease 2019 (COVID-19) and residents' perspective to better prepare for future pandemic remain unknown. We aimed to assess and make cross-country and cross-region comparisons of the global impacts of COVID-19 and preparation preferences of pandemic. Methods: We recruited adults in 30 countries covering all World Health Organization (WHO) regions from July 2020 to August 2021. 5 Likert-point scales were used to measure their perceived change in 32 aspects due to COVID-19 (-2 = substantially reduced to 2 = substantially increased) and perceived importance of 13 preparations (1 = not important to 5 = extremely important). Samples were stratified by age and gender in the corresponding countries. Multidimensional preference analysis displays disparities between 30 countries, WHO regions, economic development levels, and COVID-19 severity levels. Results: 16 512 adults participated, with 10 351 females. Among 32 aspects of impact, the most affected were having a meal at home (mean (m) = 0.84, standard error (SE) = 0.01), cooking at home (m = 0.78, SE = 0.01), social activities (m = -0.68, SE = 0.01), duration of screen time (m = 0.67, SE = 0.01), and duration of sitting (m = 0.59, SE = 0.01). Alcohol (m = -0.36, SE = 0.01) and tobacco (m = -0.38, SE = 0.01) consumption declined moderately. Among 13 preparations, respondents rated medicine delivery (m = 3.50, SE = 0.01), getting prescribed medicine in a hospital visit / follow-up in a community pharmacy (m = 3.37, SE = 0.01), and online shopping (m = 3.33, SE = 0.02) as the most important. The multidimensional preference analysis showed the European Region, Region of the Americas, Western Pacific Region and countries with a high-income level or medium to high COVID-19 severity were more adversely impacted on sitting and screen time duration and social activities, whereas other regions and countries experienced more cooking and eating at home. Countries with a high-income level or medium to high COVID-19 severity reported higher perceived mental burden and emotional distress. Except for low- and lower-middle-income countries, medicine delivery was always prioritised. Conclusions: Global increasing sitting and screen time and limiting social activities deserve as much attention as mental health. Besides, the pandemic has ushered in a notable enhancement in lifestyle of home cooking and eating, while simultaneously reducing the consumption of tobacco and alcohol. A health care system and technological infrastructure that facilitate medicine delivery, medicine prescription, and online shopping are priorities for coping with future pandemics.

The N-terminus of CXCR4 splice variants determines expression and functional properties.

C-X-C motif chemokine ligand 12(CXCL12) is an essential chemokine for organ development and homeostasis in multiple tissues. Its receptor, C-X-C chemokine receptor type 4(CXCR4), is expressed on the surface of target cells. The chemokine and receptor are expressed almost ubiquitously in human tissues and cells throughout life, and abnormal expression of CXCL12 and CXCR4 is observed in pathological conditions, such as inflammation and cancer. CXCR4 is reportedly translated into five splicing variants of different lengths, which each have different amino acids in the N-terminus. As the N-terminus is the first recognition site for chemokines, CXCR4 variants may respond differently to CXCL12. Despite these differences, the molecular and functional properties of CXCR4 variants have not been thoroughly described or compared. Here, we explored the expression of CXCR4 variants in cell lines and analyzed their roles in cellular responses using biochemical approaches. RT-PCR revealed that most cell lines express more than one CXCR4 variant. When expressed in HEK293 cells, the CXCR4 variants differed in protein expression efficiency and cell surface localization. Although variant 2 demonstrated the strongest expression and cell surface localization, variants 1, 3, and 5 also mediated chemokine signaling and induced cellular responses. Our results demonstrate that the N-terminal sequences of each CXCR4 variant determine the expression of the receptor and affect ligand recognition. Functional analyses revealed that CXCR4 variants may also affect each other or interact during CXCL12-stimulated cellular responses. Altogether, our results suggest that CXCR4 variants may have distinct functional roles that warrant additional investigation and could contribute to future development of novel drug interventions.

Clinical, cytological and ultrasonographic features of incidental thyroid cancer in a hospital-based study in vietnam.

INTRODUCTION: Thyroid nodules are common diseases of the endocrine system, with a 5% prevalence rate in the general population. This study aimed to identify prevalence, clinical, cytological and ultrasonographic features of incidental thyroid cancer and its associated factors in Vietnam. METHODS: This cross-sectional descriptive study consisted of 208 patients with incidental thyroid nodules detected by ultrasound at the Endocrinology Department, Bach Mai Hospital, Hanoi, Vietnam between November 2019 and August 2020. Clinical information, sonography characteristics of thyroid nodules, results of fine-needle aspiration biopsy (FNAB), postoperative pathology and lymph node metastasis were collected. A multiple logistic regression model was used to estimate factors associated with thyroid cancer. RESULTS: A total of 272 thyroid nodules (from 208 participants) were included in this study. The mean age was 47.2 ± 12.0 (years). The rate of incidental thyroid cancer patients detected was 17.3%. Nodules <1 cm in size were significantly more prevalent for malignant nodules. The size of more than half of thyroid cancer nodules was 0.50-0.99 cm. Postoperative pathology of all nodules with Bethesda V and VI was papillary thyroid cancer which was consistent with cytological results. 33.3% of thyroid cancer patients have lymph node metastasis. The regression model showed that thyroid cancer was more likely to occur at a younger age (≤ 45 years vs. >45 years, OR 2.8; 95% CI: 1.3-6.1), taller-than-wide nodules (OR 6.8; 95% CI: 2.3-20.2) and hypo-echoic nodules (OR 5.2; 95% CI: 1.7-15.9). CONCLUSION: The study showed that the prevalence of incidental thyroid cancers was 17.3%, of which 100% was papillary carcinoma. People under the age of 45 and the presence of ultrasound characteristics, such as taller-than-wide and hypoechoic nodules increased risk for malignancy.

Symptom Burden among Hospitalised Older Patients with Heart Failure in Hanoi, Vietnam.

This study aimed to assess the symptom burden among older patients hospitalised for heart failure. This hospital-based, cross-sectional study was conducted at the National Geriatric Hospital, Hanoi, Vietnam, from June 2019 to August 2020. Face-to-face interviews were performed to gather the following information: socio-demographic characteristics, heart failure classification, and clinical characteristics (comorbidities, polypharmacy, pro-B-type natriuretic peptide, left ventricular ejection fraction (LVEF), symptom burden, and depression). Symptom burden was assessed using the Edmonton Symptom Assessment Scale (ESAS), and depression was measured using the Patient Health Questionnaire. A total of 314 patients participated in the study. The mean participant age was 72.67 (SD = 9.42) years. The most frequently reported symptoms on the ESAS were shortness of breath (95.5%), fatigue (94.8%), and anxiety (81.2%). In univariate analyses, depression was significantly associated with heart failure class (p < 0.05). Multivariate linear regression revealed that major depression was significantly associated with total symptom burden score (Beta: 11.74; 95% CI: 9.24-14.23) and LVEF (Beta: -0.09; 95% CI: -0.17-(-0.007)). Patients hospitalised for heart failure experienced a high burden of symptoms. Further studies addressing adverse outcomes and expanding to community-dwelling older people are essential. Palliative care approaches that target symptom reduction should be considered in patients with heart failure.

Biomimetic injectable hydrogel based on silk fibroin/hyaluronic acid embedded with methylprednisolone for cartilage regeneration.

Articular cartilage injury is characterized by limited self-repair capacity due to the shortage of blood vessels, lymphatics, and nerves. Hence, this study aims to exploit a classic injectable hydrogel platform that can restore the cartilage defects with minimally invasive surgery, which is similar to the natural extracellular microenvironment, and highly porous network for cell adhesion and proliferation. In this study, an injectable scaffold system comprised of silk fibroin (SF) and hyaluronic acid (HA) was developed to adapt the above requirements. Besides, methylprednisolone (MP) was encapsulated by SF/HA scaffold for alleviating inflammation. The SF/HA hydrogel scaffold was prepared by chemical cross-linking between the lysine residues of SF via Schiff base formation, and pore diameter of the obtained hydrogels was 100.47 ± 32.09 µm. The highly porous nature of hydrogel could further benefit the soft tissue regeneration. Compared with HA-free hydrogels, SF/HA hydrogel showed more controlled release on MP. In ovo experiment of chick embryo chorioallantoic membrane (CAM) demonstrated that SF/HA hydrogels not altered the angiogenesis and formation of blood vessels, thus making it suitable for cartilage regeneration. Furthermore, in vivo gel formation was validated in mice model, suggesting in situ gel formation of SF/HA hydrogels. More importantly, SF/HA hydrogels exhibited the controlled biodegradation. Overall, SF/HA hydrogels provide further insights to the preparation of effective scaffold for tissue regeneration and pave the way to improve the articular cartilage injury treatment.

Accelerating anaerobic digestion process with novel single chamber microbial electrochemical systems with baffle.

A newly designed microbial electrochemical system (MES) with the addition of a baffle between the electrodes was integrated with the anaerobic digestion (AD) process for biogas upgradation. Novel MES configuration attained an increased methane production rate of 292.6 mL/L∙d and methane yield of 0.36 ± 0.006 [Formula: see text] /gCOD, which were higher than the values (185.3 mL/L∙d and 0.33 ± 0.009 [Formula: see text] /gCOD) from the MES operation without baffle, respectively. Moreover, the MES with baffle operation resulted in increased substrate removal (88.4 ± 0.5%) and less volatile fatty acids accumulation with a high energy efficiency of 99.6 %. Microbial community analysis revealed that acids metabolizing bacteria, Firmicutes, and Methanothrix were highly enriched in the cathode biofilm of MES with baffle. This study suggests that the baffle addition into the single chamber MES is beneficial to further improve the methanogenesis process for practical applications in the scaled-up MES-AD process.

Analysis of CCR2 splice variant expression patterns and functional properties.

BACKGROUND: C-C motif chemokine receptor 2 (CCR2), the main receptor for monocyte chemoattractant protein-1 (MCP-1), is expressed on immune cells, including monocytes, macrophages, and activated T cells, and mediates cell migration toward MCP-1 in inflammation-related diseases. The CCR2 gene encodes two isoforms: CCR2A and CCR2B. The CCR2B open reading frame is localized in a single exon, similar to other chemokine receptors, and CCR2A and CCR2B feature different amino acid sequences in their C-terminal intracellular loops due to alternative splicing. Most biochemical studies on CCR2-related cellular responses in the immune system have focused on CCR2B, with few reports focused on CCR2A. Understanding the functional properties of CCR2A in cellular responses may elucidate the roles played by MCP-1 and CCR2 in pathophysiological responses. RESULTS: CCR2 gene expression analysis in several cell types revealed that most adherent cells only expressed CCR2A, whereas CCR2B expression was dominant in monocytic cells. The C-terminal Helix 8 region of CCR2A contains few basic amino acids, which may be unfavorable for cell surface localization, as confirmed with the HiBiT assay. CCR2B contains many C-terminal Ser/Thr residues, similar to other chemokine receptors, which may be phosphorylated by G protein-coupled receptor kinases (GRKs) to promote ß-arrestin recruitment and subsequent endocytosis. By contrast, CCR2A contains few C-terminal Ser/Thr residues, which are unlikely to be phosphorylated by GRKs. CCR2A localized on the cell surface is resistant to internalization, despite the interaction between Gß and GRKs induced by ligand binding with CCR2A. CCR2A induced cellular responses at a relatively higher degree than CCR2B, although both receptors mediated signaling events through Gαq and Gαi. HeLa cells lacking CCR2A showed slowed growth compared with parent cells, regardless of MCP-1 stimulation, and their chemotactic activity toward MCP-1, in addition to basal motility, was significantly impaired. CONCLUSION: MCP-1 and CCR2 may play pivotal roles in cancer progression by recruiting macrophages into cancer tissue. This study demonstrates that CCR2A but not CCR2B is expressed in solid cancer-derived cells. CCR2A is resistant to internalization by ß-arrestin due to a distinct C-terminal region from CCR2B, which enhances MCP-1-stimulated responses, indicating that CCR2A may play essential roles in solid cancer progression.

Comprehensive Geriatric Assessment in Older Patients with Diabetes Mellitus in Hanoi, Vietnam.

INTRODUCTION: Comprehensive geriatric assessment (CGA) of older diabetic patients is thought to be of value, but there have been limited studies on the prevalence of impairments in the components of a CGA as well as the relationship between CGA and diabetic control in this group. OBJECTIVE: This study aimed to evaluate the prevalence of components of CGA in older patients with diabetes in National Geriatric Hospital, Hanoi, Vietnam, and determine the association among domains of CGA with measures of diabetic control. METHODS: A cross-sectional study of diabetic outpatients aged ≥60 years at National Geriatric Hospital in Hanoi, Vietnam, recruited over 3 months. The CGA questionnaire includes different assessments consisting of cognitive impairment (using Mini-Cog test), depression (using the 15-item Geriatric Depression Scale), urinary incontinence (using the 3-Incontinence questions), Activities of Daily Living (ADL) dependence, Instrumental Activities of Daily Living (IADL) dependence, high fall risk (using Hendrich II Fall Risk Model), hearing loss (using Whisper test), low visual acuity (using Snellen test), polypharmacy, malnutrition (using the Mini-Nutritional Assessment Short Form), and multiple geriatric conditions (patients had 2 or more geriatric conditions). Multiple logistic regression was used to analyze the association between demographic factors and CGA components with measures of diabetes control. RESULTS: A total of 412 patients were recruited (56.6% female, mean age 71.9 [7.6] years). Prevalence of impairment in components of the CGA was high and highest for vision impairment (94.2%) and multiple geriatric conditions (89.3%). Age <75 years, cognitive impairment, depressive symptom, IADL impairment, and high fall risk were significantly associated with both poor fasting plasma glucose control (>130 mg/dL) and poor HbA1c control (≥7%). CONCLUSIONS: This study highlights that geriatric syndromes are common in older diabetic patients and associated with poorer diabetic control. It suggests CGA may be important to conduct in this group by establishing an interdisciplinary Geriatric health care team.

A case of Wilson disease with the ATP7B mutation presenting movement disorders.

BACKGROUND: Wilson disease is an autosomal recessive condition manifested when abnormal copper accumulation in the body particularly involving many organs such as brain, liver, and cornea. Diagnosis is challenging with the completion of tests in blood and urine, a liver biopsy, and clinical evaluation. ATP7B mutations with more than 600 identified variants are the genetic disorders of Wilson disease. CASE DESCRIPTION: We report an adolescent case with no family history presented with extrapyramidal dyskinesia. Other symptoms include liver cirrhosis and Kayser-Fleischer ring. The typical presentation of blood test results and brain MRI images helps us to suspect Wilson disease in this case. We confirmed to have a p.R778L form and a p.S105X form in ATP7B mutations. After combining therapy with trihexyphenidyl and trientine, the patient's medical condition was stable and no side effects were observed. CONCLUSION: Screening for the diagnosis of Wilson disease is essential in helping patients benefit from early treatment and genetic counseling.

Assessing Knowledge and Attitudes Regarding Pain Management Among Nurses Working in a Geriatric Hospital in Vietnam.

BACKGROUND: Nurses play a pivotal role in pain management. Knowing more about nurses' knowledge and attitudes regarding pain is important as we develop multidisciplinary pain services. Therefore, this study aimed to assess knowledge and attitudes regarding pain management among nurses in a geriatric hospital and its associated factors. SUBJECTS AND METHODS: A survey was conducted of nurses worked at the National Geriatric Hospital over a 3-month period. The Knowledge and Attitudes Survey Regarding Pain (KASRP) was utilized to assess nurses' knowledge and attitudes toward pain management. Four domains were defined based on KASRP, included cancer-related pain, pain assessment, pharmacology and substance abuse and physical dependence. Knowledge and attitudes regarding pain were classified as poor, fair, or good (≤50%, 50% - 75%, or ≥75% of the KASRP score). Multivariate Tobit regression models were applied to identify factors associated with the knowledge and attitudes regarding pain management. RESULTS: Of 154 participants completed the survey, 72.2% (111 participants) had poor knowledge and attitudes regarding pain management. The participants had a correct mean score of 45.2% (SD = 2.2). Nurses' knowledge of pain assessment was poor, with the proportion of correct answers to nine questions ranging from 2.6% to 50%. 44.8% of nurses reported never or rarely using pain assessment tools. Nurses who had previous training regarding pain at medical universities had significantly higher scores of knowledge and attitudes compared to those without training. Nurses who often use pain assessment tools had a significantly higher level of knowledge and attitudes than those who never or rarely use them. CONCLUSION: This study highlights significant deficits of knowledge and negative attitudes regarding pain management among nurses. The subject of pain management should be applied and enhanced in the nursing undergraduate curriculum. Nurses' active participation in pain management should be encouraged by healthcare providers for older patients.

SP-8356, a (1S)-(-)-Verbenone Derivative, Inhibits the Growth and Motility of Liver Cancer Cells by Regulating NF-κB and ERK Signaling.

Liver cancer is a common tumor and currently the second leading cause of cancer-related mortality globally. Liver cancer is highly related to inflammation as more than 90% of liver cancer arises in the context of hepatic inflammation, such as hepatitis B virus and hepatitis C virus infection. Despite significant improvements in the therapeutic modalities for liver cancer, patient prognosis is not satisfactory due to the limited efficacy of current drug therapies in anti-metastatic activity. Therefore, developing new effective anti-cancer agents with anti-metastatic activity is important for the treatment of liver cancer. In this study, SP-8356, a verbenone derivative with anti-inflammatory activity, was investigated for its effect on the growth and migration of liver cancer cells. Our findings demonstrated that SP-8356 inhibits the proliferation of liver cancer cells by inducing apoptosis and suppressing the mobility and invasion ability of liver cancer cells. Functional studies revealed that SP-8356 inhibits the mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways, which are related to cell proliferation and metastasis, resulting in the downregulation of metastasis-related genes. Moreover, using an orthotopic liver cancer model, tumor growth was significantly decreased following treatment with SP-8356. Thus, this study suggests that SP-8356 may be a potential agent for the treatment of liver cancer with multimodal regulation.

Physicochemical Properties and Effects of Honeys on Key Biomarkers of Oxidative Stress and Cholesterol Homeostasis in HepG2 Cells.

Manuka honey and newly developed honeys (arjuna, guggul, jiaogulan and olive) were examined for their physicochemical, biochemical properties and effects on oxidative stress and cholesterol homeostasis in fatty acid-induced HepG2 cells. The honeys exhibited standard moisture content (<20%), electrical conductivity (<0.8 mS/cm), acidic pH, and monosaccharides (>60%), except olive honey (<60% total monosaccharides). They all expressed non-Newtonian behavior and 05 typical regions of the FTIR spectra as those of natural ones. Guggul and arjuna, manuka honeys showed the highest phenolic contents, correlating with their significant antioxidant activities. Arjuna, guggul and manuka honeys demonstrated the agreement of total cholesterol reduction and the transcriptional levels of AMPK, SREBP2, HCMGR, LDLR, LXRα. Jiaogulan honey showed the least antioxidant content and activity, but it was the most cytotoxic. Both jiaogulan and olive honeys modulated the tested gene in the pattern that should lead to a lower TC content, but this reduction did not occur after 24 h. All 2% concentrations of tested honeys elicited a clearer effect on NQO1 gene expression. In conclusion, the new honeys complied with international norms for natural honeys and we provide partial evidence for the protective effects of manuka, arjuna and guggul honeys amongst the tested ones on key biomarkers of oxidative stress and cholesterol homeostasis, pending further studies to better understand their modes of action.

CXCR7: a ß-arrestin-biased receptor that potentiates cell migration and recruits ß-arrestin2 exclusively through Gßγ subunits and GRK2.

BACKGROUND: Some chemokine receptors referred to as atypical chemokine receptors (ACKRs) are thought to non-signaling decoys because of their inability to activate typical G-protein signaling pathways. CXCR7, also known as ACKR3, binds to only two chemokines, SDF-1α and I-TAC, and recruits ß-arrestins. SDF-1α also binds to its own conventional receptor, CXCR4, involving in homeostatic modulation such as development and immune surveillance as well as pathological conditions such as inflammation, ischemia, and cancers. Recently, CXCR7 is suggested as a key therapeutic target together with CXCR4 in such conditions. However, the molecular mechanisms underlying cellular responses and functional relation with CXCR7 and CXCR4 have not been elucidated, despite massive studies. Therefore, we aimed to reveal the molecular networks of CXCR7 and CXCR4 and compare their effects on cell migration. METHODS: Base on structural complementation assay using NanoBiT technology, we characterized the distinct mechanisms underlying ß-arrestin2 recruitment by both CXCR4 and CXCR7. Crosslinking and immunoprecipitation were conducted to analyze complex formation of the receptors. Gene deletion using CRISPR and reconstitution of the receptors were applied to analysis of ligand-dependent ERK phosphorylation and cell migration. All experiments were performed in triplicate and repeated more than three times. Unpaired Student's t-tests or ANOVA using PRISM5 software were employed for statistical analyses. RESULTS: Ligand binding to CXCR7 does not result in activation of typical signaling pathways via Gα subunits but activation of GRK2 via ßγ subunits and receptor phosphorylation with subsequent ß-arrestin2 recruitment. In contrast, CXCR4 induced Gαi activation and recruited ß-arrestin2 through C-terminal phosphorylation by both GRK2 and GRK5. SDF-1α-stimulated ERK phosphorylation was facilitated by CXCR4, but not CXCR7. Heterodimerization of CXCR4 and CXCR7 was not confirmed in this study, while homodimerization of them was verified by crosslinking experiment and NanoBiT assay. Regarding chemotaxis, SDF-1α-stimulated cell migration was mediated by both CXCR4 and CXCR7. CONCLUSION: This study demonstrates that SDF-1α-stimulated CXCR7 mediates ß-arrestin2 recruitment via different molecular networking from that of CXCR4. CXCR7 may be neither a simple scavenger nor auxiliary receptor but plays an essential role in cell migration through cooperation with CXCR4.

Establishment of a NanoBiT-Based Cytosolic Ca2+ Sensor by Optimizing Calmodulin-Binding Motif and Protein Expression Levels.

Cytosolic Ca2+ levels ([Ca2+]c) change dynamically in response to inducers, repressors, and physiological conditions, and aberrant [Ca2+]c concentration regulation is associated with cancer, heart failure, and diabetes. Therefore, [Ca2+]c is considered as a good indicator of physiological and pathological cellular responses, and is a crucial biomarker for drug discovery. A genetically encoded calcium indicator (GECI) was recently developed to measure [Ca2+]c in single cells and animal models. GECI have some advantages over chemically synthesized indicators, although they also have some drawbacks such as poor signal-to-noise ratio (SNR), low positive signal, delayed response, artifactual responses due to protein overexpression, and expensive detection equipment. Here, we developed an indicator based on interactions between Ca2+-loaded calmodulin and target proteins, and generated an innovative GECI sensor using split nano-luciferase (Nluc) fragments to detect changes in [Ca2+]c. Stimulation-dependent luciferase activities were optimized by combining large and small subunits of Nluc binary technology (NanoBiT, LgBiT:SmBiT) fusion proteins and regulating the receptor expression levels. We constructed the binary [Ca2+]c sensors using a multicistronic expression system in a single vector linked via the internal ribosome entry site (IRES), and examined the detection efficiencies. Promoter optimization studies indicated that promoter-dependent protein expression levels were crucial to optimize SNR and sensitivity. This novel [Ca2+]c assay has high SNR and sensitivity, is easy to use, suitable for high-throughput assays, and may be useful to detect [Ca2+]c in single cells and animal models.

Mechano-chemical stability and water effect on gas selectivity in mixed-metal zeolitic imidazolate frameworks: a systematic investigation from van der Waals corrected density functional theory.

A series of Zn/Cu Zeolitic Imidazolate Frameworks (ZIFs) ZIF-202, -203, and -204 are systematically investigated by Density Functional Theory (DFT) with and without van der Waals (vdW) corrections. The elastic constants for non-solvent structures indicate that ZIF-202 and -204 are mechanically stable while ZIF-203 is unstable, which arises from the stiffness along the x-axis under a uniaxial strain in the PBE-D3 method. By considering the presence of solvents in ZIF-203, a structural phase transformation from a monoclinic to a triclinic structure is found which could be explained by the Jahn-Teller distortion. From the chemical bonding point of view, it is found that vdW interactions and hybridization between d-orbitals (copper) and p-orbitals (imidazolate) are the main-driving forces in stabilizing ZIF-202 and -204, respectively. The electronic structure calculations predict the presence of two optical transitions in the visible region in agreement with the experimental observation for ZIF-204 both without and with water. The DFT simulations reveal that CO2 molecules prefer to locate near imidazolate and water in dry and hydrated ZIF-204, respectively. The analysis of Canonical Monte Carlo (GCMC) simulations reveals that Coulomb interaction between CO2 and H2O molecules is mainly responsible for the enhanced CO2 uptake and selectivity under humid conditions compared to dry ones.

Polypharmacy at discharge in older hospitalised patients in Vietnam and its association with frailty.

OBJECTIVES: To investigate the prevalence of polypharmacy and the common drugs prescribed at discharge in frail and non-frail older inpatients, and to examine whether frailty is significantly associated with polypharmacy. METHODS: Cross-sectional analysis from data of a study about the prevalence of frailty in older inpatients in Vietnam in 2015. Polypharmacy was defined as using ≥5 medications. Frailty was defined by Fried's frailty criteria. RESULTS: There were 382 participants, mean age 76.4, 56.5% female and 35.9% frail. At discharge, 59.2% had polypharmacy (62.8% in the frail and 57.1% in the non-frail). Vitamin/supplements were the most common drugs prescribed, followed by antiplatelets. Frailty was not significantly associated with polypharmacy (adjusted OR 1.45, 95% CI 0.89-2.34). CONCLUSIONS: The prevalence of polypharmacy at discharge was high in both frail and non-frail participants. The association between frailty and polypharmacy needs to be investigated further in multicentre studies with larger sample sizes in Vietnam.