Regorafenib induces damage-associated molecular patterns, cancer cell death and immune modulatory effects in a murine triple negative breast cancer model.

Damage associated molecular patterns (DAMPs), including calreticulin (CRT) exposure, high-mobility group box 1 protein (HMGB1) elevation, and ATP release, characterize immunogenic cell death (ICD) and may play a role in cancer immunotherapy. Triple negative breast cancer (TNBC) is an immunogenic subtype of breast cancer with higher lymphocyte infiltration. Here, we found that regorafenib, a multi-target angiokinase inhibitor previously known to suppress STAT3 signaling, induced DAMPs and cell death in TNBC cells. Regorafenib induced the expression of HMGB1 and CRT, and the release of ATP. Regorafenib-induced HMGB1 and CRT were attenuated following STAT3 overexpression. In a 4T1 syngeneic murine model, regorafenib treatment increased HMGB1 and CRT expression in xenografts, and effectively suppressed 4T1 tumor growth. Immunohistochemical staining revealed increased CD4+ and CD8+ tumor-infiltrating T cells in 4T1 xenografts following regorafenib treatment. Regorafenib treatment or programmed death-1 (PD-1) blockade using anti-PD-1 monoclonal antibody reduced lung metastasis of 4T1 cells in immunocompetent mice. While regorafenib increases the proportion of MHC II high expression on dendritic cells in mice with smaller tumors, the combination of regorafenib and PD-1 blockade did not show a synergistic effect on anti-tumor activity. These results suggest that regorafenib induces ICD and suppresses tumor progression in TNBC. It should be carefully evaluated when developing a combination therapy with an anti-PD-1 antibody and a STAT3 inhibitor.

Quantitative Assessment of Lipiodol-Related Artifact Reduction for Dual-Energy Computed Tomography After Transcatheter Arterial Chemoembolization: A Phantom Study Evaluating the Use of Metal Artifact Reduction Algorithms.

OBJECTIVE: This study used metal artifact reduction (MAR) software to examine the computed tomography (CT) number of dual-energy CT (DECT) of hepatocellular carcinoma after transcatheter arterial chemoembolization. METHODS: Hollow columnar acrylic phantoms were filled with lipiodol and inserts of 2 sizes (large and small) were used to simulate liver tumors on a Revolution GSI CT scanner. The CT numbers of a single test object were collected twice: once with and once without the MAR algorithm. Lipiodol beam-hardening artifacts were quantified by measuring CT numbers in a region of interest around the tumor-simulating insert. RESULTS: The virtual monochromatic CT numbers of large and small tumors were closely related to energy. For small tumors, CT numbers increased with energy. For large tumors, CT numbers increased with energy at 1 cm from the margin but decreased with an increase in energy at 5 cm. Regardless of the size, distance, or location of the tumor, the CT numbers fluctuated more at low energy levels. CONCLUSIONS: At 1 cm from the margin, the CT numbers with MAR were significantly different from those without MAR. Low-energy CT numbers with MAR were near reference values. Metal artifact reduction exhibited superior performance for small tumors. Tumor margin images are affected by artifacts caused by Lipiodol. However, with MAR, CT numbers can be effectively calibrated, thus enabling clinicians to more accurately evaluate hepatocellular carcinoma development and identify residual tumors and recurrent or metastatic lesions.

Interfering B cell receptor signaling via SHP-1/p-Lyn axis shows therapeutic potential in diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B cell lymphoma (DLBCL) is an aggressive and molecularly heterogeneous non-Hodgkin's lymphoma. The B cell receptor (BCR) signaling pathway in DLBCL emerges as a new drug target. Protein phosphatase SHP-1 negatively regulates several oncogenic tyrosine kinases and plays a tumor suppressive role. METHODS: The direct SHP-1 agonists were used to evaluate the potential therapeutic implication of SHP-1 in DLBCL. Immunohistochemical staining for SHP-1 was quantified by H-score. The SHP-1 phosphatase activity was determined using tyrosine phosphatase assay. In vitro studies, including MTT, western blot analysis and cell apoptosis, were utilized to examined biological functions of SHP-1. RESULTS: Oral administration of SHP-1 agonist showed the potent anti-tumor effects compared to a selective Bruton's tyrosine kinase (BTK) inhibitor ibrutinib in mice bearing U2932 xenografts. SHP-1 agonist increased SHP-1 activity as well as downregulated p-Lyn in vivo. Here, we demonstrated that immunohistochemical staining for SHP-1 expression was positive in 76% of DLBCL samples. SHP-1 agonist exerted anti-proliferative and apoptotic effects compared with ibrutinib in DLBCL cells. Mechanistically, SHP-1 agonist decreased BCR signaling, especially p-Lyn, and led to apoptosis. CONCLUSIONS: These data suggest that SHP-1 negatively regulates phosphorylation of Lyn, and targeting SHP-1/p-Lyn using SHP-1 agonist has therapeutic potential for treatment of DLBCL.

Cell cycle checkpoints and beyond: Exploiting the ATR/CHK1/WEE1 pathway for the treatment of PARP inhibitor-resistant cancer.

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) have become a mainstay of therapy in ovarian cancer and other malignancies, including BRCA-mutant breast, prostate, and pancreatic cancers. However, a growing number of patients develop resistance to PARPis, highlighting the need to further understand the mechanisms of PARPi resistance and develop effective treatment strategies. Targeting cell cycle checkpoint protein kinases, e.g., ATR, CHK1, and WEE1, which are upregulated in response to replication stress, represents one such therapeutic approach for PARPi-resistant cancers. Mechanistically, activated cell cycle checkpoints promote cell cycle arrest, replication fork stabilization, and DNA repair, demonstrating the interplay of DNA repair proteins with replication stress in the development of PARPi resistance. Inhibitors of these cell cycle checkpoints are under investigation in PARPi-resistant ovarian and other cancers. In this review, we discuss the cell cycle checkpoints and their roles beyond mere cell cycle regulation as part of the arsenal to overcome PARPi-resistant cancers. We also address the current status and recent advancements as well as limitations of cell cycle checkpoint inhibitors in clinical trials.

Comparison between the use of hypofractionated and conventionally fractionated radiotherapy in early breast cancer: A single-center real-world study in Taiwan.

BACKGROUND/PURPOSE: This study aimed to analyze the long-term outcomes of hypofractionated whole-breast irradiation (WBI) (HF-WBI) compared with those of conventionally fractionated WBI (CF-WBI) for early breast cancer treated with breast-conservation surgery (BCS) and adjuvant WBI in Taiwan. METHODS: This study included patients treated at our institution between 2012 and 2016. All patients with early breast cancer received BCS (pT1-2, pN0, M0) and adjuvant WBI through one of two treatment schemes. Propensity score matching analysis was conducted to create comparable cohorts. The major result is ipsilateral breast tumor recurrence (IBTR) rates and overall survival rates. RESULTS: A total of 869 patients with early-stage breast cancer received adjuvant HF-WBI or CF-WBI were included. After matching, 718 patients were separated into two groups of the same number. With a median follow-up of 66 months, seven cases of IBTR were noted (three for CF, four for HF). There were no significant differences between the HF-WBI and CF-WBI groups in 5-year IBTR rates (0.9% vs 0.6%, P = 0.3887, 95% CI [0.25-7.79]) and 5-year overall survival rates (98.1% vs 98.9%, P = 0.4702, 95% CI [0.32-3.49]). In our institution, the use of HF-WBI increased significantly from 5% before 2012 (Q3) to 92% in 2016 (Q4). There was no significant difference in grade 1-2 toxicity between the two treatment groups. Fewer cases of grade 3 skin toxicity noted in the HF-WBI group (zero vs four events). CONCLUSION: HF-WBI had similar IBTR, OS and toxicity to CF-WBI.

Anti-IgE therapy inhibits chemotaxis, proliferation and transformation of circulating fibrocytes in patients with severe allergic asthma.

BACKGROUND AND OBJECTIVE: Circulating fibrocytes act as precursors of myofibroblasts, contribute to airway remodelling in chronic asthma and migrate to injured tissues by expressing CXCR4 and CCR7. Anti-IgE therapy improves severe allergic asthma (SAA) control and airway remodelling in T2-high SAA. The effects of anti-IgE therapy on fibrocyte activities were investigated in this study. METHODS: The expression of CCR7, CXCR4, ST2 and α-SMA (α-smooth muscle actin) in both circulating and cultured fibrocytes from all patients with asthma was measured, and was repeated after omalizumab treatment in SAA. Fibrocytes recruitment, proliferation and transformation were also measured in response to anti-IgE therapy. RESULTS: Omalizumab effectively improved asthma control and pulmonary function in T2-high SAA, associated with a decline in serum levels of IL-33 and IL-13. Omalizumab down-regulates CXCR4 and CCR7 expression of fibrocytes, which could suppress fibrocyte recruitment into the lungs. Omalizumab also suppressed the increased number of fibrocytes and α-SMA+ fibrocytes within the cultured non-adherent non-T (NANT) cells after 3-7 days of culture. The decrease in serum levels of IL-33 by omalizumab contributed to the effectiveness in inhibiting fibrocyte recruitment, proliferation and myofibroblast transformation through IL-33/ST2 axis. The elevated IL-13 expression in SAA patients potentiated the effects of IL-33 by increasing ST2 expression. CONCLUSION: Omalizumab reduced the number of circulating fibrocytes, cell and number of fibrocytes as well as α-SMA+ fibrocytes after 3-7 days of culture in SAA patients. IL-33 and IL-13 may be implicated in the effectiveness of omalizumab in inhibiting fibrocyte activation contributing partly to the clinical benefits in reducing lamina propria and basement membrane thickening.

Factors related to hospital-to-home transitional self-monitoring blood glucose behaviour among patients with diabetes-related foot ulcer.

AIMS: To explore the factors related to hospital-to-home transitional self-monitoring blood glucose behaviour among patients with diabetes-related foot ulcer. BACKGROUND: The 30-day readmission rate of patients with diabetes-related foot ulcer can be reduced when good glycaemic control is achieved. The practice of self-monitoring blood glucose promotes optimal glycaemic control. DESIGN: A comparative descriptive study. METHODS: In this study, 200 participants, who had been hospitalized due to diabetes-related foot ulcer, were recruited from August 2017 to July 2018. Before participants were discharged from the hospital, psychosocial factors (family support, threat belief, self-efficacy and knowledge) and pre-hospitalization self-monitoring blood glucose behaviour were collected using a structured questionnaire. Then, after discharge, self-monitoring blood glucose behaviour delivery was collected again. RESULTS: Five variables explained 47% of the variance in the delivery of self-monitoring of blood glucose at home. The delivery of hospital-to-home transitional self-monitoring blood glucose behaviour was more likely for individuals with higher pre-discharge self-efficacy, higher post-discharge self-efficacy, more attention to pre-hospitalization glycaemic status and post-discharge insulin usage and those without an insensitive foot. CONCLUSION: Self-monitoring blood-glucose behaviour should be promoted among post-discharge patients with diabetes-related foot ulcer. The modifiable factors identified in this study can be integrated into the discharge plan.

Generating Third Harmonic Vacuum Ultraviolet Light with a TiO2 Metasurface.

Dielectric metasurfaces have recently been shown to provide an excellent platform for the harmonic generation of light due to their low optical absorption and to the strong electromagnetic field enhancement that can be designed into their constituent meta-atoms. Here, we demonstrate vacuum ultraviolet (VUV) third harmonic generation from a specially designed dielectric metasurface consisting of a titanium dioxide (TiO2) nanostructure array. The metasurface was designed to enhance the generation of VUV light at a wavelength of 185 nm by tailoring its geometric design parameters to achieve an optical resonance at the fundamental laser wavelength of 555 nm. The metasurface exhibits an enhancement factor of nominally 180 compared to an unpatterned TiO2 thin film of the same thickness, evidence of strong field enhancement at the fundamental wavelength. Mode analysis reveals that the origin of the enhancement is an anapole resonance near the pump wavelength. This work demonstrates an effective strategy for the compact generation of VUV light that could enable expanded access to this useful region of the electromagnetic spectrum.

The impact of a medication reconciliation programme at geriatric hospital admission: A pre-/postintervention study.

AIMS: The aim of this study was to improve medication reconciliation and reduce the occurrence of duplicate prescriptions by pharmacists and physicians within 72 hours of hospital admission using an intelligent prescription system combined with the National Health Insurance PharmaCloud system to integrate the database with the medical institution computerized physician order entry (CPOE) system. METHODS: This 2-year intervention study was implemented in the geriatric ward of a hospital in Taiwan. We developed an integrated CPOE system linked with the PharmaCloud database and established an electronic platform for coordinated communication with all healthcare professionals. Patients provided written informed consent to access their PharmaCloud records. We compared the intervention effectiveness within 72 hours of admission for improvement in pharmacist medication reconciliation, increased at-home medications documentation and decreased costs from duplicated at-home prescriptions. RESULTS: The medication reconciliation rate within 72 hours of admission increased from 44.0% preintervention to 86.8% postintervention (relative risk = 1.97, 95% confidence interval [CI]: 1.69-2.31; P < .001). The monthly average of patients who brought and took home medications documented in the CPOE system during hospitalization increased by 7.54 (95% CI 5.58-20.49, P = .22). The monthly average of home medications documented increased by 102.52 (95% CI 38.44-166.60; P = .01). Savings on the monthly average prescription expenditures of at-home medication increased by US$ 2,795.52 (95% CI US$1310.41-4280.63; P < .01). CONCLUSION: Integrating medication data from PharmaCloud to the hospital's medical chart system improved pharmacist medication reconciliation, which decreased duplicated medications and reduced in-hospital medication costs.

Factors associated with foot ulcer self-management behaviours among hospitalised patients with diabetes.

AIMS AND OBJECTIVES: To determine prehospitalised diabetes-related foot ulcer (DFU) self-management behaviours and explore the factors associated with these behaviours. BACKGROUND: Although there are many studies that explore DFU prevention and treatment, to our knowledge, there are no quantitative studies of DFU self-management behaviours. DESIGN: Cross-sectional design. METHODS: From June 2015-June 2016, 199 hospitalised patients with DFU were given a survey questionnaire at a medical centre in northern Taiwan. DFU self-management behaviours, diabetes foot self-care behaviours, beliefs in regard to barriers to DFU self-management behaviours, and knowledge regarding warning signs of DFU deterioration were assessed by well-designed measurement tools. The Strengthening the Reporting of Observational Studies in Epidemiology checklist was used to ensure quality reporting during this observational study (see Supporting Information Appendix S1). RESULTS: The results revealed that 62.8% of participants never monitored their blood glucose level when they had foot ulcers, and 63.8% never sought treatment for their wounds when their wounds were not painful. After controlling for demographic and medical variables, stepwise multiple regression analysis revealed that the following eight significant variables were associated with DFU self-management behaviours: two DFU self-management barrier beliefs, foot self-care behaviour, no treatment for diabetes, poor financial status, employment, knowledge regarding the warning signs of DFU deterioration, and number of DFU hospitalisations. CONCLUSIONS: Diabetes-related foot ulcer self-management behaviours were insufficient. Some modifiable factors and high-risk groups for insufficient DFU self-management behaviour were identified. RELEVANCE TO CLINICAL PRACTICE: Diabetes-related foot ulcer self-management behaviours should be promoted. Interventions that modify the risk factors that were identified in this study can be designed to promote the performance of DFU self-management behaviours.

Serine/threonine protein phosphatase 5 is a potential therapeutic target in cholangiocarcinoma.

BACKGROUND & AIMS: Few molecules are currently verified to be actionable drug targets in cholangiocarcinoma (CCA). Serine/threonine protein phosphatase 5 (PP5) dysregulation is related to several malignancies. However, the role of PP5 in CCA is poorly defined. METHODS: Colony and tumorsphere formation assays were conducted to establish the role of PP5 in CCA tumorigenesis. Cantharidin (CTD) and norcantharidin (NCTD), both potent PP5 inhibitors, were used in in vitro and in vivo experiments to validate the potential therapeutic role of PP5. RESULTS: Increased cell growth, colony formation and tumorsphere formation were observed in PP5-overexpressing CCA cells, whereas PP5 knockdown by shRNA decreased cell growth and colony formation. Tumours from HuCCT1 xenograft-bearing mice treated with PP5-shRNA showed decreased growth and increased AMP-activated protein kinase (AMPK) phosphorylation. Furthermore, CTD treatment decreased cell viability, reduced PP5 activity and enhanced AMPK phosphorylation in CCA cell lines. Overexpressing PP5 or enhancing PP5 activity suppressed AMPK phosphorylation and decreased CTD-induced cell death. Suppressing p-AMPK with siRNA or inhibitors also decreased CTD-induced cell death, suggesting a pivotal role for PP5-AMPK cascades in CCA. Immunoprecipitation revealed that PP5 interacted with AMPK. Importantly, treatment of HuCCT1 xenograft-bearing mice with NCTD, a CTD analogue with a lower systemic toxicity in vivo, suppressed PP5 activity, increased p-AMPK and reduced tumour volume. CONCLUSIONS: Protein phosphatase 5 negatively regulates AMPK phosphorylation and contributes to CCA aggressiveness; thus, PP5 may be a potential therapeutic target in CCA.

Carfilzomib induces leukaemia cell apoptosis via inhibiting ELK1/KIAA1524 (Elk-1/CIP2A) and activating PP2A not related to proteasome inhibition.

Enhancing the tumour suppressive activity of protein phosphatase 2A (PP2A) has been suggested to be an anti-leukaemic strategy. KIAA1524 (also termed CIP2A), an oncoprotein inhibiting PP2A, is associated with disease progression in chronic myeloid leukaemia and may be prognostic in cytogenetically normal acute myeloid leukaemia. Here we demonstrated that the selective proteasome inhibitor, carfilzomib, induced apoptosis in sensitive primary leukaemia cells and in sensitive leukaemia cell lines, associated with KIAA1524 protein downregulation, increased PP2A activity and decreased p-Akt, but not with the proteasome inhibition effect of carfilzomib. Ectopic expression of KIAA1524, or pretreatment with the PP2A inhibitor, okadaic acid, suppressed carfilzomib-induced apoptosis and KIAA1524 downregulation in sensitive cells, whereas co-treatment with the PP2A agonist, forskolin, enhanced carfilzomib-induced apoptosis in resistant cells. Mechanistically, carfilzomib affected KIAA1524 transcription through disturbing ELK1 (Elk-1) binding to the KIAA1524 promoter. Moreover, the drug sensitivity and mechanism of carfilzomib in xenograft mouse models correlated well with the effects of carfilzomib on KIAA1524 and p-Akt expression, as well as PP2A activity. Our data disclosed a novel drug mechanism of carfilzomib in leukaemia cells and suggests the potential therapeutic implication of KIAA1524 in leukaemia treatment.

The effects of the empowerment education program in older adults with total hip replacement surgery.

AIMS: To measure the effectiveness of an education empowerment program on primary (self-efficacy and self-care competence) and secondary outcomes (Activities of Daily Life, mobility, depressive mood and quality of life) for older adults with total hip replacement surgery. BACKGROUND: Degenerative arthritis is a common and serious chronic illness that impacts the quality of life of older adults. As joints continue to degenerate and the hip damaged by arthritis, activities of daily life will be difficult to perform due to severe hip pain and joint stiffness. Therefore, hip replacement surgery should be considered and effective nursing care should be provided to improve the recovery of older adults. DESIGN: A prospective randomized control trial. METHODS: A trial was conducted from September 2013 - May 2014 in two hospitals in northern Taiwan. 108 participants were random assigned to either the education empowerment group or in the comparison group. The researchers collected baseline data at admission and outcomes on the day of discharge, one month after and three months after the discharge. RESULTS: After the interventions, the education empowerment group participants demonstrated significantly higher self-care competence and self-efficacy and lower depressive inclinations compared with those in the comparison group. Participants in both groups significantly improved on activities of daily life, mobility and quality of life over the course of the interventions. CONCLUSION: This education empowerment intervention was very effective in enhancing participants' outcomes. Moreover, involving both older adults and their caregivers for the participation this program is recommended for a greater impact.

Alteration of SHP-1/p-STAT3 Signaling: A Potential Target for Anticancer Therapy.

The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1 (SHP-1), a non-receptor protein tyrosine phosphatase, has been reported as a negative regulator of phosphorylated signal transducer and activator of transcription 3 (STAT3) and linked to tumor development. In this present review, we will discuss the importance and function of SHP-1/p-STAT3 signaling in nonmalignant conditions as well as malignancies, its cross-talk with other pathways, the current clinical development and the potential role of inhibitors of this pathway in anticancer therapy and clinical relevance of SHP-1/p-STAT3 in cancers. Lastly, we will summarize and highlight work involving novel drugs/compounds targeting SHP-1/p-STAT3 signaling and combined strategies that were/are discovered in our and our colleagues' laboratories.

Evaluation of a combined cognitive-behavioural and exercise intervention to manage fear of falling among elderly residents in nursing homes.

OBJECTIVES: Although the fear of falling is common among elderly residents in long-term care facilities, interventions developed for fear of falling management is very rare. Of these limited interventions, most were exercise interventions with only limited testing. The cognitive-behavioural intervention can decrease the fear of falling; however no intervention of the kind was developed and assessed to decrease fear of falling among the elderly in long-term care facilities. The purpose of this study was to examine the effectiveness of cognitive-behavioural strategies either with or without exercise in reducing fear of falling among elderly residents in nursing homes. METHOD: A prospective randomized control trial was conducted in six nursing homes in northern Taiwan. Seventy-five elderly participants were randomly assigned to one of the three groups: the comparison group, the cognitive-behavioural strategies with or without exercise group. The fear of falling, falls, depressive inclination, mobility, and muscle strength of extremities were collected at the two-month and five-month follow-up sessions, in which the progress of the patients were assessed. RESULTS: The mixed model analysis revealed that elderly adults in the combination experimental group had significant improvements compared with the other two groups on fear of falling, depressive inclination, mobility, and muscle strength at five months. The incidences of falls, post intervention, in both experimental groups were significantly lower than those in the comparison group. CONCLUSIONS: The results suggest that the combination intervention helped elderly residents manage their fear of falling and falls, decrease their depressive inclination, and enhance their mobility and muscle strength.

Fibrocyte trafficking in patients with chronic obstructive asthma and during an acute asthma exacerbation.

BACKGROUND: Fibrocytes express several chemokine receptors (CCR7 and CXCR4) that regulate their recruitment and trafficking into tissue-damage sites in response to specific chemokine gradients (CCL19 and CXCL12). OBJECTIVE: We investigated whether these chemoattractants and S100A9, through the receptor for advanced glycation end-products (RAGE; ie, its receptor), are involved in fibrocyte trafficking in patients with chronic obstructive asthma (COA) and during an acute exacerbation (AE) in patients without airflow obstruction (Asthma AE group). METHODS: We collected peripheral blood from 14 asthmatic patients with normal pulmonary function, 14 patients with COA, 11 patients in the Asthma AE group, and 14 healthy subjects. Isolated circulating fibrocytes were used for migration assay. Expression of CCR7, CXCR4, S100A9, and RAGE in fibrocytes was measured by using flow cytometry. CCL19 and CXCL12 expression in bronchial tissues was determined by using immunohistochemistry and RT-PCR. RESULTS: There were higher numbers of circulating fibrocytes in patients in the Asthma AE group and patients with COA. The expression of CXCL12 in bronchial tissues and CXCR4 in circulating fibrocytes was higher in the Asthma AE group and, to a lesser extent, in patients with COA. The expression of CCL19 in bronchial tissues and CCR7 in fibrocytes was higher in patients with COA. CXCL12/CXCR4 and CCL19/CCR7 enhanced fibrocyte transmigration in the Asthma AE group and in patients with COA, respectively. The upregulated expression of S100A9 and RAGE in fibrocytes of patients in the Asthma AE group and those with COA contributes to the enhanced basal migratory motility of fibrocytes. CONCLUSION: The CXCR4/CXCL12 axis contributes to chemotaxis of fibrocytes in patients in the Asthma AE group, whereas the CCR7/CCL19 axis plays an important role in patients with COA. S100A9 enhances the basal migratory motility of fibrocytes from patients in the Asthma AE group and patients with COA.

Effectiveness of individualised intervention on older residents with constipation in nursing home: a randomised controlled trial.

AIMS AND OBJECTIVES: To develop and examine the effectiveness of individualised intervention to reduce constipation among older adults in nursing homes. BACKGROUND: In long-term care facilities, approximately 60-80% of the residents have symptoms of constipation. Constipation may lead to haemorrhoids, faecal impaction, ulcers, intestinal bleeding and can also lead to a decrease in quality of life. Although a high prevalence of constipation in older adults can be seen, there is a lack of empirical evidence for delivering interventions based on individual risk factors of constipation. Many factors cause constipation but the risk factors are different for each individual. DESIGN: A prospective, randomised control trial conducted in northern Taiwan. METHODS: Nursing home residents (n = 43) were randomly assigned to either the control group or the experimental group. The control group received no extra care from the researcher while the experimental group received an individualised intervention and an eight-week follow-up. Participants were assessed using the Bristol Stool Form Scale, the Patient Assessment of Constipation Symptoms, types and dosages of laxative, and bowel sound observations. Data were taken at baseline, four weeks as well as eight weeks after the intervention. RESULTS: The participants in the experimental group had a significantly higher increase in the frequency of defecation (group effect, p = 0·029) and in bowel sounds (interaction effect, p = 0·010) compared to those in the control group. However, the two groups did not differ significantly in symptoms and the severity of the constipation symptoms, Bristol Stool Form and use of laxatives. CONCLUSIONS: The results of this trial suggest that the individualised intervention may be appropriate for decreasing constipation among nursing home residents and encourage further study and confirmation. RELEVANCE TO CLINICAL PRACTICE: Using individualised intervention to enhance the self-care ability related to constipation among older adults is recommended.

Downregulation of tumor suppressor MBP-1 by microRNA-363 in gastric carcinogenesis.

Gastric carcinoma is one of the most common malignancies and the second most lethal cancer worldwide. The mechanisms underlying aggressiveness of gastric cancer still remain obscure. c-Myc promoter binding protein 1 (MBP-1) is a negative regulator of c-myc expression and ubiquitously expressed in normal human tissues. It is produced by alternative translation initiation of α-enolase gene. Both MBP-1 and α-enolase are involved in the control of tumorigenesis including gastric cancer. MicroRNAs (miRNAs) are involved in tumorigenesis and could have diagnostic, prognostic and therapeutic potential. In this study, whether miRNAs modulate tumorigenesis of gastric cancer cells through targeting MBP-1 was evaluated. We found that miR-363 targets 3'-untranslated region of human MBP-1/α-enolase messenger RNA. The exogenous miR-363 promotes growth, viability, progression, epithelial-mesenchymal transition and tumorsphere formation of SC-M1 gastric cancer cells through downregulation of MBP-1, whereas the knockdown of endogenous miR-363 suppresses tumorigenesis and progression of SC-M1 cells via upregulation of MBP-1. The miR-363/MBP-1 axis is also involved in the control of carcinogenesis in KATO III and SNU-16 gastric cancer cells. Furthermore, miR-363 induces the xenografted tumor growth and lung metastasis of SC-M1 cells through MBP-1 in vivo. Taken together, these results suggest that miR-363 plays an important role in the increment of gastric carcinogenesis via targeting MBP-1.

Analyses of Neural Circuits Governing Behavioral Plasticity in the Nematode Caenorhabditis elegans.

Behavioral plasticity is subjected to various sensory stimuli, experiences, and physiological states, representing the temporal and spatial patterns of neural circuit dynamics. Elucidation of how genes and neural circuits in our brain actuate behavioral plasticity requires functional imaging during behavioral assays to manifest temporal and spatial neural regulation in behaviors. The exploration of the nervous systems of Caenorhabditis elegans has catalyzed substantial scientific advancements in elucidating the mechanistic link between circuit dynamics and behavioral plasticity. The analyses of the nervous system of C. elegans have technologically flourished owing to the development of optogenetic instruments and fluorescent protein-based imaging compatible with its optically transparent body and the understanding of its completely revealed neural connectome and gene expression profiles at single-neuron resolution (The C. elegans Neuronal Gene Expression Map & Network, CeNGEN project). Using examples of the two temperature learning behaviors in C. elegans, this chapter delves into a selection of pivotal imaging tools, including genetically encoded calcium indicators, biosensors for second messenger imaging, and their usage in freely moving worms that have propelled our grasp of sensory representation in C. elegans neural circuits. To further connect the circuit dynamics to behavioral plasticity, this chapter will focus on technological advancements enabling simultaneous imaging and tracking system together with methodologies to quantify multiple behavioral elements of freely behaving C. elegans in a dynamic environment.

Analyses of Genetic Regulation of the Nervous System in the Nematode Caenorhabditis elegans.

This chapter aims to provide a comprehensive overview of the methodologies available to dissect genetic regulation of the nervous systems in the nematode Caenorhabditis elegans. These techniques encompass genetic screens and genetic tools to unravel the spatial-temporal contribution of genes on neural structure and function. Unbiased genetic screens on random mutations induced by ethyl methanesulfonate (EMS) or target gene silencing by genome-wide RNA interference (RNAi) help progress our understanding of the genetic control of neural development and functions. Complement to unbiased genetic approaches, gene- and protein-targeted manipulation by Cre/LoxP recombination system and auxin-inducible degron (AID) protein degradation system, respectively, helps identify tissues/cells and the time window critical for gene and protein function during the proper execution of a particular behavior. Considering the remarkable conservation of genetic pathways between C. elegans and mammalian systems, elucidating the genetic underpinnings of neural functions and learning behaviors in C. elegans may furnish invaluable insights into analogous processes in more complex organisms. As shown in the following chapter, leveraging these diverse methodologies enable researchers to elucidate the intricate network governing neural function and structure, laying the foundation for innovating strategies to ameliorate cognitive alterations.