CLEAPA: a framework for exploring the conformational landscape of cryo-EM using energy-aware pathfinding algorithm.

MOTIVATION: Cryo-electron microscopy (cryo-EM) is a powerful technique for studying macromolecules and holds the potential for identifying kinetically preferred transition sequences between conformational states. Typically, these sequences are explored within two-dimensional energy landscapes. However, due to the complexity of biomolecules, representing conformational changes in two dimensions can be challenging. Recent advancements in reconstruction models have successfully extracted structural heterogeneity from cryo-EM images using higher-dimension latent space. Nonetheless, creating high-dimensional conformational landscapes in the latent space and then searching for preferred paths continues to be a formidable task. RESULTS: This study introduces an innovative framework for identifying preferred trajectories within high-dimensional conformational landscapes. Our method encompasses the search for the minimum energy path in the graph, where edge weights are determined based on the energy estimation at each node using local density. The effectiveness of this approach is demonstrated by identifying accurate transition states in both synthetic and real-world datasets featuring continuous conformational changes. AVAILABILITY AND IMPLEMENTATION: The CLEAPA package is available at https://github.com/tengyulin/energy_aware_pathfinding/.

Phosphorylation of sugar transporter TST2 by protein kinase CPK27 enhances drought tolerance in tomato.

Drought is a major environmental stress threatening plant growth and productivity. Calcium-dependent protein kinases (CPKs) are plant-specific Ca2+ sensors with multifaceted roles in signaling drought responses. Nonetheless, the mechanisms underpinning how CPKs transmit downstream drought signaling remain unresolved. Through genetic investigations, our study unveiled that knocking out CPK27 reduced drought tolerance in tomato (Solanum lycopersicum) plants and impaired abscisic acid (ABA)-orchestrated plant response to drought stress. Proteomics and phosphoproteomics revealed that CPK27-dependent drought-induced proteins were highly associated with the sugar metabolism pathway, which was further verified by reduced soluble sugar content in the cpk27 mutant under drought conditions. Using protein-protein interaction assays and phosphorylation assessments, we demonstrated that CPK27 directly interacted with and phosphorylated tonoplast sugar transporter 2 (TST2), promoting intercellular soluble sugar accumulation during drought stress. Furthermore, Ca2+ and ABA enhanced CPK27-mediated interaction and phosphorylation of TST2, thus revealing a role of TST2 in tomato plant drought tolerance. These findings extend the toolbox of potential interventions for enhancing plant drought stress tolerance and provide a target to improve drought tolerance by manipulating CPK27-mediated soluble sugar accumulation for rendering drought tolerance in a changing climate.

Nesprin proteins: bridging nuclear envelope dynamics to muscular dysfunction.

This review presents a comprehensive exploration of the pivotal role played by the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, with a particular focus on Nesprin proteins, in cellular mechanics and the pathogenesis of muscular diseases. Distinguishing itself from prior works, the analysis delves deeply into the intricate interplay of the LINC complex, emphasizing its indispensable contribution to maintaining cellular structural integrity, especially in mechanically sensitive tissues such as cardiac and striated muscles. Additionally, the significant association between mutations in Nesprin proteins and the onset of Dilated Cardiomyopathy (DCM) and Emery-Dreifuss Muscular Dystrophy (EDMD) is highlighted, underscoring their pivotal role in disease pathogenesis. Through a comprehensive examination of DCM and EDMD cases, the review elucidates the disruptions in the LINC complex, nuclear morphology alterations, and muscular developmental disorders, thus emphasizing the essential function of an intact LINC complex in preserving muscle physiological functions. Moreover, the review provides novel insights into the implications of Nesprin mutations for cellular dynamics in the pathogenesis of muscular diseases, particularly in maintaining cardiac structural and functional integrity. Furthermore, advanced therapeutic strategies, including rectifying Nesprin gene mutations, controlling Nesprin protein expression, enhancing LINC complex functionality, and augmenting cardiac muscle cell function are proposed. By shedding light on the intricate molecular mechanisms underlying nuclear-cytoskeletal interactions, the review lays the groundwork for future research and therapeutic interventions aimed at addressing genetic muscle disorders.

Reduced atopic march risk in pediatric atopic dermatitis patients prescribed dupilumab versus conventional immunomodulatory therapy: A population-based cohort study.

BACKGROUND: Dupilumab effectively treats atopic dermatitis (AD); however, its role in halting the atopic march remains uncertain. OBJECTIVE: To investigate dupilumab's effect on atopic march in pediatric AD patients versus conventional immunomodulators. METHODS: This retrospective cohort study utilized data from the TriNetX US Collaborative Network (2011-2024). Pediatric AD patients (≤18 years) were categorized into DUPI-cohort (newly prescribed dupilumab) or CONV-cohort (prescribed conventional immunomodulators without dupilumab). After 1:1 propensity-score matching, we analyzed atopic march progression, defined by the incident asthma or allergic rhinitis (AR). Cumulative incidence was plotted using Kaplan-Meier, with risk assessment via Cox regression. RESULTS: The study included 2192 patients in each cohort. The 3-year cumulative incidence of atopic march progression was lower in the DUPI-cohort than the CONV-cohort (20.09% vs 27.22%; P < .001). The DUPI-cohort demonstrated significant risk reduction in atopic march progression (hazard ratio [HR] 0.68, 95% CI 0.55-0.83), individual asthma (HR 0.60, 0.45-0.81), and individual AR (HR 0.69, 0.54-0.88). Younger patients on dupilumab exhibited a greater risk reduction for atopic march progression and individual asthma, contrasting with the opposite age-related pattern for individual AR. LIMITATIONS: Observational study. CONCLUSION: Among pediatric AD patients, dupilumab was associated with reduced risk of atopic march progression compared with conventional therapies.

Psoriatic arthritis risk in psoriasis patients prescribed acitretin versus disease-modifying antirheumatic drugs: a nationwide cohort study.

OBJECTIVES: To compare the risk of psoriatic arthritis (PsA) in psoriasis (PsO) patients treated with acitretin vs disease-modifying antirheumatic drugs (DMARDs). METHODS: This retrospective study used Taiwan's National Health Insurance Research Database from 1997 to 2013. Adult PsO patients without PsA prescribed acitretin or DMARDs for ≥30 days within a year were assigned to the acitretin cohort or DMARDs cohort, respectively. Patients in the acitretin cohort prescribed DMARDs for >7 days, or in the DMARDs cohort prescribed acitretin for >7 days, were excluded. Cumulative incidence of PsA were determined within both cohorts using the Kaplan-Meier method. The hazard ratio (HR) comparing acitretin to DMARDs was calculated with Cox regression models, adjusting for demographic and clinical covariates including the use of non-steroidal anti-inflammatory drugs (NSAIDs) and comorbidities. RESULTS: The study included 1,948 patients in each cohort. The 5-year cumulative incidence of PsA in the acitretin cohort was lower than that in the reference cohort (7.52% vs 9.93%; P=0.005), with a more pronounced difference in the subpopulation receiving NSAIDs treatment. However, in subpopulations without NSAIDs treatment, the 5-year cumulative incidence of PsA in the acitretin cohort was comparable to the DMARDs cohort (5.26% vs 6.98%; P = 0.106). Acitretin was not associated with PsA development in PsO (HR 0.83, 95% confidence interval 0.65-1.05). This risk remained consistent regardless of adjustments for NSAID treatment and comorbidities. Other independent risk factors for PsA included female and NSAIDs treatment. CONCLUSION: Compared with DMARDs, acitretin was not associated with increased PsA risk in PsO patients.

Risk of Psychiatric Disorders in Patients with Psoriasis Prescribed Acitretin versus Disease-Modifying Antirheumatic Drugs: A Nationwide Matched Cohort Study.

BACKGROUND: Acitretin has been linked to the development of psychiatric disturbance. OBJECTIVES: The aim of this study was to assess the psychiatric hazards in patients with psoriasis prescribed acitretin compared with those prescribed disease-modifying antirheumatic drugs (DMARDs). METHODS: This is a nationwide matched cohort study. From Taiwan's National Health Insurance Research Database, adult patients with psoriasis between 1997 and 2013 were screened. Patients prescribed acitretin for at least 30 days per year on average (acitretin cohort) were matched 1:2 with those prescribed DMARDs for at least 30 days per year on average (reference cohort), by means of age, gender, and psoriasis duration. Patients prescribed medication of the corresponding cohort for more than 7 days during the observation period were excluded. Cumulative incidences of psychiatric disorders in both cohorts were plotted with the Kaplan-Meier method. The modified Cox regression models were constructed to estimate hazard ratios (HRs). RESULTS: In total, 1,152 and 2,304 patients in the acitretin and the reference cohorts, respectively, were included. The 4-year cumulative incidence of overall psychiatric disorders (19.62% vs. 12.06%; p < 0.001), mood disorders (12.81% vs. 7.67%; p < 0.001), and psychosis (7.21% vs. 4.63%; p < 0.001) in the acitretin cohort was significantly higher than that in the reference cohort. Acitretin was independently associated with psychiatric disorders (HR 1.51, 95% confidence interval [CI] 1.23-1.85). The risk is more accentuated in the subgroups of comorbid chronic liver disease (HR 2.60, 95% CI: 1.56-4.33) or psoriatic arthritis (HR 3.23, 95% CI: 1.75-5.97). Other independent risk factors included insomnia, acute coronary syndrome, females, and age. CONCLUSIONS: Compared with DMARDs, acitretin was associated with higher hazards of psychiatric disorders among psoriasis patients.

The Tumor Necrosis Factor-α Level in Platelet-Rich Plasma Might Be Associated with Treatment Outcome in Patients with Interstitial Cystitis/Bladder Pain Syndrome or Recurrent Urinary Tract Infection.

Using platelet-rich plasma (PRP) injections to treat urological diseases has attracted great attention. This study investigated the impact of cytokine concentrations in PRP on the treatment outcome of patients with recurrent urinary tract infection (rUTI) and interstitial cystitis/bladder pain syndrome (IC/BPS). Forty patients with IC/BPS and twenty-one patients with rUTI were enrolled for four-monthly repeated PRP injections. PRP was collected at the first injection and analyzed with multiplex immunoassays for 12 target cytokines. In patients with IC/BPS, a Global Response Assessment (GRA) score ≥ 2 was defined as a successful outcome. In rUTI patients, ≤2 episodes of UTI recurrence during one year of follow-up was considered a successful outcome. Nineteen (47.5%) patients with IC/BPS and eleven (52.4%) patients with rUTI had successful outcomes. The IC/BPS patients with successful outcomes had significantly lower levels of tumor necrosis factor-α (TNF-α) in their PRP than those with unsuccessful outcomes (p = 0.041). The rUTI patients with successful outcomes also had a lower level of TNF-α (p = 0.025) and a higher level of epidermal growth factor (p = 0.035) and transforming growth factor-ß2 (p = 0.024) in PRP than those with unsuccessful outcomes. A lower level of TNF-α in PRP might be a potentially predictive factor of treatment outcome.

Activating Transcription Factor 3 Diminishes Ischemic Cerebral Infarct and Behavioral Deficit by Downregulating Carboxyl-Terminal Modulator Protein.

Activating transcription factor 3 (ATF3) is a stress-induced transcription factor and a familiar neuronal marker for nerve injury. This factor has been shown to protect neurons from hypoxic insult in vitro by suppressing carboxyl-terminal modulator protein (CTMP) transcription, and indirectly activating the anti-apoptotic Akt/PKB cascade. Despite prior studies in vitro, whether this neuroprotective pathway also exists in the brain in vivo after ischemic insult remains to be determined. In the present study, we showed a rapid and marked induction of ATF3 mRNA throughout ischemia-reperfusion in a middle cerebral artery (MCA) occlusion model. Although the level of CTMP mRNA was quickly induced upon ischemia, its level showed only a mild increase after reperfusion. With the gain-of-function approach, both pre- and post-ischemic administration of Ad-ATF3 ameliorated brain infarct and neurological deficits. Whereas, with the loss-of-function approach, ATF3 knockout (KO) mice showed bigger infarct and worse functional outcome after ischemia. In addition, these congenital defects were rescued upon reintroducing ATF3 to the brain of KO mice. ATF3 overexpression led to a lower level of CTMP and a higher level of p-Akt(473) in the ischemic brain. On the contrary, ATF3 KO resulted in upregulation of CTMP and downregulation of p-Akt(473) instead. Furthermore, post-ischemic CTMP siRNA knockdown led to smaller infarct and better behaviors. CTMP siRNA knockdown increased the level of p-Akt(473), but did not alter the ATF3 level in the ischemic brain, upholding the ATF3→CTMP signal cascade. In summary, our proof-of-principle experiments support the existence of neuroprotective ATF3→CTMP signal cascade regulating the ischemic brain. Furthermore, these results suggest the therapeutic potential for both ATF3 overexpression and CTMP knockdown for stroke treatment.

Diagnostic performance of the thyroid imaging reporting and data system improved by color-coded acoustic radiation force pulse imaging.

OBJECTIVE: To explore the value of color-coded virtual touch tissue imaging (CCV) using acoustic radiation force pulse technology (ARFI) in diagnosing malignant thyroid nodules. METHODS: Images including 189 thyroid nodules were collected as training samples and a binary logistic regression analysis was used to calculate regression coefficients for Thyroid Imaging Reporting and Data System (TI-RADS) and CCV. An integrated prediction model (TI-RADS+CCV) was then developed based on the regression coefficients. Another testing dataset involving 40 thyroid nodules was used to validate and compare the diagnostic performance of TI-RADS, CCV, and the integrated predictive models using the receiver operating characteristic (ROC) curves. RESULTS: Both TI-RADS and CCV are independent predictors. The diagnostic performance advantage of CCV is insignificant compared to TI-RADS (P = 0.61). However, the diagnostic performance of the integrated prediction model is significantly higher than that of TI-RADS or CCV (all P < 0.05). Applying to the validation image dateset, the integrated predictive model yields an area under the curve (AUC) of 0.880. CONCLUSIONS: Developing a new predictive model that integrates the regression coefficients calculated from TI-RADS and CCV enables to achieve the superior performance of thyroid nodule diagnosis to that of using TI-RADS or CCV alone.

Glucose sensing by regulator of G protein signaling 1 (RGS1) plays a crucial role in coordinating defense in response to environmental variation in tomato.

Low light intensities affect the outbreak of plant diseases. However, the underlying molecular mechanisms remain poorly understood. High-performance liquid chromatography analysis of tomato (Solanum lycopersicum) revealed that apoplastic glucose (Glc) levels decreased in response to low light. Conversely, low-light-induced susceptibility to Pseudomonas syringae pv tomato (Pst) DC3000 was significantly alleviated by exogenous Glc treatment. Using cell-based biolayer interferometry assays, we found that Glc specifically binds to the tomato regulator of G protein signaling 1 (RGS1). Laser scanning confocal microscopy imaging revealed that Glc triggers RGS1 endocytosis, which influences the uncoupling of the RGS1-Gα (GPA1) and GPA1-Gß (SlGB1) proteins, in a dose- and duration-dependent manner. Analysis of G protein single and double mutants revealed that RGS1 negatively regulates disease resistance under low light and is required for Glc-enhanced defense. Downstream of RGS1-Glc binding, GPA1 negatively mediates the light-intensity-regulated defense, whereas SlGB1 positively regulates this process. These results reveal a novel light-intensity-responsive defense system that is mediated by a Glc-RGS1-G protein signaling pathway. This information will be critical for future investigations of how plant cells sense extracellular sugars and adjust defense under different environments, as well as for genetic engineering approaches to improve stress resilience.

Association between early life laxative exposure and risk of allergic diseases A nationwide matched cohort study.

BACKGROUND: The early life microbiome can shape human immunity. Recent studies have revealed gut dysbiosis after laxative administration. OBJECTIVE: To investigate the impact of infantile laxative exposure on subsequent allergic diseases. METHODS: This nationwide matched cohort study was conducted using Taiwan's National Health Insurance Research Database for the period 1997 to 2013. A total of 32,986 patients who had complete information of maternal history and delivery modes were identified. We included 291 children having laxatives for at least 7 days within the first 6 months of life and 1164 reference children not receiving laxatives, matching by sex, propensity score, number of hospital visits, and maternal age at delivery. Demographic characteristics and maternal factors were compared, and cumulative incidences of allergic diseases were calculated. Cox proportional hazard model was used to evaluate associations. RESULTS: The 5-year cumulative incidence of allergic diseases in the laxative cohort was significantly higher than that in the reference cohort (49.81% vs 41.68%; P = .01). Early life laxative exposure (adjusted hazard ratio, 1.61; 95% confidence interval, 1.32-1.97) was independently associated with allergic disease development. Other independent risk factors included preterm, male sex, maternal allergic diseases, and prenatal laxative use. Multivariable stratified analyses verified the association between early life laxative exposure and subsequent allergic disease development in all subgroups of children, including those born to mothers without allergic diseases or prenatal laxative use. CONCLUSION: Early life laxative exposure is associated with allergic disease development.

Long-Term Risk of Autoimmune Diseases other than Systemic Lupus Erythematosus in Cutaneous Lupus Erythematosus-Alone Patients: A 10-Year Nationwide Cohort Study.

BACKGROUND: Up to 25% of patients with cutaneous lupus erythematosus (CLE) can develop systemic lupus erythematosus (SLE). However, the risk of autoimmune diseases other than SLE in CLE patients who have only skin manifestations (CLE-alone) has rarely been explored. OBJECTIVE: To investigate the long-term risk and independent factors of non-SLE autoimmune diseases among CLE-alone patients. METHOD: A nationwide cohort study using the Taiwanese National Health Insurance Research Database 1997-2013. CLE patients and matched subjects were included. Cumulative incidences of autoimmune diseases after 1 year of CLE-alone diagnosis were compared. Cox proportional hazard model was also performed. RESULTS: A total of 971 CLE-alone patients and 5,175 reference subjects were identified. The 10-year cumulative incidence of autoimmune diseases other than SLE was significantly elevated in the CLE-alone cohort (9.00%, 95% confidence interval [CI] 6.72-11.29) than in the reference cohort (4.20%, 95% CI 3.53-4.87%) (p < 0.001). CLE-alone was independently associated with non-SLE autoimmune diseases (adjusted hazard ratio 1.55, 95% CI 1.10-2.18). Among CLE-alone patients, females and those taking long-term systemic corticosteroids (a proxy for extensive disease) were associated with non-SLE autoimmune diseases after adjusting for the number of repeated autoimmune laboratory tests. CONCLUSION: CLE-alone is independently associated with future non-SLE autoimmune diseases.

Anti-Inflammatory Effects of Phytochemical Components of Clinacanthus nutans.

Recent studies on the ethnomedicinal use of Clinacanthus nutans suggest promising anti-inflammatory, anti-tumorigenic, and antiviral properties for this plant. Extraction of the leaves with polar and nonpolar solvents has yielded many C-glycosyl flavones, including schaftoside, isoorientin, orientin, isovitexin, and vitexin. Aside from studies with different extracts, there is increasing interest to understand the properties of these components, especially regarding their ability to exert anti-inflammatory effects on cells and tissues. A major focus for this review is to obtain information on the effects of C. nutans extracts and its phytochemical components on inflammatory signaling pathways in the peripheral and central nervous system. Particular emphasis is placed on their role to target the Toll-like receptor 4 (TLR4)-NF-kB pathway and pro-inflammatory cytokines, the antioxidant defense pathway involving nuclear factor erythroid-2-related factor 2 (NRF2) and heme oxygenase 1 (HO-1); and the phospholipase A2 (PLA2) pathway linking to cyclooxygenase-2 (COX-2) and production of eicosanoids. The ability to provide a better understanding of the molecular targets and mechanism of action of C. nutans extracts and their phytochemical components should encourage future studies to develop new therapeutic strategies for better use of this herb to combat inflammatory diseases.

Color-map virtual touch tissue imaging (CMV) combined with BI-RADS for the diagnosis of breast lesions.

OBJECTIVE: To investigate the importance of color-map virtual touch tissue imaging (CMV) in assisting Breast Imaging Reporting and Data Systems (BI-RADS) in diagnosing malignant breast lesions. METHODS: A dataset included 134 patients and 146 breast lesions was assembled. All patients underwent biopsy or surgical excision of breast lesions, and pathological results were obtained. All patients with breast lesions also underwent conventional ultrasound (US) and CMV. Each lesion was assigned a CMV score based on the color pattern of the lesion and surrounding breast tissue and a BI-RADS classification rating based on US characteristics. We compared the diagnostic performance of using BI-RADS and CMV separately and their combination. RESULTS: BI-RADS (odds ratio [OR]: 3.665; 95% confidence interval [CI]: 2.147, 6.258) and CMV (OR: 6.616; 95% CI: 2.272, 19.270) were independent predictors of breast malignancy (all P < 0.05). The area under the receiver operating characteristic curves (AUC) for either CMV or BI-RADS alone was inferior to that of the combination (0.877 vs. 0.962; 0.938 vs. 0.962; all P < 0.05). CONCLUSIONS: The performance of BI-RADS in diagnosing breast lesions is significantly improved by combining CMV. Therefore, we recommend CMV as an adjunct to BI-RADS.

Fracture risks in patients with atopic dermatitis: A nationwide matched cohort study.

BACKGROUND: The risk of osteoporosis has been explored in atopic dermatitis (AD). The long-term risk of fractures in patients with AD and the effects of various AD treatments on bone health remain to be elucidated. OBJECTIVE: To evaluate the long-term risk of fractures in patients with AD. METHODS: This nationwide matched cohort study was conducted using the National Health Insurance Research Database of Taiwan for the period 1997 to 2013. A total of 36,855 patients with AD and 147,420 reference subjects without AD were identified. Demographic characteristics and comorbidities were compared, and cumulative incidence of fractures was evaluated. Adjusted hazard ratios for fracture risks of AD and various AD treatments were calculated using the Cox proportional hazards model. RESULTS: A total of 1518 patients (4.12%) in the AD cohort and 5579 patients (3.78%) in the reference cohort had fractures (P = .003). The mean ages were 22.6 years in both groups. The 16-year cumulative incidence of fractures in the AD cohort (8.043%) was significantly higher than that in the reference cohort (7.366%) (P = .002). Severe AD (adjusted hazard ratio [aHR], 1.31; 95% confidence interval [CI], 1.08-1.59) was independently associated with fractures. Other independent risk factors included exposure to topical (aHR, 1.21; 95% CI, 1.05-1.39) or systemic (≥10 mg/d; aHR, 1.62; 95% CI, 1.38-1.91) corticosteroids. Use of disease-modifying antirheumatic drugs (aHR, 0.71; 95% CI, 0.53-0.90) and phototherapy (aHR, 0.73; 95% CI, 0.56-0.95) was associated with a lower risk of fractures. The results were consistent across sensitivity analyses. CONCLUSION: Patients with AD have a higher incidence of fractures. Severe AD is independently associated with fractures.

Recurrent cutaneous necrotising eosinophilic vasculitis.

Recurrent cutaneous necrotising eosinophilic vasculitis (RCNEV) is a rare disease that was first described in 1994. We report a case of RCNEV treated with corticosteroid, and 18 cases that we identified in the literature. Our review of the literature shows that RCNEV was frequently identified in middle-aged females from Asia and usually presents as erythematous to purpuric papuloplaques, angio-oedema on the extremities, as well as peripheral eosinophilia. Histopathologically, RCNEV is characterised by exclusively eosinophilic infiltration around the vascular plexus, the absence of leukocytoclasis and fibrinoid degeneration of vascular walls. Although, RCNEV responds to corticosteroid treatment, relapses have occurred during dose tapering. We also discuss the mechanisms of vascular destruction, the differential diagnosis and steroid-sparing therapies for RCNEV.

Intravesical injections of platelet-rich plasma is effective and safe in treatment of interstitial cystitis refractory to conventional treatment-A prospective clinical trial.

AIMS: Current treatments for interstitial cystitis/bladder pain syndrome (IC/BPS) are usually unsuccessful in achieving long-term bladder pain relief and irritable symptom improvement. This study investigated the clinical efficacy of platelet-rich plasma (PRP) intravesical injections on IC/BPS patients refractory to conventional therapies. METHODS: Forty patients received four monthly intravesical injections of 10 mL PRP extracted from 50 mL of whole blood. The primary end-point was Global Response Assessment (GRA) at 3 months after the 4th PRP injection. Secondary endpoints included changes in O'Leary-Sant symptom score (OSS), visual analog scale (VAS) of pain, daily frequency, nocturia, functional bladder capacity (FBC), maximum flow rate, voided volume, post-void residual volume (PVR) from baseline to 3 months after the 4th PRP injection. RESULTS: All 40 patients (37 women and 3 men, aged 55.5 ± 11.1 years) completed the four injections and follow-up visits. GRA improved after the 1st PRP injection and the satisfaction persists till the primary end-point. The success rate was 45%, 52%, 70%, 70%, and 67.5% after the 1st, 2nd, 3rd, 4th, and 3 months after the 4th PRP injection, respectively. OSS and VAS also significantly decreased. The PVR did not change after repeated PRP injections, FBC increased, frequency, and nocturia were decreased after PRP injections. All patients were free of urinary tract infection or difficulty urinating. CONCLUSION: The study demonstrated that repeated intravesical injections of autologous PRP can increase bladder capacity and provide IC symptom improvement in patients with IC/BPS refractory to conventional therapy. Autologous PRP injection is safe and effective in selected patients.

Risk of skin cancer in psoriasis patients receiving long-term narrowband ultraviolet phototherapy: Results from a Taiwanese population-based cohort study.

BACKGROUND: Narrowband ultraviolet B (NB-UVB) phototherapy is a widely used treatment for various dermatoses. The risk of skin cancer following long-term NB-UVB phototherapy has rarely been explored in skin phototypes III-V. METHODS: We conducted a nationwide-matched cohort study and identified a total of 22 891 psoriasis patients starting NB-UVB phototherapy from the Taiwan National Health Insurance Database during the period 2000-2013. Cumulative incidences of skin cancers were compared between subjects receiving less than 90 UVB treatments (S-cohort, N = 13 260) and age- as well as propensity score-matched subjects receiving more than or equal to 90 UVB treatments (L-cohort, N = 3315). RESULTS: There were no significant differences in the overall cumulative incidences of skin cancers between the two cohorts (log-rank t test, P = 0.691) during the follow-up periods. The S-cohort had a significantly lower prevalence of actinic keratosis when compared with the L-cohort (0.54% vs 1.00%, P = 0.005). CONCLUSION: Long-term NB-UVB phototherapy does not increase skin cancer risk compared with short-term NB-UVB phototherapy in psoriasis patients with skin phototypes III-V.

Study of the antitumor mechanisms of apiole derivatives (AP-02) from Petroselinum crispum through induction of G0/G1 phase cell cycle arrest in human COLO 205 cancer cells.

BACKGROUND: Apiole was isolated from the leaves of various plants and vegetables and has been demonstrated to inhibit human colon cancer cell (COLO 205 cells) growth through induction of G0/G1 cell cycle arrest and apoptotic cell death. This study further explored the antitumor effects of apiole derivatives AP-02, 04, and 05 in COLO 205 cancer cells. METHODS: Human breast (MDA-MB-231, ZR75), lung (A549, PE089), colon (COLO 205, HT 29), and hepatocellular (Hep G2, Hep 3B) cancer cells were treated with apiole and its derivatives in a dose-dependent manner. Flow cytometry analysis was subsequently performed to determine the mechanism of AP-02-induced G0/G1 cell cycle arrest. The in vivo antitumor effect of AP-02 (1 and 5 mg/kg, administered twice per week) was examined by treating athymic nude mice bearing COLO 205 tumor xenografts. The molecular mechanisms of AP-02-induced antitumor effects were determined using western blot analysis. RESULTS: AP-02 was the most effective compound, especially for inhibition of COLO 205 colon cancer cell growth. The cytotoxicity of AP-02 in normal colon epithelial (FHC) cells was significantly lower than that in other normal cells derived from the breast, lung or liver. Flow cytometry analysis indicated that AP-02-induced G0/G1 cell cycle arrest in COLO 205 cells but not in HT 29 cells (< 5 µM for 24 h, **p < 0.01). Tumor growth volume was also significantly inhibited in AP-02 (> 1 mg/kg)-treated athymic nude mice bearing COLO 205 tumor xenografts compared to control mice (*p < 0.05). Furthermore, G0/G1 phase regulatory proteins (p53 and p21/Cip1) and an invasion suppressor protein (E-cadherin) were significantly upregulated, while cyclin D1 was significantly downregulated, in AP-02-treated tumor tissues compared to the control group (> 1 mg/kg, *p < 0.05). CONCLUSIONS: Our results provide in vitro and in vivo molecular evidence of AP-02-induced anti-proliferative effects on colon cancer, indicating that this compound might have potential clinical applications.

Identifying rural-urban differences in the predictors of emergency ambulance service demand and misuse.

OBJECTIVE: This study aims to assess rural-urban differences in the predictors of emergency ambulance service (EAS) demand and misuse in New Taipei City. Identifying the predictors of EAS demand will help the EAS service managing authority in formulating focused policies to maintain service quality. METHODS: Over 160,000 electronic EAS usage records were used with a negative binomial regression model to assess rural-urban differences in the predictors of EAS demand and misuse. RESULTS: The factors of 1) ln-transformed population density, 2) percentage of residents who completed up to junior high school education, 3) accessibility of hospitals without an emergency room, and 4) accessibility of EAS were found to be predictors of EAS demand in rural areas, whereas only the factor of percentage of people aged above 65 was found to predict EAS demand in urban areas. For EAS misuse, only the factor of percentage of low-income households was found to be a predictor in rural areas, whereas no predictor was found in the urban areas. CONCLUSION: Results showed that the factors predicting EAS demand and misuse in rural areas were more complicated compared to urban areas and, therefore, formulating EAS policies for rural areas based on the results of urban studies may not be appropriate.