BPR1K653, a Novel Aurora Kinase Inhibitor, Exhibits Potent Anti-Proliferative Activity in MDR1 (P-gp170)-Mediated Multidrug-Resistant Cancer Cells

Over-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells.BPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats.BPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments

The Adjuvant Therapy of Intravenous Laser Irradiation of Blood (ILIB) on Pain and Sleep Disturbance of Musculoskeletal Disorders

(1) Background: Musculoskeletal pain is both intractable and irritating. Intravenous Laser Irradiation of Blood (ILIB) therapy has been used as pain control treatment for this condition. However, there remains a lack of clear evidence regarding ILIB on pain control. This study aimed to reveal the result of changes in patient pain intensity after receiving ILIB therapy. (2) Methods: We conducted a retrospective analysis of pain scores and sleep quality from 76 patients diagnosed with musculoskeletal disease who received three courses of ILIB therapy. Each course included ten sessions of ILIB treatment over ten consecutive days. During ILIB therapy, patients were inserted with a laser fiber optic needle which irradiated blood cells via a 632.8 nm Helium-Neon laser light over a period of 60 min. Pain scores were evaluated using the Visual Analogue Scale (VAS), whereas sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). These scores would be recorded both before and after each ILIB treatment course. (3) Results: The mean of all patients’ initial VAS score was 5.35. After completing three courses of ILIB treatment, the mean VAS score decreased to 2.2, which indicated a significant reduction in pain intensity. Additionally, patients experienced sleep quality improvement levels from PSQI 8.97 to 5.53 upon completion of three courses of ILIB treatment. (4) Conclusions: Intravenous Laser Irradiation of Blood (ILIB) resulted in a positive pain control effect on patients with musculoskeletal disease, especially for those with moderate to severe pain intensity (initial VAS score >4). Additionally, patients experienced better sleep quality as a result of their pain relief after receiving ILIB treatment

CAST as a Potential Oncogene, Identified by Machine Search, in Gastric Cancer Infiltrated with Macrophages and Associated with Lgr5

Background: Gastric cancer (GC) is one of the leading malignant diseases worldwide, especially in Asia. CAST is a potential oncogene in GC carcinogenesis. The character of macrophage infiltration in the GC microenvironment also remains unaddressed. Methods: We first applied machine searching to evaluate gene candidates for GC. CAST expression and pan-cancer surveyance were analyzed using the Human Protein Atlas (HPA) and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database. The protein–protein interaction (PPI) network was downloaded from STRING. We investigated the impact of CAST on clinical prognosis using a Kaplan–Meier plotter. The correlations between CAST and Lgr5 and macrophage infiltration in GC were determined using TIMER 2.0. Finally, GeneMANIA was also used to evaluate the possible functional linkages between genes. Results: After the machine-assisted search, CAST expression was found to significantly influence the overall survival of GC patients. STRING revealed CAST-related proteomic and transcriptomic associations, mainly concerning the CAPN family. Moreover, CAST significantly impacts the prognosis of GC based on the validation of other datasets. Notably, high CAST expression was correlated with worse overall survival in GC patients (hazard ratio = 1.59; log-rank P = 9.4 × 10−8). CAST and Lgr5 expression were both positively correlated with WNT 2 and WNT 2B. Among the GC patients in several datasets, CAST and macrophage infiltration, evaluated together, showed no obvious association with poor clinical overall survival. Conclusions: CAST plays an important role in the clinical prognosis of GC and is associated with WNT 2/WNT 2B/Lgr5. Our study demonstrates that CAST’s influence on overall survival in GC is regulated by macrophage infiltration

Association between Appendicitis and Incident Systemic Sclerosis

Objective: This nationwide study aimed to investigate the association between newly diagnosed systemic sclerosis (SSc) and previous appendicitis history. Methods: A total of 1595 patients who were newly diagnosed with SSc were recruited as the SSc cases from the 2003 to 2012 claims data of the entire population in Taiwan. The other 15,950 individuals who had never been diagnosed with SSc during 2003 and 2012 were selected as the non-SSc controls to match the SSc cases. We defined that the index date as the first date of SSc diagnosis of SSc cases and the first date of ambulatory visit for any reason of non-SSc controls. Conditional logistic regression analysis was applied for the association between appendicitis and the risk of the incident SSc, tested by estimating odds ratios (ORs) with 95% confidence intervals (CIs). Potential confounders, including the Charlson comorbidity index (CCI), a history of periodontal disease, salmonella infection, and intestinal infection, were controlled. We further designed sensitivity analyses by varying the definition of appendicitis according to the status of receiving primary appendectomy. Results: The mean age was 51 years in the case and control groups. Females accounted for 77.5%. A total of 17 (1.1%) out of 1595 SSc cases and 81 (0.5%) out of 15,950 non-SSc controls had a history of appendicitis before the index date had a history of appendicitis. A significant association between appendicitis and the risk of SSc was confirmed (OR, 2.03; 95% CI, 1.14–3.60) after adjusting potential confounders. CCI ≥ 1 (OR, 8.48; 95% CI, 7.50–9.58) and periodontal disease (OR, 1.55; 95% CI, 1.39–1.74) were also significantly associated with the risk of SSc. The association between appendicitis and SSc risk remained robust using various definitions of appendicitis. Conclusion: Our study demonstrated appendicitis was associated with the incident SSc. CCI ≥ 1 and periodontal disease also contributed to the risk of developing SSc

The effect of treatment timing and urinary drainage on the outcome of urinary tuberculosis

Background: Urinary tuberculosis (TB) has a variety of clinical manifestations and is a diagnostic challenge for urologists. Delayed treatment can lead to loss of renal function and structural destruction. In this study, we analyzed the relationship between the timing of treatment and outcomes in patients with urinary TB. Methods: We performed a retrospective chart review of all patients with urinary TB from 1978 to 2016 at our hospital and analyzed the patients' symptoms, diagnostic methods, imaging studies, time to diagnosis, treatment methods, and follow-up. Results: Twenty-one patients (median age: 49 years) had urinary TB, of whom 18 had hydronephrosis and hydroureter. No bilateral renal involvement was noted. The median duration from symptom onset to anti-TB treatment was 78.5 days. There was no significant relationship between symptom-to-treatment time and posttreatment changes in renal function (Pearson's r = 0.103, P > 0.05); however, the symptom-to-treatment time was linearly associated with pre- and posttreatment hydronephrosis grade (Pearson's r = 0.667, P= 0.03, and r = 0.710, P= 0.007, respectively). In multivariate analysis, the symptom-to-treatment time was found to be an independent predictor of improvements in hydronephrosis but was not associated with renal function change. Of nine patients with upper urinary tract drainage, hydronephrosis improved in three and was stable in five patients. Of 12 patients without drainage, four experienced renal loss. Conclusion: Urinary TB has vague clinical manifestations and is prone to a delayed diagnosis. Early diagnosis and prompt internal ureteral stenting may prevent renal loss in certain patients