RECENT FINDINGS: Several F-box containing proteins have been characterized either as tumor suppressors (FBXW8, FBXL3, FBXW8, FBXL3, FBXO1, FBXO4, and FBXO18) or as oncogenes (FBXO5, FBXO9, and SKP2). Besides, F-box members like βTrcP1 and βTrcP2, the ones with context-dependent functionality, have also been studied and reported. FBXW7 is a well-studied F-box protein and is a tumor suppressor. FBXW7 regulates the activity of a range of substrates, such as c-Myc, cyclin E, mTOR, c-Jun, NOTCH, myeloid cell leukemia sequence-1 (MCL1), AURKA, NOTCH through the well-known ubiquitin-proteasome system (UPS)-mediated degradation pathway. NOTCH signaling is a primitive pathway that plays a crucial role in maintaining normal tissue homeostasis. FBXW7 regulates NOTCH protein activity by controlling its half-life, thereby maintaining optimum protein levels in tissue. However, aberrations in the FBXW7 or NOTCH expression levels can lead to poor prognosis and detrimental outcomes in patients. Therefore, the FBXW7-NOTCH axis has been a subject of intense study and research over the years, especially around the interactome's role in driving cancer development and progression. Several studies have reported the effect of FBXW7 and NOTCH mutations on normal tissue behavior. The current review attempts to critically analyze these mutations prognostic value in a wide range of tumors. Furthermore, the review summarizes the recent findings pertaining to the FBXW7 and NOTCH interactome and its involvement in phosphorylation-related events, cell cycle, proliferation, apoptosis, and metastasis.
CONCLUSION: The review concludes by positioning FBXW7 as an effective diagnostic marker in tumors and by listing out recent advancements made in cancer therapeutics in identifying protocols targeting the FBXW7-NOTCH aberrations in tumors.
RECENT FINDINGS: Disordered immune reactions and release of cytokines with resultant gut inflammation and dysfunction appear to be key features of PI-IBS. Disordered brain-gut-microbiota interactions, type of infecting agent, and host-genetic susceptibility are risk factors but also are reasons for the varying spectrum of clinical severity. Although prognosis is generally good, symptoms and inflammation may persist for a long time. Symptomatic relief with antidiarrheals, antispasmodics, 5HT3 antagonists, mesalamine, probiotics, and low-dose antidepressants remain the primary approaches, but in some difficult cases, a combination of drugs that target the pathophysiology may be helpful. PI-IBS has many overlapping features with IBS-D and shares similar pathophysiology and management approaches.
METHOD: We completed a prospective, double-blinded, randomized placebo-control trial of azithromycin among pre-school children (12 to 60 months of age) presenting to the emergency department with wheeze. Patients were randomized to receive either five days of azithromycin or placebo. Primary outcome was time to resolution of respiratory symptoms after treatment initiation. Secondary outcomes included the number of days children used a Short-Acting Beta-Agonists during the 21 day follow-up and time to disease exacerbation during the following six months (unscheduled health care visit or treatment with an oral corticosteroid for acute respiratory symptoms).
RESULTS: Of the 300 wheezing children recruited, 222 and 169 were analyzed for the primary and secondary outcomes, respectively. The treatment groups had similar demographics and clinical parameters at baseline. Median time to resolution of respiratory symptoms was four days for both treatment arms (interquartile range (IQR) 3,6; p = 0.28). Median number of days of Short-Acting Beta-Agonist use among those who received azithromycin was four and a half days (IQR 2, 7) and five days (IQR 2, 9; p = 0.22) among those who received placebo. Participants who received azithromycin had a 0.91 hazard ratio for time to six-month exacerbation compared to placebo (95% CI 0.61, 1.36, p = 0.65). A pre-determined subgroup analysis showed no differences in outcomes for children with their first or repeat episode of wheezing. There was no significant difference in the proportion of participants experiencing an adverse event.
CONCLUSION: Azithromycin neither reduced duration of respiratory symptoms nor time to respiratory exacerbation in the following six months after treatment among wheezing preschool children presenting to an emergency department. There was no significant effect among children with either first-time or prior wheezing.
METHODS AND RESULTS: This is a 15-year retrospective cohort study of 825 hypertensive patients. Blood pressure readings every 3 months were retrieved from the 15 years of clinic visits. We used SD and coefficient of variation as a measure of systolic BPV. Serum creatinine was captured and estimated glomerular filtration rate was calculated at baseline, 5, 10, and 15 years. The mean SD of SBP was 14.2±3.1 mm Hg and coefficient of variation of SBP was 10.2±2%. Mean for estimated glomerular filtration rate slope was -1.0±1.5 mL/min per 1.73 m2 per year. There was a significant relationship between BPV and slope of estimated glomerular filtration rate (SD: r=-0.16, P<0.001; coefficient of variation: r=-0.14, P<0.001, Pearson's correlation). BPV of SBP for each individual was significantly associated with slope of estimated glomerular filtration rate after adjustment for mean SBP and other confounders. The cutoff values estimated by the receiver operating characteristic curve for the onset of chronic kidney disease for SD of SBP was 13.5 mm Hg and coefficient of variation of SBP was 9.74%.
CONCLUSIONS: Long-term visit-to-visit variability of SBP is an independent determinant of renal deterioration in patients with hypertension. Hence, every effort should be made to reduce BPV in order to slow down the decline of renal function.
Objective: To determine an association of single nucleotide polymorphisms in ESR2 with salt sensitivity of blood pressure (SSBP) and estrogen status in women.
Methods: Candidate gene association study with ESR2 and SSBP conducted in normotensive and hypertensive women and men in two cohorts: International Hypertensive Pathotype (HyperPATH) (n = 584) (discovery) and Mexican American Hypertension-Insulin Resistance Study (n = 662) (validation). Single nucleotide polymorphisms in ESR1 (ER-α) were also analyzed. Analysis conducted in younger (<51 years, premenopausal, "estrogen-replete") and older women (≥51 years, postmenopausal, "estrogen-deplete"). Men were analyzed to control for aging.
Results: Multivariate analyses of HyperPATH data between variants of ESR2 and SSBP documented that ESR2 rs10144225 minor (risk) allele carriers had a significantly positive association with SSBP driven by estrogen-replete women (β = +4.4 mm Hg per risk allele, P = 0.004). Findings were confirmed in Hypertension Insulin-Resistance Study premenopausal women. HyperPATH cohort analyses revealed risk allele carriers vs noncarriers had increased aldosterone/renin ratios. No associations were detected with ESR1.
Conclusions: The variation at rs10144225 in ESR2 was associated with SSBP in premenopausal women (estrogen-replete) and not in men or postmenopausal women (estrogen-deplete). Inappropriate aldosterone levels on a liberal salt diet may mediate the SSBP.
OBJECTIVE: This study aims to measure the economic burden of T2DM as the primary diagnosis for hospitalization from provider's perspective.
METHODS: A retrospective prevalence-based costing study was conducted in a teaching hospital. Financial administrative data and inpatient medical records of patients with primary diagnosis (International Classification Disease-10 coding) E11 in the year 2013 were included in costing analysis. Average cost per episode of care and average cost per outpatient visit were calculated using gross direct costing allocation approach.
RESULTS: Total admissions for T2DM as primary diagnosis in 2013 were 217 with total outpatient visits of 3214. Average cost per episode of care was RM 901.51 (US$ 286.20) and the average cost per outpatient visit was RM 641.02 (US$ 203.50) from provider's perspective. The annual economic burden of T2DM for hospitalized patients was RM 195,627.67 (US$ 62,104) and RM 2,061,520.32 (US$ 654,450) for those being treated in the outpatient setting.
CONCLUSIONS: Economic burden to provide T2DM care was higher in the outpatient setting due to the higher utilization of the health-care service in this setting. Thus, more focus toward improving T2DM outpatient service could mitigate further increase in health-care cost from this chronic disease.
DESIGN: Prospective, longitudinal study.
METHODS: Sixty-five NTG patients who were followed up for 5 years are included in this study. All the enrolled patients underwent baseline 24-h IOP and BP monitoring via 2-hourly measurements in their habitual position and were followed up for over 5 years with reliable VF tests. Modified Anderson criteria were used to assess VF progression. Univariable and multivariable analyses using Cox's proportional hazards model were used to identify the systemic and clinical risk factors that predict progression. Kaplan-Meier survival analyses were used to compare the time elapsed to confirmed VF progression in the presence or absence of each potential risk factor.
RESULTS: At 5-year follow-up, 35.4% of the enrolled patients demonstrated visual field progression. There were statistically significant differences in the mean diastolic blood pressure (p 43.7 mmHg (log rank = 0.018).
CONCLUSION: Diastolic parameters of BP and OPP were significantly lower in the NTG patients who progressed after 5 years. Low nocturnal DOPP is an independent predictor of glaucomatous visual field progression in NTG patients.
OBJECTIVE: To investigate the expression of human inflammatory cytokines in chronic hepatitis B patients according to the severity of the infection.
METHODS: We recruited a total of 120 patients, 40 of whom from cirrhotic, 40 non-cirrhotic, and 40 acute flare chronic hepatitis B and 40 healthy controls. For all groups total cellular RNA was extracted from whole blood samples, genomic DNA was eliminated, and cDNA was synthesized using the RT2 first strand kit, as instructed by the manufacturer. The real-time profiler PCR array was performed on a master cycler ep realplex and the data were analyzed using an online data analysis software.
RESULTS: Non-cirrhotic chronic hepatitis B patients were found to significantly upregulate interleukin 10 receptors that regulate the balance between T helpers 1 and 2. On the other hand, patients with cirrhosis were found to have significant upregulated interleukin 3 gene expression.
CONCLUSION: Our finding suggests that upregulation of anti-inflammatory and downregulation of pro-inflammatory cytokines may play a role in the progression of non-cirrhotic chronic hepatitis B patients to cirrhotic and acute flare. However, a multi-center study with a larger sample size is needed to confirm our findings.
STATEMENT OF SIGNIFICANCE: In this study, we developed a silk scaffold with increased stiffness and SDF-1 controlled release capacity for ligament repair. This advanced scaffold transplantation combined with intra-articular injection of LSPCs (which was isolated from rabbit ligament for the first time in this study) promoted the regeneration of both the tendinous and bone tunnel portion of ACL. This therapeutic strategy also ameliorated cartilage degeneration and reduced the severity of arthrofibrosis. Hence, combining LSPCs injection with SDF-1-releasing silk scaffold is demonstrated as a therapeutic strategy for ACL regeneration and OA treatment in the clinic.