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.
PURPOSE: With the rising number of older people in Malaysia, it is envisaged that the number of fragility hip fractures would also increase. The objective of this study was to determine patient characteristics and long-term outcomes of hip fracture in older individuals at a teaching hospital in Malaysia.
METHODS: This was a prospective observational study which included consecutive patients aged ≥ 65 years old admitted to the orthopedic ward with acute hip fractures between March 2016 and August 2018. Patient socio-demographic details, comorbidities, pre-fracture mobility status, fracture type, operation and anesthesia procedure, and length of stay were recorded. Post-fracture mobility status was identified at 6 months. Cox proportional hazard analysis was used to assess the risk of death in all patients.
RESULTS: 310 patients (70% women) with the mean age of 79.89 years (SD 7.24) were recruited during the study period. Of these, 284 patients (91.6%) underwent surgical intervention with a median time to surgery of 5 days (IQR 3-8) days. 60.4% of patients who underwent hip fracture surgery did not recover to their pre-fracture mobility status. One year mortality rate was 20.1% post hip fracture surgery. The independent predictor of mortality included advanced age (hazard ratio, HR = 1.05, 95% CI = 1.01-1.08; p = 0.01), dependency on activities of daily living (HR = 2.08, 95% CI = 1.26-3.45; p = 0.01), and longer length of hospitalization (HR = 1.02, 95% CI = 1.01-1.04; p
METHODS: SEIRV models were developed and validated using COVID-19 case and vaccination data from the Ministry of Health, Malaysia, from June 21, 2021 to July 21, 2021 to generate forecasts of COVID-19 cases from July 22, 2021 to December 31, 2021. Three scenarios were examined to measure the effects of vaccination on COVID-19 case trends. Scenarios 1 and 2 represented the trends taking into account the earliest and latest possible times of achieving full vaccination for 80% of the adult population by October 31, 2021 and December 31, 2021, respectively. Scenario 3 described a scenario without vaccination for comparison.
RESULTS: In scenario 1, forecasted cases peaked on August 28, 2021, which was close to the peak of observed cases on August 26, 2021. The observed peak was 20.27% higher than in scenario 1 and 10.37% lower than in scenario 2. The cumulative observed cases from July 22, 2021 to December 31, 2021 were 13.29% higher than in scenario 1 and 55.19% lower than in scenario 2. The daily COVID-19 case trends closely mirrored the forecast of COVID-19 cases in scenario 1 (best-case scenario).
CONCLUSIONS: Our study demonstrated that COVID-19 vaccination reduced COVID-19 case trends during the Delta outbreak. The compartmental models developed assisted in the management and control of the COVID-19 pandemic in Malaysia.
OBJECTIVES: QoL studies in patients with HAE have not been carried out in the Indian subcontinent. Hence, we carried out this study to assess the QoL and to identify factors associated with impaired QoL in patients with HAE.
METHODS: This was a cross-sectional observational study carried out in confirmed cases of HAE, aged >18 years, using angioedema QoL score and angioedema control test.
RESULTS: We enrolled 135 patients with HAE (aged 18-80 years) with a mean age of 40.93 years. We observed that the QoL directly correlates with angioedema control and is also affected by other factors such as gender, duration of follow-up, and the frequency of episodes. Genitalia swelling, positive family history, and presence of mortality due to HAE in the family also significantly impact the QoL of patients with HAE. In addition, patients with type 1 HAE reported a poorer QoL as compared to patients with type 2 HAE.
CONCLUSION: We report the QoL of patients with HAE from settings where none of the first-line medications are available. Results of the study suggest that disease control is the most important factor that influences the QoL.
METHODS: Plasma samples were collected in a randomised, placebo-controlled, double-blind, cross-over trial (DIAMOND, NCT03190694, n = 53) that assessed the effects of 10 mg of dapagliflozin in patients with a glomerular filtration rate ≥ 25 mL/min/1.73 m2 and proteinuria > 500 mg/day. Mixed-effects models were used to develop a pharmacokinetic model and to evaluate the association between plasma exposure and response.
RESULTS: Plasma concentrations (n = 430 observations) from 48 patients (mean age 50.8 years, mean glomerular filtration rate 57.9 mL/min/1.73 m2, median proteinuria 1115 mg/24 h) were best described using a two-compartment model with first-order elimination. Apparent clearance and volume of distribution were 11.7 (95% confidence interval 10.7-12.7) L/h and 44.9 (95% confidence interval 39.0-50.9) L, respectively. Median dapagliflozin plasma exposure was 740.9 ng h/mL (2.5th-97.5th percentiles: 434.0-1615.3). Plasma exposure increased with decreasing kidney function. Every 100-ng h/mL increment in dapagliflozin plasma exposure was associated with a decrease in the urinary albumin:creatinine ratio (β = - 2.8%, p = 0.01), glomerular filtration rate (β = - 0.5 mL/min/1.73 m2, p
OBJECTIVES: Our study intended to (i) resolve the taxonomic uncertainties between B. dorsalis and B. carambolae, (ii) reveal the population structure and global invasion routes of B. dorsalis across Asia, Africa, and Oceania, and (iii) identify genomic regions that are responsible for the thermal adaptation of B. dorsalis.
METHODS: Based on a high-quality chromosome-level reference genome assembly, we explored the population relationship using a genome-scale single nucleotide polymorphism dataset generated from the resequencing data of 487 B. dorsalis genomes and 25 B. carambolae genomes. Genome-wide association studies and silencing using RNA interference were used to identify and verify the candidate genes associated with extreme thermal stress.
RESULTS: We showed that B. dorsalis originates from the Southern India region with three independent invasion and spread routes worldwide: (i) from Northern India to Northern Southeast Asia, then to Southern Southeast Asia; (ii) from Northern India to Northern Southeast Asian, then to China and Hawaii; and (iii) from Southern India toward the African mainland, then to Madagascar, which is mainly facilitated by human activities including trade and immigration. Twenty-seven genes were identified by a genome-wide association study to be associated with 11 temperature bioclimatic variables. The Cyp6a9 gene may enhance the thermal adaptation of B. dorsalis and thus boost its invasion, which tended to be upregulated at a hardening temperature of 38 °C. Functional verification using RNA interference silencing against Cyp6a9, led to the specific decrease in Cyp6a9 expression, reducing the survival rate of dsRNA-feeding larvae exposed to extreme thermal stress of 45 °C after heat hardening treatments in B. dorsalis.
CONCLUSION: This study provides insights into the evolutionary history and genetic basis of temperature adaptation in B. dorsalis.
METHODS: EU-COVAT-1-AGED Part A is a randomised controlled, adaptive, multicentre phase II trial evaluating safety and immunogenicity of a 3rd vaccination (1st booster) in individuals ≥75 years. Fifty-three participants were randomised to full-doses of either mRNA-1273 (Spikevax®, 100 µg) or BNT162b2 (Comirnaty®, 30 µg). The primary endpoint was the rate of 2-fold circulating antibody titre increase 14 days post-vaccination measured by quantitative electrochemiluminescence (ECL) immunoassay, targeting RBD region of Wuhan wild-type SARS-CoV-2. Secondary endpoints included the changes in neutralising capacity against wild-type and 25 variants of concern at 14 days and up to 12 months. Safety was assessed by monitoring of solicited adverse events (AEs) for seven days after on-study vaccination. Unsolicited AEs were collected until the end of follow-up at 12 months, SAEs were pursued for a further 30 days.
RESULTS: Between 08th of November 2021 and 04th of January 2022, 53 participants ≥75 years received a COVID-19 vaccine as 1st booster. Fifty subjects (BNT162b2 n = 25/mRNA-1273 n = 25) were included in the analyses for immunogenicity at day 14. The primary endpoint of a 2-fold anti-RBD IgG titre increase 14 days after vaccination was reached for all subjects. A 3rd vaccination of full-dose mRNA-1273 provided higher anti-RBD IgG titres (Geometric mean titre) D14 mRNA-127310711 IU/mL (95 %-CI: 8003;14336) vs. BNT162b2: 7090 IU/mL (95 %-CI: 5688;8837). We detected a pattern showing higher neutralising capacity of full-dose mRNA-1273 against wild-type as well as for 23 out of 25 tested variants.
INTERPRETATION: Third doses of either BNT162b2 or mRNA-1273 provide substantial circulating antibody increase 14 days after vaccination. Full-dose mRNA-1273 provides higher antibody levels with an overall similar safety profile for people ≥75 years.
FUNDING: This trial was funded by the European Commission (Framework Program HORIZON 2020).