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.
METHODS: Using a 17-segment model, coronary computed tomography angiography images were analyzed for subendocardial and transmural attenuation and the corresponding blood pool. The segment with the lowest subendocardial attenuation and transmural attenuation were normalized to the segment with the highest subendocardial and transmural attenuation, respectively (SUBnormalized, and TRANSnormalized, respectively). We evaluated the independent and incremental value of myocardial attenuation to predict the composite of cardiovascular death or nonfatal myocardial infarction.
RESULTS: Of a total of 995 coronary CTA VISION (Coronary Computed Tomographic Angiography and Vascular Events in Noncardiac Surgery Patients Cohort Evaluation Study) patients, 735 had available images and complete data for these analyses. Among these patients, 60 had MACE. Based on Revised Cardiovascular Risk Index, 257, 302, 138, and 38 patients had scores of 0, 1, 2, and ≥3, respectively. On coronary computed tomography angiography, 75 patients had normal coronary arteries, 297 patients had nonobstructive coronary artery disease, 264 patients had obstructive disease, and 99 patients had extensive obstructive coronary artery disease. SUBnormalized was an independent and incremental predictor of events in the model that included Revised Cardiovascular Risk Index and coronary artery disease severity. Compared with patients in the highest tertile of SUBnormalized, patients in the second and first tertiles had an increased hazards ratio for events (2.23 [95% CI, 1.091-4.551] and 2.36 [95% CI, 1.16-4.81], respectively). TRANSnormalized, as a continuous variable, was also found to be a predictor of MACE (P=0.027).
CONCLUSIONS: Our study demonstrates that SUBnormalized and TRANSnormalized are independent and incremental predictors of MACE 30 days after elective noncardiac surgery. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01635309.
PATIENTS AND METHODS: APEC was a nonrandomized phase 2 trial conducted in the Asia-Pacific region. Patients (n = 289) received once-every-2-weeks cetuximab with investigator's choice of chemotherapy (FOLFOX or FOLFIRI). The primary end point was best confirmed overall response rate (BORR); progression-free survival (PFS) and overall survival (OS) were secondary end points. Early tumor shrinkage (ETS) and depth of response (DpR) were also evaluated.
RESULTS: In the KRAS wt population, BORR was 58.8%, median PFS 11.1 months, and median OS 26.8 months. Expanded RAS mutational analysis revealed that patients with RAS wt mCRC had better outcomes (BORR = 64.7%; median PFS = 13.0 months; median OS = 28.4 months). The data suggest that ETS and DpR may be associated with survival outcomes in the RAS wt population. Although this study was not designed to formally assess differences in outcome between treatment subgroups, efficacy results appeared similar for patients treated with FOLFOX and FOLFIRI. There were no new safety findings; in particular, grade 3/4 skin reactions were within clinical expectations.
CONCLUSION: The observed activity and safety profile is similar to that reported in prior first-line pivotal studies involving weekly cetuximab, suggesting once-every-2-weeks cetuximab is effective and tolerable as first-line therapy and may represent an alternative to weekly administration.