Mechanism of Dimer Selectivity and Binding Cooperativity of BRAF Inhibitors.

Aberrant signaling of BRAFV600E is a major cancer driver. Current FDA-approved RAF inhibitors selectively inhibit the monomeric BRAFV600E and suffer from tumor resistance. Recently, dimer-selective and equipotent RAF inhibitors have been developed; however, the mechanism of dimer selectivity is poorly understood. Here, we report extensive molecular dynamics (MD) simulations of the monomeric and dimeric BRAFV600E in the apo form or in complex with one or two dimer-selective (PHI1) or equipotent (LY3009120) inhibitor(s). The simulations uncovered the unprecedented details of the remarkable allostery in BRAFV600E dimerization and inhibitor binding. Specifically, dimerization retrains and shifts the αC helix inward and increases the flexibility of the DFG motif; dimer compatibility is due to the promotion of the αC-in conformation, which is stabilized by a hydrogen bond formation between the inhibitor and the αC Glu501. A more stable hydrogen bond further restrains and shifts the αC helix inward, which incurs a larger entropic penalty that disfavors monomer binding. This mechanism led us to propose an empirical way based on the co-crystal structure to assess the dimer selectivity of a BRAFV600E inhibitor. Simulations also revealed that the positive cooperativity of PHI1 is due to its ability to preorganize the αC and DFG conformation in the opposite protomer, priming it for binding the second inhibitor. The atomically detailed view of the interplay between BRAF dimerization and inhibitor allostery as well as cooperativity has implications for understanding kinase signaling and contributes to the design of protomer selective RAF inhibitors.

The Fanconi anemia pathway and Breast Cancer: A comprehensive review of clinical data.

The development of breast cancer depends on several risk factors, including environmental, lifestyle and genetic factors. Despite the evolution of DNA sequencing techniques and biomarker detection, the epidemiology and mechanisms of various breast cancer susceptibility genes have not been elucidated yet. Dysregulation of the DNA damage response causes genomic instability and increases the rate of mutagenesis and the risk of carcinogenesis. The Fanconi Anemia (FA) pathway is an important component of the DNA damage response and plays a critical role in the repair of DNA interstrand crosslinks and genomic stability. The FA pathway involves 22 recognized genes and specific mutations have been identified as the underlying defect in the majority of FA patients. A thorough understanding of the function and epidemiology of these genes in breast cancer is critical for the development and implementation of individualized therapies that target unique tumor profiles. Targeted therapies (PARP inhibitors) exploiting the FA pathway gene defects have been developed and have shown promising results. This narrative review summarizes the current literature on the involvement of FA genes in sporadic and familial breast cancer with a focus on clinical data derived from large cohorts.

Hyponatremia as a marker of complicated appendicitis: A systematic review.

BACKGROUND: Acute appendicitis, the most common cause of acute surgical abdomen, is associated with intra-abdominal complications, such as perforation, that increase morbidity and mortality. Early and accurate preoperative diagnosis of complicated appendicitis mandates the identification of new diagnostic markers. This systematic review summarizes current literature on the adoption of hyponatremia as an early diagnostic and predictive marker of complicated appendicitis. METHODS: Pubmed, Cochrane Library, Scopus, Google Scholar, WHO Global Health Library, System for Information on Grey Literature, ISI Web of Science, EBSCOHost and Virtual Health Library were searched in accordance with the PRISMA guidelines in order to identify original human studies investigating the association between hyponatremia and the presence or development of complicated appendicitis. RESULTS: A total of 7 studies conducted in 6 different countries were identified. A prospective diagnostic accuracy study reported a strong association between hyponatremia and complicated appendicitis in children. The largest sample size study performed in adults reported a significant association between hyponatremia and perforated or gangrenous appendicitis. CONCLUSIONS: The admission serum sodium level measurement, a routinely performed, low-cost test, should be taken into account in patients with clinical presentation compatible with acute appendicitis and suspicion of underlying complications. Future well-designed prospective diagnostic accuracy studies are required to further establish the association between hyponatremia and perforated appendicitis.

Efficacy of chalcone and xanthine derivatives on lipase inhibition: A systematic review.

Losing weight has significant impact on chronic disease management. Orlistat, a lipase inhibitor, has alternative effect for weight controlling. To find more candidates, we conducted a review of chalcone and xanthine derivatives regarding their anti-lipase activity. Eight databases were searched including PubMed, Scopus, Web of Science (ISI), Virtual Health Library (VHL), System for Information on Grey Literature in Europe (SIGLE), Global Health Library (GHL), EMBASE, and Google Scholar in August 2018. We found chalcone scaffold was more effective on lipase inhibition than xanthine scaffold. Among 19 investigated chalcones, only isoliquiritigenin and licuroside demonstrated an effect on preventing weight gain and increase in the total cholesterol and total triglycerides aside apart from their high activity on inhibiting lipase. Effect and type of inhibition of individual chalcones differed depending on their structure. In addition, very few studies investigated xanthine compounds and their activities were inconsistent. We suggest more studies investigate the ability of chalcones and modifying their structure to find out other compounds with higher efficacy.

Epiploic appendagitis: pathogenesis, clinical findings and imaging clues of a misdiagnosed mimicker.

Primary epiploic appendagitis (PEA) is a rare and frequently underdiagnosed cause of acute abdominal pain. PEA most commonly affects obese, male patients in the 4th and 5th decade of life. Clinical presentation includes acute, localized, non-migrating pain without fever, nausea, vomiting or diarrhea and the laboratory workup is usually within normal limits. PEA is commonly mistaken as other more severe causes of acute abdominal pain, such as diverticulitis, acute appendicitis or cholecystitis and thus patients undergo unnecessary diagnostic and therapeutic procedures. The emergence of computerized tomography (CT) as the gold standard imaging test in diagnostic dilemmas of acute abdominal pain has resulted in increased recognition and diagnosis of PEA. Upon confirmation, PEA is considered a self-limiting disease and is managed conservatively with analgesics, occasionally combined with nonsteroidal anti-inflammatory drugs (NSAIDS). Persistence of symptoms or recurrence mandate the consideration of surgical management with laparoscopic appendage excision as the definitive treatment. We review the current literature of PEA, with a focus on clinical and imaging findings, in order to raise awareness about this frequently misdiagnosed entity.