Research Spotlight

Posted December 15th 2017

Confirmation that MAT1A p.Ala259Val mutation causes autosomal dominant hypermethioninemia.

Teodoro Bottiglieri Ph.D.

Teodoro Bottiglieri Ph.D.E

Muriello, M. J., S. Viall, T. Bottiglieri, K. Cusmano-Ozog and C. R. Ferreira (2017). “Confirmation that mat1a p.Ala259val mutation causes autosomal dominant hypermethioninemia.” Mol Genet Metab Rep 13: 9-12.

Full text of this article.

Methionine adenosyltransferase (MAT) I/III deficiency is an inborn error of metabolism caused by mutations in MAT1A, encoding the catalytic subunit of MAT responsible for the synthesis of S-adenosylmethionine, and is characterized by persistent hypermethioninemia. While historically considered a recessive disorder, a milder autosomal dominant form of MAT I/III deficiency occurs, though only the most common mutation p.Arg264His has ample evidence to prove dominant inheritance. We report a case of hypermethioninemia caused by the p.Ala259Val substitution and provide evidence of autosomal dominant inheritance by showing both maternal inheritance of the mutation and concomitant hypermethioninemia. The p.Ala259Val mutation falls in the dimer interface, and thus likely leads to dominant inheritance by a similar mechanism to that described in the previously reported dominant negative mutation, that is, by means of interference with subunits encoded by the wild-type allele.


Posted December 15th 2017

Type of Atrial Fibrillation and Outcomes in Patients With Heart Failure and Reduced Ejection Fraction.

Milton Packer M.D.

Milton Packer M.D.

Mogensen, U. M., P. S. Jhund, W. T. Abraham, A. S. Desai, K. Dickstein, M. Packer, J. L. Rouleau, S. D. Solomon, K. Swedberg, M. R. Zile, L. Kober and J. J. V. McMurray (2017). “Type of atrial fibrillation and outcomes in patients with heart failure and reduced ejection fraction.” J Am Coll Cardiol 70(20): 2490-2500.

Full text of this article.

BACKGROUND: Atrial fibrillation (AF) is common in heart failure (HF), but the outcome by type of AF is largely unknown. OBJECTIVES: This study investigated outcomes related to type of AF (paroxysmal, persistent or permanent, or new onset) in 2 recent large trials in patients with HF with reduced ejection fraction. METHODS: The study analyzed patients in the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) and ATMOSPHERE (Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure) trials. Multivariable Cox regression models were used to estimate hazard ratios (HRs) for outcomes related to AF type. RESULTS: Of 15,415 patients, 5,481 (35.6%) had a history of AF at randomization, and of these, 1,645 (30.0%) had paroxysmal AF. Compared with patients without AF, patients with paroxysmal AF at randomization had a higher risk of the primary composite endpoint of cardiovascular death or HF hospitalization (HR: 1.20; 95% confidence interval [CI]: 1.09 to 1.32; p < 0.001), HF hospitalization (HR: 1.34; 95% CI: 1.19 to 1.51; p < 0.001), and stroke (HR: 1.34; 95% CI: 1.02 to 1.76; p = 0.037), whereas the corresponding risks in patients with persistent or permanent AF were not elevated. Neither type of AF was associated with higher mortality. New onset AF was associated with the greatest risk of adverse outcomes: primary endpoint (HR: 2.21; 95% CI: 1.80 to 2.71), HF hospitalization (HR: 2.11; 95% CI: 1.58 to 2.81), stroke (HR: 2.20; 95% CI: 1.25 to 3.88), and all-cause mortality (HR: 2.26; 95% CI: 1.86 to 2.74), all p values < 0.001, compared with patients without AF. Anticoagulants were used less often in patients with paroxysmal (53%) and new onset (16%) AF than in patients with persistent or permanent AF (71%). CONCLUSIONS: Among HF patients with a history of AF, those with paroxysmal AF were at greater risk of HF hospitalization and stroke than were patients with persistent or permanent AF, underlining the importance of anticoagulant therapy. New onset AF was associated with increased risk of all outcomes.


Posted December 15th 2017

IGF-1R: SUMO-ing its weight in chemoresistant colorectal cancer.

Ajay Goel Ph.D.

Ajay Goel Ph.D.

Goel, A. (2017). “Igf-1r: Sumo-ing its weight in chemoresistant colorectal cancer.” Br J Cancer: 2017 Nov [Epub ahead of print].

Full text of this article.

Post-translational modification of proteins by members of the small ubiquitin-related modifier (SUMO) protein family regulates multiple cellular processes, including transcription, replication, chromosome segregation and DNA repair, in various human diseases including cancer (Geiss-Friedlander and Melchior, 2007). The SUMO proteins include three ubiquitin-like peptidic modifiers; SUMO-1, -2 and -3. Their conjugation to substrates occurs through heterodimeric SUMO-activating E1 enzyme (AOS1/UBA2), a SUMO-conjugating E2 enzyme UBC9 (encoded by UBE2I) and various E3 protein ligases (e.g., PIAS1, PIAS2, PIAS3, PIAS4 and RANBP2) that facilitate reversible binding of SUMO proteins to the lysine residues of the target protein (Kerscher et al, 2006).


Posted December 15th 2017

Overall survival in MERiDiAN, a double-blind placebo-controlled randomised phase III trial evaluating first-line bevacizumab plus paclitaxel for HER2-negative metastatic breast cancer.

Joyce O'Shaughnessy M.D.

Joyce O’Shaughnessy M.D.

Miles, D., D. Cameron, M. Hilton, J. Garcia and J. O’Shaughnessy (2017). “Overall survival in meridian, a double-blind placebo-controlled randomised phase iii trial evaluating first-line bevacizumab plus paclitaxel for her2-negative metastatic breast cancer.” Eur J Cancer: 2017 Nov [Epub ahead of print].

Full text of this article.

The MERiDiAN trial was designed to investigate prospectively plasma VEGF-A as a potential predictive biomarker for bevacizumab effect on investigator-assessed PFS in HER2-negative mBC. The co-primary objectives were met: bevacizumab significantly improved PFS in both the ITT population (stratified hazard ratio [HR] 0.68, 99% confidence interval [CI]: 0.51–0.91; log-rank p = 0.0007) and the VEGF-Ahigh population (stratified HR 0.64, 96% CI: 0.47–0.88; log-rank p = 0.0038). However, results did not support the use of baseline plasma VEGF-A level to identify the patients benefitting most from bevacizumab.


Posted December 15th 2017

A study of the clinical utility of a 20-minute secretin-stimulated endoscopic pancreas function test and performance according to clinical variables.

Daniel DeMarco M.D.

Daniel DeMarco M.D.

Lara, L. F., M. Takita, J. S. Burdick, D. C. DeMarco, R. R. Pimentel, T. Erim and M. F. Levy (2017). “A study of the clinical utility of a 20-minute secretin-stimulated endoscopic pancreas function test and performance according to clinical variables.” Gastrointest Endosc 86(6): 1048-1055.e1042.

Full text of this article.

ACKGROUND AND AIMS: Direct pancreas juice testing of bicarbonate, lipase, or trypsin after stimulation by secretin or cholecystokinin is used to determine exocrine function, a surrogate for diagnosing chronic pancreatitis (CP). Endoscopic pancreas function tests (ePFTs), where a peak bicarbonate concentration (PBC) >/=80 mEq/L in pancreas juice is considered normal, are now used more frequently. In this ePFT, aspirates start 35 minutes after secretin administration because pancreas output peaks 30 minutes after secretagogue administration. The performance of ePFT in a cohort of patients with a presumptive diagnosis of CP referred to a pancreas clinic for consideration of an intervention including total pancreatectomy and islet autotransplantation was studied, compared with EUS, ERCP, histology, and consensus diagnosis. The effect of sedation, narcotic use, aspirate volume, body mass index, age, and proton pump inhibitors (PPIs) on test performance is reported. METHODS: After a test dose, synthetic human secretin was administered intravenously, and 30 minutes later sedation was achieved with midazolam and fentanyl or propofol. A gastroscope was advanced to the major papilla where 4 continuous aspiration samples were performed at 5-minute intervals in sealed bottles. PBC >/=80 mEq/L was normal. RESULTS: Eighty-one patients had ePFTs from August 2010 through October 2015. Twenty-seven patients (33%) were diagnosed with CP. Eighteen of the 27 patients with CP and 1 of the 54 patients without CP had an abnormal ePFT, producing a sensitivity of 66% (95% CI, 46.0-83.5), specificity 98% (95% CI, 90.1-99.9), positive predictive value 94.7% (95% CI, 74-99.9), and negative predictive value 85.5% (95% CI, 74.2-93.1). ERCP and PBC concordance was generally poor, but none of the patients without CP had major EUS changes, and only 3 patients with a PBC <80 mEq/L had a normal EUS. The PBC was affected by narcotics and PPI use. CONCLUSION: A 20-minute ePFT after secretin administration had a marginal sensitivity for diagnosis of CP. The diagnosis of CP should not rely on a single study and certainly not a PFT. The duodenal aspirate volume did not correlate with the PBC, which contrasts with current secretin-enhanced MRCP knowledge; therefore, further studies on this subject are warranted. Neither type of sedation, BMI, nor age affected test performance. Narcotics and PPIs may affect the PBC, so borderline results should be interpreted with caution in these groups.