Cell cycle regulatory proteins and oral squamous cell carcinoma development

Abstract no. 1279published_or_final_versio

Missense mutations cluster within the carboxyl-terminal region of DAX-1 and impair transcriptional repression

DAX-1 is an orphan nuclear receptor that plays a key role in the development and function of the adrenal gland and hypothalamic-pituitary gonadal axis. Mutations in the gene encoding DAX-1 result in X-linked adrenal hypoplasia congenita (AHC). Affected boys typically present with primary adrenal failure in infancy or childhood and hypogonadotropic hypogonadism at the time of puberty. The majority of DAX1 mutations described to date are nonsense or frameshift mutations that result in premature truncation of the DAX-1 protein and loss of DAX-1 repressor function. Relatively few missense mutations in DAX1 have been reported. Here, we describe missense mutations in three additional families with X-linked AHC. When combined with previous reports, the DAX1 missense mutations appear to cluster within restricted regions of the putative ligand-binding domain of DAX-1 and affect amino acids that are evolutionarily conserved, suggesting that these regions correspond to critical functional domains. Transcription assays, using a variety of artificial and native target genes, were performed to assess the effects of these mutations on the function of DAX-1. All DAX-1 missense mutant constructs showed marked loss of repressor function, with the exception of I439S, a mutation previously shown to be associated with delayed-onset adrenal failure and incomplete hypogonadotropic hypogonadism. These data indicate that most DAX1 missense mutations associated with classic AHC exhibit marked loss of function. The locations of these mutations thereby identify important functional domains in the carboxyl-terminus of the protein

A direct method to obtain a realization of a polynomial matrix and its applications

[EN] In this paper we present a Silverman-Ho algorithm-based method to obtain a realization of a polynomial matrix. This method provides the final formulation of a minimal realization directly from a full rank factorization of a specific given matrix. Also, some classical problems in control theory such as model reduction in singular systems or the positive realization problem in standard systems are solved with this method.Work supported by the Spanish DGI grant MTM2017-85669-P-AR.Cantó Colomina, R.; Moll López, SE.; Ricarte Benedito, B.; Urbano Salvador, AM. (2020). A direct method to obtain a realization of a polynomial matrix and its applications. Revista de la Real Academia de Ciencias Exactas Físicas y Naturales Serie A Matemáticas. 114(2):1-15. https://doi.org/10.1007/s13398-020-00819-1S1151142Anderson, B.D.O., Bongpanitlerd, S.: Network Analysis and Synthesis, A Modern Systems Theory Approach. Prentice-Hall Inc., New Jersey (1968)Benvenuti, L., Farina, L.: A tutorial on the positive realization problem. IEEE Trans. Autom. Control 49(5), 651–664 (2004). https://doi.org/10.1109/TAC.2004.826715Bru, R., Coll, C., Sánchez, E.: Structural properties of positive linear time-invariant difference-algebraic equations. Linear Algebra Appl. 349, 1–10 (2002). https://doi.org/10.1016/S0024-3795(02)00277-XCantó, R., Ricarte, B., Urbano, A.M.: Positive realizations of transfer matrices with real poles. IEEE Trans. Circuits Syst. II Expr. Br. 54(6), 517–521 (2007). https://doi.org/10.1109/TCSII.2007.894408Cantó, R., Ricarte, B., Urbano, A.M.: On positivity of discrete-time singular systems and the realization problem. Lect. Notes Control Inf. Sci. 389, 251–258 (2009). https://doi.org/10.1007/978-3-642-02894-6_24Climent, J., Napp, D., Requena, V.: Block Toeplitz matrices for burst-correcting convolutional codes. RACSAM 114, 38 (2020). https://doi.org/10.1007/s13398-019-00744-yDai, L.: Singular Control Systems. Lecture Notes in Control and Information Sciences. Springer-Verlag, New York (1989)Golub, G.H., Van Loan, C.F.: Matrix Computations, Fourth edn. Johns Hopkins University Press, Baltimore (2013)Henrion, D., Šebek, M.: Polynomial and matrix fraction description. In: Control Systems, Robotics and Automation, vol. 7, pp. 211-231, (2009). http://www.eolss.net/Sample-Chapters/C18/E6-43-13-05.pdfHo, B.L., Kalman, R.E.: Effective construction of linear state-variable models from mput/output functions. Regelungstechnik 14(12), 545–548 (1966)Kaczorek, T.: Weakly positive continuous-time linear systems. Lect. Notes Control Inf. Sci. 243, 3–16 (1999)Kaczorek, T.: Positive 1D and 2D Systems, vol. 431. Springer, London (2002)Kaczorek, T.: Externally and internally positive singular discrete-time linear systems. Int. J. Appl. Math. Comput. Sci. 12(2), 197–202 (2002)MATLAB, The Math Works, Inc., Natick, Massachusetts, United States. Official website: http://www.mathworks.comMcCrory, C., Parusinski, A.: The weight filtration for real algebraic varieties II: classical homology. RACSAM 108, 63–94 (2014). https://doi.org/10.1007/s13398-012-0098-ySilverman, L.: Realization of linear dynamical systems. IEEE Trans. Autom. Control 16(6), 554–567 (1971)Virnik, E.: Stability analysis of positive descriptor systems. Linear Algebra Appl. 429(10), 2640–2659 (2008

Equivalent forms of Dirac equations in curved spacetimes and generalized de Broglie relations

One may ask whether the relations between energy and frequency and between momentum and wave vector, introduced for matter waves by de Broglie, are rigorously valid in the presence of gravity. In this paper, we show this to be true for Dirac equations in a background of gravitational and electromagnetic fields. We first transform any Dirac equation into an equivalent canonical form, sometimes used in particular cases to solve Dirac equations in a curved spacetime. This canonical form is needed to apply the Whitham Lagrangian method. The latter method, unlike the WKB method, places no restriction on the magnitude of Planck's constant to obtain wave packets, and furthermore preserves the symmetries of the Dirac Lagrangian. We show using canonical Dirac fields in a curved spacetime, that the probability current has a Gordon decomposition into a convection current and a spin current, and that the spin current vanishes in the Whitham approximation, which explains the negligible effect of spin on wave packet solutions, independent of the size of Planck's constant. We further discuss the classical-quantum correspondence in a curved spacetime based on both Lagrangian and Hamiltonian formulations of the Whitham equations. We show that the generalized de Broglie relations in a curved spacetime are a direct consequence of Whitham's Lagrangian method, and not just a physical hypothesis as introduced by Einstein and de Broglie, and by many quantum mechanics textbooks.Comment: PDF, 32 pages in referee format. Added significant material on canonical forms of Dirac equations. Simplified Theorem 1 for normal Dirac equations. Added section on Gordon decomposition of the probability current. Encapsulated main results in the statement of Theorem

INvestigational Vertebroplasty Efficacy and Safety Trial (INVEST): a randomized controlled trial of percutaneous vertebroplasty

Background: The treatment of painful osteoporotic vertebral compression fractures has historically been limited to several weeks of bed rest, anti-inflammatory and analgesic medications, calcitonin injections, or external bracing. Percutaneous vertebroplasty (the injection of bone cement into the fractured vertebral body) is a relatively new procedure used to treat these fractures. There is increasing interest to examine the efficacy and safety of percutaneous vertebroplasty and to study the possibility of a placebo effect or whether the pain relief is from local anesthetics placed directly on the bone during the vertebroplasty procedure. Methods/Designs: Our goal is to test the hypothesis that patients with painful osteoporotic vertebral compression fractures who undergo vertebroplasty have less disability and pain at 1 month than patients who undergo a control intervention. The control intervention is placement of local anesthesia near the fracture, without placement of cement. One hundred sixty-six patients with painful osteoporotic vertebral compression fractures will be recruited over 5 years from US and foreign sites performing the vertebroplasty procedure. We will exclude patients with malignant tumor deposit (multiple myeloma), tumor mass or tumor extension into the epidural space at the level of the fracture. We will randomly assign participants to receive either vertebroplasty or the control intervention. Subjects will complete a battery of validated, standardized measures of pain, functional disability, and health related quality of life at baseline and at post-randomization time points (days 1, 2, 3, and 14, and months 1, 3, 6, and 12). Both subjects and research interviewers performing the follow-up assessments will be blinded to the randomization assignment. Subjects will have a clinic visit at months 1 and 12. Spine X-rays will be obtained at the end of the study (month 12) to determine subsequent fracture rates. Our co-primary outcomes are the modified Roland score and pain numerical rating scale at 1 month. Discussion: Although extensively utilized throughout North America for palliation of pain, vertebroplasty still has not undergone rigorous study. The study outlined above represents the first randomized, controlled study that can account for a placebo effect in the setting of vertebroplasty. Trial Registration: Current Controlled Trials ISRCTN81871888.The source of funding for the study and all authors for this publication was National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

In silico assessment of potential druggable pockets on the surface of α1-Antitrypsin conformers

The search for druggable pockets on the surface of a protein is often performed on a single conformer, treated as a rigid body. Transient druggable pockets may be missed in this approach. Here, we describe a methodology for systematic in silico analysis of surface clefts across multiple conformers of the metastable protein α1-antitrypsin (A1AT). Pathological mutations disturb the conformational landscape of A1AT, triggering polymerisation that leads to emphysema and hepatic cirrhosis. Computational screens for small molecule inhibitors of polymerisation have generally focused on one major druggable site visible in all crystal structures of native A1AT. In an alternative approach, we scan all surface clefts observed in crystal structures of A1AT and in 100 computationally produced conformers, mimicking the native solution ensemble. We assess the persistence, variability and druggability of these pockets. Finally, we employ molecular docking using publicly available libraries of small molecules to explore scaffold preferences for each site. Our approach identifies a number of novel target sites for drug design. In particular one transient site shows favourable characteristics for druggability due to high enclosure and hydrophobicity. Hits against this and other druggable sites achieve docking scores corresponding to a Kd in the µM–nM range, comparing favourably with a recently identified promising lead. Preliminary ThermoFluor studies support the docking predictions. In conclusion, our strategy shows considerable promise compared with the conventional single pocket/single conformer approach to in silico screening. Our best-scoring ligands warrant further experimental investigation

Different genes interact with particulate matter and tobacco smoke exposure in affecting lung function decline in the general population

BACKGROUND: Oxidative stress related genes modify the effects of ambient air pollution or tobacco smoking on lung function decline. The impact of interactions might be substantial, but previous studies mostly focused on main effects of single genes. OBJECTIVES: We studied the interaction of both exposures with a broad set of oxidative-stress related candidate genes and pathways on lung function decline and contrasted interactions between exposures. METHODS: For 12679 single nucleotide polymorphisms (SNPs), change in forced expiratory volume in one second (FEV(1)), FEV(1) over forced vital capacity (FEV(1)/FVC), and mean forced expiratory flow between 25 and 75% of the FVC (FEF(25-75)) was regressed on interval exposure to particulate matter >10 microm in diameter (PM10) or packyears smoked (a), additive SNP effects (b), and interaction terms between (a) and (b) in 669 adults with GWAS data. Interaction p-values for 152 genes and 14 pathways were calculated by the adaptive rank truncation product (ARTP) method, and compared between exposures. Interaction effect sizes were contrasted for the strongest SNPs of nominally significant genes (p(interaction)>0.05). Replication was attempted for SNPs with MAF<10% in 3320 SAPALDIA participants without GWAS. RESULTS: On the SNP-level, rs2035268 in gene SNCA accelerated FEV(1)/FVC decline by 3.8% (p(interaction) = 2.5x10(-6)), and rs12190800 in PARK2 attenuated FEV1 decline by 95.1 ml p(interaction) = 9.7x10(-8)) over 11 years, while interacting with PM10. Genes and pathways nominally interacting with PM10 and packyears exposure differed substantially. Gene CRISP2 presented a significant interaction with PM10 (p(interaction) = 3.0x10(-4)) on FEV(1)/FVC decline. Pathway interactions were weak. Replications for the strongest SNPs in PARK2 and CRISP2 were not successful. CONCLUSIONS: Consistent with a stratified response to increasing oxidative stress, different genes and pathways potentially mediate PM10 and tobac smoke effects on lung function decline. Ignoring environmental exposures would miss these patterns, but achieving sufficient sample size and comparability across study samples is challengin

Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial

This study evaluated azacitidine as treatment of minimal residual disease (MRD) determined by a sensitive donor chimerism analysis of CD34+ blood cells to pre-empt relapse in patients with CD34+ myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT). At a median of 169 days after HSCT, 20/59 prospectively screened patients experienced a decrease of CD34+ donor chimerism to <80% and received four azacitidine cycles (75 mg/m2/day for 7 days) while in complete hematologic remission. A total of 16 patients (80%) responded with either increasing CD34+ donor chimerism to ⩾80% (n=10; 50%) or stabilization (n=6; 30%) in the absence of relapse. Stabilized patients and those with a later drop of CD34+ donor chimerism to <80% after initial response were eligible for subsequent azacitidine cycles. A total of 11 patients (55%) received a median of 4 (range, 1–11) additional cycles. Eventually, hematologic relapse occurred in 13 patients (65%), but was delayed until a median of 231 days (range, 56–558) after initial decrease of CD34+ donor chimerism to <80%. In conclusion, pre-emptive azacitidine treatment has an acceptable safety profile and can substantially prevent or delay hematologic relapse in patients with MDS or AML and MRD after allogeneic HSCT

Expression of ABC Efflux Transporters in Placenta from Women with Insulin-Managed Diabetes

Drug efflux transporters in the placenta can significantly influence the materno-fetal transfer of a diverse array of drugs and other xenobiotics. To determine if clinically important drug efflux transporter expression is altered in pregnancies complicated by gestational diabetes mellitus (GDM-I) or type 1 diabetes mellitus (T1DM-I), we compared the expression of multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 2 (MRP2) and the breast cancer resistance protein (BCRP) via western blotting and quantitative real-time polymerase chain reaction in samples obtained from insulin-managed diabetic pregnancies to healthy term-matched controls. At the level of mRNA, we found significantly increased expression of MDR1 in the GDM-I group compared to both the T1DM-I (p<0.01) and control groups (p<0.05). Significant changes in the placental protein expression of MDR1, MRP2, and BCRP were not detected (p>0.05). Interestingly, there was a significant, positive correlation observed between plasma hemoglobin A1c levels (a retrospective marker of glycemic control) and both BCRP protein expression (r = 0.45, p<0.05) and BCRP mRNA expression (r = 0.58, p<0.01) in the insulin-managed DM groups. Collectively, the data suggest that the expression of placental efflux transporters is not altered in pregnancies complicated by diabetes when hyperglycemia is managed; however, given the relationship between BCRP expression and plasma hemoglobin A1c levels it is plausible that their expression could change in poorly managed diabetes

Adult growth hormone deficiency: clinical advances and approaches to improve adherence

Introduction: There have been significant clinical advances in the understanding of the diagnosis and benefits of long-term recombinant human growth hormone (rhGH) replacement in adults with GH deficiency (GHD) since its approval in 1996 by the United States Food and Drug Administration. Areas covered: We searched PubMed, Medline, CINAHL, EMBASE and PsychInfo databases between January 2000 and June 2019 for published studies evaluating adults with GHD. We reviewed the data of the oral macimorelin test compared to the GHRH plus arginine and the insulin tolerance tests that led to its approval by the United States FDA and European Medicines Agency for adult diagnostic testing. We summarize the clinical advances of long-term benefits of rhGH therapy and the potential effects of GH receptor polymorphisms on individual treatment responsiveness. We identify that non-adherence and discontinuation rates are high and recommend strategies to support patients to improve adherence. We also provide an overview of several long-acting GH (LAGH) preparations currently under development and their potential role in improving treatment adherence. Expert opinion: This article summarizes recent clinical advances in rhGH replacement therapy, the biological and molecular aspects that may influence rhGH action, and offers practical strategies to enhance adherence in adults with GHD