Integrated approach to designing growth factor delivery systems

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154661/1/fsb2fj067873com-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154661/2/fsb2fj067873com.pd

L-5-methyltetrahydrofolate supplementation increases blood folate concentrations to a greater extent than folic acid supplementation in Malaysian women

Background: Folic acid fortification of grains is mandated in many countries to prevent neural tube defects. Concerns regarding excessive intakes of folic acid have been raised. A synthetic analog of the circulating form of folate, l-5-methyltetrahydrofolate (l-5-MTHF), may be a potential alternative. Objective: The objective of this study was to determine the effects of folic acid or l-5-MTHF supplementation on blood folate concentrations, methyl nutrient metabolites, and DNA methylation in women living in Malaysia, where there is no mandatory fortification policy. Methods: In a 12-wk, randomized, placebo-controlled intervention trial, healthy Malaysian women (n = 142, aged 20–45 y) were randomly assigned to receive 1 of the following supplements daily: 1 mg (2.27 μmol) folic acid, 1.13 mg (2.27 μmol) l-5-MTHF, or a placebo. The primary outcomes were plasma and RBC folate and vitamin B-12 concentrations. Secondary outcomes included plasma total homocysteine, total cysteine, methionine, betaine, and choline concentrations and monocyte long interspersed nuclear element-1 (LINE-1) methylation. Results: The folic acid and l-5-MTHF groups had higher (P < 0.001) RBC folate (mean ± SD: 1498 ± 580 and 1951 ± 496 nmol/L, respectively) and plasma folate [median (25th, 75th percentiles): 40.1 nmol/L (24.9, 52.7 nmol/L) and 52.0 nmol/L (42.7, 73.1 nmol/L), respectively] concentrations compared with RBC folate (958 ± 345 nmol/L) and plasma folate [12.6 nmol/L (8.80, 17.0 nmol/L)] concentrations in the placebo group at 12 wk. The l-5-MTHF group had higher RBC folate (1951 ± 496 nmol/L; P = 0.003) and plasma folate [52.0 nmol/L (42.7, 73.1 nmol/L); P = 0.023] at 12 wk than did the folic acid group [RBC folate, 1498 ± 580 nmol/L; plasma folate, 40.1 nmol/L (24.9, 52.7 nmol/L)]. The folic acid and l-5-MTHF groups had 17% and 15%, respectively, lower (P < 0.001) plasma total homocysteine concentrations than did the placebo group at 12 wk; there were no differences between the folic acid and l-5-MTHF groups. No differences in plasma vitamin B-12, total cysteine, methionine, betaine, and choline and monocyte LINE-1 methylation were observed. Conclusion: These findings suggest differential effects of l-5-MTHF compared with folic acid supplementation on blood folate concentrations but no differences on plasma total homocysteine lowering in Malaysian women. This trial was registered at clinicaltrials.gov as NCT01584050

Host proteostasis modulates influenza evolution

Predicting and constraining RNA virus evolution require understanding the molecular factors that define the mutational landscape accessible to these pathogens. RNA viruses typically have high mutation rates, resulting in frequent production of protein variants with compromised biophysical properties. Their evolution is necessarily constrained by the consequent challenge to protein folding and function. We hypothesized that host proteostasis mechanisms may be significant determinants of the fitness of viral protein variants, serving as a critical force shaping viral evolution. Here, we test that hypothesis by propagating influenza in host cells displaying chemically-controlled, divergent proteostasis environments. We find that both the nature of selection on the influenza genome and the accessibility of specific mutational trajectories are significantly impacted by host proteostasis. These findings provide new insights into features of host-pathogen interactions that shape viral evolution, and into the potential design of host proteostasis-targeted antiviral therapeutics that are refractory to resistance.National Institutes of Health (U.S.) (Award 1DP2GM119162)National Institutes of Health (U.S.) (Grant P30-ES002109

Sign-changing tower of bubbles for a sinh-Poisson equation with asymmetric exponents

Motivated by the statistical mechanics description of stationary 2D-turbulence, for a sinh-Poisson type equation with asymmetric nonlinearity, we construct a concentrating solution sequence in the form of a tower of singular Liouville bubbles, each of which has a different degeneracy exponent. The asymmetry parameter $\gamma\in(0,1]$ corresponds to the ratio between the intensity of the negatively rotating vortices and the intensity of the positively rotating vortices. Our solutions correspond to a superposition of highly concentrated vortex configurations of alternating orientation; they extend in a nontrivial way some known results for $\gamma=1$. Thus, by analyzing the case $\gamma\neq1$ we emphasize specific properties of the physically relevant parameter $\gamma$ in the vortex concentration phenomena

Variations in Implementation of Specifications Grading in STEM Courses

Specifications grading is an assessment strategy based on mastery learning, clear learning objectives, and frequent evaluations and feedback. Twelve instructors at a southeastern four-year public college implemented the specifications grading method across eight discrete courses in four STEM areas. In this modified assessment strategy, the students controlled their grades through multiple attempts, with limitations, on assessments of course objectives. The instructors designed and executed specifications grading in unique ways that aligned with their content areas, teaching beliefs, and individual teaching styles. Preliminary observations suggest that, regardless of subject area, specifications grading can be used as an alternative to traditional assessment methodologies in STEM courses, regardless of the content area. In general, three major variations of implementation arose from this initial trial. Major differences and commonalities among these types are discussed as they relate to the course subject area in which they are used. The results of this work add a unique set of assessment practices to the current body of knowledge in that other practitioners may gain insight on variations of the specifications grading method that may be practical and applicable in their own classrooms

Clinical Translation of a Deep Learning Model of Radiation-Induced Lymphopenia for Esophageal Cancer

PURPOSE: Radiation-induced lymphopenia is a common immune toxicity that adversely impacts treatment outcomes. We report here our approach to translate a deep-learning (DL) model developed to predict severe lymphopenia risk among esophageal cancer into a strategy for incorporating the immune system as an organ-at-risk (iOAR) to mitigate the risk. MATERIALS AND METHODS: We conducted virtual clinical trials utilizing retrospective data for 10 intensity-modulated radiation therapy (IMRT) and 10 passively-scattered proton therapy (PSPT) esophageal cancer patients. For each patient, additional treatment plans of the modality other than the original were created employing standard-of-care (SOC) dose constraints. Predicted values of absolute lymphocyte count (ALC) nadir for all plans were estimated using a previously-developed DL model. The model also yielded the relative magnitudes of contributions of iOARs dosimetric factors to ALC nadir, which were used to compute iOARs dose-volume constraints, which were incorporated into optimization criteria to produce IMRT-enhanced and intensity-modulated proton therapy (IMPT)-enhanced plans. RESULTS: Model-predicted ALC nadir for the original IMRT (IMRT-SOC) and PSPT plans agreed well with actual values. IMPT-SOC showed greater immune sparing vs IMRT and PSPT. The average mean body doses were 13.10 Gy vs 7.62 Gy for IMRT-SOC vs IMPT-SOC for patients treated with IMRT-SOC; and 8.08 Gy vs 6.68 Gy for PSPT vs IMPT-SOC for patients treated with PSPT. For IMRT patients, the average predicted ALC nadir of IMRT-SOC, IMRT-enhanced, IMPT-SOC, and IMPT-enhanced was 281, 327, 351, and 392 cells/µL, respectively. For PSPT patients, the average predicted ALC nadir of PSPT, IMPT-SOC, and IMPT-enhanced was 258, 316, and 350 cells/µL, respectively. Enhanced plans achieved higher predicted ALC nadir, with an average improvement of 40.8 cells/µL (20.6%). CONCLUSION: The proposed DL model-guided strategy to incorporate the immune system as iOAR in IMRT and IMPT optimization has the potential for radiation-induced lymphopenia mitigation. A prospective clinical trial is planned

Dynamics and spectrum of the Cesàro operator on C-infinity(R+)

[EN] The spectrum and point spectrum of the Cesaro averaging operator C acting on the Frechet space C-infinity(R+) of all C-infinity functions on the interval [0, infinity) are determined. We employ an approach via C-0-semigroup theory for linear operators. A spectral mapping theorem for the resolvent of a closed operator acting on a locally convex space is established; it constitutes a useful tool needed to establish the main result. The dynamical behaviour of C is also investigated.The research of the first two authors was partially supported by the projects MTM2013-43540-P, GVA Prometeo II/2013/013 and GVA ACOMP/2015/186 (Spain).Albanese, AA.; Bonet Solves, JA.; Ricker, WJ. (2016). Dynamics and spectrum of the Cesàro operator on C-infinity(R+). Monatshefte für Mathematik. 181:267-283. https://doi.org/10.1007/s00605-015-0863-zS267283181Albanese, A.A., Bonet, J., Ricker, W.J.: Mean ergodic operators in Fréchet spaces. Ann. Acad. Sci. Fenn. Math. 34, 401–436 (2009)Albanese, A.A., Bonet, J., Ricker, W.J.: Mean ergodic semigroups of operators. Rev. R. Acad. Cien. Serie A Mat. RACSAM 106, 299–319 (2012)Albanese, A.A., Bonet, J., Ricker, W.J.: Montel resolvents and uniformly mean ergodic semigroups of linear operators. Quaest. Math. 36, 253–290 (2013)Albanese, A.A., Bonet, J., Ricker, W.J.: Convergence of arithmetic means of operators in Fréchet spaces. J. Math. Anal. Appl. 401, 160–173 (2013)Albanese, A.A., Bonet, J., Ricker, W.J.: Uniform mean ergodicity of $$C_0$$ C 0 -semigroups in a class of in Fréchet spaces. Funct. Approx. Comment. Math. 50, 307–349 (2014)Albanese, A.A., Bonet, J., Ricker, W.J.: On the continuous Cesàro operator in certain function spaces. Positivity 19, 659–679 (2015)Albanese, A.A., Bonet, J., Ricker, W.J.: The Cesàro operator in the Fréchet spaces $$\ell ^{p+}$$ ℓ p + and $$L^{p-}$$ L p - . Glasgow Math. J. (accepted)Arendt, W.: Gaussian estimates and interpolation of the spectrum in $$L^p$$ L p . Diff. Int. Equ. 7, 1153–1168 (1994)Bayart, F., Matheron, E.: Dynamics of linear operators. Cambridge Tracts in Mathematics, vol. 179. Cambridge University Press, Cambridge (2009)Boyd, D.W.: The spectrum of the Cesàro operator. Acta Sci. Math. (Szeged) 29, 31–34 (1968)Grosse-Erdmann, K.G., Manguillot, A.P.: Linear chaos. Universitext, Springer Verlag, London (2011)Hille, E.: Remarks on ergodic theorems. Trans. Am. Math. Soc. 57, 246–269 (1945)Jarchow, H.: Locally convex spaces. Teubner, Stuttgart (1981)Komura, T.: Semigroups of operators in locally convex spaces. J. Funct. Anal. 2, 258–296 (1968)Lin, M.: On the uniform ergodic theorem. Proc. Am. Math. Soc. 43, 337–340 (1974)Malgrange, B.: Idéaux de fonctions différentiables et division des distributions. Distributions, Editions École Polytechnique, Palaiseau, pp. 1–21 (2003)Meise, R., Vogt, D.: Introduction to functional analysis. Oxford Graduate Texts in Mathematics, vol. 2. The Clarendon Press. Oxford University Press, New York (1997)Seeley, R.T.: Extension of $$C^\infty$$ C ∞ functions defined in a half space. Proc. Am. Math. Soc. 15, 625–626 (1964)Siskakis, A.G.: Composition semigroups and the Cesàro operator. J. London Math. Soc. (2) 36, 153–164 (1987)Yosida, K.: Functional analysis. Springer, New York, Berlin, Heidelberg (1980)Valdivia, M.: Topics in locally convex spaces. North-Holland Math. Stud. 67, North-Holland, Amsterdam (1982

The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients

Background: Preoperative chemoradiotherapy (CRT) followed by surgery is the standard care for locally advanced rectal cancer, but tumour response to CRT and disease outcome are variable. The current study aimed to investigate the effectiveness of plasma telomerase reverse transcriptase (TERT) levels in predicting tumour response and clinical outcome. Methods: 176 rectal cancer patients were included. Plasma samples were collected at baseline (before CRT\ubcT0), 2 weeks after CRT was initiated (T1), post-CRT and before surgery (T2), and 4\u20138 months after surgery (T3) time points. Plasma TERT mRNA levels and total cell-free RNA were determined using real-time PCR. Results: Plasma levels of TERT were significantly lower at T2 (Po0.0001) in responders than in non-responders. Post-CRT TERT levels and the differences between pre- and post-CRT TERT levels independently predicted tumour response, and the prediction model had an area under curve of 0.80 (95% confidence interval (CI) 0.73\u20130.87). Multiple analysis demonstrated that patients with detectable TERT levels at T2 and T3 time points had a risk of disease progression 2.13 (95% CI 1.10\u20134.11)-fold and 4.55 (95% CI 1.48\u201313.95)-fold higher, respectively, than those with undetectable plasma TERT levels. Conclusions: Plasma TERT levels are independent markers of tumour response and are prognostic of disease progression in rectal cancer patients who undergo neoadjuvant therapy

A Phase 1a/1b Clinical Trial Design to Assess Safety, Acceptability, Pharmacokinetics and Tolerability of Intranasal Q-Griffithsin for COVID-19 Prophylaxis

Background: The COVID-19 pandemic remains an ongoing threat to global public health. Q-Griffithsin (Q-GRFT) is a lectin that has demonstrated potent broad-spectrum inhibitory activity in preclinical studies in models of Nipah virus and the beta coronaviruses SARS-CoV, MERS-CoV, and SARS-CoV-2. Methods: Here, we propose a clinical trial design to test the safety, pharmacokinetics (PK), and tolerability of intranasally administered Q-GRFT for the prevention of SARS-CoV-2 infection as a prophylaxis strategy. The initial Phase 1a study will assess the safety and PK of a single dose of intranasally administered Q-GRFT. If found safe, the safety, PK, and tolerability of multiple doses of intranasal Q-GRFT will be assessed in a Phase 1b study. Group 1 participants will receive 3 mg of intranasal Q-GRFT (200 μL/nostril) once daily for 7 days. If this dose is tolerated, participants will be enrolled in Group 2 to receive 3 mg twice daily for 7 days. Secondary endpoints of the study will be user perceptions, acceptability, and the impact of product use on participants’ olfactory sensation and quality of life. Discussion: Results from this study will support further development of Q-GRFT as a prophylactic against respiratory viral infections in future clinical trials