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BackgroundCoformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS).ObjectiveDetermine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial.MethodsAdults with El Escorial Definite ALS ≤18 months from symptom onset were randomised to PB/ TURSO or placebo for 6 months. Those completing randomised treatment could enrol in an open-label extension (OLE) phase and receive PB/TURSO for ≤30 months. Times to the following individual or combined key events were compared in the originally randomised treatment groups over a period spanning trial start through July 2020 (longest postrandomisation follow-up, 35 months): death, tracheostomy, permanent assisted ventilation (PAV) and first hospitalisation.ResultsRisk of any key event was 47% lower in those originally randomised to PB/TURSO (n=87) versus placebo (n=48, 71% of whom received delayed-start PB/TURSO in the OLE phase) (HR=0.53; 95% CI 0.35 to 0.81; p=0.003). Risks of death or tracheostomy/PAV (HR=0.51; 95% CI 0.32 to 0.84; p=0.007) and first hospitalisation (HR=0.56; 95% CI 0.34 to 0.95; p=0.03) were also decreased in those originally randomised to PB/TURSO.ConclusionsEarly PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS.Trial registration numberNCT03127514; NCT03488524.

An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P = .023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.

BackgroundSodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known.MethodsIn this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization.ResultsA total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal.ConclusionsSodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).

In vivo cells receive simultaneous signals from multiple extracellular ligands and must integrate and interpret them to respond appropriately. Here we investigate the interplay between pathways downstream of two transforming growth factor ß (TGF-ß) superfamily members, bone morphogenetic protein (BMP) and TGF-ß. We show that in multiple cell lines, TGF-ß potently inhibits BMP-induced transcription at the level of both BMP-responsive reporter genes and endogenous BMP target genes. This inhibitory effect requires the TGF-ß type I receptor ALK5 and is independent of new protein synthesis. Strikingly, we show that Smad3 is required for TGF-ß's inhibitory effects, whereas Smad2 is not. We go on to demonstrate that TGF-ß induces the formation of complexes comprising phosphorylated Smad1/5 and Smad3, which bind to BMP-responsive elements in vitro and in vivo and mediate TGF-ß-induced transcriptional repression. Furthermore, loss of Smad3 confers on TGF-ß the ability to induce transcription via BMP-responsive elements. Our results therefore suggest that not only is Smad3 important for mediating TGF-ß's inhibitory effects on BMP signaling but it also plays a critical role in restricting the transcriptional output in response to TGF-ß. [ABSTRACT FROM AUTHOR]

Presents an annotated bibliography of the history of non-western rhetorical theory before 1900. "The Ancient Word: Rhetoric in Aztec Culture," by Don P. Abbott; "Zoroaster's Influence on Greek Thought," by Ruhi Afnan; "Studies in Jewish Preaching: Middle Ages," by Israel Bettan.

Abstract: The reaction of [Rh(CO)2Cl]2 with 0.5 mol equivalent of the ligands [P′(X)(CH2–CH2P(X)Ph2)3](P′P3X4) {where X = O(a), S(b) and Se(c)} affords tetranuclear complexes of the type [Rh4(CO)8Cl4(P′P3X4)] (1a–1c). The complexes 1a–1c have been characterized by elemental analyses, mass spectrometry, IR and multinuclear NMR spectroscopy, and the ligands b and c are structurally determined by single crystal X-ray diffraction. 1a–1c undergo oxidative addition (OA) reactions with CH3I to generate Rh(III) oxidised products. Kinetic data for the reaction of 1a and 1b with excess CH3I indicate a pseudo first order reaction. The catalytic activity of 1a–1c for the carbonylation of methanol to acetic acid and its ester show a higher Turn Over Frequency (TOF = 1349–1748 h−1) compared to the well-known species [Rh(CO)2I2]− (TOF = 1000 h−1) under the similar experimental conditions. However, 1b and 1c exhibit lower TOF than 1a, which may be due to the desulfurization and deselinization of the ligands in the respective complexes under the reaction conditions. [Copyright &y& Elsevier]

Dihydropteridine reductase (DHPR) deficiency is a genetic disorder of tetrahydrobiopterin (BH4) regeneration and may present with hyperphenylalaninemia, microcephaly, hypotonia, mental retardation, and convulsions. BH4 is an essential cofactor for the hydroxylation of aromatic amino acids and a deficiency of BH4 results in decreased synthesis of dopamine and serotonin. We present a 27-month-old female patient with DHPR deficiency who was treated with L-dopa/carbidopa (2 mg/kg, four times per day), 5-hydroxytryptophan (2 mg/kg, four times per day), folinic acid (10 mg/day), and BH4 supplementation (20 mg/kg, twice a day). Although remarkable clinical improvement with normal plasma phenylalanine (Phe) levels and increased phenylalanine tolerance was noted 1 month after the treatment, CSF neurotransmitter metabolites did not improve. BH4 supplementation was increased to 40 mg/kg/day and the CSF study was repeated 1 month later. There was no significant change of CSF neurotransmitters, BH4 or BH2 levels but plasma Phe level was within normal range. Surprisingly, she had developmental improvement noted at 1-month and 3-month visits following an augmented neurotransmitter and BH4 treatment. She was able to pull herself to the standing position and sit down on her own. She was also noted to be more alert and responsive following treatment. Her expressive language did not improve, although her receptive language was markedly improved. The above treatment improved patient's clinical findings, normalized blood Phe levels, and increased Phe tolerance in the diet, but neither 20 nor 40 mg/kg/day BH4 supplementation corrected neurotransmitter or BH4 levels or increased BH2 level in CSF. Further studies are needed to find the optimal management plan for patients with DHPR deficiency.

Transforming growth factor beta (TGF-beta) signals predominantly through a receptor complex comprising ALK5 and TbetaRII to activate receptor-regulated Smads (R-Smads) Smad2 and Smad3. In endothelial cells, however, TGF-beta can additionally activate Smad1 and Smad5. Here, we report that TGF-beta also strongly induces phosphorylation of Smad1/5 in many different normal epithelial cells, epithelium-derived tumor cells, and fibroblasts. We demonstrate that TbetaRII and ALK5, as well as ALK2 and/or ALK3, are required for TGF-beta-induced Smad1/5 phosphorylation. We show that the simultaneous activation of the R-Smads Smad2/3 and Smad1/5 by TGF-beta results in the formation of mixed R-Smad complexes, containing, for example, phosphorylated Smad1 and Smad2. The prevalence of these mixed R-Smad complexes explains why TGF-beta-induced Smad1/5 phosphorylation does not result in transcriptional activation via bone morphogenetic protein (BMP)-responsive elements, which bind activated Smad1/5-Smad4 complexes that are induced by BMP stimulation. Thus, TGF-beta induces two parallel pathways: one signaling via Smad2-Smad4 or Smad3-Smad4 complexes and the other signaling via mixed R-Smad complexes. Finally, we assess the function of the novel arm of TGF-beta signaling and show that TGF-beta-induced Smad1/5 activation is not required for the growth-inhibitory effects of TGF-beta but is specifically required for TGF-beta-induced anchorage-independent growth.