Local and Systemic Peptide Therapies for Soft Tissue Regeneration: A Narrative Review.

Background: The musculoskeletal system, due to inherent structure and function, lends itself to contributing toward joint pain, whether from inflammatory disorders such as rheumatoid arthritis, degenerative diseases such as osteoarthritis, or trauma causing soft tissue injury. Administration of peptides for treatment of joint pain or inflammation is an emerging line of therapy that seeks to offer therapeutic benefits while remaining safe and relatively non-invasive. Purpose: The purpose of this study is to review the current literature on existing oral peptide agents, intra-articular peptide agents, and new developments in human trials to assess route of administration (RoA) for drug delivery in terms of soft tissue regeneration. Study Design: Narrative Review. Methods: A comprehensive literature search was conducted using the PubMed database. The search included medical subject headings (MeSH) terms related to peptide therapy, soft tissue regeneration, and RoA. Inclusion criteria comprised articles focusing on the mechanisms of action of peptides, clinical or biochemical outcomes, and review articles. Exclusion criteria included insufficient literature or studies not meeting the set evidence level. Conclusion: The review identified various peptides demonstrating efficacy in soft tissue repair. Oral and intra-articular peptides showed distinct advantages in soft tissue regeneration, with intra-articular routes providing localized effects and oral routes offering systemic benefits. However, both routes have limitations in bioavailability and absorption. Still in their infancy, further inquiries/research into the properties and efficacy of emerging peptides will be necessary before widespread use. As a viable alternative prior to surgical intervention, peptide treatments present as promising candidates for positive outcomes in soft tissue regeneration.

[Autologous Breast Reconstruction and Radiotherapy: Consensus Report of the German-Speaking Society for Reconstructive Microsurgery (GSRM)]. / Autologe Brustrekonstruktion und Bestrahlung: Konsensus-Bericht der Deutschsprachigen Arbeitsgemeinschaft für Mikrochirurgie (DAM).

Autologous postmastectomy breast reconstruction is associated with favourable long-term clinical outcomes and superior patient-reported outcomes (PROMs) compared with implant-based reconstruction. However, adjuvant radiotherapy has traditionally been considered a relative contraindication to immediate flap-based reconstruction due to its unpredictable effects on the reconstructive outcome. While modern adjuvant postmastectomy radiotherapy (PMRT) has been able to significantly reduce acute and chronic radiation-induced complications, plastic surgeons still hesitate to offer immediate autologous reconstruction to patients expected to undergo adjuvant radiotherapy. More recently, evidence has emerged suggesting a paradigm shift in favour of immediate autologous reconstruction despite subsequent radiotherapy. At the 44th Annual Meeting of the German-speaking Society for Reconstructive Microsurgery (GSRM) in Bern, Switzerland, a workshop discussed the literature on PMRT and autologous breast reconstruction, aiming to establish consensus among the participants. Several areas of agreement were identified, including the goals of postmastectomy reconstruction, specifically the creation of a soft and sensitive breast symmetrical in shape and size to the unaffected breast via the safest procedure possible. The importance of preserving the maximum amount of native breast skin envelope through skin- and nipple-sparing approaches was emphasised. Finally, a consensus was reached that PMRT should no longer be considered a contraindication to immediate autologous breast reconstruction.

Multi-reference coupled cluster theory using the normal ordered exponential ansatz.

Properly spin-adapted coupled-cluster theory for general open-shell configurations remains an active area of research in electronic structure theory. In this contribution we examine Lindgren's normal-ordered exponential ansatz to correlate specific spin states using spin-free excitation operators, with the aid of automatic equation generation software. We present an intermediately normalised and size-extensive reformulation of the unlinked working equations, and analyse the performance of the method with single and double excitations for simple molecular systems in terms of accuracy and size-consistency.

Off-Protocol Radiation Therapy in Phase 3 Metastatic Solid Tumor Trials.

PURPOSE: Increasing data suggest that radiation therapy, particularly ablative radiation therapy, alters the natural history of metastatic disease. For patients with metastatic disease enrolled in prospective trials testing systemic therapy, the use of off-protocol radiation therapy to improve clinical symptoms or extend the duration of study systemic therapy may influence study endpoints. We sought to evaluate how often off-protocol radiation therapy was permitted among systemic therapy phase 3 trials, how often off-protocol radiation therapy is used, and whether off-protocol radiation therapy correlated with study outcomes. METHODS AND MATERIALS: Two-arm, superiority-design, phase 3 randomized trials testing systemic therapy were screened from ClinicalTrials.gov. Protocol availability was required to assess the trial approach to off-protocol radiation therapy if not described in the manuscript. Adjusted odds ratios with 95% CI were calculated by logistic regression. RESULTS: A total of 112 trials enrolling 80,134 patients were included, with publication dates between 2010 and 2019. Of these, off-protocol radiation therapy was allowed, not discussed, or prohibited during study systemic therapy in 52% (N =58), 25% (N = 28), and 23% (N = 26) of trials, respectively. However, only 2% (2 of 112) of trials reported off-protocol radiation therapy utilization rates, although no data were reported on the use of ablative off-protocol radiation therapy. No trials evaluated or adjusted for the potential influence of off-protocol radiation therapy on study endpoints. Among the subset of open-label studies, trials permissive toward off-protocol radiation therapy were more likely to meet their primary endpoint (adjusted odds ratio, 4.50; 95% CI, 1.23-20.23; P = .04). CONCLUSIONS: Although most trials allowed off-protocol radiation therapy during the receipt of the study systemic therapy, the influence of off-protocol radiation therapy, especially ablative radiation therapy, on study outcomes is underevaluated among phase 3 systemic therapy trials.

CHARMM at 45: Enhancements in Accessibility, Functionality, and Speed.

Since its inception nearly a half century ago, CHARMM has been playing a central role in computational biochemistry and biophysics. Commensurate with the developments in experimental research and advances in computer hardware, the range of methods and applicability of CHARMM have also grown. This review summarizes major developments that occurred after 2009 when the last review of CHARMM was published. They include the following: new faster simulation engines, accessible user interfaces for convenient workflows, and a vast array of simulation and analysis methods that encompass quantum mechanical, atomistic, and coarse-grained levels, as well as extensive coverage of force fields. In addition to providing the current snapshot of the CHARMM development, this review may serve as a starting point for exploring relevant theories and computational methods for tackling contemporary and emerging problems in biomolecular systems. CHARMM is freely available for academic and nonprofit research at https://academiccharmm.org/program.

Evidenced-Based Prior for Estimating the Treatment Effect of Phase III Randomized Trials in Oncology.

PURPOSE: The primary results of phase III oncology trials may be challenging to interpret, given that results are generally based on P value thresholds. The probability of whether a treatment is beneficial, although more intuitive, is not usually provided. Here, we developed and released a user-friendly tool that calculates the probability of treatment benefit using trial summary statistics. METHODS: We curated 415 phase III randomized trials enrolling 338,600 patients published between 2004 and 2020. A phase III prior probability distribution for the treatment effect was developed on the basis of a three-component zero-mean mixture distribution of the observed z-scores. Using this prior, we computed the probability of clinically meaningful benefit (hazard ratio [HR] <0.8). The distribution of signal-to-noise ratios and power of phase III oncology trials were compared with that of 23,551 randomized trials from the Cochrane Database. RESULTS: The signal-to-noise ratios of phase III oncology trials tended to be much larger than randomized trials from the Cochrane Database. Still, the median power of phase III oncology trials was only 49% (IQR, 14%-95%), and the power was <80% in 65% of trials. Using the phase III oncology-specific prior, only 53% of trials claiming superiority (114 of 216) had a ≥90% probability of clinically meaningful benefits. Conversely, the probability that the experimental arm was superior to the control arm (HR <1) exceeded 90% in 17% of trials interpreted as having no benefit (34 of 199). CONCLUSION: By enabling computation of contextual probabilities for the treatment effect from summary statistics, our robust, highly practical tool, now posted on a user-friendly webpage, can aid the wider oncology community in the interpretation of phase III trials.

Topological Data Analysis for Particulate Gels.

Soft gels, formed via the self-assembly of particulate materials, exhibit intricate multiscale structures that provide them with flexibility and resilience when subjected to external stresses. This work combines particle simulations and topological data analysis (TDA) to characterize the complex multiscale structure of soft gels. Our TDA analysis focuses on the use of the Euler characteristic, which is an interpretable and computationally scalable topological descriptor that is combined with filtration operations to obtain information on the geometric (local) and topological (global) structure of soft gels. We reduce the topological information obtained with TDA using principal component analysis (PCA) and show that this provides an informative low-dimensional representation of the gel structure. We use the proposed computational framework to investigate the influence of gel preparation (e.g., quench rate, volume fraction) on soft gel structure and to explore dynamic deformations that emerge under oscillatory shear in various response regimes (linear, nonlinear, and flow). Our analysis provides evidence of the existence of hierarchical structures in soft gels, which are not easily identifiable otherwise. Moreover, our analysis reveals direct correlations between topological changes of the gel structure under deformation and mechanical phenomena distinctive of gel materials, such as stiffening and yielding. In summary, we show that TDA facilitates the mathematical representation, quantification, and analysis of soft gel structures, extending traditional network analysis methods to capture both local and global organization.

Exploring Druggable Binding Sites on the Class A GPCRs Using the Residue Interaction Network and Site Identification by Ligand Competitive Saturation.

G protein-coupled receptors (GPCRs) play a central role in cellular signaling and are linked to many diseases. Accordingly, computational methods to explore potential allosteric sites for this class of proteins to facilitate the identification of potential modulators are needed. Importantly, the availability of rich structural data providing the locations of the orthosteric ligands and allosteric modulators targeting different GPCRs allows for the validation of approaches to identify new allosteric binding sites. Here, we validate the combination of two computational techniques, the residue interaction network (RIN) model and the site identification by ligand competitive saturation (SILCS) method, to predict putative allosteric binding sites of class A GPCRs. RIN analysis identifies hub residues that mediate allosteric signaling within a receptor and have a high capacity to alter receptor dynamics upon ligand binding. The known orthosteric (and allosteric) binding sites of 18 distinct class A GPCRs were successfully predicted by RIN through a dataset of 105 crystal structures (91 ligand-bound, 14 unbound) with up to 77.8% (76.9%) sensitivity, 92.5% (95.3%) specificity, 51.9% (50%) precision, and 86.2% (92.4%) accuracy based on the experimental and theoretical binding site data. Moreover, graph spectral analysis of the residue networks revealed that the proposed sites were located at the interfaces of highly interconnected residue clusters with a high ability to coordinate the functional dynamics. Then, we employed the SILCS-Hotspots method to assess the druggability of the novel sites predicted for 7 distinct class A GPCRs that are critical for a variety of diseases. While the known orthosteric and allosteric binding sites are successfully explored by our approach, numerous putative allosteric sites with the potential to bind drug-like molecules are proposed. The computational approach presented here promises to be a highly effective tool to predict putative allosteric sites of GPCRs to facilitate the design of effective modulators.

A meta-epidemiological analysis of post-hoc comparisons and primary endpoint interpretability among randomized non-comparative trials in clinical medicine.

OBJECTIVE: Randomized non-comparative trials (RNCT) promise reduced accrual requirements versus randomized controlled comparative trials because RNCTs do not enroll a control group, and instead compare outcomes to historical controls or prespecified estimates. We hypothesized that RNCTs often suffer from two methodological concerns: (1) lack of interpretability due to group-specific inferences in non-randomly selected samples and (2) misinterpretation due to unlicensed between-group comparisons lacking pre-specification. The purpose of this study was to characterize RNCTs and the incidence of these two methodological concerns. STUDY DESIGN AND SETTING: We queried PubMed and Web of Science on September 14, 2023, to conduct a meta-epidemiological analysis of published RNCTs in any field of medicine. Trial characteristics and the incidence of methodological concerns were manually recorded. RESULTS: We identified 70 RNCTs published from 2002 through 2023. RNCTs have been increasingly published over time (slope=0.28, 95% CI 0.17 to 0.39, P<0.001). Sixty trials (60/70, 86%) had lack of interpretability for the primary endpoint due to group-specific inferences. Unlicensed between-group comparisons were present in 36 trials (36/70, 51%), including in the primary conclusion of 31 trials (31/70, 44%), and were accompanied by significance testing in 20 trials (20/70, 29%). Only 5 (5/70, 7%) trials were found to have neither of these flaws. CONCLUSION: Although RNCTs are increasing published over time, the primary analysis of nearly all published RNCTs in the medical literature were unsupported by their fundamental underlying methodological assumptions. RNCTs promise group-specific inference, which they are unable to deliver, and undermine the primary advantage of randomization, which is comparative inference. The ongoing use of the RNCT design in lieu of a traditional RCCT should therefore be reconsidered.

Deoxyhypusine synthase deficiency syndrome zebrafish model: aberrant morphology, epileptiform activity, and reduced arborization of inhibitory interneurons.

DHPS deficiency syndrome is an ultra-rare neurodevelopmental disorder (NDD) which results from biallelic mutations in the gene encoding the enzyme deoxyhypusine synthase (DHPS). DHPS is essential to synthesize hypusine, a rare amino acid formed by post-translational modification of a conserved lysine in eukaryotic initiation factor 5 A (eIF5A). DHPS deficiency syndrome causes epilepsy, cognitive and motor impairments, and mild facial dysmorphology. In mice, a brain-specific genetic deletion of Dhps at birth impairs eIF5AHYP-dependent mRNA translation. This alters expression of proteins required for neuronal development and function, and phenotypically models features of human DHPS deficiency. We studied the role of DHPS in early brain development using a zebrafish loss-of-function model generated by knockdown of dhps expression with an antisense morpholino oligomer (MO) targeting the exon 2/intron 2 (E2I2) splice site of the dhps pre-mRNA. dhps knockdown embryos exhibited dose-dependent developmental delay and dysmorphology, including microcephaly, axis truncation, and body curvature. In dhps knockdown larvae, electrophysiological analysis showed increased epileptiform activity, and confocal microscopy analysis revealed reduced arborisation of GABAergic neurons. Our findings confirm that hypusination of eIF5A by DHPS is needed for early brain development, and zebrafish with an antisense knockdown of dhps model features of DHPS deficiency syndrome.