Combinatorial Inhibition of Myostatin and Activin A Improves Femoral Bone Properties in the G610C Mouse Model of Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a collagen-related bone disorder characterized by fragile osteopenic bone and muscle weakness. We have previously shown that the soluble activin receptor type IIB decoy (sActRIIB) molecule increases muscle mass and improves bone strength in the mild to moderate G610C mouse model of OI. The sActRIIB molecule binds multiple transforming growth factor-β (TGF-β) ligands, including myostatin and activin A. Here, we investigate the musculoskeletal effects of inhibiting activin A alone, myostatin alone, or both myostatin and activin A in wild-type (Wt) and heterozygous G610C (+/G610C) mice using specific monoclonal antibodies. Male and female Wt and +/G610C mice were treated twice weekly with intraperitoneal injections of monoclonal control antibody (Ctrl-Ab, Regn1945), anti-activin A antibody (ActA-Ab, Regn2476), anti-myostatin antibody (Mstn-Ab, Regn647), or both ActA-Ab and Mstn-Ab (Combo, Regn2476, and Regn647) from 5 to 16 weeks of age. Prior to euthanasia, whole body composition, metabolism and muscle force generation assessments were performed. Post euthanasia, hindlimb muscles were evaluated for mass, and femurs were evaluated for changes in microarchitecture and biomechanical strength using micro–computed tomography (μCT) and three-point bend analyses. ActA-Ab treatment minimally impacted the +/G610C musculoskeleton, and was detrimental to bone strength in male +/G610C mice. Mstn-Ab treatment, as previously reported, resulted in substantial increases in hindlimb muscle weights and overall body weights in Wt and male +/G610C mice, but had minimal skeletal impact in +/G610C mice. Conversely, the Combo treatment outperformed ActA-Ab alone or Mstn-Ab alone, consistently increasing hindlimb muscle and body weights regardless of sex or genotype and improving bone microarchitecture and strength in both male and female +/G610C and Wt mice. Combinatorial inhibition of activin A and myostatin more potently increased muscle mass and bone microarchitecture and strength than either antibody alone, recapturing most of the observed benefits of sActRIIB treatment in +/G610C mice. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Validation of PATHFx 2.0: An open-source tool for estimating survival in patients undergoing pathologic fracture fixation

Treatment decisions in patients with metastatic bone disease rely on accurate survival estimation. We developed the original PATHFx models using expensive, proprietary software and now seek to provide a more cost-effective solution. Using open-source machine learning software to create PATHFx version 2.0, we asked whether PATHFx 2.0 could be created using open-source methods and externally validated in two unique patient populations. The training set of a well-characterized, database records of 189 patients and the bnlearn package within R Version 3.5.1 (R Foundation for Statistical Computing), was used to establish a series of Bayesian belief network models designed to predict survival at 1, 3, 6, 12, 18, and 24 months. Each was externally validated in both a Scandinavian (n = 815 patients) and a Japanese (n = 261 patients) data set. Brier scores and receiver operating characteristic curves to assessed discriminatory ability. Decision curve analysis (DCA) evaluated whether models should be used clinically. DCA showed that the model should be used clinically at all time points in the Scandinavian data set. For the 1-month time point, DCA of the Japanese data set suggested to expect better outcomes assuming all patients will survive greater than 1 month. Brier scores for each curve demonstrate that the models are accurate at each time point. Statement of Clinical Significance: we successfully transitioned to PATHFx 2.0 using open-source software and externally validated it in two unique patient populations, which can be used as a cost-effective option to guide surgical decisions in patients with metastatic bone disease.     

Prenatal Substance Use and Perceptions of Parent and Partner Use Using the 4P’s Plus Screener

Maternal and Child Health Journal - Background Prenatal substance use screening is recommended. The 4 P’s Plus screener includes questions on perceived problematic substance use in parents...     

Syringocystadenocarcinoma papilliferum associated with atypical stroma: A hitherto undocumented variant of sarcomatoid carcinoma

Carcinosarcomas are biphasic tumors composed of admixed malignant epithelial and mesenchymal components. Numerous terms have been used to name such neoplasms; therefore, terminological confusion is frequent. Most examples of carcinosarcomas are encountered in non‐cutaneous sites, with approximately 100 cases of cutaneous carcinosarcomas reported so far in the English literature. Although different theories have been suggested to explain the occurrence of these peculiar neoplasms, histogenetic mechanisms should be better hypothesized depending on each individual case. Even though prognosis tends to be related to the specific components of the lesion, especially the epithelial one, it seems that cases of cutaneous localization usually have a better outcome. We report an exceedingly rare case of syringocystadenocarcinoma papilliferum which showed an atypical stroma with sarcomatoid appearance, and highlight that the terminology used for this spectrum of lesions is disorganized and confusing.     

2‐deoxy D‐glucose treatment does not elicit a hair growth response in alopecia areata

2‐deoxy D‐glucose (2DG) was tested for efficacy in treating alopecia areata using the C3H/HeJ skin graft model. 2DG has proven to be efficacious in treatment of various mouse models of autoimmunity with minimal serious side effects noted. This agent has been shown to normalize abnormally activated T‐cell populations while also preventing cell surface expression of NKG2D; key factors defining alopecia areata disease progression. Daily oral ingestion of 2DG via drinking water to mice with patchy or diffuse alopecia areata for 16 weeks failed to prevent expansion of alopecia or cause regrowth of hair in treated mice. Histologically, there were no differences between treated and control groups. These results indicate that, while 2DG is effective for some autoimmune diseases, it was not efficacious for the cell‐mediated autoimmune mouse disease, alopecia areata.     

Assessment of backward walking unmasks mobility impairments in post-stroke community ambulators

Background: While over half of stroke survivors recover the ability to walk without assistance, deficits persist in the performance of walking adaptations necessary for safe home and community mobility. One such adaptation is the ability to walk or step backward. Post-stroke rehabilitation rarely includes backward walking (BW) assessment and BW deficits have not been quantified in post-stroke community ambulators.

Objective: To quantify spatiotemporal and kinematic BW characteristics in post-stroke community ambulators and compare their performance to controls.

Methods: Individuals post-stroke (n = 15, 60.1 ± 12.9 years, forward speed: 1.13 ± 0.23 m/s) and healthy adults (n = 12, 61.2 ± 16.2 years, forward speed: 1.40 ± 0.13 m/s) performed forward walking (FW) and BW during a single session. Step characteristics and peak lower extremity joint angles were extracted using 3D motion analysis and analyzed with mixed-method ANOVAs (group, walking condition).

Results: The stroke group demonstrated greater reductions in speed, step length and cadence and a greater increase in double-support time during BW compared to FW (p < .01). Compared to FW, the post-stroke group demonstrated greater reductions in hip extension and knee flexion during BW (p < .05). The control group demonstrated decreased plantarflexion and increased dorsiflexion during BW, but these increases were attenuated in the post-stroke group (p < .05).

Conclusions: Assessment of BW can unmask post-stroke walking impairments not detected during typical FW. BW impairments may contribute to the mobility difficulties reported by adults post-stroke. Therefore, BW should be assessed when determining readiness for home and community ambulation.     

Metabolic reprogramming in childhood acute lymphoblastic leukemia

The first observations of altered metabolism in malignant cells were made nearly 100 years ago and therapeutic strategies targeting cell metabolism have been in clinical use for several decades.  In this review, we summarize our current understanding of cell metabolism dysregulation in childhood acute lymphoblastic leukemia (cALL). Reprogramming of cellular bioenergetic processes can be expected in the three distinct stages of cALL: at diagnosis, during standard chemotherapy, and in cases of relapse. Upregulation of glycolysis, dependency on anaplerotic energy sources, and activation of the electron transport chain have all been observed in cALL. While the current treatment strategies are tackling some of these aberrations, cALL cells are likely to be able to rewire their metabolism in order to escape therapy, which may contribute to a refractory disease and relapse. Finally, here we focus on novel therapeutic approaches emerging from our evolving understanding of the alterations of different metabolic networks in lymphoblasts.