The Transformative Role of 3D Culture Models in Triple-Negative Breast Cancer Research.

Advancements in cell culturing techniques have allowed the development of three-dimensional (3D) cell culture models sourced directly from patients' tissues and tumors, faithfully replicating the native tissue environment. These models provide a more clinically relevant platform for studying disease progression and treatment responses compared to traditional two-dimensional (2D) models. Patient-derived organoids (PDOs) and patient-derived xenograft organoids (PDXOs) emerge as innovative 3D cancer models capable of accurately mimicking the tumor's unique features, enhancing our understanding of tumor complexities, and predicting clinical outcomes. Triple-negative breast cancer (TNBC) poses significant clinical challenges due to its aggressive nature, propensity for early metastasis, and limited treatment options. TNBC PDOs and PDXOs have significantly contributed to the comprehension of TNBC, providing novel insights into its underlying mechanism and identifying potential therapeutic targets. This review explores the transformative role of various 3D cancer models in elucidating TNBC pathogenesis and guiding novel therapeutic strategies. It also provides an overview of diverse 3D cell culture models, derived from cell lines and tumors, highlighting their advantages and culturing challenges. Finally, it delves into live-cell imaging techniques, endpoint assays, and alternative cell culture media and methodologies, such as scaffold-free and scaffold-based systems, essential for advancing 3D cancer model research and development.

Sublaminar Band Fixation Provides Excellent Anchors for MAGEC Rod Distraction Systems.

MAGEC rods (NuVasive) provide distraction growth in early-onset scoliosis. Pedicle screw use with MAGEC rods can lead to anchor failure. Sublaminar bands offer superior fixation points for the MAGEC system while preserving pedicles and facets, avoiding spinal cord injury, and eliminating the need for fluoroscopy. Sublaminar bands can be safely used up to cervical vertebra four (C4), substantially decreasing the risk of complications such as anchor pull-out, rod breakage, and proximal junctional kyphosis that typically occurs with pedicle screws and hooks. This case demonstrates the viable option of sublaminar band fixation as an anchor system for MAGEC rods. This is a retrospective case review of one patient with early-onset scoliosis who underwent multiple osteotomies, spinal cord decompression, and placement of MAGEC rods with sublaminar bands. The patient had successful distraction procedures conducted routinely throughout a 44-month period with no associated implant complications or neurologic sequelae during that period. The patient had achieved maximal distraction with the implanted rods and thereafter underwent removal of the MAGEC rods and replacement implantation with longer MAGEC rods. The purpose of this case review was to demonstrate the superior fixation results provided with sublaminar band fixation for MAGEC rod distraction systems.

Does Liposomal Bupivacaine Injectable Suspension Peripheral Nerve Block Further Aid in Decreasing At-home Narcotic Utilization in Children and Adolescents After Anterior Cruciate Ligament Reconstruction.

BACKGROUND: Opioid misuse and addiction among children and adolescents is an increasingly concerning problem. This study sought to determine whether liposomal bupivacaine injectable suspension admixture administered as a single-shot adductor canal peripheral nerve block (SPNB+BL) would decrease utilization of at-home opioid analgesics after anterior cruciate ligament reconstruction (ACLR) in adolescents compared with single-shot peripheral nerve block with bupivacaine (SPNB+B) alone. METHODS: Consecutive ACLR patients with or without meniscal surgery by a single surgeon were enrolled. All received a preoperative single-shot adductor canal peripheral nerve block with either admixture of liposomal bupivacaine injectable suspension with 0.25% bupivacaine (SPNB+BL) or 0.25% bupivacaine alone (SPNB+B). Postoperative pain management included cryotherapy, oral acetaminophen, and ibuprofen. A prescription for 10 doses of hydrocodone/acetaminophen (5/325 mg) was provided in a sealed envelope with instructions to only use in the case of uncontrolled pain. Pain using the visual analog scale; number of consumed narcotics, acetaminophen, ibuprofen, and pain treatment satisfaction for the first 3 postoperative days were recorded. Statistical analysis was performed. RESULTS: Fifty-eight patients were enrolled, the average age was 15±1.5 years (SPNB+B=32 patients, SPNB+BL=26 patients). Forty-seven patients (81%) did not require home opioids postoperatively. A significantly lower proportion of patients in the SPNB+BL group required opioids compared with control patients (7.7% vs. 28.1%, P =0.048). Average opioid use was 2 morphine milligram equivalents (MME), 0.4 pills (range, 0 to 20 MME). There were no differences in the visual analog scale or pain treatment satisfaction scores, other demographics, or other operative data. Inverse probability of treatment weighting analysis that was performed to account for any potential group differences revealed home opioid use between groups is significantly different ( P <0.001). CONCLUSIONS: Liposomal bupivacaine injectable suspension admixture administered as an adductor canal nerve block in adolescents undergoing ACLR effectively reduces home opioid usage postoperatively compared with bupivacaine alone. LEVEL OF EVIDENCE: Level II-prospective comparative study.

Restoration of thoracic kyphosis in adolescent idiopathic scoliosis with patient-specific rods: did the preoperative plan match postoperative sagittal alignment?

PURPOSE: To determine if the planned sagittal profile for thoracic kyphosis (TK) restoration was achieved after adolescent idiopathic scoliosis (AIS) surgery using a novel hybrid construct with apical double bands and precontoured patient-specific rods (PSR) made according to the detailed surgical plan for the desired sagittal plane. METHODS: AIS patients with a Lenke type 1-4 primary right thoracic curve who underwent corrective surgery by a single surgeon and had minimum 24-month follow-up were analyzed retrospectively from a prospective database. All patients underwent simultaneous translation on two rods with apical double bands and PSR. Clinical outcomes in terms of sagittal 2D TK (T4-T12), lumbar lordosis (LL), sagittal vertical axis (SVA), pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), PI-LL mismatch, rod angle, and rod deflection were compared between preoperative, planned, and 24-month data, while 3D apical rotation, 3D TK (T5-T12), sagittal thoracolumbar angle, degree of curvature at L1-L4 and L4-S1, proximal junctional angle, and distal junctional angle were compared at baseline and at 6 and 24 months postoperatively. SRS-22 questionnaire scores were obtained at baseline and 24 months postoperatively. RESULTS: Forty-eight patients were included. Study patients had a median coronal thoracic curve of 62.7° preoperatively and 22.4° at 24-month follow-up (p < 0.001). Median TK gain was 6.5° for the entire cohort (n = 48) and 19.1° in the Lenke type 1 and 2 hypokyphotic subgroup (n = 14). Both groups had no significant changes between planned and 24-month TK (p = 0.068 and p = 0.943, respectively), rod angle (p = 0.776 and p = 0.548, respectively), or rod deflection (p = 0.661 and p = 0.850, respectively). For the overall study cohort, median LL gain was 7.0° (p < 0.001), 3D apical derotation was 10.7° (p < 0.001), and change in 3D TK was 36° (p < 0.001). No instance of proximal junctional kyphosis was observed. SRS-22 scores for pain, self-image, and satisfaction differed significantly between the preoperative and 24-month follow-up time-points. CONCLUSIONS: With sagittal plane planning, desired TK, improved reciprocal changes in LL, and minimal changes in rod shape can be achieved in patients with AIS.

COVID-19 pandemic restrictions unmasks dangers of frequent injury mechanisms for common surgically treated pediatric fractures.

Purpose: This study examined the volume and characteristics of common surgically treated fractures in children during the COVID-19 pandemic. The worldwide spread of COVID-19 affected the society in numerous ways. Social distancing led to changes in the types of activities performed by individuals, including children. Physicians saw a shift in orthopedic trauma volume and distribution. We predicted that with the change in activities children participated in, the number or type of injuries sustained would change as well. Methods: A retrospective review was performed of children who sustained a surgically treated fracture of the forearm, supracondylar humerus, femur, or any open fracture during the COVID-19 pandemic compared to the previous 2 years (pre-pandemic). Patient demographics, insurance status, and mechanism of injury were recorded. Statistical analysis was performed. Results: Review of the medical records identified 791 children. The number of fractures decreased from an average of 295 per year pre-pandemic to 201 during the pandemic (p = 0.09). During the pandemic, there was a decrease in injuries resulting from a fall from the monkey bars for supracondylar humerus (21.2% to 8.2%, p < 0.01) and for forearm fractures (15.5% to 4.3%, p = 0.04). In contrast, the frequencies of falls from a skateboard, hoverboard, scooter, or bicycle and falls from household furniture increased during the pandemic. Conclusion: The observed decrease in monkey bar-related injuries provides further evidence as to the dangers of this piece of playground equipment in contributing to upper-extremity fractures in children. Level of evidence: Level III: Prognostic and Epidemiological.

Emerging therapeutic targets for cardiac hypertrophy.

INTRODUCTION: Cardiac hypertrophy is associated with adverse outcomes across cardiovascular disease states. Despite strides over the last three decades in identifying molecular and cellular mechanisms driving hypertrophy, the link between pathophysiological stress stimuli and specific myocyte/heart growth profiles remains unclear. Moreover, the optimal strategy for preventing pathology in the setting of hypertrophy remains controversial. AREAS COVERED: This review discusses molecular mechanisms underlying cardiac hypertrophy with a focus on factors driving the orientation of myocyte growth and the impact on heart function. We highlight recent work showing a novel role for the spectrin-based cytoskeleton, emphasizing regulation of myocyte dimensions but not hypertrophy per se. Finally, we consider opportunities for directing the orientation of myocyte growth in response to hypertrophic stimuli as an alternative therapeutic approach. Relevant publications on the topic were identified through Pubmed with open-ended search dates. EXPERT OPINION: To define new therapeutic avenues, more precision is required when describing changes in myocyte and heart structure/function in response to hypertrophic stimuli. Recent developments in computational modeling of hypertrophic networks, in concert with more refined experimental approaches will catalyze translational discovery to advance the field and further our understanding of cardiac hypertrophy and its relationship with heart disease.

Bilateral Calcaneus Transfers for the Treatment of Congenital Tibial Deficiencies: A Novel Surgical Technique and Case Report.

Tibial deficiency (also known as tibial hemimelia) is a rare condition with variable presentation. A 2-month-old patient presented with absent bilateral tibias. When the patient was 1 year, a novel reconstructive surgery was done. A bilateral fibular resection with pedicled calcaneus transfer was done, allowing for transfer of the calcaneus along with the overlying glabrous skin and soft tissues to the end of the femur. The patient was permitted to weight-bear after the 4-week postoperative follow-up. At the six-month follow-up, the patient was able to pull to stand and walk with assistance without any reports of pain.

Fibroblast growth factor-inducible 14 mediates macrophage infiltration in heart to promote pressure overload-induced cardiac dysfunction.

AIMS: Heart failure (HF) is characterized by compromised cardiac structure and function. Previous work has identified a link between upregulation of pro-inflammatory cytokines and HF. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a pro-inflammatory cytokine, which binds to fibroblast growth factor inducible 14 (Fn14), a ubiquitously expressed cell-surface receptor. The objective of this study was to investigate the role of TWEAK/Fn14 pathway in promoting cardiac inflammation under non ischemic stress conditions. MAIN METHODS: Wild type (WT) and Fn14 knock out (Fn14-/-) mice were subjected to pressure overload [transaortic constriction (TAC)] for 1 or 6 weeks. A subset of WT TAC animals were treated with the Fn14 antagonist L524-0366. Cardiac function was measured by echocardiography. Cardiac fibrosis and macrophage infiltration were quantified using immunohistochemistry and flow cytometry, respectively. Cardiac fibroblasts were isolated for quantifying TWEAK-induced chemokine release. KEY FINDINGS: Fn14-/- mice displayed improved cardiac function, reduced fibrosis and lower macrophage infiltration in heart compared to WT following TAC. L524-0366 mitigated maladaptive remodeling with TAC. TWEAK induced secretion of the pro-inflammatory chemokine, monocyte chemoattractant protein 1 from WT but not Fn14-/- fibroblasts in vitro, in part through activation of non-canonical NF-κB signaling. Finally, Fn14 expression was increased in mouse following TAC and in human failing hearts. SIGNIFICANCE: Our findings support an important role for the TWEAK/Fn14 promoting macrophage infiltration and fibrosis in heart under non-ischemic stress, with potential for therapeutic intervention to improve cardiac function in the setting of HF.

Empirical and Computational Comparison of Alternative Therapeutic Exon Skip Repairs for Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a common and devastating genetic disease primarily caused by exon deletions that create a genetic frameshift in dystrophin. Exon skipping therapy seeks to correct this by masking an exon during the mRNA maturation process, restoring dystrophin expression, but creating an edited protein missing both the original defect and the therapeutically skipped region. Crucially, it is possible to correct many defects in alternative ways, by skipping an exon either before or after the patient's defect. This results in alternatively edited, hybrid proteins that might have different properties and therapeutic consequences. We examined three such dystrophin exon-skipped edits, Δe45-53, Δe46-54, and Δe47-55, comprising two pairs of alternative repairs of Δe46-53 and Δe47-54 DMD defects. We found that in both cases, Δe46-54 was the more stable repair as determined by a variety of thermodynamic and biochemical measurements. We also examined the origin of these differences with molecular dynamics simulations, which showed that these stability differences were the result of different types of structural perturbations. For example, in one edit there was partial unfolding at the edit site that caused domain-localized perturbations while in another there was unfolding at the protein domain junctions distal to the edit site that increased molecular flexibility. These results demonstrate that alternative exon skip repairs of the same underlying defect can have very different consequences at the level of protein structure and stability and furthermore that these can arise by different mechanisms, either locally or by more subtle long-range perturbations.

Mobilizing the Next Generation of Health Advocates: Building Our Collective Capacity to Advocate for Health Education and Health Equity Through SOPHE Advocacy Summits.

In this Career Development commentary, the author highlights the benefits of attending the Society for Public Health Education Advocacy Summit in Washington, D.C. Advocacy is an increasingly necessary skill that allows health educators to advance both the field of public health and their own career development as professionals. Students and practitioners from diverse health education settings get to connect with other professionals, attend skill-building workshops, and increase their ability to influence health policy. From a career development perspective, the Summit provides opportunities to develop professional networks, gain experience and continuing education in several areas of responsibility for health education specialists, and share lessons learned with colleagues in health education and public health.

Analysis of SI models with multiple interacting populations using subpopulations.

Computing endemic equilibria and basic reproductive numbers for systems of differential equations describing epidemiological systems with multiple connections between subpopulations is often algebraically intractable. We present an alternative method which deconstructs the larger system into smaller subsystems and captures the interactions between the smaller systems as external forces using an approximate model. We bound the basic reproductive numbers of the full system in terms of the basic reproductive numbers of the smaller systems and use the alternate model to provide approximations for the endemic equilibrium. In addition to creating algebraically tractable reproductive numbers and endemic equilibria, we can demonstrate the influence of the interactions between subpopulations on the basic reproductive number of the full system. The focus of this paper is to provide analytical tools to help guide public health decisions with limited intervention resources.