Effective Nonsurgical Treatments Research Articles

CTSD upregulation as a key driver of spinal ligament abnormalities in spinal stenosis

Spinal stenosis (SS) is frequently caused by spinal ligament abnormalities, such as ossification and hypertrophy, which narrow the spinal canal and compress the spinal cord or nerve roots, leading to myelopathy or sciatic symptoms; however, the underlying pathological mechanism is poorly understood, hampering the development of effective nonsurgical treatments. Our study aims to investigate the role of co-expression hub genes in patients with spinal ligament ossification and hypertrophy. To achieve this, we conducted an integrated analysis by combining RNA-seq data of ossification of the posterior longitudinal ligament (OPLL) and microarray profiles of hypertrophy of the ligamentum flavum (HLF), consistently pinpointing CTSD as an upregulated hub gene in both OPLL and HLF. Subsequent RT-qPCR and IHC assessments confirmed the heightened expression of CTSD in human OPLL, ossification of the ligamentum flavum (OLF), and HLF samples. We observed an increase in CTSD expression in human PLL and LF primary cells during osteogenic differentiation, as indicated by western blotting (WB). To assess CTSD's impact on osteogenic differentiation, we manipulated its expression levels in human PLL and LF primary cells using siRNAs and lentivirus, as demonstrated by WB, ALP staining, and ARS. Our findings showed that suppressing CTSD hindered the osteogenic differentiation potential of PLL and LF cells, while overexpressing CTSD activated osteogenic differentiation. These findings identify CTSD as a potential therapeutic target for treating spinal stenosis associated with spinal ligament abnormalities.

Comparing Outcomes of Various Non-surgical Treatments, such as Scaling and Root Planing, Ultrasonic Therapy, and Laser Therapy

Abstract Background: Periodontitis is a prevalent inflammatory condition leading to progressive attachment loss and potential tooth loss. Nonsurgical periodontal therapy, including scaling and root planing (SRP), ultrasonic therapy, and laser therapy, is essential in managing periodontitis. This study compares the clinical and patient-reported outcomes of these three treatment modalities to determine their relative effectiveness. Objective: We aimed to compare the clinical outcomes and patient-reported experiences of SRP, ultrasonic therapy, and laser therapy in patients with chronic periodontitis. Materials and Methods: This randomized controlled trial involved 126 participants with moderate-to-severe chronic periodontitis, randomly assigned to one of three groups (42 participants each): Group 1 (SRP), Group 2 (ultrasonic therapy), and Group 3 (laser therapy). Clinical outcomes, including clinical attachment level (CAL), probing depth (PD), and bleeding on probing (BOP), were measured at baseline and 3 months post-treatment. Patient-reported outcomes such as pain, discomfort, and satisfaction were assessed using a visual analog scale. Data were analyzed using analysis of variance, with a P < 0.05 considered statistically significant. Results: All groups showed significant improvements in CAL, PD, and BOP with no significant differences between groups (P > 0.05). Laser therapy resulted in the lowest pain and discomfort scores and the highest satisfaction (P < 0.05). Conclusion: SRP, ultrasonic therapy, and laser therapy are effective nonsurgical treatments for periodontitis, with comparable clinical outcomes. Laser therapy, however, offers superior patient comfort and satisfaction, suggesting that it may be a preferred option for patients sensitive to pain or discomfort.

Patients' attitude with surgery for Peyronie's disease: results from a multicentric European study.

Despite the existence of conservative therapies for Peyronie's disease (PD), surgery is commonly utilized for the treatment of bothersome curvatures due to its potential effectiveness, although it carries intrinsic risks and may not universally lead to satisfactory outcomes. To explore the rate and factors influencing patients' willingness to undergo surgery for PD. Data were prospectively collected in 5 European academic centers between 2016 and 2020. Data included age, time from PD onset, penile pain, curvature degree, difficulty at penetration, hourglass deformity, erectile dysfunction (ED), and previous treatments. All patients were offered conservative treatments, either medications or injections. Tunical shortening or lengthening procedures were offered as an alternative to conservative treatments, when indicated. Penile prosthesis was offered to those with concomitant ED. Patients' attitudes with surgery were recorded. Logistic regression analyses tested the profile of patients who were more likely to be willing to undergo surgery. Patients' willingness to undergo surgery for PD. This study included 343 patients with a median age of 57.3years (IQR, 49.8-63.6) and a median penile curvature of 40.0° (IQR, 30.0°-65.0°). Overall, 161 (47%) experienced penetration difficulties and 134 (39%) reported ED. Additionally, hourglass deformity and penile shortening were reported by 48 (14%) and 157 (46%), respectively. As for previous treatments, 128 (37%) received tadalafil once daily; 54 (16%) and 44 (13%), intraplaque verapamil and collagenase injections; and 30 (9%), low-intensity shock wave therapy. Significant curvature reduction (≥20°) was observed in 69 (20%) cases. Only 126 (37%) patients were open to surgery for PD when suggested. At logistic regression analysis after adjusting for confounders, younger age (odds ratio [OR], 0.97; 95% CI, 0.95-1.00; P = .02), more severe curvatures (OR, 1.04; 95% CI, 1.03-1.06; P < .0001), and difficulty in penetration (OR, 1.88; 95% CI, 1.04-3.41; P = .03) were associated with a greater attitude to consider surgical treatment. The need for effective nonsurgical treatments for PD is crucial, as is comprehensive patient counseling regarding surgical risks and benefits, particularly to younger males with severe curvatures. Main limitations are the cross-sectional design and the potential neglect of confounding factors. Patients with PD, having a lower inclination toward surgery, emphasize the need for effective nonsurgical alternatives and accurate counseling on the risks and benefits of PD surgery, particularly for younger men with severe curvatures.

MicroRNA-29a: a novel target for non-operative management of symptomatic lumbar spinal stenosis.

Lumbar spinal stenosis (LSS) is the most common reason for spinal surgery in patients over the age of 65, and there are few effective non-surgical treatments. Therefore, the development of novel treatment or preventative modalities to decrease overall cost and morbidity associated with LSS is an urgent matter. The cause of LSS is multifactorial; however, a significant contributor is ligamentum flavum hypertrophy (LFH) which causes mechanical compression of the cauda equina or nerve roots. We assessed the role of a novel target, microRNA-29a (miR-29a), in LFH and investigated the potential for using miR-29a as a therapeutic means to combat LSS. Ligamentum flavum (LF) tissue was collected from patients undergoing decompressive surgery for LSS and assessed for levels of miR-29a and pro-fibrotic protein expression. LF cell cultures were then transfected with either miR-29a over-expressor (agonist) or inhibitor (antagonist). The effects of over-expression and under-expression of miR-29a on expression of pro-fibrotic proteins was assessed. We demonstrated that LF at stenotic levels had a loss of miR-29a expression. This was associated with greater LF tissue thickness and higher mRNA levels of collagen I and III. We also demonstrated that miR29-a plays a direct role in the regulation of collagen gene expression in ligamentum flavum. Specifically, agents that increase miR-29a may attenuate LFH, while those that decrease miR-29a promote fibrosis and LFH. This study demonstrates that miR-29a may potentially be used to treat LFH and provides groundwork to initiate the development of a therapeutic product for LSS.

CO2 Surgical Laser for Treatment of Stress Urinary Incontinence in Women: A Randomized Controlled Trial

ABSTRACT The common condition of stress urinary incontinence (SUI) has a reported prevalence of 10% to 39% in adult women in most studies. Although treatment of SUI via surgical means is an option, factors such as adverse effects of surgery and mesh-related risks lead many to seek alternative options. In overweight and obese patients, lifestyle changes for improving SUI symptoms entail mainly weight loss. Although pelvic floor muscle training (PFMT) can lead to improvements, further treatment is often necessary. Because of this, interest is high for developing effective nonsurgical treatments for SUI. One such possible treatment is vaginal laser therapy, which has been used as treatment for various vaginal conditions. The authors therefore carried out a randomized controlled trial (RCT) comparing CO2 laser with sham treatment for SUI. This multicenter, participant-blinded, sham-controlled, parallel-group, superiority RCT involved participants from 2 hospitals in Southeast Melbourne in the outpatient setting. Patients aged 18 to 80 years experiencing symptomatic and objective SUI and seeking conservative management participated. Women with prior surgery for SUI were excluded. A positive cough stress test with a comfortably full bladder and uroflow was used to determine objective SUI. Participants lacking positive cough stress test were still eligible for study inclusion with a positive pad weight test in the absence of urgency incontinence symptoms. Intervention took place using FemTouch delivery system in conjunction with the AcuScan 120 Microscanner and the AcuPulse CO2 laser system for fractional treatment. Laser energy was delivered via a standard foot pedal in a fractional manner. The sham treatment used identical methods and settings but used an inactive pedal, which only made mechanical clicks and no electronic beeps. A total of 3 treatments were administered to participants, 4 weeks apart, with incrementally greater density settings. The primary outcome of the study was subjective SUI (defined as positive answers to the inquiries: “Do you leak when you cough or sneeze?” or “Do you leak when physically active/exercising?”). Secondary outcomes were assessed via the Patient Global Impression of Improvement, and International Consultation on Incontinence Questionnaire–urinary incontinence change, International Consultation on Incontinence Questionnaire-overactive bladder, the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire, the Incontinence Impact Questionnaire–Short Form, and EQ-5D scores. In addition, adverse events (such as pain during the procedure as measured on a visual analog scale) and objective SUI were recorded. A sample size of 101 was chosen to provide 80% power to detect differences between groups for the primary outcome (even assuming a 10% rate of attrition). A total of 97 participants ultimately were treated. Randomization of participants occurred with equal probability to sham treatment or the CO2 laser using a computer-generated random sequence, which allocated participants to blocks of 4, 6, and 8. Unblinding of participants to their allocation occurred following the 3-month review. Participants had a mean age of 53 years and a mean body mass index of 26.1 kg/m2, and 90% were vaginally parous. Most participants had attempted PFMT either independently or under supervision. No detectable difference was found between the sham and active treatment arm in the primary outcome of leak with laughter or cough. Furthermore, there were no significant differences between groups with regard to any of the secondary, patient-reported outcomes of questionnaires. The authors tested the reliability of their masking by assessing whether patients could identify their allocation group. Between the 2 groups, 17 (54%) of the sham group and 15 (63%) of the active treatment group believed they received sham treatment. Adverse events were rare in both groups, with similar visual analog pain scores during treatment and only rare vaginal bleeding and urgency incontinence in both groups. Strengths of this study are several and include its blinded design and randomization methods. The primary outcome was focused on patient-reported outcomes. Responsive and validated questionnaires were utilized for assessment of secondary outcomes. Study limitations include a lack of blinding for investigators, which could have introduced an element of detection bias for SUI. In conclusion, no benefit was shown for 3 treatment sessions of the CO2 vaginal laser when compared with sham therapy. Additional trials with various laser modalities are necessary to determine whether this may produce varying results. Women considering CO2 vaginal laser therapy for SUI should be made aware of the lack of consistent high-quality evidence in support of this treatment.

Diagnosis and Treatment Modalities of Cholesteatomas: A Review.

A cholesteatoma is an abnormal, noncancerous skin growth that can appear beneath the eardrum in the center of your ear. Although it might be a congenital condition, frequent middle ear infections are the main culprit. A cholesteatoma frequently appears as a cyst or sac that exfoliates the skin's outer layers. As these dead skin cells build up, the growth can enlarge and penetrate intratemporal tissues, leading to various intracranial and extracranial difficulties that can compromise facial muscles, hearing, and balance. Cholesteatomas were recognized more than three centuries ago. A cholesteatoma can develop into a serious condition if it is not treated right away. Because of its fast development and invasive nature, it can cause several consequences, some of which can be fatal for people without access to advanced medical treatment. There are no effective nonsurgical treatments available right now. It will be necessary to have a thorough awareness of both previous developments and more current ones to develop an appropriate management approach for this condition. The background information on acquired middle ear cholesteatomas is briefly reviewed in this paper. We also take into account categorization-, epidemiology-, histology-, and pathogenesis-related difficulties, and we carefully review current management and diagnosis approaches.

Are there effective nonsurgical treatments of bunions?

Are there effective nonsurgical treatments of bunions?

A More Accurate Crystal Ball for Lung Surgeons

How does the saying go? Good surgeons know how to operate, better ones when to operate, and the best when not to operate.1 Risk stratification before lung resection is paramount for ensuring a safe operation and recovery period for our patients, especially with increasingly effective nonsurgical treatments for lung cancer. In this issue of The Annals of Thoracic Surgery, Yang and colleagues2 evaluated an underutilized imaging assessment for lung cancer patients.

Non-surgical treatments for basal cell skin cancer

Basal cell carcinoma is the most common nonmelanoma skin cancer. It originates from undifferentiated cells in the basal cell layer of the epidermis or from the outer root sheath of the hair follicle. The most important factor in development of basalioma is ultraviolet radiation. Surgery is considered the gold standard of treatment for basal cell cancer. However, nonsurgical options are available for individuals who are unsuitable for surgery. The purpose of this review is to summarize the efficacy and indications of alternative, nonsurgical treatments that can be used in the management of basal cell cancer&#x0D; Effective nonsurgical treatments include destructive methods (eg, curettage and electrodessication, cryosurgery, laser), photodynamic therapy, topical medications, hedgehog pathway inhibitors. Nonsurgical therapeutic alternatives are safe and effective for the treatment of BCC. Factors such as tumor location, size, and histopathological subtype should be taken into consideration when selecting optimal treatment, cosmetic results and patient preference should be considered too.&#x0D; To search for the necessary literature, the PubMed, MedLine, Web of Science and RSCI databases were used.

Abstract 9852: Targeting Mek/Erk Signaling in the Treatment of Mitral Valve Prolapse

Introduction: Mitral valve prolapse (MVP) is one of the most common forms of cardiac valve disease, affecting 1 in 40 humans and ~70% of small breed dogs. There are no effective nonsurgical treatments for MVP and therapeutic efforts have been hindered due to an incomplete understanding of its fundamental causes. Recent studies by our group have described the genetic basis for non-syndromic MVP and have provided new insights into molecular processes that underlie the disease. We have used this genetic information to identify druggable targets that can provide a non-surgical option for humans. In particular, we have identified the MEK/ERK pathway as the major disease initiating pathway and prolonged hyperactivation of MEK/ERK drives disease progression and severity. Hypothesis: Pharmacological blockade of MEK/ERK activities will sufficiently arrest the disease pathway and maintain the valves in a sub-clinical condition. Methods and Results: The FDA-approved MEK1 inhibitor Trametinib was administered to Dzip1 S24R/+ mice; a disease model that phenocopies human MVP. Preliminary results suggest safety concerns in mice associated with chronic administration of Trametinib (1 mg/kg/day). Animals demonstrated signs of cardiotoxicity on echocardiography, including left atrial enlargement; a reduction in E/A wave intensity; left ventricular wall movement abnormalities; prolonged isovolumetric relaxation time, and a reduced ejection fraction. As such, our lab has focused our efforts on identifying novel MEK1 inhibitors with a favorable safety profile. Utilizing a machine learning based workflow, we have identified highly selective MEK1 inhibitors with retained activity (&lt;100nM IC50 values); high gastrointestinal absorption (&gt;85%); favorable predicted LD50 values (&gt;1,000 mg/kg), and devoid of major cytochrome interactions. Conclusions: MEK1 may serve as a druggable target in the treatment of mitral valve prolapse; however, currently available MEK inhibitors demonstrate limiting toxicities. Future studies will involve in vivo administration of our novel compounds to Dzip1 S24R/+ mice. We envision results from this study will help guide the development of systemic or targeted therapies for the use in human patients with mitral valve prolapse.

An Evidenced-based Approach to Stress Urinary Incontinence in Women: What's New?

Stress urinary incontinence is a common condition in women potentially affecting women of any age including young women who have not yet completed childbearing. It is important to consider the impact on quality of life and offer treatment to those experiencing bother. There are several effective nonsurgical treatments for women before considering more invasive or definitive intervention. There is good data on lifestyle and behavioral changes which are often first-line recommendations. Data is also strong for pelvic muscle training and strengthening. Pessary supportive devices also play a role. Additional options also exist for limited indications.

Antioxidative Stress: Inhibiting Reactive Oxygen Species Production as a Cause of Radioresistance and Chemoresistance.

Radiotherapy and chemotherapy are the most effective nonsurgical treatments for cancer treatment. They usually induce regulated cell death by increasing the level of reactive oxygen species (ROS) in tumour cells. However, as intracellular ROS concentration increases, many antioxidant pathways are concurrently upregulated by cancer cells to inhibit ROS production, ultimately leading to drug resistance. Understanding the mechanism of antioxidant stress in tumour cells provides a new research direction for overcoming therapeutic resistance. In this review, we address (1) how radiotherapy and chemotherapy kill tumour cells by increasing the level of ROS, (2) the mechanism by which ROS activate antioxidant pathways and the subsequent cellular mitigation of ROS in radiotherapy and chemotherapy treatments, and (3) the potential research direction for targeted treatment to overcome therapeutic resistance.

The Aging neck-A Case base treatment algorithm.

Effective nonsurgical treatments for the aging face are widely accepted and utilized. Although changes in the aging neck, often patients to seek esthetic rejuvenation protocols are neither well defined nor well designed. Increasingly, patients desire less invasive cosmetic treatments with less morbidity and downtime. A significant challenge exists in managing expectations and educating patients about the pros and cons of a surgical approach compared to the plethora of nonsurgical options. When equipped with state of the art information and technique, using a multi-modality nonsurgical approach, surprisingly outstanding results may be obtained. In this paper, we aim to revisit the neck's anatomy and then demonstrate current nonsurgical techniques in managing actual cases. To achieve that, we have utilized an intuitive four-point grading scale to guide both physician and patient regarding appropriate treatment combinations. The proposed four-point scale was applied to six patients and their treatment plan was described in detail. Skin laxity is not the only factor that comes into play when assessing the neck. careful analysis of the neck and face hold the key for treatment choice and execution.

Beyond Mohs surgery and excisions: A focused review of treatment options for subtypes of basal cell carcinoma.

Basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer. It originates from undifferentiated cells in the basal cell layer of the epidermis or from the outer root sheath of the hair follicle. The most important factor in development of BCC is ultraviolet radiation. Surgery is considered the gold standard of treatment for BCC. However, nonsurgical options are available for individuals who are unsuitable for surgery. The purpose of this review is to summarize the efficacy and indications of alternative, nonsurgical treatments that can be used in the management of BCC. An extensive literature review was performed for the nonsurgical options for the treatment of BCC. Resources searched included PubMed and Google Scholars, limited to the years 1995 to 2020. Key words searched included BCC, destructive methods, photodynamic therapy (PDT), radiotherapy, topical medication, laser, hedgehog pathway inhibitors (HPIs). The most relevant results such as systematic reviews, randomized controlled trials, or comparative studies were selected to provide a summary for the most common nonsurgical methods used for treating BCC. Effective nonsurgical treatments for BCC include destructive methods (eg, curettage alone, cryosurgery, or electrodessication), PDT, topical medications, radiotherapy, laser, and HPIs. Nonsurgical therapeutic alternatives are safe and effective for the treatment of BCC. Factors such as tumor location, size, and histopathological subtype should be taken into consideration when selecting optimal treatment. In addition to clinical factors, cosmetic results and patient preference should be considered.

Cooled radiofrequency ablation provides extended clinical utility in the management of knee osteoarthritis: 12-month results from a prospective, multi-center, randomized, cross-over trial comparing cooled radiofrequency ablation to a single hyaluronic acid injection

BackgroundSafe and effective non-surgical treatments are an important part of the knee osteoarthritis (OA) treatment algorithm. Cooled radiofrequency ablation (CRFA) and hyaluronic acid (HA) injections are two commonly used modalities to manage symptoms associated with knee OA.MethodsA prospective 1:1 randomized study was conducted in 177 patients comparing CRFA to HA injection with follow-ups at 1, 3, 6 and 12 months. HA subjects with unsatisfactory outcomes at 6-months were allowed to crossover and receive CRFA. Knee pain (numeric rating scale = NRS), WOMAC Index (pain, stiffness and physical function), overall quality of life (global perceived effect = GPE, EQ-5D-5 L), and adverse events were measured.ResultsAt 12-months, 65.2% of subjects in the CRFA cohort reported ≥50% pain relief from baseline. Mean NRS pain score was 2.8 ± 2.4 at 12 months (baseline 6.9 ± 0.8). Subjects in the CRFA cohort saw a 46.2% improvement in total WOMAC score at the 12-month timepoint. 64.5% of subjects in the crossover cohort reported ≥50% pain relief from baseline, with a mean NRS pain score of 3.0 ± 2.4 at 12 months (baseline 7.0 ± 1.0). After receiving CRFA, subjects in the crossover cohort had a 27.5% improvement in total WOMAC score. All subjects receiving CRFA reported significant improvement in quality of life. There were no serious adverse events related to either procedure and overall adverse event profiles were similar.ConclusionA majority of subjects treated with CRFA demonstrated sustained knee pain relief for at least 12-months. Additionally, CRFA provided significant pain relief for HA subjects who crossed over 6 months after treatment.Trial registrationThis trial was registered on ClinicalTrials.gov, NCT03381248. Registered 27 December 2017

Do the most effective nonsurgical treatments for Achilles tendinosis differ if the tendinosis is mid-substance or insertional?

Do the most effective nonsurgical treatments for Achilles tendinosis differ if the tendinosis is mid-substance or insertional?

Mesenchymal Stem Cell Treatment of Osteoarthritis.

Treatment of canine osteoarthritis comprises a large part of the clinical practice of small animal surgeons. Some cases are post-traumatic, but most are heritable, developmental or idiopathic in origin. Although the pathological changes of osteoarthritic joints are essentially irreversible, many types of surgical procedures are aimed at restoring mobility, including prosthetic joint replacement, joint resurfacing, osteotomy, arthrodesis and excision arthroplasty. However, for a very large cohort of dogs suffering from osteoarthritis, surgical treatment of osteoarthritis is not indicated, not appropriate, not feasible or not affordable. Consequently, the search for effective non-surgical treatments such as systemic and intra-articular medications and other modalities is a critical priority. Considering that intractably painful osteoarthritis is a frequent reason for poor quality of life and even euthanasia, this is indeed an appropriate priority.

Nonsurgical Chin and Jawline Augmentation Using Calcium Hydroxylapatite and Hyaluronic Acid Fillers.

The shape of the jawline from the mandibular angle to its most forward point at the chin has a profound effect on an individual's appearance and is an area of concern for many seeking esthetic procedures. Dermal filler injections alone or in combination with other modalities, such as skin tightening energy devices, allow enhancement of the jawline while avoiding the need for surgical procedures. The authors introduce new anatomical zones and nomenclature to enhance safety and outcome when enhancing the jawline. Cadaver dissections were performed to better understand landmarks and potential risks and a topographic guide proposed to assist clinicians to create an esthetically pleasing jawline. Techniques for jawline rejuvenation with calcium hydroxylapatite (CaHA) and high G prime hyaluronic acid (HA) fillers are described. When considered as an esthetic unit, the jawline can be broken down into masseteric, buccal, and mental zones, each with their own injection protocols and safety considerations. Dermal fillers suitable for jawline rejuvenation include either CaHA with or without integral lidocaine, a high G prime HA filler, or a hybrid mixture of CaHA and HA, depending on the desired esthetic outcome and the individual's needs. Small volumes of product per injection point achieve the most natural esthetic outcome and minimize serious adverse events. With these techniques, the angle of the mandible is better defined, the pre- and postjowl hollows are filled, and as a result the jawline appears visibly straighter. CaHA and high G prime HA fillers are effective nonsurgical treatments for redefining the mandibular angle and straightening the contour of the jaw. For optimal results, the jawline should be considered as an esthetic unit and careful consideration paid to anatomical landmarks that influence efficacy and safety.

Preclinical characterization of tyrosine kinase inhibitor-based targeted therapies for neuroendocrine thyroid cancer.

Medullary thyroid carcinoma (MTC) is a slow growing neuroendocrine (NE) tumor for which few treatment options are available. Its incidence is rising and mortality rates have remained unchanged for decades. Increasing the repertoire of available treatments is thus crucial to manage MTC progression. Scarcity of patient samples and of relevant animal models are two challenges that have limited the development of effective non-surgical treatments. Here we use a clinically accurate mouse model of MTC to assess the effects and mode of action of the tyrosine kinase inhibitor (TKI) Vandetanib, one of only two drugs currently available to treat MTC. Effects on tumor progression, histopathology, and tumorigenic signaling were evaluated. Vandetanib blocked MTC growth through an anti-angiogenic mechanism. Furthermore, Vandetanib had an apparent anti-angiogenic effect in a patient MTC sample. Vandetanib displayed minimal anti-proliferative effects in vivo and in human and mouse MTC tumor-derived cells. Based on these results, we evaluated the second-generation TKI, Nintedanib, alone and in combination with the histone deacetylase (HDAC) inhibitor, Romidepsin, as potential alternative treatments to Vandetanib. Nintedanib showed an anti-angiogenic effect while Romidepsin decreased proliferation. Mechanistically, TKIs attenuated RET-, VEGFR2- and PI3K/AKT/FOXO signaling cascades. Nintedanib alone or in combination with Romidepsin, but not Vandetanib, inhibited mTOR signaling suggesting Nintedanib may have broader anti-cancer applicability. These findings validate the MTC mouse model as a clinically relevant platform for preclinical drug testing and reveal the modes of action and limitations of TKI therapies.

Muscle contracture and passive mechanics in cerebral palsy.

Skeletal muscle contractures represent the permanent shortening of a muscle-tendon unit, resulting in loss of elasticity and, in extreme cases, joint deformation. They may result from cerebral palsy, spinal cord injury, stroke, muscular dystrophy, and other neuromuscular disorders. Contractures are the prototypic and most severe clinical presentation of increased passive mechanical muscle force in humans, often requiring surgical correction. Intraoperative experiments demonstrate that high muscle passive force is associated with sarcomeres that are abnormally stretched, although otherwise normal, with fewer sarcomeres in series. Furthermore, changes in the amount and arrangement of collagen in the extracellular matrix also increase muscle stiffness. Structural light and electron microscopy studies demonstrate that large bundles of collagen, referred to as perimysial cables, may be responsible for this increased stiffness and are regulated by interaction of a number of cell types within the extracellular matrix. Loss of muscle satellite cells may be related to changes in both sarcomeres and extracellular matrix. Future studies are required to determine the underlying mechanism for changes in muscle satellite cells and their relationship (if any) to contracture. A more complete understanding of this mechanism may lead to effective nonsurgical treatments to relieve and even prevent muscle contractures.