Scalable Total Synthesis of (+)-Desmethylxestospongin B.

Herein, the execution of synthetic strategies solving scalability issues observed in the original route is reported, increasing the total yield by 50% compared to the previously disclosed synthesis. A notable restructuring of the route's initial steps to reach a common allylic alcohol intermediate employs a highly stereoselective epoxidation method and avoids superfluous protecting group manipulations while limiting dependence on kinetic resolution in establishing stereochemistry for four of the six chiral centers in (+)-desmethylxestospongin B. Different protecting group strategies to avoid problems with their subsequent removal were considered and enacted; to this end, material was retained as byproducts were suppressed. While the lactam semireduction under Birch conditions requires further investigation, the updated synthesis of (+)-desmethylxestospongin B reported here made it more scalable, affording 0.37 g of this natural product for continued biological studies.

Mindfulness-Based Stress Reduction for Symptom Management in Older Individuals with HIV-Associated Neurocognitive Disorder.

The growing number of people aging with HIV represents a group vulnerable to the symptom burdens of HIV-associated neurocognitive disorder (HAND). Among younger groups, Mindfulness-Based Stress Reduction (MBSR) has been shown to help people living with HIV manage HIV-related and other life stress, and although there is some theoretical and empirical evidence that it may be effective among those with cognitive deficits, the approach has not been studied in older populations with HAND. Participants (n = 180) 55 years or older with HIV and cognitive impairment were randomly assigned to either an 8-week MBSR arm or a waitlist control. We assessed the impact of MBSR compared to a waitlist control on psychological outcomes [stress, anxiety, depression, and quality of life (QOL)] and cognitive metrics (e.g., speed of information processing, working memory, attention, impulsivity) measured at baseline, immediately post intervention (8 weeks) and one month later (16 weeks). Intent to treat analyses showed significant improvement in the MBSR group compared to control on symptoms of depression from baseline to 8 weeks, however, the difference was not sustained at 16 weeks. The MBSR group also showed improvement in perceived QOL from baseline to 16 weeks compared to the waitlist control group. Cognitive performance did not differ between the two treatment arms. MBSR shows promise as a tool to help alleviate the symptom burden of depression and low QOL in older individuals living with HAND and future work should address methods to better sustain the beneficial impact on depression and QOL.

Exploring Cr and molten salt interfacial interactions for molten salt applications.

Molten salts play an important role in various energy-related applications such as high-temperature heat transfer fluids and reaction media. However, the extreme molten salt environment causes the degradation of materials, raising safety and sustainability challenges. A fundamental understanding of material-molten salt interfacial evolution is needed. This work studies the transformation of metallic Cr in molten 50/50 mol% KCl-MgCl2via multi-modal in situ synchrotron X-ray nano-tomography, diffraction and spectroscopy combined with density functional theory (DFT) and ab initio molecular dynamics (AIMD) simulations. Notably, in addition to the dissolution of Cr in the molten salt to form porous structures, a δ-A15 Cr phase was found to gradually form as a result of the metal-salt interaction. This phase change of Cr is associated with a change in the coordination environment of Cr at the interface. DFT and AIMD simulations provide a basis for understanding the enhanced stability of δ-A15 Cr vs. bcc Cr, by revealing their competitive phase thermodynamics at elevated temperatures and probing the interfacial behavior of the molten salt at relevant facets. This study provides critical insights into the morphological and chemical evolution of metal-molten salt interfaces. The combination of multimodal synchrotron analysis and atomic simulation also offers an opportunity to explore a broader range of systems critical to energy applications.

Spontaneous thrombosis of high flow pediatric arteriovenous fistulae: Case series of two patients and a comprehensive literature review.

Pediatric pial arteriovenous shunts in the brain and spine are challenging to understand because of low incidence, variable presentation, and associations with genetic syndromes. What is known about their natural history comes from reviews of small series. To better understand the natural history and role for intervention, two cases are presented followed by a review of the literature. In the first case, an infant with a prior history of intracranial hemorrhage from a ruptured pial fistula returns for elective embolization for a second pial fistula which was found to be spontaneously thrombosed 2 weeks later. In the second case, a 5-year-old with a vertebro-vertebral fistula, identified on work up for a heart murmur and documented with diagnostic angiography, is brought for elective embolization 6 weeks later where spontaneous thrombosis is identified. In reviewing the literature on pediatric single-hole fistulae of the brain and spine, the authors offer some morphologic considerations for identifying which high-flow fistulae may undergo spontaneous thrombosis to decrease the potentially unnecessary risk associated with interventions in small children.

SMN protein is required throughout life to prevent spinal muscular atrophy disease progression.

Spinal muscular atrophy (SMA) is caused by the loss of the survival motor neuron 1 (SMN1) gene function. The related SMN2 gene partially compensates but produces insufficient levels of SMN protein due to alternative splicing of exon 7. Evrysdi™ (risdiplam), recently approved for the treatment of SMA, and related compounds promote exon 7 inclusion to generate full-length SMN2 mRNA and increase SMN protein levels. SMNΔ7 type I SMA mice survive without treatment for ~17 days. SMN2 mRNA splicing modulators increase survival of SMN∆7 mice with treatment initiated at postnatal day 3 (PND3). To define SMN requirements for adult mice, SMNΔ7 mice were dosed with an SMN2 mRNA splicing modifier from PND3 to PND40, then dosing was stopped. Mice not treated after PND40 showed progressive weight loss, necrosis, and muscle atrophy after ~20 days. Male mice presented a more severe phenotype than female mice. Mice dosed continuously did not show disease symptoms. The estimated half-life of SMN protein is 2 days indicating that the SMA phenotype reappeared after SMN protein levels returned to baseline. Although SMN protein levels decreased with age in mice and SMN protein levels were higher in brain than in muscle, our studies suggest that SMN protein is required throughout the life of the mouse and is especially essential in adult peripheral tissues including muscle. These studies indicate that drugs such as risdiplam will be optimally therapeutic when given as early as possible after diagnosis and potentially will be required for the life of an SMA patient.

Ultrashort time-to-echo MR morphology of cartilaginous endplate correlates with disc degeneration in the lumbar spine.

PURPOSE: Using ultrashort echo time (UTE) MRI, we determined prevalence of abnormal cartilaginous endplate (CEP), and the relationship between CEP and disc degeneration in human lumbar spines. MATERIALS AND METHODS: Lumbar spines from 71 cadavers (age 14-74 years) were imaged at 3 T using sagittal UTE and spin echo T2 map sequences. On UTE images, CEP morphology was defined as "normal" with linear high signal intensity or "abnormal" with focal signal loss and/or irregularity. On spin echo images, disc grade and T2 values of the nucleus pulposus (NP) and annulus fibrosus (AF) were determined. 547 CEPs and 284 discs were analysed. Effects of age, sex, and level on CEP morphology, disc grade, and T2 values were determined. Effects of CEP abnormality on disc grade, T2 of NP, and T2 of AF were also determined. RESULTS: Overall prevalence of CEP abnormality was 33% and it tended to increase with older ages (p = 0.08) and at lower spinal levels of L5 than L2 or L3 (p = 0.001). Disc grades were higher and T2 values of the NP were lower in older spines (p < 0.001) and at lower disc level of L4-5 (p < 0.05). We found significant association between CEP and disc degeneration; discs adjacent to abnormal CEPs had high grades (p < 0.01) and lower T2 values of the NP (p < 0.05). CONCLUSION: These results suggest that abnormal CEPs are frequently found, and it associates significantly with disc degeneration, suggesting an insight into pathoetiology of disc degeneration.

Advances in Imaging Modalities for Pediatric Brain and Spinal Cord Tumors.

BACKGROUND: Neuroimaging has evolved from anatomical imaging toward a multi-modality comprehensive anatomical and functional imaging in the past decades, important functional data like perfusion-weighted imaging, permeability imaging, diffusion-weighted imaging (DWI), and diffusion tensor imaging (DTI), tractography, metabolic imaging, connectomics, event-related functional imaging, resting state functional imaging, and much more is now being offered. SUMMARY: Precision diagnostics has proven to be essential for precision treatment. Many minimal invasive techniques have been developed, taking advantage of digital subtraction angiography and interventional neuroradiology. Furthermore, intraoperative CT and/or MRI and more recently MR-guided focused ultrasound have complemented the diagnostic and therapeutic armamentarium. KEY MESSAGES: In the current manuscript, we discuss standard imaging sequences including advanced techniques like DWI, DTI, susceptibility-weighted imaging, and 1H magnetic resonance spectroscopy, various perfusion weighted imaging approaches including arterial spin labeling, dynamic contrast enhanced imaging, and dynamic susceptibility contrast imaging. Pre-, intra, and postoperative surgical imaging including visualize imaging will be discussed. The value of connectomics will be presented for its value in neuro-oncology. Minimal invasive therapeutic possibilities of interventional neuroradiology and image-guided laser ablation and MR-guided high-intensity-focused ultrasound will be presented for treatment of pediatric brain and spinal cord tumors. Finally, a comprehensive review of spinal cord tumors and matching neuropathology has been included.

Content development of the Child Community Health Inclusion Index: An evaluation tool for measuring inclusion of children with disabilities in the community.

BACKGROUND: Addressing barriers in the environment can contribute to health and quality of life for children with disabilities and their families. The Community Health Inclusion Index (CHII) is a measurement tool developed in the United States to identify environmental barriers and facilitators to community health inclusion. The CHII adopts an adult viewpoint and aspects crucial for children may have been omitted. AIMS: This study aimed to develop a comprehensive list of items that are relevant for the community inclusion of children with disabilities in the Canadian context. METHODS: The relevance and priority of items generated from a review of existing guidelines and best practice recommendations for community inclusion were rated as a dichotomous response and discussed by an expert panel in relevant fields related to children with disabilities. RESULTS: A total of 189 items from 12 instruments and best practice guidelines were identified. Expert consensus contributed to a relevant and comprehensive list of items. Expert suggestions were considered to refine and reduce the item list. CONCLUSION: This study highlights the importance of a child version of a community inclusion tool, as the needs of children with disabilities differ from those of adults. It can help communities improve inclusion of children with disabilities and inform health promotion initiatives for this population.

DNA Sequencing to Detect Residual Disease in Adults With Acute Myeloid Leukemia Prior to Hematopoietic Cell Transplant.

Importance: Preventing relapse for adults with acute myeloid leukemia (AML) in first remission is the most common indication for allogeneic hematopoietic cell transplant. The presence of AML measurable residual disease (MRD) has been associated with higher relapse rates, but testing is not standardized. Objective: To determine whether DNA sequencing to identify residual variants in the blood of adults with AML in first remission before allogeneic hematopoietic cell transplant identifies patients at increased risk of relapse and poorer overall survival compared with those without these DNA variants. Design, Setting, and Participants: In this retrospective observational study, DNA sequencing was performed on pretransplant blood from patients aged 18 years or older who had undergone their first allogeneic hematopoietic cell transplant during first remission for AML associated with variants in FLT3, NPM1, IDH1, IDH2, or KIT at 1 of 111 treatment sites from 2013 through 2019. Clinical data were collected, through May 2022, by the Center for International Blood and Marrow Transplant Research. Exposure: Centralized DNA sequencing of banked pretransplant remission blood samples. Main Outcomes and Measures: The primary outcomes were overall survival and relapse. Day of transplant was considered day 0. Hazard ratios were reported using Cox proportional hazards regression models. Results: Of 1075 patients tested, 822 had FLT3 internal tandem duplication (FLT3-ITD) and/or NPM1 mutated AML (median age, 57.1 years, 54% female). Among 371 patients in the discovery cohort, the persistence of NPM1 and/or FLT3-ITD variants in the blood of 64 patients (17.3%) in remission before undergoing transplant was associated with worse outcomes after transplant (2013-2017). Similarly, of the 451 patients in the validation cohort who had undergone transplant in 2018-2019, 78 patients (17.3%) with residual NPM1 and/or FLT3-ITD variants had higher rates of relapse at 3 years (68% vs 21%; difference, 47% [95% CI, 26% to 69%]; HR, 4.32 [95% CI, 2.98 to 6.26]; P < .001) and decreased survival at 3 years (39% vs 63%; difference, -24% [2-sided 95% CI, -39% to -9%]; HR, 2.43 [95% CI, 1.71 to 3.45]; P < .001). Conclusions and Relevance: Among patients with acute myeloid leukemia in first remission prior to allogeneic hematopoietic cell transplant, the persistence of FLT3 internal tandem duplication or NPM1 variants in the blood at an allele fraction of 0.01% or higher was associated with increased relapse and worse survival compared with those without these variants. Further study is needed to determine whether routine DNA-sequencing testing for residual variants can improve outcomes for patients with acute myeloid leukemia.

Task-Oriented and Imitation-Oriented Movements in Virtual Reality Exercise Performance and Design.

OBJECTIVE: This study investigated the influence of game features and practice type on human kinematic and muscular performance in a virtual reality exercise (VRE). Participants demonstrated changes in shoulder flexion angle and muscle activation under different virtual scenarios. BACKGROUND: Conventional VRE studies often compared the outcomes between an experimental group that underwent exercise in VR and a real-world exercise control group, whereas comparisons between VRE programs are lacking. Besides, the attributes of VREs received little attention. METHOD: Thirteen able-bodied participants performed upper extremity exercise movements in immersive VR using a head-mounted display. Participants performed task-oriented and imitation-oriented movements with different game features. Shoulder muscle activity (the deltoid, supraspinatus, and infraspinatus) and shoulder motion were collected. RESULTS: Practice type (task-oriented, imitation-oriented) significantly influenced the flexion angle of the shoulder complex (F(1,11) = 9.53, p = .01), and the muscle activity of the supraspinatus (F(1,9) = 12.61, p = .006) and the infraspinatus (F(1,9) = 12.71, p = .006). Game features did not have a statistically significant effect on shoulder flexion angle or shoulder muscles' activations. CONCLUSIONS: Compared to imitation-oriented practice, task-oriented practice elicited more intensive shoulder movements and muscular efforts but also induced greater movement variations. Substantial differences across game features levels should be further investigated to have significant effects. APPLICATIONS: This research may help guide the design of future VREs. For strength training or rehabilitation where intensive practice is required, task-oriented practice should be considered; for movement learning where movement consistency is required, imitation oriented practice should be adopted.

Influence of Potassium Metal-Support Interactions on Dendrite Growth.

Combined synchrotron X-ray nanotomography imaging, cryogenic electron microscopy (cryo-EM) and modeling elucidate how potassium (K) metal-support energetics influence electrodeposit microstructure. Three model supports are employed: O-functionalized carbon cloth (potassiophilic, fully-wetted), non-functionalized cloth and Cu foil (potassiophobic, nonwetted). Nanotomography and focused ion beam (cryo-FIB) cross-sections yield complementary three-dimensional (3D) maps of cycled electrodeposits. Electrodeposit on potassiophobic support is a triphasic sponge, with fibrous dendrites covered by solid electrolyte interphase (SEI) and interspersed with nanopores (sub-10 nm to 100 nm scale). Lage cracks and voids are also a key feature. On potassiophilic support, the deposit is dense and pore-free, with uniform surface and SEI morphology. Mesoscale modeling captures the critical role of substrate-metal interaction on K metal film nucleation and growth, as well as the associated stress state.

Tfap2a is a novel gatekeeper of nephron differentiation during kidney development.

Renal functional units known as nephrons undergo patterning events during development that create a segmental array of cellular compartments with discrete physiological identities. Here, from a forward genetic screen using zebrafish, we report the discovery that transcription factor AP-2 alpha (tfap2a) coordinates a gene regulatory network that activates the terminal differentiation program of distal segments in the pronephros. We found that tfap2a acts downstream of Iroquois homeobox 3b (irx3b), a distal lineage transcription factor, to operate a circuit consisting of tfap2b, irx1a and genes encoding solute transporters that dictate the specialized metabolic functions of distal nephron segments. Interestingly, this regulatory node is distinct from other checkpoints of differentiation, such as polarity establishment and ciliogenesis. Thus, our studies reveal insights into the genetic control of differentiation, where tfap2a is essential for regulating a suite of segment transporter traits at the final tier of zebrafish pronephros ontogeny. These findings have relevance for understanding renal birth defects, as well as efforts to recapitulate nephrogenesis in vivo to facilitate drug discovery and regenerative therapies.

Unmet needs and problems related to employment and working as reported by survivors with metastatic breast cancer.

PURPOSE: By 2020, the US population living with metastatic breast cancer (MBC) has exceeded 165,000. A knowledge gap exists regarding the factors affecting work ability for these individuals. We sought to characterize the work status, importance of work, and work-related information needs for women living with MBC. METHODS: We conducted an online survey using an MBC listserv and clinic flyers in 2014-2015. Respondents working at the time of MBC diagnosis were divided into "stably-working" and "no-longer-working" based on employment status at the time of survey. Comparisons were made with chi-square or two-tailed t test. RESULTS: Respondents (n = 133) were predominantly non-Hispanic White (93.2%); 72 were stably-working, while 61 reported no-longer-working. Those no-longer-working were older (54.0 vs 49.5 years old, p < 0.01, Cohen's d = 0.55), further from initial diagnosis of MBC (4.6 vs 3.3 years, p < 0.01, Cohen's d = 0.36), and reported high rates of life interference due to MBC (n = 51, 83.6% vs n = 39, 54.2%, p < 0.01, Cramer's V = 0.32). Stably-working respondents considered work to be important (n = 58, 80.5% vs n = 18, 29.5%, p < 0.01, Cramer's V = 0.57); the top reasons cited were financial and/or insurance (80.4%), importance of staying busy (67.9%), and desire to support themselves and family (64.3%). The stably-working respondents more often valued information on how to talk with employers or co-workers about diagnosis (n = 38, 57.6% vs n = 16, 27.1%; p < 0.01), legal rights in workplace (n = 43, 65.2% vs n = 22, 36.7%; p < 0.01), when to think about stopping work (n = 45, 68.2% vs n = 18, 30%; p < 0.01), and applying for disability (n = 42, 63.6% vs n = 26, 42.6%; p < 0.05), when compared to no-longer-working. CONCLUSION: The decision to stop working may represent a subsequent event driven by cancer progression. This research highlights the ongoing need of information targeting MBC to facilitate the management of employment and financial issues early in the MBC trajectory.

Examining the Effects of Gender Transfer in Virtual Reality on Implicit Gender Bias.

OBJECTIVE: To investigate the effect of gender transfer in virtual reality on implicit gender bias. BACKGROUND: Gender bias is a type of discrimination based on gender, which can lead to increased self-doubt and decreased self-esteem. Sexual harassment is a hostile form of gender bias that can cause anxiety, depression, and significant mental health issues. Virtual reality (VR) has been employed to help make people become aware of their biases and change their attitudes regarding gender, race, and age. METHODS: Forty participants were embodied in avatars of different genders and experienced sexual harassment scenarios in VR. A gender Implicit Association Test (IAT) was administered before and after the experience. RESULTS: There was a statistically significant main effect of participant gender (F (1,36) = 10.67, p = .002, partial η2 = .23) on ΔIAT, where males and females reported a decrease (M = -.12, SD = .24) and an increase (M = .10, SD = .25) in IAT scores, respectively. A statistically significant two-way interaction between gender transfer and participant gender was revealed (F (1,36) = 6.32, p = .02, partial η2 = .15). There was a significant simple effect of gender transfer for male participants (F (1,36) = 8.70, p = .006, partial η2 = .19). CONCLUSIONS: Implicit gender bias can be modified, at least temporarily, through embodiment in VR. Gender transfer through embodiment while encountering different sexual harassment scenarios helped reduce implicit gender bias. There was a tendency for individuals to increase bias for the gender of the avatar in which they embodied. APPLICATIONS: The current research provided promising evidence that a virtual environment system may be used as a potential training tool to improve implicit gender bias.

Usage of a Web-Based Workplace and Symptom Self-Management Intervention Tool to Improve Work Ability for Breast Cancer Survivors.

This work aimed to evaluate the usage of a web-based intervention (WISE: Work ability Improvement through Symptom and Ergonomic strategies) developed to improve work ability for women recently diagnosed with breast cancer. Twenty-two women undergoing adjuvant treatment for breast cancer were provided access to WISE. This website includes content pages (e.g., information on ergonomics, symptom management, and other work-related resources) and worksheets (e.g., journals to track symptoms or goals). It could be personalized based on individual work activities and symptoms. Measures assessed at 3 months included usage of the website and perceived usefulness. Thirteen of the 22 participants (60%) accessed WISE; 11 personalized their information. Content and worksheet pages had 97 and 79 visits, respectively. Most frequently visited pages were "setting goals" (i.e., prioritize and track symptoms; 45 visits) and "steps to creating your WISE plan" (i.e., incorporate symptom and ergonomic strategies; 16 visits). Median duration time was 11.05 (range 0.35-79.55) minutes. Usefulness of the content and worksheet pages assessed via a 7-point Likert scale (1 = strongly disagree, 7 = strongly agree) was 5.08 (SD = 1.59) and 4.26 (SD = 2.03), respectively. Participants were likely to recommend WISE to other women undergoing cancer treatment (mean = 6.11; SD = 1.05). The majority of participants personalized WISE work and symptom strategies. Overall, participants agreed that WISE content pages were useful and would recommend WISE for other breast cancer survivors. Results support that majority of breast cancer survivors, undergoing treatment with curative intent, accessed a web-based intervention that provided personalized information on workplace and symptom strategies.

Motor neuron loss in SMA is not associated with somal stress-activated JNK/c-Jun signaling.

A pathological hallmark of spinal muscular atrophy (SMA) is severe motor neuron (MN) loss, which results in muscle weakness and often infantile or childhood mortality. Although it is well established that deficient expression of survival motor neuron (SMN) protein causes SMA, the molecular pathways that execute MN cell death are poorly defined. The c-Jun NH2-terminal kinases (JNKs) are stress-activated kinases with multiple substrates including c-Jun, which can be activated during neuronal injury and neurodegenerative disease leading to neuronal apoptosis. Recently, increased JNK-c-Jun signaling was reported in SMA raising the possibility that JNK inhibitors could be a novel treatment for this disease. We examined JNK-c-Jun activity in SMA mouse and human cultured cells and tissues. Anisomycin treatment of human SMA fibroblasts and sciatic nerve ligation in SMA mice provoked robust phosphorylated-c-Jun (p-c-Jun) expression indicating that SMN-deficiency does not prevent activation of the stress-induced JNK-c-Jun signaling pathway. Despite retained capacity to activate JNK-c-Jun, we observed no basal increase of p-c-Jun levels in SMA compared to control cultured cells, human or mouse spinal cord tissues, or mouse MNs during the period of MN loss in severe SMA model mice. In both controls and SMA, ~50% of α-MN nuclei express p-c-Jun with decreasing expression during the early postnatal period. Together these studies reveal no evidence of stress-activated JNK-c-Jun signaling in MNs of SMA mice or human tissues, but do highlight the important role of JNK-c-Jun activity during normal MN development raising caution about JNK antagonism in this pediatric neuromuscular disease.

Specific inhibition of myostatin activation is beneficial in mouse models of SMA therapy.

Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by loss of α-motor neurons, leading to profound skeletal muscle atrophy. Patients also suffer from decreased bone mineral density and increased fracture risk. The majority of treatments for SMA, approved or in clinic trials, focus on addressing the underlying cause of disease, insufficient production of full-length SMN protein. While restoration of SMN has resulted in improvements in functional measures, significant deficits remain in both mice and SMA patients following treatment. Motor function in SMA patients may be additionally improved by targeting skeletal muscle to reduce atrophy and improve muscle strength. Inhibition of myostatin, a negative regulator of muscle mass, offers a promising approach to increase muscle function in SMA patients. Here we demonstrate that muSRK-015P, a monoclonal antibody which specifically inhibits myostatin activation, effectively increases muscle mass and function in two variants of the pharmacological mouse model of SMA in which pharmacologic restoration of SMN has taken place either 1 or 24 days after birth to reflect early or later therapeutic intervention. Additionally, muSRK-015P treatment improves the cortical and trabecular bone phenotypes in these mice. These data indicate that preventing myostatin activation has therapeutic potential in addressing muscle and bone deficiencies in SMA patients. An optimized variant of SRK-015P, SRK-015, is currently in clinical development for treatment of SMA.

Results from a prospective longitudinal survey of employment and work outcomes in newly diagnosed cancer patients during and after curative-intent chemotherapy: A Wisconsin Oncology Network study.

BACKGROUND: Postcancer work limitations may affect a substantial proportion of patients and contribute to the "financial toxicity" of cancer treatment. The degree and nature of work limitations and employment outcomes are poorly understood for cancer patients, particularly in the immediate period of transition after active treatment. We prospectively examined employment, work ability, and work limitations during and after treatment. METHODS: A total of 120 patients receiving curative therapy who were employed prior to their cancer diagnosis and who intended to work during or after end of treatment (EOT) completed surveys at baseline (pretreatment), EOT, and 3, 6, and 12 months after EOT. Surveys included measures of employment, work ability, and work limitations. Descriptive statistics (frequencies, percentages, means with standard deviations) were calculated. RESULTS: A total of 111 participants completed the baseline survey. On average, participants were 48 years of age and were mostly white (95%) and female (82%) with a diagnosis of breast cancer (69%). Full-time employment decreased during therapy (from 88% to 50%) and returned to near prediagnosis levels by 12-month follow-up (78%). Work-related productivity loss due to health was high during treatment. CONCLUSIONS: This study is the first to report the effects of curative intent cancer therapy on employment, work ability, and work limitations both during and after treatment. Perceived work ability was generally high overall 12 months after EOT, although a minority reported persistent difficulty. A prospective analysis of factors (eg, job type, education, symptoms) most associated with work limitations is underway to assist in identifying at-risk patients.

Prolonged Response to HER2-Directed Therapy in Three Patients with HER2-Amplified Metastatic Carcinoma of the Biliary System: Case Study and Review of the Literature.

HER2 amplification, which results in overexpression of the receptor tyrosine kinase HER2, has been described in a wide variety of malignancies. HER2-targeting agents have been incorporated into the treatment paradigms for HER2-overexpressing breast and gastric cancer. More recently, these agents have shown promise in other gastrointestinal malignancies, such as colon cancer and biliary tract tumors. This study discusses two patients with gallbladder carcinoma and a third with ampullary carcinoma who were able to achieve marked responses to HER2-directed therapy. These cases underscore the importance of molecular analysis for HER2 amplification/HER2 overexpression, irrespective of tumor histology, and highlight a need for further investigation of HER2-directed therapy beyond breast and gastroesophageal cancers. KEY POINTS: Current guidelines recommend molecular assessment for HER2 overexpression exclusively in breast and gastric adenocarcinoma. The focus of this report is on three cases (two biliary tract and one ampullary carcinoma) in which amplification of HER2 or overexpression of HER2 was detected and treatment with HER2-directed therapy resulted in robust responses. These cases exemplify responsiveness of non-breast/gastric histologies to HER2-directed therapies, highlighting several promising new settings for these agents. Testing for amplification of HER2 or overexpression of HER2 should be considered especially in rare diseases with limited treatment options.

Activation of Muscle-Specific Kinase (MuSK) Reduces Neuromuscular Defects in the Delta7 Mouse Model of Spinal Muscular Atrophy (SMA).

Spinal muscular atrophy (SMA) is a motor neuron disease caused by insufficient levels of the survival motor neuron (SMN) protein. One of the most prominent pathological characteristics of SMA involves defects of the neuromuscular junction (NMJ), such as denervation and reduced clustering of acetylcholine receptors (AChRs). Recent studies suggest that upregulation of agrin, a crucial NMJ organizer promoting AChR clustering, can improve NMJ innervation and reduce muscle atrophy in the delta7 mouse model of SMA. To test whether the muscle-specific kinase (MuSK), part of the agrin receptor complex, also plays a beneficial role in SMA, we treated the delta7 SMA mice with an agonist antibody to MuSK. MuSK agonist antibody #13, which binds to the NMJ, significantly improved innervation and synaptic efficacy in denervation-vulnerable muscles. MuSK agonist antibody #13 also significantly increased the muscle cross-sectional area and myofiber numbers in these denervation-vulnerable muscles but not in denervation-resistant muscles. Although MuSK agonist antibody #13 did not affect the body weight, our study suggests that preservation of NMJ innervation by the activation of MuSK may serve as a complementary therapy to SMN-enhancing drugs to maximize the therapeutic effectiveness for all types of SMA patients.