Cancer survivors post-chemotherapy exhibit unimpaired short-latency stretch reflexes in the proximal upper extremity.

Oxaliplatin (OX) chemotherapy can lead to long-term sensorimotor impairments in cancer survivors. The impairments are often thought to be caused by OX-induced progressive degeneration of sensory afferents known as length-dependent dying-back sensory neuropathy. However, recent preclinical work has identified functional defects in the encoding of muscle proprioceptors and in motoneuron firing. These functional defects in the proprioceptive sensorimotor circuitry could readily impair muscle stretch reflexes, a fundamental building block of motor coordination. Given that muscle proprioceptors are distributed throughout skeletal muscle, defects in stretch reflexes could be widespread, including in the proximal region where dying-back sensory neuropathy is less prominent. All previous investigations on chemotherapy-related reflex changes focused on distal joints, leading to results that could be influenced by dying-back sensory neuropathy rather than more specific changes to sensorimotor circuitry. Our study extends this earlier work by quantifying stretch reflexes in the shoulder muscles in 16 cancer survivors and 16 healthy controls. Conduction studies of the sensory nerves in hand were completed to detect distal sensory neuropathy. We found no significant differences in the short-latency stretch reflexes (amplitude and latency) of the shoulder muscles between cancer survivors and healthy controls, contrasting with the expected differences based on the preclinical work. Our results may be linked to differences between the human and preclinical testing paradigms including, among many possibilities, differences in the tested limb or species. Determining the source of these differences will be important for developing a complete picture of how OX chemotherapy contributes to long-term sensorimotor impairments.NEW & NOTEWORTHY Our results showed that cancer survivors after oxaliplatin (OX) treatment exhibited stretch reflexes that were comparable with age-matched healthy individuals in the proximal upper limb. The lack of OX effect might be linked to differences between the clinical and preclinical testing paradigms. These findings refine our expectations derived from the preclinical study and guide future assessments of OX effects that may have been insensitive to our measurement techniques.

Integrating Management of Hepatitis C Infection into Primary Care: the Key to Hepatitis C Elimination Efforts.

Elimination of hepatitis C virus (HCV), a leading cause of liver disease in the USA and globally, has been made possible with the advent of highly efficacious direct acting antivirals (DAAs). DAA regimens offer cure of HCV with 8-12 weeks of a well-tolerated once daily therapy. With increasingly straightforward diagnostic and treatment algorithms, HCV infection can be managed not only by specialists, but also by primary care providers. Engaging primary care providers greatly increases capacity to diagnose and treat chronic HCV and ultimately make HCV elimination a reality. However, barriers remain at each step in the HCV cascade of care from screening to evaluation and treatment. Since primary care is at the forefront of patient contact, it represents the ideal place to concentrate efforts to identify barriers and implement solutions to achieve universal HCV screening and increase curative treatment.

Cancer survivors post-chemotherapy exhibit unique proprioceptive deficits in proximal limbs.

BACKGROUND: Oxaliplatin (OX) chemotherapy for colorectal cancer is associated with adverse neurotoxic effects that can contribute to long-term sensorimotor impairments in cancer survivors. It is often thought that the sensorimotor impairments are dominated by OX-induced dying-back sensory neuropathy that primarily affects the distal regions of the limb. Recent preclinical studies have identified encoding dysfunction of muscle proprioceptors as an alternative mechanism. Unlike the dying-back sensory neuropathy affecting distal limbs, dysfunction of muscle proprioceptors could have more widespread effects. Most investigations of chemotherapy-induced sensorimotor impairments have considered only the effects of distal changes in sensory processing; none have evaluated proximal changes or their influence on function. Our study fills this gap by evaluating the functional use of proprioception in the shoulder and elbow joints of cancer survivors post OX chemotherapy. We implemented three multidirectional sensorimotor tasks: force matching, target reaching, and postural stability tasks to evaluate various aspects of proprioception and their use. Force and kinematic data of the sensorimotor tasks were collected in 13 cancer survivors treated with OX and 13 age-matched healthy controls. RESULTS: Cancer survivors exhibited less accuracy and precision than an age-matched control group when they had to rely only on proprioceptive information to match force, even for forces that required only torques about the shoulder. There were also small differences in the ability to maintain arm posture but no significant differences in reaching. The force deficits in cancer survivors were significantly correlated with self-reported motor dysfunction. CONCLUSIONS: These results suggest that cancer survivors post OX chemotherapy exhibit proximal proprioceptive deficits, and that the deficits in producing accurate and precise forces are larger than those for producing unloaded movements. Current clinical assessments of chemotherapy-related sensorimotor dysfunction are largely limited to distal symptoms. Our study suggests that we also need to consider changes in proximal function. Force matching tasks similar to those used here could provide a clinically meaningful approach to quantifying OX-related movement dysfunction during and after chemotherapy.

A review of movement disorders in chemotherapy-induced neurotoxicity.

Chemotherapy agents used in the standard treatments for many types of cancer are neurotoxic and can lead to lasting sensory and motor symptoms that compromise day-to-day movement functions in cancer survivors. To date, the details of movement disorders associated with chemotherapy are known largely through self-reported symptoms and functional limitations. There are few quantitative studies of specific movement deficits, limiting our understanding of dysfunction, as well as effective assessments and interventions. The aim of this narrative review is to consolidate the current understanding of sensorimotor disabilities based on quantitative measures in cancer survivors who received chemotherapy. We performed literature searches on PubMed and found 32 relevant movement studies. We categorized these studies into three themes based on the movement deficits investigated: (1) balance and postural control; (2) gait function; (3) upper limb function. This literature suggests that cancer survivors have increased postural sway, more conservative gait patterns, and suboptimal hand function compared to healthy individuals. More studies are needed that use objective measures of sensorimotor function to better characterize movement disabilities and investigate the underlying causes, as required for developing targeted assessments and interventions. By updating our understanding of movement impairments in this population, we identify significant gaps in knowledge that will help guide the direction of future research.

Impact of Critical Material Attributes (CMAs)-Particle Shape on Miniature Pharmaceutical Unit Operations.

The U.S. Food and Drug Administration (FDA) emphasizes drug product development by Quality by Design (QbD). Critical material attributes (CMAs) are a QbD element that has an impact on pharmaceutical operations and product quality. Pharmaceutical drugs often crystallize as needle-shaped (a CMA) particles and affect the process due to poor flowability, low bulk density, and high compressibility, and eventually the product performance. In this study, the product obtained from crystallization was needle-shaped Ciprofloxacin HCl (CIPRO), formed lumps during drying, and compacted during processing through feeders. To delump small amounts of materials and break the needles, multiple available devices (mortar-pestle, Krups grinder) and custom-made grinder were assessed before formulation. The processed CIPRO powder was then used to make tablets in the miniature tablet manufacturing unit developed by the team at MIT. The critical quality attributes (CQA) of the tablets, set by the United States Pharmacopeia (USP), were then assessed for the drug powder processed with each of these devices. Powder properties comparable to commercial CIPRO were obtained when the custom MIT-designed grinder was used, leading to tablets that meet the USP criteria, with comparable dissolution profiles of those for marketed CIPRO tablets. This study demonstrates how needle-shaped crystals have an impact on pharmaceutical operations, even if it is on a miniature scale, and how proper shape and subsequent flow properties can be obtained by processing the particles through the MIT team-designed grinder.

On-Demand Manufacturing of Direct Compressible Tablets: Can Formulation Be Simplified?

PURPOSE: Oral direct compressible tablets are the most frequently used drug products. Manufacturing of tablets requires design and development of formulations, which need a number of excipients. The choice of excipients depends on the concentration, manufacturability, stability, and bioavailability of the active pharmaceutical ingredients (APIs). At MIT, we developed a miniature platform for on-demand manufacturing of direct compressible tablets. This study investigated how formulations could be simplified to use a small number of excipients for a number of different API's in which long term stability is not required. METHOD: Direct compressible tablets of five pharmaceutical drugs, Diazepam, Diphenhydramine HCl, Doxycycline Monohydrate, Ibuprofen, and Ciprofloxacin HCl, with different drug loadings, were made using direct compression in an automated small scale system.. The critical quality attributes (CQA) of the tablets were assessed for the quality standards set by the United States Pharmacopeia (USP). RESULTS: This miniature system can manufacture tablets - on-demand from crystalline API using the minimum number of excipients required for drug product performance. All drug tablets met USP quality standards after manufacturing and after 2 weeks of accelerated stability test, except for slightly lower drug release for Ibuprofen. CONCLUSIONS: On-demand tablets manufacturing where there is no need for long term stability using a flexible, miniature, automated (integrated) system will simplify pharmaceutical formulation design compared to traditional formulations. This advancement will offer substantial economic benefits by decreasing product time-to-market and enhancing quality.

Continuous Improvement and Employee Engagement, Part 2: Design, Implementation, and Outcomes of a Daily Management System.

A daily management system (DMS) can be used to implement continuous quality improvement and advance employee engagement. It can empower staff to identify problems in the care environment that impact quality or work flow and to address them on a daily basis. Through a DMS, improvement becomes the work of everyone, every day. The authors of this 2-part series describe their work to develop a DMS. Part 2 describes the implementation and outcomes of the program.

Assistive Devices for Addressing Mobility Impairments Linked to Cancer and Cancer Treatment: An Expert Perspective.

OBJECTIVES: Cancer survivors often experience mobility impairments that negatively impact their ability to engage in everyday activities. Healthcare providers working with patients in the continuum of cancer care play essential roles in identifying and addressing mobility impairments. The objective of this article is to present common assistive devices valuable in managing cancer and cancer treatment-related mobility impairments. METHODS: Peer-reviewed scientific publications and expert opinions. RESULTS: This article highlights assistive devices commonly used in various settings of cancer care and describes how they address different impairments faced by cancer survivors. The information presented can potentially serve as a resource when training clinical staff (eg, oncology nursing staff) on device provision across all settings. The information can also be useful for patients and caregivers to learn about potential functional impairments linked to cancer and treatments and assistive devices that can be useful to improve patients' functional capacity and reduce caregiver burden. CONCLUSION: It is essential to involve different team members to identify and select the most appropriate assistive devices that match the patient's functional needs and physical capacity and to train them in device use so they can safely carry out their daily routine. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses are one of the first providers to identify mobility impairments in cancer patients. This article will help increase their knowledge in common assistive devices valuable for addressing various mobility impairments associated with cancer and treatments. With additional training on device provision, oncology nurses will be more empowered to collaborate with rehabilitation to identify potential mobility impairments, initiate device provision, and encourage their patients to work with therapy services. Ultimately this could reduce injuries linked to mobility impairments and improve the patient's functional independence and overall quality of life.

Disparities in presentation and management of chronic hepatitis B among Hispanics in a diverse safety net system.

BACKGROUND: Chronic hepatitis B (HBV) prevalence is highest in foreign-born Asian and African individuals in the US, though Hispanics make up the largest proportion of the immigrant population. Differences in the diagnosis and management of chronic HBV in Hispanics might exist due to the lower awareness of risk. We aim to examine racial/ethnic disparities in the diagnosis, presentation, and immediate management of chronic HBV in a diverse safety net system enriched for Hispanics. METHODS: In a large urban safety-net hospital system, we retrospectively identified patients with chronic HBV by serological data and categorized them into mutually exclusive self-identified racial/ethnic groups: Hispanics, Asians, Blacks, and Whites. We then examined differences in screening, disease phenotype and severity, follow-up testing, and referral by race/ethnicity. RESULTS: Among 1063 patients, 302 (28%) were Hispanics, 569 (54%) Asians, 161 (15%) Blacks, and 31 (3%) Whites. More Hispanics (30%) were screened in the acute setting (defined as inpatient or emergency department encounters) than Asians (13%), Blacks (17%), or Whites (23%) (p<0.01). Hispanics also had lower rates of follow-up testing after HBV diagnosis than Asians including HBeAg status (43% vs. 60%, p<0.01) and HBV DNA levels (42% vs. 58%, p<0.01) and lower rates of linkage to specialty care (32% vs. 55%, p<0.01). Among those with available testing, however, the presence of immune-active chronic HBV was infrequent and similar across racial/ethnic groups. 25% of Hispanics had cirrhosis at initial presentation, proportionally higher than other groups (p<0.01). CONCLUSION: Our results underscore the importance of raising chronic HBV awareness and increasing both screening and linkage to care among Hispanic immigrants in addition to the existing risk groups, with the goal of mitigating downstream liver-related complications.

LGR4 and LGR5 form distinct homodimers that only LGR4 complexes with RNF43/ZNRF3 to provide high affinity binding of R-spondin ligands.

LGR4 and LGR5 are two homologous receptors that potentiate Wnt/ß-catenin signaling in response to R-spondin (RSPO) ligands. The RSPO and LGR4 complex binds to and inhibits activities of two related E3 ubiquitin ligases, RNF43 and ZNRF3, and thus protects Wnt receptors from the E3 ligase-mediated degradation. The RSPO and LGR5 complex, however, does not interact with the E3 ligases, and the structural basis of this difference remained unknown. Here we examined the affinities of monovalent and bivalent RSPO ligands in binding to LGR4, RNF43/ZNRF3, and LGR5 in whole cells and found unique features among the receptors and E3 ligases. Monovalent RSPO2 furin domain had much lower affinity in binding to LGR4 or RNF43/ZNRF3 than the bivalent form. In contrast, monovalent and bivalent forms had nearly identical affinity in binding to LGR5. Co-expression of ZNRF3 with LGR4 led to much higher binding affinity of the monovalent form whereas co-expression of ZNRF3 with LGR5 had no effect on the affinity. These results suggest that LGR4 and RNF43/ZNRF3 form a 2:2 dimer that accommodates bivalent binding of RSPO whereas LGR5 forms a homodimer that does not. Structural models are proposed to illustrate how RSPOs bind to LGR4, RNF43/ZNRF3, and LGR5 in whole cells.

In Silico Investigation of the Clinical Translatability of Competitive Clearance Glucose-Responsive Insulins.

The glucose-responsive insulin (GRI) MK-2640 from Merck was a pioneer in its class to enter the clinical stage, having demonstrated promising responsiveness in in vitro and preclinical studies via a novel competitive clearance mechanism (CCM). The smaller pharmacokinetic response in humans motivates the development of new predictive, computational tools that can improve the design of therapeutics such as GRIs. Herein, we develop and use a new computational model, IM3PACT, based on the intersection of human and animal model glucoregulatory systems, to investigate the clinical translatability of CCM GRIs based on existing preclinical and clinical data of MK-2640 and regular human insulin (RHI). Simulated multi-glycemic clamps not only validated the earlier hypothesis of insufficient glucose-responsive clearance capacity in humans but also uncovered an equally important mismatch between the in vivo competitiveness profile and the physiological glycemic range, which was not observed in animals. Removing the inter-species gap increases the glucose-dependent GRI clearance from 13.0% to beyond 20% for humans and up to 33.3% when both factors were corrected. The intrinsic clearance rate, potency, and distribution volume did not apparently compromise the translation. The analysis also confirms a responsive pharmacokinetics local to the liver. By scanning a large design space for CCM GRIs, we found that the mannose receptor physiology in humans remains limiting even for the most optimally designed candidate. Overall, we show that this computational approach is able to extract quantitative and mechanistic information of value from a posteriori analysis of preclinical and clinical data to assist future therapeutic discovery and development.

Changes in shear wave propagation within skeletal muscle during active and passive force generation.

Muscle force can be generated actively through changes in neural excitation, and passively through externally imposed changes in muscle length. Disease and injury can disrupt force generation, but it can be challenging to separate passive from active contributions to these changes. Ultrasound elastography is a promising tool for characterizing the mechanical properties of muscles and the forces that they generate. Most prior work using ultrasound elastography in muscle has focused on the group velocity of shear waves, which increases with increasing muscle force. Few studies have quantified the phase velocity, which depends on the viscoelastic properties of muscle. Since passive and active forces within muscle involve different structures for force transmission, we hypothesized that measures of phase velocity could detect changes in shear wave propagation during active and passive conditions that cannot be detected when considering only group velocity. We measured phase and group velocity in the human biceps brachii during active and passive force generation and quantified the differences in estimates of shear elasticity obtained from each of these measurements. We found that measures of group velocity consistently overestimate the shear elasticity of muscle. We used a Voigt model to characterize the phase velocity and found that the estimated time constant for the Voigt model provided a way to distinguish between passive and active force generation. Our results demonstrate that shear wave elastography can be used to distinguish between passive and active force generation when it is used to characterize the phase velocity of shear waves propagating in muscle.

Shear Waves Reveal Viscoelastic Changes in Skeletal Muscles After Hemispheric Stroke.

We investigated alterations in material properties such as elasticity and viscoelasticity of stroke-affected muscles using ultrasound induced shear waves and mechanical models. We used acoustic radiation force to generate shear waves along fascicles of biceps muscles and measured their propagation velocity. The shear wave data were collected in muscles of 13 hemiplegic stroke survivors under passive conditions at 90°, 120°, and 150° elbow flexion angles. In a viscoelastic medium, as opposed to a purely elastic medium, the shear wave propagation velocity depends on the frequency content of the induced wave. Therefore, in addition to the shear wave group velocity (GpV), we also estimated a frequency-dependent phase velocity (PhV). We found significantly higher GpVs and PhVs in stroke-affected muscles ( ). The velocity data were used to estimate shear elasticity and viscosity using an elastic and viscoelastic material models. A pure elastic model showed increased shear elasticity in stroke-affected muscles ( ). The Voigt model estimates of viscoelastic properties were also significantly different between the stroke-impaired and non-impaired muscles. We observed significantly larger model-estimated viscosity values on the stroke-affected side at elbow flexion angles of 120° and 150°. Furthermore, the creep behavior (tissue strain resulting from the application of sudden constant stress) of the model was also different between muscles of the paretic and non-paretic side. We speculate that these changes are associated with the structural disruption of muscles after stroke and may potentially affect force generation from muscle fibers as well as transmission of force to tendons.

Altered viscoelastic properties of stroke-affected muscles estimated using ultrasound shear waves - Preliminary data.

As a result of a brain injury such as stroke, the skeletal muscles may undergo numerous structural and functional alterations. These abnormal changes are linked to muscle weakness, joint contracture, and abnormal muscle tone and eventually, result in motor impairment. A subset of these alterations affects passive muscle stiffness, i.e., viscoelastic properties. However, in vivo estimation of changes in viscoelastic properties is a challenging task. Here, we used the shear wave velocity, estimated through ultrasound SuperSonic imaging (SSI), as a surrogate for viscoelastic properties. We estimated shear wave group and phase velocities (dispersion), and thus, quantified both elasticity and viscosity of the muscle tissue, respectively in muscles of hemiplegic stroke survivors. In these individuals, we found significantly higher group and phase velocities in the stroke-affected muscles (p<; 05) compared to those of the contralateral non-affected side. We hypothesize that in addition to changes in neural and contractile properties, there are also, changes in elastic and tissue dispersive properties through local mechanisms. An enhanced understanding of post-stroke changes in skeletal muscles will lead to better and targeted interventions for rehabilitation.

Frizzled 7 expression is positively regulated by SIRT1 and ß-catenin in breast cancer cells.

The Wnt signaling pathway is often chronically activated in diverse human tumors, and the Frizzled (FZD) family of receptors for Wnt ligands, are central to propagating oncogenic signals in a ß-catenin-dependent and independent manner. SIRT1 is a class III histone deacetylase (HDAC) that deacetylates histone and non-histone proteins to regulate gene transcription and protein function. We previously demonstrated that SIRT1 loss of function led to a significant decrease in the levels of Dishevelled (Dvl) proteins. To further explore this connection between the sirtuins and components of the Wnt pathway, we analyzed sirtuin-mediated regulation of FZD proteins. Here we explore the contribution of sirtuin deacetylases in promoting constitutive Wnt pathway activation in breast cancer cells. We demonstrate that the use of small molecule inhibitors of SIRT1 and SIRT2, and siRNA specific to SIRT1, all reduce the levels of FZD7 mRNA. We further demonstrate that pharmacologic inhibition of SIRT1/2 causes a marked reduction in FZD7 protein levels. Additionally, we show that ß-catenin and c-Jun occupy the 7 kb region upstream of the transcription start site of the FZD7 gene, and SIRT1 inhibition leads to a reduction in the occupancy of both ß-catenin and c-Jun at points along this region. This work uncovers a new mechanism for the regulation of FZD7 and provides a critical new link between the sirtuins and FZD7, one of the earliest nodal points from which oncogenic Wnt signaling emanates. This study shows that inhibition of specific sirtuins may provide a unique strategy for inhibiting the constitutively active Wnt pathway at the level of the receptor.