Exploring clinical markers of Axon degeneration processes in Chemotherapy-induced peripheral neuropathy among young adults receiving vincristine or paclitaxel.

BACKGROUND: Approximately 70% of patients receiving neurotoxic chemotherapy (e.g., paclitaxel or vincristine) will develop chemotherapy-induced peripheral neuropathy. Despite the known negative effects of CIPN on physical functioning and chemotherapy dosing, little is known about how to prevent CIPN. The development of efficacious CIPN prevention interventions is hindered by the lack of knowledge surrounding CIPN mechanisms. Nicotinamide adenine dinucleotide (NAD+) and cyclic-adenosine diphosphate ribose (cADPR) are potential markers of axon degeneration following neurotoxic chemotherapy, however, such markers have been exclusively measured in preclinical models of chemotherapy-induced peripheral neuropathy (CIPN). The overall objective of this longitudinal, observational study was to determine the association between plasma NAD+, cADPR, and ADPR with CIPN severity in young adults receiving vincristine or paclitaxel. METHODS: Young adults (18-39 years old) beginning vincristine or paclitaxel were recruited from Dana-Farber Cancer Institute. Young adults completed the QLQ-CIPN20 sensory and motor subscales and provided a blood sample prior to starting chemotherapy (T1) and at increasing cumulative vincristine (T2: 3-5 mg, T3: 7-9 mg) and paclitaxel (T2: 300-500 mg/m2, T3: 700-900 mg/m2) dosages. NAD+, cADPR, and ADPR were quantified from plasma using mass spectrometry. Metabolite levels and QLQ-CIPN20 scores over time were compared using mixed-effects linear regression models and/or paired two-sample tests. RESULTS: Participants (N = 50) were mainly female (88%), white (80%), and receiving paclitaxel (78%). Sensory and motor CIPN severity increased from T1-T3 (p < 0.001). NAD+ (p = 0.28), cADPR (p = 0.62), and ADPR (p = 0.005) values decreased, while cADPR/NAD+ ratio increased from T1-T3 (p = 0.50). There were no statistically significant associations between NAD + and QLQ-CIPN20 scores over time. CONCLUSIONS: To our knowledge, this is the first study to measure plasma NAD+, cADPR, and ADPR among patients receiving neurotoxic chemotherapy. Although, no meaningful changes in NAD+, cADPR, or cADPR/NAD+ were observed among young adults receiving paclitaxel or vincristine. Future research in an adequately powered sample is needed to explore the clinical utility of biomarkers of axon degeneration among patients receiving neurotoxic chemotherapy to guide mechanistic research and novel CIPN treatments.

Satellite glial contact enhances differentiation and maturation of human iPSC-derived sensory neurons.

Sensory neurons generated from induced pluripotent stem cells (iSNs) are used to model human peripheral neuropathies, however current differentiation protocols produce sensory neurons with an embryonic phenotype. Peripheral glial cells contact sensory neurons early in development and contribute to formation of the canonical pseudounipolar morphology, but these signals are not encompassed in current iSN differentiation protocols. Here, we show that terminal differentiation of iSNs in co-culture with rodent Dorsal Root Ganglion satellite glia (rSG) advances their differentiation and maturation. Co-cultured iSNs develop a pseudounipolar morphology through contact with rSGs. This transition depends on semaphorin-plexin guidance cues and on glial gap junction signaling. In addition to morphological changes, iSNs terminally differentiated in co-culture exhibit enhanced spontaneous action potential firing, more mature gene expression, and increased susceptibility to paclitaxel induced axonal degeneration. Thus, iSNs differentiated in coculture with rSGs provide a better model for investigating human peripheral neuropathies.

Dissecting the neuroprotective interaction between the BH4 domain of BCL-w and the IP3 receptor.

BCL-w is a BCL-2 family protein that promotes cell survival in tissue- and disease-specific contexts. The canonical anti-apoptotic functionality of BCL-w is mediated by a surface groove that traps the BCL-2 homology 3 (BH3) α-helices of pro-apoptotic members, blocking cell death. A distinct N-terminal portion of BCL-w, termed the BCL-2 homology 4 (BH4) domain, selectively protects axons from paclitaxel-induced degeneration by modulating IP3 receptors, a noncanonical BCL-2 family target. Given the potential of BCL-w BH4 mimetics to prevent or mitigate chemotherapy-induced peripheral neuropathy, we sought to characterize the interaction between BCL-w BH4 and the IP3 receptor, combining "staple" and alanine scanning approaches with molecular dynamics simulations. We generated and identified stapled BCL-w BH4 peptides with optimized IP3 receptor binding and neuroprotective activities. Point mutagenesis further revealed the sequence determinants for BCL-w BH4 specificity, providing a blueprint for therapeutic targeting of IP3 receptors to achieve neuroprotection.

Investigating the efficiency of electrocoagulation using similar/dissimilar electrodes for the detoxification of Coralene Rubine dye: a cost effective approach.

Efficient treatment of textile dyeing wastewater can be achieved through electrocoagulation (EC) with minimal sludge production; however, the selection of the appropriate electrode is essential in lowering overall costs. Also, the reuse of the treated aqueous azo dye solution from this process has not been explored in detail. With these objectives, this study aims to treat synthetic azo dye solutions and achieve high colour removal efficiency (CRE%) using similar (Ti-Ti) and dissimilar (Ti-Cu) metal electrodes through EC with an attempt to reduce the cost. The aqueous Coralene Rubine GFL azo dye was used to examine the efficiency and cost of the EC process. X-Ray Photoelectron Spectroscopy was used to study the EC mechanism, while High Performance Liquid Chromatography was used to analyse the degradation of the dye and the formation of intermediate compounds. The concentration of metal ions in the treated dye solution was quantified using Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES), with Ti-Ti treated solution having 14.20 mg/L concentration of Ti and Ti-Cu treated solution having 0.078 mg/L of Ti and 0.001 mg/L of Cu, respectively. Colour removal efficiency of 99.49% was obtained for both electrode sets, with a lower operating time and voltage for dissimilar metal combination. Ecotoxicity studies showed negligible toxicity of Ti-Cu treated dye samples compared to untreated solutions. Survival rate, protein estimation, and catalase activity was used to validate the treatment method's efficacy. The study found that the dissimilar electrode material exhibited reduced toxicity due to the presence of heavy metals below the permissible limit.

A Benzarone Derivative Inhibits EYA to Suppress Tumor Growth in SHH Medulloblastoma.

Medulloblastoma is one of the most common malignant brain tumors of children, and 30% of medulloblastomas are driven by gain-of-function genetic lesions in the Sonic Hedgehog (SHH) signaling pathway. EYA1, a haloacid dehalogenase phosphatase and transcription factor, is critical for tumorigenesis and proliferation of SHH medulloblastoma (SHH-MB). Benzarone and benzbromarone have been identified as allosteric inhibitors of EYA proteins. Using benzarone as a point of departure, we developed a panel of 35 derivatives and tested them in SHH-MB. Among these compounds, DS-1-38 functioned as an EYA antagonist and opposed SHH signaling. DS-1-38 inhibited SHH-MB growth in vitro and in vivo, showed excellent brain penetrance, and increased the lifespan of genetically engineered mice predisposed to fatal SHH-MB. These data suggest that EYA inhibitors represent promising therapies for pediatric SHH-MB. SIGNIFICANCE: Development of a benzarone derivative that inhibits EYA1 and impedes the growth of SHH medulloblastoma provides an avenue for improving treatment of this malignant pediatric brain cancer.

Spiritual care for older people living in the community: A scoping review.

BACKGROUND: The population of older people should be supported to enjoy optimal quality of life. Health professionals should consider a range of interventions that support the older population to maintain their quality of life. One such interventional approach involves spiritual care. OBJECTIVE: To explore what is known about spiritual care approaches for older people living in the community. METHODS: Scoping review informed by Joanna Briggs Institute guidelines. Eight electronic databases were searched: CINAHL, Ageline, PubMed, ProQuest Nursing & Allied Health, PsycINFO, Scopus, Garuda, and Neliti. The review included quantitative and qualitative primary peer-reviewed research studies focusing on spiritual care interventions for older people living in the community published between 2011 and 2021 in English or Bahasa Indonesia. The search was uploaded into an electronic citation manager and imported into Covidence for screening. RESULTS: A total of 29 studies were included in the review. While the studies were conducted in five continents, most were reported from the Asian continent. Five key issues based on the outcome of interventions were found namely psychological, physical, spiritual, multidisciplinary approach, and social connection. CONCLUSION: This scoping review identifies spiritual interventions conducted across many countries have been implemented for older people living in the community. Although there are review limitations and further research is needed, these spiritual interventions, both faith-based and non-faith-based, are identified as useful to support the well-being of older people.

Electrocoagulation using Ti/Ti for the remediation and reuse of aqueous Dispersive Blue-79.

The entire ecology is contaminated by the synthetic dyes that are widely utilised in the textile industries. They can be handled using a variety of technologies, but an eco-friendly method called electrocoagulation has been used to prevent additional contamination. Textile wastewater containing disperse dyes are successfully treated in Electrocoagulation (EC) utilizing Al, Fe, and Stainless Steel (SS), but it is not cost effective, also the treated water contains certain mg/L of the metals used, along with dye components, which obstructs the reuse of the same. The effects of initial pH, applied voltage, dye concentration, supporting electrolyte, and treatment time on the colour removal efficiency (CRE) and consumption of energy were examined in EC process followed by activated charcoal filtration (hybrid process) with a monopolar Ti/Ti electrode on the remediation of aqueous solution of Dispersive Blue-79 (dye 3G). The maximum CREobtained was 99.4%, chemical oxygen demand (COD) 93%, and biological oxygen demand (BOD) 85%, under the following optimized operating conditions, applied voltage 15 V, pH = 7, concentration of dye, electrolyte 110 mg/L, 0.2 g/L and time = 15 min. The overall operating cost for the treatment of aqueous dye 3G was 0.455US/m3. The mechanism of EC was studied using XPS analysis in the sludge obtained. For the purpose of the reuse, FTIR, AAS, and ICP-OES analysis were done and compared with the aqueous dye 3G, after EC and hybrid process to ensure the maximum removal of the degraded dye components and metal. ICP-OES results showed that there were no traces of metal in the treated aqueous dye 3G using this method. Throughout the study, the experimental outcomes indicated that the hybrid process upgraded the quality of the treated aqueous dye 3G.

Rehabilitation Support via Postcard (RSVP): A Randomised Controlled Trial of a Postcard to Promote Uptake of Cardiac Rehabilitation.

PURPOSE: The aim was to increase cardiac rehabilitation (CR) uptake using a novel intervention, Rehabilitation Support Via Postcard (RSVP), among patients with acute myocardial infarction discharged from two major hospitals in Hunter New England Local Health District (HNELHD), New South Wales, Australia. METHODS: The RSVP trial was evaluated using a two-armed randomised controlled trial design. Participants (N=430) were recruited from the two main hospitals in HNELHD, and enrolled and randomised to either the intervention (n=216) or control (n=214) group over a six-month period. All participants received usual care; however, the intervention group received postcards promoting CR attendance between January and July 2020. The postcard was ostensibly written as an invitation from the patient's admitting medical officer to promote timely and early uptake of CR. The primary outcome was CR attendance at outpatient HNELHD CR services in the 30-days post-discharge. RESULTS: Fifty-four percent (54%) of participants who received RSVP attended CR, compared to 46% in the control group; however this difference was not statistically significant (odds ratio [OR]=1.4, 95% confidence interval [CI]=0.9-2.0, p=0.11). Exploratory post-hoc analysis among four sub-groups (i.e., Indigeneity, gender, age and rurality), found that the intervention significantly increased attendance in males (OR=1.6, 95%CI=1.0-2.6, p=0.03) but had no significant impact on attendance for other sub-groups. CONCLUSIONS: While not statistically significant, postcards increased overall CR attendance by 8%. This strategy may be useful to increase attendance, particularly in men. Alternative strategies are necessary to increase CR uptake among women, Indigenous people, older people and people from regional and remote locations.

Advanced Nursing Practice and Advanced Practice Nursing roles within low and lower-middle-income countries.

INTRODUCTION: Population health initiatives rely on the availability and skills of an appropriate workforce to meet required goals. One global workforce initiative with demonstrated ability to expand health care services and improve access to care is the development of Advanced Nursing Practice and Advanced Practice Nursing roles. Given the sparse published information about these roles in Low and Lower-Middle-Income countries, this study seeks to describe their development and application in these countries. DESIGN: The researchers developed a descriptive cross-sectional multilingual survey for online distribution to nursing experts within the targeted countries. Survey questions addressed demographic information on the population served, Advanced Nursing Practice and Advanced Practice Nursing titles, the time frame and rationale for creating the title, and how the roles relate to the International Council of Nurses' Advanced Practice Nursing guidelines characteristics of education, practice, and regulation. RESULTS: Of the 167 responses received, only 24 participants met the inclusion criteria. This represented five low-income countries and nineteen lower-middle-income countries from four World Bank regions. Seventy-one roles were identified. Roles emerged predominantly over the last 20 years, focusing on care for underserved populations, with an almost even spread across primary and acute care settings. There were differences in education, practice, and regulation amongst the roles. Roles that required a master's education or higher with practice-related characteristics had a broader scope of practice, which is consistent with international guidelines. CONCLUSION: This paper describes how Advanced Nursing Practice and Advanced Practice Nursing roles from Low and Lower Middle-Income Countries have been implemented to address gaps in service and highlights disparities in education, practice and regulation compared to international guidelines. Maintaining and increasing support from organizations and universities internationally may be required to assist in developing and expanding educational programs for advanced nursing roles in these countries. CLINICAL RELEVANCE: Understanding how these advanced nursing roles are operationalized in relation to education, practice, and regulation in Low and Lower-Middle-Income countries can provide baseline information that will inform workforce development policies to address healthcare needs in similar jurisdictions.

Sarm1 activation produces cADPR to increase intra-axonal Ca++ and promote axon degeneration in PIPN.

Cancer patients frequently develop chemotherapy-induced peripheral neuropathy (CIPN), a painful and long-lasting disorder with profound somatosensory deficits. There are no effective therapies to prevent or treat this disorder. Pathologically, CIPN is characterized by a "dying-back" axonopathy that begins at intra-epidermal nerve terminals of sensory neurons and progresses in a retrograde fashion. Calcium dysregulation constitutes a critical event in CIPN, but it is not known how chemotherapies such as paclitaxel alter intra-axonal calcium and cause degeneration. Here, we demonstrate that paclitaxel triggers Sarm1-dependent cADPR production in distal axons, promoting intra-axonal calcium flux from both intracellular and extracellular calcium stores. Genetic or pharmacologic antagonists of cADPR signaling prevent paclitaxel-induced axon degeneration and allodynia symptoms, without mitigating the anti-neoplastic efficacy of paclitaxel. Our data demonstrate that cADPR is a calcium-modulating factor that promotes paclitaxel-induced axon degeneration and suggest that targeting cADPR signaling provides a potential therapeutic approach for treating paclitaxel-induced peripheral neuropathy (PIPN).

Diversity of developing peripheral glia revealed by single-cell RNA sequencing.

The peripheral nervous system responds to a wide variety of sensory stimuli, a process that requires great neuronal diversity. These diverse neurons are closely associated with glial cells originating from the neural crest. However, the molecular nature and diversity among peripheral glia are not understood. Here, we used single-cell RNA sequencing to profile developing and mature glia from somatosensory dorsal root ganglia and auditory spiral ganglia. We found that glial precursors (GPs) in these two systems differ in their transcriptional profiles. Despite their unique features, somatosensory and auditory GPs undergo convergent differentiation to generate molecularly uniform myelinating and non-myelinating Schwann cells. By contrast, somatosensory and auditory satellite glial cells retain system-specific features. Lastly, we identified a glial signature gene set, providing new insights into commonalities among glia across the nervous system. This survey of gene expression in peripheral glia constitutes a resource for understanding functions of glia across different sensory modalities.

Binding and transport of SFPQ-RNA granules by KIF5A/KLC1 motors promotes axon survival.

Complex neural circuitry requires stable connections formed by lengthy axons. To maintain these functional circuits, fast transport delivers RNAs to distal axons where they undergo local translation. However, the mechanism that enables long-distance transport of RNA granules is not yet understood. Here, we demonstrate that a complex containing RNA and the RNA-binding protein (RBP) SFPQ interacts selectively with a tetrameric kinesin containing the adaptor KLC1 and the motor KIF5A. We show that the binding of SFPQ to the KIF5A/KLC1 motor complex is required for axon survival and is impacted by KIF5A mutations that cause Charcot-Marie Tooth (CMT) disease. Moreover, therapeutic approaches that bypass the need for local translation of SFPQ-bound proteins prevent axon degeneration in CMT models. Collectively, these observations indicate that KIF5A-mediated SFPQ-RNA granule transport may be a key function disrupted in KIF5A-linked neurologic diseases and that replacing axonally translated proteins serves as a therapeutic approach to axonal degenerative disorders.

Frontline barriers to effective paramedic and emergency nursing STEMI management: clinician perspectives.

BACKGROUND: Factors that hinder the pivotal role frontline clinicians play in STEMI management are under-reported. We aimed to explore perceived barriers to effective STEMI management by addressing the following questions: 1. What are the most commonly occurring barriers to timely STEMI management for paramedics and emergency nurses? 2. Are there differences in barriers experienced by paramedics and emergency nurses? 3. Are there differences in barriers experienced by frontline clinicians in rural and metropolitan settings? METHODS: A 79-item online survey was offered to paramedics and emergency nurses. Descriptive statistics and exploratory factor analysis identified the most frequently experienced types of barriers. Professional groups and geographical locations were compared. RESULTS: There were 333 respondents. Response rates for paramedics was 10% and 9% for members of an emergency nursing association. Most commonly occurring barriers across all respondents were: 'lack of skills development'; 'lack of feedback'; 'untimely support'; 'distance to scene/hospital facilities'; 'hospital-related delays'. Statistically significant differences were found by professional group and geographical location. CONCLUSION: Barriers to timely management were present, but not frequently experienced. Survey responses indicate a need for improved continuing professional development opportunity, clearer feedback mechanisms, streamlined facilitation of STEMI processes in hospitals, and enhanced access to expert advice/resources for all frontline clinicians.

The Eya1 Phosphatase Mediates Shh-Driven Symmetric Cell Division of Cerebellar Granule Cell Precursors.

During neural development, stem and precursor cells can divide either symmetrically or asymmetrically. The transition between symmetric and asymmetric cell divisions is a major determinant of precursor cell expansion and neural differentiation, but the underlying mechanisms that regulate this transition are not well understood. Here, we identify the Sonic hedgehog (Shh) pathway as a critical determinant regulating the mode of division of cerebellar granule cell precursors (GCPs). Using partial gain and loss of function mutations within the Shh pathway, we show that pathway activation determines spindle orientation of GCPs, and that mitotic spindle orientation correlates with the mode of division. Mechanistically, we show that the phosphatase Eya1 is essential for implementing Shh-dependent GCP spindle orientation. We identify atypical protein kinase C (aPKC) as a direct target of Eya1 activity and show that Eya1 dephosphorylates a critical threonine (T410) in the activation loop. Thus, Eya1 inactivates aPKC, resulting in reduced phosphorylation of Numb and other components that regulate the mode of division. This Eya1-dependent cascade is critical in linking spindle orientation, cell cycle exit and terminal differentiation. Together these findings demonstrate that a Shh-Eya1 regulatory axis selectively promotes symmetric cell divisions during cerebellar development by coordinating spindle orientation and cell fate determinants.

A large-scale drug screen identifies selective inhibitors of class I HDACs as a potential therapeutic option for SHH medulloblastoma.

BACKGROUND: Medulloblastoma (MB) is one of the most frequent malignant brain tumors of children, and a large set of these tumors is characterized by aberrant activation of the sonic hedgehog (SHH) pathway. While some tumors initially respond to inhibition of the SHH pathway component Smoothened (SMO), tumors ultimately recur due to downstream resistance mechanisms, indicating a need for novel therapeutic options. METHODS: Here we performed a targeted small-molecule screen on a stable, SHH-dependent murine MB cell line (SMB21). Comprehensive isotype profiling of histone deacetylase (HDAC) inhibitors was performed, and effects of HDAC inhibition were evaluated in cell lines both sensitive and resistant to SMO inhibition. Lastly, distinct mouse models of SHH MB were used to demonstrate pharmacologic efficacy in vivo. RESULTS: A subset of the HDAC inhibitors tested significantly inhibit tumor growth of SMB21 cells by preventing SHH pathway activation. Isotype profiling of HDAC inhibitors, together with genetic approaches suggested that concerted inhibition of multiple class I HDACs is necessary to achieve pathway inhibition. Of note, class I HDAC inhibitors were also efficacious in suppressing growth of diverse SMO inhibitor‒resistant clones of SMB21 cells. Finally, we show that the novel HDAC inhibitor quisinostat targets multiple class I HDACs, is well tolerated in mouse models, and robustly inhibits growth of SHH MB cells in vivo as well as in vitro. CONCLUSIONS: Our data provide strong evidence that quisinostat or other class I HDAC inhibitors might be therapeutically useful for patients with SHH MB, including those resistant to SMO inhibition.

Preliminary efficacy and feasibility of referral to exercise specialists, psychologists and provision of a technology-based behavior change support package to promote physical activity in school teachers 'at risk' of, or diagnosed with, type 2 diabetes: The 'SMART Health' Pilot Study Protocol.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a global public health concern. Aerobic physical activity (PA) and resistance training (RT) play significant roles in the prevention and management of T2DM. The aim of this pilot trial is to determine the preliminary efficacy and confirm feasibility of referral to exercise physiologists, psychologists, and provision of a technology-based behavior change support package to promote aerobic PA and RT in school teachers 'at risk' of or diagnosed with T2DM. RESEARCH DESIGN AND METHODS: The SMART (Support, Motivation and Physical Activity Research for Teachers') Health pilot study will be evaluated using a three-arm randomized controlled trial. The intervention will be guided by Social Cognitive Theory, Health Action Process Approach Model and Cognitive Behavioral Therapy strategies. The participants will be randomly allocated to one of three study groups: Group 1: wait-list control group; Group 2: 5 face-to-face visits with a psychologist and exercise specialist over 3 months; and Group 3: same as Group 2 plus technology-based behavior change support package for an additional 6 months. Assessments will be conducted at baseline, 3-, 9- (primary time-point) and 18-months post-baseline. The primary outcome will be PA measured with pedometers. DISCUSSION: SMART Health is an innovative, multi-component intervention, that integrates referral to exercise specialists, psychologists and provision of a technology-based behavior support package to promote PA and RT in adults diagnosed with T2DM or 'at risk' of T2DM. The findings will be used to guide future PA interventions and to develop effective community-based diabetes prevention and treatment programs. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry No: ACTRN12616001309471.

Coloproctology procedure clinic: a novel service developed to reduce suffering of patients with bleeding per rectum.

AIMS: Evaluation of the role and impact of introducing a dedicated coloproctology procedure clinic in tertiary referral colorectal unit. METHODS: A retrospective analysis of 126 consecutive patients managed in the coloproctology clinic between March2015 and September 2016 was carried out. All patients were preselected for attendance based on symptom-based protocol. RESULTS: Based on the information available in GP referrals, 126 patients with bleeding per rectum with low risk of cancer were re-triaged from the general outpatient to dedicated coloproctology procedure clinic. Those patients accounted for 14% of waiting list. The average waiting time to attend clinic was 27 months from referral to undergoing definitive procedure. A proctoscopy or/and rigid sigmoidoscopy was performed in patients. Seventy-nine (89.7%) patients were completely managed and discharged after attending their first visit. Sixty-seven (76%) patients had 2nd- or 3rd-degree haemorrhoids and were treated with rubber band ligation (RBL) or phenol injection in outpatient setting. Two patients had an anal fissure and were managed conservatively with medication. After clinic, follow-up was through telephone clinic. This avoids attendance physically in the hospital. Symptoms persisted in nine patients and were subsequently scheduled for colonoscopy, three had benign polyps. With the introduction of the procedure clinic, the waiting time from referral to treatment was reduced from 27 to 6 months (p < 0.05). CONCLUSIONS: Establishing a dedicated "Coloproctology procedure clinic" is an effective strategy in reducing number of hospital visits per patient and hospital waiting list. This innovative clinic reduces utilisation of precious endoscopy unit resources. This ultimately will improve endoscopy efficiency.

Paclitaxel Reduces Axonal Bclw to Initiate IP3R1-Dependent Axon Degeneration.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of many cancer treatments. The hallmark of CIPN is degeneration of long axons required for transmission of sensory information; axonal degeneration causes impaired tactile sensation and persistent pain. Currently the molecular mechanisms of CIPN are not understood, and there are no available treatments. Here we show that the chemotherapeutic agent paclitaxel triggers CIPN by altering IP3 receptor phosphorylation and intracellular calcium flux, and activating calcium-dependent calpain proteases. Concomitantly paclitaxel impairs axonal trafficking of RNA-granules and reduces synthesis of Bclw (bcl2l2), a Bcl2 family member that binds IP3R1 and restrains axon degeneration. Surprisingly, Bclw or a stapled peptide corresponding to the Bclw BH4 domain interact with axonal IP3R1 and prevent paclitaxel-induced degeneration, while Bcl2 and BclxL cannot do so. Together these data identify a Bclw-IP3R1-dependent cascade that causes axon degeneration and suggest that Bclw-mimetics could provide effective therapy to prevent CIPN.

A Transposon Screen Identifies Loss of Primary Cilia as a Mechanism of Resistance to SMO Inhibitors.

Drug resistance poses a great challenge to targeted cancer therapies. In Hedgehog pathway-dependent cancers, the scope of mechanisms enabling resistance to SMO inhibitors is not known. Here, we performed a transposon mutagenesis screen in medulloblastoma and identified multiple modes of resistance. Surprisingly, mutations in ciliogenesis genes represent a frequent cause of resistance, and patient datasets indicate that cilia loss constitutes a clinically relevant category of resistance. Conventionally, primary cilia are thought to enable oncogenic Hedgehog signaling. Paradoxically, we find that cilia loss protects tumor cells from susceptibility to SMO inhibitors and maintains a "persister" state that depends on continuous low output of the Hedgehog program. Persister cells can serve as a reservoir for further tumor evolution, as additional alterations synergize with cilia loss to generate aggressive recurrent tumors. Together, our findings reveal patterns of resistance and provide mechanistic insights for the role of cilia in tumor evolution and drug resistance.Significance: Using a transposon screen and clinical datasets, we identified mutations in ciliogenesis genes as a new class of resistance to SMO inhibitors. Mechanistically, cilia-mutant tumors can either grow slowly in a "persister" state or evolve and progress rapidly in an "aggressive" state. Cancer Discov; 7(12); 1436-49. ©2017 AACR.See related commentary by Goranci-Buzhala et al., p. 1374This article is highlighted in the In This Issue feature, p. 1355.

Cardiac rehabilitation in the acute care setting: Integrative review.

BACKGROUND: Phase one cardiac rehabilitation (CR) is an essential component of care for patients with coronary heart disease. With optimal program delivery, health outcomes can be improved. OBJECTIVES: To conduct an integrative review that explores Phase one CR for patients hospitalised with coronary heart disease. DESIGN: Integrative literature review (2003-2014) Data sources: The literature search included Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Experta Medica Database (EMBASE), Psycinfo, Clinical Practice Guidelines Portal, Cochrane Library, Clinical Evidence (BMJ) and Google Scholar. REVIEW METHODS: The Joanna Briggs Institute critical appraisal tools relevant to study methodology were utilised. Studies included for review were peer reviewed, published in English. Studies included Phase one CR intervention/s or the provision of education to patients diagnosed with coronary heart disease in the acute care setting prior to hospital discharge. RESULTS: In the past decade cardiac researchers have predominantly focused on patients and health professionals perceptions, CR interventions, and patient education. Factors that impede delivery of Phase one CR, such as time, workload etc. were also reported. CONCLUSIONS: The implementation of Phase one CR delivery requires optimisation to enable patients with coronary heart disease to achieve positive health outcomes post hospitalisation. Future interventions should address the factors that impede delivery of Phase one CR.