Multiomic-Based Molecular Landscape of FaDu Xenograft Tumors in Mice after a Combinatorial Treatment with Radiation and an HSP90 Inhibitor Identifies Adaptation-Induced Targets of Resistance and Therapeutic Intervention.

Treatments involving radiation and chemotherapy alone or in combination have improved patient survival and quality of life. However, cancers frequently evade these therapies due to adaptation and tumor evolution. Given the complexity of predicting response based solely on the initial genetic profile of a patient, a predetermined treatment course may miss critical adaptation that can cause resistance or induce new targets for drug and immunotherapy. To address the timescale for these evasive mechanisms, using a mouse xenograft tumor model, we investigated the rapidity of gene expression (mRNA), molecular pathway, and phosphoproteome changes after radiation, an HSP90 inhibitor, or combination. Animals received radiation, drug, or combination treatment for 1 or 2 weeks and were then euthanized along with a time-matched untreated group for comparison. Changes in gene expression occur as early as 1 week after treatment initiation. Apoptosis and cell death pathways were activated in irradiated tumor samples. For the HSP90 inhibitor and combination treatment at weeks 1 and 2 compared with Control Day 1, gene-expression changes induced inhibition of pathways including invasion of cells, vasculogenesis, and viral infection among others. The combination group included both drug-alone and radiation-alone changes. Our data demonstrate the rapidity of gene expression and functional pathway changes in the evolving tumor as it responds to treatment. Discovering these phenotypic adaptations may help elucidate the challenges in using sustained treatment regimens and could also define evolving targets for therapeutic efficacy.

Adipokines and stroke: A systematic review and meta-analysis of disease risk and patient outcomes.

Obesity is reported to increase stroke risk, with adipocyte-derived cytokines or adipokines implicated as mediators. However, the relationship between adipokines and stroke is not well clarified. Thus, we aimed to evaluate the association of adipokines with stroke using fully adjusted risk estimates that incorporated body mass index in a meta-analysis. Data from 52 studies (62,428 patients) were pooled in a random-effects meta-analysis. Adiponectin was independently associated with a lower risk of pre-existing stroke (adjusted odds ratio: 0.64 [95% confidence interval: 0.46-0.88], p < 0.01), whereas leptin (1.08 [1.00-1.17], p = 0.04), resistin (1.06 [1.04-1.08], p < 0.01) and visfatin (1.04 [1.01-1.07], p = 0.01) are associated with a higher risk of stroke, but none with incident stroke. Adipokines independently associated with an ischaemic stroke subtype were adiponectin (0.48 [0.30-0.77], p < 0.01), leptin (1.10 [1.01-1.20], p = 0.04), and resistin (1.06 [1.04-1.08], p < 0.01). Fatty acid-binding protein-4 (FABP-4) independently predicted 6-month poor functional outcomes in stroke patients (adjusted hazard ratio: 1.09 [1.06-1.12], p < 0.01); whereas both FABP-4 (1.17 [1.03-1.34], p = 0.01) and visfatin (1.24 [1.00-1.55], p = 0.05) were predictive of 6-month mortality. Adipokines are associated with a greater risk of pre-existing stroke, but not with the relationship with incident stroke. Adipokines, such as FABP-4 and visfatin, may serve as biomarkers of stroke severity and worsening of stroke outcomes.

2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Patients With Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. METHODS: A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE: Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" and the "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.

Implementation of pharmacogenomics testing for precision medicine.

Great strides have been made in the past decade to lower barriers to clinical pharmacogenomics implementation. Nevertheless, PGx consultation prior to prescribing therapeutics is not yet mainstream. This review addresses the current climate surrounding PGx implementation, focusing primarily on strategies for implementation at academic institutions, particularly at The University of Chicago, and provides an up-to-date guide of resources supporting the development of PGx programs. Remaining challenges and recent strategies for overcoming these challenges to implementation are discussed.

2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. METHODS: A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE: Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" and the "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.

Local production of reactive oxygen species drives vincristine-induced axon degeneration.

Neurological side effects arising from chemotherapy, such as severe pain and cognitive impairment, are a major concern for cancer patients. These major side effects can lead to reduction or termination of chemotherapy medication in patients, negatively impacting their prognoses. With cancer survival rates improving dramatically, addressing side effects of cancer treatment has become pressing. Here, we use iPSC-derived human neurons to investigate the molecular mechanisms that lead to neurotoxicity induced by vincristine, a common chemotherapeutic used to treat solid tumors. Our results uncover a novel mechanism by which vincristine causes a local increase in mitochondrial proteins that produce reactive oxygen species (ROS) in the axon. Vincristine triggers a cascade of axon pathology, causing mitochondrial dysfunction that leads to elevated axonal ROS levels and SARM1-dependent axon degeneration. Importantly, we show that the neurotoxic effect of increased axonal ROS can be mitigated by the small molecule mitochondrial division inhibitor 1 (mdivi-1) and antioxidants glutathione and mitoquinone, identifying a novel therapeutic avenue to treat the neurological effects of chemotherapy.

4D printed origami-inspired accordion, Kresling and Yoshimura tubes.

Applying tessellated origami patterns to the design of mechanical materials can enhance properties such as strength-to-weight ratio and impact absorption ability. Another advantage is the predictability of the deformation mechanics since origami materials typically deform through the folding and unfolding of their creases. This work focuses on creating 4D printed flexible tubular origami based on three different origami patterns: the accordion, the Kresling and the Yoshimura origami patterns, fabricated with a flexible polylactic acid (PLA) filament with heat-activated shape memory effect. The shape memory characteristics of the self-unfolding structures were then harnessed at 60°C, 75°C and 90°C. Due to differences in the folding patterns of each origami design, significant differences in behaviour were observed during shape programming and actuation. Among the three patterns, the accordion proved to be the most effective for actuation as the overall structure can be compressed following the folding crease lines. In comparison, the Kresling pattern exhibited cracking at crease locations during deformation, while the Yoshimura pattern buckled and did not fold as expected at the crease lines. To demonstrate a potential application, an accordion-patterned origami 4D printed tube for use in hand rehabilitation devices was designed and tested as a proof-of-concept prototype incorporating self-unfolding origami.

Assessing the utility of pre-course assessment and voluntary pre-work in two required integrated pharmacotherapy courses.

BACKGROUND AND PURPOSE: Self-assessment and self-learning are essential skills for student pharmacists. Data demonstrating the association between these skills in pharmacy courses are limited. The aim of this study was to evaluate the impact of providing pre-course review and administering a pre-course assessment on performance in two required integrated pharmacotherapy (IP) courses - IP: Pulmonology and IP: Cardiology. EDUCATIONAL ACTIVITY AND SETTING: This study included second-year student pharmacists enrolled in fall semester IP: Pulmonology and IP: Cardiology from 2019 to 2021. Voluntary pre-course review materials and pre-course assessments were added in fall 2021. Overall course grades and examination scores between each year were analyzed. Student perceptions of the pre-course assessment were also captured. FINDINGS: Of the 454 students analyzed, there was no difference in median overall IP: Pulmonology grades (85.93%, 86.67%, 86.29%; P = .63) or IP: Cardiology grades (80.25%, 78.3%, 79.96%; P = .41) for 2019, 2020, and 2021, respectively. IP: Pulmonology Exam 1 scores were statistically higher in 2021. For IP: Cardiology, Exam 1 and Final Exam scores were statistically higher in 2020 compared to 2019 and Exam 3 scores were significantly higher in 2021 than 2019. Pre-course assessment scores had a statistically significant, positive association with overall course grade. Half of the students surveyed agreed that completing the course prep work was an effective approach to learning. SUMMARY: Although overall course grades did not differ between years, pre-course assessment scores correlated with overall course grade. Thus, voluntary pre-course assessments could provide early identification of poor performance.

Vangl-dependent Wnt/planar cell polarity signaling mediates collective breast carcinoma motility and distant metastasis.

BACKGROUND: In light of the growing appreciation for the role of collective cell motility in metastasis, a deeper understanding of the underlying signaling pathways will be critical to translating these observations to the treatment of advanced cancers. Here, we examine the contribution of Wnt/planar cell polarity (Wnt/PCP), one of the non-canonical Wnt signaling pathways and defined by the involvement of the tetraspanin-like proteins Vangl1 and Vangl2, to breast tumor cell motility, collective cell invasiveness and mammary tumor metastasis. METHODS: Vangl1 and Vangl2 knockdown and overexpression and Wnt5a stimulation were employed to manipulate Wnt/PCP signaling in a battery of breast cancer cell lines representing all breast cancer subtypes, and in tumor organoids from MMTV-PyMT mice. Cell migration was assessed by scratch and organoid invasion assays, Vangl protein subcellular localization was assessed by confocal fluorescence microscopy, and RhoA activation was assessed in real time by fluorescence imaging with an advanced FRET biosensor. The impact of Wnt/PCP suppression on mammary tumor growth and metastasis was assessed by determining the effect of conditional Vangl2 knockout on the MMTV-NDL mouse mammary tumor model. RESULTS: We observed that Vangl2 knockdown suppresses the motility of all breast cancer cell lines examined, and overexpression drives the invasiveness of collectively migrating MMTV-PyMT organoids. Vangl2-dependent RhoA activity is localized in real time to a subpopulation of motile leader cells displaying a hyper-protrusive leading edge, Vangl protein is localized to leader cell protrusions within leader cells, and actin cytoskeletal regulator RhoA is preferentially activated in the leader cells of a migrating collective. Mammary gland-specific knockout of Vangl2 results in a striking decrease in lung metastases in MMTV-NDL mice, but does not impact primary tumor growth characteristics. CONCLUSIONS: We conclude that Vangl-dependent Wnt/PCP signaling promotes breast cancer collective cell migration independent of breast tumor subtype and facilitates distant metastasis in a genetically engineered mouse model of breast cancer. Our observations are consistent with a model whereby Vangl proteins localized at the leading edge of leader cells in a migrating collective act through RhoA to mediate the cytoskeletal rearrangements required for pro-migratory protrusion formation.

Inhibition of USP14 promotes TNFα-induced cell death in head and neck squamous cell carcinoma (HNSCC).

TNFα is a key mediator of immune, chemotherapy and radiotherapy-induced cytotoxicity, but several cancers, including head and neck squamous cell carcinomas (HNSCC), display resistance to TNFα due to activation of the canonical NFκB pro-survival pathway. However, direct targeting of this pathway is associated with significant toxicity; thus, it is vital to identify novel mechanism(s) contributing to NFκB activation and TNFα resistance in cancer cells. Here, we demonstrate that the expression of proteasome-associated deubiquitinase USP14 is significantly increased in HNSCC and correlates with worse progression free survival in Human Papillomavirus (HPV)- HNSCC. Inhibition or depletion of USP14 inhibited the proliferation and survival of HNSCC cells. Further, USP14 inhibition reduced both basal and TNFα-inducible NFκB activity, NFκB-dependent gene expression and the nuclear translocation of the NFκB subunit RELA. Mechanistically, USP14 bound to both RELA and IκBα and reduced IκBα K48-ubiquitination leading to the degradation of IκBα, a critical inhibitor of the canonical NFκB pathway. Furthermore, we demonstrated that b-AP15, an inhibitor of USP14 and UCHL5, sensitized HNSCC cells to TNFα-mediated cell death, as well as radiation-induced cell death in vitro. Finally, b-AP15 delayed tumor growth and enhanced survival, both as a monotherapy and in combination with radiation, in HNSCC tumor xenograft models in vivo, which could be significantly attenuated by TNFα depletion. These data offer new insights into the activation of NFκB signaling in HNSCC and demonstrate that small molecule inhibitors targeting the ubiquitin pathway warrant further investigation as a novel therapeutic avenue to sensitize these cancers to TNFα- and radiation-induced cytotoxicity.

Diabetic kidney disease induces transcriptome alterations associated with angiogenesis activity in human mesenchymal stromal cells.

BACKGROUND: Therapeutic interventions that optimize angiogenic activities may reduce rates of end-stage kidney disease, critical limb ischemia, and lower extremity amputations in individuals with diabetic kidney disease (DKD). Infusion of autologous mesenchymal stromal cells (MSC) is a promising novel therapy to rejuvenate vascular integrity. However, DKD-related factors, including hyperglycemia and uremia, might alter MSC angiogenic repair capacity in an autologous treatment approach. METHODS: To explore the angiogenic activity of MSC in DKD, the transcriptome of adipose tissue-derived MSC obtained from DKD subjects was compared to age-matched controls without diabetes or kidney impairment. Next-generation RNA sequencing (RNA-seq) was performed on MSC (DKD n = 29; Controls n = 9) to identify differentially expressed (DE; adjusted p < 0.05, |log2fold change|> 1) messenger RNA (mRNA) and microRNA (miRNA) involved in angiogenesis (GeneCards). Paracrine-mediated angiogenic repair capacity of MSC conditioned medium (MSCcm) was assessed in vitro using human umbilical vein endothelial cells incubated in high glucose and indoxyl sulfate for a hyperglycemic, uremic state. RESULTS: RNA-seq analyses revealed 133 DE mRNAs (77 upregulated and 56 down-regulated) and 208 DE miRNAs (119 up- and 89 down-regulated) in DKD-MSC versus Control-MSC. Interestingly, miRNA let-7a-5p, which regulates angiogenesis and participates in DKD pathogenesis, interacted with 5 angiogenesis-associated mRNAs (transgelin/TAGLN, thrombospondin 1/THBS1, lysyl oxidase-like 4/LOXL4, collagen 4A1/COL4A1 and collagen 8A1/COL8A1). DKD-MSCcm incubation with injured endothelial cells improved tube formation capacity, enhanced migration, reduced adhesion molecules E-selectin, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 mRNA expression in endothelial cells. Moreover, angiogenic repair effects did not differ between treatment groups (DKD-MSCcm vs. Control-MSCcm). CONCLUSIONS: MSC from individuals with DKD show angiogenic transcriptome alterations compared to age-matched controls. However, angiogenic repair potential may be preserved, supporting autologous MSC interventions to treat conditions requiring enhanced angiogenic activities such as DKD, diabetic foot ulcers, and critical limb ischemia.

Combined Inhibition of IAPs and WEE1 Enhances TNFα- and Radiation-Induced Cell Death in Head and Neck Squamous Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) remains a prevalent diagnosis with current treatment options that include radiotherapy and immune-mediated therapies, in which tumor necrosis factor-α (TNFα) is a key mediator of cytotoxicity. However, HNSCC and other cancers often display TNFα resistance due to activation of the canonical IKK-NFκB/RELA pathway, which is activated by, and induces expression of, cellular inhibitors of apoptosis proteins (cIAPs). Our previous studies have demonstrated that the IAP inhibitor birinapant sensitized HNSCC to TNFα-dependent cell death in vitro and radiotherapy in vivo. Furthermore, we recently demonstrated that the inhibition of the G2/M checkpoint kinase WEE1 also sensitized HNSCC cells to TNFα-dependent cell death, due to the inhibition of the pro-survival IKK-NFκB/RELA complex. Given these observations, we hypothesized that dual-antagonist therapy targeting both IAP and WEE1 proteins may have the potential to synergistically sensitize HNSCC to TNFα-dependent cell death. Using the IAP inhibitor birinapant and the WEE1 inhibitor AZD1775, we show that combination treatment reduced cell viability, proliferation and survival when compared with individual treatment. Furthermore, combination treatment enhanced the sensitivity of HNSCC cells to TNFα-induced cytotoxicity via the induction of apoptosis and DNA damage. Additionally, birinapant and AZD1775 combination treatment decreased cell proliferation and survival in combination with radiotherapy, a critical source of TNFα. These results support further investigation of IAP and WEE1 inhibitor combinations in preclinical and clinical studies in HNSCC.

Preliminary experience with a novel facet-based lateral mass drill guide for the placement of lateral mass screws compared to freehand technique: a cadaveric study.

BACKGROUND CONTEXT: Lateral mass screw fixation is the standard for posterior subaxial cervical fixation. Several freehand surgical techniques for placing lateral mass screws have been described which rely on anatomical landmarks and surgeon mastery of the technique to safely place screws. The accuracy of these freehand techniques is inherently variable and can be influenced by a surgeon's level of clinical experience. A novel technique was developed that utilizes the plane of the facet joint to create lateral mass screw pilot holes parallel with the joint line to improve the safety and accuracy of lateral mass screw placement regardless of experience. PURPOSE: To assess the safety and accuracy of lateral mass screw placement using a novel lateral mass drill guide instrument (LM Guide), compared to standard freehand technique. STUDY DESIGN: Randomized cadaveric study utilizing multiple surgeon evaluators to compare the safety and accuracy of guided cervical lateral mass placement compared to traditional freehand techniques. MATERIALS AND METHODS: Lateral mass screws were placed from C3 to C7 in 20 cadaver specimens by 8 spine surgeons of varying levels of clinical experience (4 attendings, 4 fellows). Screws were placed bilaterally using standard anatomic landmarks ("freehand") randomly allocated on one side and using the LM Guide on the other. Cadaveric specimens were imaged with high-resolution CT to assess screw placement. Zone grading for safety was conducted based on screw tip position and clinical severity of screw breach was based on proximity to surrounding neurovascular anatomy. Screws were graded as safe, at-risk, or critical, with at-risk and critical screws considered malpositioned. To assess the accuracy of screw trajectory placed using the LM Guide compared to freehand, sagittal screw angle was measured and compared to an "ideal" screw path parallel to the facet joint line. Freehand and LM Guide groups were compared using Pearson's chi-square correlation. RESULTS: Screw placement using the LM guide yielded a significantly lower rate of screw malpositioning, with 7 of 91 (7.7%) compared with 18 of 99 (18.2%) screws placed in the At-Risk or Critical Zones, p<.05. Of the 91 screws inserted using the LM Guide, 84 (92.3%) were in the Safe Zone, 7 (7.7%) were At-Risk, and 0 were in Critical zones. There was no incidence of neural or transverse foramen breaches with the LM Guide. In comparison, for the 99 screws inserted freehand, 81 (81.8%) were Safe, 14 (14.1%) were At-Risk, and 4 (4.1%) were in Critical zones. The 4 Critical zone freehand screw breaches included 1 neural foramen breach, 2 transverse foramen breaches, and 1 facet breach. The LM Guide also resulted in higher accuracy of screw trajectory, as indicated by a significant reduction in sagittal screw angle compared with freehand, p<.01. Notably, in the less-experienced surgeon cohort, the LM Guide significantly reduced the sagittal screw angle and resulted in no critical screw breaches compared to 3 critical breaches with freehand technique suggesting there might be a benefit in decreasing the learning curve associated with lateral mass screw placement. CONCLUSIONS: Lateral mass screw placement with a novel LM Guide that uses the facet joint to control screw trajectory improved the accuracy and reproducibility of screw placement with a significant reduction in screw breach rate and sagittal screw angle compared to freehand techniques regardless of surgeon experience level. CLINICAL SIGNIFICANCE: The inherent variability of freehand lateral mass screw placement can increase the risk of clinical complications associated with screw malpositioning. The technique presented in this cadaveric study may be a viable alternative to standard freehand technique that can improve the overall safety of lateral mass screw placement.

DLK-dependent mitochondrial fission drives axon degeneration and neuronal cell death.

Currently there are no effective treatments for an array of neurodegenerative disorders to a large part because cell-based models fail to recapitulate disease. Here we developed a robust human iPSCbased model where laser axotomy causes retrograde axon degeneration leading to neuronal cell death. Time-lapse confocal imaging revealed that damage triggers a wave of mitochondrial fission proceeding from the site of injury to the soma. We demonstrated that mitochondrial fission and resultant cell death is entirely dependent on phosphorylation of dynamin related protein 1 (DRP1) by dual leucine zipper kinase (DLK). Importantly, we show that CRISPR mediated Drp1 depletion protected mouse retinal ganglion neurons from mitochondrial fission and degeneration after optic nerve crush. Our results provide a powerful platform for studying degeneration of human neurons, pinpoint key early events in damage related neural death and new focus for therapeutic intervention.

Cellular transformation promotes the incorporation of docosahexaenoic acid into the endolysosome-specific lipid bis(monoacylglycerol)phosphate in breast cancer.

Bis(monoacylglycero)phosphates (BMPs), a class of lipids highly enriched within endolysosomal organelles, are key components of the lysosomal intraluminal vesicles responsible for activating sphingolipid catabolic enzymes. While BMPs are understudied relative to other phospholipids, recent reports associate BMP dysregulation with a variety of pathological states including neurodegenerative diseases and lysosomal storage disorders. Since the dramatic lysosomal remodeling characteristic of cellular transformation could impact BMP abundance and function, we employed untargeted lipidomics approaches to identify and quantify BMP species in several in vitro and in vivo models of breast cancer and comparative non-transformed cells and tissues. We observed lower BMP levels within transformed cells relative to normal cells, and consistent enrichment of docosahexaenoic acid (22:6) fatty acyl chain-containing BMP species in both human- and mouse-derived mammary tumorigenesis models. Our functional analysis points to a working model whereby 22:6 BMPs serve as reactive oxygen species scavengers in tumor cells, protecting lysosomes from oxidant-induced lysosomal membrane permeabilization. Our findings suggest that breast tumor cells might divert polyunsaturated fatty acids into BMP lipids as part of an adaptive response to protect their lysosomes from elevated reactive oxygen species levels, and raise the possibility that BMP-mediated lysosomal protection is a tumor-specific vulnerability that may be exploited therapeutically.

Spectrins: molecular organizers and targets of neurological disorders.

Spectrins are cytoskeletal proteins that are expressed ubiquitously in the mammalian nervous system. Pathogenic variants in SPTAN1, SPTBN1, SPTBN2 and SPTBN4, four of the six genes encoding neuronal spectrins, cause neurological disorders. Despite their structural similarity and shared role as molecular organizers at the cell membrane, spectrins vary in expression, subcellular localization and specialization in neurons, and this variation partly underlies non-overlapping disease presentations across spectrinopathies. Here, we summarize recent progress in discerning the local and long-range organization and diverse functions of neuronal spectrins. We provide an overview of functional studies using mouse models, which, together with growing human genetic and clinical data, are helping to illuminate the aetiology of neurological spectrinopathies. These approaches are all critical on the path to plausible therapeutic solutions.

Key Points for Pharmacists From the ACC Expert Consensus Decision Pathway for Patients Hospitalized With Heart Failure.

Heart failure (HF) is a complex condition, and its clinical course often includes periods of decompensation that represent a deterioration in clinical status. During these periods, patients may experience worsening HF symptoms requiring hospitalization. Heart failure that necessitates hospitalization increases the risk of mortality and rehospitalization. In order to help facilitate appropriate care of patients hospitalized with HF, the American College Cardiology (ACC) published an expert consensus decision pathway (ECDP) that focuses on a multidisciplinary approach. The ECDP is divided into multiple nodes and pharmacists play integral roles in each one. There are many opportunities for pharmacists to optimize medical therapy, reinforce adherence, and provide medication and disease state education throughout hospitalization. This review article will highlight inpatient medication management of HF for hospital pharmacists.

Pathogenetic role and clinical significance of interleukin-1ß in cancer.

In recent years, pro-oncogenic mechanisms of the tumour microenvironment (ТМЕ) have been actively discussed. One of the main cytokines of the TМЕ is interleukin-1 beta (IL-1ß), which exhibits proinflammatory properties. Some studies have shown an association between an increase in IL-1ß levels and tumour progression. The purpose of this review is to analyse the pathogenic mechanisms induced by IL-1ß in the TМЕ, as well as the diagnostic significance of the presence of IL-1ß in patients with cancer and the efficacy of treatment with IL-1ß inhibitors. According to the literature, IL-1ß can induce an increase in tumour angiogenesis due to its effects on the differentiation of epithelial cells, pro-angiogenic molecule secretion and expression of adhesion molecules, thus increasing tumour growth and metastasis. IL-1ß is also involved in the suppression of anti-tumour immune responses. The expression and secretion of IL-1ß has been noted in various types of tumours. In some clinical studies, an elevated level of IL-1ß was found to be associated with low efficacy of anti-cancer therapy and a poor prognosis. In most experimental and clinical studies, the use of IL-1ß inhibitors contributed to a decrease in tumour mass and an increase in the response to anti-tumour drugs.

Does fear reduction predict treatment response to exposure for social anxiety disorder?

BACKGROUND AND OBJECTIVES: Fear activation and reduction have traditionally been considered important mechanisms of exposure therapy. Evidence to date is mixed and impeded by inadequate methodology. This study examined the extent to which fear activation and reduction within and across exposures predicted treatment outcomes for social anxiety disorder within a paradigm suitable for their measurement. METHODS: Sixty-eight adults with social anxiety disorder and fear of public speaking completed seven exposure sessions, each consisting of seven speeches conducted in virtual reality. Exposures were identical in duration, task requirements, and virtual public speaking situation. Fear was measured with skin conductance and subjective distress ratings. At baseline and post-treatment, participants completed a public speaking behavioral approach test with a panel of confederate judges; subjective fear was measured. A standardized questionnaire of anxiety symptoms was administered at baseline, post-treatment, and one-month follow-up. RESULTS: No indices of within- or between-session fear reduction, measured by subjective distress and skin conductance response, predicted treatment outcome. One measure of fear activation was associated with outcomes such that less activation predicted greater symptom reduction; remaining indices did not predict outcomes. LIMITATIONS: Data were collected in the context of a randomized controlled trial of scopolamine; drug group was included in analytic models to account for drug influence. VR exposures elicited mild levels of distress that may underestimate levels of distress in clinical settings. CONCLUSIONS: Findings failed to support fear activation or reduction within or across exposure sessions as significant predictors of treatment outcome for social anxiety. Treatment implications are discussed.

The effect of modulation of gut microbiome profile on radiation-induced carcinogenesis and survival.

Non-lethal doses of ionizing radiation (IR) delivered to humans because of terrorist events, nuclear accidents or radiotherapy can result in carcinogenesis. Means of protecting against carcinogenesis are lacking. We questioned the role of the gut microbiome in IR-induced carcinogenesis. The gut microbiome was modulated by administering broad spectrum antibiotics (Ab) in the drinking water. Mice were given Ab 3 weeks before and 3 weeks after 3 Gy total body irradiation (TBI) or for 6 weeks one month after TBI. Three weeks of Ab treatment resulted in a 98% reduction in total 16S rRNA counts for 4 out of 6 of the phylum groups detected. However, 3 more weeks of Ab treatment (6 weeks total) saw an expansion in the phylum groups Proteobacteria and Actinobacteria. The Ab treatment altered the bacteria diversity in the gut, and shortened the lifespan when Ab were administered before and after TBI. Mortality studies indicated that the adverse Ab lifespan effects were due to a decrease in the time in which solid tumors started to appear and not to any changes in hematopoietic or benign tumors. In contrast, when Ab were administered one month after TBI, lifespan was unchanged compared to the control TBI group. Use of broad-spectrum antibiotics to simulate the germ-free condition did not afford an advantage on carcinogenesis or lifespan.