Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDA) is characterised by stromal desmoplasia and vascular dysfunction, which critically impair drug delivery. This study examines the role of an abundant extracellular matrix component, the megadalton glycosaminoglycan hyaluronan (HA), as a novel therapeutic target in PDA. METHODS: Using a genetically engineered mouse model of PDA, the authors enzymatically depleted HA by a clinically formulated PEGylated human recombinant PH20 hyaluronidase (PEGPH20) and examined tumour perfusion, vascular permeability and drug delivery. The preclinical utility of PEGPH20 in combination with gemcitabine was assessed by short-term and survival studies. RESULTS: PEGPH20 rapidly and sustainably depleted HA, inducing the re-expansion of PDA blood vessels and increasing the intratumoral delivery of two chemotherapeutic agents, doxorubicin and gemcitabine. Moreover, PEGPH20 triggered fenestrations and interendothelial junctional gaps in PDA tumour endothelia and promoted a tumour-specific increase in macromolecular permeability. Finally, combination therapy with PEGPH20 and gemcitabine led to inhibition of PDA tumour growth and prolonged survival over gemcitabine monotherapy, suggesting immediate clinical utility. CONCLUSIONS: The authors demonstrate that HA impedes the intratumoral vasculature in PDA and propose that its enzymatic depletion be explored as a means to improve drug delivery and response in patients with pancreatic cancer

Development of Functional Symptoms in Children Exposed to Traumatic Events

This chapter will review the typical symptoms occurring in children after stressful traumatic exposures. Unlike other chapters in this book, no specific organ system is the most likely focus of functional symptoms in this setting. Psychological distress may exacerbate symptoms of physical illness and injury associated with the traumatic events, may be expressed as almost any seemingly unrelated symptom, may intensify the age appropriate fears typical of any child, or may predominantly be exhibited behaviorally. In most nonsevere cases, the impact is self-limited and the individual’s functioning will be back to normal within days or weeks. We will suggest simple behavioral and environmental interventions intended to help relieve children’s distress. However, when large populations are affected and individuals suffer severe loss such as in a mass casualty disaster, the scale of events requires community-wide efforts to meet the needs of children and their families. The fact that some children are more psychosocially vulnerable than others will be discussed. The chapter will conclude by highlighting warning signs warranting professional mental health care

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Therapeutic genetic variation revealed in diverse Hsp104 homologs

The AAA+ protein disaggregase, Hsp104, increases fitness under stress by reversing stress-induced protein aggregation. Natural Hsp104 variants might exist with enhanced, selective activity against neurodegenerative disease substrates. However, natural Hsp104 variation remains largely unexplored. Here, we screened a cross-kingdom collection of Hsp104 homologs in yeast proteotoxicity models. Prokaryotic ClpG reduced TDP-43, FUS, and a-synuclein toxicity, whereas prokaryotic ClpB and hyperactive variants were ineffective. We uncovered therapeutic genetic variation among eukaryotic Hsp104 homologs that specifically antagonized TDP-43 condensation and toxicity in yeast and TDP-43 aggregation in human cells. We also uncovered distinct eukaryotic Hsp104 homologs that selectively antagonized a-synuclein condensation and toxicity in yeast and dopaminergic neurodegeneration in C. elegans. Surprisingly, this therapeutic variation did not manifest as enhanced disaggregase activity, but rather as increased passive inhibition of aggregation of specific substrates. By exploring natural tuning of this passive Hsp104 activity, we elucidated enhanced, substrate-specific agents that counter proteotoxicity underlying neurodegeneration

Automated Internet-based pain coping skills training to manage osteoarthritis pain

Osteoarthritis (OA) is a leading cause of disability in the United States and globally, [14; 39] and the burdens it causes are expected to increase as the world’s population ages [14; 23]. Non-pharmacological treatments are a recommended component of current guidelines for treating OA pain [53]. Although evidence is mixed that people benefit from non-pharmacological treatments such self-management interventions and patient education [e.g., 17; 25; 38; 45], one non-pharmacological therapy—pain coping skills training (PCST)—has demonstrated more consistently positive outcomes [38]. PCST focuses specifically on educating people about cognitive and behavioral pain coping skills and helping them master those skills so they can become more actively involved in managing their pain--the most common and debilitating OA symptom [33]. It includes two main components: 1) a rationale linking pain to patterns of cognitive, emotional, and behavioral pain responses, and 2) training in skills such as attention diversion (e.g., relaxation), cognitive restructuring (to address catastrophizing and other maladaptive cognitive patterns), and activity patterns (e.g., activity-rest cycling). It has traditionally been delivered in-person by a trained therapist over 10-12 weeks. Randomized controlled trials demonstrate that PCST significantly improves pain and other outcomes [e.g., 24; 29; 30; 31; 63]. Moreover, interventions such as PCST have fewer adverse effects than pharmacological pain treatments and are well-received by patients. Thus, research supports the efficacy of in-person PCST. However, access to this intervention is limited by barriers such as lack of trained therapists, the substantial resources needed to deliver it, and the need for people to travel to in-person training held at scheduled times [22; 59] There is a clear need for an approach that makes PCST more accessible. The Internet—a proven method for delivering behavioral interventions—provides an avenue for meeting this need [15; 42; 58; 65], especially given older adults’ increasing use of the Internet [69]. The present pilot study was a two-arm randomized controlled trial conducted to evaluate the potential efficacy and acceptability of an eight-week, automated, Internet-based version of PCST called PainCOACH. This program was designed to retain key therapeutic features of the in-person PCST protocol, simulating in-person PCST while presenting training in an easy-to-use format with guided instruction, individualized feedback, interactive exercises, and animated demonstrations [57]. We hypothesized that: (1) PainCOACH would reduce pain (primary outcome) and improve pain-related interference with functioning, pain-related anxiety, self-efficacy for pain management, and positive and negative affect; and (2) acceptability would be high. Our overarching goal was to use findings from this early-stage research to refine the program and study protocol in preparation for a larger-scale trial. Additionally, we explored sex differences in responses to PainCOACH, based on evidence in our own lab and others showing significant sex differences in pain, pain responses, pain behavior, and pain coping in people with OA [e.g., 1; 19; 27; 32; see 54; 62; 67]. The potential for men and women to respond differently to pain interventions is important but rarely evaluated in research