Targeting B-Raf inhibitor resistant melanoma with novel cell penetrating peptide disrupters of PDE8A – C-Raf

Background: Recent advances in the treatment of melanoma that involve immunotherapy and B-Raf inhibition have revolutionised cancer care for this disease. However, an un-met clinical need remains in B-Raf inhibitor resistant patients where first-generation B-Raf inhibitors provide only short-term disease control. In these cases, B-Raf inhibition leads to paradoxical activation of the C-Raf – MEK – ERK signalling pathway, followed by metastasis. PDE8A has been shown to directly interact with and modulate the cAMP microdomain in the vicinity of C-Raf. This interaction promotes C-Raf activation by attenuating the PKA-mediated inhibitory phosphorylation of the kinase. Methods: We have used a novel cell-penetrating peptide agent (PPL-008) that inhibits the PDE8A – C-Raf complex in a human malignant MM415 melanoma cell line and MM415 melanoma xenograft mouse model to investigate ERK MAP kinase signalling. Results: We have demonstrated that the PDE8A – C-Raf complex disruptor PPL-008 increased inhibitory C-Raf-S259 phosphorylation and significantly reduced phospho-ERK signalling. We have also discovered that the ability of PPL-008 to dampen ERK signalling can be used to counter B-Raf inhibitor-driven paradoxical activation of phospho-ERK in MM415 cells treated with PLX4032 (Vemurafenib). PPL-008 treatment also significantly retarded the growth of these cells. When applied to a MM415 melanoma xenograft mouse model, PPL-008C penetrated tumour tissue and significantly reduced phospho-ERK signalling in that domain. Conclusion: Our data suggests that the PDE8A-C-Raf complex is a promising therapeutic treatment for B-Raf inhibitor resistant melanoma

Trajectory shifts in the Arctic and Subarctic freshwater cycle

Author Posting. © The Author(s), 2006. This is the author's version of the work. It is posted here by permission of American Association for the Advancement of Science for personal use, not for redistribution. The definitive version was published in Science 313 (2006): 1061-1066, doi:10.1126/science.1122593.Manifold changes in the freshwater cycle of high-latitude lands and oceans have been reported in the past few years. A synthesis of these changes in sources of freshwater and in ocean freshwater storage illustrates the complementary and synoptic temporal pattern and magnitude of these changes over the past 50 years. Increasing river discharge anomalies and excess net precipitation on the ocean contributed ~20,000 km3 of fresh water to the Arctic and high latitude North Atlantic oceans from lows in the 1960s to highs in the 1990s. Sea ice attrition provided another ~15,000 km3, and glacial melt added ~2000 km3. The sum of anomalous inputs from these freshwater sources matched the amount and rate at which fresh water accumulated in the North Atlantic during much of the period from 1965 through 1995. The changes in freshwater inputs and ocean storage occurred in conjunction with the amplifying North Atlantic Oscillation and rising air temperatures. Fresh water may now be accumulating in the Arctic Ocean and will likely be exported southward if and when the North Atlantic Oscillation enters into a new high phase.Funding was provided by NSF (grants OPP-0229302, OPP- 0436118, OPP-0327664, OPP-0352754, OPP-0519840, OCE- 0326778), ONR (grant N00014-02-1-0305) and NASA (grant IDS-03-0000-0145)

Interleukin-6, age, and corpus callosum integrity.

The contribution of inflammation to deleterious aging outcomes is increasingly recognized; however, little is known about the complex relationship between interleukin-6 (IL-6) and brain structure, or how this association might change with increasing age. We examined the association between IL-6, white matter integrity, and cognition in 151 community dwelling older adults, and tested whether age moderated these associations. Blood levels of IL-6 and vascular risk (e.g., homocysteine), as well as health history information, were collected. Processing speed assessments were administered to assess cognitive functioning, and we employed tract-based spatial statistics to examine whole brain white matter and regions of interest. Given the association between inflammation, vascular risk, and corpus callosum (CC) integrity, fractional anisotropy (FA) of the genu, body, and splenium represented our primary dependent variables. Whole brain analysis revealed an inverse association between IL-6 and CC fractional anisotropy. Subsequent ROI linear regression and ridge regression analyses indicated that the magnitude of this effect increased with age; thus, older individuals with higher IL-6 levels displayed lower white matter integrity. Finally, higher IL-6 levels were related to worse processing speed; this association was moderated by age, and was not fully accounted for by CC volume. This study highlights that at older ages, the association between higher IL-6 levels and lower white matter integrity is more pronounced; furthermore, it underscores the important, albeit burgeoning role of inflammatory processes in cognitive aging trajectories

Diagnosing ventilator-associated pneumonia (VAP) in UK NHS ICUs:the perceived value and role of a novel optical technology

BACKGROUND: Diagnosing ventilator-associated pneumonia (VAP) in an intensive care unit (ICU) is a complex process. Our aim was to collect, evaluate and represent the information relating to current clinical practice for the diagnosis of VAP in UK NHS ICUs, and to explore the potential value and role of a novel diagnostic for VAP, which uses optical molecular alveoscopy to visualise the alveolar space. METHODS: Qualitative study performing semi-structured interviews with clinical experts. Interviews were recorded, transcribed, and thematically analysed. A flow diagram of the VAP patient pathway was elicited and validated with the expert interviewees. Fourteen clinicians were interviewed from a range of UK NHS hospitals: 12 ICU consultants, 1 professor of respiratory medicine and 1 professor of critical care. RESULTS: Five themes were identified, relating to [1] current practice for the diagnosis of VAP, [2] current clinical need in VAP diagnostics, [3] the potential value and role of the technology, [4] the barriers to adoption and [5] the evidence requirements for the technology, to help facilitate a successful adoption. These themes indicated that diagnosis of VAP is extremely difficult, as is the decision to stop antibiotic treatment. The analysis revealed that there is a clinical need for a diagnostic that provides an accurate and timely diagnosis of the causative pathogen, without the long delays associated with return of culture results, and which is not dangerous to the patient. It was determined that the technology would satisfy important aspects of this clinical need for diagnosing VAP (and pneumonia, more generally), but would require further evidence on safety and efficacy in the patient population to facilitate adoption. CONCLUSIONS: Care pathway analysis performed in this study was deemed accurate and representative of current practice for diagnosing VAP in a UK ICU as determined by relevant clinical experts, and explored the value and role of a novel diagnostic, which uses optical technology, and could streamline the diagnostic pathway for VAP and other pneumonias. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41512-022-00117-x

The STAR care pathway for patients with pain at 3 months after total knee replacement:a multicentre, pragmatic randomised controlled trial

BACKGROUND: Approximately 20% of people experience chronic pain after total knee replacement, but effective treatments are not available. We aimed to evaluate the clinical effectiveness and cost-effectiveness of a new care pathway for chronic pain after total knee replacement. METHODS: We did an unmasked, parallel group, pragmatic, superiority, randomised, controlled trial at eight UK National Health Service (NHS) hospitals. People with chronic pain at 3 months after total knee replacement surgery were randomly assigned (2:1) to the Support and Treatment After Replacement (STAR) care pathway plus usual care, or to usual care alone. The STAR intervention aimed to identify underlying causes of chronic pain and enable onward referrals for targeted treatment through a 3-month post-surgery assessment with an extended scope practitioner and telephone follow-up over 12 months. Co-primary outcomes were self-reported pain severity and pain interference in the replaced knee, assessed with the Brief Pain Inventory (BPI) pain severity and interference scales at 12 months (scored 0–10, best to worst) and analysed on an as-randomised basis. Resource use, collected from electronic hospital records and participants, was valued with UK reference costs. Quality-adjusted life-years (QALYs) were calculated from EQ-5D-5L responses. This trial is registered with ISRCTN, ISRCTN92545361. FINDINGS: Between Sept 6, 2016, and May 31, 2019, 363 participants were randomly assigned to receive the intervention plus usual care (n=242) or to receive usual care alone (n=121). Participants had a median age of 67 years (IQR 61 to 73), 217 (60%) of 363 were female, and 335 (92%) were White. 313 (86%) patients provided follow-up data at 12 months after randomisation (213 assigned to the intervention plus usual care and 100 assigned to usual care alone). At 12 months, the mean between-group difference in the BPI severity score was −0·65 (95% CI −1·17 to −0·13; p=0·014) and the mean between-group difference in the BPI interference score was −0·68 (−1·29 to −0·08; p=0·026), both favouring the intervention. From an NHS and personal social services perspective, the intervention was cost-effective (greater improvement with lower cost), with an incremental net monetary benefit of £1256 (95% CI 164 to 2348) at £20 000 per QALY threshold. One adverse reaction of participant distress was reported in the intervention group. INTERPRETATION: STAR is a clinically effective and cost-effective intervention to improve pain outcomes over 1 year for people with chronic pain at 3 months after total knee replacement surgery. FUNDING: National Institute for Health Research

Lability of DOC transported by Alaskan rivers to the Arctic Ocean

Author Posting. © American Geophysical Union, 2008. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geophysical Research Letters 35 (2008): L03402, doi:10.1029/2007GL032837.Arctic rivers transport huge quantities of dissolved organic carbon (DOC) to the Arctic Ocean. The prevailing paradigm is that DOC in arctic rivers is refractory and therefore of little significance for the biogeochemistry of the Arctic Ocean. We show that there is substantial seasonal variability in the lability of DOC transported by Alaskan rivers to the Arctic Ocean: little DOC is lost during incubations of samples collected during summer, but substantial losses (20–40%) occur during incubations of samples collected during the spring freshet when the majority of the annual DOC flux occurs. We speculate that restricting sampling to summer may have biased past studies. If so, then fluvial inputs of DOC to the Arctic Ocean may have a much larger influence on coastal ocean biogeochemistry than previously realized, and reconsideration of the role of terrigenous DOC on carbon, microbial, and food-web dynamics on the arctic shelf will be warranted.This material is based on work supported by the National Science Foundation under grant numbers OPP-0436106, OPP- 0519840, and EAR-0403962, and is a contribution to the Study of Environmental Arctic Change (SEARCH)

Hubble Space Telescope WFC3 Early Release Science: Emission-Line Galaxies from Infrared Grism Observations

We present grism spectra of emission-line galaxies (ELGs) from 0.6-1.6 microns from the Wide Field Camera 3 on the Hubble Space Telescope. These new infrared grism data augment previous optical Advanced Camera for Surveys G800L 0.6-0.95 micron grism data in GOODS-South from the PEARS program, extending the wavelength covereage well past the G800L red cutoff. The ERS grism field was observed at a depth of 2 orbits per grism, yielding spectra of hundreds of faint objects, a subset of which are presented here. ELGs are studied via the Ha, [OIII], and [OII] emission lines detected in the redshift ranges 0.2<z<1.4, 1.2<z<2.2 and 2.0<z<3.3 respectively in the G102 (0.8-1.1 microns; R~210) and G141 (1.1-1.6 microns; R~130) grisms. The higher spectral resolution afforded by the WFC3 grisms also reveals emission lines not detectable with the G800L grism (e.g., [SII] and [SIII] lines). From these relatively shallow observations, line luminosities, star-formation rates, and grism spectroscopic redshifts are determined for a total of 48 ELGs to m(AB)~25 mag. Seventeen GOODS-South galaxies that previously only had photometric redshifts now have new grism-spectroscopic redshifts, in some cases with large corrections to the photometric redshifts (Delta(z)~0.3-0.5). Additionally, one galaxy had no previously-measured redshift but now has a secure grism-spectroscopic redshift, for a total of 18 new GOODS-South spectroscopic redshifts. The faintest source in our sample has a magnitude m(AB)=26.9 mag. The ERS grism data also reflect the expected trend of lower specific star formation rates for the highest mass galaxies in the sample as a function of redshift, consistent with downsizing and discovered previously from large surveys. These results demonstrate the remarkable efficiency and capability of the WFC3 NIR grisms for measuring galaxy properties to faint magnitudes and redshifts to z>2.Comment: Accepted for publication in AJ. Updated to include referee comments. Updated sample using improved reduction contains 23 new galaxies (Table 1; Figures 2 & 3

Better post-operative prediction and management of chronic pain in adults after total knee replacement:the multidisciplinary STAR research programme including RCT

Background: The treatment of osteoarthritis with knee replacement aims to reduce pain and disability. However, some people experience chronic pain. Objectives: To improve outcomes for people with chronic pain after knee replacement by identifying post-surgical predictors and effective interventions, characterising patient pathways and resource use, developing and evaluating a new care pathway, and exploring non-use of services. Design: The programme comprised systematic reviews, national database analyses, a cohort study, intervention development, a randomised controlled trial, health economic analyses, qualitative studies and stakeholder engagement. Extensive and meaningful patient and public involvement underpinned all studies. Setting: NHS, secondary care, primary care. Participants: People with, or at risk of, chronic pain after knee replacement and health-care professionals involved in the care of people with pain. Interventions: A care pathway for the management of people with pain at 3 months after knee replacement. Main outcome measures: Patient-reported outcomes and cost-effectiveness over 12 months. Data sources: Literature databases, the National Joint Registry, Hospital Episode Statistics, patient- reported outcomes, the Clinical Practice Research Datalink, the Clinical Outcomes in Arthroplasty Study, the Support and Treatment After joint Replacement randomised trial, interviews with 90 patients and 14 health-care professionals, and stakeholder events. Review methods: Systematic reviews of cohort studies or randomised trials, using meta-analysis or narrative synthesis. Results: In the Clinical Outcomes in Arthroplasty Study cohort, 14% of people experienced chronic pain 1 year after knee replacement. By 5 years, 65% reported no pain, 31% fluctuated and 4% remained in chronic pain. People with chronic pain had a worse quality of life, higher primary care costs, and more frequent analgesia prescriptions, particularly for opioids, than those not in chronic pain. People with chronic pain after knee replacement who made little or no use of services often felt nothing more could be done, or that further treatments may have no benefit or cause harm. People described a feeling of disconnection from their replaced knee. Analysis of UK databases identified risk factors for chronic pain after knee replacement. Pre- operative predictors were mild knee pain, smoking, deprivation, body mass index between 35 and 40 kg/m2 and knee arthroscopy. Peri- and post-operative predictors were mechanical complications, infection, readmission, revision, extended hospital stay, manipulation under anaesthetic and use of opioids or antidepressants. In systematic reviews, pre-operative exercise and education showed no benefit in relation to chronic pain. Peri-operative interventions that merit further research were identified. Common peri- operative treatments were not associated with chronic pain. There was no strong evidence favouring specific post-operative physiotherapy content. We evaluated the Support and Treatment After joint Replacement care pathway in a multicentre randomised controlled trial. We randomised 363 people with pain at 3 months after knee replacement from eight NHS Trusts in England and Wales. At 12 months’ follow-up, the intervention group had lower mean pain severity (adjusted difference –0.65, 95% confidence interval –1.17 to -0.13; p = 0.014) and pain interference (adjusted difference –0.68, 95% confidence interval –1.29 to -0.08; p = 0.026), as measured on the Brief Pain Inventory subscales (scale 0–10). People receiving the Support and Treatment After joint Replacement pathway had lower NHS and Personal Social Services costs (–£724, 95% confidence interval –£150 to £51) and higher quality-adjusted life-years (0.03, 95% confidence interval –0.008 to 0.06) than those with usual care. The Support and Treatment After joint Replacement pathway was cost-effective with an incremental net monetary benefit at the £20,000 per quality-adjusted life-year threshold of £1256 (95% confidence interval £164 to £2348), indicating a 98.79% probability that the intervention is the cost-effective option. Participants found the Support and Treatment After joint Replacement pathway acceptable, with opportunities to receive information and discuss concerns while ensuring further treatment and support. In systematic reviews considering treatments for chronic pain after surgery we identified some unifactorial interventions that merit further research after knee replacement. Health-care professionals delivering and implementing the Support and Treatment After joint Replacement pathway valued its focus on neuropathic pain and psychosocial issues, enhanced patient care, formalised referrals, and improved pain management. Stakeholders supported pathway implementation. Limitations: Database analyses were limited to factors recorded in data sets. Pain was only measured 6 months after surgery. However, analyses including large numbers of centres and patients should be generalisable across the NHS. In many studies found in systematic reviews, long-term pain was not a key outcome. Conclusions: The Support and Treatment After joint Replacement pathway is a clinically effective and cost-effective, acceptable intervention for the management of chronic pain after knee replacement. Unifactorial interventions merit further study before inclusion in patient care. People with pain should be empowered to seek health care, with the support of health-care professionals. Future work: Future work should include research relating to the implementation of the Support and Treatment After joint Replacement pathway into the NHS, an assessment of its long-term clinical effectiveness and cost-effectiveness and wider application, and an evaluation of new interventions for incorporation in the pathway. It will also be important to design and conduct research to improve communication between patients and health-care professionals before surgery; explore whether or not education and support can enable earlier recognition of chronic pain; consider research that may identify how to support people’s feelings of disconnectedness from their new knee; and design and evaluate a pre-surgical intervention based on risk factors. Study registration: All systematic reviews were registered on PROSPERO (CRD42015015957, CRD42016041374 and CRD42017041382). The Support and Treatment After joint Replacement randomised trial was registered as ISRCTN92545361. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 11, No. 3. See the NIHR Journals Library website for further project information