Cancer Evolution during Immunotherapy.

Immune checkpoint blockade has revolutionized cancer treatment. In this issue of Cell, insights from a longitudinal multi-omics analysis of the largest yet-reported cohort of melanoma patients reveal how tumor and immunity co-evolve during anti-PD-1 therapy.

Potential for large-scale CO2 removal via enhanced rock weathering with croplands.

Enhanced silicate rock weathering (ERW), deployable with croplands, has potential use for atmospheric carbon dioxide (CO2) removal (CDR), which is now necessary to mitigate anthropogenic climate change1. ERW also has possible co-benefits for improved food and soil security, and reduced ocean acidification2-4. Here we use an integrated performance modelling approach to make an initial techno-economic assessment for 2050, quantifying how CDR potential and costs vary among nations in relation to business-as-usual energy policies and policies consistent with limiting future warming to 2 degrees Celsius5. China, India, the USA and Brazil have great potential to help achieve average global CDR goals of 0.5 to 2 gigatonnes of carbon dioxide (CO2) per year with extraction costs of approximately US$80-180 per tonne of CO2. These goals and costs are robust, regardless of future energy policies. Deployment within existing croplands offers opportunities to align agriculture and climate policy. However, success will depend upon overcoming political and social inertia to develop regulatory and incentive frameworks. We discuss the challenges and opportunities of ERW deployment, including the potential for excess industrial silicate materials (basalt mine overburden, concrete, and iron and steel slag) to obviate the need for new mining, as well as uncertainties in soil weathering rates and land-ocean transfer of weathered products.

The nexus of immigration regulation and health governance: a scoping review of the extent to which right to access healthcare by migrants, refugees and asylum seekers was upheld in the United Kingdom during COVID-19.

OBJECTIVES: Complementing the well-established evidence base on health inequalities experienced by migrants, refugees and asylum seekers in the UK; we examined the extent to which their right to equal non-discriminatory access to health services (promotive, preventive, curative) was upheld during the COVID-19 pandemic. STUDY DESIGN: Arksey and O'Malley's scoping review framework. METHODS: A comprehensive search was conducted on Medline, PubMed, and CINAHL using detailed MESH terms, for literature published between 01 January 2020 and 01 January 2024. The process was supported by a ten-page Google search and hand searching of reference lists. 42 records meeting the inclusion criteria were charted, coded inductively and analysed thematically in an integrated team-based approach. RESULTS: Dissonance between immigration regulation and health governance is illustrated in four themes: Health systems leveraged to (re)enforce the hostile environment; Dissonance between health rights on paper and in practice; Structural failures to overcome communication and digital exclusion; and COVID-19 vaccine (in)equity exacerbated fear, mistrust and exclusion. Migrants, refugees and asylum seekers encountered substantial individual, structural and policy-level barriers to accessing healthcare in the UK during COVID-19. Insecure immigration status, institutional mistrust, data-sharing and charging fears, communication challenges and digital exclusion impacted heavily on their ability to access healthcare in an equitable non-discriminatory manner. CONCLUSIONS: An inclusive and innovative health equity and rights-based responses reaching all migrants, refugees and asylum seekers are warranted if the National Health Service is to live up to its promise of 'leaving no one behind' in post-pandemic and future responses.

Increased yield and CO2 sequestration potential with the C4 cereal Sorghum bicolor cultivated in basaltic rock dust-amended agricultural soil.

Land-based enhanced rock weathering (ERW) is a biogeochemical carbon dioxide removal (CDR) strategy aiming to accelerate natural geological processes of carbon sequestration through application of crushed silicate rocks, such as basalt, to croplands and forested landscapes. However, the efficacy of the approach when undertaken with basalt, and its potential co-benefits for agriculture, require experimental and field evaluation. Here we report that amending a UK clay-loam agricultural soil with a high loading (10 kg/m2 ) of relatively coarse-grained crushed basalt significantly increased the yield (21 ± 9.4%, SE) of the important C4 cereal Sorghum bicolor under controlled environmental conditions, without accumulation of potentially toxic trace elements in the seeds. Yield increases resulted from the basalt treatment after 120 days without P- and K-fertilizer addition. Shoot silicon concentrations also increased significantly (26 ± 5.4%, SE), with potential benefits for crop resistance to biotic and abiotic stress. Elemental budgets indicate substantial release of base cations important for inorganic carbon removal and their accumulation mainly in the soil exchangeable pools. Geochemical reactive transport modelling, constrained by elemental budgets, indicated CO2 sequestration rates of 2-4 t CO2 /ha, 1-5 years after a single application of basaltic rock dust, including via newly formed soil carbonate minerals whose long-term fate requires assessment through field trials. This represents an approximately fourfold increase in carbon capture compared to control plant-soil systems without basalt. Our results build support for ERW deployment as a CDR technique compatible with spreading basalt powder on acidic loamy soils common across millions of hectares of western European and North American agriculture.

Transplantation of mesenchymal stem cells genetically engineered to overexpress interleukin-10 promotes alternative inflammatory response in rat model of traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a major cause for long-term disability, yet the treatments available that improve outcomes after TBI limited. Neuroinflammatory responses are key contributors to determining patient outcomes after TBI. Transplantation of mesenchymal stem cells (MSCs), which release trophic and pro-repair cytokines, represents an effective strategy to reduce inflammation after TBI. One such pro-repair cytokine is interleukin-10 (IL-10), which reduces pro-inflammatory markers and trigger alternative inflammatory markers, such as CD163. In this study, we tested the therapeutic effects of MSCs that were engineered to overexpress IL-10 when transplanted into rats following TBI in the medial frontal cortex. METHODS: Thirty-six hours following TBI, rats were transplanted with MSCs and then assessed for 3 weeks on a battery of behavioral tests that measured motor and cognitive abilities. Histological evaluation was then done to measure the activation of the inflammatory response. Additionally, immunomodulatory effects were evaluated by immunohistochemistry and Western blot analyses. RESULTS: A significant improvement in fine motor function was observed in rats that received transplants of MSCs engineered to overexpress IL-10 (MSCs + IL-10) or MSCs alone compared to TBI + vehicle-treated rats. Although tissue spared was unchanged, anti-inflammatory effects were revealed by a reduction in the number of glial fibrillary acidic protein cells and CD86 cells in both TBI + MSCs + IL-10 and TBI + MSC groups compared to TBI + vehicle rats. Microglial activation was significantly increased in the TBI + MSC group when compared to the sham + vehicle group. Western blot data suggested a reduction in tumor necrosis factor-alpha in the TBI + MSCs + IL-10 group compared to TBI + MSC group. Immunomodulatory effects were demonstrated by a shift from classical inflammation expression (CD86) to an alternative inflammation state (CD163) in both treatments with MSCs and MSCs + IL-10. Furthermore, co-labeling of both CD86 and CD163 was detected in the same cells, suggesting a temporal change in macrophage expression. CONCLUSIONS: Overall, our findings suggest that transplantation of MSCs that were engineered to overexpress IL-10 can improve functional outcomes by providing a beneficial perilesion environment. This improvement may be explained by the shifting of macrophage expression to a more pro-repair state, thereby providing a possible new therapy for treating TBI.

Modulation of the carboxamidine redox potential through photoinduced spiropyran or fulgimide isomerisation.

Carboxamidines functionalized with either a spiropyran or fulgimide photoswitch were prepared on multigram scales. The thermal, electrochemical, and photochemical ring isomerizations of these compounds were studied and the results compared with related systems. The photochemical isomerisations were found to be reversible and could be followed by 1H NMR and UV-vis spectroscopy. The spiropyran/merocyanine couple was thermally active and an activation enthalpy of 116 kJ mol-1 was measured for ring-opening. These measurements yielded an enthalpy difference of 25 kJ mol-1 between the open and closed states which is consistent with DFT calculations. DFT calculations predicted a charge transfer to the carboxamidine group upon ring closure in the fulgimide and a charge transfer from the carboxamidine group upon switching the spiropyran to the merocyanine form. This was confirmed experimentally by monitoring the change in the oxidation potential assigned to the carboxamidine group. The potential of these molecules to therefore act as a new class of photoresponsive ligands that can modulate the ligand field of a complex is discussed.

Expression of genes associated with inflammation and iron metabolism in 3T3-L1 cells induced with macrophages-conditioned medium, glucose and iron.

Obesity is characterized by a chronic inflammatory process, with an increased volume of total adipose tissue, especially visceral, which secretes pro-inflammatory cytokines such as TNF-α and IL-6. Hepcidin (Hpc), a main iron metabolism regulator, is synthetized by an IL-6 stimuli, among others, in liver and adipose tissue, favoring an association between the inflammatory process and iron metabolism. Still there are questions remain regarding the interaction of these factors. Our aim was to study the effect of a macrophage-conditioned medium (MCM) on adipocyte cells challenged with glucose and/or iron. We studied the mRNA relative abundance of genes related to inflammation in differentiated 3T3-L1 cells challenged with Fe (40 µM), glucose (20 mM) or Fe/glucose (40 µM/20 mM) with or without MCM for 24 h. We also measured the intracellular iron levels under these conditions. Our results showed that when adipocytes were challenged with MCM, glucose and/or Fe, the intracellular iron and mRNA levels of pro-inflammatory cytokines increased. These responses were higher when all the stimuli were combined with MCM from macrophages. Thus, we showed that combined high glucose/high Fe alone or with MCM may contribute to an increase on intracellular iron and inflammatory response in 3T3-L1 differentiated cells, by increased mRNA levels of IL-6, TNF-α, MCP-1, Hpc and reducing adiponectin levels, enhancing the inflammatory processes.

Opportunity for interprofessional collaborative care-findings from a sample of federally qualified health center patients in the Midwest.

OBJECTIVES: Federally qualified health centers (FQHCs) frequently serve more socio-economically disadvantaged populations; existing literature suggests that underserved groups are more likely to experience various chronic physical and mental health conditions. FQHC patients may have significant needs for various specialty services that are beyond common FQHC providers. This study examines chronic condition prevalence, healthcare satisfaction, and use of multiprovider services in a Midwest FQHC patient population. We also evaluated the potential of interprofessional collaborative practices in FQHC settings. STUDY DESIGN: Cross-sectional study. METHODS: A total of 232 participants were recruited prior to or immediately after their scheduled clinic visit within an FQHC located on the fringes of an urban area. Respondents were invited to complete a brief questionnaire and grant access to their electronic medical records. RESULTS: Nearly half of participants were covered by Medicaid, private insurance carriers (19.4%), or Medicare (17.7%). The most prevalent chronic conditions included diabetes, depression, anxiety, and chronic pain. Almost half (46.6%) of participants were seen by two or three providers; 20% had 7+ office visits in the last year. While 35.3% reported health dissatisfaction, 30.6% reported health satisfaction. When asked if they were satisfied with their health care, nearly 70% reported satisfaction with health care, while only 4.7% reported healthcare dissatisfaction. CONCLUSIONS: The authors of this study recommend an interprofessional collaborate healthcare model be explored to address the complex and multifaceted healthcare needs of this population. Future research in this area should prospectively examine the utility of monitoring patient satisfaction in a collaborative practice setting.

Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy.

BACKGROUND: Recent phase III clinical trials have established the superiority of the anti-PD-1 antibodies pembrolizumab and nivolumab over the anti-CTLA-4 antibody ipilimumab in the first-line treatment of patients with advanced melanoma. Ipilimumab will be considered for second-line treatment after the failure of anti-PD-1 therapy. METHODS: We retrospectively identified a cohort of 40 patients with metastatic melanoma who received single-agent anti-PD-1 therapy with pembrolizumab or nivolumab and were treated on progression with ipilimumab at a dose of 3 mg kg(-1) for a maximum of four doses. RESULTS: Ten percent of patients achieved an objective response to ipilimumab, and an additional 8% experienced prolonged (>6 months) stable disease. Thirty-five percent of patients developed grade 3-5 immune-related toxicity associated with ipilimumab therapy. The most common high-grade immune-related toxicity was diarrhoea. Three patients (7%) developed grade 3-5 pneumonitis leading to death in one patient. CONCLUSIONS: Ipilimumab therapy can induce responses in patients who fail the anti-PD-1 therapy with response rates comparable to previous reports. There appears to be an increased frequency of high-grade immune-related adverse events including pneumonitis that warrants close surveillance.

First Measurement of Electron Neutrino Appearance in NOvA.

We report results from the first search for ν_{µ}→ν_{e} transitions by the NOvA experiment. In an exposure equivalent to 2.74×10^{20} protons on target in the upgraded NuMI beam at Fermilab, we observe 6 events in the Far Detector, compared to a background expectation of 0.99±0.11(syst) events based on the Near Detector measurement. A secondary analysis observes 11 events with a background of 1.07±0.14(syst). The 3.3σ excess of events observed in the primary analysis disfavors 0.1π<δ_{CP}<0.5π in the inverted mass hierarchy at the 90% C.L.

Non-HIV-associated Kaposi sarcoma in an immunosuppressed melanoma patient treated with dabrafenib.

WHAT IS KNOWN AND OBJECTIVE: Cutaneous toxicities are commonly seen with BRAF inhibitors, frequently involving painful hyperkeratosis of the feet. We illustrate an unexpected diagnosis of extensive bilateral pedal Kaposi sarcoma masquerading as BRAF inhibitor-related toxicity in a patient treated with dabrafenib for metastatic melanoma. CASE SUMMARY: A HIV-negative, non-diabetic, Italian man with a history of myasthenia gravis and metastatic melanoma presented with enlarging macular/plaque-like rash on his feet preceded by bilateral plantar shooting pains. The rash progressed in the context of acute-on-chronic immunosuppression and was initially thought due to commencement of the BRAF inhibitor (BRAFi) dabrafenib. Histopathological findings from skin biopsies revealed Kaposi sarcoma. The patient was continued on dabrafenib and received superficial radiotherapy to the feet with prompt relief of pain. WHAT IS NEW AND CONCLUSION: This case illustrates the diagnostic pitfalls in patients treated with targeted therapies and highlights the importance of broad differentials for unusual presentations and early biopsy.

Response to MAPK pathway inhibitors in BRAF V600M-mutated metastatic melanoma.

WHAT IS KNOWN AND OBJECTIVE: The management of metastatic melanoma has changed significantly in the past decade with the development of immunotherapies and targeted molecular therapies. Trials of targeted therapies have focused mainly on patients with the most common BRAF V600 mutations, namely V600E/K substitutions, with very little information available on the benefit of targeted therapies on less commonly occurring mutations such as V600R/D and M. CASE SUMMARY: We present a 54-year-old man with metastatic melanoma harbouring a rare BRAF V600M mutation, who experienced clinical and radiological response to combined therapy with the BRAF inhibitor dabrafenib and MEK inhibitor trametinib. WHAT IS NEW AND CONCLUSION: As our understanding of these therapies evolves and an increasing number of patients have mutational testing performed, there is a clear imperative--as highlighted by this case--to test for rarer mutations and facilitate their inclusion both in everyday practice and in future clinical trials.

Rapid temperature-dependent wound closure following adipose fin clipping of Atlantic salmon Salmo salar L.

Three groups of Atlantic salmon were kept at a constant temperature of 4, 10 and 14 °C. The adipose fins were removed; six fish/group were sampled at 11 subsequent time points post-clipping. Samples were prepared for histopathological examination to study the course of re-epithelization. A score sheet was developed to assess the regeneration of epidermal and dermal cell types. Wounds were covered by a thin epidermal layer between 4 and 6 h post-clipping at 10 and 14 °C. In contrast, wound closure was completed between 6 and 12 h in fish held at a constant temperature of 4 °C. By 18 h post-clipping, superficial cells, cuboidal cells, prismatic basal cells and mucous cells were discernible in all temperature groups, rapidly progressing towards normal epidermal structure and thickness. Within the observation period, only minor regeneration was found in the dermal layers. A positive correlation between water temperature and healing rates was established for the epidermis. The rapid wound closure rate, epidermal normalization and the absence of inflammatory reaction signs suggest that adipose fin clipping under anaesthesia constitutes a minimally invasive method that may be used to mark large numbers of salmon presmolts without compromising fish welfare.

Community health coalitions in context: associations between geographic context, member type and length of membership with coalition functions.

The coalition literature recognizes context (geography, demographics and history) as a variable of interest, yet few coalition evaluation studies have focused on it. This study explores the association between geographic context and structures (e.g. member type) with functional characteristics (e.g. decision making or levels of conflict) in a statewide system of community health councils (coalitions). The study was part of a multiyear, statewide evaluation of New Mexico's health councils' contributions to systems-level changes. We adapted the Coalition Self-Assessment Survey (CSAS) for all county health council members and paid council coordinators. Both multilevel univariate and multivariate procedures were used to compare index scores, summaries of CSAS questions used to characterize council functions, with selected demographic variables and region. Member type was associated with decision making and policy capacity; paid staff expressed higher levels of agreement than voting members for both items. Length of membership was associated with decision making, positive leadership and shared vision. Results indicated that geographic context was significantly associated with many functional characteristics. The study highlights the idea that geographic context may influence coalition functioning. Understanding how geographic context influences coalition planning and actions may help explain differences among coalitions that on the surface share common organizational characteristics and external goals.

Auditory network connectivity in tinnitus patients: a resting-state fMRI study.

OBJECTIVE: Resting-state functional magnetic resonance imaging (fMRI) uncovers correlated activity between spatially distinct functionally related brain regions and offers clues about the integrity of functional brain circuits in people with chronic subjective tinnitus. We chose to investigate auditory network connectivity, adopting and extending previously used analyses methods to provide an independent evaluation of replicability. DESIGN: Independent components analysis (ICA) was used to identify coherent patterns arising from spontaneous brain signals within the resting-state data. The auditory network component was extracted and evaluated. Bivariate and partial correlation analyses were performed on pre-defined regions of bilateral auditory cortex to assess functional connectivity. STUDY SAMPLE: Our design carefully matched participant groups for possible confounds, such as hearing status. Twelve patients (seven male, five female; mean age 66 years) all with chronic constant tinnitus and eleven controls (eight male, three female; mean age 68 years) took part. RESULTS: No significant differences were found in auditory network connectivity between groups after correcting for multiple statistical comparisons in the analysis. This contradicts previous findings reporting reduced auditory network connectivity; albeit at a less stringent statistical threshold. CONCLUSIONS: Auditory network connectivity does not appear to be reliably altered by the experience of chronic subjective tinnitus.

Metal bioaccumulation and effects of olivine sand exposure on benthic marine invertebrates.

Due to the anthropogenic increase of atmospheric CO2 emissions, humanity is facing the negative effects of rapid global climate change. Both active emission reduction and carbon dioxide removal (CDR) technologies are needed to meet the Paris Agreement and limit global warming to 1.5 °C by 2050. One promising CDR approach is coastal enhanced weathering (CEW), which involves the placement of sand composed of (ultra)mafic minerals like olivine in coastal zones. Although the large-scale placement of olivine sand could beneficially impact the planet through the consumption of atmospheric CO2 and reduction in ocean acidification, it may also have physical and geochemical impacts on benthic communities. The dissolution of olivine can release dissolved constituents such as trace metals that may affect marine organisms. Here we tested acute and chronic responses of marine invertebrates to olivine sand exposure, as well as examined metal accumulation in invertebrate tissue resulting from olivine dissolution. Two different ecotoxicological experiments were performed on a range of benthic marine invertebrates (amphipod, polychaete, bivalve). The first experiment included acute and chronic survival and growth tests (10 and 20 days, respectively) of olivine exposure while the second had longer (28 day) exposures to measure chronic survival and bioaccumulation of trace metals (e.g. Ni, Cr, Co) released during olivine sand dissolution. Across all fauna we observed no negative effects on acute survival or chronic growth resulting solely from olivine exposure. However, over 28 days of exposure, the bent-nosed clam Macoma nasuta experienced reduced burrowing and accumulated 4.2 ± 0.7 µg g ww-1 of Ni while the polychaete Alitta virens accumulated 3.5 ± 0.9 µg g ww-1 of Ni. No significant accumulation of any other metals was observed. Future work should include longer-term laboratory studies as well as CEW field studies to validate these findings under real-world scenarios.

BMP receptor-activated Smads confer diverse functions during the development of the dorsal spinal cord.

Bone Morphogenetic Proteins (BMPs) have multiple activities in the developing spinal cord: they specify the identity of the dorsal-most neuronal populations and then direct the trajectories of dorsal interneuron (dI) 1 commissural axons. How are these activities decoded by dorsal neurons to result in different cellular outcomes? Our previous studies have shown that the diverse functions of the BMPs are mediated by the canonical family of BMP receptors and then regulated by specific inhibitory (I) Smads, which block the activity of a complex of Smad second messengers. However, the extent to which this complex translates the different activities of the BMPs in the spinal cord has remained unresolved. Here, we demonstrate that the receptor-activated (R) Smads, Smad1 and Smad5 play distinct roles mediating the abilities of the BMPs to direct cell fate specification and axon outgrowth. Smad1 and Smad5 occupy spatially distinct compartments within the spinal cord, with Smad5 primarily associated with neural progenitors and Smad1 with differentiated neurons. Consistent with this expression profile, loss of function experiments in mouse embryos reveal that Smad5 is required for the acquisition of dorsal spinal neuron identities whereas Smad1 is critical for the regulation of dI1 axon outgrowth. Thus the R-Smads, like the I-Smads, have discrete roles mediating BMP-dependent cellular processes during spinal interneuron development.