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It is widely documented that practicum students experience anxiety as a natural part of their counselor development. Within constructivist supervision, mindfulness exercises are used to help counselors-in-training (CITs) work with their anxiety by having them focus on their internal experiences. To inform and strengthen our practice, we engaged in a practitioner inquiry study to understand how practicum students experienced mindfulness as a central part of supervision. We analyzed 25 sandtray reflections and compared them to transcripts from two focus groups to uncover three major themes related to the student experience: (1) openness to the process; (2) reflection and self-care; and (3) attention to the doing. One key lesson learned was the importance of balancing mindfulness exercises to highlight the internal experiences related to anxiety while providing adequate opportunities for CITs to share stories and hear from peers during group supervision.

Immune-checkpoint inhibitors (ICI), although revolutionary in improving long-term survival outcomes, are mostly effective in patients with immune-responsive tumors. Most patients with cancer either do not respond to ICIs at all or experience disease progression after an initial period of response. Treatment resistance to ICIs remains a major challenge and defines the biggest unmet medical need in oncology worldwide. In a collaborative workshop, thought leaders from academic, biopharma, and nonprofit sectors convened to outline a resistance framework to support and guide future immune-resistance research. Here, we explore the initial part of our effort by collating seminal discoveries through the lens of known biological processes. We highlight eight biological processes and refer to them as immune resistance nodes. We examine the seminal discoveries that define each immune resistance node and pose critical questions, which, if answered, would greatly expand our notion of immune resistance. Ultimately, the expansion and application of this work calls for the integration of multiomic high-dimensional analyses from patient-level data to produce a map of resistance phenotypes that can be utilized to guide effective drug development and improved patient outcomes.

Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3+ Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8+/Granz B+ T cells homeostasis are observed in tumor regions where FOXP3+ Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.

ImportanceUse of prognostic gene expression profile (GEP) testing in cutaneous melanoma (CM) is rising despite a lack of endorsement as standard of care.ObjectiveTo develop guidelines within the national Melanoma Prevention Working Group (MPWG) on integration of GEP testing into the management of patients with CM, including (1) review of published data using GEP tests, (2) definition of acceptable performance criteria, (3) current recommendations for use of GEP testing in clinical practice, and (4) considerations for future studies.Evidence reviewThe MPWG members and other international melanoma specialists participated in 2 online surveys and then convened a summit meeting. Published data and meeting abstracts from 2015 to 2019 were reviewed.FindingsThe MPWG members are optimistic about the future use of prognostic GEP testing to improve risk stratification and enhance clinical decision-making but acknowledge that current utility is limited by test performance in patients with stage I disease. Published studies of GEP testing have not evaluated results in the context of all relevant clinicopathologic factors or as predictors of regional nodal metastasis to replace sentinel lymph node biopsy (SLNB). The performance of GEP tests has generally been reported for small groups of patients representing particular tumor stages or in aggregate form, such that stage-specific performance cannot be ascertained, and without survival outcomes compared with data from the American Joint Committee on Cancer 8th edition melanoma staging system international database. There are significant challenges to performing clinical trials incorporating GEP testing with SLNB and adjuvant therapy. The MPWG members favor conducting retrospective studies that evaluate multiple GEP testing platforms on fully annotated archived samples before embarking on costly prospective studies and recommend avoiding routine use of GEP testing to direct patient management until prospective studies support their clinical utility.Conclusions and relevanceMore evidence is needed to support using GEP testing to inform recommendations regarding SLNB, intensity of follow-up or imaging surveillance, and postoperative adjuvant therapy. The MPWG recommends further research to assess the validity and clinical applicability of existing and emerging GEP tests. Decisions on performing GEP testing and patient management based on these results should only be made in the context of discussion of testing limitations with the patient or within a multidisciplinary group.

Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1-10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11-15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.

Many risk genes for the development of Alzheimer's disease (AD) are exclusively or highly expressed in myeloid cells. Microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival. We designed and synthesized a highly selective brain-penetrant CSF1R inhibitor (PLX5622) allowing for extended and specific microglial elimination, preceding and during pathology development. We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia. Instead, Aβ deposits in cortical blood vessels reminiscent of cerebral amyloid angiopathy. Altered gene expression in the 5xFAD hippocampus is also reversed by the absence of microglia. Transcriptional analyses of the residual plaque-forming microglia show they exhibit a disease-associated microglia profile. Collectively, we describe the structure, formulation, and efficacy of PLX5622, which allows for sustained microglial depletion and identify roles of microglia in initiating plaque pathogenesis.

Less than 24 hours after police murdered George Floyd, Black Lives Matter protesters organized in several cities to demand that their elected officials defund their police and redirect this funding to better healthcare, schools, public transportation, affordable housing, and food security. Eventually, these protesters came together in rural communities and towns to push for similar demands. Journalists documented these protests, highlighting both the similarities and differences in these places and protests. This article directly addresses the oversights and stereotypes that many of these articles promoted through a careful analysis of the experiences of two rural youth--a Black, Puerto Rican young woman and a Black, Dominican young man--as the Black Lives Matter protests unfolded in their predominantly white small town. In doing so, this study illustrates the threat of visibility that rural youth experience and how this threat shaped their decision to participate or not participate in the protests.

The association among pathological response, recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma remains unclear. In this study, we pooled data from six clinical trials of anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy (104, combination of ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted therapy. A pathological complete response (pCR) occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR 50%, P < 0.001) and OS (pCR 2-year OS 95% versus no pCR 83%, P = 0.027). In patients with pCR, near pCR or partial pathological response with immunotherapy, very few relapses were seen (2-year RFS 96%), and, at this writing, no patient has died from melanoma, whereas, even with pCR from targeted therapy, the 2-year RFS was only 79%, and OS was only 91%. Pathological response should be an early surrogate endpoint for clinical trials and a new benchmark for development and approval in melanoma. A pooled analysis of neoadjuvant immunotherapy trials in melanoma shows that the degree of pathological response associates with patient survival and might represent a surrogate marker for long-term outcomes., Author(s): Alexander M. Menzies [sup.1] [sup.2] [sup.3] , Rodabe N. Amaria [sup.4] , Elisa A. Rozeman [sup.5] , Alexander C. Huang [sup.6] [sup.7] , Michael T. Tetzlaff [sup.4] , Bart [...]

UnlabelledTyrosine kinase domain mutations are a common cause of acquired clinical resistance to tyrosine kinase inhibitors (TKI) used to treat cancer, including the FLT3 inhibitor quizartinib. Mutation of kinase "gatekeeper" residues, which control access to an allosteric pocket adjacent to the ATP-binding site, has been frequently implicated in TKI resistance. The molecular underpinnings of gatekeeper mutation-mediated resistance are incompletely understood. We report the first cocrystal structure of FLT3 with the TKI quizartinib, which demonstrates that quizartinib binding relies on essential edge-to-face aromatic interactions with the gatekeeper F691 residue, and F830 within the highly conserved Asp-Phe-Gly motif in the activation loop. This reliance makes quizartinib critically vulnerable to gatekeeper and activation loop substitutions while minimizing the impact of mutations elsewhere. Moreover, we identify PLX3397, a novel FLT3 inhibitor that retains activity against the F691L mutant due to a binding mode that depends less vitally on specific interactions with the gatekeeper position.SignificanceWe report the first cocrystal structure of FLT3 with a kinase inhibitor, elucidating the structural mechanism of resistance due to the gatekeeper F691L mutation. PLX3397 is a novel FLT3 inhibitor with in vitro activity against this mutation but is vulnerable to kinase domain mutations in the FLT3 activation loop.

BRAF is the most prevalent oncogene and an important therapeutic target in melanoma. In some cancers, BRAF is activated by rearrangements that fuse its kinase domain to 5' partner genes. We examined 848 comparative genomic hybridization profiles of melanocytic tumors and found copy number transitions within BRAF in 10 tumors, of which six could be further characterized by sequencing. In all, the BRAF kinase domain was fused in-frame to six N-terminal partners. No other mutations were identified in melanoma oncogenes. One of the seven melanoma cell lines without known oncogenic mutations harbored a similar BRAF fusion, which constitutively activated the MAP kinase pathway. Sorafenib, but not vemurafenib, could block MAP kinase pathway activation and proliferation of the cell line at clinically relevant concentrations, whereas BRAF(V) (600E) mutant melanoma cell lines were significantly more sensitive to vemurafenib. The patient from whom the cell line was derived showed a durable clinical response to sorafenib.

This research roadmap reviews existing and developing technologies for the use of carbon dioxide to provide recommendations to the California Energy Commission on the further development and implementation of such technologies. The roadmap reviews and categorizes the known usage technologies currently in use or under development. Uses of carbon dioxide range from well‐developed applications, such as enhanced oil recovery, to much less mature technologies, such as the use of carbon dioxide to produce fine chemicals, chemical feedstocks, working fluids for energy‐related technologies, and building materials.  This roadmap outlines various attributes of technologies such as technology maturity and readiness, the amount of carbon dioxide that would be consumed or used if fully deployed, technology gaps and barriers to full deployment, and the companies or organizations pursuing development of the technologies. This information is then used to highlight technological advances that are needed to overcome existing barriers to deployment. The report also reviews funding from federal sources and examines the potential for California to leverage synergistic federal funding to promote investment in and deployment of usage technologies within the state. This report also discusses the relevance of carbon dioxide usage technologies to California’s greenhouse gas reduction goals.

We have developed a roadmap of CO2 utilization technologies for the California Energy Commission, a state government energy research, policy and permitting agency. The objective of the roadmap is to identify technologies that can make significant contributions to the state's 2020 and 2050 greenhouse gas (CHG) reduction goals. The state of California, under Assembly Bill 32, is committed to achieving reductions to 1990 GHG inventory levels by 2020 and, under Governor's Executive Order S-3-05, to 80 percent below those levels by 2050. The roadmap will guide future R&D investment and policy development for enabling carbon utilization technologies in California.For the purposes of the roadmap, we defined utilization as including technologies that produce a useful product from anthropogenic CO2, or through the processes of capture or sequestration of CO2. Technologies may contribute to reductions directly by permanently sequestering CO2, or indirectly by displacing the use of fossil fuels or more potent GHGs, such as CFCs. Technologies considered include: CO2 as a working fluid (including enhanced oil recovery (EOR), enhanced gas recovery (EGR), and enhanced geothermal systems (EGS)), chemical feedstocks, biofuels, building materials, compressed gas energy storage, cushion gas for natural gas storage, and water and marketable minerals produced from displaced sequestration reservoir fluids.Evaluation criteria include technological maturity, potential market size, purity of CO2 required, commercialization time frame, environmental impacts, water use, data on energy-carbon life cycle analysis, and potential local economic benefits such as job creation. In addition, we evaluated the potential impact of non-technical barriers to commercial- scale adoption, such as the need for clear accounting protocols to provide incentives for CO2 producers to adopt these technologies to meet carbon standards.It may be possible to integrate different utilization approaches. For example, CO2 can be reduced to produce methanol or formic acid, which can be converted into fuels. Other processes to functionalize the carbon atom produce saleable chemicals, such as urea. By combining these two approaches, synthesis of even more chemicals directly from CO2 could be achieved.Widespread deployment of CO2 utilization technologies also depends on integration into planning of a future carbon- energy infrastructure. While single projects for some technologies, such as EOR, may create a demand comparable to the CO2 volumes generated by large sources, other technologies may have to be aggregated and/or combined with geologic sequestration to provide the volume of sequestration required. Deployment networks provide opportunities for cost optimization of pipeline infrastructure and for focusing public or private investment to facilitate commercialization.Currently in California, utilization projects are in the research, pilot, or permitting stages, including projects to combine urea production and EOR, produce high carbon-content building materials, and develop chemical and biological CO2 recycling technologies. None of these projects have yet reached the development stage necessary to demonstrate whether the technologies can contribute effectively to reducing California's CHG emissions.

While California has been at the forefront in adopting an aggressive climate change mitigation policy, it has taken a more measured and tentative approach toward creating an enabling policy and a regulatory framework for carbon capture, utilization and sequestration (CCUS) technologies to contribute to greenhouse gas (GHG) reductions. In 2005, Governor's Executive Order S-3-05 required that California reduce GHG emissions to 1990 levels by 2020 and to 80% below 1990 levels by 2050. In 2006, State Assembly Bill 32 codified the 2020 goal into law. In 2006, the California Legislature required two California agencies, the California Energy Commission and the Department of Conservation, to produce a report recommending how the state could facilitate commercial adoption of geologic sequestration from industrial sources. In 2010, three state agencies, the Energy Commission, Public Utilities Commission, and Air Resources Board, convened the California Carbon Capture and Storage Review Panel to make recommendations on specific policy, institutional, and regulatory changes necessary for California to enable commercial-scale carbon capture and geologic storage projects. Since 2006, several legislative bills have been introduced to establish regulatory authority, liability, and address pore space ownership issues, but none have made it into law.To meet the state's aggressive targets, especially to 2050 goal, will nevertheless require widespread adoption of CCUS technologies, according to studies by the California Council on Science and Technology. California contributes 7.5% of the total GHG emissions in the USA, or 1.8% of global GHG emissions. Over half of this currently is from point sources, but that proportion will increase as the state pursues electrification of the transportation sector. Trajectories of future GHG emissions growth suggest mitigation technologies must be implemented at rates on the order of 10–20 million tonnes of GHGs removed per year.The cap-and-trade system recently adopted in California to address the GHG reduction mandates of Assembly Bill 32 would seem to encourage pursuit CCUS technology projects by industrial emitters, but uncertainties preclude developing viable business cases. Uncertainty includes a lack of data on the costs of capture and storage and the lack of cap-and-trade accounting protocols for CCUS technologies. Although these protocols are scheduled to be developed, they will lag the initialization of cap-and-trade in 2012.

Carbon capture, utilization, and storage (CCUS) is an important technology for greenhouse gas reduction worldwide, and it may be a critical component to enable California to meet its greenhouse gas emissions reduction goals. CCUS is a suite of different types of technologies used to capture carbon dioxide emissions from power plants or large industrial point sources and use this captured carbon dioxide for various purposes including storage, and injecting in rock formations deep underground. Technologies for measuring and monitoring carbon dioxide in the subsurface or in surface facilities also are part of this suite. Because of the complexity and diversity of CCUS technologies, there are numerous challenges to its deployment. The elements to undertaking a CCUS project include both technical and nontechnical—reducing the risks associated with these elements are essential to assuring CCUS is an effective and economic mitigation technology. The greatest risks are associated with the subsurface; thus, proper site characterization and monitoring are important to project success. This report reviews the findings from projects and activities in California, North America and worldwide and addresses the key questions California policy makers must answer to facilitate CCUS deployment effectively.

DRAFT Final contract report prepared by CIEE for the California Energy Commission; contribution to WESTCARB Phase II. The West Coast Regional Carbon Sequestration Partnership (WESTCARB) is one of seven partnerships that have been established by the U.S. Department of Energy (DOE) to evaluate carbon capture and sequestration (CCS) technologies best suited for different regions of the country. The West Coast Region comprises Arizona, California, Hawaii, Nevada, Oregon,Washington, Alaska, and British Columbia. Both terrestrial and geologic sequestration potential has been evaluated in the Region during Phase II of the project. A centralized Geographic Information System (GIS) database of stationary sources and geologic and terrestrial sink data was enhanced, incorporating relevant project data.

This roadmap reviews existing and developing technologies for the utilization of CO2 in order to provide recommendations to the California Energy Commission on the further development and implementation of such technologies. The roadmap reviews and categorizes the knownutilization technologies currently in use or under development. Uses of CO2 range from well-developed applications, such as enhanced oil recovery, to much less mature technologies such as the use of CO2 to produce fine chemicals, chemical feed stocks, working fluids for energy-related technologies, and building materials. This roadmap outlines attributes of technologies such as technology maturity and readiness, the amount of CO2 that would be consumed or utilized if fully deployed, technology gaps and barriers to full deployment, and the companies or organizations pursuing development of the technologies. This information is then used as a reference to highlight technological advances that are required to overcome these barriers to deployment. It also reviews funding from federal sources and examines the potential for California toleverage synergistic federal funding to facilitateinvestment in and deployment of utilization technologies within the state. This report also discusses the relevance of CO2 utilization technologies to California’s greenhouse gas reduction goals.

B-RAF is the most frequently mutated protein kinase in human cancers. The finding that oncogenic mutations in BRAF are common in melanoma, followed by the demonstration that these tumours are dependent on the RAF/MEK/ERK pathway, offered hope that inhibition of B-RAF kinase activity could benefit melanoma patients. Herein, we describe the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic B-RAF kinase activity. Preclinical experiments demonstrated that PLX4032 selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells and caused regression of BRAF mutant xenografts. Toxicology studies confirmed a wide safety margin consistent with the high degree of selectivity, enabling Phase 1 clinical trials using a crystalline formulation of PLX4032 (ref. 5). In a subset of melanoma patients, pathway inhibition was monitored in paired biopsy specimens collected before treatment initiation and following two weeks of treatment. This analysis revealed substantial inhibition of ERK phosphorylation, yet clinical evaluation did not show tumour regressions. At higher drug exposures afforded by a new amorphous drug formulation, greater than 80% inhibition of ERK phosphorylation in the tumours of patients correlated with clinical response. Indeed, the Phase 1 clinical data revealed a remarkably high 81% response rate in metastatic melanoma patients treated at an oral dose of 960 mg twice daily. These data demonstrate that BRAF-mutant melanomas are highly dependent on B-RAF kinase activity.

Hyperspectral plant signatures can be used as a short-term, as well as long-term (100-year timescale) monitoring technique to verify that CO2 sequestration fields have not been compromised. An influx of CO2 gas into the soil can stress vegetation, which causes changes in the visible to near-infrared reflectance spectral signature of the vegetation. For 29 days, beginning on July 9, 2008, pure carbon dioxide gas was released through a 100-m long horizontal injection well, at a flow rate of 300 kg day−1. Spectral signatures were recorded almost daily from an unmown patch of plants over the injection with a “FieldSpec Pro” spectrometer by Analytical Spectral Devices, Inc. Measurements were taken both inside and outside of the CO2 leak zone to normalize observations for other environmental factors affecting the plants. Four to five days after the injection began, stress was observed in the spectral signatures of plants within 1 m of the well. After approximately 10 days, moderate to high amounts of stress were measured out to 2.5 m from the well. This spatial distribution corresponded to areas of high CO2 flux from the injection. Airborne hyperspectral imagery, acquired by Resonon, Inc. of Bozeman, MT using their hyperspectral camera, also showed the same pattern of plant stress. Spectral signatures of the plants were also compared to the CO2 concentrations in the soil, which indicated that the lower limit of soil CO2 needed to stress vegetation is between 4 and 8% by volume.