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A RESPONSE TO DAVID BLANKFEIN-TABACHNICK & KEVIN A. KORDANA, ON RAWLSIAN CONTRACTUALISM AND THE PRIVATE LAW
In their 2022 essay, David Blankfein-Tabachnick and Kevin Kordana reaffirm and further develop their long-standing position that John Rawls's principles of justice, including the difference principle, should apply to determine and interpret private law, including not just property and contract law, but also torts. In recent papers, Samuel Scheffler and I have made similar arguments, though we have modestly departed from their views. I contend that, while the difference principle applies to much of the private law of property and contract, it does not apply to all tort law. Rather, in tort law, the difference principle applies primarily to economic torts in unjust economic systems that do not satisfy Rawls's difference principle in the first place. Blankfein-Tabachnick and Kordana (hereinafter \"the Authors\") contest my argument, as well as my contention that Rawls's difference principle requires maximizing the position of society's less advantaged relative to the more advantaged, not their absolute position. After a brief summary of my position, I discuss why I believe the difference principle, under Rawls's final interpretation of it, is often not suitable for consistent application in determining personal tort liability and remedies, even though the principle can play a significant role in economic torts involving the violation of economic rights and liberties. I also discuss why the difference principle is best understood to require society to maximize the relative, not absolute, position of the least advantaged. I conclude with some remarks on Rawls's own reservations regarding courts' interpretation and enforcement of the difference principle, or any principle that structures the economy, including economic efficiency and utilitarian wealth maximization.
Journal Article
محاضرات في تاريخ الفلسفة السياسية
هذا الكتاب مجموعة من المحاضرات التي ألقاها جون رولز في أثناء تدريسه في جامعة هارفرد، طوال ثلاثة عقود، اهتم فيها بالفلسفة السياسية الحديثة، وسعى فيها إلى تحديد السمات الأساسية لليبرالية بصفتها تعبر عن مفهوم سياسي للعدالة حين ينظر إلى الليبرالية بمنظار تقاليد الدستورية الديمقراطية، متناولا أصحاب نظرية العقد الاجتماعي هوبز ولوك وروسو، ومفكرو الفلسفة النفعية هيوم ومل. أما ماركس فرأى فيه رولز ناقدا لليبرالية، يتألف هذا الكتاب (640 صفحة بالقطع الوسط، موثقا ومفهرسا) من ستة أقسام، تضم تسعة عشر فصلا، إضافة إلى ملاحق تضم خمس محاضرات عن جوزف بتلر : \"التكوين الخلقي للطبيعة البشرية\"، و\"طبيعة الضمير وسلطته\"، و\"اقتصاد العواطف\"، و\"حجة بتلر ضد الأنوية\"، و\"التضارب المفترض بين الضمير وحب الذات\"
BOOK
Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors
Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing.
Identifying the mutational landscape of tumours from cell-free DNA in the blood could help diagnostics in cancer. Here, the authors present ichorCNA, software that quantifies tumour content in cell free DNA, and they demonstrate that cell-free DNA whole-exome sequencing is concordant with metastatic tumour whole-exome sequencing.
Journal Article
Landscape of helper and regulatory antitumour CD4+ T cells in melanoma
Within the tumour microenvironment, CD4
+
T cells can promote or suppress antitumour responses through the recognition of antigens presented by human leukocyte antigen (HLA) class II molecules
1
,
2
, but how cancers co-opt these physiologic processes to achieve immune evasion remains incompletely understood. Here we performed in-depth analysis of the phenotype and tumour specificity of CD4
+
T cells infiltrating human melanoma specimens, finding that exhausted cytotoxic CD4
+
T cells could be directly induced by melanoma cells through recognition of HLA class II-restricted neoantigens, and also HLA class I-restricted tumour-associated antigens. CD4
+
T regulatory (T
Reg
) cells could be indirectly elicited through presentation of tumour antigens via antigen-presenting cells. Notably, numerous tumour-reactive CD4
+
T
Reg
clones were stimulated directly by HLA class II-positive melanoma and demonstrated specificity for melanoma neoantigens. This phenomenon was observed in the presence of an extremely high tumour neoantigen load, which we confirmed to be associated with HLA class II positivity through the analysis of 116 melanoma specimens. Our data reveal the landscape of infiltrating CD4
+
T cells in melanoma and point to the presentation of HLA class II-restricted neoantigens and direct engagement of immunosuppressive CD4
+
T
Reg
cells as a mechanism of immune evasion that is favoured in HLA class II-positive melanoma.
A survey of the CD4
+
T cells in human melanomas indicates that immune evasion is mediated through direct stimulation of neoantigen-specific tumour-reactive regulatory T cells by HLA class II-positive melanoma cells.
Journal Article
In vivo CRISPR screens reveal the landscape of immune evasion pathways across cancer
The immune system can eliminate tumors, but checkpoints enable immune escape. Here, we identify immune evasion mechanisms using genome-scale in vivo CRISPR screens across cancer models treated with immune checkpoint blockade (ICB). We identify immune evasion genes and important immune inhibitory checkpoints conserved across cancers, including the non-classical major histocompatibility complex class I (MHC class I) molecule Qa-1b/HLA-E. Surprisingly, loss of tumor interferon-γ (IFNγ) signaling sensitizes many models to immunity. The immune inhibitory effects of tumor IFN sensing are mediated through two mechanisms. First, tumor upregulation of classical MHC class I inhibits natural killer cells. Second, IFN-induced expression of Qa-1b inhibits CD8+ T cells via the NKG2A/CD94 receptor, which is induced by ICB. Finally, we show that strong IFN signatures are associated with poor response to ICB in individuals with renal cell carcinoma or melanoma. This study reveals that IFN-mediated upregulation of classical and non-classical MHC class I inhibitory checkpoints can facilitate immune escape.Here, the authors use genome-scale in vivo CRISPR screens to look at immune evasion mechanisms across cancer models, showing that IFN-mediated upregulation of classical and non-classical MHC class I inhibitory checkpoints facilitate immune escape.
Journal Article
Facilitators and barriers to vaccination uptake in pregnancy: A qualitative systematic review
Vaccination during pregnancy protects both the mother and the foetus from vaccine-preventable diseases. However, uptake of the recommended vaccines (influenza, pertussis, COVID-19) by pregnant women remains low in Europe and the USA. Understanding the reasons for this is crucial to inform strategies to increase vaccination rates in pregnant women. This qualitative systematic review aimed to identify the barriers and facilitators to vaccination against influenza, pertussis/whooping cough and COVID-19 during pregnancy and identify possible strategies to increase vaccination rates.
We conducted a comprehensive search of electronic databases, including Medline, PsycINFO, CINAHL, Web of Science, WHO database, Embase and grey literature to identify qualitative studies that explored barriers and facilitators to vaccine uptake among pregnant women (PROSPERO CRD42023399488). The search was limited to studies published between 2012 and 2022 conducted in high-income countries with established vaccination programmes during pregnancy. Studies were thematically analysed and underwent quality assessment using the Joanna Briggs Institute validated critical appraisal tool for qualitative research.
Out of 2681 articles screened, 28 studies (n = 1573 participants) were eligible for inclusion. Five overarching themes emerged relating to personal, provider and systemic factors. Barriers to vaccine uptake included concerns about vaccine safety and efficacy, lack of knowledge about vaccines' benefits and necessity, fear of adverse effects on the foetus or mother and low perception of disease severity. Facilitators included recommendations from trusted healthcare providers, easy access to vaccination, clear communication on the benefits and safety of vaccination, and positive social influences from family and friends. Strategies for increasing vaccination uptake included strong and proactive vaccine recommendations by trusted healthcare professionals, provision of vaccines during routine antenatal care, and clear and consistent communication about vaccines addressing pregnant women's concerns.
This review highlights the need for interventions that address the identified barriers to vaccine uptake among pregnant women. Recommendation from a healthcare provider can play a significant role in promoting vaccine uptake, as can clear risk/benefit communication and convenient access to vaccination. Addressing concerns about vaccine safety and providing accurate information about vaccines is also important.
Journal Article
Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor–directed therapies
Seventy percent of breast cancers express the estrogen receptor (ER), and agents that target the ER are the mainstay of treatment. However, virtually all people with ER
+
breast cancer develop resistance to ER-directed agents in the metastatic setting. Beyond mutations in the ER itself, which occur in 25–30% of people treated with aromatase inhibitors
1
–
4
, knowledge about clinical resistance mechanisms remains incomplete. We identified activating HER2 mutations in metastatic biopsies from eight patients with ER
+
metastatic breast cancer who had developed resistance to aromatase inhibitors, tamoxifen or fulvestrant. Examination of treatment-naive primary tumors in five patients showed no evidence of pre-existing mutations in four of five patients, suggesting that these mutations were acquired under the selective pressure of ER-directed therapy. The HER2 mutations and ER mutations were mutually exclusive, suggesting a distinct mechanism of acquired resistance to ER-directed therapies. In vitro analysis confirmed that the HER2 mutations conferred estrogen independence as well as—in contrast to ER mutations—resistance to tamoxifen, fulvestrant and the CDK4 and CDK6 inhibitor palbociclib. Resistance was overcome by combining ER-directed therapy with the irreversible HER2 kinase inhibitor neratinib.
Activating HER2 mutations are shown to confer resistance to ER-directed therapies in patients with ER
+
metastatic breast cancer. Drug resistance caused by HER2 mutations was overcome by combining ER-directed therapy with a HER2 kinase inhibitor.
Journal Article
Human lung cancer harbors spatially organized stem-immunity hubs associated with response to immunotherapy
The organization of immune cells in human tumors is not well understood. Immunogenic tumors harbor spatially localized multicellular ‘immunity hubs’ defined by expression of the T cell-attracting chemokines
CXCL10/CXCL11
and abundant T cells. Here, we examined immunity hubs in human pre-immunotherapy lung cancer specimens and found an association with beneficial response to PD-1 blockade. Critically, we discovered the stem-immunity hub, a subtype of immunity hub strongly associated with favorable PD-1-blockade outcome. This hub is distinct from mature tertiary lymphoid structures and is enriched for stem-like TCF7
+
PD-1
+
CD8
+
T cells, activated
CCR7
+
LAMP3
+
dendritic cells and
CCL19
+
fibroblasts as well as chemokines that organize these cells. Within the stem-immunity hub, we find preferential interactions between
CXCL10
+
macrophages and
TCF7
−
CD8
+
T cells as well as between mature regulatory dendritic cells and
TCF7
+
CD4
+
and regulatory T cells. These results provide a picture of the spatial organization of the human intratumoral immune response and its relevance to patient immunotherapy outcomes.
The spatial organization of cells in solid tumors is considered to be important for immune response and response to therapy. Here the authors use multiomics including spatial transcriptomics of human lung tumors prior to patients being treated and show among other things an association of stem-immunity hubs rich in stem-like CD8
+
T cells with positive response to anti-PD-1 therapy.
Journal Article
Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer
Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example,
ATM
altered) and unfavorable (for example,
TERT
amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together, results from this cohort demonstrate the complexity of biological determinants underlying immunotherapy outcomes and reinforce the discovery potential of integrative analysis within large, well-curated, cancer-specific cohorts.
Genomic and transcriptomic analysis of 393 non-small cell lung cancer patients treated with checkpoint inhibitors identifies molecular features associated with response.
Journal Article