Large-scale genetic analysis of lethal phenotypes has elucidated the molecular underpinnings of many biological processes. Using the bacterial clustered regularly interspaced short palindromic ...repeats (CRISPR) system, we constructed a genome-wide single-guide RNA library to screen for genes required for proliferation and survival in a human cancer cell line. Our screen revealed the set of cell-essential genes, which was validated with an orthogonal gene-trap–based screen and comparison with yeast gene knockouts. This set is enriched for genes that encode components of fundamental pathways, are expressed at high levels, and contain few inactivating polymorphisms in the human population. We also uncovered a large group of uncharacterized genes involved in RNA processing, a number of whose products localize to the nucleolus. Last, screens in additional cell lines showed a high degree of overlap in gene essentiality but also revealed differences specific to each cell line and cancer type that reflect the developmental origin, oncogenic drivers, paralogous gene expression pattern, and chromosomal structure of each line. These results demonstrate the power of CRISPR-based screens and suggest a general strategy for identifying liabilities in cancer cells.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
Thyroid hormone (TH) signaling plays an important role in the regulation of long-wavelength vision in vertebrates. In the retina, thyroid hormone receptor β (thrb) is required for expression of ...long-wavelength-sensitive opsin (lws) in red cone photoreceptors, while in retinal pigment epithelium (RPE), TH regulates expression of a cytochrome P450 enzyme, cyp27c1, that converts vitamin A₁ into vitamin A₂ to produce a red-shifted chromophore. To better understand how TH controls these processes, we analyzed the phenotype of zebrafish with mutations in the three known TH nuclear receptor transcription factors (thraa, thrab, and thrb). We found that no single TH nuclear receptor is required for TH-mediated induction of cyp27c1 but that deletion of all three (thraa
−/−;thrab
−/−;thrb
−/−) completely abrogates its induction and the resulting conversion of A₁- to A₂-based retinoids. In the retina, loss of thrb resulted in an absence of red cones at both larval and adult stages without disruption of the underlying cone mosaic. RNA-sequencing analysis revealed significant down-regulation of only five genes in adult thrb
−/− retina, of which three (lws1, lws2, and miR-726) occur in a single syntenic cluster. In the thrb
−/− retina, retinal progenitors destined to become red cones were transfated into ultraviolet (UV) cones and horizontal cells. Taken together, our findings demonstrate cooperative regulation of cyp27c1 by TH receptors and a requirement for thrb in red cone fate determination. Thus, TH signaling coordinately regulates both spectral sensitivity and sensory plasticity.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The dramatic success of tyrosine kinase inhibitors (TKIs) has led to the widespread perception that chronic myeloid leukemia (CML) has become another chronic disease, where lifelong commitment to ...pharmacologic control is the paradigm. Recent trials demonstrate that some CML patients who have achieved stable deep molecular response can safely cease their therapy without relapsing (treatment free remission TFR). Furthermore, those who are unsuccessful in their cessation attempt can safely re-establish remission after restarting their TKI therapy. Based on the accumulated data on TFR, we propose that it is now time to change our approach for the many CML patients who have achieved a stable deep molecular response on long-term TKI therapy. Perhaps half of these patients could successfully achieve TFR if offered the opportunity. For many of these patients ongoing therapy is impairing quality of life and imposing a heavy financial burden while arguably achieving nothing. This recommendation is based on the evident safety of cessation attempts and TFR in the clinical trial setting. We acknowledge that there are potential risks associated with cessation attempts in wider clinical practice, but this should not deter us. Instead we need to establish criteria for safe and appropriate TKI cessation. Clinical trials will enable us to define the best strategies to achieve TFR, but clinicians need guidance today about how to approach this issue with their patients. We outline circumstances in which it would be in the patient's best interest to continue TKI, as well as criteria for a safe TFR attempt.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A phase 2, multicenter study showed that four doses of neoadjuvant cemiplimab (anti–PD-1 antibody) led to a pathological complete response in 51% of patients with locally advanced cutaneous ...squamous-cell carcinoma.
Abstract
Objectives
To compare a Bayesian clinical decision support (CDS) dose-optimizing software program with clinician judgement in individualizing vancomycin dosing regimens to achieve vancomycin ...pharmacokinetic (PK)/pharmacodynamic (PD) targets in a paediatric population.
Methods
A retrospective review combined with a model-based simulation of vancomycin dosing was performed on children aged 1 year to 18 years at the University of California, San Francisco Benioff Children’s Hospital Mission Bay. Dosing regimens recommended by the clinical pharmacists, ‘clinician-guided’, were compared with alternative ‘CDS-guided’ dosing regimens. The primary outcome was the percentage of occasions predicted to achieve steady-state trough levels within the target range of 10–15 mg/L, with a secondary outcome of predicted attainment of AUC24 ≥400 mg·h/L. Statistical comparison between approaches was performed using a standard t-test.
Results
A total of n=144 patient occasions were included. CDS-guided regimens were predicted to achieve vancomycin steady-state troughs in the target range on 70.8% (102/144) of occasions, as compared with 37.5% (54/144) in the clinician-guided arm (P<0.0001). An AUC24 of ≥400 mg·h/L was achieved on 93% (112/121) of occasions in the CDS-guided arm versus 72% (87/121) of occasions in the clinician-guided arm (P<0.0001).
Conclusions
In a simulated analysis, the use of a Bayesian CDS tool was better than clinician judgement in recommending vancomycin dosing regimens in which PK/PD targets would be attained in children.
Chronic myeloid leukaemia (CML) is driven by the activity of the BCR-ABL1 fusion oncoprotein. ABL1 kinase inhibitors have improved the clinical outcomes for patients with CML, with over 80% of ...patients treated with imatinib surviving for more than 10 years. Second-generation ABL1 kinase inhibitors induce more potent molecular responses in both previously untreated and imatinib-resistant patients with CML. Studies in patients with chronic-phase CML have shown that around 50% of patients who achieve and maintain undetectable BCR-ABL1 transcript levels for at least 2 years remain disease-free after the withdrawal of treatment. Here we characterize ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph
) acute lymphoblastic leukaemia. In contrast to catalytic-site ABL1 kinase inhibitors, ABL001 binds to the myristoyl pocket of ABL1 and induces the formation of an inactive kinase conformation. ABL001 and second-generation catalytic inhibitors have similar cellular potencies but distinct patterns of resistance mutations, with genetic barcoding studies revealing pre-existing clonal populations with no shared resistance between ABL001 and the catalytic inhibitor nilotinib. Consistent with this profile, acquired resistance was observed with single-agent therapy in mice; however, the combination of ABL001 and nilotinib led to complete disease control and eradicated CML xenograft tumours without recurrence after the cessation of treatment.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
The genetic dependencies of human cancers widely vary. Here, we catalog this heterogeneity and use it to identify functional gene interactions and genotype-dependent liabilities in cancer. By using ...genome-wide CRISPR-based screens, we generate a gene essentiality dataset across 14 human acute myeloid leukemia (AML) cell lines. Sets of genes with correlated patterns of essentiality across the lines reveal new gene relationships, the essential substrates of enzymes, and the molecular functions of uncharacterized proteins. Comparisons of differentially essential genes between Ras-dependent and -independent lines uncover synthetic lethal partners of oncogenic Ras. Screens in both human AML and engineered mouse pro-B cells converge on a surprisingly small number of genes in the Ras processing and MAPK pathways and pinpoint PREX1 as an AML-specific activator of MAPK signaling. Our findings suggest general strategies for defining mammalian gene networks and synthetic lethal interactions by exploiting the natural genetic and epigenetic diversity of human cancer cells.
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•CRISPR-based screens identify essential genes in 14 human AML cell lines•Analysis of correlated gene essentiality reveals functional gene networks•Two independent approaches uncover a restricted set of Ras synthetic lethal interactions•PREX1 and the Rac pathway are critical regulators of MAPK pathway activation
Charting global genetic interaction networks in human cells with CRISPR-based screens uncovers key Ras interactors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The aims of this systematic review and meta-analysis were to: (1) describe the prevalence of commonly reported comorbidities in psoriatic arthritis (PsA), (2) compare the incidence and/or prevalence ...of comorbidities between PsA and control populations; and (3) examine the impact of comorbidities on PsA outcomes. We systematically searched Medline, PubMed, Scopus, and Web of Science using a predefined protocol in accordance with PRISMA guidelines. Studies reporting only one comorbidity, or a few closely related diseases within one organ system, were excluded. Where possible, meta-analysis was performed using random-effects models. We included 39 studies amounting to over 152 thousand PsA patients. We performed meta-analysis for the prevalence of 21 commonly reported comorbidities. The most prevalent comorbidities were hypertension (pooled prevalence 34%), metabolic syndrome (29%), obesity (27%), hyperlipidaemia (24%) and any cardiovascular diseases (19%). Eleven studies consistently showed higher prevalence of comorbidities in PsA than controls. Five studies showed that comorbid patients had more severe disease, poorer quality of life, and increased discontinuation of treatment. Comorbidities, particularly cardiometabolic disorders, were highly prevalent in PsA and more common than in healthy controls. Comorbidities were associated with adverse disease features, but more research is needed on their impact on longitudinal outcomes such as treatment response, work productivity and mortality.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objectives This study sought to evaluate the safety and efficacy of the CoreValve transcatheter heart valve (THV) for the treatment of severe aortic stenosis in patients at extreme risk for surgery. ...Background Untreated severe aortic stenosis is a progressive disease with a poor prognosis. Transcatheter aortic valve replacement (TAVR) with a self-expanding bioprosthesis is a potentially effective therapy. Methods We performed a prospective, multicenter, nonrandomized investigation evaluating the safety and efficacy of self-expanding TAVR in patients with symptomatic severe aortic stenosis with prohibitive risks for surgery. The primary endpoint was a composite of all-cause mortality or major stroke at 12 months, which was compared with a pre-specified objective performance goal (OPG). Results A total of 41 sites in the United States recruited 506 patients, of whom 489 underwent attempted treatment with the CoreValve THV. The rate of all-cause mortality or major stroke at 12 months was 26.0% (upper 2-sided 95% confidence bound: 29.9%) versus 43.0% with the OPG (p < 0.0001). Individual 30-day and 12-month events included all-cause mortality (8.4% and 24.3%, respectively) and major stroke (2.3% and 4.3%, respectively). Procedural events at 30 days included life-threatening/disabling bleeding (12.7%), major vascular complications (8.2%), and need for permanent pacemaker placement (21.6%). The frequency of moderate or severe paravalvular aortic regurgitation was lower 12 months after self-expanding TAVR (4.2%) than at discharge (10.7%; p = 0.004 for paired analysis). Conclusions TAVR with a self-expanding bioprosthesis was safe and effective in patients with symptomatic severe aortic stenosis at prohibitive risk for surgical valve replacement. (Safety and Efficacy Study of the Medtronic CoreValve System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902 )
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Recognition of sexual and gender diversity in the 21st century challenges normative assumptions of intimacy that privilege heterosexual monogamy and the biological family unit, presume binary ...cisgender identities, essentialize binary sexual identities, and view sexual or romantic desire as necessary. We propose a queer paradigm to study relationship diversity grounded in seven axioms: intimacy may occur (1) within relationships featuring any combination of cisgender, transgender, or nonbinary identities; (2) with people of multiple gender identities across the life course; (3) in multiple relationships simultaneously with consent; (4) within relationships characterized by consensual asymmetry, power exchange, or role-play; (5) in the absence or limited experience of sexual or romantic desire; (6) in the context of a chosen rather than biological family; and (7) in other possible forms yet unknown. We review research on queer relational forms, including same-sex relationships; relationships in which one or more partners identify as transgender, gender nonbinary, bisexual, pansexual, sexually fluid, "mostly" straight, asexual, or aromantic; polyamory and other forms of consensual nonmonogamy; kink/fetish relationships; and chosen families. We argue that a queer paradigm shifts the dominant scientific conception of relationships away from the confines of normativity toward an embrace of diversity, fluidity, and possibility.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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