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1.
Adv Exp Med Biol ; 1164: 225-233, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576552

RESUMO

Immune checkpoint blockade (ICB) has proved successful in the immunotherapeutic treatment of various human cancers. Despite its success, most patients are still not cured while immunogenic cold cancers are still poorly responsive. There is a need for novel clinical interventions in immunotherapy, either alone or in conjunction with ICB. Here, we outline our recent discovery that the intracellular signaling kinase glycogen synthase kinase-3 (GSK-3) is a central regulator of PD-1 in T-cells. We demonstrate the application of small molecule inhibitor (SMI) approaches to down-regulate PD-1 in tumor immunotherapy. GSK-3 SMIs were found as effective as anti-PD-1 in the elimination of melanoma in mouse models. We propose the development of novel SMIs to target co-receptors for the future of immunotherapy.


Assuntos
Regulação Neoplásica da Expressão Gênica , Quinase 3 da Glicogênio Sintase , Imunoterapia , Melanoma , Animais , Modelos Animais de Doenças , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Melanoma/terapia , Camundongos , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/fisiologia
2.
Semin Immunol ; 42: 101295, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31604533

RESUMO

The past few years have witnessed exciting progress in the application of immune check-point blockade (ICB) for the treatment of various human cancers. ICB was first used against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to demonstrate durable anti-tumor responses followed by ICB against programmed cell death-1 (PD-1) or its ligand, PD-L1. Present approaches involve the use of combinations of blocking antibodies against CTLA-4, PD-1 and other inhibitory receptors (IRs) such as TIM3, TIGIT and LAG3. Despite this success, most patients are not cured by ICB therapy and there are limitations to the use of antibodies including cost, tumor penetration, the accessibility of receptors, and clearance from the cell surface as well as inflammatory and autoimmune complications. Recently, we demonstrated that the down-regulation or inhibition of glycogen synthase kinase 3 (GSK-3) down-regulates PD-1 expression in infectious diseases and cancer (Taylor et al., 2016 Immunity 44, 274-86; 2018 Cancer Research 78, 706-717; Krueger and Rudd 2018 Immunity 46, 529-531). In this Review, we outline the use of small molecule inhibitors (SMIs) that target intracellular pathways for co-receptor blockade in cancer immunotherapy.

3.
Nat Commun ; 10(1): 3991, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488816

RESUMO

Lung cancer shows substantial genetic and phenotypic heterogeneity across individuals, driving a need for personalised medicine. Here, we report lung cancer organoids and normal bronchial organoids established from patient tissues comprising five histological subtypes of lung cancer and non-neoplastic bronchial mucosa as in vitro models representing individual patient. The lung cancer organoids recapitulate the tissue architecture of the primary lung tumours and maintain the genomic alterations of the original tumours during long-term expansion in vitro. The normal bronchial organoids maintain cellular components of normal bronchial mucosa. Lung cancer organoids respond to drugs based on their genomic alterations: a BRCA2-mutant organoid to olaparib, an EGFR-mutant organoid to erlotinib, and an EGFR-mutant/MET-amplified organoid to crizotinib. Considering the short length of time from organoid establishment to drug testing, our newly developed model may prove useful for predicting patient-specific drug responses through in vitro patient-specific drug trials.

4.
Nurs Child Young People ; 31(5): 20-24, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31486596

RESUMO

Withdrawal of treatment from critically ill children is a contentious and ethically difficult area. The principle of best interests was central to three recent high-profile legal cases and raised questions about how this is demonstrated in healthcare for children whose treatment may be of no benefit to them. This article discusses the legal and ethical aspects of caring for such children. Nurses are important advocates and should balance their obligation to deliver holistic and family-centred care with that of keeping the child as the central focus, particularly with decision-making. In cases of disagreement between families and clinicians, children's voices are particularly vulnerable to being lost. Pre- and post-registration education, research and a higher profile for nurses in multidisciplinary decision-making are suggested as ways to improve the nursing contribution to this important debate.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31483131

RESUMO

Withdrawal of treatment from critically ill children is a contentious and ethically difficult area. The principle of best interests was central to three recent high-profile legal cases and raised questions about how this is demonstrated in healthcare for children whose treatment may be of no benefit to them. This article discusses the legal and ethical aspects of caring for such children. Nurses are important advocates and should balance their obligation to deliver holistic and family-centred care with that of keeping the child as the central focus, particularly with decision-making. In cases of disagreement between families and clinicians, children's voices are particularly vulnerable to being lost. Pre- and post-registration education, research and a higher profile for nurses in multidisciplinary decision-making are suggested as ways to improve the nursing contribution to this important debate.

6.
Midwifery ; 75: 16-23, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30981161

RESUMO

OBJECTIVE: To explore how support impacted on mothers' breastfeeding experiences in the first few weeks following birth. DESIGN: A qualitative approach explored real-time experiences of breastfeeding captured by five first-time mothers in the South of England on camcorder as video diaries. A multi-dimensional approach involving thematic analysis ensured both the audio and visual elements of the data were analysed. FINDINGS: Mothers felt 'under surveillance' by the biomedical approach to support from the healthcare team. At best mothers felt reassured that they were 'on the right track'. When mothers felt their breastfeeding was constantly being examined, criticised and threatened they felt 'scrutinised, judged and sabotaged'. When they found it difficult to access healthcare support, or they avoided it altogether to circumvent further scrutiny, they felt 'abandoned and alone'. KEY CONCLUSIONS: Collecting audio-visual data in real-time adds fresh insights into how support impacts mothers' experiences of breastfeeding. The biomedical approach to support for breastfeeding is not effective. Scrutinising, judging and/or sabotaging mothers' attempts to breastfeed can have long-lasting effects on maternal emotional wellbeing. IMPLICATIONS FOR PRACTICE: Breastfeeding support might be improved by adopting a more social model of care. Future research needs to explore how relationship-based support can be provided by the health service.

7.
Curr Biol ; 29(9): 1503-1511.e6, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31006567

RESUMO

Rapid Na+/Ca2+-based action potentials govern essential cellular functions in eukaryotes, from the motile responses of unicellular protists, such as Paramecium [1, 2], to complex animal neuromuscular activity [3]. A key innovation underpinning this fundamental signaling process has been the evolution of four-domain voltage-gated Na+/Ca2+ channels (4D-Cavs/Navs). These channels are widely distributed across eukaryote diversity [4], albeit several eukaryotes, including land plants and fungi, have lost voltage-sensitive 4D-Cav/Navs [5-7]. Because these lineages appear to lack rapid Na+/Ca2+-based action potentials, 4D-Cav/Navs are generally considered necessary for fast Na+/Ca2+-based signaling [7]. However, the cellular mechanisms underpinning the membrane physiology of many eukaryotes remain unexamined. Eukaryotic phytoplankton critically influence our climate as major primary producers. Several taxa, including the globally abundant diatoms, exhibit membrane excitability [8-10]. We previously demonstrated that certain diatom genomes encode 4D-Cav/Navs [4] but also proteins of unknown function, resembling prokaryote single-domain, voltage-gated Na+ channels (BacNavs) [4]. Here, we show that single-domain channels are actually broadly distributed across major eukaryote phytoplankton lineages and represent three novel classes of single-domain channels, which we refer collectively to as EukCats. Functional characterization of diatom EukCatAs indicates that they are voltage-gated Na+- and Ca2+-permeable channels, with rapid kinetics resembling metazoan 4D-Cavs/Navs. In Phaeodactylum tricornutum, which lacks 4D-Cav/Navs, EukCatAs underpin voltage-activated Ca2+ signaling important for membrane excitability, and mutants exhibit impaired motility. EukCatAs therefore provide alternative mechanisms for rapid Na+/Ca2+ signaling in eukaryotes and may functionally replace 4D-Cavs/Navs in pennate diatoms. Marine phytoplankton thus possess unique signaling mechanisms that may be key to environmental sensing in the oceans.

8.
Women Birth ; 2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30318405

RESUMO

BACKGROUND: Despite breastfeeding providing maximum health benefits to mother and baby, many women in the United Kingdom do not breastfeed, or do so briefly. PURPOSE: Using tenets of ethnography, this study aimed to explore the everyday experiences of first time breastfeeding mothers in the early weeks following birth. METHODS: Using a camcorder, five mothers in the United Kingdom captured their real-time experiences in a video diary, until they perceived their infant feeding was established. Using a multidimensional approach to analysis, we examined how five mothers interacted with the camcorder as they shared their emotions, feelings, thoughts and actions in real-time. FINDINGS: Mothers recorded 294 video clips, total recording time exceeded 43h. This paper focuses on one theme, the therapeutic role of the camcorder in qualitative research. Four subthemes are discussed highlighting the therapeutic impact of talking to the camcorder: personifying the camcorder; using the camcorder as a confidante; a sounding board; and a mirror and motivator. CONCLUSION: Frequent opportunities to relieve tension by talking to "someone" without interruption, judgement or advice can be therapeutic. Further research needs to explore how the video diary method can be integrated into standard postnatal care to provide benefits for a wider population.

9.
J Phycol ; 2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30239000

RESUMO

Brevetoxin (PbTx) is a neurotoxic secondary metabolite of the dinoflagellate Karenia brevis. We used a novel, fluorescent BODIPY-labeled conjugate of brevetoxin congener PbTx-2 (B-PbTx) to track absorption of the metabolite into a variety of marine microbes. The labeled toxin was taken up and brightly fluoresced in lipid-rich regions of several marine microbes including diatoms and coccolithophores. The microzooplankton (20-200 µm) tintinnid ciliate Favella sp. and the rotifer Brachionus rotundiformis also took up B-PbTx. Uptake and intracellular fluorescence of B-PbTx was weak or undetectable in phytoplankton species representative of dinoflagellates, cryptophytes, and cyanobacteria over the same (4 h) time course. The cellular fate of two additional BODIPY-conjugated K. brevis associated secondary metabolites, brevenal (B-Bn) and brevisin (B-Bs), were examined in all the species tested. All taxa exhibited minimal or undetectable fluorescence when exposed to the former conjugate, while most brightly fluoresced when treated with the latter. This is the first study to observe the uptake of fluorescently-tagged brevetoxin conjugates in non-toxic phytoplankton and zooplankton taxa, demonstrating their potential in investigating whether marine microbes can serve as a significant biological sink for algal toxins. The highly variable uptake of B-PbTx observed among taxa suggests some may play a more significant role than others in vectoring lipophilic toxins in the marine environment.

10.
New Phytol ; 220(1): 147-162, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29916209

RESUMO

Coccolithophores are globally distributed unicellular marine algae that are characterized by their covering of calcite coccoliths. Calcification by coccolithophores contributes significantly to global biogeochemical cycles. However, the physiological requirement for calcification remains poorly understood as non-calcifying strains of some commonly used model species, such as Emiliania huxleyi, grow normally in laboratory culture. To determine whether the requirement for calcification differs between coccolithophore species, we utilized multiple independent methodologies to disrupt calcification in two important species of coccolithophore: E. huxleyi and Coccolithus braarudii. We investigated their physiological response and used time-lapse imaging to visualize the processes of calcification and cell division in individual cells. Disruption of calcification resulted in major growth defects in C. braarudii, but not in E. huxleyi. We found no evidence that calcification supports photosynthesis in C. braarudii, but showed that an inability to maintain an intact coccosphere results in cell cycle arrest. We found that C. braarudii is very different from E. huxleyi as it exhibits an obligate requirement for calcification. The identification of a growth defect in C. braarudii resulting from disruption of the coccosphere may be important in considering their response to future changes in ocean carbonate chemistry.

11.
Nat Genet ; 50(7): 937-943, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29955178

RESUMO

Functional redundancy shared by paralog genes may afford protection against genetic perturbations, but it can also result in genetic vulnerabilities due to mutual interdependency1-5. Here, we surveyed genome-scale short hairpin RNA and CRISPR screening data on hundreds of cancer cell lines and identified MAGOH and MAGOHB, core members of the splicing-dependent exon junction complex, as top-ranked paralog dependencies6-8. MAGOHB is the top gene dependency in cells with hemizygous MAGOH deletion, a pervasive genetic event that frequently occurs due to chromosome 1p loss. Inhibition of MAGOHB in a MAGOH-deleted context compromises viability by globally perturbing alternative splicing and RNA surveillance. Dependency on IPO13, an importin-ß receptor that mediates nuclear import of the MAGOH/B-Y14 heterodimer9, is highly correlated with dependency on both MAGOH and MAGOHB. Both MAGOHB and IPO13 represent dependencies in murine xenografts with hemizygous MAGOH deletion. Our results identify MAGOH and MAGOHB as reciprocal paralog dependencies across cancer types and suggest a rationale for targeting the MAGOHB-IPO13 axis in cancers with chromosome 1p deletion.

12.
Cancer Cell ; 33(4): 676-689.e3, 2018 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-29622463

RESUMO

Aneuploidy, whole chromosome or chromosome arm imbalance, is a near-universal characteristic of human cancers. In 10,522 cancer genomes from The Cancer Genome Atlas, aneuploidy was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes. Aneuploidy was anti-correlated with expression of immune signaling genes, due to decreased leukocyte infiltrates in high-aneuploidy samples. Chromosome arm-level alterations show cancer-specific patterns, including loss of chromosome arm 3p in squamous cancers. We applied genome engineering to delete 3p in lung cells, causing decreased proliferation rescued in part by chromosome 3 duplication. This study defines genomic and phenotypic correlates of cancer aneuploidy and provides an experimental approach to study chromosome arm aneuploidy.

13.
Cell ; 173(2): 291-304.e6, 2018 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-29625048

RESUMO

We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.

14.
Cell ; 173(2): 305-320.e10, 2018 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-29625049

RESUMO

The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing.

15.
Cell Rep ; 23(1): 194-212.e6, 2018 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-29617660

RESUMO

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.

16.
PeerJ ; 6: e4533, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29632739

RESUMO

Background: The potent neurotoxins produced by the harmful algal bloom species Karenia brevis are activators of sodium voltage-gated channels (VGC) in animals, resulting in altered channel kinetics and membrane hyperexcitability. Recent biophysical and genomic evidence supports widespread presence of homologous sodium (Na+) and calcium (Ca2+) permeable VGCs in unicellular algae, including marine phytoplankton. We therefore hypothesized that VGCs of these phytoplankton may be an allelopathic target for waterborne neurotoxins produced by K. brevis blooms that could lead to ion channel dysfunction and disruption of signaling in a similar manner to animal Na+ VGCs. Methods: We examined the interaction of brevetoxin-3 (PbTx-3), a K. brevis neurotoxin, with the Na+/Ca2+ VGC of the non-toxic diatom Odontella sinensis using electrophysiology. Single electrode current- and voltage- clamp recordings from O. sinensis in the presence of PbTx-3 were used to examine the toxin's effect on voltage gated Na+/Ca2+ currents. In silico analysis was used to identify the putative PbTx binding site in the diatoms. We identified Na+/Ca2+ VCG homologs from the transcriptomes and genomes of 12 diatoms, including three transcripts from O. sinensis and aligned them with site-5 of Na+ VGCs, previously identified as the PbTx binding site in animals. Results: Up to 1 µM PbTx had no effect on diatom resting membrane potential or membrane excitability. The kinetics of fast inward Na+/Ca2+ currents that underlie diatom action potentials were also unaffected. However, the peak inward current was inhibited by 33%, delayed outward current was inhibited by 25%, and reversal potential of the currents shifted positive, indicating a change in permeability of the underlying channels. Sequence analysis showed a lack of conservation of the PbTx binding site in diatom VGC homologs, many of which share molecular features more similar to single-domain bacterial Na+/Ca2+ VGCs than the 4-domain eukaryote channels. Discussion: Although membrane excitability and the kinetics of action potential currents were unaffected, the permeation of the channels underlying the diatom action potential was significantly altered in the presence of PbTx-3. However, at environmentally relevant concentrations the effects of PbTx- on diatom voltage activated currents and interference of cell signaling through this pathway may be limited. The relative insensitivity of phytoplankton VGCs may be due to divergence of site-5 (the putative PbTx binding site), and in some cases, such as O. sinensis, resistance to toxin effects may be because of evolutionary loss of the 4-domain eukaryote channel, while retaining a single domain bacterial-like VGC that can substitute in the generation of fast action potentials.

17.
Clin Sci (Lond) ; 132(2): 285-294, 2018 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-29321218

RESUMO

BACKGROUND: Hypertension is prevalent in chronic kidney disease (CKD). Studies suggest that reduction in dietary salt intake reduces blood pressure (BP). We studied relationships between salt intake, BP and renin-angiotensin system regulation in order to establish if it is disordered in CKD. METHODS: Mechanistic crossover study of CKD patients versus non-CKD controls. Participants underwent modified saline suppression test prior to randomization to either low or high salt diet for 5 days and then crossed over to the alternate diet. Angiotensin-II stimulation testing was performed in both salt states. BP, urea and electrolytes, and plasma aldosterone concentration (PAC) were measured. RESULTS: Twenty-seven subjects were recruited (12 CKD, 15 control). There was no difference in age and baseline BP between the groups. Following administration of intravenous saline, systolic BP increased in CKD but not controls (131 ± 16 to 139 ± 14 mmHg, P=0.016 vs 125 ± 20 to 128 ± 22 mmHg, P=0.38). Median PAC reduced from 184 (124,340) to 95 (80,167) pmol in controls (P=0.003), but failed to suppress in CKD (230 (137,334) to 222 (147,326) pmol (P=0.17)). Following dietary salt modification, there was no change in BP in either group. Median PAC was lower following high salt compared with low salt diet in CKD and controls. There was a comparable increase in systolic BP in response to angiotensin-II in both groups. DISCUSSION: We demonstrate dysregulation of aldosterone in CKD in response to salt loading with intravenous saline, but not to dietary salt modification.

18.
Lancet ; 391(10125): 1097-1107, 2018 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-29198562

RESUMO

This report contains new and follow-up metric data relating to the eight main recommendations of the Lancet Standing Commission on Liver Disease in the UK, which aim to reduce the unacceptable harmful consequences of excess alcohol consumption, obesity, and viral hepatitis. For alcohol, we provide data on alcohol dependence, damage to families, and the documented increase in alcohol consumption since removal of the above-inflation alcohol duty escalator. Alcoholic liver disease will shortly overtake ischaemic heart disease with regard to years of working life lost. The rising prevalence of overweight and obesity, affecting more than 60% of adults in the UK, is leading to an increasing liver disease burden. Favourable responses by industry to the UK Government's soft drinks industry levy have been seen, but the government cannot continue to ignore the number of adults being affected by diabetes, hypertension, and liver disease. New direct-acting antiviral drugs for the treatment of chronic hepatitis C virus infection have reduced mortality and the number of patients requiring liver transplantation, but more screening campaigns are needed for identification of infected people in high-risk migrant communities, prisons, and addiction centres. Provision of care continues to be worst in regions with the greatest socioeconomic deprivation, and deficiencies exist in training programmes in hepatology for specialist registrars. Firm guidance is needed for primary care on the use of liver blood tests in detection of early disease and the need for specialist referral. This report also brings together all the evidence on costs to the National Health Service and wider society, in addition to the loss of tax revenue, with alcohol misuse in England and Wales costing £21 billion a year (possibly up to £52 billion) and obesity costing £27 billion a year (treasury estimates are as high as £46 billion). Voluntary restraints by the food and drinks industry have had little effect on disease burden, and concerted regulatory and fiscal action by the UK Government is essential if the scale of the medical problem, with an estimated 63 000 preventable deaths over the next 5 years, is to be addressed.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Efeitos Psicossociais da Doença , Custos de Cuidados de Saúde , Hepatite Viral Humana/complicações , Hepatopatias Alcoólicas/epidemiologia , Obesidade/complicações , Humanos , Hepatopatias Alcoólicas/economia , Hepatopatias Alcoólicas/terapia , Reino Unido/epidemiologia
19.
Cancer Discov ; 8(1): 108-125, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28963353

RESUMO

The Krüppel-like family of transcription factors plays critical roles in human development and is associated with cancer pathogenesis. Krüppel-like factor 5 gene (KLF5) has been shown to promote cancer cell proliferation and tumorigenesis and to be genomically amplified in cancer cells. We recently reported that the KLF5 gene is also subject to other types of somatic coding and noncoding genomic alterations in diverse cancer types. Here, we show that these alterations activate KLF5 by three distinct mechanisms: (i) Focal amplification of superenhancers activates KLF5 expression in squamous cell carcinomas; (ii) Missense mutations disrupt KLF5-FBXW7 interactions to increase KLF5 protein stability in colorectal cancer; (iii) Cancer type-specific hotspot mutations within a zinc-finger DNA binding domain of KLF5 change its DNA binding specificity and reshape cellular transcription. Utilizing data from CRISPR/Cas9 gene knockout screening, we reveal that cancer cells with KLF5 overexpression are dependent on KLF5 for their proliferation, suggesting KLF5 as a putative therapeutic target.Significance: Our observations, together with previous studies that identified oncogenic properties of KLF5, establish the importance of KLF5 activation in human cancers, delineate the varied genomic mechanisms underlying this occurrence, and nominate KLF5 as a putative target for therapeutic intervention in cancer. Cancer Discov; 8(1); 108-25. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1.

20.
Cancer Res ; 78(3): 706-717, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29055015

RESUMO

The impact of PD-1 immune checkpoint therapy prompts exploration of other strategies to downregulate PD-1 for cancer therapy. We previously showed that the serine/threonine kinase, glycogen synthase kinase, GSK-3α/ß, is a central regulator of PD-1 transcription in CD8+ T cells. Here, we show that the use of small-molecule inhibitors of GSK-3α/ß (GSK-3i) to reduce pcdc1 (PD-1) transcription and expression was as effective as anti-PD-1 and PD-L1-blocking antibodies in the control of B16 melanoma, or EL4 lymphoma, in primary tumor and metastatic settings. Furthermore, the conditional genetic deletion of GSK-3α/ß reduced PD-1 expression on CD8+ T cells and limited B16 pulmonary metastasis to the same degree as PD-1 gene deficiency. In each model, GSK-3i inhibited PD-1 expression on tumor-infiltrating lymphocytes, while increasing Tbx21 (T-bet) transcription, and the expression of CD107a+ (LAMP1) and granzyme B (GZMB) on CD8+ T cells. Finally, the adoptive transfer of T cells treated ex vivo with a GSK-3 inhibitor delayed the onset of EL4 lymphoma growth to a similar extent as anti-PD-1 pretreatment. Overall, our findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8+ T-cell function in cancer therapy to a similar degree as PD-1-blocking antibodies.Significance: These findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8+ T-cell function in cancer therapy to a similar degree as PD-1 blocking antibodies, offering a next-generation approach in the design of immunotherapeutic approaches for cancer management. Cancer Res; 78(3); 706-17. ©2017 AACR.

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