Although ribosomal protein S6 kinase A3 (RSK2) activation status positively correlates with patient responses to antiestrogen hormonal therapies, the mechanistic basis for these observations is unknown. Using multiple in vitro and in vivo models of estrogen receptor–positive (ER+) breast cancer, we report that ERα sequesters active RSK2 into the nucleus to promote neoplastic transformation and facilitate metastatic tumor growth. RSK2 physically interacted with ERα through its N terminus to activate a proneoplastic transcriptional network critical to the ER+ lineage in the mammary gland, thereby providing a gene signature that effectively stratified patient tumors according to ERα status. ER+ tumor growth was strongly dependent on nuclear RSK2, and transgenic mice engineered to stably express nuclear RSK2 in the mammary gland developed high-grade ductal carcinoma in situ. Mammary cells isolated from the transgenic model and introduced systemically successfully disseminated and established metastatic lesions. Antiestrogens disrupted the interaction between RSK2 and ERα, driving RSK2 into the cytoplasm and impairing tumor formation. These findings establish RSK2 as an obligate participant of ERα-mediated transcriptional programs, tumorigenesis, and divergent patient responses to antiestrogen therapies.Significance: Nuclear accumulation of active RSK drives a protumorigenic transcriptional program and renders ER+ breast cancer susceptible to endocrine-based therapies. Cancer Res; 78(8); 2014–25. ©2018 AACR.
https://ift.tt/2JE8cls
Πέμπτη 12 Απριλίου 2018
ER{alpha}-Mediated Nuclear Sequestration of RSK2 Is Required for ER+ Breast Cancer Tumorigenesis
Lessons from the Crypt: HMGA1—Amping up Wnt for Stem Cells and Tumor Progression
High mobility group A1 (HMGA1) chromatin remodeling proteins are enriched in aggressive cancers and stem cells, although their common function in these settings has remained elusive until now. Recent work in murine intestinal stem cells (ISC) revealed a novel role for Hmga1 in enhancing self-renewal by amplifying Wnt signaling, both by inducing genes expressing Wnt agonist receptors and Wnt effectors. Surprisingly, Hmga1 also "builds" a stem cell niche by upregulating Sox9, a factor required for differentiation to Paneth cells; these cells constitute an epithelial niche by secreting Wnt and other factors to support ISCs. HMGA1 is also highly upregulated in colon cancer compared with nonmalignant epithelium and SOX9 becomes overexpressed during colon carcinogenesis. Intriguingly, HMGA1 is overexpressed in diverse cancers with poor outcomes, where it regulates developmental genes. Similarly, HMGA1 induces genes responsible for pluripotency and self-renewal in embryonic stem cells. These findings demonstrate that HMGA1 maintains Wnt and other developmental transcriptional networks and suggest that HMGA1 overexpression fosters carcinogenesis and tumor progression through dysregulation of these pathways. Studies are now needed to determine more precisely how HMGA1 modulates chromatin structure to amplify developmental genes and how to disrupt this process in cancer therapy. Cancer Res; 78(8); 1890–7. ©2018 AACR.
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Small-Molecule Activators of Protein Phosphatase 2A for the Treatment of Castration-Resistant Prostate Cancer
Primary prostate cancer is generally treatable by androgen deprivation therapy, however, later recurrences of castrate-resistant prostate cancer (CRPC) that are more difficult to treat nearly always occur due to aberrant reactivation of the androgen receptor (AR). In this study, we report that CRPC cells are particularly sensitive to the growth-inhibitory effects of reengineered tricyclic sulfonamides, a class of molecules that activate the protein phosphatase PP2A, which inhibits multiple oncogenic signaling pathways. Treatment of CRPC cells with small-molecule activators of PP2A (SMAP) in vitro decreased cellular viability and clonogenicity and induced apoptosis. SMAP treatment also induced an array of significant changes in the phosphoproteome, including most notably dephosphorylation of full-length and truncated isoforms of the AR and downregulation of its regulatory kinases in a dose-dependent and time-dependent manner. In murine xenograft models of human CRPC, the potent compound SMAP-2 exhibited efficacy comparable with enzalutamide in inhibiting tumor formation. Overall, our results provide a preclinical proof of concept for the efficacy of SMAP in AR degradation and CRPC treatment.Significance: A novel class of small-molecule activators of the tumor suppressor PP2A, a serine/threonine phosphatase that inhibits many oncogenic signaling pathways, is shown to deregulate the phosphoproteome and to destabilize the androgen receptor in advanced prostate cancer. Cancer Res; 78(8); 2065–80. ©2018 AACR.
https://ift.tt/2JGTGJG
Silencing the Snail-Dependent RNA Splice Regulator ESRP1 Drives Malignant Transformation of Human Pulmonary Epithelial Cells
Epithelial-to-mesenchymal transition (EMT) is organized in cancer cells by a set of key transcription factors, but the significance of this process is still debated, including in non–small cell lung cancer (NSCLC). Here, we report increased expression of the EMT-inducing transcription factor Snail in premalignant pulmonary lesions, relative to histologically normal pulmonary epithelium. In immortalized human pulmonary epithelial cells and isogenic derivatives, we documented Snail-dependent anchorage-independent growth in vitro and primary tumor growth and metastatic behavior in vivo. Snail-mediated transformation relied upon silencing of the tumor-suppressive RNA splicing regulatory protein ESRP1. In clinical specimens of NSCLC, ESRP1 loss was documented in Snail-expressing premalignant pulmonary lesions. Mechanistic investigations showed that Snail drives malignant progression in an ALDH+CD44+CD24− pulmonary stem cell subset in which ESRP1 and stemness-repressing microRNAs are inhibited. Collectively, our results show how ESRP1 loss is a critical event in lung carcinogenesis, and they identify new candidate directions for targeted therapy of NSCLC.Significance: This study defines a Snail-ESRP1 cancer axis that is crucial for human lung carcinogenesis, with implications for new intervention strategies and translational opportunities. Cancer Res; 78(8); 1986–99. ©2018 AACR.
https://ift.tt/2JJ3DGD
HER2 Overexpression Triggers an IL1{alpha} Proinflammatory Circuit to Drive Tumorigenesis and Promote Chemotherapy Resistance
Systemic inflammation in breast cancer correlates with poor prognosis, but the molecular underpinnings of this connection are not well understood. In this study, we explored the relationship between HER2 overexpression, inflammation, and expansion of the mammary stem/progenitor and cancer stem–like cell (CSC) population in breast cancer. HER2-positive epithelial cells initiated and sustained an inflammatory milieu needed to promote tumorigenesis. HER2 induced a feedforward activation loop of IL1α and IL6 that stimulated NFκB and STAT3 pathways for generation and maintenance of breast CSC. In mice, Il1a genetic deficiency delayed MMTV-Her2–induced tumorigenesis and reduced inflammatory cytokine expression as well as CSC in primary tumors. In clinical specimens of human breast tumor tissues, tissue microarray analysis revealed a strong positive correlation between IL1α/IL6 expression and CSC-positive phenotype. Pharmacologic blockade of IL1α signaling reduced the CSC population and improved chemotherapeutic efficacy. Our findings suggest new therapeutic or prevention strategies for HER2-positive breast cancers.Significance: IL1α signaling driven by HER2 promotes chronic inflammation needed to support cancer stem-like cell maintenance in HER2-positive breast cancers. Cancer Res; 78(8); 2040–51. ©2018 AACR.
https://ift.tt/2JCCRQl
The Importance of Body Composition in Explaining the Overweight Paradox in Cancer—Counterpoint
Despite a greater risk of cancer associated with higher BMI, overweight (BMI 25–<30 kg/m2) and class I obese (BMI 30–<35 kg/m2) patients often have a paradoxically lower risk of overall mortality after a cancer diagnosis, a phenomenon called the "obesity paradox." Only when patients exceed a BMI ≥35 kg/m2 are elevations in mortality risk consistently noted. This paradox has been dismissed as the result of methodologic bias, which we will describe and debate here. However, even if such bias influences associations, there is growing evidence that body composition may in part explain the paradox. This phenomenon may more accurately be described as a BMI paradox. That is, BMI is a poor proxy for adiposity and does not distinguish muscle from adipose tissue, nor describe adipose tissue distribution. Low muscle mass is associated with higher risk of recurrence, overall and cancer-specific mortality, surgical complications, and treatment-related toxicities. Patients with who are overweight or obese have on average higher levels of muscle than their normal-weight counterparts. Also, there is some evidence that patients with moderate levels of subcutaneous adipose tissue may have lower mortality. More research utilizing body composition is needed to clarify the effects of adiposity on cancer mortality. Cancer Res; 78(8); 1906–12. ©2018 AACR.
https://ift.tt/2JGzxDL
Germline Mutations in the Mitochondrial 2-Oxoglutarate/Malate Carrier SLC25A11 Gene Confer a Predisposition to Metastatic Paragangliomas
Comprehensive genetic analyses have identified germline SDHB and FH gene mutations as predominant causes of metastatic paraganglioma and pheochromocytoma. However, some suspicious cases remain unexplained. In this study, we performed whole-exome sequencing of a paraganglioma exhibiting an SDHx-like molecular profile in the absence of SDHx or FH mutations and identified a germline mutation in the SLC25A11 gene, which encodes the mitochondrial 2-oxoglutarate/malate carrier. Germline SLC25A11 mutations were identified in six other patients, five of whom had metastatic disease. These mutations were associated with loss of heterozygosity, suggesting that SLC25A11 acts as a tumor-suppressor gene. Pseudohypoxic and hypermethylator phenotypes comparable with those described in SDHx- and FH-related tumors were observed both in tumors with mutated SLC25A11 and in Slc25a11Δ/Δ immortalized mouse chromaffin knockout cells generated by CRISPR-Cas9 technology. These data show that SLC25A11 is a novel paraganglioma susceptibility gene for which loss of function correlates with metastatic presentation.Significance: A gene encoding a mitochondrial carrier is implicated in a hereditary cancer predisposition syndrome, expanding the role of mitochondrial dysfunction in paraganglioma. Cancer Res; 78(8); 1914–22. ©2018 AACR.
https://ift.tt/2JGzvf7
NRAS-Mutated Rhabdomyosarcoma Cells Are Vulnerable to Mitochondrial Apoptosis Induced by Coinhibition of MEK and PI3K{alpha}
Sequencing studies have revealed recurrent mutations in the RAS pathway in rhabdomyosarcoma (RMS). However, RAS effector pathways in RMS are poorly defined. Here, we report that coinhibition of NRAS or MEK plus PI3Kα triggers widespread apoptosis in NRAS-mutated RMS cells. Subtoxic concentrations of the MEK inhibitor MEK162 and the PI3Kα-specific inhibitor BYL719 synergized to trigger apoptosis in NRAS-mutated RMS cells in vitro and in vivo. NRAS- or HRAS-mutated cell lines were more vulnerable to MEK162/BYL719 cotreatment than RAS wild-type cell lines, and MEK162/BYL719 cotreatment was more effective to trigger apoptosis in NRAS-mutated than RAS wild-type RMS tumors in vivo. We identified BCL-2–modifying factor (BMF) as an inhibitory target of oncogenic NRAS, with either NRAS silencing or MEK inhibition upregulating BMF mRNA and protein levels, which BYL719 further increased. BMF silencing ablated MEK162/BYL719-induced apoptosis. Mechanistic investigations implicated a proapoptotic rebalancing of BCL-2 family members and suppression of cap-dependent translation in apoptotic sensitivity upon MEK162/BYL719 cotreatment. Our results offer a rationale for combining MEK- and PI3Kα-specific inhibitors in clinical treatment of RAS-mutated RMS.Significance: These findings offer a mechanistic rationale for combining MEK- and PI3Kα-specific inhibitors in the clinical treatment of RAS-mutated forms of often untreatable rhabdomyosarcomas. Cancer Res; 78(8); 2000–13. ©2018 AACR.
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CXCL12{gamma} Promotes Metastatic Castration-Resistant Prostate Cancer by Inducing Cancer Stem Cell and Neuroendocrine Phenotypes
There is evidence that cancer stem-like cells (CSC) and neuroendocrine behavior play critical roles in the pathogenesis and clinical course of metastatic castration-resistant prostate cancer (m-CRPC). However, there is limited mechanistic understanding of how CSC and neuroendocrine phenotypes impact the development of m-CRPC. In this study, we explored the role of the intracellular chemokine CXCL12γ in CSC induction and neuroendocrine differentiation and its impact on m-CRPC. CXCL12γ expression was detected in small-cell carcinoma of metastatic tissues and circulating tumor cells from m-CRPC patients and in prostate cancer cells displaying an neuroendocrine phenotype. Mechanistic investigations demonstrated that overexpression of CXCL12γ induced CSC and neuroendocrine phenotypes in prostate cancer cells through CXCR4-mediated PKCα/NFκB signaling, which promoted prostate tumor outgrowth, metastasis, and chemoresistance in vivo. Together, our results establish a significant function for CXCL12γ in m-CRPC development and suggest it as a candidate therapeutic target to control aggressive disease.Significance: Expression of CXCL12γ induces the expression of a cancer stem cell and neuroendocrine phenotypes, resulting in the development of aggressive m-CRPC. Cancer Res; 78(8); 2026–39. ©2018 AACR.
https://ift.tt/2EEHl5f
Tumorigenic and Antiproliferative Properties of the TALE-Transcription Factors MEIS2D and MEIS2A in Neuroblastoma
Neuroblastoma is one of only a few human cancers that can spontaneously regress even after extensive dissemination, a poorly understood phenomenon that occurs in as many as 10% of patients. In this study, we identify the TALE-homeodomain transcription factor MEIS2 as a key contributor to this phenomenon. We identified MEIS2 as a MYCN-independent factor in neuroblastoma and showed that in this setting the alternatively spliced isoforms MEIS2A and MEIS2D exert antagonistic functions. Specifically, expression of MEIS2A was low in aggressive stage 4 neuroblastoma but high in spontaneously regressing stage 4S neuroblastoma. Moderate elevation of MEIS2A expression reduced proliferation of MYCN-amplified human neuroblastoma cells, induced neuronal differentiation and impaired the ability of these cells to form tumors in mice. In contrast, MEIS2A silencing or MEIS2D upregulation enhanced the aggressiveness of the tumor phenotype. Mechanistically, MEIS2A uncoupled a negative feedback loop that restricts accumulation of cellular retinoic acid, an effective agent in neuroblastoma treatment. Overall, our results illuminate the basis for spontaneous regression in neuroblastoma and identify an MEIS2A-specific signaling network as a potential therapeutic target in this common pediatric malignancy.Significance: This study illuminates the basis for spontaneous regressions that can occur in a common pediatric tumor, with implications for the development of new treatment strategies. Cancer Res; 78(8); 1935–47. ©2018 AACR.
https://ift.tt/2JG650D
Targeting Brain-Adaptive Cancer Stem Cells Prohibits Brain Metastatic Colonization of Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) exhibits more traits possessed by cancer stem cells (CSC) than other breast cancer subtypes and is more likely to develop brain metastases. TNBC patients usually have shorter survival time after diagnosis of brain metastasis, suggesting an innate ability of TNBC tumor cells in adapting to the brain. In this study, we establish novel animal models to investigate early tumor adaptation in brain metastases by introducing both patient-derived and cell line–derived CSC-enriched brain metastasis tumorsphere cells into mice. We discovered astrocyte-involved tumor activation of protocadherin 7 (PCDH7)-PLCβ-Ca2+-CaMKII/S100A4 signaling as a mediator of brain metastatic tumor outgrowth. We further identified and evaluated the efficacy of a known drug, the selective PLC inhibitor edelfosine, in suppressing the PCDH7 signaling pathway to prohibit brain metastases in the animal models. The results of this study reveal a novel signaling pathway for brain metastases in TNBC and indicate a promising strategy of metastatic breast cancer prevention and treatment by targeting organ-adaptive cancer stem cells.Significance: These findings identify a compound to block adaptive signaling between cancer stem cells and brain astrocytes. Cancer Res; 78(8); 2052–64. ©2018 AACR.
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S-Nitrosylation of cIAP1 Switches Cancer Cell Fate from TNF{alpha}/TNFR1-Mediated Cell Survival to Cell Death
TNFα is a prominent proinflammatory cytokine and a critical mediator for the development of many types of cancer such as breast, colon, prostate, cervical, skin, liver, and chronic lymphocytic leukemia. Binding of TNFα to TNFR1 can lead to divergent signaling pathways promoting predominantly NF-κB activation but also cell death. We report here that the nitric oxide (NO) donor glyceryl trinitrate (GTN) converts TNFα, generated from immune cells or cancer cells stimulated by chemotherapy, into a prodeath mediator in colon and mammary cancer cells. GTN-mediated S-nitrosylation of cIAP1 on cysteines 571 and 574 inhibited its E3 ubiquitin ligase activity, which in turn reduced Lys63-linked ubiquitination of RIP1 and initiated assembly of a death complex. These findings provide insights into how NO can harness advantageous aspects of inflammation in cancer and provide new therapeutic strategies.Significance: Combination of an NO donor with chemotherapeutic drug–induced TNFα represents a potentially valuable anticancer strategy. Cancer Res; 78(8); 1948–57. ©2018 AACR.
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Fatal cervicomediastinal necrotising fasciitis due to cholesteatoma
ANZ Journal of Surgery, EarlyView.
https://ift.tt/2v8c62R
Acute chylous peritonitis as a result of jejunal volvulus and small bowel obstruction from a congenital band adhesion
ANZ Journal of Surgery, EarlyView.
https://ift.tt/2JFxobk
Hybrid Capture-Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Cancers of the Gastrointestinal Tract or Anus
Purpose: Genomic profiling of tumor biopsies from advanced gastrointestinal and anal cancers is increasingly used to inform treatment. In some cases, tissue biopsy can be prohibitive, and we sought to investigate whether analysis of blood-derived circulating tumor DNA (ctDNA) may provide a minimally invasive alternative.
Experimental Design: Hybrid capture–based genomic profiling of 62 genes was performed on blood-based ctDNA from 417 patients with gastrointestinal carcinomas to assess the presence of genomic alterations (GA) and compare with matched tissue samples.
Results: Evidence of ctDNA was detected in 344 of 417 samples (82%), and of these, ≥1 reportable GA was detected in 89% (306/344) of samples. Frequently altered genes were TP53 (72%), KRAS (35%), PIK3CA (14%), BRAF (8%), and EGFR (7%). In temporally matched ctDNA and tissue samples available from 25 patients, 86% of alterations detected in tissue were also detected in ctDNA, including 95% of short variants, but only 50% of amplifications. Conversely, 63% of alterations detected in ctDNA were also detected in matched tissue. Examples demonstrating clinical utility are presented.
Conclusions: Genomic profiling of ctDNA detected potentially clinically relevant GAs in a significant subset of patients with gastrointestinal carcinomas. In these tumor types, most alterations detected in matched tissue were also detected in ctDNA, and with the exception of amplifications, ctDNA sequencing routinely detected additional alterations not found in matched tissue, consistent with tumor heterogeneity. These results suggest feasibility and utility of ctDNA testing in advanced gastrointestinal cancers as a complementary approach to tissue testing, and further investigation is warranted. Clin Cancer Res; 24(8); 1881–90. ©2018 AACR.
https://ift.tt/2EGWzqs
Small-Cell Neuroendocrine Tumors: Cell State Trumps the Oncogenic Driver
Small-cell neuroendocrine cancers often originate in the lung but can also arise in the bladder or prostate. Phenotypically, small-cell carcinoma of the bladder (SCCB) shares many similarities with small-cell lung cancer (SCLC). It is unknown whether SCCB and SCLC share common genetic driver mutations. Clin Cancer Res; 24(8); 1775–6. ©2018 AACR.
See related article by Chang et al., p. 1965
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Ponatinib Shows Potent Antitumor Activity in Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) through Multikinase Inhibition
Purpose: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits SMARCA4 and SMARCA2. A great need exists for effective targeted therapies for SCCOHT.
Experimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two patient-derived xenograft (PDX) models and one cell-line xenograft model of SCCOHT.
Results: The receptor tyrosine kinase (RTK) family was enriched in siRNA screen hits, with FGFRs and PDGFRs being overlapping hits between drug and siRNA screens. Of multiple potent drug classes in SCCOHT cell lines, RTK inhibitors were only one of two classes with selectivity in SCCOHT relative to three SWI/SNF wild-type ovarian cancer cell lines. We further identified ponatinib as the most effective clinically approved RTK inhibitor. Reexpression of SMARCA4 was shown to confer a 1.7-fold increase in resistance to ponatinib. Subsequent proteomic assessment of ponatinib target modulation in SCCOHT cell models confirmed inhibition of nine known ponatinib target kinases alongside 77 noncanonical ponatinib targets in SCCOHT. Finally, ponatinib delayed tumor doubling time 4-fold in SCCOHT-1 xenografts while reducing final tumor volumes in SCCOHT PDX models by 58.6% and 42.5%.
Conclusions: Ponatinib is an effective agent for SMARCA4-mutant SCCOHT in both in vitro and in vivo preclinical models through its inhibition of multiple kinases. Clinical investigation of this FDA-approved oncology drug in SCCOHT is warranted. Clin Cancer Res; 24(8); 1932–43. ©2018 AACR.
https://ift.tt/2EIhuZZ
Harnessing the Power of Patient-Reported Outcomes in Oncology
Patient-reported outcomes (PRO) represent an increasingly important mechanism for incorporating patients' experiences and perspectives into their care to enhance cancer care delivery and outcomes. In this article, we discuss the importance of integrating PROs into both the clinical and research settings in oncology and highlight potential challenges. Clin Cancer Res; 24(8); 1777–9. ©2018 AACR.
See related article by Kim et al., p. 1780
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Use of PRO Measures to Inform Tolerability in Oncology Trials: Implications for Clinical Review, IND Safety Reporting, and Clinical Site Inspections
Cancer therapeutics frequently lead to symptomatic adverse events (AE) that can affect treatment tolerability. The NCI has developed the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to assess symptomatic AEs by direct patient self-report. Although longitudinal assessment of patient-reported symptomatic AEs holds promise to better inform treatment tolerability, using patient-reported outcome (PRO) measures to assess symptomatic AEs has raised several regulatory and good clinical practice issues among those who conduct cancer clinical trials. These include concerns regarding trial monitoring, clinical review of PRO results by investigators and delegated clinical staff, whether PRO data on symptomatic AEs require investigational new drug (IND) safety reporting, and how the trial conduct and resultant PRO data will be assessed during clinical investigator site inspections. This article addresses current thinking regarding these issues in cancer clinical trials from the FDA, the NCI, and the Office for Human Research Protections. PRO measures, such as PRO-CTCAE, that assess symptomatic AEs in cancer trials are considered similar to other PRO assessments of symptoms, function, and health-related quality of life and can generate complementary data that may inform tolerability. Clarity on operational concerns related to incorporating PRO measures to inform tolerability is critical to continue the advancement of rigorous PRO assessment in cancer clinical trials. Clin Cancer Res; 24(8); 1780–4. ©2017 AACR.
See related commentary by Nipp and Temel, p. 1777
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A Combination of SAHA and Quinacrine Is Effective in Inducing Cancer Cell Death in Upper Gastrointestinal Cancers
Purpose: We aimed to investigate the therapeutic efficacy of single agent and the combination of quinacrine and suberoylanilide hydroxamic acid (SAHA) in wt- and mut-p53 upper gastrointestinal cancer (UGC) cell models.
Experimental Design: ATP-Glo, clonogenic cell survival, Annexin V, comet, DNA double-strand breaks (DSBs), qPCR, and Western blot analysis assays were utilized.
Results: Using clonogenic cell survival, ATP-Glo cell viability, Annexin V, and sub-G0 population analysis, we demonstrated that a combination of quinacrine and SAHA significantly decreased colony formation and increased cancer cell death (range, 4–20 fold) in six UGC cell models, as compared with single-agent treatments, irrespective of the p53 status (P < 0.01). The combination of quinacrine and SAHA induced high levels of DSB DNA damage (>20-fold, P < 0.01). Western blot analysis showed activation of caspases-3, 9, and -H2AX in all cell models. Of note, although quinacrine treatment induced expression of wt-p53 protein, the combination of quinacrine and SAHA substantially decreased the levels of both wt-P53 and mut-P53. Furthermore, cell models that were resistant to cisplatin (CDDP) or gefitinib treatments were sensitive to this combination. Tumor xenograft data confirmed that a combination of quinacrine and SAHA is more effective than a single-agent treatment in abrogating tumor growth in vivo (P < 0.01).
Conclusions: Our novel findings show that the combination of quinacrine and SAHA promotes DNA damage and is effective in inducing cancer cell death, irrespective of p53 status and resistance to CDDP or gefitinib in UGC models. Clin Cancer Res; 24(8); 1905–16. ©2018 AACR.
https://ift.tt/2EHTfLx
Analysis of Drug Development Paradigms for Immune Checkpoint Inhibitors
Immune checkpoint inhibitors have unique toxicities and response kinetics compared with cytotoxic and gene-targeted anticancer agents. We investigated the impact of innovative/accelerated immunotherapy drug development/approval models on the accuracy of safety and efficacy assessments by searching the FDA website. Initial phase I trials for each agent were reviewed and safety and efficacy data compared with that found in later trials leading to regulatory approvals of the same agents. As of June 2017, the FDA approved six checkpoint inhibitors for a variety of cancer types. All checkpoint inhibitors received a priority review status and access to at least two additional FDA special access programs, more often breakthrough therapy designation and accelerated approval. Median clinical development time (investigational new drug application to approval) was 60.77 months [avelumab had the shortest timeline (52.33 months)]. Response rates during early phase I trials (median = 16%) are higher than for phase I trials of other agents (with the exception of gene-targeted agents tested with a biomarker). Doses approved were usually not identical to doses recommended on phase I trials. Approximately 50% of types of immune-related and 43% of types of clinically relevant toxicities from later trials were identified in early-phase trials. Even so, treatment-related mortality remains exceedingly low in later studies (0.33% of patients). In conclusion, efficacy and safety of immune checkpoint inhibitors appear to be reasonably predicted from the dose-finding portion of phase I trials, indicating that the fast-track development of these agents is safe and justified. Clin Cancer Res; 24(8); 1785–94. ©2017 AACR.
https://ift.tt/2EIdjNQ
Drug Resistance in HER2-Positive Breast Cancer Brain Metastases: Blame the Barrier or the Brain?
The brain is the most common site of first metastasis for patients with HER2-positive breast cancer treated with HER2-targeting drugs. However, the development of effective therapies for breast cancer brain metastases (BCBM) is limited by an incomplete understanding of the mechanisms governing drug sensitivity in the central nervous system. Pharmacodynamic data from patients and in vivo models suggest that inadequate drug penetration across the "blood–tumor" barrier is not the whole story. Using HER2-positive BCBMs as a case study, we highlight recent data from orthotopic brain metastasis models that implicate brain-specific drug resistance mechanisms in BCBMs and suggest a translational research paradigm to guide drug development for treatment of BCBMs. Clin Cancer Res; 24(8); 1795–804. ©2018 AACR.
https://ift.tt/2JJ4C9E
Long Noncoding RNA LINC01234 Functions as a Competing Endogenous RNA to Regulate CBFB Expression by Sponging miR-204-5p in Gastric Cancer
Purpose: Long noncoding RNAs (lncRNAs) have emerged as important regulators in a variety of human diseases, including cancers. However, the overall biological roles and clinical significance of most lncRNAs in gastric carcinogenesis are not fully understood. We investigated the clinical significance, biological function, and mechanism of LINC01234 in gastric cancer.
Experimental Design: First, we analyzed LINC01234 alterations in gastric cancerous and noncancerous tissues through an analysis of sequencing data obtained from The Cancer Genome Atlas. Next, we evaluated the effect of LINC01234 on the gastric cancer cell proliferation and apoptosis, and its regulation of miR-204-5p by acting as a competing endogenous RNA (ceRNA). The animal model was used to support the in vitro experimental findings.
Results: We found that LINC01234 expression was significantly upregulated in gastric cancer tissues and was associated with larger tumor size, advanced TNM stage, lymph node metastasis, and shorter survival time. Furthermore, knockdown of LINC01234-induced apoptosis and growth arrest in vitro and inhibited tumorigenesis in mouse xenografts. Mechanistic investigations indicated that LINC01234 functioned as a ceRNA for miR-204-5p, thereby leading to the derepression of its endogenous target core-binding factor β (CBFB).
Conclusions: LINC01234 is significantly overexpressed in gastric cancer, and LINC01234–miR-204-5p–CBFB axis plays a critical role in gastric cancer tumorigenesis. Our findings may provide a potential new target for gastric cancer diagnosis and therapy. Clin Cancer Res; 24(8); 2002–14. ©2018 AACR.
https://ift.tt/2v9nhbI
Pembrolizumab Plus Pegylated Interferon alfa-2b or Ipilimumab for Advanced Melanoma or Renal Cell Carcinoma: Dose-Finding Results from the Phase Ib KEYNOTE-029 Study
Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC.
Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review.
Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC.
Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805–15. ©2018 AACR.
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Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA
Purpose: Decisions to continue or suspend therapy with immune checkpoint inhibitors are commonly guided by tumor dynamics seen on serial imaging. However, immunotherapy responses are uniquely challenging to interpret because tumors often shrink slowly or can appear transiently enlarged due to inflammation. We hypothesized that monitoring tumor cell death in real time by quantifying changes in circulating tumor DNA (ctDNA) levels could enable early assessment of immunotherapy efficacy.
Experimental Design: We compared longitudinal changes in ctDNA levels with changes in radiographic tumor size and with survival outcomes in 28 patients with metastatic non–small cell lung cancer (NSCLC) receiving immune checkpoint inhibitor therapy. CtDNA was quantified by determining the allele fraction of cancer-associated somatic mutations in plasma using a multigene next-generation sequencing assay. We defined a ctDNA response as a >50% decrease in mutant allele fraction from baseline, with a second confirmatory measurement.
Results: Strong agreement was observed between ctDNA response and radiographic response (Cohen's kappa, 0.753). Median time to initial response among patients who achieved responses in both categories was 24.5 days by ctDNA versus 72.5 days by imaging. Time on treatment was significantly longer for ctDNA responders versus nonresponders (median, 205.5 vs. 69 days; P < 0.001). A ctDNA response was associated with superior progression-free survival [hazard ratio (HR), 0.29; 95% CI, 0.09–0.89; P = 0.03], and superior overall survival (HR, 0.17; 95% CI, 0.05–0.62; P = 0.007).
Conclusions: A drop in ctDNA level is an early marker of therapeutic efficacy and predicts prolonged survival in patients treated with immune checkpoint inhibitors for NSCLC. Clin Cancer Res; 24(8); 1872–80. ©2018 AACR.
https://ift.tt/2JFx78i
Phase I Study of Single-Agent Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Patients with Advanced Cancer
Purpose: Utomilumab (PF-05082566) is an agonistic mAb that engages the immune costimulatory molecule 4-1BB/CD137. In this first-in-human, phase I, open-label, multicenter, multiple-dose study (NCT01307267) we evaluated safety, tolerability, pharmacokinetics, preliminary clinical activity, and pharmacodynamics of single-agent utomilumab in patients with advanced malignancies.
Experimental Design: Dose escalation was based on a standard 3+3 design for doses of utomilumab from 0.006 to 0.3 mg/kg every 4 weeks and a time-to-event continual reassessment method for utomilumab 0.6 to 10 mg/kg every 4 weeks. The primary study endpoint was dose-limiting toxicity (DLT) in the first two cycles.
Results: Utomilumab demonstrated a well-tolerated safety profile (N = 55). None of the patients experienced a DLT at the dose levels evaluated. The most common treatment-related adverse events were fatigue, pyrexia, decreased appetite, dizziness, and rash (<10% of patients). Only one (1.8%) patient experienced a grade 3–4 treatment-related adverse event (fatigue), and no clinically relevant elevations in transaminases were noted. Utomilumab demonstrated linear pharmacokinetics at doses ranging from 0.006 to 10 mg/kg, with similar safety and pharmacokinetics in anti-drug antibody (ADA)-negative and ADA-positive patients. The overall objective response rate was 3.8% (95% CI, 0.5%–13.0%) in patients with solid tumors and 13.3% in patients with Merkel cell carcinoma, including a complete response and a partial response. Circulating biomarkers support 4-1BB/CD137 engagement by utomilumab and suggest that circulating lymphocyte levels may influence probability of clinical benefit.
Conclusions: The favorable safety profile and preliminary antitumor activity demonstrated by utomilumab warrant further evaluation in patients with advanced malignancies. Clin Cancer Res; 24(8); 1816–23. ©2018 AACR.
https://ift.tt/2JJ4A1w
Nitric Oxide Production by Myeloid-Derived Suppressor Cells Plays a Role in Impairing Fc Receptor-Mediated Natural Killer Cell Function
Purpose: mAbs are used to treat solid and hematologic malignancies and work in part through Fc receptors (FcRs) on natural killer cells (NK). However, FcR-mediated functions of NK cells from patients with cancer are significantly impaired. Identifying the mechanisms of this dysfunction and impaired response to mAb therapy could lead to combination therapies and enhance mAb therapy.
Experimental Design: Cocultures of autologous NK cells and MDSC from patients with cancer were used to study the effect of myeloid-derived suppressor cells (MDSCs) on NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in vitro. Mouse breast cancer models were utilized to study the effect of MDSCs on antibody therapy in vivo and test the efficacy of combination therapies including a mAb and an MDSC-targeting agent.
Results: MDSCs from patients with cancer were found to significantly inhibit NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in a contact-independent manner. In addition, adoptive transfer of MDSCs abolished the efficacy of mAb therapy in a mouse model of pancreatic cancer. Inhibition of iNOS restored NK-cell functions and signal transduction. Finally, nonspecific elimination of MDSCs or inhibition of iNOS in vivo significantly improved the efficacy of mAb therapy in a mouse model of breast cancer.
Conclusions: MDSCs antagonize NK-cell FcR-mediated function and signal transduction leading to impaired response to mAb therapy in part through nitric oxide production. Thus, elimination of MDSCs or inhibition of nitric oxide production offers a strategy to improve mAb therapy. Clin Cancer Res; 24(8); 1891–904. ©2018 AACR.
https://ift.tt/2JJ4tTE
Measuring Processes of Care in Palliative Surgery: A Novel Approach Using Natural Language Processing
Palliative surgical procedures are often performed for patients with limited survival. Quality measures for processes of care at the end of life are appropriate in palliative surgery, but have not been applied in this patient population. In this paper, the authors propose 4 quality measures for end-of-life care in a palliative surgery, and then demonstrate the utility of natural language processing for implementing these measures.https://ift.tt/2GR2oaF
To Cut is to Cure: The Surgeon's Role in Improving Value
No abstract availablehttps://ift.tt/2GO9vR4
Cause-specific Mortality in a Population-based Cohort of 9799 Women Treated for Ductal Carcinoma In Situ
Objective: To assess cause-specific mortality in women treated for ductal carcinoma in situ (DCIS). Background: From screening and treatment perspective, it is relevant to weigh the low breast cancer mortality after DCIS against mortality from other causes and expected mortality in the general population. Methods: We conducted a population-based cohort study comprising 9799 Dutch women treated for primary DCIS between 1989 and 2004 and estimated standardized mortality ratios (SMRs). Results: After a median follow up of 9.8 years, 1429 patients had died of whom 284 caused by breast cancer (2.9% of total cohort). DCIS patients 50 had significantly lower mortality (SMR 0.9; 95% CI: 0.8–0.9). Overall, the risk of dying from general diseases and cancer other than breast cancer was lower than in the general population, whereas breast cancer mortality was increased. The SMR for breast cancer decreased from 7.5 (95% CI: 5.9–9.3) to 2.8 (95% CI: 2.4–3.2) for women aged 50 years, respectively. The cumulative breast cancer mortality 10 years after DCIS was 2.3% for women 50 years treated for DCIS between 1999 and 2004. Conclusions: DCIS patients >50 years had lower risk of dying from all causes combined compared with the general female population, which may reflect differences in health behavior. Women with DCIS had higher risk of dying from breast cancer than the general population, but absolute 10-year risks were low.https://ift.tt/2GR4B5N
ALPPS Improves Resectability Compared With Conventional Two-stage Hepatectomy in Patients With Advanced Colorectal Liver Metastasis: Results From a Scandinavian Multicenter Randomized Controlled Trial (LIGRO Trial)
Objective: The aim of the study was to evaluate if associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) could increase resection rates (RRs) compared with two-stage hepatectomy (TSH) in a randomized controlled trial (RCT). Background: Radical liver metastasis resection offers the only chance of a cure for patients with metastatic colorectal cancer. Patients with colorectal liver metastasis (CRLM) and an insufficient future liver remnant (FLR) volume are traditionally treated with chemotherapy with portal vein embolization or ligation followed by hepatectomy (TSH). This treatment sometimes fails due to insufficient liver growth or tumor progression. Methods: A prospective, multicenter RCT was conducted between June 2014 and August 2016. It included 97 patients with CRLM and a standardized FLR (sFLR) of less than 30%. Primary outcome—RRs were measured as the percentages of patients completing both stages of the treatment. Secondary outcomes were complications, radicality, and 90-day mortality measured from the final intervention. Results: Baseline characteristics, besides body mass index, did not differ between the groups. The RR was 92% [95% confidence interval (CI) 84%–100%] (44/48) in the ALPPS arm compared with 57% (95% CI 43%–72%) (28/49) in the TSH arm [rate ratio 8.25 (95% CI 2.6–26.6); Phttps://ift.tt/2GQTcmH
Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer [Research Articles]
The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of ALK mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4-ALK. Under comparable conditions, ENU mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single ALK mutations. In similar screens with EML4-ALK containing single ALK resistance mutations, numerous lorlatinib-resistant clones emerged harboring compound ALK mutations. To determine the clinical relevance of these mutations, we analyzed repeat biopsies from lorlatinib-resistant patients. Seven of 20 samples (35%) harbored compound ALK mutations, including two identified in the ENU screen. Whole exome sequencing in three cases confirmed the stepwise accumulation of ALK mutations during sequential treatment. These results suggest that sequential ALK inhibitors can foster the emergence of compound ALK mutations, identification of which is critical to informing drug design and developing effective therapeutic strategies.
https://ift.tt/2v6BJBf
PDGF-A signaling is required for secondary alveolar septation and controls epithelial proliferation in the developing lung [RESEARCH ARTICLE]
Platelet-derived growth factor A (PDGF-A) signaling through PDGF receptor α is essential for alveogenesis. Previous studies have shown that Pdgfa–/– mouse lungs have enlarged alveolar airspace with absence of secondary septation, both distinctive features of bronchopulmonary dysplasia. To study how PDGF-A signaling is involved in alveogenesis, we generated lung-specific Pdgfa knockout mice (Pdgfafl/–; Spc-cre) and characterized their phenotype postnatally. Histological differences between mutant mice and littermate controls were visible after the onset of alveogenesis and maintained until adulthood. Additionally, we generated Pdgfafl/–; Spc-cre; PdgfraGFP/+ mice in which Pdgfra+ cells exhibit nuclear GFP expression. In the absence of PDGF-A, the number of PdgfraGFP+ cells was significantly decreased. In addition, proliferation of PdgfraGFP+ cells was reduced. During alveogenesis, PdgfraGFP+ myofibroblasts failed to form the α-smooth muscle actin rings necessary for alveolar secondary septation. These results indicate that PDGF-A signaling is involved in myofibroblast proliferation and migration. In addition, we show an increase in both the number and proliferation of alveolar type II cells in Pdgfafl/–; Spc-cre lungs, suggesting that the increased alveolar airspace is not caused solely by deficient myofibroblast function.
https://ift.tt/2IOBXyL
Disrupting the three-dimensional regulatory topology of the Pitx1 locus results in overtly normal development [RESEARCH ARTICLE]
Developmental gene expression patterns are orchestrated by thousands of distant-acting transcriptional enhancers. However, identifying enhancers essential for the expression of their target genes has proven challenging. Maps of long-range regulatory interactions may provide the means to identify enhancers crucial for developmental gene expression. To investigate this hypothesis, we used circular chromosome conformation capture coupled with interaction maps in the mouse limb to characterize the regulatory topology of Pitx1, which is essential for hindlimb development. We identified a robust hindlimb-specific interaction between Pitx1 and a putative hindlimb-specific enhancer. To interrogate the role of this interaction in Pitx1 regulation, we used genome editing to delete this enhancer in mouse. Although deletion of the enhancer completely disrupts the interaction, Pitx1 expression in the hindlimb is only mildly affected, without any detectable compensatory interactions between the Pitx1 promoter and potentially redundant enhancers. Pitx1 enhancer null mice did not exhibit any of the characteristic morphological defects of the Pitx1–/– mutant. Our results suggest that robust, tissue-specific physical interactions at essential developmental genes have limited predictive value for identifying enhancer mutations with strong loss-of-function phenotypes.
https://ift.tt/2IOQv1n
Regulation and function of H3K36 di-methylation by the trithorax-group protein complex AMC [RESEARCH ARTICLE]
The Drosophila Ash1 protein is a trithorax-group (trxG) regulator that antagonizes Polycomb repression at HOX genes. Ash1 di-methylates lysine 36 in histone H3 (H3K36me2) but how this activity is controlled and at which genes it functions is not well understood. We show that Ash1 protein purified from Drosophila exists in a complex with MRG15 and Caf1 that we named AMC. In Drosophila and human AMC, MRG15 binds a conserved FxLP motif near the Ash1 SET domain and stimulates H3K36 di-methylation on nucleosomes. Drosophila MRG15-null and ash1 catalytic mutants show remarkably specific trxG phenotypes: stochastic loss of HOX gene expression and homeotic transformations in adults. In mutants lacking AMC, H3K36me2 bulk levels appear undiminished but H3K36me2 is reduced in the chromatin of HOX and other AMC-regulated genes. AMC therefore appears to act on top of the H3K36me2/me3 landscape generated by the major H3K36 methyltransferases NSD and Set2. Our analyses suggest that H3K36 di-methylation at HOX genes is the crucial physiological function of AMC and the mechanism by which the complex antagonizes Polycomb repression at these genes.
https://ift.tt/2IRCWhT
Conserved functional control, but distinct regulation, of cell proliferation in rice and Arabidopsis leaves revealed by comparative analysis of GRF-INTERACTING FACTOR 1 orthologs [RESEARCH ARTICLE]
Regulation of cell proliferation is crucial for establishing the shape of plant leaves. We have identified MAKIBA3 (MKB3), a loss-of-function mutant of which exhibits a narrowed- and rolled-leaf phenotype in rice. MKB3 was found to be an ortholog of Arabidopsis ANGUSTIFOLIA3 (AN3), which positively regulates cell proliferation. The reduced leaf size of mkb3 plants with enlarged cells and the increased size of MKB3-overexpressing leaves with normal-sized cells indicate that MKB3 is a positive regulator of leaf proliferation and that mkb3 mutation triggers a compensation syndrome, as does Arabidopsis an3. Expression analysis revealed that MKB3 is predominantly expressed on the epidermis of leaf primordia, which is different from the location of AN3. A protein movement assay demonstrated that MKB3 moves from an MKB3-expressing domain to a non-expressing domain, which is required for normal leaf development. Our results suggest that rice MKB3 and Arabidopsis AN3 have conserved functions and effects on leaf development. However, the expression pattern of MKB3 and direction of protein movement are different between rice and Arabidopsis, which might reflect differences in leaf primordia development in these two species.
https://ift.tt/2qtY2fe
Xenopus ADAM19 regulates Wnt signaling and neural crest specification by stabilizing ADAM13 [RESEARCH ARTICLE]
During vertebrate gastrulation, canonical Wnt signaling induces the formation of neural plate border (NPB). Wnt is also thought to be required for the subsequent specification of neural crest (NC) lineage at the NPB, but the direct evidence is lacking. We found previously that the disintegrin metalloproteinase ADAM13 is required for Wnt activation and NC induction in Xenopus. Here, we report that knockdown of ADAM13 or its close paralog ADAM19 severely downregulates Wnt activity at the NPB, inhibiting NC specification without affecting earlier NPB formation. Surprisingly, ADAM19 functions nonproteolytically in NC specification by interacting with ADAM13 and inhibiting its proteasomal degradation. Ectopic expression of stabilized ADAM13 mutants that function independently of ADAM19 can induce the NC marker/specifier snail2 in the future epidermis via Wnt signaling. These results unveil the essential roles of a novel protease-protease interaction in regulating a distinct wave of Wnt signaling, which directly specifies the NC lineage.
https://ift.tt/2qtXYw0
Polycomb group (PcG) proteins and Pax6 cooperate to inhibit in vivo reprogramming of the developing Drosophila eye [RESEARCH ARTICLE]
How different cells and tissues commit to and determine their fates has been a central question in developmental biology since the seminal embryological experiments conducted by Wilhelm Roux and Hans Driesch in sea urchins and frogs. Here, we demonstrate that Polycomb group (PcG) proteins maintain Drosophila eye specification by suppressing the activation of alternative fate choices. The loss of PcG in the developing eye results in a cellular reprogramming event in which the eye is redirected to a wing fate. This fate transformation occurs with either the individual loss of Polycomb proteins or the simultaneous reduction of the Pleiohomeotic repressive complex and Pax6. Interestingly, the requirement for retinal selector genes is limited to Pax6, as the removal of more downstream members does not lead to the eye-wing transformation. We also show that distinct PcG complexes are required during different developmental windows throughout eye formation. These findings build on earlier observations that the eye can be reprogrammed to initiate head epidermis, antennal and leg development.
https://ift.tt/2qtXUfK
PUF-8 facilitates homologous chromosome pairing by promoting proteasome activity during meiotic entry in C. elegans [RESEARCH ARTICLE]
Pairing of homologous chromosomes is essential for genetic recombination during gametogenesis. In many organisms, chromosome ends are attached to cytoplasmic dynein, and dynein-driven chromosomal movements facilitate the pairing process. Factors that promote or control the cytoskeletal tethering of chromosomes are largely unknown. Here, we show that the conserved RNA-binding protein PUF-8 facilitates the tethering and pairing processes in the C. elegans germline by promoting proteasome activity. We have isolated a hypomorphic allele of pas-1, which encodes a proteasome core subunit, and find that the homologous chromosomes fail to pair in the puf-8; pas-1 double mutant due to failure of chromosome tethering. Our results reveal that the puf-8; pas-1 meiotic defects are caused by the loss of proteasome activity. The axis component HTP-3 accumulates prematurely in the double mutant, and reduction of its activity partially suppresses some of the puf-8; pas-1 meiotic defects, suggesting that HTP-3 might be an important target of the proteasome in promoting early meiotic events. In summary, our results reveal a role for the proteasome in chromosome tethering and identify PUF-8 as a regulator of proteasome activity during early meiosis.
https://ift.tt/2vcDrRA
The heart tube forms and elongates through dynamic cell rearrangement coordinated with foregut extension [RESEARCH ARTICLE]
In the initiation of cardiogenesis, the heart primordia transform from bilateral flat sheets of mesoderm into an elongated midline tube. Here, we discover that this rapid architectural change is driven by actomyosin-based oriented cell rearrangement and resulting dynamic tissue reshaping (convergent extension, CE). By labeling clusters of cells spanning the entire heart primordia, we show that the heart primordia converge toward the midline to form a narrow tube, while extending perpendicularly to rapidly lengthen it. Our data for the first time visualize the process of early heart tube formation from both the medial (second) and lateral (first) heart fields, revealing that both fields form the early heart tube by essentially the same mechanism. Additionally, the adjacent endoderm coordinately forms the foregut through previously unrecognized movements that parallel those of the heart mesoderm and elongates by CE. In conclusion, our data illustrate how initially two-dimensional flat primordia rapidly change their shapes and construct the three-dimensional morphology of emerging organs in coordination with neighboring morphogenesis.
https://ift.tt/2HmVslf
In vivo imaging: shining a light on stem cells in the living animal [SPOTLIGHT]
Stem cells are undifferentiated cells that play crucial roles during development, growth and regeneration. Traditionally, these cells have been primarily characterised by histology, cell sorting, cell culture and ex vivo methods. However, as stem cells interact in a complex environment within specific tissue niches, there has been increasing interest in examining their in vivo behaviours, particularly in response to injury. Advances in imaging technologies and genetic tools have converged to enable unprecedented access to the endogenous stem cell niche. In this Spotlight article, we highlight how in vivo imaging can probe a range of biological processes that relate to stem cell activity, behaviour and control.
https://ift.tt/2HiMbdG
The ontogeny, activation and function of the epicardium during heart development and regeneration [REVIEW]
The epicardium plays a key role during cardiac development, homeostasis and repair, and has thus emerged as a potential target in the treatment of cardiovascular disease. However, therapeutically manipulating the epicardium and epicardium-derived cells (EPDCs) requires insights into their developmental origin and the mechanisms driving their activation, recruitment and contribution to both the embryonic and adult injured heart. In recent years, studies of various model systems have provided us with a deeper understanding of the microenvironment in which EPDCs reside and emerge into, of the crosstalk between the multitude of cardiovascular cell types that influence the epicardium, and of the genetic programmes that orchestrate epicardial cell behaviour. Here, we review these discoveries and discuss how technological advances could further enhance our knowledge of epicardium-based repair mechanisms and ultimately influence potential therapeutic outcomes in cardiovascular regenerative medicine.
https://ift.tt/2IPxa00
Head formation requires Dishevelled degradation that is mediated by March2 in concert with Dapper1 [RESEARCH ARTICLE]
Dishevelled (Dvl/Dsh) is a key scaffold protein that propagates Wnt signaling essential for embryogenesis and homeostasis. However, whether the antagonism of Wnt signaling that is necessary for vertebrate head formation can be achieved through regulation of Dsh protein stability is unclear. Here, we show that membrane-associated RING-CH2 (March2), a RING-type E3 ubiquitin ligase, antagonizes Wnt signaling by regulating the turnover of Dsh protein via ubiquitin-mediated lysosomal degradation in the prospective head region of Xenopus. We further found that March2 acquires regional and functional specificities for head formation from the Dsh-interacting protein Dapper1 (Dpr1). Dpr1 stabilizes the interaction between March2 and Dsh in order to mediate ubiquitylation and the subsequent degradation of Dsh protein only in the dorso-animal region of Xenopus embryo. These results suggest that March2 restricts cytosolic pools of Dsh protein and reduces the need for Wnt signaling in precise vertebrate head development.
https://ift.tt/2qsj26l
PDGF-A signaling is required for secondary alveolar septation and controls epithelial proliferation in the developing lung [RESEARCH ARTICLE]
Platelet-derived growth factor A (PDGF-A) signaling through PDGF receptor α is essential for alveogenesis. Previous studies have shown that Pdgfa–/– mouse lungs have enlarged alveolar airspace with absence of secondary septation, both distinctive features of bronchopulmonary dysplasia. To study how PDGF-A signaling is involved in alveogenesis, we generated lung-specific Pdgfa knockout mice (Pdgfafl/–; Spc-cre) and characterized their phenotype postnatally. Histological differences between mutant mice and littermate controls were visible after the onset of alveogenesis and maintained until adulthood. Additionally, we generated Pdgfafl/–; Spc-cre; PdgfraGFP/+ mice in which Pdgfra+ cells exhibit nuclear GFP expression. In the absence of PDGF-A, the number of PdgfraGFP+ cells was significantly decreased. In addition, proliferation of PdgfraGFP+ cells was reduced. During alveogenesis, PdgfraGFP+ myofibroblasts failed to form the α-smooth muscle actin rings necessary for alveolar secondary septation. These results indicate that PDGF-A signaling is involved in myofibroblast proliferation and migration. In addition, we show an increase in both the number and proliferation of alveolar type II cells in Pdgfafl/–; Spc-cre lungs, suggesting that the increased alveolar airspace is not caused solely by deficient myofibroblast function.
https://ift.tt/2IOBXyL
The mir-279/996 cluster represses receptor tyrosine kinase signaling to determine cell fates in the Drosophila eye [RESEARCH ARTICLE]
Photoreceptors in the crystalline Drosophila eye are recruited by receptor tyrosine kinase (RTK)/Ras signaling mediated by Epidermal growth factor receptor (EGFR) and the Sevenless (Sev) receptor. Analyses of an allelic deletion series of the mir-279/996 locus, along with a panel of modified genomic rescue transgenes, show that Drosophila eye patterning depends on both miRNAs. Transcriptional reporter and activity sensor transgenes reveal expression and function of miR-279/996 in non-neural cells of the developing eye. Moreover, mir-279/996 mutants exhibit substantial numbers of ectopic photoreceptors, particularly of R7, and cone cell loss. These miRNAs restrict RTK signaling in the eye, since mir-279/996 nulls are dominantly suppressed by positive components of the EGFR pathway and enhanced by heterozygosity for an EGFR repressor. miR-279/996 limit photoreceptor recruitment by targeting multiple positive RTK/Ras signaling components that promote photoreceptor/R7 specification. Strikingly, deletion of mir-279/996 sufficiently derepresses RTK/Ras signaling so as to rescue a population of R7 cells in R7-specific RTK null mutants boss and sev, which otherwise completely lack this cell fate. Altogether, we reveal a rare setting of developmental cell specification that involves substantial miRNA control.
https://ift.tt/2qqOYIa
Disrupting the three-dimensional regulatory topology of the Pitx1 locus results in overtly normal development [RESEARCH ARTICLE]
Developmental gene expression patterns are orchestrated by thousands of distant-acting transcriptional enhancers. However, identifying enhancers essential for the expression of their target genes has proven challenging. Maps of long-range regulatory interactions may provide the means to identify enhancers crucial for developmental gene expression. To investigate this hypothesis, we used circular chromosome conformation capture coupled with interaction maps in the mouse limb to characterize the regulatory topology of Pitx1, which is essential for hindlimb development. We identified a robust hindlimb-specific interaction between Pitx1 and a putative hindlimb-specific enhancer. To interrogate the role of this interaction in Pitx1 regulation, we used genome editing to delete this enhancer in mouse. Although deletion of the enhancer completely disrupts the interaction, Pitx1 expression in the hindlimb is only mildly affected, without any detectable compensatory interactions between the Pitx1 promoter and potentially redundant enhancers. Pitx1 enhancer null mice did not exhibit any of the characteristic morphological defects of the Pitx1–/– mutant. Our results suggest that robust, tissue-specific physical interactions at essential developmental genes have limited predictive value for identifying enhancer mutations with strong loss-of-function phenotypes.
https://ift.tt/2IOQv1n
Evolutionary divergence of the sex-determining gene MID uncoupled from the transition to anisogamy in volvocine algae [RESEARCH ARTICLE]
Volvocine algae constitute a unique comparative model for investigating the evolution of oogamy from isogamous mating types. The sex- or mating type-determining gene MID encodes a conserved RWP-RK transcription factor found in either the MT– or male mating locus of dioecious volvocine species. We previously found that MID from the isogamous species Chlamydomonas reinhardtii (CrMID) could not induce ectopic spermatogenesis when expressed heterologously in Volvox carteri females, suggesting coevolution of Mid function with gamete dimorphism. Here we found that ectopic expression of MID from the anisogamous species Pleodorina starrii (PsMID) could efficiently induce spermatogenesis when expressed in V. carteri females and, unexpectedly, that GpMID from the isogamous species Gonium pectorale was also able to induce V. carteri spermatogenesis. Neither VcMID nor GpMID could complement a C. reinhardtii mid mutant, at least partly owing to instability of heterologous Mid proteins. Our data show that Mid divergence was not a major contributor to the transition between isogamy and anisogamy/oogamy in volvocine algae, and instead implicate changes in cis-regulatory interactions and/or trans-acting factors of the Mid network in the evolution of sexual dimorphism.
https://ift.tt/2qylUPd
Evolutionarily conserved anterior expansion of the central nervous system promoted by a common PcG-Hox program [RESEARCH ARTICLE]
A conserved feature of the central nervous system (CNS) is the prominent expansion of anterior regions (brain) compared with posterior (nerve cord). The cellular and regulatory processes driving anterior CNS expansion are not well understood in any bilaterian species. Here, we address this expansion in Drosophila and mouse. We find that, compared with the nerve cord, the brain displays extended progenitor proliferation, more elaborate daughter cell proliferation and more rapid cell cycle speed in both Drosophila and mouse. These features contribute to anterior CNS expansion in both species. With respect to genetic control, enhanced brain proliferation is severely reduced by ectopic Hox gene expression, by either Hox misexpression or by loss of Polycomb group (PcG) function. Strikingly, in PcG mutants, early CNS proliferation appears to be unaffected, whereas subsequent brain proliferation is severely reduced. Hence, a conserved PcG-Hox program promotes the anterior expansion of the CNS. The profound differences in proliferation and in the underlying genetic mechanisms between brain and nerve cord lend support to the emerging concept of separate evolutionary origins of these two CNS regions.
https://ift.tt/2va7Xvd
L(3)mbt and the LINT complex safeguard cellular identity in the Drosophila ovary [RESEARCH ARTICLE]
Maintenance of cellular identity is essential for tissue development and homeostasis. At the molecular level, cell identity is determined by the coordinated activation and repression of defined sets of genes. The tumor suppressor L(3)mbt has been shown to secure cellular identity in Drosophila larval brains by repressing germline-specific genes. Here, we interrogate the temporal and spatial requirements for L(3)mbt in the Drosophila ovary, and show that it safeguards the integrity of both somatic and germline tissues. l(3)mbt mutant ovaries exhibit multiple developmental defects, which we find to be largely caused by the inappropriate expression of a single gene, nanos, a key regulator of germline fate, in the somatic ovarian cells. In the female germline, we find that L(3)mbt represses testis-specific and neuronal genes. At the molecular level, we show that L(3)mbt function in the ovary is mediated through its co-factor Lint-1 but independently of the dREAM complex. Together, our work uncovers a more complex role for L(3)mbt than previously understood and demonstrates that L(3)mbt secures tissue identity by preventing the simultaneous expression of original identity markers and tissue-specific misexpression signatures.
https://ift.tt/2IOBEE7
Polycomb group (PcG) proteins and Pax6 cooperate to inhibit in vivo reprogramming of the developing Drosophila eye [RESEARCH ARTICLE]
How different cells and tissues commit to and determine their fates has been a central question in developmental biology since the seminal embryological experiments conducted by Wilhelm Roux and Hans Driesch in sea urchins and frogs. Here, we demonstrate that Polycomb group (PcG) proteins maintain Drosophila eye specification by suppressing the activation of alternative fate choices. The loss of PcG in the developing eye results in a cellular reprogramming event in which the eye is redirected to a wing fate. This fate transformation occurs with either the individual loss of Polycomb proteins or the simultaneous reduction of the Pleiohomeotic repressive complex and Pax6. Interestingly, the requirement for retinal selector genes is limited to Pax6, as the removal of more downstream members does not lead to the eye-wing transformation. We also show that distinct PcG complexes are required during different developmental windows throughout eye formation. These findings build on earlier observations that the eye can be reprogrammed to initiate head epidermis, antennal and leg development.
https://ift.tt/2qtXUfK
PUF-8 facilitates homologous chromosome pairing by promoting proteasome activity during meiotic entry in C. elegans [RESEARCH ARTICLE]
Pairing of homologous chromosomes is essential for genetic recombination during gametogenesis. In many organisms, chromosome ends are attached to cytoplasmic dynein, and dynein-driven chromosomal movements facilitate the pairing process. Factors that promote or control the cytoskeletal tethering of chromosomes are largely unknown. Here, we show that the conserved RNA-binding protein PUF-8 facilitates the tethering and pairing processes in the C. elegans germline by promoting proteasome activity. We have isolated a hypomorphic allele of pas-1, which encodes a proteasome core subunit, and find that the homologous chromosomes fail to pair in the puf-8; pas-1 double mutant due to failure of chromosome tethering. Our results reveal that the puf-8; pas-1 meiotic defects are caused by the loss of proteasome activity. The axis component HTP-3 accumulates prematurely in the double mutant, and reduction of its activity partially suppresses some of the puf-8; pas-1 meiotic defects, suggesting that HTP-3 might be an important target of the proteasome in promoting early meiotic events. In summary, our results reveal a role for the proteasome in chromosome tethering and identify PUF-8 as a regulator of proteasome activity during early meiosis.
https://ift.tt/2vcDrRA
The heart tube forms and elongates through dynamic cell rearrangement coordinated with foregut extension [RESEARCH ARTICLE]
In the initiation of cardiogenesis, the heart primordia transform from bilateral flat sheets of mesoderm into an elongated midline tube. Here, we discover that this rapid architectural change is driven by actomyosin-based oriented cell rearrangement and resulting dynamic tissue reshaping (convergent extension, CE). By labeling clusters of cells spanning the entire heart primordia, we show that the heart primordia converge toward the midline to form a narrow tube, while extending perpendicularly to rapidly lengthen it. Our data for the first time visualize the process of early heart tube formation from both the medial (second) and lateral (first) heart fields, revealing that both fields form the early heart tube by essentially the same mechanism. Additionally, the adjacent endoderm coordinately forms the foregut through previously unrecognized movements that parallel those of the heart mesoderm and elongates by CE. In conclusion, our data illustrate how initially two-dimensional flat primordia rapidly change their shapes and construct the three-dimensional morphology of emerging organs in coordination with neighboring morphogenesis.
https://ift.tt/2HmVslf
Imprinted gene dysregulation in a Tet1 null mouse model is stochastic and variable in the germline and offspring [RESEARCH ARTICLE]
Imprinted genes are expressed from one parental allele and regulated by differential DNA methylation at imprinting control regions (ICRs). ICRs are reprogrammed in the germline through erasure and re-establishment of DNA methylation. Although much is known about DNA methylation establishment, DNA demethylation is less well understood. Recently, the Ten-Eleven Translocation proteins (TET1-3) have been shown to initiate DNA demethylation, with Tet1–/– mice exhibiting aberrant levels of imprinted gene expression and ICR methylation. Nevertheless, the role of TET1 in demethylating ICRs in the female germline and in controlling allele-specific expression remains unknown. Here, we examined ICR-specific DNA methylation in Tet1–/– germ cells and ascertained whether abnormal ICR methylation impacted imprinted gene expression in F1 hybrid somatic tissues derived from Tet1–/– eggs or sperm. We show that Tet1 deficiency is associated with hypermethylation of a subset of ICRs in germ cells. Moreover, ICRs with defective germline reprogramming exhibit aberrant DNA methylation and biallelic expression of linked imprinted genes in somatic tissues. Thus, we define a discrete set of genomic regions that require TET1 for germline reprogramming and discuss mechanisms for stochastic imprinting defects.
https://ift.tt/2IOQtqh
In vivo imaging: shining a light on stem cells in the living animal [SPOTLIGHT]
Stem cells are undifferentiated cells that play crucial roles during development, growth and regeneration. Traditionally, these cells have been primarily characterised by histology, cell sorting, cell culture and ex vivo methods. However, as stem cells interact in a complex environment within specific tissue niches, there has been increasing interest in examining their in vivo behaviours, particularly in response to injury. Advances in imaging technologies and genetic tools have converged to enable unprecedented access to the endogenous stem cell niche. In this Spotlight article, we highlight how in vivo imaging can probe a range of biological processes that relate to stem cell activity, behaviour and control.
https://ift.tt/2HiMbdG
The ontogeny, activation and function of the epicardium during heart development and regeneration [REVIEW]
The epicardium plays a key role during cardiac development, homeostasis and repair, and has thus emerged as a potential target in the treatment of cardiovascular disease. However, therapeutically manipulating the epicardium and epicardium-derived cells (EPDCs) requires insights into their developmental origin and the mechanisms driving their activation, recruitment and contribution to both the embryonic and adult injured heart. In recent years, studies of various model systems have provided us with a deeper understanding of the microenvironment in which EPDCs reside and emerge into, of the crosstalk between the multitude of cardiovascular cell types that influence the epicardium, and of the genetic programmes that orchestrate epicardial cell behaviour. Here, we review these discoveries and discuss how technological advances could further enhance our knowledge of epicardium-based repair mechanisms and ultimately influence potential therapeutic outcomes in cardiovascular regenerative medicine.
https://ift.tt/2IPxa00
BRAF and MEK inhibitors increase PD1-positive melanoma cells leading to a potential lymphocyte-independent synergism with anti-PD1 antibody
Purpose: BRAF and MEK inhibitors (BRAF/MEKi) favor melanoma-infiltrating lymphocytes, providing the rationale for current combinatorial trials with anti-PD1 antibody. A portion of melanoma cells may express PD1, and anti-PD1 antibody could have a direct anti-tumor effect. Here, we explore if BRAF/MEKi modulate rates of PD1+ melanoma cells, supporting an additional - lymphocyte-independent - basis for their therapeutic combination with anti-PD1 antibody. Experimental design: With data mining and flow cytometry, we assessed PD1, PDL1/2 expression on melanoma cell lines (CCLE, N=61; validation cell lines, N=7) and melanoma tumors (TCGA, N=214). We explored in-vitro how BRAF/MEKi affect rates of PD1+, PDL1/2+ melanoma cells, and characterized the proliferative and putative stemness features of PD1+ melanoma cells. We tested the functional lymphocyte-independent effect of anti-PD1 antibody alone and in combination with BRAF/MEKi in-vitro and in an in-vivo immunodeficient murine model. Results: PD1 is consistently expressed on a small subset of melanoma cells, but PD1+ cells increase to relevant rates during BRAF/MEKi treatment (7.3% [5.6-14.2] vs 1.5% [0.7-3.2], p=0.0156; N=7), together with PDL2+ melanoma cells (8.5% [0.0-63.0] vs 1.5% [0.2-43.3], p=0.0312; N=7). PD1+ cells proliferate less than PD1- cells (avg. 65% less; t=7 days), and are preferentially endowed with stemness features. In-vivo, the direct anti-melanoma activity of PD1-blockage as monotherapy was negligible, but its association with BRAF/MEKi significantly delayed the development of drug resistance and tumor relapse. Conclusions: BRAF/MEKi increase the rates of PD1+ melanoma cells that may sustain tumor relapse, providing a lymphocyte-independent rational to explore combinatory strategies with anti-PD1 antibody.
https://ift.tt/2GU0uWK
FDA Approval Summary: Niraparib for the maintenance treatment of patients with recurrent ovarian cancer in response to platinum-based chemotherapy
The Food and Drug Administration approved niraparib, a poly ADP ribose polymerase (PARP) inhibitor, on March 27, 2017, for maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response to platinum-based chemotherapy. Approval was based on data from the NOVA trial comparing niraparib with placebo in two independent cohorts, based on germline BRCA mutation status (gBRCAm vs. non-gBRCAm). Progression-free survival (PFS) in each cohort was the primary endpoint. In the gBRCAm cohort, estimated median PFS on niraparib was 21 months vs. 5.5 months on placebo (HR 0.26; 95% CI: 0.17, 0.41; p-value <0.0001). In the non-gBRCAm cohort, estimated median PFS for niraparib and placebo was 9.3 months and 3.9 months, respectively (HR 0.45; 95% CI: 0.34, 0.61; p<0.0001). Common adverse reactions (>20% and higher incidence in niraparib arm) with niraparib include thrombocytopenia, anemia, neutropenia, nausea, constipation, vomiting, mucositis, fatigue, decreased appetite, headache, insomnia, nasopharyngitis, dyspnea, rash, and hypertension. There were 5 cases of MDS/AML (1.4%) in patients treated with niraparib compared with 2 cases (1.1%) on placebo. Niraparib is the first PARP inhibitor approved as maintenance therapy for ovarian, fallopian tube, or primary peritoneal cancer patients, with improvement in PFS, for patients regardless of gBRCAm status.
https://ift.tt/2qpkhSS
Next-Generation Sequencing of the Complete Mitochondrial Genome of the Endangered Species Black Lion Tamarin Leontopithecus chrysopygus (Primates) and Mitogenomic Phylogeny Focusing on the Callitrichidae Family
We describe the complete mitochondrial genome sequence of the Black Lion Tamarin, an endangered primate species endemic to the Atlantic Rainforest of Brazil. We assembled the Leontopithecus chrysopygus mitogenome, through analysis of 523M base pairs (bp) of short reads produced by next-generation sequencing (NGS) on the Illumina Platform, and investigated the presence of nuclear mitochondrial pseudogenes and heteroplasmic sites. Additionally, we conducted phylogenetic analyses using all complete mitogenomes available for primates until June 2017. The single circular mitogenome of BLT showed organization and arrangement that are typical for other vertebrate species, with a total of 16618 bp, containing 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and 1 non-coding region (D-loop region). Our full phylogenetic tree is based on the most comprehensive mitogenomic dataset for Callitrichidae species to date, adding new data for the Leontopithecus genus, and discussing previous studies performed on primates. Moreover, the mitochondrial genome reported here consists of a robust mitogenome with 3000X coverage, which certainly will be useful for further phylogenetic and evolutionary analyses of Callitrichidae and higher taxa.
https://ift.tt/2HkZPx1
Rare Presentation of Intraductal Papillary Neoplasm of the Bile Duct in a Patient With Ulcerative Colitis
A 67-year-old man with insulin-dependent diabetes mellitus and ulcerative colitis presented with worsening pruritus and weight loss. Liver biochemistry showed the following significant cholestatic abnormalities: γ-glutamyltransferase - 1886 IU/mL (<60 IU/mL); alkaline phosphatase - 1201 IU/mL (<110 IU/mL); bilirubin - 66 μmol/L (<24 μmol/L); and near-normal transaminase levels. Magnetic resonant cholangiopancreatogram showed mild proximal dilatation of the extrahepatic bile duct and irregular, abnormally dilated, left-sided biliary radicles.
https://ift.tt/2v877zp
Pharmacists Can Help With DM Management Via Telemedicine
THURSDAY, April 12, 2018 -- Pharmacist use of telemedicine is a promising vehicle for improving patient management of diabetes, according to an article published in Drug Topics. Noting that 50 percent of all drug errors involve insulin and that 97...
https://ift.tt/2qr5ckm
Recent Years Saw Increase in Burden of Prior Authorization
THURSDAY, April 12, 2018 -- The burden of prior authorization (PA) has increased over the past five years, and 92 percent of physicians report associated delays in access to care, according to the results of a survey published by the American...
https://ift.tt/2IO5AjO
Quality of Life Predicts Mortality in Older Breast Cancer Patients
THURSDAY, April 12, 2018 -- For older women with early-stage breast cancer, measures of health-related quality of life (HRQOL) predict 10-year mortality independently of traditional breast cancer prognostic variables, according to a study published...
https://ift.tt/2qsqu1n
Negative Fateful Life Events Linked to Advanced Brain Aging
THURSDAY, April 12, 2018 -- Negative fateful life events (FLEs) in midlife are associated with advanced predicted brain aging, according to a study published in the July issue of Neurobiology of Aging. Sean N. Hatton, Ph.D., from the University of...
https://ift.tt/2v9zoFJ
Many Providers Unaware of Racial Disparities in Kidney Transplants
THURSDAY, April 12, 2018 -- Health care provider awareness of racial disparities in kidney transplant waitlisting is low, especially among nurse managers and white providers, according to a study published online April 12 in the Clinical Journal of...
https://ift.tt/2HirI8I
Correlation of listhesis on upright radiographs and central lumbar spinal canal stenosis on supine MRI: is it possible to predict lumbar spinal canal stenosis?
Abstract
Objective
To investigate whether upright radiographs can predict lumbar spinal canal stenosis using supine lumbar magnetic resonance imaging (MRI) and to investigate the detection performance for spondylolisthesis on upright radiographs compared with supine MRI in patients with suspected lumbar spinal canal stenosis (LSS).
Materials and Methods
In this retrospective study, conventional radiographs and MR images of 143 consecutive patients with suspected LSS (75 female, mean age 72 years) were evaluated. The presence and extent of listhesis (median ± interquartile range) were assessed on upright radiographs and supine MRI of L4/5. In addition, the grade of central spinal stenosis of the same level was evaluated on MRI according to the classification of Schizas and correlated with the severity/grading of anterolisthesis on radiographs.
Results
Anterolisthesis was detected in significantly more patients on radiographs (n = 54; 38%) compared with MRI (n = 28; 20%), p < 0.001. Pairwise comparison demonstrated a significantly larger extent of anterolisthesis on radiographs (9 ± 5 mm) compared with MRI (5 ± 3 mm), p < 0.001. A positive correlation was found regarding the extent of anterolisthesis measured on radiographs and the grade of stenosis on MRI (r = 0.563, p < 0.001). Applying a cutoff value of ≥5 mm anterolisthesis on radiographs results in a specificity of 90% and a positive predictive value of 78% for the detection of patients with LSS, as defined by the Schizas classification.
Conclusion
Upright radiographs demonstrated more and larger extents of anterolisthesis compared with supine MRI. In addition, in patients with suspected LSS, the extent of anterolisthesis on radiographs (particularly ≥5 mm) is indicative of LSS and warrants lumbar spine MRI.
https://ift.tt/2HilkyC
Mass cytometry: a powerful tool for dissecting the immune landscape
Yannick Simoni | Melissa Hui Yen Chng | Shamin Li | Michael Fehlings | Evan W Newell
https://ift.tt/2qpd9G6
Obesity induced T cell dysfunction and implications for cancer immunotherapy
Ethan G Aguilar | William J Murphy
https://ift.tt/2GSLpEJ
The emerging role of immunotherapy in advanced urothelial cancers
Purpose of review Recent Food and Drug Administration (FDA) approval of five new immune checkpoint inhibitors for the treatment of metastatic urothelial cancer represents the first major treatment breakthrough for this disease since the introduction of combination chemotherapy over 30 years ago. This review examines the recent clinical trials leading to FDA approval of these agents, the current challenges facing immunotherapy and areas that require further research. Recent findings The programmed death 1 receptor (PD-1) and its ligand programmed death ligand-1 (PD-L1) are important negative regulators of immune activity, preventing destruction of normal tissues and autoimmunity. Aggressive bladder cancer cells express aberrantly high levels of PD-L1, hijacking the normal immune-regulatory pathway to evade detection and destruction by the immune system. Blockade of the PD-1/PD-L1 axis with immune checkpoint inhibitors augments the immune system's ability to eradicate bladder cancer with impressive safety and tolerability profiles. Summary Recent clinical trials demonstrate that patients with metastatic urothelial carcinoma are responsive to immune checkpoint inhibitor therapy. Optimal treatment regimens are still under development, but activity has been demonstrated in both the first and second-line setting for metastatic disease.https://ift.tt/2HhdAwx
Advances in prostate-specific membrane antigen PET of prostate cancer
Purpose of review In recent years, a large number of reports have been published on prostate-specific membrane antigen (PSMA)/PET in prostate cancer (PCa). This review highlights advances in PSMA PET in PCa during the past year. Recent findings PSMA PET/computed tomography (CT) is useful in detection of biochemical recurrence, especially at low prostate-specific antigen (PSA) values. The detection rate of PSMA PET is influenced by PSA level. For primary PCa, PSMA PET/CT shows promise for tumour localization in the prostate, especially in combination with multiparametric MRI (mpMRI). For primary staging, PSMA PET/CT can be used in intermediate and high-risk PCa. Intraoperative PSMA radioligand guidance seems promising for detection of malignant lymph nodes. While the use of PSMA PET/MRI in primary localized disease is limited to high and intermediate-risk patients and localized staging, in the recurrence setting, PET/MRI can be particularly helpful when the lesions are subtle. PSMA PET/CT is superior to choline PET/CT and other conventional imaging modalities. Summary Molecular imaging with PSMA PET continues to pave the way for personalized medicine in PCa. However, large prospective clinical studies are still needed to fully evaluate the role of PSMA PET/CT and PET/MRI in the clinical workflow of PCa.https://ift.tt/2ISz14u
Recent advances in radiation oncology: multimodal targeting of high risk and recurrent prostate cancer
Purpose of review The overview summarizes recent developments in radiation oncology for high risk and recurrent prostate cancer. Recent findings A number of well known phase III prostate hypofractionated radiation therapy (HFxRT) trials were finally published with long-term follow-ups. These trials demonstrate patterns of equivalent tumor control with several showing worse toxicity rates. The ASCENDE-RT randomized trial demonstrated the superiority of brachytherapy boost in intermediate and high-risk prostate cancer. Important randomized trials show a clear benefit to androgen deprivation therapy (ADT) in both intermediate-risk prostate cancer and postprostatectomy patients with rising PSA. Finally, the first randomized trial of metastasis-directed therapy showed a delay in time to ADT and biochemical failures in oligometastatic prostate cancer. Summary The use of brachytherapy boost in high-risk disease and ADT in locally recurrent cancer after prostatectomy are practice changing given the magnitude of benefit seen in the randomized trials. The benefit of metastasis-directed therapy in oligometastatic prostate cancer must be validated in a larger randomized trial. However, hypofractionated radiation therapy requires further long-term follow-up so that late toxicity risk can be accurately assessed before it becomes a standard of care in prostate cancer.https://ift.tt/2ILAsBx
Tobacco and alcohol-induced epigenetic changes in oral carcinoma
Purpose of review The present review aims to describe the epigenetic alterations observed in oral cancer linked to the exposure to alcohol and/or tobacco. Recent findings Recent findings emphasize the importance of epigenetics in oral cancer progression and in how risk factors (as tobacco and alcohol) affect the basal epigenetic profiles. Deeper techniques and detailed approaches allowed the perception that individual CG changes and even subtle changes may represent important epigenetic alterations resulting in expression changes and other carcinogenic consequences. New classes of epigenetic alterations including noncoding RNAs have been gaining attention. Summary Many epigenetic alterations have been described in oral carcinoma progression induced by tobacco and/or alcohol, including: promoter hypermethylation in genes with tumor suppressive activity, global (genome-wide) hypomethylation, change in methylation patterns throughout the genes, alteration in noncoding RNAs, and histones modifications. These changes represent progress in the knowledge of how these risk factors act in a molecular level. There is an urgent need for large independent studies to move these potential makers further and validate them to identify risk assessment, early diagnostic markers, and therapeutic targets, as well as to be the base for prevention and intervention strategies.https://ift.tt/2HiG6Oo
Managing seminomatous and nonseminomatous germ cell tumors
Purpose of review In the present review, we summarize the recent developments in the management of germ cell tumors (GCTs). Recent findings Treatment-related acute and late-onset toxicity remains a key challenge in the management of GCTs, with recent evidence showing that the adverse health outcomes of etoposide and cisplatin for four cycles in comparison to bleomycin, etoposide, and cisplatin for three cycles appear to be similar. Recent data showed that multidisciplinary clinic approach and management in experienced academic centers were associated with improved overall survival in GCT patients. There are currently multiple conventional-dose chemotherapy options for salvage therapy in patients with refractory or recurrent disease. In addition, more efficacious high-dose chemotherapy regimens continue to be developed. The role of salvage conventional-dose chemotherapy versus high-dose chemotherapy is currently being investigated prospectively. Recent reports suggested that brentuximab vedotin could be a potential salvage option for cluster of differentiation 30 positive refractory GCTs. On the other hand the results of the first phase II clinical trial investigating pembrolizumab in refractory GCTs were disappointing showing no clinical activity. Finally, deep exploration of the immune profile of GCTs using immunohistochemistry and gene expression profiling has identified that advanced GCT stage was associated with decreased T-cell and Natural killer-cell signatures, whereas T regulatory, neutrophil, mast cell, and macrophage signatures increased with advanced stage. Even though these results indicated that activated T-cell infiltration correlated with seminoma histology and good prognosis, and could be used in the future as a biomarker, this approach needs to be validated in a large cohort. Summary Remaining challenges to be addressed include minimizing therapeutic toxicity, and improving outcomes in patients with refractory/recurrent GCTs.https://ift.tt/2vabucZ
The evolving genomic landscape in urothelial cancer
Purpose of review Recent advances in next-generation sequencing have allowed for detailed molecular analysis of urothelial carcinomas, with potentially significant clinical implications for personalized treatment. Our objective in this review is to highlight studies from the past year that have furthered the understanding of urothelial cancer genomics. Recent findings Recent studies by The Cancer Genome Atlas consortium further characterized urothelial carcinomas via molecular subtyping, and a schema was proposed to match each subtype with potential therapeutic implications. Molecular subtyping was also utilized in a separate analysis to determine which tumours benefit from neoadjuvant chemotherapy. Tumour characteristics were also explored pre and postneoadjuvant chemotherapy and a mutational signature associated with postcisplatin treatment was described. We also review a comprehensive analysis of upper tract urinary carcinomas published this past year. Summary Recent genomic analyses have revealed that the classification of urothelial carcinoma is much more complex than the traditional dichotomy of nonmuscle-invasive and muscle-invasive bladder cancers. Molecular subtyping has provided additional insights into prognoses and treatment options for these patients. Although molecular subtyping is not yet ready for implementation into clinical practice, these latest efforts offer an exciting opportunity to integrate such information into prospective clinical studies that may ultimately lead to improved treatment outcomes.https://ift.tt/2IRqBdF
False-Positive Uptake of 131I Due to Tubal Ligation in a Patient With Papillary Thyroid Cancer
A 39-year-old woman with papillary thyroid cancer underwent 131I therapy after thyroidectomy. Posttherapeutic 131I whole-body scan accidentally showed symmetric "hot spots" in the pelvic region beyond known bone metastases. SPECT/CT was immediately added and revealed metal artifacts with 131I accumulation in the nearby uterus. Further inquiry discovered that she underwent tubal ligation 19 years ago. Our case demonstrates that 131I accumulation can occur at the site of oviducts many years after tubal ligation, which should be distinguished from 131I-avid metastases.https://ift.tt/2v9tO6f
Clinical Impact of Radioguided Localization in the Treatment of Solitary Pulmonary Nodule: A 20-Year Retrospective Analysis
Purpose Incidental solitary pulmonary nodules (SPNs) have become an increasingly common CT finding worldwide. Although there are currently many imaging strategies for evaluating SPNs, the differential diagnosis and management of SPNs remains complex because of overlap between benign and malignant processes. Moreover, transbronchial or percutaneous CT-guided biopsies do not always allow definitive diagnoses. In such cases, video-assisted thoracic surgery (VATS) has become the preferred surgical procedure for diagnosis and, in selected cases, for treatment of indeterminate SPNs. The difficulties in localizing smaller, deeper, and ground-glass nodules have been approached with different techniques. The aim of this study was to report 20 years of experience with radioguided thoracoscopic resection of SPNs at the Regional Centre of Nuclear Medicine of Pisa. Methods Three hundred ninety-five patients with SPNs less than 2 cm and deeper than 5 mm below the visceral pleura underwent CT-guided injection of a suspension composed of 0.1 to 0.2 mL 99mTc-labeled human albumin macroaggregates (99mTc-MAA) and of 0.2 to 0.3 mL of nonionic contrast medium into or adjacent to the SPN. During VATS, the pulmonary area with the highest target/background ratio identified by an 11-mm-diameter collimated thoracoscopic gamma probe was resected. Results From 1997 to 2016, approximately 395 patients with SPN underwent VATS wedge resection using the radioguided technique. Mean SPN size was 13 mm (range, 5–20 mm) with mean distance of 15 mm (range, 6–39 mm) from the visceral pleura. Mean VATS procedural time was 40 minutes (range, 20–90 minutes), with an average time of 3 minutes (range, 1–5 minutes) to localize the nodule. Neither mortality nor major perioperative complication was reported. The success rate of VATS with radioguidance in our series was 99%. Histological examination revealed 206 benign lesions (52%), 59 primary lung tumors (15%), and 130 metastatic nodules (33%). Conclusions This study demonstrates that radioguided SPN localization by VATS is a feasible, safe, and rapid procedure with highly successful rate of SPN resection.https://ift.tt/2qr4Zhi
[44Sc]Sc-PSMA-617 Biodistribution and Dosimetry in Patients With Metastatic Castration-Resistant Prostate Carcinoma
Aim [44Sc]Sc-PSMA-617 with 3.9-hour half-life, in vitro and in vivo characteristics similar to [177Lu]Lu-PSMA-617 and possibility of delayed imaging after 24 hours or later, implies it to be advantageous than [68 Ga]Ga-PSMA-617 for pretherapeutic dosimetric assessment for [177Lu]Lu-PSMA-617 in metastatic castration-resistant prostate carcinoma (mCRPC) patients. In this study, we investigated biodistribution and radiation exposure to normal organs with [44Sc]Sc-PSMA-617 in mCRPC patients. Methods Five mCRPC patients (mean age, 69 years) enrolled for [177Lu]Lu-PSMA-617 therapy were injected with 40–62 MBq [44Sc]Sc-PSMA-617 intravenously; Siemens Biograph 2 PET/CT system was used to acquire dynamic PET data (30 minutes) in list mode over the abdomen, followed by the collection of static PET/CT images (skull to mid-thigh) at 45 minutes, 2 and approximately 20 hours postinjection. Time-dependent changes in percentage activity in source organs (kidneys, bladder, salivary glands, small intestine, liver, spleen, and whole body) were determined. Bone marrow and urinary bladder contents residence time were also calculated. Source organs residence time, organ-absorbed doses, and effective doses were determined using OLINDA/EXM software. Results Physiological tracer uptake was seen in kidneys, liver, spleen, small intestine, urinary bladder, and salivary glands and in metastases. Kidneys with highest radiation absorbed dose of 3.19E-01 mSv/MBq were the critical organs, followed by urinary bladder wall (2.24E-01 mSv/MBq, spleen [1.85E-01], salivary glands [1.11E-01], and liver [1.07E-01] mSv/MBq). Red marrow dose was found to be 3.31E-02 mSv/MBq. The mean effective dose of 3.89E-02 mSv/MBq and effective dose of 1.95 mSv was estimated from 50 MBq (treatment planning dose) of [44Sc]Sc-PSMA-617. Conclusions [44Sc]Sc-PSMA-617 is found to be a very promising radiopharmaceutical that can be used for pre [177Lu]Lu-PSMA-617 therapeutic dosimetric assessment.https://ift.tt/2Hhb6hH
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
