The President's Cancer Panel issued recommendations aimed at promoting value, affordability, and innovation in cancer drugs. The recommendations include increasing NIH funding, encouraging the development of generic and biosimilar drugs, and instituting value-based pricing policies to encourage the development of cost-effective drugs.
DNA damage response alterations are linked to improved responses to anti–PD-1/PD-L1 in urothelial carcinoma.
Jynarque is First Approved Drug for Serious Genetic Kidney Disease The U.S. Food and Drug Administration (FDA) has approved Otsuka's Jynarque (tolvaptan), a selective vasopressin V2-receptor antagonist, as the first medicine to slow kidney...
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Antibody–drug conjugates (ADC) are multicomponent molecules constituted by an antibody covalently linked to a potent cytotoxic agent. ADCs combine high target specificity provided by the antibody together with strong antitumoral properties provided by the attached cytotoxic agent. At present, four ADCs have been approved and over 60 are being explored in clinical trials. Despite their effectiveness, resistance to these drugs unfortunately occurs. Efforts to understand the bases underlying such resistance are being carried out with the final purpose of counteracting them. In this review, we report described mechanisms of resistance to ADCs used in the clinic along with other potential ones that may contribute to resistance acquisition. We also discuss strategies to overcome resistance to ADCs. Cancer Res; 78(9); 2159–65. ©2018 AACR.
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Progression of mitotic cell cycle and chromosome condensation and segregation are controlled by posttranslational protein modifications such as phosphorylation and SUMOylation. However, how SUMO isopeptidases (SENP) regulate cell mitotic procession is largely unknown. Here, we demonstrate that precise phosphorylation of SENP3 during mitosis suppresses SENP3 deSUMOylation activity towards chromosome-associated proteins, including topoisomerase IIα (TopoIIα). Cyclin B-dependent kinases 1 and protein phosphatase 1α were identified as the kinase and phosphatase in control of mitotic SENP3 phosphorylation, respectively. SENP3 phosphorylation decreased its interaction with TopoIIα, resulting in reduced SENP3 deSUMOylation activity on TopoIIα. Furthermore, we observed mitotic arrest, increased chromosome instability, and promotion of tumorigenesis in cells expressing a nonphosphorylatable SENP3 mutant. These data show that SENP3 phosphorylation plays a crucial role in regulating the SUMOylation of chromosome-associated proteins and chromosome stability in mitosis.Significance: Phosphorylation of SENP3 regulates SUMOylation of chromosome-associated proteins to maintain genomic stability during mitosis. Cancer Res; 78(9); 2171–8. ©2018 AACR.
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Human papillomavirus (HPV) type 16 is implicated in approximately 75% of head and neck squamous cell carcinomas (HNSCC) that arise in the oropharynx, where viral expression of the E6 and E7 oncoproteins promote cellular transformation, tumor growth, and maintenance. An important oncogenic signaling pathway activated by E6 and E7 is the PI3K pathway, a key driver of carcinogenesis. The PI3K pathway is also activated by mutation or amplification of PIK3CA in over half of HPV(+) HNSCC. In this study, we investigated the efficacy of PI3K-targeted therapies in HPV(+) HNSCC preclinical models and report that HPV(+) cell line- and patient-derived xenografts are resistant to PI3K inhibitors due to feedback signaling emanating from E6 and E7. Receptor tyrosine kinase profiling indicated that PI3K inhibition led to elevated expression of the HER3 receptor, which in turn increased the abundance of E6 and E7 to promote PI3K inhibitor resistance. Targeting HER3 with siRNA or the mAb CDX-3379 reduced E6 and E7 abundance and enhanced the efficacy of PI3K-targeted therapies. Together, these findings suggest that cross-talk between HER3 and HPV oncoproteins promotes resistance to PI3K inhibitors and that cotargeting HER3 and PI3K may be an effective therapeutic strategy in HPV(+) tumors.Significance: These findings suggest a new therapeutic combination that may improve outcomes in HPV(+) head and neck cancer patients. Cancer Res; 78(9); 2383–95. ©2018 AACR.
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Comprehensive genomic analysis has revealed that the PI3K/AKT/mTOR pathway is a feasible therapeutic target in small-cell lung carcinoma (SCLC). However, biomarkers to identify patients likely to benefit from inhibitors of this pathway have not been identified. Here, we show that metabolic features determine sensitivity to the PI3K/mTOR dual inhibitor gedatolisib in SCLC cells. Substantial phosphatidyl lipid analysis revealed that a specific phosphatidylinositol (3,4,5)-trisphosphate (PIP3) subspecies lipid product PIP3 (38:4) is predictive in assessing sensitivity to PI3K/mTOR dual inhibitor. Notably, we found that higher amounts of purine-related aqueous metabolites such as hypoxanthine, which are characteristic of SCLC biology, lead to resistance to PI3K pathway inhibition. In addition, the levels of the mRNA encoding hypoxanthine phosphoribosyl transferase 1, a key component of the purine salvage pathway, differed significantly between SCLC cells sensitive or resistant to gedatolisib. Moreover, complementation with purine metabolites could reverse the vulnerability to targeting of the PI3K pathway in SCLC cells normally sensitive to gedatolisib. These results indicate that the resistance mechanism of PI3K pathway inhibitors is mediated by the activation of the purine salvage pathway, supplying purine resource to nucleotide biosynthesis. Metabolomics is a powerful approach for finding novel therapeutic biomarkers in SCLC treatment.Significance: These findings identify features that determine sensitivity of SCLC to PI3K pathway inhibition and support metabolomics as a tool for finding novel therapeutic biomarkers. Cancer Res; 78(9); 2179–90. ©2018 AACR.
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Prostate cancer incidence and mortality rates in African and African American men are greatly elevated compared with other ethnicities. This disparity is likely explained by a combination of social, environmental, and genetic factors. A large number of susceptibility loci have been reported by genome-wide association studies (GWAS), but the contribution of these loci to prostate cancer disparities is unclear. Here, we investigated the population structure of 68 previously reported GWAS loci and calculated genetic disparity contribution statistics to identify SNPs that contribute the most to differences in prostate cancer risk across populations. By integrating GWAS results with allele frequency data, we generated genetic risk scores for 45 African and 19 non-African populations. Tests of natural selection were used to assess why some SNPs have large allele frequency differences across populations. We report that genetic predictions of prostate cancer risks are highest for West African men and lowest for East Asian men. These differences may be explained by the out-of-Africa bottleneck and natural selection. A small number of loci appear to drive elevated prostate cancer risks in men of African descent, including rs9623117, rs6983267, rs10896449, rs10993994, and rs817826. Although most prostate cancer–associated loci are evolving neutrally, there are multiple instances where alleles have hitchhiked to high frequencies with linked adaptive alleles. For example, a protective allele at 2q37 appears to have risen to high frequency in Europe due to selection acting on pigmentation. Our results suggest that evolutionary history contributes to the high rates of prostate cancer in African and African American men.Significance: A small number of genetic variants cause an elevated risk of prostate cancer in men of West African descent. Cancer Res; 78(9); 2432–43. ©2018 AACR.
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Metabolic reprogramming is a hallmark of cancer that includes increased glucose uptake and accelerated aerobic glycolysis. This phenotype is required to fulfill anabolic demands associated with aberrant cell proliferation and is often mediated by oncogenic drivers such as activated BRAF. In this study, we show that the MAPK-activated p90 ribosomal S6 kinase (RSK) is necessary to maintain glycolytic metabolism in BRAF-mutated melanoma cells. RSK directly phosphorylated the regulatory domain of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2), an enzyme that catalyzes the synthesis of fructose-2,6-bisphosphate during glycolysis. Inhibition of RSK reduced PFKFB2 activity and glycolytic flux in melanoma cells, suggesting an important role for RSK in BRAF-mediated metabolic rewiring. Consistent with this, expression of a phosphorylation-deficient mutant of PFKFB2 decreased aerobic glycolysis and reduced the growth of melanoma in mice. Together, these results indicate that RSK-mediated phosphorylation of PFKFB2 plays a key role in the metabolism and growth of BRAF-mutated melanomas.Significance: RSK promotes glycolytic metabolism and the growth of BRAF-mutated melanoma by driving phosphorylation of an important glycolytic enzyme. Cancer Res; 78(9); 2191–204. ©2018 AACR.
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The effects of anticancer treatments on cell heterogeneity and their proliferative potential play an important role in tumor persistence and metastasis. However, little is known about de-polyploidization, cell fate, and physiologic stemness of the resulting cell populations. Here, we describe a distinctive cell type termed "pregnant" P1 cells found within chemotherapy-refractory ovarian tumors, which generate and gestate daughter generation Gn cells intracytoplasmically. Release of Gn cells occurred by ejection through crevices in the P1 cell membrane by body contractions or using a funiculus-like structure. These events characterized a not yet described mechanism of cell segregation. Maternal P1 cells were principally capable of surviving parturition events and continued to breed and nurture Gn progenies. In addition, P1 cells were competent to horizontally transmit offspring Gn cells into other specific proximal cells, injecting them to receptor R1 cells via cell–cell tunneling. This process represents a new mechanism used by tumor cells to invade surrounding tissues and ensure life cycles. In contrast to the pregnant P1 cells with low expression of stem cell markers despite their physiologic stemness, the first offspring generations of daughter G1 cells expressed high levels of ovarian cancer stem cell markers. Furthermore, both P1 and Gn cells overexpressed multiple human endogenous retroviral envelope proteins. Moreover, programmed death-ligand 1 and the immunosuppressive domain of the retroviral envelope proteins were also overexpressed in P1 cells, suggesting effective protection against the host immune system. Together, our data suggest that P1 oncogenerative cancer cells exhibit a not yet described cell biological mechanism of persistence and transmission of malignant cells in patients with advanced cancers.Significance: P1 oncogenerative cell entities express low levels of CSC markers, which are characteristic of their histological origin. Cancer Res; 78(9); 2318–31. ©2018 AACR.
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The p53 and EGFR pathways are frequently altered in bladder cancer, yet their contributions to its progression remain elusive. Here we report that DEAD box polypeptide 31 (DDX31) plays a critical role in the multistep progression of muscle-invasive bladder cancer (MIBC) through its sequential interactions with mutant p53 (mutp53) and EGFR. In early MIBC cells, nuclear DDX31-bound mutp53/SP1 enhanced mutp53 transcriptional activation, leading to migration and invasion of MIBC. Cytoplasmic DDX31 also bound EGFR and phospho-nucleolin in advanced MIBC, leading to EGFR–Akt signaling activation. High expression of both cytoplasmic DDX31 and p53 proteins correlated with poor prognosis in patients with MIBC, and blocking the DDX31/NCL interaction resulted in downregulation of EGFR/Akt signaling, eliciting an in vivo antitumor effect against bladder cancer. These findings reveal that DDX31 cooperates with mutp53 and EGFR to promote progression of MIBC, and inhibition of DDX31/NCL formation may lead to potential treatment strategies for advanced MIBC.Significance: DDX31 cooperates with mutp53 and EGFR to promote progression of muscle invasive bladder cancer. Cancer Res; 78(9); 2233–47. ©2018 AACR.
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SS18–SSX usurps the PRC1.1 repressive complex to drive expression of a synovial sarcoma gene signature.
Targeting SHP2 suppresses ALK inhibitor resistance caused by tyrosine kinase reactivation.
The Metastatic Prostate Cancer Project aims to gather genomic and phenotypic data from large numbers of men with prostate cancer, creating a database that scientists can use in their own research efforts. Any man with advanced disease who wants to participate may do so.
Orthogonal IL2/IL2Rβ pairs allow selective targeting of engineered autologously transferred T cells.
Two large studies show that the genetic events driving pediatric cancers are different from those underlying adult cancers. These findings may prove useful for identifying new treatments for childhood cancers, as well as for developing tests to aid in diagnosis and the selection of therapy.
NRL and CRX are master regulators of the photoreceptor-specific differentiation program.
Oncogene activation disturbs cellular processes and accommodates a complex landscape of changes in the genome that contribute to genomic instability, which accelerates mutation rates and promotes tumorigenesis. Part of this cellular turmoil involves deregulation of physiologic DNA replication, widely described as replication stress. Oncogene-induced replication stress is an early driver of genomic instability and is attributed to a plethora of factors, most notably aberrant origin firing, replication–transcription collisions, reactive oxygen species, and defective nucleotide metabolism.
Significance: Replication stress is a fundamental step and an early driver of tumorigenesis and has been associated with many activated oncogenes. Deciphering the mechanisms that contribute to the replication stress response may provide new avenues for targeted cancer treatment. In this review, we discuss the latest findings on the DNA replication stress response and examine the various mechanisms through which activated oncogenes induce replication stress. Cancer Discov; 8(5); 537–55. ©2018 AACR.
An expert panel has concluded that more research is needed before circulating tumor DNA analyses are adopted in clinical care. This finding may slow the use of such testing among oncologists, some of whom are already basing treatment decisions on the results of these assays.
Anti-CTLA4 antibodies induce an FcR-dependent depletion of Tregs to promote tumor rejection.
Myocarditis is a rare but serious side effect that can occur in patients receiving immune checkpoint inhibitors. To better understand the condition, researchers analyzed the symptoms, timing, demographics, and treatment outcomes for 101 patients who developed it following treatment.
Tumor-repopulating cells release Kyn, which activates AhR on T cells to promote PD-1 upregulation.
PP2A mediates a metabolic switch from glycolysis to the PPP in B-cell malignancies.
Targeting cyclin-dependent kinases 4/6 (CDK4/6) represents a therapeutic option in combination with BRAF inhibitor and/or MEK inhibitor (MEKi) in melanoma; however, continuous dosing elicits toxicities in patients. Using quantitative and temporal in vivo reporting, we show that continuous MEKi with intermittent CDK4/6 inhibitor (CDK4/6i) led to more complete tumor responses versus other combination schedules. Nevertheless, some tumors acquired resistance that was associated with enhanced phosphorylation of ribosomal S6 protein. These data were supported by phospho-S6 staining of melanoma biopsies from patients treated with CDK4/6i plus targeted inhibitors. Enhanced phospho-S6 in resistant tumors provided a therapeutic window for the mTORC1/2 inhibitor AZD2014. Mechanistically, upregulation or mutation of NRAS was associated with resistance in in vivo models and patient samples, respectively, and mutant NRAS was sufficient to enhance resistance. This study utilizes an in vivo reporter model to optimize schedules and supports targeting mTORC1/2 to overcome MEKi plus CDK4/6i resistance.
Significance: Mutant BRAF and NRAS melanomas acquire resistance to combined MEK and CDK4/6 inhibition via upregulation of mTOR pathway signaling. This resistance mechanism provides the preclinical basis to utilize mTORC1/2 inhibitors to improve MEKi plus CDK4/6i drug regimens. Cancer Discov; 8(5); 568–81. ©2018 AACR.
See related commentary by Sullivan, p. 532.
See related article by Romano et al., p. 556.
This article is highlighted in the In This Issue feature, p. 517
CNS Oncology, Ahead of Print.
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CNS Oncology, Ahead of Print.
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CNS Oncology, Ahead of Print.
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CNS Oncology, Ahead of Print.
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In the prospective Korean Cancer Prevention Study-II (KCPS-II), we investigated the application of metabolomics to differentiate subjects with incident hepatocellular carcinoma (HCC group) from subjects who remained free of cancer (control group) during a mean follow-up period of 7 years with the aim of identifying valuable metabolic biomarkers for HCC. We used baseline serum samples from 75 subjects with incident HCC and 134 age- and gender-matched cancer-free subjects. Serum metabolic profiles associated with HCC incidence were investigated via metabolomics analysis. Compared with the control group, the HCC group showed significantly higher serum levels of aspartate aminotransferase (AST), alanine aminotransferase, and -glutamyl transpeptidase. At baseline, compared with the control group, the HCC group showed significantly higher levels of 9 metabolites, including leucine, 5-hydroxyhexanoic acid, phenylalanine, tyrosine, arachidonic acid, and tauroursodeoxycholic acid (TUDCA), but lower levels of 28 metabolites, including oleamide, androsterone sulfate, L-palmitoylcarnitine, lysophosphatidic acid (LPA) 16:0, LPA 18:1, and lysophosphatidylcholines (lysoPC). Multiple linear regression revealed that the incidence of HCC was associated with the levels of tyrosine, AST, lysoPCs (16:1, 20:3), oleamide, 5-hydroxyhexanoic acid, androsterone sulfate, and TUDCA (adjusted R2 = 0.514, P = 0.036). This study showed the clinical relevance of the dysregulation of not only branched amino acids, aromatic amino acids, and lysoPCs but also bile acid biosynthesis and linoleic acid, arachidonic acid, and fatty acid metabolism. In addition, tyrosine, AST, lysoPCs (16:1, 20:3), oleamide, 5-hydroxyhexanoic acid, androsterone sulfate, and TUDCA were identified as independent variables associated with the incidence of HCC. Cancer Prev Res; 11(5); 303–12. ©2018 AACR.
The dramatic increase in breast cancer incidence compels a paradigm shift in our preventive efforts. There are several barriers to overcome before prevention becomes an established part of breast cancer management. The objective of this review is to identify the clinical challenges for improved breast cancer prevention and discuss current knowledge on breast cancer risk assessment methods, risk communication, ethics, and interventional efforts with the aim of covering the aspects relevant for a breast cancer prevention trial. Herein, the following five areas are discussed: (i) Adequate tools for identification of women at high risk of breast cancer suggestively entitled Prevent! Online. (ii) Consensus on the definition of high risk, which is regarded as mandatory for all risk communication and potential prophylactic interventions. (iii) Risk perception and communication regarding risk information. (iv) Potential ethical concerns relevant for future breast cancer prevention programs. (v) Risk-reducing programs involving multileveled prevention depending on identified risk. Taken together, devoted efforts from both policy makers and health care providers are warranted to improve risk assessment and risk counseling in women at risk for breast cancer to optimize the prevention of breast cancer. Cancer Prev Res; 11(5); 255–64. ©2018 AACR.
There is a pressing need for the development of new prevention strategies for the most common worldwide malignancy, nonmelanoma skin cancer (NMSC), as sun protection efforts have not proven to be completely effective. Interestingly, despite the known circumstance that individuals undergoing chronic immunosuppression are at a substantially increased risk for developing NMSC, in this issue of Cancer Prevention Research, Blohm-Mangone and colleagues provide new evidence that topical application of the Toll-like receptor 4 (TLR4) antagonist resatorvid may be efficacious as a chemopreventive agent in NMSC specifically via blocking UV-induced inflammatory signaling. These new findings highlight a potentially delicate dichotomy between the role of innate immune receptors in the normal, protective immunosurveillance of damaged cells in the skin and the pathogenic UV-induced overstimulation of cutaneous inflammation that promotes photocarcinogenesis. Given the tremendous cancer burden incurred by NMSC, further exploration of the use of TLR4 antagonists in NMSC chemoprevention strategies is certainly warranted. Cancer Prev Res; 11(5); 251–4. ©2018 AACR.
See related article by Blohm-Mangone et al., p. 265
Background: The low uptake of antiestrogen preventive therapy among women at high risk of developing breast cancer remains a challenge. We implemented a performance improvement program to increase the uptake of preventive therapy among women with atypical hyperplasia (AH) and lobular cancer in situ (LCIS).
Methods: A performance improvement program was implemented at the MD Anderson Cancer Center (Houston, TX), November 2015 to February 2017, for patients with a new (<6 months) or existing (≥6 months) diagnosis of AH/LCIS. The program consisted of an audit of eligible women who were recommended and prescribed preventive therapy and the provision of clinical performance feedback to providers. The baseline uptake of preventive therapy was estimated from patients enrolled in a high-risk breast cohort.
Results: Baseline uptake of preventive therapy was 44%. The program registered 408 patients with a new (n = 87) or existing diagnosis (n = 321) of AH/LCIS; mean age was 57 and 71% were non-Hispanic white. Ninety-eight percent of patients received a recommendation for preventive therapy. The overall prescribing of preventive therapy to patients with a new or existing diagnosis was 82% (monthly range, 40%–100%; Ptrend = 0.76) and 48% (monthly range, 27%–57%; Ptrend < 0.01), respectively. Adherence among patients with a new or existing diagnosis was 76% and 48% (P < 0.01) at 6 months, respectively.
Conclusion: A system-level approach improved the uptake of preventive therapy. Identifying women at the time of diagnosis of AH/LCIS and offering a strong recommendation are key components for improving acceptance and adherence with preventive therapy. Cancer Prev Res; 11(5); 295–302. ©2018 AACR.
Introduction: Although aspirin/NSAIDs may have potential preventive effects on several cancers, it remains unclear on gastric cancer. The purpose of this study is to compare the risk of developing gastric cancer and the histologic changes of intestinal metaplasia and neutrophil infiltration, between aspirin/NSAID users and nonusers.
Methods: Using an electronic endoscopy database in two hospitals from 1996 to 2017, we analyzed the data from patients with chronic gastritis who received aspirin or NSAIDs prior to upper gastrointestinal endoscopy. One-to-one propensity score matching was performed to compare the proportion of gastric cancer, intestinal metaplasia, and neutrophil infiltration between these drug users and nonusers.
Results: We analyzed 2,082 aspirin users and 2,082 nonusers as well as 898 NSAID users and 898 nonusers. Six diffuse-type and 19 intestinal-type gastric cancer, 1,243 intestinal metaplasia, and 1,503 neutrophil infiltration patients were identified. The proportion of diffuse-type gastric cancer (0.05%) was 80% lower in aspirin users compared with the nonusers (0.24%), and there was no case of diffuse-type cancer in patients who took aspirin for more than 2 years. In contrast, intestinal-type gastric cancer incidence was significantly higher in aspirin users (0.72%) compared with nonusers (0.14%). No significant differences in the incidence of gastric cancer were found between NSAID use and nonusers. NSAID use was significantly associated with decreased proportion of neutrophil infiltration compared with nonusers.
Conclusion: Aspirin may have distinct effects between intestinal-type and diffuse-type gastric cancer development. Cancer Prev Res; 11(5); 279–86. ©2018 AACR.
Immunotherapy, including the use of checkpoint inhibitors, is a potent therapeutic approach for some cancers, but has limited success with prostate tumors, in which immune suppression is instigated by the tumor. The immunosuppressive capacity of mast cells, which promote adenocarcinoma development in the prostate, prompted our investigation on whether mast cells promote tolerance to SV40 Large-T antigen, the transforming oncogene in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. The incidence of adenocarcinoma was reduced in the offspring of a cross between TRAMP mice and mast cell–deficient KitWsh mice. TRAMP mice are tolerant to the SV40 Large T antigen, which is otherwise immunogenic in normal syngeneic B6 mice. Genetic ablation of mast cells in TRAMP mice restored their ability to mount a tumor-specific cytotoxic T-cell response. In KitWsh-TRAMP mice, the restored T-cell immunity correlated with the reduced activity of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), along with their reduced expression of Arg1, Nos2, and Stat3. Having found that CD40L-expressing mast cells can interact in vivo with CD40-expressing PMN-MDSC, we then determined that only KitWsh-TRAMP mice reconstituted with mast cells expressing CD40L could restore PMN-MDSCs suppressive functions, T-cell unresponsiveness and adenocarcinoma development. Thus, mast cells have an immunoregulatory effect on PMN-MDSCs activity through CD40L-CD40 interaction, favoring immunosuppression and tumor onset. In prostate cancer patients, in silico analyses correlated poor clinical outcomes with high expression of genes related to mast cells and PMN-MDSCs. Cancer Immunol Res; 6(5); 552–65. ©2018 AACR.
T cells expressing chimeric antigen receptors (CART) have shown significant promise in clinical trials to treat hematologic malignancies, but their efficacy in solid tumors has been limited. Oncolytic viruses have the potential to act in synergy with immunotherapies due to their immunogenic oncolytic properties and the opportunity of incorporating therapeutic transgenes in their genomes. Here, we hypothesized that an oncolytic adenovirus armed with an EGFR-targeting, bispecific T-cell engager (OAd-BiTE) would improve the outcome of CART-cell therapy in solid tumors. We report that CART cells targeting the folate receptor alpha (FR-α) successfully infiltrated preestablished xenograft tumors but failed to induce complete responses, presumably due to the presence of antigen-negative cancer cells. We demonstrated that OAd-BiTE–mediated oncolysis significantly improved CART-cell activation and proliferation, while increasing cytokine production and cytotoxicity, and showed an in vitro favorable safety profile compared with EGFR-targeting CARTs. BiTEs secreted from infected cells redirected CART cells toward EGFR in the absence of FR-α, thereby addressing tumor heterogeneity. BiTE secretion also redirected CAR-negative, nonspecific T cells found in CART-cell preparations toward tumor cells. The combinatorial approach improved antitumor efficacy and prolonged survival in mouse models of cancer when compared with the monotherapies, and this was the result of an increased BiTE-mediated T-cell activation in tumors. Overall, these results demonstrated that the combination of a BiTE-expressing oncolytic virus with adoptive CART-cell therapy overcomes key limitations of CART cells and BiTEs as monotherapies in solid tumors and encourage its further evaluation in human trials. Cancer Immunol Res; 6(5); 605–16. ©2018 AACR.
Although tumor-associated macrophages (TAM) display a M2-skewed tumor-promoting phenotype in most cancers, in colorectal cancer, both TAM polarization and its impact remain controversial. We investigated the role of the M2-polarizing p50 NF-B subunit in orchestrating TAM phenotype, tumor microenvironment composition, and colorectal cancer progression. We first demonstrated, by parallel studies in colitis-associated cancer (CAC) and in genetically driven ApcMin mouse models, that the p50-dependent inhibition of M1-polarized gut inflammation supported colorectal cancer development. In accordance with these studies, p50–/– mice displayed exacerbated CAC with fewer and smaller tumors, along with enhanced levels of M1/Th1 cytokines/chemokines, including IL12 and CXCL10, whose administration restrained CAC development in vivo. The inflammatory profile supporting tumor resistance in colons from p50–/– tumor bearers correlated inversely with TAM load and positively with both recruitment of NK, NKT, CD8+ T cells and number of apoptotic tumor cells. In agreement, myeloid-specific ablation of p50 promoted tumor resistance in mice, whereas in colorectal cancer patients, a high number of p50+ TAMs at the invasive margin was associated with decreased IL12A and TBX21 expression and worse postsurgical outcome. Our findings point to p50 involvement in colorectal cancer development, through its engagement in the protumor activation of macrophages, and identify a candidate for prognostic and target therapeutic intervention. Cancer Immunol Res; 6(5); 578–93. ©2018 AACR.
One major hurdle to the success of adoptive T-cell therapy is the identification of antigens that permit effective targeting of tumors in the absence of toxicities to essential organs. Previous work has demonstrated that T cells engineered to express chimeric antigen receptors (CAR-T cells) targeting the murine homolog of the colorectal cancer antigen GUCY2C treat established colorectal cancer metastases, without toxicity to the normal GUCY2C-expressing intestinal epithelium, reflecting structural compartmentalization of endogenous GUCY2C to apical membranes comprising the intestinal lumen. Here, we examined the utility of a human-specific, GUCY2C-directed single-chain variable fragment as the basis for a CAR construct targeting human GUCY2C-expressing metastases. Human GUCY2C-targeted murine CAR-T cells promoted antigen-dependent T-cell activation quantified by activation marker upregulation, cytokine production, and killing of GUCY2C-expressing, but not GUCY2C-deficient, cancer cells in vitro. GUCY2C CAR-T cells provided long-term protection against lung metastases of murine colorectal cancer cells engineered to express human GUCY2C in a syngeneic mouse model. GUCY2C murine CAR-T cells recognized and killed human colorectal cancer cells endogenously expressing GUCY2C, providing durable survival in a human xenograft model in immunodeficient mice. Thus, we have identified a human GUCY2C-specific CAR-T cell therapy approach that may be developed for the treatment of GUCY2C-expressing metastatic colorectal cancer. Cancer Immunol Res; 6(5); 509–16. ©2018 AACR.
CD16A is a potent cytotoxicity receptor on human natural killer (NK) cells, which can be exploited by therapeutic bispecific antibodies. So far, the effects of CD16A-mediated activation on NK cell effector functions beyond classical antibody-dependent cytotoxicity have remained poorly elucidated. Here, we investigated NK cell responses after exposure to therapeutic antibodies such as the tetravalent bispecific antibody AFM13 (CD30/CD16A), designed for the treatment of Hodgkin lymphoma and other CD30+ lymphomas. Our results reveal that CD16A engagement enhanced subsequent IL2- and IL15-driven NK cell proliferation and expansion. This effect involved the upregulation of CD25 (IL2Rα) and CD132 (c) on NK cells, resulting in increased sensitivity to low-dose IL2 or to IL15. CD16A engagement initially induced NK cell cytotoxicity. The lower NK cell reactivity observed 1 day after CD16A engagement could be recovered by reculture in IL2 or IL15. After reculture in IL2 or IL15, these CD16A-experienced NK cells exerted more vigorous IFN production upon restimulation with tumor cells or cytokines. Importantly, after reculture, CD16A-experienced NK cells also exerted increased cytotoxicity toward different tumor targets, mainly through the activating NK cell receptor NKG2D. Our findings uncover a role for CD16A engagement in priming NK cell responses to restimulation by cytokines and tumor cells, indicative of a memory-like functionality. Our study suggests that combination of AFM13 with IL2 or IL15 may boost NK cell antitumor activity in patients by expanding tumor-reactive NK cells and enhancing NK cell reactivity, even upon repeated tumor encounters. Cancer Immunol Res; 6(5); 517–27. ©2018 AACR.
Background: Estrogen metabolism in premenopausal women may be related to early life body fatness.
Methods: Premenopausal women participating in the Nurses' Health Study II recalled their body fatness at ages 5, 10, and 20 years using a validated 9-level pictogram. Fifteen estrogens and estrogen metabolites (EM) were measured using LC/MS-MS in luteal phase urines from 603 women ages 32–54 years. Geometric means of individual EM, metabolic pathway groups, and pathway ratios were examined by body fatness categories using linear mixed models.
Results: Body fatness at each age was inversely associated with adult concentrations of all EM combined, parent estrogens (estrone, estradiol), and the 2-hydroxylation pathway. Women in the top (vs. bottom) category of body fatness at age 10 had 21% lower levels of all EM (Ptrend = 0.003), 24% lower parent estrogens (Ptrend = 0.002), and 36% lower 2-pathway (Ptrend = 0.0003). Body fatness at age 10 was inversely associated with 2-catechols (35% lower, Ptrend = 0.0004) and 2-methylated catechols (30% lower, Ptrend = 0.002). After adjusting for premenopausal body mass index (BMI), these associations remained inverse but were attenuated; only parent estrogens remained statistically significant (21% lower, Ptrend = 0.01). Body fatness at ages 5 and 20 were similarly, but more weakly, associated with estrogen pathways.
Conclusions: Estimates of body fatness during early life were inversely associated with premenopausal levels of all EM combined, parent estrogens, and 2-pathway estrogen metabolites. These relationships were not fully explained by adult BMI.
Impact: These findings inform investigations of diseases linked to early life body fatness and estrogen metabolism. Cancer Epidemiol Biomarkers Prev; 27(5); 585–93. ©2018 AACR.
Background: Breast cancer incidence is lower in many U.S. ethnic minority and foreign-born population groups. Investigating whether migration and acculturation patterns in risk are reflected in disease biomarkers may help to elucidate the underlying mechanisms.
Methods: We compared the distribution of breast cancer risk factors across U.S.-born white, African American and Hispanic women, and foreign-born Hispanic women (n = 477, ages 40–64 years, 287 born in Caribbean countries). We used linear regression models to examine the associations of migration history and linguistic acculturation with mammographic breast density (MBD), measured using computer-assisted methods as percent and area of dense breast tissue.
Results: The distribution of most breast cancer risk factors varied by ethnicity, nativity, and age at migration. In age- and body mass index–adjusted models, U.S.-born women did not differ in average MBD according to ethnicity, but foreign-born Hispanic women had lower MBD [e.g., –4.50%; 95% confidence interval (CI), –7.12 to –1.89 lower percent density in foreign- vs. U.S.-born Hispanic women]. Lower linguistic acculturation and lower percent of life spent in the United States were also associated with lower MBD [e.g., monolingual Spanish and bilingual vs. monolingual English speakers, respectively, had 5.09% (95% CI, –8.33 to –1.85) and 3.34% (95% CI, –6.57 to –0.12) lower percent density]. Adjusting for risk factors (e.g., childhood body size, parity) attenuated some of these associations.
Conclusions: Hispanic women predominantly born in Caribbean countries have lower MBD than U.S.-born women of diverse ethnic backgrounds, including U.S.-born Hispanic women of Caribbean heritage.
Impact: MBD may provide insight into mechanisms driving geographic and migration variations in breast cancer risk. Cancer Epidemiol Biomarkers Prev; 27(5); 566–74. ©2018 AACR.
The study of nonindicated medications on cancer outcomes is challenged by potential time-related biases. The literature has strongly advocated for treating the exposure as time-varying and summarizing the outcomes through a dose–response model (an etiologic-focused analysis). An alternative is to refashion the data to resemble a hypothetical randomized trial of drug use (an action-focused analysis). To our knowledge, their relative treatment of time-related bias and aspects of interpretation have not been compared. In this commentary, using the study of metformin use on colorectal cancer risk by Bradley and colleagues (2018) as motivation, we compare the etiologic versus action-focused analysis of epidemiologic data. We examine their treatment of immortal person-time, time-varying confounding, selection bias, and the biological and clinical relevance of their results. In doing so, we aim to establish areas of common ground and points of departure that can guide future observational studies of medications on cancer risk, recurrence, and survival. Cancer Epidemiol Biomarkers Prev; 27(5); 520–4. ©2018 AACR.
See related article by Bradley et al., p. 525
Background: Several epidemiologic studies have reported strong inverse associations between metformin use and risk of colorectal cancer, although time-related biases, such as immortal time bias, may in part explain these findings. We reexamined this association using methods to minimize these biases.
Methods: A cohort study was conducted among 47,351 members of Kaiser Permanente Northern California with diabetes and no history of cancer or metformin use. Follow-up for incident colorectal cancer occurred from January 1, 1997, until June 30, 2012. Cox regression was used to calculate HRs and 95% confidence intervals (CIs) for colorectal cancer risk associated with metformin use (ever use, total duration, recency of use, and cumulative dose).
Results: No association was observed between ever use of metformin and colorectal cancer risk (HR, 0.90; 95% CI, 0.76–1.07) and there was no consistent pattern of decreasing risk with increasing total duration, dose, or recency of use. However, long-term use (≥5.0 years) appeared to be associated with reduced risk of colorectal cancer in the full population (HR, 0.78; 95% CI, 0.60–1.02), among current users (HR, 0.78; 95% CI, 0.59–1.04), and in men (HR, 0.65; 95% CI, 0.45–0.94) but not in women. Higher cumulative doses of metformin were associated with reduced risk. In initial users of sulfonylureas, switching to or adding metformin was also associated with decreased colorectal cancer risk.
Conclusions: Our findings showed an inverse association between long-term use of metformin and colorectal cancer risk. Findings, especially the risk reduction among men, need to be confirmed in large, well-conducted studies.
Impact: If our findings are confirmed, metformin may have a role in the chemoprevention of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 27(5); 525–30. ©2018 AACR.
See related commentary by Jackson and García-Albéniz, p. 520
Background: The "meeting-in-the-middle" (MITM) is a principle to identify exposure biomarkers that are also predictors of disease. The MITM statistical framework was applied in a nested case–control study of hepatocellular carcinoma (HCC) within European Prospective Investigation into Cancer and Nutrition (EPIC), where healthy lifestyle index (HLI) variables were related to targeted serum metabolites.
Methods: Lifestyle and targeted metabolomic data were available from 147 incident HCC cases and 147 matched controls. Partial least squares analysis related 7 lifestyle variables from a modified HLI to a set of 132 serum-measured metabolites and a liver function score. Mediation analysis evaluated whether metabolic profiles mediated the relationship between each lifestyle exposure and HCC risk.
Results: Exposure-related metabolic signatures were identified. Particularly, the body mass index (BMI)-associated metabolic component was positively related to glutamic acid, tyrosine, PC aaC38:3, and liver function score and negatively to lysoPC aC17:0 and aC18:2. The lifetime alcohol-specific signature had negative loadings on sphingomyelins (SM C16:1, C18:1, SM(OH) C14:1, C16:1 and C22:2). Both exposures were associated with increased HCC with total effects (TE) = 1.23 (95% confidence interval = 0.93–1.62) and 1.40 (1.14–1.72), respectively, for BMI and alcohol consumption. Both metabolic signatures mediated the association between BMI and lifetime alcohol consumption and HCC with natural indirect effects, respectively, equal to 1.56 (1.24–1.96) and 1.09 (1.03–1.15), accounting for a proportion mediated of 100% and 24%.
Conclusions: In a refined MITM framework, relevant metabolic signatures were identified as mediators in the relationship between lifestyle exposures and HCC risk.
Impact: The understanding of the biological basis for the relationship between modifiable exposures and cancer would pave avenues for clinical and public health interventions on metabolic mediators. Cancer Epidemiol Biomarkers Prev; 27(5); 531–40. ©2018 AACR.
Background: Carcinogenic exposure in early life may be critical for subsequent breast cancer risk. Dairy consumption was examined during adolescence and early adulthood in relation to incident breast cancer in the Nurses' Health Study II cohort.
Methods: For the analyses of early adulthood dairy consumption, we included 90,503 premenopausal women ages 27 to 44 years in 1991 who reported dairy consumption using a validated food-frequency questionnaire. From 1991 to 2013, 3,191 invasive breast cancer cases were identified. In 1998, 44,264 women recalled adolescent dairy consumption. This subgroup of women was followed up from 1998 to 2013; 1,318 invasive breast cancer cases were identified. Multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox proportional hazard regression.
Results: Adolescent and early adulthood total dairy consumption was not associated with overall breast cancer risk (each serving/day during adolescence, total dairy HR = 1.02, 95% CI, 0.97–1.07; for early adulthood total dairy HR = 1.01, 95% CI, 0.97–1.04), as were intakes of calcium, vitamin D, and lactose. Adolescent consumption of total and high-fat dairy was associated with higher risk of estrogen and progesterone receptor negative (each serving/day: total dairy HR = 1.11, 95% CI, 1.00–1.24; high-fat dairy HR = 1.17, 95% CI, 1.04–1.31). However, higher adolescent high-fat dairy consumption was associated with lower risk of estrogen and progesterone receptor positive tumors (each serving/day HR = 0.91, 95% CI, 0.86–0.97).
Conclusions: Our results suggest no overall association between dairy consumption during adolescence or early adulthood and breast cancer risk, but the findings may differ by hormone receptor status of tumors.
Impact: Dairy consumption in adolescence or early adulthood may not be a significant predictor of breast cancer incidence. Cancer Epidemiol Biomarkers Prev; 27(5); 575–84. ©2018 AACR.
Background: Social stressors, such as social relationship deficits, have been increasingly linked to chronic disease outcomes, including cancer. However, critical gaps exist in our understanding of the nature and strength of such links, as well as the underlying biological mechanisms relating social relationships to cancer progression and survival.
Methods: Utilizing novel questionnaire and biomarker data from the UNC Health Registry/Cancer Survivorship Cohort, this study examines the associations between diverse measures of social support and mortality risk among individuals with cancer (N = 1,004). We further assess the role of multiple serum markers of inflammation, including high-sensitivity C-reactive protein (CRP), IL6, TNFα, and VEGF, as potential mediators in the social relationship–cancer link.
Results: The findings revealed that one's appraisal of their social support was associated with cancer mortality, such that individuals reporting higher levels of social support satisfaction had lower mortality risk than individuals reporting lower levels of satisfaction. The amount of support received, on the other hand, was not predictive of cancer survival. We further found evidence that inflammatory processes may undergird the link between social support satisfaction and mortality among individuals with cancer, with individuals reporting higher levels of social support satisfaction having lower levels of CRP, IL6, and TNFα.
Conclusions: These results provide new knowledge of the biosocial processes producing population disparities in cancer outcomes.
Impact: Our study offers new insights for intervention efforts aimed at promoting social connectedness as a means for improving cancer survival. Cancer Epidemiol Biomarkers Prev; 27(5); 541–9. ©2018 AACR.
Background: Few studies have prospectively evaluated the association between oral microbiota and health outcomes. Precise estimates of the intrasubject microbial metric stability will allow better study planning. Therefore, we conducted a study to evaluate the temporal variability of oral microbiota.
Methods: Forty individuals provided six oral samples using the OMNIgene ORAL kit and Scope mouthwash oral rinses approximately every two months over 10 months. DNA was extracted using the QIAsymphony and the V4 region of the 16S rRNA gene was amplified and sequenced using the MiSeq. To estimate temporal variation, we calculated intraclass correlation coefficients (ICCs) for a variety of metrics and examined stability after clustering samples into distinct community types using Dirichlet multinomial models (DMMs).
Results: The ICCs for the alpha diversity measures were high, including for number of observed bacterial species [0.74; 95% confidence interval (CI): 0.65–0.82 and 0.79; 95% CI: 0.75–0.94] from OMNIgene ORAL and Scope mouthwash, respectively. The ICCs for the relative abundance of the top four phyla and beta diversity matrices were lower. Three clusters provided the best model fit for the DMM from the OMNIgene ORAL samples, and the probability of remaining in a specific cluster was high (59.5%–80.7%).
Conclusions: The oral microbiota appears to be stable over time for multiple metrics, but some measures, particularly relative abundance, were less stable.
Impact: We used this information to calculate stability-adjusted power calculations that will inform future field study protocols and experimental analytic designs. Cancer Epidemiol Biomarkers Prev; 27(5); 594–600. ©2018 AACR.
Background: Dysregulation of miRNA and methylation levels are epigenetic hallmarks of cancer, potentially linked via miRNA-processing genes. Studies have found genetic alterations to miRNA-processing genes in cancer cells and human population studies. Our objective was to prospectively examine changes in DNA methylation of miRNA-processing genes and their associations with cancer risk.
Methods: We examined cohort data from the Department of Veterans' Affairs Normative Aging Study. Participants were assessed every 3 to 5 years starting in 1999 through 2013 including questionnaires, medical record review, and blood collection. Blood from 686 consenting participants was analyzed using the Illumina 450K BeadChip array to measure methylation at CpG sites throughout the genome. We selected 19 genes based on a literature review, with 519 corresponding CpG sites. We then used Cox proportional hazards models to examine associations with cancer incidence, and generalized estimating equations to examine associations with cancer prevalence. Associations at false discovery rate < 0.05 were considered statistically significant.
Results: Methylation of three CpGs (DROSHA: cg23230564, TNRC6B: cg06751583, and TNRC6B: cg21034183) was prospectively associated with time to cancer development (positively for cg06751583, inversely for cg23230564 and cg21034183), whereas methylation of one CpG site (DROSHA: cg16131300) was positively associated with cancer prevalence.
Conclusions: DNA methylation of DROSHA, a key miRNA-processing gene, and TNRC6B may play a role in early carcinogenesis.
Impact: Changes in miRNA processing may exert multiple effects on cancer development, including protecting against it via altered global miRNAs, and may be a useful early detection biomarker of cancer. Cancer Epidemiol Biomarkers Prev; 27(5); 550–7. ©2018 AACR.
Background: Several epidemiological studies have shown a positive association between diabetes and increased risk of non-Hodgkin lymphoma (NHL), but the effect of diabetic treatment drugs such as metformin on the risk is unknown.
Methods: We conducted a population-based nested case–control study involving 878 NHL cases and 4,364 controls diagnosed with diabetes. Use of metformin and other medications before diagnosis and medical condition histories were assessed using administrative databases. We used conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for use of metformin, adjusting for confounders.
Results: Risk of total NHLs is not associated with ever use of metformin (OR, 0.93; 95% CI, 0.79–1.10) among diabetic patients. NHL subtypes were also not associated with metformin use.
Conclusions: Metformin use is not associated with overall or subtype NHL risk among diabetic patients.
Impact: NHLs are etiologically heterogeneous and larger scale studies are warranted to test the potential effect of metformin by NHL subtype. Cancer Epidemiol Biomarkers Prev; 27(5); 610–2. ©2018 AACR.
Background: Although endometrial cancer risk differs among white and black women, few data on its associations with exogenous hormone use in the latter group are available. Studies have reported lower endometrial cancer risk among users of oral contraceptives (OCs), but higher risk among users of estrogen-only female menopausal hormones (FMHs). Evidence for the risk among estrogen plus progestin FMHs users is equivocal.
Methods: We followed 47,555 Black Women's Health Study participants with an intact uterus from 1995 through 2013. Data on exogenous hormone use, covariates, and endometrial cancer were obtained biennially. Self-reported incident cases of endometrial cancer were confirmed by medical records or cancer registries whenever possible. We estimated incidence rate ratios (IRRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression.
Results: We observed 300 endometrial cancer cases during 689,546 person-years of follow-up. Compared with never use, ≥10 years' duration of OC use was associated with lower risk (multivariable IRR = 0.45, 95% CI, 0.27–0.74), but risk was higher among current users of estrogen-only (IRR = 3.78, 95% CI, 1.69–8.43) and estrogen plus progestin FMH (IRR = 1.55, 95% CI, 0.78–3.11). Risk was not increased among former users of estrogen-only (IRR = 0.87, 95% CI, 0.44–1.72) or estrogen plus progestin FMH (IRR = 0.63, 95% CI, 0.36–1.09).
Conclusions: Current use of estrogen-only and estrogen plus progestin FMH was associated with increased risk of endometrial cancer. Risk appeared lower among former users of estrogen plus progestin FMH. Long-term OC use was associated with reduced risk.
Impact: Our results are generally consistent with those among white women. Cancer Epidemiol Biomarkers Prev; 27(5); 558–65. ©2018 AACR.
The novel hsa-miR-12528 regulates tumourigenesis and metastasis through hypo-phosphorylation of AKT cascade by targeting IGF-1R in human lung cancer
The novel hsa-miR-12528 regulates tumourigenesis and metastasis through hypo-phosphorylation of AKT cascade by targeting IGF-1R in human lung cancer, Published online: 01 May 2018; doi:10.1038/s41419-018-0535-8
The novel hsa-miR-12528 regulates tumourigenesis and metastasis through hypo-phosphorylation of AKT cascade by targeting IGF-1R in human lung cancerDetermining the manner of death in cases involving multiple stab injuries from a knife is generally straightforward. The medico-legal investigation of a stabbing death caused by a single stab injury from a knife comprises a smaller but potentially more problematic subset of forensic cases. We reviewed our institute's experience with single stab injuries and endeavored to identify features identified at the post-mortem examination which may aid in the differentiation between cases of homicide, suicide and accidental death. The single stab injury was to the left chest in the majority of deaths from homicide and from suicide. Clothing was nearly always involved in cases of homicide, but was also seen in cases of suicide. The knife was found in situ in 9 of the 11 cases of suicide involving a chest injury, but was not seen in any of the cases of homicide. There were no cases of an accidental single stab death from a knife in our records. Clinical data on accidental stab injuries was sought via a search of the medical records of a major tertiary referral hospital. A single non-fatal case of an accidental single stab injury from a knife was identified after the conclusion of our study period. Accidental stab injuries from a knife causing injury or death are rare.
International Journal for Numerical Methods in Biomedical Engineering, EarlyView.
https://ift.tt/2w0Da4H
International Journal for Numerical Methods in Biomedical Engineering, EarlyView.
https://ift.tt/2rc81q6
This week's milestone Federal Advocacy Forum is the first of the post-hard-cap era. Huge thanks to all the PTs, PTAs, and students who stepped forward over the years to protect our most vulnerable patients! #APTAFAF
Staphylococcus epidermidis is a major opportunistic pathogen primarily recovered from device-associated healthcare associated infections (DA-HAIs). Although S. epidermidis and other coagulase-negative staphylococci (CoNS) are less virulent than Staphylococcus aureus, these bacteria are an important reservoir of antimicrobial resistance genes and resistance-associated mobile genetic elements that can be transferred between staphylococcal species. We report a whole genome sequence of a multidrug resistant S. epidermidis (strain G6_2) representing multilocus sequence type (ST) 59 and isolated from an environmental sampling of a hotel room in London, UK. The genome of S. epidermidis G6_2 comprises of a 2408357 bp chromosome and six plasmids, with an average G+C content of 32%. The strain displayed a multi-drug resistance phenotype which was associated with carriage of 7 antibiotic resistance genes (blaZ, mecA, msrA, mphC, fosB, aacA-aphD, tetK) as well as resistance-conferring mutations in fusA and ileS. Antibiotic resistance genes were located on plasmids and chromosome. Comparative genomic analysis revealed that antibiotic resistance gene composition found in G6_2 was partly preserved across the ST59 lineage.
The incidence of invasive fungal infections has risen significantly in recent decades as medical interventions have become increasingly aggressive. These infections are extremely difficult to treat due to the extremely limited repertoire of systemic antifungals, the development of drug resistance, and the extent of to which the patient's immune function is compromised. Even when the appropriate antifungal therapies are administered in a timely fashion, treatment failure is common, frequently even in the absence of in vitro microbial resistance. In this study, we screened a small collection of FDA approved oncolytic agents for compounds that impact the efficacy of the two most widely used classes of system antifungals against Candida albicans, Candida glabrata, and Aspergillus fumigatus. We have identified several drugs that enhance fungal growth in the presence of the azole antifungals and examine the potential that these drugs directly affect fungal fitness, specifically antifungal susceptibility, and may be contributing to clinical treatment failure.
Colistin is a crucial last-line drug used for the treatment of life-threatening infections caused by multi-drug resistant strains of the Gram-negative bacteria, Acinetobacter baumannii. However, colistin-resistant A. baumannii isolates can be isolated following failed colistin therapy. Resistance is most often mediated by the addition of phosphoethanolamine (pEtN) to lipid A by PmrC, following missense mutations in the pmrCAB operon encoding PmrC and the two-component signal transduction system PmrA/PmrB. We recovered a pair of A. baumannii isolates from a single patient before (6009-1) and after (6009-2) failed colistin treatment. These strains displayed low and very high levels of colistin resistance, (MICs 8-16 μg/mL and 128 μg/mL) respectively. To understand how increased colistin resistance arose, we genome sequenced each isolate which revealed that 6009-2 had an extra copy of the insertion sequence element ISAba125 within a gene encoding an H-NS-family transcriptional regulator. To confirm the role of H-NS in colistin resistance we generated an hns deletion mutant in 6009-1 and showed that colistin resistance increased upon deletion of hns. We also provided 6009-2 with an intact copy of hns and showed that the strain was no longer resistant to high concentrations of colistin. Transcriptomic analysis of the clinical isolates identified more than 150 genes as differentially expressed in the colistin-resistant, hns mutant, 6009-2. Importantly, expression of eptA, encoding a second lipid A-specific pEtN transferase, but not pmrC, was increased in the hns mutant. This is the first time an H-NS-family transcriptional regulator has been associated with a pEtN transferase and colistin resistance.
A collection of 126 pigs were screened for carriage of colistin-resistant Enterobacteriaceae in a farm in Minas Gerais, Brazil. Out of this collection, eigth colistin-resistant Escherichia coli isolates were recovered, including one from Minas Gerais State, producing a new MCR-3 variant (MCR-3.12). Analysis of the lipopolysaccharide revealed that MCR-3.12 had a similar function as MCR-1 and MCR-2 by adding a phosphoethanolamine group to the lipid A. Genetic analysis showed that the mcr-3.12 gene was carried by an IncA/C2 plasmid and was embedded in an original genetic environment. This study reports the occurrence of the MCR-3-like determinant in South America and firstly demonstrates the functionality of this group of enzymes as a phosphoethanolamine transferase.
Mycobacterium abscessus (Mab) is a major non-tuberculous mycobacterial (NTM) pathogen responsible for about 80% of all pulmonary infections caused by rapidly growing mycobacteria. Clofazimine is an effective drug active against Mab, but the mechanism of resistance to clofazimine in Mab is unknown. To investigate the molecular basis of clofazimine resistance in Mab. We isolated 29 Mab mutants resistant to clofazimine, and subjected them to whole genome sequencing to identify possible mutations associated with clofazimine resistance. We found that mutations in MAB_2299c gene which encodes possible transcriptional regulatory protein, MAB_1483 and MAB_0540 are most commonly associated with clofazimine resistance. In addition, mutations in MAB_0416c, MAB_4099c, MAB_2613, MAB_0409, and MAB_1426 were also associated with clofazimine resistance but in less frequency. Two identical mutations which are likely to be polymorphisms unrelated to clofazimine resistance were found in MAB_4605c and MAB_4323 in 13 mutants. We conclude that mutations in MAB_2299c, MAB_1483, and MAB_0540 are the major mechanisms of clofazimine resistance in Mab. Future studies are needed to address the role of the identified mutations in clofazimine resistance in Mab. Our findings have implications for understanding mechanisms of resistance of clofazimine and for rapid detection of clofazimine resistance in this organism.
Human cytomegalovirus (HCMV) is a major cause of disease in immunocompromised individuals and the most common cause of congenital infection and neuro-sensorial disease. The expanding target populations for HCMV antiviral treatment along with the limitations of the currently available HCMV DNA polymerase inhibitors underscore the need for new antiviral agents with alternative modes of action. The anti-malarial artemisinin derivative artesunate was shown to inhibit HCMV in vitro, yet has demonstrated limited antiviral efficacy in vivo, prompting our search for more potent anti-HCMV artemisinin derivatives. Here we show that the innovative artemisinin derivative artemisone, which has been screened against malaria in human clinical studies, is a potent and non-cytotoxic inhibitor of HCMV. Artemisone exhibited an antiviral efficacy comparable to ganciclovir (EC50 1.20 ± 0.46 μM) in human foreskin fibroblasts, with enhanced relative potency in lung fibroblasts and epithelial cells. Significantly, the antiviral efficacy of artemisone was consistently ≥10-fold superior to that of artesunate in all cells. Artemisone effectively inhibited both laboratory-adapted and low-passage clinical strains, as well as drug-resistant HCMV strains. By using quantitative viral kinetics and gene expression studies, we showed that artemisone is a reversible inhibitor, targeting an earlier phase of the viral replication cycle than ganciclovir. Importantly, artemisone most effectively inhibited HCMV infection ex vivo in a clinically-relevant multicellular model of integral human placental tissues maintained in organ culture. Our promising findings encourage preclinical and clinical studies of artemisone as a new inhibitor against HCMV.
ST36 Klebsiella pneumoniae distributes worldwide. We found that a ST36 K. pneumoniae clinical isolate was carbapenem resistant, carried blaKPC-2, had mucoid regulator gene rmpA and exhibited high virulence. The findings suggest the emergence of carbapenem-resistant hypervirulent K. pneumoniae of ST36 and surveillance on carbapenem-resistant hypervirulent K. pneumoniae is required.
Staphylococcal biofilms are a major cause of therapeutic failure, especially when caused by multiresistant strains. Oral fusidic acid is currently being re-developed in the US for skin and skin structure and orthopedic infections, in which biofilms play a major role. The aim of this study was to examine the activity of fusidic acid alone or combined with other anti-staphylococcal drugs against biofilms made by a reference strain and five clinical isolates of Staphylococcus aureus or Staphylococcus epidermidis in in vitro static or dynamic models (microtiter plates and CDC reactor) exposed to clinically-relevant concentrations. In microtiter plates, antibiotics alone were poorly active, with marked differences among strains. At concentrations mimicking free-drug human Cmax, combination of fusidic acid with linezolid, daptomycin or vancomycin resulted in increased activity against 4-5 strains and combination with doxycycline, rifampin, or moxifloxacin, increased activity against 1-3 strains only. In the CDC reactor, biofilms were grown under constant flow and antibiotic concentrations decreased over time according to human elimination rates. A bactericidal effect was obtained when fusidic acid was combined with daptomycin or linezolid, but not with vancomycin. The higher tolerance of biofilms to antibiotics in the CDC reactor is probably attributable to the more complex architecture they adopt when growing under constant flow. Because biofilms grown in the CDC reactor are considered more similar to those developing in vivo, the data support further testing of combinations of fusidic acid with daptomycin or linezolid in models pertinent to chronic skin and skin structure or orthopedic infections.
Penicillin-binding proteins (PBPs) are the high affinity target sites of all β-lactam antibiotics in bacteria. It is well known that each β-lactam covalently binds to and thereby inactivates different PBPs with varying affinity. Despite β-lactams serving as cornerstone of our therapeutic armamentarium against Klebsiella pneumoniae, PBP binding data are missing for this pathogen. We aimed to generate the first PBP binding data on 13 chemically diverse and clinically relevant β-lactams and β-lactamase inhibitors in K. pneumoniae. PBP binding was determined using isolated membrane fractions from K. pneumoniae strains ATCC 43816 and ATCC 13883. Binding reactions were conducted using β-lactam concentrations from 0.0075 to 256 mg/liter (or 128 mg/liter). After β-lactam exposure, unbound PBPs were labelled by Bocillin FL. Binding affinities (IC50s) were reported as the β-lactam concentrations that half-maximally inhibited Bocillin FL binding. PBP occupancy patterns by β-lactams were consistent across both strains. Carbapenems bound to all PBPs with PBP2 and PBP4 as highest affinity targets (IC50s <0.0075 mg/liter). Preferential PBP2 binding was observed by mecillinam (IC50: <0.0075 mg/liter) and avibactam (2 mg/liter). Aztreonam showed high affinity for PBP3 (IC50: 0.06 to 0.12 mg/liter). Ceftazidime bound PBP3 at low (IC50: 0.06 to 0.25 mg/liter) and PBP1a/b at higher concentrations (4 mg/liter), whereas cefepime bound PBPs 1-4 more evenly (IC50s: 0.015 to 2 mg/liter). These PBP binding data on a comprehensive set of 13 clinically relevant β-lactams and β-lactamase inhibitors in K. pneumoniae enable, for the first time, rational design and optimization of double β-lactam and β-lactam/β-lactamase inhibitor combinations.
A delayed-release solid tablet formulation that releases posaconazole in the small intestine was developed to maximize systemic absorption. This study aimed to characterize the pharmacokinetics of the posaconazole solid tablet formulation in adult subjects and to investigate the potential impact of demographic and clinical factors on posaconazole exposure through a population pharmacokinetic approach. Nonlinear mixed-effects modeling was performed using data from several studies conducted in healthy volunteers and patients. The influence of demographic and clinical factors on pharmacokinetic parameters was evaluated using a stepwise forward inclusion/backward exclusion procedure. The final pharmacokinetic model was used to simulate posaconazole exposure in patients at high risk for invasive fungal diseases treated with the proposed posaconazole dose of 300 mg twice daily on day 1, followed by 300 mg daily for 27 days. A one-compartment pharmacokinetic model with sequential zero-order and first-order absorption and a first-order disposition from the central compartment adequately described the pharmacokinetic profile of the posaconazole solid tablet formulation. Significant covariates included disease state (acute myeloid leukemia/myelodysplasia vs allogeneic hematopoietic stem cell transplantation), body weight, and formulation on bioavailability; food status on first-order absorption rate; and dosing regimen (single dose vs multiple doses) on clearance. Except for body weight, the impact of these covariates on posaconazole exposure was considered clinically irrelevant. This population pharmacokinetic analysis confirmed that the proposed dose of the posaconazole solid tablet formulation provides adequate target therapeutic exposure (>0.5 mg/l) to a broad range of patients at high risk for invasive fungal disease.
Background: We examined the rapid evaluation of susceptibility to echinocandins in Candida spp. using the Etest performed directly on positive blood cultures and anidulafungin-containing agar plates.
Methods: We prospectively collected 80 positive blood cultures (Bactec™-FX system, Becton-Dickinson, Cockeysville, Maryland, USA) with echinocandin-susceptible Candida spp (n=60) and echinocandin-intermediate C. parapsilosis (n=20) from patients with candidemia. Additionally, blood culture bottles of nonfungemic/bacteremic patients were spiked with 35 echinocandin-resistant Candida spp. isolates. A total of 2-4 drops of medium from each bottle was stroked directly both onto RPMI 1640 agar plates with micafungin and anidulafungin Etest strips (ETDIR) and on Sabouraud agar plates containing 2 mg/L of anidulafungin. Isolates were tested according to the EUCAST method and Etest standard (ETSD). Essential and categorical agreement between methods was calculated.
Results: Essential agreement and categorical agreement between EUCAST and ETDIR and ETSD were both >97.4%. The essential agreement between ETDIR and EUCAST for both echinocandins was >97%. The categorical agreement between the FKS sequence (gold standard) and ETDIR was 97.4%. The ETDIR MIC of anidulafungin and micafungin (≥ 0.19 mg/L and ≥ 0.064 mg/L, respectively) effectively separated all susceptible/FKS wild-type isolates from the resistant/FKS mutant isolates. The categorical agreement (62.6%) between EUCAST and growth on anidulafungin-containing plates was poor, with the best agreement observed for C. glabrata (94.2%).
Conclusions: When performed directly on positive blood cultures from patients with candidemia, the Etest with micafungin and anidulafungin is a reliable procedure for a rapid testing of susceptibility to echinocandins in Candida spp. isolates.
LCB01-0371 is a novel oxazolidinone with broad-spectrum activity against Gram-positive pathogens in both in vitro studies and animal infection models. The objectives of this study were to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamics following single ascending doses (NCT01554995). Single oral doses of 600 mg Linezolid, a placebo, or LCB01-0371 between 50 mg and 3200 mg were tested in 69 healthy male subjects. Blood and urine were sampled, and LCB01-0371 concentrations were measured, and the serum inhibitory and bactericidal titers of LCB01-0371 and Linezolid were determined. LCB01-0371 was well tolerated up to 2400 mg. The most common drug-related clinical and laboratory adverse events were nausea with or without vomiting, decreased neutrophil count, and increased total bilirubin. The frequency of adverse events and drug-related adverse events was similar among the treatment groups. The systemic exposure was approximately dose-proportional over the range of 50mg--800 mg, which includes the anticipated clinical dose. The mean clearance, renal clearance, and volume of distribution were significantly decreased at higher doses (above 800 mg). LCB01-0371 exhibited early bacteriostatic activity against all tested strains except for S. pneumonia, and the potency of LCB01-0371 at 800 mg was similar to that of Linezolid at the therapeutic dose (600 mg). However, LCB01-0371 had less bactericidal activity than Linezolid. Taken together, LCB01-0371 was well tolerated and exhibited approximate dose proportionality within the anticipated clinically relevant dose range, and showed bacteriostatic and bactericidal activity comparable to that of Linezolid. These results support the further clinical development of LCB01-0371.
Mosquito-borne flaviviruses are a group of RNA viruses that constitute global threats for human and animal health. Replication of these pathogens is strictly dependent on cellular lipid metabolism. We have evaluated the effect of the pharmacological activation of Adenosine Monophosphate-activated Protein Kinase (AMPK), a master regulator of lipid metabolism, on the infection of three medically relevant flaviviruses: West Nile virus (WNV), Zika virus (ZIKV) and dengue virus (DENV). WNV is responsible for recurrent outbreaks of meningitis and encephalitis affecting humans and horses worldwide. ZIKV has caused a recent pandemic associated with birth defects (microcephaly), reproductive disorders, and severe neurological complications (Guillain-Barré syndrome). DENV is the etiological agent of the most prevalent mosquito-borne viral disease that can induce a potentially lethal complication called severe dengue. Our results showed, for the first time, that activation of AMPK using the specific small molecule activator PF-06409577 reduced both WNV, ZIKV, and DENV infection. This antiviral effect was associated to an impairment of viral replication due to the modulation of host cell lipid metabolism exerted by the compound. These results support that the pharmacological activation of AMPK, which currently constitutes an important pharmacological target for human diseases, could also provide a feasible approach for broad-spectrum host-directed antiviral discovery.
In 2025, approximately one out of five adults will be obese. Physiological changes associated with obesity have shown to influence the pharmacokinetics of drugs. Anidulafungin is frequently used in critically ill patients and to achieve optimal efficacy it is essential that its dose is appropriate for each patients' characteristics. We combined data from obese subjects with data from normal-weight subjects and determined an optimal dosing regimen for obese patients by population-PK modeling.
Twenty adults, of which twelve were normal-weight healthy subjects (median weight 67.7 kg; range: 61.5-93.6 kg) and eight morbidly obese subjects (median weight 149.7 kg; range: 124.1-166.5 kg) were included in the analysis. Subjects received a single dose of 100 mg anidulafungin IV in 90 minutes upon which blood samples were obtained. Monte Carlo simulations were performed to optimize dosing in obesity.
A three-compartment model and equal volumes of distribution described the data best. Total body weight was identified as descriptor for both clearance and volume of distribution but the effect of weight on these parameters was limited. Simulations showed that with the licensed 100 mg dose more than 97% of subjects with a weight above 140 kg will have an AUC0-24 lower than 99 mg*h/L (reference of normal weight individuals).
We found that anidulafungin pharmacokinetics in obese and normal-weight subjects, weight influenced both clearance and volume of distribution implying a lower exposure to anidulafungin in (morbidly) obese individuals. Consequently, a 25% increase in loading and maintenance dose could be considered in patients weighing more than 140 kg.
Purpose: Breast cancer often requires surgical treatment including breast-conserving surgical resection. However, with current post-surgical histological margin analysis, one-quarter of breast cancer patients undergo re-excision to achieve negative margins corresponding to decreased local recurrence and better outcomes. Therefore, a method with high resolution and specificity for intraoperative margin assessment is needed. Experimental Design: First, quantitative immunofluorescence staining of B7-H3 expression was assessed in four pathological stages of breast cancer progression of the MMTV-PyMT transgenic murine model. Next, an antibody-dye contrast agent, B7-H3-ICG, was injected into mice prior to surgical resection of breast cancer. Anatomical ultrasound, spectroscopic photoacoustic (sPA), and fluorescence imaging were used to guide resection of mammary glands suspected of containing cancer. Resected tissues were processed for H&E staining and pathological assessment and compared to sPA and fluorescence imaging signals. Results: Tissue containing DCIS (46.0±4.8 a.u.) or invasive carcinoma (91.7±21.4 a.u.) showed significantly higher (P<0.05) B7-H3 expression than normal and hyperplastic tissues (1.3±0.8 a.u.). During image guided surgical resection, tissue pieces assessed as normal or hyperplastic (n=17) showed lower average sPA (3.17±0.48 a.u.) and fluorescence signal (6.83E07±2.00E06 (p/s)/(µW/cm²)) than DCIS and invasive carcinoma tissue (n=63) with an average sPA signal of 23.98±4.88 a.u. and an average fluorescence signal of 7.56E07±1.44E06 (p/s)/(µW/cm²) with AUCs of 0.93 (95% CI; 0.87, 0.99) and 0.71 (95% CI; 0.57, 0.85), respectively. Conclusions: It was demonstrated that sPA and fluorescence molecular imaging combined with B7-H3-ICG agent can assess the disease status of tissues with high diagnostic accuracy, intraoperatively, with high resolution, sensitivity, and specificity.
Purpose: Cervical cancer is one of the leading causes of cancer deaths among women worldwide. The purpose of this study is to assess the therapeutic effect of the newly developed cyclin-dependent kinase 9 (CDK9) inhibitor FIT-039 on cervical neoplasia induced by human papillomavirus (HPV) infection. Experimental Design: We examined FIT-039 for its effect on HPV gene expression in HPV+ cervical cancer cells. Primary keratinocytes monolayer and organotypic raft culture models were used to evaluate HPV viral replication and cervical intraepithelial neoplasia (CIN) phenotypes. Preclinical pharmacokinetics and toxicity tests for FIT-039 were also conducted. Finally, the anti-HPV effect of FIT-039 was further examined in vivo, using HPV+ cervical cancer xenografts. Results: FIT-039 inhibits HPV replication and expression of E6 and E7 viral oncogenes, restoring tumor suppressors p53 and pRb in HPV+ cervical cancer cells. The therapeutic effect of FIT-039 was demonstrated in CIN model of an organotypic raft culture, where FIT-039 suppressed HPV18-induced dysplasia/hyperproliferation with reduction in viral load. FIT-039 also repressed growth of HPV16+, but not HPV- cervical cancer xenografts without any significant adverse effects. Safety and pharmacokinetics of FIT-039 were confirmed for systemic and topical routes. Conclusions: The CDK9 inhibitor FIT-039 showed potent anti-HPV activity without significant toxicity in preclinical studies. Thus, FIT-039 is expected to be novel therapeutics for CIN to prevent cervical cancer.
Purpose: Adoptive T cell immunotherapy (ACT) has emerged as a viable therapeutic for peripheral and central nervous system (CNS) tumors. In peripheral cancers, optimal efficacy of ACT is reliant on dendritic cells (DCs) in the tumor microenvironment. However, the CNS is largely devoid of resident migratory DCs to function as antigen-presenting cells during immunotherapy. Herein, we demonstrate that cellular interactions between adoptively-transferred tumor-reactive T cells and bone marrow-derived HSPCs lead to the generation of potent intratumoral DCs within the CNS compartment. Experimental Design: We evaluated HSPC differentiation during ACT in vivo in glioma-bearing hosts and HSPC proliferation and differentiation in vitro using a T cell co-culture system. We utilized FACS, ELISAs, and gene expression profiling to study the phenotype and function of HSPC-derived cells ex vivo and in vivo. To demonstrate the impact of HSPC differentiation and function on anti-tumor efficacy, we performed survival experiments. Results: Transfer of HSPCs with concomitant ACT led to the production of activated CD86+CD11c+MHCII+ cells consistent with DC phenotype and function within the brain tumor microenvironment. These intratumoral DCs largely supplanted abundant host myeloid-derived suppressor cells. We determined that during ACT, HSPC-derived cells in gliomas rely on T cell-released IFN- to differentiate into DCs, activate T cells, and reject intracranial tumors. Conclusions: Our data supports the use of HSPCs as a novel cellular therapy. While DC vaccines induce robust immune responses in the periphery, our data demonstrates that HSPC transfer uniquely generates intratumoral DCs that potentiate T cell responses and promote glioma rejection in situ.
Purpose: Regulatory T (Treg) cells are important suppressive cells among tumor infiltrating lymphocytes (TIL). Treg express the well-known immune checkpoint receptor PD-1, which is reported to mark "exhausted" Treg with lower suppressive function. T cell immunoglobulin mucin (Tim)-3, a negative regulator of Th1 immunity, is expressed by a sizeable fraction of TIL Tregs, but the functional status of Tim-3+ Tregs remains unclear. Experimental Design: CD4+CTLA-4+CD25high Treg were sorted from freshly excised head and neck squamous cell carcinoma (HNSCC) TIL based on Tim-3 expression. Functional and phenotypic features of these Tim-3+ and Tim-3- TIL Tregs were tested by in vitro suppression assays and multi-color flow cytometry. Gene expression profiling and NanoString analysis of Tim-3+ TIL Treg were performed. A murine HNSCC tumor model was used to test the effect of anti-PD-1 immunotherapy on Tim-3+ Treg. Results: Despite high PD-1 expression, Tim-3+ TIL Treg displayed a greater capacity to inhibit naïve T cell proliferation than Tim-3- Treg. Tim-3+ Treg from human HNSCC TIL also displayed an effector-like phenotype, with more robust expression of CTLA-4, PD-1, CD39 and IFN- receptor. Exogenous IFN- treatment could partially reverse the suppressive function of Tim-3+ TIL Treg. Anti-PD-1 immunotherapy downregulated Tim-3 expression on Tregs isolated from murine HNSCC tumors, and this treatment reversed the suppressive function of HNSCC TIL Tregs. Conclusions: Tim-3+ Treg are functionally and phenotypically distinct in HNSCC TIL, and are highly effective at inhibiting T cell proliferation despite high PD-1 expression. IFN- induced by anti-PD-1 immunotherapy may be beneficial by reversing Tim-3+ Treg suppression.
Cancer, EarlyView.
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Cancer, EarlyView.
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Cancer, EarlyView.
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Cancer, EarlyView.
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Cancer, EarlyView.
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MONDAY, April 30, 2018 -- Even relatively low-efficacy influenza vaccines can have a high impact, especially with optimal distribution across age groups, according to a study published online April 30 in the Proceedings of the National Academy of...
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MONDAY, April 30, 2018 -- Automated and clinical Breast Imaging Reporting and Data System (BI-RADS) density measures similarly predict breast cancer risk, according to a study published online May 1 in the Annals of Internal Medicine. Karla...
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The 70th Annual Meeting of the American Academy of Neurology The annual meeting of the American Academy of Neurology was held from April 21 to 27 in Los Angeles and attracted approximately 12,000 participants from around the world, including...
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MONDAY, April 30, 2018 -- Based on findings from a systematic review of the literature, recommendations have been developed for improving the evidence for natural experiments in obesity; the review and position paper were published online May 1 in...
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MONDAY, April 30, 2018 -- Mandatory reporting of cardiac surgery outcomes for coronary artery bypass grafting (CABG) in Massachusetts from 2002 to 2014 was associated with improved outcomes, according to a study presented at the annual meeting of...
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Objectives
Out-of-hours (OOH) primary care services are a key element of community care at the end of life, yet there have been no previous attempts to describe the scope of this activity. We aimed to establish the proportion of Oxfordshire patients who were seen by the OOH service within the last 30 days of life, whether they were documented in a palliative phase of care and the demographic and clinical features of these groups.
DesignPopulation-based study linking a database of patient contacts with OOH primary care with the register of all deaths within Oxfordshire (600 000 population) during 13 months.
SettingOxfordshire.
ParticipantsBetween 1 December 2014 and 30 November 2015 there were 102 877 OOH contacts made by 67 943 patients with the OOH service.
Main outcome measuresProportion of patients dying in the Oxfordshire population who were seen by the OOH service within the last 30 days of life. Demographic and clinical features of these contacts.
Results29.5% of all population deaths were seen by the OOH service in the last 30 days of life. Among the 1530 patients seen, patients whose palliative phase was documented (n=577, 36.4%) were slightly younger (median age=83.5 vs 85.2 years, P<0.001) and were seen closer to death (median days to death=2 vs 8, P<0.001). More were assessed at home (59.8% vs 51.9%, P<0.001) and less were admitted to hospital (2.7% vs 18.0%, P<0.001).
ConclusionsOOH services see around one-third of all patients who die in a population. Most patients at the end of life are not documented as palliative by OOH services and are less likely to receive ongoing care at home.
Objectives
To categorically describe cancer research funding in the UK by gender of primary investigator (PIs).
DesignSystematic analysis of all open-access data.
MethodsData about public and philanthropic cancer research funding awarded to UK institutions between 2000 and 2013 were obtained from several sources. Fold differences were used to compare total investment, award number, mean and median award value between male and female PIs. Mann-Whitney U tests were performed to determine statistically significant associations between PI gender and median grant value.
ResultsOf the studies included in our analysis, 2890 (69%) grants with a total value of £1.82 billion (78%) were awarded to male PIs compared with 1296 (31%) grants with a total value of £512 million (22%) awarded to female PIs. Male PIs received 1.3 times the median award value of their female counterparts (P<0.001). These apparent absolute and relative differences largely persisted regardless of subanalyses.
ConclusionsWe demonstrate substantial differences in cancer research investment awarded by gender. Female PIs clearly and consistently receive less funding than their male counterparts in terms of total investment, the number of funded awards, mean funding awarded and median funding awarded.
Objectives
Anxiety is an increasingly recognised predictor of cognitive deterioration in older adults and in those with mild cognitive impairment. Often believed to be a prodromal feature of neurodegenerative disease, anxiety may also be an independent risk factor for dementia, operationally defined here as preceding dementia diagnosis by ≥10 years.
DesignA systematic review of the literature on anxiety diagnosis and long-term risk for dementia was performed following published guidelines.
Setting and participantsMedline, PsycINFO and Embase were searched for peer-reviewed journals until 8 March 2017. Publications reporting HR/OR for all-cause dementia based on clinical criteria from prospective cohort or case–control studies were selected. Included studies measured clinically significant anxiety in isolation or after controlling for symptoms of depression, and reported a mean interval between anxiety assessment and dementia diagnosis of at least 10 years. Methodological quality assessments were performed using the Newcastle-Ottawa Scale.
Outcome measureHR/OR for all-cause dementia.
ResultsSearches yielded 3510 articles, of which 4 (0.02%) were eligible. The studies had a combined sample size of 29 819, and all studies found a positive association between clinically significant anxiety and future dementia. Due to the heterogeneity between studies, a meta-analysis was not conducted.
ConclusionsClinically significant anxiety in midlife was associated with an increased risk of dementia over an interval of at least 10 years. These findings indicate that anxiety may be a risk factor for late-life dementia, excluding anxiety that is related to prodromal cognitive decline. With increasing focus on identifying modifiable risk factors for dementia, more high-quality prospective studies are required to clarify whether clinical anxiety is a risk factor for dementia, separate from a prodromal symptom.
Na página 191, onde se lê na linha de autoria:
Francisco GOIANA-DA-SILVA1,2, Alexandre Morais NUNES3,4, Marisa MIRALDO5, Alexandra BENTO6, João BREDA7, Fernando Ferreira ARAÚJO8,9
Deverá ler-se
Francisco GOIANA-DA-SILVA1,2, Alexandre Morais NUNES3,4, Marisa MIRALDO5, Alexandra BENTO6, João BREDA7,8, Fernando Ferreira ARAÚJO9,10
Na mesma página, em rodapé, onde nas afiliações dos autores se lê:
1. Estudante Doutorando em Politicas de Saúde. Department of Surgery and Cancer. Imperial College Medical School. Londres. Reino Unido.
2. Assistente Convidado de Gestão e Liderança em Saúde. Faculdade de Ciências da Saúde. Universidade da Beira Interior. Covilhã. Portugal.
3. Professor Auxiliar Convidado. Unidade Curricular de Políticas de Saúde. Instituto Superior de Ciências Sociais e Políticas. Universidade de Lisboa. Lisboa. Portugal.
4. Investigador. Centro de Administração e Políticas Públicas. Instituto Superior de Ciências Sociais e Políticas. Universidade de Lisboa. Lisboa. Portugal.
5. Associate Professor. Health Economics Department. Imperial College London Business School. Healthcare Management Group. Londres. Reino Unido.
6. Bastonária. Ordem dos Nutricionistas. Lisboa. Portugal.
7. Programme Manager. Nutrition, Physical Activity and Obesity. World Health Organisation. Lisboa. Portugal.
8. Secretário de Estado Adjunto e da Saúde. XXI Governo Constitucional. Lisboa. Portugal.
9. Professor Auxiliar Convidado. Faculdade de Medicina. Universidade do Porto. Porto. Portugal.
Deverá ler-se:
1. Estudante Doutorando em Politicas de Saúde. Department of Surgery and Cancer. Imperial College Medical School. Londres. Reino Unido.
2. Assistente Convidado de Gestão e Liderança em Saúde. Faculdade de Ciências da Saúde. Universidade da Beira Interior. Covilhã. Portugal.
3. Professor Auxiliar Convidado. Unidade Curricular de Políticas de Saúde. Instituto Superior de Ciências Sociais e Políticas. Universidade de Lisboa. Lisboa. Portugal.
4. Investigador. Centro de Administração e Políticas Públicas. Instituto Superior de Ciências Sociais e Políticas. Universidade de Lisboa. Lisboa. Portugal.
5. Associate Professor. Health Economics Department. Imperial College London Business School. Healthcare Management Group. Londres. Reino Unido.
6. Bastonária. Ordem dos Nutricionistas. Lisboa. Portugal.
7. Programme Manager. Nutrition, Physical Activity and Obesity. World Health Organisation. Lisboa. Portugal.
8. Head of the WHO European Office for Prevention and Control of Noncommunicable Diseases. Moscow. Russian Federation.
9. Secretário de Estado Adjunto e da Saúde. XXI Governo Constitucional. Lisboa. Portugal.
10. Professor Auxiliar Convidado. Faculdade de Medicina. Universidade do Porto. Porto. Portugal.
Na página 194, entre o corpo do manuscrito e a listagem final de referências, deverá ler-se o seguinte parágrafo:
OBSERVAÇÕES
João Breda é funcionário da OMS. As suas declarações no âmbito deste artigo são da sua exclusiva responsabilidade.
Artigo publicado com erros: https://ift.tt/2FuAvzF
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Cotyledonoid dissecting leiomyoma, also known as Sternberg tumor, is a rare benign uterine tumor with a gross and radiological appearance that may suggest the possibility of a malignancy. We report a case of a thirty-eight-year-old female patient who presented with menorrhagia and abdominal pain one month after delivery by cesarean section. An ultrasound scan showed a heterogeneous pelvic mass, near the isthmic region, with 25 x 24 x 23 mm without vascularization so the possibility of placenta accreta could not be excluded. During hysterectomy, we also removed a small grey mass in the right ovary. Microscopic examination revealed a proliferation of a sparsely cellular tissue with extensive hyalinization and coagulative necrosis, composed of spindle shaped muscle cells without cellular atypia or mitoses. The patient is without evidence of recurrence one year and six months post-surgery.
Introduction: Energy drinks are youth-targeted beverages that contain high amounts of caffeine and other stimulants. A number of deleterious health effects associated with consumption of these drinks have already been reported. Despite the health concerns, energy drinks research has been sparse, especially at younger ages. The main purpose of this study was to determine the prevalence of energy drinks consumption and patterns of use among adolescents.
Materials and Methods: Cross-sectional study of students aged between 11 – 17 years-old attending four public schools in Braga, cluster sampled. A self-administrated questionnaire was used to access sociodemographic data, self-reported academic performance as well as energy drinks consumption patterns, attitudes, awareness and associated symptoms.
Results: In a total of 1414 adolescents studied (mean age 15.1 ± 1.5 years; 53.9% were females), 56.7% reported to have used energy drinks at least once (62.5% in males; 52.1% in females). Of those, 34% described a regular consumption (at least once a month) and 14.1% a weekly consumption. The most common reasons for energy drinks consumption were the pleasant taste (49%), desire to increase global energy (35%) or sports performance (33%). On average, energy drinks users were older compared with non-users. Energy drinks consumption was associated with male gender and with self-reported worse academic performance. Approximately onethird experienced at least one symptom after consumption. In addition, 39.9% of energy drinks consumers reported mixing those with alcohol.
Discussion: Consumption of energy drinks has been increasing. The prevalence found for its consumption in this study is similar to that reported in the literature. Knowledge about motivation, general awareness of the risks or other variables related to consumption of these drinks might allow a better characterization of this behavior.
Conclusion: This study showed a high prevalence of energy drinks consumption among adolescents from a city in Northern Portugal, with self-reported symptoms after consumption and common concomitant use of alcohol.
