(See pages 312–3 for the Answer to the Photo Quiz.)
https://ift.tt/2IJiWNS
Κυριακή 1 Ιουλίου 2018
Multinuclear and Ground Glass-Formed Cells Detected in the Peritoneal Dialysate
herpes simplex virusimmunosuppressionperitoneal dialysisbullous pemphigoid
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Atypical Presentation of Lemierre’s Syndrome Causing Septic Shock and Acute Respiratory Distress Syndrome
Lemierre's disease is a rare but life-threatening condition characterized by an oropharyngeal infection complicating with thrombophlebitis of the internal jugular vein and disseminated abscesses. We are presenting a case of a young female who initially presented with fevers, chills, sore throat, and swollen neck later developed progressively worsening shortness of breath along with sudden onset pleuritic chest pain. She then developed progressively worsening acute hypoxic respiratory failure requiring intubation and mechanical ventilation. Interval chest X-ray showed worsening bilateral effusions. She also developed septic shock requiring pressors. Blood culture showed Fusobacterium, and antibiotics were changed accordingly following which there was a clinical improvement. The diagnosis of Lemierre's syndrome was then established based on her presenting age and bilateral pulmonary empyema in the setting of septicemia with Fusobacterium.
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CAR-T Cells Surface-Engineered with Drug-Encapsulated Nanoparticles Can Ameliorate Intratumoral T-cell Hypofunction
One limiting factor of CAR T-cell therapy for treatment of solid cancers is the suppressive tumor microenvironment (TME), which inactivates the function of tumor-infiltrating lymphocytes (TIL) through the production of immunosuppressive molecules, such as adenosine. Adenosine inhibits the function of CD4+ and CD8+ T cells by binding to and activating the A2a adenosine receptor (A2aR) expressed on their surface. This suppression pathway can be blocked using the A2aR-specific small molecule antagonist SCH-58261 (SCH), but its applications have been limited owing to difficulties delivering this drug to immune cells within the TME. To overcome this limitation, we used CAR-engineered T cells as active chaperones to deliver SCH-loaded cross-linked, multilamellar liposomal vesicles (cMLV) to tumor-infiltrating T cells deep within the immune suppressive TME. Through in vitro and in vivo studies, we have demonstrated that this system can be used to effectively deliver SCH to the TME. This treatment may prevent or rescue the emergence of hypofunctional CAR-T cells within the TME. Cancer Immunol Res; 6(7); 812–24. ©2018 AACR.
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Drug-Induced Senescent Multiple Myeloma Cells Elicit NK Cell Proliferation by Direct or Exosome-Mediated IL15 Trans-Presentation
Treatment of multiple myeloma (MM) cells with sublethal doses of genotoxic drugs leads to senescence and results in increased NK cell recognition and effector functions. Herein, we demonstrated that doxorubicin- and melphalan-treated senescent cells display increased expression of IL15, a cytokine involved in NK cell activation, proliferation, and maturation. IL15 upregulation was evident at the mRNA and protein level, both in MM cell lines and malignant plasma cells from patients' bone marrow (BM) aspirates. However, IL15 was detectable as a soluble cytokine only in vivo, thus indicating a functional role of IL15 in the BM tumor microenvironment. The increased IL15 was accompanied by enhanced expression of the IL15/IL15RA complex on the membrane of senescent myeloma cells, allowing the functional trans-presentation of this cytokine to neighboring NK cells, which consequently underwent activation and proliferation. We demonstrated that MM cell–derived exosomes, the release of which was augmented by melphalan treatment in senescent cells, also expressed IL15RA and IL15, and their interaction with NK cells in the presence of exogenous IL15 resulted in increased proliferation. Altogether, our data demonstrated that low doses of chemotherapeutic drugs, by inducing tumor cell senescence and a senescence-associated secretory phenotype, promoted IL15 trans-presentation to NK cells and, in turn, their activation and proliferation, thus enhancing NK cell–tumor immune surveillance and providing new insights for the exploitation of senescence-based cancer therapies. Cancer Immunol Res; 6(7); 860–9. ©2018 AACR.
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The Clinical Activity of PD-1/PD-L1 Inhibitors in Metastatic Non-Clear Cell Renal Cell Carcinoma
Programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors have shown activity in metastatic clear cell renal cell carcinoma (ccRCC). Data on the activity of these agents in patients with non–clear cell RCC (nccRCC) or patients with sarcomatoid/rhabdoid differentiation are limited. In this multicenter analysis, we explored the efficacy of PD-1/PD-L1 inhibitors in patients with nccRCC or sarcomatoid/rhabdoid differentiation. Baseline and follow-up demographic, clinical, treatment, and radiographic data were collected. The primary endpoint was objective response rate. Secondary endpoints include time-to-treatment failure (TTF), overall survival (OS), and biomarker correlates. Forty-three patients were included: papillary (n = 14; 33%), chromophobe (n = 10; 23%), unclassified (n = 9; 21%), translocation (n = 3; 7%), and ccRCC with sarcomatoid differentiation (n = 7, 16%). Of those 43 patients, 11 patients (26%) had sarcomatoid and/or rhabdoid differentiation (n = 7 with ccRCC; n = 4 nccRCC). Overall, 8 patients (19%) objectively responded, including 4 patients (13%) who received PD-1/PD-L1 monotherapy. Responses were observed in patients with ccRCC with sarcomatoid and/or rhabdoid differentiation (n = 3/7, 43%), translocation RCC (n = 1/3, 33%), and papillary RCC (n = 4/14, 29%). The median TTF was 4.0 months [95% confidence interval (CI), 2.8–5.5] and median OS was 12.9 months (95% CI, 7.4–not reached). No specific genomic alteration was associated with clinical benefit. Modest antitumor activity for PD-1/PD-L1–blocking agents was observed in some patients with nccRCC. Further prospective studies are warranted to investigate the efficacy of PD-1/PD-L1 blockade in this heterogeneous patient population. Cancer Immunol Res; 6(7); 758–65. ©2018 AACR.
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Subcellular Localization of Antigen in Keratinocytes Dictates Delivery of CD4+ T-cell Help for the CTL Response upon Therapeutic DNA Vaccination into the Skin
In a mouse model of therapeutic DNA vaccination, we studied how the subcellular localization of vaccine protein impacts antigen delivery to professional antigen-presenting cells and efficiency of CTL priming. Cytosolic, membrane-bound, nuclear, and secretory versions of ZsGreen fluorescent protein, conjugated to MHC class I and II ovalbumin (OVA) epitopes, were expressed in keratinocytes by DNA vaccination into the skin. ZsGreen-OVA versions reached B cells in the skin-draining lymph node (dLN) that proved irrelevant for CTL priming. ZsGreen-OVA versions were also actively transported to the dLN by dendritic cells (DC). In the dLN, vaccine proteins localized to classical (c)DCs of the migratory XCR1+ and XCR– subtypes, and—to a lesser extent—to LN-resident cDCs. Secretory ZsGreen-OVA induced the best antitumor CTL response, even though its delivery to cDCs in the dLN was significantly less efficient than for other vaccine proteins. Secretory ZsGreen-OVA protein proved superior in CTL priming, because it led to in vivo engagement of antigen-loaded XCR1+, but not XCR1–, cDCs. Secretory ZsGreen-OVA also maximally solicited CD4+ T-cell help. The suboptimal CTL response to the other ZsGreen-OVA versions was improved by engaging costimulatory receptor CD27, which mimics CD4+ T-cell help. Thus, in therapeutic DNA vaccination into the skin, mere inclusion of helper epitopes does not ensure delivery of CD4+ T-cell help for the CTL response. Targeting of the vaccine protein to the secretory route of keratinocytes is required to engage XCR1+ cDC and CD4+ T-cell help and thus to promote CTL priming. Cancer Immunol Res; 6(7); 835–47. ©2018 AACR.
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Adaptive NK Cells Resist Regulatory T-cell Suppression Driven by IL37
Natural killer (NK) cells are capable of fighting viral infections and cancer. However, these responses are inhibited by immune suppressor cells in the tumor microenvironment. Tumor progression promotes the recruitment and generation of intratumoral regulatory T cells (Treg), associated with a poor prognosis in cancer patients. Here, we show that canonical NK cells are highly susceptible to Treg-mediated suppression, in contrast to highly resistant CD57+ FcR–NKG2C+ adaptive (CD56+CD3–) NK cells that expand in cytomegalovirus exposed individuals. Specifically, Tregs suppressed canonical but not adaptive NK-cell proliferation, IFN production, degranulation, and cytotoxicity. Treg-mediated suppression was associated with canonical NK-cell downregulation of TIM3, a receptor that activates NK-cell IFN production upon ligand engagement, and upregulation of the NK-cell inhibitory receptors PD-1 and the IL1 receptor family member, IL1R8 (SIGIRR or TIR8). Treg production of the IL1R8 ligand, IL37, contributed to the phenotypic changes and diminished function in Treg-suppressed canonical NK cells. Blocking PD-1, IL1R8, or IL37 abrogated Treg suppression of canonical NK cells while maintaining NK-cell TIM3 expression. Our data uncover new mechanisms of Treg-mediated suppression of canonical NK cells and identify that adaptive NK cells are inherently resistant to Treg suppression. Strategies to enhance the frequency of adaptive NK cells in the tumor microenvironment or to blunt Treg suppression of canonical NK cells will enhance the efficacy of NK-cell cancer immunotherapy. Cancer Immunol Res; 6(7); 766–75. ©2018 AACR.
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A CS1-NKG2D Bispecific Antibody Collectively Activates Cytolytic Immune Cells against Multiple Myeloma
Multiple myeloma (MM) is an incurable hematologic malignancy of plasma cells, with an estimated 30,000 new cases diagnosed each year in the United States, signifying the need for new therapeutic approaches. We hypothesized that targeting MM using a bispecific antibody (biAb) to simultaneously engage both innate and adaptive cytolytic immune cells could present potent antitumor activity. We engineered a biAb by fusing an anti-CS1 single-chain variable fragment (scFv) and an anti-NKG2D scFv (CS1-NKG2D biAb). Although NKG2D is a potent activation receptor ubiquitously expressed on mostly cytolytic immune cells including NK cells, CD8+ T cells, T cells, and NKT cells, the CS1 tumor-associated antigen on MM represents a promising target. CS1-NKG2D biAb engaged human MM cell lines and NKG2D+ immune cells, forming immune synapses. In effector cells, CS1-NKG2D biAb triggered the phosphorylation of AKT, a downstream protein kinase of the activated NKG2D–DAP10 complex. The EC50 values of CS1-NKG2D biAb for CS1high and for CS1low MM cell lines with effector PBMCs were 10–12 and 10–9 mol/L, respectively. CS1-NKG2D biAb acted through multiple types of immune cells, and this induced cytotoxicity was both CS1- and NKG2D-specific. In vivo, survival was significantly prolonged using CS1-NKG2D biAb in a xenograft NOD-SCIDIL2c–/– (NSG) mouse model engrafted with both human PBMCs and MM cell lines. Collectively, we demonstrated that the CS1-NKG2D biAb facilitated an enhanced immune synapse between CS1+ MM cells and NKG2D+ cytolytic innate and antigen-specific effector cells, which, in turn, activated these immune cells for improved clearance of MM. Cancer Immunol Res; 6(7); 776–87. ©2018 AACR.
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Tumor-Specific Inhibition of In Situ Vaccination by Distant Untreated Tumor Sites
In situ vaccination is an emerging cancer treatment strategy that uses local therapies to stimulate a systemic antitumor immune response. We previously reported an in situ vaccination effect when combining radiation (RT) with intratumor (IT) injection of tumor-specific immunocytokine (IC), a fusion of tumor-specific antibody and IL2 cytokine. In mice bearing two tumors, we initially hypothesized that delivering RT plus IT-IC to the "primary" tumor would induce a systemic antitumor response causing regression of the "secondary" tumor. To test this, mice bearing one or two syngeneic murine tumors of B78 melanoma and/or Panc02 pancreatic cancer were treated with combined external beam RT and IT-IC to the designated "primary" tumor only. Primary and secondary tumor response as well as animal survival were monitored. Immunohistochemistry and quantitative real-time PCR were used to quantify tumor infiltration with regulatory T cells (Treg). Transgenic "DEREG" mice or IgG2a anti–CTLA-4 were used to transiently deplete tumor Tregs. Contrary to our initial hypothesis, we observed that the presence of an untreated secondary tumor antagonized the therapeutic effect of RT + IT-IC delivered to the primary tumor. We observed reciprocal tumor specificity for this effect, which was circumvented if all tumors received RT or by transient depletion of Tregs. Primary tumor treatment with RT + IT-IC together with systemic administration of Treg-depleting anti–CTLA-4 resulted in a renewed in situ vaccination effect. Our findings show that untreated tumors can exert a tumor-specific, Treg-dependent, suppressive effect on the efficacy of in situ vaccination and demonstrate clinically viable approaches to overcome this effect. Untreated tumor sites antagonize the systemic and local antitumor immune response to an in situ vaccination regimen. This effect is radiation sensitive and may be mediated by tumor-specific regulatory T cells harbored in the untreated tumor sites. Cancer Immunol Res; 6(7); 825–34. ©2018 AACR.
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IL22 Promotes Kras-Mutant Lung Cancer by Induction of a Protumor Immune Response and Protection of Stemness Properties
Somatic KRAS mutations are the most common oncogenic variants in lung cancer and are associated with poor prognosis. Using a Kras-induced lung cancer mouse model, CC-LR, we previously showed a role for inflammation in lung tumorigenesis through activation of the NF-B pathway, along with induction of interleukin 6 (IL6) and an IL17-producing CD4+ T-helper cell response. IL22 is an effector molecule secreted by CD4+ and T cells that we previously found to be expressed in CC-LR mice. IL22 mostly signals through the STAT3 pathway and is thought to act exclusively on nonhematopoietic cells with basal IL22 receptor (IL22R) expression on epithelial cells. Here, we found that higher expression of IL22R1 in patients with KRAS-mutant lung adenocarcinoma was an independent indicator of poor recurrence-free survival. We then showed that genetic ablation of Il22 in CC-LR mice (CC-LR/IL22KO mice) caused a significant reduction in tumor number and size. This was accompanied by significantly lower tumor cell proliferation, angiogenesis, and STAT3 activation. Il22 ablation was also associated with significant reduction in lung-infiltrating inflammatory cells and expression of protumor inflammatory cytokines. Conversely, this was accompanied with increased antitumor Th1 and cytotoxic CD8+ T-cell responses, while suppressing the protumor immunosuppressive T regulatory cell response. In CC-LR/IL22KO mice, we found significantly reduced expression of core stemness genes and the number of prototypical SPC+CCSP+ stem cells. Thus, we conclude that IL22 promotes Kras-mutant lung tumorigenesis by driving a protumor inflammatory microenvironment with proliferative, angiogenic, and stemness contextual cues in epithelial/tumor cells. Cancer Immunol Res; 6(7); 788–97. ©2018 AACR.
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Whole Exome and Transcriptome Analyses Integrated with Microenvironmental Immune Signatures of Lung Squamous Cell Carcinoma
The immune microenvironment in lung squamous cell carcinoma (LUSC) is not well understood, with interactions between the host immune system and the tumor, as well as the molecular pathogenesis of LUSC, awaiting better characterization. To date, no molecularly targeted agents have been developed for LUSC treatment. Identification of predictive and prognostic biomarkers for LUSC could help optimize therapy decisions. We sequenced whole exomes and RNA from 101 tumors and matched noncancer control Korean samples. We used the information to predict subtype-specific interactions within the LUSC microenvironment and to connect genomic alterations with immune signatures. Hierarchical clustering based on gene expression and mutational profiling revealed subtypes that were either immune defective or immune competent. We analyzed infiltrating stromal and immune cells to further characterize the tumor microenvironment. Elevated expression of macrophage 2 signature genes in the immune competent subtype confirmed that tumor-associated macrophages (TAM) linked inflammation and mutation-driven cancer. A negative correlation was evident between the immune score and the amount of somatic copy-number variation (SCNV) of immune genes (r = –0.58). The SCNVs showed a potential detrimental effect on immunity in the immune-deficient subtype. Knowledge of the genomic alterations in the tumor microenvironment could be used to guide design of immunotherapy options that are appropriate for patients with certain cancer subtypes. Cancer Immunol Res; 6(7); 848–59. ©2018 AACR.
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Mitochondrial Morphological and Functional Reprogramming Following CD137 (4-1BB) Costimulation
T and NK lymphocytes express CD137 (4-1BB), a costimulatory receptor of the TNFR family whose function is exploitable for cancer immunotherapy. Mitochondria regulate the function and survival of T lymphocytes. Herein, we show that CD137 costimulation provided by agonist mAb and CD137L (4-1BBL) induced mitochondria enlargement that resulted in enhanced mitochondrial mass and transmembrane potential in human and mouse CD8+ T cells. Such mitochondrial changes increased T-cell respiratory capacities and were critically dependent on mitochondrial fusion protein OPA-1 expression. Mass and function of mitochondria in tumor-reactive CD8+ T cells from cancer-bearing mice were invigorated by agonist mAb to CD137, whereas mitochondrial baseline mass and function were depressed in CD137-deficient tumor reactive T cells. Tumor rejection induced by the synergistic combination of adoptive T-cell therapy and agonistic anti-CD137 was critically dependent on OPA-1 expression in transferred CD8+ T cells. Moreover, stimulation of CD137 with CD137 mAb in short-term cultures of human tumor-infiltrating lymphocytes led to mitochondria enlargement and increased transmembrane potential. Collectively, these data point to a critical link between mitochondrial morphology and function and enhanced antitumor effector activity upon CD137 costimulation of T cells. Cancer Immunol Res; 6(7); 798–811. ©2018 AACR.
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Nanobody-Antigen Conjugates Elicit HPV-Specific Antitumor Immune Responses
High-risk human papillomavirus-associated cancers express viral oncoproteins (e.g., E6 and E7) that induce and maintain the malignant phenotype. The viral origin of these proteins makes them attractive targets for development of a therapeutic vaccine. Camelid-derived single-domain antibody fragments (nanobodies or VHHs) that recognize cell surface proteins on antigen-presenting cells (APC) can serve as targeted delivery vehicles for antigens attached to them. Such VHHs were shown to induce CD4+ and CD8+ T-cell responses against model antigens conjugated to them via sortase, but antitumor responses had not yet been investigated. Here, we tested the ability of an anti-CD11b VHH (VHHCD11b) to target APCs and serve as the basis for a therapeutic vaccine to induce CD8+ T-cell responses against HPV+ tumors. Mice immunized with VHHCD11b conjugated to an H-2Db-restricted immunodominant E7 epitope (E749-57) had more E7-specific CD8+ T cells compared with those immunized with E749-57 peptide alone. These CD8+ T cells acted prophylactically and conferred protection against a subsequent challenge with HPV E7-expressing tumor cells. In a therapeutic setting, VHHCD11b-E749-57 vaccination resulted in greater numbers of CD8+ tumor–infiltrating lymphocytes compared with mice receiving E749-57 peptide alone in HPV+ tumor-bearing mice, as measured by in vivo noninvasive VHH-based immune-positron emission tomography (immunoPET), which correlated with tumor regression and survival outcome. Together, these results demonstrate that VHHs can serve as a therapeutic cancer vaccine platform for HPV-induced cancers. Cancer Immunol Res; 6(7); 870–80. ©2018 AACR.
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Clinical and Pathological Characteristics of KEAP1- and NFE2L2-Mutated Non-Small Cell Lung Carcinoma (NSCLC)
Purpose: KEAP1 and NFE2L2 mutations are associated with impaired prognosis in a variety of cancers and with squamous cell carcinoma formation in non–small cell lung cancer (NSCLC). However, little is known about frequency, histology dependence, molecular and clinical presentation as well as response to systemic treatment in NSCLC.
Experimental Design: Tumor tissue of 1,391 patients with NSCLC was analyzed using next-generation sequencing (NGS). Clinical and pathologic characteristics, survival, and treatment outcome of patients with KEAP1 or NFE2L2 mutations were assessed.
Results: KEAP1 mutations occurred with a frequency of 11.3% (n = 157) and NFE2L2 mutations with a frequency of 3.5% (n = 49) in NSCLC patients. In the vast majority of patients, both mutations did not occur simultaneously. KEAP1 mutations were found mainly in adenocarcinoma (AD; 72%), while NFE2L2 mutations were more common in squamous cell carcinoma (LSCC; 59%). KEAP1 mutations were spread over the whole protein, whereas NFE2L2 mutations were clustered in specific hotspot regions. In over 80% of the patients both mutations co-occurred with other cancer-related mutations, among them also targetable aberrations like activating EGFR mutations or MET amplification. Both patient groups showed different patterns of metastases, stage distribution and performance state. No patient with KEAP1 mutation had a response on systemic treatment in first-, second-, or third-line setting. Of NFE2L2-mutated patients, none responded to second- or third-line therapy.
Conclusions: KEAP1- and NFE2L2-mutated NSCLC patients represent a highly heterogeneous patient cohort. Both are associated with different histologies and usually are found together with other cancer-related, partly targetable, genetic aberrations. In addition, both markers seem to be predictive for chemotherapy resistance. Clin Cancer Res; 24(13); 3087–96. ©2018 AACR.
https://ift.tt/2lK0YBU
Goldilocks Dosing of TKIs: A Dose that Is Just Right Leads to Optimal Outcomes
Higher concentrations of TKIs, such as pazopanib, are associated with improved outcomes in advanced RCC. A phase III trial failed to show disease-free survival benefit to pazopanib in the adjuvant setting, but improved DFS was seen in patients with higher Ctrough levels, supporting adequate drug exposure for optimal clinical outcome. Clin Cancer Res; 24(13); 2979–80. ©2018 AACR.
See related article by Sternberg et al., p. 3005
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SMAD4 Gene Mutation Renders Pancreatic Cancer Resistance to Radiotherapy through Promotion of Autophagy
Purpose: Understanding the mechanism of radioresistance could help develop strategies to improve therapeutic response of patients with PDAC. The SMAD4 gene is frequently mutated in pancreatic cancer. In this study, we investigated the role of SMAD4 deficiency in pancreatic cancer cells' response to radiotherapy.
Experimental Design: We downregulated SMAD4 expression with SMAD4 siRNA or SMAD4 shRNA and overexpressed SMAD4 in SMAD4 mutant pancreatic cancer cells followed by clonogenic survival assay to evaluate their effects on cell radioresistance. To study the mechanism of radioresistance, the effects of SMAD4 loss on reactive oxygen species (ROS) and autophagy were determined by flow cytometry and immunoblot analysis, respectively. Furthermore, we measured radioresistance by clonogenic survival assay after treatment with autophagy inhibitor (Chloroquine) and ROS inhibitor (N-acetyl-l-cysteine) in SMAD4-depleted pancreatic cancer cells. Finally, the effects of SMAD4 on radioresistance were also confirmed in an orthotopic tumor model derived from SMAD4-depleted Panc-1 cells.
Results: SMAD4-depleted pancreatic cancer cells were more resistant to radiotherapy based on clonogenic survival assay. Overexpression of wild-type SMAD4 in SMAD4-mutant cells rescued their radiosensitivity. Radioresistance mediated by SMAD4 depletion was associated with persistently higher levels of ROS and radiation-induced autophagy. Finally, SMAD4 depletion induced in vivo radioresistance in Panc-1-derived orthotopic tumor model (P = 0.038). More interestingly, we observed that the protein level of SMAD4 is inversely correlated with autophagy in orthotopic tumor tissue samples.
Conclusions: Our results demonstrate that defective SMAD4 is responsible for radioresistance in pancreatic cancer through induction of ROS and increased level of radiation-induced autophagy. Clin Cancer Res; 24(13); 3176–85. ©2018 AACR.
https://ift.tt/2lPmLrY
Cycling Toward Progress: Ribociclib, a CDK 4/6 Inhibitor for Breast Cancer
Ribociclib is an orally active, highly selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6. It is the second CDK 4/6 inhibitor approved for hormone receptor–positive breast cancer. The addition of ribociclib to an aromatase inhibitor has resulted in marked improvements in progression-free survival for patients with metastatic breast cancer. Clin Cancer Res; 24(13); 2981–3. ©2018 AACR.
See related article by Shah et al., p. 2999
https://ift.tt/2tQy46G
Inositol Trisphosphate Receptor Type 3-mediated Enhancement of EGFR and MET Cotargeting Efficacy in Non-Small Cell Lung Cancer Detected by 18F-fluorothymidine
Purpose: Our aim was to test whether imaging with 18F-fluorothymidine (18F-FLT) PET/CT was able to detect the combined effects of EGFR and MET inhibitors in oncogene-driven non–small cell lung cancer (NSCLC) and to elucidate the mechanisms underlying the enhanced efficacy of drug combination.
Experimental Design: NSCLC cells bearing MET amplification (H1993 and H820) were treated with EGFR and MET inhibitors either alone or in combination and then tested for cell viability and inhibition of signaling. Nude mice bearing H1993 tumors underwent 18F-FLT PET/CT scan before and after treatment with erlotinib and crizotinib alone or in combination (1:1 ratio) and posttreatment changes of 18F-FLT uptake in tumors were determined. The role of inositol trisphosphate receptor type 3 (IP3R3) in mediating the combined action of EGFR and MET inhibitors was tested by transfecting NSCLC cells with IP3R3-targeted siRNA.
Results: Imaging studies showed a significant reduction of 18F-FLT uptake in response to combined treatment with EGFR and MET inhibitors that was higher than that obtained with single agents (ANOVA, F-ratio = 6.215, P = 0.001). Imaging findings were confirmed by analysis of surgically excised tumors. Levels of IP3R3 were significantly reduced in both cells and tumors after treatment with crizotinib, whereas EGFR inhibitors caused a reduction of IP3R3 interaction with K-Ras mainly through dephosphorylation of serine residues of K-Ras.
Conclusions: Our findings indicate that 18F-FLT PET/CT is able to detect the enhanced efficacy of EGFR and MET inhibitors in oncogene-driven NSCLC and that such enhancement is mediated by IP3R3 through its interaction with K-Ras. Clin Cancer Res; 24(13); 3126–36. ©2018 AACR.
https://ift.tt/2lK0XxQ
The Airway Transcriptome as a Biomarker for Early Lung Cancer Detection
Lung cancer remains the leading cause of cancer-related death due to its advanced stage at diagnosis. Early detection of lung cancer can be improved by better defining who should be screened radiographically and determining which imaging-detected pulmonary nodules are malignant. Gene expression biomarkers measured in normal-appearing airway epithelium provide an opportunity to use lung cancer–associated molecular changes in this tissue for early detection of lung cancer. Molecular changes in the airway may result from an etiologic field of injury and/or field cancerization. The etiologic field of injury reflects the aberrant physiologic response to carcinogen exposure that creates a susceptible microenvironment for cancer initiation. In contrast, field cancerization reflects effects of "first-hit" mutations in a clone of cells from which the tumor ultimately arises or the effects of the tumor on the surrounding tissue. These fields might have value both for assessing lung cancer risk and diagnosis. Cancer-associated gene expression changes in the bronchial airway have recently been used to develop and validate a 23-gene classifier that improves the diagnostic yield of bronchoscopy for lung cancer among intermediate-risk patients. Recent studies have demonstrated that these lung cancer–related gene expression changes extend to nasal epithelial cells that can be sampled noninvasively. While the bronchial gene expression biomarker is being adopted clinically, further work is necessary to explore the potential clinical utility of gene expression profiling in the nasal epithelium for lung cancer diagnosis, lung cancer risk assessment, and precision medicine for lung cancer treatment and chemoprevention. Clin Cancer Res; 24(13); 2984–92. ©2018 AACR.
https://ift.tt/2lLgBc4
Vitamin D-Binding Protein Enhances Epithelial Ovarian Cancer Progression by Regulating the Insulin-like Growth Factor-1/Akt Pathway and Vitamin D Receptor Transcription
Purpose: Malignant ascites of epithelial ovarian cancer (EOC) helps identify prognostic biomarkers or mechanisms of tumor progression. Vitamin D–binding protein (DBP) was revealed to be upregulated in EOC ascites in our previous proteomic study. Here, we examined the role of DBP in EOC.
Experimental Design: We analyzed ascites, serum, and tissue samples of patients with newly diagnosed EOC to determine the prognostic effects of DBP. We verified DBP function using orthotopic animal models and DBP regulation in ovarian cancer cell lines.
Results: Elevated ascitic DBP was significantly associated with poor response to chemotherapy, short progression-free interval, increased cancer progression, and death. Ascitic DBP overexpression was an independent unfavorable biomarker for progression-free survival; DBP overexpression in cancerous tissue was significantly related to chemoresistance. In vivo and in vitro investigations demonstrated an important role for DBP in ovarian cancer progression. Orthotopic model mice inoculated with DBP knockdown ovarian cancer cells displayed a significant reduction in tumor formation, malignant cell number, ascitic DBP levels, invasiveness, and metastasis, and increased survival compared with controls. In presence of vitamin D receptor (VDR), DBP promoted cell aggression (invasion and doubling time) via activation of the insulin-like growth factor-1/insulin-like growth factor–binding protein-2/Akt axis, and induced suppression of vitamin D–responsive genes. A NF-B p65-binding site in the VDR promoter was identified as a major determinant of DBP-dependent VDR promoter activation.
Conclusions: This study highlights the importance of DBP in ovarian tumor progression and the potential application of DBP as a therapeutic target for EOC. Clin Cancer Res; 24(13); 3217–28. ©2018 AACR.
https://ift.tt/2lMGc4n
Erasing CD33 in Normal Myeloid Cells Averts CAR T Cell-Driven Toxicity [Leukemia]
Inactivation of CD33 in HSPCs permits CD33-directed CAR T-cell treatment of AML.
https://ift.tt/2KDnxpY
FDA Tackles Underage E-cigarette Use [News in Brief]
In recent weeks, the FDA has taken steps to address underage use of e-cigarettes: The agency has identified and warned retailers selling to minors, issued warning letters to companies selling e-cigarette cartridges in adolescent-appealing packaging, and requested information from e-cigarette companies. The steps are part of the FDA's ongoing effort to prevent middle- and high-school students from using e-cigarette products.
https://ift.tt/2KDwIDD
Microbial Signals Promote Preleukemic Myeloproliferation in Tet2-/- Mice [Microbiome]
TET2 deficiency increases systemic bacterial dissemination to promote preleukemic myeloproliferation (PMP).
https://ift.tt/2KH9SON
9/11 Firefighters at Risk for Multiple Myeloma [News in Brief]
The largest study to date of responders to the World Trade Center attacks in New York, NY, on 9/11 reports that exposed firefighters have roughly twice the risk of developing multiple myeloma precursor disease as the general population. Moreover, firefighters who go on to develop multiple myeloma exhibit a younger age of onset and more aggressive disease than is typical.
https://ift.tt/2IIX7Ok
Precision Targeted Therapy with BLU-667 for RET-Driven Cancers [Research Articles]
The receptor tyrosine kinase rearranged during transfection (RET) is an oncogenic driver activated in multiple cancers, including non–small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and papillary thyroid cancer. No approved therapies have been designed to target RET; treatment has been limited to multikinase inhibitors (MKI), which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations. In vitro, BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. In vivo, BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions without inhibiting VEGFR2. In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with RET-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting.
Significance: Patients with RET-driven cancers derive limited benefit from available MKIs. BLU-667 is a potent and selective RET inhibitor that induces tumor regression in cancer models with RET mutations and fusions. BLU-667 attenuated RET signaling and produced durable clinical responses in patients with RET-altered tumors, clinically validating selective RET targeting. Cancer Discov; 8(7); 836–49. ©2018 AACR.
See related commentary by Iams and Lovly, p. 797.
This article is highlighted in the In This Issue feature, p. 781
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Anatomic Gene Expression Atlas Fuels Glioblastoma Discovery [News in Brief]
The Ivy Glioblastoma Atlas provides detailed information about genes expressed in different anatomic regions of human brain tumors. Researchers are already drawing upon the resource to identify novel therapeutic targets for this deadly cancer.
https://ift.tt/2KA1qgN
MLL3 Mutations Disrupt COMPASS Recruitment to Enhancer Chromatin [Epigenetics]
Mutations in the MLL3 PHD domain promote oncogenesis by disrupting its interaction with BAP1.
https://ift.tt/2KqF1X4
Companies Scaling Back IDO1 Inhibitor Trials [News in Depth]
Based on negative results of the ECHO-301 trial in melanoma, as well as in the pancreatic cancer cohort of ECHO-203, Incyte halted several trials of its IDO inhibitor epacadostat. Other companies, including NewLink Genetics and Bristol-Myers Squibb, also decided to scale back and/or halt trials of their IDO inhibitors. However, researchers offered reasons for the disappointing trial results and said that trials of IDO inhibitors should not be abandoned.
https://ift.tt/2KDwxYZ
Macropinocytosis Fuels Prostate Cancer [In the Spotlight]
Summary: Kim and colleagues identify necrotic debris as a macropinocytic cargo in PTEN-deficient prostate cancer cells, which is catabolized to generate the nutrients and biomass necessary to support tumor cell growth and metabolism in nutrient-limiting conditions. Cancer Discov; 8(7); 800–2. ©2018 AACR.
See related article by Kim et al., p. 866.
https://ift.tt/2KxUbsT
[177Lu]-PSMA-617 Has Activity in Castration-Resistant Prostate Cancer [Clinical Trials]
Radionuclide treatment with [177Lu]-PSMA-617 (LuPSMA) reduced PSA levels by ≥50% in 57% of patients.
https://ift.tt/2KDwv3j
Shared Decision Making Emphasized for Prostate Screening [News in Brief]
The U.S. Preventive Services Task Force (USPSTF) now recommends that men ages 55 to 69 individually decide, in consultation with their physician, whether to undergo PSA screening for prostate cancer. The guidelines represent a change from 2012, when the USPSTF recommended against screening for all men.
https://ift.tt/2KqVieT
A Bispecific Antibody Targeting HER2 and HER3 Suppresses Tumor Growth [Drug Discovery]
Unbiased phenotypic combinatorial screening uncovers a bispecific antibody (bAb) targeting HER2 and HER3.
https://ift.tt/2IIWRyQ
3' UTR Shortening Represses Tumor Suppressor Genes in Trans [Noncoding RNA]
3' UTR shortening of ceRNA genes disrupts miRNA binding, freeing miRNAs to repress tumor suppressors.
https://ift.tt/2KAuyrC
UTX Promotes Chromatin Remodeling to Suppress Leukemogenesis [Epigenetics]
UTX-mediated suppression of myeloid leukemogenesis is independent of its demethylase activity.
https://ift.tt/2IHAVEw
The BET Inhibitor Birabresib Is Safe in Patients with Solid Tumors [Clinical Trials]
Birabresib achieved partial responses in 3 of 10 patients with NUT midline carcinoma.
https://ift.tt/2Ks7xaM
ARID1A Deficiency May Predict Response to Immune Checkpoint Blockade [Immunotherapy]
ARID1A deficiency impairs mismatch repair to increase tumor mutation load and promote tumor progression.
https://ift.tt/2KAqEvs
Epistatic Oncogenic Interactions Determine Cancer Susceptibility to Immunotherapy [In the Spotlight]
Summary: Cancer genetic alterations and epigenetics control the malignant phenotype of tumor cells and the stroma. Synergistic oncogenic alterations may cooperatively dictate immunogenicity, level of infiltration by immune system cells, and response to immunotherapy in an epistatic fashion. The work of Skoulidis and colleagues shows that concomitant RAS and STK11/LKB1 mutations in non–small cell lung adenocarcinomas result in primary resistance to PD-1–based immunotherapy and poor T-cell infiltration. Cancer Discov; 8(7); 794–6. ©2018 AACR.
See related article by Skoulidis et al., p. 822.
https://ift.tt/2KByBUo
The cis-Regulatory DERARE Element Regulates Leukemogenesis [Leukemia]
DERARE methylation suppresses HOXB gene expression and leukemogenesis to maintain normal hematopoiesis.
https://ift.tt/2KEDd9d
Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma with FGFR3 Alterations [Research Articles]
BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of FGFR3 alterations. Patients (N = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted.
Significance: BJG398 is active in patients with alterations in FGFR3, resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status. Cancer Discov; 8(7); 812–21. ©2018 AACR.
This article is highlighted in the In This Issue feature, p. 781
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Targeting Glutaminase May Overcome Resistance to mTOR Inhibition [Lung Cancer]
mTOR inhibitor–mediated suppression of glycolysis results in a compensatory increase in glutaminolysis.
https://ift.tt/2KED8SX
Dose Escalation in Stereotactic Body Radiation Therapy for Pancreatic Cancer: A Meta-Analysis
Objective: To determine whether increasing biologically effective dose (BED) with stereotactic body radiation therapy (SBRT) is associated with improved local control (LC) or toxicities in patients with locally advanced pancreatic cancer. Methods: A PICOS/PRISMA/MOOSE selection protocol was used to identify 15 studies across 12 institutions in 5 countries where patients received definitive SBRT for nonmetastatic disease. Biologically equivalent doses were calculated with an α/β of 10 (ie, BED10) for LC and acute toxicity and 3 (ie, BED3) for late toxicity. Fixed and random effects models were used to characterize LC and grade 3/4 toxicities by BED. Results: There were 508 patients included with a median follow-up time of 9.1 months. The median dose was 30 Gy, and the most common regimen was 30 Gy/5 fractions. There was no significant difference in LC rates at 1 year between the BED10200 Gy. Conclusions: SBRT for pancreatic cancer results in LC rates of 60% to 83% and clinically significant toxicity of
https://ift.tt/2lMEznx
https://ift.tt/2lMEznx
Treatment Patterns and Survival of Elderly Patients With Breast Cancer Brain Metastases
Objectives: The main objective of this study was to analyze treatment patterns of elderly patients with breast cancer brain metastases (BCBM), evaluate characteristics associated with treatment selection, and to analyze trends in overall survival (OS) over time. Materials and Methods: We included women with BCBM reported to the Surveillance, Epidemiology, and End Results Medicare Program from 1992 to 2012. Treatments were recorded from Medicare claims from the date of brain metastases diagnosis until 60 days after. Treatments included resection, radiation, and chemotherapy. Cochran-Armitage tests were used for analysis of treatment patterns. Multinomial logistic regression was applied to determine factors associated with treatment selection. Cox regression modelled OS trends within each treatment modality across time. Results: Among 5969 patients included, treatment rates increased from 50% in 1992 to 64.1% in 2012 (P
https://ift.tt/2yY0BNC
https://ift.tt/2yY0BNC
Tumor-Educated Platelets as a Noninvasive Biomarker Source for Cancer Detection and Progression Monitoring
Liquid biopsies represent a potential revolution in cancer diagnostics as a noninvasive method for detecting and monitoring diseases, complementary to or even replacing current tissue biopsy approaches. Several blood-based biosources and biomolecules, such as cell-free DNA and RNA, proteins, circulating tumor cells, and extracellular vesicles, have been explored for molecular test development. We recently discovered the potential of tumor-educated blood platelets (TEP) as a noninvasive biomarker trove for RNA biomarker panels. TEPs are involved in the progression and spread of several solid tumors, and spliced TEP RNA surrogate signatures can provide specific information on the presence, location, and molecular characteristics of cancers. So far, TEP samples from patients with different tumor types, including lung, brain, and breast cancers, have been tested, and it has been shown that TEPs from patients with cancer are distinct from those with inflammatory and other noncancerous diseases. It remains to be investigated how platelets are "educated," which mechanisms cause intraplatelet RNA splicing, and whether the relative contribution of specific platelet subpopulations changes in patients with cancer. Ultimately, TEP RNA may complement currently used biosources and biomolecules employed for liquid biopsy diagnosis, potentially enhancing the detection of cancer in an early stage and facilitating noninvasive disease monitoring. Cancer Res; 78(13); 3407–12. ©2018 AACR.
https://ift.tt/2IK7aCW
miRNA Profiling of Magnetic Nanopore-Isolated Extracellular Vesicles for the Diagnosis of Pancreatic Cancer
Improved diagnostics for pancreatic ductal adenocarcinoma (PDAC) to detect the disease at earlier, curative stages and to guide treatments is crucial to progress against this disease. The development of a liquid biopsy for PDAC has proven challenging due to the sparsity and variable phenotypic expression of circulating biomarkers. Here we report methods we developed for isolating specific subsets of extracellular vesicles (EV) from plasma using a novel magnetic nanopore capture technique. In addition, we present a workflow for identifying EV miRNA biomarkers using RNA sequencing and machine-learning algorithms, which we used in combination to classify distinct cancer states. Applying this approach to a mouse model of PDAC, we identified a biomarker panel of 11 EV miRNAs that could distinguish mice with PDAC from either healthy mice or those with precancerous lesions in a training set of n = 27 mice and a user-blinded validation set of n = 57 mice (88% accuracy in a three-way classification). These results provide strong proof-of-concept support for the feasibility of using EV miRNA profiling and machine learning for liquid biopsy.Significance: These findings present a panel of extracellular vesicle miRNA blood-based biomarkers that can detect pancreatic cancer at a precancerous stage in a transgenic mouse model. Cancer Res; 78(13); 3688–97. ©2018 AACR.
https://ift.tt/2Kn0cJD
Novel Richter Syndrome Xenograft Models to Study Genetic Architecture, Biology, and Therapy Responses
Richter syndrome represents the evolution of chronic lymphocytic leukemia into an aggressive tumor, most commonly diffuse large B-cell lymphoma. The lack of in vitro and in vivo models has severely hampered drug testing in a disease that is poorly responsive to common chemoimmunotherapeutic combinations as well as to novel kinase inhibitors. Here we report for the first time the establishment and genomic characterization of two patient-derived tumor xenograft (PDX) models of Richter syndrome, RS9737 and RS1316. Richter syndrome xenografts were genetically, morphologically, and phenotypically stable and similar to the corresponding primary tumor. RS9737 was characterized by biallelic inactivation of CDKN2A and TP53, monoallelic deletion of 11q23 (ATM), and mutations of BTK, KRAS, EGR2, and NOTCH1. RS1316 carried trisomy 12 and showed mutations in BTK, KRAS, MED12, and NOTCH2. RNA sequencing confirmed that in both cases >80% of the transcriptome was shared between primary tumor and PDX. In line with the mutational profile, pathway analyses revealed overactivation of the B-cell receptor, NFκB, and NOTCH pathways in both tumors, potentially providing novel tumor targets. In conclusion, these two novel models of Richter syndrome represent useful tools to study biology and response to therapies of this highly aggressive and still incurable tumor.Significance: Two patient-derived xenograft models of Richter syndrome represent the first ex vivo model to study biology of the disease and to test novel therapeutic strategies. Cancer Res; 78(13); 3413–20. ©2018 AACR.
https://ift.tt/2IK7gdM
The Autotaxin—Lysophosphatidic Acid Axis Promotes Lung Carcinogenesis
Pathogenesis and progression of lung cancer are governed by complex interactions between the environment and host genetic susceptibility, which is further modulated by genetic and epigenetic changes. Autotaxin (ATX, ENPP2) is a secreted glycoprotein that catalyzes the extracellular production of lysophosphatidic acid (LPA), a growth-factor–like phospholipid that is further regulated by phospholipid phosphatases (PLPP). LPA's pleiotropic effects in almost all cell types are mediated through at least six G-protein coupled LPA receptors (LPAR) that exhibit overlapping specificities, widespread distribution, and differential expression profiles. Here we use both preclinical models of lung cancer and clinical samples (from patients and healthy controls) to investigate the expression levels, activity, and biological role of the above components of the ATX/LPA axis in lung cancer. ENPP2 was genetically altered in 8% of patients with lung cancer, whereas increased ATX staining and activity were detected in patient biopsies and sera, respectively. Moreover, PLPP3 expression was consistently downregulated in patients with lung cancer. Comparable observations were made in the two most widely used animal models of lung cancer, the carcinogen urethane–induced and the genetically engineered K-rasG12D–driven models, where genetic deletion of Enpp2 or Lpar1 resulted in disease attenuation, thus confirming a procarcinogenic role of LPA signaling in the lung. Expression profiling data analysis suggested that metabolic rewiring may be implicated in the procarcinogenic effects of the ATX/LPA axis in K-ras-G12D–driven lung cancer pathogenesis.Significance: These findings establish the role of ATX/LPA in lung carcinogenesis, thus expanding the mechanistic links between pulmonary fibrosis and cancer. Cancer Res; 78(13); 3634–44. ©2018 AACR.
https://ift.tt/2Ksz9wz
SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma
Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. TP53 was the most frequently altered gene (83% of dogs have either mutations or SCNA in TP53), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species.Significance: Canine osteosarcoma genomics identify SETD2 as a possible oncogenic driver of osteosarcoma, and findings establish the canine model as a useful comparative model for the corresponding human disease. Cancer Res; 78(13); 3421–31. ©2018 AACR.
https://ift.tt/2KzWEzT
Tau Mutations Serve as a Novel Risk Factor for Cancer
In addition to its well-recognized role in neurodegeneration, tau participates in maintenance of genome stability and chromosome integrity. In particular, peripheral cells from patients affected by frontotemporal lobar degeneration carrying a mutation in tau gene (genetic tauopathies), as well as cells from animal models, show chromosome numerical and structural aberrations, chromatin anomalies, and a propensity toward abnormal recombination. As genome instability is tightly linked to cancer development, we hypothesized that mutated tau may be a susceptibility factor for cancer. Here we conducted a retrospective cohort study comparing cancer incidence in families affected by genetic tauopathies to control families. In addition, we carried out a bioinformatics analysis to highlight pathways associated with the tau protein interactome. We report that the risk of developing cancer is significantly higher in families affected by genetic tauopathies, and a high proportion of tau protein interactors are involved in cellular processes particularly relevant to cancer. These findings disclose a novel role of tau as a risk factor for cancer, providing new insights in the various pathologic roles of mutated tau.Significance: This study reveals a novel role for tau as a risk factor for cancer, providing new insights beyond its role in neurodegeneration. Cancer Res; 78(13); 3731–9. ©2018 AACR.
https://ift.tt/2KnESUp
High USP6NL Levels in Breast Cancer Sustain Chronic AKT Phosphorylation and GLUT1 Stability Fueling Aerobic Glycolysis
USP6NL, also named RN-tre, is a GTPase-activating protein involved in control of endocytosis and signal transduction. Here we report that USP6NL is overexpressed in breast cancer, mainly of the basal-like/integrative cluster 10 subtype. Increased USP6NL levels were accompanied by gene amplification and were associated with worse prognosis in the METABRIC dataset, retaining prognostic value in multivariable analysis. High levels of USP6NL in breast cancer cells delayed endocytosis and degradation of the EGFR, causing chronic AKT (protein kinase B) activation. In turn, AKT stabilized the glucose transporter GLUT1 at the plasma membrane, increasing aerobic glycolysis. In agreement, elevated USP6NL sensitized breast cancer cells to glucose deprivation, indicating that their glycolytic capacity relies on this protein. Depletion of USP6NL accelerated EGFR/AKT downregulation and GLUT1 degradation, impairing cell proliferation exclusively in breast cancer cells that harbored increased levels of USP6NL. Overall, these findings argue that USP6NL overexpression generates a metabolic rewiring that is essential to foster the glycolytic demand of breast cancer cells and promote their proliferation.Significance: USP6NL overexpression leads to glycolysis addiction of breast cancer cells and presents a point of metabolic vulnerability for therapeutic targeting in a subset of aggressive basal-like breast tumors.Graphical Abstract: https://ift.tt/2Krno9N. Cancer Res; 78(13); 3432–44. ©2018 AACR.
https://ift.tt/2IFSrcd
Autocrine Adenosine Regulates Tumor Polyfunctional CD73+CD4+ Effector T Cells Devoid of Immune Checkpoints
The production of CD73-derived adenosine (Ado) by Tregs has been proposed as a resistance mechanism to anti-PD-1 therapy in murine tumor models. We reported that human Tregs express the ectonucleotidase CD39, which generates AMP from ATP, but do not express the AMPase CD73. In contrast, CD73 defined a subset of effector CD4+ T cells (Teffs) enriched in polyfunctional Th1.17 cells characterized by expression of CXCR3, CCR6, and MDR1, and production of IL17A/IFNγ/IL22/GM-CSF. CD39+ Tregs selectively targeted CD73+ Teffs through cooperative degradation of ATP into Ado inhibiting and restricting the ability of CD73+ Teffs to secrete IL17A. CD73+ Teffs infiltrating breast and ovarian tumors were functionally blunted by Tregs expressing upregulated levels of CD39 and ATPase activity. Moreover, tumor-infiltrating CD73+ Teffs failed to express inhibitory immune checkpoints, suggesting that CD73 might be selected under pressure from immune checkpoint blockade therapy and thus may represent a nonredundant target for restoring antitumor immunity.Significance: Polyfunctional CD73+ T-cell effectors lacking other immune checkpoints are selectively targeted by CD39 overexpressing Tregs that dominate the breast tumor environment. Cancer Res; 78(13); 3604–18. ©2018 AACR.
https://ift.tt/2IK7b9Y
GFPT2-Expressing Cancer-Associated Fibroblasts Mediate Metabolic Reprogramming in Human Lung Adenocarcinoma
Metabolic reprogramming of the tumor microenvironment is recognized as a cancer hallmark. To identify new molecular processes associated with tumor metabolism, we analyzed the transcriptome of bulk and flow-sorted human primary non–small cell lung cancer (NSCLC) together with 18FDG-PET scans, which provide a clinical measure of glucose uptake. Tumors with higher glucose uptake were functionally enriched for molecular processes associated with invasion in adenocarcinoma and cell growth in squamous cell carcinoma (SCC). Next, we identified genes correlated to glucose uptake that were predominately overexpressed in a single cell–type comprising the tumor microenvironment. For SCC, most of these genes were expressed by malignant cells, whereas in adenocarcinoma, they were predominately expressed by stromal cells, particularly cancer-associated fibroblasts (CAF). Among these adenocarcinoma genes correlated to glucose uptake, we focused on glutamine-fructose-6-phosphate transaminase 2 (GFPT2), which codes for the glutamine-fructose-6-phosphate aminotransferase 2 (GFAT2), a rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which is responsible for glycosylation. GFPT2 was predictive of glucose uptake independent of GLUT1, the primary glucose transporter, and was prognostically significant at both gene and protein level. We confirmed that normal fibroblasts transformed to CAF-like cells, following TGFβ treatment, upregulated HBP genes, including GFPT2, with less change in genes driving glycolysis, pentose phosphate pathway, and TCA cycle. Our work provides new evidence of histology-specific tumor stromal properties associated with glucose uptake in NSCLC and identifies GFPT2 as a critical regulator of tumor metabolic reprogramming in adenocarcinoma.Significance: These findings implicate the hexosamine biosynthesis pathway as a potential new therapeutic target in lung adenocarcinoma. Cancer Res; 78(13); 3445–57. ©2018 AACR.
https://ift.tt/2KoM9Du
Identification of a Small Molecule That Selectively Inhibits ERG-Positive Cancer Cell Growth
Oncogenic activation of the ETS-related gene (ERG) by recurrent gene fusions (predominantly TMPRSS2–ERG) is one of the most validated and prevalent genomic alterations present in early stages of prostate cancer. In this study, we screened small-molecule libraries for inhibition of ERG protein in TMPRSS2–ERG harboring VCaP prostate cancer cells using an In-Cell Western Assay with the highly specific ERG-MAb (9FY). Among a subset of promising candidates, 1-[2-Thiazolylazo]-2-naphthol (NSC139021, hereafter ERGi-USU) was identified and further characterized. ERGi-USU selectively inhibited growth of ERG-positive cancer cell lines with minimal effect on normal prostate or endothelial cells or ERG-negative tumor cell lines. Combination of ERGi-USU with enzalutamide showed additive effects in inhibiting growth of VCaP cells. A screen of kinases revealed that ERGi-USU directly bound the ribosomal biogenesis regulator atypical kinase RIOK2 and induced ribosomal stress signature. In vivo, ERGi-USU treatment inhibited growth of ERG-positive VCaP tumor xenografts with no apparent toxicity. Structure-activity–based derivatives of ERGi-USU recapitulated the ERG-selective activity of the parental compound. Taken together, ERGi-USU acts as a highly selective inhibitor for the growth of ERG-positive cancer cells and has potential for further development of ERG-targeted therapy of prostate cancer and other malignancies.Significance: A highly selective small-molecule inhibitor of ERG, a critical driver of early stages of prostate cancer, will be imperative for prostate cancer therapy. Cancer Res; 78(13); 3659–71. ©2018 AACR.
https://ift.tt/2IIQvzA
PSMD5 Inactivation Promotes 26S Proteasome Assembly during Colorectal Tumor Progression
Protein degradation by the ubiquitin–proteasome system (UPS) is central to protein homeostasis and cell survival. The active 26S proteasome is a large protease complex consisting of a catalytic 20S subunit and 19S regulatory particles. Cancer cells are exposed to considerable protein overload due to high metabolic rates, reprogrammed energy metabolism, and aneuploidy. Here we report a mechanism that facilitates the assembly of active 26S proteasomes in malignant cells. Upon tumorigenic transformation of the gut epithelium, 26S proteasome assembly was significantly enhanced, but levels of individual subunits were not changed. This enhanced assembly of 26S proteasomes increased further with tumor progression and was observed specifically in transformed cells, but not in other rapidly dividing cells. Moreover, expression of PSMD5, an inhibitor of proteasome assembly, was reduced in intestinal tumors and silenced with tumor progression. Reexpression of PSMD5 in tumor cells caused decreased 26S assembly and accumulation of polyubiquitinated proteins. These results suggest that inhibition of cancer-associated proteasome assembly may provide a novel therapeutic strategy to selectively kill cancer cells.Significance: Enhanced cancer-associated proteasome assembly is a major stress response that allows tumors to adapt to and to withstand protein overload.Graphical Abstract: https://ift.tt/2KDXpYI. Cancer Res; 78(13); 3458–68. ©2018 AACR.
https://ift.tt/2KqBQi6
NK Cells Mediate Synergistic Antitumor Effects of Combined Inhibition of HDAC6 and BET in a SCLC Preclinical Model
Small-cell lung cancer (SCLC) has the highest malignancy among all lung cancers, exhibiting aggressive growth and early metastasis to distant sites. For 30 years, treatment options for SCLC have been limited to chemotherapy, warranting the need for more effective treatments. Frequent inactivation of TP53 and RB1 as well as histone dysmodifications in SCLC suggest that transcriptional and epigenetic regulations play a major role in SCLC disease evolution. Here we performed a synthetic lethal screen using the BET inhibitor JQ1 and an shRNA library targeting 550 epigenetic genes in treatment-refractory SCLC xenograft models and identified HDAC6 as a synthetic lethal target in combination with JQ1. Combined treatment of human and mouse SCLC cell line–derived xenograft tumors with the HDAC6 inhibitor ricolinostat (ACY-1215) and JQ1 demonstrated significant inhibition of tumor growth; this effect was abolished upon depletion of NK cells, suggesting that these innate immune lymphoid cells play a role in SCLC tumor treatment response. Collectively, these findings suggest a potential new treatment for recurrent SCLC.Significance: These findings identify a novel therapeutic strategy for SCLC using a combination of HDAC6 and BET inhibitors. Cancer Res; 78(13); 3709–17. ©2018 AACR.
https://ift.tt/2KAsGPC
TNFRSF19 Inhibits TGF{beta} Signaling through Interaction with TGF{beta} Receptor Type I to Promote Tumorigenesis
Genetic susceptibility underlies the pathogenesis of cancer. We and others have previously identified a novel susceptibility gene TNFRSF19, which encodes an orphan member of the TNF receptor superfamily known to be associated with nasopharyngeal carcinoma (NPC) and lung cancer risk. Here, we show that TNFRSF19 is highly expressed in NPC and is required for cell proliferation and NPC development. However, unlike most of the TNF receptors, TNFRSF19 was not involved in NFκB activation or associated with TRAF proteins. We identified TGFβ receptor type I (TβRI) as a specific binding partner for TNFRSF19. TNFRSF19 bound the kinase domain of TβRI in the cytoplasm, thereby blocking Smad2/3 association with TβRI and subsequent signal transduction. Ectopic expression of TNFRSF19 in normal epithelial cells conferred resistance to the cell-cycle block induced by TGFβ, whereas knockout of TNFRSF19 in NPC cells unleashed a potent TGFβ response characterized by upregulation of Smad2/3 phosphorylation and TGFβ target gene transcription. Furthermore, elevated TNFRSF19 expression correlated with reduced TGFβ activity and poor prognosis in patients with NPC. Our data reveal that gain of function of TNFRSF19 in NPC represents a mechanism by which tumor cells evade the growth-inhibitory action of TGFβ.Significance: TNFRSF19, a susceptibility gene for nasopharyngeal carcinoma and other cancers, functions as a potent inhibitor of the TGFβ signaling pathway.Graphical Abstract: https://ift.tt/2KmKv5j. Cancer Res; 78(13); 3469–83. ©2018 AACR.
https://ift.tt/2IJGYbL
A G3BP1-Interacting lncRNA Promotes Ferroptosis and Apoptosis in Cancer via Nuclear Sequestration of p53
Long noncoding RNAs (lncRNA) have been associated with various types of cancer; however, the precise role of many lncRNAs in tumorigenesis remains elusive. Here we demonstrate that the cytosolic lncRNA P53RRA is downregulated in cancers and functions as a tumor suppressor by inhibiting cancer progression. Chromatin remodeling proteins LSH and Cfp1 silenced or increased P53RRA expression, respectively. P53RRA bound Ras GTPase-activating protein-binding protein 1 (G3BP1) using nucleotides 1 and 871 of P53RRA and the RRM interaction domain of G3BP1 (aa 177-466). The cytosolic P53RRA–G3BP1 interaction displaced p53 from a G3BP1 complex, resulting in greater p53 retention in the nucleus, which led to cell-cycle arrest, apoptosis, and ferroptosis. P53RRA promoted ferroptosis and apoptosis by affecting transcription of several metabolic genes. Low P53RRA expression significantly correlated with poor survival in patients with breast and lung cancers harboring wild-type p53. These data show that lncRNAs can directly interact with the functional domain of signaling proteins in the cytoplasm, thus regulating p53 modulators to suppress cancer progression.Significance: A cytosolic lncRNA functions as a tumor suppressor by activating the p53 pathway. Cancer Res; 78(13); 3484–96. ©2018 AACR.
https://ift.tt/2KwdtPB
Nuclear IGF1R Interacts with Regulatory Regions of Chromatin to Promote RNA Polymerase II Recruitment and Gene Expression Associated with Advanced Tumor Stage
Internalization of ligand-activated type I IGF receptor (IGF1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF1R reportedly associates with clinical response to IGF1R inhibitory drugs, yet its role in the nucleus is poorly characterized. Here, we investigated the significance of nuclear IGF1R in clinical cancers and cell line models. In prostate cancers, IGF1R was predominantly membrane localized in benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic) IGF1R, and nuclear IGF1R associated significantly with advanced tumor stage. Using ChIP-seq to assess global chromatin occupancy, we identified IGF1R–binding sites at or near transcription start sites of genes including JUN and FAM21, most sites coinciding with occupancy by RNA polymerase II (RNAPol2) and histone marks of active enhancers/promoters. IGF1R was inducibly recruited to chromatin, directly binding DNA and interacting with RNAPol2 to upregulate expression of JUN and FAM21, shown to mediate tumor cell survival and IGF-induced migration. IGF1 also enriched RNAPol2 on promoters containing IGF1R–binding sites. These functions were inhibited by IGF1/II–neutralizing antibody xentuzumab (BI 836845), or by blocking receptor internalization. We detected IGF1R on JUN and FAM21 promoters in fresh prostate cancers that contained abundant nuclear IGF1R, with evidence of correlation between nuclear IGF1R content and JUN expression in malignant prostatic epithelium. Taken together, these data reveal previously unrecognized molecular mechanisms through which IGFs promote tumorigenesis, with implications for therapeutic evaluation of anti-IGF drugs.Significance: These findings reveal a noncanonical nuclear role for IGF1R in tumorigenesis, with implications for therapeutic evaluation of IGF inhibitory drugs. Cancer Res; 78(13); 3497–509. ©2018 AACR.
https://ift.tt/2KxSxYf
NFATc1 Promotes Antitumoral Effector Functions and Memory CD8+ T-cell Differentiation during Non-Small Cell Lung Cancer Development
Nuclear factor of activated T cells 1 (NFATc1) is a transcription factor activated by T-cell receptor (TCR) and Ca2+ signaling that affects T-cell activation and effector function. Upon tumor antigen challenge, TCR and calcium-release–activated channels are induced, promoting NFAT dephosphorylation and translocation into the nucleus. In this study, we report a progressive decrease of NFATc1 in lung tumor tissue and in tumor-infiltrating lymphocytes (TIL) of patients suffering from advanced-stage non–small cell lung cancer (NSCLC). Mice harboring conditionally inactivated NFATc1 in T cells (NFATc1ΔCD4) showed increased lung tumor growth associated with impaired T-cell activation and function. Furthermore, in the absence of NFATc1, reduced IL2 influenced the development of memory CD8+ T cells. We found a reduction of effector memory and CD103+ tissue-resident memory (TRM) T cells in the lung of tumor-bearing NFATc1ΔCD4 mice, underlining an impaired cytotoxic T-cell response and a reduced TRM tissue-homing capacity. In CD4+ICOS+ T cells, programmed cell death 1 (PD-1) was induced in the draining lymph nodes of these mice and associated with lung tumor cell growth. Targeting PD-1 resulted in NFATc1 induction in CD4+ and CD8+ T cells in tumor-bearing mice and was associated with increased antitumor cytotoxic functions. This study reveals a role of NFATc1 in the activation and cytotoxic functions of T cells, in the development of memory CD8+ T-cell subsets, and in the regulation of T-cell exhaustion. These data underline the indispensability of NFATc1 for successful antitumor immune responses in patients with NSCLC.Significance: The multifaceted role of NFATc1 in the activation and function of T cells during lung cancer development makes it a critical participant in antitumor immune responses in patients with NSCLC. Cancer Res; 78(13); 3619–33. ©2018 AACR.
https://ift.tt/2KH3zXV
MIR142 Loss-of-Function Mutations Derepress ASH1L to Increase HOXA Gene Expression and Promote Leukemogenesis
Point mutations in the seed sequence of miR-142-3p are present in a subset of acute myelogenous leukemia (AML) and in several subtypes of B-cell lymphoma. Here, we show that mutations associated with AML result both in loss of miR-142-3p function and in decreased miR-142-5p expression. Mir142 loss altered the hematopoietic differentiation of multipotent hematopoietic progenitors, enhancing their myeloid potential while suppressing their lymphoid potential. During hematopoietic maturation, loss of Mir142 increased ASH1L protein expression and consequently resulted in the aberrant maintenance of Hoxa gene expression in myeloid-committed hematopoietic progenitors. Mir142 loss also enhanced the disease-initiating activity of IDH2-mutant hematopoietic cells in mice. Together these data suggest a novel model in which miR-142, through repression of ASH1L activity, plays a key role in suppressing HOXA9/A10 expression during normal myeloid differentiation. AML-associated loss-of-function mutations of MIR142 disrupt this negative signaling pathway, resulting in sustained HOXA9/A10 expression in myeloid progenitors/myeloblasts and ultimately contributing to leukemic transformation.Significance: These findings provide mechanistic insights into the role of miRNAs in leukemogenesis and hematopoietic stem cell function. Cancer Res; 78(13); 3510–21. ©2018 AACR.
https://ift.tt/2Knoqnc
Diagnostic Ultrasound and Microbubbles Treatment Improves Outcomes of Coronary No-Reflow in Canine Models by Sonothrombolysis
Objectives: Effective treatment for microvascular thrombosis-induced coronary no-reflow remains an unmet clinical need. This study sought to evaluate whether diagnostic ultrasound and microbubbles treatment could improve outcomes of coronary no-reflow by dissolving platelet- and erythrocyte-rich microthrombi. Design: Randomized controlled laboratory investigation. Setting: Research laboratory. Subjects: Mongrel dogs. Interventions: Coronary no-reflow models induced by platelet- or erythrocyte-rich microthrombi were established and randomly assigned to control, ultrasound, recombinant tissue-type plasminogen activator, ultrasound + microbubbles, or ultrasound + microbubbles + recombinant tissue-type plasminogen activator group. All treatments lasted for 30 minutes. Measurements and Main Results: Percentage of microemboli-obstructed coronary arterioles was lower in ultrasound + microbubbles group than that in control group for platelet- (> 50% obstruction: 10.20% ± 3.56% vs 31.80% ± 3.96%; 50% obstruction: 8.20% ± 3.11% vs 30.60% ± 4.83%;
https://ift.tt/2tKaDNa
https://ift.tt/2tKaDNa
Acute Respiratory Failure in Pediatric Hematopoietic Cell Transplantation—A Multicenter Study
Objectives: Acute respiratory failure is common in pediatric hematopoietic cell transplant recipients and has a high mortality. However, respiratory prognostic markers have not been adequately evaluated for this population. Our objectives are to assess respiratory support strategies and indices of oxygenation and ventilation in pediatric allogeneic hematopoietic cell transplant patients receiving invasive mechanical ventilation and investigate how these strategies are associated with mortality. Design: Retrospective, multicenter investigation. Setting: Twelve U.S. pediatric centers. Patients: Pediatric allogeneic hematopoietic cell transplant recipients with respiratory failure. Interventions: None. Measurements and Main Results: Two-hundred twenty-two subjects were identified. PICU mortality was 60.4%. Nonsurvivors had higher peak oxygenation index (38.3 [21.3–57.6] vs 15.0 [7.0–30.7]; p
https://ift.tt/2IKESYT
https://ift.tt/2IKESYT
Presenting Symptoms Independently Predict Mortality in Septic Shock: Importance of a Previously Unmeasured Confounder
Objectives: Presenting symptoms in patients with sepsis may influence rapidity of diagnosis, time-to-antibiotics, and outcome. We tested the hypothesis that vague presenting symptoms are associated with delayed antibiotics and increased mortality. We further characterized individual presenting symptoms and their association with mortality. Design: Retrospective cohort study. Setting: Emergency department of large, urban, academic U.S. hospital. Patients: All adult patients with septic shock treated in the emergency department between April 2014 and March 2016. Interventions: None. Measurements and Main Results: Of 654 septic shock cases, 245 (37%) presented with vague symptoms. Time-to-antibiotics from first hypotension or elevated lactate was significantly longer for those with vague symptoms versus those with explicit symptoms of infection (1.6 vs 0.8 hr; p
https://ift.tt/2NhKtcW
https://ift.tt/2NhKtcW
Measurement Characteristics of the Knowledge Assessment of Renal Transplantation (KART)
Background Kidney transplant is the best treatment for most end-stage renal disease (ESRD) patients, but proportionally few ESRD patients receive kidney transplant. To make an informed choice about whether to pursue kidney transplant, patients must be knowledgeable of its risks and benefits. To reliably and validly measure ESRD patients' kidney transplant knowledge, rigorously tested measures are required. This paper describes the development and psychometric testing of the Knowledge Assessment of Renal Transplantation (KART). Methods We administered 17 transplant knowledge items to a sample of 1,294 ESRD patients. Item characteristics and scale scores were estimated using an item response theory (IRT) graded response model. Construct validity was tested by examining differences in scale scores between patients who had spent 1 hour receiving various types of transplant education. Results IRT modelling suggested that 15 items should be retained for the KART. This scale had a marginal reliability of 0.75 and evidenced acceptable reliability (>0.70) across most of its range. Construct validity was supported by the KART's ability to distinguish patients who had spent 1 hour receiving different types of kidney transplant education, including talking to doctors/medical staff [effect size (ES) = 0.61; p
https://ift.tt/2KEQZII
https://ift.tt/2KEQZII
Comparison of two Luminex Single-Antigen bead flow cytometry assays for detection of Donor Specific Antibodies after renal transplantation
Background Defining the clinical relevance of Donor Specific HLA antibodies (DSA) detection by Luminex Single Antigen (LSA) flow beads assay is critical in monitoring posttransplant outcome. Methods Sera of kidney transplanted patients were tested by LSA1 and LSA2 with One Lambda Labscreen (test 1) and Immucor Lifecodes (test 2), at the time of a graft biopsy. The first group (G1, n=50) had a biopsy highly suggestive of humoral rejection and the second (G2, n=50) had no criteria of rejection. Positivity criteria for DSA was MFI >500 for test 1, while specificity assignation respected provider's recommendations for test 2. Results In G1, we identified at least 1 DSA in 44 patients with test 1, and in 39 patients with test 2. In G2, test 1 identified at least 1 DSA in 16 patients (32%) and test 2 in 7 patients (14 %). Sensitivity and specificity for ABMR diagnosis was 88% and 68% respectively with One Lambda, and 78% and 86% respectively with Immucor. Correlation and agreement were found in class I and II between intensity parameters of the 2 manufacturers. The use of the sum of the intensity of DSA (sDSA) improved the sensitivity and specificity of the 2 tests. Conclusions We report the first comparative study of the 2 Luminex assays available for detecting DSA in the post kidney transplant setting. Although there is a good correlation and reliability between the 2 assays, significant differences exist. Positivity criteria for DSA determination differ and interpretation should take these specificities into account. * Corresponding author: Dominique Bertrand, MD, Rouen University Hospital, 1 rue de Germont 76000 Rouen, France, dominique.bertrand@chu-rouen.fr Authorship: DB: performed research, collected data, analyzed data, and wrote the paper. FF, FHam, FHau: collected the data, performed research. DG: contributed to the revision and approval of the paper. All the others authors: collected data and contributed to the approval of the paper. Funding The authors have declared no funding. Disclosure: All of the authors of this manuscript have no conflicts of interest to disclose as described by Transplantation. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
https://ift.tt/2KDewdj
https://ift.tt/2KDewdj
Quantifying the effect of transplanting older donor livers into younger recipients: the need for donor-recipient age matching
Background Increasing recipient and donor age are independently associated with survival after liver transplantation (LT). Whether donor age differentially impacts post-LT outcomes based on recipient age is unknown. Methods This was a retrospective cohort study using Organ Procurement and Transplantation Network data. All adult deceased-donor, single organ, primary LTs from 2002-2015 were included. Donor and recipient age were categorized as
https://ift.tt/2KGikxK
https://ift.tt/2KGikxK
PHARMACOKINETIC STUDY OF CONVERSION BETWEEN TWO FORMULATIONS OF ONCE-DAILY EXTENDED-RELEASE TACROLIMUS IN STABLE LUNG TRANSPLANT PATIENTS
BACKGROUND: The aim of this study was to compare the pharmacokinetic profile, tolerability, and safety of a novel once-daily extended-release formulation of tacrolimus (LCPT) with that of once-daily prolonged-release tacrolimus (ODT) in stable adult lung transplant (LT) recipients. METHODS: Phase II, open-label, single-arm, single-center, prospective pilot pharmacokinetic study. Study population comprised 20 stable LTR receiving ODT, mean age 55.9 (r: 38-67) years, 13 (65%) men. Patients were switched to LCPT in a 1:0.7 (mg/mg) conversion dose. Follow-up was 6 months, and cystic fibrosis patients were excluded. Two 24-hour pharmacokinetic profiles were obtained for each patient, the first on day -14 and the second on day +14 after switching to LCPT. Pharmacokinetic parameters and safety were compared. RESULTS: Mean (SD) AUC0-24 was 253.97 (61.90) ng/mL/h for ODT and 282.44 (68.2) ng/mL/h for LCPT. Systemic exposure was similar in both (Schuirmann two 1-sided test). Mean (SD) dose was 5.05 (1.67) mg in ODT and 3.36 (1.03) mg in LCPT (p: 0.0002). Time to maximum concentration was 125 minutes for ODT and 325 minutes for LCPT (p
https://ift.tt/2KF4ats
https://ift.tt/2KF4ats
Epidemiology of Nephrostomy Tube–Related Urinary Tract Infections Among US Veterans
Objective The aim of this study was to review the incidence of asymptomatic bacteriuria (AB) and pyelonephritis after placement of percutaneous nephrostomy tube (NT) in our patients. Methods We retrospectively reviewed patients who underwent NT placement from January 1, 2005, to December 31, 2015, at Northport Veterans Affairs Medical Center. We identified patients with NT-associated AB and NT-related pyelonephritis within 60 days following NT placement. We analyzed demographic data, medical history, and microbiological data. Results Seventy-one patients underwent NT placement. Indications for NT placement included intrinsic obstruction (34%) and extrinsic obstruction (66%). Prostate and urinary bladder cancers were the most common causes of extrinsic obstruction. Twenty percent (14/71) had pyelonephritis, and 24% (17/71) had AB. All patients were men, and median age was 73 years. In the pyelonephritis group, Pseudomonas aeruginosa (36%) and Enterococcus faecalis (35%) were most commonly isolated. Three cases of extended-spectrum β-lactamase–producing Enterobacteriaceae and 2 multiple drug–resistant gram-negative organisms were identified. In the AB group, P. aeruginosa (23%), Enterococcus species (23%), and coagulase-negative staphylococci (23%) were most common. Only 1 case of extended-spectrum β-lactamase organism was identified. Comparing the 2 groups, there was no difference in age (P = 0358), diabetes mellitus (P = 0.441), chronic kidney disease (P = 0.6705), and prior urinary tract infection (P = 1.000). Presence of ureteral stent was seen more in AB (P = 0.057). Conclusions Nephrostomy tube placement was associated with pyelonephritis and AB in 44% of cases overall. Pseudomonas and Enterococcus species were the most common pathogens. Isolation of resistant organisms was mostly observed in the pyelonephritis group. Correspondence to: George Psevdos, MD, Division of Infectious Diseases, Northport Veterans Affairs Medical Center, 79 Middleville Rd, Northport, NY 11768. E-mail: george.psevdos@va.gov. The authors have no funding or conflicts of interest to disclose. Parts of the data were presented in poster format (poster 5920) at IDweek, on October 26 to 30, 2016, in New Orleans, LA. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the US Government. All authors had access to the data and played a role in writing the manuscript. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
https://ift.tt/2tMFxV5
https://ift.tt/2tMFxV5
Newborn Screening Saves Lives but Cannot Replace the Need for Clinical Vigilance
Newborn screening for cystic fibrosis (CF) enables early diagnosis and treatment leading to improved health outcomes for patients with CF. Although the sensitivity of newborn screening is high, false-negative results can still occur which can be misleading if clinicians are not aware of the clinical presentation of CF. We present a case of a young male with negative newborn screen diagnosed for CF. He was diagnosed at 3 years of age despite having symptoms indicative of CF since infancy. The delayed diagnosis resulted in diffuse lung damage and poor growth.
https://ift.tt/2IGodWw
The Effects of Sample Transport by Pneumatic Tube System on Routine Hematology and Coagulation Tests
Background. Automation helps improve laboratory operational efficiency and reduce the turnaround time. Pneumatic tube systems (PTS) automate specimen transport between the lab and other areas of the hospital. Its effect on complete blood count (CBC) and coagulation is still controversial. Aim. To study the effects of pneumatic tube system sample transport on complete blood count and coagulation parameters to compare them with hand delivered samples. Methods. 75 paired samples for complete blood count and 25 paired samples for coagulation analysis were compared between samples sent via pneumatic tube system and hand delivered system. Results. PTS showed significant decrease in red cell indices such as MCV and RDW and increase in MCHC. Other red cell parameters and WBC parameters showed no statistical significant difference. Statistically significant increase in platelet count was observed with PTS samples. However, these differences were clinically insignificant. No significant effect of PTS was found in PT and APTT samples compared to the hand delivered samples. Conclusion. Despite statistically significant changes in RBC parameters such as MCV, RDW, and MCHC and platelet count, these changes were clinically insignificant. Hence, blood samples for CBC and coagulation assay can safely be transported via our hospital's PTS. However, further studies on platelet count are warranted to ensure safe transport and accuracy of the results.
https://ift.tt/2MEbwOk
An update on the NLRP3 inflammasome and influenza: the road to redemption or perdition?
Tate Michelle D | Mansell Ashley
https://ift.tt/2lO9Jek
Reference Data on Neonatal Serum N-Acetyl-β-hexosaminidase Activity
Background. Determination of neonate serum's N-acetyl-β-hexosaminidase (HEX) activity and correlation results with Apgar scale and factors routinely determined in newborn serum. Aims. Providing reference values of neonates serum HEX activities, and indicate their diagnostic significance. Study design. The study was performed using random serum samples of 111 infants (53 ♂/58 ♀), aged 1–30 days. The activity of HEX was determined colorimetrically and expressed in nKat/L. Results. Serum HEX activity of 111 newborns was 360.5 ± 114.0 nKat/L and significantly positively correlated with gestation week at the day of delivery, birth weight, weight on day of blood collection, sex, and serum CRP. Conclusions. Reference values presented for neonatal serum activities of HEX may be used in neonatal diagnostics, for example, to detect inflammation and other diseases or for early assessment of the risk of Tay-Sachs and Sandhoff diseases.
https://ift.tt/2z7kXnI
Isolated limb perfusion for unresectable extremity cutaneous squamous cell carcinoma; an effective limb saving strategy
Isolated limb perfusion for unresectable extremity cutaneous squamous cell carcinoma; an effective limb saving strategy
Isolated limb perfusion for unresectable extremity cutaneous squamous cell carcinoma; an effective limb saving strategy, Published online: 02 July 2018; doi:10.1038/s41416-018-0149-z
Isolated limb perfusion for unresectable extremity cutaneous squamous cell carcinoma; an effective limb saving strategy
https://ift.tt/2tMuLy7
Early metabolic response in sequential FDG-PET/CT under cetuximab is a predictive marker for clinical response in first-line metastatic colorectal cancer patients: results of the phase II REMOTUX trial
Early metabolic response in sequential FDG-PET/CT under cetuximab is a predictive marker for clinical response in first-line metastatic colorectal cancer patients: results of the phase II REMOTUX trial
Early metabolic response in sequential FDG-PET/CT under cetuximab is a predictive marker for clinical response in first-line metastatic colorectal cancer patients: results of the phase II REMOTUX trial, Published online: 02 July 2018; doi:10.1038/s41416-018-0152-4
Early metabolic response in sequential FDG-PET/CT under cetuximab is a predictive marker for clinical response in first-line metastatic colorectal cancer patients: results of the phase II REMOTUX trial
https://ift.tt/2IJ6WvY
Reply to ‘Comment on ‘Dairy, calcium, vitamin D and ovarian cancer risk in African–American women’’
Reply to 'Comment on 'Dairy, calcium, vitamin D and ovarian cancer risk in African–American women''
Reply to 'Comment on 'Dairy, calcium, vitamin D and ovarian cancer risk in African–American women'', Published online: 02 July 2018; doi:10.1038/s41416-018-0163-1
Reply to 'Comment on 'Dairy, calcium, vitamin D and ovarian cancer risk in African–American women''
https://ift.tt/2Nf3igE
Patients with early-stage oropharyngeal cancer can be identified with label-free serum proteomics
Patients with early-stage oropharyngeal cancer can be identified with label-free serum proteomics
Patients with early-stage oropharyngeal cancer can be identified with label-free serum proteomics, Published online: 02 July 2018; doi:10.1038/s41416-018-0162-2
Patients with early-stage oropharyngeal cancer can be identified with label-free serum proteomics
https://ift.tt/2IJ6Nsq
Comment on ‘Dairy, calcium, vitamin D, and ovarian cancer risk in African-American women’
Comment on 'Dairy, calcium, vitamin D, and ovarian cancer risk in African-American women'
Comment on 'Dairy, calcium, vitamin D, and ovarian cancer risk in African-American women', Published online: 02 July 2018; doi:10.1038/s41416-018-0166-y
Comment on 'Dairy, calcium, vitamin D, and ovarian cancer risk in African-American women'
https://ift.tt/2tJGRbm
Slipping Rib Syndrome in a Female Adult with Longstanding Intractable Upper Abdominal Pain
Slipping rib syndrome is a rare cause of abdominal or lower chest pain that can remain undiagnosed for many years. Awareness among health care personnel of this rare but significant disorder is necessary for early recognition. Prompt treatment can avoid unnecessary testing, radiographic exposure, and years of debilitating pain. A 52-year-old female was evaluated for a 3-year history of recurrent abdominal and lower chest pain. Pain was sharp, primarily located in the lower chest and subcostal region left more than right, waxing and waning, nonradiating, and aggravates with specific movements. She underwent frequent physical therapies, treated with multiple muscle relaxants and analgesics with minimal improvement. Imaging modalities including CT scan, MRI, and X-rays performed on multiple occasions failed to signify any underlying abnormality. Complete physical examination was unremarkable except for positive hooking maneuver. Dynamic flow ultrasound of lower chest was performed which showed slipping of the lowest rib over the next lowest rib bilaterally left worse than right, findings consistent with slipping rib syndrome. Slipping rib syndrome is caused by hypermobility of the floating ribs (8 to 12) which are not connected to the sternum but attached to each other with ligaments. Diagnosis is mostly clinical, and radiographic tests are rarely necessary. Hooking maneuver is a simple clinical test to reproduce pain and can aid in the diagnosis. Reassurance and avoiding postures that worsen pain are usually helpful. In refractory cases, nerve block and surgical intervention may be required.
https://ift.tt/2KAIvm8
Cronkhite-Canada Syndrome: Sustained Clinical Response with Anti-TNF Therapy
Cronkhite-Canada syndrome (CCS) is a rare, nonfamilial syndrome that occurs in the sixth to seventh decades of life. It is characterized by acquired gastrointestinal polyposis with an associated ectodermal triad, including alopecia, onchodystrophy, and hyperpigmentation. CCS is characteristically a progressive disease, with a high mortality rate despite medical interventions. Disease complications are typically secondary to severe malnutrition, malignancy, GI bleeding, and infection. CCS is believed secondary to immune dysregulation; however, the underlying etiology remains to be determined. Treatment for CCS is largely anecdotal, and randomized controlled therapeutic trials are lacking due to the rarity of the disease. Aggressive nutritional support in conjunction with immunosuppression has been used previously with inconsistent results. In this report, we describe the presentation and diagnosis of a case of CCS and report encouraging treatment response with anti-TNF therapy.
https://ift.tt/2KlheI6
A High-throughput, High-content, Liquid-based C. elegans Pathosystem
https://ift.tt/2II7dix
Recording Spatially Restricted Oscillations in the Hippocampus of Behaving Mice
https://ift.tt/2KqrgYD
Are cortisol concentrations in human breast milk associated with infant crying?
Developmental Psychobiology, EarlyView.
https://ift.tt/2Nc4UaS
Fabrication of Gradient Nanopattern by Thermal Nanoimprinting Technique and Screening of the Response of Human Endothelial Colony-forming Cells
https://ift.tt/2IHO6oQ
Intracranial Subarachnoidal Route of Infection for Investigating Roles of Streptococcus suis Biofilms in Meningitis in a Mouse Infection Model
https://ift.tt/2tIGKN5
Co-expression of Multiple Chimeric Fluorescent Fusion Proteins in an Efficient Way in Plants
https://ift.tt/2KA42uV
Three- dimensional microstructural reconstruction of the ovine intervertebral disc using ultra-high field MRI
Publication date: Available online 30 June 2018
Source:The Spine Journal
Author(s): Mirit Sharabi, Kelly R. Wade, Fabio Galbusera, Volker Rasche, Rami Haj-Ali, Hans-Joachim Wilke
BackgroundThe intervertebral disc (IVD) is a complex organ which acts as a flexible coupling between two adjacent vertebral bodies and must therefore accommodate compression, bending and torsion. It consists of three main components which are elegantly structured to allow this: the annulus fibrosus (AF), the nucleus pulposus (NP) and the end-plates (EP).PurposeThus far, it has not been possible to examine the microarchitecture of the disc directly in three dimensions in its unaltered state and thus knowledge of the overall architecture of the disc has been inferred from a range of imaging sources, or by using destructive methods.Study designA non-destructive ultra-high field MRI of 11.7T was used together with image analysis to visualize the ovine IVDs.MethodsThree-dimensional image stacks from eight IVDs harvested from sheep, half of which were 4-5 years old and the others approximately 2 years old were reconstructed and examined and their microstructure were imaged. The overall structure of the disc, including the average of 14 AF lamellae (9-28), NP and EP was then visualized with particular attention given to integrating elements as radial translamellar cross-links, AF-NP transition zone EP-AF integration and EP-NP insertion nodes (i.e. the connecting junctions between the EP and NP). Moreover, collagen fiber orientation was determined at different depths and locations throughout the annulus.ResultsIt was found that there was a clearer demarcation in the AF-NP transition zone of the younger discs compared to the older ones. This difference was reflected in the visibility of AF-NP and EP-AF integration. It was also possible to view the fiber architecture of the AF-NP integration in greater depth than was possible previously with histological techniques. These fibers were mainly observed in the younger discs and their length was measured to be of 2.6±0.2mm.ConclusionsThe present results provide a substantial advance in visualization of the three-dimensional architecture of an intact IVD and the integration of its components.
https://ift.tt/2Kps3sT
Editorial Board/Publication Information
Publication date: July 2018
Source:Injury, Volume 49, Issue 7
https://ift.tt/2KGcyJe
Nurse-Led Communication in the Intensive Care Unit
We examine him each day — the elderly patient, intubated, sedated, with a bewildered wife at his bedside. We should sit down with his wife before we ask her to make hard decisions about her husband's care, but the unit is so busy that we find ourselves scurrying by, pausing only to offer rushed…
https://ift.tt/2J0rRii
Prophylaxis against Upper Gastrointestinal Bleeding in Hospitalized Patients
Beginning approximately four decades ago, a series of randomized trials suggested that, in seriously ill hospitalized patients, primary prevention of clinically important upper gastrointestinal bleeding — stress-ulcer prophylaxis — significantly reduces the risk of bleeding. In response, practice…
https://ift.tt/2KBWPe7
Informed Consent and the Role of the Treating Physician
In the century since Justice Benjamin N. Cardozo famously declared that "[e]very human being of adult years and sound mind has a right to determine what shall be done with his own body," informed consent has become a central feature of American medical practice. In an increasingly team-based and…
https://ift.tt/2MBh4ZS
Adrenal Calcifications in an Infant
https://ift.tt/2z0MRBu
Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML
Somatic mutations within the conserved active site of isocitrate dehydrogenase (IDH) 1 and 2 occur in multiple tumors, including glioma, acute myeloid leukemia (AML), cholangiocarcinoma, and chondrosarcoma. IDH1 and IDH2 mutations confer a neomorphic enzymatic activity, resulting in the reduction…
https://ift.tt/2LgYXYB
Case 19-2018: A 15-Year-Old Girl with Acute Kidney Injury
Presentation of Case. Dr. Helen I. Healy (Pediatrics): A 15-year-old girl was admitted to this hospital during the summer because of acute kidney injury. The patient had been well until 8 days before admission, when painful cramping in the lower abdomen and bloody diarrhea developed. Bowel…
https://ift.tt/2KznoUo
Migrating Dirofilaria repens
https://ift.tt/2IFSR2i
Macular Hole from a Laser Pointer
https://ift.tt/2KEfjKL
Tongue Necrosis in Giant-Cell Arteritis
https://ift.tt/2IFLWGp
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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