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The PI3K/AKT/mTOR pathway is frequently altered at genomic level in metastatic urothelial carcinoma (mUC). Since mTOR is the last protein in the PI3K signaling cascade, it may have the largest impact on the pathway and has been a focus of targeted therapies. Sapanisertib (FTH-003/TAK-228) is an oral highly selective mTOR1 and mTOR2 inhibitor. NFE2L2mutations have been described as predictive biomarkers of response in patients with advanced squamous cell lung cancer treated with sapanisertib.

For many patients with breast cancer, symptomatic bone metastases appear after years of latency. How micrometastatic lesions remain dormant and undetectable before initiating colonization is unclear. Here, we describe a mechanism involved in bone metastatic latency of oestrogen receptor-positive (ER+) breast cancer. Using an in vivo genome-wide short hairpin RNA screening, we identified the kinase MSK1 as an important regulator of metastatic dormancy in breast cancer. In patients with ER+breast cancer, low MSK1 expression associates with early metastasis. We show that MSK1 downregulation impairs the differentiation of breast cancer cells, increasing their bone homing and growth capacities. MSK1 controls the expression of genes required for luminal cell differentiation, including the GATA3 and FOXA1 transcription factors, by modulating their promoter chromatin status. Our results indicate that MSK1 prevents metastatic progression of ER+breast cancer, suggesting that stratifying patients with breast cancer as high or low risk for early relapse based on MSK1 expression could improve prognosis. Gawrzak et al. show that MSK1 regulates bone metastatic dormancy of ER+breast cancer. MSK1 affects histone modifications at luminal transcription factor promoters to prevent cell differentiation and bone homing.

Nowadays, the demands for materials with high strength based on a titanium matrix are increasing. The manufacturing of titanium composites through low cost and near-net-shape techniques is a challenge for the industry. There are different processing routes to meet these requirements of the market. As it is well known fast powder metallurgical densification techniques could satisfy these needs. In the present work, several titanium metal matrix composites (TiMMCs) have been fabricated by using a fast hot consolidation technique, namely direct hot pressing (dHP) in order to reduce the manufacturing time. Through a pressure assisted sintering with direct heating of a pressing die the consolidated composites can be formed directly from powders in a short period of time (15 min). The matrix materials were selected from two titanium grade 1 powders and as reinforcement materials boron carbide and boron amorphous particles were employed. Varying the reinforcement’s content in addition to their particle size, their influence on the composites behaviour was expected. Furthermore in this research work, the mechanical and microstructural characterisation of the specimens was carried out in order to identify the best combination of process parameters, material reinforcement and matrix powders.Nowadays, the demands for materials with high strength based on a titanium matrix are increasing. The manufacturing of titanium composites through low cost and near-net-shape techniques is a challenge for the industry. There are different processing routes to meet these requirements of the market. As it is well known fast powder metallurgical densification techniques could satisfy these needs. In the present work, several titanium metal matrix composites (TiMMCs) have been fabricated by using a fast hot consolidation technique, namely direct hot pressing (dHP) in order to reduce the manufacturing time. Through a pressure assisted sintering with direct heating of a pressing die the consolidated composites can be formed directly from powders in a short period of time (15 min). The matrix materials were selected from two titanium grade 1 powders and as reinforcement materials boron carbide and boron amorphous particles were employed. Varying the reinforcement’s content in addition to their particle size, their influence on the composites behaviour was expected. Furthermore in this research work, the mechanical and microstructural characterisation of the specimens was carried out in order to identify the best combination of process parameters, material reinforcement and matrix powders.

The methylation status of the IGFBP-3gene is strongly associated with cisplatin sensitivity in patients with non-small cell lung cancer (NSCLC). In this study, we found in vitroevidence that linked the presence of an unmethylated promoter with poor response to radiation. Our data also indicate that radiation might sensitize chemotherapy-resistant cells by reactivating IGFBP-3-expression through promoter demethylation, inactivating the PI3K/AKT pathway. We also explored the IGFBP-3methylation effect on overall survival (OS) in a population of 40 NSCLC patients who received adjuvant therapy after R0 surgery. Our results indicate that patients harboring an unmethylated promoter could benefit more from a chemotherapy schedule alone than from a multimodality therapy involving radiotherapy and platinum-based treatments, increasing their OS by 2.5 y (p= .03). Our findings discard this epi-marker as a prognostic factor in a patient population without adjuvant therapy, indicating that radiotherapy does not improve survival for patients harboring an unmethylated IGFBP-3promoter.

Overexpression, activation, and dysregulation of various membrane receptors, signaling pathways, and other factors occur frequently in human breast cancer. Therapeutic approaches targeting these molecules and the selective estrogen receptor modulators and aromatase inhibitors have been demonstrated to have higher efficacy than conventional therapy agents in the treatment of breast cancer, and to have an extensive potential. A rapid expansion of novel diagnostics and predictive tests designed to select the best target population and to personalize cancer care is occurring, but there remain several significant needs for improving the accuracy and reliability of these tests. The use of unstandardized methods and a widespread concern that inaccuracy in interpretation of assays is leading to an unacceptably high error rate in determining the true status of a potential predictive marker in current clinical practice. A variety of factors, including preanalytic conditions, slide-scoring procedures, and other variables, that may be contributing to current testing error rates must be improved for the standardization of these assay procedures to further enable the highest possible quality of diagnoses for breast cancer patients.

The NFκB family is composed by five subunits (p65/RelA, c-Rel, RelB, p105-p50/NFκB1, p100-p52/NF-κB2) and controls the expression of many genes that participate in cell cycle, apoptosis, and other key cellular processes. In a canonical pathway, NF-κB activation depends on the IKK complex activity, which is formed by three subunits (IKKα and IKKβ and IKKγ/NEMO). There is an alternative NFκB activation pathway that does not require IKKβ or IKKγ/NEMO, in which RelB is a major player. We report in a panel of human breast cancer cells that the IKK/NFκB system is generally overexpressed in breast cancer cells and there is heterogeneity in expression levels of individual members between different cell lines. Doxorubicin, an anticancer agent used in patients with breast cancer, activated NFκB and appeared to be less effective in cells expressing predominantly members of the canonical IKK/NFκB. Two NFκB inhibitors, bortezomib and NEMO-Binding Domain Inhibitory Peptide, prevented doxorubicin-induced NFκB activation and increased doxorubicin antitumor effects in BT-474 cells. Transient downregulation of members of the canonical pathway (p65, p52, c-Rel and IKKγ/NEMO) by siRNA in HeLa cells increased doxorubicin cytotoxicity. In contrast, silencing of RelB, a key subunit of the alternative pathway, had no evident effects on doxorubicin cytotoxicity. To conclude, NFκB inhibition sensitized cells to doxorubicin, implying directly p65, p52, c-Rel and IKKγ/NEMO subunits in chemoresistance, but not RelB. These findings suggest that selective inhibition of the canonical NFκB pathway is sufficient to improve doxorubicin antitumor effects.

ABSTRACTA relatively high mutation rate is probably a major factor in the evolutionary success of retroviruses, because it generates the genetic diversity that helps them to cope with changes in the environment. When using recombinant retroviruses as vectors for gene transfer and gene therapy, it is important to consider the implications of this biological characteristic. Until now, the mutation rate has been studied by using noneukaryotic genes as reporters. Here we report point mutations in the human glucose-6-phosphate dehydrogenase (hG6PD) gene transferred by Moloney murine leukemia virus-based vectors into murine bone marrow cells and NIH 3T3 murine fibroblasts. After bone marrow transplantation, we observed an hG6PD with abnormal electrophoretic mobility for 2 out of 34 mice. Next, we studied this phenomenon quantitatively and found 1 electrophoretically abnormal hG6PD variant among 93 independently isolated NIH 3T3 clones, from which we estimate a mutation rate of 1.4 × 10-5per base pair per replication cycle. Mutations in the transferred gene can thus contribute to the impairment of the effectiveness of retrovirus-mediated gene transfer.

Many mutations of the housekeeping gene encoding glucose-6-phosphate dehydrogenase (G6PD) cause G6PD deficiency in humans. Some underlie severe forms of chronic nonspherocytic hemolytic anemia (CNSHA) for which there is no definitive treatment. By using retroviral vectors pseudotyped with the vesicular stomatitis virus G glycoprotein that harbor the human G6PD (hG6PD) complementary DNA, stable and lifelong expression of hG6PD was obtained in all the hematopoietic tissues of 16 primary bone marrow transplant (BMT) recipient mice and 14 secondary BMT recipients. These findings demonstrate the integration of a functional gene in totipotent stem cells. The average total G6PD in peripheral blood cells of these transplanted mice, measured as enzyme activity, was twice that of untransplanted control mice. This allowed the inference that the amount of G6PD produced by the transduced gene must be therapeutically effective. With the same vectors both the cloning efficiency and the ability to form embryoid bodies were restored in embryonic stem cells, in which the G6PD gene had been inactivated by targeted homologous recombination, thus effectively rescuing their defective phenotype. Finally, expression of normal human G6PD in hG6PD-deficient primary hematopoietic cells and in human hematopoietic cells engrafted in nonobese diabetic/severe combined immunodeficient mice was obtained. This approach could cure severe CNSHA caused by G6PD deficiency.

Many mutations of the housekeeping gene encoding glucose-6-phosphate dehydrogenase (G6PD) cause G6PD deficiency in humans. Some underlie severe forms of chronic nonspherocytic hemolytic anemia (CNSHA) for which there is no definitive treatment. By using retroviral vectors pseudotyped with the vesicular stomatitis virus G glycoprotein that harbor the human G6PD (hG6PD) complementary DNA, stable and lifelong expression of hG6PD was obtained in all the hematopoietic tissues of 16 primary bone marrow transplant (BMT) recipient mice and 14 secondary BMT recipients. These findings demonstrate the integration of a functional gene in totipotent stem cells. The average total G6PD in peripheral blood cells of these transplanted mice, measured as enzyme activity, was twice that of untransplanted control mice. This allowed the inference that the amount of G6PD produced by the transduced gene must be therapeutically effective. With the same vectors both the cloning efficiency and the ability to form embryoid bodies were restored in embryonic stem cells, in which the G6PDgene had been inactivated by targeted homologous recombination, thus effectively rescuing their defective phenotype. Finally, expression of normal human G6PD in hG6PD-deficient primary hematopoietic cells and in human hematopoietic cells engrafted in nonobese diabetic/severe combined immunodeficient mice was obtained. This approach could cure severe CNSHA caused by G6PD deficiency.

Typification is provided for some names of Macaronesian and Mediterranean species of dendroid Euphorbia, traditionally associated with Euphorbiasubsect. Pachycladae(Boiss.) Pax, as a nomenclatural contribution to a forthcoming taxonomic revision of this group. In addition, the inclusion of Euphorbialambii and E. melliferainto synonymy of E. bourgeanaand E. longifolia, respectively, is substantiated.

ABSTRACTBackground. Immunotherapy has shown efficacy in small cell lung cancer (SCLC), but only a subset of patients benefits. Surrogate biomarkers are urgently needed. Our aim was to evaluate serum Th1, Th2, and proinflammatory cytokines in two cohorts of SCLC patients before and during treatment with chemotherapy with or without ipilimumab and to correlate them with survival.Patients and methods. Two cohorts of SCLC patients were studied: patients treated with chemotherapy (n = 47), and patients treated with chemotherapy plus ipilimumab (n = 37). Baseline, on-treatment and after-treatment serum samples were evaluated for the presence of IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-gamma, TNF-alpha, GM-CSF, and Mip-1alpha using a Luminex assay. Differential changes in cytokines between cohorts were analyzed. Associations between cytokine levels and their changes with overall survival were evaluated.Results. Patients treated with ipilimumab showed a global increase of all cytokines after treatment initiation. A high level of IL-8 at baseline was associated with worse prognosis regardless of treatment. Baseline increased IL-2 levels predicted sensitivity to ipilimumab, while high IL-6 and TNF-alpha predicted resistance. An on-treatment increase in IL-4 levels in patients treated with immune-chemotherapy was associated with a better overall survival.Conclusions. The addition of ipilimumab to standard chemotherapy in SCLC modulates the serum levels of cytokines. Baseline levels and their change over time relate to overall survival. Blood-based biomarkers are convenient for patients, and our results support prospective validation of cytokines as predictive biomarkers for ipilimumab in SCLC.

González-Barca: Roche: Speakers Bureau; Celtrion: Consultancy; Gilead: Consultancy; janssen: Consultancy, Speakers Bureau. Martín:Celgene: Consultancy, Honoraria, Other: Travel expenses; Roche: Consultancy, Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Servier: Honoraria, Other: Travel expenses. Panizo:BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acerta Pharma: Research Funding; Roche: Consultancy, Speakers Bureau. Sanchez Blanco:Gilead: Honoraria; Roche: Honoraria; Janssen: Honoraria. Marin Niebla:Roche: Consultancy, Other: Medical education of Staff, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Medical education of Staff, Speakers Bureau; Celgene: Other: Medical education of Staff, Speakers Bureau; Amgen: Other: Medical education of Staff, Speakers Bureau. Queizan:Janssen: Consultancy. Lopez:Roche: Research Funding.

Introduction and Objective:Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL-NT) is associated with Epstein-Barr virus (EBV) and is much more common in Asia and Latin America than in western countries. Data on disease presentation and outcome from European series are very limited. The objective of the study is to analyze the clinical characteristics at diagnosis, treatment received and outcome of a series of patients from Spain.

In the version of this Article originally published, the boxes framing the two plots in Fig. 1g were misaligned from the axes due to a technical error. This has now been corrected in all versions of the Article.

IMPORTANCE: Acquired resistance to anti-EGFR therapy (epidermal growth factor receptor) is frequently due to RAS and EGFR extracellular domain (ECD) mutations in metastatic colorectal cancer (mCRC). Some anti-EGFR–refractory patients retain tumor EGFR dependency potentially targetable by agents such as Sym004, which is a mixture of 2 nonoverlapping monoclonal antibodies targeting EGFR. OBJECTIVE: To determine if continuous blockade of EGFR by Sym004 has survival benefit. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, phase 2, randomized, clinical trial comparing 2 regimens of Sym004 with investigator’s choice from March 6, 2014, through October 15, 2015. Circulating tumor DNA (ctDNA) was analyzed for biomarker and tracking clonal dynamics during treatment. Participants had wild-type KRAS exon 2 mCRC refractory to standard chemotherapy and acquired resistance to anti-EGFR monoclonal antibodies. INTERVENTIONS: Participants were randomly assigned in a 1:1:1 ratio to Sym004, 12 mg/kg/wk (arm A), Sym004, 9 mg/kg loading dose followed by 6 mg/kg/wk (arm B), or investigator’s choice of treatment (arm C). MAIN OUTCOMES AND MEASURES: Overall survival (OS). Secondary end points included preplanned exploratory biomarker analysis in ctDNA. RESULTS: A total of 254 patients were randomized (intent-to-treat [ITT] population) (median age, 63 [range, 34-91] years; 63% male; n = 160). Median OS in the ITT population was 7.9 months (95% CI, 6.5-9.9 months), 10.3 months (95% CI, 9.0-12.9 months), and 9.6 months (95% CI, 8.3-12.2 months) for arms A, B, and C, respectively (hazard ratio [HR], 1.31; 95% CI, 0.92-1.87 for A vs C; and HR, 0.97; 95% CI, 0.68-1.40 for B vs C). The ctDNA revealed high intrapatient genomic heterogeneity following anti-EGFR therapy. Sym004 effectively targeted EGFR ECD-mutated cancer cells, and a decrease in EGFR ECD ctDNA occurred in Sym004-treated patients. However, this did not translate into clinical benefit in patients with EGFR ECD mutations, likely owing to co-occurring resistance mechanisms. A subgroup of patients was defined by ctDNA (RAS/BRAF/EGFR ECD-mutation negative) associated with improved OS in Sym004-treated patients in arm B compared with arm C (median OS, 12.8 and 7.3 months, respectively). CONCLUSIONS AND RELEVANCE: Sym004 did not improve OS in an unselected population of patients with mCRC and acquired anti-EGFR resistance. A prospective clinical validation of Sym004 efficacy in a ctDNA molecularly defined subgroup of patients with refractory mCRC is warranted. TRIAL REGISTRATION: clinicaltrialsregister.eu Identifier: 2013-003829-29

ABSTRACTMonoclonal antibodies (mAbs) have become a successful therapeutic approach in cancer. However, some patients do not achieve long-term clinical benefit and most mAbs only exert modest effects as monotherapies. Therefore, combinations with chemotherapy are currently being investigated. Emerging studies have shown a synergistic therapeutic effect of PARP inhibitors and mAbs in cancer. PARP enzymes catalytically cleave β-NAD+and transfer the ADP-ribose moiety to acceptor proteins, modifying their function. In here, we update recent data about the therapeutic effect of the combination of PARP inhibitors with mAbs in cancer treatment and discuss the molecular mechanisms involved in this synergy.