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The use of recombinant interleukin-2 (IL-2) as a therapeutic protein has been limited by significant toxicities despite its demonstrated ability to induce durable tumor-regression in cancer patients. The adverse events and limited efficacy of IL-2 treatment are due to the preferential binding of IL-2 to cells that express the high-affinity, trimeric receptor, IL-2Rαβγ such as endothelial cells and T-regulatory cells, respectively. Here, we describe a novel bispecific heavy-chain only antibody which binds to and activates signaling through the heterodimeric IL-2Rβγ receptor complex that is expressed on resting T-cells and NK cells. By avoiding binding to IL-2Rα, this molecule circumvents the preferential T-reg activation of native IL-2, while maintaining the robust stimulatory effects on T-cells and NK-cells in vitro. In vivo studies in both mice and cynomolgus monkeys confirm the molecule’s in vivo biological activity, extended pharmacodynamics due to the Fc portion of the molecule, and enhanced safety profile. Together, these results demonstrate that the bispecific antibody is a safe and effective IL-2R agonist that harnesses the benefits of the IL-2 signaling pathway as a potential anti-cancer therapy.

The advanced-stage head and neck cancer (HNC) patients respond poorly to platinum-based treatments. Thus, a reliable pretreatment method for evaluating platinum treatment response would improve therapeutic efficiency and outcomes. This study describes a novel strategy to predict clinical drug responses in HNC patients by using eSelect, a lab-developed biomimetic cell culture system, which enables us to perform ex vivo expansion and drug sensitivity profiling of circulating tumor cells (CTCs). Forty liquid biopsies were collected from HNC patients, and the CTCs were expanded ex vivo using the eSelect system within four weeks. Immunofluorescence staining confirmed that the CTC-derived organoids were positive for EpCAM and negative for CD45. Two illustrative cases present the potential of this strategy for evaluating treatment response. The statistical analysis confirmed that drug sensitivity in CTC-derived organoids was associated with a clinical response. The multivariant logistic regression model predicted that the treatment accuracy of chemotherapy responses achieved 93.75%, and the area under the curves (AUCs) of prediction models was 0.8841 in the whole dataset and 0.9167 in cisplatin specific dataset. In summary, cisplatin sensitivity profiles of patient-derived CTCs expanded ex vivo correlate with a clinical response to cisplatin treatment, and this can potentially underpin predictive assays to guide HNC treatments.

PurposeThere are many proven problems associated with traditional surgical planning methods for orthognathic surgery. To address these problems, we developed a computer-aided surgical simulation (CASS) system, the AnatomicAligner, to plan orthognathic surgery following our streamlined clinical protocol.MethodsThe system includes six modules: image segmentation and three-dimensional (3D) reconstruction, registration and reorientation of models to neutral head posture, 3D cephalometric analysis, virtual osteotomy, surgical simulation, and surgical splint generation. The accuracy of the system was validated in a stepwise fashion: first to evaluate the accuracy of AnatomicAligner using 30 sets of patient data, then to evaluate the fitting of splints generated by AnatomicAligner using 10 sets of patient data. The industrial gold standard system, Mimics, was used as the reference.ResultWhen comparing the results of segmentation, virtual osteotomy and transformation achieved with AnatomicAligner to the ones achieved with Mimics, the absolute deviation between the two systems was clinically insignificant. The average surface deviation between the two models after 3D model reconstruction in AnatomicAligner and Mimics was 0.3 mm with a standard deviation (SD) of 0.03 mm. All the average surface deviations between the two models after virtual osteotomy and transformations were smaller than 0.01 mm with a SD of 0.01 mm. In addition, the fitting of splints generated by AnatomicAligner was at least as good as the ones generated by Mimics.ConclusionWe successfully developed a CASS system, the AnatomicAligner, for planning orthognathic surgery following the streamlined planning protocol. The system has been proven accurate. AnatomicAligner will soon be available freely to the boarder clinical and research communities.

This study aimed (1) to investigate the pattern of perinatal depressive symptoms, and (2) to determine the relationships between sociodemographic characteristics, obstetric factors, antenatal morbidities, postnatal conditions, and perinatal depressive symptoms using a structural equation model (SEM). A three-wave prospective longitudinal design was used for 361 women in their second trimester, third trimester, and at six weeks postpartum. The Edinburgh Postnatal Depression Scale (EPDS) was used to assess the depressive symptoms. The intensity of depressive symptoms was the highest in the second trimester among the three waves. The SEM showed that unmarried status, unplanned pregnancy, gestational diabetes, and headache were significantly associated with EPDS in the first and second waves. The EPDS in the first wave was able to predict the EPDS in the second and third waves. The SEM has satisfactorily fit with the data (chi-square/degree of freedom = 1.42, incremental fit index = 0.91, Tucker-Lewis index = 0.90, comparative fit index = 0.91, and root mean square error of approximation = 0.03). The findings highlight the significance of monitoring depressive symptoms in the second trimester. Findings from this study could be useful in the design of effective intervention among women with unmarried status, unplanned pregnancy, gestational diabetes, and headache in order to reduce risk of perinatal depressive symptoms.

Protein drugs cannot be delivered efficiently through oral routes. To address this challenge, we evaluated the effect of prolonged gastrointestinal transit on the bioavailability of insulin carried by magnetically responsive microparticles in the presence of an external magnetic field. Magnetite nanocrystals and insulin were coencapsulated into poly(lactide-co-glycolide) (PLGA) microparticles and their effects on hypoglycemia were evaluated in mice in the presence of a circumferentially applied external magnetic field. A single administration of 100 U/kg of insulin-magnetite-PLGA microparticles to fasted mice resulted in a reduction of blood glucose levels of up to 43.8% in the presence of an external magnetic field for 20 h (bioavailability = 2.77 +/- 0.46 and 0.87 +/- 0.29% based on glucose and ELISA assay, respectively), significantly higher than similarly dosed mice without a magnetic field (bioavailability = 0.66 +/- 0.56 and 0.30 +/- 0.06%, based on glucose and ELISA assay, respectively). A substantially improved hypoglycemic effect was observed in mice that were orally administered with insulin-magnetite-PLGA microparticles in the presence of an external magnetic field, suggesting that magnetic force can be used to improve the efficiency of orally delivered protein therapeutics.

Inactivation of tumour-suppressor genes by homozygous deletion is a prototypic event in the cancer genome, yet such deletions often encompass neighbouring genes. We propose that homozygous deletions in such passenger genes can expose cancer-specific therapeutic vulnerabilities when the collaterally deleted gene is a member of a functionally redundant family of genes carrying out an essential function. The glycolytic gene enolase 1 ( ENO1 ) in the 1p36 locus is deleted in glioblastoma (GBM), which is tolerated by the expression of ENO2 . Here we show that short-hairpin-RNA-mediated silencing of ENO2 selectively inhibits growth, survival and the tumorigenic potential of ENO1 -deleted GBM cells, and that the enolase inhibitor phosphonoacetohydroxamate is selectively toxic to ENO1 -deleted GBM cells relative to ENO1 -intact GBM cells or normal astrocytes. The principle of collateral vulnerability should be applicable to other passenger-deleted genes encoding functionally redundant essential activities and provide an effective treatment strategy for cancers containing such genomic events. The ‘collateral’ homozygous deletion of essential redundant housekeeping genes in cancer genomes is shown to confer therapeutic vulnerability on cancer cells with the deletion, without affecting genomically intact normal non-cancerous cells, suggesting new therapeutic opportunities. A new type of anticancer target This Article introduces the concept of 'collateral damage' in cancer genomes as a possible basis for therapeutic strategies. Ronald DePinho and colleagues examine pairs of functionally redundant 'passenger' genes with 'housekeeping' roles, for example in cellular metabolism. They hypothesize that genetic deletions in cancer that encompass one such gene (as collateral damage caused by proximity to tumour-suppressor genes) may expose a selective vulnerability of cancer cells, but not normal cells, to pharmacological inhibition of the protein encoded by the second gene. They demonstrate this concept for the glycolytic enzymes ENO1 and ENO2. There is often homozygous deletion of the ENO1 gene on chromosome 1p36 in glioblastomas, which is shown here to render glioma cells sensitive to knockdown of ENO2 or to a small-molecule enolase inhibitor. The authors further analyse existing cancer genomics data sets for other examples of pairs of redundant housekeeping genes, one of which resides close to frequently deleted tumour-suppressor genes. They suggest that this concept may be generally applicable and could offer new therapeutic opportunities.

Four-gene marker in prostate cancer Using a Smad4 / Pten null transgenic mouse model of prostate cancer, Ding et al . show that the transforming growth factor-β (TGFβ) signalling pathway limits tumour progression and metastasis. By utilizing markers of this pathway and other biologically relevant factors, they develop a four-gene signature that is associated with poorer clinical outcome and metastatic progression in several prostate cancer cohorts, especially in combination with other clinical parameters. This signature may prove useful as a basis for an improved prognostic test for those cases of prostate cancer in which deciding on the right treatment regime while avoiding over-treatment is an important clinical challenge. In a mouse model of prostate cancer it is found that that the TGF-β signalling pathway limits tumour progression and metastasis. Using markers of this pathway and other biologically relevant factors, a four-gene signature is identified that is associated with poorer clinical outcome and metastatic progression in several prostate cancer cohorts, especially in combination with other clinical parameters. This signature may prove useful for the development of a better prognostic test for those cases of prostate cancer in which deciding on the right treatment regime while avoiding over-treatment constitutes an important clinical challenge. Effective clinical management of prostate cancer (PCA) has been challenged by significant intratumoural heterogeneity on the genomic and pathological levels and limited understanding of the genetic elements governing disease progression 1 . Here, we exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten -null mouse prostate tumours and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonical pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten -null prostate cancers revealed robust activation of the TGFβ/BMP–SMAD4 signalling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten -null mouse prostate. Pathological and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumours identified cell proliferation and invasion as two cardinal tumour biological features in the metastatic Smad4 / Pten -null PCA model. Follow-on pathological and functional assessment confirmed cyclin D1 and SPP1 as key mediators of these biological processes, which together with PTEN and SMAD4, form a four-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human PCA. This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of PCA progression in mice and humans.

Nature 488, 337–342 (2012); doi:10.1038/nature11331 In this Article, during the preparation of Figures 2d and 3a, we processed digital western blot scans to remove duplicate or otherwise irrelevant lanes from single-blot images. Although all excisions/mergers originated from the same gel, these figure constructions should have been explicitly pointed out.

[...]Fig. 2 of this Corrigendum shows the corrected Fig. 3a, in which for the cell line U87, an additional non-targeting short hairpin RNA control (original lanes 7 and 8) was excised with the remaining halves of the blot and merged, which is now indicated by a dashed line.

Inactivation of tumour-suppressor genes by homozygous deletion is a prototypic event in the cancer genome, yet such deletions often encompass neighbouring genes. We propose that homozygous deletions in such passenger genes can expose cancer-specific therapeutic vulnerabilities when the collaterally deleted gene is a member of a functionally redundant family of genes carrying out an essential function. The glycolytic gene enolase 1 (ENO1) in the 1p36 locus is deleted in glioblastoma (GBM), which is tolerated by the expression of ENO2. Here we show that short-hairpin-RNA-mediated silencing of ENO2 selectively inhibits growth, survival and the tumorigenic potential of ENO1-deleted GBM cells, and that the enolase inhibitor phosphonoacetohydroxamate is selectively toxic to ENO1-deleted GBM cells relative to ENO1-intact GBM cells or normal astrocytes. The principle of collateral vulnerability should be applicable to other passenger-deleted genes encoding functionally redundant essential activities and provide an effective treatment strategy for cancers containing such genomic events.