Towards the Industrial Implementation of Mn-based Catalyst for the Hydrogenation of Ketones and Carboxylic Esters.

There is a constant pressure in industry to move away from platinum group metals (PGM) and achieve more environmentally friendly and sustainable production processes in the future. Recently developed Mn-based catalysts offer an interesting opportunity to complement established catalysts based on Ru. In this article, recent achievements in the field are highlighted and recent achievements in the collaboration of Solvias AG with the group of Prof. M. Clarke towards the implementation of these catalysts on industrial scale are outlined.

Ligand Hydrogenation during Hydroformylation Catalysis Detected by In Situ High-Pressure Infra-Red Spectroscopic Analysis of a Rhodium/Phospholene-Phosphite Catalyst.

Phospholane-phosphites are known to show highly unusual selectivity towards branched aldehydes in the hydroformylation of terminal alkenes. This paper describes the synthesis of hitherto unknown unsaturated phospholene borane precursors and their conversion to the corresponding phospholene-phosphites. The relative stereochemistry of one of these ligands and its Pd complex was assigned with the aid of X-ray crystal structure determinations. These ligands were able to approach the level of selectivity observed for phospholane-phosphites in the rhodium-catalysed hydroformylation of propene. High-pressure infra-red (HPIR) spectroscopic monitoring of the catalyst formation revealed that whilst the catalysts showed good thermal stability with respect to fragmentation, the C=C bond in the phospholene moiety was slowly hydrogenated in the presence of rhodium and syngas. The ability of this spectroscopic tool to detect even subtle changes in structure, remotely from the carbonyl ligands, underlines the usefulness of HPIR spectroscopy in hydroformylation catalyst development.

Manganese-Catalyzed Hydrogenation of Amides and Polyurethanes: Is Catalyst Inhibition an Additional Barrier to the Efficient Hydrogenation of Amides and Their Derivatives?

The hydrogenation of amides and other less electrophilic carbonyl derivatives with an N-C=O functionality requires significant improvements in scope and catalytic activity to be a genuinely useful reaction in industry. Here, we report the results of a study that examined whether such reactions are further disadvantaged by nitrogen-containing compounds such as aliphatic amines acting as inhibitors on the catalysts. In this case, an enantiomerically pure manganese catalyst previously established to be efficient in the hydrogenation of ketones, N-aryl-imines, and esters was used as a prototype of a manganese catalyst. This was accomplished by doping a model ester hydrogenation with various nitrogen-containing compounds and monitoring progress. Following from this, a protocol for the catalytic hydrogenation of amides and polyurethanes is described, including the catalytic hydrogenation of an axially chiral amide that resulted in low levels of kinetic resolution. The hypothesis of nitrogen-containing compounds acting as an inhibitor in the catalytic hydrogenation process has also been rationalized by using spectroscopy (high-pressure infrared (IR), nuclear magnetic resonance (NMR)) and mass spectrometry studies.

Managing cybersecurity risk in healthcare settings.

Cybersecurity attacks have been steadily increasing in the healthcare sector over the past decade. Health data is a valuable source of reliable and permanent personal information making it an attractive target. Institutions that have faced limited cybersecurity funding must now augment their approach to combat this threat. The Internet of Things (IoT) refers to the connection of physical operational devices to digital networks allowing for communication between devices. In the healthcare setting, this includes patient monitoring, diagnostics, and even robotic surgery devices. This increased connectivity increases the importance of agile and robust cybersecurity measures. A progressive approach must involve collaboration between information technology, clinical, and administrative leaders to be successful. Adequate protection of patient data and the integrity of digital infrastructure must be a priority mandate at the enterprise level.

Localized immune surveillance of primary melanoma in the skin deciphered through executable modeling.

While skin is a site of active immune surveillance, primary melanomas often escape detection. Here, we have developed an in silico model to determine the local cross-talk between melanomas and Langerhans cells (LCs), the primary antigen-presenting cells at the site of melanoma development. The model predicts that melanomas fail to activate LC migration to lymph nodes until tumors reach a critical size, which is determined by a positive TNF-α feedback loop within melanomas, in line with our observations of murine tumors. In silico drug screening, supported by subsequent experimental testing, shows that treatment of primary tumors with MAPK pathway inhibitors may further prevent LC migration. In addition, our in silico model predicts treatment combinations that bypass LC dysfunction. In conclusion, our combined approach of in silico and in vivo studies suggests a molecular mechanism that explains how early melanomas develop under the radar of immune surveillance by LC.

Rational Design of a Facially Coordinating P,N,N Ligand for Manganese-Catalysed Enantioselective Hydrogenation of Cyclic Ketones.

DFT calculations on the full catalytic cycle for manganese catalysed enantioselective hydrogenation of a selection of ketones have been carried out at the PBE0-D3PCM //RI-BP86PCM level. Mn complexes of an enantiomerically pure chiral P,N,N ligand have been found to be most reactive when adopting a facial coordination mode. The use of a new ligand with an ortho-substituted dimethylamino-pyridine motif has been calculated to completely transform the levels of enantioselectivity possible for the hydrogenation of cyclic ketones relative to the first-generation Mn catalysts. In silico evaluation of substrates has been used to identify those likely to be reduced with high enantiomer ratios (er), and others that would exhibit less selectivity; good agreements were then found in experiments. Various cyclic ketones and some acetophenone derivatives were hydrogenated with er's up to 99 : 1.

TORPEdO: A phase III trial of intensity-modulated proton beam therapy versus intensity-modulated radiotherapy for multi-toxicity reduction in oropharyngeal cancer.

•There is a lack of prospective level I evidence for the use of PBT for most adult cancers including oropharyngeal squamous cell carcinoma (OPSCC).•TORPEdO is the UK's first PBT clinical trial and aims to determine the benefits of PBT for OPSCC.•Training and support has been provided before and during the trial to reduce variations of contouring and radiotherapy planning.•There is a strong translational component within TORPEdO. Imaging and physics data along with blood, tissue collection will inform future studies in refining patient selection for IMPT.

Adaptation to high rates of chromosomal instability and aneuploidy through multiple pathways in budding yeast.

Both an increased frequency of chromosome missegregation (chromosomal instability, CIN) and the presence of an abnormal complement of chromosomes (aneuploidy) are hallmarks of cancer. To better understand how cells are able to adapt to high levels of chromosomal instability, we previously examined yeast cells that were deleted of the gene BIR1, a member of the chromosomal passenger complex (CPC). We found bir1Δ cells quickly adapted by acquiring specific combinations of beneficial aneuploidies. In this study, we monitored these yeast strains for longer periods of time to determine how cells adapt to high levels of both CIN and aneuploidy in the long term. We identify suppressor mutations that mitigate the chromosome missegregation phenotype. The mutated proteins fall into four main categories: outer kinetochore subunits, the SCFCdc4 ubiquitin ligase complex, the mitotic kinase Mps1, and the CPC itself. The identified suppressor mutations functioned by reducing chromosomal instability rather than alleviating the negative effects of aneuploidy. Following the accumulation of suppressor point mutations, the number of beneficial aneuploidies decreased. These experiments demonstrate a time line of adaptation to high rates of CIN.

HOXA9 has the hallmarks of a biological switch with implications in blood cancers.

Blood malignancies arise from the dysregulation of haematopoiesis. The type of blood cell and the specific order of oncogenic events initiating abnormal growth ultimately determine the cancer subtype and subsequent clinical outcome. HOXA9 plays an important role in acute myeloid leukaemia (AML) prognosis by promoting blood cell expansion and altering differentiation; however, the function of HOXA9 in other blood malignancies is still unclear. Here, we highlight the biological switch and prognosis marker properties of HOXA9 in AML and chronic myeloproliferative neoplasms (MPN). First, we establish the ability of HOXA9 to stratify AML patients with distinct cellular and clinical outcomes. Then, through the use of a computational network model of MPN, we show that the self-activation of HOXA9 and its relationship to JAK2 and TET2 can explain the branching progression of JAK2/TET2 mutant MPN patients towards divergent clinical characteristics. Finally, we predict a connection between the RUNX1 and MYB genes and a suppressive role for the NOTCH pathway in MPN diseases.

Using a Smartphone 3-Dimensional Surface Imaging Technique to Manufacture Custom 3-Dimensional-Printed Eyeglasses.

Importance: Finding a suitable fit in glasses for pediatric patients with congenital and acquired craniofacial abnormalities is difficult; consequently, these children are at high risk of vision loss secondary to refractive amblyopia as they often have poor adherence to daily glasses wearing. Custom 3-dimensional (3D)-printed glasses may have an improved design and fit, but access is limited by the availability of computed tomography and magnetic resonance imaging (MRI). Objective: To describe a method for using a commercially available smartphone 3D surface imaging (3DSI) technique to capture facial anatomy as a basis for custom glasses design. Design, Setting, and Participants: This quality improvement study analyzes data from a case series in a primary academic center with multiple referral centers throughout the United States. The evaluation included reported fit descriptions from patients with poor glasses adherence due to craniofacial abnormalities. Main Outcomes and Measures: Key anatomic parameters for glasses fit (face width, distance from ear bridge to nasal bridge, distance from center of pupil to center of nasal bridge, distance from lateral to medial canthus, ear vertical offset, and nasal bridge width) were compared between scans. A 3DSI scan was considered successful if these key parameters could be determined and the difference in measurements was less than 5% between MRI and 3DSI. A second outcome measure included the fit of glasses designed by the 3DSI method as reported by the patient, parent, or guardian. Results: Measurements of key parameters for glasses fit were similar across MRI and 3DSI scans with a mean (SD) difference of 1.47 (0.79) mm between parameters (range, 0.3-4.60 mm). Among 20 patients aged 1 to 17 years with craniofacial abnormalities, all achieved a successful fit (reporting daily glasses adherence without irritation) as judged by the patient, parent, or guardian. A mean of 1.7 revisions were made from initial prototype to final frame production using 3DSI technology. Conclusions and Relevance: This study demonstrated that smartphone-enabled 3DSI coupled with widely available 3D printing technology can produce custom frames with a successful fit for patients with craniofacial anomalies. This accessible and well-tolerated imaging process may have implications for adherence with glasses wearing among patients at risk of vision loss due to amblyopia.

Treatment planning comparison in the PROTECT-trial randomising proton versus photon beam therapy in oesophageal cancer: Results from eight European centres.

PURPOSE: To compare dose distributions and robustness in treatment plans from eight European centres in preparation for the European randomized phase-III PROTECT-trial investigating the effect of proton therapy (PT) versus photon therapy (XT) for oesophageal cancer. MATERIALS AND METHODS: All centres optimized one PT and one XT nominal plan using delineated 4DCT scans for four patients receiving 50.4 Gy (RBE) in 28 fractions. Target volume receiving 95% of prescribed dose (V95%iCTVtotal) should be >99%. Robustness towards setup, range, and respiration was evaluated. The plans were recalculated on a surveillance 4DCT (sCT) acquired at fraction ten and robustness evaluation was performed to evaluate the effect of respiration and inter-fractional anatomical changes. RESULTS: All PT and XT plans complied with V95%iCTVtotal >99% for the nominal plan and V95%iCTVtotal >97% for all respiratory and robustness scenarios. Lung and heart dose varied considerably between centres for both modalities. The difference in mean lung dose and mean heart dose between each pair of XT and PT plans was in median [range] 4.8 Gy [1.1;7.6] and 8.4 Gy [1.9;24.5], respectively. Patients B and C showed large inter-fractional anatomical changes on sCT. For patient B, the minimum V95%iCTVtotal in the worst-case robustness scenario was 45% and 94% for XT and PT, respectively. For patient C, the minimum V95%iCTVtotal was 57% and 72% for XT and PT, respectively. Patient A and D showed minor inter-fractional changes and the minimum V95%iCTVtotal was >85%. CONCLUSION: Large variability in dose to the lungs and heart was observed for both modalities. Inter-fractional anatomical changes led to larger target dose deterioration for XT than PT plans.

Narrating the South Pacific in and Beyond Great Power Politics.

Once considered a bunch of "small islands in a far sea" by outside powers, the South Pacific now looms increasingly large on the global geopolitical landscape, attracting the strategic attention of an array of great powers. This has prompted many scholars and commentators to focus on the rise of great power rivalry in the region. Yet, with few exceptions, the existing literature has paid little attention to how the regional dynamics are framed by the dominant narrative of great power politics in the first place and how as a result it has failed to adequately consider alternative voices, concerns and narratives from within the region. This Special Issue aims to tentatively address this neglect by questioning the unreflective narration of regional power dynamics as mere "great power politics" and by highlighting the competing narratives about this region and their policy implications for conducting relations between the South Pacific and "outside powers". In doing so, it seeks to provide a new critical and self-reflective angle for the debate on the South Pacific. This article first examines the extent to which "great power politics" reflects the reality of the power dynamics in the South Pacific. It then explains why it is important to focus on the theme of narratives and to understand their socially constitutive role in producing knowledge and shaping reality. The third section briefly introduces the five articles in this Issue and outlines their contributions.

Mastering humanitarianism? A survey of postgraduate humanitarian courses.

Humanitarian events are increasing globally, both in number and intensity. In response, the international community spends approximately US$30 billion annually to alleviate both the immediate consequences of these climatic, geographic, and human-induced events but also to support mitigation and recovery. Over the past two decades, the humanitarian sector has increasingly professionalised. One under-studied aspect of this professionalisation is an increase in postgraduate studies in humanitarian action over the last 20 years. Despite this increase, there is no agreement on core curriculum or pedagogy across humanitarian studies courses. How do current Masters of Humanitarian Assistance (MHA) offerings converge and differ, and how can such courses further their contribution to the humanitarian endeavour? This paper surveys 26 anglophone courses offered in the United States, Europe, the United Kingdom, Australia, India, and Nigeria, exploring key characteristics of course entry requirements, flexibility, research, practical components, and academic foci. It does not recommend what a core curriculum for humanitarian courses should be, but does argue that core curriculum for humanitarian courses should be identified by relevant and diverse stakeholders such as affected communities, humanitarian agencies, disaster management bodies, and governments, to ensure that courses in this field provide appropriate learning outcomes. The paper suggests how such a 'charter' may be developed.

Executable network of SARS-CoV-2-host interaction predicts drug combination treatments.

The COVID-19 pandemic has pushed healthcare systems globally to a breaking point. The urgent need for effective and affordable COVID-19 treatments calls for repurposing combinations of approved drugs. The challenge is to identify which combinations are likely to be most effective and at what stages of the disease. Here, we present the first disease-stage executable signalling network model of SARS-CoV-2-host interactions used to predict effective repurposed drug combinations for treating early- and late stage severe disease. Using our executable model, we performed in silico screening of 9870 pairs of 140 potential targets and have identified nine new drug combinations. Camostat and Apilimod were predicted to be the most promising combination in effectively supressing viral replication in the early stages of severe disease and were validated experimentally in human Caco-2 cells. Our study further demonstrates the power of executable mechanistic modelling to enable rapid pre-clinical evaluation of combination therapies tailored to disease progression. It also presents a novel resource and expandable model system that can respond to further needs in the pandemic.

Estimating the percentage of patients who might benefit from proton beam therapy instead of X-ray radiotherapy.

OBJECTIVES: High-energy Proton Beam Therapy (PBT) commenced in England in 2018 and NHS England commissions PBT for 1.5% of patients receiving radical radiotherapy. We sought expert opinion on the level of provision. METHODS: Invitations were sent to 41 colleagues working in PBT, most at one UK centre, to contribute by completing a spreadsheet. 39 responded: 23 (59%) completed the spreadsheet; 16 (41%) declined, arguing that clinical outcome data are lacking, but joined six additional site-specialist oncologists for two consensus meetings. The spreadsheet was pre-populated with incidence data from Cancer Research UK and radiotherapy use data from the National Cancer Registration and Analysis Service. 'Mechanisms of Benefit' of reduced growth impairment, reduced toxicity, dose escalation and reduced second cancer risk were examined. RESULTS: The most reliable figure for percentage of radical radiotherapy patients likely to benefit from PBT was that agreed by 95% of the 23 respondents at 4.3%, slightly larger than current provision. The median was 15% (range 4-92%) and consensus median 13%. The biggest estimated potential benefit was from reducing toxicity, median benefit to 15% (range 4-92%), followed by dose escalation median 3% (range 0 to 47%); consensus values were 12 and 3%. Reduced growth impairment and reduced second cancer risk were calculated to benefit 0.5% and 0.1%. CONCLUSIONS: The most secure estimate of percentage benefit was 4.3% but insufficient clinical outcome data exist for confident estimates. The study supports the NHS approach of using the evidence base and developing it through randomised trials, non-randomised studies and outcomes tracking. ADVANCES IN KNOWLEDGE: Less is known about the percentage of patients who may benefit from PBT than is generally acknowledged. Expert opinion varies widely. Insufficient clinical outcome data exist to provide robust estimates. Considerable further work is needed to address this, including international collaboration; much is already underway but will take time to provide mature data.

DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition.

The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling and drug screening in newly established patient-derived models in vitro and in vivo. We identified in vitro sensitivity to MEK inhibitors in DIPGs harboring MAPK pathway alterations, but treatment of patient-derived xenograft models and a patient at relapse failed to elicit a significant response. We generated trametinib-resistant clones in a BRAFG469V model through continuous drug exposure and identified acquired mutations in MEK1/2 with sustained pathway upregulation. These cells showed hallmarks of mesenchymal transition and expression signatures overlapping with inherently trametinib-insensitive patient-derived cells, predicting sensitivity to dasatinib. Combined trametinib and dasatinib showed highly synergistic effects in vitro and on ex vivo brain slices. We highlight the MAPK pathway as a therapeutic target in DIPG and show the importance of parallel resistance modeling and combinatorial treatments for meaningful clinical translation. SIGNIFICANCE: We report alterations in the MAPK pathway in DIPGs to confer initial sensitivity to targeted MEK inhibition. We further identify for the first time the mechanism of resistance to single-agent targeted therapy in these tumors and suggest a novel combinatorial treatment strategy to overcome it in the clinic. This article is highlighted in the In This Issue feature, p. 587.

FGF7-FGFR2 autocrine signaling increases growth and chemoresistance of fusion-positive rhabdomyosarcomas.

Rhabdomyosarcomas are aggressive pediatric soft-tissue sarcomas and include high-risk PAX3-FOXO1 fusion-gene-positive cases. Fibroblast growth factor receptor 4 (FGFR4) is known to contribute to rhabdomyosarcoma progression; here, we sought to investigate the involvement and potential for therapeutic targeting of other FGFRs in this disease. Cell-based screening of FGFR inhibitors with potential for clinical repurposing (NVP-BGJ398, nintedanib, dovitinib, and ponatinib) revealed greater sensitivity of fusion-gene-positive versus fusion-gene-negative rhabdomyosarcoma cell lines and was shown to be correlated with high expression of FGFR2 and its specific ligand, FGF7. Furthermore, patient samples exhibit higher mRNA levels of FGFR2 and FGF7 in fusion-gene-positive versus fusion-gene-negative rhabdomyosarcomas. Sustained intracellular mitogen-activated protein kinase (MAPK) activity and FGF7 secretion into culture media during serum starvation of PAX3-FOXO1 rhabdomyosarcoma cells together with decreased cell viability after genetic silencing of FGFR2 or FGF7 was in keeping with a novel FGF7-FGFR2 autocrine loop. FGFR inhibition with NVP-BGJ398 reduced viability and was synergistic with SN38, the active metabolite of irinotecan. In vivo, NVP-BGJ398 abrogated xenograft growth and warrants further investigation in combination with irinotecan as a therapeutic strategy for fusion-gene-positive rhabdomyosarcomas.

HER3 Is an Actionable Target in Advanced Prostate Cancer.

It has been recognized for decades that ERBB signaling is important in prostate cancer, but targeting ERBB receptors as a therapeutic strategy for prostate cancer has been ineffective clinically. However, we show here that membranous HER3 protein is commonly highly expressed in lethal prostate cancer, associating with reduced time to castration resistance (CR) and survival. Multiplex immunofluorescence indicated that the HER3 ligand NRG1 is detectable primarily in tumor-infiltrating myelomonocytic cells in human prostate cancer; this observation was confirmed using single-cell RNA sequencing of human prostate cancer biopsies and murine transgenic prostate cancer models. In castration-resistant prostate cancer (CRPC) patient-derived xenograft organoids with high HER3 expression as well as mouse prostate cancer organoids, recombinant NRG1 enhanced proliferation and survival. Supernatant from murine bone marrow-derived macrophages and myeloid-derived suppressor cells promoted murine prostate cancer organoid growth in vitro, which could be reversed by a neutralizing anti-NRG1 antibody and ERBB inhibition. Targeting HER3, especially with the HER3-directed antibody-drug conjugate U3-1402, exhibited antitumor activity against HER3-expressing prostate cancer. Overall, these data indicate that HER3 is commonly overexpressed in lethal prostate cancer and can be activated by NRG1 secreted by myelomonocytic cells in the tumor microenvironment, supporting HER3-targeted therapeutic strategies for treating HER3-expressing advanced CRPC. SIGNIFICANCE: HER3 is an actionable target in prostate cancer, especially with anti-HER3 immunoconjugates, and targeting HER3 warrants clinical evaluation in prospective trials.

Droplet digital PCR-based detection of circulating tumor DNA from pediatric high grade and diffuse midline glioma patients.

BACKGROUND: The use of liquid biopsy is of potential high importance for children with high grade (HGG) and diffuse midline gliomas (DMG), particularly where surgical procedures are limited, and invasive biopsy sampling not without risk. To date, however, the evidence that detection of cell-free DNA (cfDNA) or circulating tumor DNA (ctDNA) could provide useful information for these patients has been limited, or contradictory. METHODS: We optimized droplet digital PCR (ddPCR) assays for the detection of common somatic mutations observed in pediatric HGG/DMG, and applied them to liquid biopsies from plasma, serum, cerebrospinal fluid (CSF), and cystic fluid collected from 32 patients. RESULTS: Although detectable in all biomaterial types, ctDNA presented at significantly higher levels in CSF compared to plasma and/or serum. When applied to a cohort of 127 plasma specimens from 41 patients collected from 2011 to 2018 as part of a randomized clinical trial in pediatric non-brainstem HGG/DMG, ctDNA profiling by ddPCR was of limited use due to the small volumes (mean = 0.49 mL) available. In anecdotal cases where sufficient material was available, cfDNA concentration correlated with disease progression in two examples each of poor response in H3F3A_K27M-mutant DMG, and longer survival times in hemispheric BRAF_V600E-mutant cases. CONCLUSION: Tumor-specific DNA alterations are more readily detected in CSF than plasma. Although we demonstrate the potential of the approach to assessing tumor burden, our results highlight the necessity for adequate sample collection and approach to improve detection if plasma samples are to be used.