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Anastomotic stricture is the most common complication after esophageal atresia (EA) repair. We sought to determine if postoperative acid suppression is associated with reduced stricture formation.A prospective, multi-institutional cohort study of infants undergoing primary EA repair from 2016 to 2020 was performed. Landmark analysis and multivariate Cox regression were used to explore if initial duration of acid suppression was associated with stricture formation at hospital discharge (DC), 3-, 6-, and 9-months postoperatively.Of 156 patients, 79 (51%) developed strictures and 60 (76%) strictures occurred within three months following repair. Acid suppression was used in 141 patients (90%). Landmark analysis showed acid suppression was not associated with reduction in initial stricture formation at DC, 3-, 6- and 9-months, respectively (p = 0.19-0.95). Multivariate regression demonstrated use of a transanastomotic tube was significantly associated with stricture formation at DC (Hazard Ratio (HR) = 2.21 (95% CI 1.24-3.95, p0.01) and 3-months (HR 5.31, 95% CI 1.65-17.16, p0.01). There was no association between acid suppression duration and stricture formation.No association between the duration of postoperative acid suppression and anastomotic stricture was observed. Transanastomotic tube use increased the risk of anastomotic strictures at hospital discharge and 3 months after repair.

ddPCR analysis of drug-resistance mutations shows they are pre-existing in cancer cell lines and quickly introduced into a population of HCT116 cells.

Tables of biochemical and viability assays of resistant cell clones, fractional abundance of MPS1 mutants in different human cancer cell lines and refinement statistics of crystal structures of different MPS1 domains.

Expression of the p.M600T, p.Y568C and p.C604W MPS1 mutant constructs in DLD1 Flp-In TRex cells recues the spindle assembly checkpoint defect following AZ3146 treatment.

CCT251455 kills cancer cells by inhibiting the kinetochore recruitment of SAC protein.

Description of the supplementary experimental procedures figure legends and references

Crystal structures of AZD3146 and ONCOII bound to MPS1-KD.

Expression of the p.S611G, p.I531M and Dbl MPS1 mutant constructs in DLD1 Flp-In TRex cells recues the spindle assembly checkpoint defect following AZ3146 treatment.

CCT251455-resistant HCT116 clones.

Given the prevalence of Autism Spectrum Disorder (ASD) and the demand for treatment, there is a continuous seeking and uncertainty of effective interventions for people with ASD. As technology continues to advance,the application of Virtual Reality is emerging in clinical settings. This systematic review summarised findings to evaluate the application of virtual reality (VR) on the skill-specific performance in people with ASD. The purpose is to determine (1) if VR is an effective treatment for people with ASD in skill-specific performance and (2) can Occupational Therapists employ VR in their practice. Eight databases were systematically searched for peer-reviewed articles that were published from January 2012 to February 2018. Eight articles met the inclusion criteria. The measurements of specific skills were categorised into three main domains: job interviewing, driving, and other ADLs. A diverse range of outcome measures were utilised and provided various results.Despite the consistent positive results reported in the studies, the current evidence base lacks justification of sample sizes, reliability and validity of the findings. Although VR shows potential as an effective intervention, limitations and bias of studies should be considered.Results of studies must be interpreted with caution if Occupational Therapists are interested in employing VR in their practice. Refereed/Peer-reviewed

Internal tandem duplication of FLT3 (FLT3-ITD) is one of the most common somatic mutations in acute myeloid leukemia (AML); it causes constitutive activation of FLT3 kinase and is associated with high relapse rates and poor survival. Small-molecule inhibition of FLT3 represents an attractive therapeutic strategy for this subtype of AML, although resistance from secondary FLT3 tyrosine kinase domain (FLT3-TKD) mutations is an emerging clinical problem. CCT241736 is an orally bioavailable, selective, and potent dual inhibitor of FLT3 and Aurora kinases. FLT3-ITD+ cells with secondary FLT3-TKD mutations have high in vitro relative resistance to the FLT3 inhibitors quizartinib and sorafenib, but not to CCT241736. The mechanism of action of CCT241736 results in significant in vivo efficacy, with inhibition of tumor growth observed in efficacy studies in FLT3-ITD and FLT3-ITD-TKD human tumor xenograft models. The efficacy of CCT241736 was also confirmed in primary samples from AML patients, including those with quizartinib-resistant disease, which induces apoptosis through inhibition of both FLT3 and Aurora kinases. The unique combination of CCT241736 properties based on robust potency, dual selectivity, and significant in vivo activity indicate that CCT241736 is a bona fide clinical drug candidate for FLT3-ITD and TKD AML patients with resistance to current drugs.

Background: Although the technology has been available and several pilot studies have shown success, use of telemedicine has previously been limited in the United States, especially among surgeons. This study aimed to investigate the benefits and obstacles for successful implementation of telemedicine visits in paediatric surgical subspecialties amid the COVID-19 pandemic. Methods: We analysed survey data from telemedicine visits with paediatric surgical subspecialists from May 1 through June 30, 2020 at our paediatric surgery subspecialty clinics. Univariate logistic regression was used to determine associations in survey responses and various demographic factors. Results: There were 164 respondents to the survey. The most frequently cited barrier to care was ability to get time off work (46.3%). Overall satisfaction with the telemedicine visit was 93.8%, and 55.6% responded that they would choose video telemedicine rather than an in-person or telephone visit. Those living at least 25 miles from the hospital had increased odds of indicating interest in using telemedicine for future visits (OR = 2.56, 95% CI = 1.12–5.86, p = 0.026). The average respondent saved between 30 minutes and 1 hour, and 45 minutes using telemedicine. Conclusions: The implementation of telemedicine at our institution in the paediatric surgical subspecialties has proven to be effective and well-received. Given the benefits of time and money saved for families, paired with high satisfaction rates and continued interest, paediatric surgical subspecialists should work to incorporate virtual visits into regular patient care, even well after the COVID-19 pandemic. Level of Evidence: Level IV

Monopolar spindle 1 (MPS1) occupies a central role in mitosis and is one of the main components of the spindle assembly checkpoint. The MPS1 kinase is an attractive cancer target, and herein, we report the discovery of the clinical candidate BOS172722. The starting point for our work was a series of pyrido[3,4-d]pyrimidine inhibitors that demonstrated excellent potency and kinase selectivity but suffered from rapid turnover in human liver microsomes (HLM). Optimizing HLM stability proved challenging since it was not possible to identify a consistent site of metabolism and lowering lipophilicity proved unsuccessful. Key to overcoming this problem was the finding that introduction of a methyl group at the 6-position of the pyrido[3,4-d]pyrimidine core significantly improved HLM stability. Met ID studies suggested that the methyl group suppressed metabolism at the distant aniline portion of the molecule, likely by blocking the preferred pharmacophore through which P450 recognized the compound. This work ulti...

Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which translates into biomarker modulation in an in vivo human tumor xenograft model.

Acquired resistance to therapy is perhaps the greatest challenge to effective clinical management of cancer. With several inhibitors of the mitotic checkpoint kinase MPS1 in preclinical development, we sought to investigate how resistance against these inhibitors may arise so that mitigation or bypass strategies could be addressed as early as possible. Toward this end, we modeled acquired resistance to the MPS1 inhibitors AZ3146, NMS-P715, and CCT251455, identifying five point mutations in the kinase domain of MPS1 that confer resistance against multiple inhibitors. Structural studies showed how the MPS1 mutants conferred resistance by causing steric hindrance to inhibitor binding. Notably, we show that these mutations occur in nontreated cancer cell lines and primary tumor specimens, and that they also preexist in normal lymphoblast and breast tissues. In a parallel piece of work, we also show that the EGFR p.T790M mutation, the most common mutation conferring resistance to the EGFR inhibitor gefitinib, also preexists in cancer cells and normal tissue. Our results therefore suggest that mutations conferring resistance to targeted therapy occur naturally in normal and malignant cells and these mutations do not arise as a result of the increased mutagenic plasticity of cancer cells. Cancer Res; 75(16); 3340–54. ©2015 AACR.

The mitotic kinase MPS1 (also known as TTK) is one of the main components of the spindle assembly checkpoint. MPS1 is required for chromosome alignment and kinetochore-microtubule error correction. Cancer cells are dependent on MPS1 to cope with chromosomal instability resulting from aberrant numbers of chromosomes. Moreover, MPS1 has been found to be deregulated in a large number of tumor types. MPS1 kinase inhibitors induce cancer cells to prematurely exit mitosis with incorrectly attached and unaligned chromosomes, causing severe chromosome mis-segregation, aneuploidy and cell death. These data stimulated us to pursue MPS1 as a cancer target. Extensive work by us and other groups has shown that MPS1 inhibitors are effective against a variety of cancers, particularly when used in combination with other drugs, such as paclitaxel. Here we disclose CCT289346, an MPS1 inhibitor currently completing late stage preclinical development. We describe the final stages of chemical optimisation and the data driven selection and nomination of CCT289346 as our preclinical candidate. We report key in vitro and in vivo preclinical data such as kinase profiling, PK in mouse, rat and dog, PK/PD relationship and efficacy in different in vivo models. Citation Format: Hannah Woodward, Paolo Innocenti, Kwai-Ming J. Cheung, Sébastien Naud, Amir Faisal, Grace W. Mak, Angela Hayes, Lisa O'Fee, Harry Saville, Alexis De Haven Brandon, Jennie Roberts, Gary Box, Melanie Valenti, Alan T. Heneley, Katie Walsh, Rosemary Burke, Suzanne A. Eccles, Florence I. Raynaud, Rob L. van Montfort, Julian Blagg, Spiros Linardopoulos, Swen Hoelder. In vitro and in vivo profile of the preclinical candidate and MPS1 kinase inhibitor CCT289346 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1651.

MPS1 (also known as TTK), is a dual-specificity protein kinase and one of the main components of the spindle assembly checkpoint. Cancer cells heavily rely on MPS1 to cope with aneuploidy resulting from aberrant numbers of chromosomes and MPS1 has been found to be upregulated in a large number of tumor types. Extensive work by us and other groups has shown that MPS1 inhibitors are effective against a variety of cancers, particularly when used in combination with other drugs, for example, tubulin-targeting agents. We recently reported the structure-based design and discovery of a series of pyrido[3,4-d]pyrimidines inhibitors of MPS1 (1). Advanced compounds showed very potent inhibition of MPS1 in biochemical and cellular assays. However, these compounds suffered from high lipophilicity and pronounced metabolism in human liver microsomes preventing progression into preclinical development. Here we report the optimisation of this series ultimately yielding CCT289346, our preclinical candidate. CCT289346 shows excellent potency, kinase selectivity, and ADME properties including stability in human liver microsomes. The compound has been produced on a kilogram scale and is currently undergoing preclinical development. We will discuss our design approach and hypotheses leading to the discovery of CCT289346 and disclose in vivo efficacy data. References 1. Innocenti P et al. Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach. Journal of Medicinal Chemistry. 2016; 59(8):3671-88. Citation Format: Hannah L. Woodward, Paolo Innocenti, Kwai-Ming J. Cheung, Sébastien Naud, Angela Hayes, Alan T. Henley, Amir Faisal, Grace Mak, Gary Box, Isaac M. Westwood, Michael Carter, Melanie Valenti, Alexis De Haven Brandon, Lisa O’Fee, Harry Saville, Rosemary Burke, Rob van Montfort, Florence Raynaud, Suzanne A. Eccles, Spiros Linardopoulos, Julian Blagg, Swen Hoelder. Inhibitors of MPS1: Discovery of CCT289346, a highly potent, selective and orally available preclinical candidate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 193. doi:10.1158/1538-7445.AM2017-193

The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly overexpressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition.

Acquired resistance is the greatest challenge to the effectiveness of targeted anti-cancer therapies in the clinic. With several MPS1 inhibitors under pre-clinical development, we aimed to investigate how cancer cells will develop resistance against these inhibitors; therefore we modeled acquired resistance using a range of MPS1 inhibitors. We identified and characterized five point mutations in the kinase domain of MPS1 that confer resistance against multiple inhibitors. Structural studies showed that several MPS1 mutants conferred resistance by causing steric hindrance to inhibitor binding. One mutation in particular, p.C604W, which is close to the gatekeeper residue, rendered MPS1 resistant to all the inhibitors we tested. However, we were able to design new compounds to specifically overcome this mutation, which in fact targeted the mutant with more potency than the wild-type MPS1 protein. Importantly, we show that these mutations are present in untreated cancer cell lines and primary tumour samples, and also pre-exist in normal lymphoblast and breast tissues. Furthermore, to confirm this is not specific to MPS1, we show that the EGFR p.T790M mutation is also pre-existing in cancer cell lines and normal tissue. Our data therefore suggest that mutations conferring resistance to targeted therapy are naturally occurring mutations in normal and cancer cells that are not introduced due to cancer cells being more mutagenic. Citation Format: Mark D. Gurden, Isaac Westwood, Amir Faisal, Sébastien Naud, Jack Cheung, Craig McAndrew, Amy Wood, Jessica Schmitt, Kathy Boxall, Grace Mak, Paul Workman, Rosemary Burke, Swen Hoelder, Julian Blagg, Rob Van Montfort, Spiros Linardopoulos. Naturally occurring mutations in the MPS1 gene predispose cells to kinase inhibitor drug-resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5450. doi:10.1158/1538-7445.AM2015-5450

H education in Hong Kong has undergone two major phases of change in recent years. The first started in the midto late 1980s, spurred on by the drive for efficiency and the expansion of a previously elitist system; the second was marked by the return of Hong Kong’s sovereignty to China in 1997. This article describes higher education in Hong Kong two years on. The current situation is a convergence of internal systemic development, the China factor, and the recent economic downturn.

The main role of the cell cycle is to enable error-free DNA replication, chromosome segregation and cytokinesis. Surveillance mechanisms, the so-called checkpoint pathways, monitor passage through mitosis at several stages. One of the best characterised is the spindle assembly checkpoint that prevents anaphase onset until the appropriate tension and attachment across kinetochores is achieved. One of the first components of the spindle assembly checkpoint signal, identified by a genetic screen in budding yeast, was MPS1 (monopolar spindle 1; also known as TTK). MPS1 gene was shown to encode an essential dual-specificity kinase conserved from yeast to humans. MPS1 activity peaks at the G2/M transition and is enhanced upon activation of the spindle assembly checkpoint with nocodazole. We and others, have identified the autophosphorylation of T676 in the activation loop of MPS1 and shown that this is essential for MPS1 function. MPS1 has been found aberrantly overexpressed in a wide range of human tumours including breast, lung, oesophagus, and prostate. MPS1 is required for the establishment and maintenance of the spindle assembly checkpoint during mitosis. Aneuploid tumour cells possess a compromised spindle checkpoint to allow onset of anaphase and cell division. We have shown that depletion of MPS1 by siRNA induces cell death selectively in PTEN-deficient breast cancer cell lines. We have developed biochemical and cellular assays for MPS1 activity and a high throughput screening of our compound library delivered multiple hit series. We have previously reported the discovery of CCT251455 as a selective and orally bioavailable MPS1 inhibitor that inhibits the growth of a panel of human tumour cell lines, abrogates nocodazole-induced mitotic arrest and reduces the time spent in mitosis. Medicinal chemistry in combination with X-ray crystallography led to the discovery of CCT271850, a novel inhibitor of MPS1 kinase activity. CCT271850 selectively inhibits MPS1 kinase activity with an IC50 of 0.004 μM, inhibits autophosphorylation of MPS1 in cells with an IC50 of 0.07 μM and reduces the growth of a panel of human tumour cell lines, particularly PTEN-deficient cell lines. Tumour cells treated with CCT271850 contain aberrant numbers of chromosomes and the majority of cells divide their chromosomes without proper alignment. CCT271850 is orally bioavailable (F = 68%) and shows modulation of biomarkers in vivo. Citation Format: Amir Faisal, Paolo Innocenti, Isaac Westwood, Sebastan Naud, Jessica Schmitt, Angela Hayes, Grace Mak, Mark Gurden, Vassilios Bavetsias, Jack Cheung, Hannah Woodward, Peter Sheldrake, Butrus Atrash, Rosemary Burke, Ross Baker, Craig McAndrew, Martin Rowlands, Melanie Valenti, Paul Workman, Suzanne Eccles, Florence Raynaud, Rob vanMontfort, Swen Hoelder, Julian Blagg, Spiros Linardopoulos. CCT271850, a novel, selective, highly potent and orally bioavailable Mps1 kinase inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3242. doi:10.1158/1538-7445.AM2013-3242

Monopolar spindle 1 (Mps1, also known as TTK) is a dual-specificity, cell cycle-regulated kinase required for the establishment and maintenance of the spindle assembly checkpoint during mitosis. Aneuploid tumour cells possess a weak spindle checkpoint to allow onset of anaphase and cell division. Our hypothesis is that a complete inhibition of an already weakened mitotic checkpoint of cancer cells will cause gross chromosomal abnormalities leading to aneuploid cell death. We have shown that depletion of Mps1 by siRNA induces cell death selectively in aneuploid and PTEN-deficient cancer cell lines. We have demonstrated that Mps1 depletion inhibits MAD2 localisation to the kinetochores. We have developed biochemical and cellular assays for Mps1 activity and a high throughput screening of our Institute's compound library delivered multiple hit series. Medicinal chemistry in combination with X-ray crystallography led to the development of CCT251455, a small molecule inhibitor of Mps1 kinase activity. CCT251455 selectively inhibits Mps1 kinase with an IC50 of 0.003 μM, inhibits growth of a panel of human tumour cell lines with GI50 between 0.06 - 1 μM and is particularly potent in PTEN-deficient cell lines. Cells treated with CCT251455 abrogate nocodazole-induced mitotic arrest and reduce the time spent in mitosis. Mps1-inhibited cells contain aberrant numbers of chromosomes and the majority of cells divide their chromosomes without proper alignment. CCT251455 is orally bioavailable (F = 82%) and shows modulation of biomarkers in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1817. doi:1538-7445.AM2012-1817