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General control nonderepressible 2 (GCN2) protein kinase is a cellular stress sensor within the tumor microenvironment (TME), whose signaling cascade has been proposed to contribute to immune escape in tumors. Herein, we report the discovery of cell-potent GCN2 inhibitors with excellent selectivity against its closely related Integrated Stress Response (ISR) family members heme-regulated inhibitor kinase (HRI), protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase (PERK), as well as good kinome-wide selectivity and favorable PK. In mice, compound

Purpose Cystine stones are widely considered hard and difficult to treat. Hounsfield Units (HU) are used in other stone types to estimate ‘hardness’ and treatments based on that finding. Our objective was to report mean HU of cystine stones in vivo in a large case series of cystinuria patients and assess for differences in genotype. Methods A prospective case series of cystinuria patients referred to a specialist centre was analysed. CT imaging was assessed by two independent radiologists to determine in vivo attenuation of cystine calculi. Mean HU was compared for both cystinuria genes (SLC3A1 and SLC7A9) using an independent t-test. Results 164 adult cystinuric patients were identified (55% male), median age 43 years (range 18–80). Median follow up was 31 months (IQR 10–62). Genetic data available for 153/164 (93%) demonstrated 97 SLC3A1 (63%) and 55 (36%) SLC7A9 mutations (39 homozygous, 16 heterozygous) and one heterozygous for both SLC3A1/SLC7A9. 107 patients had CT images available demonstrating calculi. Median HU across the cohort was 633 (5th to 95th centile 328–780). There was no difference in mean HU between SLC3A1 and SLC7A9 genotypes (p = 0.68) or homo and heterozygous SLC7A9 (p = 0.70). Mean HU correlated with stone size (Pearson correlation coefficient = 0.51, p Conclusion In this large single centre cystinuria cohort, mean HU was low for stones that are difficult to treat. Calculi of 1000 are unlikely pure cystine, and in a known cystinuric would suggest conversion to another stone type.

This is a case report of a 67-year-old patient with castration resistant metastatic prostate cancer who developed an immune-mediated large vessel vasculitis following treatment with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1).

The Coronavirus-19 (COVID-19) pandemic has been the greatest challenge faced by the National Health Service (NHS) in its lifetime. The crisis has seen the disruption of many long-held institutions, most critically of which is specialty training. In this article, we discuss the impact of the pandemic on Radiology training in the UK. We explore the methods that have been used to combat these difficulties and suggest workable solutions. As technology platforms become ever more integral to our daily clinical routines, we discuss how these offer a new approach to training. We argue that, of all the medical disciplines, radiologists are best placed to design and implement technology-based training, and lead other specialties in doing so. Whilst the upheaval of traditional approaches to education is a challenge, we propose that this departure from the norm offers exciting opportunities for improvement.

This is a case report of a 67-year-old patient with castration resistant metastatic prostate cancer who developed an immune-mediated large vessel vasculitis following treatment with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1).

KEY POINTS Alzheimer's disease (AD) patients and transgenic mice have beta-amyloid (Aβ) aggregation in the gastrointestinal (GI) tract. It is possible that Aβ from the periphery contributes to the load of Aβ in the brain, as Aβ has prion-like properties. The present investigations demonstrate that Aβ injected into the GI tract of ICR mice is internalised into enteric cholinergic neurons; at 1 month, administration of Aβ into the body of the stomach and the proximal colon was observed to partly redistribute to the fundus and jejunum; at 1 year, vagal and cerebral β-amyloidosis was present, and mice exhibited GI dysfunction and cognitive deficits. These data reveal a previously undiscovered mechanism that potentially contributes to the development of AD. ABSTRACT Alzheimer's disease (AD) is the most common age-related cause of dementia, characterised by extracellular beta-amyloid (Aβ) plaques and intracellular phosphorylated tau tangles in the brain. Aβ deposits have also been observed in the gastrointestinal (GI) tract of AD patients and transgenic mice, with overexpression of amyloid precursor protein. In the present studies, we investigate whether intra-GI administration of Aβ can potentially induce amyloidosis in the central nervous system (CNS) and AD-related pathology such as dementia. We micro-injected Aβ1-42 oligomers (4 μg per site, five sites) or vehicle (saline, 5 μl) into the gastric wall of ICR mice under general anaesthesia. Immunofluorescence staining and in vivo imaging showed that HiLyte Fluor 555-labelled Aβ1-42 had migrated within 3 h via the submucosa to nearby areas and was internalised into cholinergic neurons. At 1 month, HiLyte Fluor 555-labelled Aβ1-42 in the body of the stomach and proximal colon had partly re-distributed to the fundus and jejunum. At 1 year, the jejunum showed functional alterations in neuromuscular coupling (P

INTRODUCTION AND OBJECTIVE:Cystine stones are widely considered hard and difficult to treat. MicroCT studies in vitro have shown that the structure of cystine stones is associated with susceptibili...

A series of imidazo[1,2-a]pyridin-6-yl-benzamide analogs was designed as inhibitors of B-RAFV600E. Medicinal chemistry techniques were employed to explore the SAR for this series and improve selectivity versus P38 and VEGFR2.

Hematopoietic progenitor kinase 1 (HPK1) is an intracellular protein kinase that negatively regulates T cell signaling and proliferation. Upon T cell receptor (TCR) activation, active HPK1 phosphorylates the adaptor protein SLP76 in the TCR complex, recruiting the negative regulator 14-3-3 and targeting components of the TCR signaling complex for degradation. HPK1 thus limits the TCR signaling important for mounting an effective immune response against tumor cells. We are employing structure-guided drug design to develop potent small-molecule inhibitors of HPK1. Our compounds potently inhibit HPK1 in biochemical assays, reduce levels of phosphorylated SLP76 and concomitantly increase IL-2 production by Jurkat T cells. Importantly, our HPK1 inhibitors enhance cytokine production by human and mouse primary T cells above that observed with TCR activation alone. Treatment of mice with orally available HPK1 inhibitors results in increased activation of antigen-specific CD8+ T cells in vivo and decreased tumor growth as single agent and in combination with clinically relevant checkpoint inhibitor antibodies. Our work confirms the importance of HPK1 for T cell function and supports HPK1 as a promising next generation immuno-oncology target. Citation Format: George Katibah, Yamini Ohol, Cyril Bucher, Lavanya Adusumilli, Deepika Kaveri, Omar Robles, Michael Sun, Cynthia Cho, Heather Milestone, Rachel Ames, Scott Jacobson, Dan Nebalasca, Justy Gomez- Guagua, Jerick Sanchez, Molly Grandcolas, Steve Wong, Martin Brovarney, Chandru Ramana, Thant Zaw, Lan Nguyen, Parcharee Tivitmahaisoon, Andrew Ng, Anqi Ma, Blanca Gomez, Michelle Ko, Paul Leger, Jeffrey Jackson, Grant Shibuya, Anton Shakhmin, Delia Bradford, Mengshu Xu, Mikhail Zibinsky, Daniel Poon, David Wustrow, Paul Kassner, Dirk Brockstedt. Development of small-molecule HPK1 inhibitors to unleash tumor-specific T cell responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1646.

While other contributions in this volume delve into the fine-grained detail and diversity of development processes in Asian countries and sub-regions, this chapter analyses the opening-up experiences of China, India, and Malaysia by triangulating between: (i) the orientation of selected policy tools in trade, technology, investment, and finance in shaping a country’s degree of economic openness; (ii) the rational co-ordination of operational controls of these policy tools; and (iii) the overall development trends observed in the Asia region. The ‘rational co-ordination of operational controls’ is interpreted with reference to the strategic use of selected policy tools in the successful cases of earlier East Asian industrialization. The chapter contends that divergence in Asian growth can be understood by variations in pragmatic policy experimentation by national policymakers in search of more effective institutional mechanisms to achieve desired development outcomes.

This chapter provides an account of China’s institutional and policy learning efforts to move from a centrally planned to a development-state model of structural transformation. What distinguishes China’s experience—as in the case of other East Asian countries—in successfully building and upgrading local sectors and firms lies not so much with a unique set of policy tools, as a willingness to experiment with those tools and to attach performance criteria that helped guide the behavior of firms towards wider national development objectives. While many other developing countries under structural adjustment programmes quickly adopted export promotion, China was closely studying East Asian countries in its transition by strategically blending an export push with selective import substitution. In short, Chinese policymakers had direct experience on how powerful industrial policies could be misused, but this did not stop them from actively trying to find better ways of using them. Doing so was a matter of political economy.

Inspired by Gunnar Myrdal's core concepts discussed in his seminal work, Asian Drama: An Inquiry into the Poverty of Nations, published in 1968, this paper analyses the opening-up experiences of three Asian countries (China, India, and Malaysia) by triangulating between the following: (i) the orientation of selected policy tools in trade, technology, investment, and finance in shaping a country's degree of economic openness; (ii) the rational coordination of operational controls of these policy tools to achieve stated objectives; and (iii) the overall development trends observed in the Asia region. The 'rational coordination of operational controls' is interpreted with reference to the strategic use of selected policy tools in the historically successful cases of earlier East Asian industrialization. Under this framework, the paper contends that divergence in Asian growth experiences can be understood by variations in institutional capabilities to address market and firm-level (and government) failures in the catch-up process, and the pragmatic experimentation by policymakers in search of more effective institutional mechanism - carrots, sticks, and competitive pressures - in pursuit of desired development outcomes.

A series of structure based drug design hypotheses and focused screening efforts led to the identification of tetrahydropyrrolo-diazepenones with striking potency against ERK2 kinase. The role of fluorination in mitigating microsomal clearance was systematically explored. Ultimately, it was found that fluorination of a cyclopentanol substructure provided significant improvement in both potency and human metabolic stability.

With Canada's main trading partners under severe economic and political duress, the pre-crisis strategy of engaging globalization primarily intermediated by leading U.S. firms and production networks is ill suited for the next stage of globalization, in which emerging economies like China are playing a larger role. The materially different post-crisis global setting requires adaptation if Canada wishes to better harness and balance the gains from globalization. Such a strategy is not without risk and will not be accomplished in the short-term, but will ultimately prove to be a crucial factor in Canada's long-term prosperity, welfare and employment prospects in a less U.S.-centric world order.

A series of structure based drug design hypotheses and focused screening efforts drove improvements in the potency and lipophilic efficiency of tetrahydro-pyrazolopyridine based ERK2 inhibitors. Elaboration of a fragment chemical lead established a new lipophilic aryl-Tyr interaction resulting in a substantial potency improvement. Subsequent cleavage of the lipophilic moiety led to reconfiguration of the ligand bound binding cleft. The reconfiguration established a polar contact between a newly liberated N-H and a vicinal Asp, resulting in further improvements in lipophilic efficiency and in vitro clearance.

Abrogation of errant signaling along the MAPK pathway through the inhibition of B-RAF kinase is a validated approach for the treatment of pathway-dependent cancers. We report the development of imidazo-benzimidazoles as potent B-RAF inhibitors. Robust in vivo efficacy coupled with correlating pharmacokinetic/pharmacodynamic (PKPD) and PD-efficacy relationships led to the identification of RAF265, 1, which has advanced into clinical trials.

Utilizing structure-based drug design, a novel dihydropyridopyrimidinone series which exhibited potent Hsp90 inhibition, good pharmacokinetics upon oral administration, and an excellent pharmacokinetic/pharmacodynamic relationship in vivo was developed from a commercial hit. The exploration of this series led to the selection of NVP-HSP990 as a development candidate.

Benzimidazole reverse amides were designed and synthesized as Pan RAF kinase inhibitors. Investigation of the structure–activity relationship of the compounds revealed that they were potent in vitro and exhibited desirable in vivo properties.

A revival in South-South economic relations has raised the possibility of a shift in global power with profound implications for economic progress and poverty reduction in the developing world. This discussion paper delves behind the headline numbers to examine the underlying factors driving South- South relations and areas of strategic developmental cooperation. For now, South-South economic flows are being driven by China and its ability to deploy an unorthodox growth model that tilts the economy in favour of investment, which is crucial to its ambitious climb up the industrial value chain. Five key sectors (food, fertilizer, cement, steel and machinery) outlined by Arthur Lewis are used to assess China’s economic trajectory, which clearly remains a work in progress, but shows signs of indigenous technological capabilities taking root – particularly in medium technology capital goods industries. The gap between China’s industrial ambitions and its current capabilities provides a strategic opening for other developing countries to bargain for enhanced opportunities for domestic investment, learning, technical change and structural transformation. At the same time, China’s “real-time” formulation and practice of industrial policy processes are a source of inspiration for other developing countries searching for an alternative growth path. In a post-crisis setting, such demonstrations act as a useful template for re-thinking development priorities and to gradually begin re-casting economic policies within a national framework more conducive to catch-up and self-sustaining growth..

cated that MBTPS2 is mainly expressed in the upper granular layer in normal skin, as previously shown (Aten et al., 2010); however, in OS skin, MBTPS2 was expressed throughout the epidermis (Figure 2c). There was no apparent difference in MBTPS2 localization in the skin of a KFSD patient with the p.N508S mutation (Aten et al., 2010). It is unclear why this is but it may be because of differences in processing of the mutants in the two diseases. In summary, we demonstrate a novel association between an MBTPS2 mutation and an X-linked form of OS. This expands the number of disorders linked to MBTPS2 mutations and reveals clinical heterogeneity associated with different MBTPS2 mutations. Written, informed consent was obtained from all family members or their legal guardians. This study was approved by the South East NHS Research Ethics Committee and was performed according to the Declaration of Helsinki Principles.

Study objectives We determine whether homeless persons present to the emergency department (ED) for food, shelter, and safety and whether the availability of alternative sites for provision of these needs might decrease their ED presentations. Methods In July to August 2006 and February to March 2007, adult homeless and control (not homeless) patients, who self-presented (nonambulance) to an urban county ED, were interviewed with a structured instrument. Results One hundred ninety-one homeless and 63 control subjects were enrolled. Homeless persons spent a mean (standard deviation [SD]) of 3.5 (3.0) nights/week sleeping without shelter and ate a mean (SD) of 2.1 (1.1) meals per day; 51% stated they had been assaulted on the street. On an analog scale, in which 0=no problem and 10=worst possible problem in their daily lives, the mean (SD) homeless subject responses for hunger, lack of shelter, and safety were 4.8 (3.7), 6.1 (4.2), and 5.1 (4.0), respectively. More homeless (29% [55/189]) than not homeless (10% [6/63]) persons replied that hunger, safety concerns, and lack of shelter were reasons they came to the ED (Δ=20%; 95% confidence interval 10% to 29%). If offered a place that would provide food, shelter, and safety at all times, 24% of homeless subjects stated they would not have come to the ED. Conclusion Homeless persons commonly come to the ED for food, shelter, and safety. Provision of these subsistence needs at all times at another site may decrease their ED presentations.

The error is on page 990 in Table 1. Compound 11 should be 3-OCF3, and compound 16 should be 4-OCF3.

Genetic alterations in the Ras/Raf/MEK/ERK pathway are among the most common in human cancers. Up to 70% of melanomas harbor B-Raf mutations, and roughly 90% of pancreatic tumors have K-Ras mutations. To address these Raf pathway-driven cancers, small molecule Raf kinase inhibitors have been developed and are currently under clinical investigation. In B-RafV600E cells, Raf compounds inhibit signaling through MEK and ERK, resulting in the expected anti-proliferative effects. Paradoxically, in wild-type Raf cells and in mutant Ras cells, these compounds induce downstream signaling and can induce cell growth in some settings in vitro. While the induction of downstream signaling has previously been attributed to published Raf pathway feedback loops, this has not been proven directly. In fact, we show here that induction of pMEK and pERK can occur within minutes of Raf compound treatment, even before reported feedback phosphorylation events are seen on B-Raf and C-Raf. Interestingly, the induction of signaling and cell growth both occur in a biphasic pattern, with low compound concentrations (0.01-0.1 uM) causing maximal induction, and higher compound concentrations (1-10 uM) causing less profound induction. Such a biphasic pattern is also observed in biochemical assays with purified wild-type B-Raf or C-Raf. The biphasic pattern is suggestive of a mechanism involving the interaction of two signaling subunits. In addition, recent literature data (Rajakulendran, Nature, 461:542-6) has demonstrated that Raf dimerization can upregulate pMEK, not through trans-phosphorylation of Raf molecules but presumably by conformational activation of the kinase. Consistent with that model, we show that Raf compound treatment induces B/C-Raf dimer formation in cells. In addition, knockdown of A-, B- or C-Raf with siRNA does not abrogate the Raf compound induction of pMEK and pERK, suggesting that induction might be mediated by Raf homo- as well as hetero-dimerization. Notably, knockdown of K-Ras in K-RasMUT cells also does not abolish the induction, implying that this effect is not mediated by Ras. Taken together, these data suggest a model in which compound binding to one Raf molecule induces dimerization and conformational activation of a partner Raf molecule in the dimer. These observations can explain why wild-type Raf and mutant Ras tumors are insensitive to selective Raf kinase inhibitors and might also have important implications for toxicity, since induction of strong mitogenic signaling could lead to hyperproliferation of normal tissues. Understanding the Raf compound induction mechanism may lead not only to the design of improved inhibitors, but also to methods for overcoming the induction seen with current development compounds. Toward that end, we show that combining a MEK inhibitor with a Raf compound causes inhibition of both pERK and cell growth and may therefore have significant advantages in the clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 20.