Fast-track Development Research Articles

Industrial substitution symbiosis and technological innovation under carbon neutrality: Evidence from resource-based industries in China

This article analyzes the substitution symbiosis between China's resource-based and non-resource-based industries through the Lotka-Volterra model, according to the panel data of 33 industries from 2005 to 2020, use a fixed effect model (FEM) to learn more about how industrial substitution symbiosis affects technological innovation. The findings indicate that a key factor in encouraging technological innovation in China is the substitution symbiosis of its resource-based and non-resource-based industries. Furthermore, substitution symbiosis within both high-tech and traditional industries significantly boosts technological innovation. Specifically, high-tech industrial symbiosis plays a more influential role in enhancing technological innovation. From the standpoint of carbon neutrality, industrial substitution symbiosis exhibits a significant threshold effect on technological innovation, with its influence intensifying under carbon neutrality. The threshold effect varies across industries, the high-tech industries have a significant single threshold effect, while the traditional industries do not. Therefore, deepening the symbiosis between resource-based and non-resource-based industries, fast-tracking high-tech industry development, and advancing carbon neutrality vision are vital to boost their role in fostering technological innovation.

Harnessing 12-lead ECG and MRI data to personalise repolarisation profiles in cardiac digital twin models for enhanced virtual drug testing

Cardiac digital twins are computational tools capturing key functional and anatomical characteristics of patient hearts for investigating disease phenotypes and predicting responses to therapy. When paired with large-scale computational resources and large clinical datasets, digital twin technology can enable virtual clinical trials on virtual cohorts to fast-track therapy development. Here, we present an open-source automated pipeline for personalising ventricular electrophysiological function based on routinely acquired magnetic resonance imaging (MRI) data and the standard 12-lead electrocardiogram (ECG).Using MRI-based anatomical models, a sequential Monte-Carlo approximate Bayesian computational inference method is extended to infer electrical activation and repolarisation characteristics from the ECG. Fast simulations are conducted with a reaction-Eikonal model, including the Purkinje network and biophysically-detailed subcellular ionic current dynamics for repolarisation. For each patient, parameter uncertainty is represented by inferring an envelope of plausible ventricular models rather than a single one, which means that parameter uncertainty can be propagated to therapy evaluation. Furthermore, we have developed techniques for translating from reaction-Eikonal to monodomain simulations, which allows more realistic simulations of cardiac electrophysiology. The pipeline is demonstrated in three healthy subjects, where our inferred pseudo-diffusion reaction-Eikonal models reproduced the patient's ECG with a median Pearson's correlation coefficient of 0.9, and then translated to monodomain simulations with a median correlation coefficient of 0.84 across all subjects. We then demonstrate our digital twins for virtual evaluation of Dofetilide with uncertainty quantification. These evaluations using our cardiac digital twins reproduced dose-dependent QTc and T peak to T end prolongations that are in keeping with large population drug response data.The methodologies for cardiac digital twinning presented here are a step towards personalised virtual therapy testing and can be scaled to generate virtual populations for clinical trials to fast-track therapy evaluation. The tools developed for this paper are open-source, documented, and made publicly available.

Novel CDKL5 targets identified in human iPSC-derived neurons

CDKL5 Deficiency Disorder (CDD) is a debilitating epileptic encephalopathy disorder affecting young children with no effective treatments. CDD is caused by pathogenic variants in Cyclin-Dependent Kinase-Like 5 (CDKL5), a protein kinase that regulates key phosphorylation events in neurons. For therapeutic intervention, it is essential to understand molecular pathways and phosphorylation targets of CDKL5. Using an unbiased phosphoproteomic approach we identified novel targets of CDKL5, including GTF2I, PPP1R35, GATAD2A and ZNF219 in human iPSC-derived neuronal cells. The phosphoserine residue in the target proteins lies in the CDKL5 consensus motif. We validated direct phosphorylation of GTF2I and PPP1R35 by CDKL5 using complementary approaches. GTF2I controls axon guidance, cell cycle and neurodevelopment by regulating expression of neuronal genes. PPP1R35 is critical for centriole elongation and cilia morphology, processes that are impaired in CDD. PPP1R35 interacts with CEP131, a known CDKL5 phospho-target. GATAD2A and ZNF219 belong to the Nucleosome Remodelling Deacetylase (NuRD) complex, which regulates neuronal activity-dependent genes and synaptic connectivity. In-depth knowledge of molecular pathways regulated by CDKL5 will allow a better understanding of druggable disease pathways to fast-track therapeutic development.

Failure to progress: breast and prostate cancer cell lines in developing targeted therapies.

Developing anticancer drugs from preclinical to clinical takes approximately a decade in a cutting-edge biomedical lab and still 97% of most fail at clinical trials. Cell line usage is critical in expediting the advancement of anticancer therapies. Yet developing appropriate cell lines has been challenging and overcoming these obstacles whilst implementing a systematic approach of utilizing 3D models that recapitulate the tumour microenvironment is prudent. Using a robust and continuous supply of cell lines representing all ethnic groups from all locales is necessary to capture the evolving tumour landscape in culture. Next, the conversion of these models to systems on a chip that can by way of high throughput cytotoxic assays identify drug leads for clinical trials should fast-track drug development while markedly improving success rates. In this review, we describe the challenges that have hindered the progression of cell line models over seven decades and methods to overcome this. We outline the gaps in breast and prostate cancer cell line pathology and racial representation alongside their involvement in relevant drug development.

Race, Time, and Architecture: Dilemmas of Africanization in Ghana, 1951–66

Abstract This article discusses the Africanization of architectural labor in Ghana during the late colonial and early postindependence periods (1951–66). It focuses on the state-supported emergence, advancement, and emancipation of Indigenous architects and institutions in the context of decolonization and the Cold War. Using archival materials held in Accra, Kumasi, and London, the article shows how professionals and administrators negotiated between their double obligations: to fast-track governmental development plans and to Africanize the Public Works Department and its successors. These decision makers addressed temporal dilemmas concerning recruitment, standards, allocation, and racialization of architectural labor. In so doing, they redefined both colonial-era racial categories and racialized Cold War imaginaries of who counted as an African and who counted as an Other. This study advances the architectural history of postcolonial Ghana and broadens the debate about racialization of architecture beyond North America and Western Europe.

Solutions to Complex Well-Testing Challenges Aid Offshore Black Sea Gasfield Development

_ This article, written by JPT Technology Editor Chris Carpenter, contains highlights of paper SPE 215123, “Frontiering Ultradeep Water Gas Field Development, Offshore Black Sea, Turkey: Solutions to Complex Well-Testing Challenges and Proving Production Potential,” by Coşan Ayan, SPE, Suat Aktepe, and Koscal Cig, Turkish Petroleum, et al. The paper has not been peer reviewed. _ Increasing demand for reliable energy resources has led to an increased exploration activity for untapped hydrocarbon resources in deep water. The recently discovered, fast-tracked Sakarya offshore natural gasfield development is a prime example. This paper describes dynamic reservoir characterization considerations, challenges, and engineering solutions to derisk field-development decisions, confirmed by a well-testing campaign in a complex setting with no tolerance for failure. Sakarya Field The Sakarya field is approximately 170 km north of the Turkish coast in the Black Sea at 2117 m (Fig. 1). The natural gas field was discovered in August 2020 and is estimated to have potential natural gas reserves of 11 Tcf of lean gas, making it the largest gas reserve discovered in the Turkish Exclusive Economic Zone as well as the Black Sea. In October 2020, a second discovery was made in the lower sections of Tuna 1, which increased the potential recoverable reserve estimate to 14.3 Tcf of lean gas. The discovery was found at the deeper part of the well, where an additional 30 m of gas pay was encountered in the sandstone reservoir of the Late Miocene. Further, the drilling of the exploratory well Amasra 1, 40 km north of the Sakarya field, led to the discovery of 4.7 Tcf of gas in June 2021, and increased the potential recoverable cumulative natural gas reserves to 19 Tcf. The first gas production from the Sakarya gas field began in 2023 into the Turkish grid from the completed wells of the first phase of the project. To accelerate the time to first gas production, it was deemed necessary to flow-test the reservoirs to acquire critical reservoir information, assess production potential and completions efficiency, and reduce the number of wells. This was achieved by drilling and testing several appraisal wells with multiple target intervals that will be used later as producers. Well-Completion Strategy Affecting Well-Test Program Formation-failure studies and wireline formation testing data have shown that these weak reservoirs are prone to sand production. As a result, downhole sand-exclusion completions are necessary. Gas permeabilities are good, with core-measured air permeabilities in the range of 1–1000 md. The reservoir pressure varies from 4,200 to 5,800 psi, depending on depth. Reservoir temperatures are relatively low, in the range of 25–60°C. Lower Completion Installation Sequences. After drilling, the main section was completed with 9⅞-in. 62.8-lbm/ft production casing. The selected interval from openhole logs and formation test results was perforated and overbalanced by individual runs of a tubing-conveyed perforation (TCP) system. On the second run, sump packers with direct wrap screens across the interval were installed and gravel was pumped. After the lower completion was in place and the drillstem test (DST) had been conducted, another part of the lower completion across the upper interval was installed and flow-tested. After completing all DST well tests, the well was suspended with the lower completion system in place, ready for installation of the upper completion with intelligent flow-control valves and permanent gauges.

Fast-Track Development and Multi-Institutional Clinical Validation of an Artificial Intelligence Algorithm for Detection of Lymph Node Metastasis in Colorectal Cancer

Lymph node metastasis (LNM) detection can be automated using artificial intelligence (AI)-based diagnostic tools. Only limited studies have addressed this task for colorectal cancer (CRC). This study aimed to develop of a clinical-grade digital pathology tool for LNM detection in CRC using the original fast-track framework.The training cohort included 432 slides from one department. A segmentation algorithm detecting 8 relevant tissue classes was trained. The test cohorts consisted of materials from 5 pathology departments digitized by 4 different scanning systems.A high-quality, large training data set was generated within 7 days and a minimal amount of annotation work using fast-track principles. The AI tool showed very high accuracy for LNM detection in all cohorts, with sensitivity, negative predictive value, and specificity ranges of 0.980 to 1.000, 0.997 to 1.000, and 0.913 to 0.990, correspondingly. Only 5 of 14,460 analyzed test slides with tumor cells over all cohorts were classified as false negative (3/5 representing clusters of tumor cells in lymphatic vessels).A clinical-grade tool was trained in a short time using fast-track development principles and validated using the largest international, multi-institutional, multiscanner cohort of cases to date, showing very high precision for LNM detection in CRC. We are releasing a part of the test data sets to facilitate academic research.

Fast-tracking drug development with biomarkers and companion diagnostics

To fully implement precision medicine, a deeper understanding of biomarkers, companion diagnostics, and their use in clinical trials is needed. Here, we describe key events in biomarker discovery and clinical trial design, and how those stages may be streamlined to fast-track approval of companion diagnostics (CDx). We discuss crucial qualities of a successful CDx that include understanding the prevalence of the marker in the intention to treat population, careful consideration of the scoring scheme that will be used in later clinical trial stages, and reliability of the performance of the CDx, in addition to other necessary features.

Government Incentives: The Role of Human Resource in Delivering Flexible Organizational Working Strategies in Singapore

Rapidly changing and turbulent business environments due to the socio-economic changes, the increased technology use and the Covid-19 pandemic crisis have forced governments to fast-track development of flexible working arrangements (FWAs). The recent initiatives have seen government FWA incentives to support FWA adoption in the workplace. Singapore is a leader among developing Asian countries regarding adopting FWA incentive-based approaches, which also emphasize human resource (HR) roles in delivering the FWA program. This paper investigates the nexus between government incentives and HR roles in managing FWAs. Additionally, during times of pandemic crisis, most businesses have no option but to implement FWAs in sustaining business continuity or ensuring survival. Therefore, strategic FWAs are critically needed. This paper has two aims; first we investigate how HR translates government FWA incentives into strategies and practices, and then we critically analyze these findings to improve the current FWA strategies by developing a conceptual framework for strategic FWAs. Twenty case studies from Singapore were used as a data set. As results, we identified ten themes representing the role HR plays in delivering organizational flexibility through their strategies and practices. We then propose a conceptual model for advancing FWA practices from policy formalization to flexibility strategy and agility working practices.

Abstract B151: Discovery and characterization of a novel small molecule brain penetrant PD-L1 inhibitor

Abstract Introduction: Immunotherapy has revolutionized cancer treatment in the last decade. Several monoclonal PD-1 and PD-L1 antibodies have been approved for treating various cancers. Small molecule PD-L1 inhibitors with brain-penetrating ability may have potential to overcome the limitations of antibodies and bring benefit for patients with intracranial tumors. Leveraging advanced computation-aided structural analysis and medicinal chemistry design, we have successfully discovered an innovative orally available small molecule PD-L1 inhibitor ABSK044. In preclinical experiments, this compound demonstrates robust T-cell activating ability, strong anti-tumor efficacy, and brain-penetrating activity. Method: ABSK044's ability to block PD-1-PD-L1 interaction was evaluated by HTRF assay and cellular luciferase reporter assay. Its biological activity was evaluated in vitro in MLR and in vivo in syngeneic tumor models. Results: ABSK044 strongly inhibits PD-1-PD-L1 interaction with an IC50 less than 1nM in vitro and very potently rescues PD-L1-induced suppression of T cell activation signaling in cells. Furthermore, it efficiently rescues cytokine production in CD8+ T cells suppressed by PD-L1, reaching a level comparable to that of PD-L1 antibodies. In in vivo studies, oral administration of ABSK044 strongly inhibits tumor growth to an extent similar to therapeutic anti-PD-L1 antibodies. Notably, ABSK044 demonstrates excellent brain penetration with a Kp value exceeding 0.4. DMPK and safety profiling demonstrate excellent drug-like properties of ABSK044. Conclusion: ABSK044, presented here by Abbisko Therapeutics, is a highly potent and orally available small molecule PD-L1 antagonist with brain-penetrating activity. Its superior profile supports its fast-track preclinical development. Citation Format: Yongxian Zhang, Mingming Zhang, Baowei Zhao, Hongping Yu, Yao-Chang Xu, Zhui Chen, Haiyan Ying. Discovery and characterization of a novel small molecule brain penetrant PD-L1 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B151.

Abstract C130: Discovery and characterization of an MTA-cooperative and brain-penetrant PRMT5 inhibitor

Abstract Introduction: MTAP is homozygous deleted in ~50% in glioblastoma and many other cancers. PRMT5*MTA inhibition has been shown to be synthetic lethal with MTAP deletion. First generation PRMT5 inhibitors could not distinguish between PRMT5*MTA or PRMT5 alone, thus limited by their shallow therapeutic windows in clinical use. Development of selective PRMT5*MTA inhibitors may improve not only safety but also therapeutic efficacy. Leveraging advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a potent and selective MTA-cooperative and brain-penetrable PRMT5 inhibitor ABK-PRMT5-1, which demonstrates strong anti-tumor activity and brain-penetrating activity in various preclinical models. Method: Isogenic cell line pairs (MTAP-/- and MTAP+/+) were used to determine the effects of ABSK-PRMT5-1 on cell proliferation and PRMT5-dependednt downstream signaling. Cancer cell line panel was also used to confirm its activity and selectivity. Its in vivo efficacy was evaluated in cell line derived xenograft (CDX) mouse models with tumors harboring MTAP gene deletion. Results: ABSK-PRMT5-1 strongly inhibits cell proliferation in MTAP-deleted cancer cell lines, with minimal effects on MTAP wildtype cell lines. Furthermore, it significantly reduces SDMA in MTAP-deleted cancer cell lines. Oral administration of ABSK-PRMT5-1 strongly inhibits tumor growth in MTAP-deleted xenograft tumor models. In addition, ABSK-PRMT5-1 demonstrates strong brain penetration with excellent Kp values in animals. DMPK and safety profiling shows good overall drug-like properties of ABK-PRMT5-1. Conclusion: ABK-PRMT5-1, presented here by Abbisko Therapeutics, is a highly selective MTA-cooperative and brain-penetrable PRMT5 inhibitor. Its superior profile supports fast-track preclinical development. Citation Format: Weiling Pan, Hui Wang, Fangfei Qi, Haibing Deng, Fei Yang, Hongping Yu, Yao-Chang Xu, Zhui Chen, Haiyan Ying. Discovery and characterization of an MTA-cooperative and brain-penetrant PRMT5 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C130.

A REVIEW OF POST-COVID TELECOMMUNICATION INVESTMENT TRENDS: IMPACTS ON INFRASTRUCTURE DEVELOPMENT

The post-COVID era has catalysed a transformative phase in the telecommunication sector, with dramatic shifts in both consumer behaviour and enterprise needs. This study offers a synthesized review of investment trends in telecommunications following the pandemic, detailing their implications on infrastructure development. The initial pandemic response saw an exponential rise in the demand for robust connectivity, necessitating rapid infrastructural adjustments to cater to remote work, online education, and digital healthcare. This paper identifies significant post-COVID investment trends in telecommunications, which include an augmented drive for broadband and fibre-optic expansion, an accelerated rollout of 5G networks, heightened investments in cloud services and data centres, and a notable surge in mergers and acquisitions. This investment influx has palpably advanced infrastructure development rates, with a focus on enhancing capacity, speed, reliability, and geographical reach. However, the ramifications of this swift expansion are multifaceted. On the socio-economic front, there has been substantial job creation, technology democratization, and improved accessibility, especially in historically underserved areas. In parallel, the environmental footprint of this growth is also scrutinized, shedding light on increased energy consumption, challenges in electronic waste management, and resource utilization. From a business perspective, while there's enhanced market competition and improved service quality, companies also grapple with new challenges in customer retention, experience management, and competitive differentiation. Furthermore, this paper elucidates evolving policy landscapes, marked by modified telecom regulations, incentivization strategies, and measures to ensure equitable access. In conclusion, the post-pandemic telecommunication investment trends have undeniably fast-tracked infrastructure development, but with nuanced implications for society, environment, business, and policy. The forward trajectory, though promising, requires a harmonized effort from stakeholders to ensure sustainable and inclusive growth. 
 Keywords: Telecommunication, Infrastructure, Investment, Government, Post-Covid, Policy.

L-Arginine in Restoring ‘Immune Dysregulation’ in Long COVID: It’s the Therapeutic Role Beyond the Routine Dietary Supplement!

COVID-19 pandemic is over now and we are in great peace of relief after three years. This pandemic has observed significant impact on quality of life globally and the put unforgettable imprints on history of mankind. Reason for more havoc in this pandemic was less studied virus by medical scientists regarding its pathophysiology, available treatment options and lack of effective vaccine to tackle this dragon. COVID-19 is the first observed and reported pandemic of corona virus related global disease apart from its previous SARS and MERS. Fast track developments in medical treatment options due to this ultrafast digital and artificial intelligence techniques have curtailed mortality on large scale globally. Although mortality is significantly reduced, morbidity is documented on a large scale worldwide in this pandemic. Morbidity due to COVID-19 now called as ‘Long COVID’, which is underreported & half-heartedly evaluated globally. Long COVID is related to persistent immune dysregulation occurs during evolution of COVID-19 as natural trend of disease. Immune dysregulation has documented during course of active viremia, during recovery of viral illness and after post viral phase. Immune dysregulation occurs in ‘selected group’ of cases irrespective of disease severity and vaccination status and observed in cases with negligible illness to advanced one mandates further research. Thus, Immune dysregulation in COVID-19 is predominant cause for long covid and leading to brainstorming effect on medical scientists and researchers as of today. Globally, one third of recovered or affected cases of COVID-19 are facing long covid and needs prompt treatment options to tackle this dragon related long term effect on body. ‘Immunomodulatory’ or immunity modifying agents are the primary targets to curtail immune dysregulation and long covid. Some experts recommend ‘disease modifying agents’ to treat long covid cases. Still, many miles to go to reach to effective treatment options for long covid and we don’t have effective options for this ‘health issue of global concern’. L-Arginine is amino acid with multiple beneficial effects such as immunomodulatory effects which will regulates immunological response in inhibit dysregulated immune system additional to its universally known antioxidant, vasodilatory and regenerative and cellular proliferation effects on immune cells. These Immunomodulatory and or diseases modifying effects of L-Arginine makes it the future candidate with ‘game changer’ role for management of Long covid resulting from immune dysregulation as a core pathophysiologic pathway of this Dragon Pandemic.

Deliberative Improvement of Oral Care Quality: The Horizon Europe DELIVER Project.

The EU DELIVER project aims to enhance the quality of oral health care through codevelopment and coproduction of solutions together with citizens/patients, providers, and policymakers. The unique multicountry nature of the project will facilitate fast-track prototype development and testing of innovative QI approaches in select countries. Reflective learning regarding the transferability of findings between different countries and settings offers unique opportunities to drive progress toward context-specific implementation of innovative oral health care QI approaches. The collective knowledge gained from the 7 European countries involved in DELIVER can also generate knowhow for improving the quality of oral health care in other countries around the globe.

Hydroxychloroquine as ‘Potential Treatment Option’ for Persistent Immune Dysregulation in Long COVID: Revisiting Its New Use as a ‘Versatile’ Molecule!

COVID-19 pandemic is over now and we are in great peace of relief after three years of first case reported in China. This pandemic has observed a significant impact on quality of life globally and this puts unforgettable imprints on the history of mankind. Reason for more havoc in this pandemic was less studied virus before this ‘unpredicted or surprise pandemic’ by medical scientists regarding its pathophysiology, available treatment options and lack of effective vaccine to tackle this dragon. Rationale would be COVID-19 is the first observed and reported pandemic of corona virus related global disease apart from its previously occurring SARS and MERS Epidemics. Fast track developments in medical treatment options with use of ultrafast digital and artificial intelligence techniques have curtailed mortality on a large scale globally. Although mortality is significantly reduced, morbidity is documented in significant number of cases worldwide after this Dragon related pandemic. Morbidity due to COVID-19 now called as ‘Long COVID’, which is underreported & half-heartedly evaluated globally. Long COVID is related to persistent immune dysregulation which occurred during evolution of COVID-19 as a natural trend of disease & documented during the course of active viremia, during recovery of viral illness and after the post viral phase. Immune dysregulation occurs in a ‘selected group’ of cases irrespective of disease severity and vaccination status, and observed in cases irrespective of severity of illness as with negligible illness resulted into brainstorming effect on medical scientists and researchers as of today to advanced and mandates further global research. Globally, one third of recovered or affected cases of COVID-19 are facing long covid and need prompt treatment options to tackle this dragon related long term effect on body. ‘Immunomodulatory’ or immunity modifying agents are the primary targets to curtail immune dysregulation and long covid. Some experts recommend ‘disease modifying agents’ to treat long covid cases. Still, many miles to go to reach effective treatment options for long covid and we don’t have effective options as of now for this ‘health issue of global concern’ related to Dragon. Hydroxychloroquine is initially used as an antimalarial and as an anti-inflammatory molecule for decades in various rheumatic conditions with satisfactory results. Despite decades of dependable use and predictable results in the treatment of rheumatic disease, HCQ remains a drug with an ever-expanding number of underlying mechanisms. HCQ was tried initially for prophylaxis treatment of COVID-19 due to its anti-inflammatory properties but has not shown any dramatic results. WHO has removed HCQ from the treatment plan after many trial results with disappointing outcomes. HCQ is a drug with multiple beneficial pleiotropic effects such as immunomodulatory effects which regulates immunological responses that inhibit dysregulated immune system. These Immunomodulatory and or diseases modifying effects of HCQ makes it the future candidate with ‘game changer’ role for management of Long covid resulting from immune dysregulation as a core pathophysiologic pathway of this Dragon Pandemic. Revisiting this old drug with ‘versatile effects’ can be used as treatment option for short time as frontline molecule for Long covid when no definitive options are available after consideration of risk benefit ratio which is a cost-effective treatment option.

Inflammatory Markers or ‘Composite Index’ in COVID-19 as ‘Point Of Care Test’: Which One is the Best Choice to Tackle Dragon!

COVID-19 is first corona virus related global pandemic after SARS and MERS and due to rapid evolution of pandemic fast track developments in diagnostics, monitoring and treatment options and vaccine developments has occurred to prevent its significant impact on mortality and morbidity. COVID-19 infection involves a complex interplay of the immunological and inflammatory responses. Inflammatory parameters are closely linked to the COVID-19 severity and mortality. Inflammatory parameters could be used to predict the transition from mild to severe/critical infection in patients of COVID-19. Numerous Inflammatory markers were analysed and used as point of care test to predict severity of illness, monitoring of illness, treatment planning and predicting final outcomes such as CRP, LDH, IL-6, D-dimer and ferritin. Robust data of these inflammatory markers is available and proved crucial in predicting pathophysiological trends such as cytokine storm, coagulation abnormalities, oxygenation status and response to therapy. Isolated assessment of inflammatory markers in absence of clinical and radiological parameters were observed as ‘double edged weapon’ due to overestimation and its impact on health burden and underprediction resulting into progression of illness and resultant poor outcome and increased health care cost. Composite index is combination clinical, radiological and laboratory inflammatory marker assessment. Combination of any two abnormalities were observed crucial role in early suspicion, diagnosis, monitoring, and recognition of complications, management and disposition of patients. Composite index rather than single biomarkers may provide more reliable information. Availability and cost issues cannot be ignored. It would be impossible for clinicians to consolidate and critically analyse the enormous data that is continuously added to the COVID-19 literature to extract practically useful information for the benefit of patients. Still, as of now Composite index should be considered as ‘point of care test’ to honour successful treatment outcome and prevent mortality and morbidity due to this ‘Dragon Pandemic’.

Doxiadis and His Legacy: Retrospective of the Lebanon Case - From Sketch to Stretch

In 1957-8 Doxiadis Associates undertook the National Housing Project of Lebanon, a fast-track national development plan created in response to the imperative to house large parts of the population living in inadequate conditions. This national reconstruction plan is indicative of a heroic period of planning post-WWII. The legacy of CIAM - the Congrès internationaux d'architecture moderne (1928-1959) – had been the spawning of modern movements, including Doxiadis’ newly born theory of Ekistics, that envisioned national scale development while furthering US hegemony in the cold war era. The National Housing Project of Lebanon arose in this context, and Doxiadis’ approach would distinguish him from his contemporaries. Consisting of a “sketching” phase involving data collection using diaries featuring photographic depictions and 500 sketches from 2.500 human settlements in Lebanon, and a “stretching” phase resulting in proposals for immediate implementation, specifically, housing schemes at the periphery of Beirut, Doxiadis’ approach was distinctive for mixing different functions to enhance social encounter, for grounding future typologies in existing localities, and for prioritizing community-sensitive planning by insisting on the importance of human scale. Unfortunately, political changes after the plan’s submission in May 1958 lead to its eventual abandonment, and problems in the wider area still prevail. The persistence in the region of violent conflicts, population flows, and the destruction of cities that leave the poorest living in slums and camps suggests that the planning strategies proposed by Doxiadis and his contemporaries did not fail, but instead, reveal the complex nature of the planning process itself, including its susceptibility to political forces. As such, the National Housing Project of Lebanon and other unrealized initiatives offer a rich resource for understanding the problems of human settlements which remain with us today.

Treatment Options Used in COVID-19 Disease

Coronavirus disease 2019 (COVID-19) is the first coronavirus-related global pandemic caused by a novel severe acute respiratory syndrome coronavirus-2, and rapid evolution of the pandemic has resulted in fast-track developments in antivirals, medical management, and vaccination for use to prevent morbidity and mortality. As of today, different institutional treatment protocols and respective national guidelines have been evolved worldwide with team of medical experts and recommended for combinations of antiviral, antibiotics, steroids, and anticoagulants with variable outcomes. Combination therapy has documented better outcome with a significant reduction in mortality and morbidity and considered frontline protocol during this pandemic.

Abstract LB328: Discovery & characterization of a next-generation FGFR4 inhibitor overcoming resistant mutations

Abstract Introduction: Aberrant activation of FGF19-FGFR4 signaling pathway plays an essential role in the tumorigenesis of Hepatocellular carcinoma (HCC) and FGFR4 inhibitors have shown preliminary efficacy in recent clinical trials for patients with FGF19 overexpression. However, the observed responses only lasted a few months before tumors relapse. Acquired FGFR4 resistant mutations were found in ~30% of FGFR4 inhibitor responsive patients. Similar FGFR4 mutations haven also been found de novo in about 7-10% of Rhabdomyosarcoma (RMS) and ER-treated invasive lobular carcinoma patients. First generation FGFR4 inhibitors have minimal activity against these de novo or acquired resistant mutations. Therefore, next-generation of FGFR4 inhibitors are needed to overcome these resistant FGFR4 mutations to provide better treatment options for patients. Using advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a next-generation small molecule FGFR4 inhibitor, ABSK012, and demonstrated its strong activities against de novo and acquired resistant FGFR4 mutations while retaining inhibition for wild-type FGFR4. Method: Inhibitory activity of ABSK012 against FGFR4 and FGFR4 mutants was evaluated by MSA assay and its inhibition on FGFR4-dependent cell proliferation was evaluated by Celltiter-Glo assay in wile type FGFR4-dependent cancer cell lines or mutant FGFR4-dependent Ba/f3 cell lines. Its selectivity against other FGFR family member and kinases was analyzed by cellular and KinomeScan profiling. Efficacy studies were conducted in HCC xenograft models and mutant FGFR4-dependent xenograft models including a RMS PDX model harboring FGFR4 V550L mutation. Results: ABSK012 demonstrated strong potency over multiple FGFR4 mutants that are insensitive to a first generation FGFR4 inhibitor BLU-554. It also inhibited wild-type FGFR4 with IC50<5 nM in biochemical assay and exhibited great selectivity against other kinases. In multiple mutant and wild-type FGFR4-dependent cell lines, ABSK012 demonstrated significantly improved anti-proliferation activity. In preclinical in vivo studies in HCC models, oral administration of ABSK012 strongly inhibited the tumor growth at doses without obvious toxicities. More importantly, in a RMS PDX xenograft harboring FGFR4 V550L mutation, ABSK012 also showed significant anti-tumor activity. Other ADME and safety profiling demonstrated excellent drug-like properties of ABSK012. Conclusion: ABSK012, presented here by Abbisko Therapeutics, is a highly potent, selective, and next-generation small molecule FGFR4 inhibitor overcoming FGFR4 mutations resistant to first-generation inhibitors. Its superior preclinical profile supports its fast-track development into clinic. Citation Format: Haiyan Ying, Nannan Zhang, Haibing Deng, Fei Yang, Wenqun Xin, Bin Shen, Hongping Yu, Zhui Chen, Yao-chang Xu. Discovery & characterization of a next-generation FGFR4 inhibitor overcoming resistant mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB328.

Abstract LB317: Discovery and characterization of a next-generation FGFR inhibitor overcoming FGFR resistant mutations

Abstract Introduction: FGFRs play important roles in cancer development and inhibition of FGFR could disrupt tumor cell proliferation and growth. Four selective FGFR inhibitors have been approved (erdafitinib, pemigatinib, infigratinib, and futibatinib) and several others are in clinical development. Unfortunately upon treatment with these first-generation FGFR inhibitors, acquired resistance often develops and is frequently associated with the emergence of secondary FGFR2/3 kinase domain mutations. Therefore, selectively targeting FGFR2/3 as well as their resistant mutations may render a second-generation treatment approach for the refractory/relapsed patients. Using advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a novel, next-generation, and highly selective FGFR inhibitor, ABSK121. This novel inhibitor demonstrated robust anti-tumor activity in FGFR-dependent tumor models with strong activities against not only de novo but also acquired resistant mutations. Method: ABSK121 was evaluated in biochemical and cellular proliferation experiments for its inhibition on wile type FGFR enzymatic activity and FGFR-dependent cancer cell proliferation. Its potency against FGFR mutations was also analyzed in relevant biochemical and cellular experiments. Efficacy studies were conducted in multiple tumor models to confirm its in vivo activities. Preliminary selectivity profile and ADME profiles were also evaluated. Results: ABSK121 inhibited wild type FGFRs with IC50<10 nM in biochemical assay. ABSK121 also displayed great potency against resistant kinase domain mutations. In cell lines harboring FGFR amplification, fusions, or resistant mutations, ABSK121 demonstrated strong anti-proliferation activity as well as strong inhibition of FGFR downstream signaling activities. In preclinical in vivo studies, oral administration of ABSK121 strongly inhibited the growth of subcutaneous xenograft tumors dependent on wild type or resistant mutant FGFR. Suppression of tumor growth was dose-dependent and well correlated with pharmacodynamic inhibition of FGFR signaling. ABSK121 also showed great kinase selectivity with no CYP or hERG inhibition. Conclusion: ABSK121, presented here by Abbisko Therapeutics, is a highly potent, selective, and next-generation small molecule FGFR inhibitor with great potency against resistant FGFR mutations. Its superior profile supports fast-track preclinical and clinical development. Citation Format: Haiyan Ying, Wenqun Xin, Haibing Deng, Yuan Zhao, Hongping Yu, Zhui Chen, Yao-chang Xu. Discovery and characterization of a next-generation FGFR inhibitor overcoming FGFR resistant mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB317.