Growth Regression Research Articles

House Prices and Rents

Abstract Variation in monthly metro area house prices unrelated to expected rents clouds the information about future rents in price-rent ratios and lagged changes in house prices. The variation in house prices unrelated to expected rents is, however, correlated across areas, and the problem is mitigated by measuring rent growth regression variables net of their monthly cross-section (across-area) means. This control for price variation unrelated to expected rents substantially enhances the information about future rents that we extract from price-rent ratios and lagged changes in house prices.

Oil Price and Long-run Economic Growth in Oil-importing Developing Countries

The recent spikes in oil prices are a significant setback for the world economy, which has already faced multiple challenges due to the COVID-19 pandemic. This is particularly concerning for developing countries as maintaining a sustained growth in real GDP is crucial for lifting their population out of poverty. While the short-run negative macroeconomic effects of a spike in oil prices are well established in the context of the developed world, the long-run growth effect has received little attention, especially in developing countries. Using the World Bank's development indicators database covering the period 1990 to 2020, this study aims to investigate the oil price-growth nexus in low and middle-income net oil-importing countries to shed light on how oil price increases could be a challenge for sustainable development. Specifically, we first set up a theoretical model to establish the relationship between growth in output per capita and oil price. Following the traditional growth regression approaches, we empirically estimate the causal effect of growth in oil prices on the economic growth of 65 net oil-importing developing countries using fixed effect panel IV regression methods. The empirical results confirm statistically significant negative effects of oil prices, indicating that a higher oil price reduces long-run economic growth in oil-importing developing countries. Our results on the other determinants of growth are consistent with the existing empirical growth literature. Oil-importing developing countries, therefore, must allocate resources towards alternative domestic energy sources, in addition to pursuing fuel efficiency and conservation strategies, to mitigate the negative effects of oil price fluctuations on their long-run economic output and uphold sustainable development.

Impact of Cohesion Funds on Convergence Club's Economic Growth

ABSTRACTThis paper empirically estimates the impact of the European Structural and Investment Funds (ESIF) on economic growth across European regions. The narrative of this paper is based on the convergence club hypothesis. In this context, we implement the data‐driven Phillips and Sul test to classify European regions into endogenously identified convergence clubs that tend to converge to different steady‐state equilibria. We find three substantially different convergence clubs in terms of both per capita output and spatial location: capital cities and metropolitan areas (along the so‐called “Blue Banana”), core countries, and the periphery. We observe a persistent core‐periphery pattern in terms of output per capita among European regions with different rates of convergence. The convergence club comprising capital cities and metropolitan areas converges almost four times faster than the rest of the EU. Subsequently, we estimate club‐specific growth regressions to investigate the impact of ESIF expenditures on short‐run economic growth. Our main identification strategy relies on two instrumental variables, namely the spatial lag of EFSI expenditures‐to‐GDP and the air distance to Brussels, to address a strong endogeneity problem in strongly biased relationship between ESIF expenditures‐to‐GDP and short‐run economic growth. Our results indicate a positive impact of ESIF expenditures‐to‐GDP on short‐run economic growth in the second (core) and third (periphery) convergence clubs, with the impact being twice as large in the latter compared to the former. These results remain robust when adjusting the growth regressions to use ESIF expenditures‐to‐population instead of ESIF expenditures‐to‐GDP, although the pronounced difference in effect magnitude among convergence clubs diminishes.

Financial resilience, growth and risk sharing in the EU

We build a financial resilience index capturing the structure and stability features of financial systems and benchmark EU financial systems against their ability to enhance stable growth and international risk sharing. The index comprises financial openness, market orientation, equity deepening, maturity structure, and institutional soundness. Our results show that: (i) EU financial systems are highly heterogeneous and converge to a clustered pattern; (ii) the index is highly significant in growth regressions, suggesting that financial structure and institutional soundness are key to enduring growth; (iii) the heterogeneity of EU financial systems has implications for the vulnerability to domestic output shocks: the risk-sharing mechanism is more effective in the market-based and institutionally sound economies that group in the top financial clusters, whereas unsmoothed consumption is higher in economies belonging to the low-resilience clusters, especially in the aftermath of the global financial crisis, when the credit channel is significantly downsized.

Educational heterogeneity of the founding team of innovative start-ups: confirmations and denials

This paper focuses on the value drivers of innovative start-ups (ISUs). Few companies can overcome the start-up stage; often, the early performance is insufficient, and the potential contribution of innovation to economic development is very poor. Studies based on a firm-level perspective show mixed results on the factors affecting the growth of ISUs. Most studies emphasize the role of “external” drivers of ISUs growth, while more knowledge is required of “internal” drivers. Consequently, this research focuses on the relationship between the features of the founding teams and the early performance of ISUs. Specifically, it concentrates on education heterogeneity and analyzes whether the heterogeneity of the founding team in terms of educational level (vertical heterogeneity) and field of studies (horizontal heterogeneity) affects the Italian ISUs performance. Growth regression and unconditional quantile regression models confirm the prior literature: the educational level affects the performance and the vertical heterogeneity in the composition of the founding team is relevant for ISUs performance. However, the results also suggest interesting denials: horizontal heterogeneity does not play any role, and no moderating effect of heterogeneity is shown. These findings are strongly attractive for new ventures and policymakers.

The Effect of Potassium Sulphate Applications on Plant Growth and Nutrient Content of Pepper Plants Grown Under High Temperature Stress

Objective: Abiotic stresses are one of the most important factors that negatively affect plant growth. Especially in recent years, regression in plant growth and product losses have occurred due to high temperature caused by global climate change. The aim of the study was to reduce the effect of high temperature stress and increase plant tolerance with potassium. One of the ways to increase plant tolerance is proper fertilizer and fertilization techniques. Material and Methods: Potassium sulfate fertilizer (K2SO4), which has a positive effect under abiotic stress conditions, was used as fertilizer in the experiment. The experiment was established according to the randomized plot design with 3 replications and 5 plants in each replication. The effects of foliar (0%, 1%, 2%, 3%) and soil (0-5-10-20 kg da-1) potassium applications on plant growth under high temperature stress were investigated. Results: As a result of the application of potassium sulfate from the leaves or roots, the effect of the plant green part scale, the membrane injury index, the dry weight ratio of the green parts, the relative moisture content of the leaves, the nitrogen (N), potassium (K) and calcium (Ca) concentrations in the leaves were found to be statistically significant. Conclusion: The results indicated that potassium applications under high-temperature stress led to increases in nitrogen (N), potassium (K), and chlorophyll concentrations, as well as in the relative moisture content of the leaves. It was found that visual damage to green parts and leaf membrane damage decreased under high-temperature stress. The experiment revealed that potassium sulfate positively influenced plant growth under stressful conditions, reducing damage severity and enhancing plant resistance. The experiment revealed that potassium sulfate positively influenced plant growth under stressful conditions, reducing damage severity and enhancing plant resistance.

KRAS-mutant non-small cell lung cancer (NSCLC) therapy based on tepotinib and omeprazole combination

BackgroundKRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions.MethodsCell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model.ResultsOur research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression.ConclusionsWe posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors.

The effects of enoxaparin treatment in a xenograft mouse model of oral squamous cell carcinoma: A pilot study.

Recent studies suggest that enoxaparin may have therapeutic effects on oral squamous cell carcinoma. We aimed to assess this effect utilizing xenograft mouse model through evaluations of proliferation and angiogenesis markers at the RNA and protein levels. Mice were divided into enoxaparin treatment (n = 4), positive control (n = 4) and negative control (n = 3) groups. Immunohistochemical analyses were performed utilizing Bcl-2, Bax and Ki-67 antibodies. Expression levels of proliferation and apoptosis related genes were calculated utilizing qRT-PCR. Time-dependent proliferation assays were performed in OSC-19 and HEK293 cell-lines. Bax antibody showed positive staining in the cytoplasm and nuclei of tumor cells, while Bcl-2 antibody displayed staining only in the cytoplasm. A proliferation index of 15%-20% was found in all groups with the Ki-67 marker indicating no metastasis. Enoxaparin treatment caused decrease in BCL2, BAX and CCNB1 genes' expressions. Compared to HEK293, proliferation assays demonstrated higher division rates in OSC-19 with a significant decrease in viability after 96 h. Reduced BCL-2 expression indicates a regression of tumor growth, but reduced BAX expression is not correlated with increased apoptosis. Despite the aggressive nature of OSC-19, our results showed a low cell viability with a high division rate when compared with the control HEK293. This paralleled our in vivo findings that showed absence of lymph node metastasis across all mice groups. This discrepancy with the literature suggests that further investigations of the underlying mechanisms and protein-level analyses are needed to draw definitive conclusions about the effect of enoxaparin on OSC-19 behavior.

A first-in-human, phase 1/2 trial of FOG-001, a β-catenin:TCF antagonist, in patients with locally advanced or metastatic solid tumors.

TPS3175 Background: The Wnt/β-catenin pathway is a frequently activated oncogenic pathway and a well-described driver of many cancers. FOG-001 is designed to be a first-in-class direct inhibitor of β-catenin that blocks β-catenin’s interaction with the T-cell factor (TCF) family of transcription factors. Preclinical studies have indicated FOG-001 can cause tumor growth inhibition and regression by disrupting β-catenin-dependent signaling. FOG-001 is unique from previously reported Wnt/β-catenin pathway modulators as it is designed to directly inhibit TCF transcription factor and β-catenin interaction, the most downstream node in the Wnt pathway. It is hypothesized FOG-001 will abrogate the hyperactivation of the Wnt pathway that is driven by most known pathway mutations. Methods: This first-in-human, Phase 1/2, multicenter, open-label, dose escalation (Parts 1a and 1b) and dose-expansion (Part 2) study is evaluating the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of FOG-001 in patients with advanced or metastatic solid tumors. Patients with the following tumor types are eligible: microsatellite stable (MSS) colorectal cancer (CRC) or any solid tumor with documented Wnt pathway activating mutation (WPAM) (Part 1a), MSS CRC only (Part 1b) and MSS CRC, gastric/gastroesophageal (GEJ) cancer, non-small cell lung cancer (NSCLC), and any solid tumors with documented WPAM in Part 2. Patients must have received ≥1 prior systemic anticancer therapy(ies) and be ineligible for curative surgery or curative chemoradiation. In Part 1, FOG-001 is administered at escalating doses via intravenous (IV) infusion on Days 1, 8, 15, and 22 of each 4-week cycle; additional dosing regimens may be explored. After selection of the preliminary recommended Phase 2 dose(s) (pRP2D) and regimen(s) in Part 1, the following cohorts will be enrolled to receive FOG-001 at the pRP2D in Part 2: (2a) MSS CRC; (2b) NSCLC with documented WPAM in adenomatous polyposis coli (APC) or β-catenin; (2c) gastric/GEJ cancer with documented WPAM in APC or β-catenin; and (2d) solid tumors with ≥1 documented WPAM in any predefined Wnt pathway genes. The primary endpoints are safety/tolerability (Parts 1 and 2), and also preliminary antitumor activity (objective response rate) (Part 2). Secondary endpoints are PK, PD, and additional antitumor activity assessments. Enrollment in Part 1 is ongoing. Clinical trial information: NCT05919264 .

A first-in-human, phase 1 study evaluating oral TACC3 inhibitor, AO-252, in advanced solid tumors.

TPS3176 Background: TACC3 is the most oncogenic member of the transforming acidic coiled-coil domain-containing protein (TACC) family, which have important roles in microtubule and centrosome-related processes. TACC3 is overexpressed in multiple cancers with centrosome amplification caused by genomic aberrations such as TP53 mutations, leading to chromosome instability and worse prognosis. AO-252 is a computationally designed, small molecule inhibitor of TACC3 protein-protein interactions. Binding assays and kinome screening suggested the specificity of AO-252 to TACC3. AO-252 targets the interactions of TACC3 with Clathrin/KIFC1, BRDA1 and MBD2/HAT complexes regulating mitosis, DNA damage response and epigenetic functions and was confirmed using co-immunoprecipitation (co-IP) assays. Gene expression analysis in multiple cell lines further confirmed the various TACC3 pathways affected by AO-252. In vitro, AO-252 showed low nanomolar potency in >200 cell line panel covering multiple different cancer indications and spared the normal cells. In vivo, AO-252 demonstrated strong tumor growth inhibition or regression in multiple xenograft models including triple-negative breast (TNBC), high-grade serous ovarian (HGSOC) and endometrial cancer with TP53 mutation/loss with a good therapeutic index. Methods: This first-in-human, multicenter, open-label phase I dose escalation and expansion study evaluates the safety, tolerability, maximum tolerated dose, and recommended phase 2 dose (RP2D) of AO-252 in solid tumors (NCT06136884). Patients with unresectable or metastatic TNBC, platinum-resistant HGSOC, primary peritoneal, fallopian-tube and serous endometrial cancers with documented TP53 mutation/loss, who have failed on at least 1 prior line of systemic therapy in advanced/metastatic setting (maximum 4 for TNBC and endometrial carcinoma) are eligible for enrollment. Part 1 follows an accelerated titration dose-escalation for cohort 1 and 2 and a traditional 3+3 study design from cohort 3. A maximum of 54 patients will be treated in the dose escalation, patients receiving AO-252 orally once or twice daily in a 28-day cycle. Part 2 consists of dose-expansion of a maximum of 30 patients into 2 RP2D levels of AO-252. Primary objectives are to evaluate the safety and tolerability as noted by dose-limiting toxicities, adverse events, serious adverse events, laboratory test results, electrocardiograms, vital signs, physical exams, and ECOG performance status. Secondary objectives are to determine the antitumor activity assessed by objective response rate per RECIST1.1, duration of response and disease control rate and to determine the pharmacokinetics of single and repeated doses of AO-252. Potential biomarkers relating to treatment outcome will be evaluated as exploratory endpoints. Enrollment in Cohort 1 is completed and enrollment to Cohort 2 will begin in February 2024. Clinical trial information: NCT06136884 .

Efficacy of GCN2 inhibition by a novel small molecule AP030 in acute leukemia.

6532 Background: GCN2 is an evolutionarily conserved kinase and a pivotal regulator of the Integrated Stress Response (ISR) that is activated in response to amino acid scarcity. Active GCN2 phosphorylates translation initiation factor eIF2α resulting in the attenuation of global protein synthesis. ISR signaling primarily promotes cell survival but may trigger cell death, dependent on the cellular context. In hematological tumors GCN2 promotes tumor cell survival under conditions of nutrient scarcity. Several GCN2 inhibitors are in clinical development for treatment of both solid and hematological tumors. Here, we describe the preclinical results of a novel, selective ATP-competitive inhibitor of GCN2. Methods: GCN2 inhibition by AP030 was determined using a biochemical Lanthascreen assay and a cell based HTRF assay measuring eIF2a phosphorylation following stimulation with Borrelidin. Kinase selectivity was determined using KinomeScan, and bespoke biochemical and cell-based assays. Interaction of AP030 with GCN2 was determined using X-ray crystallography. AP030 activity in disease-relevant tumor cell lines was determined using cell viability, caspase activation, protein expression and qPCR gene expression endpoints. Inhibition of hematological tumor growth and induction of cell death was investigated in patient samples, and ALL and AML in vivo animal models. Results: Potent inhibition of GCN2 in the Lanthascreen assay was demonstrated with AP030 (Ki of 4.4nM). Following stimulation with Borrelidin, AP030 inhibited eIF2a phosphorylation with an IC50 of 50.8nM and inhibited downstream targets CHAC1 and DDIT3 measured by qPCR. X-ray crystallography confirmed that AP030 binds to the ATP-binding site of GCN2. The KinomeScan confirmed that AP030 was highly selective against the human kinome. AP030 led to partial or complete reduction of AML cell line viability as a single agent and acted synergistically with asparaginase in ALL cell lines. Caspase 3/7 induction was observed in the AML and ALL cell lines evaluated and AP030 increased the proportion of cells undergoing apoptosis in AML patient primary samples. In the CCRF-CEM ALL systemic in vivo tumor model AP030 inhibited tumor growth in combination with asparaginase (TGI 79.33%). Treatment with 0.5-5mg/kg (q.d.) of AP030 resulted in dose-dependent tumor growth inhibition and regression of the MOLM-16 AML in vivo model (TGI 97.37% 5mg/kg). RNA sequencing of residual tumor cells revealed disruption of amino acid and protein metabolism, consistent with GCN2 inhibition. Conclusions: Targeting hematological tumor reliance on the GCN2 arm of the ISR during nutrient scarcity is a novel approach to preventing tumor cell survival. AP030 a novel, potent, selective, ATP-competitive kinase inhibitor has been shown to lead to impressive efficacy in acute leukemia. Based on these preclinical results, a phase 1/2 study has been initiated in AML.

Depletion of histone H3K27 demethylase exerts anti-tumor activity as a monotherapy and in combination therapy with ceralasertib in non-small cell lung carcinoma.

e20035 Background: Lung cancer is one of the most frequently diagnosed cancers and is the leading cause of cancer-related death worldwide. Non-small cell lung carcinoma (NSCLC) represents 85% of lung cancers and is the most common type with poor prognosis. The lysine-specific demethylase UTX (gene name KDM6A) demethylates H3K27me2/3 at genes and enhancers and have been shown to support oncogenic transcription factors. We hypothesize that UTX is a highly pleiotropic factor in tumorigenesis and may plays a critical role in controlling DNA replication-associated gene activation as well as in replication stress-related DNA damage repair. Methods: To evaluate the role of UTX in tumorigenesis, shRNA-mediated UTX knockdown was employed in NCI-H1975 cells followed by cell cycle and cell proliferation assays. In the UTX-knocked down NCI-H1975 cells, target genes involved in DNA replication and DNA damage repair were discovered by RNA sequencing and further validated with RT-qPCR. Effects of UTX depletion on DNA replication and radiation-induced DNA repair were analyzed by immunofluorescence. Effects of UTX depletion on cell cycle arrest and the ATR–CHK1 checkpoint signaling pathway were analyzed by flow cytometry and immunoblotting. In vivo response to UTX inhibition monotherapy (UTX knockdown) and combination therapy of UTX knockdown with ceralasertib, a selective ATR kinase inhibitor, was evaluated in dox-inducible UTX knockdown NCI-H1975 xenografts. Results: Induction of UTX knockdown significantly reduced the NCI-H1975 tumor volume compared to the control group, showing anti-tumor activity. Furthermore, loss of UTX induced hyperactivation of ATR–CHK1 checkpoint signaling pathway, suggesting the UTX-depleted tumor cells attempt to alleviate replication stress to escape from apoptosis. To inhibit the UTX-depletion induced ATR–CHK1 pathway, ceralasertib (formerly AZD6738), an oral potent selective inhibitor of ATR, was combined with UTX-knockdown for in vitro and in vivo evaluation. Consistent with in vitro cell-based assay, combination therapy of ceralasertib with UTX depletion showed enhanced tumor growth inhibition and regression in the NCI-H1975 xenograft model. Conclusions: Our findings provide new insights into a pro-oncogenic role of UTX in supporting tumor maintenance via engaging DNA replication and repair pathway. Depletion of UTX alone may serve as a new therapeutic target in non-small cell lung carcinoma; and further combination with ceralasertib enhances the anti-tumor activity of UTX knockdown by inhibiting the ATR–CHK1 checkpoint signaling pathway.

Boronizing of Monel K500 alloy: Microstructural characterization and modeling of boron diffusion

In this study, the thermochemical treatments were carried out using the powder-pack boronizing method at temperatures ranging from 1123 K to 1223 K for durations of 2 to 6 h, with the aim of improving the surface properties of Monel K500 alloy. Microstructural investigation of the boride layers, conducted using optical microscopy (OM) and scanning electron microscopy (SEM), revealed a needle-like layer structure with high porosity homogeneously distributed on the surface. The results of XRD analysis showed that the boride layer contained different nickel borides (Ni2B, Ni3B, Ni4B3 and NiB12), iron borides (Fe2B and Fe3B) and complex borides (Fe4.5Ni18.5B6 and Fe3Ni3B). The presence and amount of elements in the boride layer were determined by EDS analysis. This study focused mainly on diffusion kinetics studies of boronized Monel K500 alloy. Growth kinetics of the boride layer were investigated using three different approaches such as parabolic growth model, regression model and mean diffusion coefficient (MDC) model. Boron activation energy values were calculated and found to be quite similar, at 266.14 kJ mol−1 and 266.17 kJ mol−1 using the MDC model and parabolic growth model, respectively. These values were compared with similar results reported in the literature.

The implications of population ageing on economic growth: Evidence of nonlinearity

The purpose of this study is to investigate the influence of population ageing on economic growth, a topic that has received inconclusive results. The Fixed Effects Model is used to analyze 5-year non-overlapping growth regressions on a panel of 72 nations spanning three decades. Data is extracted from the World Bank database and Penn World Tables. Findings indicate that in the short-run, population ageing positively impacts economic growth; nevertheless, a nonlinear relationship is observed in the long-run, highlighting the existence of a threshold. The findings remain robust upon proxying the old-age dependency ratio for the share of the elderly. The study identifies the threshold below (above) at which ageing populations impact economic growth positively (negatively). Marginal Effects support our findings, establishing that the detrimental effect on growth intensifies as ageing deepens. The research also identifies a notable nonlinear relationship between economic growth and population ageing in developed economies. Policy implications such as promoting healthy ageing, longer working years, encouraging savings, enhancing productivity via capital investments, and contributions of experienced older workers to the knowledge economy will facilitate reaping the silver demographic dividend and will help nations cope with and minimize the adverse impact of population ageing on economic growth.

Simple Regression Models: A Comparison using Criteria Measures

The study is on simple regression models: a comparison using criteria measures. The source of the dataset used for this study was extracted from records of the Federal Medical Centre, Owerri, Imo State, on weight of babies and hemoglobin level of mothers. The response variable is weight of babies while the explanatory variable is hemoglobin level of mothers. Eleven simple regression models—Linear, Growth, Quadratic, Polynomial, Logarithmic, Hyperbolic, Power, Exponential Growth, Square Root, Sinusoidal and Arctangent—were stated and employed for the study. For ease of data analysis, E-views package was implemented. Three model selection criteria measures for comparison, known as Akaike Information Criterion (AIC), Schwarz Information Criterion (SIC) and Hannan-Quinn Information Criterion (HQIC), were employed. The result of the study showed that, when it comes to analyzing the association between baby weight and mothers' hemoglobin levels, the exponential growth regression model performs better than the other ten models that were examined. Therefore, researchers should investigate other models that were not included in this analysis and compare the findings using goodness of fit metrics other than the criteria measures used in this work.

Public sector and human capital: on the mechanics of economic development

This paper proposes a theory about the allocation of human capital along the development process that helps to understand the controversial impact of this variable in growth regressions. We build a model in which human capital is allocated to three activities: production, tax collection (bureaucracy), and public education. At the first stage of development, countries have low effective tax rates because tax collection requires human capital, which is scarce. As countries accumulate human capital throughout the transition, the effective tax rate rises, diverting human capital from production to bureaucracy and public education. Consequently, at this stage, human capital has a weak impact on production, even when the human capital allocation is efficient. Furthermore, disparities in institutional quality may diminish the correlation between human capital and GDP.

Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma

Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse.

Abstract CT111: Pharmacokinetic and pharmacodynamic evaluation of NXP800, a novel GCN2 activator, in a first in human clinical trial

Abstract Background NXP800 is an oral, small molecule that activates the integrated stress response through activation of the kinase GCN2. The drug causes growth inhibition and regression in various preclinical models, including ARID1A mutated ovarian and endometrial xenograft and cholangiocarcinoma PDX models. Methods We describe results of the dose-defining dose escalation cohort and the toxicity-pharmacokinetics and pharmacodynamic evaluation in a first-in-human phase I trial of NXP800. Dose escalation was guided by a Bayesian modified continual reassessment method that targeted a dose-limiting toxicity DLT probability (DLTp) closest to 30% but <33%. Toxicity was assessed using NCI.CTC.V5. Detailed sampling of blood for pharmacokinetic analysis and blood for mRNA and protein analysis in peripheral blood mononuclear cells was conducted on C1D-3 to -7 (run in prior to continuous dosing) and C2D1. Two schedules (once per day [QD] and twice per day [BID] and a dose range of 50 to 150 mg/day were evaluated. Results Eighteen patients were treated: at baseline, the median age was 65 years (range 42-77), 9 (50%) were female and 14/18 (78%) had an ECOG score of 1. The most common treatment emergent adverse events (more than 20% of patients) were nausea, vomiting, diarrhea, fatigue, decreased appetite, AST increase and thrombocytopenia. All these side effects were grade 1-2 except grade 3 nausea and grade 3 diarrhea reported in one patient each and grade 3 thrombocytopenia in 2 patients. The MTD for the QD schedule was 100 mg (DLTp=26%), no doses in the BID schedule had estimated DLTp of <33%. The average Cmax at 50 mg and 75 mg OD was 190 nM and 384 nM during the run-in and 495 nM and 656 nM in cycle 2 reached by 3 hours. ATF4 protein in PBMCs was elevated in 57% and 80% of patients during run in and Cycle 2 respectively, 6 hours after 50 mg and 75 mg treatment. The mRNA biomarkers in blood most consistently elevated included ATF4 transcriptional targets NUPR1, ULBP1 and TRIB3 at 2 - 24 hours after 50 mg and 75 mg treatment. Further, mRNA levels for these biomarkers were elevated in post-treatment biopsy samples in one of the two patients tested. It is envisaged that NXP800 will need to be dosed continuously and although the protocol defined MTD at 28 days at 100 mg QD, it was decided to take a dose of range of 50 mg and 75 mg OD which caused biomarker modulation, forward for further evaluation. Conclusions A tolerable dose/schedule of continuous dosing of NXP800 has been established with biomarker modulation in blood. Patients will be randomized to two dose levels 50 and 75 mg/day in a QD schedule to evaluate response in a population of ARID1A mutated, platinum-resistant, clear cell ovarian cancer (NCT05226507). Citation Format: Simon Pacey, Ching Leung, Simon Rodney, Ana Filipa Palma DosReis, Ruth Ruddle, Matthew Tall, Karen Swales, Robert te Poele, Paul Workman, Diane Marsolini, Megan Sardone, Enrique Poradosu, Shay Shemesh, Udai Banerji. Pharmacokinetic and pharmacodynamic evaluation of NXP800, a novel GCN2 activator, in a first in human clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT111.

Unraveling the Ayurvedic Protocol in the Management of Ranula

Shalakya tantra is the branch of Ayurveda which deals with Urdhwajatrugata rogas i.e., diseases occurring in supraclavicular region. Acharyas have mentioned various Mukharogas (diseases pertaining to oral cavity) which are further subdivided into various categories. Acharya Sushruta has mentioned five Jihwagata rogas (diseases of tongue) and their management. Upajihwika which is caused by vitiation of Kapha and Rakta, is the Jihwagraroopa shwathu cystic swelling under the ventral aspect of tongue. In modern, it can be correlated with Ranula which is a translucent swelling in the floor of the mouth formed due to sublingual gland trauma or obstruction of the ducts. It further leads to extravasation and accumulation of saliva in the surrounding tissue thus forming a cyst. Case and Intervention- A 49-year-old male patient presented to ENT OPD of Patanjali Ayurveda Hospital with swelling in left submandibular region for 2 months. There was no difficulty in mastication and swallowing with no history of trauma. The patient was diagnosed with plunging Ranula sized 4x3 cm based on USG findings. He underwent three months and 10 days course of Ayurvedic regime and two follow ups showing reduction in size of the cystic swelling. Conclusion: Several surgical techniques have been introduced to treat Ranula ranging from marsupialization, excision of Ranula, excision of sublingual glands, sclerotherapy with varying success and recurrence rate. Ayurvedic protocol aimed at holistic approach by pacifying the vitiated Doshas and showing marked regression in the cystic growth without making the patient undergo the pain and high cost and adverse effect as that of a surgical procedure.

Is there an ageing population Kuznets Curve?

ABSTRACT Based on a sample of 126 countries over the period of 1970 to 2019 and 5-year non-overlapping growth regressions, this study has found the existence of an inverted U-shaped ageing population Kuznets curve. The threshold levels below (above) which ageing population potentially promotes (hampers) economic and productivity growth are estimated. While the results signal the growing pressure of ageing population on economic/productivity growth, the impact is more pronounced on labour productivity growth and only for advanced economies. Our findings remain robust to alternative proxies of ageing population and longer period (10- and 15-year) non-overlapping growth regressions.