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The Survival and Financial Benefit of Investigator-Initiated Trials Conducted by Korean Cancer Study Group
No full textPurpose The Korean Cancer Study Group (KCSG) is a nationwide cancer clinical trial group dedicated to advancing investigator initiated trials (IITs) by conducting and supporting clinical trials. This study aims to review IITs conducted by KCSG and quantitatively evaluate the survival and financial benefits of IITs for patients. Materials and Methods We reviewed IITs conducted by KCSG from 1998 to 2023, analyzing progression-free survival (PFS) and overall survival (OS) gains for participants. PFS and OS benefits were calculated as the difference in median survival times between the intervention and control groups, multiplied by the number of patients in the intervention group. Financial benefits were assessed based on the cost of investigational products provided. Results From 1998 to 2023, KCSG conducted 310 IITs, with 133 completed and published. Of these, 21 were included in the survival analysis. The analysis revealed that 1,951 patients in the intervention groups gained a total of 2,558.4 months (213.2 years) of PFS and 2,501.6 months (208.5 years) of OS, with median gains of 1.31 months in PFS and 1.58 months in OS per patient. When analyzing only statistically significant results, PFS and OS gain per patients was 1.69 months and 3.02 months, respectively. Investigational drug cost analysis from six available IITs indicated that investigational products provided to 252 patients were valued at 10,400,077,294 won (approximately 8,046,481 US dollars), averaging about 41,270,148 won (approximately 31,930 US dollars) per patient. Conclusion Our findings, based on analysis of published research, suggest that IITs conducted by KCSG led to survival benefits for participants and, in some studies, may have provided financial benefits by providing investment drugs.N
Secreted LGALS3BP facilitates distant metastasis of breast cancer
No full textBackgroundPatients with estrogen receptor (ER)-positive breast cancer (BC) can be treated with endocrine therapy targeting ER, however, metastatic recurrence occurs in 25% of the patients who have initially been treated. Secreted proteins from tumors play important roles in cancer metastasis but previous methods for isolating secretory proteins had limitations in identifying novel targets.MethodsWe applied an in situ secretory protein labeling technique using TurboID to analyze secretome from tamoxifen-resistant (TAMR) BC. The increased expression of LGALS3BP was validated using western blotting, qPCR, ELISA, and IF. Chromatin immunoprecipitation was applied to analyze estrogen-dependent regulation of LGALS3BP transcription. The adhesive and angiogenic functions of LGALS3BP were evaluated by abrogating LGALS3BP expression using either shRNA-mediated knockdown or a neutralizing antibody. Xenograft mouse experiments were employed to assess the in vivo metastatic potential of TAMR cells and the LGALS3BP protein. Clinical evaluation of LGALS3BP risk was carried out with refractory clinical specimens from tamoxifen-treated ER-positive BC patients and publicly available databases.ResultsTAMR secretome analysis revealed that 176 proteins were secreted at least 2-fold more from MCF7/TAMR cells than from sensitive cells, and biological processes such as cell adhesion and angiogenesis were associated with the TAMR secretome. Galectin-3 binding protein (LGALS3BP) was one of the top 10 most highly secreted proteins in the TAMR secretome. The expression level of LGALS3BP was suppressed by estrogen signaling, which involves direct ER alpha binding to its promoter region. Secreted LGALS3BP in the TAMR secretome helped BC cells adhere to the extracellular matrix and promoted the tube formation of human umbilical vein endothelial cells. Compared with sensitive cells, xenograft animal experiments with MCF7/TAMR cells showed increased pulmonary metastasis, which completely disappeared in LGALS3BP-knockdown TAMR cells. Finally, higher levels of LGALS3BP were associated with poor prognosis in ER-positive BC patients treated with adjuvant tamoxifen in the clinic.ConclusionTAMR secretome analysis identified secretory proteins, such as LGALS3BP, that are involved in biological processes closely related to metastasis. Secreted LGALS3BP from the TAMR cells promoted adhesion of the cells to the extracellular matrix and vasculature formation, which may support metastasis of TAMR cells.Y
Four questions for teaching conflict for peace, justice, and sustainability: higher education roles and responsibilities
No full textConflict is an inescapable reality in contemporary life, and higher education (HE) is not immune. From armed conflicts to campus protests, university educators increasingly navigate volatile environments where teaching is intertwined with global struggles. Educators may face violence, displacement, or the effects of heightened militarization and censorship on campuses. As student movements advocating for peace and justice intensify, universities globally are witnessing growing tensions between academic freedom and state responses to perceived "controversial" issues, such as coloniality, human rights, and gender equity. Integrating insights from peace education (PE) and education in emergencies (EiE), the paper critically examines the role of HE in peacebuilding and/or conflict exacerbation. It raises four questions for university educators to reflect on as they teach about conflict and peace, exploring the essential role of HE in questioning and disrupting (or not) the essence of conflict and its relationships to violence, sustainability, and peacebuilding.Y
Discovery of highly active kynureninases for cancer immunotherapy through protein language model
No full textTailor-made enzymes empower a wide range of versatile applications, although searching for the desirable enzymes often requires high throughput screening and thus poses significant challenges. In this study, we employed homology searches and protein language models to discover and prioritize enzymes by their kinetic parameters. We aimed to discover kynureninases as a potentially versatile therapeutic enzyme, which hydrolyses L-kynurenine, a potent immunosuppressive metabolite, to overcome the immunosuppressive tumor microenvironment in anticancer therapy. Subsequently, we experimentally validated the efficacy of four top-ranked kynureninases under in vitro and in vivo conditions. Our findings revealed a catalytically most active one with a nearly twofold increase in turnover number over the prior best and a 3.4-fold reduction in tumor weight in mouse model comparisons. Consequently, our approach holds promise for the targeted quantitative enzyme discovery and selection suitable for specific applications with higher accuracy, significantly broadening the scope of enzyme utilization. A web-executable version of our workflow is available at seekrank.steineggerlab.com and our code is available as free open-source software at github.com/steineggerlab/SeekRank.N
Influence of prestroke glycemic status on outcomes by age in patients with acute ischemic stroke and diabetes mellitus
No full textBackground: This study aimed to explore the association between admission HbA1c and the risk of 1-year vascular outcomes stratified by age group in patients with acute ischemic stroke (AIS) and diabetes mellitus (DM). Methods: This study analyzed prospective multicenter data from patients with AIS and DM. Admission HbA1C were categorized as:<= 6.0%, 6.1%-7.0%, 7.1%-8.0%, and >8.0%. Age was analyzed in categories:<= 55 years, 56-65 years, 66-75 years, 76-85 years, and >85 years. The primary outcome was 1-year composite of stroke, MI, and all-cause mortality. The modifying effect of age on the relationships between HbA1c and 1-year primary outcome was explored by Cox proportional hazards model. Results: A total of 16,077 patients (age 69.0 +/- 12.4 years; 59.4% males) were analyzed in this study. Among patients <= 55 years, the hazard ratio (HR) of the 1-year primary outcomes increased with an HbA1C > 8.0% (adjusted HR 1.39[1.13-1.70]). For patients aged 56-65 and 66-75, the highest HRs were observed for an HbA1c of 7.1-8.0% (aHRs; 1.21 [1.01-1.46] and 1.22 [1.05-1.41], respectively). In the 85+ age group, the highest HR occurred for HbA1c <= 6.0% (aHR 1.47 [0.98-2.19]). The HbA1c 8.0% showed evident age-dependent heterogeneity in the post hoc HR plots. Conclusion: Our study revealed that in patients with AIS and diabetes under 55, higher admission hbA1c was associated with an increased risk of the 1-year primary outcome, while in patients aged over 85, lower HbA1c value (<= 6.0%) may be associated with an increased risk of vascular events. The results of our study suggest the age-stratified, heterogeneous associations between admission HbA1c and 1-year vascular outcomes in patients with AIS and diabetes.Y
Defect dynamics modeling of mesoscale plasticity
No full textThe collective motion of defects and their interaction are the basic building blocks for plastic deformation and corresponding mechanical behaviors of crystalline metals. Especially, dislocations among various defects are the "carrier" of plastic deformation in many crystalline materials, particularly ductile materials. To get a fundamental understanding of plastic deformation mechanisms, it calls for an integrated computational platform to simultaneously capture detailed defects characteristics across several length scales together with corresponding macroscopic mechanical response. In this paper, we present a three-dimensional mesoscale defect dynamics model to directly couple the three dimensional discrete dislocation dynamics model with continuum finite element method, aiming at capturing both size dependent plasticity at micron-, and submicron scale and constitutive behaviors at larger scales where such size-dependence disappear. Using non-singular dislocation theories, our model could accurately consider both short- and long-range elastic interactions between multiple dislocation segments with even higher computational efficiency than traditional dislocation dynamics simulations, together with the careful consideration of crystal/material rotation in the coupled framework. In addition, our model could directly model dislocation nucleation from stress concentrators such as a void, crack and indentor tip, which could allow us to investigate various defects' motion and their mutual interactions, predicting macroscopic mechanical response of complex structures. The developed concurrently coupled model could also consider multiphysical phenomena by solving coupled governing equations in finite element framework, which could shed light on complex defect behaviors under various physical environments.N
INTEGRATE IIa Phase III Study: Regorafenib for Refractory Advanced Gastric Cancer
No full textPURPOSETreatment options for refractory advanced gastric and esophagogastric junction cancer (AGOC) are limited. Regorafenib, an oral multikinase inhibitor, prolonged progression-free survival (PFS) versus placebo in the INTEGRATE I phase II trial. INTEGRATE IIa was designed to examine whether regorafenib improved overall survival (OS).METHODSA double-blind placebo-controlled phase III trial compared regorafenib and best supportive care (BSC) versus placebo and BSC for participants with confirmed evaluable metastatic/advanced AGOC who failed ≥two prior therapies on a 2:1 random assignment, stratified by tumor location, geographic region (Asia v rest of world), and prior vascular endothelial growth factor inhibitors. The primary end point was OS. Treatment efficacy on OS was first tested in the pooled INTEGRATE I + INTEGRATE IIa cohort and, if significant, then in the INTEGRATE IIa cohort. Secondary end points were PFS, objective response rate, safety, and quality of life (QoL).RESULTSINTEGRATE IIa enrolled 251 participants: 157 from Asia and 94 from rest of world and 169 received regorafenib and 82 received placebo. No significant heterogeneity was observed between INTEGRATE I and INTEGRATE IIa studies on OS. Pooled OS analysis hazard ratio (HR) was 0.70 (95% CI, 0.56 to 0.87; P =.001; 361 events). INTEGRATE IIa alone OS HR was 0.68 (95% CI, 0.52 to 0.90; P =.006; 238 events), the median OS was 4.5 months versus 4.0 months, and 12-month survival rates were 19% and 6%, for regorafenib versus placebo, respectively. After a preplanned adjustment for multiplicity, there were no statistically significant differences across regions or other prespecified subgroups. Regorafenib improved PFS (HR, 0.53 [95% CI, 0.40 to 0.70]; P <.0001) and delayed deterioration in global QoL (HR, 0.68 [95% CI, 0.52 to 0.89]; P =.0043). The toxicity profile was consistent with that of previous reports.CONCLUSIONRegorafenib improves survival compared with placebo in refractory AGOC.N
Amorphous IrOx nanoparticles on N-doped carbon matrix islands for enhancing proton exchange membrane water electrolysis
No full textThe development of an electrocatalyst and electrode that maintain their integrity under a high current density is vital for the advancement of PEMWE. In this context, we develop amorphous iridium oxide (IrOx) anchored on an N-doped carbon matrix island, directly formed on titanium porous transport layer through a simple method consisting of spray coating and pyrolysis. Remarkably, this configuration achieves 10 mA/cm(2) current density for oxygen evolution reaction (OER) in acidic electrolyte, with only a 240 mV overpotential required, and the durability of this structure is confirmed by long-term and accelerated stress tests. These merits enable the unit cell to achieve over 6 A/cm(2) at 2 V cell voltage without considerable degradation. This catalyst fulfills the requirement of the US Department of Energy's 2026 target in performance (> 3 A/cm(2) at 1.8 V) and in energy efficiency (> 65 %), as well as in the electricity cost for H-2 production (US $2.0/kg H-2).N
The Political Calculator in Jules Vernes De la terre à la lune and Autour de la lune
No full textThe mathematical calculations in Jules Vernes De la terre à la lune (1865) and Autour de la lune (1870) not only chart the way to the Moon but also plot out a political narrative. Specifically, as a challenge to the European colonial conquests of his time, Verne models an internationalist geographical expedition on the abstract and applicable qualities of both mathematics and fiction to construct a forward-looking yet achievable model. With numbers and words mounted on the canvas of nineteenth-century imperial Europe, Vernes lunar stories engender rich discussions on how literature, mathematics, and politics interconnect
Bintrafusp alfa and chemotherapy as first-line treatment in biliary tract cancer: A randomized phase 2/3 trial
No full textBackground and Aims: We compared the safety and efficacy of bintrafusp alfa (BA) in combination with gemcitabine+cisplatin (GemCis), to those of GemCis alone, in patients with biliary tract cancer.Y