bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic factors and nomogram for pulmonary resected high-grade neuroendocrine carcinomas: a 20-year single institutional real-world experience
Authors: Liu Lei , Zhang Jiaqi , Zhao Ke , Guo Chao , Huang Cheng , Li Shanqing , Chen Yeye
Published: June 2024

Background

Pulmonary high-grade neuroendocrine carcinomas(pHGNEC) encompassing small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are clinically aggressive tumors with poor prognosis. The role of surgery and prognostic factors guiding management remain unclear. We aimed to analyze prognosis following resection and identify predictive variables.

Methods

This retrospective study analyzed 259 patients undergoing pHGNEC resection from 2001–2023. Overall survival (OS) and disease-free survival (DFS) were evaluated using Kaplan–Meier curves. Prognostic factors were assessed with Cox regression and visualized using nomogram tools.

Results

Minimally invasive surgery was associated with better OS (p = 0.001) and DFS (p = 0.001). Higher T stage predicted worse OS (T2 p = 0.044, T4 p = 0.007) and DFS (T2 p = 0.020, T4 p = 0.004). Advanced TNM stage III (OS p = 0.018; DFS p = 0.015) and IV (OS p < 0.001; DFS p < 0.001) also correlated with poorer prognosis. In the SCLC subgroup, elevated preoperative CEA independently predicted worse OS (p = 0.012) and DFS (p = 0.004). T4 disease (OS p < 0.001; DFS p = 0.002) and advanced TNM staging (stage III OS p = 0.043; DFS p = 0.045; stage IV OS p < 0.001, DFS p < 0.001) were associated with worse outcomes. In LCNEC patients, VATS resection improved OS (p = 0.048) and DFS (p = 0.027) despite conversion. Prior malignancy predicted worse OS (p < 0.001). Advanced TNM disease (stage III OS p = 0.047; stage IV OS p = 0.003, DFS p = 0.005) were also negative prognostic factors. The prognostic nomogram incorporating above variables effectively stratified risk. Calibration plots revealed good correlation between predicted and actual survival.

Conclusions

We identified minimally invasive surgery, early TNM stage, younger age, and normal preoperative CEA as positive prognostic factors following pHGNEC resection. Our study provides an applicable prognostic nomogram to facilitate personalized pHGNEC management.
Enhanced interest in letters and numbers in autistic children
Authors: Ostrolenk Alexia , Gagnon David , Boisvert Mélanie , Lemire Océane , Dick Sophie-Catherine , Côté Marie-Pier , Mottron Laurent
Published: June 2024

Background

An intense and precocious interest in written material, together with a discrepancy between decoding and reading comprehension skills are defining criteria for hyperlexia, which is found in up to 20% of autistic individuals. It may represent the extreme end of a broader interest in written material in autism. This study examines the magnitude and nature of the interest in written material in a large population of autistic and non-autistic children.

Methods

All 701 children (391 autistic, 310 non-autistic) under the age of 7 referred to an autism assessment clinic over a span of 4 years were included. Ordinal logistic regressions assessed the association between diagnosis and the level of interest in letters and numbers. A nested sample of parents of 138 autistic, 99 non-autistic clinical, and 76 typically developing (TD) children completed a detailed questionnaire. Cox proportional hazards models analyzed the age of emergence of these interests. Linear regressions evaluated the association between diagnosis and interest level. The frequency of each behaviour showing interest and competence with letters and numbers were compared.

Results

In the two studies, 22 to 37% of autistic children had an intense or exclusive interest in letters. The odds of having a greater interest in letters was 2.78 times higher for autistic children than for non-autistic clinical children of the same age, and 3.49 times higher for the interest in numbers, even if 76% of autistic children were minimally or non-verbal. The age of emergence of these interests did not differ between autistic and TD children and did not depend on their level of oral language. Non-autistic children showed more interest in letters within a social context.

Limitations

The study holds limitations inherent to the use of a phone questionnaire with caregivers and missing sociodemographic information.

Conclusions

The emergence of the interest of autistic children toward written language is contemporaneous to the moment in their development where they display a strong deficit in oral language. Together with recent demonstrations of non-social development of oral language in some autistic children, precocious and intense interest in written material suggests that language acquisition in autism may follow an alternative developmental pathway.
Tunlametinib (HL-085) plus vemurafenib in patients with advanced BRAF V600-mutant solid tumors: an open-label, single-arm, multicenter, phase I study
Authors: Shi Yuankai , Han Xiaohong , Zhao Qian , Zheng YuLong , Chen Jianhua , Yu Xinmin , Fang Jian , Liu Yutao , Huang Dingzhi , Liu Tianshu , Shen Hong , Luo Suxia , Yu Hongsheng , Cao Yu , Zhang Xi , Hu Pei
Published: June 2024

Background

Tunlametinib (HL-085) is a novel, highly selective MEK inhibitor with substantial clinical activities in patients with NRAS-mutant melanoma. This phase I study evaluated the safety and preliminary efficacy of tunlametinib plus vemurafenib in patients with advanced BRAF V600-mutant solid tumors.

Methods

Patients with confirmed advanced BRAF V600-mutant solid tumors who had progressed on or shown intolerance or no available standard therapies were enrolled and received tunlametinib plus vemurafenib. This study consisted of a dose-escalation phase and a dose-expansion phase. Primary end points of this study were safety, the recommended phase II dose (RP2D), and preliminary efficacy.

Results

From August 17, 2018 to April 19, 2022, 72 patients were enrolled. No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. The RP2D for BRAF V600-mutant non-small cell lung cancer (NSCLC) patients was tunlametinib 9 mg plus vemurafenib 720 mg, twice daily (BID, bis in die). Until the data cut-off date of December 15, 2023, of 33 NSCLC patients with evaluable disease, the objective response rate (ORR) was 60.6% (20/33; 95% confidence interval [CI], 42.1–77.1), the median progression free survival (PFS) was 10.5 months (95%CI, 5.6–14.5) and median duration of response (DoR) was 11.3 months (95%CI, 6.8-NE). At the RP2D, ORR was 60.0% (9/15; 95% CI, 32.3–83.7), the median PFS was 10.5 months (95%CI, 5.6 -NE) and median DoR was 11.3 months (95%CI, 3.9-NE). Of 24 colorectal cancer patients with evaluable disease, the ORR was 25.0% (6/24; 95% CI, 5.6-NE). All 72 patients had treatment-related adverse events (TRAEs), and the most common grade 3–4 TRAEs were anemia (n = 13, 18.1%) and blood creatine phosphokinase increased (n = 10, 13.9%). Tunlametinib was absorbed rapidly with Tmax of 0.5–1 h. Vemurafeinib did not influence the system exposure of tunlametinib and vice versa, indicating no drug-drug interaction for this combination.

Conclusions

Tunlametinib (HL-085) plus vemurafenib had a favorable safety profile and showed promising antitumor activity in patients with BRAF V600-mutant solid tumors. The RP2D for NSCLC was tunlametinib 9 mg BID plus vemurafeinib 720 mg BID.

Trial Registration

ClinicalTrials.gov, NCT03781219.
Identification of a circulating long non-coding RNA signature panel in plasma as a novel biomarker for the detection of acute/early-stage HIV-1 infection
Authors: Biswas Santanu , Nagarajan Namrata , Hewlett Indira , Devadas Krishnakumar
Published: June 2024

Background

Individuals with acute / early HIV-1 infection are often unaware that they are infected with HIV-1 and may be involved in high-risk behavior leading to transmission of HIV-1. Identifying individuals with acute / early HIV-1 infection is critical to prevent further HIV-1 transmission, as diagnosis can lead to several effective HIV-1 prevention strategies. Identification of disease-stage specific non-viral host biomarkers would be useful as surrogate markers to accurately identify new HIV-1 infections. The goal of this study was to identify a panel of host derived plasma long non-coding RNAs (lncRNAs) that could serve as prognostic and predictive biomarkers to detect early/acute HIV-1 infection.

Methods

A total of 84 lncRNAs were analyzed in sixteen plasma samples from HIV-1 infected individuals and four healthy controls using the lncRNA PCR-array. Twenty-one lncRNAs were selected and validated in 80 plasma samples from HIV-1 infected individuals [HIV-1 infected patients in the eclipse stage (n = 20), acute stage (n = 20), post-seroconversion p31 negative stage (n = 20), and post-seroconversion p31 positive stage (n = 20) of infection] and 20 healthy controls. The validation study results were used to develop a plasma lncRNA panel that was evaluated in the panel test phase to detect early/acute HIV-1 infection in 52 independent samples.

Results

We identified a lncRNA panel (Pmodel−I) containing eight lncRNAs (DISC2, H19, IPW, KRASP1, NEAT1, PRINS, WT1-AS and ZFAS1) that could distinguish HIV-1 infection from healthy controls with high AUC 0·990 (95% CI 0.972-1.000), sensitivity (98.75%), and specificity (95%). We also found that Pmodel−II and Pmodel−III demonstrates 100% sensitivity and specificity (AUC 1·00; 95%CI:1·00–1·00) and could distinguish eclipse stage and acute stage of HIV-1 infection from healthy controls respectively. Antiretroviral treatment (ART) cumulatively restored the levels of lncRNAs to healthy controls levels.

Conclusion

lncRNA expression changes significantly in response to HIV-1 infection. Our findings also highlight the potential of using circulating lncRNAs to detect both the eclipse and acute stages of HIV-1 infection, which may help to shorten the window period and facilitate early detection and treatment initiation. Initiating ART treatment at this stage would significantly reduce HIV-1 transmission. The differentially expressed lncRNAs identified in this study could serve as potential prognostic and diagnostic biomarkers of HIV-1 infection, as well as new therapeutic targets.
Not too old to rock: ESR and OSL dating reveal Quaternary activity of the Periadriatic Fault in the Alps
Authors: Prince Erick , Tsukamoto Sumiko , Grützner Christoph , Vrabec Marko , Ustaszewski Kamil
Published: June 2024

The Periadriatic Fault system (PAF) ranks among the largest post-collisional structures of the European Alps. Recent geodetic data suggest that a fraction of the Adria–Europe convergence is still being accommodated in the Eastern Alps. However, the historical seismicity records along the easternmost segment of the PAF are ambiguous, and instrumental records indicate that seismotectonic deformation is mostly concentrated in the adjacent Southern Alps and Dinarides. Both electron spin resonance (ESR) and optically stimulated luminescence (OSL) dating methods can be used to date coseismic slip (with a combined range covering a few decades to a couple of million years) in slowly deforming fault zones, such as the PAF. Since the saturation doses of the quartz ESR signals are larger than quartz and feldspar OSL, ESR enables establishing a maximum age of the last resetting event of the system, while OSL allows constraining their minimum age when the signal is in saturation. We collected fault gouge samples from three localities along the easternmost segment of the PAF. For ESR, we measured the signals from the Al center in quartz comparing the results from the single aliquot additive dose (SAAD) and single aliquot regenerative (SAR) dose protocols. For OSL, we recorded the infrared stimulated luminescence signal at 50°C (IR50) and post-infrared infrared-stimulated luminescence signal at 225 °C (pIRIR225). Our dating results indicate that the studied segment of the PAF system accommodated seismotectonic deformation during the Quaternary, with a maximum age for the last resetting event of the system ranging from 1075 ± 48 to 552 ± 26 ka (ESR SAR) and minimum ages in the range from 196 ± 12 to 281 ± 16 ka (saturation of pIRIR225). The obtained ages suggest that the studied segment of the PAF could be considered at least as a potentially active fault.

Graphical abstract
Prevalence of vitamin B 12 deficiency and associated factors among primary school children: North East Ethiopia: multicenter cross-sectional study
Authors: Melaku Ermiyas Endewunet , Urgie Besufekad Mulugeta , Tilahun Alemnesh Tesema , Assefa Hilina Ketema , Abebe Alemayehu Abera , Tefera Aklile Semu
Published: June 2024

Background

The prevalence of Vitamin B12 deficiency is common and is more frequent in low- and middle-income countries with a poor or inadequate diet of animal foods. In Ethiopia, researches related to the status of micronutrients in children are limited. Therefore, this study aimed to assess the prevalence of vitamin B12 deficiency and associated factors among primary school children.

Methods

A cross-sectional study design was conducted from January 10-February 30/2023. A total of 514 students were selected using a systematic random sampling technique. Face-to-face interviews using a structured questionnaire, document review, anthropometric measurement, and laboratory studies were implemented to collect data. Data was analyzed by STATA version 14 and summarized by using frequency tables and graphs. Logistic regression analysis was done to identify factors associated with vitamin B12 Deficiency.

Results

About 34% of the students were found to have vitamin B12 deficiency. Not Consuming animal products (AOR = 1.83, 95% CI:1.20–2.79) and low body mass index (AOR = 1.62, 95% CI:1.05–2.47) were associated with vitamin B12 deficiency.

Conclusions

The study revealed a notable high deficiency of vitamin B12 in primary school students. Consumption of animal products and BMI were identified as statically significant associated factors with serum concentration of vitamin B12.
Doppler ultrasound compared to shear wave elastography for assessment of liver cirrhosis
Authors: Ellaban Heba Said , Afify Sameh Abdel Mawgoud , Abdelgawad Mohamed Saied
Published: June 2024

Background

The progression of liver fibrosis to cirrhosis is a dynamic process necessitating non-invasive evaluation modalities. This study aims to evaluate the ability of Doppler ultrasound studies (DUS) in defining morphological and hemodynamic blood flow changes in the hepatic vasculature coinciding with advanced liver fibrosis.

Methods

A prospective study was conducted on 100 patients with liver cirrhosis (F4). All cases underwent liver stiffness (LS) measurement by shear wave elastography (SWE), along with DUS to evaluate the liver texture, splenic size, hepatic artery resistive index (HARI), portal and splenic vein diameters, portal vein velocity (PVV), and hepatic vein waveform (HVV). All measures were assessed concurrently with a highly qualified single operator.

Results

Patients aged 55.5 ± 10.2 years with male predominance (72%). A highly significant correlation was found between LS by SWE and hepatic parenchymal texture, splenic size, portal vein width, and HVV (monophasic and biphasic) (p < 0.001). There were also high significant positive correlations (p < 0.001) between LS and PVV. However, there was no definitive correlation between LS and HARI, as well as splenic vein diameter.

Conclusion

The widely available economic Doppler studies including portal vein velocity and hepatic vein waveform changes could be of substantial diagnostic value to liver cirrhosis.

Study design

Prospective cohort study, employing descriptive and analytical statistics.
Mechanical and Fatigue behavior of G22NiMoCr5-6 and G18NiMoCr3-6 used in heavy-duty crawler track plates
Authors: Elsabbagh Ahmed , El-Kashif Emad , Sayed Sahour
Published: June 2024

G22NiMoCr5-6 and G18NiMoCr3-6 steels are commonly used in the manufacturing of crawler track plates of heavy-duty equipment due to their enhanced mechanical properties which allow them to be suitable for this particular application. This research aims to investigate the mechanical and fatigue behavior of both material grades to evaluate their performance in the manufacturing of heavy-duty crawler track plates. In the present work, experimental investigations were carried out including chemical composition, tensile, hardness, Charpy impact, and low-cycle fatigue tests. Also, metallographic examination was conducted to show the microstructure of both materials. Based on the experimental analysis results, the bainitic structure of G18NiMoCr3-6 was found to have longer fatigue life and higher toughness than the tempered-martensitic structure of G22NiMoCr5-6 which qualifies G18NiMoCr3-6 to be more suitable for manufacturing of heavy-duty crawler track plates than G22NiMoCr5-6 steel.
The impact of a zero-flaring system on gas plants, environment, and health
Authors: Taha Ayman , Abdelalim Galal , AboulFotouh Tarek
Published: June 2024

Continuous natural gas flaring wastes significant energy resources and increases greenhouse gas emissions, contributing to global warming. Our work provides an overview of a technique to recover flare gas and reduce CO2 emissions to a minimum level. There are two methods to recover flare gas: the recovery of natural gas liquids and sales gas production by existing LPG unit and the production of liquid fuels by mini-GTL unit (gas to liquid). This study was conducted using real data from the field. All cases were simulated using Aspen HYSYS software. The mini-GTL unit is modeled using an autothermal reforming method. CO2 emissions will be reduced by 107.68 tonne/day in both methods. Economic analyses revealed that the NGL and sales gas product has a net present value (NPV) of 77.03 MMUSD, while the mini-GTL product has an NPV of 73.7 MMUSD. The study showed that we could extract natural gas liquids (NGLs), including propane, LPG, and sales gas, from the flare gas or convert it to liquid products, including gasoline and diesel. The expected internal rate of return (IRR) and payout time (POT) for NGL and sales gas method are 150.73% and 0.27 years, respectively. The mini-GTL method is recommended due to Egypt’s petroleum fuel shortage and the best solution without an entry point to the Egyptian national gas grid in the plant. However, the IRR and POT for the mini-GTL method are 30.09% and 1.19 years, respectively, and it needs more CAPEX than the NGL and sales gas method.

Graphical Abstract
Clinically significant variant classification resulting from the addition of RNA sequencing: Experience at high-volume cancer genetics center.
Authors: Rudowski Sydney , Gallant Alexis , Stupar Ana , Reeves Ashley , Campian Sarah , Zakalik Dana
Published: June 2024

10603

Background: Germline cancer genetic testing plays an important role in prevention, early detection, and targeted therapy1. The increasing use of multi-gene panel testing (MGPT) underscores the importance of accurate variant classification. We report on the significant contribution of RNA analysis to variant classification with impact on clinical care. Methods: A total of 6343 patients who presented to the Nancy & James Grosfeld Cancer Genetics Center between 2019 to 2023 and underwent MGPT at a laboratory with RNA sequencing were evaluated. Patients underwent MGPT using standard DNA technology with added RNA sequencing. We analyzed these patients for clinically significant variant reclassification which includes upgrades from non-actionable variants of uncertain significance (VUS) to pathogenic/likely pathogenic (P/LP) or P/LP to VUS as a significant downgrade. Results: A total of 177 patients (2.8%) had a variant classification significantly impacted by RNA sequencing. Of those 177 patients 45 (25.4%) had clinically relevant change due to their reclassification which resulted in a change in medical or surgical management. The majority of these 45 patients were upgraded from a non-actionable result to P/LP and 14 were downgraded to non-actionable. The clinically significant upgrades included the following genes: BRCA1/2 (5), MSH2 (4), MSH6 (1), PMS2 (1), ATM (5), CHEK2 (5), RAD51C (5), CDH1 (2), and PALB2 (3), which lead to evidence-based early detection and prevention. The clinically significant downgrades included the following genes: BRCA2 (5), RAD50 (1), and RAD51D (8), which allowed for a reduction in medical burden. Of the 177 cases impacted by RNA sequencing, 61 uncertain variants (34.4%) were downgraded to benign polymorphisms, helping to reduce uncertainty regarding management. Conclusions: Our study demonstrates the importance and added benefit of RNA sequencing in variant classification for patients undergoing multigene panel testing for hereditary cancer. The addition of RNA sequencing improved identification of individuals at increased risk, while lowering the number of uncertain variants. This improved technology will allow for a more precise approach to cancer screening, treatment and prevention.
FURTHER: A global study to evaluate furmonertinib in patients with EGFR mutant NSCLC including uncommon EGFR mutations (FURMO-002).
Authors: Le Xiuning , Spira Alexander I. , Gadgeel Shirish M. , Riess Jonathan W. , Yu Yan , Zhao Yanqiu , Cheng Ying , Juan-Vidal Oscar , Gao Bo , Yoh Kiyotaka , Forster Martin , Kitazono Satoru , Hayashi Hidetoshi , Planchard David , Jiang Yong , Baio Nichole , Kowanetz Marcin , Leung William , Hsu Jerry Y. , Wang Jie
Published: June 2024

TPS8666

Background: Furmonertinib (AST2818) is an oral, highly brain-penetrant, and broadly active mutation-selective epidermal growth factor receptor ( EGFR) inhibitor engineered for broad activity and selectivity across EGFRmutations (mts) (1). Furmonertinib is approved in China for first-line advanced NSCLC with EGFR Ex19del or L858R mts based on the progression-free survival benefit observed in the Phase 3 study versus gefitinib (FURLONG). Furmonertinib has also demonstrated promising interim efficacy and safety in patients (pts) with NSCLC harboring EGFR exon 20 insertion (ex20ins) mts with a confirmed overall response rate (ORR) of 78.6% (n=28) by blinded independent central review (BICR) and a preliminary median duration of response (DoR) of 15.2 months in the front-line setting (FAVOUR study; see Han et al., WCLC 2023). Furmonertinib recently obtained FDA Breakthrough Therapy Designation for the treatment of pts with advanced NSCLC with EGFR ex20ins mts. P-loop and αC-helix Compressing (PACC) mts represent another subset of uncommon EGFR mts (2) that are similar to ex20ins mts in narrowing the drug-binding pocket; including G719X, S768I, E709X, L747X, V774M. Preclinical data indicating that furmonertinib is potent in models harboring EGFR PACC mts Developing efficacious, well-tolerated, and CNS-penetrant medicines for NSCLC pts with EGFR ex20ins mts and PACC mts remains an unmet need. Methods: FURTHER (FURMO-002) is the first global trial evaluating furmonertinib in NSCLC pts with EGFR and HER2 mts in North America, Europe, and the Asia-Pacific. FURTHER is a phase 1b, open-label, multicenter study in which pts will be treated orally with furmonertinib daily. For Stage 1 dose-escalation, the primary endpoint is incidence and severity of adverse events, including dose limiting toxicities and has been completed. For Stage 2 dose expansion, approximately 120 pts will be enrolled across 4 expansion cohorts. Stage 2 Cohorts 1-3 dose expansion cohorts will enroll pts with previously treated, locally advanced or metastatic NSCLC pts with either EGFR ex20ins mts, HER2 ex20ins mts, or EGFR activating mts, respectively. Cohorts 1-3 allow enrollment of pts with prior EGFR or HER2-directed therapy. Stage 2 Cohort 4 will enroll EGFR TKI-naïve NSCLC pts with EGFR PACC mts. Key inclusion criteria include documented EGFR or HER2 mts by local testing and measurable disease per RECIST v1.1. Stage 2 primary endpoint is ORR using RECIST v1.1. Key secondary endpoints include progression-free survival and overall survival. Stage 2 enrollment is ongoing. 1. Musib et al., NACLC 2022. 2. Robichaux et al., 2021. Clinical trial information: NCT05364073 .
REZILIENT3: Phase 3 study of zipalertinib plus chemotherapy in patients with previously untreated, advanced nonsquamous non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) mutations.
Authors: Yu Helena Alexandra , Besse Benjamin , Nishio Makoto , Cheng Ying , Wei Li , Wacheck Volker , Heymach John
Published: June 2024

TPS8671

Background: Despite recent advances, tolerable and effective treatments for patients with NSCLC harboring EGFR ex20ins mutations are needed, particularly in the first-line setting, where platinum-based chemotherapy remains the standard of care. Zipalertinib (CLN-081/TAS6417), an oral tyrosine kinase inhibitor (TKI) of EGFR with broad activity against EGFR mutations, showed encouraging antitumor activity in heavily pretreated patients with EGFR ex20ins–mutant NSCLC, leading to ‘Breakthrough Therapy’ designation by the U.S. Food and Drug Administration in January 2022. Data suggest that combining EGFR TKIs with chemotherapy can improve antitumor efficacy versus chemotherapy or TKI treatment alone in patients with EGFR-mutated nonsquamous NSCLC. REZILIENT3 is a pivotal phase 3 study designed to compare the efficacy and safety of zipalertinib plus first-line standard-of-care platinum-based chemotherapy versus chemotherapy alone in previously untreated patients with nonsquamous NSCLC harboring EGFR ex20ins mutations. Methods: This randomized, controlled, open-label, phase 3 study (NCT05973773) will be conducted in two parts. Part A (safety lead-in) will confirm the safety of zipalertinib 100 mg twice daily as the recommended dose in combination with chemotherapy in patients with locally advanced or metastatic nonsquamous NSCLC harboring uncommon EGFRmutations. In Part B (randomized part), patients with EGFR ex20ins mutations and at least one measurable lesion (per Response Evaluation Criteria in Solid Tumours, version 1.1) will be randomized 1:1 to zipalertinib plus chemotherapy or chemotherapy alone, stratified by Eastern Cooperative Oncology Group performance status (0/1), brain metastases (yes/no), and geography (Asia/rest of world). Zipalertinib will be administered orally at a starting dose of 100 mg twice daily (pending confirmation in Part A). Chemotherapy (pemetrexed 500 mg/m² plus cisplatin 75 mg/m² or carboplatin area under the curve 5 mg/mL/min) will be administered intravenously on Day 1 of each cycle (carboplatin/cisplatin for four cycles). The primary objective in Part A is safety and tolerability. In Part B, the primary objective is efficacy; progression-free survival assessed by blinded independent central review is the primary endpoint. Secondary endpoints include overall survival, investigator-assessed progression-free survival, objective response rate, duration of response, disease control rate, safety, intracranial efficacy endpoints, and quality of life. Part A is anticipated to enroll between 6 and 12 patients, while Part B is estimated to enroll approximately 300 patients. Enrollment commenced in June 2023. Clinical trial information: NCT05973773 .
Novel RNA-nanoparticle vaccine for the treatment of early melanoma recurrence following adjuvant anti-PD-1 antibody therapy.
Authors: Doonan Bently Patrick , Shaw Christiana M. , Lee Ji-Hyun , Simon Manso Eugenio , Mendez-Gomez Hector , Von Roemeling Christina , Mitchell Duane Anthony , Sayour Elias , George Thomas J.
Published: June 2024

TPS9609

Background: Melanoma is a major public health concern with an anticipated increase in prevalence and incidence in the coming years. Early detection and surgical management remain the mainstay of treatment of early-stage disease and use of adjuvant immunotherapy has improved outcomes for patients with more aggressive (IIB-IIC) local disease or those with lymph node involvement (IIIA-IIID). Based on the tolerability and efficacy across subjects with both BRAF mutated and wildtype melanoma anti-PD1 (aPD1) therapy with either nivolumab or pembrolizumab are considered first line treatment in this setting. Adjuvant aPD1 therapy has significant improvement in relapse free survival (RFS) yet 25-30% of subjects will have disease recurrence within 1 year of surgery. When disease recurs, the response rate to immunotherapy is significantly reduced, re-challenged with aPD1 therapy has shown an Objective Response Rate (ORR) of zero and a marginally better response to CTLA-4 blockade. Novel strategies are needed for this at-risk population with early aPD1 resistance. To address this need we have developed a novel multi-lamellar lipid-nanoparticle complexed with total-tumor derived mRNA administered intravenously to restore responsiveness to aPD1 through reprogramming the tumor microenvironment (TME) bridging an innate and adaptive immune response. We have designed a clinical trial in which patients who progress on while on aPD1 therapy or within 6 months of therapy will have tumor sampled and a personalized lipid-nanoparticle vaccine generated. This vaccine is then administered IV for a total of 3 doses spanning 6 weeks to reprogram the TME and restore response to aPD1 which will be resumed on completion of vaccine series. This phase I study will assess initial feasibility and safety of vaccine generation, utilize ctDNA surveillance as early detection of adjuvant failure, and provide essential biologic information on immunotherapy resistance to aPD1 therapy. Methods: We have designed a modified 3+3 phase I clinical trial that will enroll subjects who have evidence of progressive disease (PD) by ctDNA and/or RECIST 1.1 criteria while receiving adjuvant aPD1 therapy, or those who progress within 6 months of completion of treatment for stage IIB-IIID melanoma. The goal of this study is to assess safety, tolerability, and feasibility of tumor specific RNA-LPs. Important biological correlates will also be collected and analyzed including tumor tissue sampling at initial time of checkpoint resistance and following vaccination series to identify key changes to the TME and tumor induced by lipid-nanoparticle vaccine administration. Clinical trial information: NCT05264974 .
Δημιουργία on-line αρχαιοελληνικού - νέου ελληνικού θησαυρού για διδακτικές εφαρμογές
Authors: Σαλβερίδου Κυριακή
Published: June 2024

Στόχος της παρούσας έρευνας είναι η μελέτη, η σχεδίαση και η υλοποίηση ενός online δίγλωσσου Αρχαιοελληνικού - Νεοελληνικού θησαυρού, του AMGthes (Ancient Modern Greek thesaurus) που επικεντρώνεται στις εκπαιδευτικές ανάγκες μαθητών Γυμνασίου και Λυκείου. Συγκεκριμένα διερευνάται το πώς ένας σύγχρονος διαδικτυακός πόρος με εμπλουτισμένες σημασιολογικές δομές μπορεί να βοηθήσει τους μαθητές να κατανοήσουν καλύτερα το εννοιολογικό πλαίσιο των αρχαίων ελληνικών κειμένων, να εντοπίσουν συναφείς έννοιες, συνώνυμους και αντώνυμους όρους στα Αρχαία Ελληνικά αλλά και την απόδοσή τους στα Νέα Ελληνικά. Επιπρόσθετα, προτείνονται σχεδιαστικές προσεγγίσεις για την ενσωμάτωσή μηχανισμών παιχνιδοποίησης σε διαδικτυακούς γλωσσικούς πόρους.Τα λήμματα έχουν επιλεγεί από τη διδακτέα ύλη του μαθήματος των Αρχαίων Ελληνικών των τριών τάξεων του Γυμνασίου και των τριών τάξεων του Λυκείου. Πηγή αναφοράς για την ταξινόμηση των λημμάτων αποτελεί το Αντιλεξικόν του Βοσταντζόγλου, η οργάνωση του οποίου υιοθετήθηκε. Η αποτύπωση και ανάλυση επιλεγμένων όρων (ουσιαστικά, ρήματα, επίθετα και επιρρήματα) πλαισιώνουν επαρκώς τον γλωσσικό πλούτο και το κύριο νόημα των υπό μελέτη κειμένων.Προκειμένου να σχεδιαστεί η μικροδομή και η μακροδομή του θησαυρού, ακολουθήθηκε το λεξικογραφικό πρωτόκολλο που ανταποκρίνεται στις προδιαγραφές της σύγχρονης λεξικογραφίας. Λαμβάνοντας υπόψη όλες τις νεότερες προσεγγίσεις, καθορίστηκε η μεσοδομή και η μεγαδομή του AMGthes για να εξυπηρετεί τις ανάγκες του σύγχρονου χρήστη. Παράλληλα παρουσιάζονται αναλυτικά οι λειτουργικές απαιτήσεις, οι προδιαγραφές και οι τεχνολογίες που χρησιμοποιήθηκαν για τη σχεδίαση και ανάπτυξη των δεδομένων, των διεπαφών και των υπηρεσιών του online εργαλείου.Ο θησαυρός AMGthes συμβάλλει στον εμπλουτισμό των περιορισμένων σε διαθεσιμότητα παιδαγωγικών ψηφιακών πόρων για τη διδασκαλία της Αρχαίας Ελληνικής γλώσσας, αλλά και στην ενθάρρυνση για τον αποτελεσματικό σχεδιασμό διαδικτυακών εργαλείων και εξελιγμένων προγραμμάτων. Οι σύγχρονοι διαδικτυακοί γλωσσικοί πόροι μπορούν να υποστηρίξουν καλύτερα τις εκπαιδευτικές ανάγκες και να οδηγήσουν σε πιο ποιοτικά αποτελέσματα σχετικά με τις επιδόσεις των μαθητών.
Międzynarodowe aspekty toruńskich obchodów jubileuszu 500-lecia urodzin Mikołaja Kopernika w roku 1973. Wybrane wydarzenia
Authors: Bohr Iwo
Published: June 2024

W niniejszym artykule zostaną omówione najważniejsze wydarzenia międzynarodowe zorganizowane w Toruniu w roku 1973 w ramach obchodów jubileuszu 500-lecia urodzin Mikołaja Kopernika. Szczególna uwaga zostanie poświęcona dwóm kluczowym zjazdom naukowym: sympozjum pod nazwą „Badanie Układu Planetarnego” oraz Colloquia Copernicana, czyli obradom poświęconym historii astronomii i recepcji dzieła Kopernika. Wydarzenia jubileuszowe zostaną omówione w kontekście zjawisk zachodzących w polityce międzynarodowej, takich jak odprężenie czy Ostpolitik realizowanej przez RFN, a także z uwzględnieniem polityki krajowej. Szczególna uwaga zostanie poświęcona stopniowemu otwieraniu się Polski na świat w okresie późnych rządów Władysława Gomułki i wczesnych Edwarda Gierka. Uroczystości jubileuszowe miały wpisywać się w propagowanie w świecie obrazu Polski jako kraju szybko modernizującego się. W artykule przedstawiono krótko starania profesor Wilhelminy Iwanowskiej mające na celu obronę planów rozbudowy zaplecza lokalowego i instrumentalnego toruńskiej radioastronomii, którym zagrażało wycofanie finansowania.
Tajemnica koguta z „Od Nowy”
Authors: Szmak Andrzej
Published: June 2024

Znak graficzny (logo) klubu studentów Torunia „Od Nowa” w postaci stylizowanego koguta z wpisaną w ogon nazwą klubu pojawił się po raz pierwszy na zaproszeniach, kartach wstępu i programach klubowych na przełomie lat 60./70. Kogut z „Od Nowy” to jednak nie tylko symbol graficzny o ponad 50-letniej tradycji, lecz także świadek ciągłości działalności kulturalnej wielu roczników studentów toruńskiej Uczelni zwłaszcza w czasach, gdy kultura studencka była jedyną znaczącą, śmiałą i twórczą alternatywą dla kultury masowej lansowanej, narzucanej i cenzurowanej przez peerelowskie władze. Kto był autorem znaku graficznego „Od Nowy”? Na to pytanie nie ma jednoznacznej odpowiedzi.
Znaki towarowe przedsiębiorstw toruńskich zarejestrowane dla branży spożywczej w latach 1924–1939
Authors: Orłowska-Radecka Klaudia
Published: June 2024

Niniejszy artykuł stanowi syntetyczne opracowanie problematyki znaków towarowych, zarejestrowanych dla produktów spożywczych w okresie międzywojennym na rzecz przedsiębiorstw toruńskich, a jednocześnie jest pierwszą próbą podjęcia tematu znaków towarowych w przestrzeni Torunia – zagadnienie to dotychczas pozostawało poza zainteresowaniem badaczy. Jako podstawowe źródło badawcze wykorzystano ponad 180 egzemplarzy „Wiadomości Urzędu Patentowego” z lat 1924–1939. Część główna artykułu została poprzedzona wstępem z uwzględnieniem podstawowych zagadnień – definicji znaku towarowego, historii znaku towarowego na świecie i w Polsce, początków działania Urzędu Patentowego Rzeczypospolitej Polskiej oraz ogólnej charakterystyki znaków towarowych zgłoszonych przez toruńskie przedsiębiorstwa. W dalszej kolejności przedstawiono krótką historię 9 przedsiębiorstw wraz z opisem zarejestrowanych znaków towarowych. Do artykułu dołączono ilustracje z przedstawieniem najważniejszych znaków graficznych i słowno-graficznych zarejestrowanych w latach 1924–1939 dla produktów spożywczych.
Los efectos singulares de las violencias generalizadas y sus consecuencias sobre el sujeto
Authors: Gutiérrez Peláez Miguel
Published: June 2024

El siguiente trabajo, que hace parte de la investigación “Trauma y psicoanálisis contemporáneo (2017-2019)” del Programa de Psicología de la Universidad del Rosario, recoge aspectos nodales para la comprensión de las consecuencias psicológicas que pueden producir los acontecimientos traumáticos vividos en el contexto del conflicto armado colombiano. Las viñetas clínicas presentadas se derivan de mi trabajo clínico tanto en el consultorio como en el campo. La escucha derivada de esas experiencias y orientada por el psicoanálisis ha permitido discernir aspectos singulares de la especificidad del trauma y los efectos que puede llegar a producir en un sujeto. Las conclusiones procedentes del trabajo buscan aportar a la comprensión de los efectos de los diversos tipos de violencias sobre un sujeto determinado, comprensión que puede ser valiosa no solo para el profesional que interviene desde contextos clínicos, sino para todo aquel que dirige su escucha o su palabra a personas y poblaciones expuestas a contextos de violencia.
Efficient Nested Simulation Experiment Design via the Likelihood Ratio Method
Authors: Feng Ben Mingbin , Song Eunhye
Published: June 2024

In the nested simulation literature, a common assumption is that the experimenter can choose the number of outer scenarios to sample. This paper considers the case when the experimenter is given a fixed set of outer scenarios from an external entity. We propose a nested simulation experiment design that pools inner replications from one scenario to estimate another scenario’s conditional mean via the likelihood ratio method. Given the outer scenarios, we decide how many inner replications to run at each outer scenario as well as how to pool the inner replications by solving a bilevel optimization problem that minimizes the total simulation effort. We provide asymptotic analyses on the convergence rates of the performance measure estimators computed from the optimized experiment design. Under some assumptions, the optimized design achieves [Formula: see text] mean squared error of the estimators given simulation budget [Formula: see text]. Numerical experiments demonstrate that our design outperforms a state-of-the-art design that pools replications via regression.

History: Accepted by Bruno Tuffin, Area Editor for Simulation.

Funding: This work was supported by the National Science Foundation [Grant CMMI-2045400] and the Natural Sciences and Engineering Research Council of Canada [Grant RGPIN-2018-03755].

Supplemental Material: The software that supports the findings of this study is available within the paper and its Supplemental Information ( https://pubsonline.informs.org/doi/suppl/10.1287/ijoc.2022.0392 ) as well as from the IJOC GitHub software repository ( https://github.com/INFORMSJoC/2022.0392 ). The complete IJOC Software and Data Repository is available at https://informsjoc.github.io/ .
Planning Service Protocols for Extra-Long Trains with Transfers
Authors: Osorio Jesus , Shen Shiyu , Ouyang Yanfeng
Published: June 2024

This paper presents a modeling framework for optimizing operational protocols of extra-long trains (XLTs) in metro systems (i.e., trains longer than station platforms). With the rising travel demand in megacities, metro systems face challenges such as overcrowded stations, delays, and passenger anxieties. XLTs have been proposed as a promising solution to increase metro line capacity without additional infrastructure construction. The study explores the trade-offs between the additional capacity gained through complex protocols, the potential benefits of protocols with inline transfers, and the importance of effective passenger information systems from both passengers’ and operators’ perspectives. Mathematical programs are proposed to optimize protocols for a given demand distribution and to estimate the maximum line capacity of an XLT system. The benefits of implementing XLTs are evaluated in hypothetical and real-world cases with varying demand distributions and network sizes. The results demonstrate significant capacity increases ranging from 24% to 126% as compared with regular train operations, depending on system parameters and demand distribution. These findings demonstrate promise for using such systems to improve metro line capacity in the real world.

History: This paper has been accepted for the Transportation Science Special Issue on ISTTT 25 Conference.

Funding: The work was supported in part by the University of Illinois, Urbana Champaign [Grant Grainger STII Seed Fund] and the Zhejiang University-University of Illinois Urbana-Champaign Institute [Grant DREMES-202001].

Supplemental Material: The online appendix is available at https://doi.org/10.1287/trsc.2024.0527 .
When bases compete: A voting model of lexical conservatism
Authors: Breiss Canaan
Published: June 2024

Abstract: This article examines lexical conservatism (Steriade 1997), a phenomenon whereby the distribution of stem allomorphs in a morphological paradigm influences the way that paradigm accommodates derived members. Specifically, a phonological alternation applies in a derived member only if an existing form is present elsewhere in the paradigm that offers the needed phonological material. Thus illústrable undergoes stress shift because the existing word illústrative contains the illústr- stem allomorph. In contrast, * irrígable is judged worse than írrigable , since there is no existing form in * irríg- . In four experiments with speakers of English and Mexican Spanish, I demonstrate that this dependency between paradigm structure and application of phonological processes generalizes to entirely novel words in a probabilistic manner. Further, I find that a broad range of stem allomorphs in a paradigm play a role in determining the form of the novel word, rather than only those that could reduce the markedness of the novel form, contra previous studies. I propose a novel grammatical model where bases get to ‘vote’ on the shape of the novel form: all stem allomorphs in a lexical entry stand in a correspondence relation to the novel form and exert their influence via multiple faithfulness constraints, which compete with standard markedness constraints in a probabilistic phonological grammar.
Deconstructing
the Distinction
Between Religious
Experience and
Psychopathology
Authors: Rashed Mohammed Abouelleil
Published: June 2024

Debates on the distinction between religious
experience and mental disorder tend to assume, rather
than argue for, the existence of unique types of experience: the religious and the psychopathological. This paper interrogates this approach to the problem. It deconstructs the distinction by examining what the distinction
is about beyond the terms in which it is presented and
whether it matters who is trying to make it. A key idea is
that one’s standpoint in the debate—that is, whether one
adopts a religious or a secular standpoint—determines
what they can say about the distinction. This leads to
the central argument of the first part of the paper: The
distinction between religious experience and mental
disorder can only be invoked from a secular standpoint
but can only be clarified from a religious standpoint. In
other words, if you have the grounds to invoke it, you
cannot have the tools to clarify it; and if you have the
tools to clarify it, you do not have the grounds to invoke
it. In the second part, the paper follows through the
implications, from a secular standpoint, of accepting this
argument. It appeals to the politics of difference and to
mental health activism to argue against the binary view
whereby mental distress is either illness and incapacity
or a path to purpose and identity.
Detailed characterization of a high-gain, low differential modal gain and low gain flatness integrated FM-EDFA for multi-wavelength amplification
Authors: Zhou Shiqi , Shen Lei , Liao Zhaolong , Qi Junjie , Ding Yuanpeng , Zhang Hui , Chu Jun , Zhang Lei , Wang Jianshuai , Pei Li , Luo Jie
Published: June 2024

In this paper, an integrated few-mode erbium-doped fiber amplifier (FM-EDFA), with high gain, low differential modal gain (DMG), and low gain flatness for multi-wavelength amplification, is constructed using homemade weakly-coupled ring-core few-mode erbium-doped fiber (FM-EDF) and low insertion-loss passive components. The gain characteristics of the FM-EDFA for multi-wavelength amplification are analyzed in detail and compared with single-wavelength amplification. The experimental results demonstrate that, although multi-wavelength amplification in different modes has an impact on the gain characteristics, through simple LP01 core pumping only, all guided modes can achieve a gain higher than 22.4 dB when simultaneously amplifying 8 wavelength channels. The DMG is less than 1.179 dB, the minimum DMG across the C-band is as low as 0.168 dB, and the wavelength gain flatness is less than 3.232 dB. Furthermore, when the three-signal mode is multiplexed for amplification, the DMG can be stabilised at less than 2 dB. The constructed FM-EDFA can achieve gain equalization in multi-wavelength amplification across the C-band, which has essential practical applications in long-haul WDM-MDM transmission systems.
Compact low-repetition-rate femtosecond optical parametric oscillators enabled by Herriott cells
Authors: Allan Ewan , Bajek David , McCracken Richard A.
Published: June 2024

We report the design and characterization of a femtosecond optical parametric oscillator containing an intracavity Herriott cell. Pumped by a 49.16-MHz Yb:fiber laser, the signal wavelength could be tuned over 1440-1530 nm, with the Herriott cell containing 81% of the free-space cavity length required for synchronous operation. We also report a 12.29-MHz OPO using a sub-harmonic pumping approach, extending the Herriott cell OPO concept to low-repetition-rate cavities.
Integral imaging systems using interleaved Fresnel lenses and transmissive display panels
Authors: Borjigin Garimagai , Omori Hiroto , Kakeya Hideki
Published: June 2024

Integral imaging reproduces the light-ray space of a scene to realize a 3D vision. In particular, a coarse integral imaging system, featuring elemental lenses large enough to cover more pixels than the number of views, holds promise in applications like interactive visualization systems and automobile head-up displays (HUDs) for 3D display. However, conventional coarse integral imaging and coarse integral volumetric imaging systems face challenges related to visible seams in the lens array and the emergence of moiré patterns caused by layered liquid crystal panels (LCDs), that significantly degrade image quality. This paper presents a solution to these problems by employing an integrated interleaved Fresnel lens sheet to achieve seamless 3D images with smooth motion parallax while using layered transmissive panels to generate volumetric images free from moiré.
The influence of cross-border mobility on the COVID-19 epidemic in Nordic countries
Authors: Shubin Mikhail , Brustad Hilde Kjelgaard , Midtbø Jørgen Eriksson , Günther Felix , Alessandretti Laura , Ala-Nissila Tapio , Scalia Tomba Gianpaolo , Kivelä Mikko , Chan Louis Yat Hin , Leskelä Lasse
Published: June 2024

Restrictions of cross-border mobility are typically used to prevent an emerging disease from entering a country in order to slow down its spread. However, such interventions can come with a significant societal cost and should thus be based on careful analysis and quantitative understanding on their effects. To this end, we model the influence of cross-border mobility on the spread of COVID-19 during 2020 in the neighbouring Nordic countries of Denmark, Finland, Norway and Sweden. We investigate the immediate impact of cross-border travel on disease spread and employ counterfactual scenarios to explore the cumulative effects of introducing additional infected individuals into a population during the ongoing epidemic. Our results indicate that the effect of inter-country mobility on epidemic growth is non-negligible essentially when there is sizeable mobility from a high prevalence country or countries to a low prevalence one. Our findings underscore the critical importance of accurate data and models on both epidemic progression and travel patterns in informing decisions related to inter-country mobility restrictions.