bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-in-human study of simmitinib, a novel tyrosine kinase inhibitor targeting FGFR1-3, KDR and CSF-1R.
Authors: Yang Sheng , Zhang Yanqiao , Zhang Mingjun , Wu Yongzhong , Li Yongsheng , Wang Feng , Tian Xin , Luo Suxia , Sun Yuping , Wang Linlin , Li Jiancheng , Jiang Da , Wang Mingxia , Huang Yunchao , Shi Huaqiu , Yang Haiyu , Liu Xiaowen , Ji Wei , Pu Weiqing , Shi Yuankai 
Published: June 2024

3109 Background: Simmitinib, a potent tyrosine kinase inhibitor targeting FGFR1-3, KDR and CSF-1R, was evaluated in a phase I study in patients with advanced solid tumors. Methods: The study included dose-escalation cohorts and dose-expansion cohorts. In the dose-escalation cohorts, patients received simmitinib at doses from 1 to 9 mg orally. The DLT observation period consisted of a single dose over 7 days and multiple doses over 28 consecutive days. Patients were assessed for safety, pharmacokinetics, and efficacy. Results: As of October 31, 2023, 98 patients with a median age of 60 years (range 27-70) were enrolled. 24 patients were enrolled in the dose-escalation cohorts and 74 in the dose-expansion cohorts. One DLT was reported in the 9 mg group (grade 3 hypertension lasted for more than 3 days). The maximum tolerated dose (MTD) was not achieved. Furthermore, 4 mg QD, 6 mg QD and 6 mg 3 weeks on 1 week off dosing regimens were employed for expansion. Treatment-related adverse events (TRAEs) were reported in 88 patients (89.8%); detailed TRAEs of any grade occurring in ≥ 10% patients are listed in the table below. The incidence of TRAEs in the 6 mg 3 weeks on 1 week off group was the lowest among all the dosing regimens, with TRAEs any grade and grade ≥ 3 reported in 18 patients (66.7%) and 4 patients (14.8%), respectively. Of 56 patients with pretreated esophageal squamous carcinoma, the ORR was 16.1% (95% CI, 7.6-28.3%) with DCR of 46.4% (95% CI, 33.0-60.3%) and median PFS of 5.7 months (95% CI, 3.5-6.7); the ORRs for 4 mg QD, 6 mg QD, 6 mg 3 weeks on 1 week off, and 9 mg QD groups were 0 (0/6), 13.6% (3/22, 95% CI, 2.9-34.9%), 19.2% (5/26, 95% CI, 6.6-39.4%) and 50.0% (1/2, 95% CI, 1.3-98.7%), respectively. Based on the results of safety and efficacy, 6 mg 3 weeks on 1 week off was selected as recommended phase Ⅱ dose (RP2D). Statistical analysis using a power model for ln-transformed exposures (Cmax and AUC0-∞) suggested dose proportionality from 1 to 9 mg (95% CI of the slope estimate included the value of 1). Higher copy numbers of FGF3, FGF4, or FGF19 appeared to be associated with durable disease control in preliminary biomarker analysis, and further exploration is ongoing. Conclusions: Simmitinib showed manageable toxicity in the study and encouraging activity in esophageal squamous carcinoma. Accordingly, 6 mg 3 weeks on 1 week off was recommended for phase Ⅱ trials. Clinical trial information: NCT04058587 . [Table: see text]
Open-label, dose-escalation phase 1a study of SPH5030, a tyrosine kinase inhibitor (TKI) targeting HER2, in patients with HER2 positive advanced solid tumors.
Authors: Wang Jiayu , Wang Wenna , Tong Zhongsheng , Shi Yehui , Shi Yanxia , Zheng Qiufan , Yu Shunjiang , Cao Yuanyuan , Xie Ning , Fan Jianru , Xu Binghe 
Published: June 2024

3117 Background: Although existing HER2-targeted agents have driven treatment strategies of HER2-overexpressed advanced solid tumor, unmet need still occurred in clinical setting. SPH5030, is a novel tyrosine kinase inhibitor targeting HER2, with a modified structure from tucatinib and pyrotinib. It has advantages such as target selectivity of tucatinib and the irreversible inhibitory effect of pyrotinib. Methods: This Phase Ia, open-label, multi-center study was conducted to evaluate the safety, pharmacokinetics and preliminary activity of SPH5030 in patients (pts) with HER2-positive advanced solid tumor. A 3+3 dose-escalation was conducted with six dose levels of SPH5030 (50,100,200,300,400,600 mg) administered orally once every day (QD) to evaluate dose limiting toxicity (DLT). Adverse events were assessed using CTCAE V5.0; tumor response per RECIST 1.1 every 6 weeks. Results: As of Feb 2, 2024, 30 pts were enrolled with a median age of 51 years, including 28 (93.3%) pts with breast cancer (BC) and 2 (6.7%) pts with colorectal cancer (CRC). All pts were heavily treated with a median of 4 (range, 1-9) prior lines of therapy. All the 28 BC pts received previous anti-HER2 therapy, and 23 of them received anti-HER2-TKI therapy. Treatment-emerged adverse events (TEAEs) and ≥grade (G) 3 TEAEs occurred in 30 pts (100.0%) and 10 pts (33.3%), respectively. Treatment-related adverse events (TRAEs) and ≥G3 TRAEs occurred in 28 pts (93.3%) and 8 pts (26.7%), respectively; the most common TRAEs (≥20%) were diarrhea (66.7%, 16.7% ≥ G3), creatinine increased (30.0%, 0% ≥ G3), hypokalemia (23.3%, 3.3% ≥ G3), fatigue (23.3%, 3.3% ≥ G3), AST increased (20.0%, 0% ≥ G3), and bilirubin increased (20.0%, 0% ≥ G3). One in 6 pts receiving 600 mg dose experienced a DLT (diarrhea, G3). SPH5030 plasma exposures from single-dose and steady-state showed a proportional dose increase, but absorption of SPH5030 was found to reach a plateau from 400 to 600mg. Of the 28 evaluable pts for efficacy (BC = 26, CRC = 2),6 pts (21.4%) achieved partial response (PR, BC = 5, CRC = 1), while 16 pts (57.1%) achieved stable disease (4 pts SD≥ 24 weeks,14.3%). Objective response rate (ORR) was 21.4%, disease control rate was 78.6%, and clinical benefit rate was 35.7%. Three pts in the 600 mg dose group achieved PR, with ORR of 50.0%. Conclusions: This study demonstrated that SPH5030 was well tolerated at doses ranging from 50 to 600mg. A dose of 600 mg QD regimen could be considered for further clinical trials. Clinical trial information: NCT05245058 .
Socioeconomic disparities in survival outcomes of patients with SCLC with brain metastases: A nationwide analysis.
Authors: Bellur Shreyas S , Jayram Diya , Ahmad Shahzaib , Bhat Vivek , Ozair Ahmad , Ganiyani Mohammad Arfat , Khosla Atulya Aman , Podder Vivek , Ahluwalia Manmeet Singh 
Published: June 2024

e20133 Background: Despite advances in the management of cancer, socioeconomic disparities have been reported to impact survival outcomes. However, recent state of disparities in SCLC patients with brain metastases (BM) remains unknown. We explored socioeconomic disparities in survival outcomes of SCLC BM patients. Methods: We conducted a retrospective cohort study and included patients diagnosed with SCLC BM in 2018-2019 in the National Cancer Database. Patients were grouped as White, Black, American Indian, Aleutian or Pacific Islander (AAPI), or Asian. Socioeconomic and survival outcomes were analyzed and reported using median overall survival (mOS) (95% CI). Cox proportional hazard models adjusted for sex, race, facility type, education, and income and reported using hazard ratios for death (HR) (95% CI). Results: Of 2369 SCLC BM patients, 85% (N=2018) were White, 11% (N=259) Black, 0.4% (N=10), and 1.8% (N=43) Asian. 58% were Medicare-insured, and 21% earned >$74,063. 40% were treated at comprehensive cancer care centers (CCC). Log-rank test revealed no significant difference in survival between races. Hispanic did not have a significant survival benefit compared to non-Hispanic patients. Medicare-insured patients have a significantly worse mOS of 7.56 months (6.90-8.28) compared to 13.77 months (12.62-16.07) in private-insured patients. Cox multivariate analysis (Table) showed improved survival in Asian (HR - 0.55, 0.34-0.89, P=0.014) and Black (HR- 0.82, 0.69-0.98, P=0.029) compared to White patients. Patients treated at CCCC had worse survival (HR-1.26, 1.11-1.42, P<0.001) than in academic centers. Patients who earn more reported higher survival (HR-0.82, 0.68-0.98, P=0.030). Conclusions: Race did not significantly impact survival based on unadjusted analysis. Medicare-insured patients have unfavorable outcomes. On adjusted analysis, Asian and Black patients appear to have better survival. Treatment at community centers has worse survival. Focused efforts are warranted to bridge this gap and reduce disparities due to socioeconomic factors. [Table: see text]
Clinical outcomes, demographics and associative analysis of lung cancer patients with Lambert-Eaton myasthenic syndrome: Insights from the National Inpatient Sample (NIS) database.
Authors: Laxmidhar Fehmida , Patel Rushin , Patel Darshil , Patel Zalak , Patel Mrunal , Lakhatariya Khushboo , Gadhiya Dhruvkumar 
Published: June 2024

e20134 Background: Lambert-Eaton myasthenic syndrome (LEMS) is a rare neuromuscular junction disorder that may present as a paraneoplastic syndrome or a primary autoimmune disorder. Approximately 60% of LEMS patients have an underlying tumor, with the paraneoplastic form predominantly associated with small cell lung cancer (SCLC). Understanding the clinical outcomes and risks associated in lung cancer patients with LEMS is crucial in effective management of such patients. Methods: This retrospective study utilized inpatient hospitalization data from the National Inpatient Sample (NIS) between January 1, 2016, and December 31, 2019. Data of patients with a primary or secondary discharge diagnosis of lung cancer (ICD10-CM codes C34, C78.0, C46.5, D02.2) were obtained. Then, out of this population, we identified Lambert-Eaton myasthenic syndrome with ICD-10 codes (G70.80, G70.81, G73.1). The objective was to run a descriptive analysis of clinical outcomes, risks, demographics and associations of LEMS in patients with lung cancer. Results: A total of 204 cases of lung cancer hospitalizations with LEMS were analyzed. The mean age was 68.23 years, with a slight female (51.72%) preponderance as compared to male (48.28%). Race distribution revealed increased prevalence in White Caucasians (83%), followed by Black (7%), Hispanic (4.5%), Asian or Pacific Islander (3%), Native American (0.5%), and Other (2%). The majority were covered by Medicare (66.33%), followed by private insurance (26.13%). The mortality rate was 8.9%, with a mean length of stay of 10.35 days and mean hospital charges of $118,676. Clinical outcomes and risks were analyzed, with sepsis occurring in 17.6% of cases, pneumonia in 22.5%, and acute respiratory failure in 26.9%. Intubation/mechanical ventilation was necessary in 18.1% of cases. The incidence of urinary tract infection (UTI) was 16.7%, acute kidney injury (AKI) was 17.2%, and venous thromboembolism (VTE) was 6.4%. Additionally, interventions such as intravenous immunoglobulin (IVIG) therapy and blood transfusions were also noted. Conclusions: This study provides insights into the demographic characteristics and clinical outcomes of lung cancer patients with Lambert-Eaton myasthenic syndrome (LEMS). The findings highlight the need for comprehensive management strategies targeting associated complications like acute respiratory failure, intubation and need for mechanical ventilation, pneumonia, UTI, AKI, and VTE to improve patient outcomes, quality of care and effective patient education with regards to their diagnosis of LEMS in lung cancer.
Real world outcomes of patients with small cell lung cancer (SCLC) presenting with brain metastasis at diagnosis in a single institution health system.
Authors: Joseph Julia K. , Matera Robert M , Park Henry Soo-Min , Chiang Veronica , Chiang Anne C. 
Published: June 2024

e20136 Background: Extensive-stage small cell lung cancer (ES-SCLC) is an aggressive lung cancer subtype with high propensity for brain metastases (mets). Despite this, there is no consensus on the treatment of brain mets especially in the setting of frontline chemoimmunotherapy and advanced radiation techniques like Gamma Knife radiosurgery (GKRS). Methods: In this single-institution retrospective study, we queried the Yale Tumor registry for all patients diagnosed with ES-SCLC in 1/2016-4/2023. Patients with brain mets at the time of presentation were identified and underwent manual chart review for abstraction of clinical information specifically pertaining to brain mets and treatment modalities. Survival outcomes including median progression free survival (mPFS), median central nervous system-progression free survival (mcPFS) and median overall survival (mOS) measured in months were also captured. Results: 423 ES-SCLC patients were identified. Of those, 92 (22%) had brain mets at initial presentation and were reviewed. 44 (48%) of patients with brain mets were treated with frontline chemotherapy (platinum doublet) while 42 (46%) were treated with chemoimmunotherapy (platinum doublet with atezolizumab or durvalumab). Patients treated with upfront chemotherapy had mPFS 6.4 (95% CI -1.2, 14.1), mcPFS 7.7 (95% CI -1.2, 17.1), and mOS 9.3 (95% CI -13.7, 36.4), compared to patients treated with chemoimmunotherapy, who had mPFS 4.9 (p=0.23; 95% CI -3.5, 15.4), mcPFS 6.7 (p=0.99; 95% CI 3.3, 20.8), and mOS 7.7 (p=0.89; 95% CI -11.4, 33.9). 63 (68%) of patients underwent upfront brain radiation. 44 (48%) had whole brain radiation (WBRT) while 19 (30%) underwent GKRS. Of the patients undergoing GKRS, 8 (42%) were symptomatic. 7 patients (37%) presented with 1 brain met, and 12 (63%) patients presented with 2-5 brain mets. For patients treated with GKRS, mPFS 6.8 (95% CI 2.3, 10.4), mcPFS 7.2 (95% CI 2.9, 12.6), and mOS 11.1 (95% CI -13.0, 40.9). For patients undergoing WBRT, mPFS 6.5 (p = 1.0; 95% CI -4.5, 20.2), mcPFS 6.5 (p = 0.96; 95% CI -3.9, 21.6), and mOS 8.6 (p = 0.21; 95% CI -17.7, 39.9). Conclusions: GKRS is a viable option for SCLC patients presenting with brain metastases, especially in those with a low number of mets. Further studies are required to determine the optimal ES-SCLC candidates for upfront GKRS. [Table: see text]
Gestational Age-specific Reference Intervals for Androgens in Pregnancy
Authors: Lau So Ling , Yuen Lai Yuk , Ho Chung Shun , Chan Michael Ho Ming , Ma Ronald Ching Wan , Tam Wing Hung 
Published: June 2024

Abstract

Background
Androgen could impact cervical remodeling during pregnancy, and a higher level is associated with adverse pregnancy outcomes. A population-based gestation age-specific reference interval of total testosterone (TT), androstenedione (A4), and 17-hydroxyprogesterone (17-OHP) can help to diagnose maternal hyperandrogenism.

Methods
We enrolled 600 healthy Chinese women to obtain longitudinal serum samples across gestation. The serum androgen profile was measured by liquid chromatography-tandem mass spectrometry. The equations for medians of TT, A4, and 17-OHP were generated by MedCal, and the variances adjusted for 2-level modeling were generated by MLwiN, a system for the specification and analysis of a range of multilevel models.

Results
A4 and TT levels increased across the gestation, and they closely correlated with each other (R = .90, P = &lt;.001), whereas the 17-OHP level decreased from the 5th gestational week to the 16th gestational week and then increased afterward toward the end of pregnancy. Women diagnosed with preeclampsia (PE) were found to have a significantly higher level of A4, TT, and 17-OHP when compared with non-PE cases with P≤ .01, whereas mothers carrying male vs female fetuses have comparable levels of A4, TT, and 17-OHP.

Conclusion
The study highlights a methodology for constructing gestational age-specific TT, A4, and 17-OHP levels to provide a better interpretation of results in a cohort of healthy Chinese women. The observation in PE supports previous findings, and the higher levels of TT, A4, and 17-OHP were observed before the onset of PE.
microRNA-guided immunity against respiratory virus infection in human and mouse lung cells
Authors: Shibamoto Ayaka , Kitsu Yoshiaki , Shibata Keiko , Kaneko Yuka , Moriizumi Harune , Takahashi Tomoko 
Published: June 2024

ABSTRACT
Viral infectivity depends on multiple factors. Recent studies showed that the interaction between viral RNAs and endogenous microRNAs (miRNAs) regulates viral infectivity; viral RNAs function as a sponge of endogenous miRNAs and result in upregulation of its original target genes, while endogenous miRNAs target viral RNAs directly and result in repression of viral gene expression. In this study, we analyzed the possible interaction between parainfluenza virus RNA and endogenous miRNAs in human and mouse lungs. We showed that the parainfluenza virus can form base pairs with human miRNAs abundantly than mouse miRNAs. Furthermore, we analyzed that the sponge effect of endogenous miRNAs on viral RNAs may induce the upregulation of transcription regulatory factors. Then, we performed RNA-sequence analysis and observed the upregulation of transcription regulatory factors in the early stages of parainfluenza virus infection. Our studies showed how the differential expression of endogenous miRNAs in lungs could contribute to respiratory virus infection and species- or tissue-specific mechanisms and common mechanisms could be conserved in humans and mice and regulated by miRNAs during viral infection.
Linking in vivo muscle dynamics to force–length and force–velocity properties reveals that guinea fowl lateral gastrocnemius operates at shorter than optimal lengths
Authors: Janneke Schwaner M. , Mayfield Dean L. , Azizi Emanuel , Daley Monica A. 
Published: June 2024

ABSTRACT
The isometric force–length (F–L) and isotonic force–velocity (F–V) relationships characterize the contractile properties of skeletal muscle under controlled conditions, yet it remains unclear how these properties relate to in vivo muscle function. Here, we map the in situ F–L and F–V characteristics of guinea fowl (Numida meleagris) lateral gastrocnemius (LG) to the in vivo operating range during walking and running. We test the hypothesis that muscle fascicles operate on the F–L plateau, near the optimal length for force (L0) and near velocities that maximize power output (Vopt) during walking and running. We found that in vivo LG velocities are consistent with optimizing power during work production, and economy of force at higher loads. However, LG does not operate near L0 at higher loads. LG length was near L0 at the time of electromyography (EMG) onset but shortened rapidly such that force development during stance occurred on the ascending limb of the F–L curve, around 0.8L0. Shortening across L0 in late swing might optimize potential for rapid force development near the swing–stance transition, providing resistance to unexpected perturbations that require rapid force development. We also found evidence of in vivo passive force rise in late swing, without EMG activity, at lengths where in situ passive force is zero, suggesting that dynamic viscoelastic effects contribute to in vivo force development. Comparison of in vivo operating ranges with F–L and F–V properties suggests the need for new approaches to characterize muscle properties in controlled conditions that more closely resemble in vivo dynamics.
Chronic changes in developmental oxygen have little effect on mitochondria and tracheal density in the endothermic moth Manduca sexta
Authors: Wilmsen Sara M. , Dzialowski Edward M. 
Published: June 2024

ABSTRACT
Oxygen availability during development is known to impact the development of insect respiratory and metabolic systems. Drosophila adult tracheal density exhibits developmental plasticity in response to hypoxic or hyperoxic oxygen levels during larval development. Respiratory systems of insects with higher aerobic demands, such as those that are facultative endotherms, may be even more responsive to oxygen levels above or below normoxia during development. The moth Manduca sexta is a large endothermic flying insect that serves as a good study system to start answering questions about developmental plasticity. In this study, we examined the effect of developmental oxygen levels (hypoxia: 10% oxygen, and hyperoxia: 30% oxygen) on the respiratory and metabolic phenotype of adult moths, focusing on morphological and physiological cellular and intercellular changes in phenotype. Mitochondrial respiration rate in permeabilized and isolated flight muscle was measured in adults. We found that permeabilized flight muscle fibers from the hypoxic group had increased mitochondrial oxygen consumption, but this was not replicated in isolated flight muscle mitochondria. Morphological changes in the trachea were examined using confocal imaging. We used transmission electron microscopy to quantify muscle and mitochondrial density in the flight muscle. The respiratory morphology was not significantly different between developmental oxygen groups. These results suggest that the developing M. sexta trachea and mitochondrial respiration have limited developmental plasticity when faced with rearing at 10% or 30% oxygen.
IMPACTOS DO PROGRAMA INSTITUCIONAL DE BOLSAS DE INICIAÇÃO À DOCÊNCIA NA FORMAÇÃO INICIAL EM EDUCAÇÃO FÍSICA: UM RELATO DE EXPERIÊNCIA.
Authors: Rocha Raphael , Lima de Oliveira Mateus , Amorim Cruz Santos Wilker , Alves Nogueira Souza Suzana 
Published: June 2024

Este trabalho se trata de um relato de experiência que abrange a discussão dos efeitos do Programa Institucional de Bolsas de Iniciação à Docência (PIBID) na formação inicial de estudantes do Curso de Licenciatura em Educação Física de uma universidade estadual no interior da Bahia. Nesse sentido, esse relato tem como objetivo analisar os impactos na formação docente ao promover reflexões acerca das práticas pedagógicas utilizadas na Escola Municipal Doutor Clóvis Ramos Lima (EMDCRL). Trata-se de relato de experiência de natureza descritiva, que se configura como uma narrativa escrita sobre vivências, capaz de enriquecer a construção de conhecimento em contextos educacionais. Buscou-se aprofundar a compreensão dos impactos iniciais dos bolsistas do PIBID, que, por sua vez, influenciam os saberes pedagógicos da formação e a construção da identidade docente. Essa experiência proporcionou uma jornada de aprendizado enriquecedora, promovendo a integração entre teoria e prática, aprofundando a compreensão dos desafios da formação docente que podem contribuir na construção da identidade docente dos bolsistas.
Multi-excitation photoluminescence spectroscopy system for gemstone analysis
Authors: Tsai Tsung-Han , D’Haenens-Johansson Ulrika F. S. , Smith Tyler , Zhou Chunhui , Xu Wenxing 
Published: June 2024

Luminescence spectra can reveal important chemical and structural information that can be used for gemstone characterization and identification. Traditionally, gemstone UV-excited luminescence is evaluated visually under mercury vapor lamp illumination. This approach is limited by several factors, including the mixture of mercury’s emission peaks, possible filter degradation, an inability to separate overlapping emission features, and the sensitivity and subjectivity of human vision and color interpretation. A multi-excitation photoluminescence (PL) spectroscopy system has been built for gemstone analysis, incorporating 261 and 405 nm laser excitations to study gemstone emission features between 270 to 1000 nm. This system presents significant improvements, extending the detection spectral range, increasing the sensitivity, accuracy and reproducibility of gemstone luminescence analysis. Luminescence analysis of commercially valuable gemstones are presented to demonstrate the system’s suitability for gemstone identification. Examples include distinguishing natural from laboratory-grown diamonds, thermal and color treatment detection for corundum and pearls, respectively, and mineral type separation of emeralds and other green gemstones.