bluuebunny/crossref_metadata_2025 huggingface dataset:
A strategy for selective screening of dual-target bioactive compounds against hypertrophic scar through inhibiting angiotensin II type 1 receptor while stimulating type 2 receptor from Chinese herbs
Authors: Qu Lejing , Jiao Meizhi , Zhang Zilong , Ou Yuanyuan , Zhao Xue , Zhang Yajun , Zhao Xinfeng
Published: January 2025

Background

Cutaneous hypertrophic scar is a fibro-proliferative hard-curing disease. Recent studies have proved that antagonists of angiotensin II type 1 receptor (AT1R) and agonists of type 2 receptor (AT2R) were able to relieve hypertrophic scar. Therefore, establishing new methods to pursue dual-target lead compounds from Chinese herbs is in much demand for treating scar.

Methods

To this end, we immobilized AT1R or AT2R onto the surface of silica gel from cell lysates through a specific covalent bond by bioorthogonal chemistry. The columns containing immobilized AT1R or AT2R were jointly utilized to pursue potential bioactive compounds simultaneously binding to AT1R and AT2R from the extract of Rhei Radix et Rhizoma. Their functions on AT1R and AT2R expressions were investigated by in vitro and in vivo experiments.

Results

Aloe-emodin and emodin were identified as the potential bioactive compounds binding to both of the two receptors, thereby improving the appearance and pathomorphology of hypertrophic scar. They blocked the AT1R pathway to down-regulate the expression of transforming growth factor-β1 (TGF-β1) and stimulate matrix metalloproteinase-1 (MMP-1) expression. As such, the expression of collagen I/III reduced. Conversely, the bindings of the two compounds to AT2R reduced the production of nuclear factor-кB1 (NF-кB1), whereby the generation of interleukin-6 (IL-6) was blocked.

Conclusion

We reasoned that aloe-emodin and emodin had the potential to become dual-target candidates against hypertrophic scar through the regulation of AT1R and AT2R signaling pathways. It showed considerable potential to become a universal strategy for pursuing multi-target bioactive compounds from Chinese herbs by the utilization of diverse immobilized receptors in a desired order.
The association of chronotype, sleep duration and trajectories of health-risk behaviors among college students: a cohort study
Authors: Che Wanyu , Wang Chenfang , Tao Shuman , Li Tingting , Xie Yang , Tao Fangbiao , Wu Xiaoyan
Published: January 2025

Purpose

To describe the trajectories of health-risk behaviors (HRBs) among college students through four consecutive surveys and explore the relationship between chronotype, sleep duration and different trajectories of HRBs.

Methods

We used a data sample of 1,042 college students from the College Student Behavior and Health Cohort Study. Students reported sleep parameters, including chronotype (Morningness-Eveningness Questionnaire-5, MEQ-5) and sleep duration. The behavior scale was used to evaluate four HRBs (smoking, alcohol use, low physical activity, smartphone addiction). The latent class growth analysis (LCGA) was used to estimate the trajectory of self-reported HRBs. Multivariate logistic regression models were used to study whether sleep parameters (chronotype and sleep duration) correlated with HRBs’ trajectories.

Results

Four unique trajectories of behaviors were identified: unhealthy group (7.4%), increasing group (21.3%), decreasing group (10.3%) and healthy group (61.0%). Compared with the normal sleep, results from logistic regression analyses indicated that long sleep (> 9 h) was associated with the decreasing group and the unhealthy group (P < 0.05), while short sleep (< 7 h) was associated with the increasing group and the unhealthy group (P < 0.05). Compared with the M-type, the E-type were positively correlated with the unhealthy group, the increasing group, and the decreasing group (P < 0.05).

Conclusion

E-type, short sleep duration and long sleep duration were significantly associated with the trajectory of HRBs. Findings underscore the need for targeted screening and prevention of modifiable sleep behaviors with the aim of improving HRBs in college students.
Single-cell transcriptomics identify a novel macrophage population associated with bone invasion in pituitary neuroendocrine tumors
Authors: Wu Xinzhi , Han Xueshuai , Zhu Haibo , Li Mingxuan , Gong Lei , Jing Sicheng , Xie Weiyan , Liu Zhaoqi , Li Chuzhong , Zhang Yazhuo
Published: January 2025

Background

Bone-invasive Pituitary Neuroendocrine Tumors (BI PitNETs) epitomize an aggressive subtype of pituitary tumors characterized by bone invasion, culminating in extensive skull base bone destruction and fragmentation. This infiltration poses a significant surgical risk due to potential damage to vital nerves and arteries. However, the mechanisms underlying bone invasion caused by PitNETs remain elusive, and effective interventions for PitNET-induced bone invasion are lacking in clinical practice.

Methods

In this study, we performed single-cell (n = 87,287) RNA sequencing on 10 cases of bone-invasive PitNETs and 5 cases of non-bone-invasion PitNETs (Non-BI PitNETs). We identified various cell types and determined their interactions through cell-cell communication analysis, which was further validated experimentally.

Results

We identified a novel TNF-α+ TAM macrophage subset. BI PitNETs showed increased IL-34 secretion, impacting TNF-α+ TAMs via the IL34/CSF1R axis, leading to TNF-α production. TNF-α+ TAMs, in turn, communicate with CD14
+ monocytes to promote their differentiation into osteoclasts and leading to bone invasion. In addition, we defined a gene signature for TNF-α+ TAM to guide the clinical prognosis prediction of BI PitNETs.

Conclusions

Our study elucidates the tumor microenvironment changes in bone invasion and identifies the critical role of TNF-α+ TAMs in promoting bone invasion of PitNETs, laying a foundation for developing new molecular markers or therapeutic agents targeting BI PitNETs.
A new method for detecting mixed Mycobacterium tuberculosis infection and reconstructing constituent strains provides insights into transmission
Authors: Sobkowiak Benjamin , Cudahy Patrick , Chitwood Melanie H. , Clark Taane G. , Colijn Caroline , Grandjean Louis , Walter Katharine S. , Crudu Valeriu , Cohen Ted
Published: January 2025

Background

Mixed infection with multiple strains of the same pathogen in a single host can present clinical and analytical challenges. Whole genome sequence (WGS) data can identify signals of multiple strains in samples, though the precision of previous methods can be improved. Here, we present MixInfect2, a new tool to accurately detect mixed samples from Mycobacterium tuberculosis short-read WGS data. We then evaluate three approaches for reconstructing the underlying mixed constituent strain sequences. This allows these samples to be included in downstream analysis to gain insights into the epidemiology and transmission of mixed infections.

Methods

We employed a Gaussian mixture model to cluster allele frequencies at mixed sites (hSNPs) in each sample to identify signals of multiple strains. Building upon our previous tool, MixInfect, we increased the accuracy of classifying in vitro mixed samples through multiple improvements to the bioinformatic pipeline. Major and minor proportion constituent strains were reconstructed using three approaches and assessed by comparing the estimated sequence to the known constituent strain sequence. Lastly, mixed infections in a real-world Mycobacterium tuberculosis population from Moldova were detected with MixInfect2 and clusters of recent transmission that included major and minor constituent strains were built.

Results

All 36/36 in vitro mixed and 12/12 non-mixed samples were correctly classified with MixInfect2, and major strain proportions were estimated with high accuracy (within 3% of the true strain proportion), outperforming previous tools. Reconstructed major strain sequences closely matched the true constituent sequence by taking the allele at the highest frequency at hSNPs, while the best-performing approach to reconstruct the minor proportion strain sequence was identifying the closest non-mixed isolate in the same population, though no approach was effective when the minor strain proportion was at 5%. Finally, fewer mixed infections were identified in Moldova than previous estimates (6.6% vs 17.4%) and we found multiple instances where the constituent strains of mixed samples were present in transmission clusters.

Conclusions

MixInfect2 accurately detects samples with evidence of mixed infection from short-read WGS data and provides an excellent estimate of the mixture proportions. While there are limitations in reconstructing the constituent strain sequences of mixed samples, we present recommendations for the best approach to include these isolates in further analyses.
Relationship between humeral head translation, spur formations, and the locations of tendon tears in massive rotator cuff tears
Authors: Yoshida Yuki , Yoshida Atsushi
Published: January 2025

Objective

This study aimed to clarify the relationship between the directions of humeral head translation, the presence of acromial or coracoid spurs, and the locations of tendon tears in massive rotator cuff tears. Thirty shoulders from thirty patients with massive rotator cuff tears who underwent reverse shoulder arthroplasty were included. Preoperative 3DCT classified humeral head translation into three groups: minimal type, posterosuperior type, and anterosuperior type. The presence of acromial or coracoid spurs was also assessed. Preoperative MRI and intraoperative findings determined the torn tendons in each rotator cuff, along with ruptures of the anterior fascia covering the subscapularis or the long head of the biceps tendon (LHB). Relationships between humeral head translations, spur formations, and tendon tear locations were analyzed using chi-square tests and adjusted standardized residuals.

Results

Acromial spurs were more frequent in the posterosuperior type, while coracoid spurs, subscapularis tears, anterior fascia ruptures, and LHB ruptures were significantly associated with the anterosuperior type. Anterior fascia ruptures were significantly less frequent in the minimal type. Anterosuperior humeral head translation and coracoid spurs indicate subscapularis tears, anterior fascia ruptures, and LHB ruptures.
Secondary Immunodeficiency
Authors: Pourshahnazari Persia , Betschel Stephen D. , Kim Vy. H. D. , Waserman Susan , Zhu Rongbo , Kim Harold
Published: January 2025

The field of medicine is constantly changing and, as healthcare providers, we are fortunate to be practicing in a time when patients are living longer and novel therapeutic options continue to evolve. However, these new advances may be associated with adverse effects that practitioners need to be aware of. Some of these impair the immune system leading to secondary immunodeficiencies (SID) that increase host susceptibility to infections and other complications. The causes and consequences of these SID are extremely broad, and a detailed review is beyond the scope of this article. The goal of this primer is to provide a general overview and understanding of common conditions and therapies leading to SID, as well as a guide to the assessment and management of patients with SID.
Optimization, characterization and biosafety of oregano, rosemary and mint oil mixture against Penicillium digitatum in citrus using L-optimal mixture design
Authors: Khaled Rahaf , Mohamed Sara , Mohamed Amira , Khairy Aya , Elhariry Hesham , Bakry Ashraf , Elsenosy Neima K. , Ebeed Naglaa , Salem Salem S. , ElNoby Thanaa , Abu-Hussien Samah H.
Published: January 2025

The increasing demand for natural alternatives to synthetic fungicides has prompted research into natural products like essential oils for postharvest disease management. This study investigated the antifungal, antioxidant, cytotoxic, and genotoxic potential of essential oil mixtures derived from oregano, rosemary, and mint against Penicillium digitatum, the predominant fungal pathogen causing green mold in orange fruits. P. digitatum NPAGRASU 2024 was isolated and identified as the most abundant species (60.2%) from infected oranges. It was deposited in GenBank with gene accession number PP930644 and deposited in MIRCEN culture collection as EMCC 358874. The antimicrobial activity of individual essential oils was evaluated, with oregano exhibiting the highest antifungal activity (inhibition zone diameter of 4.2 cm) against P. digitatum. L-optimal mixture design of response surface methodology (RSM) optimization revealed a highly effective mixture (Run 8) comprising 46.26% oregano and 53.74% rosemary, with a 99.65% actual growth reduction. The oregano oil demonstrated potent antioxidant activity, reaching approximately 75% DPPH radical scavenging at 3.125 mg/mL. Cytotoxicity assessment using the MTT assay showed morphological changes and reduced cell viability in liver cells treated with the PEOs mixture at 300 µg/mL. However, the optimized mixture did not induce significant chromosomal aberrations compared to the control, suggesting minimal genotoxic effects. In vivo, evaluation on oranges revealed 60% inhibition of green mold by the 1% (v/v) optimized mixture for 7 days. Histological analysis indicated low toxicity to the liver at the highest tested concentration (1% mixture). GC-MS analysis identified major compounds like cavarcol, caryophyllene, eucalyptol, phenols and levomenthol in oregano oil, contributing to its bioactivities. This study demonstrates the potential of optimized essential oil mixtures as effective and eco-friendly alternatives for postharvest disease control.
Vision impairment in boys recruited to the iREAD study
Authors: Levine Jonathan , Doron Ravid , Ostrin Lisa A. , Shneor Einat
Published: January 2025

Background

Uncorrected refractive error is reported to be the most common cause globally of vision impairment in school age children. However, little is known about the extent of uncorrected refractive error in Israel. The purpose of this study was to investigate the prevalence of vision impairment in schoolchildren recruited for the Israel Refraction, Environment, And Devices (iREAD) Study.

Methods

Healthy boys, ages 5–13 years, were recruited to participate in the iREAD Study. Parents first answered a questionnaire to exclude children with a known history of amblyopia, strabismus, or hyperopia. A comprehensive eye exam was then performed. Presenting visual acuity < 6/12 was defined as vision impairment. Myopia and hyperopia were defined as cycloplegic spherical equivalent refraction  ≤ − 0.50 D, and ≥  + 0.50 D, respectively, and astigmatism as ≤ − 0.75 D. Amblyopia was defined as best corrected visual acuity ≤ 6/12 in at least one eye in the absence of any ocular pathology. Descriptive statistics were used to calculate the prevalence of each refractive error and amblyopia.

Results

Two hundred five boys (average age 8.8 ± 1.7 years) presented for a comprehensive eye exam. The prevalence of vision impairment at initial presentation was 22.9% (N = 47), with 16.1% (N = 33) and 6.8% (N = 14) for both eyes and one eye, respectively. Of the children with vision impairment, 36.2% (N = 17) were wearing habitual correction. Of the children with vision impairment, 97.9% (N = 46) had refractive error, with 85.1% (N = 40) being myopic and 12.8% (N = 6) being hyperopic. In addition, 36.2% (N = 17) with vision impairment had astigmatism. Most children with vision impairment (N = 43) achieved good vision with refractive correction. However, amblyopia was observed in 2.0% (N = 4) of the children.

Conclusions

A high prevalence of vision impairment was observed, primarily due to uncorrected or undercorrected refractive error. Children with amblyopia and/or hyperopia presented despite a parent questionnaire to exclude children with these conditions. Findings suggest that many parents are unaware of their children’s visual and refractive status, even for children who already have glasses. In conclusion, improvements to the current system in Israel of vision screenings in first grade should be made to help insure children in need receive adequate follow-up throughout their education.
Global dynamics on a delayed double-strain influenza model with vaccination and cross-immunity
Authors: Gao Shukun , Zhang Long , Li Hongli , Teng Zhidong
Published: January 2025

In this paper, a delayed double-strain influenza model with vaccination and cross-immunity is proposed to explore the effect of coinfection of double-strain on disease spread. First, the nonnegativity and ultimate boundedness of solution are proved. Second, the basic reproduction numbers of strains 1, 2, and the whole model are defined respectively, by which criteria on the local and global asymptotic stability of (disease-free, dominant) equilibria are established. The uniform persistence of (strains 1, 2 coexistent) disease is obtained as well. Finally, the validity of the theoretical results is demonstrated by numerical simulations. We find that neglecting cross-immunity and vaccination would misestimate the size of influenza outbreaks. Cross-type multivalent vaccines will be the main direction for effective control measure for influenza.
Borehole heat exchangers in coastal areas may reduce heatwave seagrass loss
Authors: Criollo Rotman , Vilarrasa Víctor , Orfila Alejandro , Marbà Núria , Fernández-Mora Angels
Published: January 2025

Mitigation of climate change, implies, among other measures, the increase on the use of carbon-free energy sources, ensuring a zero environmental footprint. Borehole heat exchangers (BHE), a renewable heat source from the ground used for thermal regulation of infrastructures, could significantly reduce CO2 emissions. Yet, BHE perturbs groundwater temperature by heating and cooling the ground in summer and winter, respectively, which may alter the temperature of Sea Groundwater Discharges. We propose a methodology to strategically locate BHE to discharge cooler temperatures into the sea during summer, alleviating the extreme marine temperatures occurring during marine heatwaves around the groundwater discharge areas, and ensuring a thermal refuge for temperature-sensitive coastal ecosystems. This study opens a new avenue to accomplish the climate targets of the Paris Agreement and mitigate the negative effects of global warming on coastal ecosystems.
Preclinical evaluation and preliminary clinical study of 68Ga-NODAGA-NM-01 for PET imaging of PD-L1 expression
Authors: Zhao Lingzhou , Gong Jiali , Liao Sisi , Huang Wenhua , Zhao Jinhua , Xing Yan
Published: January 2025

Background

Programmed cell death 1/programmed death ligand-1 (PD-L1)-based immune checkpoint blockade is an effective treatment approach for non-small-cell lung cancer (NSCLC). However, immunohistochemistry does not accurately or dynamically reflect PD-L1 expression owing to its spatiotemporal heterogeneity. Herein, we assessed the feasibility of using a 68Ga-labeled anti-PD-L1 nanobody, 68Ga-NODAGA-NM-01, for PET imaging of PD-L1.

Methods

Micro-PET/CT and biodistribution studies were performed on PD-L1-positive and -negative tumor-bearing mice. Additionally, a preliminary clinical study was performed on two patients with NSCLC. NM-01 was radiolabeled with 68Ga without further purification under mild conditions.

Results

68Ga-NODAGA-NM-01 exhibited radiochemical purity (> 98%), high stability in vitro, and rapid blood clearance in vivo. Specific accumulation of 68Ga-NODAGA-NM-01 was observed in PD-L1-positive tumor-bearing mice, with a good tumor-to-background ratio 0.5h post-injection. Furthermore, 68Ga-NODAGA-NM-01 PET/CT imaging was found to be safe with no adverse events and distinct uptake in primary and metastatic lesions of the PD-L1-positive patient, with a higher maximal standardized uptake value than that in lesions of the PD-L1-negative patient 1h post-injection.

Conclusions

68Ga-NODAGA-NM-01 can be prepared using a simple method under mild conditions and reflect PD-L1 expression in primary and metastatic lesions. However, our findings need to be confirmed in a large cohort.

Trial registration

NCT02978196. Registered February 15, 2018.
MELK prevents radiofrequency ablation-induced immunogenic cell death and antitumor immune response by stabilizing FABP5 in hepatocellular malignancies
Authors: Tang Bu-Fu , Xu Wang-Ting , Fang Shi-Ji , Zhu Jin-Yu , Qiu Rong-Fang , Shen Lin , Yang Yang , Weng Qiao-You , Wang Ya-Jie , Ding Jia-Yi , Zhang Xiao-Jie , Chen Wei-Qian , Zheng Li-Yun , Song Jing-Jing , Chen Biao , Zhao Zhong-Wei , Chen Min-Jiang , Ji Jian-Song
Published: January 2025

Background

Radiofrequency ablation (RFA) is an efficient treatment with unlimited potential for liver cancer that can effectively reduce patient mortality. Understanding the biological process related with RFA treatment is important for improving treatment strategy. This study aimed to identify the critical targets for regulating the efficacy of RFA.

Methods

The RFA treatment in hepatocellular carcinoma (HCC) tumor models in vivo, was analyzed by RNA sequencing technology. The heat treatment in vitro for HCC tumor cells was also constructed to explore the mechanism after RFA treatment in tumor cells. Nanoparticles with high affinity to tumor cells were applied as a new therapy to interfere with the expression of maternal embryonic leucine zipper kinase (MELK).

Results

It was found that RFA treatment upregulated MELK expression, and MELK inhibition promoted RFA efficacy by immunogenic cell death and the antitumor response, including anti-tumoral macrophage polarization and increased CD8+ T cell cytotoxicity in HCC. Mechanically, MELK binds to fatty acid-binding protein 5 (FABP5), and affects its ubiquitination through the K48R pathway to increase its stability, thereby activating protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling axis to weaken the RFA-mediated antitumor effect. In addition, the synthesis of arginylglycylaspartic acid (RGD)-lipid nanoparticles (LNPs) targeting tumor cell-intrinsic MELK enhanced RFA efficacy in HCC.

Conclusion

MELK is a therapeutic target by regulating RFA efficacy in HCC, and targeting MELK via RGD-LNPs provides new insight into improving RFA efficacy in HCC clinical treatment and combating the malignant progression of liver cancer.
Ethnobiological survey on medicinal plants used by gaddi and gujjar tribes of riparian region of Beas River of Himachal Pradesh in North Western Himalayas, India
Authors: Thakur Neha , Kumar Nitesh , Kumar Sanjeev , Sharma Anju , Ahlawat Yogesh K. , Malik Anurag , Ahmed Meraj
Published: January 2025

Himachal Pradesh is one of the most species-rich regions in the world and a key center for the origin and diversity of numerous plant species. Ethnobotanical research is essential for exploring these diverse biological resources for medicinal uses. This study aimed to record the traditional knowledge of the tribal communities in Himachal Pradesh concerning the use of medicinal plants for treating diseases in humans and livestock. Despite this richness, there is a lack of detailed documentation about the use of therapeutic plants in this area. The indigenous communities in this region rely on traditional knowledge of medicinal plants, making it a valuable resource for further pharmacological and phytochemical research. The ethnobotanical surveys were conducted from August 2022 to July 2023, and our fieldwork took place in four districts (Kullu (1279 m), Mandi (760 m), Hamirpur (780 m) and Kangra (1200–1300 m) under various villages. The ethnobiological data was gathered through field surveys, open interviews, discussions, and semi-structured questionnaires conducted with 193 tribal participants aged 40 to 80 years. Informants were chosen using the randomized household interview and snowball sampling methods. The study documented 64 plants from 39 families, among which 58 species are angiosperms, 5 species are pteridophytes and one species is bryophyte utilized for therapeutic purposes. Rosaceae, Lamiaceae, and Ranunculaceae were the most used medicinal herb families. Rubus ellipticus (0.75) and Trillium govanianum (0.74) demonstrated the highest UV (Use value) values. The ICF (Informant Consensus factor) value revealed that nervous system disorders-related ailments were the most treated. This study explored the ethnobiological information of therapeutic flora from riparian vegetation within tribal communities while also assessing the present state of research and the practical application of their medicinal information. It underscores the potential for additional research to delve deeper into the indigenous properties of their therapeutic floras and emphasizes the importance of preserving their traditional medicinal wisdom.
Revisiting the trading activity of high-frequency trading firms around ultra-fast flash events
Authors: Desagre Christophe , Laly Floris , Petitjean Mikael
Published: January 2025

We investigate high-frequency traders’ behavior in the context of the fastest and most extreme price movements (EPMs) that can be observed in the market, specifically ultra-fast flash events, challenging the methodologies employed in the academic and practitioner literature for identifying sudden liquidity black holes. To refine the price-shock identification methodology, we introduce a new approach called sequence-based flash events (SFEs), which relies on tick sequences instead of predetermined fixed-time intervals within which all flash events in the sample are assumed to occur. This alternative methodology offers the advantage of pinpointing the exact time and duration of a crash, which, in turn, provides a way to more accurately define the observation windows around it. We compare our sample of SFEs with both the so-called “mini flash crashes”, as identified by the Nanex detection algorithm, and the so-called EPMs, as identified by Brogaard et al. (2018). We use close and open prices, as well as high and low prices. Based on our sample of SFEs, we find no evidence that HFTs trigger extreme price shocks. However, we find that HFTs exacerbate SFEs by increasing the net imbalance in the direction of these shocks as they occur. Finally, we show that the choice of the price-shock identification methodology is critical. Thus, we urge regulators to exercise caution and avoid hasty conclusions regarding HFTs’ contribution to price stability in stressful market conditions.
Effect of thymol and propolis extract on genotoxicity, biochemical activities and expression profile of some genes on honey bee, Apis mellifera, infected with Vairimorpha (Nosema) ceranae
Authors: Sebak Salwa I. , Elelimy Heba A. S. , Seyam Heba , Elkenawy Soad A.
Published: January 2025

Background

Nosema ceranae, the predominant microsporidian parasite, weakens Apis mellifera honey bee colonies and reduces their productivity and reproduction. This research aims to detect the impact of thymol and propolis extracts on genotoxicity repair, oxidative enzymes, expression of some antimicrobial genes and some hypopharyngeal glands genes in N. ceranae-infected bees. Experimentally, infected honeybee colonies were divided into four groups: (1) untreated, (2) for propolis (3 g/L) treatment, (3) for thymol (0.1 g/L) treatment and (4) for mixed treatment with thymol and propolis. Workers from adult honeybee colonies, treated and untreated, were randomly sampled. The collected samples were used in studying the genotoxicity effect, the concentration of oxidative enzymes (superoxide-dismutases, glutathione S transferase, catalase and malondialdehyde (MDA)), measuring the relative expression of antimicrobial genes and hypopharyngeal glands genes major royal proteins 1 & 2 (MJRP1 and MJRP2).

Results

The results show that thymol and propolis extract decreased genotoxicity effect, increased expression of antimicrobial genes, increased expression levels of MJRP1 and MJRP2 genes and decreased activities of oxidative enzymes when applied to Nosema-infected bees.

Conclusion

Thymol and propolis extract positively affect honey bee health and mix of them. This study reveals that natural product extracts and their mixture may fight Nosema and prevent honey bee colonies decline and sudden death.
Danger of co-administration ferric carboxymaltose and denosumab: hypophosphatemia
Authors: Seker Aysun , Durmus Nurdan Senturk
Published: January 2025

Both denosumab-induced hypocalcemia and ferric carboxymaltose infusion-related hypophosphatemia have been extensively documented. There are significant risks associated with combining ferric carboxymaltose parenteral infusions and denosumab, including potentially life-threatening electrolyte imbalances such as hypocalcemia and hypophosphatemia. Developing monitoring strategies for electrolyte abnormalities can be facilitated by the increased awareness of this interaction. We present the case of a 62-year-old female patient who developed severe, symptomatic hypocalcemia and hypophosphatemia despite having normal renal function. These abnormalities occurred concomitantly during treatment with denosumab for osteoporosis and ferric carboxymaltose for iron deficiency anemia.
Associations between IL-6 and trajectories of depressive symptoms across the life course: Evidence from ALSPAC and UK Biobank cohorts
Authors: Edmondson-Stait Amelia J. , Davyson Ella , Shen Xueyi , Adams Mark James , Khandaker Golam M. , Miron Veronique E. , McIntosh Andrew M. , Lawrie Stephen M. , Kwong Alex S.F. , Whalley Heather C.
Published: January 2025

Background

Peripheral inflammatory markers, including serum interleukin 6 (IL-6), are associated with depression, but less is known about how these markers associate with depression at different stages of the life course.

Methods

We examined the associations between serum IL-6 levels at baseline and subsequent depression symptom trajectories in two longitudinal cohorts: ALSPAC (age 10–28 years; N = 4,835) and UK Biobank (39–86 years; N = 39,613) using multilevel growth curve modeling. Models were adjusted for sex, BMI, and socioeconomic factors. Depressive symptoms were measured using the Short Moods and Feelings Questionnaire in ALSPAC (max time points = 11) and the Patient Health Questionnaire-2 in UK Biobank (max time points = 8).

Results

Higher baseline IL-6 was associated with worse depression symptom trajectories in both cohorts (largest effect size: 0.046 [ALSPAC, age 16 years]). These associations were stronger in the younger ALSPAC cohort, where additionally higher IL-6 levels at age 9 years was associated with worse depression symptoms trajectories in females compared to males. Weaker sex differences were observed in the older cohort, UK Biobank. However, statistically significant associations (pFDR <0.05) were of smaller effect sizes, typical of large cohort studies.

Conclusions

These findings suggest that systemic inflammation may influence the severity and course of depressive symptoms across the life course, which is apparent regardless of age and differences in measures and number of time points between these large, population-based cohorts.
Survival benefits of adjuvant chemotherapy after surgical resection of para-aortic lymph node metastasis from colorectal cancer: A multicenter retrospective study.
Authors: Nozawa Hiroaki , Ito Sono , Murono Koji , Sasaki Kazuhito , Emoto Shigenobu , Yokoyama Yuichiro , Yamauchi Shinichi , Kinugasa Yusuke , Ajioka Yoichi , Ishihara Soichiro ,   Study Group for Paraaortic Lymph Node Metastases, The Japanese Society for Cancer of the Colon and Rectum
Published: January 2025

140

Background:
Surgical removal of metastasized paraaortic lymph nodes (PALNs) can prolong the survival of certain patients with colorectal cancer (CRC). However, the role of postoperative chemotherapy in such patients remains unknown.
Methods:
This multi-center retrospective study examined97 patients with PALN metastasis from CRC who underwent surgical resection at 36 centers in Japan between 2010 and 2015. Based on adjuvant chemotherapy (AC) after the lymphadenectomy, the patients were classified into Non-AC and AC groups (27 and 70 patients, respectively). After the exclusion of patients receiving irinotecan, the latter group was further categorized into 5-fluorouracil (5-FU) and oxaliplatin (L-OHP) subgroups (14 and 52 patients, respectively) according to the use of L-OHP. Background characteristics and postoperative survival were compared among the groups.
Results:
Marked differences were not seen in background characteristics, except for neoadjuvant treatment, between the Non-AC and AC groups. The AC group exhibited better recurrence-free survival (RFS, p = 0.009) and overall survival (OS, p = 0.040) than the Non-AC group. However, RFS and OS of the 5-FU group did not differ from those of the L-OHP group (p = 0.73 and p = 0.92, respectively).
Conclusions:
AC contributed to the improved prognosis of patients after the removal of PALN metastasis from CRC, but L-OHP did not offer additional survival benefits. Prospective studies comparing Non-AC with 5-FU- and L-OHP-based AC are needed to confirm these findings.
Phase II study of trifluridine/tipiracil (TAS-102) plus irinotecan in combination with bevacizumab as a second‐line therapy for patients with metastatic colorectal cancer.
Authors: Sun Yongkun , Zhang Jing , Yang Wenwei , Wu Guifu , Zhong Xiaomin , Zhang Wen , Liang Ping , Li Baoqi , Cui Chengxu
Published: January 2025

155

Background:
Metastatic colorectal cancer (mCRC) patients have poor prognoses with limited response to second-line chemotherapy. Therefore, it is urgent to refine and design an optimal second-line treatment regimen to improve the response rate and prolong the survival of patients with mCRC. This study assessed the safety and efficacy of the trifluridine/tipiracil (TAS-102), irinotecan, and bevacizumab regimen in second-line settings for mCRC patients.
Methods:
This was a multicenter, single-arm, phase II trial. The mCRC patients who are refractory to standard first-line treatment, including fluoropyrimidine and oxaliplatin, are eligible. Based on the recommended phase II dose established in phase I, enrolled patients received TAS-102 (30 mg/m2 twice daily on days 1-5) and irinotecan (150 mg/m2 on day 1) combined with bevacizumab (5 mg/kg on day 1) every two weeks. The primary endpoint was the objective response rate (ORR).
Results:
Between October 1, 2023, and August 31, 2024, 60 patients were enrolled, and all of them were evaluated for efficacy. As of August 31, 2024, efficacy was assessed in all 60 participants with an ORR of 18.3% (2 had complete response, CR; 9 had partial response, PR; 39 had stable disease, SD). Among the 39 patients with SD, 29 patients experienced tumor shrinkage. The disease control rate (DCR) was 83.3%. The median follow-up was 8.6 months (95% confidence interval [CI], 6.743-10.457). The six-month progression-free survival (PFS) was 59.6%. The median PFS was 6.9 months (95% CI 5.016-8.784), whereas the median overall survival (OS) was not reached. The 1-year OS rate was 92%. At the time of analysis, four patients have died, and 56 patients are still alive. All patients were evaluable for safety assessment. The most common treatment-related adverse events (TRAE) were nausea (100%), neutropenia (86.7%), and anemia (83.3%). The most frequent grade 3/4 TRAE were neutropenia (48.3%), febrile neutropenia (8.3%), nausea (3.3%), and anemia (3.3%). No treatment-related death occurred.
Conclusions:
The regimen of irinotecan, TAS-102, plus bevacizumab preliminarily demonstrated promising efficacy with tolerable toxicity for mCRC patients as second‐line treatment. This regimen warrants further exploration in refractory mCRC patients.
Clinical trial information: NCT06202001
.
Survival analysis using neoadjuvant rectal score in patients with locally advanced rectal cancer who underwent surgery after neoadjuvant chemoradiotherapy: An ambispective study.
Authors: Sameer Mohammed , Jacob Akhil Thomas , Muralee Madhu
Published: January 2025

172

Background:
Colorectal cancer, the third most common malignancy and a major cause of cancer deaths, is treated using a standard protocol of neoadjuvant chemoradiotherapy (NACTRT) or short-course radiotherapy (SCRT) followed by total mesorectal excision (TME) for locally advanced rectal cancers (LARC). Long-term follow-up is essential to determine study endpoints, necessitating surrogate markers for short-term outcomes. This study aims to stratify patients into risk groups based on their Neoadjuvant Rectal Cancer (NAR) score and evaluate its predictive value for oncological outcomes, including overall survival, disease-free survival (DFS), locoregional relapse-free interval (LRFI), and distant metastasis-free interval (DMFI), while also correlating clinicopathological characteristics with these outcomes.
Methods:
This ambispective observational study at the Regional Cancer Centre, Thiruvananthapuram, involved 459 patients with biopsy-proven, locally advanced rectal adenocarcinoma (T3/T4 and/or node positive) who underwent long-course neoadjuvant chemoradiotherapy (NACTRT) followed by curative surgery (Anterior Resection or Abdomino-Perineal Resection) between 2010 and 2015, with a minimum follow-up of three years. Exclusion criteria included previous malignancies, synchronous colorectal cancers, oligometastatic disease, and loss to follow-up. The study aimed to determine the predictive value of the Neoadjuvant Rectal Cancer (NAR) score for oncological outcomes. Clinicopathological details were collected from case records, imaging, and operative notes, and postoperative histopathological records were used to calculate the NAR score. Patients were categorized into three groups based on their NAR scores and followed prospectively for recurrence or death. Data were analyzed using frequency, percentages, mean, standard deviation, Chi-square test, Kaplan-Meier method, log-rank test, and Cox regression analysis, with a significance level set at p < 0.05.
Results:
459 patients were included in the study, with 41.4% females, and 44% being less than 60 years. Most of the patients had lesion 5-10 cm from anal verge (46%). 77% of patients had T3 disease prior to the start of NATCTRT. 51.9% had underwent APR, and 80.4% had open surgery. 11.1% had PCR attained. 27% had disease recurrence of which most were distant metastasis. NAR was a significant predictor of overall survival, disease free survival, distant metastasis free interval and locoregional failure free interval. Other significant predictors of overall survival were pre-NACTRT T stage, pN stage, PLNR, CRM status and PCR, but only NAR was found to be significant on multivariate analysis.
Conclusions:
NAR score is a significant predictor of OS, DFS,LRFI and DMFI and can be used as a short term surrogate for survival data in anticipated trials.
Phase I/II trial of encorafenib, cetuximab, and nivolumab in microsatellite stable
BRAF
V600E
metastatic colorectal cancer following progression on prior BRAF+EGFR targeted therapies.
Authors: Pan Kelsey , Baig Yunyu , Willis Jason , Dasari Arvind , Bent Alisha Heather , Higbie Victoria , Huey Ryan W , Kee Bryan K. , Lee Michael Sangmin , Parseghian Christine , Morelli Maria Pia , Shen John Paul Y.C. , Kopetz Scott , Morris Van K.
Published: January 2025

182

Background:
A

BRAF
V600E

mutation, present in approximately 8-10% of all colorectal cancers (CRC), is a poor prognostic biomarker for patients with metastatic CRC. The BRAF
V600E
inhibitor encorafenib (E) and the anti-EGFR antibody cetuximab (C) are approved for refractory,

BRAF
V600E

mCRC based upon on overall response rate (ORR) of 20% and median progression-free survival (PFS) of 4.2 months
.
A single-arm trial adding the anti-PD1 antibody nivolumab (N) to E+C in the same (BRAF-inhibitor naïve) population showed promising efficacy, with an ORR of 50% and median PFS of 7.4 months. We evaluated the efficacy of E+C+N in patients with microsatellite stable (MSS),

BRAF
V600E

mCRC who had progressed on prior E+C.
Methods:
Patients with MSS,

BRAF
V600E

mCRC with documented prior progression on E+C were eligible for treatment with E (300 mg PO daily), C (500 mg/m
2
q14 days), and N (480 mg IV q28days) were included in the study. Primary endpoint was best overall response by RECIST 1.1. Secondary endpoints were PFS, overall survival (OS), and toxicity (by CTCAE v5). Circulating tumor DNA assessment of molecular alterations in the MAPK pathway in association with response were performed by NGS. Descriptive statistics were used to summarize outcomes.
Results:
Among the 12 participants, none achieved a radiographic response, and 5 experienced stable disease. Disease control rate was 41.7% (95% CI, 13.8-69.6). Median PFS was 3.7 months (95% CI, 1.7-5.7), and median OS was 8.3 months (NE-NE). Four patients (16.7%) had concomitant MAPK-activating alterations at baseline, and
APC
,
TP53
, and
PIK3CA
mutations were present in 25.0%, 66.7%, and 33.3% of patients, respectively. The presence of MAPK-activating mutation was not associated with disease progression (odds ratio 1.3; 95% CI 0.11-16; p=0.82). The most common grade 1-2 treatment-related adverse events (AEs) were anemia (N=5), arthralgia (N=5), rash (N=4), headache (N=4), and fatigue (N=3); 1 of the 12 patients experienced a grade 3 small bowel obstruction.
Conclusions:
In this pilot study, addition of N to E+C did not appear to overcome resistance to prior BRAF + EGFR targeted therapies in patients with MSS,

BRAF
V600E

mCRC. While the addition of immunotherapy has demonstrated promising signal in early-phase clinical trials for this population, the benefit appears unlikely when offered sequentially after progression on BRAF combination therapies.
Clinical trial information: NCT04017650
.
Neoadjuvant PD-1 blockade in mismatch repair-deficient or microsatellite instability-high, locally advanced and resectable colorectal cancer: A retrospective real-world analysis.
Authors: Lian Yugui , Su Chang , Zhao Ruihua , Lian Yanbang , Zhou Quanbo , Jin Shui-Ling , Guo Shihao , Sun Zhenqiang , Zhang Zhiyong , Wang Guixian , Fu Yang , Wang Yunlong , Yuan Weitang , Wan Xiang-Bo
Published: January 2025

185

Background:
Neoadjuvant PD-1 blockade therapy has shown encouraging efficacy in patients with mismatch repair- deficient (dMMR)/microsatellite instability-high (MSI-H) locally advanced colorectal cancer. However, data from the real-world setting are scarce.
Methods:
We retrospectively collected clinical data of patients with dMMR/MSI-H locally advanced colorectal cancer diagnosed between 2022-2024 that received neoadjuvant anti-PD-1 monotherapy at the First Affiliated Hospital of Zhengzhou University. Pathological complete response, clinical complete response, R0 resection rate, and safety were analyzed. All statistical analyses were conducted using SPSS Statistics, version 22.0.
Results:
A total of 45 patients were enrolled. As of the data cutoff (Sep 15, 2024), the median follow-up was 14.0 months (range: 4.0-31.4). The median age was 53 years (range: 29.0–78.0) and 25 (55.6%) of 45 patients were male. 32 (71.1%) patients had clinical stage III disease and 39 (86.7%) patients had colon cancer. A higher proportion of patients (53.3%) had clinical T4 stage. 37 patients underwent the surgery of whom 29(78.9%) had a pathological complete response. The R0 resection was 100%. The median treatment duration was 4 cycles (range: 2-10). Among the 18 patients who received equal to or less than 4 cycles, the pCR rate was 77.8%, while for the remaining 17 patients who had more than 4 cycles of treatment, the pCR rate was 84.2%. Eight other patients had a clinical complete response and chose the watch and wait strategy. Treatment-related adverse events ≥3-4grade were observed in 3 patients. All patients survived without any disease recurrence.
Conclusions:
In this retrospective analysis, anti-PD-1 monotherapy is effective and tolerable for patients with dMMR/MSI-H locally advanced colorectal cancer. This study shows that pCR rate increases is associated with a longer treatment cycles probably. Further analysis of larger real-world datasets with longer follow-up will be essential to validate these results.
QL1203 vs placebo plus mFOLFOX6 as first-line therapy in RAS wild-type, metastatic colorectal cancer (mCRC): Interim analysis (IA) of a multicenter, randomized, double-blinded, parallel, phase 3 trial.
Authors: Guo Weijian , Wang Yusheng , Yang Wenhui , Li Yunfeng , Zhang Yanqiao , Zhang Zhongtao , Xiong Hailin , Li Changzheng , Wang Zhiwu , Fan Nanfeng , Yin Xianli , Du Peng , Luo Suxia , Zhang Jingdong , Yu Dajun , Zheng Weie , Kang Xiaoyan , Mao Kaisheng , Wang Zhan , Shen Lin
Published: January 2025

190

Background:
Panitumumab plus FOLFOX or FOLFIRI has been approved as the first-line therapy for RAS wild-type mCRC. QL1203 is a panitumumab biosimilar showing similarity to the originator panitumumab (Vectibix, Amgen) in preclinical studies and phase 1 clinical pharmacokinetic study. Here we present results from interim analysis of a phase 3 trial (NCT04233151) investigating QL1203 vs placebo plus mFOLFOX6 as first-line therapy in Chinese patients (pts) with RAS wild-type mCRC.
Methods:
Pts with treatment-naïve, RAS and BRAF wild-type, mCRC unsuitable for radical resection and local therapy were enrolled and randomly assigned (2:1) to receive QL1203 (6 mg/kg) plus mFOLFOX6 once every 2 weeks (Q2W) or placebo plus mFOLFOX6 Q2W, stratified by primary tumor site, liver metastases, and previous neoadjuvant/adjuvant therapy. The primary endpoint was PFS assessed by a Blinded Independ Review Committee (BICR) per RECIST v1.1. Key secondary endpoints include PFS by investigator (INV), OS, ORR, DoR, and safety. This planned IA was conducted at 338 (81.25%) of 416 PFS events occurred.
Results:
From Jan 8, 2020 to Jun 12, 2023, 641 pts were randomized (QL1203/placebo, n=426/215). 551 (86.0%) pts had left-sided tumors (QL1203/placebo, 85.9%/86.0%). 433 (67.6%) pts had liver metastases (QL1203/placebo, 68.1%/66.5%). As of data cutoff of this IA (Mar 22, 2024), median follow-up was 23.8 months. Median PFS by BIRC was 11.20 months for QL1203 and 8.34 months for placebo (hazard ratio [HR], 0.61 [97.42% confidence interval [CI], 0.47-0.79]; stratified one-sided log-rank p<0.0001). Other efficacy results are presented (Table). Incidence of grade≥ 3 adverse events (AEs) related to study drug was 59.9% for QL1203 and 32.9% for placebo. The most common grade≥3 AE related to QL1203 was neutrophil count decreased (20.3%).
Conclusions:
QL1203 demonstrated significantly improved PFS versus placebo and higher ORR.
Clinical trial information: NCT04233151
.

QL1203 (n=426)
Placebo (n=215)

PFS by BIRC

mPFS, months (95% CI)
11.20 (9.89-13.11)
8.34 (7.26-8.54)

HR (97.42% CI)
0.61 (0.47-0.79)

PFS by INV

mPFS, months (95% CI)
10.91 (9.69-11.30)
8.41 (7.39-9.07)

HR (95% CI)
0.74 (0.60-0.91)

mOS, months (95% CI)
27.66 (24.74-32.79)
24.54 (20.17-27.79)

HR (95% CI)
0.82 (0.64-1.06)

ORR by BIRC, n (%)
68.31%
47.91%

95% CI
63.66-72.70
41.07-54.81

ORR by INV, n (%)
64.08%
49.30%

95% CI
59.33-68.65
42.44-56.19