bluuebunny/crossref_metadata_2025 huggingface dataset:
Macroscopic and mesoscopic simulation of polystyrene melt in the filling process of injection molding
Authors: Liu Qingsheng , Liu Youqiong , Jiang Chuntao
Published: May 2023

In this article, a fluid flow and heat transfer model which consist of the mass, momentum, and energy conservation equations together with the level set equation and Rolie‐Poly constitution equation is proposed and applied to simulate the rheological behaviors of viscoelastic polystyrene melt in the filling process of injection molding. The macroscopic velocity, pressure, temperature, stress, and mesoscopic molecular conformation of polystyrene melt are shown and analyzed detailedly during the mold filling process. The single‐mode Rolie‐Poly model is employed to describe the stress–strain relationship of polystyrene melt, and the level set method is used to capture the evolution of melt front interface. The governing equations for polymer melt are discretized by the finite volume method on collocated mesh, and solved by the SIMPLE algorithm. Numerical simulations have been implemented based on rectangular cavities with different gate locations, and rectangular and circular inserts. Numerical results indicate that the gate locations, gate numbers, insert size and shape are major factors that affect the rheological behaviors of polystyrene melt in the filling stage of injection molding, and polymer chains experienced higher shear and extension effects in the regions near to mold walls and obstacle. In addition, the length and position of weld lines are discussed in the current study.
Effect of printing parameters on tensile, thermal and structural properties of 3D‐printed poly (ether ketone ketone) PEKK material using fused deposition modeling
Authors: El Magri Anouar , Vaudreuil Sébastien , Ben Ayad Anass , El Hakimi Abdelhadi , El Otmani Rabie , Amegouz Driss
Published: May 2023

Poly(ether ketone ketone) (PEKK) is a thermoplastic of the poly(aryl ether ketone) (PAEK) family, with excellent mechanical and thermal performances and high chemical resistance properties. This makes it an appealing material in high‐performance applications as a replacement for poly (ether ether ketone) (PEEK). PEKK was thus selected in this study as a base material for application in 3D printing. The effects of nozzle temperature, layer orientation and layer thickness on the final properties of 3D‐printed PEKK parts were investigated. Furthermore, we assessed the mechanical and morphological features of printed samples through tensile tests and scanning electron microscope, respectively. Thermal properties of samples were also evaluated through DSC and DMA analysis. Optimum printing parameters were found at 0.15 mm layer thickness, 380°C nozzle temperature, and [45/−45°] layer orientation. The printed PEKK samples were annealed at various temperatures to allow the relaxation of residual stress and enhance the degree of crystallinity. Samples annealed for 1 h at 240°C have shown an improved elastic modulus by ~14%, tensile strength by 17%, and glass transition temperature by 17.2°C from the increased by 24% degree of crystallinity.
Synthesis, Anti‐adipogenic, and Insulin‐sensitizing Potential of Benzosuberene‐alkyl Sulfone (BSAS) Analogues
Authors: Goel Abhishek , Yamini  , Gusain Chitralekha , Sharma Bhanu , Purohit Rituraj , Das Pralay , Padwad Yogendra
Published: May 2023

Obesity and diabetes are the leading cause of mortality worldwide. Promising modulators exhibiting insulin sensitivity and anti‐adipogenic actions are highly desirable. Organic sulfone analogues are prominent structural units present in diverse bioactive molecules. However, sulfones‐derived anti‐adipogenic agents are currently unavailable. Therefore, different benzosuberene‐alkyl sulfone (BSAS) analogues were synthesized inspired by the molecular diversity of the essential oil of Cedrus deodara. Among the series, five BSAS analogues were assessed in‐silico for their binding towards native Peroxisome Proliferator‐Activated Receptor Gamma (PPARγ) and further validated in‐vitro for their anti‐adipogenic potential in differentiated 3T3‐L1 pre‐adipocytes. Their ability to improve insulin sensitivity was also examined in L6 myotubes to ascertain their role in insulin resistance. Our results demonstrated that BSAS‐1 was the partial PPARγ agonist. It has reduced adipogenesis efficiently by downregulating adipogenic genes, resulting in lower triglyceride levels. BSAS‐1 lowered oxidative stress, protected myotubes from insulin resistance, and improved glucose uptake by promoting GLUT4 translocation. Overall, BSAS‐1 has the potential to treat obesity and obesity‐induced insulin resistance.
Harnessing the cooperation between DNA‐PK and cGAS in cancer therapies
Authors: Taffoni Clara , Schüssler Moritz , Vila Isabelle K. , Laguette Nadine
Published: May 2023

The cyclic GMP‐AMP synthase–stimulator of interferon genes (cGAS‐STING) pathway is central for the initiation of anti‐tumoural immune responses. Enormous effort has been made to optimise the design and administration of STING agonists to stimulate tumour immunogenicity. However, in certain contexts the cGAS‐STING axis fuels tumourigenesis. Here, we review recent findings on the regulation of cGAS expression and activity. We particularly focus our attention on the DNA‐dependent protein kinase (DNA‐PK) complex, that recently emerged as an activator of inflammatory responses in tumour cells. We propose that stratification analyses on cGAS and DNA‐PK expression/activation status should be carried out to predict treatment efficacy. We herein also provide insights into non‐canonical functions borne by cGAS and cGAMP, highlighting how they may influence tumourigenesis. All these parameters should be taken into consideration concertedly to choose strategies aiming to effectively boost tumour immunogenicity.
Improvement of enzymatic saccharification by simultaneous pulping of sugarcane bagasse and washing of its cellulose fibers in a batch reactor
Authors: Nogueira Bruno L. , Secchi Argimiro R. , Machado Fabricio , Rodrigues Carime V. S. , Gambetta Rossano , Rodrigues Dasciana S.
Published: May 2023

A modification of the conventional batch organosolv process is proposed in a way where the solid biomass remains inside a basket, physically separated from the liquid phase, with the vapor promoting the fractionation of the biomass and the extracted compounds and fragments being washed down to the liquid phase. The modified organosolv process applied to sugarcane bagasse (SB‐M) delivers a rich cellulosic solid phase that after enzymatic hydrolysis leads to a hydrolyzed with approximately 100 g L−1 of glucose. At the same enzymatic hydrolysis conditions, the conventional organosolv process (SB‐C) delivers a hydrolyzed with 80 g L−1 of glucose, while the autohydrolysis process (SB‐A) leads to 55 g L−1 of glucose. These different results are related to the cellulose content: SB‐M (70%), SB‐C (57%), e SB‐A (44%), as well the reduced lignin content in the SB‐M. The novelty of this study is the confirmation that it is possible to degrade lignin from sugarcane bagasse and simultaneously remove its fragments from the cellulose fibers in a batch reactor containing an internal basket. This study describes a simple and rapid protocol for the isolation of the main components of lignocellulosic biomass (cellulose, hemicellulose, and lignin), which may lead to the study of new catalysts for the chemical transformation of these components separately or simultaneously to the step of pretreatment.
Chemical inhibitors of hexokinase‐2 enzyme reduce lactate accumulation, alter glycosylation processing, and produce altered glycoforms in CHO cell cultures
Authors: Naik Harnish Mukesh , Kumar Swetha , Reddy Jayanth Venkatarama , Gonzalez Jacqueline E. , McConnell Brian O. , Dhara Venkata Gayatri , Wang Tiexin , Yu Marcella , Antoniewicz Maciek R. , Betenbaugh Michael J.
Published: May 2023

Chinese hamster ovary (CHO) cells, predominant hosts for recombinant biotherapeutics production, generate lactate as a major glycolysis by‐product. High lactate levels adversely impact cell growth and productivity. The goal of this study was to reduce lactate in CHO cell cultures by adding chemical inhibitors to hexokinase‐2 (HK2), the enzyme catalyzing the conversion of glucose to glucose 6‐phosphate, and examine their impact on lactate accumulation, cell growth, protein titers, and N‐glycosylation. Five inhibitors of HK2 enzyme at different concentrations were evaluated, of which 2‐deoxy‐
d‐glucose (2DG) and 5‐thio‐
d‐glucose (5TG) successfully reduced lactate accumulation with only limited impacts on CHO cell growth. Individual 2DG and 5TG supplementation led to a 35%–45% decrease in peak lactate, while their combined supplementation resulted in a 60% decrease in peak lactate. Inhibitor supplementation led to at least 50% decrease in moles of lactate produced per mol of glucose consumed. Recombinant EPO‐Fc titers peaked earlier relative to the end of culture duration in supplemented cultures leading to at least 11% and as high as 32% increase in final EPO‐Fc titers. Asparagine, pyruvate, and serine consumption rates also increased in the exponential growth phase in 2DG and 5TG treated cultures, thus, rewiring central carbon metabolism due to low glycolytic fluxes. N‐glycan analysis of EPO‐Fc revealed an increase in high mannose glycans from 5% in control cultures to 25% and 37% in 2DG and 5TG‐supplemented cultures, respectively. Inhibitor supplementation also led to a decrease in bi‐, tri‐, and tetra‐antennary structures and up to 50% lower EPO‐Fc sialylation. Interestingly, addition of 2DG led to the incorporation of 2‐deoxy‐hexose (2DH) on EPO‐Fc N‐glycans and addition of 5TG resulted in the first‐ever observed N‐glycan incorporation of 5‐thio‐hexose (5TH). Six percent to 23% of N‐glycans included 5TH moieties, most likely 5‐thio‐mannose and/or 5‐thio‐galactose and/or possibly 5‐thio‐N‐acetylglucosamine, and 14%–33% of N‐glycans included 2DH moieties, most likely 2‐deoxy‐mannose and/or 2‐deoxy‐galactose, for cultures treated with different concentrations of 5TG and 2DG, respectively. Our study is the first to evaluate the impact of these glucose analogs on CHO cell growth, protein production, cell metabolism, N‐glycosylation processing, and formation of alternative glycoforms.
Downstream process design for Gag HIV‐1 based virus‐like particles
Authors: Lorenzo Elianet , Miranda Laia , Gòdia Francesc , Cervera Laura
Published: May 2023

Virus‐like particles‐based vaccines have been gaining interest in recent years. The manufacturing of these particles includes their production by cell culture followed by their purification to meet the requirements of its final use. The presence of host cell extracellular vesicles represents a challenge for better virus‐like particles purification, because both share similar characteristics which hinders their separation. The present study aims to compare some of the most used downstream processing technologies for capture and purification of virus‐like particles. Four steps of the purification process were studied, including a clarification step by depth filtration and filtration, an intermediate step by tangential flow filtration or multimodal chromatography, a capture step by ion exchange, heparin affinity and hydrophobic interaction chromatography and finally, a polishing step by size exclusion chromatography. In each step, the yields were evaluated by percentage of recovery of the particles of interest, purity, and elimination of main contaminants. Finally, a complete purification train was implemented using the best results obtained in each step. A final concentration of 1.40 × 1010 virus‐like particles (VLPs)/mL with a purity of 64% after the polishing step was achieved, with host cell DNA and protein levels complaining with regulatory standards, and an overall recovery of 38%. This work has resulted in the development of a purification process for HIV‐1 Gag‐eGFP virus‐like particles suitable for scale‐up.
Identifying entrustable professional activities for MD program in biochemistry—A modified Delphi approach
Authors: Rajaragupathy Sujatha , Govindarajan Sumitra , Ganesan Jeyachandran , Subramanian Kavitha , Doraiswamy Vijaya , Balasubramaniam Gayathri , Andra Suryanarayana Meenakshi Sundaram , Veeruswamy Aruna
Published: May 2023

Entrustable professional activities (EPAs) facilitate competency‐based assessments. India is on the verge of implementing competency‐based training for postgraduate programs. MD degree in Biochemistry is a unique program available exclusively in India. Postgraduate programs in most specialties have started working toward EPA‐based curriculum, in both India and other countries. However, EPAs for MD Biochemistry course are yet to be defined. This study aims to identify EPAs for postgraduate training program in Biochemistry. Identification and attaining consensus on the list of EPAs for MD Biochemistry curriculum was done by modified Delphi method. The study was conducted in three rounds. In round 1, tasks expected from an MD Biochemistry graduate were identified by working group followed by expert panel validation. The tasks were organized and reframed to EPAs. Two rounds of online survey were conducted to achieve a consensus on the list of EPAs. Consensus measure was calculated. A cut‐off value of 80% and above was considered to reflect good consensus. The working group identified 59 tasks. This was validated by 10 experts based on which, 53 items were retained. These tasks were reframed into 27 EPAs. In round 2, 11 EPAs achieved good consensus. Among the remaining EPAs, 13 achieved consensus of 60%–80% and were selected for round 3. Five EPAs achieved good consensus in this round. A total of 16 EPAs were identified for MD Biochemistry curriculum. This study provides a frame of reference for experts to develop an EPA‐based curriculum in the future.
Examination performance with flipped classroom as instructional strategy in the carbohydrate metabolism course unit at a Philippine medical school: Estimation of average treatment effect from observational data
Authors: Van Haute Michael , Monzon Jan David
Published: May 2023

While the innovativeness of the flipped classroom (FC) approach promotes active participation and higher‐order thinking among students, there are concerns about its effectiveness in terms of knowledge retention. Currently, there are no studies involving medical school biochemistry that evaluate this aspect of effectiveness. Thus, we conducted a historical control study that analyzed observational data from two freshman batches of the Doctor of Medicine program in our institution. Class 2021 (n = 250) served as the traditional lecture (TL) group while Class 2022 (n = 264) served as the FC group. Data on relevant observed covariates (age, sex, National Medical Admission Test or NMAT score, undergraduate degree) and the outcome variable (carbohydrate metabolism course unit examination percentage scores, as indicator of knowledge retention) were included in the analysis. Propensity scores were calculated using logit regression conditional on these observed covariates. Afterwards, 1:1 nearest‐neighbor propensity score matching (PSM) was performed to produce an estimated average treatment effect (ATE) measure afforded by FC (as adjusted mean difference in examination scores between the two batches), balancing on the covariates. Nearest‐neighbor matching using the calculated propensity scores effectively balanced the two groups (standardized bias <10%), producing 250 matched student‐pairs that received either TL or FC. Following PSM, the FC group was found to have a significantly higher adjusted mean examination score compared to the TL group (adjusted mean difference = 5.62%, 95% CI: 2.54%, 8.72%; p < 0.001). Using this approach, we were able to demonstrate benefit of FC over TL in terms of knowledge retention, as reflected by the estimated ATE.
Aconitum carmichaelii triggers neurotoxicity and Parkinson‐like symptoms through initiation of ROS‐mitochondrial apoptosis and the Nox5/DJ‐1 signaling pathway
Authors: Pang Meijun , Song Xin , Miao Yaodong , Wang Yiwen , Zhou Chang , Geng Zihan , Du Jiayin , Moussian Bernard , Su Yanfang , Liu Xiuyun , Ming Dong
Published: May 2023

Background

Aconitum carmichaelii, the mother root of Aconitum, has a long‐applied history for treating many diseases in China. Increased use of it has prompted significant concerns regarding its extensive cardiotoxicity and neurotoxicity. The molecular mechanisms underlying A. carmichaelii‐induced neurotoxicity are poorly understood.

Methods

We took advantage of the zebrafish model to investigate the neurotoxic mechanism of A. carmichaelii. In addition to the behavior and neuronal activity testing, gene expression of neuronal oxidative stress, and apoptosis levels were also analyzed.

Results

In contrast to the excitatory effect of low‐dose A. carmichaelii decoction, hypoactivity of locomotor behavior, and neural activity, especially telencephalon, were detected in the 20 mg/mL group. High doses of A. carmichaelii induced excessive ROS by downregulating DJ‐1 and activating Nox5, and further triggered cell apoptosis through the bax/bcl2a‐caspase‐9 pathway in zebrafish larva. Mitochondrial protection‐related genes PinK1 and Parkin were upregulated to protect against mitochondrial dysfunction during cellular stress. The ROS scavenger‐NAC significantly alleviated neurotoxicity in the 20 mg/mL group.

Conclusion

The study reveals the potential mechanism of A. carmichaelii‐induced neurotoxicity and provides new insights into a significant risk marker of A. carmichaelii poisoning.
Increase in age at onset of moyamoya disease in China over 25 years
Authors: Ma Zhiyang , Chen Dayu , Wang Sheng , Zhu Yaozu , Chen Jincao
Published: May 2023

Background

To explore whether the age at onset (AAO) of Chinese patients with moyamoya disease (MMD) increased over time due to a reduced exposure to leptospiral infection.

Methods

We performed an independent, multicenter, retrospective study based on data from patients with MMD who initially attended four tertiary hospitals in Hubei, China, from 1996 to 2020. After stratifying the year of MMD onset into five periods (1996–2000, 2001–2005, 2006–2010, 2011–2015, and 2016–2020), we analyzed the temporal trends in AAO and compared different classes of AAO (early‐onset, < 20 years; intermediate‐onset, 20–49 years; late‐onset, ≥ 50 years) in each period.

Results

We included 1858 patients in this study, with 878 women and 980 men. Their median (IQR) AAO was 47 (39‒55) years. The case AAO significantly increased at the rate of 0.94 years per year (r = 0.406, p < .0001), while no trend was observed in birth years through time (p = .512). The birth cohorts who grew up in the leptospirosis epidemic years was stably susceptible to MMD. The median (IQR) AAO has increased significantly from 26 (14–37) years (1996–2000) to 51 (43–57) years (2016–2020) (p < .0001). The proportion of early‐onset MMD was significantly higher in 1996–2000 (33.3%, p < .0001) and 2001–2005 (10.4%, p < .001). The AAO shows an aging trend that the proportion of late‐onset MMD went from 4.5% (2001–2005) to 54.5% (2016–2020) (p < .0001).

Conclusions

The AAO of MMD was increasing during a recent 25‐year period in China, which may reflect a birth cohort effect that resulted from environmental changes. The disparity risk of birth cohorts with MMD changed with leptospirosis epidemics, suggesting leptospiral exposure might be a potential risk factor.
Forging organizational resilience through green value co‐creation: The role of green technology, green operations, and green transaction capabilities
Authors: Borah Prasad Siba , Dogbe Courage Simon Kofi , Dzandu Michael D. , Pomegbe Wisdom Wise Kwabla
Published: May 2023

The study assessed the mediating role of green organizational capabilities (green technology development, green operations, and green transactions), in the relationship between green value co‐creation and organizational resilience among Chinese manufacturing firms, that is, firms' ability to build strong organizational resilience in response to the COVID‐19 pandemic. It focused on manufacturing firms operating within Shenzhen, a coastal city located within the Guangdong province in southeastern China. The sample comprised 234 firms. Data were analysed using a covariance‐based structural equation modeling. Findings revealed that green value co‐creation had no direct effect on organizational resilience, rather, its effect was realized indirectly through green organizational capabilities. The study concludes that manufacturing companies can augment their organizational capabilities by leveraging the knowledge of their customers through green value co‐creation to build strong organizational resilience. Theoretical and managerial implications have been provided.
Biomimetic scaffold‐based stem cell transplantation promotes lung regeneration
Authors: Wang Linjie , Feng Meng , Zhao Yazhen , Chen Bing , Zhao Yannan , Dai Jianwu
Published: May 2023

Therapeutic options are limited for severe lung injury and disease as the spontaneous regeneration of functional alveolar is terminated owing to the weakness of the inherent stem cells and the dyscrasia of the niche. Umbilical cord mesenchymal‐derived stem cells (UC‐MSCs) have been applied to clinical trials to promote lung repair through stem cell niche restruction. However, the application of UC‐MSCs is hampered by the effectiveness of cell transplantation with few cells homing to the injury sites and poor retention, survival, and proliferation in vivo. In this study, we constructed an artificial three‐dimensional (3D) biomimetic scaffold‐based MSCs implant to establish a beneficial regeneration niche for endogenous stem cells in situ lung regeneration. The therapeutic potential of 3D biomimetic scaffold‐based MSCs implants was evaluated by 3D culture in vitro. And RNA sequencing (RNA‐Seq) was mapped to explore the gene expression involved in the niche improvement. Next, a model of partial lung resection was established in rats, and the implants were implanted into the operative region. Effects of the implants on rat resected lung injury repair were detected. The results revealed that UC‐MSCs loaded on biomimetic scaffolds exerted strong paracrine effects and some UC‐MSCs migrated to the lung from scaffolds and had long‐term retention to suppress inflammation and fibrosis in residual lungs and promoted vascular endothelial cells and alveolar type II epithelial cells to enter the scaffolds. Then, under the guidance of the ECM‐mimicking structures of scaffolds and the stimulation of the remaining UC‐MSCs, vascular and alveolar‐like structures were formed in the scaffold region. Moreover, the general morphology of the operative lung was also restored. Taken together, the artificial 3D biomimetic scaffold‐based MSCs implants induce in situ lung regeneration and recovery after lung destruction, providing a promising direction for tissue engineering and stem cell strategies in lung regeneration.
Expression of Tryptophan Metabolism Enzymes in Patients with Diffuse Large B‐cell Lymphoma and NK/T‐cell Lymphoma
Authors: Guo Dan , Wang Yuming , Wu Xunyao , Gao Yike , Wang Anqi , Zhang Zixin , Zhao Kun , Wang Xiaoxi , Liu Meiyu , Zhang Yaran , Li Mei , Chen Rui , Sun Jian , Zhang Yan
Published: May 2023

Background

Metabolites of tryptophan (Trp) metabolism in the tumor microenvironment play crucial immunosuppressive roles in various cancers. However, the role of Trp metabolism in diffuse large B‐cell lymphoma (DLBCL) or natural killer/T‐cell lymphoma (NK/TCL) remains unelucidated.

Methods

We investigated the potential role of Trp metabolism in a cohort of 43 patients with DLBCL and 23 with NK/TCL. We constructed tissue microarrays and performed in situ staining of Trp‐catabolizing enzymes and PD‐L1 using immunohistochemistry (IHC).

Results

We observed 14.0% positive staining of IDO1 in DCBCL and 60.9% in NK/TCL; 55.8% of IDO2 in DCBCL and 95.7% in NK/TCL; 79.1% of TDO2 in DCBCL and 43.5% in NK/TCL; 29.7% of IL4I1 in DCBCL and 39.1% in NK/TCL. However, IDO1, IDO2, TDO2, and IL4I1 positivity did not significantly differ between PD‐L1+ and PD‐L1− biopsy tissue samples of NK/TCL; nonetheless, a positive correlation of IDO1 (r = 0.87, p < 0.001), IDO2 (r = 0.70, p < 0.001), TDO2 (r = 0.63, p < 0.001), and IL4I1 (r = 0.53, p < 0.05) with PD‐L1 expression was observed in the TCGA‐DLBCL dataset. Finally, immunohistochemical (IHC) analysis revealed the lack of superior prognostic effect with higher expression of Trp enzymes in DLBCL and NK/TCL. Furthermore, IDO1, IDO2, TDO2, and IL4I1 expression, as well as survival rates, did not significantly differ across all groups in the TCGA‐DLBCL cohort.

Conclusion

Collectively, our findings provide novel insights into the enzymes involved in Trp metabolism in DLBCL and NK/TCL and their association with PD‐L1 expression, which offers potential strategies to combine Trp‐metabolism enzyme inhibitors with anti‐PD‐L1 or other immunotherapeutic strategies in clinical DLBCL or NK/TCL treatment.
General population reference values for the Functional Assessment of Cancer Therapy‐Lung and PROMIS‐29
Authors: Mohindra Nisha A. , Peipert John Devin , Blum Steven I. , Shaw James W. , Penrod John R. , Cella David
Published: May 2023

Background

Therapeutic advances in lung cancer have turned attention toward patient‐reported outcome measures (PROMs) as important clinical outcomes. The Functional Assessment of Cancer Therapy‐Lung (FACT‐L) is a common endpoint in lung cancer trials. This study calculated FACT‐L reference values for the United States (US) general population.

Methods

Adults from the US general population (N = 2001) were surveyed between September 2020 and November 2020. Surveys contained 126 questions, including the FACT‐L [36 items; FACT‐G and four subscales (Physical Well‐Being [PWB], Social Well‐Being [SWB], Emotional Well‐Being [EWB], and Functional Well‐Being [FWB]) and the Lung Cancer Subscale (LCS), and a Trial Outcome Index (TOI)]. Reference values for each FACT‐L scale were calculated with means for the total sample and separately for participants with: no comorbidities, COVID‐19 as only comorbidity, no COVID‐19.

Results

In the total sample, the reference scores were as follows: PWB = 23.1; SWB = 16.8; EWB = 18.5; FWB = 17.6; FACT‐G = 76.0; LCS = 23.0, TOI = 63.7, and FACT‐L Total = 99.0. Scores were lower for those reporting a prior diagnosis of COVID‐19, especially for SWB (15.7) and FWB (15.3). SWB scores were lower than previous references values.

Conclusions

These data provide US general adult population reference value set for FACT‐L. While some of the subscale results were lower than those found in the reference data for other PROMs, these data were obtained in a more contemporaneous time frame juxtaposed with the COVID‐19 pandemic and may represent a new peri‐pandemic norm. Thus, these reference values will be useful for future clinical research.
Investigating potential disparities in clinical trial eligibility and enrollment at anNCI‐designated comprehensive cancer center
Authors: Patel Monica A. , Shah Jennifer L. , Brinley Floyd John , Abrahamse Paul H. , Veenstra Christine M. , Schott Anne F.
Published: May 2023

Background

Although barriers to trial accrual are well‐reported, few studies have explored trial eligibility and trial offers as potential drivers of disparities in cancer clinical trial enrollment.

Methods

We identified patients with gastrointestinal (GI) or head/neck (HN) malignancies who were seen as new patients at the University of Michigan Health Rogel Cancer Center in 2016. By exhaustive review of the electronic medical record, we assessed the primary outcomes: (1) eligibility for, (2) documented offer of, and (3) enrollment in a clinical trial. All 41 of the clinical trials available to these patients were considered. Independent variables included clinical and non‐clinical patient‐related factors. We assessed associations between these variables and the primary outcomes using multivariable regression.

Results

Of 1446 patients, 43% were female, 15% were over age 75, 6% were Black. 305 (21%) patients were eligible for a clinical trial. Among eligible patients, 154 (50%) had documentation of a trial offer and 90 (30%) enrolled. Among the GI cohort, bivariate analyses demonstrated that older age was associated with decreased trial eligibility. Bivariate analyses also demonstrated that Black race was associated with increased trial offer. After adjustment, patients 75 or older were less likely to be eligible for a clinical trial in the GI cohort; however, we found no significant associations between race and any of the outcomes after adjustment. Among eligible GI patients, we found no significant associations between non‐clinical factors and enrollment. Among the HN cohort, bivariate analyses demonstrated that female sex, older age, Black race, and unpartnered marital status were associated with decreased likelihood of trial offer; however, we found no significant associations between race, age, and marital status and any of the outcomes after adjustment. We found no significant associations between non‐clinical factors and eligibility after adjustment; however, women were less likely to be offered and to enroll in a clinical trial in the HN cohort.

Conclusion

Factors associated with eligibility, documented offer, and enrollment differed between disease site cohorts at our institution. Future work is needed to ensure the equitable inclusion of women and elderly patients in clinical trials.
Pegylated liposomal doxorubicin (PLD) in daily practice—A single center experience of treatment with PLD in patients with comorbidities and older patients with metastatic breast cancer
Authors: Wallrabenstein T. , Daetwyler E. , Oseledchyk A. , Rochlitz C. , Vetter M.
Published: May 2023

Purpose

Real‐world data about pegylated liposomal doxorubicin (PLD) in patients with metastatic breast cancer (MBC) are limited. We have aimed to highlight the role of PLD in daily practice focusing on older patients and patients with comorbidities with MBC.

Methods

We analyzed electronic records of all patients with advanced/metastatic breast cancer treated with single‐agent PLD at the University Hospital Basel between 2003 and 2021. Primary endpoint was time to next chemotherapy or death (TTNC). Secondary endpoints were overall survival (OS), progression‐free survival (PFS), and overall response rate (ORR). We performed univariate and multivariate analysis for clinical variables.

Results

112 patients with MBC having received single‐agent PLD in any treatment line were analyzed, including 34 patient who were older than 70 years and 61 patients with relevant comorbidities. Median TTNC, OS, and PFS for treatment with PLD were 4.6, 11.9, and 4.4 months, respectively. ORR was 13.6%. Age >70 years predicted shorter OS (median 11.2 months) in multivariate analysis (hazard ratio [HR] 1.83, 95% CI 1.07–3.11, p = 0.026). Age and comorbidities did not significantly affect other endpoints. Unexpectedly, hypertension predicted longer TTNC (8.3 months, p = 0.04) in univariate analysis, maintained in multivariate analysis as a trend for both TTNC (HR 0.62, p = 0.07) and OS (HR 0.63, p = 0.1).

Conclusion

Age predicted shorter OS significantly but median OS was not relevantly shorter in older patients. PLD remains a treatment option in patients with comorbidities and older patients with MBC. However, our real‐world results of PLD appear underwhelming compared to relevant phase II trials through all age groups, pointing to an efficacy‐effectiveness gap, possibly due to sampling bias.
Development of skeletal muscle fibrosis in a rodent model of cancer cachexia
Authors: Washington Tyrone A. , Schrems Eleanor R. , Haynie Wesley S. , Rosa‐Caldwell Megan E. , Brown Jacob L. , Saling Landen , Lim Seongkyun , Perry Richard A. , Brown Lemuel A. , Lee David E. , Greene Nicholas P.
Published: May 2023

Cachexia is characterized by losses in lean body mass and its progression results in worsened quality of life and exacerbated outcomes in cancer patients. However, the role and impact of fibrosis during the early stages and development of cachexia in under‐investigated. The purpose of this study was to determine if fibrosis occurs during cachexia development, and to evaluate this in both sexes. Female and male C57BL6/J mice were injected with phosphate‐buffered saline or Lewis Lung Carcinoma (LLC) at 8‐week of age, and tumors were allowed to develop for 1, 2, 3, or 4 weeks. 3wk and 4wk female tumor‐bearing mice displayed a dichotomy in tumor growth and were reassigned to high tumor (HT) and low tumor (LT) groups. In vitro analyses were also performed on cocultured C2C12 and 3T3 cells exposed to LLC conditioned media. Immunohistochemistry and quantitative polymerase chain reaction (qPCR) analysis were used to investigate fibrosis and fibrosis‐related signaling in skeletal muscle. Collagen deposition in skeletal muscle was increased in the 1wk, LT, and HT groups in female mice. However, collagen deposition was only increased in the 4wk group in male mice. In general, female mice displayed earlier alterations in extracellular matrix (ECM)‐related genes beginning at 1wk post‐LLC injection. Whereas this was not seen in males. While overall tumor burden is tightly correlated to cachexia development in both sexes, fibrotic development is not. Male mice did not exhibit early‐stage alterations in ECM‐related genes contrary to what was noted in female mice.
Sulfonyl Diazaborine ‘Click’ Chemistry Enables Rapid and Efficient Bioorthogonal Labeling**
Authors: Chowdhury Arnab , Chatterjee Saurav , Kushwaha Apoorv , Nanda Sidhanta , Dhilip Kumar T. J. , Bandyopadhyay Anupam
Published: May 2023

Finding an ideal bioorthogonal reaction that responds to a wide range of biological queries and applications is of great interest in biomedical applications. Rapid diazaborine (DAB) formation in water by the reactions of ortho‐carbonyl phenylboronic acid with α‐nucleophiles is an attractive conjugation module. Nevertheless, these conjugation reactions demand to satisfy stringent criteria for bioorthogonal applications. Here we show that widely used sulfonyl hydrazide (SHz) offers a stable DAB conjugate by combining with ortho‐carbonyl phenylboronic acid at physiological pH, competent for an optimal biorthogonal reaction. Remarkably, the reaction conversion is quantitative and rapid (k2>103 M−1 s−1) at low micromolar concentrations, and it preserves comparable efficacy in a complex biological milieu. DFT calculations support that SHz facilitates DAB formation via the most stable hydrazone intermediate and the lowest energy transition state compared to other biocompatible α‐nucleophiles. This conjugation is extremely efficient on living cell surfaces, enabling compelling pretargeted imaging and peptide delivery. We anticipate this work will permit addressing a wide range of cell biology queries and drug discovery platforms exploiting commercially available sulfonyl hydrazide fluorophores and derivatives.
Constructing pH‐Responsive and Tunable Azo‐Phenol‐Based o‐Nitrobenzyl Photocages
Authors: Wang Tsung‐Shing Andrew , Zhang Ya‐Wen , Chen Huai‐An , Lin Shiou‐Ting , Lee Hsien‐Ming
Published: May 2023

Multiple triggered‐release strategies are widely utilized to control the release of caged target molecules. Among them, photocages with conditional triggers provide extra layers of control in photorelease. In this work, a series of pH‐responsive photocages was designed that could be triggered under irradiation and specific intracellular pH values. pH‐sensitive phenolic groups were conjugated with o‐nitrobenzyl (oNB) to form azo‐phenolic NPX photocages with tunable pKa. These azo‐phenol‐based oNB photocages showed differentiable photoreleasing profiles at pH 5.0, 7.2 and 9.0. By attaching fluorogenic cargos, it was shown that one of the photocages, NPdiCl, could be used to differentiate between acidic pH 5.0 and neutral pH 7.2 in cells under artificial pH conditions. Finally, NPdiCl was identified as a promising pH‐responsive photocage for photoreleasing cargo inside acidic tumor cells.
Peptide Stapling with Boronate Esters‐ A Reversible Folding of (Artificial) Peptide Chain to α‐Helix
Authors: Kijewska Monika , Wołczański Grzegorz , Światowska Marta , Kędziora Katarzyna , Pawlicki Miłosz , Stefanowicz Piotr
Published: May 2023

Stabilization of a peptide conformation via stapling strategy may be realized by the reversible or more often irreversible connection of side chains being in mutually appropriate geometry. An incorporation of phenylboronic acid and sugar residues (fructonic or galacturonic acid), attached to two lysine side chains via amide bonds and separated by 2, 3, or 6 other residues in the C‐terminal fragment of RNase A introduces the intramolecular interaction stabilizing the α‐helical organization. The boronate ester stapling is stabilized in mild basic conditions and may be switched off by acidification leading to unfolded organization of the peptide chain. We investigated the possibility of using switchable stapling by mass spectrometry, NMR and UV‐CD spectroscopies, and DFT calculations.
Tracking the Process of Domino Ring‐Opening and Coupling of Fused Imidazole and Direct Observation of Peroxide Intermediates
Authors: Wang Yu , Luo Mei‐Lian , Cai Jin , Zhang Tao , Wu Yu‐Jie , Song Ming‐Da , Liu Bin , Zeng Ming‐Hua
Published: May 2023

Comprehensive Summary

A domino ring‐opening and coupling of imidazolyl annulated heterocycles 1 (1a: 4‐methyl‐1‐(1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)‐4H‐ benzo[d]imidazo[1,5‐a]imidazole, 1b: 1‐(1,5‐dimethyl‐1H‐benzo[d]imidazol‐2‐yl)‐4,7‐dimethyl‐4H‐benzo[d]imidazo[1,5‐a]imidazole) with dioxygen was developed at solvothermal condition, leading to conjugated 1,2‐diamidoalkenes derivatives 2 ((E)‐ArCONHArC=CArNHCOAr (Ar: 1‐methyl‐1H‐benzo[d]imidazolyl (2a), 1,5‐dimethyl‐1H‐benzo[d]imidazolyl (2b))) as single crystals directly. The reaction process was tracked by electrospray ionization mass spectrometry (ESI‐HRMS) and a series of reaction intermediates are detected. 18O2 labeling experiment verified the source of oxygen in 2. Combining evidence from control experiments, nuclear magnetic resonance (NMR) tracking, and crystallography, a seven‐step reaction pathway involving oxygen addition, ring opening, Friedel‐Crafts alkylation, oxidation, and dehydration was proposed and further supported by DFT calculation.
Computationally modelling cell proliferation: A review
Authors: Barbosa M. I. A. , Belinha J. , Jorge R. M. Natal , Carvalho A. X.
Published: May 2023

Cell proliferation is vital for the development and homeostasis of the human body. For such to occur, cells go through the cell cycle during which they replicate their genetic material and ultimately complete cellular division, when one cell divides into two new cells with equal genetic material. However, if there are some errors or abnormalities during the cell cycle that disrupt the balance between cell death and proliferation, severe problems can occur, such as tumour development, which is currently one of the leading causes of death in the world. Nowadays, mathematical and computational models are used to understand and study several biological mechanisms and processes, namely cellular proliferation. Over the last forty‐five years, several models have attempted to describe cell proliferation and its regulation. Due to the complexity of the process, numerous assumptions and simplifications have been considered. This work presents a review of some of these models, focusing mainly on mammalian or generic eukaryotic models. Previously published continuum, discrete and hybrid approaches are presented and compared, in order to understand and highlight the relevance and capabilities of these models, their shortcomings and future challenges.
Redefining the learning mechanism in teaching‐learning‐based optimization and its applications for flowtime‐aware‐cost minimizing of the workflow in cloud
Authors: Ram Satya Deo Kumar , Srivastava Shashank , Mishra Krishn Kumar
Published: May 2023

Teaching‐learning‐based optimization (TLBO) algorithm is a population‐based meta‐heuristic algorithm that was created to solve single‐objective optimization problems. The teaching‐learning mechanism of a classroom inspires it. TLBO suffers from weak exploration. As a result, its performance is not good for solving multimodal problems. To turn TLBO into a tool for solving multimodal problems and maintaining good diversity, we made significant modifications into the learning process of the fundamental TLBO. The proposed algorithm produces more diverse solutions and works better for solving multimodal problems. This newly created variant of TLBO is called “Intelligent‐Teaching‐Learning‐Based Optimization (I‐TLBO) algorithm.” I‐TLBO's performance is evaluated against the most recent standard benchmark function, CEC‐06, 2019, and it is discovered that I‐TLBO outperforms the other algorithms. After that, I‐TLBO was applied for flowtime‐aware‐cost minimization of the workflow executions in cloud datacenter. To solve these scheduling problems, I‐TLBO and other metaheuristic algorithms are simulated in CloudSim and tested over scientific workflows such as Inspiral, Montage, SIPHT, sample, Cybershake, and Epigenomics workflows. Finally, it is found that I‐TLBO reduces flowtime and cost both by 28.48%, 11.30%, 17.64%, 13.22%, 11.45%, and 14.71% in comparison to the second best performing algorithm while executing the standard workflow in cloud.
Analysis of P2P network system based on two‐stage service and failure repairability
Authors: Zhang Yukang , Ma Zhanyou , Liu Yilin , Wang Shunzhi
Published: May 2023

Along with the rapid development of the information technology revolution, P2P technology has been more and more widely and deeply researched in the field of mobile wireless, and mobile P2P has become an emerging and popular research field. The particularity of the mobile environment has extremely high requirements on the P2P network topology, resource transition paths and network security. In this paper, a two‐stage queueing model with negative customers and asynchronous failure is established based on a hybrid mobile network model combining the semi‐distributed topology and the fully‐distributed topology. Using the matrix‐geometric solution and Gauss‐Seidel iterative method, the probability distribution of the network model in steady‐state is obtained, and expressions for performance indicators such as the average number of peers in the two stages are given. Numerical experiments were conducted using programming software to analyze the effect of parameters on each indicator. The optimal parameters were solved by constructing the average cost unit time function and social benefit function to provide decision foundation for the mobile P2P network model.
Interface Adsorption and Aggregation Behavior of Sulfonate‐Based Anionic Silicone Surfactants in Aqueous Solution
Authors: Meng Lina , Wang Wenyu , Li Lei , Feng Shengyu
Published: May 2023

A series of sulfonate silicone surfactants possessing different hydrophobic groups were synthesized. Their adsorption and thermodynamic parameters in aqueous solutions were investigated by surface tension measurements, conductivity, transmission electron microscopy (TEM) and dynamic light scattering (DLS). These sulfonate‐based anionic silicone surfactants exhibit significant surface activity and can reduce the surface tension of water to 19.6 mN m−1 at critical micelle concentration. The TEM and DLS results demonstrate that the three sulfonated silicone surfactants self‐assemble into homogeneous sized vesicle‐like aggregates in aqueous solution. Moreover, the size of the aggregates was determined to be in the range from 80 to 400 nm at 0.05 mol L−1.
Yield component QTLs identified by genome‐wide association mapping validated in a diverse tropical japonica × tropical japonica rice biparental mapping population
Authors: Eizenga Georgia C. , Rice Adam D. , Huggins Trevis D. , Shakiba Ehsan , Edwards Jeremy D. , Jackson Aaron K. , Jia Melissa H. , Ali M. Liakat
Published: May 2023

The Rice Diversity Panel 1 (RDP1) is a resource for genome‐wide association (GWA) studies to explore the five major rice (Oryza sativa L.) subpopulations indica, aus, aromatic, temperate japonica, and tropical japonica (TRJ). Previously collected phenotype data for yield‐related traits in RDP1 were reanalyzed using a recently released 4.8 million single nucleotide polymorphism (SNP) dataset to enhance GWA mapping precision. GWA mapping revealed numerous GWA quantitative trait loci (QTLs) that were specific to one or more subpopulations. Most southern US cultivars are classified tropical japonica (TRJ) or TRJ admixtures, thus TRJ was the focus for validating Rice Diversity Panel 1 GWA QTLs. Two diverse TRJ accessions, L‐202 originating from California, USA, and Trembese from Indonesia, were selected for developing a recombinant inbred line (RIL) population. This RIL population was phenotyped for 20 yield component traits, 16 of which were measured in RDP1, including six agronomic, six panicle architecture, and four seed traits. Genotyping with 1439 polymorphic markers and QTL mapping revealed 43 RIL QTLs. Examination of the GWA QTLs identified 163 GWA QTLs for the same or related traits co‐located with 37 RIL QTLs. A significant overlap was on chromosome 7 (21.8–25.4; 26.8–29.6 Mb) where the well‐known yield related genes, GRAIN WEIGHT7 (GW7) and FRIZZY PANICLE (FZP), respectively, are located and specific to TRJ. In this region, 10 RIL QTLs were co‐located with 36 GWA QTLs for panicle architecture or seed traits, especially secondary branching to increase the number of seeds. RIL QTLs co‐located with GWA QTLs are targets for developing SNP markers that can be utilized in cultivar development.
Antitumor activity of galaxamide involved in cell apoptosis and stemness by inhibiting Wnt/β‐catenin pathway in cervical cancer
Authors: Yang Guang , He Yunbiao , Chen Yingxing , Huang Zhihan , Huang Jieqiong , Ren Xinyi , Xu Shihai , Li Ping
Published: May 2023

Our previous work reported that galaxamide, a cyclopeptide extracted from the seaweed Galaxaura filamentosa, showed antiproliferative activity against HeLa cells by MTT assay. In this study, the growth‐inhibitory effects of galaxamide in HeLa cells and xenograft mouse models were investigated. It was found galaxamide significantly inhibited cell growth, colony formation, migration, and invasion and induced cell apoptosis by inhibiting the Wnt signaling pathway in HeLa cells. RNA sequencing revealed that galaxamide regulated stemness by Wnt6 signaling pathway in HeLa cells. By analyzing The Cancer Genome Atlas database, Wnt6 was found to be negatively/positively correlated with stemness‐ and apoptosis‐related genes in human cervical cancer. Cancer stem‐like cells (CSCs) isolated and enriched from HeLa cells demonstrated elevated Wnt6 and β‐catenin genes compared with nonstem HeLa cells. After galaxamide treatment, CSCs showed abrogation of sphere‐forming ability, along with inhibition of stemness‐related and Wnt pathway genes. Galaxamide treatment was also accompanied by the induction of apoptosis in HeLa cells, which was consistent with the results in BALB/c nude mice. Our results provide evidence that suppression of stemness by downregulating the Wnt signaling pathway is the molecular mechanism by which galaxamide effectively inhibits cell growth and induces apoptosis in cervical cancer cells.