bluuebunny/crossref_metadata_2025 huggingface dataset:
Review—Electroforming Process for Microsystems Fabrication
Authors: Rai Prince Kumar , Gupta Ankur
Published: November 2023

Being an unconventional technique of additive micro-manufacturing, electroforming has garnered significant interest from various industrial sectors because of its capability to offer advanced micro-manufacturing competences with high precision in achieving dimensional uniformity and replication accuracy at a small scale. This paper reports a comprehensive review of the electroforming process as a microsystem fabrication technique. This process is superior to 3D printing, stereolithography, selective laser sintering, physical and chemical vapor deposition, etc. in many aspects due to its unique properties. It can deposit a variety of metals and alloys, including precious metals, making it appropriate for various applications in the microfabrication domain. This article covers the fundamental aspects of electroforming, its history, the current state-of-the-art advancements, the modeling associated with it, and its importance in an industrial context. Additionally, the article discusses the advantages and limitations of this technique and their respective microsystem applications. Finally, it concludes with a discussion on the future prospects and potential advancements in the field of electroforming, contributing to the development of microsystems.
Modeling Strategies Based on Multiple Neural Network Systems Applied for a Monopolar and Bipolar Electrocoagulation
Authors: Piuleac Ciprian George , Godini Kazem , Rahimi Yousef , Zarei Reza , Azarian Ghasem
Published: November 2023

The objective of this research was to evaluate the efficiency of an electrocoagulation system using iron and aluminum electrodes, arranged in both monopolar and bipolar arrangements, for the removal of acid red 18 dye. Experimental and modeling approaches were employed to investigate the system’s performance. The effects of operating parameters: including initial pH (3–9), current density (0.4–5.6 mA cm−2), charge passed (2.16–21.6 C cm−2), and initial dye concentration (50–300 mg l−1) were studied. The results demonstrated that an increase in electric current intensity and passed charge enhanced the removal of COD and dye. However, to minimize energy consumption, these parameters were optimized for different dye concentrations. The monopolar arrangement exhibited favorable performance for the both electrodes, primarily due to reduced ohmic drop effect, although the iron electrode generated sludge with better settling characteristics. The monopolar iron electrode consumed the least energy (38.3 kWh kg−1 COD). Experimental evaluation was conducted to assess the influence of key electrolysis process parameters on dye and COD removal. Additionally, neural network models, employing radial basis function and multilayer perceptron approaches, were utilized to predict system outputs based on initial characteristics (COD and dye) and operation conditions. The neural network models provided accurate predictions, offering practical insights for experimental applications.
Effects of Circular Hydraulic Jump on the Material Removal Characteristics of Jet Electrochemical Machining
Authors: Wang Ji , Shen Chengwei , Zhou Ping , Yan Ying , Guo Dongming
Published: November 2023

Jet electrochemical machining (Jet-ECM) is a potential precision machining method. Due to the advantages of non-stress-free machining and high flexibility, it is widely used in surface finishing and complex structural machining. However, the “w” shaped removal profile and wide removal range caused by inappropriate process parameters reduce the stability and localizability of Jet-ECM. In this paper, the material removal characteristics of Jet-ECM were investigated both theoretically and experimentally. A multi-physics field simulation model for Jet-ECM was established, and the overall shape of the circular hydraulic jump (CHJ), current density distribution and workpiece deformation were calculated. The effects of CHJ on the material removal characteristics were investigated by experiments with jet flow rate and inter-electrode gap (IEG) distance. The results reveal the qualitative relationship between CHJ states and process parameters and give the range of parameters that can form a stable CHJ and ensure a Gaussian shaped removal profile and a narrower removal range. This study provides theoretical guidance on the process parameters of Jet-ECM to improve its processing stability and localizability, which is significant for the accuracy of surface finishing and the controllability of complex structural machining, promoting the further application of Jet-ECM.
A Simplified Equivalent Circuit Model for the Photo-Charging Process of Carbon-Based Quasi-Solid Photosupercapacitors
Authors: Gallegos-Pérez Waldo Roberto , Corpus-Mendoza Asiel N. , Lobato-Peralta Diego Ramon , Cuentas-Gallegos Ana Karina , Camacho-Cáceres Jaquelina , Arias-Ramos Carlos Fabián , Hu Hailin
Published: November 2023

Solar irradiation can be converted into electrical current by a solar cell, which in turn can be stored in a supercapacitor. The coupling of a solar cell and a supercapacitor, called photosupercapacitor, shows promising applications that demand multidisciplinary studies to understand its functionality and potential. Normally, supercapacitors are characterized with potentiostats or power sources that provide a constant current or voltage, however, we find that the photocurrent provided by a solar cell in a photosupercapacitor configuration largely depends on the voltage stored in the supercapacitor connected in parallel to the solar cell. Therefore, we use a simplified equivalent circuit model to demonstrate that the charging time of a photosupercapacitor depends mainly on its capacitance, and to a lesser extent, on its resistance. At the same time, the maximum output voltage of the photosupercapacitor depends on the saturation and short circuit currents of the solar cell. The numerical results confirm qualitatively the experimental behavior of the photo-charging curves of quasi-solid supercapacitors, which consist of polyvinyl alcohol (PVA)-H2SO4 electrolyte for both activated carbon or reduced graphene oxide-based electrodes. The latter presents better electrochemical characteristics that optimize the operation of the photosupercapacitor. The electrical circuit analysis is a useful tool to guide further improvements in the photosupercapacitor design and fabrication.
Electrochemically Reduced Graphene Oxide Supported Palladium-Cobalt Alloy Nanoparticles as Highly Efficient Electrocatalyst for Oxygen Reduction Reaction
Authors: Yasmin Sabina , Kabir Md Humayun , Shaikh Md Aftab Ali , Jeon Seungwon
Published: November 2023

Pd-Co alloy nanoparticles were synthesized on electrochemically reduced graphene oxide (ErGO) for electrocatalytic oxygen reduction reaction (ORR) in alkaline media. The morphological structure, chemical composition, and crystallinity of the afforded ErGO/Pd-Co catalyst were examined by various techniques, including transmission electron microscopy, X-ray photoelectron spectroscopy, and X-ray diffraction analysis. The Pd-Co alloy nanoparticles were evenly distributed on the ErGO sheet and had a narrow size distribution, with an average particle size of 4.25 nm. The ORR activity of the as-prepared ErGO/Pd-Co alloy catalyst was evaluated by cyclic voltammetry, linear sweep voltammetry, rotating disk electrode, and rotating ring disk electrode techniques in an alkaline electrolyte. The ErGO/Pd-Co catalyst exhibits a very high electrocatalytic activity in ORR with the mass activity more than 2.0 times of the commercial 20% Pt/C due to the synergistic catalytic effect of both ErGO and Pd-Co nanoparticles. Electrocatalytic kinetics investigation shows that, the ORR on the ErGO/Pd-Co catalyst proceeds through four electrons transferred mechanism with negligible amount of peroxide species. Moreover, the ErGO/Pd-Co shows an excellent methanol tolerance than the commercial 20% Pt/C.
Asymmetrical Optical Response of Opal Photonic Crystals with Graded Thickness
Authors: Grant Alex , O’Dwyer Colm
Published: November 2023

The influence of thickness gradient and structural order on the spectral response of opal photonic crystals (PhCs) grown by evaporation-induced self-assembly (EISA) are presented. SEM imaging and angle resolved optical transmission spectroscopy are used to investigate the evolution of the PBG along a thickness gradient for opals grown from five different colloidal sphere concentrations at two different evaporation rates. The degradation of structural order along the thickness gradient is demonstrated, the occurrence of which attenuates the PBG with the thinning of the opal film and results in asymmetrical angle-resolved transmission spectra. The asymmetry in transmission intensity becomes more pronounced for opals grown from lower volume fractions, where secondary Bragg reflections also appear at low incident angles.
Dynamic lumped cell-level model of chemical membrane degradation in PEM electrolysis: Impact of pressure and time dependence
Authors: Dörner Sven , Kinzl Markus , Mitsos Alexander , Bongartz Dominik
Published: November 2023

Chemical membrane degradation has a significant impact on the lifetime of a PEM electrolyzer. For comprehensive understanding, cell-level models are useful. However, existing cell-level models ignore the dynamic consumption process of Nafion membrane fragments over time and do not consider the influence of operating parameters, such as pressure, on chemical membrane degradation. To address these limitations, we present a dynamic lumped cell-level model to analyze chemical membrane degradation as fluoride release rates. Parameter estimation with experimental literature data is performed using a pseudo-steady state approach. The model is used to investigate the influence of pressure. The results show increased fluoride release rates and H2O2 concentrations at higher pressures due to enhanced O2 crossover. They also suggest that the maximum in degradation rate at intermediate current densities is due to changing water flux across the membrane. Time-dependent simulations with full dynamics suggest that the maximum is reached after several thousand hours.
Bone marrow stromal cell antigen-1 deficiency protects from acute kidney injury
Authors: Inoue Tsuyoshi , Umene Ryusuke , Sung Sun-Sang J. , Tanaka Shinji , Huang Liping , Yao Junlan , Hashimoto Noritatsu , Wu Chia-Hsien , Nakamura Yasuna , Nishino Tomoya , Ye Hong , Rosin Diane L. , Ishihara Katsuhiko , Okusa Mark D.
Published: November 2023

Acute kidney injury (AKI), a serious disease for which there is no effective Federal Drug Administration-approved treatment, is associated with high mortality rates. Bone marrow stromal cell antigen-1 (Bst1) is a cell surface molecule that can cause kidney fibrosis, but its role in AKI is largely unknown. Our study showed that Bst1−/− mice revealed a protective effect against renal bilateral ischemia-reperfusion injury (IRI). Adoptive transfer studies confirmed that Bst1 expression in hematopoietic cells, especially neutrophils, contributed to renal bilateral IRI.
Type 2 diabetes exacerbates changes in blood pressure-independent arterial stiffness: cross-sectional and longitudinal evidence from the SUMMIT study
Authors: Aizawa Kunihiko , Gates Phillip E. , Mawson David M. , Casanova Francesco , Gooding Kim M. , Hope Suzy V. , Goncalves Isabel , Nilsson Jan , Khan Faisel , Colhoun Helen M. , Natali Andrea , Palombo Carlo , Shore Angela C.
Published: November 2023

We demonstrate in this study a greater BP-independent arterial stiffness β0 in people with type 2 diabetes (T2DM) compared to those without, and also a greater change in β0 over 3 yr in people with T2DM than those without. These findings suggest that the intrinsic properties of the arterial wall may change in a different and more detrimental way in people with T2DM and likely represents accumulation of cardiovascular risk.
Numerical Investigation of the Finite Thin Film Flow for Hybrid Nanofluid with Kerosene Oil as Base Fluid over a Stretching Surface along with the Viscous Dissipation and Variable Thermal Conductivity Effects
Authors: Mehmood Yasir , Alsinai Ammar , Shafqat Ramsha , Bilal Muhammad , Khan Allah Yar , Qahtan Read S. A.
Published: November 2023

This study examines the flow and heat transfer of a finite thin layer of a hybrid nanofluid across an unstable stretching surface with varying thermal conductivity and viscous dissipation effects. A hybrid nanofluid model is considered to comprise two different types of nanoparticles,

Go

and

Ag

, with kerosene oil used as a base fluid. To study the phenomenon of thermal conduction, a modified version of Fourier’s law model is adopted because in the power-law model, the thermal conductivity depends on the velocity gradient. A system of nonlinear ordinary differential equations is obtained by considering the similarity transformations over the obtained rheological system of partial differential equations which is then tackled by a well-known numerical approach, i.e., the bvp4c MATLAB technique. The rheological impacts of the power-law index, solid volume fraction, film thickness, Eckert number, and modified Prandtl number on temperature and velocity fields are graphically discussed and illustrated. In the presence of nanoparticles, the temperature of the working fluid is enhanced and the power-law index has an inverse relation with the velocity of the hybrid nanofluid.
A Longitudinal Study of NADC34-Like Strains in an Intensive Farm Unravels Divergent Evolution
Authors: Xu Sijia , Liu Jing , Xing Jiabao , Gao Han , Zhu Dihua , Xu Zhiying , Zhong Jianhao , Li Yue , Gao Xiaopeng , Kuang Qiyuan , Zhang Guihong , Wang Heng , Sun Yankuo
Published: November 2023

NADC34-like porcine reproductive and respiratory virus (PRRSV) has had a significant impact on the pig industry, particularly in China. However, the evolutionary characteristics and pathogenicity of NADC34-like PRRSV strains within intensive farming systems are not well understood, particularly regarding the biological characteristic variation of successive outbreaks on a farm. In this study, we conducted continuous surveillance in an intensive farm that experienced a PRRSV outbreak. Two PRRSV strains, GDHZ109/2020 and GDYS162/2022, were isolated and fully sequenced from the same swine farm in Guangdong Province in 2020 and 2022, respectively. Evolutionary analysis based on the ORF5 gene revealed that both strains clustered with NADC34-like strains and shared 96.5% homology. Analysis of the full-length genome and NSP2 gene classified the strains into lineage 1.8, represented by the NADC30 strain. Recombination analysis suggested complex recombination patterns for both strains, involving NADC30-like, NADC34-like, and JXA1-like strains. Although many recombinant regions were nearly identical, there were differences observed in the NSP5–NSP7 region. Pathogenicity experiments conducted on piglets demonstrated that GDHZ109/2020 exhibited higher pathogenicity compared to GDYS162/2022. Piglets in the GDHZ109/2020 infected group had more severe clinical signs and higher mortality. Moreover, analysis of respiratory microbial diversity indicated a significant increase in the abundance of potentially pathogenic microbiota, such as Klebsiella and Erysipelothrix contributing to the respiratory tract of PRRSV-infected piglets, suggesting secondary infections due to differences in immune defense. These findings highlight the importance of NADC34-like recombinant strains’ evolution during the farm’s epidemic period, which may have contributed to changes in pathogenicity. This study improves our understanding of the current prevalence of PRRSV and provides novel insights into the prevention and control of PRRSV.
Engineered Decellularized Tendon Matrix Putty Preserves Native Tendon Bioactivity to Promote Cell Proliferation and Enthesis Repair
Authors: Nelson Anna-Laura , O’Hara Kelsey M. , Nolte Philip C. , Fukase Naomasa , Murata Yoichi , Nolte Anna-Katharina , Huard Johnny , Bernholt David L. , Millett Peter J. , Bahney Chelsea S.
Published: November 2023

Rotator cuff tears are a common soft tissue injury that can significantly decrease function of the shoulder and cause severe pain. Despite progress in surgical technique, rotator cuff repairs (RCRs) do not always heal efficiently. Many failures occur at the bone-tendon interface as a result of poor healing capacity of the tendon and failure to regenerate the native histological anatomy of the enthesis. While allografts are commercially available, clinical use is limited as they do not stimulate tissue regeneration and are associated with a structural failure of up to 40% in re-tear cases. Novel tissue engineering strategies are being developed with promise, but most involve addition of cells and/or growth factors which extends the timeline for clinical translation. Thus, there exists a significant unmet clinical need for easily translatable surgical augmentation approaches that can improve healing in RCR. Here we describe the development of a decellularized tendon matrix (DTM) putty that preserves native tendon bioactivity using a novel processing technique. In vitro, DTM promoted proliferation of tenocytes and adipose-derived stem cells with an increase in expression-specific transcription factors seen during enthesis development, Scleraxis and Sox9. When placed in a rabbit model of a chronic rotator cuff tear, DTM improved histological tissue repair by promoting calcification at the bone-tendon interface more similar to the normal fibrocartilaginous enthesis. Taken together, these data indicate that the engineered DTM putty retains a pro-regenerative bioactivity that presents a promising translational strategy for improving healing at the enthesis.
Antibiotic Resistance Genes (ARGs) in the Environment of Saudi Aquaculture as a New Class of Pollutants
Authors: Alotaibi Amenah Saud
Published: November 2023

Aquaculture is a productive sector that will be instrumental in addressing the challenges of the forthcoming generation, including the demand for proteins endorsing humans and environmental stewardship. Saudi Arabia (SA) economy heavily depends on aquaculture. However, aquaculture practices, which encompass applying antibiotics for both prophylaxis and treatment, impose a significant impact. Applying antibiotics in aquaculture causes the neighboring microorganisms in the water column, soil particles, and aquaculture-related bacterium species to become resistant to antibiotics. Bacteria can spread antibiotic resistance genes (ARGs) through gene transfer mechanisms, further distributing genetic determinants in aquatic habitats. SA is one of the nations with the highest projected relative growth in aquaculture antibiotic consumption. There have been reports of numerous antibiotic-resistant microorganisms in SA, but the majority of studies focused on isolates from human samples. Several ARGs developing resistance to aminoglycosides, carbapenems, tetracyclines, and beta-lactams were reported in clinical samples in SA; however, limited reviews about aquaculture-related antibiotic resistance genes (AARGs) have been published in SA. In this article, the main drivers of increasing the dissemination of AARGs were poor sanitation systems, human clinical antibiotic resistance (AR), antibiotic misuse, aquatic feed-containing antibiotics, and lack of awareness regarding antibiotics use in both clinical and (AR) aquaculture systems. Saudi national corporations are required to combat AARGs, including reiterating the threat of AR and looking for more cutting-edge knowhows or efficient administration choices to regulate it. It is necessary to educate the general population alongside organizations about AARG dissemination so as to increase understanding and alter the existing circumstances.
A Preliminary Study on the Relationship between Arthropod Diversity and Vegetation Diversity in Four Contrasting Ecosystems in Hanthana Mountain Range of Sri Lanka, during the Post-Monsoon Dry Season
Authors: Weerathunga W. A. Manasee , Athapaththu A. M. Gihan , Amarasinghe L. D.
Published: November 2023

This study assesses the relationship between arthropod and vegetation diversity in four ecosystems with different types of vegetation, during a post-monsoonal season. We determined the arthropod diversity in vegetation surrounding an aquatic environment (AQ), a broad-leaved wet, evergreen forest ecosystem (BL), a Pinus caribaea monoculture plantation (PN), and a Pinus plantation artificially enriched with indigenous broad-leaved tree species (PNEN) located in the Hanthana mountain range, Sri Lanka. Arthropods randomly sampled from three randomly selected sites (5 m × 5 m) of each ecosystem were identified up to the highest possible taxa using standard identification keys. Woody and herbal vegetation was identified via a plant census. Arthropod and vegetation diversities were computed separately for each site using the Shannon–Wiener Index (H). Arthropods of 68 species and 43 families were found. AQ had the greatest arthropod diversity (H = 2.642), dominated by Olios spp., followed by BL (H = 2.444), dominated by a tettigonid species, Oxytate spp. and Psechrus spp. PN was third (H = 1.411), dominated by Dicaldispa spp. PNEN had the lowest (H = 1.3500), dominated by an ant species. Contrastingly, PNEN had the highest plant diversity (H = 2.614) and PN, the lowest (H = 0.879). In AQ, BL, and PN, the arthropod diversity was linearly dependent on plant diversity (R2 = 0.423,

p

 ≤ 0.001), whereas it was not so when PNEN was also included (R2 = 0.008,

p

 ≤ 0.001). This shows that higher plant diversity contributes to greater arthropod diversity in ecosystems where human intervention is minimal. But this pattern was not visible in PNEN, which is an artificially created ecosystem.
Fracture Initiation and Propagation in the Hot Dry Rock Subject to the Cyclic Injection Hydraulic Fracturing Treatment
Authors: Yuan Yilong , Wang Wei , Tang Jiawei , Guo Qiang , Liu Yulong
Published: November 2023

Cyclic injection hydraulic fracturing is a promising way for the geothermal energy exploitation by reactivating the fractures in geothermal reservoir. However, fracture initiation and growth induced by cyclic injection schemes have been inadequately studied for hot dry rock (HDR), and the cyclic injection fracturing optimized often by experience. For this reason, the initiation and propagation of hydraulic fractures in the HDR under different cyclic injection methods were determined by experiment research for hydraulic fracturing. The results show that the cyclic frequency and injection rate play different roles in the stimulation of HDR. The cyclic injection with low frequency-low pressure can create more branched fractures, forming a short but complex hydraulic fracture network. However, when high flow-high frequency injection method is subjected, the branch fractures formed are significantly reduced, but each branch fracture can be fully expanded. To fully exploit the advantages of different injection methods, a numerical model that contains a fracture network was established with PFC software, and an alternating cyclic injection scheme with synergistic control of the cyclic frequency and injection rate was proposed. The comparison results indicated that the alternating cyclic injection method can effectively improve the fracturing effect in the HDR. The stimulation area of the alternating cyclic injection method is about 2.3 times and 2.7 times that of the low flow-low frequency and high flow-high frequency injection methods, respectively. The method presented here can be adopted to optimize the fracture growth regime and provide a scientific basis for EGS hydraulic fracturing design.
Mapping Connectivity Patterns: Degree-Based Topological Indices of Corona Product Graphs
Authors: Ali Nasir , Kousar Zaeema , Safdar Maimoona , Tolasa Fikadu Tesgara , Suleiman Enoch
Published: November 2023

Graph theory (GT) is a mathematical field that involves the study of graphs or diagrams that contain points and lines to represent the representation of mathematical truth in a diagrammatic format. From simple graphs, complex network architectures can be built using graph operations. Topological indices (TI) are graph invariants that correlate the physicochemical and interesting properties of different graphs. TI deal with many properties of molecular structure as well. It is important to compute the TI of complex structures. The corona product (CP) of two graphs

G
 

and

H

gives us a new graph obtained by taking one copy of

G

and

V

G

copies of

H

and joining the

i

th vertex of

G

to every vertex in the

i

th copy of

H

. In this paper, based on various CP graphs composed of paths, cycles, and complete graphs, the geometric index (GA) and atom bond connectivity (ABC) index are investigated. Particularly, we discussed the corona products

P

s

⨀

P

t

,

C

t

⨀

C

s

,

K

t

⊙

K

s

,

K

t

⊙

P

s

, and

P

s

⊙

K

t

and GA and ABC index. Moreover, a few molecular graphs and physicochemical features may be predicted by considering relevant mathematical findings supported by proofs.
First-in-Human Study with Preclinical Data of BCL-2/BCL-xL Inhibitor Pelcitoclax in Locally Advanced or Metastatic Solid Tumors
Authors: Lakhani Nehal J. , Rasco Drew , Wang Hengbang , Men Lichuang , Liang Eric , Fu Tommy , Collins Mary C. , Min Ping , Yin Yan , Davids Matthew S. , Yang Dajun , Zhai Yifan
Published: November 2023

Purpose:

B-cell lymphoma-extra-large (BCL-xL) regulates apoptosis and is an attractive anticancer therapeutic target. However, BCL-xL inhibition also kills mature platelets, hampering clinical development. Using an innovative prodrug strategy, we have developed pelcitoclax (APG-1252), a potent, dual BCL-2 and BCL-xL inhibitor. Aims of this study were to characterize the antitumor activity and safety of pelcitoclax and explore its underlying mechanisms of action (MOA).

Patients and Methods:

Cell line–derived xenograft and patient-derived xenograft (PDX) models were tested to evaluate antitumor activity and elucidate MOA. Subjects (N = 50) with metastatic small-cell lung cancer and other solid tumors received intravenous pelcitoclax once or twice weekly. Primary outcome measures were safety and tolerability; preliminary efficacy (responses every 2 cycles per RECIST version 1.1) represented a secondary endpoint.

Results:

Pelcitoclax exhibited strong BAX/BAK‒dependent and caspase-mediated antiproliferative and apoptogenic activity in various cancer cell lines. Consistent with cell-based apoptogenic activity, pelcitoclax disrupted BCL-xL:BIM and BCL-xL:PUMA complexes in lung and gastric cancer PDX models. Levels of BCL-xL complexes correlated with tumor growth inhibition by pelcitoclax. Combined with taxanes, pelcitoclax enhanced antitumor activity by downregulating antiapoptotic protein myeloid cell leukemia-1 (MCL-1). Importantly, pelcitoclax was well tolerated and demonstrated preliminary therapeutic efficacy, with overall response and disease control rates of 6.5% and 30.4%, respectively. Most common treatment-related adverse events included transaminase elevations and reduced platelets that were less frequent with a once-weekly schedule.

Conclusions:

Our data demonstrate that pelcitoclax has antitumor activity and is well tolerated, supporting its further clinical development for human solid tumors, particularly combined with agents that downregulate MCL-1.
Early-onset Colon Cancer Shows a Distinct Intestinal Microbiome and a Host–Microbe Interaction
Authors: Adnan Darbaz , Trinh Jonathan Q. , Sharma Deepak , Alsayid Muhammad , Bishehsari Faraz
Published: November 2023

The incidence rate of colorectal cancer in younger adults has been rising in developed countries. This trend may be attributed to environmental exposures as a result of lifestyle changes. Many of the lifestyle factors that promote colorectal cancer can also affect the gut microbiome, which may be associated with colorectal cancer risks. The role of the microbiome in the ongoing rise of early-onset colorectal cancer is unknown. Here, we aimed to investigate age-related differences in the gut microbiome of patients with colorectal cancer and healthy individuals by examining both the fecal and tumor microbiomes. We utilized the publicly accessible data on fecal shotgun metagenomics from CuratedMetagenomeData and TCGA via the GDC Data Portal. Comparison of 701 colorectal cancer and 693 controls revealed that microbial features were age dependent, with a significant difference in species enrichment between early-onset (<50 years) and late-onset (>65 years) patients with colorectal cancer. Analysis of the tumor-associated microbiome in a separate dataset of 85 patients with colorectal cancer verified age-specific differences in taxon abundance between early- and late-onset patients with colorectal cancer. Finally, using host gene expression data, we found a stronger microbe–host interaction in early- vs. late-onset colorectal cancers. Altogether, these findings indicate that microbial features were age-dependent with stronger microbial–host interactions at the tumor site in early-onset colorectal cancers, suggesting a direct role of microbes in tumorigenesis via interaction with cancer-related pathways in this age group.

Prevention Relevance:

Early-onset colorectal cancer is on the rise, presumably because of changes in environmental exposures. Lifestyle changes may contribute to colorectal cancer via alterations in gut microbes. Here, we show that microbial association with colorectal cancer is age-dependent, and microbe interactions with tumor pathways are stronger in young versus older colorectal cancers.
TABLE 1 from Mathematical Modeling Identifies Optimum Palbociclib-fulvestrant Dose Administration Schedules for the Treatment of Patients with Estrogen Receptor–positive Breast Cancer
Authors: Cheng Yu-Chen , Stein Shayna , Nardone Agostina , Liu Weihan , Ma Wen , Cohen Gabriella , Guarducci Cristina , McDonald Thomas O. , Jeselsohn Rinath , Michor Franziska
Published: November 2023

In silico clinical trial schedules of palbociclib
Supplementary Table S3 from Mathematical Modeling Identifies Optimum Palbociclib-fulvestrant Dose Administration Schedules for the Treatment of Patients with Estrogen Receptor–positive Breast Cancer
Authors: Cheng Yu-Chen , Stein Shayna , Nardone Agostina , Liu Weihan , Ma Wen , Cohen Gabriella , Guarducci Cristina , McDonald Thomas O. , Jeselsohn Rinath , Michor Franziska
Published: November 2023

Supplementary Table S3 shows ratio of each schedule to the standard schedule at day 100 for simulated cell lines
Supplementary Fig. S9 from Mathematical Modeling Identifies Optimum Palbociclib-fulvestrant Dose Administration Schedules for the Treatment of Patients with Estrogen Receptor–positive Breast Cancer
Authors: Cheng Yu-Chen , Stein Shayna , Nardone Agostina , Liu Weihan , Ma Wen , Cohen Gabriella , Guarducci Cristina , McDonald Thomas O. , Jeselsohn Rinath , Michor Franziska
Published: November 2023

Supplementary Fig. S9 shows in silico trial predictions of multiple palbociclib treatment administration schedules in combination with fulvestrant
Supplementary Fig. S11 from Mathematical Modeling Identifies Optimum Palbociclib-fulvestrant Dose Administration Schedules for the Treatment of Patients with Estrogen Receptor–positive Breast Cancer
Authors: Cheng Yu-Chen , Stein Shayna , Nardone Agostina , Liu Weihan , Ma Wen , Cohen Gabriella , Guarducci Cristina , McDonald Thomas O. , Jeselsohn Rinath , Michor Franziska
Published: November 2023

Supplementary Fig. S11 shows in silico simulation of palbociclib resistant MCF7 cell line
Supplementary Fig. S10 from Mathematical Modeling Identifies Optimum Palbociclib-fulvestrant Dose Administration Schedules for the Treatment of Patients with Estrogen Receptor–positive Breast Cancer
Authors: Cheng Yu-Chen , Stein Shayna , Nardone Agostina , Liu Weihan , Ma Wen , Cohen Gabriella , Guarducci Cristina , McDonald Thomas O. , Jeselsohn Rinath , Michor Franziska
Published: November 2023

Supplementary Fig. S10 shows parameter inference of palbociclib resistant cell lines
Supplementary Fig. S1 from Mathematical Modeling Identifies Optimum Palbociclib-fulvestrant Dose Administration Schedules for the Treatment of Patients with Estrogen Receptor–positive Breast Cancer
Authors: Cheng Yu-Chen , Stein Shayna , Nardone Agostina , Liu Weihan , Ma Wen , Cohen Gabriella , Guarducci Cristina , McDonald Thomas O. , Jeselsohn Rinath , Michor Franziska
Published: November 2023

Supplementary Fig. S1 shows an illustration of multistage cell-cycle model with m = 4
Supplementary Appendix S2 from Mathematical Modeling Identifies Optimum Palbociclib-fulvestrant Dose Administration Schedules for the Treatment of Patients with Estrogen Receptor–positive Breast Cancer
Authors: Cheng Yu-Chen , Stein Shayna , Nardone Agostina , Liu Weihan , Ma Wen , Cohen Gabriella , Guarducci Cristina , McDonald Thomas O. , Jeselsohn Rinath , Michor Franziska
Published: November 2023

Supplementary Appendix S2 shows Bayesian estimation of model parameters
Supplementary Appendix S1 from Mathematical Modeling Identifies Optimum Palbociclib-fulvestrant Dose Administration Schedules for the Treatment of Patients with Estrogen Receptor–positive Breast Cancer
Authors: Cheng Yu-Chen , Stein Shayna , Nardone Agostina , Liu Weihan , Ma Wen , Cohen Gabriella , Guarducci Cristina , McDonald Thomas O. , Jeselsohn Rinath , Michor Franziska
Published: November 2023

Supplementary Appendix S1 shows multistage model
FIGURE 5 from Mathematical Modeling Identifies Optimum Palbociclib-fulvestrant Dose Administration Schedules for the Treatment of Patients with Estrogen Receptor–positive Breast Cancer
Authors: Cheng Yu-Chen , Stein Shayna , Nardone Agostina , Liu Weihan , Ma Wen , Cohen Gabriella , Guarducci Cristina , McDonald Thomas O. , Jeselsohn Rinath , Michor Franziska
Published: November 2023

Prediction of drug responses in palbociclib-resistant cells. For −DOX cells (A) and for +DOX cells (B) are the estimated drug response curves of the effect of palbociclib on G1–S transition rate. The blue (−DOX) and red (+DOX) curves are given by the estimated model parameter of the palbociclib-sensitive MCF7 cell line. The green (−DOX) and orange (+DOX) curves are given by the estimated model parameter of the palbociclib-resistant MCF7 cell line. The gray shaded area corresponds to the 95% credible interval of the posterior predictive values. C–F show the box plots for the number of cells at day 100 given by the in silico trial predictions of multiple palbociclib treatment administration schedules in combination with fulvestrant. The p-values were computed using the Wilcoxon test. C and D are −DOX/+DOX cells of the palbociclib-sensitive MCF7 cell line. E and F are −DOX/+DOX cells of the palbociclib-resistant MCF7 cell line (+PR).
FIGURE 4 from Mathematical Modeling Identifies Optimum Palbociclib-fulvestrant Dose Administration Schedules for the Treatment of Patients with Estrogen Receptor–positive Breast Cancer
Authors: Cheng Yu-Chen , Stein Shayna , Nardone Agostina , Liu Weihan , Ma Wen , Cohen Gabriella , Guarducci Cristina , McDonald Thomas O. , Jeselsohn Rinath , Michor Franziska
Published: November 2023

In silico trial predictions of multiple palbociclib treatment administration schedules in combination with fulvestrant. For −DOX cells (A) and for +DOX cells (B), The panels show the box plots for the number of cells at day 100. The p-values were computed using the Wilcoxon test. In each panel, we only show the largest two p-values. The p-values not shown in the panels, for the rest of pairs of treatment schedules, are all smaller than 1e − 15 in A and 1e − 13 in B. For −DOX cells (C) and for +DOX cells (D), The panels show the waterfall charts for 150 random samples from the group of 1,500 simulations in descending order of cell number at day 100. For −DOX cells (E) and for +DOX cells (F), The panels show the predictions of in silico cell growth trajectories by taking the ratio of each schedule to the standard schedule (daily, 125 mg, 3 weeks on, 1 week off). The shaded area corresponds to the 95% credible interval of the posterior predictive values.
Data from Mathematical Modeling Identifies Optimum Palbociclib-fulvestrant Dose Administration Schedules for the Treatment of Patients with Estrogen Receptor–positive Breast Cancer
Authors: Cheng Yu-Chen , Stein Shayna , Nardone Agostina , Liu Weihan , Ma Wen , Cohen Gabriella , Guarducci Cristina , McDonald Thomas O. , Jeselsohn Rinath , Michor Franziska
Published: November 2023

Abstract
Cyclin-dependent kinases 4/6 (CDK4/6) inhibitors such as palbociclib are approved for the treatment of metastatic estrogen receptor–positive (ER+) breast cancer in combination with endocrine therapies and significantly improve outcomes in patients with this disease. However, given the large number of possible pairwise drug combinations and administration schedules, it remains unclear which clinical strategy would lead to best survival. Here, we developed a computational, cell cycle–explicit model to characterize the pharmacodynamic response to palbociclib-fulvestrant combination therapy. This pharmacodynamic model was parameterized, in a Bayesian statistical inference approach, using in vitro data from cells with wild-type estrogen receptor (WT-ER) and cells expressing the activating missense ER mutation, Y537S, which confers resistance to fulvestrant. We then incorporated pharmacokinetic models derived from clinical data into our computational modeling platform. To systematically compare dose administration schedules, we performed in silico clinical trials based on integrating our pharmacodynamic and pharmacokinetic models as well as considering clinical toxicity constraints. We found that continuous dosing of palbociclib is more effective for lowering overall tumor burden than the standard, pulsed-dose palbociclib treatment. Importantly, our mathematical modeling and statistical analysis platform provides a rational method for comparing treatment strategies in search of optimal combination dosing strategies of other cell-cycle inhibitors in ER+ breast cancer.
Significance:
We created a computational modeling platform to predict the effects of fulvestrant/palbocilib treatment on WT-ER and Y537S-mutant breast cancer cells, and found that continuous treatment schedules are more effective than the standard, pulsed-dose palbociclib treatment schedule.
Intake of Marine n-3 Polyunsaturated Fatty Acids and Risk of Hemorrhagic Stroke and Its Subtypes: A Danish Follow-Up Study
Authors: Hjelmgaard Katrin , Bork Christian Sørensen , Lundbye-Christensen Søren , Lühdorf Pernille , Bach Flemming Winther , Schmidt Erik Berg , Overvad Kim , Venø Stine Krogh
Published: November 2023

Introduction: A diet rich in marine n-3 polyunsaturated fatty acids (PUFAs) may lower the risk of coronary heart disease and ischemic stroke. However, the association between intake of marine n-3 PUFAs and risk of hemorrhagic stroke has only been sparsely explored. We aimed to investigate the associations between intake of the major marine n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and their sum, in relation to incident hemorrhagic stroke and its subtypes, intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). Methods: We analyzed data from the Danish Diet, Cancer and Health Cohort, which was established between 1993 and 1997. Information on dietary intake of marine n-3 PUFAs was obtained through a validated food frequency questionnaire. Potential hemorrhagic stroke cases were identified by linkage to the Danish National Patient Register and subsequently validated. Hazard ratios obtained by Cox proportional hazard regression analyses were used as measures of association. Results: A total of 394 subjects among 55,519 individuals developed hemorrhagic stroke during a median follow-up period of 13.5 years. In multivariable analyses including adjustment for established risk factors, we observed weak and statistically nonsignificant inverse associations between intake of EPA, DHA, and EPA + DHA and the rate of incident hemorrhagic stroke. In analyses of hemorrhagic stroke subtypes, we found indications of lower rates of ICH among participants in the highest quartile of EPA, DHA, and EPA + DHA compared with those in the lowest quartile and indications of lower rates of SAH in the highest quartile of EPA intake compared to the lowest quartile, but the findings were statistically nonsignificant. Conclusions: Inversely statistically nonsignificant associations were found between EPA, DHA, and EPA + DHA and hemorrhagic stroke.
Feasibility and Safety of Endoscopic Control for Patients with Serrated Polyposis Syndrome
Authors: Nakaoka Michiko , Chiba Hideyuki , Kobayashi Mikio , Okada Naoya , Arimoto Jun , Tachikawa Jun , Ashikari Keiichi , Kuwabara Hiroki
Published: November 2023

Introduction: Despite advances in endoscopic treatment, patients with serrated polyposis syndrome (SPS) occasionally require surgery due to numerous or unresectable polyps, recurrence, and treatment-related adverse events. Methods: We retrospectively evaluated 43 patients with SPS undergoing diagnosis and treatment at Omori Red Cross Hospital from 2011 to 2022. Resection of all polyps ≥3 mm in size was planned during the clearing phase; endoscopic control was defined as complete, endoscopic polyp removal. During the surveillance phase, patients underwent annual colonoscopy and resection of newly detected polyps ≥3 mm in size. Results: Thirty-eight patients (88%) achieved endoscopic control, two (5%) required surgery after endoscopic treatment because of colorectal cancer (CRC), and three (7%) have not yet achieved endoscopic control and are planning treatment. Endoscopic control was achieved with a median of four colonoscopies at 8 months. Ten polyps (median value) were resected per patient during the clearing phase. Three polyps ≥50 mm in size, six located in the appendiceal orifice, and seven with severe fibrosis could be resected by endoscopic submucosal dissection (ESD). All patients underwent treatment with a combination of cold snare polypectomy (CSP), endoscopic mucosal resection/hot polypectomy, and/or ESD. No case required surgery due to difficulty with endoscopic treatment. Delayed bleeding was observed in 2 cases (0.3%). Twenty-one patients underwent colonoscopies during the surveillance phase. Fifty-three polyps were resected using CSP; no CRC, sessile serrated lesions with dysplasia, or advanced adenoma were detected. Conclusion: SPS can be effectively, efficiently, and safely controlled with appropriate endoscopic management.
The Role of Hepcidin and an Oral Iron Absorption Test in Identifying the Root Cause of Iron-Restricted Anemia (Enter-Iron)
Authors: Loveikyte Roberta , van den Berg Yascha , van der Meulen-de Jong Andrea Elisabeth , Vlasveld Lodewijk Thomas
Published: November 2023

Introduction: Traditional iron parameters often fail to distinguish the cause of iron-restricted anemia in patients without an obvious underlying cause. We evaluated whether an oral iron absorption test (OIAT) and hepcidin measurement could be useful diagnostic tests in these patients. Methods: We retrospectively analyzed data extracted from medical records of all patients who underwent an OIAT and hepcidin measurement, noting subsequent clinical diagnosis. Δ Iron >15 µmol/L during the OIAT and a hepcidin level below the median (or suppressed ≤0.5 nm) were considered appropriate. Results: Thirty-nine adult patients were included in the study. Sixteen patients with adequate OIAT had suppressed hepcidin levels indicative of classical iron-deficiency anemia (IDA); 59% of patients had abnormal OIAT. In this group, most patients with low hepcidin levels had anemia associated with abnormalities in the gastrointestinal tract, whereas 83.3% patients with high hepcidin levels had iron-refractory iron-deficiency anemia (IRIDA), confirmed by genetic testing. Finally, transferrin/log ferritin ratio accurately identified patients with suppressed hepcidin: AUC 0.98 [95% CI: 0.95–1.02], p < 0.001. Conclusion: OIAT differentiates between classical IDA and other types of anemia caused by abnormalities in iron absorption or systemic iron availability. Additionally, elevated hepcidin in patients with oral iron malabsorption could indicate IRIDA.
Eradicating Atherosclerotic Events by Targeting Early Subclinical Disease: It Is Time to Retire the Therapeutic Paradigm of Too Much, Too Late
Authors: Williams Kevin Jon
Published: November 2023

Recent decades have seen spectacular advances in understanding and managing atherosclerotic cardiovascular disease, but paradoxically, clinical progress has stalled. Residual risk of atherosclerotic cardiovascular disease events is particularly vexing, given recognized lifestyle interventions and powerful modern medications. Why?

Atherosclerosis begins early in life, yet clinical trials and mechanistic studies often emphasize terminal, end-stage plaques, meaning on the verge of causing heart attacks and strokes. Thus, current clinical evidence drives us to emphasize aggressive treatments that are delayed until patients already have advanced arterial disease. I call this paradigm “too much, too late.”

This brief review covers exciting efforts that focus on preventing, or finding and treating, arterial disease before its end-stage. Also included are specific proposals to establish a new evidence base that could justify intensive short-term interventions (induction-phase therapy) to treat subclinical plaques that are early enough perhaps to heal. If we can establish that such plaques are actionable, then broad screening to find them in early midlife individuals would become imperative—and achievable. You have a lump in your coronaries! can motivate patients and clinicians.

We must stop thinking of a heart attack as a disease. The real disease is atherosclerosis. In my opinion, an atherosclerotic heart attack is a medical failure. It is a manifestation of longstanding arterial disease that we had allowed to progress to its end-stage, despite knowing that atherosclerosis begins early in life and despite the availability of remarkably safe and highly effective therapies.

The field needs a transformational advance to shift the paradigm out of end-stage management and into early interventions that hold the possibility of eradicating the clinical burden of atherosclerotic cardiovascular disease, currently the biggest killer in the world. We urgently need a new evidence base to redirect our main focus from terminal, end-stage atherosclerosis to earlier, and likely reversible, human arterial disease.
International Criminal Justice at the Russia-Ukraine Crossroads
Authors: Frulli Micaela
Published: November 2023

The international community’s judicial response to the aggression of Russia against Ukraine in February 2022 and to the ensuing conflict is unprecedented in many ways. This article focuses on the investigations into the commission of war crimes and other serious international crimes conducted by Ukrainian authorities, other national authorities, various international bodies and the International Criminal Court (ICC), whose jurisdiction was triggered by a referral by 43 States parties to the ICC Statute. Some critical remarks are offered on the ambivalent relationship between Ukraine and the ICC. Ukraine is not a party to the ICC Statute, but the Court can exercise its jurisdiction by virtue of two ad hoc declarations rendered in 2014 and 2015. Despite the time that has elapsed since these declarations, Ukraine has not yet ratified the Statute and its government seems oriented to exploit the ICC mainly in an anti-Russian perspective. More in general, the huge efforts put in place by the international community in the investigation of international crimes committed in the ongoing conflict in Ukraine are disproportionate when compared to all other situations investigated and are already attracting criticism about selective justice. Such efforts represent on the one hand a potential model for a coordinated intervention in situations where mass atrocities are committed, on the other hand they are likely to remain isolated and confirm the perception that international criminal justice and the ICC are instruments in the hands of a few States.