Phase Progression Research Articles

Abstract CT038: Preliminary efficacy and safety results of anti-TROP2 ADC SKB264 (MK-2870) in patients (pts) with previously treated advanced gastric (G) or gastroesophageal junction (GEJ) cancer from a Phase 2 study

Abstract Background: Overexpression of TROP2 (trophoblast cell surface antigen 2) in advanced gastric cancer is known as a poor prognostic factor. SKB264 (MK-2870) is a TROP2 ADC developed with a novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor. The linker is affected by both extracellular pH-sensitive cleavage and intracellular enzymatic cleavage within tumor cells, which leads to efficiently release payload inside tumor cells as well as within tumor microenvironment to exert its anti-tumor effects. Here, we report the preliminary results from a Phase 2 expansion cohort in pts with advanced G/GEJ cancer. Methods: Pts with previously treated inoperable advanced G/GEJ adenocarcinoma were enrolled to receive SKB264 monotherapy at 5 mg/kg Q2W until disease progression or unacceptable toxicity in Phase 2 expansion cohort of KL264-01 study (NCT04152499). Pts with heavily pre-treated G/GEJ cancer were enrolled first, and then the cohort was amended to enroll pts with only one prior therapy of chemotherapy and anti-PD-1/L1 therapy. Tumor assessment was performed every 8 weeks per RECIST v1.1 assessed by investigator. Results: At data cutoff date (Nov 22, 2023), a total of 48 pts were enrolled and followed up for at least 9 weeks. 24 pts (50.0%) had received one prior line of therapy (2L), while 24 pts (50.0%) had received ≥ 2 prior lines of therapy (3L+). 40 pts (83.3%) had received prior anti-PD-1/L1 inhibitors. Treatment-related adverse events (TRAEs) of ≥ Grade 3 were reported in 52.1% of pts. The most common ≥ Grade 3 TRAEs (occurred in ≥5% of pts) were anemia (20.8%), neutrophil count decreased (18.8%), WBC decreased (12.5%) and neutropenia (6.3%). TRAEs leading to dose reduction and dose delay occurred in 18.8% and 33.3% of pts, respectively. No TRAEs leading to treatment discontinuation or deaths occurred. No neuropathy or drug-related ILD/pneumonitis was reported. Of 41 response-evaluable pts (defined as ≥ 1 on-study scans), the ORR was 22.0% (9 PRs, 2 pending confirmation) and disease control rate (DCR) was 80.5%. The ORRs in the 2L and 3L+ setting were 27.3% (including 2 pending confirmation) and 15.8%, respectively. Median duration of response (DoR) was 7.5 months (mos). In the subset of 3L+ pts (n=24 including 54.2% of pts with ≥ 4 prior lines of therapy) with more mature follow-up (median follow up of 14.6 mos), median progression free survival (mPFS) was 3.7 mos (95% Cl: 2.6, 5.4); median overall survival (mOS) was 7.6 mos (95% Cl: 5.3, 15.5) with 12-mo OS rate of 32.6%. Conclusions: The preliminary data suggests that pts with heavily pre-treated advanced G/GEJ cancer could achieve durable response and potentially prolonged OS from SKB264 monotherapy, with a manageable safety profile. A Phase 3 global study of SKB264 monotherapy vs SOC in 3L+ G/GEJ adenocarcinoma is being planned. Citation Format: Jordi Rodon, Zev A. Wainberg, Mingjun Zhang, Tianshu Liu, Bo Liu, Guohua Yu, Yongmei Yin, Shuang Zhang, Yanjun Mi, Xingya Li, Xian Wang, Yunpeng Liu, Xiang Wang, Ying Cheng, Xiaoqing Zhang, Yalan Yang, Junyou Ge, Omobolaji O. Akala, Elliot Chartash, Jin Li. Preliminary efficacy and safety results of anti-TROP2 ADC SKB264 (MK-2870) in patients (pts) with previously treated advanced gastric (G) or gastroesophageal junction (GEJ) cancer from a Phase 2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT038.

Nerve Growth Factor Shows Biphasic Expression during Adjuvant-Induced Neurogenic Inflammation.

Chronic inflammatory diseases are considered the most significant cause of death worldwide. Current treatments for inflammatory diseases are limited due to the lack of understanding of the biological factors involved in early-stage disease progression. Nerve growth factor (NGF) is a neurotrophic factor directly associated with inflammatory and autoimmune diseases like osteoarthritis, multiple sclerosis, and rheumatoid arthritis. It has been shown that NGF levels are significantly upregulated at the site of inflammation and play a crucial role in developing a robust inflammatory response. However, little is known about NGF's temporal expression profile during the initial progressive phase of inflammation. This study aimed to determine the temporal expression patterns of NGF in rat skin (epidermis) during adjuvant-induced arthritis (AIA). Sprague Dawley rats were randomly divided into control and complete Freund's adjuvant (CFA)-treated groups. Levels of NGF were evaluated following unilateral AIA at different time points, and it was found that peripheral inflammation due to AIA significantly upregulated the expression of NGF mRNA and protein in a biphasic pattern. These results suggest that NGF signaling is crucial for initiating and maintaining peripheral neurogenic inflammation in rats during AIA.

Advancing clinical development for neuronopathic Hunter syndrome through a quantitatively-driven reverse translation framework.

A quantitatively-driven evaluation of existing clinical data and associated knowledge to accelerate drug discovery and development is a highly valuable approach across therapeutic areas, but remains underutilized. This is especially the case for rare diseases for which development is particularly challenging. The current work outlines an organizational framework to support a quantitatively-based reverse translation approach to clinical development. This approach was applied to characterize predictors of the trajectory of cognition in Hunter syndrome (Mucopolysaccharidosis Type II; MPS-II), a rare X-linked lysosomal storage disorder, highly heterogeneous in its course. Specifically, we considered ways to refine target populations based on age, cognitive status, and biomarkers, that is, cerebrospinal fluid glycosaminoglycans (GAG), at trial entry. Data from a total of 138 subjects (age range 2.5 to 10.1 years) from Takeda-sponsored internal studies and external natural history studies in MPS-II were included. Quantitative analyses using mixed-effects models were performed to characterize the relationships between neurocognitive outcomes and potential indicators of disease progression. Results revealed a specific trajectory in cognitive development across age with an initial progressive phase, followed by a plateau between 4 and 8 years and then a variable declining phase. Additionally, results suggest a faster decline in cognition among subjects with lower cognitive scores or with higher cerebrospinal fluid GAG at enrollment. These results support differences in the neurocognitive course of MPS-II between distinct groups of patients based on age, cognitive function, and biomarker status at enrollment. These differences should be considered when designing future clinical trials.

Abstract 2939: Harnessing in vivo CRISPR screen to uncover metabolic dependencies during cancer progression

Abstract Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with the worst prognosis and limited treatment options. TNBC cells undergo metabolic reprogramming in response to nutrient limitations and changes in the tumor microenvironment throughout cancer progression. In the early stages, tumor cells are found to prioritize nutrient uptake and biosynthesis, but as they grow, intensified competition for nutrients fosters the emergence of subpopulations of cancer cells that excel in utilizing specific nutrients. The substantial metabolic pathways and genes that regulate each phase of cancer progression remain poorly understood. To address this, we have developed a stable integration, site-specific, and inducible CRISPR-Cas9 system that allows for temporal control of genetic perturbation. We conducted an unbiased in vivo loss-of-function CRISPR screen aimed at identifying metabolic vulnerabilities at different phases of cancer progression of TNBC. The inducible CRISPR system was activated only at the desired study period of each phase, thus capable of uncovering metabolic dependencies for TNBC proliferation at each distinct phase of cancer progression. As many large-scale CRISPR screens have previously been performed to identify gene dependencies for cancer progression in vitro, our CRISPR screen could address the shortcomings of in vitro screens by identifying novel essential metabolic genes that are significantly important for cancer growth in vivo. Preliminary data from our CRISPR screen revealed different pathways to be significantly important for tumor growth and proliferation at different phases of TNBC progression. For example, we find that ferroptosis is altered during the early lag phase of TNBC cancer progression, whereas, at the later stage of cancer progression, metastatic tumors upregulate serine metabolism, suggesting that secondary tumors could have distinct metabolism from the primary sites. Altogether, the findings from this study could provide valuable insights into stepwise metabolic dependencies arising from microenvironmental limitations and identify potential therapeutic targets at each phase of cancer progression. Moreover, our CRISPR-Cas9 model holds promise for dissecting the complex mechanisms of other cancer progressions. Citation Format: Seow Qi Ng, Zhengwei Wu, Jessica A. Lidster, Wai Leong Tam. Harnessing in vivo CRISPR screen to uncover metabolic dependencies during cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2939.

Abstract 508: Determining the nuclear and cytoplasmic function of BMI-1 in diffuse intrinsic pontine glioma during M phase

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) represents one of the most aggressive malignancies of the central nervous system, predominantly affecting children. DIPG is a particularly poor prognosis brain tumor with a median overall survival of less than 1 year. Hence, there is an urgent need to develop novel therapies that not only improve outcome but mitigate long-term complications in children with DIPG. The protein BMI-1, a critical component of the Polycomb Repressive Complex 1 (PRC1), is a proto-oncogene implicated in development, stemness of normal and malignant cells, and self-renewal. BMI-1 has emerged as a potential therapeutic target in DIPG; however, its role in DIPG tumorigenesis and progression remains elusive. We have previously shown that PTC596, a potent BMI-1 modulator, induces chromosome scattering, M phase cell-cycle arrest, BMI-1 phosphorylation and translocation to the cytoplasm leading to the inhibition of its PRC1 canonical function and cell death. These findings imply the induction of the spindle assembly checkpoint (SAC), thereby preventing mitotic exit followed by BMI-1 phosphorylation, probably at multiple sites, suggesting a survival role of BMI-1 in M phase in DIPG. The objective of the present study is to delineate the molecular pathways governing BMI-1 function during M phase and to establish the temporal sequence of these biochemical events related to BMI-1. Our data demonstrated that following PTC596 treatment, BMI-1 is actively transported from the nucleus to the cytoplasm. Furthermore, we observed colocalization of BMI-1 with COX4 in the mitochondria during M phase. Moreover, using Alphafold prediction model, BMI-1 could interact with CRM1 transporter. These findings suggest a potential PRC1-independent role of BMI-1 during early M phase required for DIPG proliferation. We are currently investigating potential pathways involved in BMI-1 nuclear-cytosol translocation through bioinformatic analyses, protein-protein interaction simulations, and pharmacological inhibitor assays. Collectively, these studies aim to elucidate the molecular mechanisms underlying BMI-1 functions in DIPG, thereby potentially paving the way for the development of targeted therapeutic strategies related to M phase progression. Citation Format: Hao-Han Pang, Banlanjo Umaru, Shiva Senthil Kumar, Rachid Drissi. Determining the nuclear and cytoplasmic function of BMI-1 in diffuse intrinsic pontine glioma during M phase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 508.

Abstract 5193: Molecular evolution of chemoresistance acquisition and predictive insights into the progression of bladder cancer

Abstract Cancer heterogeneity arises from cellular features, suggesting that distinct molecular drivers may be latent within cancers diagnosed at different clinicopathological stages. We thoroughly assessed phenotypic traits and molecular alterations linked to chemoresistance and constructed chemoresistant bladder cancer cell lines representing the stepwise transformation. Model cell lines (5637GRCs, gemcitabine-resistant cells) with stepwise gemcitabine resistance representing early, intermediate, and late resistance phases were developed from non-muscle-invasive bladder cancer (NMIBC) cells. Notably, an increase in cell motility was observed at a relatively early phase. The results from the time-course analysis of molecular evolution showed changes in focal adhesion kinase signaling, PI3K-Akt signaling, and TGF-β signaling pathways during the phase of increasing cell motility. As chemoresistance increased, the levels of genes related to differentiation and MAPK signaling gradually increased. A 63-gene chemoresistance-motility (CrM) signature was constructed and weighted according to cell motility, and a strong correlation was observed between cancer metastasis and drug resistance; the signature also showed prognostic relevance in patients with NMIBC. This study affords a significant understanding of the molecular evolution of chemoresistance acquisition and enables prediction of cancer progression during chemotherapy treatment. Moreover, it provides insights into the progression of cells through all chemoresistance stages from NMIBC to MIBC. Therefore, this study proposes the feasibility of utilizing biomarkers correlated with cancer motility to predict cancer progression in the early phase of chemotherapeutic intervention in patients with non-muscle-invasive bladder cancer. Citation Format: Gi-Eun Yang, Jae-Jun Kim, Tae Hwan Shin, Sun-Hee Leem. Molecular evolution of chemoresistance acquisition and predictive insights into the progression of bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5193.

Revisiting Manifestos: An Assessment and the Prospects for the Upcoming Indian General Election 2024

India is the largest democracy and a land of multi-party-political system. During the wake of the election, every single party attempted to seize the attention of the citizenry, as they recognized their need to be legitimized by this set of political actors in India. In the phase of technological progression, while social media and alphanumeric expertise have traded almost all the old communication formats among these three political communication actors, the political parties, too, opt for more prompt forms of communication. What remains static is the party manifesto, a declared statement that is put into the movement as the proposed policy documents. In the same venture, almost a decade ago, India witnessed a political shift that was projected through the manifesto of the political party that is enjoying the position of the current Indian government. This research paper aims to analyze the released manifestoes of two national-level political giants in India, the BJP and INC, for the 2014 and 2019 general elections in India. It aims to explore the pattern of issues that are being addressed in the manifesto and to make predictions for the upcoming manifestos of the 2024 general election for both parties. The researcher has used the abductive reasoning method to make abductive predictions based on the previous manifestoes of the BJP and INC. After following the process of detailed exploration, examination, selection, and explanation, predictions have been given. The analysis explored that both political parties have their own exclusive issues of concern apart from common concerns, and these new set of issues will be posed in the manifesto of the 2024 general election

MAAP code analysis for the in-vessel phase of Fukushima-Daiichi Nuclear Power Station Unit 1 and comparison of the results among Units 1 to 3

The accident progression of the in-vessel phase of Fukushima Daiichi Nuclear Power Station Unit 1 was analyzed using the MAAP code. Although there is a large uncertainty in the initial stage of accident progression behavior in Unit 1 with little measurement data, it is presumed to have similarities to that of Unit 3. As a result, in Unit 1, since there was almost no alternative water injection during the in-vessel phase, cooling of the debris transferred to the lower plenum was small. It was likely that a large molten pool of metals had formed, and that the steam supply to the high-temperature core materials was suppressed and metal oxidation was relatively small. The analysis results for Unit 1 were compared with those for Units 2 and 3, and differences between units such as the thermal conditions of the debris that relocated to the pedestal and the degree of metal oxidation were shown.

Factors associated with clopidogrel resistance and clinical outcomes in ischemic cerebrovascular disease: A retrospective study

ObjectiveClopidogrel resistance may lead to the recurrence of cerebrovascular diseases. We aimed to identify potential factors associated with clopidogrel resistance and evaluate the clinical outcomes of the patients. Materials and methodsIn this retrospective study, patients with ischemic cerebrovascular disease treated with clopidogrel were included and classified into 2 groups according to the adenosine diphosphate (ADP)-induced platelet aggregation. Patients with the ADP inhibition rate of <30 % were included in clopidogrel resistance group, otherwise were included in clopidogrel sensitive group. CYP2C19 genotype and other clinical data were analyzed to identify factors and clinical features in the multivariate analysis. The outcomes were vascular events in 6 months. ResultsIn total, 139 patients were enrolled with 81 (58.27 %) in clopidogrel sensitive group and 58 (41.73 %) in clopidogrel resistance group. Female and CYP2C19 *2*3 carrying were risk factors for clopidogrel resistance, and female was an independent risk factor (OR 2.481, 95 % CI 1.066-5.771, P=0.035). The clopidogrel resistance group showed a higher use rate of argatroban (P=0.030) and a lower arachidonic acid-induced inhibition of platelet aggregation (P=0.036). Clopidogrel resistance was related to the progressing stroke (HR 3.521, 95 % CI 1.352-9.170, P=0.010), but had no influence on the bleeding events (P>0.05). ConclusionsThe risk of clopidogrel resistance increased significantly in female patients. Patients with clopidogrel resistance may have an increased incidence of stroke progression in the acute phase.

Rigorous design and experimental validation of non-reciprocal bandpass filter with ultrawide high reverse isolation bandwidth

This work presents a rigorous design and experimental validation of a non-reciprocal bandpass filter (NBPF) employing time-modulated resonators with progressive phase shift sinusoidal modulation signal to achieve low forward transmission insertion loss (IL) and ultrawide high reverse isolation bandwidth. Analytical design equations have been derived for numerical design of NBPF asl well as providing insights of nonreciprocal frequency response. Additionally, these proposed analytical spectral S-parameters offer the flexibility to design NBPFs with arbitrary termination port impedances. This work also demonstrates a systematic approach to find modulation parameters without relying on optimization methods. It has established empirical relationships between the modulation parameters and the filters specifications to achieve low forward transmission IL and reverse isolation exceeding 15 dB at entire frequency range. The accuracy of the proposed NBPF design has been confirmed by comparing with harmonic balance simulation results of microstrip line NBPF. For experimental validation, three prototypes of NBPF with different termination port impedances are designed, implemented, and manufactured. In experimental results, the frequency of NBPFs can be continously tuned from 1.62 GHz to 1.94 GHz (17.98 %) with maximum forward transmission IL (|S21|) of 5.40 dB and input/output return loss higher than 12 dB. For each frequency tuning state, the reverse isolation (|S12|) exceeds higher than 20 dB across the entire frequency range.

The Design and Implementation of a Phased Antenna Array System for LEO Satellite Communications.

LEO satellite constellations can provide a viable alternative to expand connectivity to remote, isolated geographical areas and complement existing IoT terrestrial communication infrastructures. This paper aims to improve LEO satellite communications by implementing a new phased antenna array system that can significantly improve the radio communication link's performance. By adjusting the progressive phase shift to each element of the antenna array system, the direction of the main radiation lobe of the phased antenna array system can be controlled with accuracy. As far as we know, it is the first time that a four-element, three-quarter wavelength phased antenna array system has been successfully realized with the intention of being optimized for implementation in LEO IoT satellite reception systems. The proposed system's high level of performance is confirmed by the measurements, which indicate effective control of the main radiation lobe orientation. The numerical analysis shows a maximum gain close to 12 dBi for about 42° elevation, a Half Power Beamwidth (HPBW) of 32° in the vertical plane, and 80° in the azimuth plane. The experimental measurement results at various main lobe orientation angles revealed an HPBW ranging from 76° to 87° in the azimuth plane and a maximum Front-to-Back ratio (F/B) of 14.5 dB.

Crucial role of obliquely propagating gravity waves in the quasi-biennial oscillation dynamics

Abstract. ​​​​​​​In climate modelling, the reality of simulated flows in the middle atmosphere is largely affected by the model's representation of gravity wave processes that are unresolved, while these processes are usually simplified to facilitate computations. The simplification commonly applied in existing climate models is to neglect wave propagation in horizontal direction and time. Here we use a model that fully represents the propagation of unresolved waves in all directions, thereby elucidating its dynamical effect upon the most important climate mode in the tropical stratosphere, i.e. the quasi-biennial oscillation. Our simulation shows that the waves in the equatorial stratosphere, which are known to drive this climate mode, can originate far away from the Equator in the troposphere. The waves propagating obliquely toward the Equator are found to play a huge role in the phase progression of the quasi-biennial oscillation as well as in its penetration into the lower stratosphere. Such waves will require further attention, given that current climate models are struggling to simulate the quasi-biennial oscillation down to the lower stratosphere, which may be needed to reproduce its observed impacts on the surface climate.

Evaluating legal age of 18 years through observation of third molars using Gambier et al. method in an orthopantomographic sample of subadults from South India

In forensic practice, medicolegal physicians are often tasked with estimating age using dental evidence. This calls for an uncomplicated, reliable, and reproducible method for dental age estimation, enabling physicians to proceed without specific odontological expertise. Among various dental methods, third molar eruption analyses are less complicated and easier to perform. In our study, we explored the effectiveness of Gambier et al.'s scoring system, which examines the eruption of all third molars. We retrospectively analysed 1032 orthopantomograms (528 males and 504 females) of individuals aged between 15 and 24 years. The mean chronological age increased with the progression of stages (1 to 3) and phases (A to D) of the third molar eruption for both sexes. In terms of stages, none showed significant discrimination between minors (<18 years) and adults (>18 years), especially for males. However, Gambier’s phase D displayed a relatively high likelihood of being 18 years or older, with an overall 85.9 % of males and 95.7 % of females having all third molars in stage 3 being 18 years or older. While the tested method could be helpful in indicating the completion of the 18th year of life, caution is advised (due to a high percentage of false positives), and it should be used alongside other age assessment methods by experts.

Triterpenoid ursolic acid regulates the environmental carcinogen benzo[a]pyrene-driven epigenetic and metabolic alterations in SKH-1 hairless mice for skin cancer interception.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental carcinogens accountable to developing skin cancers. Recently, we reported that exposure to benzo[a]pyrene (B[a]P), a common PAH, causes epigenetic and metabolic alterations in the initiation, promotion and progression of non-melanoma skin cancer (NMSC). As a follow-up investigation, this study examines how dietary triterpenoid ursolic acid (UA) regulates B[a]P-driven epigenetic and metabolic pathways in SKH-1 hairless mice. Our results show UA intercepts against B[a]P-induced tumorigenesis at different stages of NMSC. Epigenomic cytosines followed by guanine residues (CpG) methyl-seq data showed UA diminished B[a]P-mediated differentially methylated regions (DMRs) profiles. Transcriptomic RNA-seq revealed UA revoked B[a]P-induced differentially expressed genes (DEGs) of skin cancer-related genes, such as leucine-rich repeat LGI family member 2 (Lgi2) and kallikrein-related peptidase 13 (Klk13), indicating UA plays a vital role in B[a]P-mediated gene regulation and its potential consequences in NMSC interception. Association analysis of DEGs and DMRs found that the mRNA expression of KLK13 gene was correlated with the promoter CpG methylation status in the early-stage comparison group, indicating UA could regulate the KLK13 by modulating its promoter methylation at an early stage of NMSC. The metabolomic study showed UA alters B[a]P-regulated cancer-associated metabolisms like thiamin metabolism, ascorbate and aldarate metabolism during the initiation phase; pyruvate, citrate and thiamin metabolism during the promotion phase; and beta-alanine and pathothenate coenzyme A (CoA) biosynthesis during the late progression phase. Taken together, UA reverses B[a]P-driven epigenetic, transcriptomic and metabolic reprogramming, potentially contributing to the overall cancer interception against B[a]P-mediated NMSC.

He bubble-induced phase transformation of W grain boundaries revealed by accelerated molecular dynamics

The growth of He bubbles and the resulting impact on the microstructural evolution of W are of paramount importance to the plasma-facing materials community due to the application of W in Tokamak fusion reactors. Using accelerated molecular dynamics (AMD) techniques, we outline the structural evolution of grain boundaries (GBs) caused by growing He bubbles. It is discovered that when an alternative, low energy, high density GB structure or phase is available, He bubbles can induce a progressive phase transformation of the GB to the higher density phase by the continual nucleation of W Frenkel pairs. We find that the resulting W self-interstitials migrate to sites at the GB which are structurally related to the higher density phase, leading to the transformation. We discuss the implications of this progressive microstructural evolution on the growing He bubble and consider in general how He bubbles will impact the structural evolution of an arbitrary W GB. These findings of GB phase transformation are predicted to impact other damage events in W such as recrystallization, GB migration and defect segregation which must take these findings into account in order to accurately simulate a realistic W microstructure and hence extract experimentally meaningful data.

Multi-dimensional cylindrical vector beam (de)multiplexing through cascaded wavelength- and polarization-sensitive metasurfaces.

Cylindrical vector beams (CVBs) exhibit great potential for multiplexing communication, owing to their mode orthogonality and compatibility with conventional wavelength multiplexing techniques. However, the practical application of CVB multiplexing communication faces challenges due to the lack of effective spatial polarization manipulation technologies for (de)multiplexing multi-dimensional physical dimensions of CVBs. Herein, we introduce a wavelength- and polarization-sensitive cascaded phase modulation strategy that utilizes multiple coaxial metasurfaces for multi-dimensional modulation of CVBs. By leveraging the spin-dependent phase modulation mechanism, these metasurfaces enable the independent transformation of the two orthogonal polarization components of CVB modes. Combined with the wavelength sensitivity of Fresnel diffraction in progressive phase modulation, this approach establishes a high-dimensional mapping relationship among CVB modes, wavelengths, spatial positions, and Gaussian fundamental modes, thereby facilitating multi-dimensional (de)multiplexing involving CVB modes and wavelengths. As a proof of concept, we theoretically demonstrate a 9-channel multi-dimensional multiplexing system, successfully achieving joint (de)multiplexing of 3 CVB modes (1, 2, and 3) and 3 wavelengths (1550 nm, 1560 nm, and 1570 nm) with a diffraction efficiency exceeding 80%. Additionally, we show the transmission of 16-QAM signals across 9 channels with the bit-error-rates below 10-5. By combining the integrability of metasurfaces with the high-dimensional wavefront manipulation capabilities of multilevel modulation, our strategy can effectively address the diverse demands of different wavelengths and CVB modes in optical communication.

What do spouse primary caregivers of patients with glioblastoma want medical providers to know? A qualitative thematic reflexive analysis of letters written by primary caregivers from a secret Facebook support group

ObjectivesTo analyse the content of letters written by female spouse primary caregivers of patients with glioblastoma multiforme (GBM), a devastating and terminal primary brain cancer, and give voice to their...

Characterizing Acute-Onset Small Fiber Neuropathy.

Immune-mediated small fiber neuropathy (SFN) is increasingly recognized. Acute-onset SFN (AOSFN) remains poorly described. Herein, we report a series of AOSFN cases in which immune origins are debatable. We included consecutive patients with probable or definite AOSFN. Diagnosis of SFN was based on the NEURODIAB criteria. Acute onset was considered when the maximum intensity and extension of both symptoms and signs were reached within 28 days. We performed the following investigations: clinical examination, neurophysiologic assessment encompassing a nerve conduction study to rule out large fiber neuropathy, laser-evoked potentials (LEPs), warm detection thresholds (WDTs), electrochemical skin conductance (ESC), epidermal nerve fiber density (ENF), and patient serum reactivity against mouse sciatic nerve teased fibers, mouse dorsal root ganglion (DRG) sections, and cultured DRG. The serum reactivity of healthy subjects (n = 10) and diseased controls (n = 12) was also analyzed. Data on baseline characteristics, biological investigations, and disease course were collected. Twenty patients presenting AOSFN were identified (60% women; median age: 44.2 years [interquartile range: 35.7-56.2]). SFN was definite in 18 patients (90%) and probable in 2 patients. A precipitating event was present in 16 patients (80%). The median duration of the progression phase was 14 days [5-28]. Pain was present in 17 patients (85%). Twelve patients (60%) reported autonomic involvement. The clinical pattern was predominantly non-length-dependent (85%). Diagnosis was confirmed by abnormal LEPs (60%), ENF (55%), WDT (39%), or ESC (31%). CSF analysis was normal in 5 of 5 patients. Antifibroblast growth factor 3 antibodies were positive in 4 of 18 patients (22%) and anticontactin-associated protein-2 antibodies in one patient. In vitro studies showed IgG immunoreactivity against nerve tissue in 14 patients (70%), but not in healthy subjects or diseased controls. Patient serum antibodies bound to unmyelinated fibers, Schwann cells, juxtaparanodes, paranodes, or DRG. Patients' condition improved after a short course of oral corticosteroids (3/3). Thirteen patients (65%) showed partial or complete recovery. Others displayed relapses or a chronic course. AOSFN primarily presents as an acute, non-length-dependent, symmetric painful neuropathy with a variable disease course. An immune-mediated origin has been suggested based on in vitro immunohistochemical studies.

Impact of composition and knitting methods of fiberglass grid on the progression of reflective crack in asphalt pavement

In the asphalt pavement with semi-rigid base, the shrinkage cracks initiating from base course often propagate upward to surface course to develops into reflective cracks. The fiberglass grid, as a woven geotextile, is widely used to retard the occurrence of reflective cracks in China, but the impacts of material composition and knitting methods of it on reflective cracks are still not clear. In this paper, two kinds of models, including a two-scale model of fiber bundle-fiberglass grids layer and a coupled thermo-mechanical model of pavement structure, are established. In the two-scale model, the elastic constants (ECs) of fiber bundle and fiberglass grids layer are calculated under different compositions and knitting methods and then assigned to the coupled thermo-mechanical model to estimate the fatigue lives at initiation phase (FL-IP) and propagation phase (FL-PP) of reflective cracks based on an estimation theory. Moreover, this study designs the laboratory tests to validate this estimation method of fatigue life. Then, based on the predicted fatigue life at different phases of crack progression, the sensitivity analysis is implemented to analyze the impacts of composition and knitting methods on the fatigue life. As a result, the recommendations on design and preparation of fiberglass grid are proposed. The results show that, in material composition, the glass fibers with high elastic modulus and volume fraction and the coating materials with high elastic modulus are beneficial to retarding the initiation and propagation of reflective cracks and in knitting methods, increasing density of fiber bundles parallel to the traffic direction and reducing braided angle also has positive effect. These results can be used to optimizing design and preparation of fiberglass grid to reduce the occurrence of reflective cracks in asphalt pavement.

Melatonin and Its Role in the Epithelial-to-Mesenchymal Transition (EMT) in Cancer.

The epithelial-to-mesenchymal transition (EMT) is a cell-biological program that occurs during the progression of several physiological processes and that can also take place during pathological situations such as carcinogenesis. The EMT program consists of the sequential activation of a number of intracellular signaling pathways aimed at driving epithelial cells toward the acquisition of a series of intermediate phenotypic states arrayed along the epithelial-mesenchymal axis. These phenotypic features include changes in the motility, conformation, polarity and functionality of cancer cells, ultimately leading cells to stemness, increased invasiveness, chemo- and radioresistance and the formation of cancer metastasis. Amongst the different existing types of the EMT, type 3 is directly involved in carcinogenesis. A type 3 EMT occurs in neoplastic cells that have previously acquired genetic and epigenetic alterations, specifically affecting genes involved in promoting clonal outgrowth and invasion. Markers such as E-cadherin; N-cadherin; vimentin; and transcription factors (TFs) like Twist, Snail and ZEB are considered key molecules in the transition. The EMT process is also regulated by microRNA expression. Many miRNAs have been reported to repress EMT-TFs. Thus, Snail 1 is repressed by miR-29, miR-30a and miR-34a; miR-200b downregulates Slug; and ZEB1 and ZEB2 are repressed by miR-200 and miR-205, respectively. Occasionally, some microRNA target genes act downstream of the EMT master TFs; thus, Twist1 upregulates the levels of miR-10b. Melatonin is an endogenously produced hormone released mainly by the pineal gland. It is widely accepted that melatonin exerts oncostatic actions in a large variety of tumors, inhibiting the initiation, progression and invasion phases of tumorigenesis. The molecular mechanisms underlying these inhibitory actions are complex and involve a great number of processes. In this review, we will focus our attention on the ability of melatonin to regulate some key EMT-related markers, transcription factors and micro-RNAs, summarizing the multiple ways by which this hormone can regulate the EMT. Since melatonin has no known toxic side effects and is also known to help overcome drug resistance, it is a good candidate to be considered as an adjuvant drug to conventional cancer therapies.