Journals
2025 EN
Soni Harshal · Pryshchep Sergey · Johnson Thomas F.
+1 more
ABSTRACT In this work, confocal microscopy is employed to study the loading and fouling behavior in AAV affinity resins as well as the implications of resin reuse with several commercial chromatographic materials and feed mixtures. Resin samples are obtained from both batch and column experiments, and confocal microscopy is carried out to examine the adsorption profiles in the beads after loading, wash, elution, and CIP steps. A comparison of PSDVB‐based POROS CaptureSelect (PCS) AAV resins with agarose‐based AVIPure AAV9 resins revealed distinct differences in both AAV transport and resin fouling. While AAVs were able to fully access the entire PCS AAV resin under loading onto virgin resin materials, they were restricted to the surface region of the AVIPure AAV9 resin. High resolution X‐ray CT scans indicate that the large pores of the PCS media are likely responsible for this enhanced transport. However, AAV transport into full PCS AAV resin volume was found to only occur during the first AAV loading experiment and was not observed when clarified lysate was employed or upon resin reuse. Further, confocal microscopy indicated that fouling of the PCS AAV affinity resins occurred due to deposition and carryover of AAV and residual impurities upon column re‐use, likely due to incomplete elution and ineffective column CIP. Interestingly, this residual binding in the region near the resin surface resulted in limiting solute transport in subsequent cycles, likely due to pore occlusion. In contrast, AAV bound to the AVIPure resin was readily eluted and removed during CIP. This study elucidates the impact of resin characteristics, feed constituents, and process conditions on the lifetime and fouling of AAV affinity columns.
Journals
2025 EN
Le Tien V. · Parise Robert A. · Holleran Julianne L.
+6 more
ABSTRACT Ataxia‐telangiectasia and Rad3‐related (ATR) protein kinase is an essential regulator of the DNA damage response (DDR) at stalled and collapsed replication forks. Tuvusertib (M1774) is a selective, orally available small molecule ATR inhibitor currently in preclinical and clinical development for cancer treatment. This study presents a robust and simple 5‐min assay designed for the quantification of single agent tuvusertib in human plasma utilizing liquid chromatography tandem mass spectrometry (LC‐MS/MS). A 20 μL volume of plasma was subjected to protein precipitation, followed by chromatographic separation using a Phenomenex Synergi Polar‐RP (4 μm, 2.1 × 50 mm) and a gradient mobile phase system consisting of 0.1% formic acid in both water and acetonitrile during a 4‐min run time. Mass spectrometric detection was achieved using a SCIEX 6500+ tandem mass spectrometer with electrospray positive‐mode ionization. With a stable isotopic internal standard, our assay met the criteria outlined by the Food and Drug Administration guidance for bioanalytical method validation, demonstrating robust performance within the range from 5 to 5000 ng/mL. This assay will support ongoing and future clinical studies by defining tuvusertib pharmacokinetics.
Journals
2025 EN
Jiang Pengfei · Dai Yefei · Hou Yujun
+7 more
Abstract Smart biomaterials that can self‐adapt or respond to microenvironmental factors or external signals hold excellent potential for a variety of biomedical applications, from biosensing, drug delivery, and cell therapy to tissue engineering. The complexity of smart biomaterials, including the rational design of their structure and composition, the accurate analysis and prediction of their properties, and the automatic and scale‐up synthesis remains a critical challenge but can be addressed by the recent rise of artificial intelligence (AI). To bridge the literature gap, the current mini‐review will introduce the background of why marrying AI with smart biomaterials is essential and how biomaterial scientists can integrate machine learning (ML) and AI for the discovery, design, analysis, and synthesis of smart biomaterials. For this purpose, the basic principles of ML and AI will first be introduced so that biomaterial scientists can use ML and AI as a tool for basic research. Next, representative examples of using AI to high throughput screen and establish big data of structure‐function relationship of smart biomaterials responding to both chemical, biological, and physical signals. Most importantly, the applications of the AI‐designed or AI‐discovered biomaterials will be overviewed, with a focus on the field of tissue engineering. Lastly, new directions, such as robot‐chemists‐assisted fabrication of biomaterials will be highlighted. Taken together, by engaging biomaterial scientists with the most recent updates in AI material science, we expect to observe continuous growth of the field of AI for science and benefit clinical translation of smart biomaterials for treating a variety of diseases.
Journals
2025 EN
Xiao Yao · Nie Zhuang · Huang Jinsha
+12 more
ABSTRACT Purpose: The relevance of tumor‐related epilepsy (TRE) to glioma survival is controversial. This study aimed to assess the risk factors and prognostic impact of TRE in adult patients with diffuse gliomas by integrating clinical, radiological, and molecular data. Methods: This multicenter retrospective study included 1036 adult patients with diffuse gliomas from local hospitals and the POLA Network. Patients were categorized into three prognostic groups: lower‐grade oligodendroglioma/astrocytoma (OD/AC, II–III, IDH‐MT), not otherwise specified or not elsewhere classified (NOS/NEC, II–III, IDH‐WT), and high‐grade gliomas (HGG, IV). Clinico‐radiological, molecular, and therapeutic factors were analyzed using univariate and multivariate logistic regression, with the Cox proportional hazards model applied to identify independent prognostic factors for progression‐free survival (PFS) and overall survival (OS). Results: TRE occurred in 44.4% of OD/AC patients, 25.8% of NOS/NEC patients, and 16.5% of HGG patients. Multivariate analysis identified age as the only significant independent correlate of TRE in the OD/AC group (OR = 0.961; p = 0.004), while the absence of deep structure involvement was independently associated with TRE in the NOS/NEC and HGG groups. In univariate analysis, the presence of TRE was associated with longer PFS and OS across all groups, particularly in the NOS/NEC group, where patients with TRE had a median PFS of 35.2 months compared to 13.6 months in those without TRE ( p = 0.02), but was not a significant predictor in multivariate analyses. TRE was the only factor significantly associated with maintaining histological grade at recurrence (HR = 0.094; p = 0.005). Conclusion: TRE was not a strong independent prognostic factor after controlling for clinical and molecular tumor features, suggesting that the prognostic relevance of TRE is likely driven by underlying glioma biology and other associated clinical factors.
Journals
2025 EN
Kumari Pooja · Shankar Amit · Alghafes Rsha
+2 more
ABSTRACT This study examined how Bitcoin, energy prices, and geopolitical risk interact by examining the first four moments (mean, variance, skewness, and kurtosis) of their return distributions by using wavelet analysis. The findings reveal that the co‐movement patterns of energy index, geopolitical risk index, and Bitcoin prices are time and frequency sensitive. During the turbulent period of 2020–2024, significant cross effect was observed at medium‐ and long‐term time scales in the relationship between the energy index and the geopolitical risk index. Similarly, in the case of Bitcoin and the geopolitical risk index, significant cross‐effects were detected at medium‐ and short‐term time scales. From 2021 onwards, a strong coherence is observed at high and medium frequencies for all four moment pairs among Bitcoin, energy prices, and geopolitical risk. In terms of the Bitcoin‐energy relationship, significant co‐movement in mean and volatility is noted throughout most of the sample period and across different frequency bands. Moreover, cross‐skewness and cross‐kurtosis connections are more prominent at short‐ and medium‐term horizons, especially during covid pandemic. These insights are valuable for investors and policymakers in risk management.
Journals
2025 EN
Powsner Emily H. · Kronstadt Stephanie M. · Nikolov Kristin
+2 more
Abstract Mesenchymal stem cell‐derived extracellular vesicles (MSC EVs) are an attractive therapeutic option for regenerative medicine applications due to their inherently pro‐angiogenic and anti‐inflammatory properties. However, reproducible and cost‐effective production of highly potent therapeutic MSC EVs is challenging, limiting their translational potential. Here, we investigated whether the well‐characterized responsiveness of MSCs to their mechanical environment—specifically, substrate stiffness—could be exploited to generate EVs with increased therapeutic bioactivity without the need for biochemical priming or genetic manipulation. Using polydimethylsiloxane and bone marrow‐derived MSCs (BM‐MSCs), we show that decreasing the stiffness of MSC substrates to as low as 3 kPa significantly improves the pro‐angiogenic bioactivity of EVs as measured by tube formation and gap closure assays. We also demonstrate that lower substrate stiffness improves EV production and overall yield, important for clinical translation. Furthermore, we establish the mechanoresponsiveness of induced pluripotent stem cell‐derived MSC (iMSC) EVs and their comparability to BM‐MSC EVs, again using tube formation and gap closure assays. With this data, we confirm iMSCs' feasibility as an alternative, renewable cell source for EV production with reduced donor variability. Overall, these results suggest that utilizing substrate stiffness is a promising, simple, and a potentially scalable approach that does not require exogenous cargo or extraneous reagents to generate highly potent pro‐angiogenic MSC EVs.
Journals
2025 EN
Welsh John P. · Altern Scott H. · Lyall Jessica Y.
+5 more
Abstract Platforms have long been implemented for downstream process development of monoclonal antibodies (mAbs) to streamline development and reduce timelines. These platforms are also increasingly being used for other complex biologics modalities. While development has traditionally been conducted at the lab bench scale in a sequential manner, automated miniaturized and parallelized approaches like RoboColumns and resin plates have also been implemented for chromatographic screening. Additionally, mechanistic modeling for chromatographic separations has also seen increased use for development applications. In this manuscript, we propose a workflow with elements of both high‐throughput screening and modeling that provides a streamlined roadmap for early process development. The workflow utilizes automated resin plate screens to both narrow screening conditions and calibrate binding isotherm parameters. Mechanistic models are then used to characterize a robust range of conditions suitable for an early manufacturing process. Miniaturized RoboColumns then confirm the process space, thus completing the development without the use of any traditional lab‐scale columns. Case studies demonstrate the utility of this workflow for both cation‐exchange (CEX) and multimodal cation‐exchange (MMCEX) processes. Process parameter sensitivities across process ranges for the models are compared with typical design‐of‐experiment (DOE) statistical models. The models are able to predict the mAb product as well as aggregate impurities. This workflow provides a practical method to enable increased process understanding while also reducing timeline and material requirements for development.
Journals
2025 EN
Lefevre Etienne · Quang Megane Le · Chotard Guillaume
+7 more
Abstract The upper end of the central canal of the human spinal cord has been repeatedly implicated in the pathogenesis of various diseases, yet its precise normal position in the medulla oblongata and upper cervical spinal cord remains unclear. The purpose of this study is to describe the anatomy of the upper end of the central canal with quantitative measurements and a three‐dimensional (3D) model. Seven formalin‐embalmed human brainstems were included, and the central canal was identified in serial axial histological sections using epithelial membrane antigen antibody staining. Measurements included the distances between the central canal (CC) and the anterior medullary fissure (AMF) and the posterior medullary sulcus (PMS). The surface and perimeter of the CC and the spinal cord were calculated, and its anterior–posterior and maximum lateral lengths were measured for 3D modeling. The upper end of the CC was identified in six specimens, extending from the apertura canalis centralis (ACC) to its final position in the cervical cord. Positioned on the midline, it reaches its final location approximately 15 mm below the obex. No specimen showed canal dilatation, focal stenosis, or evidence of syringomyelia. At 21 mm under the ACC in the cervical cord, the median distance from the CC to the AMF was 3.14 (2.54–3.15) mm and from the CC to the PMS was 5.19 (4.52–5.43) mm, with a progressive shift from the posterior limit to the anterior third of the cervical spinal cord. The median area of the CC was consistently less than 0.1 mm 2 . The upper end of the CC originates at the ACC, in the posterior part of the MO, and reaches its normal position in the anterior third of the cervical spinal cord less than 2 cm below the obex. Establishing the normal position of the upper end of this canal is crucial for understanding its possible involvement in cranio‐cervical junction pathologies.
Journals
2025 EN
Harris Carolyn · Hammer Marilyn J. · Conley Yvette P.
+7 more
ABSTRACT Background Detailed information on patient characteristics and symptom burden associated with multimorbidity in oncology patients is extremely limited. Purposes were to determine the prevalence of low (≤ 2) and high (≥ 3) multimorbidity in a sample of oncology outpatients ( n = 1343) undergoing chemotherapy and evaluate for differences between the two multimorbidity groups in demographic and clinical characteristics; the occurrence, severity, and distress of 38 symptoms; and the stability and consistency of symptom clusters. Methods Using the Self‐Administered Comorbidity Questionnaire, patients were classified into low and high multimorbidity groups. Memorial Symptom Assessment Scale was used to assess the occurrence, severity, and distress of 38 symptoms prior to the patients' second or third cycle of chemotherapy. For each multimorbidity group, symptom clusters based on occurrence rates were identified using exploratory factor analysis. Results Compared to the low group (61.4%), patients in the high group (38.6%) were older, had fewer years of education, were less likely to be married or partnered, less likely to be employed, and had a lower annual income. In addition, they had a higher body mass index, poorer functional status, were a longer time since their cancer diagnosis, and were more likely to have received previous cancer treatments and have metastatic disease. Patients in the low and high groups reported 12.7 (±6.7) and 15.9 (±7.5) concurrent symptoms, respectively. Eight and seven symptom clusters were identified for the low and high groups, respectively. Psychological, gastrointestinal, weight gain, hormonal, and respiratory clusters were stable across multimorbidity groups. Weight gain and respiratory clusters were consistent. Three unstable clusters were identified in the low group and two in the high group. Conclusions Findings suggest that higher multimorbidity is associated with various social determinants of health and a higher symptom burden. Differences between multimorbidity groups may be related to aging, treatments, and/or comorbid conditions.
Journals
2025 EN
Graff Tara · Flinn Ian · Sharman Jeff P.
+12 more
ABSTRACT Background Preliminary data from the MorningSun study have demonstrated that outpatient subcutaneous mosunetuzumab can be safely administered. Aims This publication describes how community centers in the MorningSun phase 2 study of outpatient subcutaneous mosunetuzumab in B‐cell non‐Hodgkin lymphomas prepared workflow and logistics (staff coordination, practice networks, and patient support) to monitor patients for cytokine release syndrome (CRS) and other toxicities. Materials and Methods Ten investigators at US community practice study sites (one rural, seven urban, and two rural/urban) were interviewed between January 12 and February 22, 2024. Interview transcripts were analyzed qualitatively to identify key themes. Results Prior to the study, 7/10 had limited/no experience administering bispecific antibodies for lymphoma. Regarding preparation before treatment, staff education was the most frequent need (7/10). All sites provided in‐service training for staff involved with treatment administration. Most respondents (6/10) had multidisciplinary plans and agreed these eased logistical concerns. Out of hours, patients either called the triage team, a dedicated on‐call number, the physician, or the emergency department. Most practices had preexisting relationships with hospitals for CRS management. All practices established methods for outpatient CRS monitoring; patient education and caregivers played important roles, and all respondents encouraged patients to use self‐monitoring devices. Each community practice had different workflow and logistics based on their setting and infrastructure. Conclusion Community practices can leverage other sites' experiences and adopt an individualized approach to implementing bispecific antibodies safely and efficiently. Designating a physician champion could provide a local resource to address staff questions and concerns.