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Treatment strategies with a strong scientific rationale based on specific biomarkers are needed to improve outcomes in patients with advanced sarcomas. Suppression of cell-cycle progression through reactivation of the tumor suppressor retinoblastoma (Rb) using CDK4/6 inhibitors is a potential avenue for novel targeted therapies in sarcomas that harbor intact Rb signaling. Here, we evaluated combination treatment strategies (sequential and concomitant) with the CDK4/6 inhibitor abemacicib to identify optimal combination strategies. Expression of Rb was examined in 1,043 sarcoma tumor specimens, and 50% were found to be Rb-positive. Using in vitro and in vivo models, an effective two-step sequential combination strategy was developed. Abemaciclib was used first to prime Rb-positive sarcoma cells to reversibly arrest in G1 phase. Upon drug removal, cells synchronously traversed to S phase, where a second treatment with S-phase targeted agents (gemcitabine or Wee1 kinase inhibitor) mediated a synergistic response by inducing DNA damage. The response to treatment could be noninvasively monitored using real-time positron emission tomography imaging and serum thymidine kinase activity. Collectively, these results show that a novel, sequential treatment strategy with a CDK4/6 inhibitor followed by a DNA-damaging agent was effective, resulting in synergistic tumor cell killing. This approach can be readily translated into a clinical trial with noninvasive functional imaging and serum biomarkers as indicators of response and cell cycling.Significance:An innovative sequential therapeutic strategy targeting Rb, followed by treatment with agents that perturb DNA synthesis pathways, results in synergistic killing of Rb-positive sarcomas that can be noninvasively monitored.

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Recently, although behavioral finance is one of the most interesting topics, there is still a lack of empirical research in Vietnam. This study aims to analyze the influence of feelings after winning or losing on individual investment decisions. The research is practiced based on prospect theory and overconfidence. The experiment was conducted with 50 students of diverse disciplines, ages, and spending levels. They participate in the game of drawing a ball with 12 rounds. They have a chance to win 2.5 times the bet amount or lose nothing at each round. The Mann-Whitney test of two independent samples was employed to test the hypotheses. The results support the prospect theory that individuals feel more dissatisfied when they lose than they are satisfied when they win. This conclusion is supported by different genders, disciplines, and spending levels. However, when making new investment decisions, women are more affected by the previous results (winning or losing) than men. Furthermore, participants tend to invest more after each losing round. Thus, investors should cultivate financial knowledge and minimize personal emotions when making investment decisions to avoid wrong behaviors.

Red blood cells (RBCs) make up the overwhelming majority of cells in the vascular system, spending most of their lives wandering the vast network of vessels that permeate every tissue of our bodies. Therefore, the delivery of any class of therapeutic agent that must stay in the circulatory system may benefit from being carried by RBCs. Toward this direction, we have re-engineered a synthetic liposome with the membranes of RBCs and incorporated a magnetic resonance imaging (MRI) contrast agent gadolinium along with the chemotherapeutic drug doxorubicin (DOX) to form a biomimetic liposome (BML). The BMLs proposed herein consist of biocompatible/biodegradable synthetic phospholipids, which include 1,2-distearoyl

Low-molecular-weight cyclin E (LMW-E) is an N-terminus deleted (40 amino acid) form of cyclin E detected in breast cancer, but not in normal cells or tissues. LMW-E overexpression predicts poor survival in breast cancer patients independent of tumor proliferation rate, but the oncogenic mechanism of LMW-E and its unique function(s) independent of full-length cyclin E (FL-cycE) remain unclear. In the current study, we found LMW-E was associated with genomic instability in early-stage breast tumors (n = 725) and promoted genomic instability in human mammary epithelial cells (hMECs). Mechanistically, FL-cycE overexpression inhibited the proliferation of hMECs by replication stress and DNA damage accumulation, but LMW-E facilitated replication stress tolerance by upregulating DNA replication and damage repair. Specifically, LMW-E interacted with chromatin and upregulated the loading of minichromosome maintenance complex proteins (MCMs) in a CDC6 dependent manner and promoted DNA repair in a RAD51- and C17orf53-dependent manner. Targeting the ATR-CHK1-RAD51 pathway with ATR inhibitor (ceralasertib), CHK1 inhibitor (rabusertib), or RAD51 inhibitor (B02) significantly decreased the viability of LMW-E-overexpressing hMECs and breast cancer cells. Collectively, our findings delineate a novel role for LMW-E in tumorigenesis mediated by replication stress tolerance and genomic instability, providing novel therapeutic strategies for LMW-E-overexpressing breast cancers.

Despite toxicity concerns of chemical mordants used in natural dyeing, there is limited research on the measurement, quality, and safe disposal of the chemical mordant effluent. This study measured the aluminum ions across the premordanting process of cotton print cloth using inductively coupled plasma mass spectrometry and calculated the oxidizable organic matter in the effluent through chemical oxygen demand (COD). The amount of aluminum absorbed by the cotton print cloth was low (2.31%–5.16%). The effluent COD was 23.91g COD/kg. Upon neutralization of the acidic condition, the aluminum in the effluent met discharge to freshwater regulations, and the COD met discharge to U.S. municipal sewage systems. However, the Global Harmonized System restricts aluminum acetate dibasic from organic certification due to its boric acid content. The high mordant concentration in the effluent supports the reuse of mordant baths but not direct disposal to the land or standing waters.

Giới thiệu: Khoảng 15% nam giới vô sinh có chỉ số tinh dịch đồ bình thường, trong đó 8% những bệnh nhân này có bất thường về DNA tinh trùng. Hiện nay, phương pháp khảo sát cấu trúc nhiễm sắc chất tinh trùng là phương pháp được sử dụng rộng rãi để đánh giá sự phân mảnh DNA tinh trùng. Mục tiêu: Đánh giá tỷ lệ phân mảnh DNA tinh trùng trên bệnh nhân đến khám hiếm muộn tại hệ thống IVFMD bằng phương pháp SCSA. Đánh giá mối tương quan giữa các chỉ số của tinh dịch đồ cũng như một số yếu tố khác ảnh hưởng đến chỉ số phân mảnh DNA tinh trùng (DFI). Đối tượng và phương pháp nghiên cứu: Nghiên cứu cắt ngang mô tả, tiến cứu được thực hiện trên 99 bệnh nhân nam đến khám hiếm muộn và có chỉ định xét nghiệm tinh dịch đồ tại hệ thống IVFMD từ 07/2019 đến 09/2019. Thông tin bệnh nhân được thu nhận, DFI được xác định bằng SCSA. Kết quả: Bệnh nhân được chia thành 3 nhóm DFI thấp (≤ 15%), trung bình (15% < DFI ≤ 30%), và cao (> 30%) với tỷ lệ lần lượt là: 51,5%; 29,3% và 19,2% trên tổng số các bệnh nhân đưa vào nghiên cứu. Chỉ số khối cơ thể, hút thuốc lá, uống rượu, bia và các chỉ số tinh dịch đồ bao gồm mật độ, hình dạng, và tỷ lệ sống không ảnh hưởng đến sự phân mảnh DNA tinh trùng. Tuy nhiên, so với hai nhóm DFI trung bình và thấp, nhóm DFI cao có thời gian kiêng xuất tinh dài hơn (7,58 ± 9,06 ngày so với 3,96 ± 1,92 và 3,67 ± 1,69, p = 0,007) và độ tuổi lớn hơn (38,79 ± 6,36 tuổi so với 32,77 ± 5,41 và 34,42 ± 7,00, p = 0,002). Mặt khác, nhóm DFI thấp có tỷ lệ tinh trùng di động cao hơn hai nhóm còn lại (54,20 ± 13,61% so với 41,14 ± 15,82% và 43,21 ± 15,11%, p < 0,001). Kết luận: Bệnh nhân có chỉ số DFI cao có thời gian kiêng xuất tinh dài và lớn tuổi hơn hai nhóm DFI thấp và trung bình. Tinh trùng ở nhóm DFI thấp di động tốt hơn so với hai nhóm DFI trung bình và cao.

Mục tiêu: Phát triển mô hình tiên lượng khả năng tìm thấy tinh trùng từ kỹ thuật TESE trên nhóm bệnh nhân vô tinh không bế tắc. Đối tượng và Phương pháp nghiên cứu: Chúng tôi thực hiện một phân tích hồi cứu tại Bệnh viện Mỹ Đức trong khoảng thời gian từ năm 2016 đến năm 2018. Tìm thấy tinh trùng được định nghĩa là có sự hiện diện của ít nhất một tinh trùng di động trong mẫu mô tinh hoàn thu nhận từ kỹ thuật TESE. Các biến số nền và lâm sàng sau đó được đưa vào phân tích hồi quy đơn biến và đa biến để tìm ra các yếu tố tiên lượng độc lập có liên quan đến tỷ lệ tìm thấy tinh trùng. Các yếu tố tiên lượng sau đó được đưa vào mô hình BMA để đưa ra các mô hình tiên lượng khả dĩ. Mô hình tốt nhất là mô hình có số biến số ít nhất, chỉ số BIC thấp nhất, AUC lớn nhất và xác xuất hậu định lớn nhất. Kết quả: Có tổng cộng 125 nam giới vô tinh không bế tắc thực hiện kỹ thuật TESE trong khoảng thời gian nghiên cứu, trong đó có 36 trường hợp (28,8%) tìm thấy tinh trùng. Mô hình tiên lượng SRR tốt nhất bao gồm 2 biến số: tuổi bệnh nhân và nồng độ FSH huyết thanh (xác suất = e[-3,05 – (0,11 x FSH + 0,1 x tuổi)]); BIC: - 486; xác suất hậu định 0,331; AUC = 0,81 (KTC 95% 0,72 - 0,90). Không có sự khác biệt có ý nghĩa thống kê giữa giá trị dự đoán khả năng tìm thấy tinh trùng và kết quả tìm thấy tinh trùng trên thực tế. Kết luận: Mô hình tốt nhất dự đoán khả năng tìm thấy tinh trùng bao gồm có 2 biến số tuổi bệnh nhân và nồng độ FSH huyết thanh. Mô hình này có thể được sử dụng trên lâm sàng để tư vấn cho bệnh nhân trước điều trị.

Mục tiêu: Xác định mối tương quan giữa thời gian kiêng xuất tinh và tỷ lệ thai lâm sàng của phương pháp IUI. Đối tượng và phương pháp nghiên cứu: Nghiên cứu đoàn hệ hồi cứu thực hiện tại bệnh viện Mỹ Đức từ tháng 4/2016 đến tháng 12/2017. Bệnh nhân hiếm muộn có chỉ định IUI được thực hiện theo phác đồ điều trị tại bệnh viện. Vào ngày chỉ định IUI, các thông tin về số ngày kiêng xuất tinh, chất lượng tinh trùng trước và sau khi lọc rửa được ghi nhận lại. Yếu tố đánh giá kết quả là thai lâm sàng trong mỗi chu kỳ. Kết quả: Có 988 trường hợp thỏa mãn tiêu chuẩn nhận loại được đưa vào nghiên cứu. Kết quả của nghiên cứu cho thấy không có sự khác biệt về tỷ lệ thai lâm sàng ở các nhóm bệnh nhân có số ngày kiêng xuất tinh khác nhau. Tuy nhiên, các chỉ số tinh dịch đồ (thể tích tinh dịch, mật độ, độ di động và tổng số tinh trùng di động) trước lọc rửa có sự khác biệt ở các nhóm ngày kiêng xuất tinh khác nhau và không làm ảnh hưởng đến kết quả thai. Thời gian kiêng xuất tinh càng lâu thì thể tích tinh dịch, mật độ tinh trùng trước lọc cao hơn nhưng tỷ lệ tinh trùng di động giảm dần và ngược lại (p < 0,05). Kết luận: Kết quả IUI không bị ảnh hưởng bởi thời gian kiêng xuất tinh nhưng có thể ảnh hưởng đến chất lượng tinh trùng.

Aberrant splicing and protein interaction of Ras binding domain (RBD) are associated with melanoma drug resistance. Here, cobalt or nickel doped zinc oxide (ZnO) physiometacomposite (PMC) materials bind to RNA and peptide shown by Ninhydrin staining, UV-vis, Fourier transform infrared, and circular dichroism spectroscopy. PMCs deliver splice switching oligomer (SSO) into melanoma cells or 3-D tumor spheroids shown by flow cytometry, fluorescence microscopy, and bioluminescence. Stability in serum, liver, or tumor homogenate up to 48 h and B16F10 melanoma inhibition ≥98-99% is shown. These data suggest preclinical potential of PMC for delivery of SSO, RBD, or other nucleic acid therapeutic and anticancer peptides.

A contrast agent (CA) in magnetic resonance imaging (MRI) is now an essential add-on to obtain high-quality contrast-enhanced anatomical images for disease diagnosis and monitoring the treatment response. However, the rapid elimination of CAs by the immune system and excretion by the renal route has limited its application. As a result, the CA dose for effective contrast is ever-increasing, resulting in toxic side effects such as gadolinium (Gd) related nephrogenic systemic fibrosis (NSF) toxicity. Considering the widespread application of Gd-based CAs, it is now very important to revisit their formulation in order to improve their local concentration and minimize their dose while achieving clinical goals. Therefore, we have adapted a unique strategy to maximize Gd delivery to the target site using macrophage cell-derived extracellular vesicles (EVs) reconstructed with a Gd-conjugated liposomal system herein called gadolinium infused hybrid EVs (Gd-HEVs). We hypothesize that Gd-HEVs, owing to the presence of immune cell-derived EV protein cargo, can effectively disguise themselves as a biological entity, prolong the retention time for contrast enhancement, and show tumor specificity. Incorporation of Gd into nanoformulations can enhance the longitudinal relaxivity r1 by reducing the tumbling rate of paramagnetic metal complexes. Here, Gd-HEVs showed a higher r1 relaxivity of 9.86 mM−1 s−1 compared to 3.98 mM−1 s−1 of Magnevist® at an equivalent Gd concentration, when measured by clinical 3T MRI. This will allow us to reduce the clinically used Gd concentration about three-fold while maintaining contrast in the clinical window thereby supporting our hypothesis. Furthermore, Gd-HEVs showed a preferential cellular interaction and accumulation towards cancer cells compared to non-cancer cells, both in vitro and in vivo. More importantly, Gd-HEVs showed excellent contrast enhancement in the blood vasculature with a higher retention time compared to its counterpart, Magnevist®. Our study successfully showed that the incorporation of Gd in the EV framework can help to enhance the contrast ability, and therefore it can be a platform technology for the development of safer MRI contrast agents.

Recent progress in bioimaging nanotechnology has a great impact on the diagnosis, treatment, and prevention of diseases by enabling early intervention. Among different types of bioimaging modalities, contrast-enhanced magnetic resonance imaging using paramagnetic gadolinium-based molecular contrast agents (GBCAs) are most commonly used in clinic. However, molecular GBCAs distribute rapidly between plasma and interstitial spaces with short half-lives limiting its clinical impacts. To improve the properties of GBCAs, herein an effort has been put forth by incorporating GBCA into nanoscale system mimicking the property of red blood cell (RBC) that could facilitate contrast enhancement and prolong intraluminal retention in the body. The proposed nanoconstruct is made up of polymeric-core labeled with lipid conjugated GBCA followed by the imprint of the RBC membrane concealment layer to enhance stability and biocompatibility. Meanwhile, the confinement strategy of GBCA was implemented to accelerate magnetic properties of nanoconstruct providing longitudinal-relaxivity (r1) to 12.78 ± 0.29 (mM s)-1. Such improvement in r1 was further confirmed by enhanced contrast in the vascular angiography of the murine model. Given higher colloidal stability and tunable magnetic properties, nanoconstruct proposed herein is a promising platform technology for the applications where enhanced plasma residence time and magnetic properties are necessary for diagnosis and therapy.

Biocompatible polymeric and lipid nanoparticles are under extensive investigation as anticancer nanomedicines due to the ease of chemical modification in both polymer and lipid in order to target the respective disease environment. However, microenvironment and molecular heterogeneity in tumors pose a great challenge to delivering anticancer drugs or imaging agents precisely to the target, further limiting their applications. As a result, existing nanomedicine formulations rely on a passive-drug targeting mechanism taking advantage of leaky tumor vasculature. However, one strategy is not fit for all due to the molecular dissimilarities between cancers. Therefore, more research on tumor-specific receptors is needed to maximize drug delivery, while minimizing drug-related adverse effects. In addition, a high degree of the immunocompatibility and aqueous stability of the delivery device is essential to maximize delivery efficiency. Herein, we are addressing the aforementioned requirements in cancer management by engineering a receptor-specific anticancer nanomedicine as a composite of polymer and lipids. We are presenting a tumor seeking cyclic LyP-1 peptide integrated core–shell polymer–lipid composite nanoparticle (NP) that targets the overexpressed p32 receptor in cancer cells. The designed nanoconstruct is composed of poly(lactide-co-glycolic acid) as a skeleton and a cargo reservoir, a phospholipid with polyethylene glycol as a stabilizer, and LyP-1 as a targeting motif. We studied cellular interaction and targeting ability by accessing the full spectrum of biodistribution using NPs labeled with near-infrared dye as an imaging tracer in vivo. The NPs are spherical and monodispersed with an average size of 68 ± 6 nm and negative zeta potential. These particles are highly stable in physiological conditions over the period with a lower polydispersity index (PDI = 0.15). Furthermore, the nanoparticles showed excellent biocompatibility in vitro, with significantly higher uptake by mouse osteosarcoma compared to non-cancerous fibroblasts. Likewise, LyP-1 NP showed nearly three-fold enhancement in tumor accumulation in vivo compared to its non-targeted counterparts in the K7M2 tumor. Considering the overexpression of p32 in many cancers, the proposed nanoconstruct could hold promises in the therapeutic planning of a wide range of tumors.

The rationale for the design of drug delivery nanoparticles is traditionally based on co-solvent self-assembly following bottom-up approaches or in combination with top-down approaches leading to tailored physiochemical properties to regulate biological responses. However, the optimal design and control of material properties to achieve specific biological responses remain the central challenge in drug delivery research. Considering this goal, we herein designed discoidal polymeric particles (DPPs) whose surfaces are re-engineered with isolated red blood cell (RBC) membranes to tailor their pharmacokinetics. The RBC membrane-coated DPPs (RBC-DPPs) were found to be biocompatible in cell-based in vitro experiments and exhibited extended blood circulation half-life. They also demonstrated unique kinetics at later time points in a mouse model compared to that of bare DPPs. Our results suggested that the incorporation of biomimicry would enable the biomimetic particles to cooperate with systems in the body such as cells and biomolecules to achieve specific biomedical goals.

BACKGROUND Traumatic pediatric cervical spine injury can be challenging to diagnose, and the clinical algorithms meant to aid physicians differ from adult trauma protocols. Despite the existence of standardized guidelines, imaging decisions may vary according to physician education, subjective assessment, and experience with pediatric trauma patients. Our study investigates the rates of pediatric posttraumatic cervical spine imaging across trauma centers, hypothesizing that more specialized centers will have lower rates of advanced cervical spine imaging. METHODS The 2015 to 2016 Trauma Quality Improvement Program database was reviewed for patients younger than 18 years- to assess rates of cervical spine imaging on presentation across different trauma centers. Propensity stratification logistic regression was performed controlling for patient- and center-specific variables. p Values less than 0.05 were considered significant. RESULTS Of 110,769 pediatric trauma patients, 35.2% were female, and the average age was 9.6 years. Overall, 3.6% had cervical spine computed tomography (CT) and less than 1% had cervical spine MRI or X-ray. Compared with all others, Level I trauma centers were significantly less likely to use cervical spine CT for the initial evaluation of younger (≤14 years) but not older trauma patients (adjusted odds ratio [AOR], 0.89; 95% confidence interval [CI], 0.80-0.99; AOR, 0.97; 95% CI, 0.87-1.09); Level I centers had higher odds of cervical spine MRI use, but only for patients 14 years or younger (AOR, 1.63; 95% CI, 1.09-2.44). Pediatric-designated trauma centers had significantly lower odds of cervical spine CT (≤14 years: AOR, 0.70; 95% CI, 0.63-0.78; >14 years: AOR, 0.67; 95% CI, 0.67-0.75) and higher odds of cervical spine X-ray (≤14 years: AOR, 4.75; 95% CI, 3.55-6.36; >14 years: AOR, 4.50; 95% CI, 2.72-7.45) for all ages, but higher odds of cervical spine MRI for younger patients only (≤14 years: AOR, 2.10; 95% CI, 1.38-3.21). CONCLUSION Level I and pediatric designations were associated with lower rates of cervical spine CT. Pediatric centers were also more likely to use cervical spine X-ray. This variability of imaging use further supports the need to disseminate and educate providers on pediatric-specific cervical spine evaluation guidelines. LEVEL OF EVIDENCE Prognostic and epidemiological, level III.

Recent progress in biomedical technology, the clinical bioimaging, has a greater impact on the diagnosis, treatment, and prevention of disease, especially by early intervention and precise therapy. Varieties of organic and inorganic materials either in the form of small molecules or nano-sized materials have been engineered as a contrast agent (CA) to enhance image resolution among different tissues for the detection of abnormalities such as cancer and vascular occlusion. Among different innovative imaging agents, contrast agents coupled with biologically derived endogenous platform shows the promising application in the biomedical field, including drug delivery and bioimaging. Strategy using biocomponents such as cells or products of cells as a delivery system predominantly reduces the toxic behavior of its cargo, as these systems reduce non-specific distribution by navigating its cargo toward the targeted location. The hypothesis is that depending on the original biological role of the naive cell, the contrast agents carried by such a system can provide corresponding natural designated behavior. Therefore, by combining properties of conventional synthetic molecules and nanomaterials with endogenous cell body, new solutions in the field of bioimaging to overcome biological barriers have been offered as innovative bioengineering. In this review, we will discuss the engineering of cell and cell-derived components as a delivery system for various contrast agents to achieve clinically relevant contrast for diagnosis and study underlining mechanism of disease progression. This article is categorized under: Nanotechnology Approaches to Biology > Cells at the Nanoscale Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Introduction: Sarcomas are rare, aggressive tumors that make up a higher percentage of overall cancer mortality in children and young adults. Primary management of sarcoma patients includes surgical resection with adjuvant or neoadjuvant radiation/chemotherapy. Even with aggressive multimodal treatment regimens, patients with high-grade sarcomas experience suboptimal prognosis and advanced disease is almost universally fatal. Innovative biomarker driven targeted therapies are in urgent need to improve survival in these patients. Discoveries in molecular and genetic basis of sarcoma have revealed new targets that deserve consideration. Inactivation of retinoblastoma (Rb) pathway, which causes unabated cell proliferation, through overexpression of cyclin D1 and/or CDK4/6 has been detected in the majority of sarcomas even when wild-type Rb protein is expressed. Hence, inhibition of cell cycle progression through reactivation of the tumor suppressor function of Rb by inhibiting CDK4/6 activity poses a potential avenue for new therapeutic options. Methods: A panel of 4 sarcoma cell lines and 4 patient derived xenograft (PDX) models were used: 2 with an intact Rb pathway (Rb+ve, p16-ve) and 2 with an altered Rb pathway (Rb low/-ve, p16+ve). CDK4/6 inhibitor, abemaciclib, was used to reactivate the Rb pathway followed by treatment with gemcitabine or WEE1-kinase-inhibitor, to target the enriched S and G2/M phase cells post-abemaciclib removal. 18F-FLT PET imaging and serum thymidine kinase 1 (TK1) were used to monitor changes in cell proliferation and treatment response in both in vitro and in vivo. Changes in cell cycle biomarkers in response to treatment were also interrogated. Results: Rb+ve sarcoma cell lines were sensitive to the anti-proliferative activity of abemaciclib leading to their reversible G1 arrest, while Rb null cells did not arrest in any phase of cell cycle in response to CDK4/6 inhibition. Following abemciclib removal, Rb+ve models (but not Rb-ve) showed significant increase in 18F-FLT biotracer uptake concomitant with elevated serum TK1 and enrichment of cells in S phase. The enrichment of cells in S phase maximized therapeutic efficacy of S-phase or G2/M targeting agents leading to synergistic cell killing in Rb+ve cell lines and PDX models. Conclusion: Our study presents an innovative treatment strategy inhibiting the Rb pathway followed by S or G2/M pathway sequentially resulting in synergistic cell killing in those cells/tumors with wild-type Rb. We also incorporate real-time PET imaging and serum TK1 as non-invasive indicators of response to the treatment strategy. The study with PDX models also identified biomarkers of cell proliferation to be used in conjunction with PET imaging to provide the pre-clinical rationale to translate our findings into clinical trials for this aggressive disease. Citation Format: Tuyen Duong Nguyen, Marc A. Pina, Yan Wang, Cansu Karakas, Tuyen N. Bui, Osama Mawlawi, Alexander J. Lazar, Davis R. Ingram, Peter J. Hougton, Kelly K. Hunt, Khandan Keyomarsi. Early proliferative response via [18]FLT-PET/CT and serum TK1 activity are predictive biomarkers for synergistic effect of sequential cell cycle targeted therapy in sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1268.

Red blood cells (RBCs) are the natural resident of the vascular lumen, therefore delivery of any agents within the vascular lumen could benefit by unique natural transporting features of RBCs. RBCs continuously circulate for ∼100 days before being sequestered in the spleen, they only extravasate at sites of vascular hemorrhage. Taking advantages of these features, we engineered RBC as a carrier in order to design a unique delivery system capable of delivering X-ray computed tomography (CT) contrast agents, gold nanoparticles (AuNPs), thereby acting as CT-contrast agent. A strategic membrane fusion technique was used to engineer the surface of RBC with gold nanoparticles in this in vitro study without altering its shape, size, and surface properties.

Little is known about the benefits and risks of myeloid growth factor administration after chimeric antigen receptor (CAR) T‐cell therapy for diffuse large B‐cell lymphoma (DLBCL). We present a retrospective analysis among 22 relapsed/refractory DLBCL patients who received CAR T‐cell therapy with axicabtagene ciloleucel. Filgrastim was administered by physician discretion to seven patients (31.8%), and the median duration of neutropenia after lymphodepleting therapy was significantly shorter for those patients who received filgrastim (5 vs 15 days, P = .016). Five patients (22.7%) developed infection in the 30 days post‐CAR T‐cell therapy with three patients being Grade 3 or higher. There was no difference in the incidence and severity of infection based on filgrastim use (P = .274, P = .138). Among the seven patients that received filgrastim, six patients (85.7%) and four patients (57.1%) had evidence of cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS), respectively. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) and 7 patients (46.7%) had evidence of CRS and ICANS, respectively. There was no significant difference in the incidence of developing CRS or ICANS between the group of patients that received filgrastim and those that did not (P = .193, P = .647). However, there was a significant increase in the severity of CRS for patients that received filgrastim compared to those that did not (P = .042). Filgrastim administration after CAR T‐cell therapy may lead to an increase in severity of CRS without decreasing infection rates., What's new Chimeric antigen receptor (CAR) T‐cell therapy in patients with relapsed/refractory diffuse large B‐cell lymphoma is limited by associated cytokine release syndrome, neurotoxicity, and cytopenias. Little is known about the benefits and risks of myeloid growth factor administration in CAR T‐cell therapy. This retrospective analysis reveals a significant increase in the severity but not the incidence of cytokine release syndrome in those patients that received filgrastim. There was no association of filgrastim use with the severity or incidence of neurotoxicity and infection rates. The findings call for caution in the use of myeloid growth factors in patients undergoing CAR T‐cell therapy.

We speculate that exosomes derived from human umbilical cord mesenchymal stromal cells (HUC-MSCs) will accumulate within tumors and have the potential for both tumor location or drug delivery. Methods: To determine proof of concept, HUC-MSC exosomes were labeled with an MRI contrast agent, gadolinium, or a near infrared dye. Exosome accumulation within ectopic osteosarcoma tumor-bearing mice was determined by 14.1 T MRI or bioimaging over 24-48 h after injection. In vitro studies examine the accumulation and physiological effect of exosomes on human and mouse osteosarcoma cell lines by MTT assay, confocal microscopy, and flow cytometry. Results: Systemic HUC-MSC exosomes accumulated continuously in tumor over a 24-48 h post-injection period. In contrast, synthetic lipid nanoparticles accumulate in tumor only for the first 3 h post-injection. Conclusion: These results suggest that HUC-MSCs exosomes accumulate within human or mouse osteosarcoma cells in vitro and in vivo over a 24 to 48 h after infusion.

Mục tiêu: Xác định mối tương quan giữa chỉ số phân mảnh DNA tinh trùng (DNA Fragment Index - DFI) được đo bằng phương pháp khảo sát độ phân tán nhiễm sắc chất (Sperm Chormatin Dispersion - SCD) và kết quả tiêm tinh trùng vào bào tương noãn (Intracytoplasmic Sperm Injection – ICSI). Đối tượng và phương pháp nghiên cứu: Đây là nghiên cứu đoàn hệ tiến cứu, thực hiện trên 160 bệnh nhân điều trị ICSI tại Đơn vị Hỗ trợ sinh sản IVFMD, Bệnh viện Mỹ Đức từ tháng 06/2016 đến tháng 05/2017. Kết quả: Không có mối tương quan giữa chỉ số phân mảnh DNA và kết quả ICSI, bao gồm: tỷ lệ thụ tinh, tỷ lệ tạo phôi ngày 3 và tỷ lệ phôi hữu dụng (P > 0,05). Kết quả: thai lâm sàng ở ba nhóm DFI (< 15%, 15-30%, > 30%) không có khác biệt, bao gồm: tỷ lệ thai beta-hCG > 25 mIU/mL (tương ứng là 49%, 57% và 60%), tỷ lệ thai lâm sàng (tương ứng là 33%, 47% và 20%) và tỷ lệ sẩy thai (tương ứng là 6,5%, 13,3% và 0%) (P > 0,05). Kết luận: Tỷ lệ phân mảnh DNA tinh trùng không ảnh hưởng đến kết quả điều trị của ICSI.

Superparamagnetic iron oxide nanoparticles (SPIONs) are highly biocompatible and have a versatile synthetic technique based on coprecipitation, reduction-precipitation, and hydrothermal methods, where Fe3+ and Fe2+ react in aqueous solutions; both these ions are present in our body and have clear metabolic pathways; therefore, they have attracted extensive research interest and development in the field of diagnostic imaging and therapy. However, most SPION-based clinical diagnostic contrast agents are discontinued due to severe pain, low transverse magnetic relaxivity range of 80–180 mM−1 s−1, shorter circulation half-life, and lack of disease specificity. Therefore, in this study, we engineered a bone cancer-targeted hybrid nanoconstruct (HNC) with a high transverse magnetic relaxivity of 625 mM−1 s−1, which was significantly higher than that of clinical contrast agents. The engineered HNC is peripherally decorated with a bone-seeking agent, alendronic acid-conjugated phospholipid, exhibiting a hydrodynamic size of 80 nm with a negative surface potential, −35 mV. The interior skeleton of the HNC is composed of biodegradable and biocompatible poly(L-lactic-co-glycolic acid) (PLGA), in which 5 nm SPIONs are confined. We have successfully tuned the distance between the confined SPIONs from 0.5 to 4 nm, as revealed by transmission electron microscopy (TEM) images and magnetic resonance image (MRI) phantoms. This cluster confinement dramatically enhances magnetic relaxivity possibly due to the increase in net local magnetization due to proximal field inhomogeneity. In an in vitro examination, 80% of HNC is found to bind with hydroxyapatite (HAp), which when characterized by TEM shows a painting of SPIONs over a HAp crystal. HNC is found to accumulate in mouse osteosarcoma tumor (K7M2 tumor model); both MRI and histological examination of the tumor show the potential of HNC as targeting agents for diagnosis of tumor in the bone.

In vitro cell-nanoparticle (NP) studies involve exposure of NPs onto the monolayer cells growing at the bottom of a culture plate, and assumed that the NPs evenly distributed for a dose-responsive effect. However, only a few proportion of the administered dose reaches the cells depending on their size, shape, surface, and density. Often the amount incubated (administered dose) is misled as a responsive dose. Herein, we proposed a cell adhesion-migration (CAM) strategy, where cells incubated with the NP coated cell culture substrate to maximize the cell-NP interaction and investigated the physiological properties of the cells. In the present study, cell adhesion and migration pattern of human breast cancer cell (MCF-7) and mouse melanoma cell (B16-F10) on cell culture substrate decorated with toxic (cetyltrimethylammonium bromide, CTAB) and biocompatible (poly (sodium 4-styrenesulphonate), PSS) gold nanoparticles (AuNPs) of different sizes (5 and 40nm) were investigated and evaluated for cellular uptake efficiency, proliferation, and toxicity. Results showed enhanced cell adhesion, migration, and nanoparticle uptake only on biocompatible PSS coated AuNP, irrespective of its size. Whereas, cytotoxic NP shows retard proliferation with reduced cellular uptake efficiency. Considering the importance of cell adhesion and migration on cellular uptake and cytotoxicity assessment of nanoparticle, CAM strategy would hold great promises in cell-NP interaction studies.

Understanding the RNA nano–bio interface is critical to advance RNA based therapeutics. A relevant RNA polyinosinic:cytidilic acid (poly I:C) is perhaps the best studied in clinical trials and is now considered an antimetastatic RNA targeting agent. Also, zinc oxide nanoparticle (ZnO NP) has well-known anticancer activity. In this work, we explore the RNA nano–bio interface of poly I:C, its mononucleotides and homopolymers with ZnO NP by UV, fluorescence and fourier transform infrared (FTIR) spectroscopies. The loading method and ionic concentration (1.0 M Na+) were optimized for greater physical association of RNA with the NP, providing greater payload (150 μg/mg NP). The physical parameters of RNA nano–bio interaction, denoting the degree of association, were quantified by modified Stern–Volmer equations (Kb = 329.6 g–1 L). This interface was further studied by two-dimensional fluorescence difference spectroscopy (2D-FDS), where greater interaction was indicated by considerable quenching of the fluoresc...

Near infrared (NIR) mediated photothermal therapy and magnetic resonance imaging (MRI) are promising treatment and imaging modalities in the field of cancer theranostics. Gold nanorods are the first choice of materials for NIR-mediated photothermal therapy due to their strong localized surface plasmon resonance (LSPR) at NIR region. Similarly, gadolinium based MRI contrast agents have an ability to increase the ionic and molecular relaxivity, thereby enhancing the solvent proton relaxation rate resulting in contrast enhancement. Herein, the effort has been made to engineer a dual front theranostic agent with combined photothermal and magnetic resonance imaging capacity using gadolinium tethered gold nanorods (Gd3+-AuNR). NIR-responsive gold nanorods were surface fabricated by means of Au-thiol interaction using a thiolated macrocyclic chelator that chelates Gd3+ ions, and further stabilized by thiolated polyethylene glycol (PEG-SH). The magnetic properties of the Gd3+-AuNR displayed an enhanced r 1 relaxivity of 12.1 mM–1s–1, with higher biological stability, and contrast enhancement in both solution state and in cell pellets. In-vitro (cell-free) and ex-vivo (on pig skin) analysis of the Gd3+-AuNR shows enhanced photothermal properties as equivalent to that of the raw AuNR. Furthermore, Gd3+-AuNR showed competent cellular entry and intracellular distribution as revealed by hyperspectral microscopy. In addition, Gd3+-AuNR also exhibits significant thermal ablation of B16–F10 cells in the presence of NIR. Thus, Gd3+-AuNR features a significant theranostic potential with combined photothermal and imaging modality, suggesting a great potential in anticancer therapy.

Endosomal degradation of the nanoparticle is one of the major biological barriers associated with the drug delivery system. Nanoparticles are internalized in the cell via different endocytosis pathways, where they are first delivered to early endosomes which mature to the late endosome and to the lysosome. During this journey, NP encounters a harsh chemical environment resulting in the degradation of NP and its content. This process is collectively called as intracellular defenses against foreign materials. Therefore, to avoid this degradative fate, the endosomal escape technique has been explored following membrane fusion or membrane destabilization mechanisms. However, these methods are limited to the application due to non-specific membrane fusion. To overcome this limitation, we have designed pH-responsive liposome made up of 3s-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol hydrochloride (DC-liposome) in which the cationic nitrogen of the ammonium moiety occupies only ∼2.5 % of the molecule. Such a small percentage of the cationic moiety is sufficient enough to exhibit pH-responsive properties while maintaining the biocompatibility of the DC-liposome. DC-liposome showed pH-dependent cationic properties due to the protonation of DC-moiety at acidic pH. The fluorescence-based experiment confirmed pH-dependent fusogenic properties of DC-liposome. Furthermore, the endosomal colocalization study revealed higher localization of DC-liposome in the early endosome compared to that of the late endosome, suggesting possible endosomal escape. Elevated cationic and fusogenic properties of DC-liposome at acidic pH can mediate membrane fusion with anionic endosomal membrane via electrostatic interaction, thereby causing endosomal escape. Moreover, doxorubicin-loaded DC-liposome showed higher cytotoxicity than that of free doxorubicin further supporting our clam of endosomal escape. These findings suggest the potential of DC-liposome to break the endosomal barriers to enhance the therapeutic efficacy thereby guiding us in design consideration in the field of stimuli-responsive delivery agents.

Venetoclax (VEN) is a selective BCL-2 inhibitor that has been shown to be effective when used in combination with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) for treatment-naive, elderly acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. Data on its use in the relapsed/refractory setting are limited. A retrospective analysis was performed among 14 patients with relapsed or refractory AML treated with VEN combination therapy at the University of California Los Angeles from 2018-2019. Eight patients received VEN in combination with azacitidine, 5 patients with decitabine, and 1 patient with LDAC. The majority (10 patients, 71.4%) had adverse cytogenetics. Three patients (21.4%) had undergone an allogeneic stem cell transplant prior to VEN therapy, and 5 patients (35.7%) had leukemia that failed HMA therapy prior. The objective response rate (ORR) was 35.7% (3 patients achieved complete remission with incomplete hematologic recovery and 2 patients achieved partial remission). Three patients (21.4%) were successfully transitioned to either allogeneic bone marrow transplant (2 patients) or donor lymphocyte infusion (1 patient). Seven patients (50.0%) developed a grade 3 or greater infection following VEN therapy, and 3 patients (21.4%) developed a grade 3 or greater intracranial hemorrhage. Three patients experienced early death within 30 days of therapy (2 from infection, 1 from bleeding). The median overall survival (OS) was 4.7 months, and the 1-year OS rate was 23.6% (95% CI 4.4-51.2) for the entire patient cohort. Overall, the response rate was not inferior to that with conventional salvage chemotherapy, but there were notable complications as a result of prolonged cytopenias.

Nanotechnology has gained significant penetration to different fields of medicine including drug delivery, disease interrogation, targeting and bio-imaging. In recent years, efforts have been put forth to assess the use of this technology in biodetoxification. In this review, we will discuss the current status of nanostructured biomaterials/nanoparticle (NP)-based technologies as a candidate biodetoxifying agent. Patient hospitalization due to illicit drug consumption, suicidal attempts and accidental toxin exposure are major challenges in the medical field. Overdoses of drugs/toxic chemicals or exposure to bacterial toxins or poisons are conventionally treated by voiding the stomach, administering activated charcoal or by using specific antidotes, if the toxin is known. Because of the limitations of these methods for safe and effective detoxification, advancements in nanotechnology may offer novel ways in intoxication support by using nanostructured biomaterials, such as liposomes, micellar nanocarriers, liquid crystalline nanoassemblies and ligand-based NPs.