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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.

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.

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.

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.

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.

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.

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.

Biodegradable Nanoparticles (NPs) are under intense investigation due to their potential application in targeted drug delivery. Upon their entry to the biological system, they encounter the immune system, which limits their availability at the intended site. Most importantly, the innate immune system is the one that acts as the first line of defense against foreign materials. It can be activated by collectin proteins which recognize the structural pattern of polysaccharide on the surface of microorganisms. NPs may interact with these proteins in a similar way, and the interaction may lead to beneficial outcomes in vaccine delivery. On the other hand, in targeted drug delivery, it is desirable for the NPs not to be recognized as foreign material as this may lead to their fast elimination from the system through mechanism such as opsonization. We investigated the interaction of PEGylated and un-PEGylated PLGA NPs with Recombinant Human Mannose-Binding Protein (HMBP) in an effort to understand the effect of surface modification on their binding to the protein. Results show that both PLGA-COOH and PLGA-PEG-NH2 bind to HMBP as studied using dynamic light scattering (DLS), fluoresce and UV-vis spectroscopy. However, their binding is shown to have different effect on the structure of the protein. Study done using fluorescence spectroscopy displayed a decrease in fluorescence emission of the protein upon binding to PLGA-COOH. On the other hand the fluorescence emission of the protein increased upon binding to the PLGA-PEG-NH2 indicating conformational changes in the protein structure.

Extracellular vesicles (EVs) are phospholipid and protein constructs which are continuously secreted by cells in the form of smaller (30–200 nm) and larger (micron size) particles. While all of these vesicles are called as EVs, the smaller size are normally called as exosomes. Small EVs (sEVs) have now been explored as a potential candidate in therapeutics delivery owing to their endogenous functionality, intrinsic targeting property, and ability to cooperate with a host defense mechanism. Considering these potentials, we hypothesize that immune cell-derived sEVs can mimic immune cell to target cancer. However, different sEVs isolation technique reported poor yield and loss of functional properties. To solve this problem, herein we hybridized sEVs with synthetic liposome to engineer vesicles with size less than 200 nm to mimic the size of exosome and named as hybrid exosome (HE). To achieve this goal, sEVs from mouse macrophage was hybridized with synthetic liposome to engineer HE. The fluorescence-based experiment confirmed the successful hybridization process yielding HE with the size of 177 ± 21 nm. Major protein analysis from Blot techniques reveal the presence of EV marker proteins CD81, CD63, and CD9. Differential cellular interaction of HE was observed when treated with normal and cancerous cells thereby supporting our hypothesis. Moreover, a water-soluble doxorubicin was loaded in HE. Drug-loaded HE showed enhanced toxicity against cancer cells and pH-sensitive drug release in acidic condition, benefiting drug delivery to acidic cancer environment. These results suggest that the engineered HE would be an exciting platform for tumor-targeted drug delivery. Statement of Significance Extracellular vesicles (EVs) are phospholipid and protein constructs which are continuously secreted by cells in the human body. These vesicles can efficiently deliver their parental biomolecules to the recipient cells and assist in intracellular communication without a direct cell-to-cell contact. Moreover, they have the ability to perform some of the molecular task similar to that of its parent cells. For example, exosome derived from immune cells can seek for diseased and/or inflammatory cells by reading the cell surface proteins. However, different EVs isolation techniques reported poor yield and loss of functional properties. Therefore, to overcome this limitation, we herein propose to re-engineer immuno-exosome with a synthetic liposome as a refined biomimetic nanostructure for the delivery of doxorubicin (clinical drug) for breast cancer treatment.

Multifunctional theranostic gadolinium infused liposomes containing the chemotherapeutic drug, doxorubicin (DOX), in its core are designed as potential candidates for diagnosis and therapy of various cancers. In these theranostic liposomes, Gd3+ ions are chelated by the macrocyclic chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, which is covalently linked to the hydrophilic head moiety of the phospholipid. Therefore, the Gd3+ labels are an integral part of the lipid bilayer of liposomal construct. The physical properties of the Gd-infused liposomes were characterized including drug loading, drug release kinetics, cellular consequences, and T1 weighted magnetic properties. The theranostic liposomes exhibits uniform size distribution (hydrodynamic size of 150 ± 10 nm) and a high drug loading efficiency with sustained drug release characteristic. Due to stable Gd3+ in their lipid bilayers, the theranostic liposomes displayed an enhanced r1 relaxivity of 12.3 mM−1 s−1 at 14.1 T, which is three times higher than that of currently used Gd-based contrast agent (Magnivest®: 4.1 mM−1 s−1, 1.4 T). Moreover, cellular uptake studies revealed that these theranostic liposomes exhibit higher structural integrities inside B16-F10 melanoma cells. It shows uniform intracellular distribution throughout the cells. In vitro cytotoxicity revealed that Gd-infused liposomes have excellent biocompatibility without significant cytotoxicity, whereas they showed higher cellular toxicity when loaded with DOX against B16-F10. The observed toxicity was equivalent to the same concentration of free DOX. With regard to the ongoing development in theranostic water-dispersible nanoformulations, the current formulation where Gd3+ ions are encapsulated by a macrocyclic chelator and covalently tethered to the hydrophilic head moiety of a lipid, is rather promising and holds great promise.

An approach to reduce the nonspecific cytotoxicity of chemotherapeutics has been put-forth using a biomimetic nanoabsorbent (NAb) as a detoxifying agent. The engineered NAb possesses a tunable drug absorption ability depending on the charge of the absorbing molecule, in which the cooperative absorption ability of the core and shell significantly reduces the cellular toxicity.

Le developpement rapide des prestataires de services logistiques (PSL) est devenu une realite dans de nombreux pays developpes, mais egalement dans des economies en transition. Ils offrent aujourd’hui une large gamme de services a leurs clients, et ils font preuve d’une importante capacite d’innovation dans la creation de nouveaux services a valeur ajoutee. La question est de savoir si leurs clients ont pris conscience que cette capacite d’innovation influence positivement leur performance logistique. Si tel etait le cas, cela signifierait que les PSL les plus innovants sont en position favorable sur le marche, et qu’ils peuvent esperer une forte loyaute de leurs clients. L’article s’interroge sur le lien entre capacite d’innovation du PSL et performance logistique percue par l’industriel, a partir des resultats d’une recherche conduite aupres de 139 industriels agro-alimentaires vietnamiens.Codes JEL : L66, L87, M10, R49

Therapeutic efficacy of a systemic drug delivery largely depends on the targeting design of the delivery system, which tackles with circulatory traffic and prevents the nonspecific distribution of the drug in the wide range of vital organs. A drawing attention has been given to a biomimetic cloaking of the synthetic drug delivery nanoparticle using mammalian cell-ghosts, which has shown the installment of the biological complexity of the original cells thereby acting as naive cells, to precisely delivery drug to the intended target. Align towards this direction; we developed a membrane camouflage fusogenic liposomal delivery system “NKsome” for targeted tumor therapy using Natural Killer (NK) cell-ghost, which naturally undergoes immunosurveillance of diseased/stress cells. The engineered NKsome shows successful retention of NK cell membrane-associated targeting protein on its surface. With its excellent biocompatibility, NKsome shows a higher affinity towards cancer than normal cells as demonstrated by in vitro flow-passage assay, and exhibits enhanced tumor homing efficiency in-vivo with an extended plasma residence time of 18 h. Moreover, the therapeutic potential of doxorubicin-loaded NKsome shows promising antitumor activity in vivo against MCF-7 induced tumor model. Overall results illustrate the therapeutic advantages of NK cell biomimicry capable of communicating like immune cells for cooperative drug delivery.

A new series of fifteen 5-, 6-, and 8-appended 4-methylquinolines were synthesized and evaluated for their neural protective activities. Selected compounds were further examined for their inhibition of glycogen synthase kinase-3β (GSK-3β) and protein kinase C (PKC). Two most potent analogs, compounds 3 and 10, show nanomolar protective activities in amyloid β-induced MC65 cells and enzymatic inhibitory activities against GSK-3β, but poor PKC inhibitory activities. Using normal mouse model, the distribution of the most potent analog 3 in various tissues and possible toxic effects in the locomotors and inhibition of liver transaminases activities were carried out. No apparent decline of locomotor activity and no inhibition of liver transaminases were found. The compound appears to be safe for long-term use in Alzheimer's disease mouse model.

Introduction Venetoclax (VEN) is a selective BCL-2 inhibitor that has demonstrated activity against acute myeloid leukemia (AML) and has been shown to be effective when used in combination with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) for treatment-naïve, elderly AML patients unfit for intensive chemotherapy. Data on its use in the relapsed/refractory setting is limited. Methods A retrospective analysis was performed among 12 relapsed or refractory AML patients treated with VEN combination therapy at the University of California Los Angeles from 2018-2019. Seven patients received VEN in combination with azacitidine (75 mg/m2 x 7 days), 4 patients with decitabine (20 mg/m2 x 5 days), and 1 patient with low-dose cytarabine (20 mg/m2 x 10 days). Results The median patient age at time of VEN therapy was 58 years (range 41-79). Four patients (33.3%) had secondary AML. The majority (9 patients, 75.0%) had adverse cytogenetics. Three patients (25.0%) had received an allogeneic stem cell transplant prior to VEN therapy, and 5 patients (41.7%) had failed HMA therapy prior. Notable molecular mutations present were TP53 (4 patients, 33.3%), FLT3 (3 patients, 25.0%), and IDH2 (1 patient, 8.3%). Eight patients (66.7%) had grade 3 or greater neutropenia at time of VEN initiation, and 9 patients (75.0%) had grade 3 or greater thrombocytopenia. Four patients (33.3%) had a grade 3 or greater infection prior to VEN therapy. Dosing of VEN was by physician discretion with a median starting dose of 150 mg (range 100-800) and a median maintenance dose of 450 mg (range 200-800). The median number of cycles of VEN combination therapy was 2 (range 1-5). Seven patients (58.3%) had decreased VEN dosage due to concomitant azole for antifungal prophylaxis. Four patients (33.3%) were on an additional small molecular inhibitor while receiving VEN therapy (sorafenib in 3 patients, ruxolitinib in 1 patient). The majority (10 patients, 83.3%) had an interruption in VEN dosing for the following reasons: bone marrow functional delay (7 patients), inability to tolerate oral pills (4 patients), infection (3 patients), and bleeding (2 patients). The objective response rate (ORR) was 41.7% with 3 patients (25.0%) achieving complete remission with incomplete hematologic recovery (CRi) and 2 patients (16.7%) achieving partial remission (PR) (Table 1). Three patients (25.0%) experienced early death within 30 days due to the following: pneumonia (1 patient), multi-organ failure from infection and graft-versus-host disease (1 patient), and intracranial hemorrhage (1 patient). The median time to first and best response was 56 days (range 27-101) or after approximately 2 cycles of VEN combination therapy. During VEN therapy, all patients (100%) had grade 3 or greater neutropenia and thrombocytopenia, and 10 patients (83.3%) had grade 3 or greater anemia. The nadir of most cytopenias occurred during cycle 1. Six patients (50.0%) developed a grade 3 or greater infection following VEN therapy, and 2 patients (16.7%) developed a grade 3 or greater intracranial hemorrhage. The only other notable grade 3 or greater side effects noted during VEN therapy were dizziness (1 patient, 8.3%) and diarrhea (1 patient, 8.3%). After a median follow-up time of 3.14 months (range 1.22-13.48), 2 patients (16.7%) progressed, and the 1-year progression-free survival (PFS) rate was 71.11% (95% CI 43.40-100.00) (Figure 1). Eight out of 12 patients died as a result of infection (6 patients, 50.0%), disease progression (1 patient, 8.3%), and bleeding (1 patient, 8.3%). The median overall survival (OS) was 4.74 months (range 1.18-9.15), and the 1-year OS rate was 14.60% (95% CI 2.54-83.80) (Figure 2). VEN was discontinued in all patients because of no response (5 patients, 41.7%), adverse effects (4 patients, 33.3%), transition to donor lymphocyte infusion (1 patient, 8.3%), or transition to allogeneic stem cell transplant (2 patients, 16.7%). Conclusions We present our institutional experience with VEN combination therapy for the treatment of relapsed/refractory AML with a particularly high-risk patient cohort, predominantly characterized by adverse genetic features and grade 3 cytopenias prior to start of therapy. Overall, the response rate was modest, but not inferior to that with conventional salvage chemotherapy. Adverse events were primarily due to pre-existing bone marrow failure, likely exacerbated by treatment. Disclosures Schiller: Agios: Research Funding, Speakers Bureau; Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor approved for use in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. It does not currently have an approved use for the treatment of acute myeloid leukemia in the relapsed/refractory setting.

Introduction Chimeric Antigen Receptor (CAR) T-cell therapy is an innovative therapy for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Prior to CAR T-cell infusion, patients receive lymphodepleting chemotherapy and may receive granulocyte colony-stimulating factor (G-CSF) to decrease the duration of neutropenia and risk of infection. However, G-CSF also has the potential to increase the incidence and/or severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) by promoting antigen-presenting cell function (Mehta HM, J Immunol, 2015). More data is required to guide clinicians on the benefits and risks of G-CSF use in CAR T-cell treatment. Methods A retrospective analysis was performed among 22 DLBCL patients who received CAR T-cell therapy with Axicabtagene ciloleucel at the University of California Los Angeles from March 2018 to May 2019. All patients received standard lymphodepleting therapy with fludarabine 30 mg/m2/day and cyclophosphamide 500 mg/m2/day on days -5 through -3, except one patient who received reduced dosages for renal disease. Prophylactic tocilizumab 8 mg/kg was given to all patients at 36 hours after CAR T-cell infusion, with additional doses of tocilizumab and/or steroids given for evidence of CRS/ICANS based on the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system. G-CSF was administered by physician discretion following CAR T-cell infusion at a weight-based dosage of either 300 or 480 mcg and cumulative G-CSF dose recorded within the first 30 days. Results Patient and disease characteristics are shown in Table 1. Seven of the 22 patients (31.8%) received G-CSF at a median cumulative dosage of 2880 mcg (IQR 900-8640), with the majority (4 patients, 57.1%) receiving G-CSF in the first 5 days post CAR T-cell infusion (Table 2). The median duration of neutropenia following lymphodepleting therapy was 5 days (IQR 4.5-8.5) for those patients treated with G-CSF compared to 15 days (IQR 8.0-30.0) for those who did not receive G-CSF (p = 0.0157). Seven patients (31.8%) developed infection in the 30 days post CAR T-cell therapy with 4 infections being grade 3 or higher. There was no difference in the incidence and severity of infection between those patients who received G-CSF and those that did not (p = 0.630, p = 0.424, Figure 1). CRS was noted in 14 patients overall (63.6%), 4 of which were grade 3 or higher. ICANS was noted in 11 patients overall (50.0%), 9 of which were grade 3 or higher. Among the 7 patients that received G-CSF, 6 patients (85.7%) and 4 patients (57.1%) had evidence of CRS and ICANS, respectively. Among the 15 patients that did not receive G-CSF, 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 (any grade) or ICANS (any grade) between the group of patients that received G-CSF and those that did not (p = 0.193, p = 0.647). However, there was a significant increase in the severity of CRS for patients that received G-CSF compared to those that did not (p = 0.0418, Figure 1), but no increase in the severity of ICANS based on G-CSF use (p = 0.660, Figure 1). Thirteen patients (59.1%) received corticosteroids following CAR T-cell treatment at a median cumulative dosage of 666.7 mg prednisone equivalents (IQR 445.0-933.3), with the majority (9 patients, 69.2%) receiving steroids in the first 5 days post CAR T-cell infusion (Table 2). More than half of the cohort (14 patients, 63.6%) required more than 1 dose of tocilizumab (Table 2). There was no association between G-CSF use and steroid use or administration of more than 1 dose of tocilizumab (p = 0.648, p = 0.074). Conclusions Our data demonstrates a significant increase in severity without an increase in incidence of CRS with G-CSF use within 30 days of Axicabtagene ciloleucel administration for relapsed/refractory DLBCL. There was no association of G-CSF with severity or incidence of ICANS and no difference in infection rates with G-CSF in this setting. *Both Daria Gaut and Kevin Tang contributed equally to this work. Disclosures No relevant conflicts of interest to declare.

We engineered nanomedicine with the stealth corona made up of densely packed bone seeking ligand, alendronic acid. In a typical nanoconstruct, alendronic acid is conjugated with hydrophilic head moiety of phospholipid that has an ability to self-assemble with hydrophobic polymeric core through its hydrophobic long carbon-chain. Proposed nanomedicine has three distinct compartments namely; poly(l-lactic-co-glycolic acid) polymeric core acting as a drug reservoir and skeleton of the nanoconstruct, phospholipid monolayer covers the core acting as a diffusion barrier, and a densely packed alendronic acid corona acting as a stabilizer and targeting moiety. Thus engineered nanomedicine attain spherical entity with ~90 ± 6 nm having negative zeta potential, −37.7 ± 2 mV, and has an ability to load 7 ± 0.3 wt% of doxorubicin. In-vitro bone targeting efficiency of nanomedicine was studied using hydroxyapatite crystals as a bone model, and found significant accumulation of nanoparticle in the crystals. Moreover, cellular internalization studies with mouse osteosarcoma confirm the selectivity of nanomedicine when compared to its internalization in non-targeted mouse melanoma. This nanomedicine shows prolong stability in serum and deliver the drug into the cell exhibiting an IC50 of 3.7 μM. Given the strong interacting property of alendronic acid with bone, the proposed nanomedicine hold promises in delivering drug to bone microenvironment.

Le cadre conceptuel développé dans l’article s’appuie sur l’analyse des processus d’intégration dyadique de la chaîne logistique. Il se fonde sur une revue extensive de la littérature pour aboutir à une hypothèse de recherche relative à la relation entre intégration relationnelle de la chaîne logistique et performance logistique perçue. Le terrain est constitué par une enquête conduite par questionnaire auprès de 139 industriels du secteur alimentaire au Vietnam. Il en ressort que l’intégration relationnelle entre l’industriel et son PSL impacte fortement sur la performance logistique perçue par l’industriel. The conceptual framework developed in this paper is based on analysis of the dyadic supply chain integration process. By relying on an extensive literature review, we build a research hypothesis relating to the relationship between supply chain integration and perceived logistical performance. A questionnaire survey was conducted in Vietnam with the participation of 139 managers of food industry. The main result of the research can be summarized as following: the relational integration between manufacturer and LSP impacts heavily on logistical performance perceived by the manufacturer.

Having initiated economic liberalization in 1986, Vietnam is a particularly interesting emerging economy to study. The logistics industry in the country is developing strongly because manufacturers are willing to outsource their logistical activities to specialized businesses called logistics service providers (LSPs). To be sustainable partners of manufacturers, LSPs must adopt an informational integration policy that improves the functioning of their customers’ supply chains. To find out whether Vietnamese manufacturers value information integration, a questionnaire survey was administered to 139 food industry managers. The main research finding is that informational integration between manufacturer and LSP strongly impacts the manager’s perception of its own logistics performance. This result has major implications for foreign LSPs that want to carve out a significant place on the Vietnamese market.