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Multiple myeloma (MM) is the cancer of plasma cells within the bone marrow and remains incurable. Tumor-associated macrophages (TAMs) within the tumor microenvironment often display a pro-tumor phenotype and correlate with tumor proliferation, survival, and therapy resistance. IL-10 is a key immunosuppressive cytokine that leads to recruitment and development of TAMs. In this study, we investigated the role of IL-10 in MM TAM development as well as the therapeutic application of IL-10/IL-10R/STAT3 signaling inhibition. We demonstrated that IL-10 is overexpressed in MM BM and mediates M2-like polarization of TAMs in patient BM, 3D co-cultures in vitro, and mouse models. In turn, TAMs promote MM proliferation and drug resistance, both in vitro and in vivo. Moreover, inhibition of IL-10/IL-10R/STAT3 axis using a blocking IL-10R monoclonal antibody and STAT3 protein degrader/PROTAC prevented M2 polarization of TAMs and the consequent TAM-induced proliferation of MM, and re-sensitized MM to therapy, in vitro and in vivo. Therefore, our findings suggest that inhibition of IL-10/IL-10R/STAT3 axis is a novel therapeutic strategy with monotherapy efficacy and can be further combined with current anti-MM therapy, such as immunomodulatory drugs, to overcome drug resistance. Future investigation is warranted to evaluate the potential of such therapy in MM patients., (© 2024. The Author(s).)

Severe asthma and sinus disease are consequences of type 2 inflammation (T2I), mediated by interleukin (IL)-33 signaling through its membrane-bound receptor, ST2. Soluble (s)ST2 reduces available IL-33 and limits T2I, but little is known about its regulation. We demonstrate that prostaglandin E 2 (PGE 2 ) drives production of sST2 to limit features of lung T2I. PGE 2 -deficient mice display diminished sST2. In humans with severe respiratory T2I, urinary PGE 2 metabolites correlate with serum sST2. In mice, PGE 2 enhanced sST2 secretion by mast cells (MCs). Mice lacking MCs, ST2 expression by MCs, or E prostanoid (EP) 2 receptors by MCs showed reduced sST2 lung concentrations and strong T2I. Recombinant sST2 reduced T2I in mice lacking PGE 2 or ST2 expression by MCs back to control levels. PGE 2 deficiency also reversed the hyperinflammatory phenotype in mice lacking ST2 expression by MCs. PGE 2 thus suppresses T2I through MC-derived sST2, explaining the severe T2I observed in low PGE 2 states., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Macrophages expressing group V phospholipase A 2 (Pla2g5) release the free fatty acid (FFA) linoleic acid (LA), potentiating lung type 2 inflammation. Although Pla2g5 and LA increase in viral infections, their role remains obscure. We generated Pla2g5 flox/flox mice, deleted Pla2g5 by using the Cx3cr1 cre transgene, and activated bone marrow-derived macrophages (BM-Macs) with poly:IC, a synthetic double-stranded RNA that triggers a viral-like immune response, known Pla2g5-dependent stimuli (IL-4, LPS + IFNγ, IL-33 + IL-4 + GM-CSF) and poly:IC + LA followed by lipidomic and transcriptomic analysis. Poly:IC-activated Pla2g5 flox/flox ;Cx3cr1 cre/+ BM-Macs had downregulation of major bioactive lipids and critical enzymes producing those bioactive lipids. In addition, AKT phosphorylation was lower in poly:IC-stimulated Pla2g5 flox/flox ;Cx3cr1 cre/+ BM-Macs, which was not restored by adding LA to poly:IC-stimulated BM-Macs. Consistently, Pla2g5 flox/flox ;Cx3cr1 cre/+ mice had diminished poly:IC-induced lung inflammation, including inflammatory macrophage proliferation, while challenging Pla2g5 flox/flox ;Cx3cr1 cre/+ mice with poly:IC + LA partially restored lung inflammation and inflammatory macrophage proliferation. Finally, mice lacking FFA receptor-1 (Ffar1)-null mice had reduced poly:IC-induced lung cell recruitment and tissue macrophage proliferation, not corrected by LA. Thus, Pla2g5 contributes to poly:IC-induced lung inflammation by regulating inflammatory macrophage proliferation and LA/Ffar1-mediated lung cell recruitment and tissue macrophage proliferation., (© 2024 John Wiley & Sons Ltd.)

Background: This study aims to evaluate the efficacy and safety of a blunt cannula technique using hyaluronic acid fillers for achieving the Bratz doll lip aesthetic, characterized by enhanced volume and sharp definition., Methods: Thirty volunteers, 22-40 years of age, were selected based on specific inclusion criteria at Albany Cosmetic and Laser Center for 6 months. The technique involved precise filler injections using a Steriglide blunt cannula. Pre- and postprocedure measurements of lip dimensions and angular changes were meticulously documented and analyzed using IBM SPSS Statistics software., Results: The procedure significantly increased the average height of both the upper and lower vermilion zones, with notable changes in angular measurements and the distance between the midline and oral commissure, aligning with the Bratz doll aesthetic. Importantly, none of the participants experienced bruising, a common side effect in traditional needle-based methods. The overall satisfaction rate was high, with an average score of 8.5 out of 10, reflecting the procedure's success in meeting aesthetic goals and ensuring participant comfort., Conclusions: The blunt cannula technique for lip augmentation presents a safe and effective alternative to traditional needle-based methods. The absence of bruising and high satisfaction rates underscore the technique's precision and alignment with patient safety and comfort. This study contributes to the field of cosmetic lip enhancement, offering a novel approach that balances aesthetic aspirations with health considerations, potentially influencing future practices in cosmetic procedures., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

This study introduces the Lines and Dots (LADs) technique, a new approach for administering botulinum toxin type A (BoNT-A) in treating forehead wrinkles. (1) Background: BoNT-A application patterns in the forehead often rely solely on the anatomy of the frontalis muscle. The LADs technique proposes a combination of anatomical features with nerve pathways. (2) Methods: The technique employed a grid system aligned with the supraorbital and supratrochlear nerve pathways and used an electronic acupuncture pen for validation. This study analyzed treatment outcomes for efficacy and safety and proposed a predictive model for BoNT-A dosage. (3) Results: LADs was associated with a high satisfaction rate and low side effect incidence. The predictive model followed BoNT-A Units=0.322×Muscle Pattern Code+1.282×Line Type Code+2.905×Severity Pre-Treatment+3.947. (4) Conclusions: The LADs technique offers an alternative approach to treating forehead wrinkles, optimizing efficacy while minimizing the BoNT-A dose required.

Background: As pharmacy practice evolves, an increasing number of pharmacists are diversifying into non-traditional roles such as aesthetic procedures. Despite this shift, comprehensive research exploring demographic patterns, motivations, practice settings, and perceived support and barriers among pharmacists in this specialty, particularly in Alberta, Canada, remains scant., Objectives: This study aimed to explore the demographics, experience, practice settings, types of aesthetic services offered, and perceptions of support from the Alberta College of Pharmacy (ACP) among Alberta pharmacists. It also sought to understand the relationship between pharmacists' years of practice and the complexity of the aesthetic services they provide and to assess the impact of contacting the ACP on their perceptions of clarity in the aesthetic injection regulatory framework., Methods: An online survey was disseminated to registered pharmacists in Alberta, gathering data on demographics, experience, practice settings, aesthetic services offered, and perceived barriers and support. Statistical analysis was used to identify significant trends and associations, employing Chi-square, Kendall's tau-c, and Gamma tests., Results: The results showed a significant association between younger age and involvement in aesthetic practice, with a substantial presence in hospital settings. Part-time pharmacists showed stronger involvement, and those with less than five years of experience were more likely to practice aesthetic injections. No statistically significant relationship was found between the years of practice and the complexity of aesthetic services. Clear dissatisfaction was evident regarding the support and communication from the ACP, with contact with the ACP not necessarily resulting in clarity regarding aesthetic practice regulations., Conclusion: The findings suggest that aesthetic practices are becoming a significant part of pharmacy practice, particularly among younger, part-time pharmacists associated with hospital settings. However, this shift calls for improved support, clearer guidelines, and better communication from the ACP, particularly around aesthetic practice regulations.It also emphasizes the need for regulatory bodies to ensure pharmacists are equipped to offer these services safely and effectively, which could be crucial in shaping future policy-making and professional development initiatives., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following. Established in 2019, the Alberta Cosmetic Pharmacist Association is a professional body dedicated to supporting, educating, and representing pharmacists who are practicing in the field of aesthetic medicine within Alberta. The association is committed to promoting high standards of practice and ethical care, encouraging ongoing education, and fostering collaboration among cosmetic pharmacists. It serves as a resource for its members by providing up-to-date information, training opportunities, and a platform for networking, professional development, academic publishing, and research. Moreover, it plays a pivotal role in advocating for the rights and interests of cosmetic pharmacists to regulatory bodies and the broader healthcare community. Since its inception, the association has fielded a multitude of inquiries concerning the regulatory framework for the practice of aesthetic medicine by pharmacists. This could suggest some ambiguity regarding the legal requirements as outlined by the Alberta College of Pharmacy (ACP), the sole regulatory authority for the pharmacy profession in Alberta. The aim of this survey, conducted by the Alberta Cosmetic Pharmacist Association, was to reveal trends in the emerging practice of aesthetics among pharmacists in Alberta, and to explore the readiness and willingness of Alberta's pharmacists to embrace this new aspect of patient care and the challenges and barriers they face in doing so. These might lead to debates or legal disputes with regulatory body, including, but not exclusive to ACP., (© 2023 The Author.)

Aim The aim of this article was to review the current clinical application of computer-aided design/computer-aided manufacturing (CAD/CAM) and three-dimensional (3D) printed dentures in dental clinics.Methods A systematic approach for searching PubMed, Embase, Scopus, and Web of Science databases. The search was performed using a variety of keywords including clinical use AND 3D printed removable dentures OR clinical use AND CAD/CAM removable dentures OR clinical use AND digital removable dentures. Selection criteria included articles written in English and reporting information on clinical applications of digital dentures between 2010 to January 2022.Results The findings outlined the main clinical advantages of digital dentures such as saving working time, satisfying clinical results and securing patients' records, and also requirement of additional visits to secure aesthetic patient satisfaction, good retention and ideal vertical dimension. Many studies recommended performing clinical try-in with regards to providing better results. It was also established that 3D printers are less expensive than milling centres and therefore can be afforded by individual dental professionals.Conclusion Digital dentures are a promising option in treating edentulous patients, especially in remote areas where skilful technicians are rare. However, there are some limitations in their applications., (© 2023. The Author(s).)

Problem: Contemporary science emphasizes efficient translation of scientific discoveries into tangible, innovative products and services to improve human health. Therefore, researchers need skills in innovation and entrepreneurship (I&E) to select which problems to address and bring to market the most promising solutions. Training in this skillset is not currently available to most biomedical research trainees., Approach: The Entrepreneurship for Biomedicine (E4B) training program was created to develop biomedical researchers' I&E skills. The program comprises 2 semester-length courses: E4B1 teaches core skills; E4B2 focuses on advanced skills for those interested in pursuing funding for a new venture. In addition to traditional entrepreneurship training, E4B teaches ethics and personal skills such as resilience, communication, and team-building. Each course is delivered online and requires about 4 hours weekly. Program elements include short videos for didactic content; a team-based capstone project; mentorship from experienced entrepreneurs; and a live, virtual pitch presentation. The program is housed at Washington University School of Medicine in St. Louis and is open to pre- and postdoctoral biomedical research trainees and faculty nationwide., Outcomes: In 2020, 77 trainees completed E4B1 and 13 went on to complete E4B2. Trainees in both courses were satisfied with learning content and mentorship and would recommend the program to a friend. Pre- and postanalyses demonstrated that trainees' confidence in their knowledge about and ability to perform I&E tasks taught throughout the program increased. Since completion, 4 graduates have received external funding for an innovation and 3 have started a company., Next Steps: E4B is well accepted, and this preliminary evaluation suggests the program is effective. It could serve to support medical school curricula, business competitions, and technology transfer efforts, which are opportunities for future exploration. A more robust evaluation is planned and recruitment will be expanded to increase participation from women and underrepresented populations., (Copyright © 2022 by the Association of American Medical Colleges.)

The aim of this review is to investigate the use of 3D printing technologies for removable denture fabrication with a focus on the advantages, potentials, disadvantages and barriers., Methods: An electronic search of the English language literature from 1970 to March 2020 was carried out in databases such as PubMed/MEDLINE, Embase, Scopus, and Web of Science databases with applying the inclusion and exclusion criteria. The search was performed using a variety of keywords including 3D printing, rapid prototyping, additive manufacturing, dentures/complete dentures., Results: A total of 412 publications were retrieved. After applying the inclusion criteria and excluding the studies on CAD/CAM, studies on 3D printed crown and bridge and studies on 3D printed metal framework, 18 articles were identified for reading and analyzing in details. The results have outlined the main 3D printing advantages such as saving working time, satisfying clinical results and securing patients records. The detected disadvantages were the strength, esthetics and material biocompatibility., Conclusion: Denture fabrication by 3D printing technology is becoming more common in dental clinics. However, there is still a lack of information about biocompatibility and clinical performance of 3D printed dentures and further studies are essential., (Copyright© 2022 Dennis Barber Ltd.)

Immunotherapy is an attractive approach for treating cancer. T-cell engagers (TCEs) are a type of immunotherapy that are highly efficacious; however, they are challenged by weak T-cell activation and short persistence. Therefore, alternative solutions to induce greater activation and persistence of T cells during TCE immunotherapy is needed. Methods to activate T cells include the use of lectins, such as phytohemagglutinin (PHA). PHA has not been used to activate T cells in vivo, for immunotherapy, due to its biological instability and toxicity. An approach to overcome the limitations of PHA while also preserving its function is needed. In this study, we report a liposomal PHA which increased PHA stability, reduced toxicity and performed as an immunotherapeutic that is able to activate T cells for the use in future cancer immunotherapies to circumvent current obstacles in immunosuppression and T-cell exhaustion., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL) are hematological malignancies that remain incurable despite novel treatments. In order to improve current treatments and clinical efficacy, there remains a need for more complex in vitro models that mimic the intricate human leukemic microenvironment. This study aimed to use 3D tissue engineered plasma cultures (3DTEPC) derived from CML, AML and CLL patients to promote proliferation of leukemic cells for use as a drug screening tool for treatment. 3DTEPC supported the growth of primary CML, AML and CLL cells and also induced significantly more drug resistance in CML, AML and CLL cell lines compared to 2D. The 3DTEPC created a more physiologically relevant environment for leukemia cell proliferation, provided a reliable model for growing leukemia patient samples, and serves as a relevant tool for drug screening and personalized medicine.

Cancer patients undergo detrimental toxicities and ineffective treatments especially in the relapsed setting, due to failed treatment attempts. The development of a tool that predicts the clinical response of individual patients to therapy is greatly desired. We have developed a novel patient-derived 3D tissue engineered bone marrow (3DTEBM) technology that closely recapitulate the pathophysiological conditions in the bone marrow and allows ex vivo proliferation of tumor cells of hematologic malignancies. In this study, we used the 3DTEBM to predict the clinical response of individual multiple myeloma (MM) patients to different therapeutic regimens. We found that while no correlation was observed between in vitro efficacy in classic 2D culture systems of drugs used for MM with their clinical efficacious concentration, the efficacious concentration in the 3DTEBM were directly correlated. Furthermore, the 3DTEBM model retrospectively predicted the clinical response to different treatment regimens in 89% of the MM patient cohort. These results demonstrated that the 3DTEBM is a feasible platform which can predict MM clinical responses with high accuracy and within a clinically actionable time frame. Utilization of this technology to predict drug efficacy and the likelihood of treatment failure could significantly improve patient care and treatment in many ways, particularly in the relapsed and refractory setting. Future studies are needed to validate the 3DTEBM model as a tool for predicting clinical efficacy., (© 2021. The Author(s).)

Acute myeloid leukemia (AML) is the most common type of leukemia and has a 5-year survival rate of 25%. The standard-of-care for AML has not changed in the past few decades. Promising immunotherapy options are being developed for the treatment of AML; yet, these regimens require highly laborious and sophisticated techniques. We create nanoTCEs using liposomes conjugated to monoclonal antibodies to enable specific binding. We also recreate the bone marrow niche using our 3D culture system and use immunocompromised mice to enable use of human AML and T cells with nanoTCEs. We show that CD33 is ubiquitously present on AML cells. The CD33 nanoTCEs bind preferentially to AML cells compared to Isotype. We show that nanoTCEs effectively activate T cells and induce AML killing in vitro and in vivo . Our findings suggest that our nanoTCE technology is a novel and promising immuno-therapy for the treatment of AML and provides a basis for supplemental investigations for the validation of using nanoTCEs in larger animals and patients., Competing Interests: CONFLICTS OF INTEREST AKA and KA have filed a patent with regards to the T cell engagers described in this study. AKA is the founder and owner of Cellatrix LLC and Targeted Therapeutics LLC. Some of the experiments were performed using 3DTEBM products supplied by Cellatrix LLC; however, both companies had no role in the study. Other authors state no conflicts of interest., (Copyright: © 2021 Alhallak et al.)

T-cell-based immunotherapy, such as CAR-T cells and bispecific T-cell engagers (BiTEs), has shown promising clinical outcomes in many cancers; however, these therapies have significant limitations, such as poor pharmacokinetics and the ability to target only one antigen on the cancer cells. In multiclonal diseases, these therapies confer the development of antigen-less clones, causing tumor escape and relapse. In this study, we developed nanoparticle-based bispecific T-cell engagers (nanoBiTEs), which are liposomes decorated with anti-CD3 monoclonal antibodies (mAbs) targeting T cells, and mAbs targeting the cancer antigen. We also developed a nanoparticle that targets multiple cancer antigens by conjugating multiple mAbs against multiple cancer antigens for T-cell engagement (nanoMuTEs). NanoBiTEs and nanoMuTEs have a long half-life of about 60 h, which enables once-a-week administration instead of continuous infusion, while maintaining efficacy in vitro and in vivo. NanoMuTEs targeting multiple cancer antigens showed greater efficacy in myeloma cells in vitro and in vivo, compared to nanoBiTEs targeting only one cancer antigen. Unlike nanoBiTEs, treatment with nanoMuTEs did not cause downregulation (or loss) of a single antigen, and prevented the development of antigen-less tumor escape. Our nanoparticle-based immuno-engaging technology provides a solution for the major limitations of current immunotherapy technologies., (© 2021. The Author(s).)

MM is the second most common hematological malignancy and represents approximately 20% of deaths from hematopoietic cancers. The advent of novel agents has changed the therapeutic landscape of MM treatment; however, MM remains incurable. T cell-based immunotherapy such as BTCEs is a promising modality for the treatment of MM. This review article discusses the advancements and future directions of BTCE treatments for MM.

Purpose: Cervical cancer represents the fourth most frequent malignancy in the world among women, and mortality has remained stable for the past 4 decades. Intravenous cisplatin with concurrent radiation therapy is the standard-of-care for patients with local and regional cervical cancer. However, cisplatin induces serious dose-limiting systemic toxicities and recurrence frequently occurs. In this study, we aimed to develop an intracervical drug delivery system that allows cisplatin release directly into the tumor and minimize systemic side effects., Methods and Materials: Twenty patient biopsies and 5 cell lines treated with cisplatin were analyzed for platinum content using inductively coupled plasma mass spectrometry. Polymeric implants loaded with cisplatin were developed and evaluated for degradation and drug release. The effect of local or systemic cisplatin delivery on drug biodistribution as well as tumor burden were evaluated in vivo, in combination with radiation therapy., Results: Platinum levels in patient biopsies were 6-fold lower than the levels needed for efficacy and radiosensitization in vitro. Cisplatin local delivery implant remarkably improved drug specificity to the tumor and significantly decreased accumulation in the blood, kidney, and other distant normal organs, compared with traditional systemic delivery. The localized treatment further resulted in complete inhibition of tumor growth., Conclusions: The current standard-of-care systemic administration of cisplatin provides a subtherapeutic dose. We developed a polymeric drug delivery system that delivered high doses of cisplatin directly into the cervical tumor, while lowering drug accumulation and consequent side effects in normal tissues. Moving forward, these data will be used as the basis of a future first-in-human clinical trial to test the efficacy of localized cisplatin as adjuvant or neoadjuvant chemotherapy in local and regional cervical cancer., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Drug resistance and dose-limiting toxicities are significant barriers for treatment of multiple myeloma (MM). Bone marrow microenvironment (BMME) plays a major role in drug resistance in MM. Drug delivery with targeted nanoparticles have been shown to improve specificity and efficacy and reduce toxicity. We aim to improve treatments for MM by (1) using nanoparticle delivery to enhance efficacy and reduce toxicity; (2) targeting the tumor-associated endothelium for specific delivery of the cargo to the tumor area, and (3) synchronizing the delivery of chemotherapy (bortezomib; BTZ) and BMME-disrupting agents (ROCK inhibitor) to overcome BMME-induced drug resistance. We find that targeting the BMME with P-selectin glycoprotein ligand-1 (PSGL-1)-targeted BTZ and ROCK inhibitor-loaded liposomes is more effective than free drugs, non-targeted liposomes, and single-agent controls and reduces severe BTZ-associated side effects. These results support the use of PSGL-1-targeted multi-drug and even non-targeted liposomal BTZ formulations for the enhancement of patient outcome in MM.

Multiple myeloma (MM) remains to be incurable despite recent therapeutic advances. CD47, an immune checkpoint known as the "don't eat me" signal, is highly expressed on the surface of various cancers, allowing cancer cells to send inhibitory signals to macrophages and impede phagocytosis and immune response. In this study, we hypothesized that blocking the "don't eat me" signaling using an anti-CD47 monoclonal antibody will induce killing of MM cells. We report that CD47 expression was directly correlated with stage of the disease, from normal to MGUS to MM. Moreover, MM cells had remarkably higher CD47 expression than other cell populations in the bone marrow. These findings indicate that CD47 is specifically expressed on MM and can be used as a potential therapeutic target. Further, blocking of CD47 using an anti-CD47 antibody induced immediate activation of macrophages, which resulted in induction of phagocytosis and killing of MM cells in the 3D-tissue engineered bone marrow model, as early as 4 hours. These results suggest that macrophage checkpoint immunotherapy by blocking the CD47 "don't eat me" signal is a novel and promising strategy for the treatment of MM, providing a basis for additional studies to validate these effects in vivo and in patients., Competing Interests: Dr. Azab received research support from Vasculox Inc. to conduct this study. He also received funding from GlycoMimetic Inc.; however, this has no contribution to this study. In addition, Dr. Azab is the founder and owner of Cellatrix LLC that has an exclusive license for the 3DTEBM technology described in part of the experiments in this paper. Moreover, Dr. Azab is the founder and owner of Targeted Therapeutics LLC; however, this has no contribution to this study. Other authors state no conflicts of interest.

Objective :  Waldenström Macroglobulinemia (WM) is a rare B-cell malignancy characterized by secretion of immunoglobulin M and cancer infiltration in the bone marrow. Chemokine receptor such as CXCR4 and hypoxic condition in the bone marrow play crucial roles in cancer cell trafficking, homing, adhesion, proliferation, survival, and drug resistance. Herein, we aimed to use CXCR4 as a potential biomarker to detect hypoxic-metastatic WM cells in the bone marrow and in the circulation by using CXCR4-detecting radiopharmaceutical. Methods : We radiolabeled a CXCR4-inhibitor (AMD3100) with 64 Cu and tested its binding to WM cells with different levels of CXCR4 expression using gamma counter in vitro . The accumulation of this radiopharmaceutical tracer was tested in vivo in subcutaneous and intratibial models using PET/CT scan. In addition, PBMCs spiked with different amounts of WM cells ex vivo were detected using gamma counting. Results : In vitro , 64 Cu-AMD3100 binding to WM cell lines demonstrated a direct correlation with the level of CXCR4 expression, which was increased in cells cultured in hypoxia with elevated levels of CXCR4, and decreased in cells with CXCR4 and HIF-1α knockout. Moreover, 64 Cu-AMD3100 detected localized and circulating CXCR4 high WM cells with high metastatic potential. Conclusions : In conclusion, we developed a molecularly targeted system, 64 Cu-AMD3100, which binds to CXCR4 and specifically detects WM cells with hypoxic phenotype and metastatic potential in the subcutaneous and intratibial models. These preliminary findings using CXCR4-detecting PET radiopharmaceutical tracer indicate a potential technology to predict high-risk patients for the progression to WM due to metastatic potential.

Purpose: Boron neutron capture therapy (BNCT) has the potential to become a viable cancer treatment modality, but its clinical translation requires sufficient tumor boron delivery while minimizing nonspecific accumulation., Methods: Thermal sensitive liposomes (TSLs) were designed to have a stable drug payload at physiological temperatures but engineered to have high permeability under mild hyperthermia., Results: We found that TSLs improved the tumor-specific delivery of boronophenylalanine (BPA) and boronated 2-nitroimidazole derivative B-381 in D54 glioma cells. Uniquely, the 2-nitroimidazole moiety extended the tumor retention of boron content compared to BPA., Conclusion: This is the first study to show the delivery of boronated compounds using TSLs for BNCT, and these results will provide the basis of future clinical trials using TSLs for BNCT.

An improved technique for fractal characterization called the modified blanket method is introduced that can quantify surrounding fractal structures on a pixel by pixel basis without artifacts associated with scale-dependent image features such as object size. The method interprets images as topographical maps, obtaining information regarding the local surface area as a function of image resolution. Local fractal dimension (FD) can be quantified from the power law exponent derived from the surface area and image resolution relationship. We apply this technique on simulated cell images of known FD and compared the obtained values to power spectral density (PSD) analysis. Our method is sensitive to a wider FD range (2.0-4.5), having a mean error of 1.4% compared to 6% for PSD analysis. This increased sensitivity and an ability to compute regional FD properties enabled the discrimination of the differences in radiation resistant cancer cell responses that could not be detected using PSD analysis., Competing Interests: The authors declare that there are no conflicts of interest related to this article.

There is a critical need to identify patients with radiation-resistant tumors early after treatment commencement. In this study, we use diffuse reflectance spectroscopy (DRS) to investigate changes in vascular oxygenation and total hemoglobin concentration in A549 radiation-sensitive and resistant tumors treated with a clinically relevant dose fraction of 2 Gy. DRS spectra were acquired before, immediately after, 24, and 48 hours after radiation. Our data reveals a significantly higher reoxygenation (sO 2 ) in the radiation-resistant tumors 24 and 48h after treatment, and provides promising evidence that DRS can discern between the reoxygenation trends of radiation-sensitive and resistant tumors., Competing Interests: The authors declare that there are no conflicts of interest related to this article.

Treatment failure caused by a radiation-resistant cell phenotype remains an impediment to the success of radiation therapy in cancer. We recently showed that a radiation-resistant isogenic line of human A549 lung cancer cells had significantly elevated expression of hypoxia-inducible factor (HIF-1α), and increased glucose catabolism compared with the parental, radiation-sensitive cell line. The objective of this study was to investigate the longitudinal metabolic changes in radiation-resistant and sensitive A549 lung cancer cells after treatment with a combination of radiation therapy and YC-1, a potent HIF-1 inhibitor. Using label-free two-photon excited fluorescence microscopy, we determined changes in the optical redox ratio of FAD/(NADH and FAD) over a period of 24 hours following treatment with YC-1, radiation, and both radiation and YC-1. To complement the optical redox ratio, we also evaluated changes in mitochondrial organization, glucose uptake, reactive oxygen species (ROS), and reduced glutathione. We observed significant differences in the optical redox ratio of radiation-resistant and sensitive A549 cells in response to radiation or YC-1 treatment alone; however, combined treatment eliminated these differences. Our results demonstrate that the optical redox ratio can elucidate radiosensitization of previously radiation-resistant A549 cancer cells, and provide a method for evaluating treatment response in patient-derived tumor biopsies.

The establishment of more effective treatments that can circumvent chemoresistance in Multiple Myeloma (MM) is a priority. Although bortezomib (BTZ) is one of the most potent proteasome inhibitors available, still possesses limitations related to dose limiting side effects. Several strategies have been developed to improve the delivery of chemotherapies to MM by targeting different moieties expressed on MM cells to nanoparticle delivery systems (NPs), which have failed mainly due to their heterogeneous expression on these cells. Our goal was to test CD38 targeted chitosan NPs as novel targeting moiety for MM to improve the potency and efficacy of BTZ in MM cells and reduce the side effects in healthy tissue. We have showed preferential BTZ release in tumor-microenvironment, specific binding to MM cells, and an improved drug cellular uptake through BTZ diffusion from the surface and endocytosed NPs, which translated in enhanced proteasome inhibition and robust cytotoxic effect on MM cells when BTZ was administered through anti-CD38 chitosan NPs. Furthermore, the anti-CD38 chitosan NPs specifically delivered therapeutic agents to MM cells improving therapeutic efficacy and reducing side effects in vivo. The anti-CD38 chitosan NPs showed low toxicity profile allowing enhancement of proteasome-inhibitory activity and specificity of BTZ by endocytosis-mediated uptake of CD38 representing a promising therapy in MM., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Radiation resistance remains a significant problem for cancer patients, especially due to the time required to definitively determine treatment outcome. For fractionated radiation therapy, nearly 7 to 8 weeks can elapse before a tumor is deemed to be radiation-resistant. We used the optical redox ratio of FAD / ( FAD + NADH ) to identify early metabolic changes in radiation-resistant lung cancer cells. These radiation-resistant human A549 lung cancer cells were developed by exposing the parental A549 cells to repeated doses of radiation (2 Gy). Although there were no significant differences in the optical redox ratio between the parental and resistant cell lines prior to radiation, there was a significant decrease in the optical redox ratio of the radiation-resistant cells 24 h after a single radiation exposure ( p = 0.01 ). This change in the redox ratio was indicative of increased catabolism of glucose in the resistant cells after radiation and was associated with significantly greater protein content of hypoxia-inducible factor 1 ( HIF - 1 ? ), a key promoter of glycolytic metabolism. Our results demonstrate that the optical redox ratio could provide a rapid method of determining radiation resistance status based on early metabolic changes in cancer cells.

The development of prognostic indicators of breast cancer metastatic risk could reduce the number of patients receiving chemotherapy for tumors with low metastatic potential. Recent evidence points to a critical role for cell metabolism in driving breast cancer metastasis. Endogenous fluorescence intensity of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) can provide a label-free method for assessing cell metabolism. We report the optical redox ratio of FAD/(FAD + NADH) of four isogenic triple-negative breast cancer cell lines with varying metastatic potential. Under normoxic conditions, the redox ratio increases with increasing metastatic potential (168FARN>4T07>4T1), indicating a shift to more oxidative metabolism in cells capable of metastasis. Reoxygenation following acute hypoxia increased the redox ratio by 43 ± 9% and 33 ± 4% in the 4T1 and 4T07 cells, respectively; in contrast, the redox ratio decreased 14 ± 7% in the non-metastatic 67NR cell line. These results demonstrate that the optical redox ratio is sensitive to the metabolic adaptability of breast cancer cells with high metastatic potential and could potentially be used to measure dynamic functional changes that are indicative of invasive or metastatic potential.