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The benefits of contrast-enhancing imaging probes have become apparent over the past decade. However, there is a gap in the literature when it comes to the assessment of the phototoxic potential of imaging probes and systems emitting visible and/or near-infrared radiation. The primary mechanism of fluorescent agent phototoxicity is thought to involve the production of reactive molecular species (RMS), yet little has been published on the best practices for safety evaluation of RMS production levels for clinical products. We have proposed methods involving a cell-free assay to quantify singlet oxygen [(SO) a known RMS] generation of imaging probes, and performed testing of Indocyanine Green (ICG), Proflavine, Methylene Blue, IR700 and IR800 at clinically relevant concentrations and radiant exposures. Results indicated that SO production from IR800 and ICG were more than two orders of magnitude below that of the known SO generator Rose Bengal. Methylene Blue and IR700 produced much higher SO levels than ICG and IR800. These results were in good agreement with data from the literature. While agents that exhibit spectral overlap with the assay may be more prone to errors, our tests for one of these agents (Proflavine) appeared robust. Overall, our results indicate that this methodology shows promise for assessing the phototoxic potential of fluorophores due to SO production.

SUMMARY This article summarizes a study by Huang, Chen, Kaplan, and Lin (2021) which examines whether increases in co-working experience between the lead and concurring audit partners affect engagement audit quality and audit efficiency. The study uses data from Taiwan, where the identities of lead and concurring audit partners are known, and where the role of the concurring partner is different than that of an engagement quality reviewer. This article describes the findings of Huang et al. (2021) and discusses the study's implications to audits in Taiwan and elsewhere which may be of interest to practitioners, regulators, and academics.

Representative size distribution of nanoliposomal irinotecan (nal-IRI) and absorbance spectrum of nal-IRI in DMSO. (A) Mono-dispersed nal-IRI is approximately 115 nm in diameter with a Polydispersity index below 0.1. (B) Nal-IRI absorbance spectrum was measured in DMSO, and the irinotecan concentration was determined by UV-Vis spectroscopy with appropriate standard curves.

Polyethylene glycol (PEG) is attached to many peptides, proteins, liposomes, and nanoparticles to reduce their immunogenicity and improve their pharmacokinetic and therapeutic properties. Here, we describe hybrid antibodies that can selectively deliver PEGylated medicines, imaging agents, or nanomedicines to target cells. Human IgG1 hybrid antibodies αPEG:αHER2 and αPEG:αCD19 were shown by ELISA, FACS, and plasmon resonance to bind to both PEG and HER2 receptors on SK-BR-3 breast adenocarcinoma and BT-474 breast ductal carcinoma cells or CD19 receptors on Ramos and Raji Burkitt's lymphoma cells. In addition, αPEG:αHER2 specifically targeted PEGylated proteins, liposomes, and nanoparticles to SK-BR-3 cells that overexpressed HER2, but not to HER2-negative MCF-7 breast adenocarcinoma cells. Endocytosis of PEGylated nanoparticles into SK-BR-3 cells was induced specifically by the αPEG:αHER2 hybrid antibody, as observed by confocal imaging of the accumulation of Qdots inside SK-BR-3 cells. Treatment of HER2+ SK-BR-3 and BT-474 cancer cells with αPEG:αHER2 and the clinically used chemotherapeutic agent PEGylated liposomal doxorubicin for 3 hours enhanced the in vitro effectiveness of PEGylated liposomal doxorubicin by over two orders of magnitude. Hybrid anti-PEG antibodies offer a versatile and simple method to deliver PEGylated compounds to cellular locations and can potentially enhance the therapeutic efficacy of PEGylated medicines. Mol Cancer Ther; 14(6); 1317–26. ©2015 AACR.

Comparison of the surface HER2 expression of different human cancer cell lines.

Preliminary analysis of costs related to the side effect management for irinotecan-based combination therapies.

Preliminary analysis of combining minocycline and irinotecan regimen indicates significant cost savings compared to other irinotecan-based combination therapies.

Supplementary methods, supplementary table S1:EC50 concentrations of mouse anti-PEG antibodies binding to various PEG molecules, supplementary table S2:Kinetic constants for binding of humanized hybrid antibodies to HER2 ECD and PEG5K, supplementary figure legends

Platinum-resistant human epithelial ovarian cancer cell lines OVCAR-5 and OVCAR-4 expresses tyrosyl-DNA phosphodiesterase 1 (Tdp1). The Tdp1 protein expression levels in human epithelial ovarian carcinoma cell lines OVCAR-5 (derived from the ascitic fluid of EOC patient without prior treatment; tumor characterized to be platinum-resistant) and OVCAR-4 (derived from the ascitic fluid of platinum-refractory EOC patient) were evaluated by Western Blot. Tdp1 expression was found higher in the OVCAR-4 cells compared to that in the OVCAR-5 cells.

Supplementary Methods Supplemental Figure 1: The MIA-PaCa-2 + PCAF model exhibits histologic features consistent with desmoplasia 90 days post implantation Supplemental Figure 2: 1 μM calcipitriol activates the vitamin D receptor (VDR) in cancer associated fibroblasts Supplemental Figure 3: VDAR activation + PDP enable a 75% dose reduction in nal-IRI Supplemental Figure 4: Inhibition of the CXCL12/CXCR7 by CAL+PDP is lost by day 90 post-implantation Supplemental Figure 5: Calcipotriol and photodynamic priming cytotoxicity curves Supplemental Figure 6: MRC-5 conditioned medium does not affect the baseline metabolic activity of PDAC cell lines Supplemental Figure 7: PDP increases intratumoral nal-IRI via increased vascular and parenchymal permeability Supplemental Figure 8: Treatment with CAL+PDP+5 mg/kg nal-IRI induces global transcriptomic shifts in pancreataic tumors that correlate with a less aggressive and more responsive treatment profile compared to treatment with PDP+20 mg/kg nal-IRI

The combination of minocycline and nanoliposomal irinotecan (nal-IRI) is tolerable by mice bearing human OVCAR-4 cells. Changes in mouse body weight were monitored longitudinally before and after treatment. The following treatments were given to mice at 7 days after subcutaneous OVCAR-4 (3 x 10^6 cells in 50% culture medium and 50% Matrigel) tumor implantation: (i) No-treatment (NT); (ii) Minocycline (Mn) (50 mg/kg was administered on day 7, which is followed by eight more cycles of Mn at 25 mg/kg body weight on the following days post-implantation: 8, 9, 10, 11, 14, 15, 17, 18; (iii) nal-IRI (nal-IRI; three doses at 5 mg/kg each, on days 11, 15, and 18); and (iv) Combination of Mn and nal-IRI. Recorded mouse weights were normalized to day 7 mouse weight (n = 3 - 13 mice per group). All changes in mouse weight were within 10% compared to the start of experiment, suggesting all treatments were tolerable by mice.

Comparison of the binding of mouse anti-PEG antibodies to different PEG molecules.

Patients with cancer often confront the decision of whether to continue high-dose chemotherapy at the expense of cumulative toxicities. Reducing the dose of chemotherapy regimens while preserving efficacy is sorely needed to preserve the performance status of these vulnerable patients, yet has not been prioritized. Here, we introduce a dual pronged approach to modulate the microenvironment of desmoplastic pancreatic tumors and enable significant dose deescalation of the FDA-approved chemotherapeutic nanoliposomal irinotecan (nal-IRI) without compromising tumor control. We demonstrate that light-based photodynamic priming (PDP) coupled with vitamin D3 receptor (VDR) activation within fibroblasts increases intratumoral nal-IRI accumulation and suppresses protumorigenic CXCL12/CXCR7 crosstalk. Combined photodynamic and biochemical modulation of the tumor microenvironment enables a 75% dose reduction of nal-IRI while maintaining treatment efficacy, resulting in improved tolerability. Modifying the disease landscape to increase the susceptibility of cancer, via preferentially modulating fibroblasts, represents a promising and relatively underexplored strategy to enable dose deescalation. The approach presented here, using a combination of three clinically available therapies with nonoverlapping toxicities, can be rapidly translated with minimal modification to treatment workflow, and challenges the notion that significant improvements in chemotherapy efficacy can only be achieved at the expense of increased toxicity.

Mechanism-inspired drug repurposing that augments standard treatments offers a cost-effective and rapid route toward addressing the burgeoning problem of plateauing of effective therapeutics for drug-resistant micrometastases. We show that the antibiotic minocycline, by its ability to minimize DNA repair via reduced expression of tyrosyl-DNA phosphodiesterase-1 (Tdp1), removes a key process attenuating the efficacy of irinotecan, a frequently used chemotherapeutic against metastatic disease. Moreover, minocycline and irinotecan cooperatively mitigate each other's undesired cytokine inductions of VEGF and IL8, respectively, thereby reinforcing the benefits of each modality. These mechanistic interactions result in synergistic enhancement of irinotecan-induced platinum-resistant epithelial ovarian cancer cell death, reduced micrometastases in the omenta and mesentery by >75%, and an extended overall survival by 50% in a late-stage peritoneal carcinomatosis mouse model. Economic incentives and easy translatability make the repurposing of minocycline as a reinforcer of the topoisomerase class of chemotherapeutics extremely valuable and merits further investigations. Mol Cancer Ther; 17(2); 508–20. ©2017 AACR.

Physical characterizations of nanoliposomal irinotecan (nal-IRI) for in vivo study.

Comparison of minocycline and irinotecan doses used in this study versus in the clinic.

Outline of the hybrid antibody purification process.

Physiologic barriers to drug delivery and selection for drug resistance limit survival outcomes in cancer patients. In this study, we present preclinical evidence that a subtumoricidal photodynamic priming (PDP) strategy can relieve drug delivery barriers in the tumor microenvironment to safely widen the therapeutic window of a nanoformulated cytotoxic drug. In orthotopic xenograft models of pancreatic cancer, combining PDP with nanoliposomal irinotecan (nal-IRI) prevented tumor relapse, reduced metastasis, and increased both progression-free survival and 1-year disease-free survival. PDP enabled these durable improvements by targeting multiple tumor compartments to (i) increase intratumoral drug accumulation by >10-fold, (ii) increase the duration of drug exposure above a critical therapeutic threshold, and (iii) attenuate surges in CD44 and CXCR4 expression, which mediate chemoresistance often observed after multicycle chemotherapy. Overall, our results offer preclinical proof of concept for the effectiveness of PDP to minimize risks of tumor relapse, progression, and drug resistance and to extend patient survival.Significance: A biophysical priming approach overcomes key treatment barriers, significantly reduces metastases, and prolongs survival in orthotopic models of human pancreatic cancer. Cancer Res; 78(2); 558–71. ©2017 AACR.

Sub-tumouricidal PDP does not increase systemic toxicity of chemotherapy. Changes in mouse body weight were monitored longitudinally before and after treatment.

Combination of PDP and a single cycle of na-IRI did not achieve long-term survivial benefit. Kaplan-Meier plot of animal overall survival.

The effect of combination PDP and nal-IRI on tumour growth inhibition is synergistic in orthotopic MIA PaCa-2 mouse model.

Endpoint primary metastatic burdens were comparable mice treated with 'nal-IR' and 'PDT + nal-IRI'.

Relationship between primary tumour weight and distant metastatic burden during disease progression.

The ability of tumor cells to adapt to therapeutic regimens by activating alternative survival and growth pathways remains a major challenge in cancer therapy. Therefore, the most effective treatments will involve interactive strategies that target multiple nonoverlapping pathways while eliciting synergistic outcomes and minimizing systemic toxicities. Nanoliposomal irinotecan is approved by the FDA for gemcitabine-refractory metastatic pancreatic cancer. However, the full potential of irinotecan treatment is hindered by several cancer cell survival mechanisms, including ATP-binding cassette G2 (ABCG2) transporter-mediated irinotecan efflux from cells. Here, we demonstrate that benzoporphyrin derivative-based photodynamic therapy (PDT), a photochemical cytotoxic modality that activates the apoptotic pathway, reduced ABCG2 expression to increase intracellular irinotecan levels in pancreatic cancer. Moreover, we show that PDT inhibited survivin expression. Although PDT potentiated irinotecan treatment, we also demonstrate that irinotecan reduced the tumoral expression of monocarboxylate transporter 4, which was upregulated by PDT. Notably, using orthotopic xenograft models, we demonstrate that combination of single low-dose PDT and a subclinical dose of nanoliposomal irinotecan synergistically inhibited tumor growth by 70% for 3 weeks compared with 25% reduction after either monotherapies. Our findings offer new opportunities for the clinical translation of PDT and irinotecan combination therapy for effective pancreatic cancer treatment. Cancer Res; 76(5); 1066–77. ©2015 AACR.

(i) Supplementary Methods 1. Synthesis of L-BPD and L-IRI via freeze-thaw extrusion method 2. Pharmacokinetics and biodistribution of L-BPD and L-IRI 3. In-vitro quantification of changes in ABCG2 expression using immunofluorescence 4. Ultrasound Imaging 5. Histology and immunofluorescence of tumor samples 6. Quantification of H&E and immunofluorescence biomarkers 7. Determination of Synergism (ii) Supplementary Tables Supplementary Table S1. Comparison of PDT and irinotecan doses used in this study versus in clinic Supplementary Table S2. List of antibodies used for immunofluorescence Supplementary Table S3. The synergistic effect of combination PDT and L-IRI Supplementary Table S4. Physical parameters of L-BPD and L-IRI (iii) Supplementary Figures and Legends Supplementary Fig. S1. Treatment schedule and longitudinal monitoring of PanCa tumors in vivo Supplementary Fig. S2. Sub-cytotoxic PDT leads to decreased levels of ABCG2 and increased intracellular irinotecan in AsPC-1 cells Supplementary Fig. S3. Tumor growth kinetics of MIA PACa-2 and AsPC-1 in vivo Supplementary Fig. S4. Change in mouse body weight after combination treatment

Skin regeneration in chronic wounds is often delayed due to persistent inflammation induced by underlying conditions such as diabetes. This effect is mediated, in part, by macrophages present in the wound, which can be stimulated to adopt either pro- or anti-inflammatory phenotypes depending on the status of the local microenvironment. In this work, the prohealing chemokine stromal cell-derived factor-1 alpha (SDF-1α) is controllably released from a hydrogel-based biomaterial to promote skin tissue regeneration and wound closure. This innovative nanocomposite hydrogel system releases liposomal stromal cell-derived factor-1 alpha (lipoSDF) as a new treatment approach for dorsal full-thickness skin wounds in wild-type and diabetic mice. Using this strategy, the recruitment and polarization of macrophages primarily of the anti-inflammatory phenotype were observed, along with a decreased amount of open wound surface area in diabetic mice after 28 days. This was accompanied by histological observations of increased epidermal stratification and dermal angiogenesis. These findings represent an important step of investigation distinctive in its field for developing immunomodulatory biomaterials that are able to influence macrophage phenotype and promote healing as hydrogel-based wound dressings.

Earnings and revenue are ranked as the two most important performance measures reported to outsiders. However, prior literature primarily focuses on management’s incentives and willingness to manip...

Background Numerous vaccine strategies are being advanced to control SARS-CoV-2, the cause of the COVID-19 pandemic. EuCorVac-19 (ECV19) is a recombinant protein nanoparticle vaccine that displays the SARS-CoV-2 receptor-binding domain (RBD) on immunogenic nanoliposomes. Methods Initial study of a phase 2 randomized, observer-blind, placebo-controlled trial to assess the immunogenicity, safety, and tolerance of ECV19 was carried out between July and October 2021. Two hundred twenty-nine participants were enrolled at 5 hospital sites in South Korea. Healthy adults aged 19–75 without prior known exposure to COVID-19 were vaccinated intramuscularly on day 0 and day 21. Of the participants who received two vaccine doses according to protocol, 100 received high-dose ECV19 (20 μg RBD), 96 received low-dose ECV19 (10 μg RBD), and 27 received placebo. Local and systemic adverse events were monitored. Serum was assessed on days 0, 21, and 42 for immunogenicity analysis by ELISA and neutralizing antibody response by focus reduction neutralization test (FRNT). Results Low-grade injection site tenderness and pain were observed in most participants. Solicited systemic adverse events were less frequent, and mostly involved low-grade fatigue/malaise, myalgia, and headache. No clinical laboratory abnormalities were observed. Adverse events did not increase with the second injection and no serious adverse events were solicited by ECV19. On day 42, Spike IgG geometric mean ELISA titers were 0.8, 211, and 590 Spike binding antibody units (BAU/mL) for placebo, low-dose and high-dose ECV19, respectively (p 50 geometric mean values of 129 and 316, respectively. Boosting responses and dose responses were observed. Antibodies against the RBD correlated with antibodies against the Spike and with virus neutralization. Conclusions ECV19 was generally well-tolerated and induced antibodies in a dose-dependent manner that neutralized SARS-CoV-2. The unique liposome display approach of ECV19, which lacks any immunogenic protein components besides the antigen itself, coupled with the lack of increased adverse events during boosting suggest the vaccine platform may be amenable to multiple boosting regimes in the future. Taken together, these findings motivate further investigation of ECV19 in larger scale clinical testing that is underway. Trial registration The trial was registered at ClinicalTrials.gov as # NCT04783311.

Efforts to overcome cancer multidrug resistance through inhibition of the adenosine triphosphate-binding cassette (ABC) drug transporters ABCB1 and ABCG2 have largely failed in the clinic. The challenges faced during the development of non-toxic modulators suggest a need for a conceptual shift to new strategies for the inhibition of ABC drug transporters. Here, we reveal the fundamental mechanisms by which photodynamic therapy (PDT) can be exploited to manipulate the function and integrity of ABC drug transporters. PDT is a clinically relevant, photochemistry-based tool that involves the light activation of photosensitizers to generate reactive oxygen species. ATPase activity and

Accurate detection of ATP-binding cassette drug transporter ABCB1 expression is imperative for precise identification of drug-resistant tumors. Existing detection methods fail to provide the necessary molecular details regarding the functional state of the transporter. Photoimmunoconjugates are a unique class of antibody–dye conjugates for molecular diagnosis and therapeutic treatment. However, conjugating hydrophobic photosensitizers to hydrophilic antibodies is quite challenging. Here, we devise a photoimmunoconjugate that combines a clinically approved benzoporphyrin derivative (BPD) photosensitizer and the conformational-sensitive UIC2 monoclonal antibody to target functionally active human ABCB1 (i.e., ABCB1 in the inward-open conformation). We show that PEGylation of UIC2 enhances the BPD conjugation efficiency and reduces the amount of non-covalently conjugated BPD molecules by 17%. Size exclusion chromatography effectively separates the different molecular weight species found in the UIC2–BPD sample. The binding of UIC2–BPD to ABCB1 was demonstrated in lipidic nanodiscs and ABCB1-overexpressing triple negative breast cancer (TNBC) cells. UIC2–BPD was found to retain the conformation sensitivity of UIC2, as the addition of ABCB1 modulators increases the antibody reactivity in vitro. Thus, the inherent fluorescence capability of BPD can be used to label ABCB1-overexpressing TNBC cells using UIC2–BPD. Our findings provide insight into conjugation of hydrophobic photosensitizers to conformation-sensitive antibodies to target proteins expressed on the surface of cancer cells.

The recycling of municipal household solid waste (MHSW) is important for the environmental preservation and wellbeing of the society. In recent decades, continuous efforts in research, policy-making and municipal administration have led to improvements toward more sustainable MHSW recycling. However, MHSW recycling remains a major challenge for China. This paper analyzes the current value and potential value of MHSW recycling in order to guide residents to recycle MHSW effectively and to reduce the amount of recycle-worthy materials missing recycling. A multivariate probit model is developed to ascertain the current value and potential value of MHSW recycling. Results from a case study of Shanghai reveal that waste glass has low current value and low potential value, and waste plastics has low current value but high potential value. The results also indicate that the waste metal has high current value and high potential value, whereas waste paper has high current value but low potential value. These findings provide policymakers with useful information and rationale for directing efforts to achieve a better or optimal MHSW recycling practice. Implications: Be a multivariate probit model is developed to calculate the current value and potential value of MHSW recycling in order to guide residents to recycle MHSW and reduce an amount of miss-recycling materials. Our results have shown that waste glass has a low current value and a low potential value, waste plastics have a low current value and a high potential value. Regarding the waste metal, they have a high current value and a high potential value. For waste papers, the result indicates that it has a high current value and a low potential value.

A vaccine targeting multiple stages of thePlasmodium falciparumparasite life cycle is desirable. The sporozoite surface Circumsporozoite Protein (CSP) is the target of leading anti-infectiveP. falciparumpre-erythrocytic vaccines. Pfs230, a sexual-stageP. falciparumsurface protein, is currently in trials as the basis for a transmission-blocking vaccine, which inhibits parasite development in the mosquito vector. Here, recombinant full-length CSP and a Pfs230 fragment (Pfs230D1+) are co-displayed on immunogenic liposomes to induce immunity against both infection and transmission. Liposomes contain cobalt-porphyrin phospholipid (CoPoP), monophosphoryl lipid A and QS-21, and rapidly bind His-tagged CSP and Pfs230D1+ upon admixture to form bivalent particles that maintain reactivity with conformational monoclonal antibodies. Use of multicolor fluorophore-labeled antigens reveals liposome binding upon admixture, stability in serum and enhanced uptake in murine macrophages in vitro. Bivalent liposomes induce humoral and cellular responses against both CSP and Pfs230D1+. Vaccine-induced antibodies reduce parasite numbers in mosquito midguts in a standard membrane feeding assay. Mice immunized with liposome-displayed antigens or that passively receive antibodies from immunized rabbits have reduced parasite liver burden following challenge with transgenic sporozoites expressingP. falciparumCSP.

SUMMARYARID3 transcription factors are expressed in the nervous system, but their functions and mechanisms of action are largely unknown. Here, we generatedin vivoa genome-wide binding map for CFI-1, the soleC. elegansARID3 ortholog. We identified 6,396 protein-coding genes as putative direct targets of CFI-1, most of which (77%) are expressed in post-mitotic neurons and encode terminal differentiation markers (e.g., neurotransmitter receptors, ion channels, neuropeptides). To gain mechanistic insights, we focused on two neuron types. In sensory neurons (IL2 class), CFI-1 exerts a dual role: it acts directly to activate, and indirectly to repress, distinct terminal differentiation genes. In motor neurons, however, CFI-1 acts directly as a repressor, continuously antagonizing three transcriptional activators (UNC-3/Ebf, LIN-39/Hox4-5, MAB-5/Hox6-8). By focusing on a glutamate receptor gene (glr-4/GRIK1), we found CFI-1 exerts its repressive activity through proximal binding to theglr-4locus. Further, the core DNA binding domain of CFI-1 is partially required forglr-4repression in motor neurons. Altogether, this study uncovers cell context-dependent mechanisms through which a single ARID3 protein controls the terminal differentiation of distinct neuron types.

Short major histocompatibility complex (MHC) class I (MHC-I)-restricted peptides contain the minimal biochemical information to induce antigen (Ag)-specific CD8+ cytotoxic T cell responses but are generally ineffective in doing so. To address this, we developed a cobalt-porphyrin (CoPoP) liposome vaccine adjuvant system that induces rapid particleization of conventional, short synthetic MHC-I epitopes, leading to strong cellular immune responses at nanogram dosing. Along with CoPoP (to induce particle formation of peptides), synthetic monophosphoryl lipid A (PHAD) and QS-21 immunostimulatory molecules were included in the liposome bilayer to generate the "CPQ" adjuvant system. In mice, immunization with a short MHC-I-restricted peptide, derived from glycoprotein 70 (gp70), admixed with CPQ safely generated functional, Ag-specific CD8+ T cells, resulting in the rejection of multiple tumor cell lines, with durable immunity. When cobalt was omitted, the otherwise identical peptide and adjuvant components did not result in peptide binding and were incapable of inducing immune responses, demonstrating the importance of stable particle formation. Immunization with the liposomal vaccine was well-tolerated and could control local and metastatic disease in a therapeutic setting. Mechanistic studies showed that particle-based peptides were better taken up by antigen-presenting cells, where they were putatively released within endosomes and phagosomes for display on MHC-I surfaces. On the basis of the potency of the approach, the platform was demonstrated as a tool for in vivo epitope screening of peptide microlibraries comprising a hundred peptides.

The purpose of this study was to evaluate the feasibility and efficacy of HyperArc (HA) for recurrent nasopharyngeal cancer (NPC) by comparing it with the CyberKnife system (CK). Fifteen patients with recurrent nasopharyngeal cancer who were treated using the noncoplanar cone-based robotic CK system were enrolled. CK was delivered with a median dose of 37.5 Gy in 5 fractions. The delivered CK treatment plans were the sources for the corresponding homogeneous HA (HA-H) and inhomogeneous HA (HA-IH) plans. The HA-H plans were generated to meet the corresponding treatment plan criteria for the CK plans. The HA-IH plans were designed to emulate the corresponding inhomogeneous CK isodose distributions. These three SBRT treatment plans were compared with target coverage, sparing of organs at risk (OARs), and dose distribution metrics. The HA-H and HA-IH plans consistently exhibited CTV and PTV coverage levels similar or better to those of the CK plans but significantly reduced the dose to OARs. Using the HA techniques (both HA-H and HA-IH plans), the mean maximal doses to the spinal cord, brainstem, optic nerves, and optic chiasm were reduced by approximately 60%, compared to the CK plans. The high dose spillage, conformity, and homogeneity indices of the HA-H plans were significantly better than those of the CK plans. The HA-IH plans showed faster dose falloff and similar conformity of the HA-H plans and dose heterogeneity of the CK plans. Here we demonstrated the HA treatment plan system for recurrent NPC is feasible, either homogeneous or inhomogeneous delivery. Excellent sparing of OARs and dosimetric distribution and very efficient delivery make HA an attractive SBRT technique for recurrent NPC treatment.

Introduction Breast cancer is a common malignancy worldwide. Smartphones have gradually become indispensable to our modern lives and have already changed lifestyles of human beings. To our best knowledge, no study has investigated the relationship between smartphone use and breast cancer. This case-control study purposely investigated the relationship between smartphone use and breast cancer risk. Materials and methods This was a case-control study comprising 894 healthy controls and 211 patients with breast cancer. All participants were asked to respond to standard questionnaires to collect information on sleep quality, smartphone addiction, and smartphone use. Results Participants with smartphone addiction had a significantly higher 1.43-fold risk of breast cancer. Individuals with the habitual behavior of smartphone use >4.5 minutes before bedtime had a significantly increased 5.27-fold risk of breast cancer compared to those who used a smartphone for ≤4.5 minutes before bedtime. Additionally, a closer distance between the smartphone and the breasts when using the smartphone exhibited a significantly increased 1.59-fold risk. Participants who carried their smartphone near their chest or waist-abdomen area had significantly increased 5.03-fold and 4.06-fold risks of breast cancer, respectively, compared to those who carried the smartphone below the waist. Moreover, there was a synergistic effect of smartphone addiction and smartphone use of >4.5 minutes before bedtime which increased the breast cancer risk. Conclusion Excessive smartphone use significantly increased the risk of breast cancer, particularly for participants with smartphone addiction, a close distance between the breasts and smartphone, and the habit of smartphone use before bedtime.