Estimating time and transportation costs associated with lung cancer screening and diagnostic lung procedures in Taiwan: a cross-sectional survey in a medical centre.

OBJECTIVES: Earlier research has evaluated the non-medical costs after lung cancer diagnosis. This study estimated the time costs and transportation costs associated with low-dose CT (LDCT) screening and diagnostic lung procedures in Taiwan. DESIGN: Cross-sectional study. SETTING: A tertiary referral medical centre. PARTICIPANTS AND INTERVENTIONS: The study participants were individuals aged 50-80 years who underwent LDCT screening or diagnostic lung procedures between 2021 and 2022. Participants completed a questionnaire including items on time spent on receiving care, time spent on travel and its cost and time taken off from work by the participant and any accompanying caregiver. OUTCOME MEASURES: Time costs were valued using the age- and sex-specific average daily wage for employed participants/caregivers. Costs of informal healthcare sector consisted of time cost of the participant, transportation cost and time cost of the caregiver. RESULTS: A total of 209 participants who underwent LDCT screening (n=84) or non-surgical (n=12) or surgical (n=113) diagnostic lung procedures for the first time were enrolled. Considering the purchasing power parity, the average costs of informal healthcare sector were US$126.4 (95% CI 101.6 to 151.2), US$290.7 (95% CI 106.9 to 474.5) and US$749.8 (95% CI 567.3 to 932.4), respectively, for LDCT screening, non-surgical procedures and surgical procedures. CONCLUSIONS: This study estimated time and transportation costs associated with LDCT screening and diagnostic lung procedures, which could be used for future analysis of cost-effectiveness of lung cancer screening in Taiwan.

Inhibition of gut microbial ß-glucuronidase effectively prevents carcinogen-induced microbial dysbiosis and intestinal tumorigenesis.

The bidirectional interaction between carcinogens and gut microbiota that contributes to colorectal cancer is complicated. Reactivation of carcinogen metabolites by microbial ß-glucuronidase (ßG) in the gut potentially plays an important role in colorectal carcinogenesis. We assessed the chemoprotective effects and associated changes in gut microbiota induced by pre-administration of bacterial-specific ßG inhibitor TCH-3511 in carcinogen azoxymethane (AOM)-treated APCMin/+ mice. AOM induced intestinal ßG activity, which was reflected in increases in the incidence, formation, and number of tumors in the intestine. Notably, inhibition of gut microbial ßG by TCH-3511 significantly reduced AOM-induced intestinal ßG activity, decreased the number of polyps in both the small and large intestine to a frequency that was similar in mice without AOM exposure. AOM also led to lower diversity and altered composition in the gut microbiota with a significant increase in mucin-degrading Akkermansia genus. Conversely, mice treated with TCH-3511 and AOM exhibited a more similar gut microbiota structure as mice without AOM administration. Importantly, TCH-3511 treatment significant decreased Akkermansia genus and produced a concomitant increase in short-chain fatty acid butyrate-producing gut commensal microbes Lachnoospiraceae NK4A136 group genus in AOM-treated mice. Taken together, our results reveal a key role of gut microbial ßG in promoting AOM-induced gut microbial dysbiosis and intestinal tumorigenesis, indicating the chemoprotective benefit of gut microbial ßG inhibition against carcinogens via maintaining the gut microbiota balance and preventing cancer-associated gut microbial dysbiosis. Thus, the bacterial-specific ßG inhibitor TCH-3511 is a potential chemoprevention agent for colorectal cancer.

A universal in silico V(D)J recombination strategy for developing humanized monoclonal antibodies.

BACKGROUND: Humanization of mouse monoclonal antibodies (mAbs) is crucial for reducing their immunogenicity in humans. However, humanized mAbs often lose their binding affinities. Therefore, an in silico humanization method that can prevent the loss of the binding affinity of mAbs is needed. METHODS: We developed an in silico V(D)J recombination platform in which we used V(D)J human germline gene sequences to design five humanized candidates of anti-tumor necrosis factor (TNF)-α mAbs (C1-C5) by using different human germline templates. The candidates were subjected to molecular dynamics simulation. In addition, the structural similarities of their complementarity-determining regions (CDRs) to those of original mouse mAbs were estimated to derive the weighted interatomic root mean squared deviation (wRMSDi) value. Subsequently, the correlation of the derived wRMSDi value with the half maximal effective concentration (EC50) and the binding affinity (KD) of the humanized anti-TNF-α candidates was examined. To confirm whether our in silico estimation method can be used for other humanized mAbs, we tested our method using the anti-epidermal growth factor receptor (EGFR) a4.6.1, anti-glypican-3 (GPC3) YP9.1 and anti-α4ß1 integrin HP1/2L mAbs. RESULTS: The R2 value for the correlation between the wRMSDi and log(EC50) of the recombinant Remicade and those of the humanized anti-TNF-α candidates was 0.901, and the R2 value for the correlation between wRMSDi and log(KD) was 0.9921. The results indicated that our in silico V(D)J recombination platform could predict the binding affinity of humanized candidates and successfully identify the high-affinity humanized anti-TNF-α antibody (Ab) C1 with a binding affinity similar to that of the parental chimeric mAb (5.13 × 10-10). For the anti-EGFR a4.6.1, anti-GPC3 YP9.1, and anti-α4ß1 integrin HP1/2L mAbs, the wRMSDi and log(EC50) exhibited strong correlations (R2 = 0.9908, 0.9999, and 0.8907, respectively). CONCLUSIONS: Our in silico V(D)J recombination platform can facilitate the development of humanized mAbs with low immunogenicity and high binding affinities. This platform can directly transform numerous mAbs with therapeutic potential to humanized or even human therapeutic Abs for clinical use.

Selective activation of pro-anti-IL-1ß antibody enhances specificity for autoinflammatory disorder therapy.

Canakinumab is a fully human monoclonal antibody that specifically neutralizes human interleukin (IL)-1ß and has been approved by the US Food and Drug Administration for treating different types of autoinflammatory disorders such as cryopyrin-associated periodic syndrome, tumor necrosis factor receptor-associated periodic syndrome and systemic juvenile idiopathic arthritis. However, long-term systemic neutralization of IL-1ß by Canakinumab may cause severe adverse events such as serious upper respiratory tract infections and inflammation, thereby decreasing the quality of life of patients. Here, we used an IgG1 hinge as an Ab lock to cover the IL-1ß-binding site of Canakinumab by linking with matrix metalloprotease 9 (MMP-9) substrate to generate pro-Canakinumab that can be specifically activated in the inflamed regions in autoinflammatory diseases to enhance the selectivity and safety of treatment. The Ab lock significantly inhibited the IL-1ß-binding by 68-fold compared with Canakinumab, and MMP-9 completely restored the IL-1ß neutralizing ability of pro-Canakinumab within 60 min and blocked IL-1ß-downstream signaling and IL-1ß-regulated genes (i.e., IL-6). It is expected that MMP-9 cleavable and efficient Ab lock will be able to significantly enhance the selective reaction of Canakinumab at the disease site and reduce the on-target toxicities of Canakinumab during systemic circulation, thereby showing potential for development to improve the safety and quality of life of patients with autoinflammatory disorders in the future.

Enhancement of tumor tropism of mPEGylated nanoparticles by anti-mPEG bispecific antibody for ovarian cancer therapy.

Ovarian cancer is highly metastatic, with a high frequency of relapse, and is the most fatal gynecologic malignancy in women worldwide. It is important to elevate the drug susceptibility and cytotoxicity of ovarian cancer cells, thereby eliminating resident cancer cells for more effective therapeutic efficacy. Here, we developed a bispecific antibody (BsAb; mPEG × HER2) that can easily provide HER2+ tumor tropism to mPEGylated liposomal doxorubicin (PLD) and further increase the drug accumulation in cancer cells via receptor-mediated endocytosis, and improve the cytotoxicity and therapeutic efficacy of HER2+ ovarian tumors. The mPEG × HER2 can simultaneously bind to mPEG molecules on the surface of PLD and HER2 antigen on the surface of ovarian cancer cells. Simply mixing the mPEG × HER2 with PLD was able to confer HER2 specificity of PLD to HER2+ ovarian cancer cells and efficiently trigger endocytosis and enhance cytotoxicity by 5.4-fold as compared to non-targeted PLD. mPEG × HER2-modified PLD was able to significantly increase the targeting and accumulation of HER2+ ovarian tumor by 220% as compared with non-targeted PLD. It could also significantly improve the anti-tumor activity of PLD (P < 0.05) with minimal obvious toxicity in a tumor-bearing mouse model. We believe that the mPEG × HER2 can significantly improve the therapeutic efficacy, potentially reduce the relapse freqency and thereby achieve good prognosis in ovarian cancer patients.

Double attack strategy for leukemia using a pre-targeting bispecific antibody (CD20 Ab-mPEG scFv) and actively attracting PEGylated liposomal doxorubicin to enhance anti-tumor activity.

BACKGROUND: Tumor-targeted nanoparticles hold great promise as new tools for therapy of liquid cancers. Furthermore, the therapeutic efficacy of nanoparticles can be improved by enhancing the cancer cellular internalization. METHODS: In this study, we developed a humanized bispecific antibody (BsAbs: CD20 Ab-mPEG scFv) which retains the clinical anti-CD20 whole antibody (Ofatumumab) and is fused with an anti-mPEG single chain antibody (scFv) that can target the systemic liquid tumor cells. This combination achieves the therapeutic function and simultaneously "grabs" Lipo-Dox® (PEGylated liposomal doxorubicin, PLD) to enhance the cellular internalization and anticancer activity of PLD. RESULTS: We successfully constructed the CD20 Ab-mPEG scFv and proved that CD20 Ab-mPEG scFv can target CD20-expressing Raji cells and simultaneously grab PEGylated liposomal DiD increasing the internalization ability up to 60% in 24 h. We further showed that the combination of CD20 Ab-mPEG scFv and PLD successfully led to a ninefold increase in tumor cytotoxicity (LC50: 0.38 nM) compared to the CD20 Ab-DNS scFv and PLD (lC50: 3.45 nM) in vitro. Importantly, a combination of CD20 Ab-mPEG scFv and PLD had greater anti-liquid tumor efficacy (P = 0.0005) in Raji-bearing mice than CD20 Ab-DNS scFv and PLD. CONCLUSION: Our results indicate that this "double-attack" strategy using CD20 Ab-mPEG scFv and PLD can retain the tumor targeting (first attack) and confer PLD tumor-selectivity (second attack) to enhance PLD internalization and improve therapeutic efficacy in liquid tumors.

Developing a Web-Based Comic for Newly Diagnosed Women With Breast Cancer: An Action Research Approach.

BACKGROUND: Personal narratives have been seen as a useful way of communicating about cancer treatment options and providing recovery information. Many printed versions of such material are available, including comics that explore the individual memories of patients who have gone through cancer treatment. These studies have been used to orientate patients, patients' relatives, and physicians. However, only a few Web-based comics have been specifically designed for patients with breast cancer and used as aids to decision making. OBJECTIVE: We aimed to describe the developmental process of creating an animated comic as a Web-based surgery decision-making tool; the comic was aimed at illustrating the feelings, thoughts, and meanings when a patient suffers from breast cancer. This was done by recounting the symptoms, diagnostic process, treatments, and treatment effects of such women from the diagnosis stage onward. METHODS: Using cycles of planning, action, evaluation, and reflection, which involved collaborative work, action research was conducted to develop a Web-based animated comic. The stages of action research consisted of (1) semistructured and in-depth interviews to collect experiences of women with breast cancer; (2) construction of an animated comic by editors, graphics designers, dubbers, and information technology engineers; (3) redrawing of pictures of the comic after gathering feedback from a breast surgeon; and (4) evaluation of the Web-based animated comic using 6 patient focus groups. RESULTS: The comic was produced and showcased on the website "The Network of Making-decision Aids for Breast Cancer Surgery"; the comic was accompanied by soft music and audio explanations. The comic functions as a personal statement that describes experiencing breast cancer. The animated comic consists of 8 chapters, based on the 8 themes deducted from the findings obtained during the analysis of relevant interviews. The 8 chapters include (1) the appearance of a lump; (2) confirmation by medical diagnosis; (3) the uncertainty of waiting (4) fear of life-threatening disease; (5) choosing life over despair; (6) being brave and deciding to undergo treatment; (7) choosing the type of surgery; and (8) being reborn. CONCLUSIONS: Using action research, this study illustrated that the comic that sheds light on issues of feelings, emotions, and thoughts that are present when a woman is diagnosed with breast cancer and provides a communication medium to explain the steps in the process. Meanwhile, it implies that hope will be able to overcome the challenges that will be faced. Within the Web-based decision aid for patients with breast cancer, the animated comic acts as an information resource and is aimed at patients' understanding of impacts of emotions arising when suffering from breast cancer. It is potentially applicable as a therapeutic tool that facilitates self-reflection and self-healing among newly diagnosed patients with breast cancer.

Screening to Identify Commonly Used Chinese Herbs That Affect ERBB2 and ESR1 Gene Expression Using the Human Breast Cancer MCF-7 Cell Line.

Aim. Our aim the was to screen the commonly used Chinese herbs in order to detect changes in ERBB2 and ESR1 gene expression using MCF-7 cells. Methods. Using the MCF-7 human breast cancer cell line, cell cytotoxicity and proliferation were evaluated by MTT and trypan blue exclusion assays, respectively. A luciferase reporter assay was established by transient transfecting MCF-7 cells with plasmids containing either the ERBB2 or the ESR1 promoter region linked to the luciferase gene. Chinese herbal extracts were used to treat the cells at 24 h after transfection, followed by measurement of their luciferase activity. The screening results were verified by Western blotting to measure HER2 and ER α protein expression. Results. At concentrations that induced little cytotoxicity, thirteen single herbal extracts and five compound recipes were found to increase either ERBB2 or ESR1 luciferase activity. By Western blotting, Si-Wu-Tang, Kuan-Shin-Yin, and Suan-Tsao-Ren-Tang were found to increase either HER2 or ER α protein expression. In addition, Ligusticum chuanxiong was shown to have a great effect on ERBB2 gene expression and synergistically with estrogen to stimulate MCF-7 cell growth. Conclusion. Our results provide important information that should affect clinical treatment strategies among breast cancer patients who are receiving hormonal or targeted therapies.

In Vitro and In Vivo Effects of Jia-Wei-Xiao-Yao-San in Human Breast Cancer MCF-7 Cells Treated With Tamoxifen.

INTRODUCTION: There is epidemiological evidence that Jia-Wei-Xiao-Yao-San (JWXYS) is the most common Chinese medicine decoction coprescribed with tamoxifen (Tam) when breast cancer is treated by hormonal therapy. However, whether there is interaction between JWXYS and Tam remains to be clarified. The aim of this study was to investigate the in vitro and in vivo effects of JWXYS on human breast cancer MCF-7 cells treated with Tam. METHODS: In vitro cultured MCF-7 cells were cotreated with JWXYS and Tam. This was followed by MTT ([4,5-cimethylthiazol-2-yl]- 2,5-diphenyl tetrazolium bromide) assays and cell cycle analysis to assess cell proliferation; Western blot analysis was used to analyze the expression of various proteins involved in growth-related signal pathways. In addition, immunohistochemistry was used to detect autophagy among the cancer cells. In vivo analysis used female athymic nude mice implanted with MCF-7 cells; these mice were randomly assigned to 6 groups. All mice were killed humanely after 21 days of treatment; body weight, tumor volume, and tumor weight were then measured. RESULTS: JWXYS was not cytotoxic to MCF-7 cells, based on the fact that there were no statistically significant changes between the JWXYS + Tam groups and the Tam-alone group in cell numbers, cell cycle progression, and cell proliferation signals, the latter including the expression levels of AKT, ERK, P38, p27(Kip1), and light chain (LC3)-I, II. Furthermore, using the MCF-7 xenograft mouse model, there were no significant changes between the JWXYS (1.3-3.9 gm/kg) + Tam groups and the Tam-alone group in terms of tumor weight and the protein expression levels of AKT, ERK, P38, and p27 (Kip1). However, there was a significant decrease in LC3-II protein expression with the low-dose JWXYS + Tam group but not with the middle- or high-dose JWXYS + Tam groups compared with the Tam-alone group. CONCLUSION: Based on in vitro studies and in vivo functional studies, there is no obvious interaction between JWXYS and Tam. However, the presence of interference at the molecular level in relation to LC3-II expression provides important information and may affect treatment strategies when physicians have patients with estrogen receptor-α(+) or progesterone receptor(+) breast cancers.