Safety and Effectiveness of Trastuzumab Biosimilar SB3 in Korean Patients, a Post-Marketing Surveillance Study.

INTRODUCTION: SB3 is a trastuzumab biosimilar approved in Australia, Brazil, Canada, the European Union, the Republic of Korea, Switzerland, and the United States. This real-world study evaluated safety and effectiveness of SB3 as part of the Korean post approval safety management system. METHODS: This post-marketing surveillance in Korea included patients in line with approved indications, i.e. patients with early or metastatic breast cancer or metastatic gastric cancer. Safety outcomes were adverse events and adverse drug reactions. Effectiveness outcomes were tumor response and event-free survival. RESULTS: 424 patients were evaluated: 366 patients (86%) with early breast cancer, 53 patients (13%) with metastatic breast cancer, and 5 patients (1%) with metastatic gastric cancer. Among patients with breast cancer, adverse events (mostly mild) and adverse drug reactions were reported by 158 (37.7%) and 57 (13.6%) patients, respectively. Most patients with an AE (141, 75.9%) had no change in treatment schedule. Treatment was temporarily suspended in 14 (8.2%) patients with an AE and completely discontinued in 7 (3.7%). Among patients with early and metastatic breast cancer who were evaluated for efficacy, objective response rates were 82.7% and 38.3%, respectively. Pathological complete response was 64.6% in patients with early breast cancer. DISCUSSION/CONCLUSION: Safety and efficacy of SB3 demonstrated in this real-world study were comparable with previous studies of reference trastuzumab.

Pegteograstim prophylaxis for chemotherapy-induced neutropenia and febrile neutropenia: a prospective, observational, postmarketing surveillance study in Korea.

PURPOSE: This observational study aimed to evaluate the safety and efficacy of pegteograstim prophylaxis in patients with lymphoma and solid malignancies. METHODS: This study was conducted at 18 sites in Korea between November 2015 and August 2018. RESULTS: In total, 611 patients (female, 61.2%) with a median age of 58 (range, 18-88) years were included. Most patients had lymphomas (n = 371, 60.7%) and breast cancer (n = 230, 37.6%) and were administered R-CHOP21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone per 21 days) (n = 284, 46.5%) and AC (doxorubicin and cyclophosphamide) (n = 177, 29.0%). The total pegteograstim dose in the 611 patients was 14,970 mg (2495 doses), with each patient receiving an average daily dose of 6.0 mg. Neutropenia grade 4 occurred in 97 patients (15.9%), and febrile neutropenia (FN) occurred in 31 patients (5.1%). Among the 611 patients, 267 patients (43.7%) developed 882 adverse events (AEs), and 11 patients (1.8%) experienced 18 adverse drug reactions (ADRs). There were 62 patients (10.2%) who experienced 81 cases of serious adverse events (SAEs), with FN and pneumonia being the most frequent at 14 and 13 episodes, respectively, in 13 patients (2.1%). Meanwhile, 1 patient (0.2%) developed 2 episodes of serious ADRs (grade 1 and grade 2 hypotension). No safety concerns in the elderly and patients with liver and/or renal disease were identified. CONCLUSION: The prophylactic use of pegteograstim might have good overall safety and efficacy in patients with lymphomas and solid malignancies in routine clinical practice, even in those who are elderly and have liver and renal diseases.

Childbirth in young Korean women with previously treated breast cancer: The SMARTSHIP study.

PURPOSE: Alongside the modern trend of delaying childbirth, the high incidence of breast cancer among young women is causing significant pregnancy-related problems in Korea. We estimated the incidence of childbirth for young Korean breast cancer survivors compared with women who did not have breast cancer using a nationally representative dataset. METHODS: Using a database from the National Health Insurance Service in South Korea, we analyzed 109,680 women who were between 20 and 40 years old between 2007 and 2013. They were prospectively followed, and childbirth events were recorded until December 31, 2015. We compared childbirth rates and characteristics between the breast cancer survivors and the noncancer controls. RESULTS: Compared to 10,164 childbirths among 91,400 women without breast cancer (incidence rate: 22.3/1000), 855 childbirths occurred among 18,280 breast cancer survivors (incidence rate: 9.4/1000); the adjusted hazard ratio (HR) for childbirth was 0.41 (95% CI 0.38-0.44). Chemotherapy, endocrine therapy, and target therapy were associated with the decreasing childbirths among survivors, with corresponding adjusted HRs of 0.61 (0.53-0.70), 0.44 (0.38-0.51), and 0.62 (0.45-0.86), respectively. Breast cancer survivors had a lower probability of full-term delivery and a higher frequency of preterm labor than controls, with corresponding adjusted ORs of 0.78 (0.68-0.90) and 1.33 (1.06-1.65), respectively. CONCLUSIONS: We showed that a history of breast cancer has a negative effect on childbirth among young premenopausal women in Korea. Breast cancer survivors should be aware that they have a higher risk for preterm labor and are less likely to have a full-term delivery than women without a history of breast cancer.

Factors associated with physical activity of breast cancer patients participating in exercise intervention.

PURPOSE: Physical activity has been known to improve survival and quality of life of patients with breast cancer. To find factors associated with physical activity, we analyzed the dataset of the multicenter controlled trial of exercise intervention. METHODS: Three hundred fifty-six participants were assigned to two groups: "Smart After-Care" (smartphone application and pedometer were provided) or exercise education only. Physical activity was measured by International Physical Activity Questionnaire-Short Form (IPAQ-SF) at baseline and after 12 weeks. The association between physical activity and other clinical characteristics was analyzed. RESULTS: At baseline, physical activity amount was 2315.5 ± 3513.2 MET min/week: 33.0% inactive, 49.6% minimally active, and 17.4% health-enhancing physical activity (HEPA) active. Factors associated with HEPA include cancer stage and grip strength. A significantly lower proportion was HEPA active among those with advanced stage than among those with stage 0. After intervention, physical activity was increased to 3466.2 ± 4712.5 MET min/week: 15.3% inactive, 50.4% minimally active, and 34.2% HEPA active. Physical activity was increased in 63.4% of the participants. Factors associated with physical activity increase include cancer stage, diarrhea, and type of exercise intervention. Participants with advanced stage have a 3.3 times higher chance of increasing physical activity. Participants who received "Smart After-Care" have a 64% higher chance of increasing physical activity. CONCLUSION: Before the intervention, participants with advanced stage are less likely to be HEPA active. Exercise intervention was more beneficial for those with advanced stage or physical symptoms. "Smart After-Care" was more effective than education only in increasing physical activity.

Effects of exercise intervention in breast cancer patients: is mobile health (mHealth) with pedometer more effective than conventional program using brochure?

PURPOSE: To investigate and compare the effects of mobile health (mHealth) and pedometer with conventional exercise program using a brochure on physical function and quality of life (QOL). METHODS: The study was a prospective, quasi-randomized multicenter trial where 356 patients whose cancer treatment had been terminated were enrolled. All patients were instructed to perform a 12-week regimen of aerobic and resistance exercise. The mHealth group received a pedometer and a newly developed smartphone application to provide information and monitor the prescribed exercises. Those in the conventional group received an exercise brochure. Physical measurements were conducted at baseline, 6 weeks, and 12 weeks. Self-reported physical activity (international physical activity questionnaire-short form), general QOL (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30), and breast cancer-specific QOL (Quality of Life Questionnaire Breast Cancer Module 23) were assessed at baseline and 12 weeks. A user satisfaction survey was assessed in the mHealth group. RESULTS: Basic characteristics were not different between the two groups except for age and previous radiotherapy. Physical function, physical activity, and QOL scores were significantly improved regardless of the intervention method, and changes were not significantly different between the two groups. Additionally, the mean Likert scale response for overall satisfaction with the service was 4.27/5 in the mHealth group. CONCLUSIONS: Overall, both the mHealth coupled with pedometer and conventional exercise education using a brochure were effective in improving physical function, physical activity, and QOL. This study provides a basis of mHealth research in breast cancer patients for progressing further developing field, although superiority of the mHealth over the conventional program was not definitely evident.

Effect of selenium supplementation for protection of salivary glands from iodine-131 radiation damage in patients with differentiated thyroid cancer.

OBJECTIVE: In the current study, we examined whether selenium supplementation during iodine-131 (131I) treatment had a radio-protective effect on salivary glands. SUBJECTS AND METHODS: Sixteen patients with differentiated thyroid cancer were prospectively enrolled in the study. Patients after total thyroidectomy, before 131I treatment, were divided into two groups; 8 patients in the selenium group and 8 patients in the control group. Patients in the selenium group received 300νg of selenium orally for 10 days, from 3 days before to 6 days after 131I treatment. The control group received a placebo over the same period. To assess salivary gland function, salivary gland scintigraphy was performed before and 6 months after 131I treatment. Serum amylase and whole blood selenium levels were measured before and 2 days and 6 months after 131I treatment. Using salivary gland scintigraphy, maximum uptake ratio (MUR), maximum secretion percentage (MSP), and ejection fraction (EF) of each salivary gland were calculated. RESULTS: Baseline clinical characteristics, baseline amylase and selenium levels, and parameters of baseline salivary gland scintigraphy were not significantly different between selenium and control groups (P>0.05). On a blood test performed 2 days after 131I treatment, the selenium group showed a significantly higher whole blood selenium level (P=0.008) and significantly lower serum amylase level (P=0.009) than the control group. On follow-up salivary gland scintigraphy, the control group showed significantly decreased, MUR of the bilateral parotid and left submandibular glands, MSP of the bilateral parotid and submandibular glands, and EF of the left submandibular glands (P<0.05), while the selenium group only had a significant decrease in MSP of the right submandibular gland and EF of the left submandibular gland (P<0.05). CONCLUSION: Selenium supplementation during 131I treatment was effective to reduce salivary glands damage by 131I radiation in patients with differentiated thyroid cancer.

Chuna Manual Therapy or Electroacupuncture with Pregabalin for Chemotherapy-Induced Peripheral Neuropathy: A Randomized Controlled Pilot Study.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common side effects of chemotherapy, and effective treatments for CIPN are still lacking. For this reason, there is a growing interest in complementary and alternative medicine as a potential source of nonsurgical treatments for CIPN symptoms alongside pregabalin. One such option being explored is Chuna manual therapy (CMT), a traditional Korean manual therapy. Methods: This study compares the effectiveness and safety of using only pregabalin (PG) as a conventional method of treating breast and colorectal cancer patients with CIPN symptoms with a combination of both PG and electroacupuncture (EA) or CMT, while also assessing the feasibility of future large-scale clinical studies. Due to the COVID-19 pandemic, only 74 CIPN patients were recruited to this study. Twenty-five were assigned to the PG group, 26 to the PG + EA group, and 22 to the PG + CMT group for a five-week treatment and a four-week follow-up study. Results: For the primary outcome, we evaluated the mean differences in Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) compared to the baseline at week 5 (visit 4). Although we found that the PG + CMT group showed the biggest difference (-16.64 [95% CI: -25.16, -8.11]) compared to the PG group (-8.60 [95% CI: -14.93, -2.27]) and the PG + EA group (-6.73 [95% CI: -12.34, -1.13]), this finding lacked statistical significance (p = 0.2075). In terms of safety, two patients in the PG + CMT group reported side effects: one bruise and one headache. Conclusions: The low attrition and high adherence rates of all the groups, and the similar rates of side effects among them, support the feasibility of larger-scale follow-up studies.

Prediction of a Multi-Gene Assay (Oncotype DX and Mammaprint) Recurrence Risk Group Using Machine Learning in Estrogen Receptor-Positive, HER2-Negative Breast Cancer-The BRAIN Study.

This study aimed to develop a machine learning-based prediction model for predicting multi-gene assay (MGA) risk categories. Patients with estrogen receptor-positive (ER+)/HER2- breast cancer who had undergone Oncotype DX (ODX) or MammaPrint (MMP) were used to develop the prediction model. The development cohort consisted of a total of 2565 patients including 2039 patients tested with ODX and 526 patients tested with MMP. The MMP risk prediction model utilized a single XGBoost model, and the ODX risk prediction model utilized combined LightGBM, CatBoost, and XGBoost models through soft voting. Additionally, the ensemble (MMP + ODX) model combining MMP and ODX utilized CatBoost and XGBoost through soft voting. Ten random samples, corresponding to 10% of the modeling dataset, were extracted, and cross-validation was performed to evaluate the accuracy on each validation set. The accuracy of our predictive models was 84.8% for MMP, 87.9% for ODX, and 86.8% for the ensemble model. In the ensemble cohort, the sensitivity, specificity, and precision for predicting the low-risk category were 0.91, 0.66, and 0.92, respectively. The prediction accuracy exceeded 90% in several subgroups, with the highest prediction accuracy of 95.7% in the subgroup that met Ki-67 <20 and HG 1~2 and premenopausal status. Our machine learning-based predictive model has the potential to complement existing MGAs in ER+/HER2- breast cancer.

Loss of LPAR6 and CAB39L dysregulates the basal-to-luminal urothelial differentiation program, contributing to bladder carcinogenesis.

We describe a strategy that combines histologic and molecular mapping that permits interrogation of the chronology of changes associated with cancer development on a whole-organ scale. Using this approach, we present the sequence of alterations around RB1 in the development of bladder cancer. We show that RB1 is not involved in initial expansion of the preneoplastic clone. Instead, we found a set of contiguous genes that we term "forerunner" genes whose silencing is associated with the development of plaque-like field effects initiating carcinogenesis. Specifically, we identified five candidate forerunner genes (ITM2B, LPAR6, MLNR, CAB39L, and ARL11) mapping near RB1. Two of these genes, LPAR6 and CAB39L, are preferentially downregulated in the luminal and basal subtypes of bladder cancer, respectively. Their loss of function dysregulates urothelial differentiation, sensitizing the urothelium to N-butyl-N-(4-hydroxybutyl)nitrosamine-induced cancers, which recapitulate the luminal and basal subtypes of human bladder cancer.

An observational, prospective, open label, multicenter study to evaluate the safety and effectiveness of pegfilgrastim as secondary prophylaxis to decrease the incidence of febrile neutropenia in Korean female patients with breast cancer.

PURPOSE: Pegfilgrastim is a widely used long-acting granulocyte colony-stimulating factor (G-CSF) that prevents febrile neutropenia (FN) in patients with breast cancer receiving chemotherapy. This study aimed to evaluate the incidence of chemotherapy-related FN events and other adverse events (AEs) during chemotherapy in Korean patients with breast cancer treated with pegfilgrastim as secondary prophylactic support. MATERIALS AND METHODS: This was a multicenter, open-label, prospective, observational study. A total of 1255 patients were enrolled from 43 institutions. The incidence of FN was evaluated as the primary endpoint. The secondary endpoints included (1) incidence of bone pain, (2) proportion of patients with a relative dose intensity (RDI) of ≥85%, and (3) proportion of patients with AE. RESULTS: Pegfilgrastim administration reduced FN by 11.8-1.6%. The highest incidence of bone pain was observed at the time point of the 1st day after the administration and mild bone pain was the most common of all bone pain severity. The mean RDI was 98.5 ± 7.3%, and the proportion of the patients with and RDI≥85% was 96.9% (1169/1233). AEs were reported in 52.6% of the patients, and serious drug reactions occurred in only 0.7%. CONCLUSION: The use of pegfilgrastim as secondary prophylaxis was effective and safe for preventing FN in patients with breast cancer who were treated with chemotherapy.

Prognosis of pregnancy after breast cancer diagnosis according to the type of treatment: A population-based study in Korea by the SMARTSHIP group.

BACKGROUNDS: In this study, we evaluated the incidence and outcomes of pregnancy after breast cancer was diagnosed in women of childbearing age. Additionally, we evaluated the prognosis of patients who became pregnant after breast cancer, according to the treatment. METHODS: This was a retrospective cohort study of women aged 20-45 years who were surgically treated for breast cancer between 2004 and 2014 using the Korean National Health Insurance database. The patients were classified into six groups according to the treatment. Propensity score matching was applied to the cohort to analyze the risk of breast cancer-associated mortality after pregnancy and childbirth. RESULTS: Of the 45,765 patients who had been newly diagnosed with breast cancer, 1826 (4%) became pregnant after breast cancer diagnosis. Among the pregnant group, the HR of the risk of death was 0.15 (95% CI, 0.06 to 0.36) for patients who became pregnant ≥49 months after the diagnosis. In patients who received endocrine therapy and chemotherapy, the pregnant group had better prognosis than the non-pregnant group. There was no significant difference between the pregnant group and the non-pregnant group in patients who received chemotherapy and trastuzumab with or without endocrine therapy. CONCLUSION: The risk of death was low in women who became pregnant ≥49 months after the diagnosis of breast cancer. The prognosis of pregnant women was non-inferior to that of non-pregnant women, even in women who received trastuzumab. These findings provide reassurance to patients with HER2-positive cancer who are considering future pregnancy.

Physicians' Awareness of the Breast Cancer Survivors' Unmet Needs in Korea.

PURPOSE: Physicians' awareness of their cancer patients' unmet needs is an essential element for providing effective treatment. This study investigated the accuracy of physicians' awareness of breast cancer survivors' unmet needs in Korea. METHODS: A cross-sectional interview survey was performed among 106 physicians and 320 Korean breast cancer survivors. The Comprehensive Needs Assessment Tool was administered to physicians and cancer survivors after obtaining their written informed consent to participate. Data were analyzed using t-test, analysis of variance, and multiple regression analysis. RESULTS: The level of unmet needs was highest in the hospital service domain (mean ± standard deviation: 2.19 ± 0.82), and the top-ranked unmet need item was "wished my doctor to be easy, specific, and honest in his/her explanation" (2.44 ± 0.93). Higher unmet needs were correlated with the presence of a genetic counseling clinic. They were not associated with age, sex, marital status, religion, department, working period, type of institution, number of staff, and number of operations. In multiple regression analysis, the presence of a genetic counseling clinic was associated with a higher level of recognition for psychological problems, social support, hospital service, and information and education needs. Physicians overestimated breast cancer survivors' unmet needs in all domains, compared to their self-reported unmet needs. The discordance in the perceived unmet needs was highest in the 'family/personal relationship problems' domain. CONCLUSIONS: Physicians who treat Korean breast cancer survivors rated the level of unmet needs of breast cancer survivors as highest in the hospital service domain. The presence of a genetic counseling clinic in physicians' institutions was associated with a higher perception of survivors' unmet needs. Physicians overestimated the level of unmet needs in Korean breast cancer survivors. Efforts to reduce these discordances are needed to implement optimal survivorship care.

Clinical study on concurrent use of electro-acupuncture or Chuna manual therapy with pregabalin for chemotherapy-induced peripheral neuropathy: safety and effectiveness (open-labeled, parallel, randomized controlled trial, assessor-blinded): A study protocol.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the major side effects of chemotherapy. Its main symptoms are pain, paresthesia, and numbness. However, the mechanisms underlying the development of CIPN remain unclear and standard treatments have not been established. Recently, there has been a growing interest in various approaches to overcome the limitations of the existing treatments. This study aims to evaluate the efficacy and safety of the concurrent use of two complementary and alternative therapies: electroacupuncture (EA) and Chuna manual therapy (CMT), with pregabalin, which is the conventional pharmacotherapy for neuropathic pain. METHODS/DESIGN: This is an open-label, parallel, assessor-blinded randomized controlled trial, which includes 90 patients with colorectal and breast cancer, who developed CIPN. After a 2-week preparation period, the patients are divided into three groups (pregabalin administration group, pregabalin + EA treatment group, and pregabalin + CMT treatment group), treated for approximately 5 weeks and followed-up 4 weeks after treatment. The primary outcome is assessed using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity subscale score (version 4.0) and the secondary outcome is measured using the Quality of Life Questionnaire-CIPN 20-Item Scale (version 3.0) and the quality of life questionnaire (version 3.0) developed by the European Organisation for Research and Treatment of Cancer. Moreover, exploratory efficacy and safety evaluations will be conducted based on the chemotherapy-completion rate and nerve conduction studies.

The risk of thyroid cancer and obesity: A nationwide population-based study using the Korea National Health Insurance Corporation cohort database.

INTRODUCTION: In recent years, the incidence of thyroid cancer and obesity has increased rapidly worldwide. Many studies have been conducted on the relationship between thyroid cancer and obesity; however, the potential mechanisms are not well understood, and few studies have been performed in Asia. This study aimed to identify the relationship between the risk of thyroid cancer and obesity in the Korean population based on a large cohort of data. METHOD: We analyzed clinical data from a total of 351,402 individuals (males: 181,709, females: 169,693) aged over 20 years who received medical examinations arranged by the national insurance program from 2003 to 2008. Newly diagnosed thyroid cancer was identified using insurance claims data. The median follow-up duration was 7.01 years. RESULTS: The mean body mass index (BMI) of the subjects was 23.6 ±â€¯3.2 kg/m2 (males, 24 ±â€¯3; females, 23.1 ±â€¯3.3). A total of 3308 individuals (0.94%) developed thyroid cancer during the study period. The risk of thyroid cancer was higher with increasing BMI in both men and women. Hazard ratios (95% confidence interval) for obese (25-29.9 kg/m2) and extremely obese (≥30 kg/m2) groups were 1.23 (1.13-1.34) and 1.26 (1.02-1.50), respectively, compared to the normal group (18.5-22.9 kg/m2). In particular, the association between the risk of thyroid cancer and BMI was more remarkable in the male group than female group. CONCLUSION: Our findings show that higher BMI is positively associated with the risk of thyroid cancer. Furthermore, this study supports the positive association between obesity and the increased incidence of thyroid cancer.

The Practice Patterns and Perceptions of Korean Surgeons Regarding Margin Status after Breast-Conserving Surgery.

Two consecutive surveys for breast surgeons in Korea were conducted to comprehend the practice patterns and perceptions on margin status after breast-conserving surgery. The surveys were conducted online in 2014 (initial) and 2016 (follow-up). A total of 126 and 88 responses were obtained in the initial and follow-up survey, respectively. More than 80% of the respondents replied to routinely apply frozen section biopsy for intraoperative margin assessment in both surveys. Re-excision recommendations of the margin for invasive cancer significantly changed from a close margin to a positive margin over time (p=0.033). Most of the respondents (73.8%) defined a negative margin as "no ink on tumor" in invasive cancer, whereas more diverse responses were observed in ductal carcinoma in situ cases. The influence of guideline establishment for negative margins has been identified. A high uptake rate of intraoperative frozen section biopsy was noted and routine use needs reconsideration.

Multiplex bioimaging of piRNA molecular pathway-regulated theragnostic effects in a single breast cancer cell using a piRNA molecular beacon.

Recently, PIWI-interacting small non-coding RNAs (piRNAs) have emerged as novel cancer biomarkers candidate because of their high expression level in various cancer types and role in the control of tumor suppressor genes. In this study, a novel breast cancer theragnostics probe based on a single system targeting the piRNA-36026 (piR-36026) molecular pathway was developed using a piR-36026 molecular beacon (MB). The piR-36026 MB successfully visualized endogenous piR-36026 biogenesis, which is highly expressed in MCF7 cells (a human breast cancer cell line), and simultaneously inhibited piR-36026-mediated cancer progression in vitro and in vivo. We discovered two tumor suppressor proteins, SERPINA1 and LRAT, that were directly regulated as endogenous piR-36026 target genes in MCF7 cells. Furthermore, multiplex bioimaging of a single MCF7 cell following treatment with piR-36026 MB clearly visualized the direct molecular interaction of piRNA-36026 with SERPINA1 or LRAT and subsequent molecular therapeutic responses including caspase-3 and PI in the nucleus.

In-frame cDNA library combined with protein complementation assay identifies ARL11-binding partners.

The cDNA expression libraries that produce correct proteins are essential in facilitating the identification of protein-protein interactions. The 5'-untranslated regions (UTRs) that are present in the majority of mammalian and non-mammalian genes are predicted to alter the expression of correct proteins from cDNA libraries. We developed a novel cDNA expression library from which 5'-UTRs were removed using a mixture of polymerase chain reaction primers that complement the Kozak sequences we refer to as an "in-frame cDNA library." We used this library with the protein complementation assay to identify two novel binding partners for ras-related ADP-ribosylation factor-like 11 (ARL11), cellular retinoic acid binding protein 2 (CRABP2), and phosphoglycerate mutase 1 (PGAM1). Thus, the in-frame cDNA library without 5'-UTRs we describe here increases the chance of correctly identifying protein interactions and will have wide applications in both mammalian and non-mammalian detection systems.