Preclinical radiolabeling, in vivo biodistribution and positron emission tomography of a novel pyrrolobenzodiazepine (PBD)-based antibody drug conjugate targeting ASCT2.

INTRODUCTION: Anti-ASCT2 antibody drug conjugate (ADC) MEDI7247 has been under development as a potential anti-cancer therapy for patients with selected relapsed/refractory hematological malignancies and advanced solid tumors by MedImmune. Although promising efficacy was observed in the clinic, pharmacokinetic (PK) analyses observed low exposure of MEDI7247 in phase I hematological patients. To investigate the biodistribution properties of MEDI7247, MEDI7247 and control antibodies were radiolabeled with zirconium-89 and in vitro and in vivo properties characterized. METHODS: MEDI7247 (human anti-ASCT2 antibody conjugated with pyrrolobenzodiazepine (PBD)) and MEDI7519 (MEDI7247 without PBD drug conjugate) and an isotype control antibody drug conjugate construct were conjugated with p-isothiocyanatobenzyl-deferoxamine (Df) and radiolabeled with zirconium-89. In vitro studies included determining the radiochemical purity, protein integrity, immunoreactivity (Lindmo analysis), apparent antigen binding affinity for ASCT2-positive cells by Scatchard analysis and serum stability of the radiolabeled immunoconjugates. In vivo studies included biodistribution and PET/MRI imaging studies of the radiolabeled immunoconjugates in an ASCT2-positive tumor model, HT-29 colorectal carcinoma xenografts. RESULTS: Conditions for the Df-conjugation and radiolabeling of antibody constructs were determined to produce active radioimmunoconjugates. In vivo biodistribution and whole body PET/MRI imaging studies of [89Zr]Zr-Df-MEDI7519 and [89Zr]Zr-Df-MEDI7247 radioimmunoconjugates in HT-29 colon carcinoma xenografts in BALB/c nude mice demonstrated specific tumor localization. However, more rapid blood clearance and non-specific localization in liver was observed for [89Zr]Zr-Df-MEDI7247 and [89Zr]Zr-Df-MEDI7519 compared to isotype control ADC. Except for liver and bone, other normal tissues demonstrated clearance reflecting the blood clearance for all three constructs and no other abnormal tissue uptake. CONCLUSIONS AND ADVANCES IN KNOWLEDGE: Preclinical biodistribution analyses of [89Zr]Zr-Df-MEDI7247 and [89Zr]Zr-Df-MEDI7519 showed the biodistribution pattern of anti-ASCT2 ADC MEDI7247 was similar to parental MEDI7519, and both antibodies showed specific tumor uptake compared to an isotype control ADC. This study highlights an important role nuclear medicine imaging techniques can play in early preclinical assessment of drug specificity as part of the drug development pipeline.

Clinical Trials in the Brain Tumour Population: Challenges and Strategies for the Future.

PURPOSE OF REVIEW: This review identifies challenges and barriers to successful development of drugs in neuro-oncology trials at the preclinical, clinical and translational stages that we believe has contributed to poor outcomes for patients over the last 30 years. RECENT FINDINGS: Several key strategies have been proposed by leading groups to address these and improve patient outcomes. Better preclinical testing using more sophisticated and clinically relevant models is needed. A greater focus on assessing blood-brain barrier penetrance and targeting key biological processes such as tumour heterogeneity and immune response is vital. Adopting innovative trial designs permitting faster results and addressing key issues (including molecular heterogeneity and combinatorial approaches) is highly desirable. A stronger translational focus is also clearly needed. Implementation of these strategies is already starting to occur. Maintaining and increasing these novel approaches will require coordinated efforts between clinicians, scientists, industry and funding/regulator bodies.

Autophagy and Inflammation in Fish / 中国生物化学与分子生物学报

Autophagy and inflammation are the important physiological reactions, especially in innate immunity. Autophagy, as a conservative metabolic process, can degrade its own disorder components through lysosomes to maintain cell homeostasis. Autophagy plays a pivotal role in degrading damaged organelles, resisting pathogenic infection and regulating inflammatory response. In the past decades, the study of autophagy in yeast and mammals has greatly increased our understanding for autophagy and its relationship with the diseases. In human, the regulation on autophagy levels can be used to prevent or treat neurodegenerative diseases, inflammatory diseases, tumors and various pathogenic microbial infections. However, in fish, the researches on autophagy and application are limited. Inflammation is a highly complex biological process, which is a natural defense response under the stimulation of ultraviolet, pathogen infection, oxidative stress and mechanical damage. Fish, as a lower vertebrate, has an incomplete acquired immune system. Innate immunity plays an important role in defensing against pathogen infection. Compared with higher vertebrate animals, although the researches on autophagy in fish cells were carried out lately, the great progress has been made in recent years on autophagy phenomenon, expression regulation of autophagy-related genes, and mechanism caused by pathogenic infection. As an important part of innate immunity, autophagy is involved in a variety of fish pathogenic infections, and fish diseases are usually accompanied by inflammatory reaction. In this review, we summarized the update findings in recent references on the autophagy and inflammatory response caused by pathogenic infection in fish, and the correlation between them, in order to deeply understand the correlation relationship between autophagy and inflammatory response in fish. This review could provide the guidance for understanding the immune mechanism of fish, and supply the foundation for developing new strategy to prevent and control fish disease.

Changes of ganglion cell complex and retinal nerve fiber layer thickness in different degrees of myopia / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To compare the changes in retinal nerve fiber layer(RNFL)and macular ganglion cell complex(GCC)measured by spectral domain optical coherence tomography(SD-OCT)in non-glaucoma subjects with low, moderate, and high myopia.METHODS: A total of 400 subjects(400 eyes)with myopia who attended our hospital from December 2019 to November 2022 were selected to participate in this study, and the subjects were divided into the following groups according to their degree of myopia: low myopia group(142 cases, 142 eyes, 35.5%), moderate myopia group(139 cases, 139 eyes, 34.8%)and high myopia group(119 cases, 119 eyes, 29.8%). RNFL thickness profiles were measured, including mean, superior, inferior, nasal, and temporal RNFL thickness. GCC parameters were measured, including mean, superior, superior temporal, inferior, inferior temporal, superior nasal, and inferior nasal. Correlation between RNFL thickness measured by OCT, mean GCC parameters, and axial length was evaluated.RESULTS: The mean RNFL thickness above, below and nasal side was significantly higher in the low and moderate myopia groups and the temporal RNFL thickness was significantly lower than the high myopia group(all P<0.05); the mean GCC thickness above, above temporal, below, below temporal, above nasal, below nasal and mean GCC thickness were significantly higher in the low and moderate myopia groups than in the high myopia group(all P<0.05); In the moderate myopia group, the mean RNFL and GCC thickness were both negatively correlated with axial length(r=-0.387, -0.309, all P<0.05). In the high myopia group, both RNFL and GCC thickness means were negatively correlated with eye axis length(r=-0.499, -0.503, all P<0.01).CONCLUSION:RNFL and GCC thicknesses tend to be thinner in subjects with high myopia than in subjects with low and moderate myopia.

Poor correlation between preclinical and patient efficacy data for tumor targeted monotherapies in glioblastoma: the results of a systematic review.

PURPOSE: Limited progress has been made in treating glioblastoma, and we hypothesise that poor concordance between preclinical and clinical efficacy in this disease is a major barrier to drug development. We undertook a systematic review to quantify this issue. METHODS: We identified phase I trials (P1Ts) of tumor targeted drugs, subsequent trial results and preceding relevant preclinical data published in adult glioblastoma patients between 2006-2019 via structured searches of EMBASE/MEDLINE/PUBMED. Detailed clinical/preclinical information was extracted. Associations between preclinical and clinical efficacy metrics were determined using appropriate non-parametric statistical tests. RESULTS: A total of 28 eligible P1Ts were identified, with median ORR of 2.9% (range 0.0-33.3%). Twenty-three (82%) had published relevant preclinical data available. Five (18%) had relevant later phase clinical trial data available. There was overall poor correlation between preclinical and clinical efficacy metrics on univariate testing. However, drugs that had undergone in vivo testing had significantly longer median overall survival (7.9 vs 5.6mo, p = 0.02). Additionally, drugs tested in ≥ 2 biologically-distinct in vivo models ('multiple models') had a significantly better median response rate than those tested using only one ('single model') or those lacking in vivo data (6.8% vs 1.2% vs. 0.0% respectively, p = 0.027). CONCLUSION: Currently used preclinical models poorly predict subsequent activity in P1Ts, and generally over-estimate the anti-tumor activity of these drugs. This underscores the need for better preclinical models to aid the development of novel anti-glioblastoma drugs. Until these become widely available and used, the use of multiple biologically-distinct in vivo models should be strongly encouraged.

The Role of the Allergist in Coronavirus Disease 2019 Vaccine Allergy Safety: A Pilot Study on a "Hub-and-Spoke" Model for Population-Wide Allergy Service.

BACKGROUND: Hong Kong started its coronavirus disease 2019 (COVID-19) vaccination program in February 2021. A territory-wide Vaccine Allergy Safety (VAS) clinic was set up to assess individuals deemed at "higher risk" of COVID-19 vaccine-associated allergies. A novel "hub-and-spoke" model was piloted to tackle the overwhelming demand of services by allowing nonallergists to conduct assessment. OBJECTIVE: To evaluate the outcomes of the VAS hub-and-spoke model for allergy assessment. METHODS: Records of patients attending the VAS hub-and-spoke Clinics between March and August 2021 were reviewed (n = 2725). We studied the overall results between the Hub (allergist led) and Spoke (nonallergist led) Clinics. The Hub and the Hong Kong West Cluster Spoke Clinic were selected for subgroup analysis as they saw the largest number of patients (n = 1411). RESULTS: A total of 2725 patients were assessed under the VAS hub-and-spoke model. Overall, 2324 patients (85.3%) were recommended to proceed with vaccination. Allergists recommended significantly more patients for vaccination than nonallergists (odds ratio = 21.58; P < .001). Subgroup analysis revealed that 881 of 1055 (83.5%) patients received their first dose of COVID-19 vaccination safely after assessment. Among those recommended vaccination, more patients assessed by allergists received their first dose of vaccination (odds ratio = 4.18; P < .001). CONCLUSION: The hub-and-spoke model has proven to be successful for the vaccination campaign. This study has illustrated the crucial role of allergists in countering vaccine hesitancy. Results from the study revealed considerable differences in outcomes between allergist-led and nonallergist-led clinics. Precise reasons for these differences warrant further evaluation. We are hopeful that the hub-and-spoke model can be similarly adapted for other allergist-integrative services in the future.

Influence of phacoemulsification on macular morphology in cataract patients with idiopathic macular epiretinal membrane / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To analyze the changes of the epiretinal membrane(ERM)stage, macular status and best corrected visual acuity(BCVA, LogMAR)in cataract patients with idiopathic macular epiretinal membrane(IERM)before and after cataract surgery.METHODS:We conducted a single center retrospective observational case series of patients that underwent sequential cataract and idiopatic ERM surgeries from March 2016 to May 2019 in Anyang Eye Hospital. Full data were obtained for 51 patients(54 eyes).Preoperative and postoperative 1mo ERM stage, central macular edema(CME), central macular thickness(CMT), macular volume(MV), ellipsoid zone disruption, occurrence of neurosensory detachment(NSD)and BCVA were analyzed.RESULTS:In this group of patients, 5 eyes(9%)had ERM grade 1, 23 eyes(43%)had ERM grade 2, 21 eyes(39%)had ERM grade 3, and 5 eyes(9%)had ERM grade 4 before surgery; ERM graded 1mo after surgery were keeping steady. Compared with before operation(0.45±0.16),there was no significant change in BCVA(0.47±0.17)at 1mo after operation(<i>P</i>>0.05), but the incidence of CME, ellipsoid band interruption and NSD were significantly higher than those before operation(<i>P</i><0.05). CONCLUSION: We suggest that phacoemulsification did not significantly accelerate ERM progression and affect BCVA, but patients underwent cataract surgery in the presence of epiretinal membranes need tight follow up to treat and control eventual macular infammatory changes and eventual prompt vitrectomy if BCVA was threatened.

Antibody Drug Conjugates in Glioblastoma - Is There a Future for Them?

Glioblastoma (GBM) is an aggressive and fatal malignancy that despite decades of trials has limited therapeutic options. Antibody drug conjugates (ADCs) are composed of a monoclonal antibody which specifically recognizes a cellular surface antigen linked to a cytotoxic payload. ADCs have demonstrated superior efficacy and/or reduced toxicity in a range of haematological and solid tumors resulting in nine ADCs receiving regulatory approval. ADCs have also been explored in patients with brain tumours but with limited success to date. While earlier generations ADCs in glioma patients have had limited success and high toxicity, newer and improved ADCs characterised by low immunogenicity and more effective payloads have shown promise in a range of tumour types. These newer ADCs have also been tested in glioma patients, however, with mixed results. Factors affecting the effectiveness of ADCs to target the CNS include the blood brain barrier which acts as a physical and biochemical barrier, the pro-cancerogenic and immunosuppressive tumor microenvironment and tumour characteristics like tumour volume and antigen expression. In this paper we review the data regarding the ongoing the development of ADCs in glioma patients as well as potential strategies to overcome these barriers to maximise their therapeutic potential.

Evaluation of 18F-FMISO PET and 18F-FDG PET Scans in Assessing the Therapeutic Response of Patients With Metastatic Colorectal Cancer Treated With Anti-Angiogenic Therapy.

INTRODUCTION: Tumor hypoxia and angiogenesis are implicated in tumor growth and metastases, and anti-angiogenic therapies have an important role in treating patients with metastatic colorectal cancer. However, the prevalence of hypoxia has not been fully evaluated in colorectal liver metastases, and hypoxic response to anti-angiogenic therapy has not been clearly established. The aims of the study were to evaluate the changes seen on 18F-FMISO and 18F-FDG PET scans in patients treated with anti-angiogenic therapy, and to correlate these measures of hypoxia and metabolism with clinical outcomes, and blood biomarkers of angiogenesis. METHODS: Patients with metastatic colorectal carcinoma planned for treatment with bevacizumab and chemotherapy received routine staging investigations prior to any treatment, including a FDG PET scan. A FMISO PET scan was performed within 4 weeks of staging tests, with blood specimens collected at that time for serum VEGF and osteopontin measurement. Follow-up FDG and FMISO scans were performed after 1 cycle of treatment. Results were compared to response (RECIST), progression free survival (PFS), and overall survival (OS). RESULTS: A total of 15 patients were recruited into this prospective trial, of which 13 patients were evaluable for assessment of treatment follow-up. Baseline FDG uptake was higher than FMISO uptake, and there was a significant decrease in FDG uptake (SUVmax and TGV) but not FMISO uptake (SUVmax and TNR) after treatment. There was a positive correlation between FDG and FMISO SUVmax on both baseline and post-treatment PET scans. Blood biomarkers of serum VEGF and osteopontin were significantly correlated with the FDG and FMISO PET parameters. CONCLUSIONS: This study shows that hypoxia in metastatic colorectal cancer, assessed by FMISO PET, shows minor changes following initial treatment with anti-angiogenic therapy, but is associated with therapeutic response. FDG PET uptake changes (SUVmax, TLG) are also associated with response to anti-angiogenic therapy. These findings demonstrate the interplay between tumor metabolism and hypoxic regulation following anti-angiogenic treatment of metastatic colorectal cancer.

Inefficiencies in phase II to phase III transition impeding successful drug development in glioblastoma.

BACKGROUND: Improving outcomes of patients with glioblastoma (GBM) represents a significant challenge in neuro-oncology. We undertook a systematic review of key parameters of phase II and III trials in GBM to identify and quantify the impact of trial design on this phenomenon. METHODS: Studies between 2005 and 2019 inclusive were identified though MEDLINE search and manual bibliography searches. Phase II studies (P2T) were restricted to those referenced by the corresponding phase III trials (P3T). Clinical and statistical characteristics were extracted. For each P3T, corresponding P2T data was "optimally matched," where same drug was used in similar schedule and similar population; "suboptimally matched" if dis-similar schedule and/or treatment setting; or "lacking." Phase II/III transition data were compared by Pearson Correlation, Fisher's exact or chi-square testing. RESULTS: Of 20 P3Ts identified, 6 (30%) lacked phase II data. Of the remaining 14 P3T, 9 had 1 prior P2T, 4 had 2 P2T, and 1 had 3 P2T, for a total of 20 P3T-P2T pairs (called dyads). The 13 "optimally matched" dyads showed strong concordance for mPFS (r 2 = 0.95, P < .01) and mOS (r 2 = 0.84, P < .01), while 7 "suboptimally matched" dyads did not (P > .05). Overall, 7 P3Ts underwent an ideal transition from P2T to P3T. "Newly diagnosed" P2Ts with mPFS < 14 months and/or mOS< 22 months had subsequent negative P3Ts. "Recurrent" P2Ts with mPFS < 6 months and mOS< 12 months also had negative P3Ts. CONCLUSION: Our findings highlight the critical role of optimally designed phase II trials in informing drug development for GBM.

Radiolabelling and preclinical characterization of 89Zr-Df-radiolabelled bispecific anti-PD-L1/TGF-ßRII fusion protein bintrafusp alfa.

PURPOSE: Τhis study aimed to optimize the 89Zr-radiolabelling of bintrafusp alfa investigational drug product and controls, and perform the in vitro and in vivo characterization of 89Zr-Df-bintrafusp alfa and 89Zr-Df-control radioconjugates. METHODS: Bintrafusp alfa (anti-PD-L1 human IgG1 antibody fused to TGF-ß receptor II (TGF-ßRII), avelumab (anti-PD-L1 human IgG1 control antibody), isotype control (mutated inactive anti-PD-L1 IgG1 control antibody), and trap control (mutated inactive anti-PD-L1 human IgG1 fused to active TGF-ßRII) were chelated with p-isothiocyanatobenzyl-desferrioxamine (Df). After radiolabelling with zirconium-89 (89Zr), radioconjugates were assessed for radiochemical purity, immunoreactivity, antigen binding affinity, and serum stability in vitro. In vivo biodistribution and imaging studies were performed with PET/CT to identify and quantitate 89Zr-Df-bintrafusp alfa tumour uptake in a PD-L1/TGF-ß-positive murine breast cancer model (EMT-6). Specificity of 89Zr-Df-bintrafusp alfa was assessed via a combined biodistribution and imaging experiment in the presence of competing cold bintrafusp alfa (1 mg/kg). RESULTS: Nanomolar affinities for PD-L1 were achieved with 89Zr-Df-bintrafusp alfa and 89Zr-avelumab. Biodistribution and imaging studies in PD-L1- and TGF-ß-positive EMT-6 tumour-bearing BALB/c mice demonstrated the biologic similarity of 89Zr-Df-bintrafusp alfa and 89Zr-avelumab indicating the in vivo distribution pattern of bintrafusp alfa is driven by its PD-L1 binding arm. Competition study with 1 mg of unlabelled bintrafusp alfa or avelumab co-administered with trace dose of 89Zr-labelled bintrafusp alfa demonstrated the impact of dose and specificity of PD-L1 targeting in vivo. CONCLUSION: Molecular imaging of 89Zr-Df-bintrafusp alfa biodistribution was achievable and allows non-invasive quantitation of tumour uptake of 89Zr-Df-bintrafusp alfa, suitable for use in bioimaging clinical trials in cancer patients.

Mechanism of Chinese Medicine in Xingnao and Kaiqiao Against Cerebral Ischemia/Reperfusion Injury： A Review / 中国实验方剂学杂志

Cerebral ischemia/reperfusion injury （CIRI） is a common feature and the main pathophysiological mechanism of ischemic stroke（IS）， which is caused by a blood reperfusion injury in ischemic brain tissues. It can aggravate brain tissue injury and cause irreversible brain damage， seriously affecting the quality of life or even the life of patients. Hence， we must find out the exact mechanism as well as the effective therapeutic drugs and targets for CIRI. The Chinese medicine effective in Xingnao （restoring consciousness） and Kaiqiao （opening orifices） has been widely used in the treatment of CIRI and serves as a classic therapy for IS. In recent years， scholars have conducted extensive and in-depth studies on the mechanism and therapeutic targets of Chinese medicine in Xingnao and Kaiqiao. They found that those drugs could interfere with a series of changes after IS and achieve the remarkable curative effect. This study summarized the effect and mechanism of Chinese medicine in Xingnao and Kaiqiao in the treatment of CIRI， including reducing the inflammatory response and oxidative stress， alleviating brain edema and the toxicity of excitatory amino acids， reducing cell apoptosis， promoting angiogenesis and neurovascular remodeling， and improving blood-brain barrier injury. It is expected to provide references to clarify the mechanism and important targets of those drugs in resisting CIRI and ideas for the in-depth investigation and application of brain protection of Chinese medicine in Xingnao and Kaiqiao.

The effect of Moutan cortex carbonisata nano-components on the blood-cooling and hemostatic / 药学学报

At present, the research of Moutan cortex carbonisata (MCC) mainly focuses on the changes of chemical composition before and after charcoal production, and there is a lack of material basic research directly related to the efficacy at home and abroad. In this study, Moutan cortex, as a precursor, and was calcined to MCC at high temperature. The Moutan cortex carbonisata nano-components (MCC-NCs) were extracted and separated from MCC to explore its cooling-blood and hemostatic effects. In the experiment, the MCC was calcined at a high temperature in a muffle furnace (350 ℃, 1 h), and then MCC-NCs were extracted for MCC, and characterized by transmission electron microscopy and UV-vis absorption spectroscopy, fluorescence spectroscopy, Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. In addition, the study evaluated the blood-cooling and hemostatic effects of MCC-NCs. The results showed that MCC-NCs have a size distribution of 0.80-2.8 nm, a lattice spacing of 0.26 nm. MCC-NCs are mainly composed of C, O and N elements and have abundant surface functional groups such as OH, C=O, C-N and C=C. The fluorescence yield of MCC-NCs was 7.18%. The experiments complied with the Animal Ethics Committee of Beijing University of Chinese Medicine. The result indicated that pretreatment MCC-NCs can significantly (P < 0.05) reduce the high, medium, and low viscosity of whole blood and plasma viscosity, and reduce hematocrit, red blood cell distribution width, hemoglobin and red blood cell level. In addition, MCC-NCs significantly reduced the levels of activated partial thromboplastin time, thrombin time and fibrinogen (P < 0.05). The pathological examination results showed that MCC-NCs can significantly reduce lung tissue damage, reduce bleeding and inflammatory cell infiltration. At the same time, it can also significantly reduce the symptoms of gastric mucosal bleeding. In conclusion, the results indicated that MCC-NCs has significantly the effect of blood cooling and hemostasis, and its hemostatic effect is mainly related to the activation of endogenous coagulation pathway or fibrinogen system, which provided a novel strategy for exploring the material basis of traditional Chinese medicine for hemostasis.

Research on the correlation between driver genes of lung adenocarcinoma and venous thromboembolism / 国际肿瘤学杂志

Venous thromboembolism (VTE) is one of the common complications of lung adenocarci-noma. The state of the driver genes of lung adenocarcinoma is related to the risk of VTE. The common driver genes include epidermal growth factor receptor, anaplastic lymphoma kinase, c-ros oncogene 1 receptor kinase and Kirsten rat sarcoma viral oncogene, etc.. Based on the study of the correlation between lung adenocarci-noma driver genes and VTE, it is of great significance for the early clinical prevention of VTE in patients with lung adenocarcinoma to screen out patients with high risk of VTE according to the state of the driver genes and finally evaluate the risk of VTE in patients with lung adenocarcinoma by combining conventional risk factors with the driver genes.

Response to combined BRAF/MEK inhibition in adult BRAF V600E mutant spinal pilocytic astrocytoma.

Pilocytic astrocytomas are World Health Organisation (WHO) grade I tumors, occurring predominantly supratentorially and in the pediatric population. Although the mainstay of treatment is local therapies such as surgery, targeted systemic therapies may be necessary for recurrent or unresectable disease. The majority of sporadic pilocytic astrocytomas are associated with the BRAF-KIAA fusion gene, which results in constitutive activation of the MAP Kinase pathway. Less frequently, the BRAF V600E point mutation has been described, occurring in less than 10% of supratentorial pilocytic astrocytomas. Tumours with this mutation may respond to targeted therapy against the BRAF/MAP Kinase pathway. We report the first described case of a spinal pilocytic astrocytoma in an adult patient with a BRAF V600E mutation responding to targeted therapy using BRAF and MEK tyrosine kinase inhibitors, and share our experiences with the management of toxicity in this patient population.

Prenatal genetic diagnosis of a partial 21 trisomy fetus with nasal bone dysplasia / 中华医学遗传学杂志

OBJECTIVE@#To explore the nature of chromosomal abnormality in a fetus with nasal bone dysplasia and clarify its clinical effect.@*METHODS@#Fetal chromosome karyotype was analyzed by G-banding. Single nucleotide polymorphism array (SNP-array) was used to detect the chromosomal copy number variations, and fluorescence in situ hybridization (FISH) was used to verify the result.@*RESULTS@#Fetal karyotype analysis showed an unknown chromosomal fragment in 21q21 region. SNP-array discovered a 7.5 Mb duplication in the 21q22.12q22.3 region. FISH confirmed that the unknown fragment was derived from a 21q22.12q22.3 duplication.@*CONCLUSION@#Combined use of karyotype analysis, SNP-array and FISH has clarified the nature of chromosomal abnormality in a fetus with nasal bone dysplasia, which has enabled more accurate prenatal diagnosis and genetic counseling.

Establishment of Material Benchmark Characteristic Spectrum of Houpu Qiwutang / 中国实验方剂学杂志

Objective:To establish a characteristic spectrum to reflect the efficacy of Houpo Qiwutang. Method:Based on the correlation between the efficacy and the pharmacological action of each herb in prescription，the target substances of characteristic map were screened. The extraction solvent，detection wavelength and gradient of the active ingredients were optimized. Peak assignment was made by comparing individual drugs. Q-TOF was used to infer the molecular formula of each peak in the characteristic atlas，and the reference substance was identified by the reference substance. The reference substance was screened out according to the correlation of main efficacy and medicine. Result:The characteristic spectrum of material standard of Houpu Qiwutang was established. Five of the seven herbal medicines were attributed. Nine characteristic peaks were selected and identified by Q-TOF as glycyrrhizin，including naringin，neohesperidin，ammonium glycyrrhizinate，rhein，honokiol，magnolol. According to the main efficacy of Houpo Qiwutang，neohesperidin was selected as reference substances. According to the separation of characteristic peaks and the retention time，the mark peak of the characteristic spectrum was determined. Conclusion:The characteristic spectrum of the material basis of Houpo Qiwutang was established by selecting the characteristic peaks and controlling the key components. This method not only reflects the situation of all the effective chemical components，but also focuses on the control of the key efficacy，so as to provide a theoretical basis for the subsequent development and quality control of Houpu Qiwu Tang.

Clinical characteristics of papillary thyroid microcarcinoma less than or equal to 5 mm / 中国医师进修杂志

Objective To summarize the clinical characteristics of papillary thyroid microcarcinoma with diameter ≤ 5 mm. Methods The clinical data of 259 papillary thyroid microcarcinoma patients who had underwent radical thyroidectomy from January 2015 to December 2017 were retrospectively analyzed. The patients were divided into 2 groups according to the preoperative tumor diameter: ＞5 mm group (88 cases) and ≤ 5 mm group (171 cases); then according to the lymph node metastasis, the 2 groups were divided into non-lymph node metastasis sub-group and lymph node metastasis sub-group. The reason of lymph node metastasis was analyzed. Results There were no statistical difference in gender composition, age and combined Hashimoto thyroiditis rate between ＞5 mm group and≤5 mm group (P＞0.05). The rates of T3-4 stage, N1a-1b stage and multifocal tumors in＞5 mm group were significantly higher than those in ≤ 5 mm group: 34.1% (30/88) vs. 18.7% (32/171), 45.5% (40/88) vs. 22.8% (39/171) and 39.8% (35/88) vs. 22.8% (39/171), and there were statistical differences (P＜0.05 or＜0.01). In＞5 mm group, lymph node metastasis sub-group had 40 cases, non-lymph node metastasis sub-group had 48 cases; the rate of T3-4 stage in lymph node metastasis sub-group was significantly higher than that in non-lymph node metastasis sub-group: 55.0% (22/40) vs. 16.7% (8/48), and there was statistical difference (P＜0.01). In≤5 mm group, lymph node metastasis sub-group had 39 cases, and non-lymph node metastasis sub-group had 132 cases; the rate of T3-4 stage in lymph node metastasis sub-group was significantly higher than that in non-lymph node metastasis sub-group:51.3% (20/39) vs. 9.1% (12/132), and there was statistical difference (P＜0.01). In＞5 mm group and≤5 mm group, there were no statistical difference in gender composition, age, combined Hashimoto thyroiditis rate and multifocal tumors rate between 2 sub-groups (P＞0.05). Conclusions The clinical behavior of papillary thyroid microcarcinoma with diameter ≤ 5 mm has a less aggressive nature compared to that＞5 mm. Tumor capsular invasion or extra thyroidal extension has a great influence on lymph node metastasis in thyroid papillary microcarcinoma of different diameter.

Molecular imaging of T cell co-regulator factor B7-H3 with 89Zr-DS-5573a.

B7-H3 is a transmembrane protein widely expressed in a variety of cancers and has been shown to play a role in anti-tumor immunity. This study aims to develop a molecular imaging probe to identify B7-H3 expression in tumors and to develop 89Zr-DS-5573a as a theranostic that could aid patient selection in clinical Phase I studies. Methods: The anti-B7-H3 humanised monoclonal antibody DS-5573a was labeled with zirconium-89 (89Zr-), and assessed for radiochemical purity, immunoreactivity (Lindmo analysis), antigen binding affinity (Scatchard analysis), and serum stability in vitro. In vivo biodistribution and imaging studies were performed with positron emission tomography and magnetic resonance imaging (PET/MRI) studies to identify and quantitate 89Zr-DS-5573a tumor uptake in a B7-H3-positive breast cancer model (MDA-MB-231) and a B7-H3-negative murine colon cancer model (CT26). Imaging and biodistribution studies were also performed in MDA-MB-231 tumor-bearing SCID mice in the absence and presence of therapeutic DS-5573a antibody dose (3 mg/kg DS-5573a). Results:89Zr-DS-5573a showed high and specific binding to B7-H3-expressing MDA-MB-231 cells (immunoreactivity on day 0, 75.0 ± 2.9%), and low binding to B7-H3-negative CT26 cells (immunoreactivity on day 0, 10.85 ± 0.11%) in vitro. 89Zr-DS-5573a demonstrated good serum stability in vitro with 57.2 ± 2.0% of immunoreactivity remaining on day 7. In vivo biodistribution studies showed high uptake of 89Zr-DS-5573a in B7-H3-expressing MDA-MB-231 tumor-bearing mice, achieving 32.32 ± 6.55 %ID/g on day 7 post injection in BALB/c nu/nu mice and 25.76 ± 1.79 %ID/g in SCID mice, with minimal evidence of non-specific uptake in normal tissues, and excellent tumor localization on PET/MRI. In a combined imaging/therapy study, receptor saturation was demonstrated in tumors responding to therapy. Conclusion:89Zr-DS-5573a demonstrates specific and prolonged targeting of B7-H3-expressing tumors in vivo. Saturation of binding sites was demonstrated in tumors responding to DS-5573a therapy. These results indicate that 89Zr-DS-5573a has potential to target B7-H3-expressing tumors in cancer patients. Furthermore 89Zr-DS-5573a has the potential to provide important insights into T cell biology through its specific binding to B7-H3.