Early Drug Treatment Research Articles

Early drug treatment in preterm patients with large patent ductus arteriosus at 28 weeks or less gestational age: systematic review and meta-analysis.

Compare the use of nonsteroidal anti-inflammatory drugs (NSAIDs) with placebo/expectant management in preterm infants at 28 weeks or less gestational age with a large Patent Ductus (PDA). A meta-analysis of RCTs following PRISMA guidelines comparing the use of NSAIDs with placebo/expectant management in extremely preterm infants with a large PDA. There were no significant differences between the NSAIDs and placebo/expectant groups for all-cause mortality (RR 1.27; 95% CI 0.97-1.65; p = 0.081). However, the ibuprofen subgroup showed a significant difference in all-cause mortality (RR 1.36; 95% CI 1.03-1.80; p = 0.03) favoring the placebo/expectant group. In extremely preterm infants with a large PDA on ultrasound, early treatment with NSAIDs provides no additional clinical benefit compared to placebo/expectant treatment. Ibuprofen was associated with an increased risk ratio for all-cause mortality in the subgroup analysis.

Correlative factors of poor prognosis and abnormal cellular immune function in patients with Alzheimer's disease.

Alzheimer's disease (AD) is a serious disease causing human dementia and social problems. The quality of life and prognosis of AD patients have attracted much attention. The role of chronic immune inflammation in the pathogenesis of AD is becoming more and more important. To study the relationship among cognitive dysfunction, abnormal cellular immune function, neuroimaging results and poor prognostic factors in patients. A retrospective analysis of 62 hospitalized patients clinical diagnosed with AD who were admitted to our hospital from November 2015 to November 2020. Collect cognitive dysfunction performance characteristics, laboratory test data and neuroimaging data from medical records within 24 h of admission, including Mini Mental State Examination Scale score, drawing clock test, blood T lymphocyte subsets, and neutrophils and lymphocyte ratio (NLR), disturbance of consciousness, extrapyramidal symptoms, electroencephalogram (EEG) and head nucleus magnetic spectroscopy (MRS) and other data. Multivariate logistic regression analysis was used to determine independent prognostic factors. the modified Rankin scale (mRS) was used to determine whether the prognosis was good. The correlation between drug treatment and prognostic mRS score was tested by the rank sum test. Univariate analysis showed that abnormal cellular immune function, extrapyramidal symptoms, obvious disturbance of consciousness, abnormal EEG, increased NLR, abnormal MRS, and complicated pneumonia were related to the poor prognosis of AD patients. Multivariate logistic regression analysis showed that the decrease in the proportion of T lymphocytes in the blood after abnormal cellular immune function (odd ratio: 2.078, 95% confidence interval: 1.156-3.986, P < 0.05) was an independent risk factor for predicting the poor prognosis of AD. The number of days of donepezil treatment to improve cognitive function was negatively correlated with mRS score (r = 0.578, P < 0.05). The decrease in the proportion of T lymphocytes may have predictive value for the poor prognosis of AD. It is recommended that the proportion of T lymphocytes < 55% is used as the cut-off threshold for predicting the poor prognosis of AD. The early and continuous drug treatment is associated with a good prognosis.

Modern approaches to the treatment of Takayasu arteritis

Takayasu arteritis (AT) is a chronic granulomatous systemic vasculitis that affects large vessels and requires a multidisciplinary approach as the clinical signs are non-specific and disease activity is difficult to assess. Early rational drug treatment of AT suppresses both vascular and systemic inflammation, with glucocorticoids and immunosuppressants being of paramount importance. Advances in the understanding of the pathophysiology of AT have contributed to the development of new treatments that target key pro-inflammatory factors and involve the use of biologic disease-modifying antirheumatic drugs.

Mechanism and treatment of cell death in Alzheimer's disease

With 60 to 80% of cases, Alzheimer's disease (AD) is the primary trigger of dementia around the globe. The prevalence of people aged 65-69 years increased from 1% to about 30% of people aged 85 years, resulting in more than 50 million affected individuals globally. The AD in the formation of amyloid, the tau protein distribution, the interaction between amyloid and tau protein, clinical symptoms, the genetic background and so on various aspects are heterogeneity exists. Therefore, there is no single pathological process or mechanism of action that can explain why people develop AD. The prevalence of Alzheimer's disease is one of the largest global public health issues today. There have been many different therapy modalities investigated over time. But there is still no cure, and all that can be done for AD is to prevent and delay its progression. Current drug treatments are intended only to alleviate symptoms, not cure the root cause. Based on the universalization and decreasing age of AD, it is particularly significant to study the causes and pathogenesis of AD and how to prevent and treat it. This paper introduces the main stages of the process of AD, introduces two hypotheses -- tau hypothesis and amyloid interpretation，and the role of RNA splicing in this process is summarized. In addition, in order to provide more research ideas, the author describes the current treatment options for AD, from the risk factors that may cause AD to the latest specific treatments. The treatment approach suggests that both at-risk patients and those without underlying diseases make early lifestyle and dietary adjustments and gradually move towards a healthy lifestyle in order to reduce the incidence of Alzheimer's and the financial burden on families and society. This is in addition to early drug treatment to lessen the suffering and life experience of Alzheimer's patients.

Early Detection and Staging of Lung Fibrosis Enabled by Collagen-Targeted MRI Protein Contrast Agent.

Chronic lung diseases, such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), are major leading causes of death worldwide and are generally associated with poor prognoses. The heterogeneous distribution of collagen, mainly type I collagen associated with excessive collagen deposition, plays a pivotal role in the progressive remodeling of the lung parenchyma to chronic exertional dyspnea for both IPF and COPD. To address the pressing need for noninvasive early diagnosis and drug treatment monitoring of pulmonary fibrosis, we report the development of human collagen-targeted protein MRI contrast agent (hProCA32.collagen) to specifically bind to collagen I overexpressed in multiple lung diseases. When compared to clinically approved Gd3+ contrast agents, hProCA32.collagen exhibits significantly better r1 and r2 relaxivity values, strong metal binding affinity and selectivity, and transmetalation resistance. Here, we report the robust detection of early and late-stage lung fibrosis with stage-dependent MRI signal-to-noise ratio (SNR) increase, with good sensitivity and specificity, using a progressive bleomycin-induced IPF mouse model. Spatial heterogeneous mapping of usual interstitial pneumonia (UIP) patterns with key features closely mimicking human IPF, including cystic clustering, honeycombing, and traction bronchiectasis, were noninvasively detected by multiple MR imaging techniques and verified by histological correlation. We further report the detection of fibrosis in the lung airway of an electronic cigarette-induced COPD mouse model, using hProCA32.collagen-enabled precision MRI (pMRI), and validated by histological analysis. The developed hProCA32.collagen is expected to have strong translational potential for the noninvasive detection and staging of lung diseases, and facilitating effective treatment to halt further chronic lung disease progression.

Real-world treatment of gout and asymptomatic hyperuricaemia in Japan.

Recently a retrospective cohort study in Japan conducted by Koto et al. disclosed that the risk of the first gout flare would decrease 55% if serum uric acid was reduced to 5–6 mg/dl among people with asymptomatic hyperuricaemia receiving uric acid–lowering drugs as compared with untreated people (serum uric acid ≥ 8.0 mg/dl) [1]. Another study by Koto et al. published in Modern Rheumatology using the same database disclosed that the prevalence of gout was about 1.1% in Japan [2], which was lower than Taiwan (3.1%) [3].The authors commented that the low prevalence of gout in Japan could be attributed to the early drug treatment of asymptomatic hyperuricaemia based on the Japanese guideline [2, 4]. Both studies by Koto et al. provide the evidence that the natural course of asymptomatic hyperuricaemia can be changed by the intervention of uric acid–lowering drugs. Some points are discussed. First, hyperuricaemia and gout are closely related but are not the same disease. Most of the people with hyperuricaemia do not develop a gout flare during their lives [5]. Whether people with asymptomatic hyperuricaemia should take uric acid–lowering drugs to prevent the first gout flare, the academic community has not yet established a consensus. The American College of Rheumatology guideline suggests against the use of uric acid–lowering drugs to treat asymptomatic hyperuricaemia [6]. The Japanese guideline suggests that the treatment goal of hyperuricaemia is to prevent monosodium urate deposition in joints and viscera, not only leading to the risk reduction of gout flares but also leading to the risk reduction of organ damage and then leading to prolonged disease-free survival, especially cardiovascular diseases [4]. After lifestyle modification, if serum uric acid is still ≥ 9.0 mg/dl, clinicians may talk to people with asymptomatic hyperuricaemia about the current evidence of managing hyperuricaemia and possible adverse events of uric acid–lowering drugs, such as hepatotoxicity, urinary stones, and cutaneous adverse reactions. Only after informed consent is obtained, clinicians are able to consider prescribing uric acid–lowering drugs to those suitable patients [4]. Although serum uric acid ≥ 9.0 mg/dl is an independent risk factor for gout flares, there have been no randomized control studies focusing on the management of asymptomatic hyperuricaemia where the primary endpoint was set as the development of the first gout flare. Therefore, in the current situation, urate-lowering drugs are not strongly recommended for asymptomatic hyperuricaemia in order to prevent the first gout flare. Moreover, in the present guidelines, how to treat hyperuricaemia should be decided after assessing the patients’ concomitant diseases. Second, benzbromarone is a uricosuric drug to lower serum uric acid. Because of its potential hepatotoxicity, benzbromarone had been withdrawn from some markets since 2003, but it still can be prescribed in many countries including Taiwan and Japan [7]. Three case reports in Japan showed that benzbromarone could be related to fulminant hepatotoxicity, but none was confirmed by rechallenge tests [8–10]. However, no hepatotoxicity was reported in Taiwan and South Korea. Allopurinol is the first drug of choice to lower serum uric acid in western countries [6]. Allopurinol use has a potential risk to cause severe cutaneous adverse reactions. Among the three Asian countries, the incidence rate of allopurinol-related severe cutaneous adverse reactions was the highest in Taiwan (2.57/1000 person-years), followed by South Korea (2.31/1000 person-years), and the lowest in Japan (2.00/1000 person-years) [11]. In ethnic groups with a high frequency of HLA-B*5801, benzbromarone will be safer than allopurinol for the management of hyperuricaemia. The standard doses of benzbromarone (100 mg/day) are more effective in lowering serum uric acid than the standard doses of allopurinol (300 mg/day) [12]. Only higher doses of allopurinol (450 mg/day) are as equally effective in lowering serum uric acid as the standard doses of benzbromarone (100 mg/day) [12]. Third, current guidelines do not present which drug should be the first-line drug for asymptomatic hyperuricaemia. If we want to set up a new clinical guideline, it is necessary to determine which drug is more effective and safer to prevent the first gout flare in people with asymptomatic hyperuricaemia. It indicates a future research direction.

Knowledge of genetic test results among caregivers and individuals with spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a progressive recessive genetic disease. Early identification is critical for achieving maximal treatment benefit. Survival motor neuron (SMN) 2 copy number may be a needed descriptor of disease severity than SMA type. Therefore, we assessed knowledge of SMN2 copy number among those with SMA and their caregivers via a phone survey. Only patients with SMA (or their caregivers) registered in the Cure SMA database with no SMN2 copy number on file were eligible. Descriptive results are reported. Backward stepwise multinomial logistic regressions determined if specific factors predicted knowledge of SMN2 copy number. Engagement with the SMA community (odds ratio [OR] 1.82; p&lt;0.0001), ability to walk (OR 1.74; p = 0.006), and current age at time of survey (OR = 0.98; p&lt;0.0001) each positively predicted knowledge of SMN2 copy number. Of 806 completed surveys, the majority (n = 452; 56.3%) did not know SMN2 copy numbers for themselves (n = 190; 62.5%) or their loved ones (n = 261; 52.4%). Of these, 66 respondents (8.2%) said genetic testing had not been done. Motor function increased linearly with increasing SMN2 copy number. SMN2 copy number is emerging as a critical descriptor of severity for SMA as type becomes more obsolete with early drug treatment. Communication of SMN2 copy numbers is recommended as a standard part of the treatment plan.

Identification of Warning Transition Points from Hepatitis B to Hepatocellular Carcinoma Based on Mutation Accumulation for the Early Diagnosis and Potential Drug Treatment of HBV-HCC.

The accumulation of multiple genetic mutations is essential during the occurrence and development of hepatocellular carcinoma induced by hepatitis B (HBV-HCC), but understanding their cooperative effects and identifying the warning transition point from hepatitis B to HCC are challenges. In the genomic analysis of somatic mutations of the patient with HBV-HCC in a patient-specific protein-protein interaction (ps-PPI) network, we find mutation influence can propagate along the ps-PPI network. Therefore, in the article, we got the mutation cluster as a new research unit using the Random Walks with Restarts algorithm that is used to describe the efficient boundary of mutation influences. The connection of mutation cluster leads to dysregulation of signaling pathways corresponding to HCC, while dysregulated signaling pathways accumulate gradually and experience a process from quantitative to qualitative changes including a critical mutation cluster called transition point (TP) from hepatitis B to HCC. Moreover, two subtypes of HCC patients with different prognosis and their corresponding biological and clinical characteristics were identified according to TP. The poor prognosis HCC subtype was associated with significant metabolic pathway dysregulation and lower immune cell infiltration, while we also identified several preventive drugs to block the transformation of hepatitis B to hepatocellular carcinoma. The network-level study integrated multiomics data not only showed the sequence of multiple somatic mutations and their cooperative effect but also identified the warning transition point in HCC tumorigenesis for each patient. Our study provides new insight into exploring the cooperative molecular mechanism of chronic inflammatory malignancy in the liver and lays the foundation for the development of new approaches for early prediction and diagnosis of hepatocellular carcinoma and personalized targeted therapy.

Change in Bone Mineral Density in Stroke Patients with Osteoporosis or Osteopenia.

We aimed to investigate the correlation between changes in bone mineral density (BMD) of the lumbar spine (LS) and femoral neck (FN) and osteoporosis-related factors in stroke patients with osteoporosis or osteopenia, and we suggest the need for active rehabilitation treatment. This study included 63 osteoporosis and 34 osteopenia patients who underwent a BMD test following primary stroke onset. The osteoporosis group was followed up with a BMD test after 12 months of bisphosphonate treatment, and the osteopenia group was followed up without medication. The correlation between BMD changes and functional factors was analyzed, biochemical markers were measured, and hematology tests were performed. In the osteoporosis group, a significant increase was observed in LS BMD (p < 0.05), and in the osteopenia group, there was a significant decrease in FN BMD (p < 0.05). The group with a functional ambulatory category of 1 or more showed a significant improvement in BMD (p < 0.05). Comparative analysis was performed on various indicators, but no significant correlation was found between any variable. In stroke patients with osteoporosis or osteopenia, early appropriate drug treatment is important to prevent bone loss and reduce the risk of fractures, and comprehensive rehabilitation treatment, such as appropriate education and training to prevent falls, is essential.

Engineering an endonuclease-assisted rolling circle amplification synergistically catalyzing hairpin assembly mediated fluorescence platform for miR-21 detection

As one of the earliest miRNAs discovered in the human genome, miRNA-21 can provide vital information for the early diagnosis, drug treatment, and prognosis of cancers. Herein, we construct a fast, time-saving fluorescence detection system for miRNA-21 detection by coalescing the improved endonuclease-mediated rolling circle amplification with catalytic hairpin assembly (RCA-NESA-CHA). Firstly, the target miRNA cyclized the padlock, initiating rolling circle amplification (RCA) and extending a long-concatenated DNA. The modified Protector bonded with the long-strand DNA to generate an endonuclease-specific site and trigger the nicking process. Finally, DNA products with repetitive sequences not only recombined with the padlock to reactivate a new recycle of RCA but also triggered the catalytic hairpin assembly to form the H1–H2 complex, realizing the cooperative amplification of the signal. In this system, RCA-NESA and CHA were integrated into one step, which essentially simplifies the sensing process. Moreover, the introduction of the Protector would inhibit the extension reaction caused by the combination of the padlock and the RCA products, slowing down the non-specific reaction time and improving the sensitivity of the fluorescence detection system. Under the optimal experimental conditions, the fluorescence system achieved a limit-of-detection of 0.025 amol miR-21 in a 40 μL sample and successfully applied to miR-21 detection in serum samples from breast cancer patients, showing good agreement with the results of RT-PCR, which exhibited great potential in biomedical research and clinical diagnosis.

Value of tumor growth rate in evaluating the early therapeutic efficacy of neuroendocrine neoplasm

Objective: To determinate the value of tumor growth rate (TGR) in evaluating the efficacy of early drug treatment for neuroendocrine neoplasm (NEN). Methods: Patients with NEN who treated at Chinese Academy of Medical Sciences Cancer Hospital from January 2010 to December 2018 were retrospectively enrolled. A total of 30 patients (16 males and 14 females, aged from 26 to 73 (53±11) years) were enrolled. The sum of largest diameter of target lesions and the interval time were measured, TGR of 3 months after the first treatment was calculated using a formula. Intraclass correlation coefficient (ICC) were used to test the repeatability of TGR. Receiver operating characteristic curve (ROC) analysis was used to determine the optimal cut-off values of TGR for predicting progression-free survival (PFS). Overall patients and SD patients assessed by RECIST were grouped by the optimal cut-off values of TGR. Kaplan-Meier method was used to estimate PFS rates and plot patient survival curves of patients at different group of TGR. Cox risk proportional hazard model was used to assess the effect of TGR on the prognosis. Results: The optimal cut-off value of TGR was -5.8(%/m), the area under the curve was 0.921 (95%CI: 0.824-0.999, P<0.001). Interobserver ICC was 0.955 (95%CI: 0.907-0.978,P<0.001). Multivariate Cox analysis showed that compared with the patients with TGR<-5.8, the patients with TGR ≥-5.8 had a higher risk of progression in either overall population (HR: 10.906, 95%CI: 1.953-60.898, P=0.006) or the SD population (HR: 14.354, 95%CI: 1.602-128.627, P=0.017); TGR ≥-5.8 was an independent risk factor affecting the prognosis of NEN. Conclusions: TGR can evaluate the efficacy of NEN's early anti-tumor drug treatment, and associate with prognosis.

Genomic Variations in Drug Resistant Mycobacterium tuberculosis Strains Collected from Patients with Different Localization of Infection.

Mycobacterium tuberculosis is a highly studied pathogen due to public health importance. Despite this, problems like early drug resistance, diagnostics and treatment success prediction are still not fully resolved. Here, we analyze the incidence of point mutations widely used for drug resistance detection in laboratory practice and conduct comparative analysis of whole-genome sequence (WGS) for clinical M. tuberculosis strains collected from patients with pulmonary tuberculosis (PTB) and extra-pulmonary tuberculosis (XPTB) localization. A total of 72 pulmonary and 73 extrapulmonary microbiologically characterized M. tuberculosis isolates were collected from patients from 2007 to 2014 in Russia. Genomic DNA was used for WGS and obtained data allowed identifying major mutations known to be associated with drug resistance to first-line and second-line antituberculous drugs. In some cases previously described mutations were not identified. Using genome-based phylogenetic analysis we identified M. tuberculosis substrains associated with distinctions in the occurrence in PTB vs. XPTB cases. Phylogenetic analyses did reveal M. tuberculosis genetic substrains associated with TB localization. XPTB was associated with Beijing sublineages Central Asia (Beijing CAO), Central Asia Clade A (Beijing A) and 4.8 groups, while PTB localization was associated with group LAM (4.3). Further, the XPTB strain in some cases showed elevated drug resistance patterns relative to PTB isolates. HIV was significantly associated with the development of XPTB in the Beijing B0/W148 group and among unclustered Beijing isolates.

Seventy years of development and prospects of the ocular oncology specialty in China

Ocular tumors include intraocular tumors and tumors of the eyelid, orbit, conjunctiva and lacrimal apparatus. After seventy years of continued growth, ocular oncology in China, from small to large and from weak to strong, has made great achievements. Especially since the beginning of the new century, there has been all-round and rapid development. The mechanism of ocular tumorigenesis has been elucidated based on the biobank and animal models. New therapeutic techniques and treatment modalities have been established based on multi-center cohort studies. The team competence and the discipline level have been improved based on academic organization constructions and international exchanges. Looking into the future, ocular oncology in China will move on in gene detection and early diagnosis, basic research and drug targeting, interdisciplinary, intelligent diagnosis and treatment, clinical research and translational medicine, with the support of national strategies and scientific and technological innovation, to further improve the survival rate, the ocular salvage rate and the quality of life for patients with ocular tumors. This article is written to congratulate the Chinese Journal of Ophthalmology on the 70th anniversary of its publication. (Chin J Ophthalmol, 2020, 56: 646-652).

Molecular imaging of extracellular matrix proteins with targeted probes using magnetic resonance imaging.

The extracellular matrix (ECM) consists of proteins and carbohydrates that supports different biological structures and processes such as tissue development, elasticity, and preservation of organ structure. Diseases involving inflammation, fibrosis, tumor invasion, and injury are all attributed to the transition of the ECM from homeostasis to remodeling, which can significantly change the biochemical and biomechanical features of ECM components. While contrast agents have played an indispensable role in facilitating clinical diagnosis of diseases using magnetic resonance imaging (MRI), there is a strong need to develop novel biomarker-targeted imaging probes for in vivo visualization of biological processes and pathological alterations at a cellular and molecular level, for both early diagnosis and monitoring drug treatment. Herein, we will first review the pathological accumulation and characterization of ECM proteins recognized as important molecular features of diseases. Developments in MRI probes targeting ECM proteins such as collagen, fibronectin, and elastin via conjugation of existing contrast agents to targeting moieties and their applications to various diseases, are also reviewed. We have also reviewed our progress in the development of collagen-targeted protein MRI contrast agent with significant improvement in relaxivity and metal binding specificity, and their applications in early detection of fibrosis and metastatic cancer. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Biology-Inspired Nanomaterials > Peptide-Based Structures Biology-Inspired Nanomaterials > Protein and Virus-Based Structures.

Associated factors with interstitial lung disease and health-related quality of life in Chinese patients with primary Sjögren's syndrome.

The main purpose of this study was to investigate the current situation of primary Sjögren's syndrome (pSS) patients with interstitial lung disease (ILD) in China. The relationships between social demography, disease activity, psychological status, clinical variables, and ILD were analyzed. Besides that, the quality of life (QoL) in pSS with ILD was also analyzed. In the cross-sectional study, 101 pSS patients participated in this study. Under the guidance of the researchers, the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI), EULAR Sjögren's Syndrome Patient-Reported Index (ESSPRI), the Short-Form 36 health survey (SF-36), Hospital Anxiety and Depression Scale (HADS), Pittsburgh sleep quality index (PSQI), Summated Xerostomia Inventory (SXI), and other related questionnaires were completed. Independent sample t tests, Mann-Whitney U test, chi-square test, and correlational analysis were used. The data showed that 28 (30.1%) pSS people with ILD. The occurrence and development of ILD were associated with disease duration, fatigue, alanine aminotransferase (ALT), neutrophils, albumin, and use of hormone. The survey also found that the QoL of pSS-ILD was significantly lower than non-ILD, especially the score in the dimension of role physical function. ILD was very common in pSS. ILD had a significant negative impact on the QoL of patients. Therefore, it is of great significance to strengthen the early intervention and drug treatment of pSS patients to prevent ILD and improve their QoL.Key Points• This cross-sectional study finds that the incidence of ILD in patients with pSS is 30.1%.• The occurrence and development of ILD is associated with disease duration, fatigue, alanine aminotransferase (ALT), neutrophils, albumin, and use of hormone.•The study also finds that the QoL of pSS-ILD is significantly lower than in patients with non-ILD, especially the score in the dimension of role physical function.

Abstract 1066: Drug resistant PDX models for testing targeted drug sensitivity

Abstract Advanced lung cancer of late stage patients is selectively sensitive to available targeted therapeutics and often develops resistance to early sensitive drug treatment, thus, the patient-derived xenograft (PDX) models are critical to evaluate drug sensitivity and resistance. We established PDX models from routine surgery tissues, as well as from tumor cells in pleural effusion specimens and from biopsies of advanced cancer patients who are refractory to treatments. Genetic profiling of the PDX lung models revealed a group of them with TKI drug-associated EGFR mutations (L858R, T790M, Exon19del, C797S). Among them, are an AZD9291-resistant sub-group with EGFR double mutations (Exon19Δ, T790M) in the clinic before AZD9291 treatment, and yet, acquired resistance to AZD9291 either through emergence C797S mutation or T790M loss in EGFR or through mutations in other pathways, providing insights into potential combo therapies. Indeed, combinations of AZD9291 with Cetuximab as well as with inhibitors targeting other signaling pathways such as MEK, are efficacious against an AZD9291-resistant lung PDX model with EGFR triple mutations (Exon19Δ, T790M, C797S). We also establish valuable lung models resistant to ALK inhibitors, Avastin, PD-1 antibody drugs, and resistant hematopoietic models. In summary, functional drug sensitivity profiling and genetic profiling with drug resistant PDX models provide insights into resistance mechanisms as well as precise therapeutic options against resistance emergence. Citation Format: Jijun Cheng, Feifei Zhang, Zhen Zhou, Yuan Long, Wenhua Xu, Shizhu Zhao, Hongkui Chen, Shun Lu, Danyi Wen. Drug resistant PDX models for testing targeted drug sensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1066.

Fluorogenic Probe for Detecting Active Matrix Metalloproteinase-3 (MMP-3) in Plasma and Peripheral Blood Neutrophils to Indicate the Severity of Rheumatoid Arthritis.

Diagnosis of patients with rheumatoid arthritis (RA) is essential for early and accurate drug treatment to protect the patient from joint bone erosion and relieve symptoms of the disease. In some cases, the RA patient's X-ray images and other clinical diagnostic methods are often difficult to distinguish from different diseases, such as gout, osteoarthritis, and other inflammatory conditions. Thus, methods for diagnosis of disease activity and real-time monitoring of therapeutic effect and accurate differentiation from other bone diseases are needed. In this article, we suggest a matrix metalloproteinase-3 (MMP-3)-specific protease-activated probe immobilized in vitro kit and cell staining for flow cytometry analysis as methods to support clinical diagnosis. To overcome interindividual differences, we used phorbol 12-myristate 13-acetate (PMA)-activated plasma from 269 RA patients, 49 osteoarthritis patients, and 30 healthy volunteers. The in vitro kit developed for PMA-activated plasma showed potential for identifying disease severity and distinguishing RA from other bone diseases. In particular, expression of active MMP-3 increased until the moderate disease activity and then sharply decreased at severe disease. We suggest an analysis of intracellular MMP-3-specific protease-activated probe staining by flow cytometry. Compared with anti-MMP-3 antibody staining, the results for active MMP-3 in neutrophils using the probe exactly matched the results obtained with the in vitro kit. We also confirmed that expression of active MMP-3 was mainly from neutrophils. Together, these results suggest that the MMP-3-specific protease-activated probe might be a promising noninvasive tool for accurate diagnosis of disease severity and differentiation from similar bone diseases as well as for monitoring therapeutic efficacy.

High prevalence of genetic determined familial hypercholesterolemia in premature coronary artery disease.

Background: Premature coronary artery disease (CAD) is a major cause of mortality and morbidity. Increased low-density lipoprotein-cholesterol (LDL-C) level is a major risk factor for CAD and thus the main target for its prevention. Familial Hypercholesterolemia (FH) is a genetic inherited disorder characterized by high LDL-C, and subsequent premature CAD development. Early drug treatment with lipid-lowering medications in FH prevents cardiovascular disease onset.The FH prevalence in the Northern European general population is 0.3%, and it is estimated that it explains 20% of premature CAD cases in individuals with familial clustering. Despite the wide number of papers showing the prevalence of clinical FH in cardiovascular disease, the prevalence of genetic FH in individuals with premature CAD is not yet well known. Here, we examined the prevalence of genetically determined FH in individuals with premature CAD.Patients and methods: 66 patients who underwent coronary angiography with suspected premature acute coronary syndrome (age <50 years for men and <55 years for women) underwent genetic screening to identify FH-causing mutations. All patients underwent physical and clinical examinations. Information about family and personal history, drug therapy and habits were also collected.Results: We found FH-causative mutations in 3/66 (4.5%) screened individuals with premature CAD. When considering individuals with confirmed CAD after coronary angiography, the FH mutation prevalence was 6.1% (3/49). After excluding individuals with classical risk factors for CAD other than hypercholesterolemia, the FH mutation prevalence raised to 15.8% (3/19).Conclusion: In conclusion, we found that individuals with premature CAD have a more than 15-fold increased prevalence of FH mutations compared to the general population.

Influence of early treatment of pregnancy combined with subclinical hypothyroidism on pregnancy outcome

Objective To analyze the influence of early treatment of pregnancy combined with subclinical hypothyroidism (SCH) during pregnancy on pregnancy outcome. Methods From January 2013 to June 2015, 128 pregnant women who were diagnosed as SCH in the Maternal and Child Health Hospital of Beilun District were randomly divided into the observation group and control group according to the digital table, with 64 cases in each group.The observation group was given levothyroxine early treatment, while the control group adopted conventional hospitalization, unexposed.Pregnancy outcomes of the two groups were analyzed. Results After treatment, the incidence rates of complications in the observation group: preeclampsia (4.69%), poor fetal growth (1.56%), premature rupture of membranes (7.81%), less amniotic fluid volume (4.69%), placental abruption (0%), postpartum hemorrhage (3.12%); the incidence rates of complications in the control group: preeclampsia (17.19%), poor fetal growth (10.94%), premature rupture of membranes (21.88%), less amniotic fluid volume (15.63%), placental abruption (6.25%), postpartum hemorrhage (12.50%), and there were statistically significant differences between two groups (χ2=5.133, 4.800, 5.006, 4.195, 4.129, 3.905, P=0.023, 0.028, 0.025, 0.041, 0.042.0.048). After treatment, the incidence rates of adverse pregnancy outcomes: preterm birth (3.12%), cesarean section(60.94%), abortion(0.00%), fetal distress(4.69%), perinatal death (0.00%); the incidence rates of adverse pregnancy outcomes in the control group: preterm birth(12.50%), cesarean section (79.69%), abortion (7.81%), fetal distress (15.63%), perinatal death (6.25%), and the differences between the two groups were statistically significant (χ2=3.905, 5.389, 5.203, 4.195, 4.129, P=0.048, 0.020, 0.023, 0.041, 0.042). Conclusion Pregnancy complicated with SCH has different degree influence on patients with obstetric complications and outcome of pregnancy, early effective drug treatment can significantly reduce the incidence of obstetric complications and adverse pregnancy outcomes. Key words: Pregnancy; Hypothyroidism, subclinical; L-thyroxine; Pregnancy outcome; Cesarean delivery; Prematue rupture of memmbranes

Epithelial-to-Mesenchymal Transition (EMT) and Drug Response in Dynamic Bioengineered Lung Cancer Microenvironment.

Tumor microenvironment and the interplay of physical and mechanical forces are key determinants of cancer initiation, progression, and response to drug treatment. However, the impact of tumor microenvironment on cancer progression is poorly understood, in large due to the lack of in vitro models that recapitulate the physical aspects of tumor microenvironment. Herein, a simple, dynamic 3D nonsmall cell lung carcinoma culture using a multichannel microfluidic model platform is developed for evaluating the contribution of flow-induced hydrodynamic shear stress on epithelial-to-mesenchymal transition (EMT). It is found that flow induces changes in cellular morphology and EMT in 2D and 3D when lung cancer A549 cells are cultured on a microfluidic chip under laminar flow for 4-5 days compared to traditional static cultures. The role of dynamic cell culture on chemotherapeutic effects is monitored. Drug response with an existing anti-cancer drug, e.g., erlotinib and an investigational drug (NSC-750212), shows distinct cytotoxic effects in flow compared to static cultures, suggesting a potential influence of flow on drug efficacy in 2D and 3D models. The platform demonstrates the ability to create a dynamic microscale tumor model, which could be explored as a tool for early drug screening and treatment monitoring in cancer and other diseases.