The non-cell-autonomous function of ID1 promotes AML progression via ANGPTL7 from the microenvironment.

The bone marrow microenvironment (BMM) can regulate leukemia stem cells (LSCs) via secreted factors. Increasing evidence suggests that dissecting the mechanisms by which the BMM maintains LSCs may lead to the development of effective therapies for the eradication of leukemia. Inhibitor of DNA binding 1 (ID1), a key transcriptional regulator in LSCs, previously identified by us, controls cytokine production in the BMM, but the role of ID1 in acute myeloid leukemia (AML) BMM remains obscure. Here, we report that ID1 is highly expressed in the BMM of patients with AML, especially in BM mesenchymal stem cells, and that the high expression of ID1 in the AML BMM is induced by BMP6, secreted from AML cells. Knocking out ID1 in mesenchymal cells significantly suppresses the proliferation of cocultured AML cells. Loss of Id1 in the BMM results in impaired AML progression in AML mouse models. Mechanistically, we found that Id1 deficiency significantly reduces SP1 protein levels in mesenchymal cells cocultured with AML cells. Using ID1-interactome analysis, we found that ID1 interacts with RNF4, an E3 ubiquitin ligase, and causes a decrease in SP1 ubiquitination. Disrupting the ID1-RNF4 interaction via truncation in mesenchymal cells significantly reduces SP1 protein levels and delays AML cell proliferation. We identify that the target of Sp1, Angptl7, is the primary differentially expression protein factor in Id1-deficient BM supernatant fluid to regulate AML progression in mice. Our study highlights the critical role of ID1 in the AML BMM and aids the development of therapeutic strategies for AML.

S100a9 deficiency accelerates MDS-associated tumor escape via PD-1/PD-L1 overexpression.

In recent studies, the tolerable safety profile and positive bone marrow (BM) response suggest a beneficial use of anti-PD-1 agents in the treatment of Myelodysplastic Syndromes (MDS), but the underlying mechanism is still unknown. MDS is mainly characterized by ineffective hematopoiesis, which may contribute to inflammatory signaling or immune dysfunction. Our previous studies focused on inflammatory signaling, and the results showed that S100a9 expression was higher in low-risk MDS and lower in high-risk MDS. In this study, we combine the inflammatory signaling and immune dysfunction. SKM-1 cells and K562 cells co-cultured with S100a9 acquire apoptotic features. Moreover, we confirm the inhibitory effect of S100a9 on PD-1/PD-L1. Importantly, PD-1/PD-L1 blockade and S100a9 can both activate the PI3K/AKT/mTOR signaling pathway. The cytotoxicity is higher in lower-risk MDS-lymphocytes than in high-risk MDS-lymphocytes, and S100a9 partially rescues the exhausted cytotoxicity in lymphocytes. Our study demonstrates that S100a9 may inhibit MDS-associated tumor escape via PD-1/PD-L1 blockade through PI3K/AKT/mTOR signaling pathway activation. Our findings indicate the possible mechanisms by which anti-PD-1 agents may contribute to the treatment of MDS. These insights may provide mutation-specific treatment as a supplementary therapy for MDS patients with high-risk mutations, such as TP53, N-RAS or other complex mutations.

Suppression of Hematopoietic Primitive Cells in Patients with Secondary Failure of Platelet Recovery after Acute Graft-versus-Host Disease.

Secondary failure of platelet recovery (SFPR) can occur after allogeneic hematopoietic stem cell transplantation (alloHSCT), and 20% of cases are related to acute graft-versus-host disease (aGVHD). The underlying mechanisms of this association are unclear, however. The aim of the present study was to investigate the potential mechanisms of SFPR secondary to aGVHD, which may provide a new therapeutic strategy for these patients. A total of 468 patients with malignant hematologic disease who underwent alloHSCT were included. Sixty-six patients developed SFPR after alloHSCT, and in 45 of these 66 patients (68.2%), SFPR was secondary to grade II-IV aGVHD (SFPR/aGVHD). Compared with patients with good graft function (GGF), patients with SFPR had poor overall survival (20.72% versus 88.01%; P < .0001). Grade II-IV aGVHD was identified as an independent risk factor for SFPR in multivariate analysis (hazard ratio, 9.512; P < .0001). We observed reduced erythroid and megakaryocyte colony formation in bone marrow (BM) samples isolated from SFPR/aGVHD patients, consistent with the lower frequency of megakaryocyte and erythrocyte progenitors in BM. Levels of the inflammatory cytokines IL-2R and TNF-R1 were significantly higher in the SFPR/aGVHD group compared with the GGF group (P = .002 and .001, respectively), as were the frequencies of proinflammatory T helper subsets. Furthermore, the pathways that regulate hematopoiesis and immune responses were universally underexpressed in CD34+ cells isolated from SFPR/aGVHD patients. Differentially expressed genes were significantly enriched in the hematopoietic cell lineage pathway and other pathways involved in both immune responses and megakaryopoiesis. In summary, we found that both the immune microenvironment and compromised proliferation of hematopoietic primitive cells contribute to the development of SFPR secondary to aGVHD, and our data provide new insight into the mechanisms of SFPR in the context of aGVHD.

Simultaneous determination of 11 illicit drugs and metabolites in wastewater by UPLC-MS/MS.

Assessing collective drug consumption based on the concentrations of illicit drugs and their metabolites in wastewater is a new technology. Currently, this technology is receiving attention in China, and methods for multiple illicit drug detection in wastewater are urgently needed. In our study, a method with a short runtime (7 min), a small solid-phase extraction (SPE) loading volume (50 mL) and high sensitivity (lower limits of quantitation (LLOQs) ranged from 0.2 to 5 ng/L) was developed for the simultaneous determination of amphetamines, ketamine, opiates, cocaine and their metabolites in wastewater. Samples were enriched by SPE on a mixed-mode sorbent (Oasis MCX) and analyzed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The limits of detection (LODs) ranged from 0.1 to 2 ng/L, and the LLOQs varied between 0.2 and 5 ng/L. Moreover, the method developed was applied to real wastewater samples collected from 15 different wastewater treatment plants (WWTPs). In the results, the most abundant compounds were morphine (1.8-46.6 ng/L) and codeine (3.7-24.9 ng/L), which were detected in 13 WWTPs. After successful optimization of the UPLC-MS/MS conditions and sample loading pH, the method developed is able to meet the needs of common illicit drug monitoring and high-throughput analysis requirements.

[Effects of non-physical factors on neck and shoulder pain and low back pain of adolescents].

OBJECTIVE: To explore the incidence of self-reported neck/shoulder pain (NSP) and lower back pain (LBP) among Chinese adolescents in Shanghai and identify the influencing factors for the incidences of these musculoskeletal disorders. METHODS: A total of 3 600 students were selected from 30 high schools randomly chosen from 237 regular full-time high schools registered in Shanghai. From each school, 40 students were selected from each of the tenth, eleventh and twelfth grades for a total of 120 students per school. The questionnaire involved questions pertaining to demographic information, learning environment and exercise habits of each student. The questionnaire also contained questions regarding the amount of weight carried by each student while commuting to and from school. And it was also used to collect specific information related with the occurrence of NSP and LBP. Logistic regression was performed to analyze the potential risk factors for NSP and LBP. RESULTS: Among 3 600 distributed questionnaires, a total of 2 842 valid questionnaires were returned. The results revealed that the incidences of NSP and LBP in the Chinese adolescent population were 41.1% and 32.8%, respectively. Both NSP and LBP were more common in girls than in boys. And 6.3% students reported at least one NSP- or LBP-induced absence from school. Chinese adolescents generally experienced a heavy academic burden (32.7% failing to achieve daily academic goals) and mental stress (16.3% suffering from insomnia); the problem of insufficient sleep was even more pronounced (52.0% falling asleep after midnight and 64.3% suffering insufficient sleep while only 31.9% feeling physically relaxed after awaking). The multivariate Logistic regression analysis suggested that gender, grade, academic burden, stress and sleep situation had a significant correlation with NSP and LBP in adolescents. CONCLUSION: The incidences of NSP and LBP are relatively high among adolescents in Shanghai. And several factors, including sedentary behaviors, personal exercise habits and backpack weight, influences the occurrences of NSP and LBP in youth.

Incorporating mutations and bone marrow fibrosis into the revised international prognostic scoring system in myelodysplastic syndromes.

The independent prognostic significance of bone marrow fibrosis (BMF) in myelodysplastic syndromes (MDS) is challenged under currently molecular prognostic models. In this study, the clinical and genetic data from 438 MDS patients were analyzed retrospectively. The patients were randomly divided into training (n = 306) and validation (n = 132) cohorts. The independent significant prognostic factors included age, IPSS-R, BMF, TP53 and U2AF1. Using their weighted coefficients, we developed a simplified prognostic system. Four risk groups were produced: low, intermediate, high and very high. The new model yielded more clearly separated survival curves than the IPSS-R. In addition, our model achieved higher C-indexes (0.61 in the training cohort and 0.63 in the validation cohort) than the IPSS-RM model (0.59 and 0.58) and IPSS-R (0.57 and 0.56). In conclusion, BMF was an independent significant prognostic factor for MDS, and adding BMF into the IPSS-R improved its predictive capability.

A color-based tumor segmentation method for clinical ex vivo breast tissue assessment utilizing a multi-contrast brightfield imaging strategy.

We demonstrate an automated two-step tumor segmentation method leveraging color information from brightfield images of fresh core needle biopsies of breast tissue. Three different color spaces (HSV, CIELAB, YCbCr) were explored for the segmentation task. By leveraging white-light and green-light images, we identified two different types of color transformations that could separate adipose from benign and tumor or cancerous tissue. We leveraged these two distinct color transformation methods in a two-step process where adipose tissue segmentation was followed by benign tissue segmentation thereby isolating the malignant region of the biopsy. Our tumor segmentation algorithm and imaging probe could highlight suspicious regions on unprocessed biopsy tissue to guide selection of areas most similar to malignant tissues for tissue pathology whether it be formalin fixed or frozen sections, expedite tissue selection for molecular testing, detect positive tumor margins, or serve an alternative to tissue pathology, in countries where these services are lacking.

SMARCA5 reprograms AKR1B1-mediated fructose metabolism to control leukemogenesis.

A significant variation in chromatin accessibility is an epigenetic feature of leukemia. The cause of this variation in leukemia, however, remains elusive. Here, we identify SMARCA5, a core ATPase of the imitation switch (ISWI) chromatin remodeling complex, as being responsible for aberrant chromatin accessibility in leukemia cells. We find that SMARCA5 is required to maintain aberrant chromatin accessibility for leukemogenesis and then promotes transcriptional activation of AKR1B1, an aldo/keto reductase, by recruiting transcription co-activator DDX5 and transcription factor SP1. Higher levels of AKR1B1 are associated with a poor prognosis in leukemia patients and promote leukemogenesis by reprogramming fructose metabolism. Moreover, pharmacological inhibition of AKR1B1 has been shown to have significant therapeutic effects in leukemia mice and leukemia patient cells. Thus, our findings link the aberrant chromatin state mediated by SMARCA5 to AKR1B1-mediated endogenous fructose metabolism reprogramming and shed light on the essential role of AKR1B1 in leukemogenesis, which may provide therapeutic strategies for leukemia.

Adaptive Design of Fluorescence Imaging Systems for Custom Resolution, Fields of View, and Geometries.

Objective and Impact Statement: We developed a generalized computational approach to design uniform, high-intensity excitation light for low-cost, quantitative fluorescence imaging of in vitro, ex vivo, and in vivo samples with a single device. Introduction: Fluorescence imaging is a ubiquitous tool for biomedical applications. Researchers extensively modify existing systems for tissue imaging, increasing the time and effort needed for translational research and thick tissue imaging. These modifications are application-specific, requiring new designs to scale across sample types. Methods: We implemented a computational model to simulate light propagation from multiple sources. Using a global optimization algorithm and a custom cost function, we determined the spatial positioning of optical fibers to generate 2 illumination profiles. These results were implemented to image core needle biopsies, preclinical mammary tumors, or tumor-derived organoids. Samples were stained with molecular probes and imaged with uniform and nonuniform illumination. Results: Simulation results were faithfully translated to benchtop systems. We demonstrated that uniform illumination increased the reliability of intraimage analysis compared to nonuniform illumination and was concordant with traditional histological findings. The computational approach was used to optimize the illumination geometry for the purposes of imaging 3 different fluorophores through a mammary window chamber model. Illumination specifically designed for intravital tumor imaging generated higher image contrast compared to the case in which illumination originally optimized for biopsy images was used. Conclusion: We demonstrate the significance of using a computationally designed illumination for in vitro, ex vivo, and in vivo fluorescence imaging. Application-specific illumination increased the reliability of intraimage analysis and enhanced the local contrast of biological features. This approach is generalizable across light sources, biological applications, and detectors.

Association between admission heart rate and major adverse cardiovascular events in acute myocardial infarction participants with different left ventricular ejection fraction.

BACKGROUND: This study intended to investigate the independent effect of admission heart rate (HR) on the risk of major adverse cardiovascular events (MACEs) in acute myocardial infarction (AMI) patients with different left ventricular ejection fraction (LVEF) levels. METHODS: The study was a secondary analysis of the Acute Coronary Syndrome Quality Improvement in Kerela Trial. The relationship between admission HR and 30-day adverse outcomes in AMI patients with different LVEF levels was detected using a Logistic regression model. Interaction tests were used to compare the effects of different subgroups on HR and MACEs. RESULTS: Our study enrolled 18,819 patients. In both partially and fully adjusted models (Model1 and Model2), the risk of MACEs was highest in patients with HR ≥ 120 (OR: 1.62, 95%CI: (1.16, 2.26), P = 0.004, Model1; OR: 1.46, 95%CI: (1.00, 2.12), P = 0.047, Model2). There was a significant interaction between LVEF and HR (P for interaction = 0.003). Meanwhile, the trend test for this association showed that HR was positively and significantly associated with the MACEs in LVEF≥40% group (OR (95%CI): 1.27 (1.12, 1.45), P < 0.001). However, in LVEF<40% group, the trend test was not statistically significant (OR (95%CI): 1.09 (0.93, 1.29), P = 0.269). CONCLUSION: This study found that elevated admission HR was associated with a significantly higher risk for MACEs in patients admitted with AMI. Elevated admission HR was significantly associated with the risk of MACEs in AMI patients without low LVEF but not those with low LVEF (<40%). LVEF levels should be considered when evaluating the association between admission HR and the prognosis of AMI patients in the future.

Bone Marrow Fibrosis at Diagnosis and during the Course of Disease Is Associated with TP53 Mutations and Adverse Prognosis in Primary Myelodysplastic Syndrome.

The prognostic significance of bone marrow fibrosis (MF) grade in patients with myelodysplastic syndrome (MDS) is still debated and the molecular changes remain unclear. In our large cohort, a normal reticulum was found in 211 (25.9%) patients, whereas MF1, MF2 and MF3 were detected in 478 (58.7%), 90 (11.1%) and 35 (4.3%) patients at initial diagnosis, respectively. Patients with MF often correlated with some poor prognostic characteristics, including older age, anemia, unfavorable karyotype, higher BM blast and a higher IPSS-R category. For the entire cohort, the median OS was not reached, 30, 16 and 15 months for patients with MF 0, 1, 2 and 3, respectively. After adjusting for IPSS-R, the hazard ratio for mortality was 1.56 (95% CI, 1.18-2.06) for patients with MF1, 2.29 (95% CI, 1.61-3.27) for patients with MF2 and 2.75 (95% CI, 1.69-4.49) for patients with MF3 compared with those with MF0. The mutational landscape of 370 patients showed that TP53, U2AF1 and KMT2D mutations were more frequent in patients with MF2-3. In addition, of the 408 patients with MF0-1, 62 patients (15.1%) progressed to MF2-3 during the follow-up interval. The clinical features, mutation landscape and prognosis of patients with progressed fibrosis were similar to those of patients with MF2-3 at diagnosis. We concluded that BM fibrosis (MF1, 2 and 3) was an adverse prognosis feature in primary MDS and correlated with TP53 mutations both at the time of initial diagnosis and during the course of the disease. Therefore, BM fibrosis should be included in the revised prognostic scoring system and carefully considered in treatment selection.

Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia.

Aberrant self-renewal of leukemia initiation cells (LICs) drives aggressive acute myeloid leukemia (AML). Here, we report that UHRF1, an epigenetic regulator that recruits DNMT1 to methylate DNA, is highly expressed in AML and predicts poor prognosis. UHRF1 is required for myeloid leukemogenesis by maintaining self-renewal of LICs. Mechanistically, UHRF1 directly interacts with Sin3A-associated protein 30 (SAP30) through two critical amino acids, G572 and F573 in its SRA domain, to repress gene expression. Depletion of UHRF1 or SAP30 derepresses an important target gene, MXD4, which encodes a MYC antagonist, and leads to suppression of leukemogenesis. Further knockdown of MXD4 can rescue the leukemogenesis by activating the MYC pathway. Lastly, we identified a UHRF1 inhibitor, UF146, and demonstrated its significant therapeutic efficacy in the myeloid leukemia PDX model. Taken together, our study reveals the mechanisms for altered epigenetic programs in AML and provides a promising targeted therapeutic strategy against AML.

Understanding the sources of errors in ex vivo Hsp90 molecular imaging for rapid-on-site breast cancer diagnosis.

Overexpression of heat shock protein 90 (Hsp90) on the surface of breast cancer cells makes it an attractive molecular biomarker for breast cancer diagnosis. Before a ubiquitous diagnostic method can be established, an understanding of the systematic errors in Hsp90-based imaging is essential. In this study, we investigated three factors that may influence the sensitivity of ex vivo Hsp90 molecular imaging: time-dependent tissue viability, nonspecific diffusion of an Hsp90 specific probe (HS-27), and contact-based imaging. These three factors will be important considerations when designing any diagnostic imaging strategy based on fluorescence imaging of a molecular target on tissue samples.

In Vivo Optical Metabolic Imaging of Long-Chain Fatty Acid Uptake in Orthotopic Models of Triple-Negative Breast Cancer.

Targeting a tumor's metabolic dependencies is a clinically actionable therapeutic approach; however, identifying subtypes of tumors likely to respond remains difficult. The use of lipids as a nutrient source is of particular importance, especially in breast cancer. Imaging techniques offer the opportunity to quantify nutrient use in preclinical tumor models to guide development of new drugs that restrict uptake or utilization of these nutrients. We describe a fast and dynamic approach to image fatty acid uptake in vivo and demonstrate its relevance to study both tumor metabolic reprogramming directly, as well as the effectiveness of drugs targeting lipid metabolism. Specifically, we developed a quantitative optical approach to spatially and longitudinally map the kinetics of long-chain fatty acid uptake in in vivo murine models of breast cancer using a fluorescently labeled palmitate molecule, Bodipy FL c16. We chose intra-vital microscopy of mammary tumor windows to validate our approach in two orthotopic breast cancer models: a MYC-overexpressing, transgenic, triple-negative breast cancer (TNBC) model and a murine model of the 4T1 family. Following injection, Bodipy FL c16 fluorescence increased and reached its maximum after approximately 30 min, with the signal remaining stable during the 30-80 min post-injection period. We used the fluorescence at 60 min (Bodipy60), the mid-point in the plateau region, as a summary parameter to quantify Bodipy FL c16 fluorescence in subsequent experiments. Using our imaging platform, we observed a two- to four-fold decrease in fatty acid uptake in response to the downregulation of the MYC oncogene, consistent with findings from in vitro metabolic assays. In contrast, our imaging studies report an increase in fatty acid uptake with tumor aggressiveness (6NR, 4T07, and 4T1), and uptake was significantly decreased after treatment with a fatty acid transport inhibitor, perphenazine, in both normal mammary pads and in the most aggressive 4T1 tumor model. Our approach fills an important gap between in vitro assays providing rich metabolic information at static time points and imaging approaches visualizing metabolism in whole organs at a reduced resolution.

UHPLC-MS/MS method for simultaneously detecting 16 tryptamines and their metabolites in human hair and applications to real forensics cases.

Tryptamines are hallucinogenic substances many of which have appeared recently as novel psychoactive substances (NPS). Herein, we describe the establishment of a rapid UHPLC-MS/MS quantitative method for the targeted screening of 16 tryptamines of abuse in hair. Twenty milligram pieces of hair were pulverized below 4 °C in 0.5 mL of deionized water containing 0.1% formic acid and an internal standard (2 ng/mL psilocin-d10 and psilocybin-d4). After subsequent centrifugation, 5 µL of the supernatant was injected into a LC-MS/MS system fitted with a Waters Acquity UPLC HSS T3 column (100 mm × 2.1 mm, 1.8 µm). The column was gradient eluted at 0.3 mL/min with mobile phases composed of 20 mmol/L ammonium acetate, 5% acetonitrile, and 0.1% formic acid in water (solvent A) and acetonitrile (solvent B). Limits of detection ranged between 0.1 and 20 pg/mg, with limits of quantitation ranging from 3 to 50 pg/mg. The calibration curves for all analytes were linear (r > 0.992). Accuracies varied between 91% and 114%, with intraday precision RSDs < 14% and interday precision RSDs of between 1.3% and 14%. The recoveries of all tryptamines were in the 85-115% range, with the matrix effect ranging from 95% to 112%. The validated method was successfully used to analyse 191 hair samples from suspected tryptamine users, 77 of which were 5-MeO-DiPT-positive, while the 16 tryptamines and their metabolites were not detected in the remaining 114 hair samples. 5-MeO-DiPT and its 5-MeO-NiPT, 5-OH-DiPT, and 4-OH-DiPT metabolites were concurrently detected in 34 hair samples. 5-MeO-DiPT, as the parent drug, was the parent substance found in the hair samples.

Rapid characterization of chemical constituents of Gansuibanxia decoction by UHPLC-FT-ICR-MS analysis.

Gansuibanxia decoction (GSBXD) is one of the most famous traditional Chinese medicine (TCM). It is a herbal formula used for treating hydrops, such as cancerous ascites, pleural effusion, pericardial effusion, etc. However, the chemical constituents of GSBXD were still unclear. In this study, an UHPLC-FT-ICR-MS method was established and applied to the separation and characterization of the chemical constituents of GSBXD. A total of 62 components were chemically defined or tentatively identified, including diterpenoids, triterpenoids, flavonoids, monoterpene glycosides and alkaloids. The results is meaningful for a better understanding of the material basis of GSBXD and can be the basis for its further in vitro and in vivo studies.

Quantitative assessment of distant recurrence risk in early stage breast cancer using a nonlinear combination of pathological, clinical and imaging variables.

Use of genomic assays to determine distant recurrence risk in patients with early stage breast cancer has expanded and is now included in the American Joint Committee on Cancer staging manual. Algorithmic alternatives using standard clinical and pathology information may provide equivalent benefit in settings where genomic tests, such as OncotypeDx, are unavailable. We developed an artificial neural network (ANN) model to nonlinearly estimate risk of distant cancer recurrence. In addition to clinical and pathological variables, we enhanced our model using intraoperatively determined global mammographic breast density (MBD) and local breast density (LBD). LBD was measured with optical spectral imaging capable of sensing regional concentrations of tissue constituents. A cohort of 56 ER+ patients with an OncotypeDx score was evaluated. We demonstrated that combining MBD/LBD measurements with clinical and pathological variables improves distant recurrence risk prediction accuracy, with high correlation (r = 0.98) to the OncotypeDx recurrence score.

Application of hair analysis to document illegal 5-methoxy-N,N-dissopropyltrptamine (5-MeO-DiPT) use.

5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DiPT) is a designer hallucinogen that is a synthetic tryptamine derivative. It is highly abused and is involved in criminal activities because of its psychotropic properties. Herein, we presented an UHPLC-MS/MS method allowing for the qualitative and quantitative determination of 5-MeO-DiPT in human hair. The hair was first decontaminated and then cut into pieces. Thirty milligrams of hair samples was pulverized below 4°C in the presence of 0.5mL deionized water containing 0.1% formic acid. After centrifuging twice, 5µL of supernatant was injected into the LC-MS/MS system. A T3 column (100mm×2.1mm, 1.8µm) was used, and mobile phases consisted of 20mmol/L ammonium acetate, 5% acetonitrile and 0.1% formic acid in water (solvent A) and acetonitrile (solvent B). The gradient elution was used at a flow rate of 0.3mL/min. The resulting calibration curve for 5-MeO-DiPT was y=281.50213x+0.00231 (R2=0.992), the limit of detection (LOD) was 0.05pg/mg, and the lower limit of quantification (LLOQ) was 0.1pg/mg. The accuracy was between 92.1% and 105.6%, and the intra- and interday precision, recovery and matrix effect were acceptable. The validated method was successfully used in 106 real cases, and the concentration of 5-MeO-DiPT in hair samples of these suspected users was 0.2-7532.5pg/mg. These cases present data to document illegal 5-MeO-DiPT use.

The Taiji Model of Self.

An important theme in the development of self-psychology is the attempt by scholars to construct a self-model with universal cultural adaptability. Among them, representatives are the tripartite model of self-built by Triandis, the theory of the independent self and interdependent self-proposed by Markus and Kitayama, Yang Kuo-Shu's four-part theory of the Chinese self, Hwang Kwang-Kwo's Mandala model of self, and Shiah Yung-Jong's Non-self-Theory. However, these models have a difficult time explaining the structure and development of the Chinese self in Chinese cultural background. After pondering over Chinese traditional culture and the Chinese self, inspired by the archetype of Taiji diagram, in this paper, we construct the Taiji Model of Self. The Taiji Model of Self can not only properly represent the Chinese self-structure, but also explain the growth course of the Chinese self and four kinds of life realms of Chinese people with satisfactory cultural and ecological validity.

Exploiting heat shock protein expression to develop a non-invasive diagnostic tool for breast cancer.

Leveraging the unique surface expression of heat shock protein 90 (Hsp90) in breast cancer provides an exciting opportunity to develop rapid diagnostic tests at the point-of-care setting. Hsp90 has previously been shown to have elevated expression levels across all breast cancer receptor subtypes. We have developed a non-destructive strategy using HS-27, a fluorescently-tethered Hsp90 inhibitor, to assay surface Hsp90 expression on intact tissue specimens and validated our approach in clinical samples from breast cancer patients across estrogen receptor positive, Her2-overexpressing, and triple negative receptor subtypes. Utilizing a pre-clinical biopsy model, we optimized three imaging parameters that may affect the specificity of HS-27 based diagnostics - time between tissue excision and staining, agent incubation time, and agent dose, and translated our strategy to clinical breast cancer samples. Findings indicated that HS-27 florescence was highest in tumor tissue, followed by benign tissue, and finally followed by mammoplasty negative control samples. Interestingly, fluorescence in tumor samples was highest in Her2+ and triple negative subtypes, and inversely correlated with the presence of tumor infiltrating lymphocytes indicating that HS-27 fluorescence increases in aggressive breast cancer phenotypes. Development of a Gaussian support vector machine classifier based on HS-27 fluorescence features resulted in a sensitivity and specificity of 82% and 100% respectively when classifying tumor and benign conditions, setting the stage for rapid and automated tissue diagnosis at the point-of-care.