Microarray-Based CD38 Peptide Probe Screening for Multiple Myeloma Imaging.

Assessing CD38 expression in vivo has become a significant element in multiple myeloma (MM) therapy, as it can be used to detect lesions and forecast the effectiveness of treatment. Accurate diagnosis requires a multifunctional, high-throughput probe screening platform to develop molecular probes for tumor-targeted multimodal imaging and treatment. Here, we investigated a microarray chip-based strategy for high-throughput screening of peptide probes for CD38. We obtained two new target peptides, CA-1 and CA-2, from a 105 peptide library with a dissociation constant (KD) of 10-7 M. The specificity and affinity of the target peptides were confirmed at the molecular and cellular levels. Peptide probes were labeled with indocyanine green (ICG) dye and 68Ga-DOTA, which were injected into a CD38-positive Ramos tumor-bearing mouse via its tail vein, and small animal fluorescence and positron emission tomography (PET) imaging showed that the peptide probes could show specific enrichment in the tumor tissue. Our study shows that a microchip-based screening of peptide probes can be used as a promising imaging tool for MM diagnosis.

Ultrasonic-responsive piezoelectric stimulation enhances sonodynamic therapy for HER2-positive breast cancer.

INTRODUCTION: Breast cancer ranks second as the most common malignancy globally, after lung cancer. Among the various subtypes of breast cancer, HER2 positive breast cancer (HER2 BC)poses a particularly challenging prognosis due to its heightened invasiveness and metastatic potential. The objective of this study was to construct a composite piezoelectric nanoparticle based on poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)) for imaging and treatment of HER2 BC. METHOD: By reshaping the crystal structure of P(VDF-TrFE) piezoelectric nanoparticles, improving hydrophilicity, and incorporating imaging capabilities, we developed piezoelectric composite nanoparticles (PGd@tNBs) that integrate imaging and therapeutic functions. The in vitro characterization encompassed the assessment of piezoelectric properties, hydrophilicity, imaging performance, and therapeutic efficacy of these particles. The targeting and therapeutic effectiveness of PGd@tNBs particles were further validated in the SK-BR3 cell line and subsequently confirmed in HER2-positive tumor-bearing mice. RESULTS: The nanoparticle demonstrated excellent biocompatibility and impressive multimodal imaging performance. Magnetic resonance imaging (MRI) observations revealed significant accumulation of PGd@tNBs particles in the HER2 positive tumor, exhibiting superior contrast-enhanced ultrasound performance compared to traditional ultrasound contrast agents, and small animal in vivo imaging showed that PGd@tNBs particles were primarily excreted through respiration and urinary metabolism. Piezoforce Microscopy characterization highlighted the outstanding piezoelectric properties of PGd@tNBs particles. Upon targeted binding to HER2-BC, ultrasound stimulation influenced the cell membrane potential, leading to reversible electroporation. This, in turn, affected the balance of calcium ions inside and outside the cells and the mitochondrial membrane potential. Following ingestion by cells, PGd@tNBs, when exposed to ultrasound, triggered the generation of reactive oxygen species (ROS), resulting in the consumption of glutathione and superoxide dismutase and achieving sonodynamic therapy. Notably, repeated ultrasound stimulation, post PGd@tNBs particles binding and entry into cells, increased ROS production and elevated the apoptosis rate by approximately 45%. CONCLUSION: In conclusion, the PGd@tNBs particles developed exhibit outstanding imaging and therapeutic efficacy, holding potential for precise diagnosis and personalized treatment of HER2 BC.

A gadoxetic acid-enhanced MRI-based model using LI-RADS v2018 features for preoperatively predicting Ki-67 expression in hepatocellular carcinoma.

PURPOSE: To construct a gadoxetic acid-enhanced MRI (EOB-MRI) -based multivariable model to predict Ki-67 expression levels in hepatocellular carcinoma (HCC) using LI-RADS v2018 imaging features. METHODS: A total of 121 patients with HCC who underwent EOB-MRI were enrolled in this study. The patients were divided into three groups according to Ki-67 cut-offs: Ki-67 ≥ 20% (n = 86) vs. Ki-67 < 20% (n = 35); Ki-67 ≥ 30% (n = 73) vs. Ki-67 < 30% (n = 48); Ki-67 ≥ 50% (n = 45) vs. Ki-67 < 50% (n = 76). MRI features were analyzed to be associated with high Ki-67 expression using logistic regression to construct multivariable models. The performance characteristic of the models for the prediction of high Ki-67 expression was assessed using receiver operating characteristic curves. RESULTS: The presence of mosaic architecture (p = 0.045), the presence of infiltrative appearance (p = 0.039), and the absence of targetoid hepatobiliary phase (HBP, p = 0.035) were independent differential factors for the prediction of high Ki-67 status (≥ 50% vs. < 50%) in HCC patients, while no features could predict high Ki-67 status with thresholds of 20% (≥ 20% vs. < 20%) and 30% (≥ 30% vs. < 30%) (p > 0.05). Four models were constructed including model A (mosaic architecture and infiltrated appearance), model B (mosaic architecture and targetoid HBP), model C (infiltrated appearance and targetoid HBP), and model D (mosaic architecture, infiltrated appearance and targetoid HBP). The model D yielded better diagnostic performance than the model C (0.776 vs. 0.669, p = 0.002), but a comparable AUC than model A (0.776 vs. 0.781, p = 0.855) and model B (0.776 vs. 0.746, p = 0.076). CONCLUSIONS: Mosaic architecture, infiltrated appearance and targetoid HBP were sensitive imaging features for predicting Ki-67 index ≥ 50% and EOB-MRI model based on LI-RADS v2018 features may be an effective imaging approach for the risk stratification of patients with HCC before surgery.

Accurate measurement of microsatellite length by disrupting its tandem repeat structure.

Tandem repeats of simple sequence motifs, also known as microsatellites, are abundant in the genome. Because their repeat structure makes replication error-prone, variant microsatellite lengths are often generated during germline and other somatic expansions. As such, microsatellite length variations can serve as markers for cancer. However, accurate error-free measurement of microsatellite lengths is difficult with current methods precisely because of this high error rate during amplification. We have solved this problem by using partial mutagenesis to disrupt enough of the repeat structure of initial templates so that their sequence lengths replicate faithfully. In this work, we use bisulfite mutagenesis to convert a C to a U, later read as T. Compared to untreated templates, we achieve three orders of magnitude reduction in the error rate per round of replication. By requiring agreement from two independent first copies of an initial template, we reach error rates below one in a million. We apply this method to a thousand microsatellite loci from the human genome, revealing microsatellite length distributions not observable without mutagenesis.

Copolymerization of single-cell nucleic acids into balls of acrylamide gel.

We show the use of 5'-Acrydite oligonucleotides to copolymerize single-cell DNA or RNA into balls of acrylamide gel (BAGs). Combining this step with split-and-pool techniques for creating barcodes yields a method with advantages in cost and scalability, depth of coverage, ease of operation, minimal cross-contamination, and efficient use of samples. We perform DNA copy number profiling on mixtures of cell lines, nuclei from frozen prostate tumors, and biopsy washes. As applied to RNA, the method has high capture efficiency of transcripts and sufficient consistency to clearly distinguish the expression patterns of cell lines and individual nuclei from neurons dissected from the mouse brain. By using varietal tags (UMIs) to achieve sequence error correction, we show extremely low levels of cross-contamination by tracking source-specific SNVs. The method is readily modifiable, and we will discuss its adaptability and diverse applications.

A Reactive Oxygen Species-Responsive Targeted Nanoscavenger to Promote Mitophagy for the Treatment of Alzheimer's Disease.

Mitophagy modulators are proposed as potential therapeutic intervention that enhance neuronal health and brain homeostasis in Alzheimer's disease (AD). Nevertheless, the lack of specific mitophagy inducers, low efficacies, and the severe side effects of nonselective autophagy during AD treatment have hindered their application. In this study, the P@NB nanoscavenger is designed with a reactive-oxygen-species-responsive (ROS-responsive) poly(l-lactide-co-glycolide) core and a surface modified with the Beclin1 and angiopoietin-2 peptides. Notably, nicotinamide adenine dinucleotide (NAD+ ) and Beclin1, which act as mitophagy promoters, are quickly released from P@NB in the presence of high ROS levels in lesions to restore mitochondrial homeostasis and induce microglia polarization toward the M2-type, thereby enabling it to phagocytose amyloid-peptide (Aß). These studies demonstrate that P@NB accelerates Aß degradation and alleviates excessive inflammatory responses by restoring autophagic flux, which ameliorates cognitive impairment in AD mice. This multitarget strategy induces autophagy/mitophagy through synergy, thereby normalizing mitochondrial dysfunction. Therefore, the developed method provides a promising AD-therapy strategy.

Phononically shielded photonic-crystal mirror membranes for cavity quantum optomechanics.

We present a highly reflective, sub-wavelength-thick membrane resonator featuring high mechanical quality factor and discuss its applicability for cavity optomechanics. The 88.5 nm thin stoichiometric silicon-nitride membrane, designed and fabricated to combine 2D-photonic and phononic crystal patterns, reaches reflectivities up to 99.89 % and a mechanical quality factor of 2.9 × 107 at room temperature. We construct a Fabry-Perot-type optical cavity, with the membrane forming one terminating mirror. The optical beam shape in cavity transmission shows a stark deviation from a simple Gaussian mode-shape, consistent with theoretical predictions. We demonstrate optomechanical sideband cooling to mK-mode temperatures, starting from room temperature. At higher intracavity powers we observe an optomechanically induced optical bistability. The demonstrated device has potential to reach high cooperativities at low light levels desirable, for example, for optomechanical sensing and squeezing applications or fundamental studies in cavity quantum optomechanics; and meets the requirements for cooling to the quantum ground state of mechanical motion from room temperature.

Optimizing CT and MRI criteria for differentiating intrahepatic mass-forming cholangiocarcinoma and hepatocellular carcinoma.

BACKGROUND: Accurate diagnosis of intrahepatic mass-forming cholangiocarcinoma (IMCC) is crucial with regard to the choice of patient management and treatment options. PURPOSE: To evaluate the feasibility and diagnostic performance of the LI-RADS M (LR-M) targetoid criteria on computed tomography (CT) and gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) in differentiating IMCC from hepatocellular carcinoma (HCC). MATERIAL AND METHODS: A total of 118 patients with IMCC and HCC were included who underwent CT and EOB-MRI examinations. Multivariate analysis was used to determine the strongest predictors differentiating IMCC from HCC. Using these predictors, a predictive model for differentiating IMCC from HCC was constructed and the performance of the model was confirmed using the receiver operating characteristic curve. RESULTS: Multivariate analyses revealed rim-like arterial phase hyperenhancement (rim APHE) on CT and rim APHE, delayed central enhancement (DCE), and targetoid hepatobiliary phase (HBP) on MRI as independent variables significantly differentiating IMCC from HCC. The multivariate logistic regression model incorporating the three variables on EOB-MRI was constructed with an area under the curve (AUC) of 0.946, sensitivity of 87.80%, specificity of 92.21%, and accuracy of 94.60%. Per the DeLong test, the multivariate logistic regression model showed significantly higher AUC than rim APHE on CT (0.946 vs. 0.871; P = 0.008) and MRI (0.946 vs. 0.876; P = 0.003), whereas rim APHE on CT and MRI did not differ significantly (P = 0.809). CONCLUSION: The multivariate logistic regression model based on rim APHE, DCE, and targetoid HBP on EOB-MRI can effectively distinguish IMCC from HCC and is superior to any other targetoid appearance criterion of LI-RADS on CT and EOB-MRI.

A Novel Homodimer Peptide-Drug Conjugate Improves the Efficacy of HER2-Positive Breast Cancer Therapy.

Tumor-targeting peptide-drug conjugates (PDCs) have become a focus of research in recent years. However, due to the instability of peptides and their short in vivo effective half-life, they have limited clinical application. Herein, we propose a new DOX PDC based on a homodimer HER-2-targeting peptide and acid-sensitive hydrazone bond, which could enhance the anti-tumor effect of DOX and reduce systemic toxicities. The PDC could accurately deliver DOX into HER2-positive SKBR-3 cells, with it showing 2.9 times higher cellular uptake than free DOX and enhanced cytotoxicity with respect to IC50 of 140 nM (vs. 410 nM for free DOX). In vitro assays showed that the PDC had high cellular internalization efficiency and cytotoxicity. In vivo anti-tumor experiments indicated that the PDC could significantly inhibit the growth of HER2-positive breast cancer xenografts in mice and reduce the side effects of DOX. In summary, we constructed a novel PDC molecule targeting HER2-positive tumors, which may overcome some deficiencies of DOX in breast cancer therapy.

Fibroblast Activation Protein-α Responsive Peptide Assembling Prodrug Nanoparticles for Remodeling the Immunosuppressive Microenvironment and Boosting Cancer Immunotherapy.

Checkpoint blockade immunotherapy has broad application prospects in the clinical treatment of malignant tumors. However, the low response rate of the checkpoint blockade is due to low tumor immunogenicity and immunosuppression within the tumor microenvironment. Herein, the authors design an amphiphilic bifunctional PD-1/PD-L1 peptide antagonist PCP, and co-deliver doxorubicin (DOX) and R848 through co-assembly of a multi-agent prodrug (PCP@R848/DOX), which can be specifically cleaved by fibroblast activation protein-α (FAP-α) in the tumor stroma. Upon reaching the tumor tissue, the PCP@R848/DOX prodrug nanostructure is disassembled by FAP-α. The localized release of DOX and R848 triggers immunogenic cell death (ICD) and reprograms tumor-associated macrophages (TAMs) to elicit antitumor immunity. Furthermore, sustained release of PD-1 or PD-L1 peptide antagonists mediates the PD-L1 pathway blockade for further propagated activation of cytotoxic T lymphocytes. Notably, a tumor microenvironment activatable prodrug nanoparticle is presented for triple-modality cancer therapy that functions by simultaneously activating ICD and altering the phenotype of TAMs when combined with PD-1 blockade therapy, which efficiently elicits a strong systemic antitumor immune response. This strategy may emerge as a new paradigm in the treatment of cancer by combination immunotherapy.

Optically Triggering and Monitoring Single-Cell-Level Metabolism Using Ormosil-Decorated Ultrathin Fibers.

The integration of biological components and artificial devices requires a bio-machine interface that can simultaneously trigger and monitor the activities in biosystems. Herein, we use an organically modified silicate (ormosil) composite coating containing a light-responsive nanocapsule and a fluorescent bioprobe for reactive oxygen species (ROS) to decorate ultrathin optical fibers, namely, ormosil-decorated ultrathin fibers (OD-UFs), and demonstrate that these OD-UFs can optically trigger and monitor the intracellular metabolism activities in living cells. The sizes and shapes of UF tips were finely controlled to match the dimension and mechanical properties of living cells. The increased elasticity of the ormosil coating of OD-UFs reduces possible mechanical damage during the cell membrane penetration. The light-responsive nanocapsule was physically absorbed on the surface of the ormosil coating and could release a stimulant to trigger the metabolism activities in cells upon the guided laser through OD-UFs. The fluorescent bioprobe was covalently linked with the ormosil matrix for monitoring the intracellular ROS generation, which was verified by the in vitro experiments on the microdroplets of a hydrogen peroxide solution. Finally, we found that the living cells could maintain most of their viability after being inserted with OD-UFs, and the intracellular metabolism activities were successfully triggered and monitored at the single-cell level. The OD-UF provides a new platform for the investigation of intracellular behaviors for drug stimulations and represents a new proof of concept for a bio-machine interface based on the optical and chemical activities of organic functional molecules.

Rheumatoid arthritis drug sinomenine induces apoptosis of cervical tumor cells by targeting thioredoxin reductase in vitro and in vivo.

Overexpression of thioredoxin reductase (TrxR) has been linked to tumorigenesis and phenotypic maintenance of malignant tumors. Thus, targeting TrxR with natural molecules is a promising strategy for developing anticancer drugs. Sinomenine is a naturally occurring alkaloid isolated from Sinomenium acutum. The drug, Zhengqing Fengtongning made from sinomenine, has been universally applied in rheumatoid arthritis treatment in China as well as other Asian countries for decades. Recently, increasing evidence indicates that sinomenine appears to be a promising therapeutic agent against various cancer cells. However, the exact mechanism underlying the anticancer activity of sinomenine remains unclear. In this study, we identified sinomenine as a kind of new inhibitor for TrxR. Pharmacological inhibition of TrxR by sinomenine results in the decrease of thiols content, increases the levels of reactive oxygen species, and finally facilitates oxidative stress-mediated cancer cell apoptosis. It is vital that knockdown in TrxR1 by shRNA can increase cell sensitivity to sinomenine. Treatment with sinomenine in vivo leads to a decrease in TrxR activity and tumor growth, and an increase in apoptosis. Our findings provide a novel action mechanism related to sinomenine and presents an insight on how to develop sinomenine as a chemotherapeutic agent for cancer therapy.

Multiplex accurate sensitive quantitation (MASQ) with application to minimal residual disease in acute myeloid leukemia.

Measuring minimal residual disease in cancer has applications for prognosis, monitoring treatment and detection of recurrence. Simple sequence-based methods to detect nucleotide substitution variants have error rates (about 10-3) that limit sensitive detection. We developed and characterized the performance of MASQ (multiplex accurate sensitive quantitation), a method with an error rate below 10-6. MASQ counts variant templates accurately in the presence of millions of host genomes by using tags to identify each template and demanding consensus over multiple reads. Since the MASQ protocol multiplexes 50 target loci, we can both integrate signal from multiple variants and capture subclonal response to treatment. Compared to existing methods for variant detection, MASQ achieves an excellent combination of sensitivity, specificity and yield. We tested MASQ in a pilot study in acute myeloid leukemia (AML) patients who entered complete remission. We detect leukemic variants in the blood and bone marrow samples of all five patients, after induction therapy, at levels ranging from 10-2 to nearly 10-6. We observe evidence of sub-clonal structure and find higher target variant frequencies in patients who go on to relapse, demonstrating the potential for MASQ to quantify residual disease in AML.

Novel Peptide-Based Magnetic Nanoparticle for Mesenchymal Circulating Tumor Cells Detection.

The monitoring of circulating tumor cells (CTCs) has recently served as a promising approach for assessing prognosis and evaluating cancer treatment. We have already developed a CTCs enrichment platform by EpCAM recognition peptide-functionalized magnetic nanoparticles (EP@MNPs). However, considering heterogeneous CTCs generated through epithelial-mesenchymal transition (EMT), mesenchymal CTCs would be missed with this method. Notably, N-cadherin, overexpressed on mesenchymal CTCs, can facilitate the migration of cancer cells. Hence, we screened a novel peptide targeting N-cadherin, NP, and developed a new CTCs isolation approach via NP@MNPs to complement EpCAM methods' deficiencies. NP@MNPs had a high capture efficiency (about 85%) of mesenchymal CTCs from spiked human blood. Subsequently, CTCs were captured and sequenced at the single-cell level via NP@MNPs and EP@MNPs, RNA profiles of which showed that epithelial and mesenchymal subgroups could be distinguished. Here, a novel CTCs isolation platform laid the foundation for mesenchymal CTCs isolation and subsequent molecular analysis.

Ultrasensitive Gastric Cancer Circulating Tumor Cellular CLDN18.2 RNA Detection Based on a Molecular Beacon.

Gastric cancer (GC) is a major global cancer burden, and only HER2-targeted therapies have been approved in first line clinical therapy. CLDN18.2 has been regarded as a potential therapeutic target for gastrointestinal tumors, and global clinical trials have been in process. Hence, the precise, efficient, and noninvasive detection of CLDN18.2 expression is important for the effective application of this attractive target. A high similarity of protein sequence between CLDN18.1 and -18.2 made RNA become more suitable for the detection of CLDN18.2 expression. In this study, CLDN18.2 molecular beacon (MB) with a stem-loop hairpin structure was optimized by phosphorothioate and 2'-O-methyl for stability and efficiency. The MB could recognize CLDN18.2 RNA rapidly. Its resolution and selectivity has been verified in several model cells, demonstrating that MB can distinguish CLDN18.2 expression in several model cells. Furthermore, it was applied successfully to the circulating tumor cell (CTC) assay. The concordance in the expression of CLDN18.2 between CTCs and tissue biopsy is 100% (negative: 3 vs 3; positive: 7 vs 7), indicating that CLDN18.2 RNA detection in CTCs based on a MB will be a promising approach for searching potential patients to CLDN 18.2 targeted drug.

Novel Environmentally Friendly Waterborne Epoxy Coating with Long-Term Antiscaling and Anticorrosion Properties.

Metal pipes in industrial production are exposed to various corrosive ions. The combined action of these ions with oxygen in water causes corrosion and contamination of the metal pipes and equipment. In addition, metallic ions in water react with anions to form scale on the surface of the metal, which significantly reduces the service life of the metal and equipment, resulting in safety hazards. Waterborne coatings have attracted tremendous attention due to the less negative impact on the environment, but their practical applications are severely restricted by poor barrier properties and poor mechanical durability. Herein, the barrier properties of water-based coatings are successfully improved by adding functional slow-release nanofillers, and the fillers also endow the coating with excellent antiscaling properties. A functional slow-release nanofiller (lecithin/SiO2/HEDP) was prepared using HEDP (etidronic acid) as the scale inhibitor active material and SiO2 as the carrier, combined with a phospholipid membrane with slow-release permeability. With the addition of slow-release fillers, compared with the EP coating, the impedance modulus of composite coatings increases about 1 order of magnitude, the scale inhibition rate is as high as 80.7%, and the antiscaling life is double that of the coating without the phospholipid-coated filler. Thus, this study is expected to provide a new perspective for the preparation of new slow-release fillers and high-efficiency scale inhibitor coatings.

Identification of genetic variants in a pedigree associated with epilepsy by using whole exome sequencing and whole genome sequencing.

Epilepsy is a common heterogeneous group of neurological disorders including electroencephalographic and brain imaging. We used whole exome sequencing and whole genome sequencing to identify variants in a pedigree associated with epilepsy. Cranium CT scan showed that the lateral right parietal lobe was hyperdense, and there were no clear boundaries with brain tissue in affected cases. Using WES, one exclusive nonsynonymous mutant in gene TSC2 (Chr16:2138307; c.5240 T > G; p.Ile1747Ser) was involved in this disease. Further analysis showed that de novo variant in TSC2 was high conserved across different species. Moreover, the two affected sisters and their father had the same compound heterozygous variants in TSC2, while the father had no epilepsy but depigmentation. These variants demonstrated that variant in TSC2 may result in epilepsy with incomplete penetrance in humans, and the CNV and SV variants we identified probably be involved in this disease.

Synergetic Tumor Probes for Facilitating Therapeutic Delivery by Combined-Functionalized Peptide Ligands.

Both targeting and penetrating ability are the key characteristics for tissue probing and precise delivery. To construct an efficient nano probing and delivery system toward human epidermal growth factor receptor 2 (HER2) positive cancer, we established a nano liposomal system functionalized with a newly screened HER2 targeting peptide (HP2, YDLKEPEH) and the cell-penetrating peptide TAT simultaneously. Compared with the monofunctionalized liposomal probes, the dual-functional ones demonstrated a synergetic effect in cell uptake, drug delivery, and in vivo imaging. The improved efficacy of the synergetic system provides a prospective strategy for cancer diagnosis and therapy.

Imaging and monitoring HER2 expression in breast cancer during trastuzumab therapy with a peptide probe 99mTc-HYNIC-H10F.

PURPOSE: The novel molecular imaging probe 99mTc-HYNIC-H10F was developed for patient screening and efficacy monitoring of trastuzumab therapy by SPECT imaging of HER2 expression in breast cancer. METHODS: 99mTc-HYNIC-H10F was developed by labeling H10F peptide with 99mTc following an optimized protocol. Biodistribution and SPECT/CT were performed in mouse models bearing HER2-positive SK-BR3 and HER2-negative MDA-MB-231 human breast cancer xenografts, respectively. The treatment response to trastuzumab was monitored and quantified by SPECT/CT in two HER2-positive breast cancer models (SK-BR3 and MDA-MB-361). The preliminary clinical study was performed in two patients with breast cancer. RESULTS: SPECT/CT with 99mTc-HYNIC-H10F showed that the SK-BR3 tumors were clearly visualized, while the signals from MDA-MB-231 tumors were much lower. The tumor uptake of 99mTc-HYNIC-H10F could be blocked by excess unlabeled H10F peptide but not by excess trastuzumab. The growth of two HER2-positive tumors was prominently suppressed at day 11 post-treatment. However, SPECT/CT reflected much earlier therapy response at day 4 post-treatment. The HER2 expression in tumors of breast cancer patients could be detected by 99mTc-HYNIC-H10F SPECT/CT imaging. CONCLUSIONS: 99mTc-HYNIC-H10F specifically accumulates in HER2-positive tumors. Compared with trastuzumab, 99mTc-HYNIC-H10F binds to a different domain of HER2 antigen, providing new opportunities to monitor HER2 expression levels before/during/after trastuzumab treatment for more effective personalized treatment.

The contribution of de novo coding mutations to autism spectrum disorder.

Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.