A calcineurin-Hoxb13 axis regulates growth mode of mammalian cardiomyocytes.

A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting cardiomyocytes1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest3. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of cardiomyocyte proliferation and reactivate the cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1-Hoxb13 double-knockout hearts display widespread cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of cardiomyocytes.

Antibody array-based proteome approach reveals proteins involved in grape seed development.

Grape (Vitis vinifera) is one of the most widely cultivated fruits globally, primarily used for processing and fresh consumption. Seedless grapes are favored by consumers for their convenience, making the study of seedlessness a subject of great interest to scientists. To identify regulators involved in this process in grape, a monoclonal antibody (mAb)-array-based proteomics approach, which contains 21,120 mAbs, was employed for screening proteins/antigens differentially accumulated in grape during development. Differences in antigen signals were detected between seeded and seedless grapes revealing the differential accumulation of 2,587 proteins. After immunoblotting validation, 71 antigens were further immunoprecipitated and identified by mass spectrometry (MS). An in planta protein-protein interaction (PPI) network of those differentially accumulated proteins was established using mAb antibody by immunoprecipitation (IP)-MS, which reveals the alteration of pathways related to carbon metabolism and glycolysis. To validate our result, a seedless-related protein, DUF642 domain-containing protein (VvDUF642), which is functionally uncharacterized in grapes, was ectopically overexpressed in tomato (Solanum lycopersicum "MicroTom") and led to a reduction in seed production. PPI network indicated that VvDUF642 interacts with pectin acetylesterase (VvPAE) in grapes, which was validated by BiFC and Co-IP. As anticipated, overexpression of VvPAE substantially reduced seed production in tomato. Moreover, S. lycopersicum colourless non-ripening expression was altered in VvDUF642- and VvPAE-overexpressing plants. Taken together, we provided a high-throughput method for the identification of proteins involved in the seed formation process. Among those, VvDUF642 and VvPAE are potential targets for breeding seedless grapes and other important fruits in the future.

Nasal allergen-neutralizing antibodies correlate closely with tolerated intranasal allergen challenge dose following grass pollen subcutaneous immunotherapy in patients with local allergic rhinitis.

BACKGROUND: Local allergic rhinitis (LAR) is defined by chronic nasal symptoms, absence of atopy, positive nasal allergen challenge (NAC) and a good response to subcutaneous allergen immunotherapy (SCIT). We sought to investigate SCIT capacity to induce local and systemic blocking antibodies in LAR patients. METHODS: A RDBPC study of grass SCIT was performed, with participants receiving either SCIT (Group A; n = 10) or placebo (Group B; n = 14) in the first 6 months. Both groups subsequently received SCIT for 12 months at Year 2. Nasal and serum antibodies (IgG4 , IgA1 and IgA2 ) and their inhibitory capacity were measured at multiple timepoints. RESULTS: The allergen concentration tolerated increased significantly at 6 months (Group A; p = .047) and 24 months (Group B; p = .049) compared with baseline and persisted until the end of the study. Induction of serum sIgA1 to Phl p was seen in Groups A and B, albeit the former being induced earlier (1.71-fold, p = .027). A significant induction in sIgG4 to Phl p 1 and 5 was observed in serum of Group A (p = .047 and p = .0039) and sIgA2 to Phl p in Group B (p = .032 and p = .0098) at 18 and 24 months, respectively. Both local and systemic blocking antibodies can inhibit allergen-IgE complexes binding to CD23 on B cells, and this correlated with level of allergen tolerated intra-nasally in Group A (serum; 𝜌 = -.47, p = .0006, nasal; 𝜌 = -.38, p = .0294). CONCLUSIONS: Grass pollen SCIT induced functional systemic blocking antibodies that correlate with the concentration of allergen tolerated following NAC, highlighting their potential as a biomarker of SCIT in LAR.

Application of deep learning in isolated tooth identification.

BACKGROUND: Teeth identification has a pivotal role in the dental curriculum and provides one of the important foundations of clinical practice. Accurately identifying teeth is a vital aspect of dental education and clinical practice, but can be challenging due to the anatomical similarities between categories. In this study, we aim to explore the possibility of using a deep learning model to classify isolated tooth by a set of photographs. METHODS: A collection of 5,100 photographs from 850 isolated human tooth specimens were assembled to serve as the dataset for this study. Each tooth was carefully labeled during the data collection phase through direct observation. We developed a deep learning model that incorporates the state-of-the-art feature extractor and attention mechanism to classify each tooth based on a set of 6 photographs captured from multiple angles. To increase the validity of model evaluation, a voting-based strategy was applied to refine the test set to generate a more reliable label, and the model was evaluated under different types of classification granularities. RESULTS: This deep learning model achieved top-3 accuracies of over 90% in all classification types, with an average AUC of 0.95. The Cohen's Kappa demonstrated good agreement between model prediction and the test set. CONCLUSIONS: This deep learning model can achieve performance comparable to that of human experts and has the potential to become a valuable tool for dental education and various applications in accurately identifying isolated tooth.

Effect of open surgical and percutaneous dilatational tracheostomy on postoperative wound complications in patients: A meta-analysis.

Tracheostomy is one of the most common operations. The two main methods of tracheostomy are open surgical tracheostomy (OST) and percutaneous dilatational tracheostomy (PDT). In critical cases, the combination of these two approaches is especially crucial, with the possibility of successful outcomes and low complications. Thus, the purpose of this system is to analyse the effects of both methods on the outcome of postoperative wound. In this research, we performed a systematic review of Cochrane Library, PubMed, Web of Science and Embase, to determine all randomized controlled trials (RCTs) that are comparable in terms of postoperative injury outcomes. Eleven RCTs were found after screening. This study will take the necessary data from the selected trials and evaluate the documentation for RCTs. PDT was associated with a lower incidence of infection at the wound site than OST (OR, 4.46; 95% CI: 2.84-7.02 p < 0.0001), and PDT decreased blood loss (OR, 2.88; 95% CI: 1.62-5.12 p = 0.0003). But the operation time did not differ significantly in both PDT to OST (MD, 4.65; 95% CI: -1.19-10.48 p = 0.12). The meta-analyses will assist physicians in selecting the best operative procedure for critical cases of tracheostomy. These data can serve as guidelines for clinical management and in the design of future randomized, controlled studies.

Stromal interaction molecule 1 promotes tumor growth in Esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a disease with poor prognosis which urgently is in need of effective prognostic marker. To discover novel prognostic protein marker for ESCC, we applied a high-throughput monoclonal antibody microarray to compare tumor and adjacent non-tumor tissues from ESCC patients. Antibody #ESmAb270 was consistent higher expressed in tumors and it was identified via mass spectrometry to be stromal interaction molecule 1 (STIM1). STIM1 H scores in tumor tissues were significantly up-regulated in esophageal tumor tissues compared to non-tumor tissues in 105 ESCC patients. We also observed that high STIM1 expression was correlated with advanced tumor grade and poor prognosis of ESCC. In addition, attenuation of STIM1 by siRNA or chemical inhibitors significantly inhibited cell viability and migration of ESCC cells. Evidence from high-throughput monoclonal antibody microarray, IHC microarray with associated survival data and functional analysis show that STIM1 is an unfavorable prognostic biomarker in ESCC.

TADILOF: Time Aware Density-Based Incremental Local Outlier Detection in Data Streams.

Outlier detection in data streams is crucial to successful data mining. However, this task is made increasingly difficult by the enormous growth in the quantity of data generated by the expansion of Internet of Things (IoT). Recent advances in outlier detection based on the density-based local outlier factor (LOF) algorithms do not consider variations in data that change over time. For example, there may appear a new cluster of data points over time in the data stream. Therefore, we present a novel algorithm for streaming data, referred to as time-aware density-based incremental local outlier detection (TADILOF) to overcome this issue. In addition, we have developed a means for estimating the LOF score, termed "approximate LOF," based on historical information following the removal of outdated data. The results of experiments demonstrate that TADILOF outperforms current state-of-the-art methods in terms of AUC while achieving similar performance in terms of execution time. Moreover, we present an application of the proposed scheme to the development of an air-quality monitoring system.

Transcriptome analysis of differential expressed genes in hepatopancreas of Procambarus clarkii challenged with peptidoglycan.

Procambarus clarkii is one of the most economically important species in Chinese aquaculture, and is widely cultured. Infection of P. clarkii populations with bacterial pathogens causes high mortality and great economic loss, therefore disease control is of significant economic importance. P. clarkii is a model system for studying immune responses in invertebrates, and its immune system consists solely of the innate response. In the present study, we examined gene expression related to immune function in P. clarkii in response to pathogen challenge. The transcriptome of hepatopancreas tissue from P. clarkii challenged with peptidoclycan (PGN) was analyzed and compared to control specimens. After assembly and annotation, 48,661 unigenes were identified with an average length of 671.54 bp. A total of 2533 differentially expressed genes (DEGs) were obtained, including 765 significantly up-regulated unigenes and 1757 significantly down-regulated unigenes. Gene ontology (GO) analysis demonstrated 19 biological process subcategories, 16 cellular component subcategories, and 17 molecular function subcategories that were enriched among these DEGs. Enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database revealed enrichment among immune responses pathways. Taken together, this study not only enriches the existing P. clarkii transcriptome database, but also elucidates immune responses of crayfish that are activated in response to PGN challenge.

Transcriptome-wide identification of differentially expressed genes in Procambarus clarkii in response to chromium challenge.

Because of the high protein content and rich meat quality of crayfish Procambarus clarkii, it has become widely popular in China in recent years and has a high economic value. When P. clarkii is stimulated by heavy metals, it reacts to oxidation. P. clarkii has evolved antioxidant defense systems, including antioxidant enzymes such as catalase (CAT). The hexavalent form of Cr (VI) is a pathogenic factor that is of particular concern in aqueous systems because of its great toxicity to living organisms. In this study, we characterized the transcriptome of P. clarkii using a RNA sequencing method and performed a comparison between K2Cr2O7-treated samples and controls. In total, 34,237 unigenes were annotated. We identified 5098 significantly differentially expressed genes (DEGs), including 2536 and 2562 were significantly up-regulated and down-regulated, respectively. In addition, quantitative real time-PCR (qRT-PCR) confirmed the up-regulation of a random selection of DEGs. Our results contribute to a more comprehensive understanding of the antioxidant defense system used by P. clarkii in response to heavy metal stress.

Elevated serum levels of periostin in patients with allergic bronchopulmonary aspergillosis.

BACKGROUND: Serum periostin levels have been reported to be an indicator of Th2 inflammation in asthmatic patients. OBJECTIVE: This study aimed to investigate serum levels of periostin in patients with allergic bronchopulmonary aspergillosis (ABPA) and to evaluate its diagnostic and monitoring value in the disease. METHODS: Patients with ABPA (n = 19) and asthma (n = 24), including severe asthma with fungal sensitisation (SAFS, n = 11) and severe asthma without fungal sensitization (SAwFS, n = 13), were enrolled. Serum levels of periostin were analysed by enzyme-linked immunosorbent assay. Serum total IgE and Aspergillus fumigatus specific IgE, IgG were measured by ImmunoCAP. Levels of cytokines (IFN-γ, IL-4, IL-5, IL-8, IL-10, IL-13 and IL-17A) were measured by Meso Scale Discovery (MSD). RESULTS: Serum levels of periostin in ABPA patients (85.55 ng/mL, [68.28-166] ng/mL) were higher than those in SAFS (50.99 ng/mL, [32.02-71.80] ng/mL; P < 0.01). Among the analysed cytokines, IL-5 levels in ABPA (1.55 pg/mL, [0.96-3.33] pg/mL) were higher than those in SAFS (0.31 pg/mL, [0.26-0.56] pg/mL; P < 0.05) or SAwFS (0.34 pg/mL, [0.21-0.56] pg/mL; P < 0.01). Serum periostin levels was positively associated with total IgE levels (r = 0.319, P < 0.05), serum IL-5 levels (r = 0.484, P < 0.01) and blood eosinophil counts (r = 0.428, P < 0.05). In ROC analysis, the clinical reference value of periostin was 68.8 ng/mL for differential diagnosis of ABPA and SAFS, with the area under the curve (AUC) of 0.81. Longitudinally, serum periostin levels did not change significantly after treatment in ABPA. CONCLUSIONS: These findings suggested that serum levels of periostin were up-regulated in ABPA patients, which may be associated with eosinophilic inflammation.

The diagnostic dilemma of tumor induced osteomalacia: a retrospective analysis of 144 cases.

Diagnostic delay of tumor induced osteomalacia (TIO) is common in clinic practice. To investigate the diagnostic condition of TIO in China and raise clinicians' awareness of TIO, we retrospectively analyzed clinical manifestations, biochemical features, and specially evaluated missed diagnoses and misdiagnoses among 144 TIO patients from Peking Union Medical College Hospital during December 1982 to December 2014. Clinical presentations of TIO mainly included bone pain, difficulty in walking, pathological fractures, muscle weakness, and height loss. TIO patients demonstrated hypophosphatemia (0.48±0.13 mmol/L), elevated serum alkaline phosphatase (277.9±152.6 U/L), reduced tubular maximum for phosphorus/glomerular filtration rate (0.39±0.14) and markedly elevated serum fibroblast growth factor 23 (FGF23) (median level 302.9 pg/mL). The average time from onset to a correct diagnosis was 2.9±2.3 years while the mean duration from onset to tumor resection was 5.4±4.2 years. The initial misdiagnosis rate was 95.1% (137/144) and 240 case-times of misdiagnoses occurred among the 144 cases. The most frequent misdiagnoses were intervertebral disc herniation, spondyloarthritis (including ankylosing spondylitis) and osteoporosis. A total of 43.1% (62/144) cases with hypophosphatemia presented on their laboratory sheets were neglected and missed diagnosed. Our study showed that TIO was frequently misdiagnosed and missed diagnosed due to its rarity, insidious onset, nonspecific clinical manifestations and clinicians' poor recognition. It is necessary to test serum phosphorus in patients with musculoskeletal symptoms and difficulty in walking. The measurement of serum FGF23 is rather valuable. Once hypophosphatemia is discovered, TIO should be suspected and it is highly recommended to search for tumors and perform curative surgery.

Brachial plexus injury after microwave-based treatment for axillary hyperhidrosis and osmidrosis.

Axillary hyperhidrosis combined with osmidrosis is a common problem, especially in Asian communities, that patients find annoying. Even though several surgical techniques have been reported to treat hyperhidrosis/osmidrosis permanently, patients would prefer a non-surgical approach. A microwave-based device was invented during this decade, and it has proven to be a safe and efficient way to treat axillary hyperhidrosis/osmidrosis without major complications. Mild complications reported are vacuum-associated marks, oedema, tenderness and temporary altered skin sensation. We herein report a rare case of brachial plexus injury with sensory and motor dysfunction that occurred after microwave-based treatment. The patient did not fully recover after 6 months of rehabilitation. Our case suggests that a lower initial energy level should be used for thin patients with less fat tissue on the underarm areas, regardless of the patient's sex.

Effects of spironolactone towards rabbit atrial remodeling with rapid pacing.

This study aimed to observe the effects of spironolactone towards the rabbit atrial remodeling with rapid atrial pacing (RAP). 30 rabbits were randomly divided into control group, RAP group and spironolactone group, with 10 rabbits in each group. RAP was performed at the speed of 800 beats/min for 8 h, atrial effective refractory period (AERP) was determined before and at the 1(st), 2(nd), 4(th), 6(th) and 8(th) of the pacing, the expressions of atrial muscular calcium channel α1C subunit and ß1 subunit mRNA were performed the RT-PCR detection, and ultrastructural changes of atrial myocytes were observed. AERP of RAP group shortened, with poor frequency adaptability; the expressions of calcium channel α1C subunit and ß1 subunit mRNA decreased 22% and 26%, respectively, when compared with the control group; ultrastructure of atrial myocytes changed significantly. AERP of spironotlactone group shortened less that RAP group, and the frequency adaptability was maintained, the decreased expressions of calcium channel α1C subunit and ß1 subunit mRNA significantly reduced. RAP could cause atrial remodeling, while spironolactone could inhibit RAP-induced atrial remodeling.

Clinical Evaluation of Coronary In-Stent Restenosis Using Dual-Source Computed Tomography.

OBJECTIVE: To explore the feasibility of dual-source computed tomography (DSCT) in the evaluation of coronary in-stent restenosis (ISR) by comparing the results of DSCT and selective coronary angiography (CAG). METHODS: In-stent restenosis examination results from DSCT were compared with those obtained using CAG. RESULTS: Among 173 stents studied, 156 yielded good quality images when evaluated with DSCT. CAG identified 38 ISR cases, while DSCT found 40. Among the 112 stents in the study with an inner diameter ≥3.0 mm, CAG identified 29 as having ISR, while DSCT reported the same finding in 30; among the 44 stents with inner diameter <3.0 mm, CAG identified ISR in 9, while DSCT found ISR in 10. CONCLUSIONS: Stent inner diameter is a key factor influencing the imaging of the stent lumen. DSCT demonstrated a higher negative predictive value in ISR assessment, suggesting that it could replace CAG for assessing the patency of stents with a larger inner diameter (≥3 mm).

Equivalent analytical model for liquid sloshing in a 2-D rectangular container with multiple vertical baffles by subdomain partition approach.

An equivalent analytical model of sloshing in a two-dimensional (2-D) rigid rectangular container equipped with multiple vertical baffles is presented. Firstly, according to the subdomain partition approach, the total liquid domain is partitioned into subdomains with the pure interface and boundary conditions. The separation of variables is utilized to achieve the velocity potential for subdomains. Then, sloshing characteristics are solved according to continuity and free surface conditions. According to the mode orthogonality of sloshing, the governing motion equation for sloshing under horizontal excitation is given by introducing generalized time coordinates. Besides, by producing the same hydrodynamic shear and overturning moment as those from the original container-liquid-baffle system, a mass-spring analytical model of the continuous liquid sloshing is established. The equivalent masses and corresponding locations are presented in the model. The feasibility of the present approach is verified by conducting comparative investigations. Finally, by utilizing normalized equivalent model parameters, the sloshing behaviors of the baffled container are investigated regarding baffle positions and heights as well as the liquid height, respectively.

Chicken muscle antibody array reveals the regulations of LDHA on myoblast differentiation through energy metabolism.

Myoblast proliferation and differentiation are highly dynamic and regulated processes in skeletal muscle development. Given that proteins serve as the executors for the majority of biological processes, exploring key regulatory factors and mechanisms at the protein level offers substantial opportunities for understanding the skeletal muscle development. In this study, a total of 607 differentially expressed proteins between proliferation and differentiation in myoblasts were screened out using our chicken muscle antibody array. Biological function analysis revealed the importance of energy production processes and compound metabolic processes in myogenesis. Our antibody array specifically identified an upregulation of LDHA during differentiation, which was associated with the energy metabolism. Subsequent investigation demonstrated that LDHA promoted the glycolysis and TCA cycle, thereby enhancing myoblasts differentiation. Mechanistically, LDHA promotes the glycolysis and TCA cycle but inhibits the ETC oxidative phosphorylation through enhancing the NADH cycle, providing the intermediate metabolites that improve the myoblasts differentiation. Additionally, increased glycolytic ATP by LDHA induces Akt phosphorylation and activate the PI3K-Akt pathway, which might also contribute to the promotion of myoblasts differentiation. Our studies not only present a powerful tool for exploring myogenic regulatory factors in chicken muscle, but also identify a novel role for LDHA in modulating myoblast differentiation through its regulation of cellular NAD+ levels and subsequent downstream effects on mitochondrial function.

[CDC73 gene mutation and parafibromin expression status of parathyroid carcinoma in Chinese].

OBJECTIVE: To explore the clinico-genetic characteristics and protein status of parathyroid carcinoma (PC) diagnosed at Peking Union Medical College Hospital from January 1980 to December 2012. METHODS: Genomic DNA was extracted from peripheral blood lymphocytes and paraffin-embedded tissue for analysis. The mutations of CDC73 gene were detected by direct sequencing. And the expression of parafibromin in tumor tissues was evaluated by immunohistochemical analysis. RESULTS: Twenty-four PC patients were recruited. The mean ages at the diagnosis of PHPT and PC were 42.2 and 42.6 years respectively. The serum calcium at the diagnosis of PHPT was 3.78 mmol/L, serum phosphorus 0.65 mmol/L and the median increment of serum parathyroid hormone (PTH) level 20.0. The recurrent rate was 76.2% during a 5-year follow-up.Genetic analysis identified 11 mutations of CDC73 gene (45.8%), among which c.34_35 insCT, c.626_629 delAACA, c.260_261 delGA, c.570 delG, c.40 C>T and IVS3+1 G>A were novel mutation first identified in our cohort. Nine of them had germline mutations. All tissue samples from normal parathyroid displayed strong positive immunostaining of parafibromin. Complete (55%, 11/20) or partial (45%, 9/20) loss of parafibromin expression was observed in PC tissues. The age at the diagnosis of PHPT, serum calcium, serum phosphorus, PTH, alkaline phosphatase (ALP), bone involvement rate, kidney stone/calcification rate, recurrent rate, metastatic rate and immunostaining level showed no significant difference between the patients with and without CDC73 mutation. CONCLUSION: In Chinese population, CDC73 mutation and complete/partial loss of immunohistochemical staining for parafibromin occur frequently in PC. Therefore it may be useful in the subset of tumors with equivocal histological examination.

Immunological mechanisms of tolerance: Central, peripheral and the role of T and B cells.

T and B cells are key components of the adaptive immune system. Through their immune properties and their interactions with other immune cells and cytokines around them, they build a complex network to achieve immune tolerance and maintain homeostasis of the body. This is achieved through mechanisms of central and peripheral tolerance, both of which are associated with advantages and disadvantages. For this reason, the immune system is tightly regulated and their dysregulation can result in the subsequent initiation of various diseases. In this review, we will summarize the roles played by T cells and B cells within immune tolerance with specific examples in the context of different diseases that include allergic disease. In addition, we will also provide an overview on their suitability as biomarkers of allergen-specific immunotherapy.

MTX-13, a Novel PTK7-Directed Antibody-Drug Conjugate with Widened Therapeutic Index Shows Sustained Tumor Regressions for a Broader Spectrum of PTK7-Positive Tumors.

Protein tyrosine kinase 7 (PTK7) is a Wnt signaling pathway protein implicated in cancer development and metastasis. When using a potent microtubule inhibitor (Aur0101), PTK7-targeting antibody-drug conjugate (ADC), h6M24-vc0101 (PF-06647020/cofetuzumab pelidotin) is efficacious only in limited tumor types with low response rates in a phase I trial. To improve patient response and to expand responding tumor types, we designed MTX-13, a PTK7-targeting ADC consisting of a novel antibody (Ab13) conjugated to eight molecules of topoisomerase I inhibitor exatecan through T1000, a novel self-immolative moiety. MTX-13 exhibited PTK7-specific cell binding, efficient internalization, and exatecan release to cause cytotoxic activity through DNA damage and apoptosis induction, and a strong bystander killing. MTX-13 displayed potent antitumor activities on cell line-derived xenograft and patient-derived xenograft models from a wide range of solid tumors, significantly outperforming h6M24-vc0101. PTK7 was shown to be an actionable target in small cell lung cancer for which MTX-13 showed complete and durable responses. With a consistent overexpression of PTK7 in squamous cell carcinomas derived from diverse anatomic sites, strong potency of MTX-13 in this group of heterogenous tumors suggested a common treatment strategy. Finally, MTX-13 inhibited tumor growth and metastasis in an orthotopic colon cancer xenograft model. MTX-13 displayed a favorable pharmacokinetic and safety profile in monkeys with the highest non-severely toxic dose (HNSTD) of ≥30 mg/kg, significantly higher than 3-5 mg/kg of HNSTD for h6M24-vc0101. The higher therapeutic index of MTX-13 bodes well for its clinical translation with the potential to expand the responding patient population beyond that of current PTK7-targeting ADCs.

AMT-562, a Novel HER3-targeting Antibody-Drug Conjugate, Demonstrates a Potential to Broaden Therapeutic Opportunities for HER3-expressing Tumors.

HER3 is a unique member of the EGFR family of tyrosine kinases, which is broadly expressed in several cancers, including breast, lung, pancreatic, colorectal, gastric, prostate, and bladder cancers and is often associated with poor patient outcomes and therapeutic resistance. U3-1402/Patritumab-GGFG-DXd is the first successful HER3-targeting antibody-drug conjugate (ADC) with clinical efficacy in non-small cell lung cancer. However, over 60% of patients are nonresponsive to U3-1402 due to low target expression levels and responses tend to be in patients with higher target expression levels. U3-1402 is also ineffective in more challenging tumor types such as colorectal cancer. AMT-562 was generated by a novel anti-HER3 antibody Ab562 and a modified self-immolative PABC spacer (T800) to conjugate exatecan. Exatecan showed higher cytotoxic potency than its derivative DXd. Ab562 was selected because of its moderate affinity for minimizing potential toxicity and improving tumor penetration purposes. Both alone or in combination therapies, AMT-562 showed potent and durable antitumor response in low HER3 expression xenograft and heterogeneous patient-derived xenograft/organoid models, including digestive system and lung tumors representing of unmet needs. Combination therapies pairing AMT-562 with therapeutic antibodies, inhibitors of CHEK1, KRAS, and tyrosine kinase inhibitor showed higher synergistic efficacy than Patritumab-GGFG-DXd. Pharmacokinetic and safety profiles of AMT-562 were favorable and the highest dose lacking severe toxicity was 30 mg/kg in cynomolgus monkeys. AMT-562 has potential to be a superior HER3-targeting ADC with a higher therapeutic window that can overcome resistance to generate higher percentage and more durable responses in U3-1402-insensitive tumors.