YES1 activation induces acquired resistance to neratinib in HER2‐amplified breast and lung cancers

Molecular‐targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan‐HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2‐positive breast cancer. However, acquired resistance of various cancers to molecular‐targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib‐resistant cell lines from HER2‐amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib‐resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1‐amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2‐targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome.     

Robot-Assisted Radical Prostatectomy for Potential Cancer Control in Patients with Metastatic Prostate Cancer

Recently, cytoreductive prostatectomy for metastatic prostate cancer (mPCa) has been associated with improved oncological outcomes. This study was aimed at evaluating whether robot-assisted radical prostatectomy (RARP) as a form of cytoreductive prostatectomy can improve oncological outcomes in patients with mPCa. We conducted a retrospective study of twelve patients with mPCa who had undergone neoadjuvant therapy followed by RARP. The endpoints were biochemical recurrence-free survival, treatment-free survival, and de novo metastasis-free survival. At the end of the follow-up period, none of the enrolled patients had died from PCa. The 1- and 2-year biochemical recurrence-free survival rates were 83.3% and 66.7%, respectively, and treatment-free survival rates were 75.0% and 56.3%, respectively. One patient developed de novo bone metastases 6.4 months postoperatively, and castration-resistant prostate cancer 8.9 months postoperatively. After RARP, the median duration of recovery of urinary continence was 5.2 months. One patient had severe incontinence (>2 pads/day) 24 months postoperatively. RARP may be a treatment option in patients with mPCa who have achieved a serum prostate-specific antigen level < 0.2 ng/mL, and present without new lesions on imaging.     

A modified MethyLight assay predicts the clinical outcomes of anti‐epidermal growth factor receptor treatment in metastatic colorectal cancer

DNA methylation status correlates with clinical outcomes of anti‐epidermal growth factor receptor (EGFR) treatment. There is a strong need to develop a simple assay for measuring DNA methylation status for the clinical application of drug selection based on it. In this study, we collected data from 186 patients with metastatic colorectal cancer (mCRC) who had previously received anti‐EGFR treatment. We modified MethyLite to develop a novel assay to classify patients as having highly methylated colorectal cancer (HMCC) or low‐methylated colorectal cancer (LMCC) based on the methylation status of 16 CpG sites of tumor‐derived genomic DNA in the development cohort (n = 30). Clinical outcomes were then compared between the HMCC and LMCC groups in the validation cohort (n = 156). The results showed that HMCC had a significantly worse response rate (4.2% vs 33.3%; P = .004), progression‐free survival (median: 2.5 vs 6.6 mo, P < .001, hazard ratio [HR] = 0.22), and overall survival (median: 5.6 vs 15.5 mo, P < .001, HR = 0.23) than did LMCC in patients with RAS wild‐type mCRC who were refractory or intolerable to oxaliplatin‐ and irinotecan‐based chemotherapy (n = 101). The DNA methylation status was an independent predictive factor and a more accurate biomarker than was the primary site of anti‐EGFR treatment. In conclusion, our novel DNA methylation measurement assay based on MethyLight was simple and useful, suggesting its implementation as a complementary diagnostic tool in a clinical setting.     

AI Implementation Science for Social Issues: Pitfalls and Tips

The social implementation of knowledge and technologies that are effective in epidemiological and observational studies is essential for solving social issues. In particular, there have been few attempts to implement clinical practices and information communication technologies that utilize data in the field. We describe the four stages of social implementation: 1) redefining social issues as solvable problems, 2) finding technological solutions to solvable problems, 3) social implementation contributing to the solutions, and 4) horizontal deployment of effective methods for solving social issues. Introducing a use case of artificial intelligence (AI) social implementation in child-abuse response conducted by our team, we discuss pitfalls and tips as a frame of reference to demonstrate data utilization as social infrastructure for solving social issues and to consider practical solutions in a logical manner.Key words: child abuse, child maltreatment, AI, implementation, machine learning     

Exposure time reduction of secondary radiographs used in digital subtraction radiography in detecting intrabony change

Objectives

Digital subtraction radiography (DSR) is a suitable technique for detecting incipient bone changes. However, in DSR, one or more follow-up radiographs must be taken. The aim of this study was to assess the possibility of reducing the exposure time for the radiographs that follow the initial one.

Methods

Maxillary premolar and molar radiographic images of a dry skull were taken with a digital radiography system. The initial radiographs, without bone chips, were taken at 0.32 and 0.16 s. Then, five bone chips (weight range 7–15 mg) were placed on the maxillary molar buccal side of the dry skull. Secondary radiographs were taken at 0.32-, 0.16-, 0.08-, 0.04-, and 0.02-s exposure times. For each bone chip, radiographs were taken three times. The secondary and initial images were subtracted to yield subtraction images. Four observers were asked to evaluate bone change visibility in the subtraction images. The Friedman test was used for statistical analysis.

Results

Significant differences were seen at each of the settings for the 0.32-s group (p = 1.24e?030) and 0.16-s group (p = 7.52e?009). By comparing the different groups, observer evaluations indicated that visibility changed when the secondary radiograph was taken at 1/8 of the exposure time of the initial radiograph. In both groups, the visibility of the 0.02-s subtraction image was significantly lower than that of the other subtraction images.

Conclusion

In DSR, the exposure time of the secondary radiograph can be reduced to 1/4 of the exposure time of the initial radiograph.     

Nematode ascarosides attenuate mammalian type 2 inflammatory responses

Mounting evidence suggests that nematode infection can protect against disorders of immune dysregulation. Administration of live parasites or their excretory/secretory (ES) products has shown therapeutic effects across a wide range of animal models for immune disorders, including asthma. Human clinical trials of live parasite ingestion for the treatment of immune disorders have produced promising results, yet concerns persist regarding the ingestion of pathogenic organisms and the immunogenicity of protein components. Despite extensive efforts to define the active components of ES products, no small molecules with immune regulatory activity have been identified from nematodes. Here we show that an evolutionarily conserved family of nematode pheromones called ascarosides strongly modulates the pulmonary immune response and reduces asthma severity in mice. Screening the inhibitory effects of ascarosides produced by animal-parasitic nematodes on the development of asthma in an ovalbumin (OVA) murine model, we found that administration of nanogram quantities of ascr#7 prevented the development of lung eosinophilia, goblet cell metaplasia, and airway hyperreactivity. Ascr#7 suppressed the production of IL-33 from lung epithelial cells and reduced the number of memory-type pathogenic Th2 cells and ILC2s in the lung, both key drivers of the pathology of asthma. Our findings suggest that the mammalian immune system recognizes ascarosides as an evolutionarily conserved molecular signature of parasitic nematodes. The identification of a nematode-produced small molecule underlying the well-documented immunomodulatory effects of ES products may enable the development of treatment strategies for allergic diseases.

Parasitic nematodes are associated with almost all groups of vertebrates, and nearly one-third of the human population is infected with these helminths (1). Their omnipresence is in part due to their ability to modulate host immune responses to prevent immune attack and expulsion (2). The elimination of nematode infections has been proposed as a possible cause of the increased incidence of autoimmune disorders and allergic diseases in developed countries (3), based on epidemiological data showing a correlation between the decline in helminth infection and the rise in allergic and autoimmune diseases, including asthma, multiple sclerosis (MS), type 1 diabetes, and inflammatory bowel diseases (IBDs) (4).The administration of live nematodes or their excretory/secretory (ES) products has shown therapeutic effects across a wide range of animal models for these immune disorders (5–8). The US Food and Drug Administration recently approved live helminth administration as an investigational drug for the treatment of immune disorders, and relevant human clinical trials are ongoing (9). Despite mounting evidence that helminths have significant therapeutic potential, we do not yet have a comprehensive understanding of the molecules that underlie their immunomodulatory effects; and, in particular, the possible relevance of low-molecular-weight components of ES products has remained largely unexplored.A wide range of nematodes, including many parasitic species, produce ascarosides, a family of small-molecule signals based on glycosides of the dideoxysugar ascarylose (10). Ascarosides have not yet been identified in any other animal phylum, suggesting that they may be a nematode-specific class of small molecules (SI Appendix, Fig. S1A). The first ascaroside-based signaling molecules were identified in the free-living model nematode Caenorhabditis elegans (11, 12). Ascarosides regulate almost every aspect of C. elegans life history, including diapause (dauer) induction, aging, mate finding, and aggregation (11, 12). Subsequently, ascarosides have been shown to be detected by organisms other than nematodes, such as nematophagous fungi that set traps to capture and digest nematodes (13). The perception of ascarosides is sufficient to trigger trap formation in these fungi, demonstrating their longstanding evolutionary association with nematodes. Furthermore, ascarosides produced by plant-pathogenic nematodes have been shown to trigger innate immune responses in monocot and dicot plants (14). Cumulatively, these findings suggest that ascarosides represent a nematode-specific molecular signature that is recognized and interpreted by nematode predators and hosts across multiple kingdoms.In this study, we collected ES products from the gut-resident, rodent-parasitic nematode Nippostrongylus brasiliensis. Previous studies showed that the administration of N. brasiliensis ES (NES) products fully inhibits the development of airway hyperresponsiveness (AHR) in the ovalbumin (OVA) murine model of asthma (15). Specifically, NES products substantially prevented lung eosinophilia, mucus production, and resistance to airflow. Notably, it was found that heat-treated or proteinase K–treated NES mimicked the full effect of untreated NES products in reducing lung eosinophilia and OVA-specific IgG in serum. Therefore, we hypothesized that the therapeutic effect of NES products may be due to the presence of specific small molecules that may in part be bound to secreted proteins, explaining the activity of heat- or proteinase K–treated NES. To test this hypothesis, we isolated the small molecule fraction of heat-treated NES (small molecule ES [smES]) products via filtration through a 3-kDa filter and found that smES products strongly suppresses OVA-induced allergic immune responses. Parallel chemical analyses of several other mammalian parasitic nematodes confirmed the presence of specific ascarosides in smES products of all tested species. Next, we tested synthetic samples of ascarosides and found that ascr#7, a compound produced by N. brasiliensis and other parasitic species, markedly inhibited the development of allergic airway inflammation, comparable to the full effect of smES products. Mechanistically, we found that ascr#7 administration attenuated IL-33 production from lung epithelial cells and suppressed the proliferation of memory-type IL-5–producing pathogenic T helper 2 (Th2) cells and type 2 innate lymphoid cells (ILC2s) in the lung, both key drivers for the pathology of asthma. We thus demonstrate that ascarosides have an immunomodulatory role that attenuates OVA-induced allergic inflammation in a murine model.     

Wedging of vertebral bodies at the thoracolumbar junction in asymptomatic healthy subjects on magnetic resonance imaging

Purpose

Wedging of the vertebral body on radiological examination is a valuable indicator of a vertebral compression fracture, although it can also be observed in subjects with no history of trauma. The purpose of this study was to elucidate the normative value of vertebral wedging at the thoracolumbar junction in asymptomatic healthy subjects for differential diagnosis of vertebral compression fractures using MRI.

Methods

A total of 115 subjects without back pain at the time of the examination and without history of spinal trauma was included (68 males, 47 females, mean age 49.5?years). They underwent MRI of the thoracic and lumbar spine, and the ratio of anterior vertical height to posterior vertical height of the vertebral body (APR) was determined from T10 to L2 on T2 weighted sagittal images.

Results

APR was 0.92?±?0.08 at T10, 0.92?±?0.08 at T11, 0.90?±?0.06 at T12, 0.89?±?0.06 at L1, and 0.90?±?0.07 at L2, indicating that vertebral bodies at the thoracolumbar junction appear wedge-shaped rather than rectangular. Males, thinner subjects, smokers, and subjects with abnormalities of the endplates such as a Schmorl nodule had a significantly smaller APR than females, fatter subjects, non-smokers, and those without endplate abnormalities.

Conclusion

The normative values of APR obtained in the present study can represent a valuable reference in the diagnosis of vertebral compression fracture to help prevent confusion with physiological vertebral wedging.