Talk to us about your skin: The relationship between spoken language and haptic exploratory procedures.

OBJECTIVE: To enhance satisfaction, the cosmetics industry needs to clearly understand consumers' descriptions of their key tactile preferences. It is difficult for researchers to understand verbal descriptions from people whose native language is different from their own. Previous research has implied that some sensory words with the same lexical meanings have been observed in different haptic exploratory procedures (HEPs). Therefore, our study aims to investigate and understand the key tactile perceptions of people from five different countries based on their descriptions and their HEPs. METHODS: In Experiment 1, 1545 participants living in the US, Japan, China, Italy, and Thailand described their major tactile perceptions as efficacy in skincare, and we analysed the frequency of each word used in their answers. In Experiment 2, we confirmed the task to observe HEPs for Chinese, Italian, and Thai participants. A total of 24 participants in China, 33 participants in Italy, and 30 participants in Thailand freely explored their faces with their hands and answered which side more closely matched the major tactile adjectives. Experts classified the observed HEPs into six classifications within two categories and three contact area sizes and investigated the cultural differences. RESULTS: More than 2% of the Chinese, Italian, Thai, US, and Japanese participants described 33, 20, 29, 22, and 18 words, respectively, as efficacy in skincare. Verified words that described the major tactile perceptions in each native language had the same meanings as moistness, firmness, softness, smoothness, and so on. We could confirm the HEPs of these major feelings for the participants from each culture. Chinese and Thai participants' HEPs for moistness or softness were observed with a pressing movement. Conversely, Italian participants' HEPs for moistness or softness were observed with a rubbing movement. CONCLUSION: This study showed that words with the same lexical meanings evoked different HEPs. The results imply that different HEPs can provide different physical stimuli on the skin. Therefore, it is important to survey both objects and HEPs to better understand the tactile experience.

OBJECTIF: Pour améliorer la satisfaction, l'industrie cosmétique doit bien comprendre les descriptions que font les consommateurs de leurs principales préférences tactiles. Il est difficile pour les chercheurs de comprendre les descriptions verbales des personnes dont la langue maternelle est différente de la leur. Des recherches antérieures ont suggéré que certains mots sensoriels ayant les mêmes significations lexicales ont été observés dans différentes procédures exploratoires haptiques (PEH). Par conséquent, notre étude vise à étudier et à comprendre les perceptions tactiles clés des personnes de cinq pays différents en fonction de leurs descriptions et de leurs PEH. MÉTHODES: Dans l'expérience 1 545 participantes vivant aux États­Unis, au Japon, en Chine, en Italie et en Thaïlande ont décrit leurs principales perceptions tactiles comme l'efficacité dans les soins de la peau, et nous avons analysé la fréquence de chaque mot utilisé dans leurs réponses. Dans l'expérience 2, nous l'avons confirmé en observant les PEH pour les participantes chinoises, italiennes et thaïs. 24 participantes en Chine, 33 participantes en Italie et 30 participantes en Thaïlande ont librement exploré leur visage avec leurs mains et ont répondu à la question de savoir quel côté correspondait le mieux aux principaux adjectifs tactiles. Les experts ont classé les PEH observées en six classifications dans deux catégories et trois tailles de surface de contact, et ont étudié les différences culturelles. RÉSULTAT: Plus de deux pour cent des participantes chinoises, italiennes, thaïs, américaines et japonaises ont décrit 33, 20, 29, 22 et 18 mots, respectivement, comme une efficacité dans les soins de la peau. Les mots vérifiés qui décrivaient les principales perceptions tactiles dans chaque langue maternelle ayant les mêmes significations sont l'humidité, la fermeté, la douceur, la texture lisse, etc. Nous avons pu confirmer les PEH de ces sensations majeures pour les participants de chaque culture. Les PEH des participantes chinoises et thaïs pour l'humidité ou la douceur ont été observées avec un mouvement de pression. A l'inverse, les PEH pour l'humidité ou la douceur des participantes italiennes ont été observées avec un mouvement de frottement. CONCLUSION: Cette étude a montré que les mots ayant les mêmes significations lexicales évoquaient différentes PEH. Les résultats impliquent que différentes PEH peuvent fournir différents stimuli physiques sur la peau. Par conséquent, il est important d'étudier les objets et les PEH pour mieux comprendre l'expérience tactile.

A complex rearrangement between APC and TP63 associated with familial adenomatous polyposis identified by multimodal genomic analysis: a case report.

Genetic testing of the APC gene by sequencing analysis and MLPA is available across commercial laboratories for the definitive genetic diagnosis of familial adenomatous polyposis (FAP). However, some genetic alterations are difficult to detect using conventional analyses. Here, we report a case of a complex genomic APC-TP63 rearrangement, which was identified in a patient with FAP by a series of genomic analyses, including multigene panel testing, chromosomal analyses, and long-read sequencing. A woman in her thirties was diagnosed with FAP due to multiple polyps in her colon and underwent total colectomy. Subsequent examination revealed fundic gland polyposis. No family history suggesting FAP was noted except for a first-degree relative with desmoid fibromatosis. The conventional APC gene testing was performed by her former doctor, but no pathogenic variant was detected, except for 2 variants of unknown significance. The patient was referred to our hospital for further genetic analysis. After obtaining informed consent in genetic counseling, we conducted a multigene panel analysis. As insertion of a part of the TP63 sequence was detected within exon16 of APC, further analyses, including chromosomal analysis and long-read sequencing, were performed and a complex translocation between chromosomes 3 and 5 containing several breakpoints in TP63 and APC was identified. No phenotype associated with TP63 pathogenic variants, such as split-hand/foot malformation (SHFM) or ectrodactyly, ectodermal dysplasia, or cleft lip/palate syndrome (EEC) was identified in the patient or her relatives. Multimodal genomic analyses should be considered in cases where no pathogenic germline variants are detected by conventional genetic testing despite an evident medical or family history of hereditary cancer syndromes.

Pediatric Precision Medicine at the National Cancer Center Japan: Prospective Genomic Study of Pediatric Patients with Cancer as Part of the TOP-GEAR Project.

PURPOSE: This single-center, prospective molecular profiling study characterizes genomic alterations and identifies therapeutic targets in advanced pediatric solid tumors. METHODS: As part of the TOP-GEAR (Trial of Onco-Panel for Gene profiling to Estimate both Adverse events and Response by cancer treatment) project at the National Cancer Center (NCC), Japan, we enrolled pediatric patients with a refractory or recurrent disease during August 2016-December 2021 and performed genomic analysis of matched tumors and blood using originally developed cancer gene panels, NCC Oncopanel (ver. 4.0) and NCC Oncopanel Ped (ver. 1.0). RESULTS: Of 142 patients (age, 1-28 years) enrolled, 128 (90%) were evaluable for genomic analysis; 76 (59%) patients harbored at least one reportable somatic or germline alteration. The tumor samples were collected during the initial diagnosis in 65 (51%) patients, after treatment initiation in 11 (9%) patients, and upon either disease progression or relapse in 52 (41%) patients. The leading altered gene was TP53, followed by MYCN, MYC, CDKN2A, and CDK4. The commonly affected molecular processes were transcription, cell-cycle regulation, epigenetic modifiers, and RAS/mitogen-activated protein kinase signaling. Twelve (9%) patients carried pathogenic germline variants in cancer-predisposing genes. Potentially actionable findings were identified in 40 (31%) patients; to date, 13 (10%) patients have received the recommended therapy on the basis of their genomic profiles. Although four patients had access to targeted therapy through clinical trials, the agents were used in nine patients in an off-label setting. CONCLUSION: The implementation of genomic medicine has furthered our understanding of tumor biology and provided new therapeutic strategies. However, the paucity of proposed agents limits the full potential of actionability, emphasizing the significance of facilitating access to targeted cancer therapies.

Lectin Blotting of Cell Lysates.

Glycans are composed of branched structures consisting of monosaccharides, such as glucose and galactose linked by glycosidic bonds. Glycans are often bound to proteins and lipids and are localized at the cell surface. They are deeply involved in a wide range of multicellular systems inside and outside the cells, such as the quality control of glycoproteins, cell-cell communication, and various diseases. While western blotting uses antibodies to detect proteins, lectin blotting uses lectins, which are glycan-binding proteins, to detect glycans on glycoconjugates, such as glycoproteins. Lectin blotting was first reported in the early 1980s and has been widely used in life science for several decades. However, it is not straightforward to obtain consistent data using lectin blotting, which tends to show high backgrounds and lab-to-lab variation. Here, we describe the protocol used in our laboratory for lectin blotting following protein separation by SDS-PAGE to detect glycoproteins extracted from cell membrane fractions. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Extraction and quantification of proteins from cell lysate Basic Protocol 2: Lectin peroxidase labeling and lectin blotting.

Genotype-phenotype correlation of small-intestinal polyps on small-bowel capsule endoscopy in familial adenomatous polyposis.

BACKGROUND AND AIMS: In familial adenomatous polyposis (FAP), neoplastic lesions outside the colon have become increasingly important. The genotype-phenotype correlation has been established for duodenal polyps, and regular screening is recommended. However, this correlation remains unclear for small-intestinal lesions, except for reports on the relationship between their occurrence and Spigelman stage. Here, we used small-bowel capsule endoscopy (SBCE) to investigate the genotype-phenotype correlation of small-intestinal polyps in FAP. METHODS: The genotype-phenotype correlation of small-intestinal polyps was investigated in patients with FAP who underwent SBCE, Esophagogastroduodenoscopy (EGD), and adenomatous polyposis coli (APC) gene analysis. Of 64 patients with FAP who underwent SBCE, 41 were included in the final analysis, 4 did not undergo a complete small intestine examination, and 19 did not undergo genetic analysis. RESULTS: The prevalence (median number) of small-intestinal polyps by Spigelman stage was 26% (1.5), 0% (0), 44% (5), 60% (4), and 73% (25.5) for stages 0 to IV, respectively. Significantly more small-intestinal polyps were found in Spigelman stage III and IV groups than in the stage 0 group (P < .05). The APC variant was negative for 6 patients (15%), and the sites associated with more than 5 small-intestinal polyps were codons 278, 1062, 1114, 1281, 1307, 1314, and 1504. CONCLUSIONS: In FAP patients, SBCE surveillance is potentially recommended for patients with pathogenic variants in the APC gene at codons 278 and 1062 to 1504 or with Spigelman stage III or higher.

Taxonomic revision of the Tetraneura akinire species group (Insecta, Aphididae, Eriosomatinae), with description of a new species and a correction of a nomenclatural confusion.

Gall-forming aphid species Tetraneura nigriabdominalis and T. fusiformis and its closely related species are taxonomically revised. By referring to the original descriptions, the name T. nigriabdominalis (Sasaki, 1899) is discarded as an erroneous combination, and T. akinire Sasaki, 1904 is adopted as a valid name. The T. akinire species group is defined as having long claws in the first instar nymphs of the root generation. Of the T. akinire species group distributed in Korea and Japan, T. ovaliformis sp. nov., which induces globular galls on the leaves of Ulmus davidiana var. japonica, is described, and T. akinire and T. sorini Hille Ris Lambers, 1970 are redescribed. A molecular phylogeny based on partial sequences of mitochondrial cytochrome c oxidase subunit I (COI) indicates that T. akinire is composed of two clusters, one (type A) which is distributed widely from Europe to East Asia on Ulmus spp., and the other (type B) which is found in Hokkaido, northern Japan on U. davidiana var. japonica and in tropical regions as anholocyclic lineages. Tetraneura fusiformis Matsumura, 1917, which has often been treated as a junior synonym of T. nigriabdominalis, likely corresponds to type B. The taxonomic status of T. fusiformis is discussed and this species is tentatively considered as a junior synonym of T. akinire sensu novo.

Case report: Response to platinum agents and poly (adenosine diphosphate-ribose) polymerase inhibitor in a patient with BRCA1 c.5096G>A (R1699Q) intermediate-risk variant.

BACKGROUND: BRCA1 c.5096G>A (p. Arg1699Gln) (hereinafter BRCA1 R1699Q) is classified as a pathogenic genetic variant despite its lower penetrance of breast and ovarian cancers compared to other BRCA1 variants. However, this mutation is currently reported as a 'special interpretation' variant in the BRACAnalysis® because the response to platinum agents and poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors remains unknown in patients with this mutation. CASE PRESENTATION: We present a case of stage IIIc high-grade primary peritoneal cancer in a 69-year-old woman with germline BRCA1 R1699Q variant. She received platinum-containing chemotherapy followed by surgery. Eight months later, the patient experienced recurrence and received six cycles of chemotherapy and olaparib maintenance therapy. However, the disease progressed after only 5 months, and she received another chemotherapy drug. This patient responded slightly to platinum agents and had shorter progression-free survival on olaparib compared with clinical trial data. myChoice® CDx also showed Genomic Instability Score (GIS) was 50. This patient had no other gene mutations which could cause homologous recombination deficiency. CONCLUSION: This is the first report of the clinical outcome of PARP inhibitor and platinum-containing chemotherapy in a patient with a BRCA1 R1699Q variant. Despite BRCA1 mutation and high GIS, used as indicators of drug sensitivity, the recurrent tumor did not respond well to platinum agents and olaparib. BRCA1 R1699Q variant could differ from others in cancer risk and in drug response. Further studies are needed to confirm these observations.

Xenopus Dusp6 modulates FGF signaling to precisely pattern pre-placodal ectoderm.

Pre-placodal ectoderm (PPE), a horseshoe-shaped narrow region formed during early vertebrate development, gives rise to multiple types of sensory organs and ganglia. For PPE induction, a certain level of FGF signal activation is required. However, it is difficult to reproducibly induce the narrow region with variations in gene expression, including FGF, among individuals. An intracellular regulatory factor of FGF signaling, Dusp6, is expressed by FGF signal activation and inactivates a downstream regulator, ERK1/2, in adult tissues; however, its role in early development is not well known. Here, we reveal that Dusp6 is expressed in an FGF-dependent manner in Xenopus PPE. Gain- and loss-of-function experiments showed that Dusp6 is required for expression of a PPE gene, Six1, and patterning of adjacent regions, neural plate, and neural crest. To reveal the importance of Dusp6 in variable FGF production, we performed Dusp6 knockdown with FGF-bead implantation, which resulted in varying Six1 expression patterns. Taken together, these results suggest that Dusp6 is required for PPE formation and that it contributes to the robust patterning of PPE by mediating FGF signaling.

Prediction of human pharmacokinetics for low-clearance compounds using pharmacokinetic data from chimeric mice with humanized livers.

Development of low-clearance (CL) compounds that are slowly metabolized is a major goal in the pharmaceutical industry. However, the pursuit of low intrinsic CL (CLint ) often leads to significant challenges in evaluating the pharmacokinetics of such compounds. Although in vitro-in vivo extrapolation is widely used to predict human CL, its application has been limited for low-CLint compounds because of the low turnover of parent compounds in metabolic stability assays. To address this issue, we focused on chimeric mice with humanized livers (PXB-mice), which have been increasingly reported to accurately predict human CL in recent years. The predictive accuracy for nine low-CLint compounds with no significant turnover in a human hepatocyte assay was investigated using PXB-mouse methods, such as single-species allometric scaling (PXB-SSS) approach and a novel physiologically based scaling (PXB-PBS) approach that assumes that the CLint per hepatocyte is equal between humans and PXB-mice. The percentages of compounds with predicted CL within 2- and 3-fold ranges of the observed CL for low-CLint compounds were 89% and 100%, respectively, for both PXB-SSS and PXB-PBS approaches. Moreover, the predicted CL was mostly consistent among the methods. Conversely, the percentages of compounds with predicted CL within 2- and 3-fold ranges of the observed CL for low-CLint compounds were 50% and 63%, respectively, for multispecies allometric (MA) scaling. Overall, these PXB-mouse methods were much more accurate than conventional MA scaling approaches, suggesting that PXB-mice are useful tools for predicting the human CL of low-CLint compounds that are slowly metabolized.

Myxofibrosarcoma harboring an MLH1 pathogenic germline variant associated with Muir-Torre syndrome: a case report.

BACKGROUND: Muir-Torre syndrome (MTS), which accounts for a small subset (1-3 %) of Lynch syndrome (LS), is an autosomal dominant genetic disorder characterized by sebaceous gland or keratoacanthoma associated with visceral malignancies. Most families with MTS have pathogenic germline variants (PGV) in MSH2. Sarcomas are not common on the LS tumor spectrum, and sarcomas associated with MTS are extremely rare. CASE PRESENTATION: Here we report a myxofibrosarcoma of the abdominal wall in a 73-year-old man with a sebaceoma that occurred synchronically, leading to a diagnosis of MTS. The loss of MLH1 and PMS2 protein expression was detected in immunohistochemistry, and high-frequency microsatellite instability (MSI-H) was also confirmed. A germline genetic analysis revealed that he harbored the MLH1 PGV. CONCLUSIONS: This is the first case of MSI-H myxofibrosarcoma with MTS in an MLH1 PGV carrier. Although rare, we should recognize that sarcomas can be part of the spectrum of LS and MTS.

A glycosaminoglycan microarray identifies the binding of SARS-CoV-2 spike protein to chondroitin sulfate E.

Heparan sulfate (HS), a sulfated glycosaminoglycan (GAG), was reported to be a necessary host attachment factor that promotes SARS-CoV-2 infection. In this study, we developed GAG microarrays based on fluorescence detection for high-sensitivity screening of the GAG-binding specificity of proteins and applied it for the analysis of SARS-CoV-2 spike (S) protein. Among the 20 distinct GAGs, the S protein bound not only to heparin (HEP)/HS but also to chondroitin sulfate E (CSE) in a concentration-dependent manner. We then analyzed the specificity of each subunit of the S protein. While the S1 subunit showed exclusive binding to HEP, the S2 subunit also bound to CSE and HEP/HS. CSE might act as an alternative attachment factor for HS in SARS-CoV-2 infection.

Distribution of genetic alterations in high-risk early-stage cervical cancer patients treated with postoperative radiation therapy.

Somatic genetic alteration analysis was performed for post-hysterectomy high-risk early-stage uterine cervical cancer patients who underwent post-operative radiation therapy. Post-operative radiation therapy was performed for patients with pathological features of pelvic lymph node metastasis, parametrium invasion, or positive vaginal margin, which corresponded to the post-operative high-risk category. DNA was extracted from paraffin-embedded surgical specimens, and 50 somatic hotspot genetic alternations were detected using Ion AmpliSeq Cancer Hotspot Panel. The existence of actionable mutation was assessed based on OncoKB evidence level > 3A. Between January 2008 and November 2019, 89 patients who underwent abdominal radical hysterectomy followed by post-operative radiation therapy were identified. The follow-up period for living patients was 82.3 months (range 9.3-153.9), and the 5-year relapse-free survival and overall survival rates were 72.6% and 85.9%, respectively. The most frequently detected somatic mutation was PIK3CA (26 [29.2%] patients); however, no prognostic somatic genetic alterations were identified. Actionable mutations were detected in 30 (33.7%) patients. Actionable mutations were detected in approximately one-third of patients, suggesting that precision medicine can be offered to patients with post-operative high-risk uterine cervical cancer in the near future.

Elimination of cells deviated from human induced pluripotent stem cells with a photoactivatable IR700-labelled antibody.

Human induced pluripotent stem cells (hiPSCs) are important starting materials for cell therapy products (CTPs) used for transplantation. During cell culture, hiPSCs often spontaneously undergo morphological changes and lose pluripotency. Such cells are called 'deviated cells', which are deviated from the undifferentiated state of hiPSCs, lack the expression of hiPSC markers and become positive for the early differentiation marker SSEA1 (stage-specific embryonic antigen 1, Lewis X glycan). Previously, we identified fibronectin (FN) as a predominant carrier protein of SSEA1 secreted from deviated cells, but not hiPSCs. A sandwich assay using antibodies (Abs) against FN and SSEA1 was developed for non-destructive quantitative evaluation of deviated cells present in hiPSC cultures. In this study, a novel technology was developed to specifically eliminate deviated cells using an anti-FN Ab along with a near-infrared (NIR) photoabsorber, IRDye700DX N-hydroxysuccinimide ester (IR700), which has been used for cancer photoimmunotherapy. The anti-FN Ab conjugated with the IR700 dye (IR700-αFN) bound to and induced the death of deviated cells upon NIR irradiation. In contrast, IR700-αFN failed to stain the hiPSCs, and IR700-αFN/NIR had little or no effect on survival. Finally, IR700-αFN/NIR irradiation induced selective removal of deviated cells from a mixed culture with hiPSCs, demonstrating that the proposed method is suitable for the removal of unwanted deviated cells present in hiPSC culture for the production of CTPs.

Effect of Compound Muscle Action Potential After Peripheral Nerve Stimulation Normalization on Anesthetic Fade of Intraoperative Transcranial Motor-Evoked Potential.

PURPOSE: Anesthetic fade refers to the time-dependent decrease in the amplitude of the intraoperative motor-evoked potential. It is thought to be caused by the accumulation of propofol. The authors examined whether normalization by the compound muscle action potential (CMAP) after peripheral nerve stimulation could compensate for anesthetic fade. METHODS: In 1,842 muscles in 578 surgeries, which did not exhibit a motor-neurologic change after the operation, the motor-evoked potential amplitude was normalized by the CMAP amplitude after peripheral nerve stimulation, and the CMAP amplitude and operation times were analyzed. RESULTS: The amplitudes of both motor-evoked potential and CMAP increased over time after peripheral nerve stimulation because of the disappearance of muscle-relaxant action. Especially, after peripheral nerve stimulation, CMAP significantly increased from the beginning to the end of the operation. Anesthetic fade in transcranial motor-evoked potential monitoring seemed to occur at more than 235 minutes of surgery based on the results of a receiver operating characteristic analysis of the operation time and relative amplitudes. Although the mean amplitude without CMAP normalization at more than 235 minutes was significantly lower than that at less than 235 minutes, the mean amplitude with normalization by CMAP after peripheral nerve stimulation at more than 235 minutes was not significantly different from that at less than 235 minutes. CONCLUSIONS: Compound muscle action potential after peripheral nerve stimulation normalization was able to avoid the effect of anesthetic fade. Anesthetic fade was seemed to be caused by a decrease in synaptic transmission at the neuromuscular junction because of propofol accumulation by this result.

Sensory words may facilitate certain haptic exploratory procedures in facial cosmetics.

OBJECTIVE: Many people want to have healthy facial skin. They tend to check their skin's condition by touching their face with their hands. In the cosmetic industry, we need to understand what consumers are perceiving in a tactile sense when touching their own facial skin. The purpose of this study was to investigate these observation methods in order to systematically understand people's haptic exploratory procedures (HEPs). METHODS: Thirty-four participants living in the United States and twenty-two participants living in Japan freely explored their faces and answered which side felt more closely related to the six tactile adjectives. A new analysis was applied to classify the observed HEPs into six classifications within two categories and three sizes of contact area by experts. RESULT: It was confirmed that the new task was useful to observe the HEPs for participants from United States and Japan. The US participants' HEPs for 'moisturized' were mainly a middle-sized contact area using a stroking motion. On the other hand, Japanese participants' HEPs for 'moisturized' ('shittori' in Japanese) mainly used a pushing movement. Moreover, the US participants' HEPs for 'soft' included both pushing and stroking, but Japanese participants HEPs for 'soft' ('yawarakai' in Japanese) were again mainly pushing. CONCLUSION: This study suggests that the proposed analysis method enables the systematic understanding of HEPs when checking the skin, along with the cross-cultural differences affecting those procedures. These systematic findings could allow cosmetic formulators to have a better understanding of the tactile sensations consumers themselves are feeling in a variety of different global markets.

OBJECTIF: de nombreuses personnes veulent avoir une peau du visage en bonne santé. Elles ont tendance à examiner l'état de leur peau en se touchant le visage avec les mains. Dans l'industrie cosmétique, nous devons comprendre ce que les consommateurs perçoivent d'un point de vue tactile lorsqu'ils se touchent la peau du visage. L'objectif de cette étude était d'évaluer ces méthodes d'observation afin de comprendre de manière systématique les procédures exploratoires haptiques (PEH) des individus. MÉTHODES: trente-quatre participants vivant aux États-Unis et vingt-deux vivant au Japon ont librement examiné leur visage en le touchant et indiqué quel côté semblait le plus proche des six adjectifs tactiles. Une nouvelle analyse a été appliquée pour classer les PEH observées en six groupes de classification au sein de deux catégories et trois tailles de zone de contact par des experts. RÉSULTAT: il a été confirmé que cette nouvelle étude était utile pour observer les PEH chez les participants provenant des États-Unis et du Japon. Les PEH des participants américains pour l'adjectif « hydratée ¼ correspondaient principalement à des mouvements de caresse sur une zone de contact de taille moyenne. En revanche, les PEH des participants japonais pour « hydratée ¼ (« shittori ¼ en japonais) correspondaient principalement à des mouvements de pression. De plus, les PEH des participants américains pour l'adjectif « douce ¼ comprenaient à la fois des mouvements de caresse et de pression, mais celles des participants japonais pour « douce ¼ (« yawarakai ¼ en japonais) correspondaient de nouveau principalement à des mouvements de pression. CONCLUSION: cette étude suggère que la méthode d'analyse proposée permet une compréhension systématique des PEH lors de l'examen de la peau, ainsi que des différences interculturelles influençant ces procédures. Ces résultats systématiques pourraient permettre aux formulateurs de cosmétiques de mieux comprendre les sensations tactiles des consommateurs eux-mêmes pour un ensemble de marchés mondiaux différents.

Monoclonal antibodies specific for podocalyxin expressed on human induced pluripotent stem cells.

Human induced pluripotent stem cells (hiPSCs) are useful starting materials for the generation of cell therapy products, due to their pluripotency and ability to self-renew. Quality control of hiPSCs is extremely important in creating a stable supply of hPSC-derived products. Previously we identified an hiPSC-specific lectin probe, rBC2LCN, which binds specifically to α1,2-fucosylated glycan and recognizes podocalyxin (PODXL) as a glycoprotein ligand. In this study, we produced monoclonal antibodies (mAbs) specific for α1,2-fucosylated PODXL expressed on hiPSCs. PODXL was recombinantly expressed in fucosyltransferase 1 (FUT1)-transfected HEK293, followed by immunization into mice. Monoclonal antibodies, which bind to PODXL/FUT1-transfected cells, but not to cells transfected with only one of PODXL or FUT1, were screened by flow cytometry. The two mAbs generated (179-6B8C9 and 179-7E12E10), termed α1,2-fucosylated PODXL-specific mAbs (FpMabs), showed binding specificity to PODXL/FUT1-transfected cells. The FpMabs bound to hiPSCs but never to human adipose-derived mesenchymal stem cells, human dermal fibroblasts, or hiPSC-derived mesoderm. Altogether, FpMabs are highly specific probes for hiPSCs, which might be a powerful tool for the characterization of hiPSCs used in regenerative medicine.

SSEA-1-positive fibronectin is secreted by cells deviated from the undifferentiated state of human induced pluripotent stem cells.

Quality control for human induced pluripotent stem cells (hiPSCs) is important for efficient and stable production of hiPSC-derived cell therapy products to be used for transplantation. During cell culture, hiPSCs spontaneously undergo morphological changes and lose pluripotent properties. Such cells are termed deviated cells, which are altered from the undifferentiated state of hiPSCs, and express the early differentiation marker stage-specific embryonic antigen 1 (SSEA-1). In this study, we searched for soluble SSEA-1+ glycoproteins secreted from deviated cells generated by culturing hiPSCs in cell culture medium containing heat-inactivated supplements. Glycoproteins obtained from cell culture supernatants of SSEA-1+ deviated cells were enriched by an O-glycan binding lectin and blotted with anti-SSEA-1 antibody. A single protein band at >250 kDa specifically detected by anti-SSEA-1 antibody was identified as fibronectin (FN) by LC-MS/MS analysis and immunoprecipitation combined with western blotting, indicating that FN is a carrier protein of SSEA-1. We then constructed a sandwich enzyme-linked immunosorbent assay to detect SSEA-1+ FN secreted from deviated cells. This FN-SSEA-1 test proved to be both sensitive and specific, allowing for non-destructive detection of SSEA-1+ deviated cells within mixed cell population, with a lower limit of detection of 100 cells/mL. The developed assay may provide a standard technology for quality control of hiPSCs used for regenerative medicine.

Pyrazolo[4,3-d]pyrimidine Derivatives as a Novel Hypoxia-Inducible Factor Prolyl Hydroxylase Domain Inhibitor for the Treatment of Anemia.

Inhibition of hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) promotes erythropoietin (EPO) production by stabilizing the HIFα subunit. Thieno[2,3-d]pyrimidine 8 identified based on X-ray crystal structure analysis was optimized to lead to the discovery of pyrazolo[4,3-d]pyrimidine 13 as the lead compound of orally bioavailable HIF-PHD inhibitors. Conversion of the benzyl moiety in 13 gave pyrazolopyrimidine 19 with high solubility and bioavailability, which increased hemoglobin levels in anemic model rats after repeated oral administration. It was shown that pyrazolo[4,3-d]pyrimidine derivatives are promising therapeutic agents for renal anemia through the inhibition of HIF-PHD.

Simple prediction model for homologous recombination deficiency in breast cancers in adolescents and young adults.

PURPOSE: Homologous recombination deficiency (HRD), which influences the efficacy of PARP inhibitor- and platinum agent-based therapies, is a prevalent phenotype of breast cancer in adolescents and young adults (AYAs; 15-39 years old). However, HRD score, indicating HRD status, is not routinely assessed in the breast oncology clinic, particularly in patients without germline BRCA1/2 mutations. Hence, we sought to develop a model for determining HRD status based on genetic and clinicopathological factors. METHODS: Subjects were our own cohort of 46 Japanese AYA breast cancer patients and two existing breast cancer cohorts of US and European patients. Models for prediction of the HRD-high phenotype, defined as HRD score ≥ 42, were constructed by logistic regression analysis, using as explanatory variables genetic and clinicopathological factors assessable in the clinical setting. RESULTS: In all three cohorts, the HRD-high phenotype was associated with germline BRCA1/2 mutation, somatic TP53 mutation, triple-negative subtype, and higher tumor grade. A model based on these four factors, developed using the US cohort, was validated in the Japanese and European AYA cases: area under the receiver operating characteristic curve [AUC] was 0.90 and 0.96, respectively. A model based on three factors excluding germline BRCA1/2 mutation also yielded high-predictive power in cases from these two cohorts without germline BRCA1/2 mutations: AUC was 0.92 and 0.90, respectively. CONCLUSIONS: The HRD-high phenotype of AYA breast cancer patients can be deduced from genomic and pathological factors that are routinely examined in the oncology clinic, irrespective of germline BRCA1/2 mutations.

Genomic alterations in STK11 can predict clinical outcomes in cervical cancer patients.

OBJECTIVE: Cervical cancer is the fourth most common cause of cancer-related deaths in Asian women, due to its poor prognosis. This study aimed to decipher genomic alteration profiles of a cohort of Japanese cervical cancer patients to understand why certain patients benefited from molecular targeted therapies and their prognostic significance. METHODS: During 2008-2018, 154 cervical cancer patients underwent a potentially curative resection procedure at the National Cancer Center Hospital. Genomic DNA samples were analyzed using Ion AmpliSeq™ Cancer Hotspot Panel v2. Alterations in the copy number of PIK3CA, ERBB2, PTEN, and STK11 were detected using the TaqMan assay. HPV-positive results were confirmed by genomic testing and in situ hybridization assay. RESULTS: The frequency of genomic alterations in PIK3CA (36%), STK11 (16%), PTEN (11%), TP53 (11%), and KRAS (8%) was >5%. KRAS mutations were preferentially detected in patients with adenocarcinomas, and the frequency of PIK3CA mutations in patients with squamous cell carcinomas was higher than that in patients with other histological cancer types. HPV-positive results were observed in 139/154 (90.3%) patients, and TP53 mutants were detected in HPV-negative specimens. In this study, the overall survival of patients with genomic alterations in STK11 was worse than in patients with wild-type STK11 (hazard ratio = 10.6, P = 0.0079) and TCGA dataset (hazard ratio = 2.46, P = 0.029). CONCLUSIONS: More than one-third of Japanese cervical cancer patients exhibit mutations targeted by molecular targeted therapies. We have proposed the prognostic value of STK11 genomic alterations.