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Implosive consonants have drawn the attention of researchers over time, partially due to their relative rarity in the world’s languages, and partially due to their unique ingressive air flow. This sound category has varying complex features from an articulatory and acoustic perspective. This study explores the sound category by analyzing the acoustic features of a language whose implosives have yet to be acoustically considered: Shimaore, a Bantu-Sabaki language spoken in Mayotte. Specifically, it compares the bilabial plosive /b/ and the bilabial implosive /ɓ/ in terms of Voice Onset Time (VOT), fundamental frequency, amplitude, and voice quality via H1*–H2*, harmonics-to-noise ratios (HNR), and cepstral peak prominence (CPP). Analyses show that VOT is shorter for implosives than for plosives. At oral closure and vowel onset, amplitude and f0 are higher than plosives. H1*–H2* values read alongside HNR and CPP values suggest that implosives in Shimaore have glottal constriction. Some individual differences are explored for question of variation in implosives. Implications regarding sociophonetic studies in Mayotte as well as general implications for implosives are discussed.

Aims To examine the effects of a 24-month treatment with ipragliflozin on carotid intima-media thickness (IMT) in type 2 diabetes patients. Methods and results In this multicenter, prospective, randomized, open-label, and blinded-endpoint investigator-initiated clinical trial, adults with type 2 diabetes and haemoglobin A1C (HbA1c) of 6.0–10.0% (42–86 mmol/mol) were randomized equally to ipragliflozin (50 mg daily) and non-sodium-glucose cotransporter-2 (SGLT2) inhibitor use of standard-care (control group) for type 2 diabetes and were followed-up to 24 months. The primary endpoint was the change in mean common carotid artery IMT (CCA-IMT) from baseline to 24 months. A total of 482 patients were equally allocated to the ipragliflozin (N = 241) and control (N = 241) groups, and 464 patients (median age 68 years, female 31.7%, median type 2 diabetes duration 8 years, median HbA1c 7.3%) were included in the analyses. For the primary endpoint, the changes in the mean CCA-IMT from baseline to 24 months were 0.0013 [95% confidence interval (CI), −0.0155–0.0182] mm and 0.0015 (95% CI, −0.0155–0.0184) mm in the ipragliflozin and control groups, respectively, with an estimated group difference (ipragliflozin-control) of −0.0001 mm (95% CI, −0.0191–0.0189; P = 0.989). A group difference in HbA1c change at 24 months was also non-significant between the treatment groups [−0.1% (95% CI, −0.2–0.1); P = 0.359]. Conclusion Twenty-four months of ipragliflozin treatment did not affect carotid IMT status in patients with type 2 diabetes recruited in the PROTECT study, relative to the non-SGLT2 inhibitor-use standard care for type 2 diabetes.

La notion de « continuité pédagogique » pose des questions complexes sur le plan culturel, linguistique et sémantique. C’est à travers un corpus de journaux locaux de Mayotte recueillis pendant une année de confinement-déconfinement-reconfinement, que nous étudions la représentation sociale de la continuité pédagogique dans la culture mahoraise telle que présentée par la presse écrite locale. Nous tentons de mettre en valeur les mythes qui participent ou font obstacle à l’incorporation des outils et des usages numériques dans la culture scolaire à Mayotte. À partir de 266 articles issus de six journaux de presse écrite locale, les analyses sémantiques et lexicométriques ont permis de mettre en valeur trois aspects du discours : une verticalité du message autour de la continuité pédagogique portée par des personnifications ciblées (notamment celle du recteur), un discours propagandiste sur la notion de continuité pédagogique, et un discours anti puis pro-numérique qui passe par sa mise à distance dans ce distanciel contraint. Des questionnements autour de la mise en place d’une hybridation numérique dans la pédagogie des enseignants, et des enjeux identitaires à Mayotte sont alors abordés. The notion of « pedagogical continuity » raises complex cultural, linguistic and semantic issues. Through a corpus of local Mayotte newspapers collected during a year of confinement-deconfinement-reconfinement, we study the social representation of pedagogical continuity in the Maore culture as presented by the local print media. We study social representations and myths that participate in, or stumbling block to, the incorporation of digital tools and uses in school culture in Mayotte. Based on 266 articles from 6 local newspapers, semantic and lexical analyses show three aspects of the discourse: a verticality of the pedagogical continuity message carried out by targeted individuals, a propagandist discourse on the ambiguous meaning of pedagogical continuity, and an anti- and then pro-digital discourse that exists in the background of this constrained distance learning. Questions about the implementation of a digital hybrid pedagogy and about identity issues in Mayotte are then addressed.

SUMMARYDifferentiated cell nuclei can be reprogrammed after nuclear transfer (NT) to oocytes and the produced NT embryos can give rise to cloned animals. However, development of NT embryos is often hampered by recurrent reprogramming failures, including the incomplete activation of developmental genes, yet specific genes responsible for the arrest of NT embryos are not well understood. Here, we searched for developmentally important genes among the reprogramming-resistant H3K9me3-repressed genes, and identified Alyref and Gabpb1 by siRNA screening. Gene knockout of Alyref and Gabpb1 by the CRISPR/Cas9 system resulted in early developmental arrest in mice. Single embryo RNA-seq revealed that Alyref is needed for the formation of inner cell mass. The supplement of Alyref and Gabpb1 by mRNA injection supported efficient preimplantation development of cloned embryos. Thus, our study shows that the H3K9me3-repressed genes contain developmentally required genes and the incomplete activation of such genes results in preimplantation arrest of cloned embryos.

Transmembrane anion transport is an important biological process in maintaining cellular functions. Thus, synthetic anion transporters are widely developed for their biological applications. Imidazolinium was introduced as anion recognition site to a multiblock amphiphilic structure that consists of octa(ethylene glycol) and aromatic units. Ion transport assay using halide-sensitive lucigenin and pH-sensitive 8-hydroxypyrene-1,3,6-trisulfonate (HPTS) revealed that imidazolinium-based multiblock amphiphile (IMA) transports anions and showed high selectivity for nitrate, which plays crucial roles in many biological events. Temperature-dependent ion transport assay using 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) indicated that IMA works as a mobile carrier. 1 H NMR titration experiments indicated that the C2 proton of the imidazolinium ring recognizes anions via a (C-H)+ ⋅⋅⋅X- hydrogen bond. Furthermore, all-atom molecular dynamics simulations revealed a dynamic feature of IMA within the membranes during ion transportation.

Patients with cancer are concerned about the effects of the COVID-19 vaccination. We conducted an online survey on the COVID-19 vaccination status and side effects among patients with cancer in Japan between August 8 and 14, 2021. We included 1182 female patients with cancer aged 20–70 years and registered on an online patient website. Of the patients, 944 had breast cancer, 216 had gynecological cancer, 798 were undergoing drug/radiation therapy, and 370 were in follow-up therapy. At the time of the survey, 885 patients had already received at least one dose. Of these, 580 had also received their second dose. The incidence rate of side effects was equivalent to previous reports. In patients with breast cancer, problems such as the onset or worsening of lymphedema or axillary lymphadenopathy metastasis requiring differential diagnosis were encountered following vaccination. A total of 768 patients were concerned about the vaccine at some point, and 726 consulted with their attending physicians about the timing or side effects of the vaccination. Of the 110 patients undergoing chemotherapy or radiation therapy, 75 adjusted the timing of the vaccination based on their therapy. The cross-analysis revealed that 81% of those who consulted their physician had received at least one dose of the COVID-19 vaccination compared with 65% of those who had not consulted their physician. Consulting with a physician about the COVID-19 vaccination was found to alleviate the concerns of patients with cancer and encourage them to get vaccinated.

Although Latino enrollment has increased at postsecondary institutions, this minority population is not graduating at the same rate as others. The current study looks at the intersection of educati...

Objectives To compare gynaecological and breast cancer patients in their information-seeking behaviours, usefulness of information sources and ongoing care needs after discharge to prevent the onset of lymphoedema. Methods We conducted a consecutive cross-sectional survey in an oncology hospital. Adult patients with stage I, II or III gynaecological or breast cancer who had undergone lymph node dissection and had not been diagnosed with lymphoedema were eligible for inclusion. The survey explored physical health status, knowledge of self-care, information-seeking behaviours, information sources and need for ongoing care from an oncology hospital and/or community health centre. Results Among 254 patients recruited, 202 responded (79.5% response rate). In total, 147 patients were eligible for statistical analysis. Irrespective of cancer type, the most commonly sought information was lymph drainage. Information on preventing weight gain was sought more often by breast cancer patients than gynaecological cancer patients. Regardless of cancer type, the most common information sources were nurses at an oncology hospital. Gynaecological cancer patients perceived nurses at the oncology hospital as useful for understanding risks, symptoms and prevention of lymphoedema. Irrespective of cancer type, ongoing need for help with lymphoedema prevention was reported both from the oncology hospital and the community centre. Limb symptoms, poor health status and poor knowledge affected the ongoing needs of gynaecological cancer patients at the oncology hospital, whereas poor health status affected ongoing needs in community health centres among both types of cancer patients. Conclusions Both gynaecological and breast cancer patients reported ongoing care needs, but that details of information-seeking behaviours differed.

Aim Currently, there is no provision for continuous care to monitor lymphedema risk-reduction behavior for survivors of cancer. The aim was to explore the possibility of community-based lymphedema education programs by investigating the knowledge, training needs, and intention to organize such programs and barriers among government-employed public health nurses. Methods A cross-sectional Internet survey was conducted among government-employed public health nurses in Japan. The participants were recruited from 2841 health center and community health centers. Results The final sample included 641 government-employed public health nurses. The participants' knowledge about lymphedema risk-reduction strategies was relatively good, especially on the importance of observation, detection of early signs, and referral to lymphedema clinics. A small proportion of participants indicated an intention to organize community-based lymphedema education programs. Three determinants for this intention were identified: a general interest in lymphedema education, past experience of undertaking training in lymphedema risk-reduction strategies, and the perceived difficulty in organizing community-based lymphedema education programs. The participants' perceptions of difficulty included not knowing the needs for lymphedema education in their community with survivors of cancer. Conclusions The results suggest that working collaboratively with government-employed public health nurses to organize community-based lymphedema education programs is possible. Achieving this requires further investigation of the needs of survivors of cancer in the community, communicating these needs to governmental agencies, and organizing and delivering comprehensive training programs about lymphedema risk-reduction strategies for government-employed public health nurses.

Contrast-enhanced spectral mammography to compare clinical efficacy of contrast-enhanced spectral mammography (CESM) and conventional digital mammography (MMG) with histopathology as gold standard in dense breasts. A total of 143 breasts of 72 women who underwent CESM and MMG between 2011 and 2014 at Showa University Hospital were analyzed. 129 (90.2 %) of 143 breasts revealed dense breasts on MMG. 58 (40.6 %) of 143 breasts were diagnosed with breast cancer at histopathology. The remaining 85 breasts were diagnosed with benign findings after image assessments and/or core needle biopsy. CESM revealed 8 false-negative cases among 58 breast cancer cases (sensitivity 86.2 %) and 5 false-positive cases (specificity 94.1 %). Accuracy was 90.9 %. Conventional MMG was assessed true positive in 31 of 58 breast cancer cases (sensitivity 53.4 %) and false positive in 12 cases (specificity 85.9 %). Accuracy was 72.7 %. Sensitivity (p

Integration of laser sintering of plastic powder and laser direct structuring using CO 2 laser for the both of laser sintering and laser activation is discussed. Feasibility of activation by CO 2 laser is investigated, and chromium copper oxide can be used as an agent for the integrated system. Activation can be enhanced by adding active carbon. It is revealed that surface of a part is melted on activation, and flow of the melt affects the activation quality while high flowability of the melt preferable for improvement of relative density.

Outbreaks of methicillin-resistant Staphylococcus aureus (MRSA) in the neonatal intensive care unit (NICU) have been reported worldwide. Some outbreaks were caused by USA300, which is a community-associated MRSA clone. In 2011, polymerase chain reaction-based open reading frame typing (POT) for the initial MRSA isolates from all inpatients was started at the Tokyo Metropolitan Children's Medical Center. From March 2014 to April 2015, a total of 131 MRSA strains were isolated, 104 of which were analyzed as healthcare-associated MRSA. Thirteen stains (12.5%) had a POT number of 106-9-93, which strongly suggested USA300; these included 6 from nasal swabs, 6 from blood cultures and 1 from subcutaneous pus. All the MRSA strains were isolated from patients in the NICU; were typed as sequence type 8, spa type t008, and staphylococcal cassette chromosome type mec IVa; and possessed the lukS-lukF and arginine catabolic mobile element-arcA gene. Pulsed-field gel electrophoresis of all the strains, with USA300-0114 as a reference, showed indistinguishable banding pattern. Based on these results, POT was useful in recognizing this first MRSA outbreak of USA300 in a Japanese NICU and was advantageous in terms of swiftness, less cost and monitoring change of the epidemic MRSA lineage.

To identify social–cognitive factors predicting lymphoedema risk-reduction behaviours (hereafter, self-care) after discharge among patients in Japan with breast or gynaecological cancers, using the extended model of the theory of planned behaviour. A cross-sectional questionnaire study was conducted in an oncology hospital. Items measured were (1) knowledge about self-care; (2) the Cancer Fatigue Scale; (3) social–cognitive factors in the theory of planned behaviour (attitudes, subjective norms, and perceived behavioural control); (4) self-care (limb hygiene, observation, articular movement, recommended risk-reduction behaviours in daily life, and diet and weight control); and (5) demographics. Of 202 respondents, 147 who had not been diagnosed with lymphoedema were eligible for statistical analysis (65.3% with gynaecological cancer, 34.7% with breast cancer). Structural equation modelling was used to examine a hypothesised model based on the theory of planned behaviour. The results revealed that a longer time since surgery, higher levels of fatigue, less knowledge, higher expected efficacy of self-care, and lower perceived behavioural control directly and significantly predicted less self-care behaviour. Besides education about self-care behaviour, levels of fatigue and perceived behavioural control should be taken into account to encourage female patients with cancer to perform self-care after discharge. Continuous psycho-educational programmes after discharge may help to facilitate self-care behaviours among long-term female cancer survivors.

While the field of applied linguistics has rightfully focused on experiences of multilingual students in k-12 settings, a space remains for understanding the post-secondary academic lives of these ...

A key element of academic writing involves incorporation of external voices, which is a complex rhetorical and linguistic task. Student writers must face this challenge of using sources to strengthen their own arguments. Appraisal, specifically Engagement, provides a useful framework for analyzing source use in texts, as it considers evaluation and dialogic voicing. This article describes a semi-ethnographic case study that contrasts two undergraduate writers and their writing drafts. Results show similarities and differences based on the linguistic abilities of the students and their experience in writing, but overall improvement in terms of dialogic voicing in the final drafts. Applications to research and instruction for ESL and mainstream writing are discussed.

Currently, there is no provision for continuous care to monitor lymphedema risk-reduction behavior for survivors of cancer. The aim was to explore the possibility of community-based lymphedema education programs by investigating the knowledge, training needs, and intention to organize such programs and barriers among government-employed public health nurses.A cross-sectional Internet survey was conducted among government-employed public health nurses in Japan. The participants were recruited from 2841 health center and community health centers.The final sample included 641 government-employed public health nurses. The participants' knowledge about lymphedema risk-reduction strategies was relatively good, especially on the importance of observation, detection of early signs, and referral to lymphedema clinics. A small proportion of participants indicated an intention to organize community-based lymphedema education programs. Three determinants for this intention were identified: a general interest in lymphedema education, past experience of undertaking training in lymphedema risk-reduction strategies, and the perceived difficulty in organizing community-based lymphedema education programs. The participants' perceptions of difficulty included not knowing the needs for lymphedema education in their community with survivors of cancer.The results suggest that working collaboratively with government-employed public health nurses to organize community-based lymphedema education programs is possible. Achieving this requires further investigation of the needs of survivors of cancer in the community, communicating these needs to governmental agencies, and organizing and delivering comprehensive training programs about lymphedema risk-reduction strategies for government-employed public health nurses.

本報告は、兵庫県西宮市の神戸女学院岡田山キャンパスに生息または飛来する野鳥についてとりまとめたものである。神戸女学院は1875年に神戸市山本通に設立されたが、1933年に西宮市岡田山に移転し、この地で80有余年の歴史をもつ。キャンパスの総面積は14ha、その35％に相当する約5haがクスノキやヒメユズリハ、コナラなどからなる鬱蒼とした天然林に被われており、良好な自然環境が保たれている。岡田山キャンパスの鳥類相については、1974年刊行の「岡田山の自然」に43種、1982年の増補改訂版に8種が追加され、計51種の野鳥が記録されている。また、2010年にはキャンパスの自然環境に関する報告書がまとめられ、34科88種の野鳥が報告されている。既存資料および1991年以降の主として第一著者のよる観察、および2003年度から2005年度にかけて行われたルートセンサスの結果を合わせると、岡田山キャンパスではこれまでに35科93種の野鳥が確認されていることが明らかになった。ヒヨドリ、スズメ、ハシブトカラス、キジバト、ムクドリ、メジロなどが主なものである。夏季日本で繁殖し、東南アジア等の熱帯域で越冬する夏鳥は26種で、ツバメ、サンショウクイ、センダイムシクイ、キビタキ、オオルリなどが主なものである。このうち、本学とその周辺域で確実に繁殖しているのはツバメのみで、他は本学を春と秋の2回通過する旅鳥型の夏鳥である。おもに日本以外の北方域で夏季繁殖し、岡田山を含む西日本で越冬する冬鳥は12種で、ツグミ、シロハラ、ジョウビタキ、シメなどが主なものである。北日本や山岳域で夏季繁殖し、岡田山を含む西日本で越冬する漂鳥は18種で、ウグイス、ルリビタキ、アオジなどが主なものである。日本以外の地域で繁殖、越冬し、春と秋に岡田山キャンパスを通過する旅鳥は4種で、オオムシクイ、マミチャジナイなどが主なものである。, To clarify the avifauna of the Okadayama Campus, Kobe College, western Japan, we investigated the wild bird species that inhabit or come flying over the campus, by observations and the route census method. Okadayama campus is located in the southeast corner of Hyogo Prefecture and has an area of ca. 14 ha and elevations from 8 to 50 m above sea level. The campus lies in the warm-temperate zoneand is under the influence fo Seto Inland Sea climate. Nearly 35％ of the campus is occupied by semi-natural forests dominated by evergreen broad-leaved trees such as Cinnamomum camphora, Daphniphyllum teijsmannii, Quercus glauca, and Ilex rotunda and deciduous broad-leaved trees such as Quercus serrata, Celtis sinensis, and Aphananthe aspera. The forest has been isolated by urbanization, and appears as a "green island" in an urban landscape, In the Okadayama Campus, 93 bird species belonging to 35 families have been recorded thus far. Out of the 93 bird species, 33 are resident breeders that breed in and around the campus, such as Hypsipetes amaurotis, Passer mountanus, Steptopelia orientalis, Corrvus macrorhynchos, and Spodiopsar cineraceus. Twnty-six species are migrant breeders that breed in the Japanese Archipelago and winter in the Asia tropics. However, most of the migrant breeders do not breed in and around the campus; they merely pass through the campus in the spring and autumn seasons, except for Hirundo rustica. Twelve species are winter visitors that breed in boreal regions and winter in southwestern Japan, including the Okadayama Campus, such as Turdus pallidus, T.naumanni, Phoenicurus auroreus, and Coccthraustes coccothraustes, Eighteen speces are vagrants that breed in the northern or Emberiza spodocephala. Four species are migrants that breed in boreal regions writer in the Asian tropics, such as phylloscopus examinandus and Turdus obscurus.

This study looks at how language ideologies affect and are revealed in language socialization practices in a majority-L1 adult ESL classroom, particularly looking at language use and policy. It draws on recent theories and critiques of language socialization (Bayley & Langman, 2011; Bronson & Watson-Gegeo, 2008; Garrett & Baquedano-Lopez, 2002; Kulick & Schieffelin, 2004), language ideologies (Woolard, 1998; Woolard & Schieffelin, 1994; Wortham, 2008) and second language learning (Auerbach, 1993; Cook, 1997). Qualitative, semi-ethnographic methods are used to address the intersection of language learning, socialization, and ideologies as related to classroom language use. The study reveals complex language ideologies that value students’ L1s, as well as adherence and resistance to socialization practices. It also reveals complications related to the teacher’s accommodation of languages besides English, particularly Spanish, for minority non-Spanish-speaking students. This paper concludes with implications...

国際交流基金では経済連携協定に基づいて来日するインドネシア人・フィリピン人看護師・介護福祉士候補者を対象とする来日前の日本語予備教育事業を実施している。本稿では2010年から3回にわたって実施した日本語研修の概要と成果を紹介する。本研修のコースデザインは、「初級からの専門日本語教育」「自律学習支援」等の考え方をベースに、特に「縦型アーティキュレーション」に配慮して組まれている。カリキュラムは「日本語授業」「自律学習支援」「社会文化理解」に大きく三分される。3回の研修を通して7割以上(マッチングが成立し来日した者に限ればほぼ8割以上)の候補者が学習到達目標に達していることから、本研修は看護師・介護福祉士国家試験に向けての日本語能力向上に貢献したと言えるだろう。今後はポートフォリオ等を見直し、現地研修から国内研修への「学習の連続性」をさらに強固なものにしていきたい。, The Japan Foundation has been implementing the Preparatory Japanese−Language Training forIndonesian and Filipino Nurse and Certified Care Worker Candidates under the Economic Partnership Agreement since 2010. The training course design was based on concepts like "Japanese−Language Education for Specific Purposes" for beginners, "Autonomous Learning", etc., and focused specifically on "vertical articulation". The curriculum has three branches: "Japanese−Language lessons", "Autonomous Learning" and "Understanding Japanese Society and Culture". Since 70% of the total number of candidates have attained the learning goals (more than 80% when limited to those who came to Japan via matching), thus, this training has helped improve the Japanese−language proficiency essential to handle the Nurses and Certified Care Workers National Examination. The goal from here is to strengthen the "continuity of learning" from local training to domestic training in Japan, including the reevaluation of the portfolio, etc.

Microinvasive breast cancer (T1mi) is considered as a precursor of invasive cancer developing from ductal carcinoma in situ (DCIS). This study discussed the clinicopathological and immunohistochemical features of T1mi by comparing those of ductal carcinoma in situ (Tis) and T1a to assess the nature and causes of the progression of Tis into invasive cancer. Three hundred and ninety-two Tis, 32 T1mi, and 141 T1a lesions which were pathologically diagnosed in surgical specimens between 2006 and 2009 were analyzed retrospectively. T1mi was defined as a tumor no greater than 1 mm in its greatest dimensions, and T1a was defined as a tumor larger than 1 mm but no greater than 5 mm. The frequency of the comedo type was significantly higher in T1mi (68.8%) than in Tis (13.8%) (p

Elastography is widely used as a diagnostic tool for the diagnosis of invasive breast cancer. However, no study has yet shown if elastography for diagnosing mucinous carcinoma is as useful as that for diagnosing the usual invasive carcinoma. Mucinous carcinoma is considered as a soft tumor. In this study, we used elastography to evaluate the elasticity of mucinous carcinoma. Among 1,015 patients who underwent surgery for primary breast cancer between February 2007 and August 2008 in our facility, the final pathological diagnosis showed only 32 mucinous carcinomas. We evaluated 16 of the 32 mucinous carcinoma patients who underwent preoperative elastography. There were 13 cases of the pure-type and 3 cases of the mixed-type mucinous carcinoma. B-mode ultrasound (US) imaging showed mass formation in 16 patients. The elasticity score was 2 in 1 case (8%), 3 in 3 cases (23%), 4 in 7 cases (54%), and 5 in 2 cases (15%). The fat-to-lesion ratio (FLR) was evaluated in 7 cases. The mean value of the FLR was 12 (range 3–30). Twelve of the 16 (75%) cases had an elastography score of 4 or 5. Although mucinous carcinoma had an elastography score similar to that of usual invasive carcinoma, elastography may be useful for distinguishing mucinous carcinoma from benign fibroadenoma.

Triple-negative breast cancer (TNBC) accounts for around 15% of all breast cancer, with over 35,000 newly diagnosed women per year in the US. TNBC patients are at highest risk for recurrence, and neoadjuvant standard chemotherapy gives pathologic complete response in about 30% of these patients. Currently, no targeted therapy has been conclusively established to improve the outcome of TNBC patients, though successful phase II studies have been completed (1, 2). Identification of mechanisms that are targetable is of great importance to improve the management of TNBC significantly. The aim of this study is to validate the accuracy and determine kinome interconnectivity of our enlarged peptide library used for a newly developed high-throughput kinase activity-mapping (HT-KAM) assay. The HT-KAM assay is our new screening technology to assess the catalytic activity of many kinases in parallel, which relies on collections of peptide probes that are used as combinatorial sensors to measure the phospho-catalytic activity of kinases in large-scale high-throughput ATP-consumption assays (3). The HT-KAM system provides access to a new, untapped, and large resource of biologically meaningful measurements, both as a means to map the entire cancer kinome and as a means to convert global phospho-signatures into functional patterns of kinase activity signatures. Kinome maps represent how kinase-signaling networks are rewired by overactive kinases, or drugs/targeted therapies in the context of different cellular backgrounds and exogenously mutated proteins/pathways, and provide insight into potentially targetable kinases. We previously established PhosphoAtlas, a heavily curated, comprehensive catalog database of 1,733 functionally interconnected proteins comprising the human phospho-reactome, including 4,748 unique edges that connect kinases to a target (776 kinase genes, 1,276 substrate protein genes, 2,492 heptameric peptide sequences [HPS]) (4). Previously, the HT-KAM assay with our initial set of 225 peptide probe sensors measuring the phosphorylating activity of >50 kinases, such as kinases belonging to EGFR/HER, MAPK, and RAF kinase families, was applied to explore mechanisms driving the unresponsiveness of colorectal and melanoma cancers to anti-BRAFV600E therapy in cell culture and patient-derived xenografts (PDX) (3). This successfully produced the predictive oncogenic kinome of melanoma tissues from patients suffering from fatal metastatic disease and, more importantly, identified new kinases/nodes that could be targeted to overcome drug resistance (3). Now, we made a selection of 640 peptide probe sensors, capturing the functionality of >110 kinases over >900 kinase-substrate nodes directly relevant to tumor biology that represent the majority of the curated interconnected proteins, from our PhosphoAtlas (4). In this HT-KAM study, we assessed the catalytic activity of selected purified recombinant kinases and 10 TNBC cell lines (BT-549, HCC1143, HCC1395, HCC1937, HCC38, HCC70, HS578T, MDA-MB-231, MDA-MB-436, MDA-MB-468) to investigate whether our enlarged peptide library provides insight into further interconnectivity. We anticipate that expanding our peptide library is key to the comprehensive exploration of cancer kinome, and in particular for complex conditions such as TNBC. References: 1. Engebraaten O, Vollan HKM, Børresen-Dale A-L. Triple-negative breast cancer and the need for new therapeutic targets. Am J Pathol 2013;183(4):1064-74. http://www.sciencedirect.com/science/article/pii/S0002944013004616. 2. Rugo HS, Olopade OI, DeMichele A, et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med 2016;375:23-34. PMID: 27406347. 3. Coppé JP, Mori M, Pan B, et al. Functional detection of phospho-catalytic circuits identifies new vulnerabilities of cancer. Submitted. 4. Olow A, Chen Z, Niedner RH, et al. An atlas of the human kinome reveals the mutational landscape underlying dysregulated phosphorylation cascades in cancer. Cancer Res 2016;76:1733-45. PMID: 26921330. Citation Format: Nina M. Koemans, Carolien L. Van Der Borden, Miki Mori, Bo Pan, Changjun Wang, Laura J. Van ‘t Veer, Jean-Philippe Coppé. Comprehensive kinome activity mapping of triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A38.

Triple-negative breast cancer (TNBC) accounts for approximately 15% of all breast cancer cases, with over 35,000 newly diagnosed women per year in the USA. TNBC patients are at high risk of recurrence, and neoadjuvant standard chemotherapy leads to pathologic complete response in only about 30% of patients. No targeted therapy has yet been conclusively established to improve outcome. The management of TNBC will significantly improve once mechanisms responsible for TNBC resistance to chemotherapies are identified. Here, we applied a new functional proteomic strategy to reveal which (dys)regulated phospho-signaling circuits are the effective dependencies of chemotherapy-resistant TNBC cells. The high-throughput kinase activity-mapping (HT-KAM) assay is our new screening technology to assess the catalytic activity of many kinases in parallel. HT-KAM relies on collections of biologic peptide probes that are computationally derived from PhosphoAtlas (Olow and Chen et al., Cancer Research 2016) and are physically used as combinatorial sensors to measure the activity of kinase enzymes in biologic extracts. The HT-KAM system provides access to a vast, untapped resource of meaningful measurements, whether readouts are interpreted irrespective of which enzymes phosphorylate which probes, or analyzed to convert global phospho-signatures into functional profiles of kinase activities. Kinome maps reveal how signaling networks are rewired by drug interventions in the context of different cellular backgrounds or exogenously mutated proteins/pathways, and provide insight into potentially targetable pathways. We previously successfully showed that the HT-KAM platform identifies new, actionable kinases responsible for intrinsic or acquired targeted-therapy resistance in BRAFV600E colorectal cancer cells and melanoma tumors from patients. To study TNBC, we used a 615-peptide sensor library that supports the mapping of >100 kinases and represents >900 functional kinase-substrate interactions relevant to tumor biology, and matches hundreds of druggable components of signaling circuits. We characterized the phospho-catalytic signatures of 10 TNBC cell lines, either untreated or treated with chemotherapeutic drugs (5-FU, carboplatin, doxorubicin) at IC50 concentrations. We also included a panel of 8 luminal BC cells. Based on our advanced preliminary data, we anticipate showing a comprehensive map of the oncogenic kinome of TNBC, and how it rewires its signaling network in response to chemotherapies. The most hyperactive and conserved pathways establish a priority map of strategic kinase hot spots to explore as therapeutic candidates. We find that chemotherapy-induced kinases such as SRC, AKT, CHEK, or regulating NFkB or PARP pathways can be inhibited to improve therapeutic sensitivity in TNBC. Citation Format: Jean-Philippe F. Coppe, Pan Bo, Carolien van der Borden, Nina Koemans, Changjun Wang, Denise Wolf, Christina Yau, Sietske Bakker, Marij Hartog, Miki Mori, Ana Ruiz-Saenz, Zhongzhong Chen, Aleksandra Olow, Pei Rong Evelyn Lee, Laura van 't Veer. Systematic identification of the actionable kinase dependencies of chemotherapy-resistant triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 956.