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PURPOSE Lehmann et al have identified four molecular subtypes of triple-negative breast cancer (TNBC)—basal-like (BL) 1, BL2, mesenchymal (M), and luminal androgen receptor—and an immunomodulatory (IM) gene expression signature modifier. Our group previously showed that the response of TNBC to neoadjuvant systemic chemotherapy (NST) differs by molecular subtype, but whether NST affects the subtype was unknown. Here, we tested the hypothesis that in patients without pathologic complete response, TNBC subtypes can change after NST. Moreover, in cases with the changed subtype, we determined whether epithelial-to-mesenchymal transition (EMT) had occurred. MATERIALS AND METHODS From the Pan-Pacific TNBC Consortium data set containing TNBC patient samples from four countries, we examined 64 formalin-fixed, paraffin-embedded pairs of matched pre- and post-NST tumor samples. The TNBC subtype was determined using the TNBCtype-IM assay. We analyzed a partial EMT gene expression scoring metric using mRNA data. RESULTS Of the 64 matched pairs, 36 (56%) showed a change in the TNBC subtype after NST. The most frequent change was from BL1 to M subtypes (38%). No tumors changed from M to BL1. The IM signature was positive in 14 (22%) patients before NST and eight (12.5%) patients after NST. The EMT score increased after NST in 28 (78%) of the 36 patients with the changed subtype ( v 39% of the 28 patients without change; P = .002254). CONCLUSION We report, to our knowledge, for the first time that the TNBC molecular subtype and IM signature frequently change after NST. Our results also suggest that EMT is promoted by NST. Our findings may lead to innovative adjuvant therapy strategies in TNBC cases with residual tumor after NST.

Probing the inversion kinetics of a molecular helix is inherently a challenging task. We demonstrate herein that a fast-rotating pentiptycene component could function as an external NMR probe to afford the kinetic information on the inversion of a neighboring helical stiff-stilbene unit.

An onset of cervical myelopathy due to ossification of the posterior atlantoaxial membrane (PAAM) is extremely rare in older patients, and its clinical characteristics are still unclear. We report an onset of ossification of PAAM with congenital atlas hypoplasia in an 81-year-old man who presented with a 2-year history of progressive cervical myelopathy. Cervical computed tomography (CT) revealed canal stenosis secondary to a hypoplastic posterior arch of the atlas with a diameter of 20.3 mm between the anterior and posterior process. Magnetic resonance imaging showed marked spinal cord compression at the level of C1–2 secondary to atlas hypoplasia as well as ossification of PAAM. The patient underwent laminectomy of C1 and partial C2, as well as removal of the ossification, without atlantoaxial fusion. His neurological status improved 1 year postoperatively. In older patients, cervical myelopathy secondary to PAAM ossification, in the absence of trauma and atlantoaxial instability, may be induced by age-related pathophysiology associated with congenital atlas hypoplasia.

Background Cerebral infarction accounts for 85% of all stroke cases. Even in an era of rapid and effective recanalization using an intravascular approach, the majority of patients have poor functional outcomes. Thus, there is an urgent need for the development of therapeutic agents to treat acute ischemic stroke. We evaluated the effect of fasudil, a Rho kinase inhibitor, on blood brain barrier (BBB) functions under normoxia or oxygen-glucose deprivation (OGD) conditions using a primary cell-based in vitro BBB model. Medhods: BBB models from rat primary cultures (brain capillary endothelial cells, astrocytes, and pericytes) were subjected to either normoxia or 6-hour OGD/24-hour reoxygenation. To assess the effects of fasudil on BBB functions, we evaluated real time impedance, transendothelial electrical resistance (TEER), sodium fluorescein permeability, and tight junction protein expression using immunohistochemistry and western blotting. Lastly, to understand the observed protective mechanism on BBB functions by fasudil we examined the role of cyclooxygenase-2 and thromboxane A2 receptor agonist U-46619 in BBB-forming cells. Results We found that treatment with 0.3–30 µM of fasudil increased cellular impedance. Fasudil enhanced barrier properties in a concentration-dependent manner, as measured by an increased (TEER) and decreased permeability. Fasudil also increased the expression of tight junction protein claudin-5. Reductions in TEER and increased permeability were observed after OGD/reoxygenation exposure in mono- and co-culture models. The improvement in BBB integrity by fasudil was confirmed in both of the models, but was significantly higher in the co-culture than in the monoculture model. Treatment with U-46619 did not show significant changes in TEER in the monoculture model, whereas it showed a significant reduction in TEER in the co-culture model. Fasudil significantly improved the U-46619-induced TEER reduction in the co-culture models. Pericytes and astrocytes have opposite effects on endothelial cells and may contribute to endothelial injury in hyperacute ischemic stroke. Overall, fasudil protects the integrity of BBB both by a direct protective effect on endothelial cells and by a pathway mediated via pericytes and astrocytes. Conclusions Our findings suggest that fasudil is a BBB-protective agent against acute ischemic stroke.

Background Cerebral infarction accounts for 85% of all stroke cases. Even in an era of rapid and effective recanalization using an intravascular approach, the majority of patients have poor functional outcomes. Thus, there is an urgent need for the development of therapeutic agents to treat acute ischemic stroke. We evaluated the effect of fasudil, a Rho kinase inhibitor, on blood brain barrier (BBB) functions under normoxia or oxygen–glucose deprivation (OGD) conditions using a primary cell-based in vitro BBB model. Methods BBB models from rat primary cultures (brain capillary endothelial cells, astrocytes, and pericytes) were subjected to either normoxia or 6 h OGD/24 h reoxygenation. To assess the effects of fasudil on BBB functions, we evaluated real time impedance, transendothelial electrical resistance (TEER), sodium fluorescein permeability, and tight junction protein expression using western blotting. Lastly, to understand the observed protective mechanism on BBB functions by fasudil we examined the role of cyclooxygenase-2 and thromboxane A2 receptor agonist U-46619 in BBB-forming cells. Results We found that treatment with 0.3–30 µM of fasudil increased cellular impedance. Fasudil enhanced barrier properties in a concentration-dependent manner, as measured by an increased (TEER) and decreased permeability. Fasudil also increased the expression of tight junction protein claudin-5. Reductions in TEER and increased permeability were observed after OGD/reoxygenation exposure in mono- and co-culture models. The improvement in BBB integrity by fasudil was confirmed in both of the models, but was significantly higher in the co-culture than in the monoculture model. Treatment with U-46619 did not show significant changes in TEER in the monoculture model, whereas it showed a significant reduction in TEER in the co-culture model. Fasudil significantly improved the U-46619-induced TEER reduction in the co-culture models. Pericytes and astrocytes have opposite effects on endothelial cells and may contribute to endothelial injury in hyperacute ischemic stroke. Overall, fasudil protects the integrity of BBB both by a direct protective effect on endothelial cells and by a pathway mediated via pericytes and astrocytes. Conclusions Our findings suggest that fasudil is a BBB-protective agent against acute ischemic stroke.

Objective Simultanagnosia is a rare neuropsychological symptom characterized by difficulty recognizing global structures while preserving perception of local detail. The condition is classified into ventral and dorsal types. Clinical presentation of ventral simultanagnosia includes a reduced ability to recognize multiple visual stimuli rapidly, that is, part-by-part recognition. Here, we report a case of ventral simultanagnosia with a unique presentation; when short-duration visual stimuli were presented, the patient could perform global recognition by improving his part-by-part approach. To investigate the relationship between local and global perception bias and the duration of the present stimulus, we conducted a visual perception test using hierarchically organized Navon figures. Methods/Results The patient was a 62-year-old right-handed man who suffered from cerebral infarction in the right occipitotemporal lobe. He had no language dysfunction but exhibited left unilateral neglect, prosopagnosia, and ventral-type simultanagnosia. We conducted a visual perception test using the Navon figures and control figures as a visual stimulus. We randomly presented the figures for intervals of 0.2 or 20 s and let the patient report all the letters (global and/or local element) that he recognized. Global elements of the Navon letter were recognized a rate of 0% and 78.3% at intervals of 20 and 0.2 s, respectively, indicating that shorter presentation made the part-by-part approach less likely to manifest. Conclusions We assumed that the simultanagnosia in this case was caused by failure to maintain the initially perceived global information for a long period of time during visual presentation, due to right occipitotemporal damage.

Vasospasm related to mechanical thrombectomy for acute ischemic stroke sometimes occurs as a periprocedural complication, although it is usually a transient and asymptomatic event. Herein we describe the second case of symptomatic delayed vasospasm associated with mechanical thrombectomy, highlighting its unique device-related adverse event. When intraoperative vasospasm occurs, we should pay attention to this phenomenon, and close follow-up is necessary.

Purpose A subset of patients with intermediate 21-gene signature assay recurrence score may benefit from adjuvant chemoendocrine therapy, but a predictive strategy is needed to identify such patients. The 95-gene signature assay was tested to stratify patients with intermediate RS into high (95GC-H) and low (95GC-L) groups that were associated with invasive recurrence risk.Methods Patients with ER-positive, HER2-negative, node-negative breast cancer and RS 11-25 who underwent definitive surgery and adjuvant endocrine therapy without any cytotoxic agents were included. RNA was extracted from archived formalin-fixed, paraffin-embedded samples, and 95-gene signature was calculated. Results Two hundred six patients had RS of 11-25 (95GC-L, N = 163; 95GC-H, N = 43). In Cox proportional hazards model, 95GC-H was significantly associated with shorter time to recurrence than was 95GC-L (HR 5.94; 95%CI 1.81-19.53; P = 0.005). The correlation between 95-gene signature and 21-gene signature assay scores was not strong (correlation coefficient r = 0.27), which might suggest that 95-gene signature reflects biological characteristics differing from what 21-gene signature shows.Conclusions The 95-gene signature stratifies patients with ER-positive, HER2-negative, node-negative invasive breast cancer and intermediate RS of 11-25 into high and low groups that are associated with recurrence risk of invasive disease. Further retrospective analysis in the prospectively-accrued TAILORx population is warranted to confirm that 95-gene signature can identify patients who would benefit from adjuvant chemoendocrine therapy.

A 78‒year‒old man was admitted to our hospital with the chief complaint of 5 kg weight loss in 6 months. An esophagogastroduodenoscopy revealed a 0‒Ⅱa lesion in the posterior wall of the antrum, and biopsy findings showed a well‒differentiated adenocarcinoma. Endoscopic ultrasonography did not show an obvious invasion of the submucosal layer. Contrast‒ enhanced abdominal computed tomography(CT)revealed an enlargement of the #11p lymph node to approximately 30 mm, and positron emission tomography(PET)‒CT showed an accumulation in the same lymph node. Since no other apparent distant metastases were observed, laparoscopic distal gastrectomy and D2 dissection were performed. The postoperative pathological diagnosis was L, 7×8 mm, 0‒Ⅱa, tub1, pT1a, ly0, v0, pPM0(73 mm), pDM0(35 mm), N2, and pStage ⅡA. We report this case because the successful laparoscopic resection of a differentiated gastric mucosal cancer with lymph node metastasis has been considered to be extremely rare.

The patient was a 58-year-old man who had undergone wide gastrectomy for gastric ulcer at 22 years of age. Endoscopic examination revealed an advanced type 3 gastric cancer in the anastomotic region. We performed total gastrectomy and D1 lymph node dissection because of the bleeding from the tumor, although peritoneal dissemination was found during the surgery. A post-operative pathological diagnosis of gastric cancer pT4b(SI, abdominal wall)N0M1(PER), pStage Ⅳ, was made. After the surgery, he was administered chemotherapy with S-1 and cisplatin. After 9 courses of the treatment, the treatment protocol was changed to an S-1 therapy regimen because of general fatigue. Four years and 8 months after the surgery, the tumor marker had increased, and CT scans revealed a dissemination nodule at the left back side of the bladder. Therefore, PTX plus Rmab therapy was administered as a second-line chemotherapy. Treatment with PTX plus Rmab resulted in tumor reduction, with an improvement of the QOL of the patient; partial response was maintained for 12 months. After 16 courses of the PTX plus Rmab treatment, tumor regrowth was detected. The treatment protocol was changed again to a nivolumab regimen. After 4 courses, the tumor marker was normalized, and CT scans revealed that the peritoneal dissemination had shrunk. Although the prognosis of gastric cancer with dissemination is very poor, it is possible to prolong survival with chemotherapy.

A 75-year-old man presented to a local clinic with anal pain, and a palpable anal tumor on was found on digital examination of the rectum. A biopsy led to the diagnosis of neuroendocrine carcinoma. Besides the anal tumor, an right-inguinal lymph node was revealed on computed tomography(CT). Positron emission tomography-CT showed abnormal uptake in the 2 regions. He was diagnosed with lymph node metastases from anal canal carcinoma, and an abdominoperineal resection was performed. The resected specimen included the anal canal tumor with a size of 27×18 mm in diameter. On immunohistochemistry, the anal canal tumor was strongly positive for synaptophysin and positive for chromogranin A, with a Ki- 67 positivity index of 70%. After the surgery, he was administered chemotherapy with 4 courses of cisplatin and CPT-11. One year after the surgery, CT revealed lymph node recurrence. Therefore, cisplatin and CPT-11 therapy was repeated. After 11 courses of the cisplatin and CPT-11 treatment, tumor regrowth was still detected. The treatment protocol was changed to an amrubicin monotherapy regimen. However, the patient's general condition worsened after the therapies, and he died 38 months after the surgery.

Antibody–drug conjugates (ADCs), which are currently being developed, may become promising cancer therapeutics. Folate receptor α (FOLR1), a glycosylphosphatidylinositol-anchored membrane protein, is an attractive target of ADCs, as it is largely absent from normal tissues but is overexpressed in malignant tumors of epithelial origin, including ovarian, lung, and breast cancer. In this study, we tested the effects of novel anti-FOLR1 antibody–eribulin conjugate MORAb-202 in breast cancer and non-small cell lung cancer (NSCLC) cell lines. FOLR1 expression, cell proliferation, bystander killing effects, and apoptosis were evaluated in seven breast cancer and nine NSCLC cell lines treated with MORAb-202. Tumor growth and FOLR1 expression were assessed in T47D and MCF7 orthotopic xenograft mouse models after a single intravenous administration of MORAb-202 (5 mg/kg). MORAb-202 was associated with inhibited cell proliferation, with specific selectivity toward FOLR1-expressing breast cancer cell lines. Eribulin, the payload of MORAb-202, was unleashed in HCC1954 cells, diffused into intercellular spaces, and then killed the non-FOLR1-expressing MCF7 cells in co-culture systems. In orthotopic xenograft mouse models, FOLR1-expressing T47D tumors and non-FOLR1-expressing MCF7 tumors were suppressed upon MORAb-202 administration. The novel anti-FOLR1 antibody–eribulin conjugate MORAb-202 has potential antitumor effects in breast cancer.

BACKGROUND Pituitary apoplexy associated with aneurysmal rupture is extremely rare and may be misdiagnosed as primary pituitary adenoma apoplexy. The authors present a case of a patient with pituitary apoplexy caused by rupture of an anterior cerebral artery aneurysm embedded within a giant pituitary adenoma, and they review the relevant literature. OBSERVATIONS A 78-year-old man experienced sudden headache with progressive vision loss. Magnetic resonance imaging (MRI) revealed a giant pituitary tumor with abnormal signal intensity. Magnetic resonance angiography immediately before surgery showed a right A1 segment aneurysm, suggesting coexisting pituitary apoplexy and ruptured aneurysm. The patient underwent urgent transsphenoidal surgery for pituitary apoplexy. The tumor was partially removed, but the perianeurysmal component was left behind. Subsequent cerebral angiography showed a 5-mm right A1 aneurysm with a bleb that was successfully embolized with coils. Retrospective review of preoperative dynamic MRI showed extravasation of contrast medium from the ruptured aneurysm into the pituitary adenoma. Histopathologic examination showed gonadotroph adenoma with hemorrhagic necrosis. Postoperatively, the patient’s visual function improved. LESSONS MRI identification of pituitary apoplexy caused by aneurysmal rupture has not been reported previously. Aneurysmal rupture should be considered in the differential diagnosis of pituitary apoplexy. When a ruptured aneurysm is encountered, the authors recommend treating it before addressing pituitary apoplexy.

BRCAness is defined as a phenotypic copy of germline BRCA mutations, which describes presence of homologous recombination defects in sporadic cancers. We detected BRCAness by multiplex ligation-dependent probe amplification (MLPA) and explored whether BRCAness can be used as a predictor of prognosis. BRCAness status was classified for total 121 breast cancer patients. Forty-eight patients (39.7%) were identified as BRCAness positive. Tumors of BRCAness were more likely to be hormone receptors negative (95.8% vs. 50.7%, P P = 0.001) and triple-negative breast cancer subtype (91.6% vs. 42.5%, P P P = 0.002) were significantly lower in BRCAness patients. In neoadjuvant chemotherapy subgroup analysis, clinical response rate for taxane-based regimen was significantly lower in BRCAness patients (58.3% vs. 77.8%, P = 0.041). Cox regression multivariate analysis showed that BRCAness was the independent prognostic factor for DFS (HR 2.962, 95%CI 1.184–7.412, P = 0.020), but not for OS (HR 2.681, 95%CI 0.618–11.630, P = 0.188). BRCAness is associated with specific characteristics and may suggest resistance to taxane-based chemotherapy. BRCAness can be used as a negative prognostic indicator for breast cancer.

Probing the inversion kinetics of a molecular helix is inherently a challenging task. We demonstrate herein that a fast-rotating pentiptycene component could function as an external NMR probe to afford the kinetic information on the inversion of a neighboring helical

A 66-year-old man underwent chemotherapy with S-1 plus cisplatin plus trastuzumab to treat advanced gastric cancer that was diagnosed as cStage Ⅳ adenocarcinoma(T3N1M1[P0, CYX, H1]). After 8 courses, liver metastases were absent on contrast-enhanced MRI. The patient underwent a laparoscopic distal gastrectomy with D2 lymphadenectomy. The gross appearance of the surgically resected specimen showed a shrunk gastric tumor measuring 1 mm. The postoperative course was uneventful, and the patient has been well, receiving maintenance chemotherapy of S-1 plus trastuzumab without evidence of recurrence for 15 months following the operation. Conversion surgery following chemotherapy might be an effective treatment for patients with advanced gastric cancer; however, further studies are needed to establish this treatment strategy.

The widespread use of breast screening programs has contributed to the detection of early stage breast cancer, which is often asymptomatic. Early diagnosis is essential to avoid overtreatment and improve clinical outcomes, as early stage breast cancer is rarely life-threatening if detected quickly. Despite this, tissue biopsy remains the principle method for detecting these cancers. Liquid biopsy has been recently proposed as a promising detection method in oncology that is not only less invasive but also contributes to the early diagnosis of breast cancer. Here, we describe the clinical utility of liquid biopsy as a tool for the early detection of breast cancer.

Many patients develop a prolonged decrease of muscle strength after total hip arthroplasty (THA) despite their reconstructed hip joint. Physical exercise combined with branched-chain amino acid (BCAA) supplementation has been reported to improve muscle strength in elderly persons with sarcopenia. However, the effect of BCAA supplementation in patients after THA is unknown. This study examined the effects of BCAA supplementation combined with exercise therapy on the improvement of physical function in elderly patients after THA.The subjects were 31 elderly women who underwent THA. The participants were randomly assigned to two groups: BCAA (n=18) and control (n=13). The combined therapy was carried out for one month after THA. For the exercise intervention, a 3-set physical exercise program was conducted. For the nutritional intervention, the participants consumed 3.4 g of BCAA supplement or 1.2 g of starch immediately after the exercise intervention.BCAA supplementation combined with muscle strengthening exercises had a significant effect on knee extension strength of the contralateral side and on upper arm cross-sectional area. The improvement ratio of knee extension strength before and after intervention on the operated side was also significantly higher in the BCAA group.BCAA supplementation is effective for patients to improve the strength of some muscles when combined with physical exercises, but hip abductor muscle strength of the operated leg did not improve. A future study is needed to determine the efficacy of this combined therapy for hip abductor muscle strength.

Reelin is an essential glycoprotein for the establishment of the highly organized six-layered structure of neurons of the mammalian neocortex. Although the role of Reelin in the control of neuronal migration has been extensively studied at the molecular level, the mechanisms underlying Reelin-dependent neuronal layer organization are not yet fully understood. In this study, we directly showed that Reelin promotes adhesion among dissociated neocortical neurons in culture. The Reelin-mediated neuronal aggregation occurs in an N-cadherin-dependent manner, both in vivo and in vitro. Unexpectedly, however, in a rotation culture of dissociated neocortical cells that gradually reaggregated over time, we found that it was the neural progenitor cells [radial glial cells (RGCs)], rather than the neurons, that tended to form clusters in the presence of Reelin. Mathematical modeling suggested that this clustering of RGCs could be recapitulated if the Reelin-dependent promotion of neuronal adhesion were to occur only transiently. Thus, we directly measured the adhesive force between neurons and N-cadherin by atomic force microscopy, and found that Reelin indeed enhanced the adhesiveness of neurons to N-cadherin; this enhanced adhesiveness began to be observed at 30 min after Reelin stimulation, but declined by 3 h. These results suggest that Reelin transiently (and not persistently) promotes N-cadherin-mediated neuronal aggregation. When N-cadherin and stabilized β-catenin were overexpressed in the migrating neurons, the transfected neurons were abnormally distributed in the superficial region of the neocortex, suggesting that appropriate regulation of N-cadherin-mediated adhesion is important for correct positioning of the neurons during neocortical development.

Carotid endarterectomy(CEA)is well-established and performed for carotid artery stenosis all over the world. However, some severe complications and pitfalls have been reported. Carotid artery stenting(CAS)in high-surgical-risk patients is considered an effective alternative to CEA. We reviewed our clinical experience of CEA and CAS and discuss the advantages and disadvantages of each treatment.For 13 years, we performed CEA for 133 patients(135 lesions)and CAS for 127 patients with carotid artery stenosis(129 lesions). CAS is indicated for the CEA high-risk patients. Perioperative imaging studies and post-operative statuses were evaluated especially in cases with complications.In our CEA series, ischemic stroke occurred in 3 cases, myocardial infarction in 1, cranial nerve palsy in 2, internal carotid artery occlusion in 1, wound hematoma in 2, and hyperperfusion syndrome in 4. The procedure was halted in one case because of an internal shunt problem. All cases of CAS were successfully performed except for one case complicated with myocardial infarction. Ischemic stroke occurred in 7 cases, hyperperfusion syndrome in 2, stent occlusion in 2, and puncture site hematoma in 2. Restenosis appeared in CAS significantly more than in CEA.CEA is a first-line treatment for carotid artery stenosis. However, complications of CEA may result in severe situations. Recognizing pitfalls and careful perioperative management is required. The results of CAS are comparable to those of CEA. Radiological evaluation for the presence of plaque and appropriate selection of an embolus protection device are important.

The accessory middle cerebral artery(AMCA)is an anatomical variant of the MCA. It originates from the anterior cerebral artery, reaches the sylvian fissure, and supplies the territory of the middle cerebral artery. We report a case of embolic infarction associated with the AMCA that was treated using mechanical thrombectomy. An 82-year-old man with chronic atrial fibrillation experienced a sudden onset of left hemiparesis and was brought to our hospital. Magnetic resonance imaging showed a right temporal lobe, parietal lobe, and basal ganglion infarction, and indicated right internal carotid artery(ICA)occlusion. Mechanical thrombectomy using a Penumbra system was performed with complete recanalization. Final angiography revealed the existence of the AMCA, and the thrombus was located at the right ICA C2 portion to the main MCA. There have been twelve reported cases of ischemic stroke associated with the AMCA, including the present case. We summarized the data from the reported cases of ischemic stroke with an AMCA and evaluated their clinical characteristics and the pitfalls of endovascular treatment. These cases suggest that the AMCA may play a role in collateral flow around the main MCA occlusion, but provides insufficient collateral blood supply. Owing to the anatomical characteristics of the AMCA, we should pay attention to possible complications of endovascular treatment.

Acquired resistance to molecular target inhibitors is a severe problem in cancer therapy. Lung cancer remains the leading cause of cancer-related death in most countries. The discovery of "oncogenic driver mutations," such as epidermal growth factor receptor (EGFR)-activating mutations, and subsequent development of molecular targeted agents of EGFR tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib) have dramatically altered lung cancer treatment in recent decades. However, these drugs are still not effective in patients with non-small cell lung cancer (NSCLC) carrying EGFR-activating mutations. Following acquired resistance, the systemic progression of NSCLC remains a significant obstacle in treating patients with EGFR mutation-positive NSCLC. Here, we present a stepwise dose escalation method for establishing three independent acquired afatinib-resistant cell lines from NSCLC PC-9 cells harboring EGFR-activating mutations of 15-base pair deletions in EGFR exon 19. Methods for characterizing the three independent afatinib-resistance cell lines are briefly presented. The acquired resistance mechanisms to EGFR TKIs are heterogeneous. Therefore, multiple cell lines with acquired resistance to EGFR-TKIs must be examined. Ten to twelve months are required to obtain cell lines with acquired resistance using this stepwise dose escalation approach. The discovery of novel acquired resistance mechanisms will contribute to the development of more effective and safe therapeutic strategies.

Although many studies have evaluated the retrieved thrombus to assess the cause of stroke after mechanical thrombectomy for acute large vessel occlusion, the results remain controversial. We investigated the hypothesis that histology of the retrieved thrombus is enhanced by mechanical thrombectomy devices.Thrombi were collected from consecutive patients who had undergone endovascular mechanical recanalization for large intracranial vessel occlusion. The mechanical thrombectomy device used was either an aspiration catheter or a stent retriever. The hematoxylin and eosin-stained specimens were quantitatively analyzed with respect to the relative fractions of the main constituents (erythrocytes and fibrin). Clinical and radiologic findings were also evaluated.Of 65 patients, an aspiration catheter was used in 27, and a stent retriever was used in 38. The presence of a preoperative susceptibility vessel sign on magnetic resonance imaging was not correlated with the percentage of erythrocytes. Thrombus cross-sectional area was larger in the aspiration group than in the stent group (P0.01). Conversely, the percentage of the fibrin component was higher in the stent group (P0.001). Preoperative intravenous administration of recombinant tissue plasminogen activator reduced thrombus cross-sectional area with a trend of increased percentage of fibrin and reduced percentage of erythrocyte in the stent group.Histologic differences in retrieved thrombi are enhanced by mechanical thrombectomy devices. Stent retrievers may crush the thrombus, which may have a synergistic effect with recombinant tissue plasminogen activator. Histology of the retrieved thrombi might be different from histology of the original thrombi.

This paper proposes paint-type dye-sensitized solar cells (DSCs). DSCs, one type of solar cell, generally consist of a dye-attached semiconducting electrode, a metallic electrode, and an electrolyte. The DSC generates power through the excitation of the electrons in the dyes and the oxidation-reduction reaction between the dyes and the electrolyte. For our paint-type DSC, we made two electrodes by painting two types of paint on substrates. We used carbon nanotubes (CNTs) as the paint material because they have both semiconducting and metallic properties. This enabled us to prepare semiconducting and metallic electrodes easily by simply painting with the CNT paint. As a result of testing, we determined that our DSCs were capable of power generation. Our paint-type DSCs have the potential to provide power as a unique and useful device for daily life in the near future.

The gel column chromatographic separation technique is one of the most rapid and reliable methods to prepare high-purity semiconducting single-wall carbon nanotubes (SWCNTs). However, the use of the expensive dextran-based gels limits the utility and scalability of this technique. Herein, we report the cross-linking gelation of a cost-efficient polysaccharide isomaltodextrin (IMD) for the high-purity separation of s-SWCNTs by column chromatography. The cross-linking reaction with epichlorohydrin under precisely controlled basic conditions gave the sub-micrometer porous IMD gels, which was important for achieving gel chromatographic SWCNT separation. Furthermore, the thin-film transistors prepared from the separated s-SWCNTs exhibited excellent on/off ratios.

Background Ductal carcinoma in situ (DCIS) is considered a component of the clinical spectrum of breast cancer even in those with BRCA1/2 mutation. The aim of this study was to report the feature of DCIS raised in Japanese women with BRCA1/2 mutations. Methods A total of 325 Japanese women with breast cancer (BC) (with or without invasive cancer) were referred for genetic counseling and underwent genetic testing for mutations in the BRCA1 and BRCA2 genes in Showa University Hospital between December 2011 and August 2016. And 49 of them who were pathologically diagnosed as DCIS were included in this study. Logistic regression models were fit to determine the associations between potential predictive factors and BRCA status. A Cox proportional hazards model is used to predictive value of parameters for Ipsilateral breast tumor recurrence (IBTR) and contralateral breast tumor recurrence (CBTR). Results (a) Of 325 patients (with or without invasive cancer), 19.1% (62/325) tested positive for BRCA1/BRCA2 mutations. And 18.4% (9/49) was positive for BRCA1/BRCA2 mutations in DCIS, compared with 19.2% (53/276) in IDC (p = 1.000). Among BRCA mutations, 14.5% (9/62) had DCIS compared with nonmutations (15.2%, 40/263). Incidence of DCIS was 3.0% (1/33) of BRCA1 mutations and 27.5% (8/29) of BRCA2 mutation (p = 0.009). (b) Median age of diagnosis in BRCA mutation carriers was 39 years, compared with 46 years in noncarriers. Age, Family history (FH) of BC, FH of first or second BC and total number of relatives with BC diagnosis (DX) has significant difference between BRCA mutation carriers and noncarriers in univariate analysis. In a multivariate logistic model, total relatives with BC DX ≥ 2 (odds ratio [OR], 5.128; 95% confidence interval [CI], 1.266–20.763; p = 0.022), age at diagnosis ≤35 years (OR 0.149, 95% CI 0.023–0.954, p = 0.045) and ER+/HER2+ status (OR 5.034, 95% CI 1.092–23.210, p = 0.038) remained as independent significant predictors for BRCA mutation. Ki67 index (cut off by 14% or 30%) did not differ between BRCA mutation carriers and noncarriers (p = 0.459 and p = 0.651). (c) There was a significant difference in ER‐positive tumors among BRCA2 carriers and noncarriers (p = 0.042). Subgroup analysis showed BRCA2 carriers tend to be of higher grade (Grade 2 and 3), more frequently ER+/PR+ (p = 0.041) and lower proliferation (Ki67 index) than noncarriers, whereas differences in nuclear grade and ki67 index were not found significantly in our study. (d) BRCA mutation was not associated with an increased risk of IBTR and CBTR. Conclusion DCIS is equally as prevalent in patients who were BRCA mutation carriers as in high familial‐risk women who were noncarriers, but occurs at earlier age. BRCA2 carriers have higher incidence in DCIS than that of BRCA1 carriers, and tend to be higher grade and more frequently ER positive and lower proliferation. Total relatives with BC DX ≥2, age at diagnosis ≤35 years and ER+/HER2+ might be independent predictors for BRCA mutation in Japanese women with DCIS and patients of these risk factors should be recommended to receive genetic counseling and BRCA testing.

A new strategy is reported for multicolor fluorescence writing on thin solid films with mechanical forces. This concept is illustrated by the use of a green-fluorescent pentiptycene derivative 1, which forms variably colored fluorescent exciplexes: a change from yellow to red was observed with anilines, and fluorescence quenching (a change to black) occurred in the presence of benzoquinone. Mechanical forces, such as grinding and shearing, induced a crystalline-to-amorphous phase transition in both the pristine and guest-adsorbed solids that led to a change in the fluorescence color (mechanofluorochromism) and a memory of the resulting color. Fluorescence drawings of five or more colors were created on glass or paper and could be readily erased by exposure to air and dichloromethane fumes. The structural and mechanistic aspects of the observations are also discussed.

Background Because infective endocarditis (IE) carries a high risk of morbidity and mortality, rapid diagnosis and effective treatment are essential to achieving a good patient outcome. However, the diagnosis of IE is often difficult in patients presenting with nonspecific clinical manifestations. An association between IE and hypointense signal spots on brain T2*-weighted magnetic resonance imaging (MRI) has been reported, but the clinical significance remains unclear.Methods and Results:To assess the clinical importance of silent lesions in the brains of IE patients, hypointense signal spots detected on their brain T2*-weighted MRI scans were investigated in a retrospective review of 44 consecutive patients with definite or suspected IE evaluated by MRI between June 2006 and January 2014. Hypointense signal spots on T2*-weighted MRI were detected in 37 (84%) patients; of these, 21 (46%) had ischemic lesions, 10 (22%) had subarachnoid hemorrhage, 4 (9%) had intraparenchymal hemorrhage, and 4 (9%) had infectious aneurysm. The hypointense signal spots on T2*-weighted images were preferentially distributed in cortical areas. Conclusions T2*-weighted hypointense signal spots are highly frequent in patients with IE and their presence may be informative in the monitoring of IE-associated brain lesions, even those that are neurologically asymptomatic. The strong association between IE and T2*-weighted hypointense signal spots supports the need to consider additional criteria in the diagnosis of IE.

Many extremely preterm infants (born before 28 gestational weeks [GWs]) develop cognitive impairment in later life, although the underlying pathogenesis is not yet completely understood. Our examinations of the developing human neocortex confirmed that neuronal migration continues beyond 23 GWs, the gestational week at which extremely preterm infants have live births. We observed larger numbers of ectopic neurons in the white matter of the neocortex in human extremely preterm infants with brain injury and hypothesized that altered neuronal migration may be associated with cognitive impairment in later life. To confirm whether preterm brain injury affects neuronal migration, we produced brain damage in mouse embryos by occluding the maternal uterine arteries. The mice showed delayed neuronal migration, ectopic neurons in the white matter, altered neuronal alignment, and abnormal corticocortical axonal wiring. Similar to human extremely preterm infants with brain injury, the surviving mice exhibited cognitive deficits. Activation of the affected medial prefrontal cortices of the surviving mice improved working memory deficits, indicating that decreased neuronal activity caused the cognitive deficits. These findings suggest that altered neuronal migration altered by brain injury might contribute to the subsequent development of cognitive impairment in extremely preterm infants.

The hippocampus plays important roles in brain functions. Despite the importance of hippocampal functions, recent analyses of neuronal migration have mainly been performed on the cerebral neocortex, and the cellular mechanisms responsible for the formation of the hippocampus are not yet completely understood. Moreover, why a prolonged time is required for hippocampal neurons to complete their migration has been unexplainable for several decades. We analyzed the migratory profile of neurons in the developing mouse hippocampal CA1 region and found that the hippocampal pyramidal neurons generated near the ventricle became postmitotic multipolar cells and accumulated in the multipolar cell accumulation zone (MAZ) in the late stage of development. The hippocampal neurons passed through the pyramidal layer by a unique mode of migration. Their leading processes were highly branched and made contact with many radial fibers. Time-lapse imaging revealed that the migrating cells changed their scaffolds from the original radial fibers to other radial fibers, and as a result they proceed in a zigzag manner, with long intervals. The migrating cells in the hippocampus reminded us of “rock climbers” that instead of using their hands to pull up their bodies were using their leading processes to pull up their cell bodies. Because this mode of migration had never been described, we called it the “climbing” mode. The change from the “climbing” mode in the hippocampus to the “locomotion” mode in the neocortex may have contributed to the brain expansion during evolution.