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Objectives Patients with concomitant advanced non-small cell lung cancer (NSCLC) and interstitial lung disease (ILD) are excluded from most clinical chemotherapy trials because of the high risk of exacerbating the latter condition. This study prospectively investigated the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) in combination with carboplatin in patients with both advanced NSCLC and ILD. Patients and methods The enrolled patients had treatment-naive, advanced NSCLC with ILD. Patients received 100 mg/m2 nab-paclitaxel weekly and carboplatin at an area under the concentration-time curve of 6 once every 3 weeks for 4–6 cycles. The primary endpoint was the overall response rate (ORR); secondary endpoints included toxicity, progression-free survival (PFS), and overall survival (OS). Results Thirty-six patients were enrolled between April 2014 and September 2017. Sixteen patients (44.4%) had adenocarcinoma, 15 (41.7%) had squamous cell carcinoma (Sq), and 5 (13.9%) had non-small cell carcinoma. The median number of cycles administered were 4 (range: 1–6). The ORR was 55.6% (95% confidence interval [CI]: 39.6–70.5). The median PFS and OS were 5.3 months (95% CI: 3.9–8.2) and 15.4 months (95% CI: 9.4–18.7), respectively. A greater proportion of patients with Sq experienced improvements than did those with non-Sq: ORRs, 66.7% (95% CI: 41.7–84.8) vs. 47.6% (95% CI: 28.3–67.6) (P = 0.254); median PFS, 8.2 months (95% CI: 4.0–10.2) vs. 4.1 months (95% CI: 3.3–5.4) (HR, 0.60 [95% CI, 0.30–1.20]; P = 0.15); and median OS, 16.8 months (95% CI: 9.8–not reached) vs. 11.9 months (95% CI: 7.3–17.4) (HR, 0.56 [95% CI, 0.24–1.28]; P = 0.17). Two patients (5.6%) experienced grade ≥2 pneumonitis and 1 patient (2.8%) died. Conclusion Weekly nab-paclitaxel combined with carboplatin showed favorable efficacy with acceptable toxicity in patients with both advanced NSCLC and ILD.

We have proposed a novel concept of a digital watermarking technique for music data that focuses on the use of sound synthesis and sound effect techniques. This paper describes the details of our proposed technique that employs the distortion effect, one of the most common sound effects frequently utilized especially for guitar and bass instruments. This paper describes the experimental results of evaluating the resistance of the proposed technique against some basic malicious attacks utilizing MP3 coding, tempo alteration, pitch alteration, and high-pass filtering. It is demonstrated that the proposed technique potentially has appropriate resistance against such attacks except for the high-pass filtering attack. A technique for increasing the resistance against the high-pass filtering attack is also supplementarily discussed.

UV response switch of a wing color in Papilio polytes butterflies is important for dimorphic female-limited Batesian mimicry., In a Batesian mimic butterfly Papilio polytes, mimetic females resemble an unpalatable model, Pachliopta aristolochiae, but exhibit a different color pattern from nonmimetic females and males. In particular, the pale-yellow region on hind wings, which correspondingly sends important putative signals for mimicry and mate preference, is different in shape and chemical features between nonmimetic and mimetic morphs. Recently, we found that mimetic-type doublesex [dsx (H)] causes mimetic traits; however, the control of dimorphic pale-yellow colors remains unclear. Here, we revealed that dsx (H) switched the pale-yellow colors from UV-excited fluorescent type (nonmimetic) to UV-reflecting type (mimetic), by repressing the papiliochrome II synthesis genes and nanostructural changes in wing scales. Photoreceptor reactivities showed that some birds and butterflies could effectively recognize mimetic and nonmimetic pale-yellow colors, suggesting that a genetic switch in the UV response of pale-yellow colors may play essential roles in establishing the dimorphic female-limited Batesian mimicry.

OX40 (CD134) is a co-stimulatory molecule mostly expressed on activated T lymphocytes. Previous reports have shown that OX40 can be an immuno-oncology target and a clinical biomarker for cancers of various organs. In this study, we collected formalin-fixed paraffin-embedded tumor samples from 124 patients with small-cell lung cancer (SCLC) who had undergone surgery. We analyzed the expression profiles of OX40 and other relevant molecules, such as CD4, CD8, and Foxp3, in tumor stroma and cancer nest using immunohistochemistry and investigated their association with survival. High infiltration of OX40+ lymphocytes (OX40high) in tumor stroma was positively associated with relapse-free survival (RFS) and overall survival (OS) compared with low infiltration of OX40+ lymphocytes (OX40low) (RFS, median, 26.0 months [95% confidence interval (CI), not reached (NR)–NR] vs 13.2 months [9.1–17.2], p = .024; OS, NR [95% CI, NR–NR] vs 29.8 months [21.3–38.2], p = .049). Multivariate analysis revealed that OX40high in tumor stroma was an independent indicator of prolonged RFS. Moreover, RFS of patients with OX40high/CD4high in tumor stroma was significantly longer than that of patients with OX40low/CD4low. The RFS of patients with tumor stroma with OX40high/CD8high was significantly longer than that of patients with tumor stroma with OX40low/CD8high, OX40high/CD8low, or OX40low/CD8low. These findings suggest that OX40+ lymphocytes in tumor stroma play a complementary role in regulating the relapse of early-stage SCLC. Reinforcing immunity by coordinating the recruitment of OX40+ lymphocytes with CD4+ and CD8+ T cells in tumor stroma may constitute a potential immunotherapeutic strategy for patients with SCLC.

Objectives Few reports have explored clinical biomarkers, including those identified by targeted exome sequencing (TES) of surgically resected small-cell lung cancer (SCLC) and correlation with patient survival. Patients and methods We collected formalin-fixed paraffin-embedded tumor samples from 127 patients with SCLC who had undergone surgery and analysed nonsynonymous somatic gene mutation profiles by TES of 26 cancer-related genes using next-generation sequencing (NGS) and web databases (UMIN Registration No. 000010117). Results We detected 38 nonsynonymous somatic tumor protein p53 (TP53) mutations in 43 (54.4%) patients. Among these TP53 lesions, we identified clinically relevant mutations including those encoding Y220C, R248W, R249M, M237I, and R273L substitutions in the p53 protein. These mutations have been reported to be associated with certain clinical outcomes or biology in other types of malignancies but not in SCLC. Moreover, nonsynonymous somatic mutations of TP53 were positively associated with relapse-free survival (RFS) (median, 17.33 months [95% confidence interval (CI), 3.86–30.79] in a mutation-positive group vs 10.39 months (6.96–13.82) in a mutation-negative group, p = 0.042). Multivariate analysis revealed that nonsynonymous somatic TP53 mutation was an independent factor of prolongation of RFS (hazard ratio: 0.51, 95% CI: 0.29–0.89, p = 0.019) but not overall survival (OS). Conclusion These data suggested that TES may play a critical role for promoting reverse-translational studies, including investigations of the biology of TP53 mutations in different stages of SCLC. Accumulation of the data using cancer panels with a broader range of genes, including TP53, is expected to be useful for future clinical applications for patients with SCLC., Bioinformatics; Genetics; Cancer research; Respiratory system; Clinical genetics; Surgery; Oncology; Clinical research; Small-cell lung cancer; Mutation; Next-generation sequencing; TP53.

Background Antennae are multi-segmented appendages and main odor-sensing organs in insects. In Lepidoptera (moths and butterflies), antennal morphologies have diversified according to their ecological requirements. While diurnal butterflies have simple, rod-shaped antennae, nocturnal moths have antennae with protrusions or lateral branches on each antennal segment for high-sensitive pheromone detection. A previous study on the Bombyx mori (silk moth) antenna, forming two lateral branches per segment, during metamorphosis has revealed the dramatic change in expression of antennal patterning genes to segmentally reiterated, branch-associated pattern and abundant proliferation of cells contributing almost all the dorsal half of the lateral branch. Thus, localized cell proliferation possibly controlled by the branch-associated expression of antennal patterning genes is implicated in lateral branch formation. Yet, actual gene function in lateral branch formation in Bombyx mori and evolutionary mechanism of various antennal morphologies in Lepidoptera remain elusive. Results We investigated the function of several genes and signaling specifically in lateral branch formation in Bombyx mori by the electroporation-mediated incorporation of siRNAs or morpholino oligomers. Knock down of aristaless, a homeobox gene expressed specifically in the region of abundant cell proliferation within each antennal segment, during metamorphosis resulted in missing or substantial shortening of lateral branches, indicating its importance for lateral branch formation. aristaless expression during metamorphosis was lost by knock down of Distal-less and WNT signaling but derepressed by knock down of Notch signaling, suggesting the strict determination of the aristaless expression domain within each antennal segment by the combinatorial action of them. In addition, analyses of pupal aristaless expression in antennae with various morphologies of several lepidopteran species revealed that the aristaless expression pattern has a striking correlation with antennal shapes, whereas the segmentally reiterated expression pattern was observed irrespective of antennal morphologies. Conclusions Our results presented here indicate the significance of aristaless function in lateral branch formation in B. mori and imply that the diversification in the aristaless expression pattern within each antennal segment during metamorphosis is one of the significant determinants of antennal morphologies. According to these findings, we propose a mechanism underlying development and evolution of lepidopteran antennae with various morphologies. Electronic supplementary material The online version of this article (10.1186/s12862-018-1124-2) contains supplementary material, which is available to authorized users.

// Hajime Kikuchi 1 , Jun Sakakibara-Konishi 1 , Megumi Furuta 1 , Hiroshi Yokouchi 2 , Hiroshi Nishihara 3 , Shigeo Yamazaki 4 , Hidetaka Uramoto 5, 6 , Fumihiro Tanaka 5 , Masao Harada 7 , Kenji Akie 8 , Fumiko Sugaya 9 , Yuka Fujita 10 , Kei Takamura 11 , Tetsuya Kojima 12 , Toshiyuki Harada 13 , Mitsunori Higuchi 14, 15 , Osamu Honjo 9, 16 , Yoshinori Minami 17 , Naomi Watanabe 18 , Satoshi Oizumi 1, 7 , Hiroyuki Suzuki 15 , Takashi Ishida 2, 19 , Hirotoshi Dosaka-Akita 20 , Hiroshi Isobe 12 , Mitsuru Munakata 2 , Masaharu Nishimura 6 1 Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan 2 Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan 3 Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan 4 Department of Thoracic Surgery, Keiyukai Sapporo Hospital, Sapporo, Japan 5 Department of Surgery, University of Occupational and Environmental Health, Kita-kyushu, Japan 6 Department of Thoracic Surgery, Kanazawa Medical University, Uchinada, Japan 7 Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan 8 Department of Respiratory Disease, Sapporo City General Hospital, Sapporo, Japan 9 Department of Respiratory Medicine, Teine Keijinkai Hospital, Sapporo, Japan 10 Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center, Asahikawa, Japan 11 Department of Medicine, Obihiro Kosei Hospital, Obihiro, Japan 12 Department of Medical Oncology, KKR Sapporo Medical Center, Sapporo, Japan 13 Center for Respiratory Diseases, JCHO Hokkaido Hospital, Sapporo, Japan 14 Department of Thoracic Surgery, Fukushima Red Cross Hospital, Fukushima, Japan 15 Department of Thoracic Surgery, Fukushima Medical University, Fukushima, Japan 16 Department of Respiratory Medicine, Sapporo-Kosei General Hospital, Sapporo, Japan 17 Respiratory Center, Asahikawa Medical University, Asahikawa, Japan 18 Department of Internal Medicine, Sunagawa City Medical Center, Sunagawa, Japan 19 Clinical Oncology Center, Fukushima Medical University Hospital, Fukushima, Japan 20 Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan Correspondence to: Jun Sakakibara-Konishi, email: konishj@med.hokudai.ac.jp Keywords: small cell lung cancer, Notch1, Numb, immunohistochemistry, surgery Received: August 04, 2016 Accepted: December 12, 2016 Published: January 02, 2017 ABSTRACT Notch signaling in tumorigenesis functions as an oncogene or tumor suppressor according to the type of malignancy. Numb represses intracellular Notch signaling. Previous studies have demonstrated that Notch signaling suppresses the proliferation of small cell lung cancer (SCLC) cell lines. However, in SCLC, the association between Notch1 and Numb expression and clinicopathological factors or prognosis has remained unclear. In this study, we evaluated the expression of Notch1 and Numb in SCLC. We immunohistochemically assessed 125 SCLCs that were surgically resected at 16 institutions participating in either the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) or the Fukushima Investigative Group for Healing Thoracic Malignancy (FIGHT) between 2003 and 2013. Correlations between Notch1 or Numb expression and various clinicopathological features were evaluated. Notch1 expression was associated with ECOG performance status. Numb expression was associated with age, sex, and pathological histology (SCLC or Combined SCLC). Analysis of cellular biological expression did not demonstrate a significant correlation between the expression of Notch1 and of Numb. Multivariate Cox regression analysis showed that high Notch1 expression was an independent favorable prognostic factor for SCLC(hazard ratio = 0.503, P = 0.023). High Notch1 expression, but not Numb expression, is associated with favorable prognosis in SCLC.

Various sizes of chemical reaction network exist, from small graphs of linear networks with several inorganic species to huge complex networks composed of protein reactions or metabolic systems. Huge complex networks of organic substrates have been well studied using statistical properties such as degree distributions. However, when the size is relatively small, statistical data suffers from significant errors coming from irregular effects by species, and a macroscopic analysis is frequently unsuccessful. In this study, we demonstrate a graphical classification method for chemical networks that contain tens of species. Betweenness and closeness centrality indices of a graph can create a two-dimensional diagram with information of node distribution for a complex chemical network. This diagram successfully reveals systematic sharing of roles among species as a semi-statistical property in chemical reactions, and distinguishes it from the ones in random networks, which has no functional node distributions. This analytical approach is applicable for rapid and approximate understanding of complex chemical network systems such as plasma-enhanced reactions as well as visualization and classification of other graphs.

Objective: Platinum-free regimens can represent an alternative for advanced non-small cell lung cancer (NSCLC) if similar efficacy is provided with better tolerability. This study evaluated the efficacy and safety of combined irinotecan and S-1 for chemotherapy-naïve advanced NSCLC. Methods: Chemotherapy consisted of 4-week cycles of intravenous irinotecan (100 mg/m2, days 1 and 15) and oral S-1 (80 mg/m2, days 1–14). The primary endpoint was response rate, while secondary endpoints were overall survival, progression-free survival (PFS), and safety. Results: A total of 112 cycles was administered to 40 patients (median 3 cycles; range 1–6 cycles). Twelve patients showed partial response and 17 patients had stable disease, representing a response rate of 30% and a disease control rate of 72.5%. Median survival time and median PFS were 16.1 and 4.8 months, respectively. Hematological toxicities of grade 3 or 4 were neutropenia (32.5%) and anemia (5.0%). The most common nonhematological toxicities of grade 3 or 4 included diarrhea (15.0%) and anorexia (17.5%). Patients homo- or heterozygous for UGTA1A*6 tended to show a higher incidence of grade 3 diarrhea (p = 0.055). Conclusion: The combination of irinotecan and S-1 offers good efficacy and tolerability for previously untreated advanced NSCLC.

The results of oceanographic observations on board the icebreaker "Shirase" and tidal observations at Syowa Station, Antarctica, are presented in this report. The oceanographic observations were carried out by the summer party of the 42nd Japanese Antarctic Research Expedition (JARE-42) during the austral summer of 2000/2001. The tidal observations were carried out by the winter party of JARE-41 from February 2000 to January 2001.

The Bar mutation B of Drosophila melanogaster and optic morphology mutation Om(1D) of Drosophila ananassae result in suppression of ommatidium differentiation at the anterior portion of the eye. Examinations was made to determine the genes responsible for these mutations. Both loci were found to share in common a different type of homeobox gene, which we call "BarH1." Polyptides encoded by D. melanogaster and D. ananassae BarH1 genes consist of 543 and 604 amino acids, respectively, with homeodomains identical in sequence except for one amino acid substitution. A unique feature of these homeodomains is that the phenylalanine residue in helix 3, conserved in all metazoan homeodomains so far examined, is replaced by a tyrosine residue. By Northern blotting, considerably more BarH1 RNA was detected in the Bar mutant than in wild type. P element-mediated transformation showed Bar-like eye malformation to be induced by transient overexpression of the BarH1 gene in the late third-instar larvae. Somatic recombination analysis indicated normal gene functions of the Bar region, including the BarH1 gene, to be required for normal eye morphogenesis.

Domain boundary formation in development involves sorting of different types of cells into separate spatial domains. The segment boundary between tarsus 5 (Ta5) and the pretarsus (Pre) of the Drosophila leg initially appears at the center of the leg disc and progressively sharpens and expands to its final position, accompanied by down-regulation of the cell recognition molecule Capricious and Tartan and cell displacement from Ta5 to Pre across the boundary. Capricious and Tartan are controlled by transcription factor Bar and Al, and their loss of function leads to reduction of cell affinity to wild type neighbors and cell displacement activities. In addition, although the mutant cells formed Ta5/Pre boundary, its progression and sharpening were compromised. Cells overexpressing Capricious or Tartan became invasive within Ta5 and Pre, sometimes escaping the compartmental restriction of cell movement. Dynamic spatiotemporal regulation of cell affinity mediated by Capricious and Tartan is a key property of refinement of the Ta5/Pre boundary.

The spatial and temporal regulation of genes encoding transcription factors is essential for the proper development of multicellular organisms. In Drosophila leg development, the distal-most tarsus (ta5) is specified by the strong expression of a pair of Bar homeobox genes in late third instar. This expression is regulated under the control of the ta5 enhancer activated by Bar. No activation of the ta5 enhancer, however, occurs in early third instar when considerable Bar is produced. The ta5 enhancer was comprised of a basal enhancer required for driving Bar expression and a negative regulatory motif serving as a binding site for the heterodimer of Spineless and Tango, homologs of the mammalian dioxin receptor and aryl hydrocarbon nuclear translocator, respectively. The spineless and tango were essential for suppressing the basal enhancer activation in early third instar. The spineless was transiently expressed in early third instar in the Bar expression domain. ta5 Bar expression may thus be temporally regulated through transient inhibition of premature activation of the basal enhancer via specific binding of the Spineless/Tango heterodimer to the negative regulatory motif in early third instar and subsequent release from the inhibition due to the disappearance of spineless expression at later stages.

Background The insect cuticle is composed of various proteins and formed during the molt under hormonal regulation, although its precise composition and formation mechanism are largely unknown. The exhaustive catalogue of genes expressed in epidermis at the molt constitutes a massive amount of information from which to draw a complete picture of the molt and cuticle formation in insects. Therefore, we have catalogued a library of full-length cDNAs (designated epM) from epidermal cells during the last larval molt of Bombyx mori. Results Of the 10,368 sequences in the library, we isolated 6,653 usable expressed sequence tags (ESTs), which were categorized into 1,451 nonredundant gene clusters. Seventy-one clusters were considered to be isoforms or premature forms of other clusters. Therefore, we have identified 1,380 putative genes. Of the 6,653 expressed sequences, 48% were derived from 92 cuticular protein genes (RR-1, 24; RR-2, 17; glycine-rich, 29; other classes, 22). A comparison of epM with another epidermal EST data set, epV3 (feeding stage: fifth instar, day 3), showed marked differences in cuticular protein gene. Various types of cuticular proteins are expressed in epM but virtually only RR-1 proteins were expressed in epV3. Cuticular protein genes expressed specifically in epidermis, with several types of expression patterns during the molt, suggest different types of responses to the ecdysteroid pulse. Compared with other Bombyx EST libraries, 13 genes were preferentially included in epM data set. We isolated 290 genes for proteins other than cuticular proteins, whose amino acid sequences retain putative signal peptides, suggesting that they play some role in cuticle formation or in other molting events. Several gene groups were also included in this data set: hormone metabolism, P450, modifier of cuticular protein structure, small-ligand-binding protein, transcription factor, and pigmentation genes. Conclusion We have identified 1,380 genes in epM data set and 13 preferentially expressed genes in epidermis at the molt. The comparison of the epM and other EST libraries clarified the totally different gene expression patterns in epidermis between the molting and feeding stages and many novel tissue- and stage-specifically expressed epidermal genes. These data should further our understanding of cuticle formation and the insect molt.