Search

Aim Bovine respiratory disease (BRD) and bovine enteric disease (BED) are two major diseases in cattle, resulting in severe economic losses in the dairy and beef industries. The two major diseases are associated with several factors such as viruses, bacteria, the health condition of the host and environmental factors. We aimed to design a new efficient diagnostic method, which rapidly detect causative pathogens, minimizing economic loss due to BRD and BED. Methods and results We designed a multiplex quantitative reverse transcription-PCR (qRT-PCR) system for the simultaneous diagnosis of 16 pathogens, including 12 viruses and 4 bacteria related to BRD and BED, based on single qRT-PCR assays in previous studies. The designed multiplex qRT-PCR was highly sensitive and has minimal detection levels which will be no different from those of single qRT-PCR. Moreover, the multiplex qRT-PCR could more efficiently detect the causative pathogens than conventional RT-PCR in test using a part of BRD and BED clinical samples. Furthermore, our data revealed that the multiplex qRT-PCR had high performance in its specificity and reproducibility tests. Conclusions Our system can effectively detect multiple BRD or BED related pathogens from each animal while testing several clinical samples via the multiplex qRT-PCR. It is more time-, cost- and labour-efficient than other diagnostic methods. Significance and impact of the study Rapid detection of infected animals from the herd using our system will greatly contribute to infection control and prompt treatment in field.

Foam separation promotes the removal of dissolved materials from solutions by adsorbing the molecules onto a surfactant. The zwitterion of rhodamine B was removed by using both anionic (sodium dodecyl sulfate: SDS) and cationic (dodecyltrimethylammonium chloride: DTAC) surfactants through foam separation. However, rhodamine B could not be removed from a strongly acidic DTAC solution (pH 2), because the molecular form changes from the zwitterion to cation. Moreover, the cationic dye of rhodamine 6G could not be removed from the DTAC solution. Therefore, these results demonstrate that the electrostatic interaction between a surfactant and target ion is an important factor in foam separation.

We studied the autumn (September–November) food habits of the raccoon dog (Nyctereutes procyonoides) by sampling the stomach contents of 64 individuals (male, n = 31; female, n = 33) killed on national roads in Ibaraki Prefecture. Our aim was to examine sex differences in the autumn food habits of raccoon dogs in suburban area where human related disturbances can occur on the raccoon dogs. The frequency of occurrence (FO) and the percent volume (PV) of fruits and insects were high for both males and females and FO and PV of garbage were low for both males and females. There were no significant differences between the sexes for food items. FO and PV were not significantly different between sexes for adults and yearlings. This is likely because males and females may use the same area even in suburban area, and they likely both forage on the most abundant food resources that are easily accessible within their habitats.

Mapping protein interactions driving cancer Cancer is a genetic disease, and much cancer research is focused on identifying carcinogenic mutations and determining how they relate to disease progression. Three papers demonstrate how mutations are processed through networks of protein interactions to promote cancer (see the Perspective by Cheng and Jackson). Swaney et al . focus on head and neck cancer and identify cancer-enriched interactions, demonstrating how point mutant–dependent interactions of PIK3CA, a kinase frequently mutated in human cancers, are predictive of drug response. Kim et al . focus on breast cancer and identify two proteins functionally connected to the tumor-suppressor gene BRCA1 and two proteins that regulate PIK3CA. Zheng et al . developed a statistical model that identifies protein networks that are under mutation pressure across different cancer types, including a complex bringing together PIK3CA with actomyosin proteins. These papers provide a resource that will be helpful in interpreting cancer genomic data. —VV

We experimentally demonstrate the observation of a frequency-shift dynamics at a temporal boundary in the terahertz (THz) region relying on a scheme that controls the structural dispersion of a metal-semiconductor waveguide. Ultrafast structural-dispersion switching is achieved within a subpicosecond timescale by illuminating a waveguide surface with an optical pump pulse during the propagation of a THz pulse in the waveguide. Owing to the relatively high conversion efficiency, up to 23%, under the condition that the frequency shift is sufficiently larger than the bandwidth of the incident pulse, the rapid variation of the THz frequency around the temporal boundary is directly observed in the time domain.

Monoammonium glycyrrhizinate is produced by the neutralization of glycyrrhizic acid from plant licorice with ammonia. In this study, the physicochemical properties of aqueous monoammonium glycyrrhizinate were investigated from the viewpoint of surface chemistry. The structure of the amphiphilic molecule is bola type, comprising two glucuronic acid moieties having two carboxylic acids groups and an aglycone part having a carboxylic acid at the opposite end of the molecule from the glucuronic acids. We found that the physicochemical properties of aqueous monoammonium glycyrrhizinate are dependent on the ionization of the carboxylic acid groups. The solubility of monoammonium glycyrrhizinate gradually increased above pH 4 in the buffer solution. The critical micelle concentration (CMC) and surface tension at the CMC (γCMC) of monoammonium glycyrrhizinate were determined by the surface tension method to be 1.5 mmol L-1 and 50 mN m-1 in pH 5 buffer and 3.7 mmol L-1 and 51 mN m-1 in pH 6 buffer, respectively. The surface tension gradually decreased with increasing concentration of monoammonium glycyrrhizinate in the pH 7 buffer, but the CMC was not defined by the curve. Light scattering measurements also did not reveal a clear CMC in the pH 7 buffer. The ionization of the carboxylic acid groups in the bola-type amphiphilic molecule with increasing pH is disadvantageous for micelle formation. Cryo-transmission electron microscopy showed that monoammonium glycyrrhizinate forms rod-like micelles in pH 5 buffer, and small angle X-ray scattering experiments confirmed that the average micellar structure was rod-like in pH 5 buffer. Thus, it was found that monoammonium glycyrrhizinate can form micelles only in weakly acidic aqueous solutions.

We identified the microRNA (miRNA) expression signature of head and neck squamous cell carcinoma (HNSCC) tissues by RNA sequencing, in which 168 miRNAs were significantly upregulated, including both strands of the miR-31 duplex (miR-31-5p and miR-31-3p). The aims of this study were to identify networks of tumor suppressor genes regulated by miR-31-5p and miR-31-3p in HNSCC cells. Our functional assays showed that inhibition of miR-31-5p and miR-31-3p attenuated cancer cell malignant phenotypes (cell proliferation, migration, and invasion), suggesting that they had oncogenic potential in HNSCC cells. Our in silico analysis revealed 146 genes regulated by miR-31 in HNSCC cells. Among these targets, the low expression of seven genes (miR-31-5p targets: CACNB2 and IL34, miR-31-3p targets: CGNL1, CNTN3, GAS7, HOPX, and PBX1) was closely associated with poor prognosis in HNSCC. According to multivariate Cox regression analyses, the expression levels of five of those genes (CACNB2: p = 0.0189, IL34: p = 0.0425, CGNL1: p = 0.0014, CNTN3: p = 0.0304, and GAS7: p = 0.0412) were independent prognostic factors in patients with HNSCC. Our miRNA signature and miRNA-based approach will provide new insights into the molecular pathogenesis of HNSCC.

In this report, we present two cases in which benzodiazepines (BZDs) were able to be successfully reduced or discontinued by treatment with traditional Japanese herbal medicine (Kampo medicine), including Hangekobokuto (HKT). These two patients with long‐term use of BZDs due to mental disorders suffered epigastric symptoms. After starting Kampo therapy including HKT, their epigastric symptoms were improved and they were able to reduce or discontinue the use of BZDs. This suggests that HKT is a potentially promising substitutive pharmacotherapy for patients with long‐term use of BZDs. HKT should be considered as a treatment for patients with mental disorders who have taken BZDs for a long time and suffer from medically unexplained epigastric symptoms., In this report, we present two cases in which benzodiazepines were able to be successfully reduced or discontinued by treatment with traditional Japanese herbal medicine (Kampo medicine), including Hangekoubokutou (HKT). HKT is a potentially promising substitutive pharmacotherapy for patients with long‐term use of benzodiazepines.

Nanopore DNA sequencing offers a new paradigm owing to its extensive potential for long-read, high-throughput detection of nucleotide modification and direct RNA sequencing. Given the remarkable advances in protein nanopore sequencing technology, there is still a strong enthusiasm in exploring alternative nanopore-sequencing techniques, particularly those based on a solid-state nanopore using a semiconductor material. Since solid-state nanopores provide superior material robustness and large-scale integrability with on-chip electronics, they have the potential to surpass the limitations of their biological counterparts. However, there are key technical challenges to be addressed: the creation of an ultrasmall nanopore, fabrication of an ultrathin membrane, control of the ultrafast DNA speed and detection of four nucleotides. Extensive research efforts have been devoted to resolving these issues over the past two decades. In this review, we briefly introduce recent updates regarding solid-state nanopore technologies towards DNA sequencing. It can be envisioned that emerging technologies will offer a brand new future in DNA-sequencing technology.

Breakfast skipping has become an increasing trend in the modern lifestyle and may play a role in obesity and type 2 diabetes. In our previous studies in healthy young individuals, a single incident of breakfast skipping increased the overall 24-h blood glucose and elevated the postprandial glycaemic response after lunch; however, it was difficult to determine whether this response was due to breakfast omission or the extra energy (i.e. lunch plus breakfast contents). The present study aimed to assess the postprandial glycaemic response and to measure their hormone levels when healthy young individuals had identical lunch and dinner, and the 24-h average blood glucose as a secondary outcome. Nine healthy young men (19−24 years) participated in two-meal trials: with breakfast (three-meal condition) or without breakfast (breakfast skipping condition). During the meals, each individual’s blood glucose was continuously monitored. Skipping breakfast resulted in a significantly higher (P < 0·001) glycaemic response after lunch as compared with the glycaemic response after an identical lunch when breakfast was consumed. Despite the difference in the total energy intake, the 24-h average blood glucose was similar between the two-meal conditions (P = 0·179). Plasma NEFA level was significantly higher (P < 0·05) after lunch when breakfast was omitted, and NEFA level positively correlated with the postprandial glycaemic response (r 0·631, P < 0·01). In conclusion, a single incident of breakfast skipping increases postprandial hyperglycaemia, and associated impaired insulin response, after lunch. The present study showed that skipping breakfast influences glucose regulation even in healthy young individuals.

A reverse transcription-polymerase chain reaction (RT-PCR) method was developed for broadly detecting the avian encephalomyelitis virus (AEV). The new primers were based on conserved sequences of the 5’-untranslated region of AEV, because the virus was not detected using previous reported RT-PCR. By applying this method to the chicken samples with suspected AEV infection in Japan, we successfully obtained PCR products of the predicted size from all samples, and we confirmed the presence of AEV via sequence analysis.

Various measures have been taken to curb the COVID-19 epidemic, but their effect has been limited. Vaccines are expected to make a definite improvement. In Japan, vaccination began in February 2021. However, there are very few reports of adverse reactions to mRNA vaccines for the new coronavirus (SARS-CoV-2) in Japanese people. Therefore, adverse reactions in 576 vaccinated medical staff at the author's hospital were investigated.The subjects were 576 medical staff who wished to receive the new coronavirus (SARS-CoV-2) vaccine. The first vaccination was performed with Pfizer's new coronavirus mRNA vaccine (commercial name: Comirnaty intramuscular injection) from March 8 to March 15, 2021. The second vaccination was performed from March 29 to April 5, 2021, at an interval of more than 21 days from the first vaccination.Adverse reactions were seen in six subjects in the first vaccination. There was dyspnea in one subject, arthralgia in one subject, fever/malaise in three subjects, and left axillary pain and lymphadenopathy in one subject. One subject had a reaction at the vaccination site that needed to be addressed. At the second vaccination, adverse reactions were observed in 64 subjects. There was fever in 58 subjects, malaise in 21 subjects, arthralgia in 12 subjects, aching pain in 11 subjects, headache in six subjects, chills in six subjects, nausea in three subjects, redness in two subjects, dizziness in two subjects, hives in two subjects, swelling in two subjects, cough in one subject, and itching in one subject (some had multiple adverse reactions). Fever was observed in the range of body temperature from 37.4 to 38.9 degrees.Most of the adverse reactions to the COVID-19 vaccine were mild, and no serious anaphylaxis was observed. Vaccination was considered perfectly feasible if attention is paid to adverse reactions.

Sago palm (Metroxylon sagu Rottb.) is the most promising starch producing palm species. Sago palm accumulates around 200 kg starch or more per plant or in the trunk. This palm species is recognized as one of the crops used by human beings since ancient times. The growing area of sago palm spreads across several land conditions such as upland, tidal, and submerged areas which do not have a proper water drainage system. It can grow in swamp, alluvial, and peat soils where almost no other major crops can grow without drainage or soil improvement. It is adaptive to an extremely wide range of environmental conditions from brackish water to fresh water. However, its growth performance and starch yield vary depending on the growth environment such as soil types and water conditions. Considering the recent social backgrounds, namely a new competition between biofuel production and food production as well as demand for food diversification, the efficient use of carbohydrates from the sago palm and related species as well as predicted increase in the sustainable development and utilization of land in swampy areas are currently anticipated. This chapter provides a brief review on future prospects of sago palm growth and production in different soil conditions mostly in accordance with the publications from the Society of Sago Palm Studies.

We previously found that both the guide and passenger strands of the miR-139 duplex (miR-139-5p and miR-139-3p, respectively) were downregulated in cancer tissues. Analysis of TCGA datasets revealed that low expression of miR-139-5p (p &lt, 0.0001) and miR-139-3p (p &lt, 0.0001) was closely associated with 5-year survival rates of patients with renal cell carcinoma (RCC). Ectopic expression assays showed that miR-139-5p and miR-139-3p acted as tumor-suppressive miRNAs in RCC cells. Here, 19 and 22 genes were identified as putative targets of miR-139-5p and miR-139-3p in RCC cells, respectively. Among these genes, high expression of PLXDC1, TET3, PXN, ARHGEF19, ELK1, DCBLD1, IKBKB, and CSF1 significantly predicted shorter survival in RCC patients according to TCGA analyses (p &lt, 0.05). Importantly, the expression levels of four of these genes, PXN, ARHGEF19, ELK1, and IKBKB, were independent prognostic factors for patient survival (p &lt, 0.05). We focused on PXN (paxillin) and investigated its potential oncogenic role in RCC cells. PXN knockdown significantly inhibited cancer cell migration and invasion, possibly by regulating epithelial&ndash, mesenchymal transition. Involvement of the miR-139-3p passenger strand in RCC molecular pathogenesis is a new concept. Analyses of tumor-suppressive-miRNA-mediated molecular networks provide important insights into the molecular pathogenesis of RCC.

In this paper, we introduce a distribution system of synthesized data of Japanese population using Interdisciplinary Large-scale Information Infra-structures in Japan. Synthetic population is synthesized based on the statistics of the census that are conducted by the government and publicly released. Therefore, the synthesized data have no privacy data. However, it is easy to estimate the compositions of households, working status in a certain area from the synthetic population. Therefore, we currently distribute the synthesized data only for public or academic purposes. For academic purposes, it is important to encourage scholars or researchers to use a large-scale data of households, we define protection levels for the attributes in the synthetic populations. According to the protection levels, we distribute the data with proper attributes to those who try to use them. We encourage researchers to use the synthetic populations to be familiar to large-scale data processing.

SummaryThe largest extinct volant birds (Pelagornis sandersiandArgentavis magnificens) and pterosaurs (PteranodonandQuetzalcoatlus) are thought to have used wind-dependent soaring flight, similar to modern large birds. There are two types of soaring: thermal soaring, used by condors and frigatebirds, which involves the use of updrafts to ascend and then glide horizontally over the land or the sea; and dynamic soaring, used by albatrosses, which involves the use of wind speed differences with height above the sea surface. Previous studies have suggested thatPelagornis sandersiused dynamic soaring, whileArgenthavis magnificens, Pteranodon, andQuetzalcoatlusused thermal soaring. However, the performance and wind speed requirements of dynamic and thermal soaring for these species have not yet been quantified comprehensively. We quantified these values using aerodynamic models and compared them with that of extant birds. For dynamic soaring, we quantified maximum flight speeds and maximum upwind flight speeds. For thermal soaring, we quantified the animal’s sinking speed circling at a given radius and how far it could glide losing a given height. Our results confirmed those from previous studies thatPteranodonandArgentavis magnificensused thermal soaring. Conversely, the results forPelagornis sandersiandQuetzalcoatluswere contrary to those from previous studies.Pelagornis sandersiused thermal soaring, andQuetzalcoatlushad a poor ability both in dynamic and thermal soaring. Our results demonstrate the need for comprehensive assessments of performance and required wind conditions when estimating soaring styles of extinct flying species.

ID-POS data has been analyzed in many retail stores for several decades, and the results have been used to support decision making such as sales promotion and item arrangement in the stores. Such analysis has effect on various business performance like total sales. Although the data is so useful, it is difficult to grasp extent of customer's interest about items that were not purchased, and to identify that it is planned purchase or not. Therefore, we need to use in-store customer journey data to reveal that complementary. In this paper, we propose an in-store journey simulation model, and carry out the agent-based simulation using actual in-store customer journey data acquired by using the Bluetooth beacons. From several computational experiments, we show that our model reproduces in-store customer journey and evaluate our model from the viewpoint of difference between our results and actual data.

Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FTase). FTase catalyzes the posttranslational attachment of farnesyl groups to signaling proteins that are required for localization to cell membranes. Although all RAS isoforms are FTase substrates, only HRAS is exclusively dependent upon farnesylation, raising the possibility that HRAS-mutant tumors might be susceptible to tipifarnib-mediated inhibition of FTase. Here, we report the characterization of tipifarnib activity in a wide panel of HRAS-mutant and wild-type head and neck squamous cell carcinoma (HNSCC) xenograft models. Tipifarnib treatment displaced both mutant and wild-type HRAS from membranes but only inhibited proliferation, survival, and spheroid formation of HRAS-mutant cells. In vivo, tipifarnib treatment induced tumor stasis or regression in all six HRAS-mutant xenografts tested but displayed no activity in six HRAS wild-type patient-derived xenograft (PDX) models. Mechanistically, drug treatment resulted in the reduction of MAPK pathway signaling, inhibition of proliferation, induction of apoptosis, and robust abrogation of neovascularization, apparently via effects on both tumor cells and endothelial cells. Bioinformatics and quantitative image analysis further revealed that FTase inhibition induces progressive squamous cell differentiation in tipifarnib-treated HNSCC PDXs. These preclinical findings support that HRAS represents a druggable oncogene in HNSCC through FTase inhibition by tipifarnib, thereby identifying a precision therapeutic option for HNSCCs harboring HRAS mutations.

Foam separation can selectively remove a target substance from a solution via adsorption of the substance with the surfactant at the surface of the bubble. A cationic dye, methylene blue, and an anionic dye, Fast Green FCF, were prepared as substances to be removed via foam separation. Anionic (sodium dodecyl sulfate, SDS), cationic (dodecyltrimethylammonium chloride, DTAC), and amphoteric (3-(dodecyldimethylammonio)propane-1-sulfonate, SB-12) surfactants were used in the foam separation process. The effectiveness of the surfactants for removing the cationic methylene blue increased as follows: DTAC < SB-12 < SDS. On the other hand, the effectiveness of the surfactants for removing the anionic Fast Green FCF was in the opposite order. The dyes were effectively adsorbed by the foams via electrostatic interactions between the oppositely charged surfactant and the dye molecules. Since amphoteric surfactants have both anionic and cationic charges in a molecule, they could effectively remove both dyes in the foam separation process. Therefore, it was found that the amphoteric surfactant was highly versatile. Analysis of the kinetics of the removal rate showed that the aqueous solutions of monomers could remove the dyes more effectively than micellar solutions in foam separation.

Nanopore-based biosensors have attracted attention as highly sensitive microscopes for detecting single molecules in aqueous solutions. However, the ionic current noise through a nanopore degrades the measurement accuracy. In this study, the magnitude of the low-frequency noise in the ionic current through a silicon nitride nanopore was found to change depending on the metal ion species in the aqueous solution. The order of the low-frequency noise magnitudes of the alkali metal ionic current was consistent with the order of the adsorption affinities of the metal ions for the silanol surface of the nanopore (Li i.e., metal ions having a very high or low adsorption affinity causing a reduction in low-frequency noise, suggests that the low-frequency noise was induced by the exchange reactions between protons and metal ions occurring on the silanol surface. In addition, the low-frequency noise in the ionic current remained low even after replacing the CaCl2 aqueous solution with a CsCl aqueous solution, indicating that Ca ions continued being adsorbed onto silanol groups even after removing the aqueous solution.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobacco-associated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity (≤20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately mimic the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report a mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 (≤20%) immunotherapy as human HNSCCs. Remarkably, we find that >70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform to accelerate the development of immunotherapeutic options for HNSCC., Tobacco use is one of the major risk factors for Head and neck squamous cell carcinoma (HNSCC). Here, the authors report an immune-competent syngeneic mouse model that mimics human tobacco-related HNSCC, and develops tumors in the tongue, and report a high response rate to anti-CTLA-4 therapy.

We report a rare case of a 27-year-old woman with Takayasu arteritis (TAK) complicated by diffuse sclerosing osteomyelitis. She first presented with sclerosing osteomyelitis of the right mandible without evidence of arteritis in the carotid arteries. Eight months later, she complained of left neck pain, and imaging studies revealed the presence of arteritis in the left carotid artery. She was diagnosed with TAK, and immunosuppressive treatment was initiated, which was effective for both the arteritis and the osteomyelitis. Osteomyelitis is an important complication of TAK and bone scintigraphy is useful for its detection.

A series of group 14 element bridged bithiophene dimers bearing dicyanovinyl (DC) or thiobarbiturylmethylene (TB) electron-withdrawing groups at the molecular termini (series E-1a and series E-1b; E = C, Si, and Ge) were developed as red absorbing singlet oxygen (1O2) photosensitizing dyes. These dyes exhibited broad and strong absorption in the red-to-deep red regions and efficient red-to-NIR fluorescence (photoluminescence quantum yield ΦPL; 0.32–0.45 in dichloromethane). The terminal TB groups led to more red-shifted electronic absorption and fluorescence emission than the DC groups, owing to more intense intramolecular charge transfer. The 1O2 generation photosensitization abilities of series E-1a and series E-1b were evaluated by the 1,3-diphenylisobenzofuran method, and large 1O2 generation quantum yields (ΦΔ) were obtained upon irradiation of 630 nm light, ranging from 0.35 to 0.68 in dichloromethane. Therefore, these dyes show fluorescence properties as well as 1O2 generation photosensitization ability. Introduction of bromo groups at the 3,3′-positions in Si-1a and Si-1b afforded the new potential photosensitizers Si-2a and Si-2b that accompanied blue-shifted electronic absorption as well as blue-shifted fluorescence emission with the low ΦPL. Unfortunately, as Si-2a exhibited quite low absorptivity in the red region, 1O2 generation photosensitization with 630 nm light was not evaluated for Si-2a. On the other hand, Si-2b showed significantly efficient 1O2 generation photosensitization upon irradiation of 630 nm light (ΦΔ; 0.88). Considering the result of theoretical calculations showing that the bromo groups effectively contribute to the frontier orbitals, these bromo substituents should facilitate the intersystem crossing from the excited singlet state to the triplet excited state through the strong spin‒orbit coupling.

(Purpose) Targeted therapy has been standard therapeutic approach for advanced renal cell carcinoma (RCC). General fatigue is frequently observed in patients who receive targeted therapies for advanced RCC. General fatigue makes it difficult to continue a standard schedule of treatment in many cases. In this preliminary report, we explored the effect of Koujin powder (red ginseng powder) with Ninjin-youeito for general fatigue induced by targeted therapies for advanced RCC. (Material and method) The patients who complained of general fatigue during the treatment of Tyrosine Kinase Inhibitors (TKIs) as targeted therapies for advanced RCC were included in this retrospective analysis. Thirty patients with advanced RCC were enrolled from January 2016 to December 2016 at Chiba University Hospital. Twelve patients were given 3 g of Koujin powder with 9 g of Ninjin-youeito orally for two to four weeks (ginseng combination group). Eighteen patients who were not orally administered were compared as a control group (ginseng non-combination group). General fatigue was assessed with the Cancer Fatigue Scale (CFS), which divides quality of fatigue into three subgroups by using a "physical subscale", an "affective subscale", and a "cognitive subscale". We compared CFS scores at baseline and 2-8 weeks after administration. (Results) There was no statistical difference in the clinical variables between the two groups. The total CFS score was significantly decreased after treatment in the ginseng combination group (average score, 21.8 points at baseline vs 18.5 points after treatment; p=0.041). On subgroup analyses, the physical subscale score was significantly reduced after treatment in the ginseng combination group (average score, 9.7 points at baseline vs 7 points after treatment; p=0.0042). In the ginseng non-combination group, the total CFS score was significantly increased during the course (average score, 16.2 points at baseline vs 20.6 points during the course; p=0.047). On subgroup analyses, the physical subscale score was significantly increased during the course (average score, 4.4 points at baseline vs 7.3 points during the course; p=0.0042). (Conclusions) Koujin powder with Ninjin-youeito can be a therapeutic approach for general fatigue induced by targeted therapies. The precise management for general fatigue can keep patients on therapy, consequently provides a survival benefit.

Background: Despite recent advancements, metastatic castration-resistant prostate cancer (CRPC) is not considered curative. Novel approaches for identification of therapeutic targets of CRPC are needed. Methods: Next-generation sequencing revealed 945–1248 miRNAs from each lethal mCRPC sample. We constructed miRNA expression signatures of CRPC by comparing the expression of miRNAs between CRPC and normal prostate tissue or hormone-sensitive prostate cancer (HSPC). Genome-wide gene expression studies and in silico analyses were carried out to predict miRNA regulation and investigate the functional significance and clinical utility of the novel oncogenic pathways regulated by these miRNAs in prostate cancer (PCa). Results: Based on the novel miRNA expression signature of CRPC, miR-145-5p and miR-145-3p were downregulated in CRPC. By focusing on miR-145-3p, which is a passenger strand and has not been well studied in previous reports, we showed that miR-145-3p targeted 4 key molecules, i.e., MELK, NCAPG, BUB1, and CDK1, in CPRC. These 4 genes significantly predicted survival in patients with PCa. Conclusions: Small RNA sequencing for lethal CRPC and in silico analyses provided novel therapeutic targets for CRPC.

We have previously reported the development of a far-ultraviolet (FUV) absorbance detector capable of detecting wavelengths down to 175 nm in high-performance liquid chromatography (HPLC). Although the FUV detector can detect substances with weak to non-existent ultraviolet (UV) absorption (e.g., sugars at 185 nm and peptides at 190 nm), a large baseline drift occurs in the gradient elution due to differences in the FUV absorbance properties of water and acetonitrile. To overcome the problem of baseline drift, we have proposed a new baseline correction method using the absorption of water at 1450 nm. It is well known that water has a relatively large absorption peak at 1450 nm in the near-infrared (NIR) region. By contrast, acetonitrile used in reversed-phase HPLC shows negligible absorbance compared to water at 1450 nm. Sugars and peptides also show negligible absorbance at 1450 nm. Thus, it is expected that changes in absorbance at 1450 nm only reflect the volume fraction of water in the gradient elution. The baseline correction method by a linear combination of FUV and NIR chromatograms was applied to the HPLC separation of sugars and peptides in water/acetonitrile-gradient HPLC coupled with FUV detection. The results showed that flat baselines were successfully obtained in the gradient HPLC coupled with FUV detection.

Cetuximab, a monoclonal antibody targeting EGFR, is a standard of care for the treatment for locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC). However, despite overexpression of EGFR in over 90% of HNSCC lesions, most HNSCC patients fail to respond to cetuximab treatment. In addition, there are no available biomarkers to predict sensitivity or resistance to cetuximab in the clinic. Here, we sought to advance precision medicine approaches for HNSCC by identifying PI3K-mTOR signaling-network-specific cetuximab resistance mechanisms. We first analyzed the frequency of genomic alterations in genes involved in the PI3K-mTOR signaling circuitry in the HNSCC TCGA dataset. Experimentally, we took advantage of CRISPR/Cas9 genome editing approaches to systematically explore the contribution of genomic alterations in each tumor suppressor gene (TSG) controlling the PI3K-mTOR pathway to cetuximab resistance in HNSCC cases that do not exhibit PIK3CA mutations. Remarkably, we found that many HNSCC cases exhibit pathway-specific gene copy number loss of multiple TSGs that normally restrain PI3K-mTOR signaling. Among them, we found that both engineered and endogenous PTEN gene deletions can mediate resistance to cetuximab. Our findings suggest that PTEN gene copy number loss, which is highly prevalent in HNSCC, may result in sustained PI3K/mTOR signaling independent of EGFR, thereby representing a promising mechanistic biomarker predictive of cetuximab resistance in this cancer type. Further prospective studies are needed to investigate the impact of PTEN loss on cetuximab efficacy in the clinic.

Prostate cancer innervation contributes to the progression of prostate cancer (PCa). However, the precise impact of innervation on PCa cells is still poorly understood. By focusing on muscarinic receptors, which are activated by the nerve-derived neurotransmitter acetylcholine, we show that muscarinic receptors 1 and 3 (m1 and m3) are highly expressed in PCa clinical specimens compared to all other cancer types, and that amplification or gain of their corresponding encoding genes (CHRM1 and CHRM3, respectively) represent a worse prognostic factor for PCa progression free survival. Moreover, m1 and m3 gene gain or amplification are frequent in castration-resistant PCa (CRPC) compared with hormone-sensitive PCa (HSPC) specimens. This was reflected in HSPC-derived cells, which show aberrantly high expression of m1 and m3 under androgen deprivation mimicking castration and androgen receptor inhibition. We also show that pharmacological activation of m1 and m3 signaling is sufficient to induce the castration-resistant growth of PCa cells. Mechanistically, we found that m1 and m3 stimulation induces YAP activation through FAK, whose encoding gene, PTK2 is frequently amplified in CRPC cases. Pharmacological inhibition of FAK and knockdown of YAP abolished m1 and m3-induced castration-resistant growth of PCa cells. Our findings provide novel therapeutic opportunities for muscarinic-signal-driven CRPC progression by targeting the FAK-YAP signaling axis.

Nanopore DNA sequencing with a solid-state nanopore requires deceleration of the ultrafast translocation speed of single-stranded DNA (ssDNA). We report an unexpected phenomenon: controlled dielectric breakdown (CBD) with a divalent metal cation, especially Ca2+, provides a silicon nitride nanopore with the ability to decelerate ssDNA speed to 100 μs per base even after solution replacement. This speed is two orders of magnitude slower than that for CBD with a conventional monovalent metal cation. Temperature dependence experiments revealed that the enthalpic barrier for a nanopore created via CBD with Ca2+ is 25–30kBT, comparable to that of a biological nanopore. The slowing effect originates from the strong interaction between ssDNA and divalent cations, which were coated on the sidewall of the nanopore during the CBD process. In addition, we found that the nanopore created via CBD with Ca2+ can decelerate the speed of even single-nucleotide monomers, dNMPs, to 0.1–10 ms per base. The four single nucleotides could be statistically identified according to their blockade currents. Our approach is simple and practical because it simultaneously allows nanopore fabrication, ssDNA deceleration and the identification of nucleotide monomers.

In this paper, we describe how synthesized populations are essential in real-scale social simulations (RSSS), and the current situation of the population synthesis for whole populations in Japan. RSSS is simulations using the real number of populations or households in social simulations. This paper describes how we have completed to synthesize multiple sets of populations based on the statistics of each local government in Japanese national census in 2000,2005,2010 and 2015. We have started to distribute those multiple sets of the synthesized populations for researchers of RSSSs in Japan. In distributing the synthesized populations, we should set some regulations in order to protect personal or private information in the synthesized populations.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobacco-associated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity (≤20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately reflect the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report the first mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 (≤20%) immunotherapy as human HNSCCs. Remarkably, we found that >70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform for the development of novel immunotherapeutic options for HNSCC.

A powerful DNA sequencing tool with high accuracy, long read length and high-throughput would be required more and more for decoding the complicated genetic code. Solid-state nanopore has attracted many researchers for its promising future as a next-generation DNA sequencing platform due to the processability, the robustness and the large-scale integratability. While the diverse materials have been widely explored for a solid-state nanopore, silicon nitride (Si

A powerful DNA sequencing tool with high accuracy, long read length and high-throughput would be required more and more for decoding the complicated genetic code. Solid-state nanopore has attracted many researchers for its promising future as a next-generation DNA sequencing platform due to the processability, the robustness and the large-scale integratability. While the diverse materials have been widely explored for a solid-state nanopore, silicon nitride (Si3N4) is especially preferable from the viewpoint of mass production based on semiconductor fabrication process. Here, as a nanopore sensing mechanism, we focused on the ionic blockade current method which is the most developed technique. We also highlight the main challenges of Si3N4 nanopore-based DNA sequencer that should be addressed: the fabrication of ultra-small nanopore and ultra-thin membrane, the modulation of DNA translocation speed and the detection of base-specific signals. In this chapter, we discuss the recent progress relating to solid-state nanopore DNA sequencing, which helps to provide a comprehensive information about the current technical situation.

The development of targeted molecular therapies has greatly benefited patients with lung adenocarcinomas. In contrast, these treatments have had little benefit in the management of lung squamous cell carcinoma (lung SCC). Therefore, new treatment options based on current genomic approaches are needed for lung SCC. Aberrant microRNA (miRNA) expression has been shown to promote lung cancer development and aggressiveness. Downregulation of microRNA-218 (miR-218) was frequently observed in our miRNA expression signatures of cancers, and previous studies have shown an antitumor function of miR-218 in several types of cancers. However, the impact of miR-218 on lung SCC is still ambiguous. The present study investigated the antitumor roles of miR-218 in lung SCC to identify the target genes regulated by this miRNA. Ectopic expression of miR-218 greatly inhibited cancer cell migration and invasion in the lung SCC cell lines EBC-1 and SK-MES-1. Through a combination of in silico analysis and gene expression data searching, tumor protein D52 (TPD52) was selected as a putative target of miR-218 regulation. Moreover, direct binding of miR-218 to the 3′-UTR of TPD52 was observed by dual luciferase reporter assay. Overexpression of TPD52 was observed in lung SCC clinical specimens, and knockdown of TPD52 significantly suppressed cancer cell migration and invasion in lung SCC cell lines. Furthermore, the downstream pathways mediated by TPD52 involved critical regulators of genomic stability and mitotic checkpoint genes. Taken together, our data showed that downregulation of miR-218 enhances overexpression of TPD52 in lung SCC cells, promoting cancer cell aggressiveness. Identification of tumor-suppressive miRNA-mediated RNA networks of lung SCC will provide new insights into the potential mechanisms of the molecular pathogenesis of the disease.