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Although paclitaxel plus cetuximab for recurrent/metastatic oral squamous cell carcinoma (OSCC) has a relatively high success rate, many cases are refractory. We investigated the change in nuclear factor-kappa B (NF-B) expression after this combination therapy using microcollagen 3D cell culture. We also investigated changes in antitumor efficacy using low doses of paclitaxel-cetuximab combined with the proteasome inhibitor bortezomib on a cell line with low sensitivity to paclitaxel plus cetuximab.Eight human OSCC cell lines were cultured in 3D and exposed to paclitaxel-cetuximab. real-time polymerase chain reaction was used to evaluate NF-B mRNA expression in OSCC cell lines in vivo and in vitro after exposure to anticancer agents. Activity at the protein level was confirmed using western blotting. Bortezomib (0.002-0.4 μg/ml) was added to paclitaxel-cetuximab and its effects assessed in OSCC cell lines with low paclitaxel-cetuximab sensitivity.mRNA and protein expression of NF-B was significantly reduced after treatment with paclitaxel-cetuximab in cell lines sensitive to this combination. In contrast, both mRNA and protein expression significantly increased in the cell lines with low sensitivity to paclitaxel plus cetuximab. The addition of low concentrations of bortezomib to cell lines with low sensitivity to paclitaxel-cetuximab was found to enhance antitumor efficacy.Increased NF-B expression strongly contributes to resistance to paclitaxel-cetuximab, suggesting that the administration of small doses of bortezomib, which inhibits NF-B, combined with paclitaxel-cetuximab may enhance antitumor efficacy against cancer cells with low sensitivity to the combination therapy.

[Image: see text] Krüppel-like factor 5 (KLF5) is a potential target for anticancer drugs. However, as an intrinsically disordered protein (IDP) whose tertiary structure cannot be solved, innovative strategies are needed. We focused on its hydrophobic α-helix structure, defined as an induced helical motif (IHM), which is a possible interface for protein–protein interaction. Using mathematical analyses predicting the α-helix’s structure and hydrophobicity, a 4-amino-acid site (V-A-I-F) was identified as an IHM. Low-molecular-weight compounds that mimic the main chain conformation of the α-helix with the four side chains of V-A-I-F were synthesized using bicyclic pyrazinooxadiazine-4,7-dione. These compounds selectively suppressed the proliferation and survival of cancer cells but not noncancer cells and decreased the protein but not mRNA levels of KLF5 in addition to reducing proteins of Wnt signaling. The compounds further suppressed transplanted colorectal cancer cells in vivo without side effects. Our approach appears promising for developing drugs against key IDPs.

The solution of the ordinary kernel ridge regression, based on the squared loss function and the squared norm-based regularizer, can be easily interpreted as a stochastic linear estimator by considering the autocorrelation prior for an unknown true function. As is well known, a stochastic affine estimator is one of the simplest extensions of the stochastic linear estimator. However, its corresponding kernel regression problem is not revealed so far. In this paper, we give a formulation of the kernel regression problem, whose solution is reduced to a stochastic affine estimator, and also give interpretations of the formulation.

This chapter explores the development of procurement systems for the mass production of steel in the United States, Japan, and China over the past 120 years. It shows that the evolution of global procurement systems in the steel industry is the result of the creative adaptations of the industries of the three countries based on the historical conditions in each of them. Thus, in the first half of the 20th century, US steel mills established the captive mine system and extended their vertical integration into iron mines; in the second half of the 20th century, Japanese steel producers adopted a long-term contract system with overseas iron ore suppliers. The rapid growth of China’s steel industry in the early 21st century created a spot market for iron ore. Facing the decline of the long-term contract system, Chinese steel companies adopted a pluralistic strategy that combined all three procurement systems.

Objective The concept of early chronic pancreatitis (ECP) and its diagnostic criteria were first proposed by Japan, using endoscopic ultrasonography (EUS) findings for diagnosis. However, these findings have not been supported by pathological findings. We aimed to examine the association between the EUS and pathological findings of the same area of the pancreas. Methods In 12 patients who underwent pancreaticoduodenectomy for distal bile duct cancer without accompanying pancreatitis, a comparative analysis between preoperative EUS and pathological findings was performed. The part of the pancreas adjoining the portal vein was evaluated. Results In 7 cases, abnormal EUS findings included in the diagnostic criteria for ECP were seen; the correlation of the accuracy of lobularity seen on EUS compared with the pathological findings of the pancreatic parenchyma (inflammatory cell infiltration, atrophy of acinar cells, and fibrosis) was high (83.3%-91.7%). Pancreatic duct findings revealed that the accuracy of the hyperechoic margin of the pancreatic duct on EUS compared with pathological findings (wall thickness of pancreatic duct) was high (83.3%). Conclusions Endoscopic ultrasonography findings for ECP, according to Japan's 2019 revised criteria, lobularity, and the hyperechoic margin of the pancreatic duct may highly correspond to the pathological findings of chronic inflammation.

Maternal T cells from perinatal transplacental passage have been identified in up to 40% of patients with severe combined immunodeficiency (SCID). Although engrafted maternal T cells sometimes injure newborn tissue, liver failure due to maternal T cells has not been reported. We rescued a boy with X-linked SCID who developed liver failure due to engrafted maternal T cell invasion following living donor liver transplantation (LDLT) following unrelated umbilical cord blood transplantation (UCBT). After developing respiratory failure 3 weeks postpartum, he was diagnosed with X-linked SCID. Pathological findings showed maternal T cells engrafted in his liver and hepatic fibrosis gradually progressed. He underwent UCBT at 6 months, but hepatic function did not recover and liver failure progressed. Therefore, he underwent LDLT using an S2 monosegment graft at age 1.3 years. The patient had a leak at the Roux-en-Y anastomosis, which was repaired. Despite occasional episodes of pneumonia and otitis media, he is generally doing well 6 years after LDLT with continued immunosuppression agents. In conclusion, the combination of hematopoietic stem cell transplantation (HSCT) and liver transplantation may be efficacious, and HSCT should precede liver transplantation for children with X-linked SCID and liver failure.

The immunotherapy approach using anti-programmed cell death 1 (PD-1) antibody has been demonstrated in oral cancer treatment. However, serious immune-related adverse events (irAE) have been reported. If local administration of small doses of anti-PD-1 antibody via intraarterial chemoradiotherapy could have the same antitumor effect of systemic administration, this can reduce irAE and medical expenses. In this study, we investigate the antitumor effects of local and systemic administration of a small amount of anti-PD-1 antibody, the overall survival (OS), and the immune environment around cancer.A mouse buccal mucosal oral squamous cell carcinoma cell line (Sq-1979) was used, and anti-mouse PD-1 was used as the drug. The cell line was transplanted to mouse, and the drug was locally (30 mg/body) and systemically (300 mg/body) administered in a dose. The tumor shrinkage rate and antitumor effect were examined 21 and 29 days after the start of administration. The OS was also compared in each of the groups. Furthermore, the subcutaneous growth of the tumors was inhibited, and the expressions of PD-L1, CD8T cells, perforin, and granzyme B were examined.We found that the local low-dose and systemic groups had the same antitumor effect, OS also showed a significant prolongation. In addition, indicated that the expression of granzyme B was higher in the local low-dose group.Local low-dose administration of anti-PD-1 antibody showed the same antitumor effect and OS as systemic normal-dose administration. Therefore, local low-dose administration in oral cancer can be useful.

Background The rate at which patients are accurately diagnosed with hereditary angioedema (HAE), as well as diagnosed patients access to modern treatments differs greatly among countries. Moreover, the severity and burden of HAE on patients have been reported mostly on the basis of physician-reported surveys. To gain insight into the real-world conditions of patients with HAE through a patient-reported survey in Japan and identify any unmet needs. Methods A questionnaire was distributed to 121 patients with HAE via a Japanese HAE patient organization during 2016–2017. Responses were collected from 70 patients (57.9%) and subjected to analysis. Results The average periods from the initial appearance of symptoms (e.g. edema) to a HAE diagnosis was 15.6 years (min–max, 0–53). Patients visited an average of 4.6 different departments until receiving a definitive diagnosis. The average age at the first visit was 25.6 years (3–73) and at diagnosis 32.8 years (0–73). Patients reported an average of 15.7 (0–100) attacks per year, but only 53.1% of attacks were treated. The days of hospitalization due to severe attacks was 14.3 (0–200) before diagnosis, but these declined to 4.3 (0–50) after diagnosis. In the treatment for attacks, 82% of the patients were treated with the plasma-derived C1 inhibitor concentrate, and 69% of the patients reported experiencing a therapeutic effect. Conclusions There is a long gap between first attack and diagnosis of HAE, and the number of non-treated attacks is high in Japan. Steps are needed to improve the diagnostic and treatment environments to address these issues.

Highlights • We experienced a case of small intestinal perforation caused by intestinal Burkitt lymphoma. • Pretreatment BL may present with bowel perforation. • This is the first report of such a case., Introduction and importance Small intestinal perforation in patients with Burkitt lymphoma is extremely rare. We present the first report of such a case. Case presentation A 53-year-old woman was admitted with abdominal pain and vomiting. Abdominal examination revealed rigidity and tenderness in the upper abdomen. Computed tomography scan showed thickening of the wall of the jejunum, intra-abdominal free gas, and ascites; the patient was diagnosed with small intestinal perforation, and underwent emergency surgery on the same day. Laparoscopic findings were a 50 mm jejunal perforation and perforation in the transverse mesocolon. A partial jejunal resection of the perforated area, partial transverse colectomy, temporary colostomy, and intra-abdominal drainage were performed. Histological examination showed diffuse infiltration of medium-sized atypical lymphocytes in the perforated area, exhibiting a “starry sky” appearance. Immunostaining results showed that the atypical lymphocytes were CD20 and virtually 100% Ki-67 positive, and CD56, CD30, and EBER negative. The lesion was identified as Burkitt lymphoma (BL). The postoperative course was favorable. On postoperative day 18 the patient began chemotherapy through the hematology department. Currently, the patient is in remission. Clinical discussion The majority of the malignant lymphomas occurring in the digestive tract are identified in the stomach; over 90% are B-cell lymphomas and mucosa-associated lymphoid tissue lymphoma Nakamura et al. BL originating from the small intestine accounts for only about 9%. Conclusion The incidence of BL in the small intestine is low. Pretreatment BL can lead to bowel perforation. Prompt involvement of the hemato-oncologist after definitive diagnosis, and commencing chemotherapy as early as possible after surgery, are thought to improve prognosis.

Background/purpose The prevalence of oral adverse events and dental treatments related complications during the molecular targeted drugs therapy remains unclear. The purpose of this study was to investigate the contents of dental treatment-related complications in Japanese patients during molecular targeted therapy. Materials and methods The nation-wide survey of dental treatment related complications was performed by the Japanese Society of Dentistry for Medically Compromised Patient as retrospective cohort study. Results Among 212 dentists, 87.3% recognized the possibility of dental treatments related complications in patients with angiogenesis inhibitors. The oral adverse events including dental treatment-related complications associated with angiogenesis inhibitors were 79 cases. In patients with angiogenesis inhibitors, 73.4% of patients were administrated with bevacizumab. The average administration period of angiogenesis inhibitors was 14.0 ± 10.0 months. As the dental treatment related complications, delayed wound healing was most commonly seen in 45 patients (57.0%), followed by osteonecrosis of the jaw in 25 (31.6%). The triggered factor of complications was tooth extraction in 51 cases (96.2%). Conclusion The extraction of the tooth with pre-existing inflammation may be suggested as one of risk factors for angiogenesis inhibitor-related dental treatment complications.

This study investigated the development of fermented meat sauce from pig kidneys (PKs) to promote the use of underutilized livestock byproducts. To this end, we examined the effect of ureter removal and soy sauce yeast (SSY) inoculation on the physicochemical characteristics of the PK sauce mashes (moromis) and the quality of the final products. Ureter removal resulted in a decrease in the L* value of the moromis and an increase in the a* and b* values during the fermentation process. In contrast, SSY inoculation caused the opposite effect in CIE Lab color parameters. A principal component analysis with taste sensor data from the final products after heat treatment and filtration showed that the differences in taste among the four final products were distinguishable. The umami and bitterness tastes were derived from the fermentation of pig kidney sauce and enhanced with SSY inoculation and ureter removal, respectively.

This chapter addresses the type of government in Japan. It emphasizes that the legal system of Japan is a civil law system and there is no separation between federal and state law. The chapter also presents a brief description of formalities for different types of will under the Civil Code of Japan ("CC"): holographic wills, notary deed wills, secret certificate wills. The testator/trix may, at any time, revoke the will by following the same formalities as those applied to the will itself. This chapter then shifts to discuss the priority of successors under Japanese law. The deceased’s spouse, together with the deceased’s child/ren will be the successor/s by law. The deceased’s spouse will be entitled to one-half of the estate and the child/ren will be entitled to the remaining one-half. Ultimately, the chapter concludes by showing the categories of persons who legally secured portions of the total estate of the deceased (iryu-bun): spouses; children (including lineal descendants); and lineal ascendants. It also considers the property acquired by a husband or wife as well as the share of the deceased in jointly owned property.

A 71-year-old woman with dermatomyositis (DM) received glucocorticoid steroid (GCS) and tacrolimus treatment. Relapse of skin symptoms was observed after tapering the GCS dose, and the patient tested positive for anti-transcriptional intermediary factor-1 gamma (TIF1-γ) antibody. Examinations for malignancy were repeatedly performed. However, no obvious findings indicative of a tumour were observed. Two years after, a retroperitoneal tumour was detected and pathologically diagnosed as poorly differentiated adenocarcinoma. The patient developed intestinal and biliary obstruction and eventually died of sepsis. Herein, we report the presence of anti-TIF1-γ antibodies in a DM patient with cancer of unknown primary site.

Leukotriene B4 receptor 1 (BLT1), a high-affinity G-protein-coupled receptor for leukotriene B4 (LTB4 ), is expressed on various inflammatory cells and plays critical roles in several inflammatory diseases. In myocardial infarction (MI), various inflammatory cells are known to be recruited to the infarcted area, but the function of BLT1 in MI is poorly understood. Here, we investigated the role of BLT1 in MI and the therapeutic effect of a BLT1 antagonist, ONO-4057, on MI. Mice with infarcted hearts showed increased BLT1 expression and LTB4 levels. BLT1-knockout mice with infarcted hearts exhibited attenuated leukocyte infiltration, proinflammatory cytokine production, and cell death, which led to reduced mortality and improved cardiac function after MI. Bone-marrow transplantation studies showed that BLT1 expressed on bone marrow-derived cells was responsible for the exacerbation of inflammation in infarcted hearts. Furthermore, ONO-4057 administration attenuated the inflammatory responses in hearts surgically treated for MI, which resulted in reduced mortality and improved cardiac function after MI. Our study demonstrated that BLT1 contributes to excessive inflammation after MI and could represent a new therapeutic target for MI.

The collapse of a long-term contract-based (LTC) benchmark system and the rise of a market-based index system in international negotiations of iron ore prices in the Asia-Pacific region has attracted much media attention. However, a systematic analysis of why and how such a change occurred from a negotiation point of view is absent. Drawing upon a relationship-behavior-conditions (RBC) perspective from the international business (IB) negotiation literature, this article investigates how negotiations between parties unfolded during the 2009–2010 period. Specifically, the article contributes to a deeper understanding of the subject by evaluating the relationships between various negotiating parties, investigating some intriguing behaviors by negotiating parties, and identifying important conditions surrounding the negotiation process. The case of iron ore price negotiation also offers a vehicle to advance the RBC perspective in untangling complex IB negotiation problems and generate some broad implications for IB negotiation research and practices.

This in vitro study evaluated the effect of different antiseptics and different concentrations thereof in a model of wound healing using human gingival fibroblasts. The fibroblasts were rinsed with four different antiseptic solutions: sodium hypochlorite (HYP), hydrogen peroxide (H2O2), chlorhexidine digluconate (CHX), and benzalkonium chloride (BC). The effect on the release of interleukin-6 (IL-6) and transforming growth factor beta 1 (TGF-β1) was investigated using enzyme-linked immunosorbent assays (ELISAs). In addition, the effects of the antiseptics on wound healing at 1, 12, 24, and 48 h were assessed through a wound healing assay. The viability of the fibroblasts rinsed with antiseptics was investigated with respect to the concentrations inhibiting cell growth by 50% (IC50), 25% (IC25), and ≤2% (IC2). A statistically significant increased release of IL-6 was obtained with BC IC25 and IC2 after 12, 24, and 48 h (P < 0.01). For TGF-β1, no significant release was found for CHX IC2 after 24 and 48 h or for IC50 and IC25 after 12 h. There was no significant effect on wound healing capacity for CHX or for BC IC25 and IC2. This study demonstrated that antiseptic rinses of human gingival fibroblasts alter the release of IL-6 and TGF-β1 and impact wound healing capacity, with both BC and CHX conferring neutral effects.

BACKGROUND Nonocclusive mesenteric ischemia (NOMI) is a life-threatening disease. We present the first case to indicate an association between NOMI and renal infarction caused by renal artery vasoconstriction. CASE REPORT An 84-year-old Japanese man with no relevant past medical history was evaluated in the Emergency Department for disturbance of consciousness. The patient had a consciousness level of E₁V₁M₄ on the Glasgow Coma Scale, temperature of 29.4°C, blood pressure of 90/40 mmHg, regular pulse rate of 48 beats/min, oxygen saturation of 72% while breathing ambient air, abdominal distention, and abdominal tenderness with peritoneal signs. His hemoglobin levels were 3.6 g/dL, blood urea nitrogen per creatinine 54/1.12 mg/dL, plasma glucose 10 mg/dL, and lactate 12.5 mmol/L. Enhanced computed tomography revealed a dilated and distended large transverse colon, spotted poorly enhanced areas in the bilateral kidneys, and poor contrast enhancement of the bilateral renal arteries. The patient died 48 h after admission due to multiple organ failure. An autopsy revealed dappled hemostasis and ischemia in the transverse colon and bilateral kidneys, with no thrombotic infarction in the superior mesenteric artery and/or bilateral renal arteries. We diagnosed NOMI with acute renal tubular necrosis caused by vasoconstriction of the bilateral renal arteries. CONCLUSIONS NOMI can occur simultaneously with renal vasoconstriction, suggesting that NOMI and renal artery vasoconstriction may share mechanisms. This case demonstrates that when enhanced computed tomography shows nonenhancing parenchymal regions in both kidneys, clinicians should check for renal artery vasoconstriction and the life-threatening disease of NOMI.

This article comparatively examines news avoidance in a rapidly changing media environment. We utilize findings from a large dataset of 488 in-depth interviews with media consumers, conducted in Argentina, Finland, Israel, Japan, and the US. We aim to make a contribution to the study of news avoidance by providing a comprehensive and nuanced understanding of the drivers, practices, and patterns of news avoidance as they occur in and are shaped by a variety of national contexts. We argue that news avoidance is shaped not only by individual characteristics, but is also manifested and performed as part of specific time frames and socio-cultural factors. We distinguish two drivers of intentional news avoidance: cognitive and emotional. The cognitive drivers are accentuated by distinct country-level contextual factors, whereas the emotional drivers for news avoidance are shared across diverse national contexts. peerReviewed

Many social phenomena are triggered by public opinion that is formed in the process of opinion exchange among individuals. To date, from the engineering point of view, a large body of work has been devoted to studying how to manipulate individual opinions so as to guide public opinion towards the desired state. Recently, Abebe et al. (KDD 2018) have initiated the study of the impact of interventions at the level of susceptibility rather than the interventions that directly modify individual opinions themselves. For the model, Chan et al. (The Web Conference 2019) designed a local search algorithm to find an optimal solution in polynomial time. However, it can be seen that the solution obtained by solving the above model might not be implemented in real-world scenarios. In fact, as we do not consider the amount of changes of the susceptibility, it would be too costly to change the susceptibility values for agents based on the solution. In this paper, we study an opinion optimization model that is able to limit the amount of changes of the susceptibility in various forms. First we introduce a novel opinion optimization model, where the initial susceptibility values are given as additional input and the feasible region is defined using the $\ell_p$-ball centered at the initial susceptibility vector. For the proposed model, we design a projected gradient method that is applicable to the case where there are millions of agents. Finally we conduct thorough experiments using a variety of real-world social networks and demonstrate that the proposed algorithm outperforms baseline methods., CIKM 2021

Model selection of the kernel ridge regression is discussed in this paper. The cross-validation approach is one of popular and powerful model selection techniques for many machine learning methods including the kernel ridge regression. However, the cross-validation approach is not suitable for extrapolation scenarios due to its principle. In this paper, we propose a novel model selection criterion for the kernel ridge regression which is applicable to extrapolation scenarios. The key idea of the proposed criterion is direct evaluation of the generalization error, defined in a certain reproducing kernel Hilbert spaces, which is feasible under a certain assumption on a set of kernel candidates.

The management of macrolide-resistant Mycobacterium avium complex (MAC) disease is challenging. It is extremely rare for non-human immunodeficiency virus (HIV)-infected patients to develop disseminated MAC disease. A 73-year-old non-HIV-infected woman was diagnosed with MAC lung disease (MAC-LD) for 20 years and subsequently chronic necrotizing pulmonary aspergillosis for three years. To avoid drug interaction between rifampicin and voriconazole, MAC-LD was treated with clarithromycin (CLR) alone. The results of the bone biopsy and bone marrow culture conducted for back pain were compatible with CLR-resistant MAC vertebral osteomyelitis. The clinical management of CLR-resistant disseminated MAC disease consisting of lung and spinal lesions with no established treatment and a poor prognosis is challenging. In this case, the patient was treated with multidrug antibiotic therapy, including CLR, ethambutol, rifampicin, amikacin, and moxifloxacin. The results show the effectiveness of multidrug antibiotic therapy in treating CLR-resistant disseminated MAC disease.