The Kuchi-kara Taberu index as a predictive marker of oral intake recovery in patients with aspiration pneumonia.

AIM: In recent years, the Kuchi-kara Taberu (KT) index has been used as a new tool for the evaluation of dysphagia; however, its predictive ability remains unknown. This study was conducted to examine the validity of oral intake recovery prediction using the KT index in patients with aspiration pneumonia. METHODS: The subjects were older inpatients admitted to an acute-care hospital for the treatment of aspiration pneumonia. A logistic regression analysis was conducted to clarify factors significantly associated with oral intake recovery. In addition, cut-off values of the predictors were calculated using a receiver operating characteristic curve analysis with the area under the curve (P < 0.05). RESULTS: A total of 124 patients (mean age 84.3 ± 7.9 years old, 70 males, 54 females) were enrolled in this study and divided into two groups at discharge: the oral intake group (62.1%) and the non-oral intake group (37.9%). The significant predictors of the recovery of oral intake were the pre-treatment period, treatment period, and the total score of the KT index; the respective odds ratios were 1.082 (95% confidence interval [CI] 1.013-1.156), 1.018 (1.003-1.033) and 0.850 (0.780-0.927), and the respective areas under the curve were 0.407 (95% CI 0.300-0.515), 0.304 (0.208-0.399), and 0.732 (0.640-0.824). The cut-off value of the total score of the KT index was 30. The model showed 85.7% sensitivity and 57.4% specificity. CONCLUSION: The KT index is suggested to be a valid variable for predicting whether or not a patient with aspiration pneumonia can recover their oral intake ability during acute-care hospitalization. Geriatr Gerontol Int 2023; 23: 221-226.

Olfactory dysfunction in LATY136F knock-in mice.

OBJECTIVE: This study examined olfactory dysfunction in LATY136F knock-in mice and its pathogenic mechanism. METHODS: The olfactory function of LATY136F knock-in mice was assessed by a behavioral test using cycloheximide solution, which has been used as a mice repellant because of its peculiar smell and unpleasant taste. The tests were administered to each group of LATY136F knock-in mice and WT mice at 8, 12, 16, 20, and 24 weeks of age. After the behavioral tests to evaluate olfactory function, the mice were sacrificed for evaluations by immunohistochemistry. RESULTS: Behavioral tests to evaluate olfactory function showed that the LATY136F knock-in mice had a statistically significant level of olfactory dysfunction (P < 0.05). Histological analysis showed that the thickness of the olfactory epithelium in these mice was thinner than that in the age-matched wild type mice. There was no IgG4-RD like lesion in the olfactory epithelium of LATY136F knock-in mice. Olfactory marker protein and growth-associated protein 43 expressions in the olfactory epithelium of the LATY136F knock-in mice were markedly lesser than those in the wild type mice (P < 0.05). CONCLUSION: The present study demonstrated that olfactory disturbances occurred in LATY136F knock-in mice. Furthermore, the mechanism was suggested to be reduced regeneration of the olfactory epithelium.

A role for IL-34 in osteolytic disease of multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy that grows in multiple sites of the axial skeleton and causes debilitating osteolytic disease. Interleukin-34 (IL-34) is a newly discovered cytokine that acts as a ligand of colony-stimulating factor-1 (CSF-1) receptor and can replace CSF-1 for osteoclast differentiation. In this study, we identify IL-34 as an osteoclastogenic cytokine that accelerates osteolytic disease in MM. IL-34 was found to be expressed in the murine MM cell line MOPC315.BM, and the expression of IL-34 was enhanced by stimulation with proinflammatory cytokines or by bone marrow (BM) stromal cells. MM-cell-derived IL-34 promoted osteoclast formation from mouse BM cells in vitro. Targeting Il34 by specific small interfering RNA impaired osteoclast formation in vitro and attenuated osteolytic disease in vivo. In BM aspirates from MM patients, the expression levels of IL-34 in CD138+ populations vary among patients from high to weak to absent. MM cell-derived IL-34 promoted osteoclast formation from human CD14+ monocytes, which was reduced by a neutralizing antibody against IL-34. Taken together, this study describes for the first time the expression of IL-34 in MM cells, indicating that it may enhance osteolysis and suggesting IL-34 as a potential therapeutic target to control pathological osteoclastogenesis in MM patients.

Chemotherapy-Induced IL34 Enhances Immunosuppression by Tumor-Associated Macrophages and Mediates Survival of Chemoresistant Lung Cancer Cells.

The ability of tumor cells to escape immune destruction and their acquired resistance to chemotherapy are major obstacles to effective cancer therapy. Although immune checkpoint therapies such as anti-PD-1 address these issues in part, clinical responses remain limited to a subpopulation of patients. In this report, we identified IL34 produced by cancer cells as a driver of chemoresistance. In particular, we found that IL34 modulated the functions of tumor-associated macrophages to enhance local immunosuppression and to promote the survival of chemoresistant cancer cells by activating AKT signaling. Targeting IL34 in chemoresistant tumors resulted in a remarkable inhibition of tumor growth when accompanied with chemotherapy. Our results define a pathogenic role for IL34 in mediating immunosuppression and chemoresistance and identify it as a tractable target for anticancer therapy. Cancer Res; 76(20); 6030-42. ©2016 AACR.

Olfactory Dysfunction in IgG4-Related Disease.

IgG4-related disease is a newly recognized systemic disease, and its elucidation is progressing. However, little is known about its sinonasal manifestations. The aim of this study was to assess the olfaction of patients with IgG4-related disease. Twenty-five patients with IgG4-related disease underwent T&T olfactometry to measure olfactory function. We analyzed the clinical features, including serum IgG4 and IgE levels, involved organs, and sinonasal computed tomography scores to explore the etiology of olfactory dysfunction. Thirteen patients with IgG4-related disease were found to have moderate to severe olfactory dysfunction (52%). There were no differences in the clinical features between the olfactory dysfunction group and the normal group. In 7 patients, the inferior turbinate was biopsied to study the correlation between olfaction score and the number of IgG4-positive cells, but no such correlation was found. Six hyposmia patients recovered to a normal state. Five patients recovered after corticosteroid treatment and 1 recovered spontaneously. We found that the prevalence of olfactory dysfunction was high in patients with IgG4-related disease and that it could be reversed. Olfactory dysfunction appears to be a novel important manifestation of IgG4-related disease.

Identification of a highly immunogenic mouse breast cancer sub cell line, 4T1-S.

Cancer vaccines serve as a promising clinical immunotherapeutic strategy that help to trigger an effective and specific antitumor immune response compared to conventional therapies. However, poor immunogenicity of tumor cells remains a major obstacle for clinical application, and developing new methods to modify the immunogenicity of tumor cells may help to improve the clinical outcome of cancer vaccines. 4T1 mouse breast cancer cell line has been known as poorly immunogenic and highly metastatic cell line. Using this model, we identified a sub cell line of 4T1-designated as 4T1-Sapporo (4T1-S)-which shows immunogenic properties when used as a vaccine against the same line. In 4T1-S-vaccinated mice, subcutaneous injection of 4T1-S resulted in an antitumor inflammatory response represented by significant enlargement of draining lymph nodes, accompanied with increased frequencies of activated CD8 T cells and a subpopulation of myeloid cells. Additionally, 4T1-S vaccine was ineffective to induce tumor rejection in nude mice, which importantly indicate that 4T1-S vaccine rely on T cell response to induce tumor rejection. Further analysis to identify mechanisms that control tumor immunogenicity in this model may help to develop new methods for improving the efficacies of clinical cancer vaccines.

Massive Hemorrhage from the Posterior Ethmoidal Artery during Transsphenoidal Surgery: Report of 2 Cases.

Nasal bleeding is a major complication that can occur during and after transsphenoidal surgery (TSS) for intra- and suprasellar tumors. In most cases, the cause of this bleeding can be attributed to a branch of the maxillary artery called the sphenopalatine artery, injury to which can lead to life-threatening situations. Upon exposure of the suprasellar region and planum sphenoidale during surgery, it is also important to avoid damaging the posterior ethmoidal artery (PEA), a branch of the ophthalmic artery. While recent advancement in endoscopic techniques enables the performance of extended TSS, the chances of PEA injury seem to be increasing. In the current report, we present two cases that showed massive PEA bleeding during regular (not extended) TSS. The total blood loss was 2280 ml and 2150 ml, and endoscopic views disturbed by the massive hemorrhages remarkably delayed accurate stanching of the responsive artery. Therefore, anatomical recognition of the PEA is required to avoid fatal hemorrhaging during even regular TSS, especially for the beginners of this surgery.

Chemotherapy-Derived Inflammatory Responses Accelerate the Formation of Immunosuppressive Myeloid Cells in the Tissue Microenvironment of Human Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic malignancies. PDAC builds a tumor microenvironment that plays critical roles in tumor progression and metastasis. However, the relationship between chemotherapy and modulation of PDAC-induced tumor microenvironment remains poorly understood. In this study, we report a role of chemotherapy-derived inflammatory response in the enrichment of PDAC microenvironment with immunosuppressive myeloid cells. Granulocyte macrophage colony-stimulating factor (GM-CSF) is a major cytokine associated with oncogenic KRAS in PDAC cells. GM-CSF production was significantly enhanced in various PDAC cell lines or PDAC tumor tissues from patients after treatment with chemotherapy, which induced the differentiation of monocytes into myeloid-derived suppressor cells (MDSC). Furthermore, blockade of GM-CSF with monoclonal antibodies helped to restore T-cell proliferation when cocultured with monocytes stimulated with tumor supernatants. GM-CSF expression was also observed in primary tumors and correlated with poor prognosis in PDAC patients. Together, these results describe a role of GM-CSF in the modification of chemotherapy-treated PDAC microenvironment and suggest that the targeting of GM-CSF may benefit PDAC patients' refractory to current anticancer regimens by defeating MDSC-mediated immune escape.

Progress and controversy for the role of chemotherapy in nasopharyngeal carcinoma.

Since the publication of Intergroup Study 0099, representing a superiority of concurrent chemoradiotherapy with cisplatin followed by adjuvant chemotherapy to radiotherapy alone for the treatment of locoregionally advanced nasopharyngeal carcinoma, an efficacy of concurrent setting of cisplatin-based chemotherapy with radiotherapy has been repeatedly validated. In meanwhile, the role of adjuvant part of the protocol has been controversial. There is an increasing evidence for the positive role of neoadjuvant chemotherapy with following concurrent chemoradiotherapy whereas favorable contribution was not proven in the last century. This article reviews the role of chemotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma.

Aspergillus Sphenoiditis Associated with an Artificial Bone Graft Used for Transsphenoidal Surgery.

Cerebrospinal fluid (CSF) leakage is a major complication during and after transsphenoidal surgery (TSS) for intra- and suprasellar tumors. To prevent postoperative CSF leakage, various surgical techniques have been used, including sellar floor reconstruction with artificial bone grafts. However, some authors have recently reported infections associated with artificial bone grafts. Most cases are associated with bacterial infection, and fungal infection is extremely rare. We present the case of a 53-year-old woman with sphenoiditis caused by Aspergillus infection that developed 8 years after TSS and following local radiation therapy for a non-functioning pituitary adenoma. An artificial bone graft prepared from polymethylmethacrylate was used for sellar floor reconstruction. The patient presented to our department with a complaint of bloody nasal discharge. Magnetic resonance imaging showed that a fungal lump had formed around the bone graft, which had broken into two pieces and dropped out into the sphenoid sinus, without tumor recurrence. Histological examination of an endoscopic biopsy specimen led to a diagnosis of aspergillosis. Subsequent complete removal of both the bone graft and fungal lump resulted in a good postoperative outcome. Although fungal infection is an extremely rare complication after TSS using artificial bone grafts, it should be diagnosed as early as possible, and removal of both the fungal lump and the bone graft should be performed in a timely manner after clinical and radiological confirmation.

Expression of interleukin-33 is correlated with poor prognosis of patients with squamous cell carcinoma of the tongue.

OBJECTIVE: The aim of this study was to clarify the role of IL-33 in tumor progression. METHODS: Surgical specimens from 81 patients with squamous cell carcinoma of the tongue were studied using immunohistochemistry. Primary tumor sections were analyzed for IL-33 and ST2 expression. To examine the influence of IL-33 on the microenvironment of the tumor, we determined the mast cell density (MCD) and microvessel density of the stroma. RESULTS: Patients with high IL-33 expression had a significantly worse prognosis (p=0.004). IL-33 expression was significantly elevated in patients with local and nodal recurrence (p=0.014 and p=0.019). ST2 expression was also associated with a worse prognosis (p=0.024) and was significantly elevated in patients with nodal recurrence (p=0.004). MCD was associated with worse prognosis (p=0.038) and correlated significantly with IL-33 expression (r=0.626, p<0.001). Micovessels in the stroma were significantly increased in the high IL-33 group (p<0.001). CONCLUSION: These data suggest that the IL-33/ST2 axis contributes to tumor aggressiveness and affects the tumor microenvironment. Immunohistochemical evaluation of IL-33 and ST2 is useful for identifying patients at a high risk for poor prognosis.

Immunoglobulin class switching to IgG4 in Warthin tumor and analysis of serum IgG4 levels and IgG4-positive plasma cells in the tumor.

We previously reported a case of immunoglobulin (Ig)G4-related immune inflammation in Warthin tumor. Increased serum IgG4 levels and tissue infiltration of IgG4-positive plasma cells are characteristics of IgG4-related disease (IgG4-RD), a newly emerging clinicopathological entity. However, the relationship between IgG4-RD and Warthin tumor remains to be elucidated. We aimed to investigate the involvement of systemic and local IgG4 production and class-switch recombination in Warthin tumor. We examined serum IgG4 levels and also analyzed the involvement of IgG4-positive plasma cells in Warthin tumors (18 cases) compared with those of pleomorphic adenomas (19 cases) as controls. Furthermore, in specimens of Warthin tumors (3 cases), pleomorphic adenomas (2 cases), and IgG4-RDs (2 cases), we examined messenger RNA expression of activation-induced cytidine deaminase, IgG4 germline transcripts and productive IgG4 by reverse transcription polymerase chain reaction. Serum IgG4 levels were increased in 5 of 18 Warthin tumors and not in any of the 19 pleomorphic adenomas. Infiltration of IgG4-positive plasma cells was detected in 4 Warthin tumors and none in the pleomorphic adenomas. Moreover, activation-induced cytidine deaminase, IgG4 germline transcripts, and productive IgG4 messenger RNA were found to be expressed in 2 of 3 Warthin tumors as well as IgG4-RDs by reverse transcription polymerase chain reaction, but not in pleomorphic adenomas. In conclusion, immunoglobulin class switching to IgG4 may be involved in the pathogenesis of Warthin tumor, and it is possible that certain inflammatory background with an immune reaction is involved in the pathogenesis of Warthin tumor.

Pathogenic role of Epstein-Barr virus latent membrane protein-1 in the development of nasopharyngeal carcinoma.

Undifferentiated nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignant tumor. A consistent elevation in EBV antibody titers is a well-established risk factor for the development of NPC. The pathophysiological relationship and molecular mechanisms of EBV-mediated carcinogenesis have not been fully elucidated. While NPC tumors are known to express three EBV-encoded proteins, EBNA1, LMP1, and LMP2, they also express a large number of virus-encoded small RNAs (EBERs) and microRNAs (miRNAs). Among them, LMP1 may be a central player in the development of NPC. LMP1, an EBV-encoded primary oncogene, functions as a viral mimic of the TNFR family member, CD40, and engages in a number of signaling pathways that induce morphological and phenotypic alterations in epithelial cells. LMP1 upregulates EMT, and contributes to the highly metastatic features of NPC. Moreover, LMP1-associated EMT is accompanied by the expression of cancer stem cell (CSC)/cancer progenitor cell (CPC) markers (CD44high/CD24low) and the acquisition of stem cell/progenitor cell-like properties. BART miRNAs, encoded from the BamHI-A region of the viral genome, are the most abundant transcripts. They modulate apoptosis and host innate immune defense mechanisms. Some BART1 miRNAs are considered to negatively regulate LMP1 protein expression. LMP1 is secreted via exosomes, is incorporated into EBV-uninfected cells by endocytosis, and affects the environment surrounding the tumor. Here we reviewed the contribution of EBV gene products to NPC pathogenesis in relation with LMP1.

Warthin's tumor associated with IgG4-related disease.

Immunoglobulin G4-related disease (IgG4-RD) is an inflammatory condition associated with elevated serum IgG4 levels and tissue infiltration by IgG4-expressing plasma cells. Several inflammatory conditions associated with IgG4-RD have been reported. Warthin's tumor is a benign parotid gland tumor consisting of oncocytic epithelial cells and lymphoid stroma containing lymphoid follicles with reactive germinal centers. This is the first report describing a case of Warthin's tumor with possible involvement of IgG4-RD. The patient was a 71-year-old man presenting with swollen right parotid and bilateral submandibular glands. He had a history of a Warthin's tumor of the left parotid gland, autoimmune pancreatitis, and an inflammatory abdominal aortic aneurysm. Laboratory tests revealed a high serum IgG4 level. Histological examination of the resected parotid gland showed a Warthin's tumor and a nodule showing severe lymphocytic infiltration containing many IgG4-positive plasma cells. This case shows the possible involvement of Warthin's tumor with IgG4-RD.

Efficacy and safety of garenoxacin in the treatment of upper respiratory tract infections.

OBJECTIVE: To determine the efficacy and safety of garenoxacin, a new generation of quinolone antimicrobial agent, in the treatment of adult upper respiratory tract infections. METHODS: A total of 113 subjects were enrolled in this study. Garenoxacin (400mg/day) was administered to patients with pharyngolaryngitis, tonsillitis, and otitis media for 5-7 days and to those with sinusitis for 7-10 days. Clinical symptoms and findings were examined and quantitatively evaluated using a scoring system. RESULTS: We found 80 to 100% improvement rate in symptoms and findings for each infection. In addition, we found significant improvement in subjective evaluations from patient questionnaires even in the early stage of the treatment. X-ray examination for acute sinusitis demonstrated that the clinical efficacy was 84% (27/32) and 76% (19/25) patients were already improved within seven days. Among the detected 84 bacteria, 75 (89%) were identified as the major pathogenic bacteria of respiratory tract infections such as Streptococcus pneumoniae (27 strains) and Haemophillus influenzae (14 strains). Garenoxacin administration completely eradicated bacteria in 53 out of 54 cases (98%). There were 8 adverse events (8.3%) including 3 diarrhea cases (3.1%). CONCLUSION: These results suggest that garenoxacin is a highly effective and safe antimicrobial agent in the treatment of community-acquired upper respiratory infections. Additionally, garenoxacin did not induce the growth of resistant bacteria because of its strong antimicrobial activity.

Evaluation of the physicochemical characteristics of crospovidone that influence solid dispersion preparation.

A solid dispersion (SD) powder of indomethacin (IM) with crospovidone (CrosPVP) shows useful characteristics for manufacturing dosage forms. Four types of commercial CroPVP, Polyplasdone XL (XL) used as the initial carrier, Polyplasdone XL10 and INF-10 manufactured by milling XL, and Kollidon CL (CL) marketed by another company, were compared. The limit of the IM-CrosPVP weight ratio with which an SD can be prepared (maximum IM content) was calculated on the basis of the heat of fusion of physical mixtures of IM and CrosPVP with various weight ratios. When Polyplasdones were used, the maximum IM content increased with the specific surface area of the CrosPVP. When CL was used, however, it was about half of that obtained with XL, even though the difference between XL and CL was not observed in the physicochemical characteristics (particle size, specific surface area, flowability, glass transition temperature, IR spectra, and solid state NMR spectra). As determined by pore size distribution measurement, the volume of pore of which size is larger than the particle size of IM was less in CL than in XL. Therefore, the effective surface area of CrosPVP that comes in contact with IM is important for the preparation of the SD.

Effect of particle size of drug on conversion of crystals to an amorphous state in a solid dispersion with crospovidone.

The effect of particle size on amorphization of drugs in a solid dispersion (SD) was investigated for two drugs, indomethacin (IM) and nifedipine (NP). The SD of drugs were prepared in a mixture with crospovidone by a variety of mechanical methods, and their properties investigated by particle sizing, thermal analysis, and powder X-ray diffraction. IM, which had an initial particle size of 1 µm and tends to aggregate, was forced through a sieve to break up the particles. NP, which had a large initial particle size, was jet-milled. In both cases, reduction of the particle size of the drugs enabled transition to an amorphous state below the melting point of the drug. The reduction in particle size is considered to enable increased contact between the crospovidone and drug particles, increasing interactions between the two compounds.

The preparation of a solid dispersion powder of indomethacin with crospovidone using a twin-screw extruder or kneader.

A solid dispersion (SD) powder of indomethacin (IM) with CrosPVP was prepared continuously using a twin-screw extruder (extruder) or twin-screw kneader (kneader), which made it possible to simultaneously control kneading, mixing, and heating. For the extruder or kneader, IM existed in an amorphous state while it was treated with a screw rotation speed of 15 min(-1) or 50 min(-1), respectively, while being heated to 140 degrees C. IM and CrosPVP interacted to maintain IM in an amorphous state. The solubility of SD powders of IM was improved about four-fold compared to crystalline IM. The retention time of the samples in the machine, screw rotation speed, and heating temperature play important roles in the preparation of SD. Although SD was prepared using a theta composer followed by heating at 125 degrees C for 30 min, it is more useful to be able to continuously prepare powdered SD by heating below the melting point (140 degrees C) in a short time (4 min) using an extruder or a kneader from the viewpoint of manufacturing.

Oct-3/4 and Sox2 regulate Oct-3/4 gene in embryonic stem cells.

Oct-3/4 is a key transcriptional factor whose expression level governs the fate of primitive inner cell mass and embryonic stem (ES) cells. Previously, an upstream 3.3-kb distal enhancer (DE) fragment was identified to be responsible for the specific expression of mouse Oct-3/4 in the inner cell mass and ES cells. However, little is known about the cis-elements and trans-factors required for DE activity. In this study, we identified a novel cis-element, called Site 2B here, located approximately 30 bp downstream from Site 2A, which was previously revealed in DE by an in vivo chemical modification experiment. Using the luciferase reporter assay, we demonstrated that both Site 2A and Site 2B are necessary and sufficient for activating DE in the contexts of both the native Oct-3/4 promoter and the heterologous thymidine kinase minimal promoter. In an electrophoretic mobility shift assay we showed that Site 2B specifically binds to Oct-3/4 and Sox2 when ES-derived cell extracts were used, whereas Site 2A binds to a factor(s) present in both ES and NIH 3T3 cells. Furthermore, we showed that the physiological level of Oct-3/4 in ES cells is required for Site 2B-mediated DE activity using the inducible knock-out system of Oct-3/4 in ES cells. These results indicate that Oct-3/4 is a member of the gene family regulated by Oct-3/4 and Sox2, as reported before for the FGF-4, UTF1, Sox2, and Fbx15 genes. Thus, Oct-3/4 and Sox2 comprise a regulatory complex that controls the expression of genes important for the maintenance of the primitive state, including themselves. This autoregulatory circuit of the Sox2.Oct-3/4 complex may contribute to maintaining robustly the precise expression level of Oct-3/4 in primitive cells.