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Severe intraoral pain induces difficulty in eating and speaking, leading to a decline in the quality of life. However, the molecular mechanisms underlying intraoral pain remain unclear. Here, we investigated gene modulation in the trigeminal ganglion and intraoral pain-related behavior in a rat model of acetic acid-induced oral ulcerative mucositis. Oral ulceration was observed on day 2 after acetic acid treatment to the oral mucosa of male Wistar rats, causing spontaneous pain and mechanical allodynia. Deoxyribonucleic acid microarray analysis of trigeminal ganglion tissue indicated that Hamp (a hepcidin gene that regulates cellular iron transport) was the most upregulated gene. In the oral ulcerative mucositis model, the upregulation of Hamp was also induced in the ulcer region but not in the liver, with no increase in hepcidin levels in the plasma and saliva, indicating that hepcidin was produced locally in the ulcer region in the model. Systemic antibiotic pretreatment did not increase the mRNA levels of Hamp in the trigeminal ganglion and ulcer regions. Hepcidin injection into the oral mucosa enhanced neuronal excitability in response to noxious mechanical stimulation of the oral mucosa in trigeminal spinal subnucleus interpolaris/caudalis neurons. These results imply that oral ulcerative mucositis induces oral mucosal pain because of infectious inflammation of the ulcerative area and potentiates Hamp, which represents anti-bacterial and anti-peptidase gene expression in the ulcer region and trigeminal ganglion. The regulation of cellular iron transport by hepcidin is likely involved in oral ulcerative mucositis-induced pain.

Introduction The end-expiratory occlusion test (EEOT) may predict the response to fluid administration in patients undergoing lung-protective ventilation, but arterial catheter insertion is necessary to evaluate changes in stroke volume (SV). The peripheral perfusion index is a potential noninvasive alternative to evaluate SV. The aim of this study is to investigate whether changes in perfusion index during an intraoperative EEOT can predict the response to fluid administration in patients undergoing lung-protective ventilation (tidal volume 7 ml/kg predicted body weight). Methods Forty-one elective surgical patients were enrolled. The SV and perfusion index were recorded before (baseline), during a 40-s EEOT and after volume expansion (250 ml of lactated Ringer's solution over 10 min). Patients with an increase in SV greater than 10% after volume expansion were defined as responders. [DELTA]PI (change in perfusion index between baseline and 20 ([DELTA]PI.sub.20) or 40 s ([DELTA]PI.sub.40) after the beginning of EEOT were calculated using: [DELTA]PI.sub.20 (%) = [(PI at 20 s after EEOT beginning - PI.sub.baseline)/PI.sub.baseline] x 100, [DELTA]PI.sub.40 (%) = [(PI at 40 s after EEO beginning - PI.sub.baseline)/PI.sub.baseline] x 100). Results Sixteen patients were responders, and 25 were non-responders. The area under the receiver operating characteristics curves generated for [DELTA]PI.sub.20 and [DELTA]PI.sub.40 to predict response to a fluid challenge were 0.561 (95% CI 0.374-0.749) and 0.688 (95% CI 0.523-0.852), respectively. Conclusion Changes in perfusion index during intraoperative EEOT in patients undergoing lung-protective ventilation (7 ml/kg) were unable to predict the response to fluid administration., Author(s): Yusuke Iizuka [sup.1], Masamitsu Sanui [sup.1], Yuji Otsuka [sup.1], Koichi Yoshinaga [sup.1], Takeshi Nakatomi [sup.1], Alan Kawarai Lefor [sup.2] Author Affiliations: (1) grid.415020.2, 0000 0004 0467 0255, Department of [...]

Abstract Background S‐1 and pemetrexed (PEM) are key treatments for non‐small cell lung cancer (NSCLC). However, the mechanism of anticancer activity of S‐1 and PEM is similar. Cross‐resistance between S‐1 and PEM is of concern. This exploratory study was designed to evaluate the treatment effect of S‐1 following PEM‐containing treatment. Methods This retrospective study included patients with advanced (c‐stage III or IV, UICC seventh edition) or recurrent NSCLC who received S‐1 monotherapy following the failure of previous PEM‐containing chemotherapy at six hospitals in Japan. The primary endpoint of the study was the overall response rate (ORR). The secondary endpoint was the disease control rate (DCR), time to treatment failure (TTF), progression‐free survival (PFS), and overall survival (OS). Results A total of 53 NSCLC patients met the criteria for inclusion in the study. Forty‐six patients had adenocarcinoma (88.7%) and no patients had squamous cell carcinoma. Thirty‐one patients (58.5%) received the standard S‐1 regimen and 18 patients (34.0%) received the modified S‐1 regimen. ORR was 1.9% (95% confidence interval [CI]: 0.00%–10.1%). Median TTF, PFS, and OS were 65, 84, and 385 days, respectively. Conclusions Although there were several limitations in this study, the ORR of S‐1 after PEM in patients with nonsquamous (non‐SQ) NSCLC was low compared to the historical control. One of the options in the future might be to avoid S‐1 treatment in PEM‐treated patients who need tumor shrinkage.

Abstract Background Schwannomas are neoplasms that typically arise from the myelin sheath of peripheral nerves and rarely originate within the brain parenchyma. Some case reports present schwannomas arising from the brainstem, but regrowth of the tumor and the efficacy of postoperative irradiation have not been examined. In addition, the genetic background of schwannomas arising from the brainstem has not been investigated. Case presentation A 21-year-old male presented with diplopia, dysphagia, and left-sided hemiparesis, dysesthesia, and ataxia. Intracranial imaging showed a heterogeneous mass with a cystic lesion in the pontomedullary junction. Since the tumor caused obstructive hydrocephalus, the patient underwent subtotal tumor resection. A histopathologic evaluation aided a diagnosis of brainstem intraparenchymal schwannoma. Gradual postoperative mass regrowth was recognized. Three-dimensional conformal radiotherapy was performed on the residual mass and surgical cavity. No tumor regrowth was observed 4 years after surgery. To investigate the genetic background of the tumor, target sequences for 36 genes, including NF2, SMARCB1, and LZTR1, and microsatellite analysis for loss of 22q did not show any somatic variants or 22q loss. Conclusions We suggest that brainstem schwannomas might differ from conventional schwannomas in their genetic background.

Abstract Background EGFR mutations are good predictive markers of efficacy of EGFR tyrosine kinase inhibitors (EGFR‐TKI), but whether comprehensive genomic analysis beyond EGFR itself with circulating tumor DNA (ctDNA) adds further predictive or prognostic value has not been clarified. Methods Patients with NSCLC who progressed after treatment with EGFR‐TKI, and with EGFR T790 M detected by an approved companion diagnostic test (cobas®), were treated with osimertinib. Plasma samples were collected before and after treatment. Retrospective comprehensive next‐generation sequencing (NGS) of ctDNA was performed with Guardant360®. Correlation between relevant mutations in ctDNA prior to treatment and clinical outcomes, as well as mechanisms of acquired resistance, were analyzed. Results Among 147 patients tested, 57 patients received osimertinib, with an overall response rate (ORR) of 58%. NGS was successful in 54 of 55 available banked plasma samples; EGFR driver mutations were detected in 43 (80%) and T790 M in 32 (59%). The ORR differed significantly depending on the ratio (T790 M allele fraction [AF])/(sum of variant AF) in ctDNA (p = 0.044). The total number of alterations detected in plasma by NGS was higher in early resistance patients (p = 0.025). T790 M was lost in 32% of patients (6 out of 19) after acquired resistance to osimertinib. One patient with RB1 deletion and copy number gains of EGFR, PIK3CA, and MYC in addition to T790 M, showed rapid progression due to suspected small cell transformation. Conclusions NGS of ctDNA could be a promising method for predicting osimertinib efficacy in patients with advanced NSCLC harboring EGFR T790 M.

The article discusses the importance of maintaining a balance between free trade and security perspectives in the global trade framework. It highlights the conflict between the United States and the WTO panel regarding the authority to make decisions on security exceptions. The article also emphasizes the need to restore the WTO's dispute settlement and rule-making functions. It mentions the growing trend of developing trade policies based on security, particularly in the context of the US-China confrontation. The article suggests utilizing the monitoring function of the WTO and establishing a committee to address security-related measures. It also discusses the dispute resolution functions of the WTO and the conflict surrounding the right to decide on security exceptions. The text calls for strategic utilization and dissemination of the trade framework to contribute to the maintenance and expansion of free trade. [Extracted from the article]

Abstract Certain driver mutations and pathological diagnoses are associated with the anatomical site of meningioma, based on which the meninges have different embryological origins. We hypothesized that mutations and pathological diagnoses of meningiomas are associated with different embryological origins. We comprehensively evaluated associations among tumor location, pathological diagnosis (histological type), and genetic alterations including AKT1, KLF4, SMO, POLR2A, and NF2 mutations and 22q deletion in 269 meningioma cases. Based on the embryological origin of meninges, the tumor locations were as follows: neural crest, paraxial mesodermal, and dorsal mesodermal origins. Tumors originating from the dura of certain embryologic origin displayed a significantly different pathological diagnoses and genetic abnormality ratio. For instance, driver genetic mutations with AKT1, KLF4, SMO, and POLR2A, were significantly associated with the paraxial mesodermal origin (p = 1.7 × 10−10). However, meningiomas with NF2-associated mutations were significantly associated with neural crest origin (p = 3.9 × 10–12). On analysis of recurrence, no difference was observed in embryological origin. However, POLR2A mutation was a risk factor for the tumor recurrence (p = 1.7 × 10−2, Hazard Ratio 4.08, 95% Confidence Interval 1.28–13.0). Assessment of the embryological origin of the meninges may provide novel insights into the pathomechanism of meningiomas.

Neurofibromatosis type 2 (NF2) causes bilateral vestibular schwannomas (VSs), leading to deafness. VS is treated by surgery or radiation, but neither treatments prevent hearing loss. Bevacizumab was found to be effective in suppressing the tumor’s growth and may help to improve hearing. We are conducting a randomized, double-blind, multicenter clinical trial to verify the efficacy and safety of bevacizumab in NF2-related VS. The primary objective is to evaluate the efficacy of bevacizumab in improving hearing in the affected ear. One of the secondary objectives is to evaluate bevacizumab’s efficacy in rechallenge treatment in relapsed cases. Sixty patients will randomly receive either bevacizumab or a placebo and will be clinically observed for 48 weeks in the initial intervention phase. In the first half (24 weeks), they will receive either 5 mg/kg of bevacizumab or a placebo drug. In the second half, all patients will receive 5 mg/kg of bevacizumab. If hearing function deteriorated in a patient who had shown improvement during the first phase, a rechallenge dose with bevacizumab would be offered.

Osteoblasts release adenosine triphosphate (ATP) out of the cell following mechanical stress. Although it is well established that extracellular ATP affects bone metabolism via P2 receptors [such as purinergic receptor P2X7 (P2X7R) and purinergic receptor P2Y2 (P2Y2R)], the mechanism of ATP release from osteoblasts remains unknown. Recently, a vesicular nucleotide transporter [VNUT, solute carrier family 17 member 9 (SLC17A9)] that preserves ATP in vesicles has been identified. The purpose of this study was to elucidate the role of VNUT in osteoblast bone metabolism. mRNA and protein expression of VNUT were confirmed in mouse bone and in osteoblasts by quantitative real‐time PCR (qPCR) and immunohistochemistry. Next, when compressive force was applied to MC3T3‐E1 cells by centrifugation, the expression of Slc17a9, P2x7r, and P2y2r was increased concomitant with an increase in extracellular ATP levels. Furthermore, compressive force decreased the osteoblast differentiation capacity of MC3T3‐E1 cells. shRNA knockdown of Slc17a9 in MC3T3‐E1 cells reduced levels of extracellular ATP and also led to increased osteoblast differentiation after the application of compressive force as assessed by qPCR analysis of osteoblast markers such as Runx2, Osterix, and alkaline phosphatase (ALP) as well as ALP activity. Consistent with these observations, knockdown of P2x7r or P2y2r by siRNA partially rescued the downregulation of osteoblast differentiation markers, caused by mechanical loading. In conclusion, our results demonstrate that VNUT is expressed in osteoblasts and that VNUT inhibits osteoblast differentiation in response to compressive force by mechanisms related to ATP release and P2X7R and/or P2Y2R activity.

Introduction: Human periodontal ligament mesenchymal stem cells (hPDLMSCs) have been known that they play important roles in homeostasis and regeneration of periodontal tissues. Additionally, spheroids are superior to monolayer-cultured cells. We investigated the characteristics and potential of periodontal tissue regeneration in co-cultured spheroids of hPDLMSCs and human umbilical vein endothelial cells (HUVECs) in vitro and in vivo. Methods: Co-cultured spheroids were prepared with cell ratios of hPDLMSCs: HUVECs = 1:1, 1:2, and 2:1, using microwell chips. Real-time polymerase chain reaction (PCR) analysis, Enzyme-Linked Immuno Sorbent Assay (ELISA), and nodule formation assay were performed to examine the properties of co-cultured spheroids. Periodontal tissue defects were prepared in the maxillary first molars of rats and subjected to transplantation assay. Results: The expression levels of stemness markers, vascular endothelial growth factor (VEGF), osteogenesis-related genes were up-regulated in co-cultured spheroids, compared with monolayer and spheroid-cultured hPDLMSCs. The nodule formation was also increased in co-cultured spheroids, compared with monolayer and spheroid cultures of hPDLMSCs. Treatment with co-cultured spheroids enhanced new cementum formation after 4 or 8 weeks of transplantation, although there was no significant difference in the new bone formation between co-cultured spheroids and hPDLMSC spheroids. Conclusions: We found that co-cultured spheroids enhance the periodontal tissue regeneration. Co-cultured spheroids of hPDLMSCs and HUVECs may be a useful therapy that can induce periodontal tissue regeneration.

Introduction Anti‐vascular endothelial growth factor therapy has been shown to be effective in non‐small cell lung cancer (NSCLC) patients with malignant pleural effusion (MPE); however, there are no data to suggest that ramucirumab has the same effects. Methods We therefore decided to conduct a phase II study of ramucirumab plus docetaxel for NSCLC patients with MPE. The MPE control rate at eight weeks after the start of treatment will be the primary endpoint, and the objective response rate, progression‐free survival, one‐year survival rate, overall survival, and toxicity profile will be secondary endpoints. Discussion A previous study indicated that administering chemotherapy in combination with bevacizumab was effective at controlling pleural effusion in patients with NSCLC with carcinomatous pleurisy. It is expected that ramucirumab will have a similar effect to the same group.

Psoriasis is a relevant topic for publication in general medical journals. We conducted a search of the Thomson Reuters’ Science Citation using the search term of “psoriasis” in five high-impact general medical journals. All citation classics from 1970 to 2012 were included and each author’s total number of citations was summated. A total of 51 citation classics were collected. The most common topic of publication was psoriasis treatment (37), especially biologic agents (16). A total of 1037 authors of psoriasis articles were identified in our study and the top 25 most-cited authors were compiled. We hope our citation analysis provides a historical perspective and highlights the work of our colleagues and predecessors.