Search

A simple graph G admits an H-covering if every edge in E(G) belongs to at least to one subgraph of G isomorphic to a given graph H. For the subgraph H ⊆ G under a total k-labeling we define the associated H-weight as the sum of labels of all vertices and edges belonging to H. The total k-labeling is called the H-irregular total k-labeling of a graph G admitting an H-covering if all subgraphs of G isomorphic to H have distinct weights. The total H-irregularity strength of a graph G is the smallest integer k such that G has an H-irregular total k-labeling.

The beta-number, β (G), of a graph G is defined to be either the smallest positive integer n for which there exists an injective function f : V (G) → {0, 1, . . . , n} such that each uv ∈ E (G) is labeled |f (u) − f (v)| and the resulting set of edge labels is {c, c + 1, . . . , c + |E (G)| − 1} for some positive integer c or +∞ if there exists no such integer n. If c = 1, then the resulting beta-number is called the strong beta-number of G and is denoted by βs (G). In this paper, we show that if G is a bipartite graph and m is odd, then β (mG) ≤ mβ (G) + m − 1. This leads us to conclude that β (mG) = m|V (G)|−1 if G has the additional property that G is a graceful nontrivial tree. In addition to these, we examine the (strong) beta-number of forests whose components are isomorphic to either paths or stars.

Abstract Precision medicine has drastically changed cancer treatment strategies including KRAS-mutant cancers which have been undruggable for decades. While intrinsic or acquired treatment resistance remains unresolved in many cases, epigenome-targeted therapy may be an option to overcome. We recently discovered the effectiveness of blocking small ubiquitin-like modifier (SUMO) signaling cascade (SUMOylation) in MYC-expressing KRAS-mutant cancer cells using a SUMO-activating enzyme E inhibitor TAK-981 that results in SUMOylation inhibition. Interestingly, TAK-981 promoted the degradation of MYC via the ubiquitin–proteasome system. Moreover, combination therapy with TAK-981 and MEK inhibitor trametinib remarkably regressed xenografted KRAS-mutant tumors by accumulating DNA damage and inducing apoptosis. Whereas our recent study revealed immune-independent antitumor efficacy, we evaluated the immune responses of cancer cells and immune cells in this study. We found that TAK-981-induced MYC downregulation promoted the activation of STING followed by Stat1 and MHC class I in KRAS-mutant cancer cells. Activation of dendritic cells or T cells treated with TAK-981 was also verified by upregulated activation markers in dendritic cells or skew-toward effector-like phenotypes in T cells. Furthermore, the enhanced immune-dependent antitumor efficacy of the combination therapy with TAK-981 and trametinib was confirmed by infiltration of immune cells into tumor tissues and immunodepleting-test using immunodepleting antibodies in syngeneic immunocompetent mouse models. Together with our recent study and here, the findings support that combination inhibition of SUMOylation and MEK comprehensively conquers MYC-expressing KRAS-mutant cancers by both immune-dependent and immune-independent antitumor responses.

Abstract Background Meningioma in the parasellar region may lead to visual impairment, so intraoperative neurological monitoring is essential for enucleation surgery. However, intraoperative neurological monitoring in pregnant women is challenging, as the anesthesia management must consider the effects and risks to the fetus. Remimazolam is a newly introduced intravenous anesthetic that has little effect on blood pressure. However, the effects of remimazolam on intraoperative neuromonitoring are little known. We treated a pregnant patient with parasellar meningioma who developed visual impairment, using remimazolam for anesthesia and intraoperative neurophysiological monitoring of the visual evoked potential. Case presentation A 34-year-old woman who was 20 weeks pregnant presented with visual acuity disturbances. Neuroimaging demonstrated a parasellar meningioma, and rapid tumor growth and worsening of symptoms subsequently occurred. Craniotomy for tumor removal was performed under anesthesia with remimazolam, which allowed monitoring of the visual evoked potentials. Her visual acuity was restored postoperatively, and no adverse events occurred in the fetus. Conclusion Our experience with intraoperative neuromonitoring of a pregnant woman in the third trimester showed that anesthesia with remimazolam allows safe brain surgery combined with intraoperative visual evoked potential monitoring. Further research is needed to determine the effects of remimazolam on the fetus, as well as the safe dosage and duration of exposure.

Abstract Background Platelet-rich plasma (PRP), which is prepared by concentrating platelets in autologous blood, shows efficacy in chronic skin wounds via multiple growth factors. However, it exhibits heterogeneity across patients, leading to unstable therapeutic efficacy. Human induced pluripotent stem cell (iPSC)-derived megakaryocytes and platelets (iMPs) are capable of providing a stable supply, holding promise as materials for novel platelet concentrate-based therapies. In this context, we evaluated the effect of iMPs on wound healing and validated lyophilization for clinical applications. Methods The growth factors released by activated iMPs were measured. The effect of the administration of iMPs on human fibroblasts and human umbilical vein endothelial cells (HUVECs) was investigated in vitro. iMPs were applied to dorsal skin defects of diabetic mice to assess the wound closure rate and quantify collagen deposition and angiogenesis. Following the storage of freeze-dried iMPs (FD-iMPs) for three months, the stability of growth factors and their efficacy in animal models were determined. Result Multiple growth factors that promote wound healing were detected in activated iMPs. iMPs specifically released FGF2 and exhibited a superior enhancement of HUVEC proliferation compared to PRP. Moreover, an RNA-seq analysis revealed that iMPs induce polarization to stalk cells and enhance ANGPTL4 gene expression in HUVECs. Animal studies demonstrated that iMPs promoted wound closure and angiogenesis in chronic wounds caused by diabetes. We also confirmed the long-term stability of growth factors in FD-iMPs and their comparable effects to those of original iMPs in the animal model. Conclusion Our study demonstrates that iMPs promote angiogenesis and wound healing through the activation of vascular endothelial cells. iMPs exhibited more effectiveness than PRP, an effect attributed to the exclusive presence of specific factors including FGF2. Lyophilization enabled the long-term maintenance of the composition of the growth factors and efficacy of the iMPs, therefore contributing to stable supply for clinical application. These findings suggest that iMPs provide a novel treatment for chronic wounds.

Abstract Importin α4, which is encoded by the Kpna4 gene, is a well-characterized nuclear-cytoplasmic transport factor known to mediate transport of transcription factors including NF-κB. Here, we report that Kpna4 knock-out (KO) mice exhibit psychiatric disorder-related behavioral abnormalities such as anxiety-related behaviors, decreased social interaction, and sensorimotor gating deficits. Contrary to a previous study predicting attenuated NF-κB activity as a result of Kpna4 deficiency, we observed a significant increase in expression levels of NF-κB genes and proinflammatory cytokines such as TNFα, Il-1β or Il-6 in the prefrontal cortex or basolateral amygdala of the KO mice. Moreover, examination of inflammatory responses in primary cells revealed that Kpna4 deficient cells have an increased inflammatory response, which was rescued by addition of not only full length, but also a nuclear transport-deficient truncation mutant of importin α4, suggesting contribution of its non-transport functions. Furthermore, RNAseq of sorted adult microglia and astrocytes and subsequent transcription factor analysis suggested increases in polycomb repressor complex 2 (PRC2) activity in Kpna4 KO cells. Taken together, importin α4 deficiency induces psychiatric disorder-related behavioral deficits in mice, along with an increased inflammatory response and possible alteration of PRC2 activity in glial cells.

Ovarian neuroendocrine carcinoma is a rare and aggressive tumor with a poor prognosis. Ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) are often used for diagnosis. However, no specific features exist, and preoperative diagnosis is often difficult. We present a case in which ovarian neuroendocrine carcinoma was diagnosed postoperatively, with the intention to discuss its imaging features on 18F fluoro-deoxy-glucose positron emission tomography/computed tomography (18F-FDG PET/CT). A 70-year-old woman presented to a local hospital with abdominal pain. CT showed a uterine mass and multiple swollen lymph nodes. The mass expanded from the uterus into the left ovarian vessels on dynamic MRI. The SUVmax of the mass and lymph nodes on 18F-FDG PET/CT were notably elevated to 53.2 and 33.0 respectively. Considering the tumor location and high SUVmax, a malignant uterine tumor was suspected. Total abdominal hysterectomy, bilateral salpingo-oophorectomy, omental biopsy, and resection of the left ovarian vessels were performed. Histological examination confirmed that the tumor was a neuroendocrine carcinoma derived from the left ovary. To the best of our knowledge, there are only few reports on the 18F-FDG uptake in ovarian neuroendocrine carcinomas. Conversely, in other organs, the carcinomas frequently exhibit markedly elevated SUVmax on 18F-FDG PET/CT. It is possible that ovarian neuroendocrine carcinomas share similar traits, and elevated SUVmax could indicate the potential presence of this histological type.

Introduction: For older adults, dysphagia is a serious problem that can occur after spinal cord injury (SCI), but its risk factors are unclear. This study aimed to identify risk factors for dysphagia in elderly patients (65 years) with cervical SCI. Methods: This multicenter study included 707 patients with cervical SCI (mean age 75.3 years). Univariate and multivariate analyses were conducted for patient characteristics and geriatric nutritional risk index (GNRI). Results: Dysphagia occurred in 69 patients (9.8%). The significant factors were as follows: male sex (odds ratio [OR] 3.43), GNRI

Abstract Hypertension is a significant contributor to premature mortality, and the regular monitoring of blood pressure (BP) enables the early detection of hypertension and cardiovascular disease. There is an urgent need for the development of highly accurate cuffless BP devices. We examined BP measurements based on a target spectral camera’s recordings and evaluated their accuracy. Images of 215 adults’ palms and faces were recorded, and BP was measured. The camera captured RGB wavelength data at 640 × 480 pixels and 150 frames per second (fps). These recordings were analyzed to extract pulse transit time (PTT) values between the face and palm, a key parameter for estimating BP. Continuous BP measurements were taken using a CNAPmonitor500 for validation. Three frequency wavelengths were measured from video images. A machine learning model was constructed to determine hypertension, defined as a systolic BP of 130 mmHg or higher or a diastolic BP of 80 mmHg or higher, using the visualized data. The discrimination between hypertension and normal BP was 95.0% accurate within 30 s and 90.3% within 5 s, based on the captured images. The results of heartbeat-by-heartbeat analyses can be used to determine hypertension based on only one second of camera footage or one heartbeat. The data extracted from a video recorded by a target spectral camera enabled accurate hypertension diagnoses, suggesting the potential for simplified BP monitoring.

Abstract The roles of Arctic aerosols as ice-nucleating particles remain poorly understood, even though their effects on cloud microphysics are crucial for assessing the climate sensitivity of Arctic mixed-phase clouds and predicting their response to Arctic warming. Here we present a full-year record of ice-nucleating particle concentrations over Svalbard, where surface warming has been anomalously faster than the Arctic average. While the variation of ice-nucleating particles active at around −30 °C was relatively small, those active at higher temperatures (i.e., highly active ice-nucleating particles) tended to increase exponentially with rising surface air temperatures when the surface air temperatures rose above 0 °C and snow/ice-free barren and vegetated areas appeared in Svalbard. The aerosol population relevant to their increase was largely characterized by dust and biological organic materials that likely originated from local/regional terrestrial sources. Our results suggest that highly active ice-nucleating particles could be actively released from Arctic natural sources in response to surface warming.

Abstract The Scibar Cosmic-Ray Telescope (SciCRT) is the most promising detector of the Sierra Negra Cosmic Rays Observatory (SN-CRO). At this location, being a target and a tracker of secondary cosmic rays, the SciCRT offers a high probability of observing solar energetic particles and lower energy galactic cosmic rays (LEGCR); also, it allows the identification of incoming particles by measuring their energy deposition. In this work we present a Geant4-based simulation of the energy deposited by neutrons, $$\gamma $$ γ -rays, protons, electrons and muons in the optimally running SciCRT components. We also calculated the detection efficiency of the SciCRT at its current state. Our simulation results provide new information about the SciCRT detection response that may be used as a basis to estimate and analyze the energy spectra of primary particles.

Abstract Background Robot-assisted radical prostatectomy (RARP) is a preferred minimally invasive surgical treatment for prostate cancer. The number of elderly patients and those with cardiovascular and/or cerebrovascular issues undergoing surgery is increasing, and many of them are taking antithrombotic (AT) agents. However, the effect of AT agents on postoperative urinary recovery has not been adequately studied. In this study, we analyzed the differences in the postoperative recovery of urinary continence and oncological outcomes in patients undergoing RARP for localized prostate cancer between AT agent adherents and non-adherents. Methods A total of 394 patients who underwent conventional anterior RARP between February 2015 and February 2021 were categorized into two groups: those taking oral AT agents (AT group) and the control group. Urinary continence recovery, complications, and oncological outcomes were compared between the groups. A Cox proportional hazards analysis was performed to identify clinical factors that affect urinary continence recovery. Results The background data and bleeding complications did not differ significantly between the groups. The recovery of continence was significantly poorer in the AT group in terms of complete pad free (HR: 0.53 [95% CI: 0.39–0.71]) and use of ≤ 1 safety pad (HR: 0.74 [95% CI: 0.59–0.94]). The rate of anastomotic leakage on cystography was significantly higher in the AT group (20.9% vs. 6.7%). A univariate analysis revealed that taking antithrombotic agents, higher prostate-specific antigen levels, and a more advanced clinical stage were associated with a poor urinary continence recovery; a multivariate analysis showed that taking AT agents was an independent factor negatively associated with urinary continence recovery. There was no significant difference between the groups in the positive surgical margin rate (19.0% vs. 23.8%) or the biochemical-recurrence-free rate. Conclusion Taking oral AT agents may be associated with poor urinary continence recovery after RARP.

Abstract Background Esophageal cancer is one of the most common types of cancer in Japan. Herein, we report the efficacy and safety of E7389-LF plus the immune checkpoint inhibitor, nivolumab, from the esophageal cancer cohort of the phase 2 part of Study 120. Methods Eligible patients received E7389-LF 2.1 mg/m2 plus nivolumab 360 mg intravenously Q3W. The primary objective was to evaluate the objective response rate (ORR); other objectives included safety, progression-free survival (PFS), and overall survival (OS). Results Of the 35 Japanese patients enrolled, 7 (20.0%) had a partial response as their best overall response, and 14 (40.0%) had stable disease. The ORR was 20.0% (95% CI 8.4–36.9). The duration of response was 5.6 months (95% CI 1.7–not estimable [NE]). The median PFS was 2.81 months (95% CI 1.31–4.17). The median OS was not reached (95% CI 6.54 months–NE). The most common treatment-emergent adverse events were neutropenia (65.7%), pyrexia (60.0%), and leukopenia (57.1%). Select plasma endothelial cell markers levels increased from day 1 of cycle 1 and changes were pronounced between days 8–15 of each cycle. Conclusions E7389-LF plus nivolumab showed antitumor activity in patients with unresectable and pretreated esophageal cancer and should be evaluated further in a broader population. Clinical Trial Registration NCT04078295.

Abstract Background Pembrolizumab plus cisplatin and 5-fluorouracil administered as first-line therapy for advanced esophageal cancer patients has shown a better objective response and survival than conventional chemotherapy with less severe hematological adverse events. The safety and efficacy of this regimen were evaluated in patients with T4b esophageal squamous cell carcinoma (ESCC). Methods Eight consecutive patients with T4b ESCC received this regimen according to KEYNOTE-590 as induction, and they were evaluated after 1–3 courses. The programmed death-ligand 1 (PD-L1) combined positive score (CPS) was also evaluated before chemotherapy. Efficacy for the primary lesion was evaluated by our original formula for the tumor reduction rate. Results The numbers of patients with partial response (PR), stable disease, and progressive disease (PD) were 5, 1, and 2, respectively. The tumor reduction rate ranged from 69 to 87% in PR patients, and all PR patients had relief from T4b. Two patients underwent conversion surgery with R0 resection. PD-L1 CPS was over 90 in 2 PR patients, but under 10 in 2 other PR patients. PD-L1 CPS was under 10 in PD patients. One patient had hyperprogression, resulting in an esophago-pulmonary fistula. Greater than grade 3 adverse events were bleeding gastric ulcer in one patient (12.5%), neutropenia without G-CSF in 3 patients (37.5%), and hypopotassemia in 1 patient (12.5%). No patient had febrile neutropenia. Conclusions Marked tumor reduction was confirmed in 62.5% of patients with pembrolizumab plus cisplatin and 5-fluorouracil with less adverse events. This regimen could be administered as induction chemotherapy for patients with T4b ESCC.

Purpose: Corticosteroids are widely used in total knee arthroplasty (TKA) to ameliorate post-operative pain. This study compared the effects of intravenous administration (IVA) and periarticular injection (PAI) of dexamethasone on pain, nausea, and blood glucose levels following TKA. Methods: An institutional database was used to retrospectively examine two cohorts of patients who had undergone unilateral TKA from August 2018 to September 2020. The IVA group (n ​= ​50) received 10 ​mg dexamethasone 1 ​h before surgery and 24 ​h after surgery. The PAI group (n ​= ​50) received 10 ​mg dexamethasone during surgery. Pain scores at rest and during walking as well as nausea scores were recorded using the 0–10 numerical rating scale after surgery. Fasting blood glucose (FBG) levels were measured post-operatively. Results: A total of 100 patients were enrolled (mean age, 71 years; 86% female). The rest pain score 24 ​h post-operatively was significantly lower in the PAI group than in the IVA group (3.3 vs. 4.3; absolute difference 1.0, 95% confidence interval, 0.4–1.3; P ​= ​0.007). The nausea score did not differ markedly between groups. FBG was significantly higher in the PAI group than in the IVA group in the morning of post-operative Day 1. Conclusion: PAI with dexamethasone was found to control pain more effectively at 24 ​h than IVA. FBG on the morning of post-operative Day 1 was significantly higher in the PAI group. Level of evidence, III; retrospective cohort.

Using a habituation paradigm with a three-switch design, the present study investigated whether 20-month-old French-learning infants use noun and verb morphosyntactic cues to learn novel words in dynamic events differentially when both the agent and the action interpretations are possible. Of particular interest was whether infants' initial interpretation of novel nouns referring to novel animate objects in dynamic events includes not only the novel agents but also their actions. The following two contrastive hypotheses were specifically tested: (1) infants map novel verbs to the novel actions only and novel nouns to the novel agents only. Alternatively, (2) they map novel verbs to the novel actions only but novel nouns to both the novel agents and their actions. Infants watched dynamic events in which novel agents performed novel intransitive actions, while hearing novel words in a noun phrase or a verb sentence. When novel words were preceded by a pronoun "il", infants were able to map novel verbs to the actions but not to the agents. However, when novel words were preceded by a determiner "un", they mapped the novel nouns to both the agents and their actions. Two follow-up noun experiments showed that they mapped the novel nouns onto the agents and their actions, even when additional noun morphosyntactic cues were given. These findings demonstrate that 20-month-old infants are able to use noun and verb morphosyntactic cues to learn novel words in dynamic events differentially and provide some evidence to support that infants' initial representations of novel nouns referring to novel animate objects in dynamic events include both the agents and their actions.

The purpose of this study was to examine the effectiveness of a multimodal approach in which an additional camera was used to deliver online explicit reading strategy instruction. Targeting 20 Japanese beginner-level EFL college students taking online Zoom lessons during one academic semester, two research questions were investigated: (a) To what extent does online reading strategy training using a camera to show the teacher's pointing gestures enhance beginner-level students' comprehension of written texts?; and (b) How do beginner-level students perceive the teacher's online reading strategy training? The results showed that the multimodal explicit strategy instruction increased students' attentional focus, encouraged them to use target reading strategies, and facilitated their understanding of the reading texts. The students' responses to a self-reflection questionnaire and interviews showed that their perceptions of this online reading strategy instruction were positive. Further, they reported that their ability to comprehend English texts improved over the length of the course.

Abstract Background KRAS mutations frequently occur in cancers, particularly pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer. Although KRAS G12C inhibitors have recently been approved, effective precision therapies have not yet been established for all KRAS-mutant cancers. Many treatments for KRAS-mutant cancers, including epigenome-targeted drugs, are currently under investigation. Small ubiquitin-like modifier (SUMO) proteins are a family of small proteins covalently attached to and detached from other proteins in cells via the processes called SUMOylation and de-SUMOylation. We assessed whether SUMOylation inhibition was effective in KRAS-mutant cancer cells. Methods The efficacy of the first-in-class SUMO-activating enzyme E inhibitor TAK-981 (subasumstat) was assessed in multiple human and mouse KRAS-mutated cancer cell lines. A gene expression assay using a TaqMan array was used to identify biomarkers of TAK-981 efficacy. The biological roles of SUMOylation inhibition and subsequent regulatory mechanisms were investigated using immunoblot analysis, immunofluorescence assays, and mouse models. Results We discovered that TAK-981 downregulated the expression of the currently undruggable MYC and effectively suppressed the growth of MYC-expressing KRAS-mutant cancers across different tissue types. Moreover, TAK-981-resistant cells were sensitized to SUMOylation inhibition via MYC-overexpression. TAK-981 induced proteasomal degradation of MYC by altering the balance between SUMOylation and ubiquitination and promoting the binding of MYC and Fbxw7, a key factor in the ubiquitin–proteasome system. The efficacy of TAK-981 monotherapy in immunocompetent and immunodeficient mouse models using a mouse-derived CMT167 cell line was significant but modest. Since MAPK inhibition of the KRAS downstream pathway is crucial in KRAS-mutant cancer, we expected that co-inhibition of SUMOylation and MEK might be a good option. Surprisingly, combination treatment with TAK-981 and trametinib dramatically induced apoptosis in multiple cell lines and gene-engineered mouse-derived organoids. Moreover, combination therapy resulted in long-term tumor regression in mouse models using cell lines of different tissue types. Finally, we revealed that combination therapy complementally inhibited Rad51 and BRCA1 and accumulated DNA damage. Conclusions We found that MYC downregulation occurred via SUMOylation inhibition in KRAS-mutant cancer cells. Our findings indicate that dual inhibition of SUMOylation and MEK may be a promising treatment for MYC-expressing KRAS-mutant cancers by enhancing DNA damage accumulation.