Anti-VEGFR therapy is one of the healing inhibitors of antiresorptive-related osteonecrosis of the jaw.

INTRODUCTION: Antiresorptive-related osteonecrosis of the jaw (ARONJ) is a rare but serious adverse event associated with bone-modifying agents (BMAs) and affects patients in the terminal stages of cancer. Molecular targeting drugs (MTDs), anti-vascular endothelial growth factor receptor (VEGFR), and anti-epidermal growth factor receptor (EGFR) drugs are essential in various cancer treatments, although MTDs are risk factors for ARONJ. However, the mechanism through which MTDs affect treatment prognosis of ARONJ remains unclear. Therefore, we investigated the potential inhibitory factors for healing in the conservative therapy of ARONJ with a focus on MTDs. MATERIALS AND METHODS: Sixty patients who were administered BMAs for the treatment of malignancies and who underwent conservative treatment for ARONJ were assessed. The healing rate of ARONJ for each risk factor was retrospectively evaluated. RESULTS: Among the 60 patients, 27 were male and 33 were female. The median age was 67 years, and the median follow-up period was 292 (range 91-1758) days. The healing rate was lower in those treated with both zoledronic acid (Za) and denosumab (Dmab) than in those treated with Za or Dmab alone (0% vs. 28.8%, p = 0.03). Regarding the administration of MTDs, the treatment rate with anti-VEGFR drugs was 7.1% (p = 0.04), anti-EGFR drugs was 12.5% (p = 0.18), and without MTDs was 36.8%. CONCLUSION: In the conservative treatment of ARONJ, the administration of several BMAs and anti-VEGFR drugs was the factor contributing to the inhibition of healing.

A Novel Platform for Cancer Vaccines: Antigen-Selective Delivery to Splenic Marginal Zone B Cells via Repeated Injections of PEGylated Liposomes.

Treating cancer with vaccines has been a challenge. In this study, we introduce a novel Ag delivery platform for cancer vaccines that delivers an encapsulated Ag to splenic marginal zone B (MZ-B) cells via the aid of a PEGylated liposome (PL) system. Splenic MZ-B cells have recently attracted interest as alternative APCs. In mice, preimmunization with empty (no Ag encapsulation) PLs triggered the efficient delivery of a subsequent dose of Ag-containing PLs, injected 3 d later, to the spleen compared with a single dose of Ag-containing PLs. In addition, immunization with empty PLs allowed three subsequent sequential injections of OVA-PLs to efficiently induce a CTL response against OVA-expressing murine thymoma (EG7-OVA) cells and resulted in in vivo growth inhibition of subsequently inoculated EG7-OVA cells. However, these sequential treatments require repeated immunizations to achieve their antitumor effect. Therefore, to improve the antitumor effect of our novel vaccine system, an adjuvant, α-galactosylceramide (αGC), was incorporated into the OVA-PLs (αGC/OVA-PLs). As expected, the incorporation of αGC reduced the required number of immunizations with OVA-PLs to the point that a single immunization treatment with empty PLs and an injection of αGC/OVA-PL efficiently triggered a potent CTL induction, resulting in a rejection of the development and a suppression of the growth of tumors that had already developed s.c. Results of this study indicate that a novel Ag delivery platform that grants efficient Ag delivery to splenic MZ-B cells shows promise as a therapeutic modality for conquering tumor growth and/or progression.

Efficacy of initial conservative treatment options for temporomandibular disorders: A network meta-analysis of randomized clinical trials.

PURPOSE: This network meta-analysis (NMA) of randomized controlled trials (RCTs) aimed to identify effective initial conservative treatment strategies for patients with temporomandibular joint disorders (TMD). STUDY SELECTION: RCTs comparing treatment options for TMD published between January 2000 and July 2021 were retrieved from the databases of PubMed and Embase via a comprehensive electronic search. Patients diagnosed with myalgia (muscle pain) or arthralgia (joint pain) according to pain-related Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) and the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) were eligible for inclusion. Twelve treatment options and a placebo were included in the mutual comparisons. The risk of bias was assessed using Risk of Bias 2.0. Forest plots of direct comparisons between individual studies were created using MetaInsight. NMA was performed using R statistical software (netmeta). RESULTS: Twenty-four RCTs involving 1336 patients assessing pain and 12 RCTs involving 614 patients assessing maximal mouth opening were identified. Low-level laser therapy (standard mean difference [SMD]: -2.12, 95% confidence interval [CI]: -3.18, -1.06), self-exercise (SMD: -1.51, 95% CI: -2.82, -0.2), and stabilization splints (SMD: -1.16, 95% CI: -2.02, -0.29) were effective in improving pain; however, the certainty of evidence was very low. Self-exercise (SMD: 0.71, 95% CI: -0.58, 2.01), stabilization splints (SMD: 0.65, 95% CI: -0.09, 1.39), and low-level laser therapy (SMD: 0.63, 95% CI: -0.34, 1.6) were effective in improving maximal mouth opening; however, the certainty of evidence was very low. CONCLUSIONS: Stabilization splints, self-exercise, and low-level laser therapy may be effective in the initial treatment of TMD.

An unmasked mutation of EIF2B2 due to submicroscopic deletion of 14q24.3 in a patient with vanishing white matter disease.

Leukodystrophy with vanishing white matter (VWM) is a neurodegenerative disorder with autosomal recessive traits that is caused by alteration of the eukaryotic translation initiation factor-2B (EIF2B). An 11-month-old patient with distinctive features began to exhibit progressive developmental deterioration associated with intractable epilepsy, which was triggered by recurrent acute infectious diseases. Brain magnetic resonance imaging (MRI) revealed abnormal white matter intensity. Chromosomal microarray testing identified a submicroscopic deletion at 14q24.3 that included EIF2B2, the gene encoding one of the subunits of EIF2B. Because the patient's clinical findings were distinctive for VWM, compound heterozygous mutations of EIF2B2 were suspected, and subsequent sequencing analysis of the remaining allele unmasked the existence of a novel missense mutation of EIF2B2 (V85W). Some distinctive features including small palpebral fissures, bushy eyebrows, ear abnormalities, small upturned nose, downturned corners of the mouth, and micrognathia may be the common features of the patients with 14q24.3 deletions.

Therapy outcome measures in temporomandibular disorder: a scoping review.

OBJECTIVES: Therapy outcome measures (TOMs) in temporomandibular disorders (TMDs) have not been systematically evaluated. We systematically explored the main TOM assessment methods for TMD TOMs used in previous studies. DESIGN: Scoping review. DATA SOURCES: According to Preferred Reporting Items for Systematic reviews and Meta-Analysis extension for Scoping Review reporting guidelines, we systematically searched five key databases (MEDLINE/PubMed, Web of Science, Embase, Epistemonikos and ClinicalTrials) and thoroughly scanned relevant grey literature using Medical Subject Headings, Emtree and index terms. ELIGIBILITY CRITERIA: We considered primary research papers published from January 2010 to December 2020 that included patients with TMD aged ≥18 years, diagnosed according to the Diagnostic Criteria for Temporomandibular Disorders. DATA EXTRACTION AND SYNTHESIS: Four reviewers extracted general information and information on study design and setting, target, interventions, and outcome type. RESULTS: One hundred and seventy-two of the 3726 screened articles (3704 by search engines and 22 manually) were included. The TOMs analysed included pain (n=161 articles), maximal mouth opening (MMO) (91), jaw function (32), jaw movement (26), joint sound (16), quality of life (QOL) (15), depression/anxiety (14), oral QOL (10) or others (30). Evaluation periods were <4 weeks (111), <8 weeks (62), <12 weeks (59), >12 weeks (75) or 'not mentioned' (12). Pain outcomes (229) included general pain (115), tenderness (45), pain during functioning (44), resting pain (16) and others (8). Pain outcome evaluation methods included Visual Analogue Scale (VAS; 121), Numerical Rating Scale (21) and other methods (21). Pain outcome indicators were binary (10) or continuous (158); only five studies reported the least significant difference in treatment efficacy. MMO evaluation using painless methods (19) and jaw function evaluation using methods assessing mandibular movement range (23) were the most frequent. CONCLUSIONS: TMD TOMs are diverse; the major outcomes were pain, MMO, jaw function and jaw movement. Most pain outcomes are evaluated by VAS Score changes.

Simultaneous concentration enrichment and electrophoretic separation of weak acids on a microchip, using in situ photopolymerized carboxylate-type polyacrylamide gels as the permselective preconcentrator.

A method for the simultaneous concentration and separation of weak acids using an acidic polyacrylamide gel, fabricated in the microfluidic channel of a commercial poly(methyl methacrylate)-made microchip, is reported. This approach is based on simple photochemical copolymerization for the fabrication of a permselective preconcentrator. The intersection of the poly(methyl methacrylate)-made microchip was filled with a gel solution comprising acrylamide, N,N'-methylene-bis-acrylamide, and 2-acrylamidoglycolic acid, with riboflavin as a photocatalytic initiator. In situ polymerization, near the cross of the sample outlet channel, was performed by irradiation with an argon ion laser beam that is also used as the light source for fluorimetric detection. The electrokinetic properties, combined with electrostatic repulsion between sample components and the anionic groups on the polyacrylamide gel, enable the entrapment and concentration of weak acids at the interface of the cathodic side of the gel plug. This method displays concentration factors of up to 10(5) within 3 min. The effectiveness of the ionic preconcentrator was demonstrated by the sensitive analysis of fluorescein isothiocyanate-labeled amino acids.

Lymphoid follicle antigen (Ag) delivery and enhanced rodent humoral immune responses mediated by Ag-containing PEGylated liposomes.

Antigen (Ag) delivery to lymphoid follicles is important in achieving adaptive immunity. We recently developed a novel two-step Ag delivery system that efficiently induces cellular immune responses to Ags in mice by using priming intravenous (i.v.) injections of empty PEGylated liposomes (PEG-Lip) followed 3 days later by Ag-entrapped PEG-Lip (Ag-PEG-lip). In this study, we looked for humoral immune responses in rats and mice with IgG production specific to the encapsulated Ags. We observed that initial i.v. injections of empty PEG-Lip triggered accumulation of subsequent doses ovalbumin-PEG-Lip (OVA-PEG-lip) in splenic follicles and enhanced IgG production against OVA in both rats and mice. Anti-OVA IgG production was diminished by inhibition of splenic follicular accumulation of OVA-PEG-Lip by fingolimod (FTY720), which inhibits lymphocyte egress from lymphoid tissues. Thisindicates that the follicular accumulation of Ags that we observed is an indispensable and unique step in the production of anti-OVA IgG. Interestingly, in BALB/c nude mice, which are T cell deficient, a high follicular accumulation of OVA-PEG-Lip was observed, but anti-OVA IgG production was not observed. This suggests that T cells are also indispensable for the induction of cellular immune responses by our two-step immunization procedure. Our unique Ag delivery platform, which efficiently delivers Ags to splenic follicles, may be a useful technique for the enhancement of cellular immunity, as well as humoral immunity. Further experimental evaluation should be undertaken in relevant animal models in order for efficacy, safety and immunological correlates to be determined.

Effects of cognitive behavioral therapy on orofacial pain conditions.

Numerous studies have confirmed the effectiveness of cognitive behavioral therapy (CBT) for chronic pain, and it is generally regarded as an appropriate intervention. However, it may not be effective for some pain sites, and the duration of the effect may be limited. In addition, some studies of CBT lacked a comparison group. This review summarizes evidence for the effectiveness of CBT for orofacial pain and assists in the development of guidelines for orofacial pain management. A literature search in PubMed was performed for studies published from April 1990 through March 2020. The search keywords were "burning mouth syndrome," "temporomandibular disorders," "myofascial pain syndrome,""chronic orofacial pain conditions," "cognitive behavioral therapy," and "non-pharmacological therapy." The results indicate that CBT alone or in combination with other treatments, such as intraoral appliance, stress management, or biofeedback, is effective for the vast majority of orofacial pain cases. Therefore, dentists should consider using CBT to manage orofacial pain in their patients.

Effects of surface roughness and dimorphism on the adhesion of Candida albicans to the surface of resins: scanning electron microscope analyses of mode and number of adhesions.

AIM: Candida albicans is a common oral fungus but can cause serious conditions such as Candida stomatitis. We investigated C. albicans adhesion to the surface of denture-base resins at two growth phases. METHODS: Fungal suspensions of logarithmic (9 h) and stationary phase (24 h) C. albicans (JCM2085) were used. Scanning electron microscopy (SEM) confirmed that yeast and mycelial forms were predominant in 9-h and 24-h cultures, respectively. Resin strips were polished to three surface roughness levels (Ra 3.2 µm, Ra 0.48 µm and Ra 0.06 µm) and were then immersed in C. albicans suspensions for both phases. The SEM images were taken at five sites on each strip. RESULTS: Adhesion of mycelial-form C. albicans on rough surfaces (Ra = 3.2) was 2.2 times higher than on smooth surfaces (Ra = 0.06; 7030 vs 3580 adhesions/mm(2), P < 0.01). The hyphae of these mycelial forms fully penetrated the surface cracks. Fewer adhesions occurred for yeast-form C. albicans, regardless of surface type (440-620 adhesions/mm(2), P = n.s.). CONCLUSION: Adhesion of yeast-form C. albicans was indifferent to surface roughness. In contrast, mycelial adhesion increased with surface roughness of the resin because mycelia infiltrated the minute protuberances on rough surfaces.

Genetic polymorphisms in human CYP2A6 gene causing impaired nicotine metabolism.

AIMS: Previously, we determined the phenotyping of in vivo nicotine metabolism and the genotyping of the CYP2A6 gene (CYP2A6*1 A, CYP2A6*1B, CYP2A6*2, CYP2A6*3, CYP2A6*4 and CYP2A6*5 ) in 92 Japanese and 209 Koreans. In the study, we found one Korean and four Japanese subjects genotyped as CYP2A6*1B/CYP2A6*4 who revealed impaired nicotine metabolism, although other many heterozygotes of CYP2A6*4 demonstrated normal nicotine metabolism (CYP2A6*4 is a whole deletion type). After our previous report, several CYP2A6 alleles, CYP2A6*6 (R128Q), CYP2A6*7 (I471T), and CYP2A6*8 (R485L), have been reported. The purpose of the present study was to clarify whether the impaired nicotine metabolism can be ascribed to these CYP2A6 alleles. Furthermore, we also determined whether the subjects possessing CYP2A6*1x2 (duplication) reveal higher nicotine metabolism. METHODS: Genotyping of CYP2A6 alleles, CYP2A6*6, CYP2A6*7, CYP2A6*8, and CYP2A6*1x2 was determined by PCR. RESULTS: The five poor metabolizers were re-genotyped as CYP2A6*7/CYP2A6*4, suggesting that a single nucleotide polymorphism (SNP) causing I471T decreases nicotine metabolism in vivo. Furthermore, we found that two subjects out of five with a lower potency of nicotine metabolism possessed SNPs of CYP2A6*7 and CYP2A6*8 simultaneously. The novel allele was termed CYP2A6*10. In the 92 Japanese and 209 Koreans, the CYP2A6*6 allele was not found. The allele frequencies of CYP2A6*7, CYP2A6*8, and CYP2A6*10 were 6.5%, 2.2%, and 1.1%, respectively, in Japanese, and 3.6%, 1.4%, and 0.5%, respectively, in Koreans. The CYP2A6*1x2 allele was found in only one Korean subject (0.5%) whose nicotine metabolic potency was not very high. CONCLUSIONS: It was clarified that the impaired in vivo nicotine metabolism was caused by CYP2A6*7 and CYP2A6*10 alleles.