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Aims To investigate the antibacterial effects of tea theaflavins and catechins against Bacillus coagulans and the underlying mechanism of antibacterial action. Methods and Results Bactericidal activities of theaflavin and its analogues were evaluated and compared with that of epigallocatechin gallate. Theaflavin derivatives exhibited high bactericidal activity at 50 μmol L−1, whereas epigallocatechin gallate did not, even at 500 μmol L−1. Furthermore, we investigated the adsorption of theaflavins to model phospholipid membranes and corresponding effects on membrane fluidity to reveal their effects on the B. coagulans cell surface. Cell membrane fluidity was decreased after treatment with theaflavin derivatives with one or more galloyl moieties. Quartz-crystal microbalance analysis showed a strong affinity of the membrane phosphatidyl glycerol (PG) bilayers for theaflavin derivatives, correlating their bactericidal activity. Conclusion These findings suggest that theaflavins could effectively inhibit B. coagulans by decreasing cell membrane fluidity. Significance and Impact Bacillus coagulans is a spore-forming heat-resistant bacterium responsible for spoilage in low-acidic beverages. Natural antimicrobial components in tea-based beverages are central to reducing microbial contamination and product quality deterioration, although mechanisms underlying their antimicrobial action remain obscure. This study highlights the inhibitory action of theaflavins on B. coagulans and their potential application in food and beverage industries.

Tricyclic β-lactam antibiotics show significant antibacterial activities against carbapenem-resistant Enterobacterales (CREs), but the synthesis of a key intermediate for tricyclic β-lactam antibiotics requires eight steps from penicillin with a low total yield of 3% via non-stereoselective lactone formation. Here we report the stereoselective synthesis of the tricyclic β-lactam core by sulfoxide-directed oxidative lactonization from an accessible and inexpensive commercially available cephalosporin intermediate in 23% total yield in six steps.

This study aimed to determine the factors associated with the co-infection of Candida albicans and Candida glabrata. This retrospective study conducted between January 2015 and 2020 comprised 131 patients who were diagnosed with oral candidiasis. The factors associated with this condition were analyzed by univariate and multivariate logistic regression. Age and denture use were identified as significant risk factors in the univariate analysis. The multivariate logistic regression analysis revealed that denture use (odds ratio [OR], 8.44 95% confidence interval [CI], 1.99-28.3) and immunosuppressive therapy (OR, 9.20; 95% CI, 1.19 -62.0) had significant effects on co-infection with the two Candida species. These findings suggest that immunosuppressive therapy using and dentures is significantly associated with oral candidiasis caused by co-infection of C. albicans and C. glabrata. (C) 2021 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.

Background: Older adults compose the significant proportion of patients undergoing minor oral surgery to restore oral function worldwide; however, these procedures possess certain risks of late complications, particularly delayed healing. Therefore, this study mainly aims to assess the frequency of this type of adverse effects and identify the predictors of delayed healing among patients aged over 65 years. Methods: A total of 106 participants aged over 65 years who underwent minor oral surgical interventions at the Department of Oral Medicine, Hokkaido University Hospital from 2015 to 2022 were selected from the database and were divided into two healing groups: the non-delayed (n = 87) and delayed (n = 19). The delayed healing was defined as lack of healing for more than 10 days. The clinical parameters for comparison included those of clinical examination and laboratory tests assessed before surgery. Fisher’s exact test, the Wilcoxon rank-sum test, and logistic regression analysis were used to evaluate the results. Results: Delayed healing was the most frequent postsurgical complication (17.9%) among all the patients. Serum albumin level (odds ratio, 10.0; 95% confidence interval, 2.15–46.6) significantly differed between the groups of patients with and without delayed healing. The multivariate logistic regression analysis demonstrated that serum albumin level of Conclusions: This study revealed that the level of serum albumin can predict delayed healing among patients aged over 65 years who undergo minor oral surgery. Trial registration: Retrospectively registered.

Background The long waiting time for bone uptake after radiopharmaceutical injection in bone scintigraphy is a burden for patients with poor health. Thus, we aimed to investigate the equivalence between maximum standardized uptake values (SUVmax) for imaging with 2- and 3-h uptake times.Methods Thirty patients with jaw osteomyelitis or medication-related osteonecrosis of the jaw who underwent single-photon emission computed tomography (SPECT) twice in the same day were enrolled. The SUVmax for the normal parietal bones and jawbone lesion was calculated using a quantitative analysis software, and values for 2- and 3-h uptake times were compared. Bland–Altman plots were used to determine the limits of agreement (LOAs) for the difference in SUVmax between 2- and 3-h uptake times for the parietal bones and jawbone lesion.Results The LOA ranged from − 0.33 to 0.25 in the parietal bones and %LOA ranged from − 9.8–17.3% in the jawbone lesion, proving high equivalence. The SUVmax showed no clinical differences between 2- and 3-h uptake times for technetium-99m hydroxymethylene diphosphonate SPECT of the jawbone.Conclusions This is the first study to demonstrate that the uptake time in jawbone SPECT can be reduced to only 2 h, justifying a 2–3-h uptake time margin.

Purpose:We report the dose-escalation part of a phase I study of liposomal eribulin (E7389-LF) in Japanese patients with advanced solid tumors and no alternative standard therapy.Patients and Methods:Patients ≥20 years old were enrolled. E7389-LF doses of 1.0 to 1.5 mg/m2 once every two weeks (Q2W) or 1.0 to 2.5 mg/m2 once every three weeks (Q3W) were planned. The primary objective was to determine the MTD by evaluating dose-limiting toxicities (DLT). Secondary objectives included safety/tolerability assessments, objective response rate (ORR), and progression-free survival; serum biomarker assessment was an exploratory objective.Results:Twenty-one patients were enrolled and treated; 12 in the Q3W group (1.0 mg/m2, n = 3; 1.5 mg/m2, n = 3; 2.0 mg/m2, n = 6) and 9 in the Q2W group (1.0 mg/m2, n=3; 1.5 mg/m2, n = 6). The Q3W and Q2W MTDs were 2.0 mg/m2 and 1.5 mg/m2, respectively. One patient receiving 2.0 mg/m2 Q3W had a DLT of grade 3 febrile neutropenia. The most common grade 3 treatment-emergent adverse events were neutropenia (66.7% in Q3W and Q2W) and leukopenia (Q3W, 58.3%; Q2W, 33.3%). One patient in the Q3W group (2.0 mg/m2) and 3 in the Q2W group (1.0 mg/m2, n = 1; 1.5 mg/m2, n = 2) achieved a partial response [overall ORR, 19.0%; 95% confidence interval (CI), 5.4–41.9]. Endothelial [TEK receptor tyrosine kinase (TEK), intercellular adhesion molecule 1 (ICAM1), vascular endothelial growth factor receptor 3 (VEGFR3), platelet/endothelial cell adhesion molecule 1 (PECAM1)], vasculature (collagen IV), and immune-related [interferon gamma (IFNγ), C-X-C motif chemokine ligand 11 (CXCL11), C-X-C motif chemokine ligand 10 (CXCL10)] biomarker levels were increased.Conclusions:E7389-LF was well tolerated at 2.0 mg/m2 Q3W and 1.5 mg/m2 Q2W. Considering the toxicity profile of both regimens, the recommended dose was 2.0 mg/m2 Q3W. Expansion cohorts are ongoing.

Supplementary Data S1 from First-in-Human Phase 1 Study of MORAb-202, an Antibody–Drug Conjugate Comprising Farletuzumab Linked to Eribulin Mesylate, in Patients with Folate Receptor-α–Positive Advanced Solid Tumors

Supplementary Figure from Dose Escalation Data from the Phase 1 Study of the Liposomal Formulation of Eribulin (E7389-LF) in Japanese Patients with Advanced Solid Tumors

Purpose:MORAb-202, an antibody–drug conjugate containing farletuzumab and eribulin with a cathepsin-B cleavable linker, targets folate receptor α (FRα)–expressing tumor cells. The primary objective of this first-in-human study was to evaluate the safety and tolerability of MORAb-202 in patients with solid tumors.Patients and Methods:Patients ≥20 years with adequate organ function and FRα-positive solid tumors who failed to respond to standard therapy were eligible. Patients received MORAb-202 intravenously at doses of 0.3 to 1.2 mg/kg once every three weeks. Endpoints included dose-limiting toxicities, safety, tumor responses, pharmacokinetics, and pharmacodynamics. Trial registration number: NCT03386942 (ClinicalTrials.gov).Results:Between November 28, 2017 and June 4, 2019, 22 patients (median age, 58.0 years) with advanced solid tumors were enrolled. Treatment-emergent adverse events occurred in 21 (95%) patients, with leukopenia and neutropenia in 10 (45%) patients each. One patient (0.9 mg/kg cohort) experienced two grade 3 dose-limiting toxicities: serum alanine aminotransferase and γ-glutamyl transferase increases. Following review by an independent adjudication committee, grade 1/2 interstitial lung disease thought to be related to MORAb-202 was identified in five (23%) patients. Complete response, partial response, and stable disease were observed in one, nine, and eight patients, respectively. The normalized predose serum FRα tended to be positively correlated with the maximum tumor shrinkage (R2 = 0.2379; P = 0.0291).Conclusions:The MTD of MORAb-202 was not reached. MORAb-202 demonstrated promising antitumor activity in FRα-positive solid tumors and was generally well-tolerated at the tested doses. Further investigations are required to establish appropriate dosage and clinical utility of MORAb-202.

Purpose: In first-in-human (FIH) trials, sequential tumor biopsies, i.e., two consecutive tumor biopsies, the first perfomed at baseline (pretreatment) and the second during the early treatment period (on-treatment), provide proof of concept in investigational new drugs. Methods: We evaluated the success of sequential tumor biopsies in FIH trials, and explored approaches for improved success rates. We retrospectively reviewed the sequential tumor biopsies required in 17 of 52 FIH trials conducted from 2015 to 2020. Results: One hundred and thirty-eight patients were identified. Success of either pretreatment or on-treatment biopsy alone, and of sequential tumor biopsies, was defined as the acquisition of viable tumor cells and as obtaining tumor cells from both biopsy specimens, respectively. The success rates of pretreatment and on-treatment biopsy were 98.6% and 94.2%, respectively, and of sequential tumor biopsies was 70.3%. Adverse events associated with the pretreatment biopsies (33.3% positive; 72.0% negative) and timing of the first imaging assessment (before on-treatment biopsy = 40.0%; after on-treatment biopsy = 82.7%) correlated with successful sequential tumor biopsies. The reasons for unsuccessful sequential tumor biopsies could be categorized into two groups: 1) patient refusal of the on-treatment biopsy (most frequently due to early disease progression); and 2) absence of tumor cells in the pretreatment or on-treatment biopsy specimen. Conclusion: We propose an approach to achieving greater success in sequential tumor biopsies in FIH trials; the first imaging assessment during the study should be scheduled after on-treatment biopsy.(Registration number UMIN000042487, Date of registration November 18, 2020)

Two cases of focal atrial tachycardia probably originating from the pulmonary vein with onset later than 3 years of age are presented. Both cases had associated variable atrioventricular conduction and showed no signs of heart failure, and they converted to sinus rhythm at the time of puberty. In cases of focal atrial tachycardia originating from the pulmonary vein with onset later than 3 years of age, drug therapy may be effective. Even if drug therapy is not effective, changes in the autonomic nervous system are reflected strongly in the pulmonary veins, so that changes in autonomic nervous system regulation with growth might terminate focal atrial tachycardia. Therefore, focal atrial tachycardia originating from the pulmonary vein with onset later than 3 years of age might have a better prognosis.

Tracing the movements of foreign bodies is challenging after they aberrantly migrate into the soft tissues. Oral soft tissues are extremely mobile and move in a coordinated and highly complex manner during mastication, deglutition, and phonation. This report presents three cases of aberrantly migrated foreign bodies within the soft tissues of the oral cavity. In the first case, a fractured broach used for root canal treatment entered the oral cavity and moved within the soft tissues, making it difficult to identify its position. In the second case, the tip of a chopstick was embedded within the tissues in the palate, and in the third case, a broken needle was embedded in the left maxilla. It was possible to locate and remove the objects in Cases 1 and 2 (broach and chopstick, respectively); however, attempts to remove the object in Case 3 were unsuccessful due to its location behind the maxillary tuberosity. Foreign bodies that enter into the soft tissues migrate in response to the complex and frequent movements of the oral cavity and, ultimately, get embedded at locations away from their original point of entry. Therefore, dentists need to exercise caution while using instruments such as endodontic file and dental needle, and be completely aware of the difficulties involved in removing migrated and embedded foreign bodies.