ITC-6102RO, a novel B7-H3 antibody-drug conjugate, exhibits potent therapeutic effects against B7-H3 expressing solid tumors.

BACKGROUND: The B7-H3 protein, encoded by the CD276 gene, is a member of the B7 family of proteins and a transmembrane glycoprotein. It is highly expressed in various solid tumors, such as lung and breast cancer, and has been associated with limited expression in normal tissues and poor clinical outcomes across different malignancies. Additionally, B7-H3 plays a crucial role in anticancer immune responses. Antibody-drug conjugates (ADCs) are a promising therapeutic modality, utilizing antibodies targeting tumor antigens to selectively and effectively deliver potent cytotoxic agents to tumors. METHODS: In this study, we demonstrate the potential of a novel B7-H3-targeting ADC, ITC-6102RO, for B7-H3-targeted therapy. ITC-6102RO was developed and conjugated with dHBD, a soluble derivative of pyrrolobenzodiazepine (PBD), using Ortho Hydroxy-Protected Aryl Sulfate (OHPAS) linkers with high biostability. We assessed the cytotoxicity and internalization of ITC-6102RO in B7-H3 overexpressing cell lines in vitro and evaluated its anticancer efficacy and mode of action in B7-H3 overexpressing cell-derived and patient-derived xenograft models in vivo. RESULTS: ITC-6102RO inhibited cell viability in B7-H3-positive lung and breast cancer cell lines, inducing cell cycle arrest in the S phase, DNA damage, and apoptosis in vitro. The binding activity and selectivity of ITC-6102RO with B7-H3 were comparable to those of the unconjugated anti-B7-H3 antibody. Furthermore, ITC-6102RO proved effective in B7-H3-positive JIMT-1 subcutaneously xenografted mice and exhibited a potent antitumor effect on B7-H3-positive lung cancer patient-derived xenograft (PDX) models. The mode of action, including S phase arrest and DNA damage induced by dHBD, was confirmed in JIMT-1 tumor tissues. CONCLUSIONS: Our preclinical data indicate that ITC-6102RO is a promising therapeutic agent for B7-H3-targeted therapy. Moreover, we anticipate that OHPAS linkers will serve as a valuable platform for developing novel ADCs targeting a wide range of targets.

Clinical Outcomes of Transarterial Embolization for Chronic Achilles Tendinopathy Refractory to Conservative Treatment: A Pilot Study.

PURPOSE: To evaluate the effectiveness and safety of transarterial embolization (TAE) for chronic Achilles tendinopathy (AT) refractory to conservative treatment. MATERIALS AND METHODS: This retrospective study included 20 patients (12 men and 8 women; mean age, 30.3 years) who received TAE using imipenem/cilastatin sodium for refractory chronic AT from May 2019 to April 2021. Nine patients had bilateral involvement. A total of 29 procedures were performed (8 for nonathletes and 21 for athletes). If feasible, embolization was performed superselectively of the arterial branch demonstrating hypervascularity, early venous drainage, and/or supplying the pain site noted using a radiopaque marker. The visual analog scale (VAS, 0-10) score was used to assess pain symptoms at baseline and during the follow-up period (1 day; 1 week; 1, 3, and 6 months; and open period). Clinical success was defined as a decrease of >50% in the VAS score at 6 months when compared with baseline. RESULTS: In 25 (86.2%) of 29 procedures, clinical success was achieved. Significant decreases in the VAS scores were noted at 1 day, 1 week, 1 month, 3 months, and 6 months (6.86 at the baseline vs 3.48, 3.41, 3.10, 2.55, and 1.62, respectively; all P < .01). For patients available for the 12- and 24-month follow-ups (n = 19 and 6, respectively), the mean VAS scores significantly decreased (6.84 vs 2.00 and 7.33 vs 1.17, respectively; all P < .01). No serious adverse events were observed during follow-up. CONCLUSIONS: TAE may alleviate pain for patients with chronic AT refractory to the conservative treatment with a low risk of adverse events.

Measurement of the tibial plateau angle of normal small-breed dogs and the application of the tibial plateau angle in cranial cruciate ligament rupture.

OBJECTIVE: In Korea, small dogs are more common than large breeds. This study was performed to measure the influence of body weight, sex, breed, age, and cranial cruciate ligament rupture (RCCL) on the tibial plateau angle (TPA) in small-breed dogs. MATERIALS AND METHODS: A total of 274 dogs (221 normal dogs and 53 RCCL dogs) were selected for this study based on medical records. The TPA was measured from stifle joint radiographs. The dogs were divided according to body weight, sex (male and female; normal and neutered), age, breed, and RCCL, and the TPAs of the dogs were compared. RESULTS: In general, the TPAs of male dogs were significantly (p < 0.05) higher than those of female dogs, and those of healthy neutered dogs were higher than those of healthy intact dogs. The TPA had a tendency to increase along with the animal's age but was not significantly different among the four age groups. In general, the TPA of RCCL dogs was 27.12° ± 0.62°, which was significantly higher (p < 0.001) than that of normal dogs (20.21° ± 0.32°), indicating that an increased TPA is associated with a higher risk for RCCL. Similar results were also observed among dogs with similar body weights, breeds, and ages for male and female RCCL dogs. CONCLUSION: This study suggested that the sex and neutering status of dogs could affect the TPA. This study also confirmed the use of TPA in the veterinary clinic as a possible indicator of RCCL, as the TPA is higher in RCCL dogs than in normal dogs.

Phenology and Seed Yield Performance of Determinate Soybean Cultivars Grown at Elevated Temperatures in a Temperate Region.

Increased temperature means and fluctuations associated with climate change are predicted to exert profound effects on the seed yield of soybean. We conducted an experiment to evaluate the impacts of global warming on the phenology and yield of two determinate soybean cultivars in a temperate region (37.27°N, 126.99°E; Suwon, South Korea). These two soybean cultivars, Sinpaldalkong [maturity group (MG) IV] and Daewonkong (MG VI), were cultured on various sowing dates within a four-year period, under no water-stress conditions. Soybeans were kept in greenhouses controlled at the current ambient temperature (AT), AT+1.5°C, AT+3.0°C, and AT+5.0°C throughout the growth periods. Growth periods (VE-R7) were significantly prolonged by the elevated temperatures, especially the R1-R5 period. Cultivars exhibited no significant differences in seed yield at the AT+1.5°C and AT+3.0°C treatments, compared to AT, while a significant yield reduction was observed at the AT+5.0°C treatment. Yield reductions resulted from limited seed number, which was due to an overall low numbers of pods and seeds per pod. Heat stress conditions induced a decrease in pod number to a greater degree than in seed number per pod. Individual seed weight exhibited no significant variation among temperature elevation treatments; thus, seed weight likely had negligible impacts on overall seed yield. A boundary line analysis (using quantile regression) estimated optimum temperatures for seed number at 26.4 to 26.8°C (VE-R5) for both cultivars; the optimum temperatures (R5-R7) for single seed weight were estimated at 25.2°C for the Sinpaldalkong smaller-seeded cultivar, and at 22.3°C for the Daewonkong larger-seeded cultivar. The optimum growing season (VE-R7) temperatures for seed yield, which were estimated by combining the two boundary lines for seed number and seed weight, were 26.4 and 25.0°C for the Sinpaldalkong and Daewonkong cultivars, respectively. Considering the current soybean growing season temperature, which ranges from 21.7 (in the north) to 24.6°C (in the south) in South Korea, and the temperature response of potential soybean yields, further warming of less than approximately 1°C would not become a critical limiting factor for soybean production in South Korea.

Dectin-1 agonist selectively induces IgG1 class switching by LPS-activated mouse B cells.

Heat-killed Saccharomyces cerevisiae (HKSC) is an agonist for Dectin-1, a major fungal cell wall ß-glucan receptor. We previously reported that HKSC selectively enhances IgG1 production by LPS-activated mouse B cells. To determine if this IgG1 selectivity is caused by selective IgG1 class switching, we performed RT-PCRs for measuring germline transcripts (GLTs), flow cytometric analyses for detecting Ig-expressing cells, and ELISPOT assays for measuring the number of Ig-secreting cells in HKSC/LPS-stimulated mouse B cell cultures. HKSC selectively enhanced expression of GLTγ1, the number of IgG1-expressing cells, and the number of IgG1-secreting B cells in the presence of LPS stimulation. In addition, HKSC induced the expression of CD69, an activation marker for B lymphocytes, and the expression of surface Dectin-1. Two Dectin-1 antagonists, laminarin and a neutralizing Dectin-1 antibody, selectively diminished HKSC-reinforced IgG1 production by LPS-stimulated B cells. Furthermore, depleted zymosan (dzn), a Dectin-1 agonist with increased selectivity, also selectively enhanced GLTγ1 transcription. The Dectin-1 antagonists blocked dzn-induced IgG1 production by LPS-activated B cells. Collectively, these results suggest that Dectin-1 agonists selectively induce IgG1 class switching by direct stimulation of Dectin-1 on LPS-activated B cells resulting in selective production of IgG1.

Dectin-1 Stimulation Selectively Reinforces LPS-driven IgG1 Production by Mouse B Cells.

Dectin-1, which specifically recognizes ß-glucan of fungal cell walls, is a non-Toll-like receptor (TLR) pattern recognition receptor and a representative of C-type lectin receptors (CLRs). The importance of Dectin-1 in innate immune cells, such as dendritic cells and macrophages, has previously been well studied. However, the function of Dectin-1 in B cells is very poorly understood. To determine the role of Dectin-1 in B cell activation, we first investigated whether mouse B cells express Dectin-1 and then assessed the effect of Dectin-1 stimulation on B cell proliferation and antibody production. Mouse B cells express mRNAs encoding CLRs, including Dectin-1, and surface Dectin-1 was expressed in B cells of C57BL/6 rather than BALB/c strain. Dectin-1 agonists, heat-killed Candida albicans (HKCA) and heat-killed Saccharomyces cerevisiae (HKSC), alone induced B cell proliferation but not antibody production. Interestingly, HKSC, HKCA, and depleted zymosan (a selective Dectin-1 agonist) selectively enhanced LPS-driven IgG1 production. Taken together, these results suggest that, during fungal infection, ß-glucan-stimulated Dectin-1 may cooperate with TLR4 to specifically enhance IgG1 production by mouse B cells.

Determinants of treatment outcome after use of the mandibular advancement device in patients with obstructive sleep apnea.

OBJECTIVE: To determine the predictors affecting treatment outcome after application of the mandibular advancement device (MAD). DESIGN: Retrospective analysis. SETTING: Tertiary care university hospital. PATIENTS: A total of 76 patients (68 men and 8 women) who were treated with the MAD for obstructive sleep apnea (OSA) were included from September 2005 through August 2008. All the subjects underwent cephalometry, nocturnal polysomnography, and sleep videofluoroscopy (SVF) before and at least 3 months after receipt of a custom-made MAD. Sleep videofluoroscopy was performed before and after sleep induction and was analyzed during 3 states of awakeness, normoxygenation sleep, and desaturation sleep. Subjects were divided into success and nonsuccess groups depending on treatment outcome. MAIN OUTCOME MEASURES: Multiple variables from cephalometry and SVF including the length of the soft palate, retropalatal space, retrolingual space, and mouth opening angle were evaluated during sleep events with or without the MAD between success and nonsuccess group. RESULTS: The soft palate was significantly longer in the nonsuccess group than in the success group. The retropalatal and retrolingual airway spaces and mouth opening angle were not different between 2 groups. Application of the MAD increased the retrolingual space and decreased the length of the soft palate and the mouth opening angle significantly in both success and nonsuccess groups. However, retropalatal space was widened only in the success group, which showed that retropalatal space may be important in determining treatment response of the MAD. CONCLUSION: The length of the soft palate showed a difference between success and nonsuccess groups, and widening of retropalatal space might be an important factor for successful outcome with MAD application.

Transplantation of neural stem cells in anosmic mice.

OBJECTIVES: Treating olfactory dysfunction is a challenge for physicians. One of the therapeutic options could be transplantation of stem cells. In this study, neural stem cells were transplanted into anosmic mice. METHODS: Neural stem cells were generated from the olfactory bulb of green fluorescent protein (GFP)-transgenic C57BL6 mice. Anosmia were induced by injection of intraperitoneal 3-methylindole. The neural stem cells were transplanted transnasally on the next day. The olfactory function was evaluated by a food-finding test once a week. The olfactory neuroepithelium was harvested for histologic examination and protein analysis at 4 weeks. RESULTS: Twenty-five percent (6/24) of the control mice that were not transplanted with neural stem cells survived at 4 weeks while 67% (8/12) of the transplanted mice survived (P=0.029). The food finding test showed that the transplanted mice resumed finding food at 3 weeks while the control mice resumed finding food at 4 weeks. GFP-positive cells were observed in the olfactory neuroepithelium of the transplanted mice. Western blotting revealed that the olfactory marker protein expression was significantly lower in the control mice than that in the transplanted mice. CONCLUSION: This study demonstrated that improvement of mouse survival was achieved and recovery of olfactory function was promoted by transnasal transplantation of neural stem cells in the anosmic mouse model. These results indicate that stem cells might be one of the future modalities for treating olfactory impairment.

Mouth opening during sleep may be a critical predictor of surgical outcome after uvulopalatopharyngoplasty for obstructive sleep apnea.

STUDY OBJECTIVES: To evaluate the value of mouth opening during sleep for predicting surgical outcomes after uvulopalatopharyngoplasty (UPPP). METHODS: Retrospectively, 69 out of 120 consecutive patients with obstructive sleep apnea who underwent uvulopalatopharyngoplasty at an academic tertiary referral center were included in this study. Sixty-nine subjects underwent cephalometry, nocturnal polysomnography and sleep videofluoroscopy before and after UPPP. Multiple parameters from the above studies were evaluated as potential predictors of UPPP outcomes. RESULTS: Multivariate analysis showed that an increased angle of mouth opening during sleep was the only significant predictor for surgical failure (p < 0.001). The angle of mouth opening could predict surgical outcome with predictive values of 72.4% and 82.5% for success and failure, respectively. CONCLUSIONS: Sleep videofluoroscopy during sleep revealed that the simple measurement of mouth-opening angle could outstandingly predict surgical outcome.

Treatment of postviral olfactory loss with glucocorticoids, Ginkgo biloba, and mometasone nasal spray.

OBJECTIVE: To analyze the efficacy of treating postviral olfactory loss with glucocorticoids, Ginkgo biloba, and mometasone furoate nasal spray. DESIGN: Randomized trial. SETTING: Academic research. PATIENTS: Seventy-one patients who were diagnosed as having postviral olfactory loss. MAIN OUTCOME MEASURES: All patients underwent olfactory function tests, including the butanol threshold test (BTT) and the cross-cultural smell identification test (CCSIT), and follow-up tests were performed 4 weeks later. In the interim, 28 patients were treated with prednisolone for 2 weeks (monotherapy), and the other 43 patients were treated with prednisolone for 2 weeks plus G biloba for 4 weeks (combination therapy). All patients used mometasone nasal spray twice daily for 4 weeks. RESULTS: Scores on the BTT and CCSIT significantly increased after treatment in both groups (P < .001 for both). The mean (SD) BTT score changes were 1.4 (2.2) in the monotherapy group and 2.2 (2.9) in the combination therapy group (P = .22). The mean (SD) CCSIT score changes were 0.9 (1.7) in the monotherapy group and 1.9 (2.7) in the combination therapy group (P = .11). On the BTT, the treatment response (defined as a score increase of > or =3) rates were 32% (9 of 28) in the monotherapy group and 37% (16 of 43) in the combination therapy group (P = .66), and the odds ratio was 1.25 (95% confidence interval, 0.46-3.42). On the CCSIT, the treatment response rates were 14% (4 of 28) in the monotherapy group and 33% (14 of 43) in the combination therapy group (P = .08), and the odds ratio was 2.89 (95% confidence interval, 0.84-9.97). CONCLUSIONS: Olfactory function in patients with postviral olfactory loss was significantly improved by both treatment modalities. Although the treatment response was not statistically different between the monotherapy group and the combination therapy group, the addition of G biloba showed a tendency of greater efficacy in the treatment of postviral olfactory loss.

An investigation of upper airway changes associated with mandibular advancement device using sleep videofluoroscopy in patients with obstructive sleep apnea.

OBJECTIVE: To quantitatively evaluate the effects of the mandibular advancement device (MAD) on changes in the upper respiratory tract during sleep using sleep videofluoroscopy (SVF) in patients with obstructive sleep apnea (OSA). DESIGN: Retrospective analysis. SETTING: Academic tertiary referral center. PATIENTS: Seventy-six patients (68 men and 8 women) who were treated with the MAD for OSA were included from September 1, 2005, through August 31, 2008. INTERVENTION: All patients underwent nocturnal polysomnography and SVF before and at least 3 months after receipt of the custom-made MAD. Sleep videofluoroscopy was performed before and after sleep induction and was analyzed during 3 states of awakeness, normoxygenation sleep, and desaturation sleep. MAIN OUTCOME MEASURES: Changes in the length of the soft palate, retropalatal space, retrolingual space, and angle of mouth opening were evaluated during sleep events with or without the MAD. RESULTS: Without the MAD, the length of the soft palate and the angle of mouth opening increased during sleep events, especially in desaturation sleep, compared with the awake state. The retropalatal space and retrolingual space became much narrower during sleep compared with the awake state. The MAD had marked effects on the length of the soft palate, retropalatal space, retrolingual space, and angle of mouth opening. The retropalatal space and retrolingual space were widened, and the length of the soft palate was decreased. The MAD kept the mouth closed. CONCLUSIONS: Sleep videofluoroscopy showed dynamic upper airway changes in patients with OSA, and the MAD exerted multiple effects on the size and configuration of the airway. Sleep videofluoroscopy demonstrated the mechanism of action of the MAD in patients with OSA. The MAD increased the retropalatal and retrolingual spaces and decreased the length of the soft palate and the angle of mouth opening, resulting in improvement of OSA.

The mandibular advancement device and patient selection in the treatment of obstructive sleep apnea.

OBJECTIVES: To evaluate retrospectively the efficacy of the mandibular advancement device (MAD) in Korean patients with obstructive sleep apnea (OSA) in terms of severity and to evaluate prognostic factors deciding the success of MAD application. DESIGN: Retrospective analysis. SETTING: Academic tertiary referral center. PATIENTS: Of 142 patients who underwent MAD application for OSA management, 50 (46 men and 4 women; mean [SD] age, 50.2 [9.8] years) were included from March 2005 through August 2007. INTERVENTION: Full-overnight polysomnography was performed before and at least 3 months after intraoral MAD application in 50 patients. Questionnaires for sleep quality, Epworth sleepiness scale, and cephalometry were also studied. MAIN OUTCOME MEASURES: Treatment results were evaluated and prognostic factors deciding success of MAD application were assessed. RESULTS: The mean (SD) apnea-hypopnea index (AHI) decreased significantly (P < .001) from 36.6 (18.9) to 12.3 (11.4). The success rate, defined by an AHI of lower than 20 and a 50% decrease in AHI, were 74% (37 of 50 patients). Even patients who were not categorized into the success group had a decreased AHI. The success rates of patients with mild, moderate, and severe OSA were 43% (3 of 7), 82% (22 of 27), and 75% (12 of 16), respectively, and a higher success rate in patients with severe OSA showed that MAD could be applied even in patients with severe OSA. The duration of apnea and hypopnea, percentage of patients with snoring, and the Pittsburgh Sleep Quality Index were improved significantly after treatment. Epworth sleepiness scale scores and lowest oxygen saturation did not change significantly. An analysis of prognostic factors did not reveal any significant difference between the success and nonsuccess groups. CONCLUSIONS: The application of MAD significantly improved nocturnal respiratory function and sleep quality in patients with OSA, even in patients with severe OSA. In patients with OSA, MAD can be used as a good alternative treatment modality regardless of severity because it is noninvasive, easy to manufacture, and has good treatment results.

Results of intratympanic dexamethasone injection as salvage treatment in idiopathic sudden hearing loss.

OBJECTIVE: To evaluate the efficacy of intratympanic (IT) dexamethasone injection as a salvage treatment in idiopathic sudden hearing loss (ISHL) patients. DESIGN: A prospective study. SETTING: A secondary care hospital. METHODS: Fifty-two subjects whose pure-tone averages (PTAs) after a 2-week standard treatment were > 30 dB or worse than 10 dB from the contralateral ear were included. Thirty-four patients underwent IT dexamethasone injection and 18 patients (control) received no further treatment. Final hearing outcome was compared between the two groups. MAIN OUTCOME MEASURES: At 2 weeks after IT dexamethasone injection, audiograms were obtained and compared between the two groups. RESULTS: Sixteen patients (47.1%) in the IT dexamethasone group and 8 patients (44.4%) in the control group finally showed an improvement of 10 dB or more in PTA or a 15% or more change in speech discrimination score (p > .05). The average improvement in PTAs was 8.2 dB in the IT dexamethasone group and 3.6 dB in the control group (p = .184). Patients responsive to the initial treatment showed better final outcomes, irrespective of IT dexamethasone injection. CONCLUSIONS: The present study does not support IT dexamethasone injection as a beneficial salvage treatment for ISHL patients. The true efficacy of this procedure still needs to be investigated.

Functional interactions between heterologously expressed starch-branching enzymes of maize and the glycogen synthases of Brewer's yeast.

Starch-branching enzymes (SBEs) catalyze the formation of alpha(1-->6) glycoside bonds in glucan polymers, thus, affecting the structure of amylopectin and starch granules. Two distinct classes of SBE are generally conserved in higher plants, although the specific role(s) of each isoform in determination of starch structure is not clearly understood. This study used a heterologous in vivo system to isolate the function of each of the three known SBE isoforms of maize (Zea mays) away from the other plant enzymes involved in starch biosynthesis. The ascomycete Brewer's yeast (Saccharomyces cerevisiae) was employed as the host species. All possible combinations of maize SBEs were expressed in the absence of the endogenous glucan-branching enzyme. Each maize SBE was functional in yeast cells, although SBEI had a significant effect only if SBEIIa and SBEIIb also were present. SBEI by itself did not support glucan accumulation, whereas SBEIIa and SBEIIb both functioned along with the native glycogen synthases (GSs) to produce significant quantities of alpha-glucan polymers. SBEIIa was phenotypically dominant to SBEIIb in terms of glucan structure. The specific branching enzyme present had a significant effect on the molecular weight of the product. From these data we suggest that SBEs and GSs work in a cyclically interdependent fashion, such that SBE action is needed for optimal GS activity; and GS, in turn, influences the further effects of SBE. Also, SBEIIa and SBEIIb appear to act before SBEI during polymer assembly in this heterologous system.