Background: Recurrent gynecological clear cell carcinoma (rGCCC) has a low objective response rate (ORR) to chemotherapy. Previous preclinical and clinical data suggest a potential synergy between immune checkpoint inhibitors and bevacizumab in rGCCC.Dostarlimab, a humanized monoclonal antibody targeting programmed cell death protein 1 (PD-1), combined with the anti-angiogenic bevacizumab, presents a novel therapeutic approach. This study will investigate the efficacy of dostarlimab +/− bevacizumab in rGCCC. Methods DOVE is a global, multicenter, international, open-label, randomized phase 2 study of dostarlimab +/− bevacizumab with standard chemotherapy in rGCCC. We will enroll 198 patients with rGCCC and assign them to one of three groups in a 1:1:1 ratio: arm A (dostarlimab monotherapy), B (dostarlimab + bevacizumab), and C (investigator’s choice of chemotherapy [weekly paclitaxel, pegylated liposomal doxorubicin, doxorubicin, or gemcitabine]). Patients with disease progression in arm A or C will be allowed to cross over to arm B. Stratification factors include prior bevacizumab use, prior lines of therapy (1 vs. >1), and primary site (ovarian vs. non-ovarian). Key inclusion criteria are histologically proven recurrent or persistent clear cell carcinoma of the ovary, endometrium, cervix, vagina, or vulva; up to five prior lines of therapy; disease progression within 12 months after platinumbased chemotherapy; and measurable disease. Key exclusion criteria are prior treatment with an anti–PD-1, anti–programmed death-ligand 1, or anti–programmed death-ligand 2 agent.The primary endpoint is progression-free survival determined by investigators. Secondary endpoints are ORR, disease control rate, clinical benefit rate, progression-free survival 2, overall survival, and toxicity. Exploratory objectives include immune biomarkers.

Background: Recurrent gynecological clear cell carcinoma (rGCCC) has a low objective response rate (ORR) to chemotherapy. Previous preclinical and clinical data suggest a potential synergy between immune checkpoint inhibitors and bevacizumab in rGCCC.Dostarlimab, a humanized monoclonal antibody targeting programmed cell death protein 1 (PD-1), combined with the anti-angiogenic bevacizumab, presents a novel therapeutic approach. This study will investigate the efficacy of dostarlimab +/− bevacizumab in rGCCC. Methods DOVE is a global, multicenter, international, open-label, randomized phase 2 study of dostarlimab +/− bevacizumab with standard chemotherapy in rGCCC. We will enroll 198 patients with rGCCC and assign them to one of three groups in a 1:1:1 ratio: arm A (dostarlimab monotherapy), B (dostarlimab + bevacizumab), and C (investigator’s choice of chemotherapy [weekly paclitaxel, pegylated liposomal doxorubicin, doxorubicin, or gemcitabine]). Patients with disease progression in arm A or C will be allowed to cross over to arm B. Stratification factors include prior bevacizumab use, prior lines of therapy (1 vs. >1), and primary site (ovarian vs. non-ovarian). Key inclusion criteria are histologically proven recurrent or persistent clear cell carcinoma of the ovary, endometrium, cervix, vagina, or vulva; up to five prior lines of therapy; disease progression within 12 months after platinumbased chemotherapy; and measurable disease. Key exclusion criteria are prior treatment with an anti–PD-1, anti–programmed death-ligand 1, or anti–programmed death-ligand 2 agent.The primary endpoint is progression-free survival determined by investigators. Secondary endpoints are ORR, disease control rate, clinical benefit rate, progression-free survival 2, overall survival, and toxicity. Exploratory objectives include immune biomarkers.

Background: Recurrent gynecological clear cell carcinoma (rGCCC) has a low objective response rate (ORR) to chemotherapy. Previous preclinical and clinical data suggest a potential synergy between immune checkpoint inhibitors and bevacizumab in rGCCC.Dostarlimab, a humanized monoclonal antibody targeting programmed cell death protein 1 (PD-1), combined with the anti-angiogenic bevacizumab, presents a novel therapeutic approach. This study will investigate the efficacy of dostarlimab +/− bevacizumab in rGCCC. Methods DOVE is a global, multicenter, international, open-label, randomized phase 2 study of dostarlimab +/− bevacizumab with standard chemotherapy in rGCCC. We will enroll 198 patients with rGCCC and assign them to one of three groups in a 1:1:1 ratio: arm A (dostarlimab monotherapy), B (dostarlimab + bevacizumab), and C (investigator’s choice of chemotherapy [weekly paclitaxel, pegylated liposomal doxorubicin, doxorubicin, or gemcitabine]). Patients with disease progression in arm A or C will be allowed to cross over to arm B. Stratification factors include prior bevacizumab use, prior lines of therapy (1 vs. >1), and primary site (ovarian vs. non-ovarian). Key inclusion criteria are histologically proven recurrent or persistent clear cell carcinoma of the ovary, endometrium, cervix, vagina, or vulva; up to five prior lines of therapy; disease progression within 12 months after platinumbased chemotherapy; and measurable disease. Key exclusion criteria are prior treatment with an anti–PD-1, anti–programmed death-ligand 1, or anti–programmed death-ligand 2 agent.The primary endpoint is progression-free survival determined by investigators. Secondary endpoints are ORR, disease control rate, clinical benefit rate, progression-free survival 2, overall survival, and toxicity. Exploratory objectives include immune biomarkers.

Background: Atopic dermatitis (AD) is a chronic pruritic inflammatory dermatosis. Whether gamma-linolenic acid (GLA) supplementation is beneficial in AD patients remains debatable. Objective: This study investigated whether adjuvant GLA supplementation is associated with clinical improvement in AD patients receiving systemic treatment, as assessed by patient-reported outcome measures. Methods: We enrolled 70 AD patients. Patients who received GLA at a dose of 80∼160 mg/d for over 1 month were included in the GLA group, while others were included in the non-GLA group. Each group was subgrouped into control, immunomodulator, and dupilumab groups based on treatment history. The patients evaluated their symptoms using the Atopic Dermatitis Control Tool (ADCT), Patient Global Assessment of Disease (PGA), and Dermatology Life Quality Index (DLQI). Results: The Mann-Whitney U-test was used to compare differences in ADCT, PGA, and DLQI between both groups. The ADCT scores were significantly lower in the control and immunomodulatory group supplemented with GLA (control U=13.5, p=0.04; immunomodulatory U=28.0, p=0.01), but not in patients taking dupilumab (U=44.5, p=0.70). The PGA and DLQI scores also tended to be lower in the GLA group than those in the non-GLA group. Conclusion GLA supplementation is a potential adjuvant to systemic therapy may yield additional symptomatic relief in AD patients.

Objective: To investigate the clinical features and associated underlying conditions of isolated tuberculous myositis (ITBM), a rare extrapulmonary tuberculosis (TB). Methods: A systematic literature search and a multicenter survey were performed using a triangulation strategy. Data from the identified ITBM cases were extracted and analyzed to determine the underlying conditions, clinical presentations, treatments, and outcomes. Results: Based on the systematic review, we identified 58 ITBM, including 9 pediatric, cases in the literature published from 1981 to 2021: 25 (43.1%) immunocompromised and 33 (56.9%) non-immunocompromised patients. Immunocompromised cases had a significant shorter symptom duration (median 30.0 vs. 75.0 days) and a higher prevalence of multilocular involvement (20.8% vs. 0%). Among 24 immunocompromised adult patients, dermatomyositis/polymyositis (DM/PM; n=10, 41.7%) were the most common underlying diseases in adults with ITBM identified in the systematic review. Over the past 20 years, 11 Korean adults with ITBM were identified in the multicenter survey. Of 7 immunocompromised cases, two (28.6%) were DM/PM patients. TB death rate of immunocompromised patients was 0.0% and 5/23 (21.7%) in the pediatric and adult ITBM cases identified in the systematic review, respectively, and 3/7 (42.9%) in survey-identified ITBM cases. Conclusion ITBM has a unique clinical presentation including fever, tenderness, local swelling, overlying erythema, abscess formation and was associated with a grave outcome, especially in immunocompromised hosts. DM/PM was a highly prevalent underlying disease in both systematic review-identified and survey-identified immunocompromised ITBM patients.

The long setting time of dental MTA (Mineral Trioxide Aggregate) cement is a major disadvantage in clinical use. In this study, the setting time (ST) of nine commercial MTA cements was tested according to the ISO 6876:2012 standard (n = 5).Materials evaluated were ProRoot MTA (PR), Ortho MTA (Ortho), Retro MTA (Retro), Endocem MTA (Endocem), Endoseal MTA (Endoseal), One-Fil (OF), MTA Cem (MC), EZ-Seal (EZ), and Biodentine (BD). XRD and XRF analysis were performed to evaluate the effect of composition on ST. Kruskal-Wallis test as a non-parametric ANOVA followed by Duncan’s post hoc test was used for statistical analysis. The ST was PR > EZ > OF > Ortho > Retro > MC > Endoseal > BD > Endocem in decreasing order (p < 0.001). PR showed the longest (369.4 min) and Endocem showed the shortest (2.4 min) ST. Endocem (2.4 min), BD (16.0 min) and Endoseal (47.0 min) contained calcium carbonate. MC (48.8 min), Retro (43.6 min), Ortho (65.0), and OF (165.4 min), which had the next short setting time, contained dicalcium aluminate. In EZ (182.4 min), dicalcium silicate was the main crystalline phase rather than tricalcium silicate, which contributes to the early strength, and it contained calcium sulfate. Endocem, which showed the shortest setting time, showed the smallest d90 particle size of 6.12 µm. The information obtained from this study would be helpful in developing a composition for controlling the setting time of MTA cement and selecting a product with a setting time suitable for each clinical case.

The long setting time of dental MTA (Mineral Trioxide Aggregate) cement is a major disadvantage in clinical use. In this study, the setting time (ST) of nine commercial MTA cements was tested according to the ISO 6876:2012 standard (n = 5).Materials evaluated were ProRoot MTA (PR), Ortho MTA (Ortho), Retro MTA (Retro), Endocem MTA (Endocem), Endoseal MTA (Endoseal), One-Fil (OF), MTA Cem (MC), EZ-Seal (EZ), and Biodentine (BD). XRD and XRF analysis were performed to evaluate the effect of composition on ST. Kruskal-Wallis test as a non-parametric ANOVA followed by Duncan’s post hoc test was used for statistical analysis. The ST was PR > EZ > OF > Ortho > Retro > MC > Endoseal > BD > Endocem in decreasing order (p < 0.001). PR showed the longest (369.4 min) and Endocem showed the shortest (2.4 min) ST. Endocem (2.4 min), BD (16.0 min) and Endoseal (47.0 min) contained calcium carbonate. MC (48.8 min), Retro (43.6 min), Ortho (65.0), and OF (165.4 min), which had the next short setting time, contained dicalcium aluminate. In EZ (182.4 min), dicalcium silicate was the main crystalline phase rather than tricalcium silicate, which contributes to the early strength, and it contained calcium sulfate. Endocem, which showed the shortest setting time, showed the smallest d90 particle size of 6.12 µm. The information obtained from this study would be helpful in developing a composition for controlling the setting time of MTA cement and selecting a product with a setting time suitable for each clinical case.

Signal transducer and activator of transcription 3 (STAT3) modulates a variety of genes involved in the regulation of critical functions, including cell proliferation, differentiation, apoptosis, angiogenesis, metastasis, and immunity. For many cancers, elevated levels of STAT3 signaling have been associated with a poor prognosis and the development of chemotherapy resistance. In this study, we investigated the inhibitory effects of a novel small-molecule inhibitor of STAT3, STX-0119, on the cell viability and survival of human lung cancer cells. STX-0119 inhibited activated STAT3 and the expression of STAT3-regulated oncoproteins such as c-Myc, cyclin D1, and survivin in lung cancer cells. STX-0119 also decreased the amount of STAT3 in the nuclear fraction as well as induced apoptosis of these lung cancer cell lines as evidenced by increases in apoptotic cells (Annexin V positive) and poly (ADP-ribose) polymerase (PARP) cleavage. The efficacy of STX-0119 in a mouse xenograft model was confirmed. However, a hematological side effect, which had not been previously reported, was observed. The level of white blood cells was significantly lowered when treated at the dose at which STX-0119 alone showed a significant tumor-suppressive effect. In conclusion, we suggest that STX-0119 may be a potent therapeutic agent against lung cancer. Consideration of the side effect suggests, it is necessary to study whether low-dose STX-0119 is effective for lung treatment with a combination of classic lung cancer therapeutics.
Animals ; Apoptosis ; Cell Line ; Cell Proliferation ; Cell Survival ; Cyclin D1 ; Drug Therapy ; Heterografts ; Humans ; Leukocytes ; Lung Neoplasms ; Lung ; Mice ; Neoplasm Metastasis ; Oncogene Proteins ; Prognosis ; STAT3 Transcription Factor

This study was aimed to disclose the prevalence rate of tick-borne pathogens from ticks collected from cattle and wild animals in Tanzania in 2012. Ticks were collected from slaughtered cattle and dead wild animals from November 5 to December 23, 2012 and identified. PCR for detecting Anaplasmataceae, Piroplamidae, Rickettsiaceae, Borrelia spp., and Coxiella spp. were done. Among those tested, Rickettsiaceae, Piroplasmidae, and Anaplasmataceae, were detected in ticks from the 2 regions. Rickettsiaceae represented the major tick-borne pathogens of the 2 regions. Ticks from animals in Maswa were associated with a higher pathogen detection rate compared to that in ticks from Iringa. In addition, a higher pathogen detection rate was observed in ticks infesting cattle than in ticks infesting wild animals. All examined ticks of the genus Amblyomma were infected with diverse pathogens. Ticks of the genera Rhipicephalus and Hyalomma were infected with 1 or 2 pathogens. Collectively, this study provides important information regarding differences in pathogen status among various regions, hosts, and tick species in Tanzania. Results in this study will affect the programs to prevent tick-borne diseases (TBD) of humans and livestock in Tanzania.
Anaplasmataceae ; Animals ; Animals, Wild ; Borrelia ; Cattle ; Coxiella ; Humans ; Livestock ; Piroplasmida ; Polymerase Chain Reaction ; Prevalence ; Rhipicephalus ; Rickettsiaceae ; Tanzania ; Tick-Borne Diseases ; Ticks

In order to discover lifespan-extending compounds made from natural resources, activity-guided fractionation of Zingiber officinale Roscoe (Zingiberaceae) ethanol extract was performed using the Caenorhabditis elegans (C. elegans) model system. The compound 6-gingerol was isolated from the most active ethyl acetate soluble fraction, and showed potent longevity-promoting activity. It also elevated the survival rate of worms against stressful environment including thermal, osmotic, and oxidative conditions. Additionally, 6-gingerol elevated the antioxidant enzyme activities of C. elegans, and showed a dose-depend reduction of intracellular reactive oxygen species (ROS) accumulation in worms. Further studies demonstrated that the increased stress tolerance of 6-gingerol-mediated worms could result from the promotion of stress resistance proteins such as heat shock protein (HSP-16.2) and superoxide dismutase (SOD-3). The lipofuscin levels in 6-gingerol treated intestinal worms were decreased in comparison to the control group. No significant 6-gingerol-related changes, including growth, food intake, reproduction, and movement were noted. These results suggest that 6-gingerol exerted longevity-promoting activities independently of these factors and could extend the human lifespan.
Caenorhabditis elegans* ; Caenorhabditis* ; Eating ; Ethanol ; Ginger* ; Heat-Shock Proteins ; Humans ; Lipofuscin ; Longevity* ; Natural Resources ; Reactive Oxygen Species ; Reproduction ; Superoxide Dismutase ; Survival Rate