BRD2-specific inhibitor, BBC0403, inhibits the progression of osteoarthritis pathogenesis in osteoarthritis-induced C57BL/6 male mice.

BACKGROUND AND PURPOSE: The discovery of new bromo- and extra-terminal inhibitors presents new drugs to treat osteoarthritis (OA). EXPERIMENTAL APPROACH: The new drug, BBC0403, was identified in the DNA-encoded library screening system by searching for compounds that target BRD (bromodomain-containing) proteins. The binding force with BRD proteins was evaluated using time-resolved fluorescence energy transfer (TR-FRET) and binding kinetics assays. Subsequently, in vitro and ex vivo analyses demonstrated the effects of the BRD2 inhibitor, BBC0403, on OA. For animal experiments, medial meniscus destabilization was performed to create a 12-week-old male C57BL/6 mouse model, and intra-articular (i.a.) injections were administered. Histological and immunohistochemical analyses were then performed. The underlying mechanism was confirmed by gene set enrichment analysis (GSEA) using RNA-seq. KEY RESULTS: TR-FRET and binding kinetics assays revealed that BBC0403 exhibited higher binding specificity for BRD2 compared to BRD3 and BRD4. The anti-OA effects of BBC0403 were tested at concentrations of 5, 10 and 20 µM (no cell toxicity in the range tested). The expression of catabolic factors, prostaglandin E2 (PGE2) production and extracellular matrix (ECM) degradation was reduced. Additionally, the i.a. injection of BBC0403 prevented OA cartilage degradation in mice. Finally, BBC0403 was demonstrated to suppress NF-κB and MAPK signalling pathways. CONCLUSION AND IMPLICATIONS: This study demonstrated that BBC0403 is a novel BRD2-specific inhibitor and a potential i.a.-injectable therapeutic agent to treat OA.

Changing trends in the management of ductal carcinoma in situ in Republic of Korea: a comprehensive analysis using Health Insurance Review and Assessment data [2009-2020].

Background: Increasing rates of diagnosis of ductal carcinoma in situ (DCIS), given the widespread use of mammography, is a global trend. Various attempts have been made in the selection of surgical methods and application of radiation therapy (RT), and the prevalence of infectious diseases has also affected these attempts. This study aimed to investigate evolving treatment patterns and trends in the management of DCIS in South Korea. Methods: We conducted a comprehensive search of the Korean Health Insurance Review and Assessment Service-National Patient Sample (HIRA-NPS) database and selected patients who underwent breast surgery following a DCIS diagnosis between 2009 and 2020. Based on this sample, the analyses were weighted according to the Korean population. We examined annual variations in mastectomy types, reconstructive procedures, and RT utilization from a multidisciplinary perspective. Results: In our weighted sample, 43,780 patients with DCIS underwent surgery, with a consistent annual increase of 10%. The proportion of lumpectomy procedures increased from 56.7% to 65.4%, showing a greater growth rate than that of total mastectomies (TMs). Following the availability of reconstruction data in 2015, shifts have emerged toward a preference for implant-based autologous tissue reconstruction. As we transitioned to the latter part of our study, the trend was marked by the increasing adoption of hypofractionated RT and omission of RT. Of the patients who underwent lumpectomy in 2020, 25.6% adopted hypofractionated RT and 53.8% omitted RT. This transformation was particularly evident among older patients, individuals treated in metropolitan areas, and those treated in small-sized healthcare facilities. Conclusions: Our study sheds light on the changing landscape of DCIS treatment in South Korea incorporating perspectives from surgeons, plastic surgeons, and radiation oncologists. We observed an increase in the rates of lumpectomy and implant-based reconstruction. Adoption of hypofractionated RT and omission of RT showed increasing trends.

Low albumin-to-alkaline phosphatase ratio is associated with inferior prognosis in patients with head and neck cancer underwent concurrent chemoradiation: A propensity score-matched analysis.

Background: Low albumin-to-alkaline phosphatase ratio (AAPR) is associated with tumor progression and poor survival outcome in some malignancies. Purpose: We aimed to determine the prognostic value of AAPR in head and neck cancer (HNC) patients underwent concurrent chemoradiotherapy (CCRT). Materials and Methods: We retrospectively reviewed medical records of 342 patients with HNC treated with definitive or adjuvant CCRT from 2007 to 2017. Receiver-operator characteristic curve assessed the cut-off value and predictive accuracy of AAPR for disease progression. Propensity score-matched (PSM) method was performed to balance baseline characteristics. Multivariate Cox regression analyses screened the independent prognostic factors for progression-free survival (PFS) and overall survival (OS). Results: The median follow-up duration was 40 months. The optimal cut-off level of AAPR was 0.523. In the PSM cohort, an AAPR < 0.523 was related to worse PFS and OS (PFS: Hazard ratio [HR], 1.936; 95% confidence interval [CI], 1.212 to 3.249; P = 0.001 and OS: HR, 1.832; 95% CI, 1.117 to 3.478; P = 0.02) compared with those with an AAPR ≥ 0.523. AJCC stage IVA-B also showed poor survival outcome compared with patients with AJCC stage II--III (PFS: HR, 1.855; 95% CI, 1.173 to 2.933; P = 0.008 and OS: HR, 1.905; 95% CI, 1.131 to 3.211; P = 0.015). Conclusions: HNC patients with low AAPR independently have worse survival outcomes than do high AAPR patients. These findings might help physicians predict treatment outcome and guide treatment strategy in patients with HNC underwent CCRT.

A malignant glomus tumor in the nasal cavity responding to radiation therapy.

Malignant glomus tumors of the head and neck are extremely rare, and to our knowledge, a response to high-dose radiation has not been described previously. We report one case in an 80-year-old woman with right nasal cavity mass. Histological examination revealed sheets of atypical round glomus cells. The presence of increased mitotic activity (25 per 10 high-power fields), cellular atypism, and tumor necrosis suggested malignancy. The smooth muscle actin, vimentin, and h-caldesmon immunohistochemistry stains the tumor cells. Two cycles of doxorubicin and cyclophosphamide chemotherapy were done and the tumor size was slightly increased. Salvage radiation therapy (RT) was delivered to the primary mass over 4 weeks (50 Gy in 20 fractions) and leading to nearly complete regression of tumor. Additional investigations are warranted so that we may determine the usefulness of RT in the management of this rare tumor.

Novel molecule BBC0901 inhibits BRD4 and acts as a catabolic regulator in the pathogenesis of osteoarthritis.

Osteoarthritis (OA) is induced by matrix degradation and inflammation mediated by bromo-domain-containing protein 4 (BRD4)-dependent catabolic factors. BRD4 acts as both a transcriptional regulator and an epigenetic reader. BBC0901 was identified as an inhibitor of BRD4 using a DNA-encoded library screening system. We aimed to demonstrate the effects of BBC0901 on OA pathogenesis by in vitro, ex vivo, and in vivo analyses. BBC0901 inhibited the expression of catabolic factors that degrade cartilage without significantly affecting the viability of mouse articular chondrocytes. Additionally, ex vivo experiments under conditions mimicking OA showed that BBC0901 suppressed extracellular matrix degradation. RNA sequencing analysis of gene expression patterns showed that BBC0901 inhibited the expression of catabolic factors, such as matrix metalloproteinases (MMPs) and cyclooxygenase (COX)2, along with reactive oxygen species (ROS) production. Furthermore, intra-articular (IA) injection of BBC0901 into the knee joint blocked osteoarthritic cartilage destruction by inhibition of MMP3, MMP13, COX2, interleukin (IL)6, and ROS production, thereby obstructing the nuclear factor kappa-light-chain-enhancer of activated B cell and mitogen activated protein kinase signaling. In conclusion, BBC0901-mediated BRD4 inhibition prevented OA development by attenuating catabolic signaling and hence, can be considered a promising IA therapeutic for OA.

Predictive Power of the Albumin-Bilirubin Score for Hepatotoxicity in Stereotactic Ablative Radiation Therapy for Hepatocellular Carcinoma.

Assessment of liver function is crucial in predicting treatment outcomes for hepatocellular carcinoma (HCC). This study aimed to evaluate the prognostic performance of the albumin-bilirubin (ALBI) score for predicting hepatotoxicity following stereotactic body radiation therapy (SBRT) in HCC patients. A retrospective analysis was conducted on 123 HCC cases treated between 2018 and 2020. ALBI and Child-Turcotte-Pugh (CTP) scores were calculated, and hepatotoxicity was defined as a post-SBRT CTP score increase ≥2. Receiver operating characteristic (ROC) curves were used for comparison. The optimal cutoff value of the ALBI score was determined. Among the 121 patients analyzed, hepatotoxicity occurred in 5%. The ALBI score showed better predictive accuracy (area under the ROC curve: 0.77) than the CTP score. The optimal cutoff value of the ALBI score was -2.47, with a sensitivity of 85.7% and a specificity of 71.1%. Multivariable analysis revealed that ALBI score and PTV were significant factors for hepatotoxicity. In conclusion, the ALBI score demonstrated prognostic value for hepatotoxicity prediction after SBRT in HCC patients. Considering the ALBI score and PTV provides valuable insights for assessing hepatotoxicity risk during SBRT treatment for HCC.

Schisandra extract ameliorates arthritis pathogenesis by suppressing the NF-κB and MAPK signalling pathways.

Schisandra chinensis is a medicinal plant used to treat various diseases. Extracts from the leaves or fruits of S. chinensis and their components are used in osteoarthritis (OA). The OA inhibitory effect of schisandrol A, one of its components, has been previously confirmed. We aimed to confirm the OA inhibitory effect of Schisandra (including components like schisandrol A) to identify why the inhibitory effect of the Schisandra extract is better. First, we investigated the effects of the Schisandra extract on OA as a potential therapeutic. Experimental OA was induced in a mouse model via destabilized medial meniscus surgery. The animals were orally administered the Schisandra extract; the inhibition of cartilage destruction was confirmed using histological analysis. In vitro analysis showed that the Schisandra extract attenuated osteoarthritic cartilage destruction by regulating IL-1ß-induced MMP3 and COX-2 levels. The Schisandra extract inhibited IL-1ß-induced degradation of IκB (NF-κB pathway) and IL-1ß-induced phosphorylation of p38 and JNK (mitogen-activated protein kinase (MAPK) pathway). RNA-sequencing analysis showed that the Schisandra extract decreased the expression of IL-1ß-induced MAPK and NF-κB signalling pathway-related genes more than schisandrol A alone. Therefore, Schisandra extract may be more effective than schisandrol A in preventing OA progression by regulating MAPK and NF-κB signalling.

Risk factors for primary site necrosis after definitive concurrent chemoradiotherapy in head and neck cancer.

OBJECTIVE: To identify risk factors of primary site necrosis (PSN) after definitive concurrent chemoradiation therapy (CCRT) in patients with nonoral cavity head and neck cancer (HNC). METHODS: We retrospectively reviewed the records of 256 patients treated with CCRT for HNC during 2010-2018. Patient-related (age, sex, history of smoking, hypertension, diabetes mellitus, serum hemoglobin and albumin), tumor-related (tumor site, American Joint Committee on Cancer stage), and treatment-related (induction chemotherapy, maximum point dose and mean dose of planning target volume [PTV] of primary site, absolute volumes of the PTV receiving >50-75 Gy [V50-V75]) variables were analyzed. Critical dosimetric parameters of PSN were identified using receiver operating characteristic (ROC) curve analysis. Univariate and multivariate Cox regression analyses were used to select the significant variables for PSN development. RESULTS: After median follow-up of 44 months (range, 5-127), 7 patients (2.7%) developed PSN with a median time to event of 10 months (range, 3-12). V70 ⩾79.8 mL was the most critical dosimetric parameter for PSN (area under the ROC curve 0.873, sensitivity 0.857, specificity 0.747). In univariate analyses, pretreatment serum hemoglobin <11.0 g/dL and V70 ⩾79.8 mL were significantly associated with higher risk of PSN occurrence. V70 ⩾79.8 mL (hazard ratio 5.960, 95% confidence interval 1.289-27.548; p = 0.022) remained significant predictors of PSN in multivariate analyses. CONCLUSIONS: V70 ⩾79.8 mL is significantly related to the risk of developing PSN. These findings offer valuable clues for clinicians to minimize PSN incidence in HNC treated with curative CCRT.

Influence of respiratory movement during post mastectomy radiotherapy on targets and heart for breast cancer.

BACKGROUND/AIM: This study aimed to compare the dosimetric consequences of respiratory movement in volumetric-modulated arc therapy (VMAT) and three-dimensional conformal radiation therapy (3D-CRT) during postmastectomy radiation therapy, including internal mammary nodes (IMNs). MATERIALS AND METHODS: Respiratory motion was implemented to a phantom using a dynamic device. The plans were delivered during cranial-caudal and ventral-dorsal movement in 5-mm (R05) and 10-mm (R10) amplitudes. RESULTS: At the IMN, the dose errors were -2.8% (R05) and -6.2% (R10) for 3D-CRT and -4.9% (R05) and -8.5% (R10) for VMAT. The dose errors in chest wall were -.5% (R05) and -6.0% (R10) for 3D-CRT and -1.9% (R05) and -5.3% (R10) for VMAT. The left anterior descending doses showed significantly small absolute values. The gamma pass rates of VMAT were higher than those of 3D-CRT. CONCLUSIONS: The benefit of VMAT technique in dose distribution was maintained, except in occasional instances of large breathing motion.

Incidence of hypothyroidism after treatment for breast cancer: A Korean population-based study.

This Korean population-based study aimed to describe the patterns of hypothyroidism after adjuvant radiation therapy (RT) in patients with breast cancer. The Korean Health Insurance Review and Assessment Service database was searched for patients with invasive breast carcinomas. We calculated the cumulative incidence and incidence rates per 1,000 person-years of subsequent hypothyroidism and compared them using the log-rank test and the Cox proportional hazards model. Between 2007 and 2018, 117,135 women diagnosed with breast cancer with a median follow-up time of 4.6 years were identified. The 8-year incidence of hypothyroidism was 9.3% in patients treated with radiation and 8.6% in those treated without radiation (p = 0.002). The incidence rates per 1,000 person-years in the corresponding treatment groups were 6.2 and 5.7 cases, respectively. The hazard ratio (HR) in patients receiving RT was 1.081 (95% confidence interval [CI], 1.013-1.134; p = 0.002). After mastectomy, RT showed a trend toward a higher risk of hypothyroidism (HR = 1.248; 95% CI, 0.977-1.595; p = 0.076). Our study provides one of the largest population-based data analyses regarding the risk of hypothyroidism among Korean patients with breast cancer. The adjusted risk for patients treated with RT exceeded that for patients with breast cancer treated without RT. The effect was evident immediately after treatment and lasted up to approximately 9 years.

Wrinkle reduction using a Sasang constitutional medicine-based topical herbal cream in So-eum subjects: A split-face randomized double-blind placebo-controlled study.

BACKGROUND: Skin aging is caused by exogenous and endogenous factors and is commonly manifested as wrinkling, sagging, and looseness of the skin. The herbal extract including Zingiber officinale Roscoe, Atractylodes chinensis (Bunge) Kodiz, Curcuma longa L., and Cinnamomum cassia (L.) J.Presl (ZACC extract), is widely used for So-eum (SE) Sasang constitutional type individuals. This study aimed to examine the protective effects of the ZACC extract against skin aging in 21 SE type subjects. METHODS: The safety and clinical efficacy of herbal cream were evaluated after application on human skin in a split-face randomized, double-blind, placebo-controlled study. The Sasang Constitution Analysis Tool (SCAT) was used to select 21 SE type subjects, who applied herbal cream and placebo cream for 12 weeks. Visual assessment, wrinkle parameters, questionnaires, and skin safety were evaluated. RESULTS: The visual assessment score was decreased by using of the herbal cream, but there were no significant differences between groups. Among the wrinkle parameters, R1 (skin roughness) and R4 (smoothness depth) values were significantly improved after the application of the herbal cream compared to those observed after application of the placebo cream for 12 weeks. No significant differences were observed in evaluation of the product efficacy and usability by questionnaires. There were no adverse dermatologic reactions in the SE type subjects during the evaluation period. CONCLUSION: The ZACC herbal cream may be used to prevent or slow skin aging, including wrinkle formation, in SE type individuals.

Radiotherapy dose-volume parameters predict facial lymphedema after concurrent chemoradiation for nasopharyngeal carcinoma.

BACKGROUND: To investigate risk factors for developing radiation-associated facial lymphedema (FL) in nasopharyngeal carcinoma (NPC) patients after concurrent chemoradiation (CCRT). METHODS: Clinical data from 87 patients who underwent definitive CCRT for NPC in 2010-2018 was retrospectively evaluated. FL severity was graded using MD Anderson Cancer Center head and neck lymphedema rating scale. Logistic regression analysis was used to examine the factors associated with the presence of moderate/severe FL (grade ≥ 2). RESULTS: At a median follow-up of 34 months (range, 18-96), 26/87 (29.9%) patients experienced grade ≥ 2 FL. A majority (84.6%) was experienced grade ≥ 2 FL 3-6 months after CCRT. Mean dose to the level IV, level I-VII neck node and N stage were significantly correlated with grade ≥ 2 FL at univariate analysis. At multivariate analysis, mean dose of level IV neck node (hazard ratio [HR], 1.238; 95% confidence interval [CI] = 1.084-1.414; p = 0.002) and level I-VII neck node (HR, 1.384; 95% CI = 1.121-1.708; p = 0.003) were independent predictors. Receiver Operating Characteristics (ROC) curve analysis showed that cut-off value of mean level IV neck node dose was 58.7 Gy (area under the curve [AUC] = 0.726; 95% CI = 0.614-0.839, p = 0.001) and mean level I-VII neck node dose was 58.6 Gy (AUC = 0.720; 95% CI = 0.614-0.826, p = 0.001) for grade ≥ 2 FL. CONCLUSIONS: Keeping mean dose to the level IV and level I-VII below 58.7 Gy and 58.6 Gy may reduce the likelihood of moderate/severe FL after CCRT for NPC.

Pattern of local recurrence after mastectomy and reconstruction in breast cancer patients: a systematic review.

BACKGROUND: This study aimed to describe the locations of local recurrences based on the mastectomy and reconstruction type in breast cancer patients. METHODS: In November 2020, a systematic literature review was performed through MEDLINE/PubMed and the Cochrane Centre Register of Controlled Trials. Publications that included skin-sparing or nipple-sparing mastectomy followed by breast reconstruction and described the location of local recurrences were analyzed. Exclusion criteria included salvage or prophylactic mastectomy, unclear distinction between local and regional recurrences, rare tumor types. RESULTS: From 19 publications, 272 local recurrences lesions were reported in a total of 4,787 patients. After autologous reconstruction (n=2,465), local recurrences were located in the skin in 45 (1.8%) patients, in the chest wall in 18 (0.7%), and in the nipple-areolar complex in 9 (0.4%). After implant reconstruction (n=1,917), local recurrences sites included the skin in 91 (4.7%) patients, chest wall in 8 (0.4%), and nipple-areolar complex in 8 (0.4%). Of the 70 lesions with reported in-breast location, 57 (81.4%) relapsed in the original tumor location. DISCUSSION: Although meta-analysis was not conducted, present analysis demonstrated that most local recurrences after skin-sparing or nipple-sparing mastectomy occurred within the skin or subcutaneous tissues. It was found that the original tumor location was the most frequent site of relapse. Therefore, special attention should be paid to the original tumor overlying the skin while planning postmastectomy radiation therapy.

Obtusifolin, an Anthraquinone Extracted from Senna obtusifolia (L.) H.S.Irwin & Barneby, Reduces Inflammation in a Mouse Osteoarthritis Model.

Osteoarthritis (OA) is an age-related degenerative disease that causes cartilage dysfunction and inflammation. Obtusifolin, an anthraquinone extracted from Senna obtusifolia (L.) H.S.Irwin & Barneby seeds, has anti-inflammatory functions; it could be used as a drug component to relieve OA symptoms. In this study, we investigated the effects of obtusifolin on OA inflammation. In vitro, interleukin (IL)-1ß (1 ng/mL)-treated mouse chondrocytes were co-treated with obtusifolin at different concentrations. The expression of matrix metalloproteinase (Mmp) 3, Mmp13, cyclooxygenase 2 (Cox2), and signaling proteins was measured by polymerase chain reaction and Western blotting; collagenase activity and the PGE2 level were also determined. In vivo, OA-induced C57BL/6 mice were administered obtusifolin, and their cartilage was stained with Safranin O to observe damage. Obtusifolin inhibited Mmp3, Mmp13, and Cox2 expression to levels similar to or more than those after treatment with celecoxib. Additionally, obtusifolin decreased collagenase activity and the PGE2 level. Furthermore, obtusifolin regulated OA via the NF-κB signaling pathway. In surgically induced OA mouse models, the cartilage destruction decreased when obtusifolin was administered orally. Taken together, our results show that obtusifolin effectively reduces cartilage damage via the regulation of MMPs and Cox2 expression. Hence, we suggest that obtusifolin could be a component of another OA symptom reliever.

Adaptive Image Rescaling for Weakly Contrast-Enhanced Lesions in Dedicated Breast CT: A Phantom Study.

Purpose: Dedicated breast CT is an emerging volumetric X-ray imaging modality for diagnosis that does not require any painful breast compression. To improve the detection rate of weakly enhanced lesions, an adaptive image rescaling (AIR) technique was proposed. Materials and Methods: Two disks containing five identical holes and five holes of different diameters were scanned using 60/100 kVp to obtain single-energy CT (SECT), dual-energy CT (DECT), and AIR images. A piece of pork was also scanned as a subclinical trial. The image quality was evaluated using image contrast and contrast-to-noise ratio (CNR). The difference of imaging performances was confirmed using student's t test. Results: Total mean image contrast of AIR (0.70) reached 74.5% of that of DECT (0.94) and was higher than that of SECT (0.22) by 318.2%. Total mean CNR of AIR (5.08) was 35.5% of that of SECT (14.30) and was higher than that of DECT (2.28) by 222.8%. A similar trend was observed in the subclinical study. Conclusion: The results demonstrated superior image contrast of AIR over SECT, and its higher overall image quality compared to DECT with half the exposure. Therefore, AIR seems to have the potential to improve the detectability of lesions with dedicated breast CT.

Prognostic value of the maximum standardized uptake value for the locoregional control in early glottic cancer.

PURPOSE: To evaluate the prognostic value of the pretreatment maximum standardized uptake value (SUVmax) for locoregional control (LRC) of early glottic cancer treated with primary radiotherapy. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 101 patients with T1-T2N0 glottic cancer treated with helical tomotherapy between 2013 and 2016. The clinical T-stages were T1 in 87 (86.1%) and T2 in 14 (13.9%) patients. The median total dose was 63 Gy (63-67.5 Gy) in 2.25 Gy per fraction. The survival outcomes were plotted using Kaplan-Meier curves. Receiver operating characteristic curves were used to assess the optimal SUVmax cut-off value for predicting locoregional recurrence. RESULTS: The median follow-up period was 58 months (range, 11 to 90 months). The 5-year overall survival (OS) and locoregional recurrence-free survival rates were 96.8% and 85.4%, respectively. The median pretreatment SUVmax of the primary tumor for all 101 patients was 2.3 (range, 1.1 to 9.1). The best cut-off value for SUVmax for predicting LRC was 3.3, with a sensitivity of 78.6% and specificity of 73.6%. Univariate analysis showed that T-stage, overall treatment time (≥43 days), and high SUVmax (≥3.3) were significant predictors of LRC. Multivariate analysis showed that LRC was independently affected by a high SUVmax (≥3.3) (hazard ratio = 5.505, p = 0.020). CONCLUSION: High pretreatment SUVmax (≥3.3) is a negative prognostic factor for LRC in early glottic cancer patients treated with primary radiotherapy.

Comparison of local recurrence after mastectomy for pure ductal carcinoma in situ with close or positive margins: A meta-analysis.

BACKGROUND: There is controversy regarding the relationship between margin status and risk of local recurrence (LR) in patients with Ductal carcinoma in situ(DCIS) treated by mastectomy. PURPOSE: We sought to assess the LR rates for patients with DCIS breast cancer treated by mastectomy with respect to the resection margin (RM) status. MATERIALS AND METHODS: Systematic search of MEDLINE, EMBASE, and Cochrane library published was performed. Studies of pure DCIS breast cancer with treatment of mastectomy and studies that reported surgical RM and LR were included. RESULTS: A total of 12 retrospective studies were included, encompassing 2902 patients with a mean follow-up of 86.4 months. Overall LR rates were 5.3% (27/508) for positive or close margins and 1.6% (37/2367) for negative margin, and most of the recurrences (93.7%) are invasive cancers. Patients with positive or close margins showed a 3.72-fold (95% confidence interval [CI] = 2.30-6.01,P < 0.01, I[2] = 11%) higher risk of LR than patients with negative margin. Patients with positive margin showed a 2.91-fold (95% CI = 1.14-7.41,P = 0.03, I[2] = 0%) higher risk of LR than patients with close margin. Postmastectomy radiation therapy (RT) was not associated with a decreased risk of LR (Risk ratio 0.50; 95% CI = 0.06-4.08,P= 0.52, I[2] = 0%) in patients with positive or close margins. CONCLUSIONS: The RM status after mastectomy has a great impact on LR. However, the recurrence rate was insufficient to warrant a recommendation for postmastectomy RT in patients with close or positive margins.

Seomae mugwort and jaceosidin attenuate osteoarthritic cartilage damage by blocking IκB degradation in mice.

Seomae mugwort, a Korean native variety of Artemisia argyi, exhibits physiological effects against various diseases. However, its effects on osteoarthritis (OA) are unclear. In this study, a Seomae mugwort extract prevented cartilage destruction in an OA mouse model. In vitro and ex vivo analyses revealed that the extract suppressed MMP3, MMP13, ADAMTS4 and ADAMTS5 expression induced by IL-1ß, IL-6 and TNF-α and inhibited the loss of extracellular sulphated proteoglycans. In vivo analysis revealed that oral administration of the extract suppressed DMM-induced cartilage destruction. We identified jaceosidin in Seomae mugwort and showed that this compound decreased MMP3, MMP13, ADAMTS4 and ADAMTS5 expression levels, similar to the action of the Seomae mugwort extract in cultured chondrocytes. Interestingly, jaceosidin and eupatilin combined had similar effects to Seomae mugwort in the DMM-induced OA model. Induction of IκB degradation by IL-1ß was blocked by the extract and jaceosidin, whereas JNK phosphorylation was only suppressed by the extract. These results suggest that the Seomae mugwort extract and jaceosidin can attenuate cartilage destruction by suppressing MMPs, ADAMTS4/5 and the nuclear factor-κB signalling pathway by blocking IκB degradation. Thus, the findings support the potential application of Seomae mugwort, and particularly jaceosidin, as natural therapeutics for OA.

3'-Sialyllactose prebiotics prevents skin inflammation via regulatory T cell differentiation in atopic dermatitis mouse models.

3'-Sialyllactose (3'-SL), a natural prebiotic, maintains immune homeostasis and exerts anti-inflammatory and anti-arthritic effects. Although regulatory T cells (Tregs) prevent excessive inflammation and maintain immune tolerance, the effect of 3'-SL on Treg regulation is unclear. This study aimed to investigate the effect of 3'-SL on Treg responses in atopic dermatitis (AD) pathogenesis. Oral administration of 3'-SL reduced AD-like symptoms such as ear, epidermal, and dermal thickness in repeated topical application of house dust mites (HDM) and 2,4-dinitrochlorobenzene (DNCB). 3'-SL inhibited IgE, IL-1ß, IL-6, and TNF-α secretion and markedly downregulated AD-related cytokines including IL-4, IL-5, IL-6, IL-13, IL-17, IFN-γ, TNF-α, and Tslp through regulation of NF-κB in ear tissue. Additionally, in vitro assessment of Treg differentiation revealed that 3'-SL directly induced TGF-ß-mediated Treg differentiation. Furthermore, 3'-SL administration also ameliorated sensitization and elicitation of AD pathogenesis by suppressing mast cell infiltration and production of IgE and pro-inflammatory cytokines in mouse serum by mediating the Treg response. Furthermore, Bifidobacterium population was also increased by 3'-SL administration as prebiotics. Our data collectively show that 3'-SL has therapeutic effects against AD progression by inducing Treg differentiation, downregulating AD-related cytokines, and increasing the Bifidobacterium population.

Cirsium japonicum var. maackii and apigenin block Hif-2α-induced osteoarthritic cartilage destruction.

Although Hif-2α is a master regulator of catabolic factor expression in osteoarthritis development, Hif-2α inhibitors remain undeveloped. The aim of this study was to determine whether Cirsium japonicum var. maackii (CJM) extract and one of its constituents, apigenin, could attenuate the Hif-2α-induced cartilage destruction implicated in osteoarthritis progression. In vitro and in vivo studies demonstrated that CJM reduced the IL-1ß-, IL-6, IL-17- and TNF-α-induced up-regulation of MMP3, MMP13, ADAMTS4, ADAMTS5 and COX-2 and blocked osteoarthritis development in a destabilization of the medial meniscus mouse model. Activation of Hif-2α, which directly up-regulates MMP3, MMP13, ADAMTS4, IL-6 and COX-2 expression, is inhibited by CJM extract. Although cirsimarin, cirsimaritin and apigenin are components of CJM and can reduce inflammation, only apigenin effectively reduced Hif-2α expression and inhibited Hif-2α-induced MMP3, MMP13, ADAMTS4, IL-6 and COX-2 expression in articular chondrocytes. IL-1ß induction of JNK phosphorylation and IκB degradation, representing a critical pathway for Hif-2α expression, was completely blocked by apigenin in a concentration-dependent manner. Collectively, these effects indicate that CJM and one of its most potent constituents, apigenin, can lead to the development of therapeutic agents for blocking osteoarthritis development as novel Hif-2α inhibitors.