Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy.

Neoadjuvant immune checkpoint blockade has shown promising clinical activity. Here, we characterized early kinetics in tumor-infiltrating and circulating immune cells in oral cancer patients treated with neoadjuvant anti-PD-1 or anti-PD-1/CTLA-4 in a clinical trial (NCT02919683). Tumor-infiltrating CD8 T cells that clonally expanded during immunotherapy expressed elevated tissue-resident memory and cytotoxicity programs, which were already active prior to therapy, supporting the capacity for rapid response. Systematic target discovery revealed that treatment-expanded tumor T cell clones in responding patients recognized several self-antigens, including the cancer-specific antigen MAGEA1. Treatment also induced a systemic immune response characterized by expansion of activated T cells enriched for tumor-infiltrating T cell clonotypes, including both pre-existing and emergent clonotypes undetectable prior to therapy. The frequency of activated blood CD8 T cells, notably pre-treatment PD-1-positive KLRG1-negative T cells, was strongly associated with intra-tumoral pathological response. These results demonstrate how neoadjuvant checkpoint blockade induces local and systemic tumor immunity.

Exploring the relationship between cleft type and speech outcome in 4-to-6-year-olds with non-syndromic cleft palate using different measures: A preliminary report.

Cleft type affects speech outcomes, but exact relationships remain unclear as outcome measures vary. The primary aim was to investigate the relationship between cleft type and speech outcome using different measures in 4-to-6-year-olds with non-syndromic clefts. Secondary aims were to explore the relationships between (i) speech measures used; and (ii) parent perception of speech intelligibility and listener familiarity. Twenty-two pre-schoolers with clefts, plus one parent for each child, were recruited through a hospital outpatient clinic. Children with cleft lip and palate (CLP; n = 11) and those with cleft palate only (CP; n = 11), matched on age and time of palate repair, were compared on Percentage Consonants Correct (PCC), clinician-reported speech intelligibility, and parent rating on the Intelligibility-in-Context Scale (ICS). Children with CLP had significantly lower PCC scores than children with CP (p = .020), but had no significant differences in their clinician- or parent-reported speech intelligibility. Clinician-reported speech intelligibility correlated significantly with both PCC (τ = .594, p < 0.01) and ICS (τ = .424, p = 0.009). No significant correlation was found between PCC and ICS (τ =.197, p = 0.113). Overall, parents rated their child's intelligibility higher for familiar compared to unfamiliar communication partners (τ = 2.325, p = 0.001, r = .76). Cleft type is crucial for intervention planning when objective measures are employed. Speech outcomes should be evaluated at impairment, activity, and participation levels, and by different communication partners, to comprehensively evaluate communicative effectiveness.

Which patients with metastatic hormone-sensitive prostate cancer benefit from docetaxel: a systematic review and meta-analysis of individual participant data from randomised trials.

BACKGROUND: Adding docetaxel to androgen deprivation therapy (ADT) improves survival in patients with metastatic, hormone-sensitive prostate cancer, but uncertainty remains about who benefits most. We therefore aimed to obtain up-to-date estimates of the overall effects of docetaxel and to assess whether these effects varied according to prespecified characteristics of the patients or their tumours. METHODS: The STOPCAP M1 collaboration conducted a systematic review and meta-analysis of individual participant data. We searched MEDLINE (from database inception to March 31, 2022), Embase (from database inception to March 31, 2022), the Cochrane Central Register of Controlled Trials (from database inception to March 31, 2022), proceedings of relevant conferences (from Jan 1, 1990, to Dec 31, 2022), and ClinicalTrials.gov (from database inception to March 28, 2023) to identify eligible randomised trials that assessed docetaxel plus ADT compared with ADT alone in patients with metastatic, hormone-sensitive prostate cancer. Detailed and updated individual participant data were requested directly from study investigators or through relevant repositories. The primary outcome was overall survival. Secondary outcomes were progression-free survival and failure-free survival. Overall pooled effects were estimated using an adjusted, intention-to-treat, two-stage, fixed-effect meta-analysis, with one-stage and random-effects sensitivity analyses. Missing covariate values were imputed. Differences in effect by participant characteristics were estimated using adjusted two-stage, fixed-effect meta-analysis of within-trial interactions on the basis of progression-free survival to maximise power. Identified effect modifiers were also assessed on the basis of overall survival. To explore multiple subgroup interactions and derive subgroup-specific absolute treatment effects we used one-stage flexible parametric modelling and regression standardisation. We assessed the risk of bias using the Cochrane Risk of Bias 2 tool. This study is registered with PROSPERO, CRD42019140591. FINDINGS: We obtained individual participant data from 2261 patients (98% of those randomised) from three eligible trials (GETUG-AFU15, CHAARTED, and STAMPEDE trials), with a median follow-up of 72 months (IQR 55-85). Individual participant data were not obtained from two additional small trials. Based on all included trials and patients, there were clear benefits of docetaxel on overall survival (hazard ratio [HR] 0·79, 95% CI 0·70 to 0·88; p<0·0001), progression-free survival (0·70, 0·63 to 0·77; p<0·0001), and failure-free survival (0·64, 0·58 to 0·71; p<0·0001), representing 5-year absolute improvements of around 9-11%. The overall risk of bias was assessed to be low, and there was no strong evidence of differences in effect between trials for all three main outcomes. The relative effect of docetaxel on progression-free survival appeared to be greater with increasing clinical T stage (pinteraction=0·0019), higher volume of metastases (pinteraction=0·020), and, to a lesser extent, synchronous diagnosis of metastatic disease (pinteraction=0·077). Taking into account the other interactions, the effect of docetaxel was independently modified by volume and clinical T stage, but not timing. There was no strong evidence that docetaxel improved absolute effects at 5 years for patients with low-volume, metachronous disease (-1%, 95% CI -15 to 12, for progression-free survival; 0%, -10 to 12, for overall survival). The largest absolute improvement at 5 years was observed for those with high-volume, clinical T stage 4 disease (27%, 95% CI 17 to 37, for progression-free survival; 35%, 24 to 47, for overall survival). INTERPRETATION: The addition of docetaxel to hormone therapy is best suited to patients with poorer prognosis for metastatic, hormone-sensitive prostate cancer based on a high volume of disease and potentially the bulkiness of the primary tumour. There is no evidence of meaningful benefit for patients with metachronous, low-volume disease who should therefore be managed differently. These results will better characterise patients most and, importantly, least likely to gain benefit from docetaxel, potentially changing international practice, guiding clinical decision making, better informing treatment policy, and improving patient outcomes. FUNDING: UK Medical Research Council and Prostate Cancer UK.

Acute toxicity comparison of magnetic resonance-guided adaptive versus fiducial or computed tomography-guided non-adaptive prostate stereotactic body radiotherapy: A systematic review and meta-analysis.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is gaining wider adoption for prostate cancer management but there remain significant toxicity risks when delivering prostate SBRT with standard techniques. Magnetic resonance-guided daily adaptive SBRT (MRg-A-SBRT) offers technological advantages in precision of radiation dose delivery, but the toxicity profile associated with MRg-A-SBRT compared to more standardly used fiducial or computed tomography-guided non-adaptive prostate SBRT (CT-SBRT) remains unknown. METHODS: A meta-analysis to compare acute toxicity rates associated with MRg-A-SBRT and CT-SBRT for prostate cancer was performed in compliance with PRISMA guidelines. MEDLINE (PubMed) and Google Scholar were searched for prospective studies of prostate SBRT that were published between January 1, 2018 and August 31, 2022. Random effects and fixed effects models were used to estimate pooled toxicity rates, and meta-regression was performed to compare toxicity between MRg-A-SBRT and CT-SBRT study groups. RESULTS: Twenty-nine prospective studies were identified that met the inclusion criteria and included a total of 2547 patients. The pooled estimates for acute grade 2 or higher (G2+) genitourinary (GU) and gastrointestinal (GI) toxicity for MRg-A-SBRT were 16% (95% confidence interval [CI], 10%-24%) and 4% (95% CI, 2%-7%) and for CT-SBRT they were 28% (95% CI, 23%-33%) and 9% (95% CI, 6%-12%), respectively. On meta-regression, the odds ratios for acute G2+ GU and GI toxicities comparing MRg-A-SBRT and CT-SBRT were 0.56 (95% CI, 0.33-0.97, p = .04) and 0.40 (95% CI, 0.17-0.96, p = .04), respectively. CONCLUSION: MRg-A-SBRT is associated with a significantly reduced risk of acute G2+ GU or GI toxicity compared to CT-SBRT. Longer follow-up will be needed to evaluate late toxicity and disease control outcomes. PLAIN LANGUAGE SUMMARY: Magnetic resonance imaging-guided daily adaptive prostate stereotactic radiation (MRg-A-SBRT) is a treatment that may allow for delivery of prostate radiation more precisely than other radiotherapy techniques, but it is unknown whether this reduces side effects compared to standardly used computed tomography-guided SBRT (CT-SBRT). In this systematic review and meta-analysis combining data from 29 clinical trials including 2547 patients, it was found that the risk of short-term urinary side effects was reduced by 44% and the risk of short-term bowel side effects was reduced by 60% with MRg-A-SBRT compared to CT-SBRT.

New Triterpenoids and Anti-Inflammatory Constituents from Glinus oppositifolius.

Three new triterpenoids-spergulagenin B (1), spergulagenin C (2), and spergulagenin D (3)-were isolated from the aerial part of Glinus oppositifolius, along with 17 known compounds (4-20). The structures of these new compounds were identified by spectroscopic and MS analyses. Compounds 3, 5, 19, and 20 were evaluated for inhibition of nitric oxide production in LPS-stimulated RAW 264.7 cells with IC50 values of 17.03, 18.21, 16.30, and 12.64 µM, respectively. Compounds 3, 5, and 20 exhibited inhibitory effects on LPS-induced nitric oxide production in RAW 264.7 cells with IC50 values of 18.35 ± 1.34, 17.56 ± 1.41, and 14.27 ± 1.29 µM, respectively.

Association between baseline body mass index and survival in men with metastatic hormone-sensitive prostate cancer: ECOG-ACRIN CHAARTED E3805.

BACKGROUND: E3805 (CHAARTED) is a phase 3 trial demonstrating improved survival for men with metastatic hormone-sensitive prostate cancer (mHSPC) randomized to treatment with docetaxel (D) and androgen-deprivation therapy (ADT) versus ADT alone. We assessed the association of baseline body mass index (BMI) and metformin exposure with quality of life (QOL) and prostate cancer outcomes including survival in patients enrolled in the CHAARTED study. METHODS: We performed a posthoc exploratory analysis of the CHAARTED trial of men with mHSPC randomized to treatment with ADT with or without D between 2006 and 2012. Cox proportional hazards models and Kruskal-Wallis test were used to evaluate the association between BMI with QOL and prostate cancer outcomes and between metformin exposure and survival. RESULTS: In 788 of 790 enrolled patients with prospectively recorded baseline BMI and metformin exposure status, lower BMI was not associated with survival, but was associated with high volume disease (p < 0.0001) and poorer baseline QOL on functional assessment of cancer therapy-prostate (p = 0.008). Only 68 patients had prevalent metformin exposure at baseline in the CHAARTED trial. Four groups were identified: ADT + D + metformin (n = 39); ADT + D (n = 357); ADT + metformin (n = 29); and ADT alone (n = 363). Baseline clinicopathologic characteristics were similar between groups. In this small exploratory multivariable analysis, metformin exposure was not associated with survival (hazard ratio: 1.15; 95% confidence interval: 0.81-1.63, p = 0.44). CONCLUSIONS: There was no link between baseline BMI and survival, but lower baseline BMI was associated with features of greater cancer burden and poorer QOL.

Optically Unstable Phase from Ion-Ion Interactions in an Erbium-Doped Crystal.

Optical many-body systems naturally possess strong light-matter interactions and are thus of central importance for photonic applications. However, these applications are so far limited within the regime of intrinsic dynamically stable phases, and the possibility of unstable phases remains unidentified. Here we experimentally revealed a new dynamical phase of intrinsic optical instability by using a continuous-wave laser to drive an erbium-doped crystal. The transmission through the sample became unstable for intense laser inputs, and transient net gain was observed if the light passed the sample twice. The phase transition, between states in and out of a dynamical equilibrium, was induced by the dipole-dipole interactions between nearby erbium ions.

National Surveillance of Antimicrobial Susceptibility of Bacteremic Gram-Negative Bacteria with Emphasis on Community-Acquired Resistant Isolates: Report from the 2019 Surveillance of Multicenter Antimicrobial Resistance in Taiwan (SMART).

A multicenter collection of bacteremic isolates of Escherichia coli (n = 423), Klebsiella pneumoniae (n = 372), Pseudomonas aeruginosa (n = 300), and Acinetobacter baumannii complex (n = 199) was analyzed for susceptibility. Xpert Carba-R assay and sequencing for mcr genes were performed for carbapenem- or colistin-resistant isolates. Nineteen (67.8%) carbapenem-resistant K. pneumoniae (n = 28) and one (20%) carbapenem-resistant E. coli (n = 5) isolate harbored blaKPC (n = 17), blaOXA-48 (n = 2), and blaVIM (n = 1) genes.

Revealing Strong Plasmon-Exciton Coupling between Nanogap Resonators and Two-Dimensional Semiconductors at Ambient Conditions.

Strong coupling of two-dimensional semiconductor excitons with plasmonic resonators enables control of light-matter interaction at the subwavelength scale. Here we develop such strong coupling in plasmonic nanogap resonators, which allows modification of exciton strength by altering electromagnetic environments in nearby semiconductor monolayers. Using this system, we not only demonstrate a large vacuum Rabi splitting up to 163 meV and splitting features in photoluminescence spectra but also reveal that the effective exciton number contributing to the coupling can be reduced down to the single-digit level (N<10), which is 2 orders lower than that of previous systems, close to single-exciton based strong coupling. In addition, we prove that the strong coupling process is not affected by the large exciton coherence size that was previously believed to be detrimental to the formation of plasmon-exciton interaction. We provide a deeper understanding of strong coupling in two-dimensional semiconductors, paving the way for room-temperature quantum optics applications.

Supplemental 25-hydroxycholecalciferol Alleviates Inflammation and Cardiac Fibrosis in Hens.

Broiler breeder hens with efficient feed conversion rate under restricted feed intake (R-hens) or allowed unlimited access to feed (Ad-hens) progressed with cardiac functional failure and suffered early sudden death. A supplement of 69 µg 25-hydroxycholecalciferol (25-OH-D3)/kg feed improved heart health and rescued livability in both R- and Ad-hens throughout laying stage (26-60 wks). Improvements occurred through cardiac hypertrophic remodeling, reduced arrhythmias, and pathological cues. Here, we further demonstrated consistently decreased circulating and cardiac IL-6 and IL-1ß levels in conjunction with reduced cardiac chemoattraction and leukocyte infiltration by 25-OH-D3 in Ad-hens and in R-hens at later time points (35 and 47 wks) (p < 0.05). Supplemental 25-OH-D3 also ameliorated cardiac fibrosis, endoplasmic reticulum (ER) stress, and autophagy, mostly in Ad-hens, as both collagen content and expression of COL3A1, as well as CCAAT box binding enhancer homologous protein (CHOP) and activating transcription factor 6 (ATF6), were consistently decreased, and suppression of microtubule-associated protein 1 light Chain 3 beta (LC3B) and Sequestosome 1 (SQSTM1) was rescued at 35 and 47 wks (p < 0.05). Vitamin D receptor-NF-κB signaling was shown to mediate these beneficial effects. The present results demonstrate that ER stress and autophagic processes along the sequence from inflammation to fibrotic changes contribute to pathological cardiac remodeling and functional compromise by Ad-feed intake. 25-OH-D3 is an effective anti-inflammatory and anti-fibrotic supplement to ameliorate cardiac pathogenesis in broiler breeder hens.

Long-term outcomes of breast-conserving therapy for women with ductal carcinoma in situ.

PURPOSE: Improved imaging, surgical techniques, and pathologic evaluation likely have decreased local recurrence rates for patients with ductal carcinoma in situ (DCIS). We present long-term outcomes of a large single-institution series after breast-conserving surgery (BCS) and adjuvant radiation therapy (RT). METHODS: We retrospectively reviewed the records of 245 women treated for DCIS with BCS and RT between 2001 and 2007. Competing risk analysis was used to calculate local recurrence (LR) as a first event with the development of a second non-breast malignancy, contralateral breast cancer, and death as competing first events. RESULTS: At a median follow-up of 10.6 years, 4 patients had a LR (2 DCIS, 2 invasive) as a first event with a cumulative LR incidence of 0.0% and 1.5% at 5 and 10 years, respectively. Most patients had > 2 mm margins (90%), specimen radiographs (93%), and received a tumor bed boost (99%). The majority (60%) of patients with hormone receptor-positive disease received adjuvant endocrine therapy. Ten-year cumulative incidence of contralateral breast cancer (CBC) was 7.9%, second non-breast malignancy was 4.5%, and death unrelated to breast cancer was 3.5%. Family history, age at diagnosis, and receipt of endocrine therapy were not significantly associated with the development of CBC (all P > 0.05). CONCLUSIONS: With mature follow-up, our rates of local recurrence following breast-conserving therapy for DCIS remain very low (1.5% at 10 years). The incidence of CBC was higher than the LR incidence. Predisposing factors for the development of CBC are worthy of investigation.

Salvage radiation therapy for localized recurrent ovarian cancer.

INTRODUCTION: To evaluate clinical outcomes for patients with localized recurrent ovarian cancer treated with salvage radiotherapy. METHODS: In a retrospective single institutional analysis, we identified 40 patients who received salvage radiotherapy for localized ovarian cancer recurrence from January 1995 to June 2011. Recurrent disease was categorized as: pelvic peritoneal (45%, 18), extraperitoneal/nodal (35%, 14), or vaginal (20%, eight). Actuarial disease-free and overall survival estimates were calculated by Kaplan-Meier and prognostic factors evaluated by the Cox proportional hazards model. RESULTS: Median follow-up was 42 months. Median patient age was 54 years (range, 27-78). Histologic subtypes were: serous (58%, 23), endometrioid (15%, six), clear cell (13%, five), mucinous (8%, three), and other (8%, three). At the time of salvage radiotherapy, surgical cytoreduction was performed in 60% (24) and 68% (27) had platinum-sensitive disease. Most patients (63%, 25) received salvage radiotherapy at the time of first recurrence. Relapse after salvage radiotherapy occurred in 29 patients at a median time of 16 months and was outside the radiotherapy field in 62%. 18 At 3 years, disease-free and overall survival rates were 18% and 80%, respectively. On multivariate analysis, non-serous histology (hazards ratio 0.3, 95% CI 0.1-0.7) and platinum-sensitivity (hazards ratio 0.2, 95% CI 0.1-0.5) were associated with lower relapse risk. Platinum-sensitivity was also associated with overall survival (hazards ratio 0.4, 95% CI 0.1-1.0). Four patients (10%) were long-term survivors without recurrence 5 years after salvage radiotherapy. Of the five patients with clear cell histology, none experienced relapse at the time of last follow-up. DISCUSSION: Patients with non-serous and/or platinum-sensitive ovarian cancer had the greatest benefit from salvage radiotherapy for localized recurrent disease. Although relapse was common, radiotherapy prolonged recurrence for > 1 year in most patients and four were long-term survivors.

Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer.

BACKGROUND: Androgen-deprivation therapy (ADT) has been the backbone of treatment for metastatic prostate cancer since the 1940s. We assessed whether concomitant treatment with ADT plus docetaxel would result in longer overall survival than that with ADT alone. METHODS: We assigned men with metastatic, hormone-sensitive prostate cancer to receive either ADT plus docetaxel (at a dose of 75 mg per square meter of body-surface area every 3 weeks for six cycles) or ADT alone. The primary objective was to test the hypothesis that the median overall survival would be 33.3% longer among patients receiving docetaxel added to ADT early during therapy than among patients receiving ADT alone. RESULTS: A total of 790 patients (median age, 63 years) underwent randomization. After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT plus docetaxel (combination therapy) than with ADT alone (57.6 months vs. 44.0 months; hazard ratio for death in the combination group, 0.61; 95% confidence interval [CI], 0.47 to 0.80; P<0.001). The median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the combination group, as compared with 11.7 months in the ADT-alone group (hazard ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). The rate of a prostate-specific antigen level of less than 0.2 ng per milliliter at 12 months was 27.7% in the combination group versus 16.8% in the ADT-alone group (P<0.001). In the combination group, the rate of grade 3 or 4 febrile neutropenia was 6.2%, the rate of grade 3 or 4 infection with neutropenia was 2.3%, and the rate of grade 3 sensory neuropathy and of grade 3 motor neuropathy was 0.5%. CONCLUSIONS: Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00309985.).

Mode Modification of Plasmonic Gap Resonances Induced by Strong Coupling with Molecular Excitons.

Plasmonic cavities can be used to control the atom-photon coupling process at the nanoscale, since they provide an ultrahigh density of optical states in an exceptionally small mode volume. Here we demonstrate strong coupling between molecular excitons and plasmonic resonances (so-called plexcitonic coupling) in a film-coupled nanocube cavity, which can induce profound and significant spectral and spatial modifications to the plasmonic gap modes. Within the spectral span of a single gap mode in the nanocube-film cavity with a 3 nm wide gap, the introduction of narrow-band J-aggregate dye molecules not only enables an anticrossing behavior in the spectral response but also splits the single spatial mode into two distinct modes that are easily identified by their far-field scattering profiles. Simulation results confirm the experimental findings, and the sensitivity of the plexcitonic coupling is explored using digital control of the gap spacing. Our work opens up a new perspective to study the strong coupling process, greatly extending the functionality of nanophotonic systems, with the potential to be applied in cavity quantum electrodynamic systems.

Impact of ethnicity on the outcome of men with metastatic, hormone-sensitive prostate cancer.

BACKGROUND: Prostate cancer (PCa) outcomes are impacted by socioeconomic and biologic factors. Ethnicity plays a role in the former, but little is known about the responsiveness of metastatic PCa to androgen-deprivation therapy (ADT) among races. METHODS: The Surveillance, Epidemiology, and End Results (SEER) registry was used to identify men who were diagnosed with distant, de novo, metastatic PCa from 2004 to 2012. Patterns of presentation, overall survival (OS), and PCa-specific mortality (PCSM) were determined for each race. E3805 clinical trial data also were retrospectively reviewed to assess outcomes of ADT and ADT plus docetaxel by race. RESULTS: Of all PCa diagnoses in SEER, distant, de novo, metastatic disease was diagnosed in 4.2% of non-Hispanic whites, 5.8% of Hispanic whites, 5.7% of blacks, 5.5% of Asians/Pacific Islanders, and 8.8% of American Indians/Alaska Natives (P < .001; chi-square test). The median OS differed by race, with superior OS observed among Asian men (30 months) than among men of other races (range, 24-25 months; P < .001). Asians also had a superior median PCSM (54 months) compared with the other races (range, 35-40 months; P < .001). In E3805, chemohormonal therapy was associated with a median OS of 58.1 months (95% confidence interval, 48.8-72.9 months) and 57.6 months (95% confidence interval, 27.7-57.6 months) in non-Hispanic whites and blacks, respectively. Few Asians participated in the E3805 trial. CONCLUSIONS: Asian men have superior median OS and PCSM for distant, de novo, metastatic PCa than men of other race. Non-Hispanic whites and blacks who receive treatment with ADT or chemohormonal therapy have comparable outcomes. Cancer 2017;123:1536-1544. © 2017 American Cancer Society.

Tenuigenin promotes the osteogenic differentiation of bone mesenchymal stem cells in vitro and in vivo.

Osteoporosis, which is a systemic skeletal disease characterized by low bone mineral density and microarchitectural deterioration of bone quality, is a global and increasing public health problem. Recent studies have suggested that Tenuigenin (TEN), a class of native compounds with numerous biological activities such as anti-resorptive properties, exerts protective effects against postmenopausal bone loss. The present study aims to investigate the osteogenic effects of TEN on bone mesenchymal stem cells (BMSCs) in vitro and in vivo. Alkaline phosphatase (ALP) activity/staining, Alizarin red staining and the expression of osteogenic markers, including runt-related transcription factor 2, osterix, osteocalcin, collagen Iα1, ß-catenin and glycogen synthase kinase-3ß were investigated in primary femoral BMSCs from C57/BL6 mice cultured under osteogenic conditions for 2 weeks to examine the effects of TEN. An ovariectomized (OVX) mouse model was used to investigate the effect of TEN treatment for 3 months in vivo. We found that ALP activity, mineralized nodules and the expression of osteogenic markers were increased and WNT/ß-catenin signaling was enhanced in vitro and in vivo. Bone parameters, including trabecular thickness, trabecular number and bone mineral density were higher in the OVX+TEN group than in control OVX mice. Our results suggest the therapeutic potential of TEN for the treatment of patients with postmenopausal osteoporosis.

Body Mass Index and Locoregional Recurrence in Women with Early-Stage Breast Cancer.

BACKGROUND: Higher body mass index (BMI) has been associated with increased distant recurrence and decreased survival for women with breast cancer. However, the relationship between BMI and locoregional recurrence (LRR) has been less well studied and was therefore the subject of this investigation. METHODS: The study identified 878 women with early-stage invasive breast cancer who underwent breast-conservation therapy (BCT) between June 1997 and October 2007. Time from diagnosis to LRR was calculated using a competing risk analysis with contralateral breast cancer (CBC), distant metastases (DM), and death as the competing risks. Gray's competing risks analysis, which included an interaction term between menopausal status and BMI, was used to identify significant risk factors for the development of LRR. RESULTS: After a median follow-up period of 10.8 years, LRR was diagnosed as a first event for 45 women. In a multivariable analysis, BMI was positively associated with LRR but only in premenopausal women. Specifically, when these women were compared with normal- and underweight women, both the overweight women (hazard ratio (HR), 2.97; 95 % confidence interval (CI) 1.04-8.46; p = 0.04) and the obese women (HR, 3.36; 95 % CI 1.07-10.63; p = 0.04) showed a higher risk of LRR. A similar association between BMI and disease-free survival was noted for premenopausal but not postmenopausal women. CONCLUSION: For premenopausal women with invasive breast cancer who undergo BCT, BMI is an independent prognostic factor for LRR. If confirmed, these findings suggest that more aggressive treatment strategies may be warranted for these women.

Invasive lobular carcinoma of the breast: local recurrence after breast-conserving therapy by subtype approximation and surgical margin.

Invasive lobular carcinoma (ILC) typically presents at a later stage than invasive ductal carcinoma (IDC) and poses unique radiographic and surgical challenges. However, current principles of breast-conserving therapy (BCT) do not distinguish between histologic subtypes, raising uncertainty about the optimal approach for patients with ILC. We studied 998 BCT patients from 1998-2007, comprised 74 % IDC, 8 % ILC, and 18 % with mixed ILC/IDC. In light of recent guidelines addressing surgical margins, specimens were assessed for margin width and biologic subtype. The Kaplan-Meier method and Cox proportional hazards models were used to analyze effects of patient and disease characteristics on local recurrence (LR). At a median of 119 months, 45 patients had an isolated LR. 10-year LR was 5.5 % for patients with IDC, 4.4 % for ILC, and 1.2 % for mixed histology (p = 0.08). The majority of ILC cases had luminal A biologic subtype (91.1 %), and analysis among all luminal A cases revealed 10-year LR of 2.6 % for IDC, 3.4 % for ILC, and 0 % for mixed tumors (p = 0.12). Patients with ILC were more likely to have initially positive surgical margins (45.0 vs 17.5 %; p < 0.001) resulting in more frequent re-excision (57.1 % vs 40.4 %; p = 0.02), though final margins were similar between ILC and IDC (p = 0.88). No LR was observed among ILC or mixed histology patients with margins <2 mm (n = 28). On multivariate analysis, histologic subtype was not associated with LR (p = 0.52). Modern approaches confer similarly favorable LR rates for ILC, IDC, and mixed histology breast cancers despite inherent histologic differences. Patients with ILC did not require more extensive surgical margins than those with IDC.

Salvage whole brain radiotherapy or stereotactic radiosurgery after initial stereotactic radiosurgery for 1-4 brain metastases.

Patients with limited brain metastases are often candidates for stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT). Among patients who receive SRS, the likelihood and timing of salvage WBRT or SRS remains unclear. We examined rates of salvage WBRT or SRS among 180 patients with 1-4 newly diagnosed brain metastases who received index SRS from 2008-2013. Competing risks multivariable analysis was used to examine factors associated with time to WBRT. Patients had non-small cell lung (53 %), melanoma (23 %), breast (10 %), renal (6 %), or other (8 %) cancers. Median age was 62 years. Patients received index SRS to 1 (60 %), 2 (21 %), 3 (13 %), or 4 (7 %) brain metastases. Median survival after SRS was 9.7 months (range, 0.3-67.6 months). No further brain-directed radiotherapy was delivered after index SRS in 55 % of patients. Twenty-seven percent of patients ever received salvage WBRT, and 30 % ever received salvage SRS; 12 % of patients received both salvage WBRT and salvage SRS. Median time to salvage WBRT or salvage SRS were 5.6 and 6.1 months, respectively. Age ≤60 years (adjusted hazard ratio [AHR] = 2.80; 95 % CI 1.05-7.51; P = 0.04) and controlled/absent extracranial disease (AHR = 6.76; 95 % CI 1.60-28.7; P = 0.01) were associated with shorter time to salvage WBRT. Isolated brain progression caused death in only 11 % of decedents. In summary, most patients with 1-4 brain metastases receiving SRS never require salvage WBRT or SRS, and the remainder do not require salvage treatment for a median of 6 months.

Three new cyathane diterpenoids from the medicinal fungus Cyathus africanus.

Three new cyathane diterpenoids, cyathin W (1), cyathin V (2), and cyathin T (3), were isolated from the solid culture of Cyathus africanus. The structures and configurations of these new compounds were elucidated on the basis of comprehensive spectroscopic analysis including 1D NMR, 2D NMR (HSQC, HMBC, NOESY), and HR-ESI-MS experiments. Compounds 1 and 3 showed moderate inhibition against nitric oxide production in lipopolysaccaride-activated macrophages with IC50 value of 80.07 and 88.87 µM, respectively. In cytotoxicity assay, compound 1 showed weak cytotoxicity against K562 cell line with IC50 value of 12.1 µM.