The MIP Timing Detector of the CMS detector will provide precision timestamps with 40 ps resolution for all charged particles up to a pseudorapidity of η=3.0. This upgrade will mitigate the effects ...of pile-up expected under the High-Luminosity LHC running conditions and bring new and unique capabilities to the CMS detector. The endcap region of the MIP Timing Detector, called the Endcap Timing Layer, will be instrumented with silicon Low-Gain Avalanche Diodes, covering the high-radiation pseudorapidity region 1.6<η<3.0. The LGAD sensors will be read out by the ETROC readout chip, which is being designed for precision timing measurements. We present recent progress in the characterization of LGAD sensors for the Endcap Timing Layer and the development of ETROC, including test beam and bench measurements.
Ammonia is of emerging interest as a liquefied, renewable-energy-sourced energy carrier for global use in the future. Electrochemical reduction of N
(NRR) is widely recognised as an alternative to ...the traditional Haber-Bosch production process for ammonia. However, though the challenges of NRR experiments have become better understood, the reported rates are often too low to be convincing that reduction of the highly unreactive N
molecule has actually been achieved. This perspective critically reassesses a wide range of the NRR reports, describes experimental case studies of potential origins of false-positives, and presents an updated, simplified experimental protocol dealing with the recently emerging issues.
Anti-HER2 therapies are associated with a risk of increased cardiac toxicity, particularly when part of anthracycline-containing regimens. We report cardiac safety of pertuzumab, trastuzumab, and ...chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer.
BERENICE (NCT02132949) is a nonrandomized, phase II, open-label, multicenter, multinational study in patients with normal cardiac function. In the neoadjuvant period, cohort A patients received four cycles of dose-dense doxorubicin and cyclophosphamide, then 12 doses of standard paclitaxel plus four standard trastuzumab and pertuzumab cycles. Cohort B patients received four standard fluorouracil/epirubicin/cyclophosphamide cycles, then four docetaxel cycles with four standard trastuzumab and pertuzumab cycles. The primary end point was cardiac safety during neoadjuvant treatment, assessed by the incidence of New York Heart Association class III/IV heart failure and of left ventricular ejection fraction declines (≥10 percentage-points from baseline and to a value of<50%). The main efficacy end point was pathologic complete response (pCR, ypT0/is ypN0). Results are descriptive.
Safety populations were 199 and 198 patients in cohorts A and B, respectively. Three patients 1.5%; 95% confidence interval (CI) 0.31% to 4.34% in cohort A experienced four New York Heart Association class III/IV heart failure events. Thirteen patients (6.5%; 95% CI 3.5% to 10.9%) in cohort A and four (2.0%; 95% CI 0.6% to 5.1%) in cohort B experienced at least one left ventricular ejection fraction decline. No new safety signals were identified. pCR rates were 61.8% and 60.7% in cohorts A and B, respectively. The highest pCR rates were in the HER2-enriched PAM50 subtype (75.0% and 73.7%, respectively).
Treatment with pertuzumab, trastuzumab, and common anthracycline-containing regimens for the neoadjuvant treatment of early breast cancer resulted in cardiac and general safety profiles, and pCR rates, consistent with prior studies with pertuzumab.
NCT02132949
Between May 1999 and April 2002 a total of 69 consecutive thumb carpometacarpal joint arthoplasties were performed in a total of 64 patients for carpometacarpal joint osteoarthritis using the ...cementless hydroxyapatite (HA)-coated unconstrained ARPE implant. Clinical, functional and radiological results at 10-year follow-up are presented. Survival analysis was performed using the Kaplan–Meier method. Of the 64 patients, four were lost to follow-up, 60 implants (92.3%) were functional and five (7.7%) were not (two dislocated, two were removed and one with aseptic loosening). Survival estimate for functional implants over 10 years was 93.9% (95% confidence interval 82.3–97.9). The radiographs were satisfactory in 82.4%. There was subsidence of the cup in 15.8%. Thumb carpometacarpal joint arthroplasty with the ARPE implant offers a reliable treatment alternative in patients with Eaton grade III or IV thumb carpometacarpal joint arthritis in the presence of good bone stock.
Background: Treatment of metastatic breast cancer (MBC) remains palliative. Patients with MBC represent a heterogeneous group whose prognosis and outcome may be dependent on host factors. The purpose ...of the present study was dual: first, to draw up a list of factors easily available in everyday clinical practice requiring no sophisticated or costly methods and second, to provide results from a large cohort of women who underwent diagnostic and treatment at a single institution. Patients and methods: From 1975 to 2005, a total of 1038 women with MBC during their follow-up were included in this retrospective analysis. Patients were subsequently assigned to five groups according to the period of metastatic diagnosis. Results: It is shown that age at initial diagnosis, hormonal receptor status and site of metastasis are the most relevant prognostic factors for predicting survival from the time of metastastic occurrence. It is also shown that a metastasis-free interval is an easily and immediately available multifactorial prognostic index reflecting the multiparametric variability of the disease. Conclusion: These fundamental observations may assist physicians in evaluating the survival potential of patients and in directing them toward the appropriate therapeutic decision.
In the chronic stage of myocardial infarction, a significant number of patients develop life-threatening ventricular tachycardias (VT) due to the arrhythmogenic nature of the remodeled myocardium. ...Radiofrequency ablation (RFA) is a common procedure to isolate reentry pathways across the infarct scar that are responsible for VT. Unfortunately, this strategy show relatively low success rates; up to 50% of patients experience recurrent VT after the procedure. In the last decade, intensive research in the field of computational cardiac electrophysiology (EP) has demonstrated the ability of three-dimensional (3D) cardiac computational models to perform
EP studies. However, the personalization and modeling of certain key components remain challenging, particularly in the case of the infarct border zone (BZ). In this study, we used a clinical dataset from a patient with a history of infarct-related VT to build an image-based 3D ventricular model aimed at computational simulation of cardiac EP, including detailed
cardiac anatomy and infarct scar geometry. We modeled the BZ in eight different ways by combining the presence or absence of electrical remodeling with four different levels of image-based patchy fibrosis (0, 10, 20, and 30%). A 3D torso model was also constructed to compute the ECG.
sinus activation patterns were simulated and validated against the patient's ECG. Subsequently, the pacing protocol used to induce reentrant VTs in the EP laboratory was reproduced
. The clinical VT was induced with different versions of the model and from different pacing points, thus identifying the slow conducting channel responsible for such VT. Finally, the real patient's ECG recorded during VT episodes was used to validate our simulation results and to assess different strategies to model the BZ. Our study showed that reduced conduction velocities and heterogeneity in action potential duration in the BZ are the main factors in promoting reentrant activity. Either electrical remodeling or fibrosis in a degree of at least 30% in the BZ were required to initiate VT. Moreover, this proof-of-concept study confirms the feasibility of developing 3D computational models for cardiac EP able to reproduce cardiac activation in sinus rhythm and during VT, using exclusively non-invasive clinical data.
Rodents use olfactory cues for species-specific behaviors. For example, mice emit odors to attract mates of the same species, but not competitors of closely related species. This implies rapid ...evolution of olfactory signaling, although odors and chemosensory receptors involved are unknown.
Here, we identify a mouse chemosignal, trimethylamine, and its olfactory receptor, trace amine-associated receptor 5 (TAAR5), to be involved in species-specific social communication. Abundant (>1,000-fold increased) and sex-dependent trimethylamine production arose de novo along the Mus lineage after divergence from Mus caroli. The two-step trimethylamine biosynthesis pathway involves synergy between commensal microflora and a sex-dependent liver enzyme, flavin-containing monooxygenase 3 (FMO3), which oxidizes trimethylamine. One key evolutionary alteration in this pathway is the recent acquisition in Mus of male-specific Fmo3 gene repression. Coincident with its evolving biosynthesis, trimethylamine evokes species-specific behaviors, attracting mice, but repelling rats. Attraction to trimethylamine is abolished in TAAR5 knockout mice, and furthermore, attraction to mouse scent is impaired by enzymatic depletion of trimethylamine or TAAR5 knockout.
TAAR5 is an evolutionarily conserved olfactory receptor required for a species-specific behavior. Synchronized changes in odor biosynthesis pathways and odor-evoked behaviors could ensure species-appropriate social interactions.
► Evolution of a two-step biosynthesis pathway for the mouse odor trimethylamine ► Male-specific repression of FMO3, a key biosynthetic enzyme, arose de novo in Mus ► Trimethylamine evokes species-specific behaviors, attracting mice but repelling rats ► Knockout of TAAR5 or trimethylamine depletion impairs scent-attraction responses
Cedrela species occur within the Tropical montane cloud forest (TMCF) and rainforest in North America (Mexico), Central and South America. We assessed the hypothesis that functional xylem hydraulic ...architecture might be influenced by specific climatic variations. We investigated the effect of climate on tree-ring width and vessel traits (diameter, vessel density, vulnerability index and hydraulic diameter) of three relict-endemic and threatened Cedrela species (Cedrela fissilis, C. nebulosa and C. angustifolia) inhabiting Peruvian Tropical Andean cloud forests. All Cedrela species showed a significant reduction in radial growth and adjusted vessel trait linked with temperature, precipitation, and evapotranspiration. Ring-width and vessel traits showed adaptation within Cedrela species, crucial to understanding a rough indication of the plant's ability to withstand drought-induced embolism or cavitation. Our results provide evidence for hydraulic mechanisms that determine specific wood anatomical functionality to climatic variation and drought responses. Therefore, changing the frequency or intensity of future drought events might exceed the adaptive limits of TMCF tree species, resulting in a substantial reduction of hydraulic functionality in Peruvian Cedrela species.
Efficacy of endocrine therapy in HR+/HER2- metastatic breast cancer could differ depending on the presence of BRCA1/2 germline mutation.
The ESME metastatic breast cancer platform (NCT03275311) is a ...French real world database. Multivariable models including a time-varying approach and landmark analyses assessed the association between time-dependent gBRCA status (categorised as gBRCAm, gBRCAwt (wild type), and untested), overall survival (OS), and first-line progression-free survival (PFS1).
A total of 170 patients were gBRCAm carriers, 676 gBRCAwt, and 12,930 were untested at baseline. In the multivariable analysis, gBRCAm carriers overall had a lower OS compared to gBRCAwt (adjusted HR 95% CI 1.26 1.03-1.55). gBRCAm patients treated with front-line endocrine therapy had lower adjusted OS (adjusted HR 95% CI = 1.54 1.03-2.32) and PFS1 (adjusted HR 95% CI 1.58 1.17-2.12) compared to gBRCAwt patients. However, for patients who received frontline chemotherapy, neither OS nor PFS1 differed between gBRCAm carriers and the other groups (HR versus gBRCAwt for OS: 1.12 0.88-1.41, p = 0.350; PFS1: 1.09 0.90-1.31, p = 0.379).
In this large cohort of HR+/HER2- MBC patients treated in a pre-CDK4/6 inhibitors era, gBRCAm status was associated with a lower OS and lower PFS following first-line endocrine therapy, but not following first-line chemotherapy.
Everolimus is an agent frequently associated with specific toxicities. Predictive markers of efficacy are needed to help define which patients could benefit from it. The goal of this exploratory ...study was to identify potential predictive biomarkers in the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activation pathway using primary tumor samples collected during the phase II tamoxifen plus everolimus (TAMRAD) trial.
Tumor tissues were collected retrospectively from the TAMRAD trial. Immunohistochemistry was carried out using specific antibodies directed toward proteins that result in mTORC1 activation canonical phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mTOR or alternative pathways. DNA was extracted from the tumor tissue; mutation screening in the PIK3CA gene (exons 9 and 20) and the KRAS gene (exons 2 and 3) was first carried out using Sanger direct sequencing, and then completed by next-generation sequencing for PIK3CA. An exploratory analysis of everolimus efficacy in terms of a time-to-progression (TTP) increase was carried out in each biomarker subgroup (high versus low expression referring to the median percentage of marked cells).
A total of 55 primary tumor samples from the TAMRAD trial—25 from the tamoxifen-alone group and 30 from the tamoxifen/everolimus group—were evaluated for biomarkers. The subgroups most likely to have an improvement in TTP with tamoxifen/everolimus therapy, compared with tamoxifen alone, were patients with high p4EBP1, low 4EBP1, low liver kinase B1, low pAkt, and low PI3K. Among the 45 samples screened for mutation status, nine samples (20%; 95% CI 9.6–34.6) had a PIK3CA mutation. KRAS mutation was observed in one patient.
A positive correlation between late effectors of mTORC1 activation, a positive correlation between Akt-independent mTORC1 activation, and an inverse correlation between canonical PI3K/Akt/mTOR pathway and everolimus efficacy were observed in this exploratory analysis. However, these correlations need to be validated in larger studies before applying the findings to routine clinical practice.
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