Polarization charge densities provide a predictive quantification of hydrogen bond energies

A systematic density functional theory based study of hydrogen bond energies of 2465 single hydrogen bonds has been performed. In order to be closer to liquid phase conditions, different from the usual reference state of individual donor and acceptor molecules in vacuum, the reference state of donors and acceptors embedded in a perfect conductor as simulated by the COSMO solvation model has been used for the calculation of the hydrogen bond energies. The relationship between vacuum and conductor reference hydrogen bond energies is investigated and interpreted in the light of different physical contributions, such as electrostatic energy and dispersion. A very good correlation of the DFT/COSMO hydrogen bond energies with conductor polarization charge densities of separated donor and acceptor atoms was found. This provides a method to predict hydrogen bond strength in solution with a root mean square error of 0.36 kcal mol−1 relative to the quantum chemical dimer calculations. The observed correlation is broadly applicable and allows for a predictive quantification of hydrogen bonding, which can be of great value in many areas of computational, medicinal and physical chemistry

Interpretation of experimental hydrogen-bond enthalpies and entropies from COSMO polarisation charge densities

In this work, experimental hydrogen-bond (HB) enthalpies measured in previous works for a wide range of acceptor molecules in dilute mixtures of 4-fluorophenol in non-polar solvents are quantified from COSMO polarisation charge densities σ of HB acceptors (HBA). As well as previously demonstrated for quantum chemically calculated HB enthalpies, a good correlation of the experimental data with the polarisation charge densities is observed, covering an extended range of HBA (O, N, S, π systems and halogens) ranging from very weak to strong hydrogen bonds. Furthermore, for the first time, a quantitative analysis of experimental HB entropies is performed for such a chemical diversity of HBA. A good quantification of these entropies is achieved using the polarisation charge density σ as a descriptor in combination with the logarithm of a directional partition function ΩHB. This partition function covers the directional and multiplicity entropy of HBA and is based on the σ-proportional HB enthalpy expression taken from COSMO-RS. As a result, the experimental HB enthalpies and free energies of the ∼300 HB complexes are quantified with an accuracy of ∼2 kJ mol−1 based on COSMO polarisation charge densities

pilot ionosonde network for identification of traveling ionospheric disturbances

Travelling Ionospheric Disturbances (TIDs) are the ionospheric signatures of atmospheric gravity waves (AGWs). Their identification and tracking is important because the TIDs affect all services that rely on predictable ionospheric radio wave propagation. Although various techniques have been proposed to measure TID characteristics, their real-time implementation still has several difficulties. In this contribution, we present a new technique, based on the analysis of oblique Digisonde-to-Digisonde (D2D) "skymap" observations, to directly identify TIDs and specify the TID wave parameters based on the measurement of angle-of-arrival, Doppler frequency, and time-of-flight of ionospherically reflected high-frequency (HF) radio pulses. The technique has been implemented for the first time for the Net-TIDE project with data streaming from the network of European Digisonde DPS4D observatories. The performance is demonstrated during a period of moderate auroral activity, assessing its consistency with independent measurements such as data from auroral magnetometers and electron density perturbations from Digisondes and GNSS stations. Given that the different types of measurements used for this assessment were not made at exactly the same time and location, and that there was insufficient coverage in the area between the AGW sources and the measurement lo cations, we can only consider our interpretation as plausible and indicative for the reliability of the extracted TID characteristics. In the framework of the new TechTIDE project (European Commission H2020), a retrospective analysis of the Net-TIDE results in comparison with those extracted from GNSS TEC-based methodologies is currently being attempted, and the results will be the objective of a follow up paper

HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

Introduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in-situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, p<0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, p<0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (p=0.004), but not in HER2-positive/ESR1-negative tumors. Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group

Development of central nervous system metastases as a first site of metastatic disease in breast cancer patients treated in the neoadjuvant trials GeparQuinto and GeparSixto

Background: The incidence of central nervous system (CNS) metastases in breast cancer patients is rising and has become a major clinical challenge. Only few data are published concerning risk factors for the development of CNS metastases as a first site of metastatic disease in breast cancer patients. Moreover, the incidence of CNS metastases after modern neoadjuvant treatment is not clear. Methods: We analyzed clinical factors associated with the occurrence of CNS metastases as the first site of metastatic disease in breast cancer patients after neoadjuvant treatment in the trials GeparQuinto and GeparSixto (n = 3160) where patients received targeted treatment in addition to taxane and anthracycline-based chemotherapy. Results: After a median follow-up of 61 months, 108 (3%) of a total of 3160 patients developed CNS metastases as the first site of recurrence and 411 (13%) patients had metastatic disease outside the CNS. Thirty-six patients (1%) developed both CNS metastases and other distant metastases as the first site of metastatic disease. Regarding subtypes of the primary tumor, 1% of luminal A-like (11/954), 2% of luminal B-like (7/381), 4% of HER2-positive (34/809), and 6% of triple-negative patients (56/1008) developed CNS metastases as the first site of metastatic disease. In multivariate analysis, risk factors for the development of CNS metastases were larger tumor size (cT3–4; HR 1.63, 95% CI 1.08–2.46, p = 0.021), node-positive disease (HR 2.57, 95% CI 1.64–4.04, p &lt; 0.001), no pCR after neoadjuvant chemotherapy (HR 2.29, 95% CI 1.32–3.97, p = 0.003), and HER2-positive (HR 3.80, 95% CI 1.89–7.64, p &lt; 0.001) or triple-negative subtype (HR 6.38, 95% CI 3.28–12.44, p &lt; 0.001). Conclusions: Especially patients with HER2-positive and triple-negative tumors are at risk of developing CNS metastases despite effective systemic treatment. A better understanding of the underlying mechanisms is required in order to develop potential preventive strategies

RESPONDER – diagnosis of pathological complete response by vacuum-assisted biopsy after neoadjuvant chemotherapy in breast Cancer - a multicenter, confirmative, one-armed, intra-individually-controlled, open, diagnostic trial

Background: Neoadjuvant chemotherapy (NACT) is a standard approach of the multidisciplinary treatment of breast cancer. Depending on the biological subtype a pathological complete response in the breast (bpCR) can be achieved in up to 60% of the patients. However, only limited accuracy can be reached when using imaging for prediction of bpCR prior to surgery. Due to this diagnostic uncertainty, surgery after NACT is considered to be obligatory for all patients in order to either completely remove residual disease or to diagnose a bpCR histologically. The purpose of this trial is to evaluate the accuracy of a vacuum-assisted biopsy (VAB) to diagnose a bpCR after NACT prior to surgery. Methods: This study is a multicenter, confirmative, one-armed, intra-individually-controlled, open, diagnostic trial. The study will take place at 21 trial sites in Germany. Six hundred female patients with breast cancer after completed NACT showing at least a partial response to NACT treatment will be enrolled. A vacuum-assisted biopsy (VAB) guided either by ultrasound or mammography will be performed followed by histopathological evaluation of the VAB specimen before standard, guideline-adherent breast surgery. The study is designed to prove that the false negative rate of the VAB is below 10%. Discussion: As a bpCR is becoming a more frequent result after NACT, the question arises whether breast surgery is therapeutically necessary in such cases. To study this subject further, it will be crucial to develop a reliable test to diagnose a bpCR without surgery. During the study we anticipate possible problems in patient recruitment as the VAB intervention does not provide participating patients with any personal benefit. Hence, a proficient informed consent discussion with the patient and a detailed explanation of the study aim will be crucial for patient recruitment. Another critical issue is the histopathological VAB evaluation of a non-tumorous specimen as this may have been taken either from the former tumor region (bpCR) or outside of the (former) tumor region (non-representative VAB, sampling error). Trial registration: The trial has been registered at clinicaltrials.gov with the identifier NCT02948764 on October 28, 2016 and at the German Clinical Trials Register ( DRKS00011761 ) on February 20, 2017. The date of enrolment of the first participant to the trial was on March 8, 2017

COSMO-RS based predictions for the SAMPL6 logP challenge

Within the framework of the 6th physical property blind challenge (SAMPL6) the authors have participated in predicting the octanol-water partition coefficients (logP) for several small drug like molecules. Those logP values where experimentally known by the organizers but only revealed after the submissions of the predictions. Two different sets of predictions were submitted by the authors, both based on the COSMOtherm implementation of COSMO-RS theory. COSMOtherm predictions using the FINE parametrization level (hmz0n) obtained the highest accuracy among all submissions as measured by the root mean squared error. COSMOquick predictions using a fast algorithm to estimate sigma-profiles and an a posterio machine learning correction on top of the COSMOtherm results (3vqbi) scored 3rd out of 91 submissions. Both results underline the high quality of COSMO-RS derived molecular free energies in solution

Predicting Flash Points of Pure Compounds and Mixtures with COSMO-RS

Flash point (FP) is an important parameter for assessing the safety of chemical compounds. Many empirical approaches have been developed to predict FPs based on molecular structure, sometimes involving a large number of descriptors and resulting in class-specific equations. We demonstrate in this work that a satisfying and rather general prediction of the saturation pressure at the FP can be achieved using only the molecular surface area. This relation in combination with any experimental or computational method for calculating temperature-dependent vapor pressures thus allows for the prediction of the FP. In a second step, we calculate the FPs of mixtures using COSMO-RS activity coefficients. By using the proposed method, we were able to calculate flash points without the need for data typically generated in experiments such as normal boiling points or enthalpies of combustion, although experimental pure-compound FPs and vapor-pressure data still can be used to increase the prediction quality