Solitary fibrous tumours of the pleura: do we need a different perspective on malignancy?

OBJECTIVES: Solitary fibrous tumours of the pleura (SFTP) are historically considered to be benign soft tissue neoplasms. However, a clinical relevant number of these neoplasms have malignant histological features. The objective of this study was to evaluate the percentage of SFTP presenting unfavourable clinical behaviour in order to predict negative long-term outcome. METHODS: A retrospective review of 74 patients treated at 4 hospitals between 1990 and 2013 was performed. The median follow-up was 10 years (range: 1-20 years). Risk of tumour recurrence and metastases (unfavourable clinical behaviour) with regard to histology using the Kaplan-Meier and Cox proportional hazards methods. RESULTS: The mean age was 61 years (SD 12.75 years). There were 31 male patients (58%) and 43 female patients (42%). Tumour size ranged from 1 to 30 cm (mean 9.09 cm; SD 6.22 cm). Complete resection (R0) was achieved by minimally invasive thoracoscopic resection in 29% and thoracotomy in 57%; 25% of SFTPs showed histological evidence of malignancy, according to England criteria. Recurrence occurred in 21% and 10% of patients had metastases; 83% of patients with metastases and 39% of patients with recurrence died within 5 years. The median recurrence-free survival for histologically benign SFTP was not reached, compared to 8 years for malignant SFTP. The five-year overall survival rate was 84%. Mitotic rate ≥1/10 HPF, high cellularity, nuclear atypia, Ki-67 level >5% and poorly circumscribed (sessile) growth pattern were associated with poor long-term outcome. CONCLUSIONS: Pathological differentiation of SFTP morphology into pedunculated, well circumscribed and poorly circumscribed (sessile) growth pattern is recommended. Due to the misleading classification into histologically benign and malignant, all unpedunculated SFTP should be classified as potentially aggressive. Lifelong follow-up is mandatory.

Relevance of tumor markers for prognosis and predicting therapy response in non-small cell lung cancer patients: A CEPAC-TDM biomarker substudy.

BACKGROUND: Protein tumor markers are released in high amounts into the blood in advanced non-small cell lung cancer (NSCLC). OBJECTIVE: To investigate the relevance of serum tumor markers (STM) for prognosis, prediction and monitoring of therapy response in NSCLC patients receiving chemotherapy. METHODS: In a biomarker substudy of a prospective, multicentric clinical trial (CEPAC-TDM) on 261 advanced NSCLC patients, CYFRA 21-1, CEA, SCC, NSE, ProGRP, CA125, CA15-3 and HE4 were assessed in serial serum samples and correlated with radiological response after two cycles of chemotherapy and overall (OS) and progression-free survival (PFS). RESULTS: While pretherapeutic STM levels at staging did not discriminate between progressive and non-progressive patients, CYFRA 21-1, CA125, NSE and SCC at time of staging did, and yielded AUCs of 0.75, 0.70, 0.69 and 0.67 in ROC curves, respectively. High pretherapeutic CA15-3 and CA125 as well as high CYFRA 21-1, SCC, CA125 and CA15-3 levels at staging were prognostic for shorter PFS and OS -also when clinical variables were added to the models. CONCLUSIONS: STM at the time of first radiological staging and pretherapeutic CA15-3, CA125 are predictive for first-line treatment response and highly prognostic in patients with advanced NSCLC.

Package delivered: folate receptor-mediated transporters in cancer therapy and diagnosis.

Neoplasias pose a significant threat to aging society, underscoring the urgent need to overcome the limitations of traditional chemotherapy through pioneering strategies. Targeted drug delivery is an evolving frontier in cancer therapy, aiming to enhance treatment efficacy while mitigating undesirable side effects. One promising avenue utilizes cell membrane receptors like the folate receptor to guide drug transporters precisely to malignant cells. Based on the cellular folate receptor as a cancer cell hallmark, targeted nanocarriers and small molecule-drug conjugates have been developed that comprise different (bio) chemistries and/or mechanical properties with individual advantages and challenges. Such modern folic acid-conjugated stimuli-responsive drug transporters provide systemic drug delivery and controlled release, enabling reduced dosages, circumvention of drug resistance, and diminished adverse effects. Since the drug transporters' structure-based de novo design is increasingly relevant for precision cancer remediation and diagnosis, this review seeks to collect and debate the recent approaches to deliver therapeutics or diagnostics based on folic acid conjugated Trojan Horses and to facilitate the understanding of the relevant chemistry and biochemical pathways. Focusing exemplarily on brain and breast cancer, recent advances spanning 2017 to 2023 in conjugated nanocarriers and small molecule drug conjugates were considered, evaluating the chemical and biological aspects in order to improve accessibility to the field and to bridge chemical and biomedical points of view ultimately guiding future research in FR-targeted cancer therapy and diagnosis.

Missing prognostic value of soluble PD-1, PD-L1 and PD-L2 in lung cancer patients undergoing chemotherapy - A CEPAC-TDM biomarker substudy.

BACKGROUND: Programmed cell death receptors and ligands in cancer tissue samples are established companion diagnostics for immune checkpoint inhibitor (ICI) therapies. OBJECTIVE: To investigate the relevance of soluble PD-1, PD-L1 and PD-L2 for estimating therapy response and prognosis in non-small cell lung cancer patients (NSCLC) undergoing platin-based combination chemotherapies. METHODS: In a biomarker substudy of a prospective, multicentric clinical trial (CEPAC-TDM) on advanced NSCLC patients, soluble PD-1, PD-L1 and PD-L2 were assessed in serial serum samples by highly sensitive enzyme-linked immunosorbent assays and correlated with radiological response after two cycles of chemotherapy and with overall survival (OS). RESULTS: Among 243 NSCLC patients, 185 achieved response (partial remission and stable disease) and 58 non-response (progression). The distribution of PD-1, PD-L1 and PD-L2 at baseline (C1), prior to staging (C3) and the relative changes (C3/C1) greatly overlapped between the patient groups with response and non-response, thus hindering the discrimination between the two groups. None of the PD markers had prognostic value regarding OS. CONCLUSIONS: Neither soluble PD-1, PD-L1 nor PD-L2 did provide clinical utility for predicting response to chemotherapy and prognosis. Studies on the relevance of PD markers in ICI therapies are warranted.

Vaccination Training for Pharmacy Undergraduates as a Compulsory Part of the Curriculum?-A Multicentric Observation.

In order to increase vaccination rates, the Government of Germany introduced vaccination against influenza and COVID-19 into the regular care administered by pharmacists. However, vaccination training is yet not integrated into the German pharmacy curriculum. Therefore, the Institute for Clinical Pharmacy and Pharmacotherapy in Duesseldorf had developed an innovative vaccination course using high-fidelity simulation for students. To investigate the acceptance further, the course was carried out at three different German universities (Bonn, Duesseldorf, Greifswald). Students were asked to give their self-assessment before and after and satisfaction only after the training course. Responses from 33 participants from the University of Bonn, 42 from the University of Duesseldorf and 49 from the University of Greifswald were analyzed. Every participant at the respective universities showed a significant increase in their self-assessment and indicated a high level of satisfaction with the course. The results also did not differ significantly between the respective universities. Consequently, the results lead to the hypothesis that the satisfaction of pharmacy students with this kind of training using high-fidelity simulation is very high and attractive, and can be recommended for other German universities. The integration of such vaccination training into the German pharmacy curriculum might be a future step.

Loss of Key EMT-Regulating miRNAs Highlight the Role of ZEB1 in EGFR Tyrosine Kinase Inhibitor-Resistant NSCLC.

Despite recent advances in the treatment of non-small cell lung cancer (NSCLC), acquired drug resistance to targeted therapy remains a major obstacle. Epithelial-mesenchymal transition (EMT) has been identified as a key resistance mechanism in NSCLC. Here, we investigated the mechanistic role of key EMT-regulating small non-coding microRNAs (miRNAs) in sublines of the NSCLC cell line HCC4006 adapted to afatinib, erlotinib, gefitinib, or osimertinib. The most differentially expressed miRNAs derived from extracellular vesicles were associated with EMT, and their predicted target ZEB1 was significantly overexpressed in all resistant cell lines. Transfection of a miR-205-5p mimic partially reversed EMT by inhibiting ZEB1, restoring CDH1 expression, and inhibiting migration in erlotinib-resistant cells. Gene expression of EMT-markers, transcription factors, and miRNAs were correlated during stepwise osimertinib adaptation of HCC4006 cells. Temporally relieving cells of osimertinib reversed transition trends, suggesting that the implementation of treatment pauses could provide prolonged benefits for patients. Our results provide new insights into the contribution of miRNAs to drug-resistant NSCLC harboring EGFR-activating mutations and highlight their role as potential biomarkers and therapeutic targets.

Spatio-temporal evolution of long-range transported mineral desert dust properties over rural and urban sites in Central Europe.

An exceptionally strong and very fast (120h) mineral dust inflow from North Africa to Poland was predicted by NMMB/BSC-Dust and NAAPS models on 10-11 June 2019. Simultaneous measurements with two complex lidar systems at the EARLINET-ACTRIS urban site in Warsaw (Central Poland) and the PolWET peatland site in Rzecin (Western Poland) captured the evolution of this dust event. The advected air masses had different source areas in North Africa, they were reaching each station via independent pathways, and thus, were unlikely mixed with each other. The excellent capabilities of the next generation PollyXT lidar and the mobile EMORAL lidar allowed for the derivation of full datasets of aerosol optical properties profiles that enabled comparative study of the advected dust properties evolution. Within a mere 350 km distance between Warsaw and Rzecin, distinctly different dust properties were measured, respectively: dry mineral dust composed mainly of coarse mode dust particles (50 ± 5 % of the total particle backscattering profile) versus the wet mineral dust dominated by fine dust particles (58 ± 4 %). A new parameter fine-to-coarse dust ratio (FCDR) is proposed to describe more intuitively mineral dust composition.

Accurate machine learning prediction of sexual orientation based on brain morphology and intrinsic functional connectivity.

BACKGROUND: Sexual orientation in humans represents a multilevel construct that is grounded in both neurobiological and environmental factors. OBJECTIVE: Here, we bring to bear a machine learning approach to predict sexual orientation from gray matter volumes (GMVs) or resting-state functional connectivity (RSFC) in a cohort of 45 heterosexual and 41 homosexual participants. METHODS: In both brain assessments, we used penalized logistic regression models and nonparametric permutation. RESULTS: We found an average accuracy of 62% (±6.72) for predicting sexual orientation based on GMV and an average predictive accuracy of 92% (±9.89) using RSFC. Regions in the precentral gyrus, precuneus and the prefrontal cortex were significantly informative for distinguishing heterosexual from homosexual participants in both the GMV and RSFC settings. CONCLUSIONS: These results indicate that, aside from self-reports, RSFC offers neurobiological information valuable for highly accurate prediction of sexual orientation. We demonstrate for the first time that sexual orientation is reflected in specific patterns of RSFC, which enable personalized, brain-based predictions of this highly complex human trait. While these results are preliminary, our neurobiologically based prediction framework illustrates the great value and potential of RSFC for revealing biologically meaningful and generalizable predictive patterns in the human brain.

Immunophenotyping of Circulating and Intratumoral Myeloid and T Cells in Glioblastoma Patients.

Glioblastoma is the most common and lethal primary brain malignancy that almost inevitably recurs as therapy-refractory cancer. While the success of immune checkpoint blockade (ICB) revealed the immense potential of immune-targeted therapies in several types of cancers outside the central nervous system, it failed to show objective responses in glioblastoma patients as of now. The ability of glioblastoma cells to drive multiple modes of T cell dysfunction while exhibiting low-quality neoepitopes, low-mutational load, and poor antigen priming limits anti-tumor immunity and efficacy of antigen-unspecific immunotherapies such as ICB. An in-depth understanding of the GBM immune landscape is essential to delineate and reprogram such immunosuppressive circuits during disease progression. In this view, the present study aimed to characterize the peripheral and intratumoral immune compartments of 35 glioblastoma patients compared to age- and sex-matched healthy control probands, particularly focusing on exhaustion signatures on myeloid and T cell subsets. Compared to healthy control participants, different immune signatures were already found in the peripheral circulation, partially related to the steroid medication the patients received. Intratumoral CD4+ and CD8+ TEM cells (CD62Llow/CD45ROhigh) revealed a high expression of PD1, which was also increased on intratumoral, pro-tumorigenic macrophages/microglia. Histopathological analysis further identified high PSGL-1 expression levels of the latter, which has recently been linked to increased metastasis in melanoma and colon cancer via P-selectin-mediated platelet activation. Overall, the present study comprises immunophenotyping of a patient cohort to give implications for eligible immunotherapeutic targets in neurooncology in the future.

Correction: Döring et al. Discovery of Novel Symmetrical 1,4-Dihydropyridines as Inhibitors of Multidrug-Resistant Protein (MRP4) Efflux Pump for Anticancer Therapy. Molecules 2021, 26, 18.

The authors would like to correct an error made through no fault of their own in the title paper [...].

Hippocampus mediates nocebo impairment of opioid analgesia through changes in functional connectivity.

The neural mechanisms underlying placebo analgesia have attracted considerable attention over the recent years. In contrast, little is known about the neural underpinnings of a nocebo-induced increase in pain. We previously showed that nocebo-induced hyperalgesia is accompanied by increased activity in the hippocampus that scaled with the perceived level of anxiety. As a key node of the neural circuitry of perceived threat and fear, the hippocampus has recently been proposed to coordinate defensive behaviour in a context-dependent manner. Such a role requires close interactions with other regions involved in the detection of and responses to threat. Here, we investigated the functional connectivity of the hippocampus during nocebo-induced hyperalgesia. Our results show an increase in functional connectivity between hippocampus and brain regions implicated in the processing of sensory-discriminative aspects of pain (posterior insula and primary somatosensory/motor cortex) as well as the periaqueductal grey. This nocebo-induced increase in connectivity scaled with an individual's increase in anxiety. Moreover, hippocampus connectivity with the amygdala was negatively correlated with the pain intensity reported during nocebo hyperalgesia relative to the placebo condition. Our findings suggest that the hippocampus links nocebo-induced anxiety to a heightened responsiveness to nociceptive input through changes in its crosstalk with pain-modulatory brain areas.

Gas Plasma Exposure of Glioblastoma Is Cytotoxic and Immunomodulatory in Patient-Derived GBM Tissue.

Glioblastoma multiforme (GBM) is the most common primary malignant adult brain tumor. Therapeutic options for glioblastoma are maximal surgical resection, chemotherapy, and radiotherapy. Therapy resistance and tumor recurrence demand, however, new strategies. Several experimental studies have suggested gas plasma technology, a partially ionized gas that generates a potent mixture of reactive oxygen species (ROS), as a future complement to the existing treatment arsenal. However, aspects such as immunomodulation, inflammatory consequences, and feasibility studies using GBM tissue have not been addressed so far. In vitro, gas plasma generated ROS that oxidized cells and led to a treatment time-dependent metabolic activity decline and G2 cell cycle arrest. In addition, peripheral blood-derived monocytes were co-cultured with glioblastoma cells, and immunomodulatory surface expression markers and cytokine release were screened. Gas plasma treatment of either cell type, for instance, decreased the expression of the M2-macrophage marker CD163 and the tolerogenic molecule SIGLEC1 (CD169). In patient-derived GBM tissue samples exposed to the plasma jet kINPen ex vivo, apoptosis was significantly increased. Quantitative chemokine/cytokine release screening revealed gas plasma exposure to significantly decrease 5 out of 11 tested chemokines and cytokines, namely IL-6, TGF-ß, sTREM-2, b-NGF, and TNF-α involved in GBM apoptosis and immunomodulation. In summary, the immuno-modulatory and proapoptotic action shown in this study might be an important step forward to first clinical observational studies on the future discovery of gas plasma technology's potential in neurosurgery and neuro-oncology especially in putative adjuvant or combinatory GBM treatment settings.

Respiratory function modulated during execution, observation, and imagination of walking via SII.

The Mirror Neurons System (MNS) consists of brain areas active during actions execution, as well as observation-imagination of the same actions. MNS represents a potential mechanism by which we understand other's action goals. We investigated MNS activation for legs actions, and its interaction with the autonomic nervous system. We performed a physiological and fMRI investigation on the common neural structures recruited during the execution, observation, and imagination of walking, and their effects on respiratory activity. Bilateral SMA were activated by all three tasks, suggesting that these areas are responsible for the core of the MNS effect for walking. Moreover, we observed in bilateral parietal opercula (OP1, secondary somatosensory cortex-SII) evidence of an MNS subtending walking execution-observation-imagination that also modulated the respiratory function. We suggest that SII, in modulating the vegetative response during motor activity but also during observation-imagination, consists of a re-enacting function which facilitates the understanding of motor actions.

Novel Symmetrical Cage Compounds as Inhibitors of the Symmetrical MRP4-Efflux Pump for Anticancer Therapy.

Within the last decades cancer treatment improved by the availability of more specifically acting drugs that address molecular target structures in cancer cells. However, those target-sensitive drugs suffer from ongoing resistances resulting from mutations and moreover they are affected by the cancer phenomenon of multidrug resistance. A multidrug resistant cancer can hardly be treated with the common drugs, so that there have been long efforts to develop drugs to combat that resistance. Transmembrane efflux pumps are the main cause of the multidrug resistance in cancer. Early inhibitors disappointed in cancer treatment without a proof of expression of a respective efflux pump. Recent studies in efflux pump expressing cancer show convincing effects of those inhibitors. Based on the molecular symmetry of the efflux pump multidrug resistant protein (MRP) 4 we synthesized symmetric inhibitors with varied substitution patterns. They were evaluated in a MRP4-overexpressing cancer cell line model to prove structure-dependent effects on the inhibition of the efflux pump activity in an uptake assay of a fluorescent MRP4 substrate. The most active compound was tested to resentisize the MRP4-overexpressing cell line towards a clinically relevant anticancer drug as proof-of-principle to encourage for further preclinical studies.

Constitutive Cell Proliferation Regulating Inhibitor of Protein Phosphatase 2A (CIP2A) Mediates Drug Resistance to Erlotinib in an EGFR Activating Mutated NSCLC Cell Line.

Exploring mechanisms of drug resistance to targeted small molecule drugs is critical for an extended clinical benefit in the treatment of non-small cell lung cancer (NSCLC) patients carrying activating epidermal growth factor receptor (EGFR) mutations. Here, we identified constitutive cell proliferation regulating inhibitor of protein phosphatase 2A (CIP2A) in the HCC4006rErlo0.5 NSCLC cell line adapted to erlotinib as a model of acquired drug resistance. Constitutive CIP2A resulted in a constitutive activation of Akt signaling. The proteasome inhibitor bortezomib was able to reduce CIP2A levels, which resulted in an activation of protein phosphatase 2A and deactivation of Akt. Combination experiments with erlotinib and bortezomib revealed a lack of interaction between the two drugs. However, the effect size of bortezomib was higher in HCC4006rErlo0.5, compared to the erlotinib-sensitive HCC4006 cells, as indicated by an increase in Emax (0.911 (95%CI 0.867-0.954) vs. 0.585 (95%CI 0.568-0.622), respectively) and decrease in EC50 (52.4 µM (95%CI 46.1-58.8 µM) vs. 73.0 µM (95%CI 60.4-111 µM), respectively) in the concentration-effect model, an earlier onset of cell death induction, and a reduced colony surviving fraction (0.38 ± 0.18 vs. 0.95 ± 0.25, respectively, n = 3, p < 0.05). Therefore, modulation of CIP2A with bortezomib could be an interesting approach to overcome drug resistance to erlotinib treatment in NSCLC.

An extended lidar-based cirrus cloud retrieval scheme: first application over an Arctic site.

Accurate and precise characterization of cirrus cloud geometrical and optical properties is essential for better constraining their radiative footprint. A lidar-based retrieval scheme is proposed here, with its performance assessed on fine spatio-temporal observations over the Arctic site of Ny-Ålesund, Svalbard. Two contributions related to cirrus geometrical (dynamic Wavelet Covariance Transform (WCT)) and optical properties (constrained Klett) are reported. The dynamic WCT rendered cirrus detection more robust, especially for thin cirrus layers that frequently remained undetected by the classical WCT method. Regarding optical characterization, we developed an iterative scheme for determining the cirrus lidar ratio (LRci) that is a crucial parameter for aerosol - cloud discrimination. Building upon the Klett-Fernald method, the LRci was constrained by an additional reference value. In established methods, such as the double-ended Klett, an aerosol-free reference value is applied. In the proposed constrained Klett, however, the reference value was approximated from cloud-free or low cloud optical depth (COD up to 0.2) profiles and proved to agree with independent Raman estimates. For optically thin cirrus, the constrained Klett inherent uncertainties reached 50% (60-74%) in terms of COD (LRci). However, for opaque cirrus COD (LRci) uncertainties were lower than 10% (15%). The detection method discrepancies (dynamic versus static WCT) had a higher impact on the optical properties of low COD layers (up to 90%) compared to optically thicker ones (less than 10%). The constrained Klett presented high agreement with two established retrievals. For an exemplary cirrus cloud, the constrained Klett estimated the COD355 (LRci355) at 0.28 ± 0.17 (29 ± 4 sr), the double-ended Klett at 0.27 ± 0.15 (32 ± 4 sr) and the Raman retrievals at 0.22 ± 0.12 (26 ± 11 sr). Our approach to determine the necessary reference value can also be applied in established methods and increase their accuracy. In contrast, the classical aerosol-free assumption led to 44  sr LRci overestimation in optically thin layers and 2-8 sr in thicker ones. The multiple scattering effect was corrected using Eloranta (1998) and accounted for 50-60% extinction underestimation near the cloud base and 20-30% within the cirrus layers.

Discovery of Novel Symmetrical 1,4-Dihydropyridines as Inhibitors of Multidrug-Resistant Protein (MRP4) Efflux Pump for Anticancer Therapy.

Despite the development of targeted therapies in cancer, the problem of multidrug resistance (MDR) is still unsolved. Most patients with metastatic cancer die from MDR. Transmembrane efflux pumps as the main cause of MDR have been addressed by developed inhibitors, but early inhibitors of the most prominent and longest known efflux pump P-glycoprotein (P-gp) were disappointing. Those inhibitors have been used without knowledge about the expression of P-gp by the treated tumor. Therefore the use of inhibitors of transmembrane efflux pumps in clinical settings is reconsidered as a promising strategy in the case of the respective efflux pump expression. We discovered novel symmetric inhibitors of the symmetric efflux pump MRP4 encoded by the ABCC4 gene. MRP4 is involved in many kinds of cancer with resistance to anticancer drugs. All compounds showed better activities than the best known MRP4 inhibitor MK571 in an MRP4-overexpressing cell line assay, and the activities could be related to the various substitution patterns of aromatic residues within the symmetric molecular framework. One of the best compounds was demonstrated to overcome the MRP4-mediated resistance in the cell line model to restore the anticancer drug sensitivity as a proof of concept.

Water vapor satellite products in the European Arctic: An inter-comparison against GNSS data.

The European Arctic is a region of high interest for climate change. Water vapor plays a fundamental role in global warming; therefore, high-quality water vapor monitoring is essential for assimilation in forecast simulations. The seven analyzed instruments on-board satellite platforms are: Atmospheric Infrared Sounder (AIRS), Global Ozone Monitoring Instrument 2 (GOME-2), Moderate-Resolution Imaging Spectroradiometer (MODIS), Ozone Monitoring Instrument (OMI), SCanning Imaging Absorption Spectrometer for Atmospheric Carthography (SCIAMACHY) and Polarization and Directionality of the Earth's Reflectances (POLDER). The GNSS data from Ny-Ålesund are matched to satellite observations of IWV in a 30-min temporal window, and 100-km radius. Then, statistics and the distribution of satellite-ground differences under different conditions are studied. The correlation coefficient (R2) with ground-based measurements is about 0.7 for all products except OMI (R2=0.5), and MODIS NIR and POLDER (R2=0.3). OMI shows high bias and variability compared to the rest of products. RMSE values are of the order of 3 mm for all satellites, except OMI (7 mm) and POLDER (5 mm). Bias (MBE) is negligible for AIRS, close to +1.6 mm for GOME-2 and MODIS IR, +0.8 mm for MODIS NIR, +5.9 mm for OMI, -2.7 mm for POLDER and -1.2 mm for SCIAMCHY. All satellite products tend to overestimate small IWV values and underestimate large IWV values. Variability also increases with IWV. An underestimation of the satellite products and an increase on the variability is generally observed for large Solar Zenith Angle (SZA) values. Under cloudy conditions, underestimation and variability are increased. Seasonal behavior is driven by the typical cloud cover (CC), SZA, and IWV values. In summer, it is typical to find conditions with large IWV, small SZA and large CC values. Therefore, in summer months satellite products are more biased (either positively or negatively) and with more variability, but in relative terms they are less biased and exhibit less variability.

Novel Nonsymmetrical 1,4-Dihydropyridines as Inhibitors of Nonsymmetrical MRP-Efflux Pumps for Anticancer Therapy.

Cancer is a strong global burden with increasing numbers of diseases and ongoing anticancer drug resistance. The number of structurally novel anticancer drugs is strongly limited. They cause high costs for the social health systems. Most critical so-called multidrug resistances (MDR) are caused by transmembrane efflux pumps that transport drugs with various structures out of the cancer cells. Multidrug resistance proteins (MRPs) type 1 and 2 are found overexpressed in various kinds of cancer. There is a strong need for inhibitors of those efflux pumps. We developed novel nonsymmetrical 1,4-dihydropyridines as novel inhibitors of cancer relevant MRP types 1 and 2. The structure-dependent activities of the differently substituted derivatives were evaluated in cellular assays of respective cancer cells and are discussed. Promising candidates were identified. One candidate was demonstrated to resensitize a cisplatin resistant cancer cell line and thus to overcome the anticancer drug resistance.

KOKON: A Germany-Wide Collaborative Research Project to Identify Needs, Provide Information, Foster Communication and Support Decision-Making about Complementary and Alternative Medicine in Oncology.

BACKGROUND: The German Cancer Aid set up a priority research programme with the intention to generate high-quality information based on evidence and to make this information easily accessible for health-care professionals and advisors, researchers, patients, and the general public. SUMMARY: The Kompetenznetz Komplementärmedizin in der Onkologie (KOKON) received 2 funding periods within this programme. During the first funding period, KOKON assessed patients' and health-care professionals' informational needs, developed a consulting manual for physicians, developed an education programme for self-help groups, set up a knowledge database, and developed a pilot information website for patients. Funding period 2 continues with work that allows cancer patients and health-care professionals to make informed decisions about complementary and alternative medicine (CAM). For this aim, KOKON evaluates training programmes for physicians (oncology physicians, paediatric oncologists, and general practitioners) and for self-help groups. All training programmes integrate results from an analysis of the ethical, psychological, and medical challenges of CAM in the medical encounter, and the knowledge database is being extended with issues related to CAM for supportive and palliative care. Key Message: A Germany-wide collaborative research project to identify needs, provide information, foster communication, and support decision-making about CAM in oncology is being set up.