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Herein, we report the synthesis and sensing characteristics of 4,4′‐methoxy‐substituted BODIPY fluorescent probes (O‐BODIPYs) 3, 4 and 5 equipped with differently sized benzo‐crown ethers (cf. Scheme 1, 3 (benzo‐15‐crown‐5), 4 (benzo‐18‐crown‐6) and 5 (benzo‐21‐crown7)). O‐BODIPYs 3, 4 and 5 exhibited in comparison to their known F‐BODIPY analogues 3a, 4a and 5a (cf. Scheme 1) an improved solubility in aqueous medium and higher fluorescence quantum yields. Fluorometric study in aqueous solutions of 3, 4 and 5 in the presence of different cations show cation induced fluorescence enhancements (FE). Compared to the benzo‐crown ether substituted F‐BODIPY analogues 3a, 4a and 5a, we found for the free O‐BODIPYs 3, 4 and 5 higher fluorescence quantum yields (φf) but lower cation induced FEs. We show that in aqueous medium the fluorescence quenching process (OFF switching), a photoinduced electron transfer, in O‐BODIPYs 3, 4 and 5 is less effective and consequently sensitive and selective ON switching of the fluorescence by cations, too. Albeit these observations the novel benzo‐21‐crown‐7 equipped fluorescent probe 5 exhibits a good fluorometric Ba2+ selectivity and Ba2+ sensitivity in conjunction to their aqueous solubility. [ABSTRACT FROM AUTHOR]

Herein, we report the synthesis and sensing characteristics of 4,4′‐methoxy‐substituted BODIPY fluorescent probes (O‐BODIPYs) 3, 4 and 5 equipped with differently sized benzo‐crown ethers (cf. Scheme 1, 3 (benzo‐15‐crown‐5), 4 (benzo‐18‐crown‐6) and 5 (benzo‐21‐crown7)). O‐BODIPYs 3, 4 and 5 exhibited in comparison to their known F‐BODIPY analogues 3a, 4a and 5a (cf. Scheme 1) an improved solubility in aqueous medium and higher fluorescence quantum yields. Fluorometric study in aqueous solutions of 3, 4 and 5 in the presence of different cations show cation induced fluorescence enhancements (FE). Compared to the benzo‐crown ether substituted F‐BODIPY analogues 3a, 4a and 5a, we found for the free O‐BODIPYs 3, 4 and 5 higher fluorescence quantum yields (φf) but lower cation induced FEs. We show that in aqueous medium the fluorescence quenching process (OFF switching), a photoinduced electron transfer, in O‐BODIPYs 3, 4 and 5 is less effective and consequently sensitive and selective ON switching of the fluorescence by cations, too. Albeit these observations the novel benzo‐21‐crown‐7 equipped fluorescent probe 5 exhibits a good fluorometric Ba2+ selectivity and Ba2+ sensitivity in conjunction to their aqueous solubility. [ABSTRACT FROM AUTHOR]

Herein, we report on highly Ba2+ selective fluorescence sensing in water by a fluorescent probe consisting of a benzo‐21‐crown‐7 as a Ba2+ binding unit (ionophore) and a tetramethylated BODIPY fluorophore as a fluorescence reporter. This fluorescent probe showed a Ba2+ induced fluorescence enhancement (FE) by a factor of 12±1 independently of the pH value and a high Ba2+ sensitivity with a limit of detection (LOD) of (17.2±0.3) μM. Moreover, a second fluorescent probe consisting of the same BODIPY fluorophore, but a benzo‐18‐crown‐6 as a cation‐responsive binding moiety, showed an even higher FE upon Ba2+ complexation by a factor of 85±3 and a lower LOD of (13±3) μM albeit a lower Ba2+ selectivity. The fluorescence sensing mechanism of Ba2+ was further investigated by time‐resolved fluorescence as well as transient absorption spectroscopy (TAS) and it turned out that within these probes a blocking of a photoinduced electron transfer (PET) by Ba2+ is very likely responsible for the FE. [ABSTRACT FROM AUTHOR]

The fundamental aim of healthcare is to improve overall health of the population by providing state-of-the-art healthcare for individuals at an affordable cost. The foundation for this system is largely referred to as "evidence-based medicine". Too often, evidence-based medicine is based solely on so-called "best research evidence", collected through randomized controlled trials while disregarding clinical expertise and patient expectations. As healthcare gravitates towards personalized and individualized medicine, such external clinical (research) evidence can inform, but never replace, individual clinical expertise. This applies in particular to orphan diseases, for which clinical trials are methodologically particularly problematic, and evidence derived from them is often questionable. Evidence-based medicine constitutes a complex process to allow doctors and patients to select the best possible solutions for each individual based on rapidly developing new therapeutic directions. This requires a revisit of the foundations of evidence-based medicine. A proposition as to how to manage evidence-based data in individualized immune-oncology is presented here. [ABSTRACT FROM AUTHOR]

Simple Summary: The standard of care for patients with primary glioblastoma multiforme consists of neurosurgery, radiochemotherapy, and maintenance chemotherapy. We added individualized multimodal immunotherapy to this treatment. During maintenance chemotherapy, immunogenic cell death immunotherapy (oncolytic virus injections and sessions of modulated electrohyperthermia) was inserted. After chemotherapy, active specific immunotherapy with dendritic cell vaccines (IO-Vac®) and modulatory immunotherapy were given. The manuscript describes the retrospective analysis of a group of 50 adults taken out of the database following a predefined clinical profile without further bias. We observed a clearly improved overall survival in comparison to published data. There were no major adverse reactions. The proposed treatment concept takes into account dynamic changes in tumor biology and tumor–host interaction, proposing an additional perspective besides the paradigm of protocol medicine in clinical trials. This report on real-world data has great scientific value and high relevance for patients. Synergistic activity between maintenance temozolomide (TMZm) and individualized multimodal immunotherapy (IMI) during/after first-line treatment has been suggested to improve the overall survival (OS) of adults with IDH1 wild-type MGMT promoter-unmethylated (unmeth) GBM. We expand the data and include the OS of MGMT promoter-methylated (meth) adults with GBM. Unmeth (10 f, 18 m) and meth (12 f, 10 m) patients treated between 27 May 2015 and 1 January 2022 were analyzed retrospectively. There were no differences in age (median: 48 y) or Karnofsky performance index (median: 80). The IMI consisted of 5-day immunogenic cell death (ICD) therapies during TMZm: Newcastle disease virus (NDV) bolus injections and sessions of modulated electrohyperthermia (mEHT); subsequent active specific immunotherapy: dendritic cell (DC) vaccines plus modulatory immunotherapy; and maintenance ICD therapy. There were no differences in the number of vaccines (median: 2), total number of DCs (median: 25.6 × 106), number of NDV injections (median: 31), and number of mEHT sessions (median: 28) between both groups. The median OS of 28 unmeth patients was 22 m (2y-OS: 39%), confirming previous results. OS of 22 meth patients was significantly better (p = 0.0414) with 38 m (2y-OS: 81%). There were no major treatment-related adverse reactions. The addition of IMI during/after standard of care should be prospectively explored. [ABSTRACT FROM AUTHOR]

Herein, we report on fluorescent probes which enable the selective quantification of Na+ and K+ in water by fluorescence enhancement (FE) independent of the pH value. These fluorescent probes, so called fluoroionophores, consist of benzo‐crown‐ether derivatives as ionophores, a benzo‐15‐crown‐5 (cf. 5) or a benzo‐18‐crown‐6 (cf. 6), respectively, to selectively bind either Na+ or K+ and a 4,4‐difluoro‐1,3,5,7‐tetramethyl‐4‐bora‐3a,4a‐diaza‐s‐indacene (BODIPY) fluorophore. The fluoroionophore 5 shows a FE factor of 7.3 in the presence of 1000 mM Na+ and 6 of 4.7 upon addition of 250 mM K+ in an acidic environment. The dissociation constants (Kd) for 5+Na+ is 276 mM and for 6+K+ is 18 mM enabling the fluorometric determination of biological relevant Na+ or K+ levels. The fluorescence intensities of 5 and 6 were not impacted over a broad range of proton concentrations (pH stable from 3.5 to 9.5) and by the presence of other biologically relevant cations. [ABSTRACT FROM AUTHOR]

Herein, we represent cation‐responsive fluorescent probes for the divalent cations Zn2+, Mg2+ and Ca2+, which show cation‐induced fluorescence enhancements (FE) in water. The Zn2+‐responsive probes Zn1, Zn2, Zn3 and Zn4 are based on o‐aminoanisole‐N,N‐diacetic acid (AADA) derivatives and show in the presence of Zn2+ FE factors of 11.4, 13.9, 6.1 and 8.2, respectively. Most of all, Zn1 and Zn2 show higher Zn2+ induced FE than the regioisomeric triazole linked fluorescent probes Zn3 and Zn4, respectively. In this set, ZN2 is the most suitable probe to detect extracellular Zn2+ levels. For the Mg2+‐responsive fluorescent probes Mg1, Mg2 and Mg3 based on o‐aminophenol‐N,N,O‐triacetic acid (APTRA) derivatives, we also found that the regioisomeric linkage influences the fluorescence responds towards Mg2+ (Mg1+100 mM Mg2+ (FEF=13.2) and Mg3+100 mM Mg2+ (FEF=2.1)). Mg2 shows the highest Mg2+‐induced FE by a factor of 25.7 and an appropriate Kd value of 3 mM to measure intracellular Mg2+ levels. Further, the Ca2+‐responsive fluorescent probes Ca1 and Ca2 equipped with a 1,2‐bis(o‐aminophenoxy)ethane‐N,N,N',N'‐tetraacetic acid (BAPTA) derivative show high Ca2+‐induced FEs (Ca1 (FEF=22.1) and Ca2 (FEF=23.0)). Herein, only Ca1 (Kd=313 nM) is a suitable Ca2+ fluorescent indicator to determine intracellular Ca2+ levels. [ABSTRACT FROM AUTHOR]

Introduction: Prospective double-blind placebo-controlled randomized clinical trials (RCTs) are considered standard for the proof of the efficacy of oncologic therapies. Molecular methods have provided new insights into tumor biology and led to the development of targeted therapies. Due to the increasing complexity of molecular tumor characteristics and of the individuality of specific anti-tumor immune reactivity, RCTs are unfortunately only of limited use.Areas Covered: The historical methods of drug research and approval and the related practices of reimbursement by statutory and private health insurance companies are being questioned. New, innovative methods for the documentation of evidence in personalized medicine will be addressed. Possible perspectives and new approaches are discussed, in particular with regard to glioblastoma.Expert Opinion: Highly specialized translational oncology groups like the IOZK can contribute to medical progress and quick transfer 'from bench to bedside.' Their contribution should be acknowledged and taken into account more strongly in the development of guidelines and the reimbursement of therapy costs. Methodological plurality should be encouraged. [ABSTRACT FROM AUTHOR]

The present study reports the case of a patient with hormone-refractory metastatic prostate cancer who had failed standard therapy, but then achieved complete remission following combined treatment with local hyperthermia (LHT), Newcastle disease virus and dendritic cell (DC) vaccination, which was an unusual combination. In August 2005, the patient underwent a radical prostatectomy. Despite standard treatment, the patient developed progressive bone metastases and stopped conventional therapy in June 2007. Starting in October 2007, the patient was treated with LHT, oncolytic virotherapy and DC vaccination. Prostate-specific antigen (PSA)-levels, with the highest level of 233.8 ng/ml in January 2008, decreased to 0.8 ng/ml in late February 2008. In March 2008, a reduction in bone metastases could be detected by positron emission tomography/computed tomography. Since then, the PSA levels have remained low and the patient is doing well. The treatment induced a long-lasting antitumor memory T-cell response. This possibly explains the long-term effectiveness of this novel experimental combined treatment approach. [ABSTRACT FROM AUTHOR]

Simple Summary: Although multiple meta-analyses on active specific immunotherapy treatment for glioblastoma multiforme (GBM) have demonstrated a significant prolongation of overall survival, no single research group has succeeded in demonstrating the efficacy of this type of treatment in a prospective, double-blind, placebo-controlled, randomized clinical trial. In this paper, we explain how the complexity of the tumor biology and tumor–host interactions make proper stratification of a control group impossible. The individualized characteristics of advanced therapy medicinal products for immunotherapy contribute to heterogeneity within an experimental group. The dynamics of each tumor and in each patient aggravate comparative stable patient groups. Finally, combinations of immunotherapy strategies should be integrated with first-line treatment. We illustrate the complexity of a combined first-line treatment with individualized multimodal immunotherapy in a group of 70 adults with GBM and demonstrate that the integration of immunogenic cell death treatment within maintenance chemotherapy followed by dendritic cell vaccines and maintenance immunotherapy might provide a step towards improving the overall survival rate of GBM patients. Immunotherapies represent a promising strategy for glioblastoma multiforme (GBM) treatment. Different immunotherapies include the use of checkpoint inhibitors, adoptive cell therapies such as chimeric antigen receptor (CAR) T cells, and vaccines such as dendritic cell vaccines. Antibodies have also been used as toxin or radioactive particle delivery vehicles to eliminate target cells in the treatment of GBM. Oncolytic viral therapy and other immunogenic cell death-inducing treatments bridge the antitumor strategy with immunization and installation of immune control over the disease. These strategies should be included in the standard treatment protocol for GBM. Some immunotherapies are individualized in terms of the medicinal product, the immune target, and the immune tumor–host contact. Current individualized immunotherapy strategies focus on combinations of approaches. Standardization appears to be impossible in the face of complex controlled trial designs. To define appropriate control groups, stratification according to the Recursive Partitioning Analysis classification, MGMT promotor methylation, epigenetic GBM sub-typing, tumor microenvironment, systemic immune functioning before and after radiochemotherapy, and the need for/type of symptom-relieving drugs is required. Moreover, maintenance of a fixed treatment protocol for a dynamic, deadly cancer disease in a permanently changing tumor–host immune context might be inappropriate. This complexity is illustrated using our own data on individualized multimodal immunotherapies for GBM. Individualized medicines, including multimodal immunotherapies, are a rational and optimal yet also flexible approach to induce long-term tumor control. However, innovative methods are needed to assess the efficacy of complex individualized treatments and implement them more quickly into the general health system. [ABSTRACT FROM AUTHOR]

At times of personalized and individualized medicine the concept of randomized- controlled clinical trials (RCTs) is being questioned. This review article explains principles of evidence-based medicine in oncology and shows an example of how evidence can be generated independently from RCTs. Personalized medicine involves molecular analysis of tumor properties and targeted therapy with small molecule inhibitors. Individualized medicine involves the whole patient (tumor and host) in the context of immunotherapy. The example is called Individualized Multimodal Immunotherapy (IMI). It is based on the individuality of immunological tumor–host interactions and on the concept of immunogenic tumor cell death (ICD) induced by an oncolytic virus. The evidence is generated by systematic data collection and analysis. The outcome is then shared with the scientific and medical community. The priority of big pharma studies is commercial benefit. Methods used to achieve this are described and have damaged the image of RCT studies in general. A critical discussion is recommended between all partners of the medical health system with regard to the conduct of RCTs by big pharma companies. Several clinics and institutions in Europe try to become more independent from pharma industry and to develop their own modern cancer therapeutics. Medical associations should include references to such studies from personalized and individualized medicine in their guidelines. [ABSTRACT FROM AUTHOR]

Herein, we report the synthesis and sensing characteristics of 4,4'-methoxy-substituted BODIPY fluorescent probes (O-BODIPYs) 3, 4 and 5 equipped with differently sized benzo-crown ethers (cf. Scheme 1, 3 (benzo-15-crown-5), 4 (benzo-18-crown-6) and 5 (benzo-21-crown7)). O-BODIPYs 3, 4 and 5 exhibited in comparison to their known F-BODIPY analogues 3a, 4a and 5a (cf. Scheme 1) an improved solubility in aqueous medium and higher fluorescence quantum yields. Fluorometric study in aqueous solutions of 3, 4 and 5 in the presence of different cations show cation induced fluorescence enhancements (FE). Compared to the benzo-crown ether substituted F-BODIPY analogues 3a, 4a and 5a, we found for the free O-BODIPYs 3, 4 and 5 higher fluorescence quantum yields (φ f ) but lower cation induced FEs. We show that in aqueous medium the fluorescence quenching process (OFF switching), a photoinduced electron transfer, in O-BODIPYs 3, 4 and 5 is less effective and consequently sensitive and selective ON switching of the fluorescence by cations, too. Albeit these observations the novel benzo-21-crown-7 equipped fluorescent probe 5 exhibits a good fluorometric Ba 2+ selectivity and Ba 2+ sensitivity in conjunction to their aqueous solubility., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Glioblastoma (GBM) remains an orphan cancer disease with poor outcome. Novel treatment strategies are needed. Immunotherapy has several modes of action. The addition of active specific immunotherapy with dendritic cell vaccines resulted in improved overall survival of patients. Integration of DC vaccination within the first-line combined treatment became a challenge, and immunogenic cell death immunotherapy during chemotherapy was introduced. We used a retrospective analysis using real world data to evaluate the complex combined treatment, which included individualized multimodal immunotherapy during and after standard of care, and which required adaptations during treatment, and found a further improvement of overall survival. We also discuss the use of real world data as evidence. Novel strategies to move the field of individualized multimodal immunotherapy forward for GBM patients are reviewed., (Copyright © 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Herein, we report on highly Ba 2+ selective fluorescence sensing in water by a fluorescent probe consisting of a benzo-21-crown-7 as a Ba 2+ binding unit (ionophore) and a tetramethylated BODIPY fluorophore as a fluorescence reporter. This fluorescent probe showed a Ba 2+ induced fluorescence enhancement (FE) by a factor of 12±1 independently of the pH value and a high Ba 2+ sensitivity with a limit of detection (LOD) of (17.2±0.3) μM. Moreover, a second fluorescent probe consisting of the same BODIPY fluorophore, but a benzo-18-crown-6 as a cation-responsive binding moiety, showed an even higher FE upon Ba 2+ complexation by a factor of 85±3 and a lower LOD of (13±3) μM albeit a lower Ba 2+ selectivity. The fluorescence sensing mechanism of Ba 2+ was further investigated by time-resolved fluorescence as well as transient absorption spectroscopy (TAS) and it turned out that within these probes a blocking of a photoinduced electron transfer (PET) by Ba 2+ is very likely responsible for the FE., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Immunotherapies represent a promising strategy for glioblastoma multiforme (GBM) treatment. Different immunotherapies include the use of checkpoint inhibitors, adoptive cell therapies such as chimeric antigen receptor (CAR) T cells, and vaccines such as dendritic cell vaccines. Antibodies have also been used as toxin or radioactive particle delivery vehicles to eliminate target cells in the treatment of GBM. Oncolytic viral therapy and other immunogenic cell death-inducing treatments bridge the antitumor strategy with immunization and installation of immune control over the disease. These strategies should be included in the standard treatment protocol for GBM. Some immunotherapies are individualized in terms of the medicinal product, the immune target, and the immune tumor-host contact. Current individualized immunotherapy strategies focus on combinations of approaches. Standardization appears to be impossible in the face of complex controlled trial designs. To define appropriate control groups, stratification according to the Recursive Partitioning Analysis classification, MGMT promotor methylation, epigenetic GBM sub-typing, tumor microenvironment, systemic immune functioning before and after radiochemotherapy, and the need for/type of symptom-relieving drugs is required. Moreover, maintenance of a fixed treatment protocol for a dynamic, deadly cancer disease in a permanently changing tumor-host immune context might be inappropriate. This complexity is illustrated using our own data on individualized multimodal immunotherapies for GBM. Individualized medicines, including multimodal immunotherapies, are a rational and optimal yet also flexible approach to induce long-term tumor control. However, innovative methods are needed to assess the efficacy of complex individualized treatments and implement them more quickly into the general health system.