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Prostate cancer is the second most common cancer and the fifth leading cause of cancer deaths worldwide. Despite improvements in diagnosis and treatment, new treatment options are urgently needed for advanced stages of the disease. Targeted toxins are chemical conjugates or fully recombinant proteins consisting of a binding domain directed against a target antigen on the surface of cancer cells and a toxin domain, which is transported into the cell for the induction of apoptosis. In the last decades, targeted toxins against prostate cancer have been developed. Several challenges, however, became apparent that prevented their direct clinical use. They comprise immunogenicity, low target antigen binding, endosomal entrapment, and lysosomal/proteasomal degradation of the targeted toxins. Moreover, their efficacy is impaired by prostate tumors, which are marked by a dense microenvironment, low target antigen expression, and apoptosis resistance. In this review, current findings in the development of targeted toxins against prostate cancer in view of effective targeting, reduction of immunogenicity, improvement of intracellular trafficking, and overcoming apoptosis resistance are discussed. There are promising approaches that should lead to the clinical use of targeted toxins as therapeutic alternatives for advanced prostate cancer in the future.

Despite improved diagnostic and therapeutic intervention, advanced prostate cancer (PC) remains incurable. The acquired resistance of PC cells to current treatment protocols has been traced to apoptosis resistance based on the upregulation of anti-apoptotic proteins of the Bcl-2 family. The use of BH3 mimetics, mimicking pro-apoptotic activator or sensitizer proteins of the intrinsic apoptotic pathway, is therefore a promising treatment strategy. The present review gives an overview of preclinical and clinical studies with pan- and specific BH3 mimetics as sensitizers for cell death and gives an outlook how they could be effectively used for the therapy of advanced PC in future.

For brain–computer interfaces, a variety of technologies and applications already exist. However, current approaches use visual evoked potentials (VEP) only as action triggers or in combination with other input technologies. This paper shows that the losing visually evoked potentials after looking away from a stimulus is a reliable temporal parameter. The associated latency can be used to control time-varying variables using the VEP. In this context, we introduced VEP interaction elements (VEP widgets) for a value input of numbers, which can be applied in various ways and is purely based on VEP technology. We carried out a user study in a desktop as well as in a virtual reality setting. The results for both settings showed that the temporal control approach using latency correction could be applied to the input of values using the proposed VEP widgets. Even though value input is not very accurate under untrained conditions, users could input numerical values. Our concept of applying latency correction to VEP widgets is not limited to the input of numbers.

The clinical interest in mechanisms controlling the biosynthesis and release of the pro-inflammatory cytokine interleukin (IL)-1β is outstanding, as IL-1β is associated with life-threatening inflammatory diseases including hyperinflammation caused by extracellular ATP originating from damaged cells. Previously, we identified a cholinergic mechanism controlling ATP-dependent IL-1β release via metabotropic signaling of unconventional nicotinic acetylcholine receptors (nAChRs) containing subunits α7 and α9* (denoting homomeric or heteromeric α9) in monocytes. This study examines whether this mechanism is active in human macrophages (THP-1 cell-derived, peripheral blood mononuclear cell-derived, and peritoneal macrophages). Expression of nAChR subtypes ( , , , ) was analyzed using real-time RT-PCR. The efficiency of the differentiation protocols used was assessed by surface markers and metabolic conversion rate analysis. Cholinergic control of ATP-induced IL-1β, IL-18, and IL-1α release was tested using nAChR agonists and conopeptides antagonizing α7 and α9* nAChRs. All nAChR subunits were expressed by all cells analyzed. Activation of nAChRs efficiently inhibited the ATP-mediated IL-1β release by macrophages, while ATP-independent release remained unaffected. Moreover, the nAChR agonists inhibited the release of IL-18 and IL-1α. The inhibitory effect was reversed by subunit-specific conopeptides, indicating the involvement of unconventional nAChRs containing subunits α7 and α9*. We conclude that the cholinergic control of ATP-mediated IL-1β release is active in human monocytes and in macrophages and that nAChR agonists can also regulate the release of IL-18 and IL-1α. This mechanism specifically regulates the ATP-induced cytokine release, without suppressing ATP-independent cytokine release. Thus, unconventional α9* nAChRs are promising therapeutic targets for ATP-induced inflammatory diseases, including sterile hyperinflammation.

The regulated cell death apoptosis enables redundant or compromised cells in ontogeny and homeostasis to remove themselves receptor-dependent after extrinsic signaling or after internal stress by BCL-2 proteins on the outer mitochondrial membrane (OMM). Mitochondrial BCL-2 proteins are also often needed for receptor-mediated signaling in apoptosis. Then, the truncated BH3-only protein BID (tBID) blocks retrotranslocation of the pro-apoptotic BCL-2 proteins BAX and BAK from the mitochondria into the cytosol. BAX and BAK in turn permeabilize the OMM. Although the BCL-2 proteins are controlled by a complex regulatory network, a specific mechanism for the inhibition of tBID remained unknown. Curiously, it was suggested that hexokinases, which channel glucose into the metabolism, have an intriguing function in the regulation of apoptosis. Recent analysis of transient hexokinase interactions with BAX revealed its participation in the inhibition of BAX and also BAK by retrotranslocation from mitochondria to the cytosol. In contrast to general apoptosis inhibition by anti-apoptotic BCL-2 proteins, hexokinase I and hexokinase 2 specifically inhibit tBID and thus the mitochondrial apoptosis pathway in response to death receptor signaling. Mitochondrial hexokinase localization and BH3 binding of cytosolic hexokinase domains are prerequisites for protection against receptor-mediated cell death, whereas glucose metabolism is not. This mechanism protects cells from apoptosis induced by cytotoxic T cells.

Activation of nicotinic acetylcholine receptors (nAChRs) expressed by innate immune cells can attenuate pro-inflammatory responses. Silent nAChR agonists, which down-modulate inflammation but have little or no ionotropic activity, are of outstanding clinical interest for the prevention and therapy of numerous inflammatory diseases. Here, we compare two silent nAChR agonists, phosphocholine, which is known to interact with nAChR subunits α7, α9 and α10, and pCF3-N,N-diethyl-N′-phenyl-piperazine (pCF3-diEPP), a previously identifiedd as an α7 nAChR silent agonist, regarding their anti-inflammatory properties and their effects on ionotropic nAChR functions. The lipopolysaccharide (LPS)-induced release of interleukin (IL)-6 by primary murine macrophages was inhibited by pCF3-diEPP, while phosphocholine was ineffective presumably because of instability. In human whole blood cultures pCF3-diEPP inhibited the LPS-induced secretion of IL-6, TNF-α and IL-1β. The ATP-mediated release of IL-1β by LPS-primed human peripheral blood mononuclear leukocytes, monocytic THP-1 -cells and THP-1-derived M1-like macrophages was reduced by both phosphocholine and femtomolar concentrations of pCF3-diEPP. These effects were sensitive to mecamylamine and to conopeptides RgIA4 and [V11L;V16D]ArIB, suggesting the involvement of nAChR subunits α7, α9 and/or α10. In two-electrode voltage-clamp measurements pCF3-diEPP functioned as a partial agonist and a strong desensitizer of classical human α9 and α9α10 nAChRs. Interestingly, pCF3-diEPP was more effective as an ionotropic agonist at these nAChRs than at α7 nAChRs. In conclusion, phosphocholine and pCF3-diEPP are potent agonists at unconventional nAChRs expressed by monocytic and macrophage-like cells. pCF3-diEPP inhibits the LPS-induced release of pro-inflammatory cytokines, while phosphocholine is ineffective. However, both agonists signal via nAChR subunits α7, α9 and/or α10 to efficiently down-modulate the ATP-induced release of IL-1β. Compared to phosphocholine, pCF3-diEPP is expected to have better pharmacological properties. Thus, low concentrations of pCF3-diEPP may be a therapeutic option for the treatment of inflammatory diseases including trauma-induced sterile inflammation.

Background/Objectives: Photoimmunotherapy (PIT) is an innovative approach for the targeted therapy of cancer. In PIT, photosensitizer dyes are conjugated to tumor-specific antibodies for targeted delivery into cancer cells. Upon irradiation with visible light, the photosensitizer dye is activated and induces cancer-specific cell death. In the present article, we describe the PIT of prostate cancer (PC) as a therapeutic option for the targeted treatment of localized prostate cancer. Methods: We conjugated the silicon phthalocyanine dye WB692-CB2 to recombinant cysteine-modified anti-CD44 and anti-EpCAM antibodies via a maleimide linker and tested the antibody dye conjugates for PIT on PC cells and prostate cancer stem cell (PCSC)-like cells. Results: The anti-CD44 and anti-EpCAM antibody dye conjugates showed specific binding and high cytotoxicity against PC and PCSC-like cells following irradiation with red light. Combined treatment with both conjugates led to enhanced cytotoxic effects. Conclusions: PIT with our dye WB692-CB2 can serve as an effective focal therapy against prostate cancer, preserving the prostate gland and minimizing side effects. It can be employed during radical prostatectomy (RP) to treat residual tumor cells or lymph node metastases in areas where further surgical intervention is not feasible. Utilizing multiple conjugates against antigens expressed on differentiated PC and PCSC-like cells, such as CD44 and EpCAM, could be an effective method to eradicate residual cancer cells in heterogeneous tumors. This approach could reduce the risk of local recurrence after RP and thus increase the therapeutic outcome of PC patients.

This work investigates the cost-efficient integration of renewable hydrogen into steelworks for the production of methane and methanol as an efficient way to decarbonize the steel industry. Three case studies that utilize a mixture of steelworks off-gases (blast furnace gas, coke oven gas, and basic oxygen furnace gas), which differ on the amount of used off-gases as well as on the end product (methane and/or methanol), are analyzed and evaluated in terms of their economic performance. The most influential cost factors are identified and sensitivity analyses are conducted for different operating and economic parameters. Renewable hydrogen produced by PEM electrolysis is the most expensive component in this scheme and responsible for over 80% of the total costs. Progress in the hydrogen economy (lower electrolyzer capital costs, improved electrolyzer efficiency, and lower electricity prices) is necessary to establish this technology in the future.

The epidermal growth factor receptor (EGFR) was found to be a valuable target on prostate cancer (PCa) cells. However, EGFR inhibitors mostly failed in clinical studies with patients suffering from PCa. We therefore tested the targeted toxins EGF-PE40 and EGF-PE24mut consisting of the natural ligand EGF as binding domain and PE40, the natural toxin domain of Pseudomonas Exotoxin A, or PE24mut, the de-immunized variant thereof, as toxin domains. Both targeted toxins were expressed in the periplasm of E.coli and evoked an inhibition of protein biosynthesis in EGFR-expressing PCa cells. Concentration- and time-dependent killing of PCa cells was found with IC50 values after 48 and 72 h in the low nanomolar or picomolar range based on the induction of apoptosis. EGF-PE24mut was found to be about 11- to 120-fold less toxic than EGF-PE40. Both targeted toxins were more than 600 to 140,000-fold more cytotoxic than the EGFR inhibitor erlotinib. Due to their high and specific cytotoxicity, the EGF-based targeted toxins EGF-PE40 and EGF-PE24mut represent promising candidates for the future treatment of PCa.

Photoimmunotherapy (PIT) combines the specificity of antibodies with the cytotoxicity of light activatable photosensitizers (PS) and is a promising new cancer therapy. We designed and synthesized, in a highly convergent manner, the silicon phthalocyanine dye WB692-CB2, which is novel for being the first light-activatable PS that can be directly conjugated via a maleimide linker to cysteines. In the present study we conjugated WB692-CB2 to a humanized antibody with engineered cysteines in the heavy chains that specifically targets the prostate-specific membrane antigen (PSMA). The resulting antibody dye conjugate revealed high affinity and specificity towards PSMA-expressing prostate cancer cells and induced cell death after irradiation with red light. Treated cells exhibited morphological characteristics associated with pyroptosis. Mechanistic studies revealed the generation of reactive oxygen species, triggering a cascade of intracellular events involving lipid peroxidation, caspase-1 activation, gasdermin D cleavage and membrane rupture followed by release of pro-inflammatory cellular contents. In first in vivo experiments, PIT with our antibody dye conjugate led to a significant reduction of tumor growth and enhanced overall survival in mice bearing subcutaneous prostate tumor xenografts. Our study highlights the future potential of the new phthalocyanine dye WB692-CB2 as PS for the fluorescence-based detection and PIT of cancer, including local prostate tumor lesions, and systemic activation of anti-tumor immune responses by the induction of pyroptosis. [Display omitted] •The silicon phthalocyanine dye WB692-CB2 was synthesized as new photosensitizer.•It is the first phtalocyanine dye that can be specifically conjugated to cysteine engineered antibodies for photoimmunotherapy.•An anti-PSMA antibody WB692-CB2 dye conjugate effectively eliminated prostate cancer cells after irradiation with red light.•We identified pyroptosis as key cell death mechanism of WB692-CB2 based photoimmunotherapy.