Making the invisible visible: improved electrospray ion formation of metalloporphyrins/-phthalocyanines by attachment of the formate anion (HCOO(-)).

A protocol is developed for the coordination of the formate anion (HCOO(-)) to neutral metalloporphyrins (Pors) and -phthalocyanines (Pcs) containing divalent metals as a means to improve their ion formation in electrospray ionization (ESI). This method is particularly useful when the oxidation of the neutral metallomacrocycle fails. While focusing on Zn(II)Pors and Zn(II)Pcs, we show that formate is also readily attached to Mn(II), Mg(II) and Co(II)Pcs. However, for the Co(II)Pc secondary reactions can be observed. Upon collision-induced dissociation (CID), Zn(II)Por/Pc·formate supramolecular complexes can undergo the loss of CO2 in combination with transfer of a hydride anion (H(-)) to the zinc metal center. Further dissociation leads to electron transfer and hydrogen atom loss, generating a route to the radical anion of the Zn(II)Por/Pc without the need for electrochemical reduction, although the Zn(II)Por/Pc may have a too low electron affinity to allow electron transfer directly from the formate anion. In addition to single Por molecules, multi Por arrays were successfully analyzed by this method. In this case, multiple addition of formate occurs, giving rise to multiply charged species. In these multi Por arrays, complexation of the formate anion occurs by two surrounding Por units (sandwich). Therefore, the maximum attainment of formate anions in these arrays corresponds to the number of such sandwich complexes rather than the number of porphyrin moieties. The same bonding motif leads to dimers of the composition [(Zn(II)Por/Pc)2·HCOO](-). In these, the formate anion can act as a structural probe, allowing the distinction of isomeric ions with the formate bridging two macrocycles or being attached to a dimer of directly connected macrocycles.

A facile route to water-soluble coronenes and benzo[ghi]perylenes.

Click reactions at the bay-position of perylenes and a new route to benzo[ghi]perylenes and coronenes are presented. Irradiation with light leads to an electrocyclic reaction of the newly formed triazole ring(s) with the neighbouring bay-positions of the perylene core and after oxidation by air, the benzo[ghi]perylenes and coronenes are obtained. By using Newkome dendrimers as substituents for perylene diimides (PDIs), water solubility can be achieved after removal of the tert-butyl protecting groups. The aggregation and optical properties of the bay-functionalised PDIs, benzo[ghi]perylenes and coronenes are investigated by absorption and fluorescence spectroscopy.

Soluble immune checkpoints and T-cell subsets in blood as biomarkers for resistance to immunotherapy in melanoma patients.

Different mechanisms lead to immune checkpoint inhibitor (ICI) resistance. Identifying clinically useful biomarkers might improve drug selection and patients' therapy. We analyzed the soluble immune checkpoints sPD1, sPDL1, sLAG3, and sTIM3 using ELISA and their expression on circulating T cells using FACS in pre- and on-treatment blood samples of ICI treated melanoma patients. In addition, pre-treatment melanoma metastases were stained for TIM3 and LAG3 expression by IHC. Results were correlated with treatment response and progression-free survival (PFS). Resistance to anti-PD1 treatment (n = 48) was associated with high pre-treatment serum levels of sLAG3 (DCR: p = .009; PFS: p = .018; ROC cutoff >148 pg/ml) but not sPD1, sPDL1 or sTIM3. In contrast, resistance to ipilimumab plus nivolumab (n = 42) was associated with high levels of sPD1 (DCR: p = .019, PFS: p = .046; ROC cutoff >167 pg/ml) but not sPDL1, sLAG3 or sTIM3. Both treatment regimens shared a profound increase of sPD1 serum levels with treatment (p < .0001). FACS analysis revealed reduced frequencies of CD3+ CD8+ PD1 + T cells (p = .028) in anti-PD1-resistant patients, whereas increased frequencies of CD3+ CD4+ LAG3 + T cells characterized patients resistant to ipilimumab plus nivolumab (p = .033). Unlike anti-PD1 monotherapy, combination blockade significantly increased proliferating T cells (CD3+ CD8+ Ki67 + T cells; p < .0001) and eosinophils (p = .001). In melanoma metastases, an increased infiltration with TIM3+ or LAG3 + T cells in the tumor microenvironment correlated with a shorter PFS under anti-PD1 treatment (TIM3: p = .019, LAG3: p = .07). Different soluble immune checkpoints characterized checkpoint inhibitor-resistant melanoma. Measuring these serum markers may have the potential to be used in clinical routine.

Efficient synthetic access to cationic dendrons and their application for ZnO nanoparticles surface functionalization: new building blocks for dye-sensitized solar cells.

A new concept for the efficient synthesis of cationic dendrons, 4-tert-butyl-1-(3-(3,4-dihydroxybenzamido)benzyl)pyridinium bromide (17), 1,1'-(5-(3,4-dihydroxybenzamido)-1,3-phenylene)bis(methylene)bis(4-tert-butylpyridinium) bromide (18), N1,N7-bis(3-(4-tert-butyl-pyridium-methyl)phenyl)-4-(3-(3-(4-tert-butyl-pyridinium-methyl)phenyl-amino)-3-oxopropyl)-4-(3,4-dihydroxybenzamido)heptanediamide tribromide (19), and N1,N7-bis(3,5-bis(4-tert-butyl-pyridium-methyl)phenyl)-4-(3-(3,5-bis(4-tert-butyl-pyridinium-methyl)phenylamino)-3-oxopropyl)-4-(3,4-dihydroxybenzamido)heptanediamide hexabromide (20), and their facile binding to zinc oxide (ZnO) nanostructures is introduced. Dendrons containing highly reactive benzylic bromides reacted readily with 4-tert-butyl-pyridine and resulted in cationic dendrons. Furthermore, these permanently positively charged dendrons were equipped with a catechol anchor group. This enabled ZnO surface functionalization by simple immersion. The adsorption of 17, 18, 19, and 20 on the colloidal nanoparticles was monitored by Langmuir isotherms. The highest obtained experimental loadings correspond to 99.5%, 98.6%, 99.1%, and 42.5% of the particle surface for 17, 18, 19, and 20, respectively. These results indicate insufficient adsorption of the largest molecule 20 leading to reduced colloidal stability of the nanoparticles, while an enhanced stability after grafting with 17, 18, and 19 was observed. Mesoporous films suitable for the use as electrodes in dye-sensitized solar cells (DSSCs) were prepared. Subsequently, the films were functionalized with 18, 19, or 20 and sensitized with zinc-5,15-bis-[2',6'-bis-{2'',2''-bis-(carboxy)-ethyl}-methyl-4'-tert-butyl-pheny]-10,20-bis-(4'-tert-butylphenyl)porphyrin-octasodium-salt. UV-vis absorption spectra confirmed that 18, 19, and 20 are suitable for the stable electrostatic attachment of the dye. Current-voltage characteristics of complete cells demonstrated that increasing positive functionalization of the ZnO surface leads to decreased open circuit voltages (V(oc)). All V(oc) values were around 0.4 V with a maximum for the 18 functionalized ZnO film of 0.45 V. The maximum cell efficiency obtained (0.31%) is rather high, considering the narrow spectral absorption of the dye and the rather thin ZnO films used. Finally, incident photon to current efficiency (IPCE) measurements confirmed photoinduced electron injection from the dye. These features are important assets for applications in particle technology and even facilitated advanced devices like a supramolecular DSSC complete with a subsequent layer of negatively charged porphyrins.

Doxazosin for the treatment of nightmare disorder: A diary-based case study.

The α1-adrenergic antagonist prazosin has showed good effect against posttraumatic stress disorder-related nightmares in several randomized controlled trials. The α1-adrenergic antagonist doxazosin, which has a longer half-live than prazosin, has received far less attention in the treatment of such nightmares. Here, we report a case of a patient suffering from severe nightmares following an erroneous medical administration of adrenaline (causing severe physiological hyper-activation) who was treated with doxazosin. Over a period of 280 days, the patient kept a nightmare diary and took 0, 4, or 8 mg doxazosin. The analyses showed that 8 mg doxazosin (55.2% nightmare-free nights) worked better (odds ratio = 28.2; 95% confidence interval = 3.7-213.9) compared to nights without doxazosin (4.3% nightmare-free nights). Except dizziness, which was not regarded as particularly bothersome by the patient, doxazosin was well tolerated. It is concluded that doxazosin may be indicated as a pharmacological treatment for patients suffering from posttraumatic stress disorder-related nightmares.

Clinical significance of signs of autoimmune colitis in 18F-fluorodeoxyglucose positron emission tomography-computed tomography of 100 stage-IV melanoma patients.

Aim: Autoimmune colitis is a typical and possible severe side effect among patients treated with ipilimumab. Patients & methods: We prospectively included 100 patients with metastasized melanoma under ipilimumab treatment in a radiological study of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT). PET evidence of pancolitis ('PET-colitis') was correlated with clinical variables. Results: We observed a significant correlation between PET-colitis and clinically significant diarrhoea, although PET-colitis was more frequent (49 vs 29% of patients, respectively). Neither PET-colitis nor diarrhoea was significantly correlated with response to therapy. Other immune-related adverse events, however, such as hypophysitis and hepatitis were associated with response to therapy and overall survival. Conclusion: Increased 18F-FDG uptake in the colon correlated with clinical symptoms but did not predict clinical outcome to ipilimumab.

Amyloidosis Cutis Dyschromica, a Rare Cause of Hyperpigmentation: A New Case and Literature Review.

Amyloidosis cutis dyschromica is a rare form of primary cutaneous amyloidosis without systemic involvement and characterized by asymptomatic, progressive hyper- and hypopigmentation. We present the first case of a patient with amyloidosis cutis dyschromica diagnosed previously elsewhere as having Addison disease with generalized hyperpigmentation of the skin. This case suggests that in patients presenting with asymptomatic cutaneous dyschromia a skin biopsy for histopathological examination should be considered.

Safe Administration of An Anti-PD-1 Antibody to Kidney-transplant Patients: 2 Clinical Cases and Review of the Literature.

Antiprogrammed cell-death protein 1 (PD-1) antibodies have revolutionized therapy of metastatic melanoma and other tumors, but some subgroups of patients such as immunosuppressed patients after solid-organ transplantation, have regularly been excluded from clinical studies. We report 2 cases of kidney-transplant patients who received an anti-PD-1 antibody to treat metastatic melanoma. Treatment was tolerated well with no relevant adverse events and stable kidney functions, but the melanoma progressed in both patients. Factors potentially affecting risk of allograft rejection and response to treatment, for example, immunosuppressive regimen and therapeutic sequence, are discussed on the basis of current literature. Further studies are necessary to determine the risk of allograft rejection and the therapeutic benefit of anti-PD-1 antibodies for organ-transplanted patients, in particular as these checkpoint inhibitors have become therapeutic standard in a variety of tumors other than melanoma.