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Prostate cancer (PC) is the second most common cancer and the fifth most frequent cause of cancer death among men. Prostate-specific membrane antigen (PSMA) expression is associated with aggressive PC, with expression in over 90% of patients with metastatic disease. Those characteristics have led to its use for PC diagnosis and therapies with radiopharmaceuticals, antibody-drug conjugates, and nanoparticles. Despite these advancements, none of the current therapeutics are curative and show some degree of toxicity. Here we present the synthesis and preclinical evaluation of a multimodal, PSMA-targeted dendrimer-drug conjugate (PT-DDC), synthesized using poly(amidoamine) (PAMAM) dendrimers. PT-DDC was designed to enable imaging of drug delivery, providing valuable insights to understand and enhance therapeutic response. The PT-DDC was synthesized through consecutive conjugation of generation-4 PAMAM dendrimers with maytansinoid-1 (DM1) a highly potent antimitotic agent, Cy5 infrared dye for optical imaging, 2,2',2\"-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA) chelator for radiolabeling with copper-64 and positron emission tomography tomography/computed tomography (PET/CT), lysine-urea-glutamate (KEU) PSMA-targeting moiety and the remaining terminal primary amines were capped with butane-1,2-diol. Non-targeted control dendrimer-drug conjugate (Ctrl-DDC) was formulated without conjugation of KEU. PT-DDC and Ctrl-DDC were characterized using high-performance liquid chromatography, matrix assisted laser desorption ionization mass spectrometry and dynamic light scattering. In vitro and in vivo evaluation of PT-DDC and Ctrl-DDC were carried out in isogenic human prostate cancer PSMA  PC3 PIP and PSMA  PC3 flu cell lines, and in mice bearing the corresponding xenografts. PT-DDC was stable in 1×PBS and human blood plasma and required glutathione for DM1 release. Optical, PET/CT and biodistribution studies confirmed the in vivo PSMA-specificity of PT-DDC. PT-DDC demonstrated dose-dependent accumulation and cytotoxicity in PSMA PC3 PIP cells, and also showed growth inhibition of the corresponding tumors. PT-DDC did not accumulate in PSMA PC3 flu tumors and did not inhibit their growth. Ctrl-DDC did not show PSMA specificity. In this study, we synthesized a multimodal theranostic agent capable of delivering DM1 and a radionuclide to PSMA tumors. This approach holds promise for enhancing image-guided treatment of aggressive, metastatic subtypes of prostate cancer.

Purpose We aimed to assess the outcomes and patterns of toxicity in patients with melanoma brain metastases (MBM) treated with stereotactic radiosurgery (SRS) with or without immunotherapy (IO). Methods From a prospective registry, we reviewed MBM patients treated with single fraction Gamma Knife SRS between 2008 and 2021 at our center. We recorded all systemic therapies (chemotherapy, targeted therapy, or immunotherapy) administered before, during, or after SRS. Patients with prior brain surgery were excluded. We captured adverse events following SRS, including intralesional hemorrhage (IH), radiation necrosis (RN) and local failure (LF), as well as extracranial disease status. Distant brain failure (DBF), extracranial progression-free survival (PFS) and overall survival (OS) were determined using a cumulative Incidence function and the Kaplan–Meier method. Results Our analysis included 165 patients with 570 SRS-treated MBM. Median OS for patients who received IO was 1.41 years versus 0.79 years in patients who did not (p = 0.04). Ipilimumab monotherapy was the most frequent IO regimen (30%). In the absence of IO, the cumulative incidence of symptomatic (grade 2 +) RN was 3% at 24 months and remained unchanged with respect to the type or timing of IO. The incidence of post-SRS g2 + IH in patients who did not receive systemic therapy was 19% at 1- and 2 years compared to 7% at 1- and 2 years among patients who did (HR: 0.33, 95% CI 0.11–0.98; p = 0.046). Overall, neither timing nor type of IO correlated to rates of DBF, OS, or LF. Among patients treated with IO, the median time to extracranial PFS was 5.4 months (95% IC 3.2 – 9.1). Conclusion The risk of g2 + IH exceeds that of g2 + RN in MBM patients undergoing SRS, with or without IO. IH should be considered a critical adverse event following MBM treatments . Graphical Abstract

Cerebral radionecrosis, a subacute or late effect of radiotherapy, can be debilitating and difficult to treat. Steroids can reduce symptoms, but have significant long-term side effects. Bevacizumab has been shown to reduce edema and other radiologic features associated with radionecrosis and improve patient symptoms. We report our experience using bevacizumab for cerebral radionecrosis. We retrospectively reviewed the charts of all patients treated at our institution with bevacizumab for non-glioma-associated cerebral radionecrosis. We recorded change in symptoms, change in steroids, change in performance status, time to tumor progression, and time to death. We delineated the volume of necrosis pre- and post-bevacizumab on T1-post-gadolinium and fluid-attenuated inversion recovery (FLAIR) MRI scans. We identified 15 patients, 8 with brain metastases, 6 with meningioma, and 1 with nasopharyngeal carcinoma. Most received four doses of bevacizumab, 7.5 mg/kg q 3 weeks × 4 doses. Neuroimaging demonstrated a reduced T1 gadolinium-enhancing volume and edema in 14/15 patients (the average reduction in T1-post-gadolinium volume was 3.0 cm , and average reduction in FLAIR volume was 27.9 cm ). There was no appreciable change in patient performance status. Steroid doses decreased in five of nine patients. There was a high rate (26%) of adverse events, including pulmonary embolism, stroke, and wound dehiscence. The median progression-free survival was 6.5 months. Although bevacizumab is commonly prescribed for cerebral radionecrosis, in our retrospective cohort, the clinical benefits were modest and there was significant toxicity.

We hereby provide the first documented data on the occurrence of a viable Procambarus virginalis population in a nature reserve in Poland and the steps that were taken to prevent further introductions of the species in the country. To date, Poland represents the most north-eastward distribution area in Europe, where the species occurs in ecosystems with natural water temperature regimes. The ecological plasticity of P. virginalis and its obligate parthenogenetic reproduction make this crayfish an exceptional invader. The crayfish may have detrimental effects on the native invertebrates, amphibians, and fish, and alter the state of the entire ecosystem. Therefore, we investigated the presence of the species in the nature reserve of Pojezierze Łęczyńskie Landscape Park after a suspected P. virginalis individual was found by a local citizen. The nature reserve also includes an area designated to protect native amphibians and turtles. Our study revealed the presence of a thriving population of P. virginalis in the protected area and clear indications of its impact on native and invasive species, both in aquatic and terrestrial environments. If no action is taken, the species will likely expand to other water bodies across the country. An extensive sensibilization campaign allowed us to find additional invaded areas and significantly contribute to the effective ban of this and other invasive crayfish species from private and commercial online trade. Raising public awareness and banning invasive crayfish species trade is essential for successfully detecting and preventing further introductions.

Only 14 species of aquatic oligochaetes occurring in inland waters of Iran have been recorded until now. Our investigations based on samples collected in 2003 and 2005 revealed the presence of six species, including five new to the fauna of Iran: Haplotaxis gordioides, Dero dorsalis, Pristina breviseta, Embolocephalus velutinus and Psammoryctides albicola. The provided checklist of Iranian aquatic oligochaetes is still very short (19 species). It is mostly represented by common, cosmopolitan species. However, taking into account the large area of the country, its mountainous terrain and peculiar hydrological network, more species may be discovered in the future.

The cosmopolitan freshwater oligochaete Aulodrilus pigueti Kowalewski, 1914 (Naididae: Tubificinae) was recorded for the first time in Poland. The species was found at a few groyne field sites and in the main flow of the middle and lower course of the Oder River. Forty two other species of oligochaetes were found in the analyzed material, including rarely found in Poland Aulodrilus japonicus and Bothrioneurum vejdovskyanum, as well as alien species: Branchiura sowerbyi and Quistadrilus multisetosus.

Doc number: A62

The ovaries of Petrobius brevistylis (Archaeognatha) and Tricholepidion gertschi (Zygentoma) are composed of seven metamerically arranged panoistic ovarioles that are covered with the external epithelial sheath (=tunica externa) and the basal lamina (=tunica propria). The germaria are small and enclose oogonial cells and somatic prefollicular cells. The vitellaria contain 10–15 linearly arranged oocytes that are surrounded by a one-layered follicular epithelium. Oocyte nuclei (=germinal vesicles) are large and possess giant, compact ( P. brevistylis) or lobate ( T. gertschi) nucleoli. In both studied species the majority of yolk is incorporated to the oocyte via endocytosis; however, appearance of numerous Golgi complexes and rough endoplasmic reticulum cisternae at the onset of vitellogenesis suggests the involvement of these organelles in synthesis of yolk precursors. The obtained results are discussed in the phylogenetic context and support the idea that Lepidotrichidae are the most basal zygentoman clade.

The stability constants and structure of the complexes of Cd^sup II^ and Zn^sup II^ with 1-ethoxymethylimidazole (ExMeIm), 1-propoxymethylimidazole (PxMeIm), 1-ethoxymethyl-2-methylimidazole (ExMe-2-MeIm) and 1-propoxymethyl-2-methylimidazole (PxMe-2-MeIm) in aqueous solution have been determined by potentiometric methods. Zn^sup II^ form both tetrahedral and octahedral species with the cited ligands according to the configurational equilibrium type: octahedron tetrahedron, but Cd^sup II^ prefers octahedral coordination of alkoxymethylimidazole complexes in aqueous solution. Retention of the six-coordination form of Cd^sup II^ has also been confirmed by the data obtained for two novel compounds which have been synthesized in the solid state. The crystal and molecular structure of [Cd(ExMeIm)^sub 4^(NO^sub 3^)^sub 2^] (1) has been determined by X-ray diffraction. The coordination geometry around the Cd^sup II^ ion can be considered as slightly distorted tetragonal bipyramidal (CdN^sub 4^O^sub 2^). Additionally, another six-coordinate Cd^sup II^ compound with ethoxymethyl-2-methylimidazole [Cd(ExMe-2-MeIm)^sub 4^(H^sub 2^O)](NO^sub 3^)^sub 2^ (2) has been characterized by spectroscopic (i.r., far i.r., Raman) ES-MS and t.g.a. methods.[PUBLICATION ABSTRACT]