Evaluation of maSSS/maSES-PEG2-RM26 for their potential therapeutic use after labeling with Re-188. Could their [Tc]Tc-labeled counterparts be used to estimate dosimetry?

Background: Gastrin releasing peptide receptor (GRPR)-directed radiopharmaceuticals for targeted radionuclide therapy may be a very promising addition in prostate and breast cancer patient management. Aiming to provide a GRPR-targeting theranostic pair, we have utilized the Tc-99m/Re-188 radiometal pair, in combination with two bombesin based antagonists, maSSS-PEG2-RM26 and maSES-PEG2-RM26. The two main aims of the current study were (i) to elucidate the influence of the radiometal-exchange on the biodistribution profile of the two peptides and (ii) to evaluate the feasibility of using the [Tc]Tc labeled counterparts for the dosimetry estimation for the [Re]Re-labeled conjugates.

Diagnosis of Prostate Cancer with a Neurotensin-Bombesin Radioligand Combination-First Preclinical Results.

The concept of radiotheranostics relies on the overexpression of a biomolecular target on malignant cells to direct diagnostic/therapeutic radionuclide-carriers specifically to cancer lesions. The concomitant expression of more than one target in pathological lesions may be elegantly exploited to improve diagnostic sensitivity and therapeutic efficacy. Toward this goal, we explored a first example of a combined application of [Tc]Tc-DT11 (DT11, N-Lys(MPBA-PEG4)-Arg-Arg-Pro-Tyr-Ile-Leu-OH; NTSR-specific) and [Tc]Tc-DB7(DB7, N-PEG2-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt; GRPR-specific) in prostate cancer models.

Two Novel [Ga]Ga-Labeled Radiotracers Based on Metabolically Stable [Sar]RM26 Antagonistic Peptide for Diagnostic Positron Emission Tomography Imaging of GRPR-Positive Prostate Cancer.

Gastrin releasing peptide receptor (GRPR) is overexpressed in prostate cancer (PC-3) and can be used for diagnostic purposes. We herein present the design and preclinical evaluation of two novel NOTA/NODAGA-containing peptides suitable for labeling with the positron emission tomography (PET) radionuclide Ga-68. These analogs are based on the previously reported GRPR-antagonist DOTAGA-PEG2-[Sar]RM26, developed for targeted radiotheraostic applications.

GRPR-Antagonists Carrying DOTAGA-Chelator via Positively Charged Linkers: Perspectives for Prostate Cancer Theranostics.

Gastrin-releasing peptide receptor (GRPR)-antagonists have served as motifs in the development of theranostic radioligands for prostate cancer. Our efforts have been focused on the development of radiolabeled RM26 (H-DPhe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH) analogs, such as [In]In-DOTAGA-PEG2-RM26. We recently showed that its Gly/Sar-substituted version, [In]In-AU-RM26-M1, resisted degradation by neprilysin (NEP) while in circulation and achieved higher tumor uptake in mice.

Influence of Molecular Design on the Tumor Targeting and Biodistribution of PSMA-Binding Tracers Labeled with Technetium-99m.

Previously, we designed the EuK-based PSMA ligand BQ0413 with an maE chelator for labeling with technetium-99m. It showed efficient tumor targeting, but our preclinical data and preliminary clinical results indicated that the renal excretion levels need to be decreased. We hypothesized that this could be achieved by a decrease in the ligand's total negative charge, achieved by substituting negatively charged glutamate residues in the chelator with glycine.

Amide-to-Triazole Switch in Somatostatin-14-Based Radioligands: Impact on Receptor Affinity and In Vivo Stability.

The use of metabolically stabilized, radiolabeled somatostatin (SST) analogs ([Ga]Ga/[Lu]Lu-DOTA-TATE/TOC/NOC) is well established in nuclear medicine. Despite the pivotal role of these radioligands in the diagnosis and therapy of neuroendocrine tumors (NETs), their inability to interact with all five somatostatin receptors (SSTR) limits their clinical potential. [In]In-AT2S is a radiolabeled DOTA-conjugate derived from the parent peptide SST-14 that exhibits high binding affinity to all SSTR subtypes, but its poor metabolic stability represents a serious disadvantage for clinical use.

Preclinical evaluation of new GRPR-antagonists with improved metabolic stability for radiotheranostic use in oncology.

Background: The gastrin-releasing peptide receptor (GRPR) has been extensively studied as a biomolecular target for peptide-based radiotheranostics. However, the lack of metabolic stability and the rapid clearance of peptide radioligands, including radiolabeled GRPR-antagonists, often impede clinical application. Aiming at circumventing these drawbacks, we have designed three new GRPR-antagonist radioligands using [Tc]Tc-DB15 ([Tc]Tc-N-AMA-DIG-Phe-Gln-Trp-Ala-Val-Sar-His-Leu-NHEt; AMA: p-aminomethylaniline; DIG: diglycolate) as a motif, due to its high GRPR-affinity and stability to neprilysin (NEP).

Central Venous Catheters versus Peripherally Inserted Central Catheters: A Comparison of Indwelling Time Resulting in Colonization by Multidrug-Resistant Pathogens.

Background: The use of peripherally inserted central catheters (PICCs) as an alternative to central venous catheters (CVCs) has steadily risen over the last two decades. However, there is an ongoing debate regarding research evidence that supports any clear advantages or disadvantages of them compared to traditional central venous lines. The present study was conducted to compare the indwelling time of CVC and PICC placements leading to microbial colonization by multidrug-resistant microorganisms (MDROs) in critically ill patients.

Preclinical Evaluation of a Novel High-Affinity Radioligand [Tc]Tc-BQ0413 Targeting Prostate-Specific Membrane Antigen (PSMA).

Radionuclide imaging using radiolabeled inhibitors of prostate-specific membrane antigen (PSMA) can be used for the staging of prostate cancer. Previously, we optimized the Glu-urea-Lys binding moiety using a linker structure containing 2-napththyl-L-alanine and L-tyrosine. We have now designed a molecule that contains mercaptoacetyl-triglutamate chelator for labeling with Tc-99m (designated as BQ0413).

Side-Chain Modified [Tc]Tc-DT1 Mimics: A Comparative Study in NTSR-Positive Models.

Radiolabeled neurotensin analogs have been developed as candidates for theranostic use against neurotensin subtype 1 receptor (NTSR)-expressing cancer. However, their fast degradation by two major peptidases, neprilysin (NEP) and angiotensin-converting enzyme (ACE), has hitherto limited clinical success. We have recently shown that palmitoylation at the -amine of Lys in [Tc]Tc-[Lys]DT1 (DT1, N-Gly-Arg-Arg-Pro-Tyr-Ile-Leu-OH, N = 6-(carboxy)-1,4,8,11-tetraazaundecane) led to the fully stabilized [Tc]Tc-DT9 analog, displaying high uptake in human pancreatic cancer AsPC-1 xenografts but unfavorable pharmacokinetics in mice.

Toward Stability Enhancement of NTSR-Targeted Radioligands: Structural Interventions on [Tc]Tc-DT1.

The neurotensin subtype 1 receptor (NTSR) is overexpressed in a number of human tumors, thereby representing a valid target for cancer theranostics with radiolabeled neurotensin (NT) analogs like [Tc]Tc-DT1 (DT1, N-Gly-NT(8-13)). Thus far, the fast degradation of intravenously injected NT-radioligands by neprilysin (NEP) and angiotensin-converting enzyme (ACE) has compromised their clinical applicability. Aiming at metabolic stability enhancements, we herein introduce (i) DT7 ([DAsn]DT1) and (ii) DT8 ([β-Homoleucine]DT1), modified at the C-terminus, along with (iii) DT9 ([(palmitoyl)Lys]DT1), carrying an albumin-binding domain (ABD) at Lys.

Preclinical Characterization of a Stabilized Gastrin-Releasing Peptide Receptor Antagonist for Targeted Cancer Theranostics.

Radiolabeled gastrin-releasing peptide receptor (GRPR) antagonists have shown great promise for the theranostics of prostate cancer; however, their suboptimal metabolic stability leaves room for improvements. It was recently shown that the replacement of Gly with Sar in the peptidic [D-Phe,Leu-NHEt,-Met]BBN(6-14) chain stabilized the [Tc]Tc-DB15 radiotracer against neprilysin (NEP). We herein present DOTAGA-PEG-(Sar)RM26 (AU-RM26-M1), after Gly to Sar-replacement.

Peptide Radioligands in Cancer Theranostics: Agonists and Antagonists.

The clinical success of radiolabeled somatostatin analogs in the diagnosis and therapy-"theranostics"-of tumors expressing the somatostatin subtype 2 receptor (SSTR) has paved the way for the development of a broader panel of peptide radioligands targeting different human tumors. This approach relies on the overexpression of other receptor-targets in different cancer types. In recent years, a shift in paradigm from internalizing agonists to antagonists has occurred.

[In]In/[Lu]Lu-AAZTA-LM4 SSTR-Antagonists in Cancer Theranostics: From Preclinical Testing to First Patient Results.

Aiming to expand the application of the SSTR-antagonist LM4 (DPhe-c[DCys-4Pal-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH) beyond [Ga]Ga-DATA-LM4 PET/CT (DATA, (6-pentanoic acid)-6-(amino)methy-1,4-diazepinetriacetate), we now introduce AAZTA-LM4 (AAZTA, 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-[pentanoic-acid]perhydro-1,4-diazepine), allowing for the convenient coordination of trivalent radiometals of clinical interest, such as In-111 (for SPECT/CT) or Lu-177 (for radionuclide therapy). After labeling, the preclinical profiles of [In]In-AAZTA-LM4 and [Lu]Lu-AAZTA-LM4 were compared in HEK293-SSTR cells and double HEK293-SSTR/wtHEK293 tumor-bearing mice using [In]In-DOTA-LM3 and [Lu]Lu-DOTA-LM3 as references. The biodistribution of [Lu]Lu-AAZTA-LM4 was additionally studied for the first time in a NET patient.

[Ga]Ga-DATA-LM4, a PET Radiotracer in the Diagnosis of SSTR-Positive Tumors: Preclinical and First Clinical Results.

Radiolabeled somatostatin subtype 2 receptor (SST2R)-antagonists have shown advantageous profiles for cancer theranostics compared with agonists. On the other hand, the newly introduced hybrid chelator (6-pentanoic acid)-6-(amino)methyl-1,4-diazepinetriacetate (DATA) rapidly binds Ga-68 (t: 67.7 min) at much lower temperature, thus allowing for quick access to "ready-for-injection" [Ga]Ga-tracers in hospitals.

Lower risk of bloodstream infections for peripherally inserted central catheters compared to central venous catheters in critically ill patients.

Background: Peripherally inserted central venous catheters (PICCs) serve as an alternative to short-term central venous catheters (CVCs) for providing intravenous access in hospitalized patients. Although a number of studies suggest that PICCs are associated with a lower risk of central line-associated bloodstream infections (CLABSIs) than CVCs, recent data concerning specific patient groups support the contrary. In this regard, we are comparing CVC- and PICC-related CLABSI rates developed in a selected group of critically ill inpatients and evaluating the CLABSI microbiological distribution.

Duration of central venous catheter placement and central line-associated bloodstream infections after the adoption of prevention bundles: a two-year retrospective study.

Background: Central line-associated bloodstream infections (CLABSIs) remain a critical and possibly fatal outcome of hospitalization. Use of central venous catheter (CVC) bundles can considerably reduce CLABSI rates in hospitalized patients. However, despite widespread adoption of these bundles in hospitals worldwide, CLABSIs still remain prevalent.

Nonpeptidic Z360-Analogs Tagged with Trivalent Radiometals as Anti-CCKR Cancer Theranostic Agents: A Preclinical Study.

(1) Background: Theranostic approaches in the management of cholecystokinin subtype 2 receptor (CCKR)-positive tumors include radiolabeled gastrin and CCK motifs. Moving toward antagonist-based CCKR-radioligands instead, we herein present three analogs of the nonpeptidic CCKR-antagonist Z360, GAS1/2/3. Each was conjugated to a different chelator (DOTA, NODAGA or DOTAGA) for labeling with medically relevant trivalent radiometals (e.

PM-bound organosulfates in two Eastern Mediterranean cities: The dominance of isoprene organosulfates.

PM samples were collected during 2017-2018 at two Eastern Mediterranean urban sites in Greece, Athens and Patra, in order to study the abundances, the seasonal trends, the sources and the possible impact of gas phase pollutants on organosulfate formation. Each of the studied groups, except that of aromatic organosulfates, presented higher concentrations in Patra compared to those measured in Athens, from 1.1 (nitro-oxy organosulfates) to 3.

Bounding the Inefficiency of Compromise in Opinion Formation.

Social networks on the Internet have seen an enormous growth recently and play a crucial role in different aspects of today's life. They have facilitated information dissemination in ways that have been beneficial for their users but they are often used strategically in order to spread information that only serves the objectives of particular users. These properties have inspired a revision of classical opinion formation models from sociology using game-theoretic notions and tools.

[Tc]Tc-DB15 in GRPR-Targeted Tumor Imaging with SPECT: From Preclinical Evaluation to the First Clinical Outcomes.

Diagnostic imaging and radionuclide therapy of prostate (PC) and breast cancer (BC) using radiolabeled gastrin-releasing peptide receptor (GRPR)-antagonists represents a promising approach. We herein propose the GRPR-antagonist based radiotracer [Tc]Tc-DB15 ([Tc]Tc-N-AMA-DGA-Phe,Sar,LeuNHEt]BBN(6-13); N: 6-carboxy-1,4,8,11-tetraazaundecane, AMA: aminomethyl-aniline, DGA: diglycolic acid) as a new diagnostic tool for GRPR-positive tumors applying SPECT/CT. The uptake of [Tc]Tc-DB15 was tested in vitro in mammary (T-47D) and prostate cancer (PC-3) cells and in vivo in T-47D or PC-3 xenograft-bearing mice as well as in BC patients.

Human serum elements' levels and leukemia: A first pilot study from an adult Greek cohort.

Background: The present study focuses on the evaluation of potential relationships between trace elements and acute and chronic types of leukemia, via the determination of their levels in human blood serum.

Methods: A total of 199 serum samples from a Greek cohort were examined, including both leukemia cases and controls. Elements' analysis was carried out using inductively coupled plasma mass spectrometry (ICP-MS) and demographic features such as age, gender, smoking habits and area of residence were recorded and statistically treated applying Shapiro-Wilk, Kolmogorov-Smirnov, Mann Whitney and Kruskal Wallis tests (p < 0.

Heart Failure and PAHs, OHPAHs, and Trace Elements Levels in Human Serum: Results from a Preliminary Pilot Study in Greek Population and the Possible Impact of Air Pollution.

Cardiovascular diseases (CVDs) have been associated with environmental pollutants. The scope of this study is to assess any potential relation of polycyclic aromatic hydrocarbons (PAHs), their hydroxylated derivatives, and trace elements with heart failure via their direct determination in human serum of Greek citizens residing in different areas. Therefore, we analyzed 131 samples including cases (heart failure patients) and controls (healthy donors), and the respective demographic data were collected.