Safety and efficacy of peptide receptor radionuclide therapy with 177Lu-DOTA0-Tyr3-octreotate in combination with amino acid solution infusion in Japanese patients with somatostatin receptor-positive, progressive neuroendocrine tumors

Purpose Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA0-Tyr3-octreotate (177Lu-DOTATATE) is one of the most reliable treatments for unresectable, progressive neuroendocrine tumors (NETs) with somatostatin receptor expression. We have, for the first time, reported the results of the tolerability, safety, pharmacokinetics, dosimetry, and efficacy of this treatment for Japanese patients with NET. Methods Patients with unresectable, somatostatin receptor scintigraphy (SRS)-positive NETs were enrolled in this phase I clinical trial. They were treated with 29.6 GBq of 177Lu-DOTATATE (four doses of 7.4 GBq) combined with amino acid solution infusion plus octreotide long-acting release (LAR) 30 mg. The primary objective of this study was to evaluate the tolerability, safety, pharmacokinetics, and dosimetry of a single administration of this treatment in patients with SRS-positive NETs. Results Six Japanese patients (three men and three women; mean age 61.5 years; range 50–70 years) with SRS-positive unresectable NETs were recruited. 177Lu-DOTATATE was eliminated from the blood in a two-phase manner. Cumulative urinary excretion of radioactivity was 60.1% (range 49.0%–69.8%) within the initial 6 h. The cumulative renal absorbed dose for 29.6 GBq of 177Lu-DOTATATE was 16.8 Gy (range 12.0–21.2 Gy), and the biological effective dose was 17.0 Gy (range 12.2–21.5 Gy). Administration of 177Lu-DOTATATE was well tolerated, with no dose-limiting toxicities. Grade 3 lymphopenia occurred in two (33.3%) cases, but there were no other severe toxicities. Four patients achieved partial response (objective response rate, 66.7%), one patient had stable disease, and one patient had progressive disease. Conclusion PRRT with 177Lu-DOTATATE was well-tolerated and showed good outcomes in Japanese patients with unresectable NETs. Peptide receptor radionuclide therapy, 177Lu-DOTA0-Tyr3-octreotate .

Alkaline intracellular pH activates AMPK-mTORC2 signaling to promote cell survival during growth factor limitation

mTORC2 controls cell metabolism and promotes cell survival, yet its upstream regulation by diverse cellular cues remains poorly defined. While considerable evidence indicates that mTORC1 but not mTORC2 responds dynamically to amino acid levels, several studies reported activation of mTORC2 signaling by amino acids, a paradox that remains unresolved. Following amino acid starvation, we noted that addition of a commercial amino acid solution but not re-feeding with DMEM containing amino acids increased mTORC2 signaling. Interestingly, the pH of the amino acid solution was ~ 10. These key observations enabled us to discover that alkaline intracellular pH (pHi) represents a previously unknown activator of mTORC2. Using a fluorescent pH-sensitive dye (cSNARF-1-AM) coupled to live-cell imaging, we demonstrate that alkaline extracellular pH (pHe) increases intracellular pHi, which increases mTORC2 catalytic activity and downstream signaling to Akt. Alkaline pHi also activates AMPK, a sensor of energetic stress. Functionally, alkaline pHi attenuates apoptosis caused by growth factor withdrawal, which requires AMPK in part and mTOR in full. Collectively, these findings reveal that alkaline pHi increases AMPK-mTORC2 signaling to promote cell survival during growth factor limitation. As elevated pHi represents an under-appreciated hallmark of cancer cells, alkaline pH sensing by AMPK-mTORC2 may contribute to tumorigenesis.

The Effect of Foliar Application of an Amino Acid-Based Biostimulant on Lawn Functional Value

The purpose of this research was to assess the functional value of the “Super Trawnik” lawn mixture. The studies were carried out between 2017 and 2019 at the Experimental Station of the University of Agriculture in Krakow (50°07′ N, 20°05′ E), and the experimental factor was the AGRO-SORB® Folium, a biostimulant containing amino acids and applied at three doses: 1, 2, and 3 L·ha−1. Lawn visual quality was assessed on a 9-point scale, with 10–11 mowings at 4 cm during the growing period. An increase in the concentration of the stimulant applied as a spray resulted in a significant increase in its effectiveness; plants in plots with the highest dose of amino acid solution (Variant III) had the highest aesthetic and functional values. The AGRO-SORB® Folium reduced the occurrence of fungal diseases; compared to control plants, there was a 16% reduction of Fusarium patch (Microdochium nivale) infection and a 20% reduction of Dreschlera leaf spot (Drechslera siccans). Satisfactory effects were also recorded on plots where the product was applied at a dose of 2 L·ha−1 (Variant II). Those plots had more favourably rated turf, with higher resistance of plants to Fusarium patch by 12% and to Dreschlera leaf spot by 20% compared to control.

Evaluation of the incidence of acute nausea and vomiting after administration of an amino acid solution containing only arginine and lysine with lutetium Lu-177 dotatate.

12113 Background: Lutetium Lu-177 dotatate is used to treat patients with gastroenteropancreatic neuroendocrine tumors, and an amino acid (AA) solution must be administered concurrently to mitigate nephrotoxicity. AA solutions may lead to increased rates of nausea and vomiting (NV) due to the inclusion of unnecessary non-essential and essential AA. Methods: This study is a single academic center retrospective chart review from October 6th, 2015 to December 17th, 2019 evaluating the incidence of acute NV in adult patients after administration of an AA solution containing only arginine 25 grams and lysine 25 grams in 1 liter of normal saline (Arginine-Lysine amino acid [AL AA]) with lutetium Lu-177 dotatate. The incidence of acute NV will be compared to the historical incidence in patients administered Parenteral amino acids 10%, Aminosyn II 10% or Clinisol 15% (commercial AA). Secondary endpoints include the incidence of rescue anti-emetic usage and the percentage of patients that require interruption of the AA infusion. Acute NV are defined as any occurrence of NV within twenty-four hours of the AA infusion. Results: 53 patients received a total of 164 treatments with the AL AA, while 18 patients received a total of 48 treatments with the commercial AA. The AL AA significantly decreased the incidence of acute NV, the mean AA infusion time, the interruption of the AA infusion, and the utilization of rescue anti-emetics compared to the commercial AA (Table) in patients on lutetium Lu-177 dotatate. Conclusions: The study findings support the use of an AL AA to be administered concurrently with lutetium Lu-177 dotatate to minimize commercial AA related acute NV. [Table: see text]

SORPTION OF AMINO ACID AND CHANGES IN HYDRATION OF HETEROGENEOUS CATION- AND ANION-EXCHANGE MEMBRANES FUMASEP

Hydration of heterogeneous cation-exchange membranes Fumasep FTCM and anion-exchange membranes Fumasep FTAM in hydrogen and hydroxyl forms, respectively, sorbing tyrosine as well as of the samples being used in electrodialysis concentration of tyrosine solution was studied using the methods of thermogravimetry and IR-spectroscopy. It was revealed that tyrosine sorption and membranes application in electrodialysis of this amino acid solution causes membranes hydration decrease. The decrease in membrane hydration after its contact with tyrosine leads to membrane surface hydrophobicity grow up and, consequently, make significant influence on amino acid’s mass transfer.