Preclinical Study of Therapeutic Efficacy of a New Russian Radiopharmaceutical 177Lu-DOTA-PSMA.

The therapeutic efficacy of a Russian radiopharmaceutical 177Lu-DOTA-PSMA was studied in vivo using male BALB/c nu/nu (nude) mice with prostate carcinoma 22Rv1 xenografts by tumor growth inhibition criterion. The mean tumor volumes in mice treated with 177Lu-DOTA-PSMA were significantly lower than in animals of the control group. There were no significant differences in the values of tumor growth inhibition between the groups of animals receiving 3.7 or 7.4 MBq of 177Lu-DOTA-PSMA.

CRAC (Clinical Relevance of Alterations in Cancer): a Knowledge Base for the Selection of Molecularly Matched Therapy for Solid Tumors.

Multigene testing using NGS (next-generation sequencing) provides a large amount of information and can detect multiple molecular alterations. Subsequent clinical interpretation is a time-consuming process necessary to select a treatment strategy. Existing databases often contain inconsistent information and are not regularly updated. The use of ESCAT levels of evidence requires a deep understanding of the nature of alterations and does not answer the question of which therapy option to select when multiple biomarkers with the same level of evidence are detected. To address these issues, we created the Clinical Relevance of Alterations in Cancer (CRAC) database on the relevance of detected alterations in specific genes, which are often analyzed as part of NGS panels. The team of oncologists and biologists assigned a CRAC score from 1 to 10 to each biomarker (a type of genomic alteration characteristic of specific genes) for 15 malignancies; an average score was entered into the database. CRAC scores are a numerical reflection of the following factors: therapy availability and the prospects of drug treatment with experimental drugs for patients with a particular type of tumor. A total of 134 genes and 15 of the most common tumor types have been selected for CRAC. The biomarker-nosology associations with CRAC scores in the range of 1-3 are the most frequent (n=2719 out of 3495; 77.8%), the least frequent ones (n=52 out of 3495; 1.5%) are with the highest CRAC scores 9 and 10. To estimate the practical effectiveness of the CRAC database, 208 reports on comprehensive molecular profiling were retrospectively analyzed; the applicability of CRAC was compared with the ESCAT level of evidence system. The highest CRAC scores corresponded to the ESCAT maximum levels of evidence: the range of scores 8-10 corresponded to evidence levels I and II. No biomarker within the same level of evidence was represented by the same CRAC score; the largest range of CRAC scores was observed for biomarkers of levels evidence IIIA and IV - from 2 to 10 and from 1 to 9, respectively. The use of CRAC scores allowed to identify additional 95 alterations with CRAC scores of 1-5 in the studied patients. The developed database is available at: https://crac.oncoatlas.ru/.

Ruxolitinib versus dexamethasone in hospitalized adults with COVID-19: multicenter matched cohort study.

BACKGROUND: Several anti-cytokine therapies were tested in the randomized trials in hospitalized patients with severe acute respiratory syndrome coronavirus 2 infection (COVID-19). Previously, dexamethasone demonstrated a reduction of case-fatality rate in hospitalized patients with respiratory failure. In this matched control study we compared dexamethasone to a Janus kinase inhibitor, ruxolitinib. METHODS: The matched cohort study included 146 hospitalized patients with COVID-19 and oxygen support requirement. The control group was selected 1:1 from 1355 dexamethasone-treated patients and was matched by main clinical and laboratory parameters predicting survival. Recruitment period was April 7, 2020 through September 9, 2020. RESULTS: Ruxolitinib treatment in the general cohort of patients was associated with case-fatality rate similar to dexamethasone treatment: 9.6% (95% CI [4.6-14.6%]) vs 13.0% (95% CI [7.5-18.5%]) respectively (p = 0.35, OR = 0.71, 95% CI [0.31-1.57]). Median time to discharge without oxygen support requirement was also not different between these groups: 13 vs. 11 days (p = 0.13). Subgroup analysis without adjustment for multiple comparisons demonstrated a reduced case-fatality rate in ruxolitnib-treated patients with a high fever (≥ 38.5 °C) (OR 0.33, 95% CI [0.11-1.00]). Except higher incidence of grade 1 thrombocytopenia (37% vs 23%, p = 0.042), ruxolitinib therapy was associated with a better safety profile due to a reduced rate of severe cardiovascular adverse events (6.8% vs 15%, p = 0.025). For 32 patients from ruxolitinib group (21.9%) with ongoing progression of respiratory failure after 72 h of treatment, additional anti-cytokine therapy was prescribed (8-16 mg dexamethasone). CONCLUSIONS: Ruxolitinib may be an alternative initial anti-cytokine therapy with comparable effectiveness in patients with potential risks of steroid administration. Patients with a high fever (≥ 38.5 °C) at admission may potentially benefit from ruxolitinib administration. Trial registration The Ruxolitinib Managed Access Program (MAP) for Patients Diagnosed With Severe/Very Severe COVID-19 Illness NCT04337359, CINC424A2001M, registered April, 7, 2020. First participant was recruited after registration date.

[Retroperitoneoscopic approach for treatment of acute obstructive calculous pyelonephritis. Alternative or a method of choice?]

AIM: to compare the results of treatment of patients with acute obstructive calculous pyelonephritis, who underwent to retroperitoneoscopic procedure, with patients, who underwent to drainage of the collecting system by means of ureteral stent or nephrostomy tube as the first stage. MATERIALS AND METHODS: A total of 121 patients were treated from 2011 to 2019. Of these, 78 patients were included in the main group. The stones were located in the ureteropelvic junction (n = 20) and the upper and middle ureter (n = 58). The average size of the stone was 12.9 +/- 4.8 mm. Preliminary upper urinary tract drainage was not carried out and the stone was removed completely. The group 2 consisted of 26 people. The stones were located in the upper (n = 18) and the middle ureter (n = 8); the average size was 9 +/- 2.8 mm. Renal drainage was done using ureteral stent and when pyelonephritis resolved, ureterolithotripsy was performed. The group 3 was represented by 17 patients. All stones were located in the ureteropelvic junction. The average size was 20.3 +/- 10.7 mm. Renal drainage was done using percutaneous nephrostomy; when there were no inflammatory changes, percutaneous nephrolithotripsy was performed. RESULTS: In the main group, normalization of body temperature and resolution of inflammatory changes in the blood and urine occurred earlier. The stone was removed completely and there were no residual fragments. Period of rehabilitation was are also significantly shorter than in groups 2 and 3. The retroperitoneoscopic method was more effective and safer for the treatment of patients with acute obstructive pyelonephritis caused by large stones located in the upper or middle ureter and ureteropelvic junction.

Immunomodulating and Revascularizing Activity of Kalanchoe pinnata Synergize with Fungicide Activity of Biogenic Peptide Cecropin P1.

Previously transgenic Kalanchoe pinnata plants producing an antimicrobial peptide cecropin P1 (CecP1) have been reported. Now we report biological testing K. pinnata extracts containing CecP1 as a candidate drug for treatment of wounds infected with Candida albicans. The drug constitutes the whole juice from K. pinnata leaves (not ethanol extract) sterilized with nanofiltration. A microbicide activity of CecP1 against an animal fungal pathogen in vivo was demonstrated for the first time. However, a favorable therapeutic effect of the transgenic K. pinnata extract was attributed to a synergism between the fungicide activity of CecP1 and wound healing (antiscar), revascularizing, and immunomodulating effect of natural biologically active components of K. pinnata. A commercial fungicide preparation clotrimazole eliminated C. albicans cells within infected wounds in rats with efficiency comparable to CecP1-enriched K. pinnata extract. But in contrast to K. pinnata extract, clotrimazole did not exhibit neither wound healing activity nor remodeling of the scar matrix. Taken together, our results allow assumption that CecP1-enriched K. pinnata extracts should be considered as a candidate drug for treatment of dermatomycoses, wounds infected with fungi, and bedsores.

Bactericide, Immunomodulating, and Wound Healing Properties of Transgenic Kalanchoe pinnata Synergize with Antimicrobial Peptide Cecropin P1 In Vivo.

Procedure of manufacturing K. pinnata water extracts containing cecropin P1 (CecP1) from the formerly described transgenic plants is established. It included incubation of leaves at +4°C for 7 days, mechanical homogenization of leaves using water as extraction solvent, and heating at +70°C for inactivating plant enzymes. Yield of CecP1 (after heating and sterilizing filtration) was 0.3% of total protein in the extract. The water extract of K. pinnata + CecP1 exhibits favorable effect on healing of wounds infected with S. aureus (equal to Cefazolin) and with a combination of S. aureus with P. aeruginosa (better than Cefazolin). Wild-type K. pinnata extract exhibited evident microbicide activity against S. aureus with P. aeruginosa but it was substantially strengthened in K. pinnata + CecP1 extract. K. pinnata extracts (both wild-type and transgenic) did not exhibit general toxicity and accelerated wound recovery. Due to immunomodulating activity, wild-type K. pinnata extract accelerated granulation of the wound bed and marginal epithelialization even better than K. pinnata + CecP1 extract. Immunomodulating and microbicide activity of K. pinnata synergizes with microbicide activity of CecP1 accelerating elimination of bacteria.

[The obtainment and characteristics of Kalanchoe pinnata L. plants expressing the artificial gene of the cecropin P1 antimicrobial peptide].

Kalanchoe pinnata L. plants bearing an artificial CP1 gene encoding the cecropin P1 antimicrobial peptide have been obtained. The presence of the CP1 gene in the plant genome has been confirmed by PCR. Cecropin P1 synthesis in transgenic plants has been shown by MALDI mass spectrometry and Western blotting. The obtained plants have been highly resistant to bacterial and fungal phytopathogens, and their extracts have demonstrated antimicrobial activity towards human and animal pathogens. It has been shown that transgenic plants bearing the CP1 gene can be colonized by the beneficial associative microorganisms Methylovorus mays.