Glyco-Polypeptides (Comosain) in Treating of Various Types of Late-Stage Refractory Solid Carcinoma in Humans - A DoubleBlind Study-Case Report of 126 Patients

Glyco-polypeptides (Comosain, Bromelain) induced leucocyte binding ability to tumor surface antigens, such as interleukin 2, 6, 8, and TNFs, is known as an immuno-target therapy. Using different concentration of Bromelain proteinases in 6 types of cancer cell, it resulted in hydrolysis, fibrinolysis, necrosis, and anti-metastatic effects in tumor cells. Anti-cancer effects were achieved in carcinoma of lung, breast, colon, ovary, cervix, and uterus. Investigation of anti-metastatic effects in Bromelain were carried out in a double-blind study: low dose cohort was on 10 mg/kg/day and a high dose cohort which was on 50 mg/kg/day for a period of over six months. A total of 83 patients with 3rd and 4th stage of refractory solid tumors were enrolled, whom at least previously failed on two regimens of chemotherapy and/or failed on radiation therapy. The rates of Complete Response (CR) and Partial Responses (PR) in high dose cohort are astonishing with 52% and 27% respectively. The Progress Disease (PD) was 10%, and the Stable Disease (SD) was 11%. The implications and results of the findings are discussed with in view of the reported anti-metastatic activity of orally administrated Bromelain.

Thoracic fascial planes blocks in operative bed of modified radical mastectomy and their role in alleviating post-mastectomy pain: a prospective randomized study

Background: Proper pain management after modified radical mastectomy is crucial for improving postoperative outcomes, reducing tumor recurrence, enhancing anti-metastatic activity and achieving excellent patient`s satisfaction. Thoracic fascial planes (TFP) blocks are novel, and safe analgesia modalities to control postmastectomy pain. This study was designed to assess the efficacy and safety of intraoperative TFP blocks for providing postoperative analgesia after modified radical mastectomy.Methods: During the period from March 2020 to April 2021, 30 females (ages 25–67 years) were scheduled for elective MRM and selected randomly to one of two groups; group-A included 15 patients who underwent MRM and anesthetized with both general anesthesia and regional anesthesia (TFP blocks), group-B included 15 patients who underwent MRM and anesthetized with only general anesthesia.Results: The group-A had statistically significantly lower pain scores. The time of first rescue nalbuphine dose post-operatively was statistically significantly longer in group-A compared to group-B. The total 24h nalbuphine consumption and postoperative non-steroidal ketorolac requirements/48h were significantly lower in group-A compared to group-B. Satisfaction score in group-A was statistically significantly better than that in group-B.Conclusions: Intraoperative thoracic fascial planes blocks are simple, safe, and highly effective analgesic modalities after breast surgery.

HISTOPATHOLOGICAL DIAGNOSTICS OF TESTICULAR SERTOLI CELL TUMOR IN INGUINAL CRYPTORCHIDISM

The research was carried out in the Interdepartmental Scientific Veterinary Center of Veterinary Medicine based in the Ulyanovsk State Agricultural University. We studied the testis tumor - sertoli cell tumor, according to histological classification, in a male dog with inguinal cryptorchidism. The research goal was to study possible changes in the differentiation, hormonal and metastatic activity of sertoli cell tumor in case of inguinal cryptorchidism in comparison with this type of tumor in physiologically located testes, described in literature. The clinical examination revealed the presence of left-sided inguinal cryptorchidism as well as signs of hyperestrogenism: hyperpigmentation and non-inflammatory alopecia of scrotum, prepuce, located sym-metrically in the right and left iliac regions of the abdomen. The studied neoplasm showed the presence of a dense capsule, the absence of infiltrative growth and metastases in the regional lymph nodes, distinct secretory activity. Fragments of tumor tissue from the testis, epididymis and spermatic cord were obtained for histological examination by the means of excisional biopsy. As a result, the neo-plasm was found to be a sertoli cell tumor of a high degree of differentiation. The tissues of the epididymis showed a significant thickening of the stroma due to the proliferation of connective tissue - a sign of severe sclerosis. The mi-croslides of the spermatic cord and epididymis did not show any signs of infiltrative growth or metastatic spread of tumor cells which meant that the relative benign quality of sertoli cell tumor was found in this clinical study of inguinal cryptorchidism.

Regorafenib in metastatic colorectal cancer: more data for clinical decisions

Regorafenib is a multiple kinase inhibitor. It influences/blocks angiogenesis (VEGFR1-3, TIE2), proliferation (KIT, RET, RAF-1, BRAF), metastatic activity (VEGFR2-3, PDGFR), tumor immunogenicity (CSF1R), tumor microenvironment (PDGFR-, PDGFR-, FGFR1-2). Regorafenib has several indications including metastatic colorectal cancer. Efficacy and safety of regorafenib data from clinical trials (CORRECT, CONCUR, CONSIGN) and observational trials from real world (REBECCA, CORRELATE, RECORA, PMS, REGOTAS) are summarized and presented in this issue. State of the matter of molecular-biologic predictors (KRAS, PIK3CA ANG-2, VEGF-A, LDH, CCL5/CCR5, CA 19-9) and radiological predictors (RadioCORRECT and other trials) is highlighted. Regimens with dose modification and its influence on effectiveness and tolerability of regorafenib are described according to the data from ReDOS, RESET, REARRANGE trials. The results from retrospective trials comparing regorafenib and another approved for refractory metastatic colorectal cancer drug trifluridine/tipiracil are presented.

Elevated METTL9 is associated with peritoneal dissemination in human scirrhous gastric cancers

Methylation, the most common chemical modification of cellular components such as DNA, RNA, and proteins, impacts biological processes including transcription, RNA processing, and protein dynamics. Although abnormal expression of methyltransferase can lead to various diseases including cancers, little is known about the relationship between methyltransferase and cancers. Here we aimed to understand the role of methyltransferase in cancer metastasis. We found that elevated methyltransferase-like 9 (METTL9) is closely associated with the acquisition of metastatic activity in human scirrhous gastric cancers. The stable knockdown of METTL9 via an shRNA vector technique in our original metastatic cells from scirrhous gastric cancer patients significantly inhibited migration and invasion. In metastatic cells, METTL9 protein is predominantly localized in mitochondria, and the METTL9 knockdown significantly reduced mitochondrial Complex I activity. METTL9 can be a promising molecular target to inhibit peritoneal dissemination of scirrhous gastric cancers. This report is the first to describe the relationship between METTL9 and cancer metastasis.

Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases

BackgroundThe interferon response can influence the primary and metastatic activity of breast cancers and can interact with checkpoint immunotherapy to modulate its effects. Using N-ethyl-N-nitrosourea mutagenesis we found a mouse with an activating mutation in oligoadenylate synthetase 2 ( Oas2 ), a sensor of viral double stranded RNA, that resulted in an interferon response and prevented lactation in otherwise healthy mice. MethodsTo determine if activation of Oas2 could alter the course of mammary cancer we combined the Oas2 mutation with the MMTV-PyMT oncogene model of breast cancer and examined disease progression and the effects of checkpoint immunotherapy using Kaplan-Meier survival analysis with immunohistochemistry and flow cytometry. ResultsOas2 mutation prevented pregnancy from increasing metastases to lung. Checkpoint immunotherapy with antibodies against programmed death-ligand 1 (PD-L1) was more effective when the Oas2 mutation was present. ConclusionsThese data establish OAS2 as a therapeutic target for agents designed to reduce metastases and increase the effectiveness of checkpoint immunotherapy in cases of pregnancy-associated breast cancer and outside of pregnancy in cases showing the lactation and involution-mimicry phenotypes.

Thromboelastometric Analysis of Anticancer Cerrena unicolor Subfractions Reveal Their Potential as Fibrin Glue Drug Carrier Enhancers

In this study, the influence of two subfractions (with previously proven anti-cancer properties) isolated from wood rot fungus Cerrena unicolor on the formation of a fibrin clot was investigated in the context of potential use as fibrin glue and sealant enhancers and potential wound healing agents. With the use of ROTEM thromboelastometry, we demonstrated that, in the presence of fibrinogen and thrombin, the S6 fraction accelerated the formation of a fibrin clot, had a positive effect on its elasticity modulus, and enhanced the degree of fibrin cross-linking. The S5 fraction alone showed no influence on the fibrin coagulation process; however, in the presence of fibrin, it exhibited a decrease in anti-proliferative properties against the HT-29 line, while it increased the proliferation of cells in general at a concentration of 100 µg/mL. Both fractions retained their proapoptotic properties to a lesser degree. In combination with the S6 fraction in the ratio of 1:1 and 1:3, the fractions contributed to increased inhibition of the activity of matrix metalloproteinases (MMPs). This may suggest anti-metastatic activity of the combined fractions. In conclusion, the potential of the fractions isolated from the C. unicolor secretome to be used as a means of improving the wound healing process was presented. The potential for delivering agents with cytostatic properties introduced far from the site of action or exerting a pro-proliferative effect at the wound site with the aid of a fibrin sealant was demonstrated.

Cellular Immune Response Induced by DNA Immunization of Mice with Drug Resistant Integrases of HIV-1 Clade A Offers Partial Protection against Growth and Metastatic Activity of Integrase-Expressing Adenocarcinoma Cells

Therapeutic DNA-vaccination against drug-resistant HIV-1 may hinder emergence and spread of drug-resistant HIV-1, allowing for longer successful antiretroviral treatment (ART) up-to relief of ART. We designed DNA-vaccines against drug-resistant HIV-1 based on consensus clade A integrase (IN) resistant to raltegravir: IN_in_r1 (L74M/E92Q/V151I/N155H/G163R) or IN_in_r2 (E138K/G140S/Q148K) carrying D64V abrogating IN activity. INs, overexpressed in mammalian cells from synthetic genes, were assessed for stability, route of proteolytic degradation, and ability to induce oxidative stress. Both were found safe in immunotoxicity tests in mice, with no inherent carcinogenicity: their expression did not enhance tumorigenic or metastatic potential of adenocarcinoma 4T1 cells. DNA-immunization of mice with INs induced potent multicytokine T-cell response mainly against aa 209–239, and moderate IgG response cross-recognizing diverse IN variants. DNA-immunization with IN_in_r1 protected 60% of mice from challenge with 4Tlluc2 cells expressing non-mutated IN, while DNA-immunization with IN_in_r2 protected only 20% of mice, although tumor cells expressed IN matching the immunogen. Tumor size inversely correlated with IN-specific IFN-γ/IL-2 T-cell response. IN-expressing tumors displayed compromised metastatic activity restricted to lungs with reduced metastases size. Protective potential of IN immunogens relied on their immunogenicity for CD8+ T-cells, dependent on proteasomal processing and low level of oxidative stress.