Antineoplastic effect of compounds C14 and P8 on TNBC and radioresistant TNBC cells by stabilizing the K-Ras4BG13D/PDE6δ complex.

Introduction: Breast cancer (BC) is the leading cause of cancer-related deaths among women, with triple-negative breast cancer (TNBC) representing one of the most aggressive and treatment-resistant subtypes. In this study, we aimed to evaluate the antitumor potential of C14 and P8 molecules in both TNBC and radioresistant TNBC cells. These compounds were chosen for their ability to stabilize the complex formed by the overactivated form of K-Ras4BG13D and its membrane transporter (PDE6δ). Methods: The antitumor potential of C14 and P8 was assessed using TNBC cell lines, MDA-MB-231, and the radioresistant derivative MDA-MB-231RR, both carrying the K-Ras4B> G13D mutation. We investigated the compounds' effects on K-Ras signaling pathways, cell viability, and tumor growth in vivo. Results: Western blotting analysis determined the negative impact of C14 and P8 on the activation of mutant K-Ras signaling pathways in MDA-MB-231 and MDA-MB-231RR cells. Proliferation assays demonstrated their efficacy as cytotoxic agents against K-RasG13D mutant cancer cells and in inducing apoptosis. Clonogenic assays proven their ability to inhibit TNBC and radioresistant TNBC cell clonogenicity. In In vivo studies, C14 and P8 inhibited tumor growth and reduced proliferation, angiogenesis, and cell cycle progression markers. Discussion: These findings suggest that C14 and P8 could serve as promising adjuvant treatments for TNBC, particularly for non-responders to standard therapies. By targeting overactivated K-Ras and its membrane transporter, these compounds offer potential therapeutic benefits against TNBC, including its radioresistant form. Further research and clinical trials are warranted to validate their efficacy and safety as novel TNBC treatments.

[Pain relief by Ketorol Express after oral surgery procedures]. / Kupirovanie bolevogo sindroma preparatom Ketorol Ekspress posle stomatologicheskikh vmeshatel'stv, soprovozhdayushchikhsya travmoi tkanei.

The aim of the study was providing rationale for using a new form of Ketorol Express for pain relief in outpatient dental practice. The study comprised 85 patients with an average age of 43.2 years, who were prescribed a three-day course of Ketorol Express therapy after a complex traumatic tooth extraction. Three different visual-analog scales were used to assess the severity of pain, the patient's General well-being, and the doctor's General well-being. After treatment with dispersed Ketorol Express tablets, the severity of the pain syndrome decreased from 4 to 1.8 points within three days. Anesthesia occurred on average in 10 minutes. This therapy was safe and well tolerated. There were no one serious adverse events, and no one patient stopped therapy due to side effects.

Testicular germ line cell identification, isolation, and transplantation in two North American catfish species.

Our aim was to transplant blue catfish germ line stem cells into blastulae of triploid channel catfish embryos to produce interspecific xenogenic catfish. The morphological structure of the gonads of blue catfish (Ictalurus furcatus) in ~ 90- to 100-day-old juveniles, two-year-old juveniles, and mature adults was studied histologically. Both oogonia (12-15 µm, diameter with distinct nucleus 7-8 µm diameter) and spermatogonia (12-15 µm, with distinct nucleus 6-7.5 µm diameter) were found in all ages of fish. The percentage of germ line stem cells was higher in younger blue catfish of both sexes. After the testicular tissue was trypsinized, a discontinuous density gradient centrifugation was performed using 70, 45, and 35% Percoll to enrich the percentage of spermatogonial stem cells (SSCs). Four distinct cell bands were generated after the centrifugation. It was estimated that 50% of the total cells in the top band were type A spermatogonia (diameter 12-15 µm) and type B spermatogonia (diameter 10-11 µm). Germ cells were confirmed with expression of vasa. Blastula-stage embryos of channel catfish (I. punctatus) were injected with freshly dissociated blue catfish testicular germ cells as donor cells for transplantation. Seventeen days after the transplantation, 33.3% of the triploid channel catfish fry were determined to be xenogenic catfish. This transplantation technique was efficient, and these xenogenic channel catfish need to be grown to maturity to verify their reproductive capacity and to verify that for the first time SSCs injected into blastulae were able to migrate to the genital ridge and colonize. These results open the possibility of artificially producing xenogenic channel catfish males that can produce blue catfish sperm and mate with normal channel catfish females naturally. The progeny would be all C × B hybrid catfish, and the efficiency of hybrid catfish production could be improved tremendously in the catfish industry.

[Nutraceuticals in the combat against oral cancer].

Head and neck squamous cell carcinoma (HNSCC), the eighth most common cancer worldwide, accounts for approximately 600,000 new cases per year. The mobile tongue is the most common site for oral cancer and is associated with a poorer survival than other HNSCC sites. Standard therapeutic strategies have failed to significantly improve survival rates that have remained around 50% over the past four decades. In the last decade intense investigations on oral cancer highlighted the mandatory role of the tumor microenvironment (TME), in addition to the genetic aberrations and molecular biology changes within the cancer cells. Furthermore, the molecular crosstalk between cancer cells and TME components (i.e., cancer-associated fibroblasts, inflammatory pro-tumorigenic cells, etc.) has a crucial role in growth, invasion, spread and metastases of the cancer cells and consequently leads to poor prognosis. Recent studies suggest that plant-derived dietary agents nutraceuticals, especially curcumin and green tea, have the advantage to combat both malignant cells and TME components, unlike standard anti-cancer protocols that target only cancer cells. However, due to a very low bioavailability, nutraceuticals do not currently constitute an integral part of these protocols. Ongoing developments in nanotechnology for improved delivery are expected to overcome their challenging pharmacokinetics.

Toxicology study assessing efficacy and safety of repeated administration of lipid/DNA complexes to mouse lung.

For gene therapy to improve lung function in cystic fibrosis (CF) subjects, repeated administration of the gene transfer agent over the lifetime of patients is likely to be necessary. This requirement limits the utility of adenoviral and adeno-associated viral vectors (both previously evaluated in CF gene therapy trials) because of induced adaptive immune responses that render repeated dosing ineffective. For CF gene therapy trials, non-viral vectors are currently the only viable option. We previously showed that the cationic lipid formulation GL67A is the most efficient of several non-viral vectors analysed for airway gene transfer. Here, we assessed the efficacy and safety of administering 12 inhaled doses of GL67A complexed with pGM169, a CpG-free plasmid encoding human CFTR complementary DNA, into mice. We show that repeated administration of pGM169/GL67A to murine lungs is feasible, safe and achieves reproducible, dose-related and persistent gene expression (>140 days after each dose) using an aerosol generated by a clinically relevant nebuliser. This study supports progression into the first non-viral multidose lung trial in CF patients.

A review of mammalian carcinogenicity study design and potential effects of alternate test procedures on the safety evaluation of food ingredients.

Extensive experience in conducting long term cancer bioassays has been gained over the past 50 years of animal testing on drugs, pesticides, industrial chemicals, food additives and consumer products. Testing protocols for the conduct of carcinogenicity studies in rodents have been developed in Guidelines promulgated by regulatory agencies, including the US EPA (Environmental Protection Agency), the US FDA (Food and Drug Administration), the OECD (Organization for Economic Co-operation and Development) for the EU member states and the MAFF (Ministries of Agriculture, Forestries and Fisheries) and MHW (Ministry of Health and Welfare) in Japan. The basis of critical elements of the study design that lead to an accepted identification of the carcinogenic hazard of substances in food and beverages is the focus of this review. The approaches used by entities well-known for carcinogenicity testing and/or guideline development are discussed. Particular focus is placed on comparison of testing programs used by the US National Toxicology Program (NTP) and advocated in OECD guidelines to the testing programs of the European Ramazzini Foundation (ERF), an organization with numerous published carcinogenicity studies. This focus allows for a good comparison of differences in approaches to carcinogenicity testing and allows for a critical consideration of elements important to appropriate carcinogenicity study designs and practices. OECD protocols serve as good standard models for carcinogenicity testing protocol design. Additionally, the detailed design of any protocol should include attention to the rationale for inclusion of particular elements, including the impact of those elements on study interpretations. Appropriate interpretation of study results is dependent on rigorous evaluation of the study design and conduct, including differences from standard practices. Important considerations are differences in the strain of animal used, diet and housing practices, rigorousness of test procedures, dose selection, histopathology procedures, application of historical control data, statistical evaluations and whether statistical extrapolations are supported by, or are beyond the limits of, the data generated. Without due consideration, there can be result conflicting data interpretations and uncertainty about the relevance of a study's results to human risk. This paper discusses the critical elements of rodent (rat) carcinogenicity studies, particularly with respect to the study of food ingredients. It also highlights study practices and procedures that can detract from the appropriate evaluation of human relevance of results, indicating the importance of adherence to international consensus protocols, such as those detailed by OECD.

Laparoscopic colectomy for transverse colon carcinoma.

BACKGROUND: Laparoscopic resection of transverse colon carcinoma is technically demanding and was excluded from most of the large trials of laparoscopic colectomy. The aim of this study was to assess the safety, feasibility, and outcome of laparoscopic resection of carcinoma of the transverse colon. METHODS: A retrospective review was performed to identify patients who underwent laparoscopic resection of transverse colon carcinoma. These patients were compared to patients who had laparoscopic resection for right and sigmoid colon carcinoma. In addition, they were compared to a historical series of patients who underwent open resection for transverse colon cancer. RESULTS: A total of 22 patients underwent laparoscopic resection for transverse colon carcinoma. Sixty-eight patients operated for right colon cancer and 64 operated for sigmoid colon cancer served as comparison groups. Twenty-four patients were identified for the historical open group. Intraoperative complications occurred in 4.5% of patients with transverse colon cancer compared to 5.9% (P = 1.0) and 7.8% (P = 1.0) of patients with right and sigmoid colon cancer, respectively. The early postoperative complication rate was 45, 50 (P = 1.0), and 37.5% (P = 0.22) in the three groups, respectively. Conversion was required in 1 (5%) patient in the laparoscopic transverse colon group. The conversion rate and late complications were not significantly different in the three groups. There was no significant difference in the number of lymph nodes harvested in the laparoscopic and open groups. Operative time was significantly longer in the laparoscopic transverse colectomy group when compared to all other groups (P = 0.001, 0.008, and <0.001 compared to right, sigmoid, and open transverse colectomy, respectively). CONCLUSIONS: The results of laparoscopic colon resection for transverse colon carcinoma are comparable to the results of laparoscopic resection of right or sigmoid colon cancer and open resection of transverse colon carcinoma. These results suggest that laparoscopic resection of transverse colon carcinoma is safe and feasible.

Preperitoneal bupivacaine attenuates pain following laparoscopic inguinal hernia repair.

BACKGROUND: Laparoscopic preperitoneal inguinal hernia repair is associated with a short hospital stay and an early return to normal activity. Therefore, early postoperative pain control is important. The aim of this study was to evaluate the effect of preperitoneal Bupivacaine instilled into the preperitoneal cavity on pain following laparoscopic mesh repair of inguinal hernia. METHODS: After institutional review board approval, 44 patients undergoing elective laparoscopic inguinal hernia repair were prospectively randomized into two groups. Upon completion of the Prolene mesh repair, group A received 80 mg of Bupivacaine in 25 cc of saline installed into the preperitoneal space, whereas group B received normal saline installed into the preperitoneal space. Pain was assessed using a visual analog scale at fixed time intervals; the amount of analgesics required was also recorded. RESULTS: Twenty-two patients were included in each group. The demographic characteristics and type of surgery (unilateral vs bilateral) did not significantly differ between the two groups. The average pain levels were significantly attenuated in group A compared to group B at 1 (4.0 vs 5.0, respectively; p = 0.0038), 2 (4.0 vs 5.9, respectively; p = 0.0015), and 4 (4.3 vs 5.8, respectively; p = 0.0038) h after surgery. Furthermore, the analgesic intake was significantly decreased in group A compared to group B. CONCLUSION: Preperitoneal Bupivacaine attenuates pain following laparoscopic inguinal hernia repair and should be considered in these cases.

Albendazole, mebendazole and praziquantel. Review of non-clinical toxicity and pharmacokinetics.

The pharmacokinetics and toxicity of albendazole, mebendazole and praziquantel are extensively reviewed, drawing on original published work and reviews in the open scientific literature and on assessments by international agencies and official regulatory bodies in Europe and the USA. Information about human and veterinary medical uses and adverse reactions is evaluated. The totality of the non-clinical information available about these long-established drugs may not comply with current official guidelines for new medicines but reasons are given why the "deficiencies" are only apparent and the data gaps can be replaced by other results, largely obtained from the target species and the many years of clinical experience of safe use of these drugs in humans and animals.

Carcinogenicity testing of IL-10: principles and practicalities.

IL-10 is a cytokine with actions at many levels of the immune system. In the course of development of recombinant human IL-10 (rhuIL-10) as a potential treatment for a number of chronic diseases of man, the question 'What about its carcinogenicity testing?' was repeatedly asked, based on scientific evaluation by toxicologists, beliefs about regulatory requirements, and questions considered likely to be raised by physicians, patients, and lawyers. The feasibility of various approaches to the carcinogenicity testing of rhuIL-10 is critically discussed here as a contribution to rational consideration of the general need for and value of such testing, and its particular feasibility for a recombinant human protein with profound effects on the immune system. The physiological functions of IL-10 in man and rodents are reviewed in detail, as there are notable differences between species in its normal activities, followed by detailed evaluation of the potential procedures and practical problems of its carcinogenicity testing as a heterologous, immunogenic protein in rodents. The value of information that might be obtained from transgenic mice is also evaluated, and so are the results of studies exploring its actions on human tumour cell biopsies and rodent and human cell lines. It is concluded that despite the probable popular and regulatory expectations that carcinogenicity test results would be provided, all the physiological and pathological information reveals no indication that rhuIL-10 would pose a carcinogenic risk to humans on prolonged administration, and that it would not be feasible to undertake such experimentation. It is argued that in this, as in other instances, professional and popular expectations have run beyond practical feasibility or theoretical justification. Cautious and critical evaluation should be made every time shorter or longer term toxicity studies of any candidate drug are planned or even considered, especially if it is a recombinant protein, to decide on objective grounds whether the studies are really necessary and whether they can be done in a way that will give meaningful results that will help in risk assessment.

Mechanisms of chromium toxicity, carcinogenicity and allergenicity: review of the literature from 1985 to 2000.

Laboratory and clinical reports about the pathogenesis of the carcinogenicity and allergenicity of chromium compounds published between 1985 and 2000 have been reviewed as a basis for consideration of the pathogenetic mechanisms involved. There is good evidence from the clinic and the laboratory that Cr[VI] is the ion responsible for most of the toxic actions, although much of the underlying molecular damage may be due to its intracellular reduction to the even more highly reactive and short-lived chemical species Cr[III] and Cr[V]. Exposure to Cr[VI] can result in various point mutations in DNA and to chromosomal damage, as well as to oxidative changes in proteins and to adduct formation. The relative importance of these effects of chromium ions and of the free oxidising radicals they may generate in the body in causing tumours and allergic sensitisation remain to be demonstrated. Biochemical studies of the DNA-damaging effects and of the pathogenesis of the allergic reactions to chromium ions have not kept up with advances in understanding of the molecular basis of the effects of other carcinogens and allergens.

Pharmacokinetic and toxicology assessment of INTERCEPT (S-59 and UVA treated) platelets.

The pathogen inactivation process developed by Cerus and Baxter Healthcare Corporations uses the psoralen, S-59 (amotosalen) in an ex vivo photochemical treatment (PCT) process to inactivate viruses, bacteria, protozoans, and leukocytes in platelet concentrates and plasma. Studies were performed by intravenous infusion of S-59 PCT formulations +/- compound adsorption device (CAD) treatment and with non-UVA illuminated S-59, using doses that were multiples of potential clinical exposures. The studies comprised full pharmacokinetic, single- and repeated-dose (up to 13 weeks duration) toxicity, safety pharmacology (CNS, renal, and cardiovascular), reproductive toxicity, genotoxicity, carcinogenicity testing in the p53(+/-) mouse, vein irritation, and phototoxicity. No specific target organ toxicity (clinical or histopathological), reproductive toxicity, or carcinogenicity was observed. S-59 and/or PCT formulations demonstrated CNS, ECG, and phototoxicity only at supraclinical doses. Based on the extremely large safety margins (>30,000-fold expected clinical exposures), the CNS and ECG observations are not considered to have any toxicological relevance. Additionally, after a complete assessment, mutagenicity and phototoxicity results are not considered relevant for the proposed use of INTERCEPT platelets. Thus, the results of an extensive series of in vitro and in vivo studies have not demonstrated any toxicologically relevant effects of platelet concentrates prepared by the INTERCEPT system.

Laparoscopic resection of huge omental cyst.

Mesenteric cysts are uncommon, and their pathological type includes pseudocyst, mesothelial cyst, lymphangioma, and omental cyst. We describe a case of a giant omental cyst treated successfully by a minimally invasive approach.

Safety evaluation of human living skin equivalents.

Human living skin equivalents (LSEs) offer an alternative to the use of split-thickness autografts for the treatment of hard-to-heal wounds. LSEs consist of 4 active components: a well-differentiated stratum corneum derived from epidermal keratinocytes, dermal fibroblasts, and an extracellular collagen matrix. Neonatal foreskins are used as the source of keratinocytes and dermal fibroblasts for the manufacture of LSEs. Following isolation and expansion in vitro, the cells are cultured on a 3-dimensional scaffold to give an upper epidermal layer and supporting dermal layer. The resulting product has the appearance and handling characteristics of human skin. Safety evaluation of LSEs begins with insuring that foreskins are obtained only from healthy infants whose mothers are negative for a panel of adventitious agents. Keratinocyte and fibroblast cell banks are characterized using morphologic, biochemical, and histologic criteria; checked for the absence of contaminating cell types such as melanocytes, macrophages, lymphocytes, and Langerhans cells; subjected to rigorous microbiological testing (with any production materials of biological origin); and evaluated for in vivo tumorigenicity. The consistency of certain key morphologic and functional characteristics are regularly assessed. Because an LSE represents an allogeneic graft, preclinical safety studies include in vitro and in vivo determinations of its potential immunogenicity. Immunocompromised (SCID) mice reconstituted with human leukocytes or engrafted with human fetal hematolymphoid organs have been useful animal models for assessing possible immunologic responses to LSEs. Additional preclinical studies are being conducted to show that LSEs are noncytotoxic and lack allergenic, sensitizing, or irritation potential.

Catastrophic failure of the acetabular component in a ceramic-polyethylene bearing total hip arthroplasty.

Recent research in total hip arthroplasty has focused on attempts to decrease wear at the femoral head-acetabulum articulation, to limit the production of debris that is believed to lead to osteolysis and prosthetic loosening. The use of ceramic-on-polyethylene bearing surfaces has been reported to produce lower wear rates and therefore may increase the life expectancy of the joint arthroplasty. Problems with this bearing have been reported to be due to ceramic femoral head fracture. Reported here are 2 cases of catastrophic failure of total hip arthroplasties, involving a ceramic femoral head, caused by failure of the polyethylene acetabular liner, with subsequent penetration of the femoral head through the acetabular shell.

Endometrial carcinoma in the south of Israel: study of 231 cases.

BACKGROUND AND OBJECTIVES: Endometrial carcinoma is the commonest female genital tract malignancy in the south of Israel. The purpose of this study was to investigate the clinical and histologic findings, treatment and outcome of patients with endometrial carcinoma in the south of Israel. METHODS: Data from the files of 231 patients with endometrial carcinoma who were managed at the Soroka Medical Center between January 1961 and December 1994 were evaluated. RESULTS: Endometrial carcinoma was more prevalent among Jewish as compared to Arab-Beduin women, and among Ashkenazi as compared to Sephardic Jewish women. The prevailing presenting symptom was postmenopausal bleeding and most patients (68.8%) had Stage I disease. Most patients (209/225, 92.9%) underwent surgery, 131/222 (59%) had radiotherapy and 15/214 (7%) received chemotherapy. The 5-year survival rate was 79.1% overall; 89% for Stage I, 71.7% for Stage II, 21.6% for Stage III and 0% for Stage IV; 89.8% for Grade 1, 70% for Grade 2 and 60.9% for Grade 3; 100% for adenoacanthoma, 82% for endometrioid carcinoma, 65.8% for adenosquamous carcinoma and 51.6% for papillary serous carcinoma. CONCLUSIONS: Endometrial carcinomas are characterized by a relatively favorable prognosis with a 5-year survival of about 80%. Surgical stage, histologic differentiation and histologic subtype are sensitive predictors of survival. The mainstay of treatment is surgery with adjuvant pelvic radiotherapy when necessary.

Risk factors for ciliochoroidal effusion after panretinal photocoagulation.

PURPOSE: To determine the incidence, duration, and risk factors for ciliochoroidal effusion after panretinal photocoagulation. METHODS: Thirty-nine consecutive patients with diabetic retinopathy underwent ultrasound biomicroscopy of both eyes to image the ciliochoroidal space immediately before and 1 day after unilateral argon-green panretinal photocoagulation. Imaging was repeated on days 3, 7, and 14 in patients in whom ciliochoroidal effusion developed. RESULTS: Low-lying ciliochoroidal effusions were imaged in 23 (59%) of 39 eyes. Of 23 eyes, effusions resolved in 6 (26%), 12 (52%), and 5 (22%) eyes by 3, 7, and 14 days respectively. The number of laser applications (P = 0.02), shorter axial length (P = 0.01), and percentage of retinal surface area treated (P = 0.02) were associated with systemic hypertension, location of treatment, previous panretinal photocoagulation of cataract surgery, retinal surface area treated, and mean blood pressure before photocoagulation were not associated with effusion. All fellow, untreated eyes remained effusion-free. CONCLUSION: Ciliochoroidal effusion develops commonly after panretinal photocoagulation. Limiting the number of laser applications and the percentage of retinal surface area treated reduces the likelihood of this complication. Eyes with shorter axial lengths are at higher risk

Biochemical and molecular studies of human methenyltetrahydrofolate synthetase.

5-FormylH4folate is administered clinically under the name Leucovorin in association with the antineoplastic agent 5-fluorouracil (5-FU) to enhance the cytotoxic effects of 5-FU. The combination has been shown to be superior to 5-FU alone in the treatment of patients with metastatic colorectal carcinoma. Methenyltetrahydrofolate synthetase (MTHFS) catalyzes the transformation of 5-formyl-tetrahydrofolate to methenylH4folate, which is the obligatory initial metabolic step prior to the intracellular conversion of 5-formylH4folate to other reduced folates and the increase in intracellular folate pools required for 5-FU potentiation. In the following paper, we will summarize results of biochemical and molecular studies of human MTHFS.