Muramyl peptides in the complex treatment of cervical intraepithelial neoplasia associated with human papillomavirus

Research objective: the use of an immunomodulator III generation with a wide range of action (muramyl peptide drug Liastenum) to increase the effectiveness of treatment of cervical intraepithelial neoplasia grade I associated with human papilloma virus (HPV) and to reduce the recurrence of cervical pathology.Materials and methods. The study included 60 women with histologically confirmed cervical intraepithelial neoplasia associated with highly oncogenic HPV. The mean age of patients was 25.92 ± 0.61 years. The first group included 30 women who received traditional treatment, the second group included 30 women who additional received Liastenum 0.002 g intramuscularly 1 time per day, 5 injections per course, after that patients took 1 tablets Liastenum twice a day for 20 days.Traditional treatment included antibiotic therapy (doxycycline monohydrate), metronidazole, nystatin in standard dosage. Patients with herpes viruses received valaciclovir 500 mg twice/day for 5 days. Evaluation of treatment efficacy was performed at 6 and 12 months with co-testing, fluid cytology, HPV quantification, and colposcopy.Results. There was a significant decrease in the exposure level of highly oncogenic HPV in the second group compared to the first: after 12 months in the first group HPV was not detected in 2 women (6.67%), and in the second group HPV was no detected in 17 women (56.67%) (p < 0.05). Improvement of the colposcopic picture occurred in 70% of patients in the second group, and in 12 (40.0%) of patients colposcopic conclusion on the Swedish scale was less than 3 points after 12 months of observation. Only 8 (26.67%) women received improvement of the colposcopic picture with a score of 3 points on the Swedish scale in the first group, which was significantly different from the second group (p < 0.05).Conclusions. Advanced therapy with muramyl peptide Liastenum in the treatment of cervix for 12 months can increase the effectiveness of HPV elimination, improves the colposcopic picture by reducing the area of cervical lesions and normalized cytological picture in 70% of patients with cervical intraepithelial neoplasia grade I.

Feasibility of using industrial boiler ash in the dosing of structural concrete

Industrialization and accelerated population growth generate side effects on various social aspects, and the environmental issue is worrisome due to the impacts caused by social evolution. The management of industrial waste is a great challenge that involves both control of its generation and the proper disposal, ensuring environmental sustainability. Boiler ash residue is found in abundance in factories that use this equipment for steam generation. This abundance occurs due to the lack of a place for proper disposal or reuse of the residue. In view of this scenario, this article had as a guide question: Would it be possible to use this residue in the production of structural concrete? The aim of this study was to classify the residue by defining its possible form of use in concrete dosage and to perform experimental dosages with the use of industrial boiler ash to evaluate its possible technical contributions to basic properties of concrete. For this, samples were collected by an industry installed in the city of Uberlândia, State of Minas Gerais, active in several sectors such as agriculture, animal nutrition, pharmaceutical and others. The classification of boiler ash was performed by applying the Brazilian normative procedures and parameters used for classification of binders and aggregates for concrete. Considering its granulometric curve and density, the residue was classified as light and very thin aggregate, thus adopting the methodology of partial replacement of the thin aggregate by boiler ash. It was verified that there was a reduction in the workability of concrete in the fresh state proportionally to the residue content used. Therefore, it is necessary to use superplasticizer additives in these cases to maintain the expected workability. A reduction in the density of concrete was noticed when the residue was used, considering as necessary the attention to this property of the concrete in relation to the content used of the residue in the dosage. It was also observed when comparing the dosages with the use of the residue at the standard dosage, that there was a reduction in compressive strength. However, there was no great variation in compressive strength between the dosages with different substitution levels used. It was concluded, therefore, considering the levels used in this study, as feasible the use of this residue in the production of structural concrete.

Clinical Outcomes of Advanced-Stage Cutaneous Lymphoma under Low-Dose Gemcitabine Treatment: Real-Life Data from the German Cutaneous Lymphoma Network

<b><i>Background:</i></b> Gemcitabine is an effective single-agent chemotherapy used in advanced stages of cutaneous T-cell lymphoma (CTCL). However, gemcitabine used in the current standard regimen is frequently associated with adverse events (AE), such as an increased risk for myelosuppression and severe infections. <b><i>Objectives:</i></b> We investigated in this retrospective study the effect of low-dose gemcitabine in pretreated advanced-stage CTCL and in blastic plasmacytoid dendritic cell neoplasia (BPDCN) regarding overall response (OR), progression-free survival (PFS), and AE. <b><i>Material and Methods:</i></b> A retrospective, multicenter study was conducted on 64 CTCL and BPDCN patients treated with gemcitabine in average absolute dosage of 1,800 mg/m² per cycle, which is 50% lower compared to standard dosage of 3,600 mg/m² per cycle (1,200 mg/m² day 1, 8, 15). Evaluation of response to therapy and AE was done 4–6 weeks after the sixth cycle. <b><i>Results:</i></b> OR was 62% with 11% demonstrating a complete response. The median time of PFS was 12 months and median time to next treatment was 7 months. Only 3/63 patients showed serious side effects, e.g., port infection or acute renal failure. Almost 73% of the patients experienced minor to moderate side effects (CTCAE grade 0–2). Fatigue (27.2%), fever (22.7%), and mild blood count alteration (18.2%) were the most common AE. <b><i>Conclusions:</i></b> This retrospective analysis supports the use of low-dose gemcitabine therapy in CTCL, demonstrating with 62% OR and PFS of 12 months an almost identical response rate and survival as compared to the standard dose therapy reported in previous studies but with a significantly improved safety profile and tolerability.

Clinical case of the use of oral metronomic vinorelbin in patient with metastatic Her2 negative breast cancer

Endocrine therapy in combination with inhibitors of cyclin-dependent kinases 4/6 in first lines is the current standard of treatment of metastatic ER positive Her2 negative breast cancer. After progression on several lines of endocrine therapy according to current principles we apply sequential lines of monochemotherapy. If possible non-toxic agents are prefered in order to maintain high quality of life. The special role in this context may play oral agents, when regular visits in clinic and intravenous injection are not needed. The efficacy of oral vinorelbine is well explored, unfortunately the standard dosage regimen сan have quite high especially hematologic toxicity. The metronomic dosing regimen is believed to be as effective as the standard, but is less toxic. In addition, the anti-angiogenic properties of the metronomic mode are described. Taking into account the increasing use of combination of endocrine therapy with CDK4/6 inhibitors in first treatment lines, it is extremely important to study the efficacy and tolerability of various regimens and drugs after progression on combined endocrine therapy. In this article, we represent a clinical case of the use of oral vinorelbine in the metronomic mode in the patient after progression on combination of fulvestrant and palbociclib. Long-term disease control with satisfactory quality of life has been demonstrated.

Management of the grape mealy bug, Maconellicoccus hirsutus (Green), using entomopathogenic fungi and botanical oils: a laboratory study

Background Laboratory experiments were conducted to evaluate the bio-efficacy and cumulative effect of entomopathogenic fungi (EPF), viz., Lecanicillium lecanii (Zimmermann) Zare and Gams, and Beauveria bassiana (Balsamo) Vuillemin and different botanical oils against grape mealy bug, Maconellicoccus hirsutus (Green). M. hirsutus infestation during berry formation has left no option other than chemical management. However, the pesticide application during this stage leads to residues. Thus, safer and sustainable biological need was tested for their effectiveness against M. hirsutus. Results Dipping bioassay technique was used to determine the cumulative mortality. When L. lecanii was used as sole (at 6 and 4 g/l), significant mortality was observed (51.63 and 50.18%). However, the maximum cumulative nymphal mortality was achieved when the combination of EPF formulations was used, i.e., 57.64% with B. bassiana + L. lecanii (6 g/l + 6 g/l). Their effectiveness was at par with the same combination but with minimal concentration, i.e., 4 g/l + 4 g/l (56.29%). Concerning the botanical oils evaluated, neem oil at 15 ml/l achieved a higher mortality of 81.36%. Consecutive effective treatment was a combination of neem oil and pongamia oil (at 10 + 10 ml/l) with 79.65% mortality. However, the standard dosage of neem oil (at 10 ml/l) and IIHR neem soap (at 10 g/l) also recorded the significant mortality of 78.09 and 77.67%, respectively. When compared, the neem oil was found significantly superior in sole and compatible combination than pongamia oil. Conclusions Lecanicillium lecanii and neem oil (sole and in combination with other compatible bioagents) proved significantly better for the management against M. hirsutus with an efficacy of 90.21 and 96.67 % mortality, respectively against the standard chemical control (more than 97%).

Arterial hypertension in ophthalmic surgical patients

Purpose. Analysis of the frequency and structure of arterial hypertension (AH) among ophthalmic surgical patients, assessment of the adequacy of prescribed antihypertensive therapy. Material and methods. Clinical material is presented by 157 patients with hypertension. Its structure was assessed. Its structure was assessed according to the stage, the degree of increase in the level of blood pressure (BP) and the category of cardiovascular risk. We analyzed the proportion of cases of uncontrolled hypertension, including those with a sudden pronounced individually significant increase in blood pressure without affecting target organs. Results. The prevalence of patients was stage III hypertension (62.4%), grade 3 hypertension (53.5%), with a very high and high risk of cardiovascular complications (73.2 and 20.4%, respectively). 93.6% of patients received antihypertensive therapy, but only 57.1% of them, mostly women (69.1%), regularly took medications and monitored their blood pressure. With a sudden pronounced individually significant increase in blood pressure, we used oral antihypertensive drugs – captopril and nifedipine, which made it possible to achieve a decrease in blood pressure and relief of clinical symptoms in all cases. Conclusion. 33.1% of patients had no hypertension control at the time of hospitalization. The proportion of patients with a sudden pronounced individually significant increase in blood pressure was 12.7%. Typical reasons for loss of control over hypertension were interruptions in taking antihypertensive drugs and high stress levels before surgery. The use of standard dosage captopril and nifedipine was effective in all cases. Key words: arterial hypertension, sudden pronounced individually significant increase in blood pressure, antihypertensive therapy.

Modern Research in the Field of Microencapsulation (Review)

Introduction. Microencapsulation is one of the promising areas for obtaining new dosage forms. The peculiarity of microencapsulated forms is that the substance is protected from the effects of various environmental factors that can cause their destruction (acidity of gastric juice, the effect of food, joint intake of other drugs, diseases of the gastrointestinal tract, etc.). This method is used for various groups of drugs, such as antibiotics, nootropics, vitamins, probiotics, anticonvulsants, enzymes. Particular attention should be paid to antibacterial drugs, since the possibility of microencapsulation solves one of the most important problems in antibiotic therapy – the resistance of microorganisms.Text. The purpose of the review is to analyze modern research in the field of microencapsulation, to study trends and directions for the creation of microcapsules with high activity and bioavailability and with minimal side effects. The article provides brief information and main conclusions on the development of techniques and selection of conditions for microencapsulation of individual medicinal substances, on the study of polymers of various natures for use as carriers, on the methods of forming double shells of microcapsules, and also investigated the efficiency of microencapsulation of biologically active substances, such as antibacterial preparations, substances of plant and animal origin and preparations from various pharmacological groups. Variants of microencapsulation techniques for specific compounds that are suitable for substances similar in composition and action, as well as methods for creating microcapsules with double shells for compounds insoluble in water, are presented.Conclusion. The article shows the achievements and prospects of using microencapsulation of medicinal substances and their advantages over standard dosage forms. The active introduction of the developed methods into production will allow the creation of new dosage forms with known medicinal substances that have a prolonged effect, which will reduce the frequency of use of the drug, as well as retain their activity under the influence of negative factors of the internal environment of the body. Also, in the form of microcapsules, the substances are more active in comparison with non-encapsulated substances.

Improvement of water and nutrient efficiencies oil palm through bio-silicic acid application

Crop water use efficiency is critical for high yields in conditions of limited water supplies. This study aims at determining the effect of application bio-silicic acid (BioSilAc) on water use efficiency and nutrient availability for immature (2 years after planting) and mature (5 years after planting) oil palms in sandy soil during a period of low rainfall. A field experiment was conducted on sandy soil at an oil palm plantation in Central Kalimantan. The experiment was arranged in a randomized block design with seven treatments and three replicates using a combination of composted empty fruit bunches of oil palm (CEFBOP) and BioSilAc applications. The treatments (tree-1 year-1) were as follows (tree-1 year-1): (T1) 100% NPK standard dosage; (T2) T1 + 1.5 kg quartz sand; (T3) 75% (T1) + 1.5 kg quartz sand; (T4) T1+ 4 tablets BioSilAc; (T5) 75% (T1) + 4 tablets BioSilAc; (T6) T1 + 50 kg CEFBOP + 2 tablets BioSilAc; and (T7) 75% (T1) + 50 kg CEFBOP + 2 tablets BioSilAc. The parameters observed were soil and leaf nutrient contents, average weight, and number of fresh fruit bunch (FFB), and daily water usage and water potential using a sap flow meter and stem psychrometer to calculate water use efficiency in T1 (control) and T5 which represents the application of BioSilAc. The results indicated that the application of 75-100% NPK + 4 tablets BioSilAc tree-1 year-1 in mature oil palm was capable of improving yield of11.9% (T5) and 12.1% (T4) and water use efficiency of 31.3% (mature) and 50.4% (immature) of the control treatment.

P465 One year endoscopic and histologic outcomes to tofacitinib therapy in refractory ulcerative colitis

Background Long-term real-life data on the efficacy of the Janus kinase inhibitor tofacitinib in moderate-to-severe ulcerative colitis (UC) are limited. We here report efficacy of tofacitinib in refractory UC patients with an emphasis on endoscopic and histologic outcome. Methods Fifty-four consecutive UC patients (Mayo endoscopic sub-score ≥2) initiating tofacitinib in 2 tertiary IBD referral centres were prospectively included (Table 1). Almost all were refractory to both anti-TNF (96.4%) and vedolizumab (92.7%) and received tofacitinib in standard dosage. Steroid-free clinical remission was defined as partial Mayo score of ≤2 with no single sub-score &gt;1 and without any steroid exposure at assessment. Biological remission was defined as faecal calprotectin &lt;250mcg/g, endoscopic remission as Mayo endoscopic sub-score of 0, endoscopic improvement as Mayo endoscopic sub-score of ≤1, and histologic remission as Nancy histology index of 0. A combination of endoscopic and histologic remission was referred as mucosal healing. All outcomes were assessed at year 1. Non-responder imputation and last observation carried forward analysis were applied. Results Patients were followed for a median [IQR] of 91.7 [67.2–102.4] weeks, with an exposure to tofacitinib of 23.9 [14.6–51.6] weeks. By year one, 31.5% of patients were in steroid-free clinical remission (Figure 1). Biological remission was observed in 26.9% of patients. Endoscopic improvement, endoscopic remission, histologic remission and mucosal healing, were observed in 31.5%, 24.1%, 22.0% and 18.0% of patients, respectively. Multivariate analysis identified baseline Mayo endoscopic sub score (OR 0.03, p=0.03); endoscopic improvement by week 16 (OR 36.5, p=0.008) and disease extent (OR 0.11, p=0.05) as independent predictors for endoscopic remission at year 1. Patients with left-sided colitis or proctitis experienced higher endoscopic remission rates (33.3% and 25.0%) then patients with extensive colitis (10.5%, p=0.09; p=0.6). Ultimately, 61.1% of all patients discontinued tofacitinib therapy after a median of 15.9 [9.2–24.5] weeks, due to primary non-response (n=25), loss-of-response (n=6) or (serious) adverse events (n=2). Thirteen patients (24.1%) required colectomy. During follow-up, no venous thrombo-embolisms or cancers were observed. One patient had to be admitted at ICU due to several life-threatening opportunistic infections. Conclusion In this highly refractory cohort of UC patients, tofacitinib induced and maintained endoscopic and histologic remission in up to one quarter of patients. UC patients with moderate left-sided colitis and proctitis had a numeric higher likelihood for a sustained effect than patients with extensive colitis.

Evaluation of Hsp90 and mTOR inhibitors as potential drugs for the treatment of TSC1/TSC2 deficient cancer

Inactivating mutations in either TSC1 or TSC2 cause Tuberous Sclerosis Complex, an autosomal dominant disorder, characterized by multi-system tumor and hamartoma development. Mutation and loss of function of TSC1 and/or TSC2 also occur in a variety of sporadic cancers, and rapamycin and related drugs show highly variable treatment benefit in patients with such cancers. The TSC1 and TSC2 proteins function in a complex that inhibits mTORC1, a key regulator of cell growth, which acts to enhance anabolic biosynthetic pathways. In this study, we identified and validated five cancer cell lines with TSC1 or TSC2 mutations and performed a kinase inhibitor drug screen with 197 compounds. The five cell lines were sensitive to several mTOR inhibitors, and cell cycle kinase and HSP90 kinase inhibitors. The IC50 for Torin1 and INK128, both mTOR kinase inhibitors, was significantly increased in three TSC2 null cell lines in which TSC2 expression was restored. Rapamycin was significantly more effective than either INK128 or ganetespib (an HSP90 inhibitor) in reducing the growth of TSC2 null SNU-398 cells in a xenograft model. Combination ganetespib-rapamycin showed no significant enhancement of growth suppression over rapamycin. Hence, although HSP90 inhibitors show strong inhibition of TSC1/TSC2 null cell line growth in vitro, ganetespib showed little benefit at standard dosage in vivo. In contrast, rapamycin which showed very modest growth inhibition in vitro was the best agent for in vivo treatment, but did not cause tumor regression, only growth delay.