A computational framework for finding parameter sets associated with chaotic dynamics.

Many biological ecosystems exhibit chaotic behavior, demonstrated either analytically using parameter choices in an associated dynamical systems model or empirically through analysis of experimental data. In this paper, we use existing software tools (COPASI, R) to explore dynamical systems and uncover regions with positive Lyapunov exponents where thus chaos exists. We evaluate the ability of the software's optimization algorithms to find these positive values with several dynamical systems used to model biological populations. The algorithms have been able to identify parameter sets which lead to positive Lyapunov exponents, even when those exponents lie in regions with small support. For one of the examined systems, we observed that positive Lyapunov exponents were not uncovered when executing a search over the parameter space with small spacings between values of the independent variables.

Sarcopenia and high NLR are associated with the development of hyperprogressive disease after second-line pembrolizumab in patients with non-small-cell lung cancer.

The aim of this multi-center retrospective study was to evaluate the incidence of hyperprogressive disease (HPD) after second-line treatment with pembrolizumab in patients (n = 167) with metastatic non-small-cell lung cancer (NSCLC) whose tumors expressed programmed cell death ligand 1 (PD-L1) in ≥ 1% and to search for hematological and imaging biomarkers associated with its development. Prior to chemotherapy, neutrophil : lymphocyte ratio (NLR1) and platelet : lymphocyte ratio (PLR1), and prior to immunotherapy, NLR2 and PLR2 were retrospectively analyzed. The psoas major muscle area (PMMA) was calculated at the L3 position on computed tomography before chemotherapy (PMMA1) and before immunotherapy (PMMA2) (n = 112). Patients with ∆PMMA (1-PMMA2/PMMA1) × 100 ≥ 10% were considered to have sarcopenia (low muscle mass). After treatment with pembrolizumab on the first computerized tomography (CT) scan evaluation, patients were subdivided as follows as: hyperprogressors (HPs), progressors (Ps), non-progressors (NPs) and pseudoprogressors (PPs). HPs had significantly higher ∆PMMA levels, NLR2 and PLR2 than the other patients. Moreover, in multinomial logistic regression analysis, higher levels of ∆PMMA were associated with a decreased likelihood of being a P [odds ratio (OR) = 0·81; 95% confidence interval (CI) = 0·65-0·99; P = 0·047] or an NP (OR = 0·76; 95% CI = 0·62-0·94; P = 0·012) versus an HP. Higher NLRs tended to decrease the likelihood of being a P versus an HP (OR = 0·66; 95% CI = 0·42-1·06; P = 0·09) and significantly decreased the likelihood of being an NP versus an HP (OR = 0·44; 95% CI = 0·28-0·69; P < 0·0001). Our data suggest that a high pre-immunotherapy NLR2 and the presence of sarcopenia are potential risk factors for the development of HPD.

PlantSimLab - a modeling and simulation web tool for plant biologists.

BACKGROUND: At the molecular level, nonlinear networks of heterogeneous molecules control many biological processes, so that systems biology provides a valuable approach in this field, building on the integration of experimental biology with mathematical modeling. One of the biggest challenges to making this integration a reality is that many life scientists do not possess the mathematical expertise needed to build and manipulate mathematical models well enough to use them as tools for hypothesis generation. Available modeling software packages often assume some modeling expertise. There is a need for software tools that are easy to use and intuitive for experimentalists. RESULTS: This paper introduces PlantSimLab, a web-based application developed to allow plant biologists to construct dynamic mathematical models of molecular networks, interrogate them in a manner similar to what is done in the laboratory, and use them as a tool for biological hypothesis generation. It is designed to be used by experimentalists, without direct assistance from mathematical modelers. CONCLUSIONS: Mathematical modeling techniques are a useful tool for analyzing complex biological systems, and there is a need for accessible, efficient analysis tools within the biological community. PlantSimLab enables users to build, validate, and use intuitive qualitative dynamic computer models, with a graphical user interface that does not require mathematical modeling expertise. It makes analysis of complex models accessible to a larger community, as it is platform-independent and does not require extensive mathematical expertise.

Prevalence and prognosis of PIK3CA mutations in Bulgarian patients with metastatic breast cancer receiving endocrine therapy in first-line setting.

BACKGROUND AND AIMS: In approximately 40% of patients with HER2-negative/HR-positive breast cancer tumors, the PIK3CA gene is mutated. Despite this, clinical outcomes vary between studies in this cohort. We aimed to ascertain the prevalence of PIK3CA mutations in patients with metastatic HR+/HER2- breast in Bulgaria, as well the evaluation and comparison of progression free survival (PFS) between wild-type (WT) and mutation-positive groups in the real-world setting. METHODS: Three oncology centers in Bulgaria collected 250 tissue samples between 2016 and 2022 for this multicentric retrospective study. PIK3CA mutations were identified using Real-Time qPCR. The median follow-up period was 35 months. RESULTS: The mean age of the mutant cohort was 57.6 ± 11.6 years, compared to 56.5 ± 12.2 years for the WT cohort (p = .52). The percentage of patients with visceral metastasis was 58.8% (n = 147). Approximately 84.3% (n = 210) of the patients had reached postmenopause. 29.2% (n = 73) of the patients had PIK3CA mutations. The predominant mutation was present in exon 20, H1047R (46.5%). We found a significant correlation only between the presence of a mutation and the metastatic diseases at diagnosis (p = .002). As first-line therapy, 67.1% of patients received endocrine therapy (ET) plus cyclin dependent kinase (CDK4/6) inhibitor, while the remainder received ET alone. The median PFS of patients in the group with the mutation was 32 months (95%, CI: 22-40) compared to 24 months in the WT cohort ((95%, CI: 21-36) (p = .45)); HR = 0.86 (95%, CI: 0.5-1.3) (p = .46). We corroborated our conclusion using propensity matching score analysis, (36 months [95% CI: 20-40] vs. 26 months [95% CI: 21-38], [p = .69]). CONCLUSIONS: We found that the prevalence of PIK3CA mutations in our patients was comparable to what has been reported in other nations. Our results suggest that PIK3CA mutational status has no bearing to ET efficacy in first-line setting.

[A clinical case of twin pregnancy with intrauterine death of one of the twin (foetus papiraceus)].

Multiple pregnancy is associated with some specific syndromes: twin to twin transfusion syndrome, syndrome of the disappeared twin, intrauterine loss of one of the twin, development of foetus papiraceus and syndrome of asymmetric growth of the twin. We present a case of term pregnancy with death of one of the twin and normal delivery of healthy baby and Foetus papiraceus.

Infrarenal abdominal aortic dissection with aberrant renal arteries and lead-ing symptom right leg ischemia: case report.

INTRODUCTION: Isolated infrarenal abdominal aortic dissection is a rare clinical entity. Most cases are treated by endovascular techniques, and open surgery is seldom necessary. CASE DESCRIPTION: We present a rare case of spontaneous symptomatic infrarenal aortic dissection with leading symptom right leg ischemia. We opted for abdominal surgery as the attempt for open surgical fenestration of the dissecting flap exit through right femoral access was unsuccessful. Dacron vascular prosthesis was implanted with aortoiliofemoral bypass on the right side. One of the two accessory right renal arteries was ligated, which led to a confined zone of renal ischemia. Upon follow-up, complete restoration of the renal parenchyma was observed; kidney function remained unaffected. CONCLUSION: By infrarenal abdominal aortic dissection with accessory renal arteries, abdominal surgery with selective clamping is a reliable therapeutic approach allowing maximal preservation of renal blood flow. HIPPOKRATIA 2019, 23(4): 186-189.

[Using phlebodia in pregnant women during preterm delivery].

Phlebodia possess complex mechanism of action; except the venotonic one, it blocks the production of mediators of inflammation-prostaglandins and leukotriens; thus stops the uterine contractions and the preterm delivery. We use the tablet at pregnant women for preterm delivery. It was given one tablet a day /600 mg/ along with the tocolytic therapy.

[A case of Guillain-Barre syndrome in puerperium].

Guillain-Barre Syndrome is an acquired neurologic disease associated with demyelinisation of the peripheral nerves. It affected 6-24/100,000 population during pregnancy; the frequency is increased after delivery in puerperium. We present a case of Syndrome of Guillain-Barre in puerperium. We discuss the clinical presentation of the disease during pregnancy and in puerperium, diagnosis and treatment.

Effects of radial extracorporeal shock wave therapy on hand spasticity in poststroke patient.

BACKGROUND: Hand spasticity after a stroke greatly increases the difficulties of the daily living activities and limits the effectiveness of rehabilitation. Radial extracorporeal shock wave therapy (RESWT) has been suggested as an alternative treatment for spasticity reduction. We demonstrate the effectiveness of RESWT regarding hand spasticity in a stroke patient. CASE DESCRIPTION: We describe the case of a 42-year-old woman with right hemiparesis after ischaemic stroke. Her right arm was plegic with increased spasticity. The patient received a total of six RESWT treatments. Clinical evaluation was performed using the Modified Ashworth Scale, passive dorsal flexion of the wrist and the Disability Assessment Scale (DAS). The measurements were made before initiation, immediately after the sixth treatment, one and three months after the RESWT. Immediately after the RESWT there was a reduction of the spasticity of the hand and fingers and increased passive range of motion of the affected wrist, as well as decreased DAS score. These effects lasted for four weeks. With time, the therapeutic effect regarding spasticity decreased, but three months following termination of treatment there was a better clinical result than before initiation of treatment. CONCLUSION: RESWT is a safe alternative treatment for hand and fingers spasticity reduction after stroke.  Hippokratia 2016, 20(4): 309-312.

Rehabilitation procedures in the management of gait disorders in the elderly.

Gait disorders are common and very disabling in elderly people, leading to an increase of risk of falling and reductions in quality of life. So far, many clinical classifications of gait disorders in the elderly population have been proposed. Here we suggest a novel categorization of gait disorders in elderly people, which takes into account the several resources required during gait. The biomechanical constraints, movement and sensory strategies, orientation in space, control of dynamics and cognitive processing are essential to perform safely gait. Moreover, the strictly connection between gait and balance has been discussed. According to this perspective, a literature search was performed including studies investigating the rehabilitation procedures in the management of balance and gait disorders in elderly people. Training aimed at improving muscle strength and flexibility, movement strategies, sensorimotor integration and sensory reweighting processes, balance in static and dynamic conditions and cognitive strategies have been proposed as possible therapeutic approaches in elderly people affected by gait disorders. Moreover, the role of new technological devices in improving balance and gait control has been also described. A multidisciplinary and interdisciplinary approach is fundamental for the management of gait disorders in elderly people. Rehabilitation procedures should take into consideration all the potential constraints involved in gait disorders in order to select the most appropriate intervention.

Expression of 1D8--a novel non-sialylated B-cell-associated carbohydrate epitope in lymphoproliferative disorders.

The expression of a novel B-cell-associated carbohydrate epitope (1D8) was studied by means of flow cytometry in 153 well defined cases of leukemias and lymphomas and 19 cases of lymphadenopathy used as controls. The 1D8 epitope was detected preferentially in proliferations of mature B-lymphocytes (11/15 CD20+ acute lymphoblastic leukemia (ALL), 14/16 chronic lymphocytic leukemia (CLL), 4/7 mantle cell non-Hodgkins lymphoma (NHL), 3/8 follicle cell NHL. However its expression did not appear lineage- or differentiation stage-restricted. Intensive expression on in vivo and in vitro-activated lymphocytes as well as in some high grade malignancies indicated a relationship to the functional state of cells. Bearing in mind the enhanced detection of 1D8 upon desialylation, the epitope might be involved in the regulation of adhesion/migration potential of normal leukocytes and their malignant counterparts.

Immunological subtypes of childhood acute lymphoblastic leukemia in Bulgaria.

With regards to the geographical variation in acute lymphoblastic leukemia (ALL) distribution, we present data from the immunophenotyping of 171 newly diagnosed cases of childhood ALL in Bulgaria during a 4 year period (1990-1994). On the basis of 17 phenotypic markers the distribution of immunological subtypes was as follows: AUL 4%; Pro-B ALL 13%; common ALL 42%; Pre-B ALL 11%; B-ALL 1%; T-ALL 28% and unclassified 2%. Most of the cases were between 2 and 5 years of age. Common ALL was predominant (53%) in this age group. The male:female ratio was 1.7:1. The frequency of T-ALL (28%) was significantly higher (P < 0.01; t = 3.49) in comparison to that reported for the U.S.A. and West European countries (mean 13%). It was close to the frequency reported by some authors for France (20%), Greece (26%) and south Italy (28.1%). These countries and Bulgaria might form an environmental area with a moderate frequency of T-ALL.

Levels of expression of CAF7 (CD98) have prognostic significance in adult acute leukemia.

The levels of CD98 antigen expression were studied in 62 consecutive cases of adult acute leukemia including 24 acute lymphoblastic leukemia (ALL) and 38 acute myeloid leukemia (AML) using the monoclonal antibody CAF7 and flow cytometry. The mean follow-up was 13.5 months. The mean relative fluorescence intensity (MIF) of CAF7 varied between 6 and 83 channels (256 channels resolution). No correlation was established between CAF7 cell surface density and most of the predictive parameters such as age, sex, blood counts, immunophenotype, proliferative index (PI) or DNA index. Nevertheless expression of CAF7 correlated positively with survival duration (mean 210 vs 391 days, P = 0.048) and complete remission (CR) duration (mean 132 vs 361, days P = 0.032). The levels of CAF7 differed significantly between ALL and AML (P < 0.001), the ALL cases being all CAF7intermediate or CAF7high. In the AML group the low levels of CAF7 expression correlated with shorter CR duration (mean 132 vs 414 days, P = 0.017). The lack of correlation with other clinical and biological parameters suggested that CAF7 might have an independent prognostic significance in adult AML. Although PI was also positively related to survival duration (P = 0.02), it did not correlate with CR duration or the expression of CAF7. We suppose that the prognostic impact of CD98 is related to the control of cell growth and survival in which the molecule normally participates.

Humoral and cellular immune response to elastin in patients with systemic sclerosis.

The humoral immune response against elastin and collagen was studied in parallel with the delayed type hypersensitivity (DTH) reaction to elastin and the percentage of lymphocyte subpopulations in peripheral blood in 20 patients with systemic sclerosis (SSc). An increase of anti-elastin antibodies of all subclasses was found with a significant prevalence of IgE and IgA antibodies. The profile of anti-collagen type I and type IV antibodies showed an increase of IgE isotypes. In 25% of the patients (5 out of 20) positive DTH reactions to elastin were observed as compared to the negative skin reactions in all control individuals. At the same time a significant hyporeactivity to common bacterial and mould antigens was found in 40% of the patients (versus 16% in the control group) which could be an explanation for the low incidence of positive anti-elastin DTH reaction. The DTH hyporeactivity in SSc cases was in contrast with the increased percentage of CD4 T cells (58.4 vs. 42.0) and increased CD4/CD8 ratio (2.5 vs. 1.5) in the peripheral blood of the patients. This finding together with the increased IgE antibodies to elastin and collagen type I and type IV might suggest a possible shift of the immune balance towards the Th2 type of immune response. This is in line with the increased CD8+CD57+ cells which correlated with the highest number of other parameters studied - disease duration, total skin score, IgE anti-elastin antibodies, IgG anti-collagen type I antibodies, CD4/CD8 ratio and CD19 B cells. The results of this study demonstrated the existence of both humoral and cell-mediated immune response against elastin in SSc patients. However, we could not define whether this was an essential part of pathogenetic mechanisms or a secondary phenomenon reflecting the extent of the damage of connective tissue.

Monoclonal antibodies to porcine zona pellucida that block the initial stages of fertilization.

Zona pellucida (ZP) is thought to be of utmost biological importance in the early stages of fertilization and implantation. Current hybridoma technology was used to produce monoclonal antibodies (MAbs) against specific antigens to porcine ZP. Two monoclonal antibodies (4F2 and 2D9) were raised that reacted against ZP antigens shared by human and porcine ZP. These antibodies were shown to block fertilization of human oocytes in in vitro fertilization (IVF). It is likely that MAb 4F2 recognized a protein epitope localized on the outer surface of ZP. These antibodies may be quite useful immunologic probes for studying the precise mechanisms of the early events of fertilization in mammals.

Incidence of childhood tumors in Slovakia.

During the decade 1968-1977 a total of 1488 cases of neoplasms were registered in Slovakia in children aged 0-14 years giving an average annual age-specific rate of 120.7 per million. Tumors prevailed in boys with 131.2 in comparison with girls showing 109.7 incidence rate/10(6). The most common malignancies were leukemias (28.2%), tumors of nervous system (23.9%), lymphomas (14.9%) and Wilm's tumors of kidney (6.7%). The proportion of remaining histologic types was lower. The necessity of the use of standard international classification based on morphology for mutual international comparison of childhood tumors incidence rates as well as for other epidemiological investigations is emphasised.

Prediction of cancer incidence in Cracow and Bratislava.

Projections for the incidence of all and selected major sites of cancer in the cities of Cracow and Bratislava were constructed for each year of the period 1978-1982 on the basis of data observed in the years 1968-1977. More or less increasing of unchanging trends were predicted for the malignant neoplasms of bladder, larynx and lung in males and of breast and ovaries together with decreasing trends of uterine cervix in females in the both cities. The trends predicted for the cancer of stomach in both sexes, of prostate and uterine corpus as well as of all sites in males showed different orientations in the compared cities. The factors connected with and usefulness of the adequate predictions of cancer incidence are discussed.

Recent trends in uterine cervix cancer in Slovakia, 1968-1987.

The temporal trends in the incidence and mortality of uterine cervix cancer in Slovakia were evaluated. Only highly reliable and complete data from 1968-1987 derived from the National Cancer Registry of Slovakia were used. Incidence rates have fallen in the first part of the period studied, but this trend has reversed and the incidence rates of this cancer site have risen since about 1976. The mortality rates showed continuous and unchanged increase over the whole mentioned period. The analysis of the age specific incidence rates indicated the responsibility of the youngest age groups of women for the overall recent increase of the uterine cervix cancer incidence in this country, while the age specific mortality rates increased in nearly all age groups. The relatively high incidence and mortality rates of uterine cervix cancer in Slovakia in comparison with the same rates in other countries as well as the recent increase of both indicators, together with low proportion of the in situ forms could be attributed mainly to the deficiencies in the organization and performance of the cervical screening.

Geographic patterns and trends of liver, biliary tract and pancreas cancer mortality in Slovakia.

The age-adjusted mortality rates and trends of primary liver cancer in Slovakia showed during the investigated decade 1968-1977 small reduction in males, accompanied with statistically significant decline in females. The slightly increasing trends of mortality from the cancer of gallbladder and extrahepatic bile ducts were not significant while the growing rates and upward trends of mortality from pancreatic malignant neoplasms were statistically significant for both sexes. Geographic distribution of standardized mortality rates from these cancer sites displayed various differences within the districts of Slovakia during the whole investigated period. The need for further descriptive and analytical studies of these less common cancer sites of the alimentary system using more detailed and classified data on incidence and mortality is stressed.

Trends in cancer mortality in Czechoslovakia 1949-1978.

The analysis of the trends of the principal causes of deaths in Czechoslovakia indicated leading second position of malignant neoplasms in the whole mortality over the period 1949 through 1978. The rapidly growing all sites cancer mortality trends in males together with their unimportant changes in females resulted in the steadily increasing overmortality of males. Among digestive organs important decrease of stomach and in lesser extent also of oesophageal cancers with simultaneously increasing mortality trends of malignant neoplasms of colon, pancreas and rectum in both sexes were observed. The trends in the cancer mortality of respiratory organs as well as the increasing rates of the whole male cancer mortality were strongly influenced with dramatical increase of lung cancers while these of larynx showed slow increase in males and decrease in females. The rapidly growing mortality trends showed also breast cancer, reaching at the end of the investigated period the first position in the whole female cancer mortality, while the increasing mortality from the malignant neoplasms of the different genital and urinary organs of females were less or more expressed. The relatively high average annual increase was characteristic for the mortality trends of the malignant neoplasms of bladder and other urinary organs and of prostate gland and testis in males. Among other sites the increasing mortality trends from malignant neoplasms of brain and leukemias were of interest.