Real-world analysis of teclistamab in 123 RRMM patients from Germany.

Teclistamab, a B-cell maturation antigen (BCMA) × CD3 directed bispecific antibody, has shown high response rates and durable remissions in the MAJESTEC-1 trial in patients with relapsed and refractory multiple myeloma (RRMM). We retrospectively assessed efficacy and tolerability in 123 patients treated at 18 different German centers to determine whether outcome is comparable in the real-world setting. Most patients had triple-class (93%) or penta-drug (60%) refractory disease, 37% of patients had received BCMA-directed pretreatment including idecabtagene vicleucel (ide-cel) CAR-T cell therapy (21/123, 17.1%). With a follow-up of 5.5 months, we observed an overall response rate (ORR) of 59.3% and a median progression-free survival (PFS) of 8.7 months. In subgroup analyses, we found significantly lower ORR and median PFS in patients with extramedullary disease (37%/2.1 months), and/or an ISS of 3 (37%/1.3 months), and ide-cel pretreated patients (33%/1.8 months). Nonetheless, the duration of response in ide-cel pretreated patients was comparable to that of anti-BCMA naive patients. Infections and grade ≥3 cytopenias were the most frequent adverse events. In summary, we found that teclistamab exhibited a comparable efficacy and safety profile in the real-world setting as in the pivotal trial.

Endovascular Repair of an Iliac Arteriovenous Fistula in a 30-Year-Old Female Patient with Suspected Severe Cardiac Insufficiency: A Case Report.

A 30-year-old female was initially diagnosed with cardiac insufficiency and severe claudication. Additional imaging revealed a large iliac arteriovenous fistula, which was treated with an endovascular technique. A custom-made, self-expanding, polytetrafluorethylene-covered stent was implanted to restore the physiologic hemodynamic environment. The patient was asymptomatic at the 12-month clinical follow-up.

Comparison of mouse, rat and rabbit models for adipose - Derived stem cells (ASC) research.

PURPOSE OF THE STUDY: Cellular therapies are becoming more popular and there is a big demand for suitable animal model for research in field of tissue engineering. Both the small (rodents) and large animals have their advantages for cellular therapy experiments. Appropriate animal research model would be a bridge between basic research and clinical medicine. The aim of this study was to compare mouse, rat and rabbit as animal models useful for adipose - derived stem cell research. MATERIALS AND METHODS: Quantity, phenotype, clonogenic and differentiation potential of cells isolated from different localizations of adipose tissue from WAG and LEW/W rat strains, rabbit and mouse were analysed. RESULTS: The highest number of cells from 1 g of tissue were isolated from cervical white fat of LEW/W rat. ASCs isolated from rat had also the highest clonogenic potential. Phenotype and capability to differentiate into osteogenic, adipogenic and chondrogenic lineages are at the same level for rat and rabbit. CONCLUSIONS: Rat as a research model can be a rational solution between large animal models and typical laboratory mice because of their size, genetic homogenity, availability of genetically modified stains and possibility to perform research mimicking clinical applications.

[Therapeutic advances in cystic fibrosis in 2014]. / La mucoviscidose en 2014 : actualités thérapeutiques.

Twenty-five years after the cystic fibrosis (CF) gene identification, this discovery actually begins to benefit to patients. Increasing our knowledge on CFTR biology, as well as technical progress made in order to screen for new drugs have made therapeutic strategies move an important step forward. It is likely that in the forthcoming years, the panel of molecules available for CF patients will be larger, with new activators and potentiators. The disease by itself may consequently change in its natural history. CF is an example of the so-called personalized medicine, aiming to fit treatment according to patient's genetic background. Ongoing clinical trials may enlarge the actually limited eligible number of CF patients for new drugs such as ivacaftor. Beyond this exciting and promising new therapeutic approach, one may not push symptomatic treatments on the side. Improvements have been made for inhaled antibiotics administration, aiming to simplify patient's life; clinical trials using new molecules able to liquefy mucus or with anti-inflammatory properties are actually underway. One important next step in the care for CF will be to design and conduct early intervention trials in CF infants. Newborn screening program have been widely implanted around the word, and cohorts studies have shown that both functional and structural abnormalities occurred very early, making the therapeutic window of opportunity tight.

The pluripotency factor nanog promotes breast cancer tumorigenesis and metastasis.

Nanog is a transcription factor required for maintaining the pluripotency of embryonic stem cells, and is not expressed in most normal adult tissues. However, recent studies have indicated that Nanog is overexpressed in many types of human cancers, including breast cancer. To elucidate the physiological roles of Nanog in tumorigenesis, we developed an inducible Nanog transgenic mouse model, in which the expression of Nanog in adult tissues can be induced via LoxP/Cre-mediated deletion. Our findings indicate that overexpression of Nanog in the mammary gland is not sufficient to induce mammary tumor. However, when coexpressed with Wnt-1 in the mouse mammary gland, it promotes mammary tumorigenesis and metastasis. In this context, Nanog promotes the migration and invasion of breast cancer cells. Microarray analysis has shown that the ectopic expression of Nanog deregulates the expression of numerous genes associated with tumorigenesis and metastasis, such as the PDGFRα gene. Our findings demonstrate the involvement of Nanog in breast cancer metastasis, and provide the basis for the reported correlation between Nanog expression and poor prognosis of human breast cancer patients. As Nanog is not expressed in most adult tissues, these findings identify Nanog as a potential therapeutic target in the treatment of Nanog-expressing metastatic breast cancer.

[Combined surgical treatment of the carotid arteries stenosis of high degree and estimation of its efficacy using method of ultrasound duplex scanning].

The carotid arteries (CA) passability and integral indices of cerebral hemodynamics were studied up in the CA high-degree stenosis, using ultrasound duplex scanning before and after its operative correction. In the clinic in 62 patients, suffering CA stenosis, in 2003-2011 yrs the carotid angioplasty and stenting were performed, and in some of them--simultaneously with the carotid endarterectomy. In a high-degree stenosis of CA there were established significant disorders of integral indices of cerebral blood flow: a significant reduction of the index of general blood flow cerebral volume (GBFCV) in account of its carotid component. While a high-degree stenosis of one of internal CA occurrence in conjunction with occlusion of contrlateral internal CA hemodynamic the indices were characterized by more significant disorder occurrence and more profound stress for the compensation mechanisms presence, demonstrated by trustworthy reduction of GBFCV on background of a trustworthy enhancement of its vertebral component. When occlusive affection of a contrlateral internal CA have had occurred after performance of a high-grade stenosis correction of internal CA a positive dynamics of the blood flow changes in carotid and vertebra-basilar basins was observed, witnessing a presence of the compensation-adaptive mechanisms of the brain blood flow autoregulation.

The use of catalytic carbon deposits as 3D carriers for human bone marrow stromal cells.

We studied the possibility of using 3D structures based on carbon catalytic deposits as carriers for human bone marrow stromal cells. It was found that carbon catalytic deposits obtained by gas deposition method using FeCl(3) × 6H(2)O as the catalyst are a biocompatible material for human bone marrow stromal cells promoting adhesion, proliferation, and distribution of cells within the 3D carrier, and therefore can be used for tissue engineering.

Persistence of Mycobacterium bovis Bacillus Calmette-Guérin in white-tailed deer (Odocoileus virginianus) after oral or parenteral vaccination.

Mycobacterium bovis is the cause of tuberculosis in cattle and a serious zoonotic pathogen, most commonly contracted through consumption of unpasteurized dairy products. To control this zoonosis, many countries have developed bovine tuberculosis eradication programmes. Although relatively successful, efforts are hindered in many regions by spillover from wildlife reservoirs of M. bovis to cattle. Such is the case in the United States where spillover of M. bovis from free-ranging white-tailed deer to cattle occurs. One approach to control such inter-species transmission is vaccination of wildlife. The live, attenuated human vaccine M. bovis Bacillus Calmette-Guérin (BCG) has been shown to reduce disease severity in white-tailed deer; however, vaccine persistence within tissues has also been noted. Consumption of venison containing BCG by hunters may present a public health concern as BCG exposure, although unlikely to cause disease, could cause false positive tuberculin skin test results. To examine BCG persistence further, 42 white-tailed deer were vaccinated orally or subcutaneously (SC) with BCG Danish. Three deer from each group were killed and examined at periods ranging from 2 weeks to 11 months after vaccination. BCG was recovered from orally vaccinated deer as late as 3 months after vaccination, while BCG persisted in SC vaccinated deer for as long as 9 months. At no time was BCG isolated from meat; however, prolonged persistence was seen in lymphoid organs. Although vaccine persistence was noted, especially in SC vaccinated deer, the distribution of culture-positive tissues makes human exposure through consumption unlikely.

Cancer initiating properties of fumonisin B1 in a short-term rat liver carcinogenesis assay.

The nature of cancer initiation by fumonisin B(1) (FB(1)) was investigated in rat liver by monitoring the effect of phenobarbital (PB) as cancer promoter and evaluating the involvement of spontaneously initiated cells. A PB promoting regimen (0.05% in the diet) stimulated the outgrowth of FB(1)-induced placental glutathione S-transferase (GSTP) positive initiated hepatocytes. Reversion of the FB(1)-induced GSTP(+) foci was noticed in the absence of a promoting regimen. Younger rats were shown to be more sensitive to the induction of GSTP(+) foci by FB(1). Cancer initiation by FB(1) was associated with a hepatotoxic effect, which was less pronounced in older rats presumably due to a reduced intake. A specific role of spontaneously initiated cells and their promotion by FB(1) into the development of eosinophilic clear cell foci could not be established under the present experimental conditions. The ability of different stimuli to selectively promote the outgrowth of FB(1) initiated cells further verifies the cancer initiating potency of this apparent non-genotoxic mycotoxin. The underlying mechanism(s) involved in the genesis of the initiated hepatocytes is not known at present.

Exposure of sheep scrapie brain homogenate to rumen-simulating conditions does not result in a reduction of PrP(Sc) levels.

AIMS: Experiments were designed to evaluate the potential of rumen-simulating conditions to reduce PrP(Sc) levels. METHODS AND RESULTS: Scrapie-positive brain material was incubated under rumen-simulating conditions. Time points were taken over a 24-h period and PrP(Sc) levels were analysed by Western blot. No loss of PrP(Sc) was observed over a 24-h time period. CONCLUSIONS: Our results indicate that a fully developed rumen fermentation does not provide significant protection against prion infection via the oral route. Developmental changes including senescence of immune system function or other developmental changes in the gastrointestinal tract are potential mechanisms by which relative bovine spongiform encephalopathy (BSE) susceptibility might vary with age. SIGNIFICANCE AND IMPACT OF THE STUDY: Epidemiology of the BSE outbreak in the United Kingdom indicates that younger animals were at higher risk of infection. The rumen undergoes pronounced developmental changes early in life, coinciding with the introduction of fibre into the diet. The timeframe of highest risk of infection overlaps the time in life prior to full rumen development. This work indicates that a fully developed rumen does not provide significant protection against prion infection via the oral route of infection. This result implicates other developmental changes that are responsible for the age-dependent susceptibility of cattle to BSE.

The effect of Pythium oligandrum and chitosan used in control of potato against late blight and the occurrence of fungal diseases on tuber peel.

The aim of two year investigation was the valuation the effect of biopreparate Polyversum (B.A.S. Pythium oligandrum) and preparate Biochikol 020 PC (B.A.S. chitosan) used in control of potato against Phytophthora blight on the tuber infestation during storage by Helminthosporium solani and tuber infestation by sclerotia of Rhizoctonia solani. As the standard fungicide Vitavax 200 FS (B.A.S. karboxin and thiuram) was used. After harvesting 100 tubers from each plots was collected and put in storage. The analysis of tuber infestation by Rhizoctonia solani and Helminthosporium solani was made after harvesting (September) and later every 3 months during storage period (December, March). The percent of diseased tubers in tested sample and also infestation degree of bulbs using 5-degree scale was estimated. The received results of investigations ascertained, that all tested preparations during potato vegetation influenced on lower (in comparison with control) degree of bulbs infestation by sclerots of Rhizoctonia solani and the mean degree of infestation by Helminthosporium solani. Moreover the percent of diseased tubers infected by pathogens with tested preparations combination was significant lower than in control.

Occurence of fungal diseases on lemon balm (Mellisa officinalis L.) and peppermint (Mentha x piperita L.) in the region of Malopolska.

This paper presents the results of the researches carried out on the subject of the diseases on herbs such as lemon balm and peppermint focusing on the health status of the plants grown in the region of Malopolska. The field and laboratory research proved that perpetrators of the diseases on the examined plants were fungi species with the numerical majority. On lemon balm septoria leaf spot (Septoria melissae) was most often observed. Moreover, fungal genera of different taxonomic groups were detected. Alternaria, Epicoccum, Fusarium, and Sclerotinia sclerotiorum occurred most often on the medicinal plant samples. The disease mint rust Puccinia menthae, has caused major problems for the peppermint growers. In the populations of fungi found on the diseased leaves the dominating were Alternaria, Epicoccum and Sphaceloma menthae. It has been stated that among all fungi isolated from lemon balm, the species Fusarium avenaceum had the highest pathogenicity to seedlings (80% of diseased seedlings). For peppermint plants the highest pathogenicity had species Epicoccum purpurascens, and caused 82% of diseased seedlings. Conducted evaluation of health status of plants showed that the lemon balm mean disease index was yearly differentiated and was the highest in 2003 (44.39). For peppermint, the highest disease index was in third year of cultivation (62.75) and was statistically higher than in previous years.

Photodynamic diagnosis (PDD) and photodynamic therapy (PDT) in dermatology: "How we do it".

In dermatology PDT has been proven to be effective in the treatment of actinic keratoses, basal cell carcinomas (BCC), Bowen's disease, superficial squamous cell carcinomas (SCC).

A new look at the prognostic value of the estrogen, progesterone and epidermal growth factor receptors in breast cancer tissue.

The aim of the study was to evaluate the influence of the receptor status of primary breast cancer and of a number of selected clinical and morphological patient characteristics. The receptors were determined by biochemical radiocompetitive methods. Disease free survival (DFS) and overall survival (OS) were determined by Cox proportional hazard model. The influence of ER, PR, and EGFR on patient survival was analyzed in two ways: 1) as a separate parameter of each receptor and 2) as a common parameter consisting of 8 variables of concomitant presence or absence of the receptors. The first set of analyses had shown that EGFR as an independent parameter had no prognostic value either for DFS or OS because of a lack of statistical significance. Higher ER concentrations were positive and lower concentrations were negative prognostic factors, but only for DFS. PR was always a positive prognostic factor for DFS and OS and its prognostic value increased with concentration increase. In the second analysis it was found that patients with receptor status ER+PR+EGFR+; ER-PR+EGFR-; ER+PR+EGFR-; and ER-PR-EGFR- were having better parameters of DFS and OS (relative risks for DFS or OS were between 0.22-1.16). The patients with receptor status: ER-PR+EGFR+; ER+PR-EGFR-, ER-PR-EGFR+ and ER+PR-EGFR+ exhibited a more aggressive disease course (relative risks for DFS and OS were between 1.46-3.95). Moreover, it was found that tumor size, nodal status and patient age were independent prognostic factors for DFS and OS of patients.

The biological evaluation of Zato 50 WG in protection of carrot against Alternaria blight.

Effectiveness of new fungicide Zato 50 WG (biologically active substances BAS - trifloxystrobin 50%) in the control of Alternaria blight on carrot was studied. Field experiments were carried out in the years 2003-2004 on carrot cv. Koral. As the standard fungicide Amistar 250 SC (BAS - azoxystrobin 250 g/dm3) was used. The results of health status of carrot leaves analysis in first and second year of experiment showed, that development of disease symptoms was lower on leaves of chemical protected plants than on leaves of control plants. The last estimation of infestation degree of carrot leaves made immediately before harvest showed, that standard fungicide Amistar had longer systemic influence on plants. This was confirmed the lower (statistically significant) infestation index of protected carrot in combination with Amistar. The estimations of health status of carrot roots were made directly after digging up indicate, that there wasn't difference of value of infestation index between protected combination and control. Experiment showed, significant effect of tested fungicides on crop quantity of carrot roots per 1 m2. Especially in the second year of study the crop of carrot roots in combination with Zato was higher - statistically significant - than in the rest combinations.

Effectiveness of some means using against root rot on parsley seedling root.

The results of a two-year study concern the effectiveness of 4 substances--biopreparate Chitosol (beta-1,4 D-glucosamine polymer) and fungicides: Rovral Flo 255 SC (BAS iprodione 255 g/dm3), Sportak Alpha 380 EC (BAS prochloraz 0,300 dm3/dm3 and carbendazim 80 g/dm3) and Zaprawa Funaben T (carbendazim 20% + tiuram 45%)--used against root rot and plant rot was described. These experiments were conducted in glasshouse and field conditions. Root of parsley cultivar Berlinska were treated one of tested substances autumn before storage period in clamp or spring immediately before planting seedling roots. The results showed that autumn dressing was ineffective, indices of root infestation were similar in each combination including control in both years of observation. Spring dressing was better, but not only in controls were many parsley plants decaying in the fields. Among substances used for spring dressing of seedling roots, the best efficacy exhibited Zaprawa Funaben T and Sportak Alpha 380 EC.

Comparison of rapid methods for the extraction of bacterial DNA from colonic and caecal lumen contents of the pig.

AIMS: The increasing uses of DNA methodologies to study the micro flora of the pig gastrointestinal tract requires an efficient recovery of bacterial DNA from the intestinal sample. Thus, the objective of this study was to determine which DNA extraction methods are most effective for luminal samples from pigs. Several routinely used nucleic acid extraction procedures were compared based upon quantity and purity of extracted DNA. METHODS AND RESULTS: DNA was extracted from pig colonic and caecal lumen samples using 19 methods for bacterial DNA extraction. The quantity of total DNA recovered by each extraction method was determined and compared. Two methods using extraction with polyvinylpolypyrrolidone (PVPP) or phenol and two methods involving bead mill homogenization were found to provide the greatest quantity of extracted DNA for both colonic and caecal lumen. Extracted DNA from these four methods was further analysed for purity based upon the presence of PCR inhibitors, which was ascertained by determining the efficiency of amplification of a segment of the 16S rDNA. PCR amplification could be readily achieved with DNA extracted by each of these four methods, but efficiency of amplification tended to be higher with DNA from two of the methods (one extracted with PVPP and one with bead mill homogenization). CONCLUSIONS: Four extraction methods proved to be significantly superior in quantity of DNA extracted from luminal samples. Of these four, no strong inhibitors of PCR amplification were detected in any of the extracted DNA. However, the efficiency of amplification tended to be lower in DNA samples from two of the methods, suggesting the presence of low levels of PCR inhibitors. SIGNIFICANCE AND IMPACT OF THE STUDY: Results of this study provide a basis for choosing which DNA extraction procedures are most effective for use with samples of pig lumen.

Interaction of fumonisin B(1) and aflatoxin B(1) in a short-term carcinogenesis model in rat liver.

The co-existence of the fumonisin and aflatoxin mycotoxins in corn merited studies to investigate their possible synergistic toxicological and carcinogenic effects. When utilising a short-term carcinogenesis model in rat liver, both the compounds exhibited slow cancer initiating potency as monitored by the induction of foci and nodules stained positively for the placental form of gluthatione-S-transferase (GSTP(+)). However, when rats were treated in a sequential manner with AFB(1) and FB(1) the number and size of GSTP(+) lesions significantly increased as compared to the separate treatments. Histopathological analyses indicated that the individual treatments showed far less toxic effects, including occasional hepatocytes with dysplastic nuclei, oval cell proliferation and, in the case of FB(1), a few apoptotic bodies in the central vein regions. The sequential treatment regimen induced numerous foci and dysplastic hepatocyte nodules, and with oval cells extending from the periportal regions into the centrilobular regions. This would imply that, in addition to the cancer promoting activity of FB(1) of AFB(1)-initiated hepatocytes, the AFB(1) pre-treatment enhanced the FB(1) initiating potency, presumably by rendering the liver more susceptible to the toxic effects of FB(1). The co-occurrence of AFB(1) and FB(1) in corn consumed as a staple diet could pose an increased risk and should be included in establishing risk assessment parameters in humans.

Spontaneous pneumomediastinum, pneumothorax and ecstasy abuse.

A case report is presented of a patient with bilateral pneumothoraces and spontaneous pneumomediastinum associated with ecstasy use. Pneumothorax and spontaneous pneumomediastinum should be considered in an ecstasy user who complains of chest pain, neck pain or shortness of breath.

Toxicological effects in rats chronically fed low dietary levels of fumonisin B(1).

The toxicity of low dietary levels of fumonisin B(1) (FB(1)), i.e. 1, 10 and 25 mg FB(1)/kg diet, were monitored in rats over a period of 24 months. No effects on the body weight gain and feed intake profiles were noticed, while the relative liver weight was significantly (P<0.05) reduced in the FB(1)-treated rats. Mild toxic effects, including single cell necrosis (apoptosis), proliferation of bile duct epithelial cells (DEC), and early signs of fibrosis, bile duct hyperplasia and in one case, adenofibrosis, were noticed in the liver of the rats fed the highest (25 mg/FB(1)/kg diet) dietary level. A significant (P<0.05) increase in the level of oxidative damage was also noticed in the liver of the rats of high dosage dietary group. The toxic effects were less severe in the 10 mg FB(1)/kg dietary group, whilst only a few ground glass foci were observed in the 1 mg FB(1)/kg dietary group. Hepatocyte nodules, staining positively for glutathione-S-transferase (placental form, PGST), were observed macroscopically in the 25 mg FB(1)/kg treated group and to a lesser extent in the 10 mg FB(1)/kg treated rats. The most prominent toxic lesions by FB(1) (10 and 25 mg FB(1)/kg dietary groups) in the kidneys were restricted to the tubular epithelium manifesting as granular cast, necrosis, apoptosis, calcification and the presence of regenerative foci in the proximal convoluted tubules. The existence of a cytotoxic/proliferative threshold with respect to cancer induction by FB(1) in rat liver became apparent, with a dietary level of <10-mg FB(1)/kg diet as a no effect threshold for the induction of hepatocyte nodules.