Osteoclasts play a central role in cancer -cell -induced osteolysis, but the molecular mechanisms of osteoclast activation during bone metastasis formation are incompletely understood. By performing RNA sequencing on a mouse breast carcinoma cell line with higher bone -metastatic potential, here we identify the enzyme CYP11A1 strongly upregulated in osteotropic tumor cells. Genetic deletion of Cyp11a1 in tumor cells leads to a decreased number of bone metastases but does not alter primary tumor growth and lung metastasis formation in mice. The product of CYP11A1 activity, pregnenolone, increases the number and function of mouse and human osteoclasts in vitro but does not alter osteoclast-specific gene expression. Instead, tumor -derived pregnenolone strongly enhances the fusion of pre-osteoclasts via prolyl 4-hydroxylase subunit beta (P4HB), identified as a potential interaction partner of pregnenolone. Taken together, our results demonstrate that Cyp11a1-expressing tumor cells produce pregnenolone, which is capable of promoting bone metastasis formation and osteoclast development via P4HB.

Lysosomal degradation, the common destination of autophagy and endocytosis, is one of the most important elements of eukaryotic metabolism. The small GTPases Rab39A and B are potential new effectors of this pathway, as their malfunction is implicated in severe human diseases like cancer and neurodegeneration. In this study, the lysosomal regulatory role of the single Drosophila Rab39 ortholog was characterized, providing valuable insight into the potential cell biological mechanisms mediated by these proteins. Using a de novo CRISPR-generated rab39 mutant, we found no failure in the early steps of endocytosis and autophagy. On the contrary, we found that Rab39 mutant nephrocytes internalize and degrade endocytic cargo at a higher rate compared to control cells. In addition, Rab39 mutant fat body cells contain small yet functional autolysosomes without lysosomal fusion defect. Our data identify Drosophila Rab39 as a negative regulator of lysosomal clearance during both endocytosis and autophagy.

Endocytosis and autophagy are evolutionarily conserved degradative processes in all eukaryotes. Both pathways converge to the lysosome where cargo is degraded. Improper lysosomal degradation is observed in many human pathologies, so its regulatory mechanisms are important to understand. Sec20/BNIP1 (BCL2/adenovirus E1B 19 kDa protein-interacting protein 1) is a BH3 (Bcl-2 homology 3) domain-containing SNARE (soluble N-ethylmaleimide-sensitive factor-attachment protein receptors) protein that has been suggested to promote Golgi-ER retrograde transport, mitochondrial fission, apoptosis and mitophagy in yeast and vertebrates. Here, we show that loss of Sec20 in Drosophila fat cells causes the accumulation of autophagic vesicles and prevents proper lysosomal acidification and degradation during bulk, starvation-induced autophagy. Furthermore, Sec20 knockdown leads to the enlargement of late endosomes and accumulation of defective endolysosomes in larval Drosophila nephrocytes. Importantly, the loss of Syx18 (Syntaxin 18), one of the known partners of Sec20, led to similar changes in nephrocytes and fat cells. Interestingly. Sec20 appears to function independent of its role in Golgi-ER retrograde transport in regulating lysosomal degradation, as the loss of its other partner SNAREs Use1 (Unconventional SNARE In The ER 1) and Sec22 or tethering factor Zw10 (Zeste white 10), which function together in the Golgi-ER pathway, does not cause defects in autophagy or endocytosis. Thus, our data identify a potential new transport route specific to lysosome biogenesis and function.

INTRODUCTION:In some surgical wards residents start to do laparoscopic operations using both hands, while in other places they only use their dominant hand, and only start to use both hands later. There are no data at the moment about which method is more effective.METHODS:We divided 20 students with no laparoscopic experience into 2 groups: one group practised one hand at a time (1K), the other group used both hands (2K) during the 5 days. On the last day both groups had to do every exercise with one hand and two hands as well, then they had to do 3 new exercises, which needed both hands. We measured the time taken, and gave points for the videos taken inside the training box based on OSATS. For statistical analysis we used t-tests, p < 0.05 being significant.RESULTS:On the first day, there was no significant difference between the 1K and 2K groups considering the time taken (518/500 s) and the OSATS points (87/84; 54/55 points). Both groups improved in the mean time and points (1K: 52%, 77% 2K: 50%, 70%) as well, but there was no significant difference between them. In the case of new exercises on the last day, there was no difference between mean time (1K: 425 s, 2K: 411 s) and points (53/59 and 56/52), but there was a significant difference considering the points given for bimanuality.CONCLUSION:Based on our study, we cannot exactly state that the bimanuality needed for expert laparoscopic surgery would be easier to learn with immediately practising with both hands.

Rab7 promotes fusion of autophagosomes and late endosomes with lysosomes in yeast and metazoan cells, acting together with its effector, the tethering complex HOPS. Here we show that another small GTPase, Rab2, is also required for autophagosome and endosome maturation and proper lysosome function in Drosophila melanogaster. We demonstrate that Rab2 binds to HOPS, and that its active, GTP-locked form associates with autolysosomes. Importantly, expression of active Rab2 promotes autolysosomal fusions unlike that of GTP-locked Rab7, suggesting that its amount is normally rate limiting. We also demonstrate that RAB2A is required for autophagosome clearance in human breast cancer cells. In conclusion, we identify Rab2 as a key factor for autophagic and endocytic cargo delivery to and degradation in lysosomes.

INTRODUCTION In some surgical wards residents start to do laparoscopic operations using both hands, while in other places they only use their dominant hand, and only start to use both hands later. There are no data at the moment about which method is more effective. METHODS We divided 20 students with no laparoscopic experience into 2 groups: one group practised one hand at a time (1K), the other group used both hands (2K) during the 5 days. On the last day both groups had to do every exercise with one hand and two hands as well, then they had to do 3 new exercises, which needed both hands. We measured the time taken, and gave points for the videos taken inside the training box based on OSATS. For statistical analysis we used t-tests, p < 0.05 being significant. RESULTS On the first day, there was no significant difference between the 1K and 2K groups considering the time taken (518/500 s) and the OSATS points (87/84; 54/55 points). Both groups improved in the mean time and points (1K: 52%, 77% 2K: 50%, 70%) as well, but there was no significant difference between them. In the case of new exercises on the last day, there was no difference between mean time (1K: 425 s, 2K: 411 s) and points (53/59 and 56/52), but there was a significant difference considering the points given for bimanuality. CONCLUSION Based on our study, we cannot exactly state that the bimanuality needed for expert laparoscopic surgery would be easier to learn with immediately practising with both hands.

Yeast studies identified two heterohexameric tethering complexes, which consist of 4 shared (Vps11, Vps16, Vps18 and Vps33) and 2 specific subunits: Vps3 and Vps8 (CORVET) versus Vps39 and Vps41 (HOPS). CORVET is an early and HOPS is a late endosomal tether. The function of HOPS is well known in animal cells, while CORVET is poorly characterized. Here we show that Drosophila Vps8 is highly expressed in hemocytes and nephrocytes, and localizes to early endosomes despite the lack of a clear Vps3 homolog. We find that Vps8 forms a complex and acts together with Vps16A, Dor/Vps18 and Car/Vps33A, and loss of any of these proteins leads to fragmentation of endosomes. Surprisingly, Vps11 deletion causes enlargement of endosomes, similar to loss of the HOPS-specific subunits Vps39 and Lt/Vps41. We thus identify a 4 subunit-containing miniCORVET complex as an unconventional early endosomal tether in Drosophila.

INTRODUCTION:Operating room is not the ideal place to acquire laparoscopic skills since patients can be put at risk and it is also relatively expensive. Using training boxes seems to be a more appropriate way of teaching and learning the technique, but there is little data about measuring the technique of experienced specialists and comparing their results with residents.METHODS:At the 1st Department of Surgery, Semmelweis University we tested 30 residents and 25 specialists in general surgery and urology on MENTOR® training box. Before training, all participants completed a questionnaire on professional experience, previous usage of training boxes, virtual simulators, and video games, and whether they played a musical instrument earlier. Subjects were asked to complete in a defined time limit 3 of the Fundamentals of Laparoscopic Surgery tasks (which is required for American surgical residents for surgical board examination), and 3 tasks decided by us. Linear regression analysis (ANOVA table) was used to evaluate the data.RESULTS:16% of the specialists and 6.66% of the residents completed all tasks within time limit. Statistically significant correlation (p < 0.05) was demonstrated between the number of previous laparoscopic surgeries and task completion time, while there were no significant correlations between other factors, which may influence laparoscopic technique and task completion time.CONCLUSIONS:Training boxes are suitable for developing eye-hand coordination and bimanuality, as well as for learning instrument handling. Nonetheless, residents acquire most of their laparoscopic surgical skills on patients in Hungary, yet. For this reason there is a need for organized training opportunities.

Absztrakt Bevezetés: A laparoscopos technika betegen történő elsajátítása financiális és betegbiztonsági szempontból sem előnyös. A technika oktatására és elsajátítására jelenleg a tréningboksz tűnik a legmegfelelőbbnek, de a laparoscopos gyakorlattal már rendelkező szakorvosok technikájának mérésére és rezidensekkel történő összehasonlítására még kevés a releváns adat. Módszer: A SE I. sz. Sebészeti Klinikán 25 sebész és urológus szakorvost, illetve 30 rezidenst vizsgáltunk MENTOR® tréningbokszon egy kérdőív kitöltése után, melyben többek között rákérdeztünk a szakmai gyakorlatukra, korábbi tréningboksz-, virtuális szimulátor-, hangszer- és videojáték-használatukra. A vizsgált személyeknek 3, az Amerikai Sebész Társaság szakvizsgájához megkövetelt gyakorlatot (FLS) és 3 általunk meghatározott feladatot kellett el-végezniük meghatározott idő alatt. A statisztikai számításokhoz lineáris regresszióanalízist használtunk (ANOVA táblázat). Eredmények: A szakorvosok 16%-a, a rezidensek 6,66%-a tudta teljesíteni időkorláton belül az összes feladatot. A feladatok elvégzéséhez szükséges idő és a saját laparoscopos műtétek száma között szignifikáns (p < 0,05) kapcsolatot igazoltunk, míg a többi befolyásoló tényező és az idő között nem találtunk szignifikáns kapcsolatot. A résztvevők 66%-a az általunk készített feladatokat tartotta hasznosabbnak. Következtetések: Magyarországon jelenleg a rezidensek jellemzően a betegen sajátítják el a laparoscopos műtéti technikát, holott a tréningbokszok alkalmasak a szem-kéz koordináció, a kétkezesség begyakorlására, valamint az eszközhasználat megtanulására. Ezért szükség lenne szervezett gyakorlási lehetőségek biztosítására.

Drawing up cultural macro-regions in Hungary is har dly possible as not even two of the highly developed mezo-regions are contacting, not s peaking about forming a bloc; they rather constitut e a mosaic on the country map. Those on medium cultural level make up two groups, while, though the ones with a low standard are mostly found along the Danube as a single bloc, they are isolated by Pest county, statistically grouped in one region with th em, with a genuine cultural level far exceeding the low cluster. Consequently, it is only justified to speak about cultural regions in the sense that, on the whole, Dunantul is on a higher standard than the ea stern half of the country. When measuring the cultural development of territor ial units, as well as any other subsystems, I based my work on the reports by KSH (Central Statistics Authority). For the purpose of the topic, I found relevant information in the numbers of studen ts studying in the different types of schools of th e regions, the numbers of those attending public libr aries, museums, theatres and cinemas, as well as in the data concerning education registered and publis hed from the censuses and micro-censuses carried out every five years. In developmental measuring, it is usually the rate of students studying in secondary schools of the region that is taken into account, but I have t he following reservations regarding this practice. In some counties, a considerable part of the 14-18 age group attends the secondary schools of a mezo- region other than those in its domicile. The reason is that if a big city in the neighbouring county o r the capital city is located near the county examined, t he students living in its vicinity will attend in l arge numbers the schools of the latter settlement, thus improving the data of the neighbouring mezo-region, and worsening their own. A typical case is Somogy county, where part of the teenagers living on the western edge of the county study in Nagykanizsa in Zala county; another example can be Nograd, from the western part of which, as well as from the agglomeration of Pest county, the dominant part of secondary school students study in Budapest. The ra te of students attending secondary schools, or even higher education institutions, does not really indicate the cultural development of a region. It is worth noting that the use of colleges or universiti es located in territorial units outside the domicil e further distorts the findings. Migration from the r egion affects, for the most part, the people with competitive qualifications, so the picture shown by the rate of secondary and higher education student s in a region often significantly differs from the ac tual measures of education. However, there are no d ata related to the latter in the annual reports, except those provided by the micro-censuses conducted every five years, this is what we have to take into account in our analysis as well.

A szerb nép államiságának első négy évszázadát idegen birodalmak keretében, korlátozott szuverenitású fejedelemségekben, tehát politikai régiókban élte. Ezt követte a 13-14. században a figgetlen királyság időszaka, majd ismét egy évszázadnyi tartományokra szakadt állapot, részben magyar impérium alatt. A török uralom utolsó évszázadában, a 19. században ismét korlátozott szuverenitású fejedelemség, a 20. században pedig a jugoszláv állam birodalmi jellegű országa következett. A két nép közös politikai régiói: a 18. századi Temesi Bánság és a 20. században létrejött Vajdaság

A magyar közigazgatás történetében a kétségtelenül meghatározó megyerendszer mellett kezdettől és folyamatosan nyomon követhetők a kevésbé ismert regionalizáló törekevések. Az Árpád-házi királyok idején a hercegségek, a középkori magyar állam virágkorában a katonai és pénzügyi körzetesítések, a Habsburg abszolutizmus időszakaiban a megyéket időnként alárendelő, illetve a folyamatosan működő szakigazgatási kerületek, a teljes évezred során pedig az egyházmegyék alkottak sajátos régiókat.