The narrowing of literature use and the restricted mobility of papers in the sciences.

It is a matter of debate whether a shrinking proportion of scholarly literature is getting most of the citations over time. It is also less well understood how a narrowing use of literature would affect the circulation of ideas in the sciences. Here, I show that the utilization of scientific literature follows dual tendencies over time: while a larger proportion of literature is cited at least a few times, citations are also concentrated more at the top of the citation distribution. Parallel to the latter trend, a paper's future importance increasingly depends on its past citation performance. A random network model shows that the citation concentration is directly related to the greater stability of citation performance. The presented evidence suggests that the growing heterogeneity of citation impact restricts the mobility of research articles that do not gain attention early on. While concentration grows from the beginning of the studied period in 1970, citation dispersion manifests itself significantly only from the mid-1990s, when the popularity of freshly published papers also increased. Most likely, advanced information technologies to disseminate papers are behind both of these latter trends.

Novel Erlotinib-Chalcone Hybrids Diminish Resistance in Head and Neck Cancer by Inducing Multiple Cell Death Mechanisms.

In a search for novel therapeutic options for head and neck squamous cell carcinomas (HNSCCs) generally treated with limited therapeutic success, we synthesized a series of novel erlotinib-chalcone molecular hybrids with 1,2,3-triazole and alkyne linkers and evaluated them for their anticancer activity on Fadu, Detroit 562 and SCC-25 HNSCC cell lines. Time- and dose-dependent cell viability measurements disclosed a significantly increased efficiency of the hybrids compared to the 1:1 combination of erlotinib and a reference chalcone. The clonogenic assay demonstrated that hybrids eradicate HNSCC cells in low micromolar concentrations. Experiments focusing on potential molecular targets indicate that the hybrids trigger the anticancer effect by a complementary mechanism of action that is independent of the canonical targets of their molecular fragments. Confocal microscopic imaging and real-time apoptosis/necrosis detection assay pointed to slightly different cell death mechanisms induced by the most prominent triazole- and alkyne-tethered hybrids (6a and 13, respectively). While 6a featured the lowest IC50 values on each of the three HNSCC cell lines, in Detroit 562 cells, this hybrid induced necrosis more markedly compared to 13. The therapeutic potential indicated by the observed anticancer efficacy of our selected hybrid molecules validates the concept of development and justifies further investigation to reveal the underlying mechanism of action.

MEK Is a Potential Indirect Target in Subtypes of Head and Neck Cancers.

The poor prognosis of head-and-neck squamous cell carcinoma (HNSCC) is partly due to the lack of reliable prognostic and predictive markers. The Ras/Raf/MEK/ERK signaling pathway is often activated by overexpressed epidermal growth factor receptor (EGFR) and stimulates the progression of HNSCCs. Our research was performed on three human papillomavirus (HPV)-negative HNSCC-cell lines: Detroit 562, FaDu and SCC25. Changes in cell viability upon EGFR and/or MEK inhibitors were measured by the MTT method. The protein-expression and phosphorylation profiles of the EGFR-initiated signaling pathways were assessed using Western-blot analysis. The EGFR expression and pY1068-EGFR levels were also studied in the patient-derived HNSCC samples. We found significant differences between the sensitivity of the tumor-cell lines used. The SCC25 line was found to be the most sensitive to the MEK inhibitors, possibly due to the lack of feedback Akt activation through EGFR. By contrast, this feedback activation had an important role in the FaDu cells. The observed insensitivity of the Detroit 562 cells to the MEK inhibitors might have been caused by their PIK3CA mutation. Among HNSCC cell lines, EGFR-initiated signaling pathways are particularly versatile. An ERK/EGFR feedback loop can lead to Akt-pathway activation upon MEK inhibition, and it is related not only to increased amounts of EGFR but also to the elevation of pY1068-EGFR levels. The presence of this mechanism may justify the combined application of EGFR and MEK inhibitors.

Shorter distances between papers over time are due to more cross-field references and increased citation rate to higher-impact papers.

The exponential increase in the number of scientific publications raises the question of whether the sciences are expanding into a fractured structure, making cross-field communication difficult. On the other hand, scientists may be motivated to learn extensively across fields to enhance their innovative capacity, and this may offset the negative effects of fragmentation. Through an investigation of the distances within and clustering of cross-sectional citation networks, this study presents evidence that fields of science become more integrated over time. The average citation distance between papers published in the same year decreased from ∼5.33 to 3.18 steps between 1950 and 2018. This observation is attributed to the growth of cross-field communication throughout the entire period as well as the growing importance of high-impact papers to bridge networks in the same year. Three empirical findings support this conclusion. First, distances decreased between almost all disciplines throughout the time period. Second, inequality in the number of citations received by papers increased, and, as a consequence, the shortest paths in the network depend more on high-impact papers later in the period. Third, the dispersion of connections between fields increased continually. Moreover, these changes did not entail a lower level of clustering of citations. Both within- and cross-field citations show a similar rate of slowly growing clustering values in all years. The latter findings suggest that domain-spanning scholarly communication is partly enabled by new fields that connect disciplines.

Novel Crizotinib-GnRH Conjugates Revealed the Significance of Lysosomal Trapping in GnRH-Based Drug Delivery Systems.

Several promising anti-cancer drug-GnRH (gonadotropin-releasing hormone) conjugates have been developed in the last two decades, although none of them have been approved for clinical use yet. Crizotinib is an effective multi-target kinase inhibitor, approved against anaplastic lymphoma kinase (ALK)- or ROS proto-oncogene 1 (ROS-1)-positive non-small cell lung carcinoma (NSCLC); however, its application is accompanied by serious side effects. In order to deliver crizotinib selectively into the tumor cells, we synthesized novel crizotinib analogues and conjugated them to a [d-Lys6]-GnRH-I targeting peptide. Our most prominent crizotinib-GnRH conjugates, the amide-bond-containing [d-Lys6(crizotinib*)]-GnRH-I and the ester-bond-containing [d-Lys6(MJ55*)]-GnRH-I, were able to bind to GnRH-receptor (GnRHR) and exert a potent c-Met kinase inhibitory effect. The efficacy of compounds was tested on the MET-amplified and GnRHR-expressing EBC-1 NSCLC cells. In vitro pharmacological profiling led to the conclusion that that crizotinib-GnRH conjugates are transported directly into lysosomes, where the membrane permeability of crizotinib is diminished. As a consequence of GnRHR-mediated endocytosis, GnRH-conjugated crizotinib bypasses its molecular targets-the ATP-binding site of RTKs- and is sequestered in the lysosomes. These results explained the lower efficacy of crizotinib-GnRH conjugates in EBC-1 cells, and led to the conclusion that drug escape from the lysosomes is a major challenge in the development of clinically relevant anti-cancer drug-GnRH conjugates.

Discovery and optimization of novel benzothiophene-3-carboxamides as highly potent inhibitors of Aurora kinases A and B.

Aurora kinases as regulators of cell division have become promising therapeutic targets recently. Here we report novel, low molecular weight benzothiophene-3-carboxamide derivatives designed and optimized for inhibiting Aurora kinases. The most effective compound 36 inhibits Aurora kinases in vitro in the nanomolar range and diminishes HCT 116 cell viability blocking cytokinesis and inducing apoptosis. According to western blot analysis, the lead molecule inhibits Aurora kinases equipotently to VX-680 (Tozasertib) and similarly synergizes with other targeted drugs.

Synthesis, characterization and systematic comparison of FITC-labelled GnRH-I, -II and -III analogues on various tumour cells.

Targeted tumour therapy is the focus of recent cancer research. Gonadotropin-releasing hormone (GnRH) analogues are able to deliver anticancer agents selectively into tumour cells, which highly express GnRH receptors. However, the effectiveness of different analogues as targeting moiety in drug delivery systems is rarely compared, and the investigated types of cancer are also limited. Therefore, we prepared selectively labelled, fluorescent derivatives of GnRH-I, -II and -III analogues, which were successfully used for drug targeting. In this manuscript, we investigated these analogues' solubility, stability and passive membrane permeability and compared their cellular uptake by various cancer cells. We found that these labelled GnRH conjugates provide great detectability, without undesired cytotoxicity and passive membrane permeability. The introduced experiments with these conjugates proved their reliable tracking, quantification and comparison. Cellular uptake efficiency was studied on human breast, colon, pancreas and prostate cancer cells (MCF-7, HT-29, BxPC-3, LNCaP) and on dog kidney cells (Madin-Darby canine kidney). Each of the three conjugates was taken up by GnRH-I receptor-expressing cells, but the different cells preferred different analogues. Furthermore, we demonstrated for the first time the high cell surface expression of GnRH-I receptors and the effective cellular uptake of GnRH analogues on human pharynx tumour (Detroit-562) cells. In summary, our presented results detail that the introduced conjugates could be innovative tools for the examination of the GnRH-based drug delivery systems on various cells and offer novel information about these peptides. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

Sexual activity of young men is not related to their anthropometric parameters.

INTRODUCTION: Many articles have been written about the deterioration of male sexual function, mainly in relation to metabolic diseases and aging. With younger men, unless they have a complaint, sexual issues are rarely discussed during medical consultations. No articles could be found about anthropometric parameters as factors potentially influencing sexual performance. AIM: The aim of this study was to find the anthropometric parameters with the closest correlation with sexual activity. MAIN OUTCOME MEASURES: Main outcome measures included self-reported weekly intercourses, age, body weight and height, body mass index (BMI), and waist circumference. METHODS: Data for 531 heterosexual men aged 20-54 years were collected in three andrological centers. Past and recent morbidity, medications, and some lifestyle elements were recorded; anthropometric parameters were measured; and andrological examination was performed. The average weekly number of intercourses was asked confidentially. RESULTS: The mean weekly coital frequency (±SD) was 2.55 ± 1.08. The highest self-reported weekly coital frequency was recorded for men between the ages of 25 and 29 (3.02 ± 1.27). Coital frequency was higher among men with a height of less than 175 cm (2.69 ± 1.24), weight of less than 78 kg (2.74 ± 1.18), normal BMI (2.74 ± 1.16), normal waist circumference (2.69 ± 1.19), and no metabolic disease (2.57 ± 1.11). Logistic regression described an inverse, statistically significant association between age and coital frequency, with the following odds ratios for coital frequency (ORcf ): ORcf≥2 = 0.932, P < 0.001; ORcf≥2.5 = 0.935, P < 0.001; ORcf≥3 = 0.940, P < 0.001; ORcf≥3.5 = 0.965, P = 0.041. Among men who reported a coital frequency of more than 3.5 times a week, waist circumference (ORcf≥3.5 = 0.986, P = 0.066) showed borderline association with lower sexual activity, while lesser height (ORcf≥3.5 = 0.951, P = 0.005) was associated with higher activity. CONCLUSION: In this study's age range, none of the examined anthropometric parameters was perfectly correlated with sexual activity. Obesity and metabolic diseases can cause all types of sexual function to deteriorate in older age, whereas their effects may not yet be prominent at younger ages (below 45 years). Health promotion for all ages should focus on prevention of obesity so as to improve quality of life and sexual health.

[Influence of malignant tumors occurring in the reproductive age on spermiogenesis: studies on patients with testicular tumor and lymphoma]. / Reproduktív korban eloforduló daganatok hatása a spermiogenezisre: heredaganatos és lymphomás betegek vizsgálata.

INTRODUCTION: The application of chemo- and radiotherapy results in good survival prognosis for young men with malignant tumors, but long-term gonadoxic effect has to be considered. In addition, malignant disease itself has a negative impact on spermiogenesis. AIM: The aim of the authors was to examine the spermiogenetic effect of the most common tumors occurring in the reproductive age in men: testicular cancer, Hodgkin disease and non-Hodgkin disease. METHOD: Spermiogram of men with testicular cancer (N = 68), Hodgkin disease (N = 37) and non-Hodgkin disease (N = 14) who were referred for sperm cryopreservation were analysed in the Reproductive Andrology Laboratory of the authors. RESULTS: Azoospermia was found in 11.8% of all patients (N = 119), while 58.8% of the patients had oligozoospermia even before the treatment. Sperm concentration of men with testicular cancer was significantly lower than those with lymphomas (32.8 M/mL vs. 24.9 M/mL, p = 0.03). There was no difference in sperm concentration between the Hodgkin and non-Hodgkin lymphoma groups. CONCLUSIONS: Spermiogenetic defect is more pronounced in men with testicular cancer than those with lymphomas. Cryopreservation before treatment for fertility preservation should be offered for all reproductive aged men with malignant disease, especially for those with testicular cancer.

Nicotine interferes with purinergic signaling in smooth muscle cells isolated from urinary bladders of patients with lower urinary tract symptoms.

In patients with outlet obstruction, the contraction of the base is reduced compared to that of healthy individuals, while the contraction of the dome is not affected. Here, we investigated the cellular mechanisms that might be responsible for cholinergic effects blocking non-adrenergic non-cholinergic contractions in the base of the urinary bladder. Smooth muscle cells either from the base or from the dome of human urinary bladders were cultured to determine the contribution of cholinergic and purinergic mechanisms to their Ca2+ homeostasis. While ATP evoked Ca2+ transients in all the cells, nicotine and carbachol induced Ca2+ transients only in 56% and 44% of the cells, respectively. When ATP was administered together with nicotine or carbachol, the amplitudes of the Ca2+ transients recorded from cells prepared from the base of bladders were significantly smaller (42 ± 6% with nicotine and 56 ± 9% with carbachol) than those evoked by ATP alone. This inhibition was much less apparent in the dome of bladders. The inhibition between the cholinergic and purinergic signaling pathways reported in this work may decrease the strength of the contraction of the base of the urinary bladder in patients with outlet obstruction during voiding.

[Citogenetic and molecular genetic studies in infertility in eastern Hungary]. / Infertilitásban végzett citogenetikai és molekuláris genetikai vizsgálatok a kelet-magyarországi régióban.

INTRODUCTION: In developed countries 10-15% of the couples are affected by infertility. In half of them genetic factors can be identified. AIMS: We studied genetic alterations in infertility in Hungarian patients. METHODS: Cyogenetic analyses were performed in 195 females and 305 males. In 17 females FMR1 mutations, in 150 males Y microdeletions, and aneuploidy were studied in the sperm of 28 males. In a carrier male sperm meiotic segregation was studied. RESULTS: The most common aberrations in females were X chromosome aneuploidia and inversion (3.6%), while the same in males Klinefelter-syndrome (3.3%) and autosomal translocations (2%). In two females FMR1 premutation was found. While Y microdeletions were identified only in azoospermic and severe oligozoospermic men, partial microdeletions could also be detected in normozoospermic males. A higher aberration rate was found in cases with abnormality in both the number and motility of sperm. In a male patient with 46,XY,t(3;6)(q21;q23) karyotype, 53.2% of spem carried unbalanced chromosome assortment. CONCLUSIONS: Knowledge of abnormalities may help in genetic counseling and choosing the most effective reproduction technique.

Protein Kinase D3 (PKD3) Requires Hsp90 for Stability and Promotion of Prostate Cancer Cell Migration.

Prostate cancer metastasis is a significant cause of mortality in men. PKD3 facilitates tumor growth and metastasis, however, its regulation is largely unclear. The Hsp90 chaperone stabilizes an array of signaling client proteins, thus is an enabler of the malignant phenotype. Here, using different prostate cancer cell lines, we report that Hsp90 ensures PKD3 conformational stability and function to promote cancer cell migration. We found that pharmacological inhibition of either PKDs or Hsp90 dose-dependently abrogated the migration of DU145 and PC3 metastatic prostate cancer cells. Hsp90 inhibition by ganetespib caused a dose-dependent depletion of PKD2, PKD3, and Akt, which are all involved in metastasis formation. Proximity ligation assay and immunoprecipitation experiments demonstrated a physical interaction between Hsp90 and PKD3. Inhibition of the chaperone-client interaction induced misfolding and proteasomal degradation of PKD3. PKD3 siRNA combined with ganetespib treatment demonstrated a specific involvement of PKD3 in DU145 and PC3 cell migration, which was entirely dependent on Hsp90. Finally, ectopic expression of PKD3 enhanced migration of non-metastatic LNCaP cells in an Hsp90-dependent manner. Altogether, our findings identify PKD3 as an Hsp90 client and uncover a potential mechanism of Hsp90 in prostate cancer metastasis. The molecular interaction revealed here may regulate other biological and pathological functions.

Correlation study between sperm concentration, hyaluronic acid-binding capacity and sperm aneuploidy in Hungarian patients.

Infertile men with low sperm concentration and/or less motile spermatozoa have an increased risk of producing aneuploid spermatozoa. Selecting spermatozoa by hyaluronic acid (HA) binding may reduce genetic risks such as chromosomal rearrangements and numerical aberrations. Fluorescence in-situ hybridization (FISH) has been used to evaluate the presence of aneuploidies. This study examined spermatozoa of 10 oligozoospermic, 9 asthenozoospermic, 9 oligoasthenozoospermic and 17 normozoospermic men by HA binding and FISH. Mean percentage of HA-bound spermatozoa in the normozoospermic group was 81%, which was significantly higher than in the oligozoospermic (P<0.001), asthenozoospermic (P<0.001) and oligoasthenozoospermic (P<0.001) groups. Disomy of sex chromosomes (P=0.014) and chromosome 17 (P=0.0019), diploidy (P=0.03) and estimated numerical chromosome aberrations (P=0.004) were significantly higher in the oligoasthenozoospermic group compared with the other groups. There were statistically significant relationships (P<0.001) between sperm concentration and HA binding (r=0.658), between sperm concentration and estimated numerical chromosome aberrations (r=-0.668) and between HA binding and estimated numerical chromosome aberrations (r=-0.682). HA binding and aneuploidy studies of spermatozoa in individual cases allow prediction of reproductive prognosis and provision of appropriate genetic counselling. Infertile men with normal karyotypes and low sperm concentrations and/or less motile spermatozoa have significantly increased risks of producing aneuploid (diminished mature) spermatozoa. Selecting spermatozoa by hyaluronic acid (HA) binding, based on a binding between sperm receptors for zona pellucida and HA, may reduce the potential genetic risks such as chromosomal rearrangements and numerical aberrations. In the present study we examined sperm samples of 45 men with different sperm parameters by HA-binding assay and fluorescence in-situ hybridization (FISH). Mean percentage of HA-bound spermatozoa in the normozoospermic group was significantly higher than the oligozoospermic, the asthenozoospermic and the oligoasthenozoospermic groups. Using FISH, disomy of sex chromosomes and chromosome 17, diploidy and estimated numerical chromosome aberration frequencies were significantly higher in the oligoasthenozoospermic group compared with the three other groups. A significant positive correlation was found between the sperm concentration and the HA-binding capacity, and significant negative correlations between the sperm concentration and the estimated numerical chromosomes aberrations as well as between the HA-binding ability and the estimated numerical chromosome aberrations were identified. We conclude that HA-binding assay and sperm aneuploidy study using FISH may help to predict the reproductive ability of selected infertile male patients and to provide appropriate genetic counselling.

The Potential Impact of Connexin 43 Expression on Bcl-2 Protein Level and Taxane Sensitivity in Head and Neck Cancers-In Vitro Studies.

The poor prognosis of head and neck squamous cell carcinoma (HNSCC) is partly due to the lack of reliable predictive markers. Connexin 43 (Cx43) protein and its cell-communication channels have been assigned tumor suppressor functions while the anti-apoptotic Bcl-2 (B-cell lymphoma-2) protein has been associated with negative prognostic significance in cancer. This study aimed to test the role of Cx43 protein on Bcl-2 expression, tumor progression and response to taxane-based treatment in HNSCC. Human papillomavirus (HPV) negative HNSCC cell lines were tested for paclitaxel sensitivity through measuring apoptosis induction, cell viability and changes in Cx43 and Bcl-2 levels using flow cytometry, cell viability assay, immunocytochemistry and western blot. Inhibition of Cx43 expression using siRNA increased Bcl-2 protein levels in SCC25 (tongue squamous cell carcinoma) cells, while forced Cx43 expression reduced Bcl-2 levels and supported paclitaxel cytotoxicity in FaDu (hypopharynx squamous cell carcinoma) cells. In vitro results were in line with protein expression and clinicopathological features tested in tissue microarray samples of HNSCC patients. Our data demonstrate that elevated Cx43 and reduced Bcl-2 levels may indicate HNSCC sensitivity to taxane-based treatments. On the contrary, silencing of the Cx43 gene GJA1 (gap junction protein alpha-1) can result in increased Bcl-2 expression and reduced paclitaxel efficiency. Clinical tumor-based analysis also confirmed the inverse correlation between Cx43 and Bcl-2 expression.

[Ostiolitholapaxy]. / Ostiolitholapaxia.

The authors developed a new, minimally invasive technique for the removal of impacted iuxtavesical ureteral stones, using nephroscope and a grasping forceps. They named this technique ostiolitholapaxy. The authors present their detailed technique and results. Between 1. 1. 1995 and 31. 12. 2006 48 operations were performed. In 41 cases the stones were removed successfully. In seven unsuccessful cases the stones were extracted by ureteroscopy. The authors worked up 41 successful cases presenting the steps and technical details of the procedure. Average stone size was 5,2 (3-12) mm. Male and female ratio was 23/18. In 19 patients local and in 22 patients spinal anaesthesia was performed. Among the patients who underwent local anaesthesia there were 13 (68,4%) female and 6 (31,6%) male patients. Average operating time was 8,5 (3,5-35) minutes. Mean follow-up time was 95,3 (2-143) months. The success rate of the procedure was 85,41%. There were no intraoperative complications. In the mentioned period no ureteral stricture and/or reflux-uropathy has developed. Due to the simplicity, efficacy of this technique and the fact that it can be performed even in local anaesthesia, this procedure can be useful in case of small symptomatic iuxtavesical stones as a quick and safe stone removal intervention.

In Vitro Imaging and Quantification of the Drug Targeting Efficiency of Fluorescently Labeled GnRH Analogues.

GnRH analogues are effective targeting moieties and able to deliver anticancer agents selectively into malignant tumor cells which highly express GnRH receptors. However, the quantitative analysis of GnRH analogues' cellular uptake and the investigated cell types in GnRH-based drug delivery systems are currently limited. Previously introduced, selectively labeled fluorescent GnRH I, -II and -III derivatives provide great detectability, and they have suitable chemical properties for reproducible and robust experiments. We also found that the appropriate up-to-date methods with these labeled GnRH analogues could offer novel information about the GnRH-based drug delivery systems. This manuscript introduces some simple and fast experiments regarding the cellular uptake of [D-Lys6(FITC)]-GnRH-I, [D-Lys6(FITC)]-GnRH-II and [Lys8(FITC)]-GnRH-III on the EBC-1 (lung), the BxPC-3 (pancreas) and on the Detroit-562- (pharynx) malignant tumor cells. In parallel with these GnRH-FITC conjugates, the cell surface level of GnRH-I receptors was also examined on these cell lines before and after the GnRH treatment by confocal laser scanning microscopy. The cellular uptake of GnRH-FITC conjugates was quantified by fluorescence-activated cell sorting. In these experiments minor differences among GnRH analogues and major differences among cell types was observed. The significant differences among cell lines are correlated with their distinct level of cell surface GnRH-I receptors. The introduced experiments contain practical methods to visualize, quantify and compare the uptake efficiency of GnRH-FITC conjugates in a time- and concentration-dependent manner on various adherent cell cultures. These results could predict the drug targeting efficiency of GnRH conjugates on the given cell culture, and offer a good basis for further experiments in the examination of GnRH-based drug delivery systems.

Molecular subtype specific efficacy of MEK inhibitors in pancreatic cancers.

Pancreatic cancer is an increasing cause of cancer related death worldwide. KRAS is the dominant oncogene in this cancer type and molecular rationale would indicate, that inhibitors of the downstream target MEK could be appropriate targeted agents, but clinical trials have failed so far to achieve statistically significant benefit in unselected patients. We aimed to identify predictive molecular biomarkers that can help to define subgroups where MEK inhibitors might be beneficial alone or in combination. Next-generation sequencing data of 50 genes in three pancreatic cancer cell lines (MiaPaCa2, BxPC3 and Panc1) were analyzed and compared to the molecular profile of 138 clinical pancreatic cancer samples to identify the molecular subtypes of pancreatic cancer these cell lines represent. Luminescent cell viability assay was used to determine the sensitivity of cell lines to kinase inhibitors. Western blot was used to analyze the pathway activity of the examined cell lines. According to our cell viability and pathway activity data on these model cell lines only cells harboring the rare G12C KRAS mutation and low EGFR expression are sensitive to single MEK inhibitor (trametinib) treatment. The common G12D KRAS mutation leads to elevated baseline Akt activity, thus treatment with single MEK inhibitors fails. However, combination of MEK and Akt inhibitors are synergistic in this case. In case of wild-type KRAS and high EGFR expression MEK inhibitor induced Akt phosphorylation leads to trametinib resistance which necessitates for MEK and EGFR or Akt inhibitor combination treatment. In all we provide strong preclinical rational and possible molecular mechanism to revisit MEK inhibitor therapy in pancreatic cancer in both monotherapy and combination, based on molecular profile analysis of pancreatic cancer samples and cell lines. According to our most remarkable finding, a small subgroup of patients with G12C KRAS mutation may still benefit from MEK inhibitor monotherapy.

Single-session laparoscopic radical and contralateral partial nephrectomy.

Renal tumor is likely to become one of the most important indications for laparoscopic surgery. We present an old woman, who underwent single-session laparoscopic nephrectomy and contralateral partial nephrectomy due to bilateral kidney tumor. The advantages of simultaneous bilateral intervention are reduced psychological stress, single anaesthesia, less medication, less blood loss, shorter hospital stay and convalescence, and considerable cost-effectiveness.

Percutaneous nephrolithotomy in early pregnancy.

We report on an 11-weeks pregnant woman, who under went a percutaneous nephrolithotomy without the use of X-rays during the procedure due to 8-mm left upper ureteric stone. In the available literature, we didn't find any reported case about percutaneous stone removal without the use of X-rays.

Geographies of an Online Social Network.

How is online social media activity structured in the geographical space? Recent studies have shown that in spite of earlier visions about the "death of distance", physical proximity is still a major factor in social tie formation and maintenance in virtual social networks. Yet, it is unclear, what are the characteristics of the distance dependence in online social networks. In order to explore this issue the complete network of the former major Hungarian online social network is analyzed. We find that the distance dependence is weaker for the online social network ties than what was found earlier for phone communication networks. For a further analysis we introduced a coarser granularity: We identified the settlements with the nodes of a network and assigned two kinds of weights to the links between them. When the weights are proportional to the number of contacts we observed weakly formed, but spatially based modules resemble to the borders of macro-regions, the highest level of regional administration in the country. If the weights are defined relative to an uncorrelated null model, the next level of administrative regions, counties are reflected.