A simplified cluster model and a tool adapted for collaborative labeling of lung cancer CT scans.

BACKGROUND AND OBJECTIVE: Lung cancer is the most common type of cancer with a high mortality rate. Early detection using medical imaging is critically important for the long-term survival of the patients. Computer-aided diagnosis (CAD) tools can potentially reduce the number of incorrect interpretations of medical image data by radiologists. Datasets with adequate sample size, annotation, and truth are the dominant factors in developing and training effective CAD algorithms. The objective of this study was to produce a practical approach and a tool for the creation of medical image datasets. METHODS: The proposed model uses the modified maximum transverse diameter approach to mark a putative lung nodule. The modification involves the possibility to use a set of overlapping spheres of appropriate size to approximate the shape of the nodule. The algorithm embedded in the model also groups the marks made by different readers for the same lesion. We used the data of 536 randomly selected patients of Moscow outpatient clinics to create a dataset of standard-dose chest computed tomography (CT) scans utilizing the double-reading approach with arbitration. Six volunteer radiologists independently produced a report for each scan using the proposed model with the main focus on the detection of lesions with sizes ranging from 3 to 30 mm. After this, an arbitrator reviewed their marks and annotations. RESULTS: The maximum transverse diameter approach outperformed the alternative methods (3D box, ellipsoid, and complete outline construction) in a study of 10,000 computer-generated tumor models of different shapes in terms of accuracy and speed of nodule shape approximation. The markup and annotation of the CTLungCa-500 dataset revealed 72 studies containing no lung nodules. The remaining 464 CT scans contained 3151 lesions marked by at least one radiologist: 56%, 14%, and 29% of the lesions were malignant, benign, and non-nodular, respectively. 2887 lesions have the target size of 3-30 mm. Only 70 nodules were uniformly identified by all the six readers. An increase in the number of independent readers providing CT scans interpretations led to an accuracy increase associated with a decrease in agreement. The dataset markup process took three working weeks. CONCLUSIONS: The developed cluster model simplifies the collaborative and crowdsourced creation of image repositories and makes it time-efficient. Our proof-of-concept dataset provides a valuable source of annotated medical imaging data for training CAD algorithms aimed at early detection of lung nodules. The tool and the dataset are publicly available at https://github.com/Center-of-Diagnostics-and-Telemedicine/FAnTom.git and https://mosmed.ai/en/datasets/ct_lungcancer_500/, respectively.

[Far remote results of radical prostatectomy in patients suffering localized and locally advanced prostatic cancer].

Basing on analysis of results, obtained after conduction of radical prostatectomy for prostatic cancer (PC), there was stated, that an overall survival indices in terms of follow-up 3, 5 and 7 yrs have constituted (95.5 +/- 3.5), (84.1 +/- 4.7) and (71.7 +/- 6.8)%; and for the disease-free survival in the same terms--(87.05 +/- 3.20), (79.64 +/- 3.62) and (67.11 +/- 3.93)%; for the survival in terms up to 5 yrs in a localized PC--(97.18 +/- 3.27)%. In 48 (28.2%) patients a biochemical recurrence was revealed, for which the adjuvant therapy was administered. Statistically significant factors, permitting to prognosticate in patients, suffering PC stages T>T2 and biochemical recurrence, are the indices 7 points and more (in accordance to Glison scale), and initial level of a prostate speciphic antigen (PSA) 20 ng/ml and more, as well as their coincidence. Trustworthy increase of the disease recurrences rate was noted, when postoperatively a perineural invasion, positive tumoral margin and a lymph node affection were revealed. Presence of biochemical recurrence, positive surgical margin, perineural invasion and metastasis were associated with the enhanced risk of lethal outcome for the patients. Conduction of neoadjuvant hormonal therapy do not prevent a biochemical recurrence occurrence after conduction of radical prostatectomy. The tumoral process postoperative upstaging witnesses the necessity of the patients selection, owing unfavorable prognosis for administration of adjuvant hormonotherapy and radiation therapy, what impacts essentially positively a late results of surgical treatment. Application of a differentiated approach for the PC treatment permits to achieve high indices of survival in terms up to 5 yrs--(84.1 +/- 4.7)%.

[Effect of histone deacetylases inhibitor sodium butyrate (NaB) on transformants E1A + cHa-Ras expressing wild type p53 with supressed transactivation function].

Induction of cellular senescence by various antitumour agents is a promising strategy of cancer treatment. We assessed the ability of sodium butyrate (NaB), a histone deacetylase inhibitor (HDACi), to reactivate the cellular senescence program in either E1A + cHa-Ras-transformed rat embryo fibroblasts with wild-type p53 (ERas(WT)) and in the isogenic cell line where p53 was inactivated due to expression of the potent genetic suppressor element GSE56 (ERas(GSE56)). NaB treatment increased p53 transcriptional activity and induced an irreversible G1/S cell cycle arrest in ERas(WT), but not in ERas(GSE56) cells. By the transient transfections method using reporter luciferase (p53-LUC) constructions, it was shown that p53-LUC activity as a marker of p53 transactivation function did not increase after X-rays exposure of transformants ERas(GSE56). p53 activity in transformants ERas(WT) increased both after irradiation or upon NaB treatment. Interestingly, the expression of senescence-associated beta-galactosidase (SA-beta-Gal), widely used as a marker of senescence, as well as loss of clonogenic ability, were observed in both cell lines following NaB treatment. Thus, our results suggest that induction of p53 transcription activity could be the key determinant of HDACi-induced cell cycle arrest and senescence in transformed cells and provide an additional evidence of SA-beta-Gal invalidity as a sufficient senescence marker.

Human papillomavirus infection in women with and without cervical cancer in Warsaw, Poland.

Cervical cancer incidence and mortality in Poland is among the highest in Europe. To investigate infection with different human papillomaviruses (HPV) in Warsaw, Poland, we obtained cervical cell specimens from 834 women aged 18-59 years from the general population, and 88 cervical cancers. DNA of 44 HPV types was detected using a GP5+/6+-based PCR assay. HPV prevalence was 16.6% in the general female population, being highest (24.2%) in women aged 25-34 years, notably among unmarried women (37.3%). HPV prevalence fell to 8.6% at ages 55-59. High-risk HPV prevalence was 11.3%, with HPV16 being the most common type (3.7%). All but one cervical cancer were high-risk HPV-positive, although the importance of HPV16 (73%) was much greater, and multiple infections fewer (1%), than among HPV-positive women in the general female population. In summary, we report a relatively high burden of HPV infection in Warsaw, Poland, where 79% of cervical cancers are theoretically preventable by HPV16/18 vaccines.

Chordin is underexpressed in ovarian tumors and reduces tumor cell motility.

Ovarian cancers mostly derive from the monolayer epithelium that covers the ovary. There are currently very few molecular clues to the etiology of this cancer. Bone morphogenetic proteins (BMPs) are required for follicular development and female fertility and are expressed in the ovarian surface epithelium (OSE). We previously reported the expression of human chordin (CHRD), a BMP extracellular regulator, in the ovary. Here we show that CHRD is underexpressed in epithelium ovary cancer and epithelial cancer cell lines as compared with normal tissues and OSE, respectively. Besides, we detected BMP expression in all ovarian cell lines analyzed. To determine the functional relevance of the absence of CHRD mRNA in tumors and cancer cell lines, we studied the effects of CHRD on two cancer cell lines, BG1 and PEO14. Migratory and invasive properties were greatly reduced, whereas cell adhesion to the support was enhanced. In addition, we detected chordin (Chrd) expression in OSE of rat ovaries in a pattern similar to that of BMP4. Altogether, these results suggest that CHRD could participate in regulating BMP activity in normal OSE physiology, and that its mis-expression in OSE may facilitate cancer incidence and/or progression.

Transcriptional and posttranscriptional regulation of fibulin-1 by estrogens leads to differential induction of messenger ribonucleic acid variants in ovarian and breast cancer cells.

Fibulin-1 is an extracellular matrix protein overexpressed in epithelial ovarian and breast cancers. In estrogen receptor (ER)-positive ovarian and breast cancer cell lines, fibulin-1 mRNA levels are markedly increased by estrogens. Transfection experiments using fibulin-1 promoter constructs indicate that 17beta-estradiol (E2) increases fibulin-1 gene transcription and that ERalpha is more potent than ERbeta to mediate E2 regulation of the transfected fibulin-1 promoter. Using SL2 cells devoid of specificity protein 1 (Sp1) and site-directed mutagenesis of GC boxes, we evidenced that the E2 regulation occurs through a proximal specificity protein 1 binding site. In addition, we show that fibulin-1C and -1D mRNAs, the two major fibulin-1 splicing variants, are differentially induced by E2. The induction of both mRNAs variants is direct and independent of a newly synthesized protein intermediate. Interestingly, actinomycin D chase experiments demonstrate that E2 treatment selectively shortens the fibulin-1D mRNA half-life. This indicates that estrogens affect differentially the stability of fibulin-1 variants and may explain the lower accumulation of fibulin-1D mRNA on E2 treatment. In conclusion, our data show that estrogens, via ERalpha, are key regulators of fibulin-1 expression at both the transcriptional and posttranscriptional levels. The preferential induction of the fibulin-1C variant, which is overexpressed in ovarian and breast cancer, might play an important role in estrogen-promoted carcinogenesis.

Loss of ERbeta expression as a common step in estrogen-dependent tumor progression.

The characterization of estrogen receptor beta (ERbeta) brought new insight into the mechanisms underlying estrogen signaling. Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues, and the mitogenic effects of estrogen in these tissues (such as breast, endometrium and ovary) are well documented both in vitro and in vivo. There is also an emerging body of evidence that colon and prostate cancer growth is influenced by estrogens. In all of these tissues, most studies have shown decreased ERbeta expression in cancer as compared with benign tumors or normal tissues, whereas ERalpha expression persists. The loss of ERbeta expression in cancer cells could reflect tumor cell dedifferentiation but may also represent a critical stage in estrogen-dependent tumor progression. Modulation of the expression of ERalpha target genes by ERbeta or ERbeta-specific gene induction could explain that ERbeta has a differential effect on proliferation as compared with ERalpha. ERbeta may exert a protective effect and thus constitute a new target for hormone therapy, such as ligand specific activation. The potential distinct roles of ERalpha and ERbeta expression in carcinogenesis, as suggested by experimental and clinical data, are discussed in this review.

Men and sin: what's the difference?

A conserved signalling cascade--termed the mitotic-exit network in budding yeast and the septation-initiation network in fission yeast--controls key events during exit from mitosis and cytokinesis. Although the components of these signalling networks are highly conserved between the two yeasts, the outputs seem quite different. How, then, do these two pathways function, and how are they regulated?

[H2O2-induced activation of transcription factors STAT1 and STAT3: the role of EGF receptor and tyrosine kinase JAK2]. / H2O2-indutsiruemaia aktivatsiia transkriptsionnykh faktorov STAT1 i STAT3: rol' retseptora EGF i tirozinkinazy JAK2.

Reactive oxygen species initiate multiple signal transduction pathways including tyrosine kinase signaling. Here, we demonstrate tyrosine phosphorylation of EGF receptor, STAT3, and, to a lesser extent, STAT1 upon H2O2 treatment of HER14 cells (NIH3T3 fibroblasts transfected with full-length EGF receptor). Maximum phosphorylation levels were observed in 5 min of stimulation at 1-2 mM H2O2. It has been shown that the intrinsic EGF-receptor tyrosine kinase is responsible for the receptor phosphorylation upon H2O2 stimulation. STAT3 and STAT1 activation in HER14 cells was demonstrated to depend on EGF receptor kinase activity, rather than JAK2 activity, while in both K721A and CD126 cells (NIH3T3 transfected with kinase-dead EGF receptor, and EGF receptor lacking major autophosphorylation sites, respectively) STAT1 and STAT3 tyrosine phosphorylation requires JAK2 kinase activity. Furthermore, STAT3 is constitutively phosphorylated in K721A and CD126 cells, and STAT1 H2O2-stimulated activation in these cells is much more prominent than in HER14. In all the cell lines used, Src-kinase activity was demonstrated to be unnecessary for ROS-initiated phosphorylation of STATs. Herein, we postulate that EGF receptor plays a role in H2O2-induced STAT activation in HER14 cells. Our data also prompted a hypothesis of constitutive inhibition of JAK2-dependent STAT activation in this cell line.

A mechanism for coupling exit from mitosis to partitioning of the nucleus.

Exit from mitosis must not occur prior to partitioning of chromosomes between daughter cells. We find that the GTP binding protein Tem1, a regulator of mitotic exit, is present on the spindle pole body that migrates into the bud during S phase and mitosis. Tem1's exchange factor, Lte1, localizes to the bud. Thus, Tem1 and Lte1 are present in the same cellular compartment (the bud) only after the nucleus enters the bud during nuclear division. We also find that the presence of Tem1 and Lte1 in the bud is required for mitotic exit. Our results suggest that the spatial segregation of Tem1 and Lte1 ensures that exit from mitosis only occurs after the genetic material is partitioned between mother and daughter cell.

[Study of atherogenic, coagulant and cardio-cerebral risk factors in the pathogenesis of minor strokes in arterial hypertension]. / K izucheniiu aterogennykh, koaguliantnykh i kardiotserebral'nykh faktorov riska v patogeneze malykh insul'tov pri arterial'noi gipertonii.

The paper is concerned with the results of studying risk factors correlations in patients who suffered minor brain stroke (MBS) associated with different forms of arterial hypertension (AH). As regards their importance in the pathogenesis of MBS, risk factors may be distributed into the two categories: atherogenic, coagulant and vascular alterations and ++cardio-cerebral ones characterizing the status of heart pump function. The atherogenic and coagulant risk factors (perivascular and intravascular lesions, agglutination of the capillaries by formed elements of the blood, aggregation of red blood cells, a high level of TH and beta-lipoproteins, fibrinogen and prothrombin) are significantly marked more widely and intensely among persons suffering from stable AH, with a history of MBS. Risk factors characterizing a decrease of heart pump function (myocardial contractility, ejection fractions) were demonstrable without significant differences among persons who suffered MBS associated with stable and labile AH. As to further studies, of the main interest is the pathogenesis of MBS in persons suffering from mild, episodic AH, since the data obtained may cast doubt on the thrombocoagulant mechanism thereof.

[Interrelations between personality characteristics and the autonomic pattern in mild strokes developed in various forms of arterial hypertension]. / K voprosu o vzaimosviazi kharakterologicheskikh osobennostei lichnosti i vegetativnogo patterna pri malykh insul'takh voznik- shikh na fone razlichnykh form arterial'noi gipertenzii.

The data on the characterological personality traits and the vegetative pattern in persons with cerebrovascular pathology (minor brain stroke-MBS) associated with different forms of arterial hypertension (AH) (stable, malignant, labile) make it possible to delineate two psychovegetative personality types. The first one is the hysterical one with an initial sympathetic tone and excess vegetative supply, the second one is the ++anxio-hypochondriac or depressive (more rarely) with an initial parasympathetic or combined vegetative tone with an insufficient level of vegetative supply, and vegetative reactivity. The labile (mild, episodic) forms of AH aggravated by cerebrovascular pathology (MBS) are likely to be the constituent part of the psychovegetative syndrome (the first psychovegetative personality type). The stable forms of AH (including malignant ones) aggravated by episodes of vascular dyscirculatory disorders (MBS) are similar to the second psychovegetative personality type as regards their characterological and vegetative traits. The data obtained can be used not only in subsequent studies of the etiopathogenesis of MBS associated with different forms of AH but also in terms of practical and preventive aspects.

Further characterization of protein secondary structures in purple membrane by circular dichroism and polarized infrared spectroscopies.

The conformation and the orientation of the protein secondary structures in purple membrane was analyzed by infrared absorption and linear dichroism of oriented membranes as well as by UV circular dichroism of bacteriorhodopsin in intact purple membrane and in lipid vesicles. A large amount (74 +/- 5%) of transmembrane alpha-helices is detected with no significant contribution of beta-sheet strands running perpendicular to the membrane plane. Thus, these data do not support the recent structural model proposed by Jap et al. (Biophys. J. 1983, 43:81-89).