Clinical Significance of 3D Ultrasound Compared to MRI in Uterine Malformations

Purpose: Congenital uterine anomalies often remain asymptomatic until they cause problems, for example during pregnancy. We studied the diagnostic aspects of two- and three-dimensional ultrasound and MRI. Materials and Methods: 63 women referred for suspected uterine anomalies were studied: In the first group (until July 2008) with 2 D-US and MRI, in the second group (from August 2008) additionally with 3 D-US; these women also had diagnostic or therapeutic operative confirmation. In the third group, only 3D-US was used. Results: In all women 3D-US was possible and successful. The most common anomaly was a subseptate uterus, while a septate uterus was less frequent, and uterus bicornis (unicollis) and uterus didelphys (bicornis bicollis) were rare. The women in the first two groups all underwent at least diagnostic hysteroscopy, and some (subseptate or septate uterus) underwent operative hysteroscopy. After preoperative volume imaging, laparoscopies were required less often. 3D-US diagnoses as judged by intraoperative findings were correct in 100 % of cases, while the MRI diagnoses in the same group were correct in only 7/13 cases. Conclusion: Since the introduction of volume imaging (MRI, later 3 D-US), laparoscopy during hysteroscopic septum resection was not necessary in the majority of cases. 3D-US brings the diagnostics of uterine anomalies back into the hands of the gynecologist and can provide the gynecological surgeon with a higher subjective degree of certainty during operative hysteroscopy.

Prevalence and Clinical Significance of DSM-5-Attenuated Psychosis Syndrome in Adolescents and Young Adults in the General Population: The Bern Epidemiological At-Risk (BEAR) Study

Objective: Section III of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) lists attenuated psychosis syndrome as a condition for further study. One important question is its prevalence and clinical significance in the general population. Method: Analyses involved 1229 participants (age 16-40 years) from the general population of Canton Bern, Switzerland, enrolled from June 2011 to July 2012. "Symptom," "onset/worsening," "frequency," and "distress/disability" criteria of attenuated psychosis syndrome were assessed using the structured interview for psychosis-risk syndromes. Furthermore, help-seeking, psychosocial functioning, and current nonpsychotic axis I disorders were surveyed. Well-trained psychologists performed assessments using the computer-assisted telephone interviewing technique. Results: The symptom criterion was met by 12.9% of participants, onset/worsening by 1.1%, frequency by 3.8%, and distress/disability by 7.0%. Symptom, frequency, and distress/disability were met by 3.2%. Excluding trait-like attenuated psychotic symptoms (APS) decreased the prevalence to 2.6%, while adding onset/worsening reduced it to 0.3%. APS were associated with functional impairments, current mental disorders, and help-seeking although they were not a reason for help-seeking. These associations were weaker for attenuated psychosis syndrome. Conclusions: At the population level, only 0.3% met current attenuated psychosis syndrome criteria. Particularly, the onset/worsening criterion, originally included to increase the likelihood of progression to psychosis, lowered its prevalence. Because progression is not required for a self-contained syndrome, a revision of the restrictive onset criterion is proposed to avoid the exclusion of 2.3% of persons who experience and are distressed by APS from mental health care. Secondary analyses suggest that a revised syndrome would also possess higher clinical significance than the current syndrome.

Significance of Increased Tissue Transglutaminase in Hormone Refractory Prostate Cancer

The progression of hormone responsive to hormone refractory prostate cancer poses a major clinical challenge in the successful treatment of prostate cancer. The hormone refractory prostate cancer cells exhibit resistance not only to castrate levels of testosterone, but also to other therapeutic modalities and hence become lethal. Currently, there is no effective treatment available for managing this cancer. These observations underscore the urgency to investigate mechanism(s) that contribute to the progression of hormone-responsive to hormone-refractory prostate cancer and to target them for improved clinical outcomes. Tissue transglutaminase (TG2) is a multifunctional pro-inflammatory protein involved in diverse physiological processes such as inflammation, tissue repair, and wound healing. Its expression is also implicated in pathological conditions such as cancer and fibrosis. Interestingly, we found that the androgen-independent prostate cancer cell lines, which lacked androgen receptor (AR) expression, contained high basal levels of tissue transglutaminase. Inversely, the cell lines that expressed androgen receptor lacked transglutaminase expression. This attracted our attention to investigate the possible role this protein may play in the progression of prostate cancer, especially in view of recent observations that its expression is linked with increased invasion, metastasis, and drug resistance in multiple cancer cell types. The results we obtained were rather surprising and revealed that stable expression of tissue transglutaminase in androgen-sensitive LNCaP prostate cancer cells rendered these cells independent of androgen for growth and survival by silencing the AR expression. The AR silencing in TG2 expressing cells (TG2-infected LNCaP and PC-3 cells) was due to TG2-induced activation of the inflammatory nuclear transcription factor-kB (NF-kB). Thus, TG2 induced NF-kB was found to directly bind to the AR promoter. Importantly, TG2 protein was specifically recruited to the AR promoter in complex with the p65 subunit of NF-kB. Moreover, TG2 expressing LNCaP and PC-3 cells exhibited epithelial-to-mesenchymal transition, as evidenced by gain of mesenchymal (such as fibronectin, vimentin, etc.) and loss of epithelial markers (such as E-cadherin, b-catenin). Taken together, these results suggested a new function for TG2 and revealed a novel mechanism that is responsible for the progression of prostate cancer to the aggressive hormone-refractory phenotype.

Prognostic significance of xCT polymorphisms and expression in patients with advanced pancreatic cancer treated with chemotherapy

The plasma membrane xc- cystine/glutamate transporter mediates cellular uptake of cystine in exchange for intracellular glutamate and is highly expressed by pancreatic cancer cells. The xCT gene, encoding the cystine-specific xCT protein subunit of xc-, is important in regulating intracellular glutathione (GSH) levels, critical for cancer cell protection against oxidative stress, tumor growth and resistance to chemotherapeutic agents including platinum. We examined 4 single nucleotide polymorphisms (SNPs) of the xCT gene in 269 advanced pancreatic cancer patients who received first line gemcitabine with or without cisplatin or oxaliplatin. Genotyping was performed using Taqman real-time PCR assays. A statistically significant correlation was noted between the 3' untranslated region (UTR) xCT SNP rs7674870 and overall survival (OS): Median survival time (MST) was 10.9 and 13.6 months, respectively, for the TT and TC/CC genotypes (p = 0.027). Stratified analysis showed the genotype effect was significant in patients receiving gemcitabine in combination with platinum therapy (n = 145): MST was 10.5 versus 14.1 months for the TT and TC/CC genotypes, respectively (p = 0.013). The 3' UTR xCT SNP rs7674870 may correlate with OS in pancreatic cancer patients receiving gemcitabine and platinum combination therapy. Paraffin-embedded core and surgical biopsy tumor specimens from 98 patients with metastatic pancreatic adenocarcinoma were analyzed by immunohistochemistry using an xCT specific antibody. xCT protein IHC expression scores were analyzed in relation to overall survival in 86 patients and genotype in 12 patients and no statistically significant association was found between the level of xCT IHC expression score and overall survival (p = 0.514). When xCT expression was analyzed in terms of treatment response, no statistically significant associations could be determined (p = 0.908). These data suggest that polymorphic variants of xCT may have predictive value, and that the xc- transporter may represent an important target for therapy in pancreatic cancer.

Maintenance of phosphatidylserine asymmetry in erythroid cells during differentiation, aging, and its significance for macrophage recognition

Phosphatidylserine (PS) is distributed almost entirely in the inner leaflet of the erythrocyte membrane bilayer, and appears to be maintained by a 32 kDa integral membrane protein (PS translocase). The expression of PS on the outer leaflet may serve as a recognition signal for macrophages, since insertion of PS into erythrocytes enhances their adherence to macrophages and clearance from the circulation. Therefore I have hypothesized that erythroid cells display PS on their outer leaflet early in differentiation and upon aging. Analysis of murine erythroleukemia cells (MELC, undifferentiated erythroid progenitor cells) showed high levels of PS on the outer leaflet that decreased during differentiation, correlating with the pattern of macrophage adherence. The activity of the PS translocase during differentiation appears to be unchanged although the equilibrium distribution of PS differs. This difference may be due to qualitative changes in the PS translocase. $\sp{125}$I-Bolton/Hunter-labeled-pyridyldithioethylamine ($\sp{125}$I-B/H-PDA), a radiolabeled probe for the PS translocase, labeled a 32 kDa protein in mature erythrocytes whereas in MELC a 45 kDa protein as well as a 32 kDa protein was identified. The abundance of the 45 kDa protein in relation to the 32 kDa protein declined during differentiation, possibly indicating this protein was a precursor of the 32 kDa protein. Analysis of the 45 kDa protein by N-glycosidase F and endoproteinase cleavage suggested this protein was not a glycosylated form of the 32 kDa protein but appeared to share some structural homology. Aged murine erythrocytes had elevated levels of PS on their outer leaflet, as well as decreased PS translocase activity. $\sp{125}$I-B/H-PDA labeled a 32 kDa protein in both normal and aged erythrocytes. However, the latter cells also contained a 28 kDa protein. Experimental evidence suggests that the appearance of the 28 kDa protein may be due to increased oxidation of aged erythrocytes. Examination of PS distribution showed that the levels of PS on the outer leaflet were elevated early in differentiation, decreased during the mature state, and returned to high levels as the erythrocyte aged. In conclusion,the levels of outer leaflet PS correlated with the differentiation status and macrophage recognition of erythroid cells. ^

c-{\it mos\/} RNA expression in somatic cells and its physiological significance in cell cycle progression

The c-mos proto-oncogene, which is expressed at relatively high levels in male and female germ cells, plays a key role in oocyte meiotic maturation. The c-mos gene product in oocytes (p39$\sp{\rm c-mos}$) is necessary and sufficient to initiate meiosis. p39$\sp{\rm c-mos}$ is also an essential component of the cytostatic factor, which is responsible for arresting vertebrate oocytes at the second meiotic metaphase by stabilizing the maturation promoting factor (MPF). MPF is a universal regulator of both meiosis and mitosis. Much less is understood about c-mos expression and function in somatic cells. In addition to gonadal tissues, c-Mos has been detected in some somatic tissues and non-germ cell lines including NIH 3T3 cells as a protein termed p43$\sp{\rm c-mos}$. Since c-mos RNA transcripts were not previously detected in this cell line by Northern blot or S1 protection analyses, a search was made for c-mos RNA in NIH 3T3 cells. c-mos transcripts were detected using the highly sensitive RNA-PCR method and RNase protection assays. Furthermore, cell cycle analyses indicated that expression of c-mos RNA is tightly controlled in a cell cycle dependent manner with highest levels of transcripts (approximately 5 copies/cell) during the G2 phase.^ In order to determine the physiological significance of c-mos RNA expression in somatic cells, antisense mos was placed under the control of an inducible promoter and introduced into either NIH 3T3 cells or C2 cells. It was found that a basal level of expression of antisense mos resulted in interference with mitotic progression and growth arrest. Several nuclear abnormalities were observed, especially the appearance of binucleated and multinucleated cells as well as the extrusion of microvesicles containing cellular material. These results indicate that antisense mos expression results in a block in cytokinesis. In summary, these results establish that c-mos expression is not restricted to germ cells, but instead indicate that c-mos RNA expression occurs during the G2 stage of the cell cycle. Furthermore, these studies demonstrate that the c-mos proto-oncogene plays an important role in cell cycle progression. As in meiosis, c-mos may have a similar but not identical function in regulating cell cycle events in somatic cells, particularly in controlling mitotic progression via activation/stabilization of MPF. ^

The prognostic significance of sialyl-Tn antigen in women treated with adjuvant chemotherapy for breast cancer

Background and purpose. Sialyl-Tn(STn) represents an aberrantly glycosylated mucin epitope which is expressed in breast cancer and other adenocarcinomas and is an important target for the development of novel immunotherapeutic approaches. It is a marker of adverse prognosis in colon and ovarian cancer, but information about its prognostic impact in breast cancer is limited. The primary aim of the present study was to investigate the influence of STn expression on outcome of invasive breast cancer in 207 women who received anthracyline-containing adjuvant chemotherapy in a prospective clinical trial.^ Methods. Expression of STn was determined by an immunohistochemical procedure using the B72.3 monoclonal antibody. The extent of staining was determined by two observers using a 0 through 4 point scale, with 0 representing $<$5% of cells staining; 1: 5-25%; 2: 26-50%; 3: 51-75%; and 4: $>$75%. Intraobserver and interobserver agreement was.78-.92 (kappa). Kaplan-Meier and Cox proportional regression survival analyses were used to compare STn-negative and STn-positive patients.^ Results. Forty-eight (23%) of the 207 specimens demonstrated positive staining of STn. With a median follow-up of five years, STn-positivity was associated with a higher 5-year recurrence-free survival time than STn-negativity (67% vs. 80%, respectively; p = 0.03). STn expression was significantly associated with menopausal status (p = 0.04) but not other conventional prognostic markers. The risk of breast cancer recurrence and death was assessed by multivariate Cox regression analyses with adjustment for lymph node status, tumor size, menopausal status, hormone receptor status, nuclear grade, S-phase fraction and ploidy. In the final multivariate model for recurrence-free survival, the three factors that showed prognostic significance were: lymph node status (hazard ratio (HR) 3.04, 95% confidence interval (CI) 1.08-8.49), STn expression (HR 2.02, 95% CI 1.09-3.73), and tumor size (HR 1.96, 95% CI 1.05-3.64). STn was also associated with worse overall survival (HR 2.16, 95% CI 0.95-4.92) in multivariate analysis.^ Conclusion. STn antigen was shown to be a predictor of poor outcome in breast cancer. This tumor-associated antigen may be a valuable marker for identifying individuals at high risk of developing recurrent disease who may benefit from adjuvant therapy targeted at STn following definitive local therapy. Further study is needed to clarify the biologic and prognostic role of STn in breast cancer. ^

Significance of telecoupling for exploration of land-use change

Land systems are increasingly influenced by distal connections: the externalities and unintended consequences of social and ecological processes which occur in distant locations, and the feedback mechanisms that lead to new institutional developments and governance arrangements. Economic globalization and urbanization accentuate these novel telecoupling relationships. The prevalence of telecoupling in land systems demands new approaches to research and analysis in land science. This chapter presents a working definition of a telecoupled system, emphasizing the role of governance and institutional change in telecoupled interactions. The social, institutional, and ecological processes and conditions through which telecoupling emerges are described. The analysis of these relationships in land science demands both integrative and diverse epistemological perspectives and methods. Such analyses require a focus on how the motivations and values of social actors relate to telecoupling processes, as well as on the mechanisms that produce unanticipated outcomes and feedback relationships among distal land systems.

Landscape Evolution of the Dry Valleys, Transantarctic Mountains: Tectonic Implications

There are different views about the amount and timing of surface uplift in the Transantarctic Mountains and the geophysical mechanisms involved. Our new interpretation of the landscape evolution and tectonic history of the Dry Valleys area of the Transantarctic Mountains is based on geomorphic mapping of an area of 10,000 km(2). The landforms are dated mainly by their association with volcanic ashes and glaciomarine deposits and this permits a reconstruction of the stages and timing of landscape evolution. Following a lowering of base level about 55 m.y. ago, there was a phase of rapid denudation associated with planation and escarpment retreat, probably under semiarid conditions. Eventually, downcutting by rivers, aided in places by glaciers, graded valleys to near present sea level. The main valleys were flooded by the sea in the Miocene during a phase of subsidence before experiencing a final stage of modest upwarping near the coast. There has been remarkably little landform change under the stable, cold, polar conditions of the last 15 m.y. It is difficult to explain the Sirius Group deposits, which occur at high elevations in the area, if they are Pliocene in age. Overall, denudation may have removed a wedge of rock with a thickness of over 4 km at the coast declining to 1 km at a point 75 km inland, which is in good agreement with the results of existing apatite fission track analyses. It is suggested that denudation reflects the differences in base level caused by high elevation at the time of extension due to underplating and the subsequent role of thermal uplift and flexural isostasy. Most crustal uplift (2-4 km) is inferred to have occurred in the early Cenozoic with 400 m of subsidence in the Miocene followed by 300 m of uplift in the Pliocene.

Significance of social cognitive remediation therapy within a comprehensive treatment concept

Objectives: The final goal in the successful treatment of schizophrenia patients is defined in improved functional recovery. Thus the integration of social cognitive tasks within a comprehensive treatment concept should offer significant advantages in generalization and transfer of therapy effects. Recent therapy outcome research supports these advantages. Empirical modeling identified social cognition as a mediating factor between neurocognition and functional recovery. Regarding this, we first developed the Integrated Psychological Therapy Program (IPT). It consists of 5 subprograms and combines interventions on neurocognition, social cognition, and social competence. As a further development of the cognitive part of IPT we developed the Integrated Neurocognitive Therapy (INT), which focuses on all social and neurocognitive domains defined by MATRICS. Methods: The aim was to investigate whether the application of the complete IPT is superior in comparison to the use of single IPT subprograms. Data were based on 37 independent IPT studies including a total sample of 1692 schizophrenia patients. Additionally, the proximal outcome in cognitive domains as well as in more distal outcome areas was investigated in an international RCT on INT including 169 schizophrenia outpatients. Results: All IPT subprogram variations obtained significant effects in proximal outcome. Each subprogram domain reached the largest effects in the targeted area. With regard to distal outcomes, combinations of subprograms showed a significant reduction of negative symptoms and an improvement in not targeted areas of functioning. This strongly supports vertical generalization effects to other functional domains. Regarding INT, results support efficacy compared to TAU in various cognitive domains, in psychosocial functioning and symptoms after therapy and at 1-year-follow-up. Conclusion: Results support evidence for the efficacy of longer lasting integrated therapy. The success of these treatment concepts is strongly based on successful therapy of social cognitive functions.