[Acute abdomen-Rare cause in an 80-year-old female patient under immunosuppressive treatment]. / Akutes Abdomen ­ seltene Ursache bei einer 80-jährigen Patientin unter immunsuppressiver Therapie.

An 80-year-old woman presented to the emergency department due to abdominal pain. She had a history of opportunistic pneumonia under the effects of immunosuppression after the diagnosis of autoimmune hepatitis. The imaging showed an omental cake formation and the suspicion of peritoneal carcinomatosis. The patient developed an acute abdomen during the hospital stay, followed by exploratory laparotomy. In the presence of extensive intra-abdominal abscess formation both surgically acquired material and blood culture revealed disseminated nocardiosis. The course was fatal due to fulminant septic shock.

Sterically encumbered ß-diketonates and base metal catalysis.

Metal coordination complexes of the sterically hindered ß-diketonate, 2,6-dimesitylbenzoyl pinacolone (esac), are reported for Co, Ni, Cu, and Zn. All four form ML2-type complexes with typical coordination behavior for late-metal ß-diketonates, however the effects on established electrochemistry and reactivity vary somewhat per metal. For example, the striking chemical and electrochemical inertness of CoII(esac)2 to oxidation and disproportionation is atypical. Conversely, the behavior of CuII(esac)2 is rather typical relative to other CuII(ß-diketonate)2 complexes. These data suggest a relative disfavoring of certain reaction pathways, and represent an important step in modulating the catalysis of the base metals via sterically hindered ß-diketonates.

Synthesis of Sterically Hindered ß-Diketones via Condensation of Acid Chlorides with Enolates.

Bulky ß-diketones have rarely exceeded dipivaloylmethane (DPM) in steric demand, largely due to synthetic limitations of the Claisen condensation. This work demonstrates hindered acid chlorides to be selective electrophiles in noncoordinating solvents for condensations with enolates. An improved synthesis of DPM is described (90% yield), and crowded ß-diketones featuring bulky o-biphenyl or m-terphenyl fragments were prepared in good to excellent yields. These compounds are anticipated to have a steric profile far greater than that of DPM. General reaction conditions and mechanistic considerations are included.

Seropositivity for the human heat shock protein (Hsp)60 accompanying seropositivity for Chlamydia trachomatis is less prevalent among tubal ectopic pregnancy cases than individuals with normal reproductive history.

OBJECTIVES: To investigate the role of anti-human heat shock protein 60 (hHsp60) antibody positivity in the pathogenesis of ectopic pregnancy, following Chlamydia trachomatis (CT) infection. STUDY DESIGN: In a case-control study, serological tests for anti-hHsp60 were performed in ectopic pregnancies (study group) and parturients with normal reproductive histories (control group). All participants in both groups were CT IgG(+). hHsp60 IgG(+) prevalences were compared between the two groups, by semiquantitative ELISA. Data were evaluated using nonparametric and parametric tests and multivariable regression. RESULTS: After an initial pilot study, two groups were formed: 63 ectopic gestations (study group) and 95 normal parturients (control group), all CT IgG(+). Blood samples from all cases were tested for anti-hHsp60 IgG. Age, gravidity, and practising contraception were higher in the control group, while a history of pelvic infections were more common in the study group. Hsp60 IgG(+) was found to be significantly higher in the control group (63/95, 66.3%) compared to study group (30/63, 47.6%). Regression analysis revealed anti-hHsp60 positivity was an independent factor delineating the two groups. CONCLUSION: Immunity to hHsp60 is less common in CT IgG(+) ectopic pregnancies than CT IgG(+) fertile subjects without a history of ectopic pregnancies. Hence, our findings suggest that hHsp60 seropositivity may decrease the probability of an ectopic gestation in subjects with previous CT infections.

Association of basal serum androgen levels with ovarian response and ICSI cycle outcome.

BACKGROUND: The purpose of this study was to assess the predictive value of basal serum testosterone (T) and dehydroepiandrosterone sulfate (DHEAS) levels during follicular phase for ovarian response and outcome in intracytoplasmic sperm injection (ICSI) cycles of women with diminished ovarian reserve. METHODS: We prospectively gathered data of basal serum androgen levels and ICSI cycle characteristics of 120 women with diminished ovarian reserve. Association of basal serum T and DHEAS levels with ovarian response was analyzed. RESULTS: Basal T and DHEAS levels were similar between pregnant and non-pregnant cases (P > 0.05). There were significant differences between groups with and without successful embryo implantation in terms of serum follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH), gonadotropin starting and total dose, and peak estradiol level (P < 0.05). There were 58 (49.2%) cases who did not reach to the embryo transfer stage due to several reasons including cancelation of stimulation due to unresponsiveness (n = 26, 21.7%), no oocyte at oocyte pickup (n = 11, 9.2%), no mature oocyte (n = 6, 5%), and failure of fertilization or embryo development (n = 15, 12.5%). Basal androgen levels were not significant predictors for any of the cycle outcome. AMH level was a significant predictor for failure of fertilization or embryo development (AUC 0.722, P = 0.01) and cancelation of stimulation (AUC 0.801, P < 0.001). FSH was a significant predictor for cancelation of stimulation (AUC 0.774, P < 0.001). CONCLUSION: In women with diminished ovarian reserve, basal T and DHEAS levels have no value in predicting any of the cycle outcome parameters.

Bulky ß-Diketones Enabling New Lewis Acidic Ligand Platforms.

The synthesis of a sterically encumbered ß-diketone ligand (Aracac) substituted with 2,6-(2,4,6-Me3C6H2)2C6H3 is described. Coordination complexes of the type M(Aracac)2Cl(solv) (M = Ti, V, Cr; solv = THF, CH3CN) were prepared by the reaction of Aracac with MCl3 (M = V, Cr) or with TiCl4 to generate Ti(Aracac)2Cl2, followed by reduction. These complexes show a trend of alternating the cis/trans geometric preference with increasing dn electron count (n = 0, 1, 2, 3), which is rationalized in part by the unusual ability of ß-diketonates to behave as either a weak π donor or a π acceptor in the cis and trans geometries, respectively. In this way, the bis-ß-diketonate platform can accommodate the varying electronic demands of the coordinated metal ion. These results demonstrate the ability to limit the coordination of ß-diketonates on metal complexes for the first time, providing a chemically robust and coordinatively versatile platform for mechanistic investigations, metal functionalization, and improved catalyst design.

Appendectomy in the surgical treatment of benign ovarian mucinous cystadenomas - is it necessary?

OBJECTIVES: To determine if appendectomy as an adjunctive procedure is necessary in the surgical treatment of benign ovarian mucinous cystadenomas. MATERIAL AND METHODS: Retrospective analysis of clinical data: in a research hospital, obstetrics and gynecology depart-ment setting, 63 cases of benign ovarian mucinous cystadenomas confirmed in the pathological evaluation were revised. 59 had the complete clinical, final pathological and follow-up data available and were included. RESULTS: 20.6% (13/59) went through an appendectomy. Basic characteristics of patients with different appendiceal pathologies did not show any significant differences. In the study group the mean age, parity, adnexial mass size were (40.1 ± 12.4); (1.3 ± 1.1) and (9.1 ± 5.3 cm), respectively. Patients were either operated laparoscopically (20), laparotomically (39) to perform a unilateral salpingoopherectomy/cystectomy. In 7 patients, oopherectomy was an additional procedure with: 2 abdominal hysterectomies, 4 cesarean sections and 1 total laparoscopic hysterectomy. 2 synchronous appendiceal pathologies (mucinous cystadenomas of the appendix) were defined in appendectomies performed. In these cases, the ovarian tumour sizes were: 7 cm and 4 cm. CONCLUSIONS: In the presence of a benign or borderline unilateral ovarian mucinous tumour as defined during the operation and especially if it is larger than 10-12 cm and with normal peritoneal and appendiceal gross morphology, appendectomy is not a necessary adjunctive procedure.

A porcine model of osteosarcoma.

We previously produced pigs with a latent oncogenic TP53 mutation. Humans with TP53 germline mutations are predisposed to a wide spectrum of early-onset cancers, predominantly breast, brain, adrenal gland cancer, soft tissue sarcomas and osteosarcomas. Loss of p53 function has been observed in >50% of human cancers. Here we demonstrate that porcine mesenchymal stem cells (MSCs) convert to a transformed phenotype after activation of latent oncogenic TP53(R167H) and KRAS(G12D), and overexpression of MYC promotes tumorigenesis. The process mimics key molecular aspects of human sarcomagenesis. Transformed porcine MSCs exhibit genomic instability, with complex karyotypes, and develop into sarcomas on transplantation into immune-deficient mice. In pigs, heterozygous knockout of TP53 was sufficient for spontaneous osteosarcoma development in older animals, whereas homozygous TP53 knockout resulted in multiple large osteosarcomas in 7-8-month-old animals. This is the first report that engineered mutation of an endogenous tumour-suppressor gene leads to invasive cancer in pigs. Unlike in Trp53 mutant mice, osteosarcoma developed in the long bones and skull, closely recapitulating the human disease. These animals thus promise a model for juvenile osteosarcoma, a relatively uncommon but devastating disease.

Dioxygen Activation by Non-Adiabatic Oxidative Addition to a Single Metal Center.

A chromium(I) dinitrogen complex reacts rapidly with O2 to form the mononuclear dioxo complex [Tp(tBu,Me)Cr(V)(O)2] (Tp(tBu,Me) = hydrotris(3-tert-butyl-5-methylpyrazolyl)borate), whereas the analogous reaction with sulfur stops at the persulfido complex [Tp(tBu,Me)Cr(III)(S2)]. The transformation of the putative peroxo intermediate [Tp(tBu,Me)Cr(III)(O2)] (S = 3/2) into [Tp(tBu,Me)Cr(V)(O)2] (S = 1/2) is spin-forbidden. The minimum-energy crossing point for the two potential energy surfaces has been identified. Although the dinuclear complex [(Tp(tBu,Me)Cr)2(µ-O)2] exists, mechanistic experiments suggest that O2 activation occurs on a single metal center, by an oxidative addition on the quartet surface followed by crossover to the doublet surface.

Mechanism-based design of labile precursors for chromium(I) chemistry.

Dinitrogen complexes of the type Tp(R,R)Cr-N2-CrTp(R,R) are not the most labile precursors for Cr(i) chemistry, as they are sterically protected from obligatory associative ligand substitution. A mononuclear alkyne complex - Tp(tBu,Me)Cr(η(2)-C2(SiMe3)2) - proved to be much more reactive.

Oncogenic KRAS signalling in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is almost universally fatal. The annual number of deaths equals the number of newly diagnosed cases, despite maximal treatment. The overall 5-year survival rate of <5% has remained stubbornly unchanged over the last 30 years, despite tremendous efforts in preclinical and clinical science. There is unquestionably an urgent need to further improve our understanding of pancreatic cancer biology, treatment response and relapse, and to identify novel therapeutic targets. Rigorous research in the field has uncovered genetic aberrations that occur during PDAC development and progression. In most cases, PDAC is initiated by oncogenic mutant KRAS, which has been shown to drive pancreatic neoplasia. However, all attempts to target KRAS directly have failed in the clinic and KRAS is widely assumed to be undruggable. This has led to intense efforts to identify druggable critical downstream targets and nodes orchestrated by mutationally activated KRAS. This includes context-specific KRAS effector pathways, synthetic lethal interaction partners and KRAS-driven metabolic changes. Here, we review recent advances in oncogenic KRAS signalling and discuss how these might benefit PDAC treatment in the future.

Improved syntheses, and structural and electronic characterization of carboxamide-substituted Tp(CONHPh,Me) and Tp(CONHt-Bu,Me) ligands.

Improvements in the syntheses of the carboxamide-substituted tris(pyrazolyl)borate ligands Tp(CONHPh,Me) [tris(3-anilinocarbonyl-5-methylpyrazol-1-yl)borate] and Tp(CONHt-Bu,Me) [tris(3-tert-butylaminocarbonyl-5-methylpyrazol-1-yl)borate] are reported. Their Tl(I) salts, namely [tris(3-anilinocarbonyl-5-methylpyrazol-1-yl-κN(2))borato]thallium(I), [Tl(C33H31BN9O3)], (II), and [tris(3-tert-butylaminocarbonyl-5-methylpyrazol-1-yl-κN(2))borato]thallium(I), [Tl(C27H43BN9O3)], (III), as well as the Cu(I) carbonyl complexes (Tp(CONHPh,Me))Cu(CO), namely carbonyl[tris(3-anilinocarbonyl-5-methylpyrazol-1-yl-κN(2))borato]copper(I) tetrahydrofuran trisolvate, [Cu(C33H31BN9O3)(CO)]·3C4H8O, (IV), and (Tp(CONHt-Bu,Me))Cu(CO), namely carbonyl[tris(3-tert-butylaminocarbonyl-5-methylpyrazol-1-yl-κN(2))borato]copper(I) tetrahydrofuran hemisolvate, [Cu(C27H43BN9O3)(CO)]·0.5C4H8O, (V), have been prepared. Their spectroscopic properties and structures are compared with those of related compounds. The molecules of (II)-(V) show hydrogen bonding to either solvent molecules or neighboring complex molecules via amide groups. The title compounds feature the ability to engage other ligands in hydrogen bonding and they show strong electron-withdrawing character. Compound (V) displays voids of ca 800 Å(3) in the crystal structure.

Cancer survival in Izmir, Turkey, 1995-1997.

The Izmir cancer registry, the first population-based cancer registry in Turkey, was established in 1992. Cancer registration is now done by active methods. The registry contributed data on survival for 12 cancer sites or types registered in 1995-1997. Follow-up was predominantly done by active methods with median follow-up ranging between 17-72 months for different cancers. The proportion with histologically verified diagnosis for various cancers ranged between 84-100%; there were no death certificate only (DCO) cases; 98-100% of total registered cases were included for the survival analysis. Complete follow-up at five years ranged from 79-98% for different cancers. Five-year age-standardized relative survival rates of common cancers were breast (77%), urinary bladder (70%), Larynx (69%), colon (53%), rectum (52%), non-Hodgkin Lymphoma (50%) and cervix (58%). Five-year relative survival by age group portrayed decreasing survival with increasing age at diagnosis for cancer of the cervix, and was fluctuating for other cancers. Decreasing survival with increasing clinical extent of disease was also noted.

Quality, comparability and methods of analysis of data on childhood cancer in Europe (1978-1997): report from the Automated Childhood Cancer Information System project.

In collaboration with 62 population-based cancer registries contributing to the Automated Childhood Cancer Information System (ACCIS), we built a database to study incidence and survival of children and adolescents with cancer in Europe. We describe the methods and evaluate the quality and internal comparability of the database, by geographical region, period of registration, type of registry and other characteristics. Data on 88,465 childhood and 15,369 adolescent tumours registered during 1978-1997 were available. Geographical differences in incidence are caused partly by differences in definition of eligible cases. The observed increase in incidence rates cannot be explained by biases due to the selection of datasets for analyses, and only partially by the registration of non-malignant or multiple primary tumours. Part of the observed differences in survival between the regions may be due to variable completeness of follow-up, but most is probably explained by resource availability and organisation of care. Further standardisation of data and collection of additional variables are required so that this study may continue to yield valuable results with reliable interpretation.

Incidence in Izmir in 1993-1994: first results from Izmir Cancer Registry.

A population-based cancer registry, covering the province of Izmir (population 2.7 million, 1993-1994) in Western Turkey was established in 1992. Results for 1993-1994 are presented. Overall cancer incidence was higher in males than in females (age-standardised rates 157.5 and 94.0 per 100000, respectively), as in previous non-population-based series. The principal cancers in males were tobacco-related - lung (age-standardised incidence rate (ASR) 61.6), bladder (ASR 11.0) and larynx (ASR 10.6), consistent with the high prevalence of smoking, and use of traditional high-tar tobaccos. Skin cancers were also relatively common (ASR 11.5 for cancers excluding melanoma). Gastrointestinal cancers were relatively rare. In women, breast cancer was by far the most common malignancy (ASR 24.4); cervical cancer was relatively rare (ASR 5.4). There is probably an underestimate of incidence, due to an inability to use data from certain sources (e.g. death certificates), resulting in a rather high proportion of histologically verified cases (93.7% overall). Nevertheless, the overall profile is an accurate reflection of incidence in this region of Turkey and provides much of the information required for planning strategies to control cancer.

Cell type-specific activation of mitogen-activated protein kinases by CpG-DNA controls interleukin-12 release from antigen-presenting cells.

Activation of antigen-presenting cells (APCs) by invariant constituents of pathogens such as lipopolysaccharide (LPS) or bacterial DNA (CpG-DNA) initiates immune responses. We have analyzed the mitogen-activated protein kinase (MAPK) pathways triggered by CpG-DNA and their significance for cytokine production in two subsets of APCs, i.e. macrophages and dendritic cells (DCs). We found that CpG-DNA induced extracellular signal-regulated kinase (ERK) activity in macrophages in a classic MEK-dependent way. This pathway up-regulated tumor necrosis factor production but down-regulated interleukin (IL)-12 production. However, in DCs, which produce large amounts of IL-12, CpG-DNA and LPS failed to induce ERK activity. Consistent with a specific negative regulatory role for ERK in macrophages, chemical activation of this pathway in DCs suppressed CpG-DNA-induced IL-12 production. Overall, these results imply that differential activation of MAP kinase pathways is a basic mechanism by which distinct subsets of innate immune cells regulate their effector functions.