Resilience in cancer patients and how it correlates with demographics, psychological factors, and lifestyle.

BACKGROUND: Being diagnosed with cancer is challenging. Many patients wish to be actively involved in treatment and contribute to therapy, but the patients' coping abilities and desire for involvement differ. The individual level of resilience seems to play a major role. Our study aims to learn more about the associations of resilience and factors as demographics and psychological factors. METHODS: This multicentric cross-sectional study was conducted in ten oncological centers in Germany in summer 2021. The questionnaire collected information on demographics, resilience, self-efficacy, general satisfaction with life, and sense of coherence. Considered lifestyle-aspects were diet and physical activity. 416 patients were included in the analyses. RESULTS: A moderate mean resilience score was achieved (M = 69). Significant correlations in demographics were found for resilience and education (r = 0.146, p = 0.003), income (r = 0.205, p = 0.001), and time since receiving diagnosis (r = - 0.115, p = 0.021). Resilience and self-efficacy correlated on a high level (r = 0.595, p < 0.001), resilience and sense of coherence, and resilience and general satisfaction with life in a moderate way (r = 0.339, p < 0.001; r = 0.461, p = 0.001). CONCLUSIONS: Resilience portrays an important aspect in cancer treatment. Detecting patients at risk, stabilizing, or improving resilience are important to focus on and strengthen them accordingly. Possible negatively influencing factors (e.g., low self-efficacy) need to be considered. Factors affecting resilience but difficult to influence, as educational background, should be screened for. Also, the combination of low resilience and low income seems to describe a vulnerable patient group.

Joint consensus statement on the vaccination of adult and paediatric haematopoietic stem cell transplant recipients: Prepared on behalf of the British society of blood and marrow transplantation and cellular therapy (BSBMTCT), the Children's cancer and Leukaemia Group (CCLG), and British Infection Association (BIA).

Haematopoietic stem cell transplant (HSCT) recipients have deficiencies in their adaptive immunity against vaccine preventable diseases. National and International guidance recommends that HSCT recipients are considered 'never vaccinated' and offered a comprehensive course of revaccination. This position statement aims to draw upon the current evidence base and existing guidelines, and align this with national vaccine availability and licensing considerations in order to recommend a pragmatic and standardised re-vaccination schedule for adult and paediatric HSCT recipients in the UK.

Striking sex differences in magnetic resonance imaging findings in the sacroiliac joints in the population.

BACKGROUND: In patients with axial spondyloarthritis (axSpA), magnetic resonance imaging (MRI) is used to detect bone marrow edema (BME) in sacroiliac joints (SIJ) but SIJ BME are also detected in the population. Not much is known about sex differences in that regard. OBJECTIVE: To explore sex-specific differences associated with the extent of BME in the SIJ suggestive of axSpA in a general population cohort study. METHODS: Taking advantage of 793 recently evaluated MRIs of subjects < 45 years taking part in the SHIP cohort, we used negative-binomial (NB) count data regression to analyze factors associated with the extent of SIJ BME. Predictors were explored by model-based boosting (MBB), a machine learning approach. RESULTS: Estimates of NB regression showed strong effects of sex in interaction with age, BMI, back pain, and particularly HLA-B27. The NB regression model showed incidence rate ratios (IRR) for the main effect of sex (females vs. males): 0.94 [95% CI: 0.63; 1.41], HLA-B27: 4.32 [2.09; 9.8], and for the interaction of sex to HLA-B27: 0.22 [0.06; 0.75]. According to MBB, HLA-B27 positivity, BMI, current smoking, back pain in the last 3 months, the interaction of sex and HLA-B27, and delivery in the last 12 months were of highest importance to explain the extent of SIJ BME. CONCLUSIONS: Different factors were associated with the extent of SIJ BME in females and males. Most importantly, HLA-B27 was relevant only in males but not in females in whom a postpartal state was important. This finding may be relevant for the pathogenesis of axSpA.

Proteomic profiling of cisplatin-resistant and cisplatin-sensitive germ cell tumour cell lines using quantitative mass spectrometry.

PURPOSE: Advanced testicular germ cell tumours (GCT) generally have a good prognosis owing to their unique sensitivity towards cisplatin-based chemotherapies. However, cisplatin-resistant GCT have a poor outcome. Further studies are mandatory to better understand resistance mechanisms and develop therapeutic strategies for refractory GCTs. METHODS: Protein levels in cisplatin-resistant GCT cell lines of NTERA-2, NCCIT and 2102EP were analyzed by quantitative proteomic mass spectrometry (MS) in combination with stable isotope labelling by amino acids in cell culture (SILAC). Differentially abundant protein markers of acquired cisplatin resistance were validated by Western blotting. Comprehensive bioinformatical annotation using gene set enrichment analyses (GSEA) and STRING interaction analysis were performed to identify commonly affected pathways in cisplatin resistance and the data were compared to the GCT cohort of the 'The Cancer Genome Atlas'. RESULTS: A total of 4375 proteins were quantified by MS, 144 of which were found to be differentially abundant between isogenic resistant and sensitive cell line pairs (24 proteins for NTERA-2, 60 proteins for NCCIT, 75 proteins for 2102EP). Western blotting confirmed regulation of key resistance-associated proteins (CBS, ANXA1, LDHA, CTH, FDXR). GSEA revealed a statistically significant enrichment of DNA repair-associated proteins in all three resistant cell lines and specific additional processes for individual cell lines. CONCLUSION: High resolution MS combined with SILAC is a powerful tool and 144 significantly deregulated proteins were found in cisplatin-resistant GCT cell lines. Our study provides the largest proteomic in vitro library for cisplatin resistance in GCT, yet, enabling further studies to develop new treatment options for patients with refractory GCT.

Antibody responses after first and second Covid-19 vaccination in patients with chronic lymphocytic leukaemia.

B-cell chronic lymphocytic leukaemia (CLL) is associated with immunosuppression and patients are at increased clinical risk following SARS-CoV-2 infection. Covid-19 vaccines offer the potential for protection against severe infection but relatively little is known regarding the profile of the antibody response following first or second vaccination. We studied spike-specific antibody responses following first and/or second Covid-19 vaccination in 299 patients with CLL compared with healthy donors. 286 patients underwent extended interval (10-12 week) vaccination. 154 patients received the BNT162b2 mRNA vaccine and 145 patients received ChAdOx1. Blood samples were taken either by venepuncture or as dried blood spots on filter paper. Spike-specific antibody responses were detectable in 34% of patients with CLL after one vaccine (n = 267) compared to 94% in healthy donors with antibody titres 104-fold lower in the patient group. Antibody responses increased to 75% after second vaccine (n = 55), compared to 100% in healthy donors, although titres remained lower. Multivariate analysis showed that current treatment with BTK inhibitors or IgA deficiency were independently associated with failure to generate an antibody response after the second vaccine. This work supports the need for optimisation of vaccination strategy in patients with CLL including the potential utility of booster vaccines.

Confocal Raman microscopy in life sciences.

Microscopy techniques are widely used in life sciences to study cells and tissues. Fluorescence microscopy, for example, is a very common method in many laboratories. While reliable and strong fluorescence signals are a clear advantage of this method, the labelling procedure with fluorescent dyes, the availability of required antibodies or the potentially necessary genetic modifications of the studied organism all introduce potential complications. By contrast, confocal Raman microscopy is a label-free and non-destructive imaging technique. In contrast to infrared microscopy, it is easily applicable in aqueous environments. Different microscope setups and combinations allow for the examination of various solid and liquid samples, even in their typical environments. The article demonstrates the analyzing capability of confocal Raman microscopy and correlative techniques through application examples of eukaryotic and prokaryotic cells, and cancerous and normal tissues and shows how confocal Raman microscopy provides valuable information for a more comprehensive understanding of the investigated sample.

The United Kingdom Primary Immune Deficiency (UKPID) registry 2012 to 2017.

This is the second report of the United Kingdom Primary Immunodeficiency (UKPID) registry. The registry will be a decade old in 2018 and, as of August 2017, had recruited 4758 patients encompassing 97% of immunology centres within the United Kingdom. This represents a doubling of recruitment into the registry since we reported on 2229 patients included in our first report of 2013. Minimum PID prevalence in the United Kingdom is currently 5·90/100 000 and an average incidence of PID between 1980 and 2000 of 7·6 cases per 100 000 UK live births. Data are presented on the frequency of diseases recorded, disease prevalence, diagnostic delay and treatment modality, including haematopoietic stem cell transplantation (HSCT) and gene therapy. The registry provides valuable information to clinicians, researchers, service commissioners and industry alike on PID within the United Kingdom, which may not otherwise be available without the existence of a well-established registry.

Decitabine demonstrates antileukemic activity in B cell precursor acute lymphoblastic leukemia with MLL rearrangements.

BACKGROUND: Promotor hypermethylation of CpG islands is common in B cell precursor acute lymphoblastic leukemia (BCP-ALL) with mixed lineage leukemia (MLL) gene rearrangements. Hypomethylating agents (HMA) such as azacitidine (AZA) and decitabine (DEC) reduce DNA hypermethylation by incorporation into DNA and were successfully introduced into the clinic for the treatment of myeloid neoplasias. METHODS: Here, we investigated whether HMA induce comparable biological effects in MLL-positive BCP-ALL. Further, efficacy of HMA and concomitant application of cytostatic drugs (cytarabine and doxorubicin) were evaluated on established SEM and RS4;11 cell lines. In addition, promising approaches were studied on BCP-ALL cell line- and patient-derived xenograft models. RESULTS: In general, DEC effects were stronger compared to AZA on MLL-positive BCP-ALL cells. DEC significantly reduced proliferation by induction of cell cycle arrest in G0/G1 phase and apoptosis. Most sensitive to HMA were SEM cells which are characterized by a fast cell doubling time. The combination of low-dose HMA and conventional cytostatic agents revealed a heterogeneous response pattern. The strongest antiproliferative effects were observed when ALL cells were simultaneously exposed to HMA and cytostatic drugs. Most potent synergistic effects of HMA were induced with cytarabine. Finally, the therapeutic potential of DEC was evaluated on BCP-ALL xenograft models. DEC significantly delayed leukemic proliferation in xenograft models as demonstrated longitudinally by non-invasive bioluminescence as well as 18F-FDG-PET/CT imaging. Unexpectedly, in vivo concomitant application of DEC and cytarabine did not enhance the antiproliferative effect compared to DEC monotherapy. CONCLUSIONS: Our data reveal that DEC is active in MLL-positive BCP-ALL and warrant clinical evaluation.

Serious adverse events and the risk of stroke in patients with rheumatoid arthritis: results from the German RABBIT cohort.

OBJECTIVE: In the general population, the incidence of stroke is increased following other serious events and hospitalisation. We investigated the impact of serious adverse events on the risk of stroke in patients with rheumatoid arthritis (RA), taking risk factors and treatment into account. METHODS: Using data of the German biologics register RABBIT (Rheumatoid Arthritis: Observation of Biologic Therapy) with 12354 patients with RA, incidence rates (IRs) and risk factors for stroke were investigated using multi-state and Cox proportional hazard models. In addition, in a nested case-control study, all patients with stroke were matched 1:2 to patients with identical baseline risk profile and analysed using a shared frailty model. RESULTS: During follow-up, 166 strokes were reported. The overall IR was 3.2/1000 patient-years (PY) (95% CI 2.7 to 3.7). It was higher after a serious adverse event (IR: 9.0 (7.3 to 11.0)), particularly within 30 days after the event (IR: 94.9 (72.6 to 121.9)). The adjusted Cox model showed increased risks of age per 5 years (HR: 1.4 (1.3 to 1.5)), hyperlipoproteinaemia (HR: 1.6 (1.0 to 2.5)) and smoking (HR: 1.9 (1.3 to 2.6)). The risk decreased with better physical function (HR: 0.9 (0.8 to 0.96)). In the case-control study, 163 patients were matched to 326 controls. Major risk factors for stroke were untreated cardiovascular disease (HR: 3.3 (1.5 to 7.2)) and serious infections (HR:4.4 (1.6 to 12.5)) or other serious adverse events (HR: 2.6 (1.4 to 4.8)). CONCLUSIONS: Incident adverse events, in particular serious infections, and insufficient treatment of cardiovascular diseases are independent drivers of the risk of stroke. Physicians should be aware that patients who experience a serious event are at increased risk of subsequent stroke.

Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs.

OBJECTIVE: To investigate the risk of developing lower intestinal perforations (LIPs) in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ). METHODS: In 13 310 patients with RA observed in the German biologics register Rheumatoid Arthritis: Observation of Biologic Therapy, 141 serious gastrointestinal events possibly associated with perforations were reported until 31 October 2015. All events were validated independently by two physicians, blinded for treatment exposure. RESULTS: 37 LIPs (32 in the colon/sigma) were observed in 53 972 patient years (PYs). Only two patients had a history of diverticulitis (one in TCZ). Age, current/cumulative glucocorticoids and non-steroidal anti-inflammatory drugs were significantly associated with the risk of LIP. The crude incidence rate of LIP was significantly increased in TCZ (2.7/1000 PYs) as compared with all other treatments (0.2-0.6/1000 PYs). The adjusted HR (ref: conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs)) in TCZ was 4.48 (95% CI 2.0 to 10.0), in tumour necrosis factor-α inhibitor (TNFi) 1.04 (0.5 to 2.3) and in other biologic DMARDs 0.33 (0.1 to 1.4). 4/11 patients treated with TCZ presented without typical symptoms of LIP (acute abdomen, severe pain). Only one patient had highly elevated C reactive protein (CRP). One quarter of patients died within 30 days after LIP (9/37), 5/11 under TCZ, 2/13 under TNFi and 2/11 under csDMARD treatment. CONCLUSIONS: The incidence rates of LIP under TCZ found in this real world study are in line with those seen in randomised controlled trials of TCZ and higher than in all other DMARD treatments. To ensure safe use of TCZ in daily practice, physicians and patients should be aware that, under TCZ, LIP may occur with mild symptoms only and without CRP elevation.

[The first biologic for rheumatoid arthritis: factors influencing the therapeutic decision]. / Das erste Biologikum bei rheumatoider Arthritis: Einflussfaktoren auf die Therapieentscheidung.

BACKGROUND AND AIMS: Biologics (disease modifying antirheumatic drugs, bDMARD) have been in use in Germany for the treatment of rheumatoid arthritis (RA) since 2001, usually after failure of at least one conventional synthetic (cs)DMARD. We analyzed temporal changes in factors that influence the decision for either a first bDMARD or a further csDMARD. MATERIAL AND METHODS: We analyzed data from 9513 bDMARD-naive RA patients in the German biologics register RABBIT who switched to a new therapy. For three recruitment periods (2001-2003, 2004-2006 and 2009-2015) factors influencing the therapeutic decision were analyzed by means of machine learning methods and logistic regression analysis. RESULTS: In all recruitment periods the number of previous csDMARDs, high dosages of glucocorticoids (>7.5 mg/day) and a higher DAS28 (>5.1) were significantly associated with the decision for a first bDMARD. Over time, the chance of receiving a bDMARD increased in patients with moderate disease activity, moderate glucocorticoid dosages (5-7.5 mg/day) and those with comorbidities, such as congestive heart failure or prior malignancy. Men had a higher chance of receiving a bDMARD than women only in the first recruitment period. Private health insurance, high education and gainful employment were significantly associated with more frequent prescription of bDMARDs in all recruitment periods. DISCUSSION: The time-dependent changes in the impact of disease activity, concomitant drugs, gender and comorbidity on the prescription of bDMARDs mirror the increasing therapeutic options and the growing experience in the application of the new substances in patients at higher risk. The influence of demographic and social factors may reflect safety concerns in patients at increased risk of adverse events but also the need to economize drug costs..

Arthrodesis for septic arthritis of the ankle: risk factors and complications.

INTRODUCTION: Septic ankle joint arthrodesis is a good therapeutic option in cases of infection after trauma or orthopedic surgical procedures. Many different procedures have been described, but external fixation seems to be standard. Aim of this study is to identify risk factors for complications in septic ankle joint arthrodesis with the external AO frame fixator. MATERIALS AND METHODS: Patients who received septic ankle joint arthrodesis between January 2008 and December 2012 were included in this study. Patients were evaluated clinically and with radiographs or CT scans. RESULTS: Follow-up of 74 of 79 patients with an external AO frame fixator could be evaluated; follow-up was 411 days (105-991). The mean age at surgery was 57.7 years (19-87). At this time, complications occurred in 41 patients (52 %) with wound healing problems (17 patients, 22 %) and non-union (12 patients, 15 %), and some needed surgical revision. In our collective, men had a significant higher non-union rate (p = 0.031), age or BMI showed no difference. Patients with diabetes and alcohol consumption showed a higher risk for complications (p = 0.049 and p = 0.031, respectively). 62 % of primary arthrodesis showed union, whereas in the case of revision, arthrodesis only 39 % showed union. CONCLUSIONS: Septic ankle joint arthrodesis with the external AO frame fixator is a probable tool to achieve union. This study showed that there is a high complication rate and some risk factors for complications could be identified. A blinded and prospective study is needed to compare intramedullary nailing and external fixation to evaluate the possible advantage of intramedullary devices in septic ankle arthrodesis.

[How do register data support clinical decision-making?]. / Wie unterstützen Registerdaten die klinische Entscheidungsfindung?

BACKGROUND: Patients in daily rheumatological care differ in their individual risk profiles from participants in randomized controlled trials (RCT), e.g. due to comorbidities and age. Transferring results from RCTs into routine daily practice is therefore limited. OBJECTIVE: The aim of this study was to evaluate the contribution of observational studies for decision-making in routine rheumatology practice. MATERIAL AND METHODS: We used data from the German biologics register RABBIT which includes patients with rheumatoid arthritis (RA) when starting synthetic (s) or biologic (b) disease-modifying antirheumatic drugs (DMARD). They are observed for at least 5 years. Comorbidities and clinically relevant aspects (e.g. history of malignancies) are reported at baseline and adverse events at regular follow-up. RESULTS: Only one out of three patients treated with bDMARDs in RABBIT would have fulfilled the inclusion criteria of the respective pivotal study. Register data enabled developing a risk scoring model which evaluates the individual risk of a patient for serious infections depending on different risk factors and the respective DMARD treatment. Open online access to the score provides the possibility of risk estimation for all rheumatologists. Further results identified long-standing high disease activity as a dominant risk factor for a worsening of prevalent comorbidities. In patients with heart failure it was shown that effective treatment and control of disease activity with tumor necrosis factor (TNF) inhibitors was more likely to be protective than harmful. CONCLUSION: Observational studies contribute essentially to the assessment of individual risks of patients. The results provide valuable information to support clinical decision-making and therefore strengthen the evidence when treating patients of higher age or with existing comorbidities.

[Mortality follow-up of the German Health Interview and Examination Survey for Adults (DEGS) : methods and first results]. / Mortalitäts-Follow-up der Studie zur Gesundheit Erwachsener in Deutschland (DEGS) : Methodik und erste Ergebnisse.

OBJECTIVES: Within the framework of the German Health Interview and Examination Survey for Adults (DEGS), the Robert Koch Institute (RKI) conducted a nationwide mortality follow-up study. As there is no national mortality register in Germany, mortality and causes of death were investigated individually and under observance of state-specific data protection conditions. METHODS: The German Health Interview and Examination Survey 1998 (GNHIES98) provided the database including 7,124 participants aged 18-79 years. A total of 6,979 participants of GNHIES98 (98 %) who consented to be re-contacted were invited between October 2008 and October 2011 to also participate in the first data collection wave of DEGS (DEGS1). In this context, the vital status and the causes of death for deceased participants were assessed. Age- and sex-specific probabilities of survival and death rates were calculated and grouped by main causes of death according to ICD-10 groups. RESULTS: A total of 671 individuals (285 women, 386 men) died between the two survey contacts. For all deceased persons the date of death and for 539 (80.3 %) the causes of death could be determined. With a median follow-up time of 12.0 years, 8,0742.5 person years were available for survival analysis. The crude overall death rate amounted to 8.3 per 1,000 persons-years (women: 7.2; men: 9.5). Among 539 persons with available information on causes of death, 209 (38.8 %) were attributable to cardiovascular diseases, 188 (34.9 %) to cancer, 135 (25.0 %) to other causes, and seven (1.3 %) could not be unambiguously assigned. CONCLUSIONS: A mortality follow-up was successfully integrated in the longitudinal component of DEGS as part of the national health monitoring at the RKI. Death rates and cause-specific mortality in relation to highly prevalent chronic diseases and risk factors provide essential information for assessing the potential of prevention and quality of care among adults in Germany. This requires a regular and complete conduction of mortality follow-ups.

Anticalins: exploiting a non-Ig scaffold with hypervariable loops for the engineering of binding proteins.

Antibodies, which can recognize a plethora of possible antigens, have been considered as a paradigm of protein engineering performed by nature itself. Lipocalins constitute a distinct family of proteins with functions in ligand binding and transport that occur in many organisms, including man. Like antibodies, lipocalins exhibit a structurally conserved framework - a ß-barrel with an attached α-helix - which supports four structurally hypervariable loops forming a cup-shaped binding site. Thus, lipocalins offer an ideal platform for protein engineering to generate novel binding reagents. Using recombinant/synthetic DNA technology and methods of combinatorial library selection, 'Anticalins' with prescribed target specificities can be easily generated. Anticalins with picomolar affinities have been developed for three classes of ligands having relevance in basic research and/or medical application: small molecules, peptides, and proteinaceous signalling molecules as well as cell surface receptors. Anticalins derived from human lipocalins have already reached the clinical trial stage. Due to their very small size and simple composition of a single polypeptide chain, which also facilitates the construction of bifunctional fusion proteins, Anticalins promise benefits as a next class of biopharmaceuticals.

Targeted therapy of the XIAP/proteasome pathway overcomes TRAIL-resistance in carcinoma by switching apoptosis signaling to a Bax/Bak-independent 'type I' mode.

TRAIL is a promising anticancer agent, capable of inducing apoptosis in a wide range of treatment-resistant tumor cells. In 'type II' cells, the death signal triggered by TRAIL requires amplification via the mitochondrial apoptosis pathway. Consequently, deregulation of the intrinsic apoptosis-signaling pathway, for example, by loss of Bax and Bak, confers TRAIL-resistance and limits its application. Here, we show that despite resistance of Bax/Bak double-deficient cells, TRAIL-treatment resulted in caspase-8 activation and complete processing of the caspase-3 proenzymes. However, active caspase-3 was degraded by the proteasome and not detectable unless the XIAP/proteasome pathway was inhibited. Direct or indirect inhibition of XIAP by RNAi, Mithramycin A or by the SMAC mimetic LBW-242 as well as inhibition of the proteasome by Bortezomib overcomes TRAIL-resistance of Bax/Bak double-deficient tumor cells. Moreover, activation and stabilization of caspase-3 becomes independent of mitochondrial death signaling, demonstrating that inhibition of the XIAP/proteasome pathway overcomes resistance by converting 'type II' to 'type I' cells. Our results further demonstrate that the E3 ubiquitin ligase XIAP is a gatekeeper critical for the 'type II' phenotype. Pharmacological manipulation of XIAP therefore is a promising strategy to sensitize cells for TRAIL and to overcome TRAIL-resistance in case of central defects in the intrinsic apoptosis-signaling pathway.

[Surgical standards in perioperative treatment]. / Chirurgische Standards der perioperativen Patientenbehandlung.

Perioperative medicine includes the areas of clarification, patient safety, hygiene standards, prophylaxis for thrombosis and antibiotics, pain therapy and morbidity and mortality conference. All these procedures show how complex perioperative medicine is.

A SNP in steroid receptor coactivator-1 disrupts a GSK3ß phosphorylation site and is associated with altered tamoxifen response in bone.

The coregulator steroid receptor coactivator (SRC)-1 increases transcriptional activity of the estrogen receptor (ER) in a number of tissues including bone. Mice deficient in SRC-1 are osteopenic and display skeletal resistance to estrogen treatment. SRC-1 is also known to modulate effects of selective ER modulators like tamoxifen. We hypothesized that single nucleotide polymorphisms (SNP) in SRC-1 may impact estrogen and/or tamoxifen action. Because the only nonsynonymous SNP in SRC-1 (rs1804645; P1272S) is located in an activation domain, it was examined for effects on estrogen and tamoxifen action. SRC-1 P1272S showed a decreased ability to coactivate ER compared with wild-type SRC-1 in multiple cell lines. Paradoxically, SRC-1 P1272S had an increased protein half-life. The Pro to Ser change disrupts a putative glycogen synthase 3 (GSK3)ß phosphorylation site that was confirmed by in vitro kinase assays. Finally, knockdown of GSK3ß increased SRC-1 protein levels, mimicking the loss of phosphorylation at P1272S. These findings are similar to the GSK3ß-mediated phospho-ubiquitin clock previously described for the related coregulator SRC-3. To assess the potential clinical significance of this SNP, we examined whether there was an association between SRC-1 P1272S and selective ER modulators response in bone. SRC-1 P1272S was associated with a decrease in hip and lumbar bone mineral density in women receiving tamoxifen treatment, supporting our in vitro findings for decreased ER coactivation. In summary, we have identified a functional genetic variant of SRC-1 with decreased activity, resulting, at least in part, from the loss of a GSK3ß phosphorylation site, which was also associated with decreased bone mineral density in tamoxifen-treated women.

Sequential targeting of CFTR by BAC vectors generates a novel pig model of cystic fibrosis.

Cystic fibrosis (CF) is the most common lethal inherited disease in Caucasians and is caused by mutations in the CFTR gene. The disease is incurable and medical treatment is limited to the amelioration of symptoms or secondary complications. A comprehensive understanding of the disease mechanisms and the development of novel treatment options require appropriate animal models. Existing CF mouse models fail to reflect important aspects of human CF. We thus generated a CF pig model by inactivating the CFTR gene in primary porcine cells by sequential targeting using modified bacterial artificial chromosome vectors. These cells were then used to generate homozygous CFTR mutant piglets by somatic cell nuclear transfer. The homozygous CFTR mutants lack CFTR protein expression and display severe malformations in the intestine, respiratory tract, pancreas, liver, gallbladder, and male reproductive tract. These phenotypic abnormalities closely resemble both the human CF pathology as well as alterations observed in a recently published CF pig model which was generated by a different gene targeting strategy. Our new CF pig model underlines the value of the CFTR-deficient pig for gaining new insight into the disease mechanisms of CF and for the development and evaluation of new therapeutic strategies. This model will furthermore increase the availability of CF pigs to the scientific community.

[Transforaminal lumbar interbody fusion for the treatment of degenerative spondylolisthesis]. / Transforaminale lumbale interkorporelle Fusion zur Versorgung der degenerativen Spondylolisthese.

INTRODUCTION: Degenerative spondylolisthesis (DS) is a common cause of lumbal and lumbosacral pain as well as radicular pain. Retention and fusion is a good treatment option. Some patients have a symptomatic adjacent degenerative disc disease (DDD) in addition to DS. In these cases the adjacent segments should be fused as well. There are different techniques of fusion available, such as posterior with instrumentation or additional anterior support. This study evaluated results of transforaminal lumbar interbody fusion (TLIF) in patients with monosegmental DS and adjacent DDD. MATERIAL AND METHODS: A total of 28 patients with monosegmental DS and adjacent DDD were included into the study (all patients with bisegmental posterior instrumentation and fusion, 14 patients 1 level TLIF, 14 patients 2 level TLIF). Before surgery and 12 months after surgery the following measurements were made: pain (visual analog scale VAS), Oswestry disability index (ODI) and plain radiographs with radiometric analysis. In a sub-analysis patients with 1 and 2 level TLIF were compared. RESULTS: Pain reduction (average VAS from 8.7-3.1) and ODI (63% to 28%) showed significant improvements. Radiometric analysis showed a significant disc height reconstruction and a significant reduction of spondylolisthesis (TLIF level with spondylolisthesis). Bisegmental anterior support showed a significantly better relordosation compared to monosegmental anterior support. The complication rate was 21.4% including hemorrhages, dura leakage, wound infection and adjacent segment degeneration. There were no fatal complications. DISCUSSION: The TLIF procedure is a safe and effective treatment for monosegmental DS with adjacent symptomatic DDD. Clinical results (pain, function) show no difference between both kinds of fusion (dorsal fusion and instrumentation versus dorsal fusion with instrumentation and TLIF) for the adjacent DDD. However, additional anterior support is more effective for relordosation of the segment. This could have impact on the mid-term and long-term outcome or in cases of adjacent segment fusion.