Prerequisites for Clinical Implementation of Whole-Heart 4D-Flow MRI: A Delphi Analysis.

Whole-heart 4D-flow MRI is a valuable tool for advanced visualization and quantification of blood flow in cardiovascular imaging. Despite advantages over 2D-phase-contrast flow, clinical implementation remains only partially exploited due to many hurdles in all steps, from image acquisition, reconstruction, postprocessing and analysis, clinical embedment, reporting, legislation, and regulation to data storage. The intent of this manuscript was 1) to evaluate the extent of clinical implementation of whole-heart 4D-flow MRI, 2) to identify hurdles hampering clinical implementation, and 3) to reach consensus on requirements for clinical implementation of whole-heart 4D-flow MRI. This study is based on Delphi analysis. This study involves a panel of 18 experts in the field on whole-heart 4D-flow MRI. The experience with and opinions of experts (mean 13 years of experience, interquartile range 6) in the field were aggregated. This study showed that among experts in the cardiovascular field, whole-heart 4D-flow MRI is currently used for both clinical and research purposes. Overall, the panelists agreed that major hurdles currently hamper implementation and utilization. The sequence-specific hurdles identified were long scan time and lack of standardization. Further hurdles included cumbersome and time-consuming segmentation and postprocessing. The study concludes that implementation of whole-heart 4D-flow MRI in clinical routine is feasible, but the implementation process is complex and requires a dedicated, multidisciplinary team. A predefined plan, including risk assessment and technique validation, is essential. The reported consensus statements may guide further tool development and facilitate broader implementation and clinical use. LEVEL OF EVIDENCE: NA TECHNICAL EFFICACY: Stage 5.

ARF6 is a host factor for SARS-CoV-2 infection in vitro.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerged beta-coronavirus that enter cells via two routes, direct fusion at the plasma membrane or endocytosis followed by fusion with the late endosome/lysosome. While the viral receptor, ACE2, multiple entry factors and the mechanism of fusion of the virus at the plasma membrane have been investigated extensively, viral entry via the endocytic pathway is less understood. By using a human hepatocarcinoma cell line, Huh-7, which is resistant to the antiviral action of the TMPRSS2 inhibitor camostat, we discovered that SARS-CoV-2 entry is not dependent on dynamin but on cholesterol. ADP-ribosylation factor 6 (ARF6) has been described as a host factor for SARS-CoV-2 replication and is involved in the entry and infection of several pathogenic viruses. Using CRISPR/Cas9 genetic deletion, a modest reduction in SARS-CoV-2 uptake and infection in Huh-7 was observed. In addition, pharmacological inhibition of ARF6 with the small molecule NAV-2729 showed a dose-dependent reduction of viral infection. Importantly, NAV-2729 also reduced SARS-CoV-2 viral loads in more physiological models of infection: Calu-3 cells and kidney organoids. This highlighted a role for ARF6 in multiple cell contexts. Together, these experiments point to ARF6 as a putative target to develop antiviral strategies against SARS-CoV-2.

Immune and stem cell compartments of acetabular and femoral bone marrow in hip osteoarthritis patients.

OBJECTIVE: Hip osteoarthritis (OA) affects all components of the osteochondral unit, leading to bone marrow (BM) lesions, and unknown consequences on BM cell functionality. We analyzed the cellular composition in OA-affected acetabula compared to proximal femur shafts obtained of hip OA patients to reveal yet not explored immune and stem cell compartments. DESIGN: Combining flow cytometry, cellular assays and transcription analyses, we performed extensive ex vivo phenotyping of acetabular BM cells from 18 hip OA patients, comparing them with their counterparts from patient-matched femoral shaft BM samples. Findings were related to differences in skeletal sites and age. RESULTS: Acetabular BM had a greater frequency of T-lymphocytes, non-hematopoietic cells and colony-forming units fibroblastic potential than femoral BM. The incidence of acetabular CD45+CD3+ T-lymphocytes increased (95% CI: 0.1770 to 0.0.8416), while clonogenic hematopoietic progenitors declined (95% CI: -0.9023 to -0.2399) with age of patients. On the other side, in femoral BM, we observed higher B-lymphocyte, myeloid and erythroid cell frequencies. Acetabular mesenchymal stromal cells (MSCs) showed a senescent profile associated with the expression of survival and inflammation-related genes. Efficient osteogenic and chondrogenic differentiation was detected in acetabular MSCs, while adipogenesis was more pronounced in their femoral counterparts. CONCLUSION: Our results suggest that distinctions in BM cellular compartments and MSCs may be due to the influence of the OA-stressed microenvironment, but also acetabular vs femoral shaft-specific peculiarities cannot be excluded. These results bring new knowledge on acetabular BM cell populations and may be addressed as novel pathogenic mechanisms and therapeutic targets in OA.

Ultrasound and MR muscle imaging in new onset idiopathic inflammatory myopathies at diagnosis and after treatment: a comparative pilot study.

OBJECTIVES: To prospectively compare ultrasound (US) and whole-body MRI for detection of muscle abnormalities compatible with idiopathic inflammatory myopathies (IIM). METHODS: Newly diagnosed IIM patients underwent US (14 muscles) and MRI (36 muscles) at diagnosis and after nine weeks monotherapy with intravenous immunoglobulin. Muscles were compatible with IIM when quantitative US echo-intensity (EI) z scores was ≥1.5, semi-quantitative US Heckmatt score was ≥2, qualitative US was abnormal, or when MRI showed oedema on T2-weighted images. At patient level, findings were classified as abnormal when quantitative US EI z scores was >1.5 (n = 3 muscles), >2.5 (n = 2 muscles) or >3.5 (n = 1 muscle), or if ≥3 muscles showed abnormalities as described above for the other diagnostic methods. RESULTS: At diagnosis, in 18 patients US of 252 muscles revealed abnormalities in 36 muscles (14%) with quantitative, in 153 (61%) with semi-quantitative and in 168 (67%) with qualitative analysis. MRI showed oedema in 476 out of 623 muscles (76%). Five patients (28%) reached abnormal classification with quantitative US, 16 (89%) with semi-quantitative and qualitative US, and all patients (100%) with MRI. Nine-week follow-up of 12 patients showed no change over time with quantitative US or MRI, and a decrease in abnormalities with semi-quantitative US (P <0.01), and qualitative US (P <0.01). CONCLUSION: At diagnosis, MRI was more sensitive than US to detect muscle abnormalities compatible with IIM. Semi-quantitative US and qualitative US detected abnormalities in the majority of the patients while evaluating fewer muscles than MRI and showed change over time after nine weeks of treatment.

TNF-α and its soluble receptors mediate the relationship between prior severe mood episodes and cognitive dysfunction in euthymic bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is one of the most disabling mental health conditions in the world. Symptoms of cognitive impairment in BD contribute directly to occupational and social deficiencies and are very difficult to treat. Converging evidence suggests that BD patients have increased peripheral markers of inflammation. The hypothesis of neuroprogression in BD postulates that cognitive deficits develop over the course of the illness and are influenced by prior severe mood episodes, leading to wear-and-tear on the brain- however, there exists a paucity of data statistically testing a mediating role of immune molecules in cognitive dysfunction in BD. METHODS: This is a cross-sectional study. We measured serum levels of tumor necrosis factor alpha (TNF-α), and soluble (s) TNF receptors one and two (sTNF-R1 and sTNF-R2) in 219 euthymic BD patients and 52 Healthy Controls (HCs). Structural equation modeling (SEM) was used for the primary purpose of assessing whether TNF markers (measured by the multiple indicators TNF-α, sTNF-R1 and sTNF-R2) mediate the effect or number of prior severe mood episodes (number of prior psychiatric hospitalizations) on cognitive performance. RESULTS: BD and HC groups did not differ on circulating levels of TNF molecules in the present study. However, we found higher sTNF-R1 concentration in 'late-stage' BD illness (>1 prior psychiatric hospitalization) compared to those in early stage illness. In the subsequent SEM, we found that the model fits the data acceptably (Chi-square = 49.2, p = 0.3), and had a 'close fit' (RMSEA = 0.02, PCLOSE = 0.9). Holding covariates constant (age, sex, premorbid IQ, education, and race), we found that the standardized indirect effect was significant, p = 0.015, 90%CI [-0.07, -0.01], indicating that the estimated model was consistent with peripheral TNF markers partially mediating a causal effect of severe mood episodes on executive function. CONCLUSIONS: Our results indicate that circulating levels of TNF molecules partially mediate the relationship between prior severe mood episodes and executive function in BD. These results may implicate TNF variables in the neuroprogressive course of BD and could point to novel interventions for cognition.

RNase 7 downregulates TH2 cytokine production by activated human T cells.

BACKGROUND: The antimicrobial peptide (AMP) RNase 7 is constitutively expressed in the epidermis of healthy human skin and has been found to be upregulated in chronic inflammatory skin diseases such as atopic dermatitis and psoriasis. Activated T cells in lesional skin of patients with atopic dermatitis (AD) and psoriasis (PSO) might be directly exposed to RNase 7. In addition to their antimicrobial activity, immunoregulatory functions have been published for several AMPs. In this study, we investigated immunoregulatory effects of the antimicrobial peptide RNase 7 on activated T cells. METHODS: Isolated human CD3+T cells were stimulated with RNase 7 and screened for possible effects by mRNA microarray analysis. The results of the mRNA microarray were confirmed in isolated CD4+T cells and in polarized TH2 cells using skin-derived native RNase 7 and a recombinant ribonuclease-inactive RNase 7 mutant. Activation of GATA3 was analysed by electrophoretic mobility shift assay. RESULTS: Treatment of activated human CD4+T cells and TH2 cells with RNase 7 selectively reduced the expression of TH2 cytokines (IL-13, IL-4 and IL-5). Experiments with a ribonuclease-inactive recombinant RNase 7 mutant showed that RNase 7 ribonuclease activity is dispensable for the observed regulatory effect. We further demonstrate that CD4+T cells from AD patients revealed a significantly less pronounced downregulation of IL-13 in response to RNase 7 compared to healthy control. Finally, we show that GATA3 activation was diminished upon cultivation of T cells with RNase 7. CONCLUSION: Our data indicate that RNase 7 has immunomodulatory functions on TH2 cells and decreases the production of TH2 cytokines in the skin.

Differential expression of antimicrobial peptides in psoriasis and psoriatic arthritis as a novel contributory mechanism for skin and joint disease heterogeneity.

OBJECTIVES: This study tested the hypothesis that a differential innate immune antimicrobial peptide (AMP) profile was evident between the skin and joints in psoriasis and psoriatic arthritis (PsA) and that PsA synovitis may have a distinct AMP pattern compared to other arthropathies. METHOD: Twenty-two cases had knee biopsies [10 PsA, eight rheumatoid arthritis (RA), and four osteoarthritis (OA)]. Lesional and non-lesional skin biopsies in psoriasis and control tissue were also obtained (n = 4 each). Immunohistochemistry with semi-quantitative scoring of both synovium and skin was performed using the following panel of AMPs: S100 A8, S100 A9, human neutrophil peptides 1-3 (HNP1-3), human ß-defensins 2 and 3 (hBD-2 and hBD-3), cathelicidin LL-37, psoriasin (S100 A7), and ribonuclease 7 (RNase 7). RESULTS: Similar expression of S100 A8, S100 A9, and HNP1-3 was detectable in PsA and RA synovium but only in the synovium sublining layer (SSL). No expression of psoriasin, RNase 7, hBD-2, and hBD-3 could be detected in the synovial tissue of PsA, RA, or OA. All psoriasis skin samples exhibited broad expression of all investigated AMPs, with strong keratinocyte expression. CONCLUSIONS: Given that some AMPs, especially hBD-2, are genetically linked to psoriasis and are only expressed in the skin, these findings show how differential AMP expression in innate immune responses may contribute to disease heterogeneity between PsA and psoriasis and provides a genetic basis for the non-progression of psoriasis subgroups to PsA.

Off-resonance suppression for multispectral MR imaging near metallic implants.

PURPOSE: Metal artifact reduction in MRI within clinically feasible scan-times without through-plane aliasing. THEORY AND METHODS: Existing metal artifact reduction techniques include view angle tilting (VAT), which resolves in-plane distortions, and multispectral imaging (MSI) techniques, such as slice encoding for metal artifact correction (SEMAC) and multi-acquisition with variable resonances image combination (MAVRIC), that further reduce image distortions, but significantly increase scan-time. Scan-time depends on anatomy size and anticipated total spectral content of the signal. Signals outside the anticipated spatial region may cause through-plane back-folding. Off-resonance suppression (ORS), using different gradient amplitudes for excitation and refocusing, is proposed to provide well-defined spatial-spectral selectivity in MSI to allow scan-time reduction and flexibility of scan-orientation. Comparisons of MSI techniques with and without ORS were made in phantom and volunteer experiments. RESULTS: Off-resonance suppressed SEMAC (ORS-SEMAC) and outer-region suppressed MAVRIC (ORS-MAVRIC) required limited through-plane phase encoding steps compared with original MSI. Whereas SEMAC (scan time: 5'46") and MAVRIC (4'12") suffered from through-plane aliasing, ORS-SEMAC and ORS-MAVRIC allowed alias-free imaging in the same scan-times. CONCLUSION: ORS can be used in MSI to limit the selected spatial-spectral region and contribute to metal artifact reduction in clinically feasible scan-times while avoiding slice aliasing.

Ripple artifact reduction using slice overlap in slice encoding for metal artifact correction.

PURPOSE: Multispectral imaging (MSI) significantly reduces metal artifacts. Yet, especially in techniques that use gradient selection, such as slice encoding for metal artifact correction (SEMAC), a residual ripple artifact may be prominent. Here, an analysis is presented of the ripple artifact and of slice overlap as an approach to reduce the artifact. METHODS: The ripple artifact was analyzed theoretically to clarify its cause. Slice overlap, conceptually similar to spectral bin overlap in multi-acquisition with variable resonances image combination (MAVRIC), was achieved by reducing the selection gradient and, thus, increasing the slice profile width. Time domain simulations and phantom experiments were performed to validate the analyses and proposed solution. RESULTS: Discontinuities between slices are aggravated by signal displacement in the frequency encoding direction in areas with deviating B0. Specifically, it was demonstrated that ripple artifacts appear only where B0 varies both in-plane and through-plane. Simulations and phantom studies of metal implants confirmed the efficacy of slice overlap to reduce the artifact. CONCLUSION: The ripple artifact is an important limitation of gradient selection based MSI techniques, and can be understood using the presented simulations. At a scan-time penalty, slice overlap effectively addressed the artifact, thereby improving image quality near metal implants.

The role of particle shape in active depletion.

Using numerical simulations, we study how a solution of small active disks, acting as depletants, induces effective interactions on large passive colloids. Specifically, we analyze how the range, strength, and sign of these interactions are crucially dependent on the shape of the colloids. Our findings indicate that while colloidal rods experience a long-ranged predominantly attractive interaction, colloidal disks feel a repulsive force that is short-ranged in nature and grows in strength with the size ratio between the colloids and active depletants. For colloidal rods, simple scaling arguments are proposed to characterize the strength of these induced interactions.

[The skin's own antibiotics. Important features of antimicrobial peptides for clinical practice]. / Hauteigene Antibiotika. Wichtige Erkenntnisse über antimikrobielle Peptide für Klinik und Praxis.

Despite permanent confrontation with a potentially harmful environment, its own microbiota and the fact that minor injuries occur frequently in everyday life, skin infections are a rare event. A chemical barrier of antimicrobial peptides (AMP), some of them constitutively expressed, others inducible by various stimuli, contributes to the integument's resistance. AMP are evolutionarily old components of the innate immunity which became the focus of interest due to their broad spectrum of activity against microorganisms and the rare occurrence of antimicrobial resistance. These attributes make them promising alternative candidates for future antibiotics. Furthermore various dermatological diseases are associated with an altered expression of these molecules, which might then play a pathogenetic role. In addition to their antimicrobial activity, some AMP have immunomodulatory effects and can promote wound healing, properties which currently are under intensive research.

[Functional and audiological results of tympanoplasty type I using pure perichondrial grafts]. / Funktionelles und audiologisches Ergebnis der Tympanoplastik Typ I mit reinem Perichondrium.

BACKGROUND: There are very few studies analyzing the functional und audiological results of tympanoplasty type I using pure perichondrium. MATERIALS AND METHODS: Data of 80 randomly selected patients, who had tympanoplasty surgery between 1998 and 2008 with pure perichondrium were evaluated retrospectively. Average postoperative follow-up was 9 months. The preoperative- and postoperative status of tympanic membrane, air-bone gap (ABG) and influence of perforation size and perforation etiology on closure rate served as study parameters. RESULTS: The closure rate for tympanoplasty type I with pure perichondrium was 85% and the mean ABG reduction was 10.8±7.22 dB. Size and etiology of the perforation had no influence on operative results. CONCLUSIONS: Concerning closure rates pure perichondrium is very suitable for repairing tympanic membrane defects. Postoperative audiological results can be compared to other transplants, such as temporal fascia or combined cartilage-perichondrium grafts and the intraoperative handling and positioning seem to be more comfortable.

Legionella pneumophila macrophage infectivity potentiator protein appendage domains modulate protein dynamics and inhibitor binding.

Macrophage infectivity potentiator (MIP) proteins are widespread in human pathogens including Legionella pneumophila, the causative agent of Legionnaires' disease and protozoans such as Trypanosoma cruzi. All MIP proteins contain a FKBP (FK506 binding protein)-like prolyl-cis/trans-isomerase domain that hence presents an attractive drug target. Some MIPs such as the Legionella pneumophila protein (LpMIP) have additional appendage domains of mostly unknown function. In full-length, homodimeric LpMIP, the N-terminal dimerization domain is linked to the FKBP-like domain via a long, free-standing stalk helix. Combining X-ray crystallography, NMR and EPR spectroscopy and SAXS, we elucidated the importance of the stalk helix for protein dynamics and inhibitor binding to the FKBP-like domain and bidirectional crosstalk between the different protein regions. The first comparison of a microbial MIP and a human FKBP in complex with the same synthetic inhibitor was made possible by high-resolution structures of LpMIP with a [4.3.1]-aza-bicyclic sulfonamide and provides a basis for designing pathogen-selective inhibitors. Through stereospecific methylation, the affinity of inhibitors to L. pneumophila and T. cruzi MIP was greatly improved. The resulting X-ray inhibitor-complex structures of LpMIP and TcMIP at 1.49 and 1.34 Å, respectively, provide a starting point for developing potent inhibitors against MIPs from multiple pathogenic microorganisms.

Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer.

BACKGROUND: New therapeutic options for metastatic pancreatic cancer are urgently needed. In pancreatic cancer, overexpression of the epidermal growth factor receptor 2 (HER2) has been reported in up to 45%. This multicentre phase II study investigated the efficacy and toxicity of the HER2 antibody trastuzumab combined with capecitabine in the patients with pancreatic cancer and HER2 overexpression. METHODS: Primary endpoint was progression-free survival (PFS) after 12 weeks. A total of 212 patients were screened for HER2 expression. RESULTS: Immunohistochemical (IHC) HER2 expression was: 83 (40%) grade 0, 71 (34%) grade 1, 31 (15%) grade 2, 22 (11%) grade 3. A total of 17 patients with IHC +3 HER2 expression or gene amplification could be assessed for the treatment response. Grade 3/4 treatment toxicities were: each 7% leucopenia, diarrhoea, nausea and hand-foot syndrome. Progression-free survival after 12 weeks was 23.5%, median overall survival (OS) 6.9 months. CONCLUSION: This study demonstrates +3 HER2 expression or gene amplification in 11% of patients. Contrary to breast and gastric cancer, only 7 out of 11 (64%) patients with IHC +3 HER2 expression showed gene amplification. Although the therapy was well tolerated, PFS and OS did not perform favourably compared with standard chemotherapy. Together, we do not recommend further evaluation of anti-HER2 treatment in patients with metastatic pancreatic cancer.

ARF6 is a host factor for SARS-CoV-2 infection in vitro.

SARS-CoV-2 is a newly emerged beta-coronavirus that enter cells via two routes, direct fusion at the plasma membrane or endocytosis followed by fusion with the late endosome/lysosome. While the viral receptor, ACE2, multiple entry factors, and the mechanism of fusion of the virus at the plasma membrane have been extensively investigated, viral entry via the endocytic pathway is less understood. By using a human hepatocarcinoma cell line, Huh-7, which is resistant to the antiviral action of the TMPRSS2 inhibitor camostat, we discovered that SARS-CoV-2 entry is not dependent on dynamin but dependent on cholesterol. ADP-ribosylation factor 6 (ARF6) has been described as a host factor for SARS-CoV-2 replication and it is involved in the entry and infection of several pathogenic viruses. Using CRISPR-Cas9 genetic deletion, we observed that ARF6 is important for SARS-CoV-2 uptake and infection in Huh-7. This finding was corroborated using a pharmacologic inhibitor, whereby the ARF6 inhibitor NAV-2729 showed a dose-dependent inhibition of viral infection. Importantly, NAV-2729 reduced SARS-CoV-2 viral loads also in more physiologic models of infection: Calu-3 and kidney organoids. This highlighted the importance of ARF6 in multiple cell contexts. Together, these experiments points to ARF6 as a putative target to develop antiviral strategies against SARS-CoV-2.

Double inversion recovery MRI versus contrast-enhanced MRI for evaluation of knee synovitis in juvenile idiopathic arthritis.

BACKGROUND: Double inversion recovery (DIR) MRI has the potential to accentuate the synovium without using contrast agents, as it allows simultaneous signal suppression of fluid and fat. The purpose of this study was (1) to compare DIR MRI to conventional contrast-enhanced (CE) MRI for delineation of the synovium in the knee in children with juvenile idiopathic arthritis (JIA) and (2) to assess the agreement between DIR MRI and CE-MRI regarding maximal synovial thickness measurements. RESULTS: In this prospective study, 26 children with JIA who consecutively underwent 3.0-T knee MRI between January 2018 and January 2021 were included (presence of knee arthritis: 13 [50%]; median age: 14 years [interquartile range [IQR]: 11-17]; 14 girls). Median confidence to depict the synovium (0-100 mm visual analogue scale; scored by 2 readers [consensus based]) was 88 (IQR: 79-97) for DIR MRI versus 100 (IQR: 100-100) for CE-MRI (p value = < .001). Maximal synovial thickness per child (millimeters; scored by 4 individual readers) on DIR MRI was greater (p value = < .001) in the children with knee arthritis (2.4 mm [IQR: 2.1-3.1]) than in those without knee arthritis (1.4 mm [IQR: 1.0-1.6]). Good inter-technique agreement for maximal synovial thickness per child was observed (rs = 0.93 [p value = < .001]; inter-reader reliability: ICC DIR MRI = 0.87 [p value = < .001], ICC CE-MRI = 0.90 [p value = < .001]). CONCLUSION: DIR MRI adequately delineated the synovium in the knee of children with JIA and enabled synovial thickness measurement similar to that of CE-MRI. Our results demonstrate that DIR MRI should be considered as a child-friendly alternative to CE-MRI for evaluation of synovitis in children with (suspected) JIA.

KRAS mutation in metastatic pancreatic ductal adenocarcinoma: results of a multicenter phase II study evaluating efficacy of cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line therapy.

BACKGROUND: Genetic alterations within the epidermal growth factor receptor (EGFR) pathway, including KRAS mutations, have been demonstrated to be associated with response to EGFR inhibitors like cetuximab in colorectal cancers. Mutations in the KRAS gene have been found in 70-90% of pancreatic cancers. Unfortunately, the addition of cetuximab to chemotherapy did not increase response or survival in patients with advanced pancreatic cancer in phase II and phase III studies. The aim of this study was to evaluate the relationship between KRAS mutations and response or survival in patients with metastatic pancreatic cancer treated with cetuximab plus chemotherapy. METHODS: Within a multicenter phase II trial, 64 patients with metastatic pancreatic cancer were treated with cetuximab in combination with gemcitabine and oxaliplatin until disease progression. Analyses of the EGFR pathway, including KRAS mutations, could be performed in 25 patients. Analyses were carried out following microdissection of the tumor. RESULTS: Fourteen (56%) of the 25 patients examined harbored a point mutation in codon 12 of the KRAS gene. No differences between the groups were noted in median progression-free survival (104 days in KRAS wild-type patients vs. 118 days in patients with KRAS mutations). Overall survival was longer in wild-type patients compared to patients with KRAS mutations (263 vs. 162 days), but the difference did not reach statistical significance. A further analysis of our clinical phase II trial showed that the presence of a rash was significantly correlated with overall survival. CONCLUSIONS: KRAS mutation in codon 12 may be associated with reduced survival compared to KRAS wild type. The role of KRAS mutations for cetuximab therapy in pancreatic cancer warrants further investigation in larger trials to exclude an epiphenomenon. Furthermore, the development of a rash is indicative of clinical benefit.

Progesterone inhibits arterial smooth muscle cell proliferation.

Mortality from atherosclerotic cardiovascular disease is lower in premenopausal women than in age-matched men. It is also lower in postmenopausal women who take estrogens and progestins together rather than estrogens alone. Progesterone receptors were detected in human and rat aortic smooth muscle cells in vivo and in vitro (in subculture). We examined the effect of progesterone on proliferation of smooth muscle cells, important constituents of atherosclerotic plaques. Progesterone at physiologic levels inhibited DNA synthesis and proliferation in these cells in a dose-dependent manner, and pretreatment with the progesterone receptor antagonist RU486 blocked inhibition. Cyclin A and E messenger RNA levels decreased after progesterone treatment but those of cyclin B and D1 did not change. This cell cycle-dependent inhibition of arterial smooth muscle cell proliferation by progesterone may represent a mechanism for the hormone's protective effect against atherosclerosis.

The value of MRI STIR signal intensity on return to play prognosis and reinjury risk estimation in athletes with acute hamstring injuries.

OBJECTIVES: Previous studies have shown low to moderate evidence for a variety of magnetic resonance imaging (MRI) features as prognostic factors in athletes with hamstring injuries. Short-tau inversion recovery (STIR) signal intensity has not yet been investigated for assessing the prognosis of acute muscle injuries. Our aim was to explore the relationship between MRI STIR signal intensity and time to return to play (RTP) and to investigate the association between MRI STIR and reinjury risk in athletes with acute hamstring injuries. STUDY DESIGN: Case-control study. METHODS: We used MRI STIR to measure intramuscular signal intensity in patients with clinically diagnosed hamstring injuries at two time points: at injury and RTP. At injury, we calculated the association of MRI STIR signal intensity with the time to RTP and reinjury risk. At RTP, the association of MRI STIR signal intensity and reinjury risk and the change in MRI STIR signal intensity over time on reinjury risk was evaluated. RESULTS: 51 patients were included. We found increased MRI STIR signal intensity: (1) at time of injury not to be associated with time to RTP, (2) at time of injury to be associated with a slightly lower risk for reinjury: odds 0.986 (0.975-0.998, p=0.02) and (3) at RTP not to be associated with reinjury risk. (4) We found no association between the change in MRI STIR signal intensity over time and reinjury risk. CONCLUSION: Increased MRI STIR signal intensity at injury has no value in time to RTP prognosis, but is associated with a reduced reinjury risk.