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Biomedical subjects

P Schlag

Publications and source records attributed to P Schlag.

At least 19 recordsLinked to original sources

[Comparison between endorectal MRI (EMRTI) and endorectal sonography (ES) after surgery or therapy for rectal tumors to exclude recurrent or residual tumor].

PURPOSE: This study was designed to evaluate the accuracy and limitations for staging of contrast-enhanced endorectal MR imaging comparing with transrectal US for restaging of rectal lesions after surgery or after therapeutic radiation. Both methods were correlated with histologic findings. METHOD/MATERIALS: The efficacy of these both methods was evaluated in 30 patients with supposed residual or recurrent rectal neoplasms. Contrast enhanced (bolus injection of 0.1 mmol/kg b.w. Gd-DTPA) endorectal MR imaging was performed using a 1.5 Tesla Magnetom. In addition endosonography (7.5 x or 10-MHz transducer) was used. RESULTS: In 8 patients with rectal adenoma after electro-laser resection, 8 patients with rectal carcinoma stage pT1 after transanal resection, 8 patients with rectal carcinoma stage pT2 and 6 patients with rectal carcinoma stage pT3 after regional hyperthermia with radiochemo-therapy, the following results were obtained during the postsurgical or posttherapeutical follow-up with respect to histopathological evaluation: exact staging in 86.6 % with EMRI and 63.3 % in ES, overstaging in 8 % (EMRI) and 23 % (ES), understaging in 0 % (EMRI) and 7 % (ES). The highest diagnostic accuracy was shown in EMRT in patients with rectal adenoma and rectal carcinoma (pT1) and after electro-laser resection or transanal resection during follow-up. CONCLUSIONS: Contrast enhanced endorectal MR imaging appears to be very promising for accurate posttherapeutical staging of rectal cancer and helpful in the diagnosis of recurrence or the differentiation between scar tissue and residual rectal tumor.

Adenoma↗

Constitutional genomic instability with inversions, duplications, and amplifications in 9p23-24 in BRCA2 mutation carriers.

Germ-line mutations of the BRCA2 gene (13q12-13) account for a large proportion of familial breast cancer cases in females and the majority of familial breast cancers in males. Recent studies provide evidence for a role of the BRCA2 protein in the maintenance of genomic integrity by involvement in DNA repair and recombination. In pursuit of identifying in humans genetic damage resulting from mutated BRCA2, we have analyzed constitutional karyotypes of BRCA2 mutation carriers. The present study establishes that constitutional distal 9p rearrangements without obvious additional gross chromosomal alterations are a recurrent feature of independently ascertained families. From our cytogenetic analyses we have no indication of additional gross rearrangements, but we cannot exclude more subtle recombinations in other genomic regions. We also show that the topography of the 9p rearrangements can differ among family members, even within an individual that can have cell populations with different 9p rearrangements. Collectively these results raise point to an association of mutant BRCA2 with genomic instability and gene alteration in 9p23-24 in at least a subset of BRCA2 mutation carriers.

Adult↗

Lymphatic mapping and retrieval of the sentinel lymph node in treatment of early breast cancer.

Lymphatic mapping and sentinel lymph node biopsy is an important step to surgical individualization of breast cancer therapy. With lymphatic mapping and minimally invasive biopsy of one or two detected lymph nodes the method provides an exact evaluation of the nodal status. Using sentinel lymph node biopsy (SLNB), costs and morbidity of an axillary lymph node dissection (ALND) can be avoided in nodal negative patients, whereas nodal positive patients are chosen for ALND very selectively according to the detection of an increased percentage of micrometastases. While experienced centers are introducing this method into clinical practice for the benefit of patients with early-stage breast cancer in Europe, further research should focus on quality control, definition of standards considering the individual needs of the individual patient, and the evaluation of the impact of micrometastases. This article gives an overview of the current knowledge of SLNB and discusses critically current indications and methods as well as application techniques.

Axilla↗

[Radiological-guided liver-port implantation: Evaluation, technical approach, interventional procedure and follow up].

UNLABELLED: Radiological-guided liver-port implantation: Evaluation, technical approach, interventional procedure and follow up. PURPOSE: Description of evaluation, technical approach, interventional procedure and follow up of radiological-guided liver-port implantation. METHOD: Percutaneous implantation of a liver-port system was performed in twelve patients through a transfemoral approach and in one patient via the superficial epigastric artery after surgical exploration. In four patients we used port systems which are accessible via ventral puncture. Strecker-port systems were implanted in the remaining nine patients. RESULTS: The liver-port implantation was technically successful in all cases. No dislocation of the distal catheter tip, no thrombosis of the hepatic or splenic artery, no leakage near connections of the catheters or connections of catheter and port system and no thrombosis of the femoral arteries were observed. Correction of a kink in the catheter was performed in one patient. Another patient showed prolonged healing of the subcutaneous pocket. CONCLUSIONS: Interventional liver-port implantation is a safe procedure and leads to good clinical results. From the view of the radiologist the Strecker-system shows a good performance. The approach via the superficial epigastric artery demands excellent interdisciplinary cooperation.

Angiography↗

Two regions of deletion in 9p23-24 in sporadic breast cancer.

Allelic deletions of 9p including band 21-22 are common in various types of human carcinomas including breast cancer. Our previous cytogenetic studies had identified constitutional chromosomal changes in 9p23-24 in patients of a male-breast-cancer family and 9p23-24 alterations in a cell line established from a sporadic female breast cancer. To find out whether this genomic region is involved more frequently in alterations in sporadic breast cancers, we have surveyed 80 microdissected tumor samples for both loss of heterozygosity (LOH) and homozygous deletion at 22 microsatellite loci spanning 9p22 to 9p24 using fluorescent multiplex PCR. LOH at one or more loci was observed in 32 (40%) of these tumors. Homozygous deletion was detected in four cases. Eleven tumors had LOH at all of the informative loci analyzed, whereas 21 tumors showed partial-terminal or interstitial allelic loss of 9p. Deletion mapping identified two common regions of deletion: (a) 4 cM including D9S281 to D9S286; and (b) 1 cM including D9S1808 to D9S268.

Breast Neoplasms↗

Secretory type II phospholipase A2 (PLA2G2A) expression status in colorectal carcinoma derived cell lines and in normal colonic mucosa.

There is good evidence now that the secretory type II phospholipase A2 (Pla2g2a) gene represents the Mom1 locus, a genetic modifier of tumor resistance in the multiple intestinal neoplasia (Min) mouse. Previously we have mapped the human homolog PLA2G2A to 1p35-36.1 within a region that is the target of frequent deletions in sporadic colorectal tumors. Here we show 64% loss of heterozygosity (LOH) at the PLA2G2A locus in primary tumors. We studied PLA2G2A expression in both colorectal tumor cell lines and normal mucosa. Most of the lines lacked detectable PLA2G2A transcripts by Northern analysis. Large differences in expression were seen among normal mucosa of different patients with sporadic tumors. We analysed the coding region of PLA2G2A in eight colorectal cancer cell lines with hemizygous deletion at 1p35-36/PLA2G2A, in none we did detect a mutation. Biallelic expression of PLA2G2A was observed in a cell line heterozygous for an exon 3 polymorphism, rendering unlikely that imprinting is a pathway participating in the loss of PLA2G2A function. It remains uncertain if PLA2G2A, in particular its apparent lack of expression in tumor cells, might be a factor in human colorectal tumorigenesis.

Animals↗

Rationale for using invasive thermometry for regional hyperthermia of pelvic tumors.

PURPOSE: Invasive thermometry for regional hyperthermia is time-consuming, uncomfortable, and risky for the patient. We tried to estimate the benefit/cost ratio of invasive thermometry in regional hyperthermia using the radiofrequency system BSD-2000. METHODS AND MATERIALS: We evaluated 182 patients with locally advanced pelvic tumors that underwent regional hyperthermia. In every patient a tumor-related temperature measurement point was obtained either by invasive or minimally invasive catheter measurement tracks. In the earlier period for every patient an intratumoral measurement point was decided as obligatory and intratumoral catheters were implanted intraoperatively, CT guided, or under fluoroscopy. In the later period, invasive thermometry often was avoided, if a measurement point in or near the tumor was reached by an endoluminally inserted catheter (rectal, vaginal, cervical, urethral, or vesical). For every patient side effects and complications referred to thermometry were evaluated and compared with the potential benefit of the invasively achieved temperature data. The suitability of endolumimally registered temperatures is analyzed to estimate local feasibility (specific absorption rate achieved) and local effectiveness (thermal parameters correlated with response). RESULTS: In 74 of 182 patients invasive thermometry was performed, at most CT-guided for soft tissue sarcomas and rectal recurrences. In 14 of 74 (19%) side effects such as local inflammation, pain, or abscess formation occurred that enforced removal of the catheter. However, local problems were strongly correlated with the dwell time of the catheter and nearly never occurred for dwell times less than 5 days. Fortunately, no fatal complications (e.g., bleeding or perforation) occurred during or after implantation which could be attributed to the invasive thermometry procedure. Endoluminal tumor-related temperature rises per time unit (to estimate power density) were correlated with intratumoral rises at the same patients (where both measurements were available). For a subgroup of patients pooled in two Phase II studies with rectal (n = 37) and cervical (n = 18) carcinomas thermal parameters derived from endoluminal measurements were correlated with response or local control, resp. CONCLUSIONS: If a tumor-related endoluminal temperature measurement point is available, additional invasive thermometry gives no further information to improve the power deposition pattern. For primary rectal and cervical cancer, and probably as well for prostate, bladder and anal cancer, endoluminal measurements are suitable to estimate local feasibility and effectiveness. Therefore, invasive thermometry is dispensable in the majority of patients. In some selected cases, temperature measurement in the tumor center is required to estimate the maximum temperature. In those cases, dwell time of catheters should be minimized--and it should be considered to perform invasive thermometry at the beginning (one or two heat treatments).

Catheterization↗

An interstitial tandem duplication of 9p23-24 coexists with a mutation in the BRCA2 gene in the germ line of three brothers with breast cancer.

Germ-line mutations of the BRCA2 gene account for the majority of families with both male and female breast cancer. However, among independently ascertained families with the same mutation, cases of male breast cancer often appear to cluster in a single family or in a particular branch of one family. This suggests that the risk of male breast cancer conferred by BRCA2 mutations may be modified by other genetic or environmental factors. We report a family in which three brothers with breast cancer carry in their germ line two genetic abnormalities: an insertion A at nucleotide 2041 in exon 10 of BRCA2, which leads to premature termination of the encoded protein at codon 615, and a tandem interstitial duplication involving chromosome bands 9p23-24. We propose that the coexistence of this rare chromosomal abnormality with BRCA2 mutation may be augmenting the risk of male breast cancer conferred by the BRCA2 mutation.

BRCA2 Protein↗

[Phase II study on preoperative radio-chemo-thermotherapy in locally advanced rectal carcinoma].

BACKGROUND: Recent studies show that preoperative radio-chemotherapy can increase resectability and local control of locally advanced rectal carcinomas. Additional regional hyperthermia might increase remission rates and tumor response. We therefore tested regional hyperthermia together with radio-chemotherapy in a phase-II study on locally advanced rectal carcinomas. PATIENTS AND METHODS: Thirty-seven patients with primary advanced stage uT3/T4 rectal carcinomas were treated with preoperative radio-chemo-thermo-therapy. The initial tumor depth was determined using endosonography, CT, and MRI. Radiotherapy was carried out in prone position (on a belly board) using standard techniques, with 5 x 1.8 Gy per week up to 45 Gy at the reference point. 5-Fluorouracil (300 to 500 mg/m2) was administered with low doses of leucovorin (50 mg) on days 1 to 5 and 22 to 28. The patients were treated with regional hyperthermia each week prior to radiotherapy and simultaneously with chemotherapy, using the Sigma 60 ring from the BSD-2000 system. Temperature/position curves and temperature/time curves were recorded in endocavitary (endorectal) catheters in tumor contact and as well in bladder and vagina. Following endosonographic restaging, the operation was carried out 4 to 6 weeks after the end of preoperative therapy and adjuvant chemotherapy continued in four cycles. In cases where tumors were non-resectable, a boost up to 64 Gy was aimed. RESULTS: Thirty-one of the 37 patients (84%) with primary carcinoma proved locally R0-resectable. In addition we had 1 R1-resection (3%) and 5 non-resectable tumors (13%). Among the resected tumors, 53% experienced a reduction of depth infiltration from the initial endosonographic stage during preoperative therapy. The actuarial survival rate after 4 years is 65% (free of progression 57%). The actuarial 4-year survival rate was particularly favorable for the group of responders. Overall, the preoperative multimodal therapy was well tolerated, and premature termination was only necessary in 1 case (3%). Grade III/IV toxicities in the intestine and skin were reduced as far as possible by field blockings and cooling of the perineal region. They occurred only in 5/37 patients (13%) at the intestine and in 6/37 patients (16%) at the skin. The thermal data were subjected to a statistical analysis. The quality of temperature distribution (T90, cum min T90 > or = 40.5 degrees C) depends on the power level and relative power density. The response (reduction of tumor size or depth infiltration) correlated significantly with quality parameters of the temperature distributions. This dependency is found as a trend for progression-free survival, too. CONCLUSIONS: Preoperative radio-chemo-thermo-therapy proved to be practical and effective, with encouraging remission rates and excellent local control rates. For this reason, a phase-III study to test regional hyperthermia has been initiated. At the same time, certain technical improvements are still under development for regional hyperthermia.

Adult↗

Preparation and characterization of differently aggregated colorectal carcinoma cell subpopulations from surgical specimens.

The loss of intercellular adhesion within the primary tumor is one of the key events leading to metastasis. Although a number of adhesion molecules involved in intercellular adhesion have been described in experimental systems, the clinical relevance of many of these molecules still has to be determined. We tried to assess the contribution of membrane-bound carbohydrates and of E-Cadherin, CEA, and Sia-LeA for intercellular adhesion of cells isolated from colorectal carcinoma tissue directly obtained from the surgeon. A subpopulation of nonaggregating cells was prepared by means of slowly passing of freshly isolated cells through a series of sieves with decreasing mesh widths. Nonaggregating cells differed mainly in two aspects from aggregated cells: (i) determination of lectin binding and of specific sialytransferase activities revealed enhanced alpha2,6-sialylation of nonaggregating cells, and (ii) staining with specific antibodies documented a loss of E-Cadherin reactivity of such cells. An enhanced activity of beta-galactoside alpha2,6-sialytransferase (ST6Gal 1) was found in metastasizing colorectal carcinomas; however, its biological function has to be shown. Our results suggest that ST6Gal 1 is responsible for reduced homotypic aggregation of colorectal carcinoma cells and may thus facilitate the release of single cells from the primary tumor.

Agglutinins↗

Intravenous and intra-arterial oxygen-15-labeled water and fluorine-18-labeled fluorouracil in patients with liver metastases from colorectal carcinoma.

UNLABELLED: Intra-arterial chemotherapy can potentially increase drug delivery at the tumor sites and has therefore been used for the therapy of metastatic colorectal cancer. METHODS: Dynamic PET and [18F]fluorouracil (18F-FU) were used in patients with liver metastases from colorectal cancer to examine the pharmacokinetics of the drug up to 120 min after intravenous and intra-arterial injection of the same dose of fluorouracil (FU). All patients included in the study (n = 15) had surgically implanted catheters in the gastroduodenal artery. Dynamic PET studies (up to 5 min) with 15O-labeled water were performed for the evaluation of the access to the lesions immediately before the 18F-FU study using both administration routes. The final evaluation included 24 metastases, obtained from 15 patients. RESULTS: Of 24 lesions, 21 (87.5%) showed an improved access using the intra-arterial approach, and 20 (83.3%) demonstrated a better FU influx after intra-arterial 18F-FU infusion. Metastases reached the highest 18F-FU concentrations after intra-arterial administration, with a maximum standardized uptake values of 18.75 for the FU influx and of 5.03 for FU trapping. Of 24 metastases, eight (33.3%) demonstrated enhanced FU trapping after the intra-arterial administration. Cluster analysis revealed a group of metastases (n = 6) with a nonperfusion-dependent FU transport using the intravenous application. Of these six lesions, five (83.3%) did not show any enhancement of the 18F-FU trapping after intra-arterial application. The data gave evidence for at least one different, energy-dependent transport system, which can be saturated even after intravenous administration of the drug. CONCLUSION: The data show that the main limiting factor for a therapy response is the very high and rapid elimination of the cytostatic agent out of the tumor cells. Furthermore, it was not possible to predict the pharmacokinetics of FU after intra-arterial application using an intravenous PET study. It may be possible, using intravenous PET double-tracer studies, to identify metastases having a nonperfusion-dependent transport system and exclude them from an intra-arterial treatment protocol.

Antimetabolites, Antineoplastic↗

Fluorine-18-fluorouracil to predict therapy response in liver metastases from colorectal carcinoma.

UNLABELLED: Prediction of chemotherapy response is still a problem in oncological patients. METHODS: Studies with PET and 18F-fluorouracil (FU) were used for measurements of drug concentrations in patients with liver metastases from colorectal carcinoma. The PET data obtained before onset of FU chemotherapy were correlated to the growth rate of the metastases after therapy. The final evaluation included 25 metastases obtained in 17 patients. CT preceded the first chemotherapeutic cycle and was repeated within 3-11 mo after onset of treatment. The uptake of the cytostatic agent was evaluated in the liver metastases using the SUV at 120 min after tracer infusion. Tumor growth rate of the metastases was calculated based on CT volumetric data. RESULTS: The trapping of 18F-FU was highly variable even for multiple metastases in the same patients. Six metastases with high 18F-FU uptake values exceeding 3.0 SUV correlated with negative growth rate values, 5 of 25 metastases with intermediate uptake values ranging from 2.0-3.0 SUV were associated with almost stable growth rate values nearly zero and 14 of 25 metastases with low uptake values <2.0 SUV demonstrated positive growth rate values. Only metastases with a 18F-FU uptake exceeding 3.0 SUV at 120 min postinjection demonstrated a response to therapy. A significant correlation of 0.86 (p < 0.001) was found between the 18F-FU uptake values in the metastases measured before chemotherapy and the growth rate of the lesions after treatment. CONCLUSION: The data show, that FU chemotherapy outcome can be predicted using a single PET study with 18F-FU before onset to therapy.

Antimetabolites, Antineoplastic↗

[Magnetic resonance tomography and endosonography in the preoperative staging of advanced rectal carcinomas after hyperthermoradiochemotherapy].

PURPOSE: Comparison of diagnostic accuracy of staging of endorectal sonography (ES) and body coil MRI after preoperative hyperthermoradiochemotherapy in patients with advanced rectal cancer. METHODS: Prospective analysis of MRI and ES in 30 patients after hyperthermoradiochemotherapy and correlation with histopathological patterns. RESULTS: T-staging by MRI was correct in 47% and by ES in 53% of the cases. Despite similar accuracy of staging in T0- and T1-tumours, we found different accuracies concerning T2-tumour staging about 63% versus 73% (MRI/ES), concerning perirectal infiltration 70% for both techniques, concerning invasion of adjacent organs 90% versus 87%, and concerning lymph node metastases without respect to the N-stage 63% versus 63%. CONCLUSION: Both imaging modalities provide useful information for operation planning despite limited accuracy after hyperthermoradiochemotherapy. The body coil MRI does not seem to be severely inferior to ES in post-therapeutic staging, despite better contour line imaging by ES. With respect to the determination of invasion of other organs, MRI seems to be more useful.

Adult↗

Accuracy of staging rectal tumors with contrast-enhanced transrectal MR imaging.

OBJECTIVE: Our objective was to evaluate the accuracy of contrast-enhanced transrectal MR imaging in staging rectal adenoma and carcinoma by correlating with histopathologic findings. SUBJECTS AND METHODS: Thirty-five patients underwent transrectal MR imaging on a 1.5-T superconducting unit using unenhanced T1-weighted and T2-weighted spin-echo and turbo spin-echo sequences, a dynamic gadopentetate dimeglumine-enhanced turbo fast low-angle shot sequence, and enhanced T1-weighted spin-echo sequences. For all patients, histopathologic correlation was available from biopsy (n = 15) or surgical resection (n = 20). Two radiologists unaware of each other's interpretations of the scans interpreted each case from which we evaluated qualitative and quantitative data. RESULTS: Rectal adenomas (n = 15) were identified when imaging revealed an intact muscularis mucosae, a homogeneous internal structure, and high contrast enhancement of the lesion. Carcinomas staged as T1 by TNM criteria (n = 6) were best revealed by dynamic turbo fast low-angle shot sequences, in which an intact muscularis propria could be seen. Visualization of enhancing tumor tissue in the muscularis propria indicated T2 carcinoma (n = 5). All T3 (n = 5) and T4 (n = 4) carcinomas were correctly staged with dynamic and static MR imaging. The stage revealed by MR imaging correlated well with histologic staging results in 89% (observer 1) and 86% (observer 2) of interpretations. However, when interpreting MR imaging, observers tended to overstage and never understaged. CONCLUSION: Transrectal surface-coil MR imaging provided reliable information in staging patients before surgery and in evaluating rectal adenoma and carcinoma.

Adenoma, Villous↗

[Diagnostic value of 123iodine-ibzm scintigraphy for staging of malignant melanomas].

AIM: We performed 123I-(S)-2-hydroxy 3-iodo-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide (123I-IBZM)-scintigraphy to evaluate one usefulness of this radiopharmaceutic agent for the diagnosis of malignant melanomas. METHODS: We performed whole body scintigraphies after intravenous application of 123I-IBZM in 20 patients and compared the scintigraphic findings with the results of other imaging methods. RESULTS: In four patients no melanotic lesions were detectable, neither by 123I-IBZM-scintigraphy nor by other imaging procedures. A scintigraphic detection of cutaneous or subcutaneous lesions was possible in our of ten patients. 123I-IBZM-scintigraphy showed pathological findings in five of ten patients with lymph node metastases. Two patients had brain metastases, in four patients lung localizations were present. None of these organic manifestations was discovered by scintigraphic means. Amelanotic lesions never showed an accumulation of 123I-IBZM. It was not possible to detect any "new" lesions, i.e. lesions not visualized by other imaging procedures. CONCLUSION: 123I-IBZM-scintigraphy did not present additional information important for the therapy of patients with malignant melanoma.

Benzamides↗

Gene transfer into hepatocytes and human liver tissue by baculovirus vectors.

Gene therapy of liver diseases requires the development of efficient vectors for gene transfer in vivo. Retroviral and adenoviral vectors have been shown to deliver genes efficiently into hepatocytes in vitro and in vivo. However, these vectors do not allow for exclusive infection of the liver which would be highly advantageous for in vivo gene therapy strategies. We have recently demonstrated that genetically modified baculoviruses (Autographa californica nuclear polyhedrosis virus) efficiently deliver genes into cultured cells and have a strong preference for hepatocytes of different origin. Baculoviral gene transduction efficiency into human hepatocytes was determined to approach 100% and expression levels are high, provided that gene expression is controlled by mammalian promoters. In this report, we present further properties of baculoviruses regarding their use for hepatocyte gene transfer. Baculovirus-mediated gene expression declines rapidly in the hepatocellular carcinoma cell line Huh7 and more slowly in primary cultures of mouse hepatocytes. Direct application of baculoviruses for gene delivery to the liver in vivo is hampered by serum components, presumably by complement. However, we demonstrate here that baculoviral gene transfer is feasible in ex vivo perfused human liver tissue. This result suggests the development of a strategy using baculoviral vectors for liver-directed gene therapy.

Animals↗

Lipopolysaccharide induces the rapid tyrosine phosphorylation of the mitogen-activated protein kinases erk-1 and p38 in cultured human vascular endothelial cells requiring the presence of soluble CD14.

Human vascular endothelial cells (HUVECs), which do not display the lipopolysaccharide (LPS) receptor CD14, were examined for protein tyrosine phosphorylation after LPS stimulation in the presence and absence of soluble CD14 (sCD14). By phosphotyrosine Western blotting and immunocomplex kinase assays we show that LPS was capable of inducing in these cells rapid protein tyrosine phosphorylation and kinase activation of two members of the mitogen-activated protein kinase (MAPK) family erk-1 and the newly discovered p38, requiring the presence of sCD14. LPS-induced tyrosine phosphorylation of MAPK was associated with increased transcript- and surface protein expression of intracellular adhesion molecule-1 by HUVECs. MAPK phosphorylation and activation was induced by LPS in concentrations as little as 30 ng/mL and as early as 15 minutes after stimulation. Furthermore, tyrosine kinase inhibitors such as Genistein partially inhibited this effect. These results show that LPS triggers similar signaling events in both CD14+ myelo-monocytic cells and cells lacking the putative LPS-receptor CD14, suggesting the presence of a common, yet unidentified element in LPS-signaling in both cell types.

Calcium-Calmodulin-Dependent Protein Kinases↗