Fragility and compressibility at the glass transition

Isothermal compressibilities and Brillouin sound velocities from the literature allow to separate the compressibility at the glass transition into a high-frequency vibrational and a low-frequency relaxational part. Their ratio shows the linear fragility relation discovered by x-ray Brillouin scattering [1], though the data bend away from the line at higher fragilities. Using the concept of constrained degrees of freedom, one can show that the vibrational part follows the fragility-independent Lindemann criterion; the fragility dependence seems to stem from the relaxational part. The physical meaning of this finding is discussed. [1] T. Scopigno, G. Ruocco, F. Sette and G. Monaco, Science 302, 849 (2003)Comment: 4 pages, 2 figures, 2 tables, 33 references. Slightly changed after refereein

Optimizing the parameters for hydro-jet dissection in fatty tissue — A morphological Ex Vivo analysis

Summary: Background: The advantage of water-jet dissection is the preservation of vessels and nerves. Especially in liver surgery, blood loss can be significantly decreased. The use of water-jet dissectors in other fields of surgery is currently under investigation. The preparation of vessels in fatty tissue is of special interest for plastic surgeons. The optimal technical parameters were investigated. Methods: Abdominal fat tissue of fresh cadavers was cut under standardized conditions with different parameters of the water-jet dissector. Results: One single pass at a cutting pressure between 20 and 60 Bar makes an incision of 8 mm. Deeper cuts can be achieved by repeated application on the same cut. Five passes at 40 Bar results in a depth of 1.7 cm without vessel damage. If the applied pressure is 50 or 60 Bar, up to 7% damaged vessels can be found. The water-jet dissection leads to a water uptake of the cut tissue. Conclusions: The optimal pressure for water-jet dissection of fatty tissue lies between 30 and 40 Bar. The effect of the mechanical irritation of the vessels has to be investigatedin vivo before using the water-jet dissector for preparation of blood vessels in humans, e.g. for flap dissectio

Thoracic wall reconstruction using both portions of the latissimus dorsi previously divided in the course of posterolateral thoracotomy

Objective: Besides other factors, the choice of reconstructive method for full thickness thoracic wall defects depends on the morbidity of preceding surgical procedures. The pedicled latissimus dorsi flap is a reliable and safe option for reconstruction of the thorax. A posterolateral thoracotomy, however, results in division of the muscle. Both parts of the muscle can be employed to close full thickness defects of the chest wall. The proximal part can be pedicled on the thoracodorsal vessels or the serratus branch; the distal part can be pedicled on paravertebral or intercostal perforators. This retrospective study was undertaken to evaluate the reconstructive potential of both parts of the latissimus dorsi in thoracic wall reconstruction after posterolateral thoracotomy. Methods: Between 1987 and 1999, 36 consecutive patients underwent reconstruction of full-thickness thoracic wall defects with latissimus dorsi-flaps after posterolateral thoracotomies. The defects resulted from infection and open window thoracostomy (n=31), trauma (n=3) and resection of tumours (n=2). The patients' average age was 57 years (range 22-76 years). Twenty-five patients were male, 11 were female. In 31 cases the split latissimus dorsi alone was employed; in five cases additional flaps had to be used due to the size of the defects, additional intrathoracic problems or neighbouring defects. Results: In 34 cases defect closure could be achieved without major complications. Empyema recurred in the pleural cavity in one case and one patient died of septicaemia. The 15 patients who had required a respirator in the preoperative phase could be extubated 4.8 days (average) after thoracic wall reconstruction. Postoperative hospital stay averaged 16 days. Conclusions: Different methods are available for reconstruction of full thickness defects of the thoracic wall. After posterolateral thoracotomy in the surgical treatment of empyema, oncologic surgery and traumatology, the latissimus dorsi muscle still retains some reconstructive potential. Advantages are low additional donor site morbidity and anatomical reliability. As it is located near the site of the defect, there is no need for additional surgical sites or intraoperative repositioning. In our service, the split latissimus dorsi muscle flap has proven to be a valuable and reliable option in thoracic wall reconstructio

Mechanical Relaxation in Glasses and at the Glass Transition

The Gilroy-Phillips model of relaxational jumps in asymmetric double-well potentials, developed for the Arrhenius-type secondary relaxations of the glass phase, is extended to a formal description of the breakdown of the shear modulus at the glass transition, the flow process.Comment: 13 pages, 11 figures, 49 ref

The long non-coding {RNA} {H19} suppresses carcinogenesis and chemoresistance in hepatocellular carcinoma

The long non-coding RNA (lncRNA) H19 represents a maternally expressed and epigenetically regulated imprinted gene product and is discussed to have either tumor-promoting or tumor-suppressive actions. Recently, H19 was shown to be regulated under inflammatory conditions. Therefore, aim of this study was to determine the function of H19 in hepatocellular carcinoma (HCC), an inflammation-associated type of tumor. In four different human HCC patient cohorts H19 was distinctly downregulated in tumor tissue compared to normal or non-tumorous adjacent tissue. We therefore determined the action of H19 in three different human hepatoma cell lines (HepG2, Plc/Prf5, and Huh7). Clonogenicity and proliferation assays showed that H19 overexpression could suppress tumor cell survival and proliferation after treatment with either sorafenib or doxorubicin, suggesting chemosensitizing actions of H19. Since HCC displays a highly chemoresistant tumor entity, cell lines resistant to doxorubicin or sorafenib were established. In all six chemoresistant cell lines H19 expression was significantly downregulated. The promoter methylation of the H19 gene was significantly different in chemoresistant cell lines compared to their sensitive counterparts. Chemoresistant cells were sensitized after H19 overexpression by either increasing the cytotoxic action of doxorubicin or decreasing cell proliferation upon sorafenib treatment. An H19 knockout mouse model (H19Δ3) showed increased tumor development and tumor cell proliferation after treatment with the carcinogen diethylnitrosamine (DEN) independent of the reciprocally imprinted insulin-like growth factor 2 (IGF2). In conclusion, H19 suppresses hepatocarcinogenesis, hepatoma cell growth, and HCC chemoresistance. Thus, mimicking H19 action might be a potential target to overcome chemoresistance in future HCC therapy

Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-kB-dependent manner

Hepatocyte death is an important contributing factor in a number of diseases of the liver. PHD1 confers hypoxic sensitivity upon transcription factors including the hypoxia inducible factor (HIF) and nuclear factor-kappaB (NF-κB). Reduced PHD1 activity is linked to decreased apoptosis. Here, we investigated the underlying mechanism(s) in hepatocytes. Basal NF-κB activity was elevated in PHD1(-/-) hepatocytes compared to wild type controls. ChIP-seq analysis confirmed enhanced binding of NF-κB to chromatin in regions proximal to the promoters of genes involved in the regulation of apoptosis. Inhibition of NF-κB (but not knock-out of HIF-1 or HIF-2) reversed the anti-apoptotic effects of pharmacologic hydroxylase inhibition. We hypothesize that PHD1 inhibition leads to altered expression of NF-κB-dependent genes resulting in reduced apoptosis. This study provides new information relating to the possible mechanism of therapeutic action of hydroxylase inhibitors that has been reported in pre-clinical models of intestinal and hepatic disease.status: publishe

A constitutive representation for linear aging, environmental-dependent viscoelastic materials

This study is concerned with developing a constitutive law for aging and environmental-dependent materials. The development rests on the assumption that the mechanical properties of the aforementioned materials can be mathematically represented by a functional of the strain and environmental histories, and this functional depends on the present time and the time the material is created. This constitutive assumption leads to two equivalent integral forms of the constitutive law after asserting that the functional is linear in the strain history. The first form of the integral law contains a material response functional analogous to the creep and relaxation functions of classical linear viscoelasticity. The second integral law has the same basic mathematical form but the physical interpretation of the mechanical response functional is different. It is demonstrated that both forms of the aging law reduce to the same non-aging law which is the usual starting for an analysis of only environmental-dependent materials. In the Appendix an operator algebra is presented for convenience in manipulating the integral laws for aging materials. Diese Untersuchung beschäftigt sich mit der Darstellung eines Werkstoffgesetzes für Altern und für umgebungsabhängige Stoffe. Die Entwicklung beruht auf der Annahme, daß die mechanischen Eigenschaften der oben erwähnten Stoffe mathematisch durch ein Funktional der Verzerrungs- und der Umgebungsgeschichten dargestellt werden kann und daß dieses Funktional von der augenblicklichen Zeit und der Zeit der Erzeugung des Stoffes abhängt. Diese Werkstoffannahme führt, unter der Voraussetzung einer linearen Abhängigkeit des Funktionals von der Verzerrungsgeschichte, auf zwei äquivalente Integraldarstellungen des Werkstoffgesetzes. Die erste Darstellung des Integralgesetzes enthält ein Materialantwort-Funktional analog der Kriech- und Relaxationsfunktionen der klassischen linearen Viskoelastizität. Das zweite Gesetz hat die gleiche mathematische Gestalt, aber verschiedene physikalische Interpretation des mechanischen Antwort-Funktionals. Es wird gezeigt, daß für nicht-alternde Stoffe beide Darstellungen dasselbe Gesetz, das der übliche Ausgangspunkt einer Untersuchung umgebungsbeeinflußter Stoffe ist, ergeben. Im Anhang werden einige für das Rechnen mit den Integralgesetzen alternder Stoffe handliche Sätze der Operatorenrechnung angegeben.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41700/1/707_2005_Article_BF01179657.pd

A combined computational and functional approach identifies IGF2BP2 as a driver of chemoresistance in a wide array of pre-clinical models of colorectal cancer

Aim Chemoresistance is a major cause of treatment failure in colorectal cancer (CRC) therapy. In this study, the impact of the IGF2BP family of RNA-binding proteins on CRC chemoresistance was investigated using in silico, in vitro, and in vivo approaches. Methods Gene expression data from a well-characterized cohort and publicly available cross-linking immunoprecipi‑ tation sequencing (CLIP-Seq) data were collected. Resistance to chemotherapeutics was assessed in patient-derived xenografts (PDXs) and patient-derived organoids (PDOs). Functional studies were performed in 2D and 3D cell culture models, including proliferation, spheroid growth, and mitochondrial respiration analyses. Results We identifed IGF2BP2 as the most abundant IGF2BP in primary and metastastatic CRC, correlating with tumor stage in patient samples and tumor growth in PDXs. IGF2BP2 expression in primary tumor tissue was signif‑ cantly associated with resistance to selumetinib, geftinib, and regorafenib in PDOs and to 5-fuorouracil and oxalipl‑ atin in PDX in vivo. IGF2BP2 knockout (KO) HCT116 cells were more susceptible to regorafenib in 2D and to oxaliplatin, selumitinib, and nintedanib in 3D cell culture. Further, a bioinformatic analysis using CLIP data suggested stabiliza‑ tion of target transcripts in primary and metastatic tumors. Measurement of oxygen consumption rate (OCR) and extracellular acidifcation rate (ECAR) revealed a decreased basal OCR and an increase in glycolytic ATP production rate in IGF2BP2 KO. In addition, real-time reverse transcriptase polymerase chain reaction (qPCR) analysis confrmed decreased expression of genes of the respiratory chain complex I, complex IV, and the outer mitochondrial membrane in IGF2BP2 KO cells. Conclusions IGF2BP2 correlates with CRC tumor growth in vivo and promotes chemoresistance by altering mito‑ chondrial respiratory chain metabolism. As a druggable target, IGF2BP2 could be used in future CRC therapy to overcome CRC chemoresistance

A combined computational and functional approach identifies IGF2BP2 as a driver of chemoresistance in a wide array of pre-clinical models of colorectal cancer

Aim: Chemoresistance is a major cause of treatment failure in colorectal cancer (CRC) therapy. In this study, the impact of the IGF2BP family of RNA-binding proteins on CRC chemoresistance was investigated using in silico, in vitro, and in vivo approaches. Methods: Gene expression data from a well-characterized cohort and publicly available cross-linking immunoprecipitation sequencing (CLIP-Seq) data were collected. Resistance to chemotherapeutics was assessed in patient-derived xenografts (PDXs) and patient-derived organoids (PDOs). Functional studies were performed in 2D and 3D cell culture models, including proliferation, spheroid growth, and mitochondrial respiration analyses. Results: We identified IGF2BP2 as the most abundant IGF2BP in primary and metastastatic CRC, correlating with tumor stage in patient samples and tumor growth in PDXs. IGF2BP2 expression in primary tumor tissue was significantly associated with resistance to selumetinib, gefitinib, and regorafenib in PDOs and to 5-fluorouracil and oxaliplatin in PDX in vivo. IGF2BP2 knockout (KO) HCT116 cells were more susceptible to regorafenib in 2D and to oxaliplatin, selumitinib, and nintedanib in 3D cell culture. Further, a bioinformatic analysis using CLIP data suggested stabilization of target transcripts in primary and metastatic tumors. Measurement of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) revealed a decreased basal OCR and an increase in glycolytic ATP production rate in IGF2BP2 KO. In addition, real-time reverse transcriptase polymerase chain reaction (qPCR) analysis confirmed decreased expression of genes of the respiratory chain complex I, complex IV, and the outer mitochondrial membrane in IGF2BP2 KO cells. Conclusions: IGF2BP2 correlates with CRC tumor growth in vivo and promotes chemoresistance by altering mitochondrial respiratory chain metabolism. As a druggable target, IGF2BP2 could be used in future CRC therapy to overcome CRC chemoresistance