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Biomedical subjects

Martin Schneider

Publications and source records attributed to Martin Schneider.

At least 19 recordsLinked to original sources
PubMed2025

Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma.

The embryonic transcription factor TBXT (brachyury) drives chordoma, a spinal neoplasm without effective drug therapies. TBXT's regulatory network is poorly understood, and strategies to disrupt its activity for therapeutic purposes are lacking. We developed designed ankyrin repeat proteins that block TBXT-DNA binding (T-DARPins). In chordoma cells, T-DARPins reduced cell cycle progression, spheroid formation, and tumor growth in mice and induced signs of senescence and differentiation. Transcriptomic and proteomic analyses identified gene networks involved in cell cycle regulation, embryonic cell identity, and interferon response and revealed features of regulome components, such as susceptibility to pharmacologic inhibition and the fine-tuning of TBXT downstream effectors through IGFBP3. Finally, we found high interferon signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with sensitivity to JAK2 inhibitors. These findings demonstrate the potential of DARPins for probing nuclear proteins to understand the regulatory networks of transcription factor-driven cancers, including entry points for therapies that warrant testing in patients.

Humans↗
PubMed2006

Congenital pulmonary sling, aorto-pulmonary window and pulmonary vein obstruction as a diagnostic and therapeutic challenge in an infant with VACTERL association.

In a newborn with anal atresia and urethral valves an incomplete VACTERL association, was diagnosed and a colon anus praeter was placed. Sweating and heart murmur led to cardiac diagnostics. By 2D colour Doppler echocardiography a huge atrial septal defect and pulmonary venous stenoses were diagnosed. Additionally, a pulmonary sling combined with an aortopulmonary window (AoPAw) was suspected and later confirmed by angiography. Heart failure developed and closure of the AoPAw, transplantation of the left pulmonary artery and closure of the atrial septal defect was performed at the age of 4 weeks. But the patient did not improve. Pulmonary hypertension with suprasystemic pressure in the right ventricle originating from a stenosis of the new orifice of the left pulmonary artery and obstruction of the right pulmonary veins was diagnosed by echocardiography and confirmed by angiography. At the age of 8 months the orifice of the left pulmonary artery was enlarged by a patch, the obstruction of left sided pulmonary veins was opened, and the rightsided pulmonary veins were newly implanted into the left atrium. Finally the inter-atrial communication was closed by a patch plastic. Again, postoperatively the patient improved only slightly. At the age of 10 months trans-septal catheterisation was performed. Angiography revealed a successful balloon dilatation of the long obstruction of the right pulmonary veins. Later on, an absorbable magnesium stent was implanted into the right upper pulmonary vein and medication with an endothelin antagonist was started. Temporarily the patient improved significantly. Within 6 weeks, right ventricular systolic pressure was again suprasystemic due to extreme inflow obstruction of the right pulmonary vein diagnosed by echocardiography. Severe heart failure developed and at the age of 1 year the patient died.

Abnormalities, Multiple↗
PubMed2006

Optimal pulmonary to systemic blood flow ratio for best hemodynamic status and outcome early after Norwood operation.

OBJECTIVE: Imbalances of pulmonary to systemic blood flow ratio (Q(p)/Q(s)) compounded with inadequate systemic oxygen delivery correlate with mortality after first-stage Norwood palliation of hypoplastic left heart syndrome. Mathematical models suggest that maximal systemic oxygen delivery occurs with Q(p)/Q(s) of less than 1. Whether this applies to clinical practice is unclear. This study evaluates the level of Q(p)/Q(s) that correlates with best hemodynamic status in the first 48 postoperative hours. METHODS: Hemodynamic data of 25 consecutive patients who underwent Norwood procedure from October 2002 to January 2005 were retrospectively analyzed. Data included, in particular, systemic venous and arterial oxygen saturation (SvO(2) and SaO(2), respectively), Q(p)/Q(s), lactate levels, and doses of required inotropes. Parameters were recorded 3 hourly. Data were assigned to three groups according to their corresponding Q(p)/Q(s): Groups 1, 2, and 3 for Q(p)/Q(s)< or =1, Q(p)/Q(s) between 1 and 2, and Q(p)/Q(s)> or =2, respectively. Thereafter, independent t-test or Fisher's exact test was used to reveal significant differences. Q(p)/Q(s) ratios and lactate levels were compared in hospital survivors and non-survivors. RESULTS: Out of 343 samples, 110, 184, and 49 were assigned to groups 1, 2, and 3, respectively. Group 1 (Q(p)/Q(s)< or =1) was characterized by lower SaO(2) (p<0.001) with similar SvO(2) (p=0.3 and p=0.5) and, therefore, higher systemic oxygen delivery (arteriovenous oxygen saturation difference, p<0.001; oxygen excess factor, p<0.001) compared to groups 2 and 3. However, lower mean arterial pressure (p=0.07 and p<0.001), higher lactate levels (p=0.009 and p=0.01), and norepinephrine doses (p=0.006 and p<0.001) highlighted worse hemodynamics. The best hemodynamic status corresponded to group 2. Q(p)/Q(s) remained above 1 in 21 survivors and was, most of the times, below 1 in four patients who died. Lactate levels were almost always above 4 mmol/l or increasing in non-survivors. CONCLUSIONS: Maximum oxygen delivery after Norwood operation occurs at Q(p)/Q(s) of less than 1. However, optimal hemodynamic status and end-organ function and higher survival correlates with Q(p)/Q(s) between 1 and 2. Thus, Q(p)/Q(s) should be targeted at 1.5 for improved course early after first-stage Norwood palliation.

Hemodynamics↗
PubMed2006

Transcatheter closure of perimembranous ventricular septal defects using umbrella devices.

UNLABELLED: There is only limited experience of interventional closure of perimembranous ventricular septal defects (pmVSDs), particularly on the long-term follow-up. This is a report on our long-term results after transcatheter closure of pmVSDs using the Cardioseal, Starflex, or Rashkind devices. PATIENTS: Between 1993 and 2005, we performed interventional occlusions of pmVSDs in 18 patients. The size of the defect ranged between 4 and 8.5 mm, Q(p)/Q(s) was calculated between 1.3 and 2.2. Except for two, the patients had no other structural heart defect. In the early days, we used the Rashkind PDA occluder (17 mm) in seven, followed by the Cardioseal device (17 mm) in nine, and the 23 mm Starflex device in two patients. RESULTS: Interventional closure of the defects was performed successfully in all patients without any complication during the procedure. Fluoroscopy times were 11.8-53.7 min (median 28.65 min). We achieved a complete closure in 13 patients, three patients with recently implanted devices still show minimal shunting. In two patients the occluder had to be removed surgically because of embolization into the pulmonary artery and significant residual shunting resulting in severe hemolysis in the second patient. In long- (mean 10.7 years) and short-term (mean 0.85 years) follow-up we have not observed any hemolysis, arrhythmias, device dislocations, or device-related aortic or tricuspid regurgitation. CONCLUSION: Transcatheter closure of small pmVSDs using non-selfcentering devices can be performed successfully. Long-term follow-up investigations show encouraging results. Complications like device-embolization and significant residual shunting occur in the presence of large defects and/or concomitant malformations.

Adolescent↗
PubMed2006

Role of lymphangiogenesis and lymphangiogenic factors during pancreatic cancer progression and lymphatic spread.

Treatment options for ductal adenocarcinoma of the pancreas are limited by early lymphatic spread, but the lymphatic vessels in pancreatic carcinoma have not been studied to date. Here, we present a histomorphological analysis of lymphatic vessels in pancreatic cancer resection specimens. Both intratumoral and peritumoral tissue were devoid of active lymphangiogenesis. Intratumoral lymphatics were frequently collapsed and non-functional, whereas peritumoral lymphatic vessels were enlarged, and numerous lymphatic vessels were seen in metastases. In addition, we screened pancreatic cancer tissue and pancreatic carcinoma cell lines for mRNA expression of the lymphangiogenic growth factor, VEGF-C; its receptor, VEGFR-3/flt4; and Prox1, a transcription factor essential for embryonic development of both lymphatic vessels and the pancreatic bud. VEGF-C was abundantly expressed in pancreatic cancer tissue and -cell lines and VEGFR-3/flt4 was expressed in cancer stromal cells. Prox1 was strongly expressed in the normal exocrine pancreas but significantly reduced in pancreatic cancer specimens from patients with short survival rates. Well-differentiated cell lines displayed higher levels of Prox1 mRNA than poorly differentiated ones. These results suggest that active lymphangiogenesis is not required for lymphovascular spread of pancreatic cancer. VEGF-C may promote local tumor growth via paracrine signaling to stromal cells expressing VEGFR-3 and support the entry of cancer cells into peritumoral lymphatics. Furthermore, loss of Prox1 function may be a driving force behind pancreatic carcinoma progression.

Angiogenesis Inducing Agents↗
PubMed2005

A genetic Xenopus laevis tadpole model to study lymphangiogenesis.

Lymph vessels control fluid homeostasis, immunity and metastasis. Unraveling the molecular basis of lymphangiogenesis has been hampered by the lack of a small animal model that can be genetically manipulated. Here, we show that Xenopus tadpoles develop lymph vessels from lymphangioblasts or, through transdifferentiation, from venous endothelial cells. Lymphangiography showed that these lymph vessels drain lymph, through the lymph heart, to the venous circulation. Morpholino-mediated knockdown of the lymphangiogenic factor Prox1 caused lymph vessel defects and lymphedema by impairing lymphatic commitment. Knockdown of vascular endothelial growth factor C (VEGF-C) also induced lymph vessel defects and lymphedema, but primarily by affecting migration of lymphatic endothelial cells. Knockdown of VEGF-C also resulted in aberrant blood vessel formation in tadpoles. This tadpole model offers opportunities for the discovery of new regulators of lymphangiogenesis.

Animals↗
PubMed2005

Restrictive left atrial outflow adversely affects outcome after the modified Norwood procedure.

OBJECTIVE: Moderate restrictive foramen ovale in neonates with hypoplastic left heart syndrome (HLHS) is considered to be favourable, reducing pulmonary overcirculation, before modified Norwood operation. However, some newborns with severe restriction of interatrial communication will have pulmonary vascular disease at birth, which correlates with increased perioperative mortality. This article studies the post-Norwood hemodynamic patterns and outcome for the particular group of HLHS newborns with restrictive left atrial outflow compared to other patients. METHODS: Restrictive left atrial outflow is defined as mitral and/or aortic atresia with intact ventricular septum, and restrictive foramen ovale, with 3 mm diameter or less with mean interatrial pressure gradient more than 5 mmHg at preoperative echo-Doppler. Four neonates fulfilled these criteriae among 18 consecutive patients, who underwent Norwood procedure from October 2002 to December 2003. Mean arterial pressure, heart rate, mean common atrial pressure, urinary output, central venous and arterial oximetry data, serum lactate levels, and dosages of milrinone, phentolamine and norepinephrine were collected at 0, 6, 12, 18 and 24 h after operation. Data were summarized as mean+/-SEM. For univariate comparison of different variables, Student's t-test was used. RESULTS: The postoperative hemodynamic pattern of patients with restrictive left atrial outflow was characterized by hypoxemia and low cardiac output. Arterial (66+/-3.0% vs 76+/-1.0%, P=0.01) and central venous (37+/-1.2 vs 52+/-1.1%, P=0.001) oxygen saturations were much lower than in patients without restriction. Arterio-venous oxygen saturation difference was wider (29+/-2.4% vs 23+/-0.9%, P=0.02) and serum lactate levels were higher (10.8+/-3.0 vs 2.8+/-0.2 mmol/l, P=0.03). Common atrial pressures were more elevated (12+/-0.8 vs 8+/-0.3 mmHg, P<0.001) and higher norepinephrine doses were needed (0.44+/-0.15 vs 0.06+/-0.01 microg/kg/min, P=0.03). The difference for the mean arterial pressures did not reach the significance level (48+/-2.0 vs 51+/-2.0 mmHg, P=0.2). Operative mortality was higher 75% (3/4) compared to 14.3% (2/14, P=0.04) for the other patients. CONCLUSIONS: Restrictive left atrial outflow adversely affects outcome after modified Norwood procedure. Abnormal pulmonary vasculature leading to insufficient pulmonary perfusion is incriminated. To improve outcome, implantation of larger size modified Blalock-Taussig or right ventricle-to-pulmonary artery shunts and routine use of postoperative mechanical assist device should be considered.

Aortic Valve↗
PubMed2005

The target discovery process.

In order to minimise attrition rates in drug development projects, a target discovery process is implemented to select and characterise the most suitable candidate kinase targets, before lead identification and lead optimisation are embarked upon. The process consists of 1) target selection, 2) target assessment, and 3) target validation. This rational approach to target discovery, as a prerequisite for lead discovery, ensures that new therapeutic targets fulfil a set of general criteria, as well as indication-specific, descriptive and functional ones. The approach should ultimately maximise the likelihood of achieving target-selective inhibition by small-molecule inhibitors with minimal in vivo side effects and a therapeutic effect based on a sound biological hypothesis.

Drug Design↗
PubMed2005

Retrograde use of the Cardioseal/Starflex occluder device.

The Cardioseal/Starflex septal occluder is usually deployed through a long transvenous sheath for closure of atrial septal defects, persistent foramen ovale, and, less commonly, ventricular septal defects. We describe two patients with residual left-to-right shunting after surgical palliation of congenital heart defects and illustrate the successful use of the double-umbrella device in these situations using a retrograde transarterial approach. This is exemplified by two previously not described interventions: retrograde closure of a large muscular ventricular septal defect in a patient after a palliative Mustard operation and a transcatheter closure of a Waterston-Cooley anastomosis. Effective and safe closure of left-to-right shunting can be achieved by retrograde use of the Cardioseal/Starflex device in selected adolescents and grown-ups with congenital heart disease.

Adolescent↗
PubMed2005

Late results after PTCA for coronary stenosis after the arterial switch procedure for transposition of the great arteries.

BACKGROUND: The arterial switch operation has become the surgical approach of choice for d-transposition of the great arteries, but there is an increased awareness of adverse sequelae in some survivors. Long-term patency and normal function of the translocated coronary arteries must be achieved. It is reported that dependent of the prior coronary status, 3% to 11% of all survivors have proximal coronary stenosis or complete occlusion develop after arterial switch operations. However, treatment of these stenoses is still a matter of debate. Late results after percutaneous transluminal coronary angioplasty (PTCA) for coronary stenosis after the arterial switch operation for d-transposition of the great arteries are reported. METHODS: Seven children after arterial switch operation for d-transposition of the great arteries who had subsequently undergone PTCA for coronary stenosis were angiographically re-evaluated 3 to 15 months after the initial PTCA and again after 3 to 5 years. RESULTS: All children survived the initial PTCA procedure. There were no late deaths. The degree of stenosis before PTCA ranged from 74% to 97%; immediately after PTCA from 5% to 10%; at 3 to 15 months after PTCA from zero to 6%; and at 3 to 5 years after PTCA from zero to 3%. Three to 5 years after PTCA all children showed normal development of the treated coronary artery. CONCLUSIONS: Primary PTCA of stenotic proximal coronary arteries after the arterial switch procedure for d-transposition of the great arteries seems to be an effective treatment with excellent long-term results.

Angioplasty, Balloon, Coronary↗
PubMed2005

A surrogate marker to monitor angiogenesis at last.

The first angiogenesis inhibitor has recently been approved for cancer treatment. Nonetheless, optimizing the dose of novel angiogenesis inhibitors remains a formidable challenge--primarily because we lack reliable surrogate markers of tumor angiogenesis. In this issue, Shaked et al. provide evidence that the levels of circulating endothelial precursor cells (CEPs), which contribute to the formation of tumor vessels, are genetically predetermined and regulated by angiogenic factors, and reflect the antitumor efficacy of angiogenesis inhibitors. These findings highlight the potential usefulness of CEPs as a surrogate marker to monitor and adjust antiangiogenic therapy.

Angiogenesis Inhibitors↗
PubMed2004

Partnership for the heart. German-Estonian health project for the treatment of congenital heart defects in Estonia.

Congenital heart defects (CHD) occur in 8 per 1000 live births. If they remain untreated, 70-80% of these patients die in early childhood. With modern diagnostic and treatment procedures, 90% of these patients reach adulthood. Within 8 years following reunification of Germany, it was possible to improve treatment for CHD in former East Germany to West German standards. Based on the experience gained in this process, a plan for improvement of care of Estonian patients with CHD was developed and implemented in the German-Estonian project, "Partnership for the Heart". The main elements of the project were (1) the training of Estonian physicians in Germany, (2) training courses conducted by German and Estonian specialists in Estonia and (3) use of telemedicine for consultation on a continuous basis. During the project 15 Estonian patients underwent cardiac surgery and/or catheter interventions performed by a joint team of German and Estonian specialists. The infant mortality due to CHD in Estonia fell by 28% during the project period. Key techniques of cardiac surgery are now being employed in Estonia without outside support, indicating the success of the training program and the long-term improvements to cardiac health care in Estonia. The total project costs were 314,252 Euro (euro), which is 50% lower than the estimated cost of treating the 15 patients abroad in Western Europe. The structure of "Partnership for the Heart" and the modified self-sufficiency model of medical care have not only produced results for Estonia but can be taken as a template for future bilateral health projects with other transition countries and for other fields of medical specialisation, and thus might aid a European health policy.

Adolescent↗
PubMed2004

A rational approach to maximize success rate in target discovery.

To overcome the problem of high attrition rates in the drug discovery process, an efficient strategy how to identify, select, characterize and validate the most suitable drug targets before embarking on the resource-intense steps of lead discovery and lead optimization is mandatory. We have implemented such an efficient strategy consisting of (i) Target Selection based on gene expression analyses of drugable target genes in clinical samples and relevant in vitro model systems, to identify candidate targets with a specific tissue distribution and presence in human disease; (ii) Target Assessment exploiting the three-dimensional structure of proteins for detailed binding site analysis, to estimate the drugability of the protein for small-molecule inhibitor binding as well as selectivity profiles; and (iii) Target Validation providing evidence for a functional role in in vitro model systems, thus corroborating the biological hypothesis underlying the therapeutic concept. This rational approach has led to the discovery of drug targets for Lead Discovery, maximizing the likelihood for achieving target-selective inhibition by small-molecule inhibitors with minimal in vivo side effects and a therapeutic effect based on a sound biological hypothesis.

Binding Sites↗
PubMed2004

Treatment of acute heart failure in an infant after cardiac surgery using levosimendan.

An infant, 2 months old, underwent cardiac surgery because of congenital heart defects and pulmonary hypertension. Surgery was performed in hypothermia and cardiac standstill. On the second day after surgery the infant had to be resuscitated due to a combination of acute left-ventricular failure, pulmonary vascular hypertension and a slight right-to-left-shunt. A breakthrough in the treatment was achieved by using levosimendan to improve left-ventricular function and to decrease vascular resistance.

Cardiotonic Agents↗