Publications by authors named "Ulrich Abel"

Article Synopsis
  • The goal of peptide drug design is to enhance pharmacokinetics while preserving biological activity through modifications, but these changes can create unintended impurities.
  • Researchers studied the degradation of the GnRH antagonist degarelix in biological media using a specialized HPLC method to identify a specific impurity, namely the 5-Aph(Hyd)-degarelix isomer.
  • They found that degarelix can quickly convert to a hydantoin isomer in serum, implying this impurity could act as a drug metabolite, highlighting the need for better analytical methods to understand drug chemistry and behavior in the body.
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A multistage single arm phase II trial with binary endpoint is considered. Bayesian posterior probabilities are used to monitor futility in interim analyses and efficacy in the final analysis. For a beta-binomial model, decision rules based on Bayesian posterior probabilities are converted to "traditional" decision rules in terms of number of responders among patients observed so far.

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  • - This study evaluated how early metabolic responses (ΔSUV) after two weeks of cetuximab treatment can predict clinical outcomes in patients with RAS-wildtype metastatic colorectal cancer (mCRC).
  • - A total of 40 patients participated, with results showing that those who responded to treatment had a significantly higher ΔSUV, indicating a clear link between metabolic response and early clinical response.
  • - The findings suggest that ΔSUV could be an important indicator of survival rates, with a median progression-free survival of 11.7 months and overall survival of 33.5 months, but further validation with larger groups is needed.
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Although tumor-initiating cell (TIC) self-renewal has been postulated to be essential in progression and metastasis formation of human pancreatic adenocarcinoma (PDAC), clonal dynamics of TICs within PDAC tumors are yet unknown. Here, we show that long-term progression of PDAC in serial xenotransplantation is driven by a succession of transiently active TICs producing tumor cells in temporally restricted bursts. Clonal tracking of individual, genetically marked TICs revealed that individual tumors are generated by distinct sets of TICs with very little overlap between subsequent xenograft generations.

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Background: Patients with advanced stage non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) often experience multidimensional impairments, affecting quality of life during their course of disease. In lung cancer patients with operable disease, several studies have shown that exercise has a positive impact on quality of life and physical functioning. There is limited evidence regarding efficacy for advanced lung cancer patients undergoing palliative treatment.

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A series of 2-substituted 3,4-dihydro-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxides were synthesized and evaluated for their affinity to the glycine binding site of the N-methyl-d-aspartate (NMDA) receptor. The binding affinity was determined by the displacement of radioligand [(3)H]MDL-105,519 from rat cortical membrane preparations. The most attractive structures in the search for prospective NMDA receptor ligands were identified to be 2-arylcarbonylmethyl substituted 3,4-dihydro-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxides.

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This article deals with seven special issues related to the assumptions, applicability, and practical use of formulas for calculating power or sample size, respectively, for comparative clinical trials with time-to-event endpoints, with particular focus on the well-known Freedman and Schoenfeld methods. All problems addressed are illustrated by numerical examples, and recommendations are given on how to deal with them in the planning of clinical trials.

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Article Synopsis
  • - The study focused on elderly patients (≥70 years) with advanced pancreatic cancer, analyzing their safety and outcomes while receiving palliative chemotherapy at a university hospital.
  • - Results showed a median survival of 6.7 months, with significant differences in survival based on patients' performance status; better performance correlating with longer survival.
  • - The findings suggest that elderly patients can benefit from palliative chemotherapy similarly to younger patients, emphasizing the importance of performance status in treatment decisions and considering second-line therapy after initial treatment progression.
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The metabotropic glutamate receptor subtype 5 has evolved into a promising target for the treatment of various diseases of the central nervous system, such as Fragile X and L-DOPA induced dyskinesia. One of the most advanced clinical compound is Novartis' AFQ-056 (Mavoglurant), which served us as a template for a scaffold hopping approach, generating a structurally diverse set of potent analogs. Both the limited aqueous solubility and the relatively poor metabolic stability of AFQ-056 were improved with hexahydrocyclopenta[c]pyrrole derivative 54a, which proved to be a valuable candidate for further development.

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  • The study evaluated the safety and effectiveness of an 8-week combined resistance and endurance exercise program for patients with advanced non-small cell lung cancer (NSCLC) during their treatment.
  • Forty patients participated, with a focus on adherence to the exercise regimen and assessments of physical performance, quality of life, fatigue, and depression.
  • Results showed high adherence rates and significant improvements in physical strength and endurance for those who completed the exercise program, indicating that exercise is feasible and beneficial for this patient group during treatment.
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A virtual screening approach using various in silico methodologies led to the discovery of 2-(m-tolylamino)-7,8-dihydroquinazolin-5(6H)-one (1) as a moderately active negative allosteric modulator (NAM) of the metabotropic glutamate receptor subtype 5 (mGluR5) showing high selectivity against the subtype mGluR1. Modifications of the parent compound by rational design yielded a series of highly potent derivatives which will serve as valuable starting points for further hit-to-lead optimization efforts toward a suitable drug candidate for the treatment of L-DOPA induced dyskinesia.

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The farnesoid X receptor (FXR) is expressed predominantly in tissues exposed to high levels of bile acids and controls bile acid and lipid homeostasis. FXR(-/-) mice develop hepatocellular carcinoma (HCC) and show an increased prevalence for intestinal malignancies, suggesting a role of FXR as a tumor suppressor in enterohepatic tissues. The N-myc downstream-regulated gene 2 (NDRG2) has been recognized as a tumor suppressor gene, which is downregulated in human hepatocellular carcinoma, colorectal carcinoma and many other malignancies.

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Purpose: Adjuvant chemotherapy prolongs survival in patients with pancreatic cancer, but its benefit is limited. Long-term survival times of up to 44 months after adjuvant chemoradioimmunotherapy in phase II trials motivated the present study.

Patients And Methods: Between 2004 and 2007, 132 R0/R1 resected patients received either fluorouracil (FU), cisplatin, and interferon alfa-2b (IFN α-2b) plus radiotherapy followed by two cycles of FU (arm A, n=64) or six cycles of FU monotherapy (arm B, n=68).

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Article Synopsis
  • Cetuximab, an antibody used in colorectal cancer treatment, has shown effectiveness, but its impact on tumor metabolism and vascularization is not fully understood, highlighting the need for further research.
  • The REMOTUX trial aims to investigate how changes in tumor glucose uptake (measured by (18)F-FDG PET-CT) during early treatment with cetuximab can predict clinical response and influence treatment decisions.
  • This study is designed as a prospective, open-label trial that will track patients' responses and biochemical markers from baseline through treatment phases to evaluate the potential of using glucose metabolism as a predictive tool for treatment efficacy.
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This note addresses the questions of whether one should safeguard against a potential loss of power due to random variations of the accrual time, how this "insurance" can be formulated, and how much the sample size needs to be increased to obtain it.

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Vectors based on γ-retroviruses or lentiviruses have been shown to stably express therapeutical transgenes and effectively cure different hematological diseases. Molecular follow up of the insertional repertoire of gene corrected cells in patients and preclinical animal models revealed different integration preferences in the host genome including clusters of integrations in small genomic areas (CIS; common integrations sites). In the majority, these CIS were found in or near genes, with the potential to influence the clonal fate of the affected cell.

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Human colon cancer harbors a small subfraction of tumor-initiating cells (TICs) that is assumed to be a functionally homogeneous stem-cell-like population driving tumor maintenance and metastasis formation. We found unexpected cellular heterogeneity within the TIC compartment, which contains three types of TICs. Extensively self-renewing long-term TICs (LT-TICs) maintained tumor formation in serial xenotransplants.

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Article Synopsis
  • Clinical gene therapy has revealed that vector-associated side effects can help us understand how blood cell regulation works in living organisms.
  • Research shows that many retrovirus insertion sites in treated cells cluster near specific genes, which affect the behavior of blood cell clones.
  • Analyzing over 7,000 insertion sites from multiple studies indicates that more than 40% are found in just 0.36% of the genome, primarily linked to genes related to blood cell functions, suggesting that these insertions follow predictable patterns and need further research.
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Background: 18-Fluorodeoxyglucose-PET (18F-FDG-PET) can be used for early response assessment in patients with locally advanced adenocarcinomas of the oesophagogastric junction (AEG) undergoing neoadjuvant chemotherapy. It has been recently shown in the MUNICON trials that response-guided treatment algorithms based on early changes of the FDG tumor uptake detected by PET are feasible and that they can be implemented into clinical practice. Only 40%-50% of the patients respond metabolically to therapy.

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Lentiviral vectors with self-inactivating (SIN) long terminal repeats (LTRs) are promising for safe and sustained transgene expression in dividing as well as quiescent cells. As genome organization and transcription substantially differs between actively dividing and postmitotic cells in vivo, we hypothesized that genomic vector integration preferences might be distinct between these biological states. We performed integration site (IS) analyses on mouse dividing cells (fibroblasts and hematopoietic progenitor cells (HPCs)) transduced ex vivo and postmitotic cells (eye and brain) transduced in vivo.

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To overcome the known liabilities of GW4064 a series of analogs were synthesized where the stilbene double bond is replaced by an oxymethylene or amino-methylene linker connecting a terminal benzoic acid with a substituted heteroaryl in the middle ring position. As a result we discovered compounds with increased potency in vitro that cause dose-dependent reduction of plasma triglycerides and cholesterol in db/db mice down to 2 x 1 mg/kg/day upon oral administration.

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X-linked adrenoleukodystrophy (ALD) is a severe brain demyelinating disease in boys that is caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. ALD progression can be halted by allogeneic hematopoietic cell transplantation (HCT). We initiated a gene therapy trial in two ALD patients for whom there were no matched donors.

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Background: The 5-year survival of patients with resected pancreatic adenocarcinoma is still unsatisfying. The ESPAC-1 and the CONKO 001 trial proofed that adjuvant chemotherapy improves 5-year survival significantly from approximately 14% to 21%. In parallel, investigators from the Virginia Mason Clinic reported a 5-year survival rate of 55% in a phase II trial evaluating a combination of adjuvant chemotherapy, immunotherapy and external beam radiation (CapRI-scheme).

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Objectives: Second-line chemotherapy is widely used in advanced pancreatic cancer. However, only few data exist concerning the question who might benefit from second-line therapy. We intended to identify prognostic factors for time to second progression (TTP2) and residual survival following second-line chemotherapy of patients with advanced pancreatic cancer.

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Article Synopsis
  • The study aimed to find effective surrogate markers for a trial on mistletoe treatment in breast cancer patients, focusing on tolerability, quality of life, and immune responses during chemotherapy.
  • It involved 66 patients (33 receiving mistletoe alongside chemotherapy and 33 acting as a control) with evaluations before and after treatment regarding various health parameters and quality of life metrics.
  • Results showed a slight increase in platelets and reduced nausea/vomiting in the mistletoe group, but overall laboratory parameters were similar to controls, suggesting mistletoe treatment might help improve quality of life but needs more investigation.
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