20 research outputs found
a randomized, placebo-controlled phase II AIO trial with serum biomarker program
Background As a multi-targeted anti-angiogenic receptor tyrosine kinase (RTK)
inhibitor sunitinib (SUN) has been established for renal cancer and
gastrointestinal stromal tumors. In advanced refractory esophagogastric cancer
patients, monotherapy with SUN was associated with good tolerability but
limited tumor response. Methods This double-blind, placebo-controlled,
multicenter, phase II clinical trial was conducted to evaluate the efficacy,
safety and tolerability of SUN as an adjunct to second and third-line FOLFIRI
(NCT01020630). Patients were randomized to receive 6-week cycles including
FOLFIRI plus sodium folinate (Na-FOLFIRI) once every two weeks and SUN or
placebo (PL) continuously for four weeks followed by a 2-week rest period. The
primary study endpoint was progression-free survival (PFS). Preplanned serum
analyses of VEGF-A, VEGF-D, VEGFR2 and SDF-1α were performed retrospectively.
Results Overall, 91 patients were randomized, 45 in each group (one patient
withdrew). The main grade ≥3 AEs were neutropenia and leucopenia, observed in
56 %/20 % and 27 %/16 % for FOLFIRI + SUN/FOLFIRI + PL, respectively. Median
PFS was similar, 3.5 vs. 3.3 months (hazard ratio (HR) 1.11, 95 % CI
0.70–1.74, P = 0.66) for FOLFIRI + SUN vs. FOLFIRI + PL, respectively. For
FOLFIRI + SUN, a trend towards longer median overall survival (OS) compared
with placebo was observed (10.4 vs. 8.9 months, HR 0.82, 95 % CI 0.50–1.34,
one-sided P = 0.21). In subgroup serum analyses, significant changes in VEGF-A
(P = 0.017), VEGFR2 (P = 0.012) and VEGF-D (P < 0.001) serum levels were
observed. Conclusions Although sunitinib combined with FOLFIRI did not improve
PFS and response in chemotherapy-resistant gastric cancer, a trend towards
better OS was observed. Further biomarker-driven studies with other anti-
angiogenic RTK inhibitors are warranted. Trial registration This study was
registered prospectively in the NCT Clinical Trials Registry
(ClinicalTrials.gov) under NCT01020630 on November 23, 2009 after approval by
the leading ethics committee of the Medical Association of Rhineland-
Palatinate, Mainz, in coordination with the participating ethics committees
(see Additional file 2) on September 16, 2009
Post-Translational Inhibition of IP-10 Secretion in IEC by Probiotic Bacteria: Impact on Chronic Inflammation
Peer reviewedPublisher PD
Exploring DNA methylation changes in promoter, intragenic, and intergenic regions as early and late events in breast cancer formation
The role of lifestyle, quality of life preferences and geographical context in personal air travel
Injectable Chemotherapy Downstaged Oral Squamous Cell Carcinoma from Nonresectable to Resectable in a Rescue Dog: Diagnosis, Treatment, and Outcome
This case report documents the diagnosis, treatment, and outcome of a nonresectable oral squamous cell carcinoma in a dog with initial poor prognosis. An approximately 4-year-old female Staffordshire Bull Terrier presented with a large mass on the front of lower jaw which was diagnosed as oral papillary squamous cell carcinoma by histopathology. CT scans revealed invasion of the cancer to the frenulum of the tongue. The mass was inoperable due to location, expansiveness, and metastatic lymph nodes. The dog received 4 treatments of intralesional hyaluronan-platinum conjugates (HylaPlat™, HylaPharm LLC, Lawrence, Kansas) at 3-week intervals. Clinical chemistry and complete blood count were performed one week after each treatment and results were within normal limits. Complications included bleeding due to tumor tissue sloughing, as well as a single seizure due to unknown causes. Upon completion of chemotherapy, CT showed that the mass had regressed and was no longer invading the lingual frenulum, and multiple lymph nodes were free of metastasis. The mass thus became resectable and the dog successfully underwent rostral bilateral mandibulectomy. Over one year after chemotherapy and surgery, the cancer remains in complete remission
Eine Weight-of-Evidence-Studie zur Bewertung der Sedimentbelastung und des Fischrückgangs in der Oberen Donau
Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development
Glutamine is conditionally essential in cancer cells, being utilized as a carbon and nitrogen source for macromolecule production, as well as for anaplerotic reactions fuelling the tricarboxylic acid (TCA) cycle. In this study, we demonstrated that the glutamine transporter ASCT2 (SLC1A5) is highly expressed in prostate cancer patient samples. Using LNCaP and PC-3 prostate cancer cell lines, we showed that chemical or shRNA-mediated inhibition of ASCT2 function in vitro decreases glutamine uptake, cell cycle progression through E2F transcription factors, mTORC1 pathway activation and cell growth. Chemical inhibition also reduces basal oxygen consumption and fatty acid synthesis, showing that downstream metabolic function is reliant on ASCT2-mediated glutamine uptake. Furthermore, shRNA knockdown of ASCT2 in PC-3 cell xenografts significantly inhibits tumour growth and metastasis in vivo, associated with the down-regulation of E2F cell cycle pathway proteins. In conclusion, ASCT2-mediated glutamine uptake is essential for multiple pathways regulating the cell cycle and cell growth, and is therefore a putative therapeutic target in prostate cancer
Sunitinib added to FOLFIRI versus FOLFIRI in patients with chemorefractory advanced adenocarcinoma of the stomach or lower esophagus : a randomized, placebo-controlled phase II AIO trial with serum biomarker program
Background: As a multi-targeted anti-angiogenic receptor tyrosine kinase (RTK) inhibitor sunitinib (SUN) has been established for renal cancer and gastrointestinal stromal tumors. In advanced refractory esophagogastric cancer patients, monotherapy with SUN was associated with good tolerability but limited tumor response.
Methods: This double-blind, placebo-controlled, multicenter, phase II clinical trial was conducted to evaluate the efficacy, safety and tolerability of SUN as an adjunct to second and third-line FOLFIRI (NCT01020630). Patients were randomized to receive 6-week cycles including FOLFIRI plus sodium folinate (Na-FOLFIRI) once every two weeks and SUN or placebo (PL) continuously for four weeks followed by a 2-week rest period. The primary study endpoint was progression-free survival (PFS). Preplanned serum analyses of VEGF-A, VEGF-D, VEGFR2 and SDF-1α were performed retrospectively.
Results: Overall, 91 patients were randomized, 45 in each group (one patient withdrew). The main grade ≥3 AEs were neutropenia and leucopenia, observed in 56 %/20 % and 27 %/16 % for FOLFIRI + SUN/FOLFIRI + PL, respectively. Median PFS was similar, 3.5 vs. 3.3 months (hazard ratio (HR) 1.11, 95 % CI 0.70–1.74, P = 0.66) for FOLFIRI + SUN vs. FOLFIRI + PL, respectively. For FOLFIRI + SUN, a trend towards longer median overall survival (OS) compared with placebo was observed (10.4 vs. 8.9 months, HR 0.82, 95 % CI 0.50–1.34, one-sided P = 0.21). In subgroup serum analyses, significant changes in VEGF-A (P = 0.017), VEGFR2 (P = 0.012) and VEGF-D (P < 0.001) serum levels were observed.
Conclusions: Although sunitinib combined with FOLFIRI did not improve PFS and response in chemotherapy-resistant gastric cancer, a trend towards better OS was observed. Further biomarker-driven studies with other anti-angiogenic RTK inhibitors are warranted.
Trial registration: This study was registered prospectively in the NCT Clinical Trials Registry (ClinicalTrials.gov) under NCT01020630 on November 23, 2009 after approval by the leading ethics committee of the Medical Association of Rhineland-Palatinate, Mainz, in coordination with the participating ethics committees (see Additional file 2) on September 16, 2009
The Ubiquitin-Protein Ligase Nedd4-2 Differentially Interacts with and Regulates Members of the Tweety Family of Chloride Ion Channels*
The Tweety proteins comprise a family of chloride ion channels with three
members identified in humans (TTYH1-3) and orthologues in fly and murine
species. In humans, increased TTYH2 expression is associated with cancer
progression, whereas fly Tweety is associated with developmental
processes. Structurally, Tweety proteins are characterized by five
membrane-spanning domains and N-glycan modifications important for
trafficking to the plasma membrane, where these proteins are oriented with the
amino terminus located extracellularly and the carboxyl terminus
cytoplasmically. In addition to N-glycosylation, ubiquitination
mediated by the HECT type E3 ubiquitin ligase Nedd4-2 is a post-translation
modification important in regulating membrane proteins. In the present study,
we performed a comprehensive analysis of the ability of each of TTYH1-3 to
interact with Nedd4-2 and to be ubiquitinated and regulated by this ligase.
Our data indicate that Nedd4-2 binds to two family members, TTYH2 and TTYH3,
which contain consensus PY ((L/P)PXY) binding sites for HECT type E3
ubiquitin ligases, but not to TTYH1, which lacks this motif. Consistently,
Nedd4-2 ubiquitinates both TTYH2 and TTYH3. Importantly, we have shown that
endogenous TTYH2 and Nedd4-2 are binding partners and demonstrated that the
TTYH2 PY motif is essential for these interactions. We have also shown that
Nedd4-2-mediated ubiquitination of TTYH2 is a critical regulator of cell
surface and total cellular levels of this protein. These data, indicating that
Nedd4-2 differentially interacts with and regulates TTYH1-3, will be important
for understanding mechanisms controlling Tweety proteins in physiology and
disease