Rapid systematic review of clinical trials on pharmacological therapies for rare gynecological cancers

The purpose of this study is to systematically review clinical trials on pharmacological therapies for rare gynecological cancers and analyze their characteristics. The PRISMA guidelines for systematic reviews were followed and two databases were searched (WHO´s International Clinical Trials Registry Platform and clinicaltrials.gov). The Jadad score was used to assess the methodological quality of completed clinical trials. A total of 212 records, covering trials from 1993 to 2022, were included in the final review. More than half were phase II trials (110; 51.89%) and the status of recruiting was mainly completed (80; 37.74%). There were 26 (12.26%) terminated or withdrawn clinical trials. Just 42.45% of the trials were specific only for rare types of gynecological cancers. The most common type of investigated therapy was chemotherapy (89; 41.98%), followed by targeted therapy (64; 30.19%) and a combination of therapies (23.11%). However, in the last five years there was an increase in trials investigating targeted therapies such as immunotherapy, overgrowth-related and angiogenesis-related therapies. All completed trials except one, had a Jadad score 0-2, indicating low-quality. Thirty-six (45.00%) completed clinical trials had neither posted results, nor publications. Higher quality clinical trials with better reporting of results are needed for rare gynecological cancers.peer-reviewe

Totarol content and cytotoxicity varies significantly in different types of propolis

Propolis is a complex honeybee product deposited in the beehives, where it protects the hive and its occupants from microbial infection. Propolis has several reported medical applications in view of its numerous bioactive properties. The water insoluble fraction of crude Maltese honeybee propolis was extracted in methanol. Analysis by gas chromatography – mass spectrometry (GC-MS) showed the diterpenoid totarol to be the predominant constituent in all samples. The evaporated methanol residue was dissolved in dimethyl sulphoxide (DMSO) and used for cytotoxicity testing on human cancer cell lines using standard 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assays. Results obtained show that the propolis collected from Malta has cytotoxic activity in cancer cells in vitro. However, propolis collected from different sites, only a few miles apart and at different times of the year, showed marked variations in the cytotoxicity, which correlated clearly with totarol content. This reflects the differences in the species of plants, on which the bees had foraged and indicates the importance of collection site and season of collection on the bioactivity of propolis products.peer-reviewe

A Novel FRET-Based Biosensor for the Measurement of BCR-ABL Activity and Its Response to Drugs in Living Cells

Purpose: To develop a novel diagnostic method for the assessment of drug efficacy in CML patients individually, we generated a biosensor that enables the evaluation of BCR-ABL kinase activity in living cells using the principle of fluorescence resonance energy transfer (FRET). Experimental Design: To develop FRET-based biosensors, we utilized CrkL, the most characteristic substrate of BCR-ABL, and designed a protein in which CrkL is sandwiched between Venus, a variant of YFP, and ECFP, so that CrkL intra-molecular binding of the SH2 domain to phosphorylated tyrosine (Y207) increases FRET efficiency. After evaluation of the properties of this biosensor by comparison to established methods including western blotting and flow cytometry, BCR-ABL activity and its response to drugs were examined in CML patient cells. Results: After optimization, we obtained a biosensor that possesses higher sensitivity than that of established techniques with respect to measuring BCR-ABL activity and its suppression by imatinib. Thanks to its high sensitivity, this biosensor accurately gauges BCR-ABL activity in relatively small cell numbers and can also detect less than 1% minor drug-resistant populations within heterogeneous ones. We also noticed that this method enabled us to predict future onset of drug resistance as well as to monitor the disease status during imatinib therapy, using patient cells. Conclusion: In consideration of its quick and practical nature, this method is potentially a promising tool for the prediction of both current and future therapeutic responses in individual CML patients, which will be surely beneficial for both patients and clinicians

FIP1L1 presence in FIP1L1-RARA or FIP1L1-PDGFRA differentially contributes to the pathogenesis of distinct types of leukemia

FIP1-like 1 (FIP1L1) is associated with two leukemogenic fusion genes: FIP1L1-retinoic acid receptor alpha (RARA) and FIP1L1-platelet-derived growth factor receptor alpha (PDGFRA). Analyses of a series of deletion mutants revealed that the FIP1 motif in FIP1L1-RARA plays a pivotal role in its homodimerization and transcriptional repressor activity. However, in FIP1L1-PDGFRA, the C-terminal PDGFRA portion possesses the ability of forming a homodimer by itself, making FIP1L1 dispensable for constitutive activation of this kinase. Both the full-length and the C-terminal PDGFRA portion of FIP1L1-PDGFRA could transform the IL-3-dependent hematopoietic cell line, BAF-B03. Moreover, when either the full-length or the C-terminal PDGFRA portion of FIP1L1-PDGFRA was introduced in these cells, they grew in the absence of IL-3. The cells having the C-terminal PDGFRA portion of FIP1L1-PDGFRA, however, were partially IL-3 dependent, whereas the cells having the full-length FIP1L1-PDGFRA became completely IL-3 independent for their growth. Taken together, these results show that FIP1L1 differentially contributes to the pathogenesis of distinct types of leukemia

Hypoxia suppresses the production of matrix metalloproteinases and migration of human monocyte-derived dendritic cells

As most solid tumors are hypoxic, dendritic cells (DC) in solid tumors are also exposed to hypoxia. While many adaptation responses of tumor cells to hypoxia are known, it is yet to be determined how hypoxia affects the functions of DC. To explore the effects of hypoxia on the functions of DC, we compared the expression of surface markers, cytokines, chemokine receptors and matrix metalloproteinases (MMP) of human monocyte-derived DC (hmDC) differentiated under hypoxia to those differentiated under normoxia. Both groups of hmDC expressed similar levels of surface markers and cytokines. However, expression of MMP-9 and membrane type-1-MMP, as well as migrating activity, was significantly suppressed in hmDC differentiated under hypoxia compared with their normoxia counterparts. We also demonstrated that trichostatin A restored the production of MMP-9 in hmDC, under hypoxia. Collectively, our findings show that a hypoxic microenvironment suppresses the production of MMP in hmDC, most probably through the deacetylation of promoter regions of MMP, thus suppressing the migrating activity of hmDC. Our results suggest that the hypoxic microenvironment in solid tumor tissues may suppress the function of D

Synergistic up-regulation of Hexokinase-2, glucose transporters and angiogenic factors in pancreatic cancer cells by glucose deprivation and hypoxia

There is accumulating evidence demonstrating that HIF-1 functions as a key regulator of the adaptation responses to hypoxia in cancer tissues. To this evidence, we add that adaptation responses to glucose deprivation plus hypoxia are also necessary for the survival of tumor cells in the tumor microenvironment as cancer tissues are exposed to glucose deprivation as well as hypoxia. We found that adrenomedullin (AM), VEGF, Glut-1, Glut-3, and Hexokinase-2 among 45 hypoxia-inducible genes investigated were expressed at higher levels under glucose-deprived hypoxic conditions than under hypoxic conditions. Glucose deprivation activated the AMPK under normoxia and hypoxia. Compound C, an inhibitor of AMPK, suppressed the expressions of AM and VEGF which had already been enhanced under glucose-deprived hypoxic conditions. siRNAs for both AMPKα1 and AMPKα2 suppressed the expressions of AM and VEGF. HIF-1α protein level and the transcriptional activity of HIF-1 under glucose-deprived hypoxic conditions were thus found to be similar to those under hypoxic conditions. Furthermore, tumor cells in 15 out of 20 human pancreatic cancer tissue specimens were stained by anti-phospho-AMPKα antibody. Our results thus suggest that the enhanced expressions of those genes mediated by the activation of AMPK and HIF-1 therefore play a pivotal role in the tumor formation of pancreatic cancers

HB vaccine to prevent viral reactivation in allogeneic hematopoietic stem cell transplantation recipients with previous HBV infection

HBV-reverse seroconversion (RS) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a frequent late-onset complication in recipients with previous HBV infection. We conducted post-transplant HB vaccine intervention in 38 allo-HSCT recipients with previous HBV infection. Firstly, we followed the recipients without any intervention (historical control) until 2003; hence we commenced HB vaccination. Out of the patients who underwent transplantation after 2003, 13 recipients were immunized by a standard 3-dose regimen after immunosuppressant cessation (vaccine group), while 12 recipients were observed without any intervention (non-vaccine group). Eight of the 13 historical control group recipients and 3 of the 12 non-vaccine group recipients, but none of the 13 vaccine group recipients, suffered HBV-RS. Cumulative risks of HBV-RS at 3 years post-HSCT in the historical control, non-vaccine and vaccine groups were 41%, 39% and 0% respectively (P = 0.022). We therefore conclude that intervention with HB vaccines is significantly effective in preventing post-HSCT HBV-RS