Transketolase-Like 1 Expression Is Modulated during Colorectal Cancer Progression and Metastasis Formation

Background Transketolase-like 1 (TKTL1) induces glucose degradation through anaerobic pathways, even in presence of oxygen, favoring the malignant aerobic glycolytic phenotype characteristic of tumor cells. As TKTL1 appears to be a valid biomarker for cancer prognosis, the aim of the current study was to correlate its expression with tumor stage, probability of tumor recurrence and survival, in a series of colorectal cancer patients. Methodolody/Principal Findings Tumor tissues from 63 patients diagnosed with colorectal cancer at different stages of progression were analyzed for TKTL1 by immunohistochemistry. Staining was quantified by computational image analysis, and correlations between enzyme expression, local growth, lymph-node involvement and metastasis were assessed. The highest values for TKTL1 expression were detected in the group of stage III tumors, which showed significant differences from the other groups (Kruskal-Wallis test, P = 0.000008). Deeper analyses of T, N and M classifications revealed a weak correlation between local tumor growth and enzyme expression (Mann-Whitney test, P = 0.029), a significant association of the enzyme expression with lymph-node involvement (Mann-Whitney test, P = 0.0014) and a significant decrease in TKTL1 expression associated with metastasis (Mann-Whitney test, P = 0.0004). Conclusions/Significance To our knowledge, few studies have explored the association between variations in TKTL1 expression in the primary tumor and metastasis formation. Here we report downregulation of enzyme expression when metastasis appears, and a correlation between enzyme expression and regional lymph-node involvement in colon cancer. This finding may improve our understanding of metastasis and lead to new and more efficient therapies against cancer

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Chemical Composition and Bioactivity Dataset Integration to Identify Antiproliferative Compounds in Phyllanthus Plants

Background/Objectives: Phyllanthus species are renowned in traditional medicine for their diverse therapeutic properties, including potential anticancer activities. This study explored the antiproliferative potential of six Phyllanthus species by integrating chemical composition with bioactivity assays to identify key antiproliferative compounds. Methods: The integration of liquid chromatography–mass spectrometry (LC-MS)-based chemical composition data with antiproliferative activity against three cancer cell lines—PC-3 (prostate adenocarcinoma), SiHa (cervical carcinoma), and A549 (lung carcinoma)—as well as a normal mouse fibroblast line (L929) was performed by covariate analysis. These compounds were subsequently isolated and structurally characterized using spectroscopic methods. Results: Through covariate statistics, seven m/z features were found to be plausible active compounds, and after isolation, they were related to butyrolactone and arylnaphthalide lignans. Among the active isolates, an unreported compound, (+)-phyllanlathyrin 6, was discovered in the aerial part of Phyllanthus lathyroides. The isolated compounds exhibited moderate to good antiproliferative activity (IC50 < 20 µM) with selectivity to SiHa, validating the covariate-based identification approach. Conclusions: These findings highlight the potential of Phyllanthus species as sources of novel anticancer agents, with specific arylnaphthalide lignans showing promising cytotoxic effects that could be further developed into therapeutic leads. Additionally, this study underscores the value of combining advanced analytical techniques with bioactivity testing to uncover bioactive compounds from natural sources. The results contribute to the growing body of evidence supporting the therapeutic relevance of Phyllanthus species and provide a foundation for future drug development efforts targeting cancer treatment

Stimulation of cyclic AMP accumulation and corticotropin release by synthetic ovine corticotropin-releasing factor in rat anterior pituitary cells: site of glucocorticoid action.

A 2.5-fold stimulation of cyclic AMP cellular content is measured 60 sec after addition of 100 nM synthetic ovine corticotropin-releasing factor (C-RF; corticoliberin) to rat anterior pituitary cells in culture. A maximal response of cyclic AMP content at 400% above control is observed between 2 and 30 min after addition of the peptide, whereas an 8-fold stimulation of cyclic AMP released into the incubation medium is measured between 10 and 180 min. A linear 7-fold increase of corticotropin release is observed for up to 3 hr. Preincubation from 18 hr with the potent glucocorticoid dexamethasone has no effect on C-RF-induced cyclic AMP accumulation. The same treatment with dexamethasone causes an 80% inhibition of corticotropin release induced by both C-RF and the cyclic AMP derivative 8-bromoadenosine 3',5'-cyclic monophosphate. The present data show that ovine C-RF is a potent stimulator of cyclic AMP accumulation in rat anterior pituitary cells and that the process is insensitive to the action of dexamethasone. The marked inhibition by dexamethasone of corticotropin secretion induced by a cyclic AMP derivative indicates that glucocorticoids exert their potent inhibitory effects on corticotropin secretion at a step distant to cyclic AMP formation

Corticotropin-releasing factor stimulates accumulation of adenosine 3', 5'-monophosphate in rat pituitary corticotrophs

The presence of synthetic ovine corticotropin-releasing factor leads to a rapid and marked stimulation of adenosine 3', 5'-monophosphate accumulation in an enriched population of rat pituitary corticotrophs in primary culture. The increase, observed as early as 60 seconds after the addition of corticotropin-releasing factor, suggests that changes in the intracellular concentration of the cyclic nucleotide coincide with or precede the secretion of adrenocorticotropic hormone in response to corticotropin-releasing factor

Corticotropin Releasing Factor (CRF): Immunocytochemical localization and Radioimmunoassay (RIA)

Recent isolation, structural identification, and synthesis of ovine CRF has made possible the generation of specific antibodies against this hypothalamic peptide. Two fragments of the amino acid sequence corresponding to ovine CRF (CRF 37-41 and CRF 22-41), as well as the full sequence of 41 residues (CRF 1-41), synthesized in our laboratories by solid-phase methods, were coupled to bovine serum albumin (BSA) with glutaraldehyde. New Zealand white rabbits were immunized with the emulsified mixtures of peptide-BSA conjugates and Freund's adjuvant as immunogens. The specificity of the generated antibodies was studied by agar-gel diffusion, absorption tests in the immunohistochemical system, and with the aid of displacement curves in RIA. 125I-Tyr(35)-CRF 36-41 and 125I-Tyr(0)-CRF 1-41 were used as radioligands in the RIA. The minimum detectable dose was 20 pg. The linearity observed in RIA for immunoreactive CRF in extracts of rat hypothalami, together with the immunocytochemical findings in the rat brain, indicate the presence of substance(s) immunologically indistinguishable from CRF. Immunohistochemistry with the peroxidase-antiperoxidase (PAP) technique detected the following CRF-immunoreactive structures in vibratome sections of hypothalami of colchicine-treated rats: CRF-containing cell bodies were observed mainly in smaller neurons of the paraventricular nucleus. CRF-positive nerve fibers and/or terminals were present in the external zone of the median eminence, with some immunoreactive CRF also present in the internal zone. The CRF-positive terminals were localized in the central regions of the median eminence. These morphological data reinforce the view that this polypeptide plays a physiological role in the control of ACTH release