Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in a variety of cancer types, including malignant gliomas. STAT3 is activated by phosphorylation of a tyrosine residue, after which it dimerizes and translocates into the nucleus. There it regulates the expression of several genes responsible for proliferation and survival at the transcriptional level. A selective inhibitor of STAT3 phosphorylation, AG490, has been shown to inhibit growth and induce apoptosis in some cancer cell types. However, although AG490 routinely shows in vitro anticancer activity, it has not consistently demonstrated an in vivo anticancer effect in animal models. Here, we have tested WP1066, a novel inhibitor structurally related to AG490 but significantly more potent and active, against human malignant glioma U87-MG and U373-MG cells in vitro and in vivo. IC 50 values for WP1066 were 5.6 lM in U87-MG cells and 3.7 lM in U373-MG cells, which represents 18-fold and eightfold increases in potency, respectively, over that of AG490. WP1066 activated Bax, suppressed the expression of c-myc, Bcl-X L and Mcl-1, and induced apoptosis. Systemic intraperitoneal administration of WP1066 in mice significantly (Po0.001) inhibited the growth of subcutaneous malignant glioma xenografts during the 30-day follow-up period. Immunohistochemical analysis of the excised tumors revealed that phosphorylated STAT3 levels in the WP1066 treatment group remained inhibited at 3 weeks after the final WP1066 injection, whereas tumors from the control group expressed high levels of phosphorylated STAT3. We conclude that WP1066 holds promise as a therapeutic agent against malignant gliomas.

Overall, our in vitro results suggest that 2-FG is more potent than 2-DG in killing hypoxic tumor cells, and therefore may be more clinically effective when combined with standard chemotherapeutic protocols.

Use of chimeric antigen receptors (CARs) as the basis of targeted adoptive T cell therapies has enabled dramatic efficacy against multiple hematopoietic malignancies, but potency against bulky and solid tumors has lagged, potentially due to insufficient CAR-T cell expansion and persistence. To improve CAR-T cell efficacy, we utilized a potent activation switch based on rimiducid-inducible MyD88 and CD40 (iMC)-signaling elements. To offset potential toxicity risks by this enhanced CAR, an orthogonally regulated, rapamycin-induced, caspase-9-based safety switch (iRC9) was developed to allow in vivo elimination of CAR-T cells. iMC costimulation induced by systemic rimiducid administration enhanced CAR-T cell proliferation, cytokine secretion, and antitumor efficacy in both in vitro assays and xenograft tumor models. Conversely, rapamycin-mediated iRC9 dimerization rapidly induced apoptosis in a dose-dependent fashion as an approach to mitigate therapy-related toxicity. This novel, regulatable dual-switch system may promote greater CAR-T cell expansion and prolonged persistence in a drug-dependent manner while providing a safety switch to mitigate toxicity concerns.

Glioma stem-like cells (GSCs) may be the initiating cells in glioblastoma (GBM) and contribute to the resistance of these tumors to conventional therapies. Development of novel chemotherapeutic agents and treatment approaches against GBM, especially those specifically targeting GSCs are thus necessary. In the present study, we found that a novel Janus kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) pathway inhibitor (WP1193) significantly decreased the proliferation of established glioma cell lines in vitro and inhibit the growth of glioma in vivo. To test the efficacy of WP1193 against GSCs, we then administrated WP1193 to GSCs isolated and expanded from multiple human GBM tumors. We revealed that WP1193 suppressed phosphorylation of JAK2 and STAT3 with high potency and demonstrated a dose-dependent inhibition of proliferation and neurosphere formation of GSCs. These effects were at least due in part to G1 arrest associated with down-regulation of cyclin D1 and up-regulation of p21( Cip1/Waf-1 ). Furthermore, WP1193 exposure decreased expression of stem cell markers including CD133 and c-myc, and induced cell death in GSCs through apoptosis. Taken together, our data indicate that WP1193 is a potent small molecule inhibitor of the JAK2/STAT3 pathway that shows promise as a therapeutic agent against GBM by targeting GSCs.

The aim of the study was to investigate relationships between the concentrations of macroelements (Ca), microelements (Cr, Cu, Fe, Mn, Mo, Ni, Sn, Sr, V, Zn) and heavy metals (Ag, Cd, Pb) in the placenta, fetal membrane and umbilical cord. ‪Furthermore, we examined relationships between the concentrations of these metals in the studied afterbirths and maternal age, gestational age, placenta parameters (breadth, length, weight) and newborn parameters (length, weight and Apgar score). This study confirms previously reported Zn-Cd, Pb-Cd and Ni-Pb interactions in the placenta. New types of interactions in the placenta, fetal membrane and umbilical cord were also noted. Analysis of the correlations between metal elements in the afterbirths (placenta, fetal membrane and umbilical cord) and biological parameters showed the following relationships: maternal age and Mn (in the fetal membrane); gestational age and Cr, Fe, Zn (in the fetal membrane), Ag and Cu (in the umbilical cord); newborn’s length and Sr (in the placenta), Ag (in the umbilical cord); newborn’s weight and Sr (in the placenta), Cu (in the fetal membrane), Ag (in the umbilical cord); Apgar score and Ca, Cr and Ni (in the umbilical cord); placenta’s length and Cr and Sn (in the fetal membrane), Cu (in the umbilical cord); placenta’s width and Mo, Pb (in the placenta) and placenta weight and Sr (in the placenta), Ag, Fe, Mn (in the fetal membrane). The results show the influence of metals on the placenta, mother and newborn parameters, and the same point indicates the essential trace elements during the course of pregnancy.

The aim of the study was to perform an evaluation of chosen body surface temperatures in neonates immediately after birth, and to seek a relationship between those temperatures and the factors related both to the mother and newborn. The study included 74 healthy newborns. Maternal age, body weight, body mass index before pregnancy and on delivery day, birth and pregnancy order, newborn sex, birth weight, body length, pregnancy week on delivery, as well as newborn gasometric test results were collected. The highest temperature values were observed in the chest of the newborn. Significant relationships between the temperature of the evaluated areas were found. The parameters that correlated positively with the temperature of the back region were maternal body weight (both before pregnancy and on delivery day) as well as weight gain during pregnancy. The core and surface temperatures of the body are one of the most important elements of neonatal homeostasis and any changes constitute a risk to the newborn’s health. It seemed that according to the surface temperature, the most important area that must be evaluated is the neonate’s back, as it is most affected by appropriate weight gain during pregnancy.

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