Growth and progression of solid tumors depend on the integration of multiple pro-growth and survival signals, including the induction of angiogenesis. TWIST1 is a transcription factor whose reactivation in tumors leads to epithelial to mesenchymal transition (EMT), including increased cancer cell stemness, survival, and invasiveness. Additionally, TWIST1 drives angiogenesis via activation of IL-8 and CCL2, independent of VEGF signaling. In this work, results suggest that chemically modified siRNA against TWIST1 reverses EMT both in vitro and in vivo. siRNA delivery with a polyethyleneimine-coated mesoporous silica nanoparticle (MSN) led to reduction of TWIST1 target genes and migratory potential in vitro. In mice bearing xenograft tumors, weekly intravenous injections of the siRNA-nanoparticle complexes resulted in decreased tumor burden together with a loss of CCL2 suggesting a possible anti-angiogenic response. Therapeutic use of TWIST1 siRNA delivered via MSNs has the potential to inhibit tumor growth and progression in many solid tumor types.

From the clinical editor

Tumor progression and metastasis eventually lead to patient mortality in the clinical setting. In other studies, it has been found that TWIST1, a transcription factor, if reactivated in tumors, would lead to downstream events including angiogenesis and result in poor prognosis in cancer patients. In this article, the authors were able to show that when siRNA against TWIST1 was delivered via mesoporous silica nanoparticle, there was tumor reduction in an in-vivo model. The results have opened up a new avenue for further research in this field.

Epithelial ovarian cancer (EOC) is the most deadly gynecologic malignancy on account of its late stage at diagnosis and frequency of drug resistant recurrences. Novel therapies to overcome these barriers are urgently needed. TWIST is a developmental transcription factor reactivated in cancers and linked to angiogenesis, metastasis, cancer stem cell phenotype, and drug resistance, making it a promising therapeutic target. In this work, we demonstrate the efficacy of TWIST siRNA (siTWIST) and two nanoparticle delivery platforms to reverse chemoresistance in EOC models. Polyamidoamine dendrimers and mesoporous silica nanoparticles (MSNs) carried siTWIST into target cells and led to sustained TWIST knockdown in vitro. Mice treated with cisplatin plus MSN-siTWIST exhibited lower tumor burden than mice treated with cisplatin alone, with most of the effect coming from reduction in disseminated tumors. This platform has potential application for overcoming the clinical challenges of metastasis and chemoresistance in EOC and other TWIST overexpressing cancers.

In particle collider experiments, elementary particle interactions with large momentum transfer produce quarks and gluons (known as partons) whose evolution is governed by the strong force, as described by the theory of quantum chromodynamics (QCD)¹. These partons subsequently emit further partons in a process that can be described as a parton shower², which culminates in the formation of detectable hadrons. Studying the pattern of the parton shower is one of the key experimental tools for testing QCD. This pattern is expected to depend on the mass of the initiating parton, through a phenomenon known as the dead-cone effect, which predicts a suppression of the gluon spectrum emitted by a heavy quark of mass m_Q and energy E, within a cone of angular size m_Q/E around the emitter³. Previously, a direct observation of the dead-cone effect in QCD had not been possible, owing to the challenge of reconstructing the cascading quarks and gluons from the experimentally accessible hadrons. We report the direct observation of the QCD dead cone by using new iterative declustering techniques^4,5 to reconstruct the parton shower of charm quarks. This result confirms a fundamental feature of QCD. Furthermore, the measurement of a dead-cone angle constitutes a direct experimental observation of the non-zero mass of the charm quark, which is a fundamental constant in the standard model of particle physics.

Recent pT-integrated cross-section measurements of the ground-state charm mesons and baryons, D0, D+, Ds+, Λc+, and Ξc0, are used to evaluate the charm fragmentation fractions and production cross section per unit of rapidity at midrapidity (|y|<0.5), in pp collisions at s=5.02 TeV at the LHC. The latter is dσcc¯/dy||y|<0.5=1165±44(stat)-101+134(syst) μb. These measurements were obtained for the first time in hadronic collisions at the LHC, including the charm baryon states, recently measured by ALICE at midrapidity. The charm fragmentation fractions differ significantly from the values measured in e+e- and ep collisions, providing evidence of the dependence of the parton-to-hadron fragmentation fractions on the collision system, indicating that the assumption of their universality is not supported by the measured cross sections. An increase of a factor of about 3.3 for the fragmentation fraction for the Λc+ with a significance of 5σ between the values obtained in pp collisions and those obtained in e+e- (ep) collisions is reported. The fragmentation fraction for the Ξc0 was obtained for the first time in any collision system. The measured fragmentation fractions were used to update the cc¯ cross sections per unit of rapidity at |y|<0.5 at s=2.76 and 7 TeV, which are about 40% higher than the previously published results. The data were compared with perturbative-QCD calculations and lie at the upper edge of the theoretical bands.

The transverse momentum (pT) differential cross section of the charm-strange baryon Ξc0 is measured at midrapidity (|y| < 0.5) via its semileptonic decay into e+Ξ−νe in pp collisions at s = 5.02 TeV with the ALICE detector at the LHC. The ratio of the pT-differential Ξc0-baryon and D0-meson production cross sections is also reported. The measurements are compared with simulations with different tunes of the PYTHIA 8 event generator, with predictions from a statistical hadronisation model (SHM) with a largely augmented set of charm-baryon states beyond the current lists of the Particle Data Group, and with models including hadronisation via quark coalescence. The pT-integrated cross section of prompt Ξc0-baryon production at midrapidity is also reported, which is used to calculate the baryon-to-meson ratio Ξc0/D0 = 0.20 ± 0.04 (stat.)−0.07+0.08 (syst.). These results provide an additional indication of a modification of the charm fragmentation from e+e− and e−p collisions to pp collisions. [Figure not available: see fulltext.]