New insights into the activities and toxicities of the old anticancer drug doxorubicin

The anthracycline drug doxorubicin is among the most used-and useful-chemotherapeutics. While doxorubicin is highly effective in the treatment of various hematopoietic malignancies and solid tumours, its application is limited by severe adverse effects, including irreversible cardiotoxicity, therapy-related malignancies and gonadotoxicity. This continues to motivate investigation into the mechanisms of anthracycline activities and toxicities, with the aim to overcome the latter without sacrificing the former. It has long been appreciated that doxorubicin causes DNA double-strand breaks due to poisoning topoisomerase II. More recently, it became clear that doxorubicin also leads to chromatin damage achieved through eviction of histones from select sites in the genome. Evaluation of these activities in various anthracycline analogues has revealed that chromatin damage makes a major contribution to the efficacy of anthracycline drugs. Furthermore, the DNA-damaging effect conspires with chromatin damage to cause a number of adverse effects. Structure-activity relationships within the anthracycline family offer opportunities for chemical separation of these activities towards development of effective analogues with limited adverse effects. In this review, we elaborate on our current understanding of the different activities of doxorubicin and their contributions to drug efficacy and side effects. We then offer our perspective on how the activities of this old anticancer drug can be amended in new ways to benefit cancer patients, by providing effective treatment with improved quality of life.Chemical Immunolog

A Dithienylbenzothiadiazole Pure Red Molecular Emitter with Electron Transport and Exciton Self-Confinement for Nondoped Organic Red-Light-Emitting Diodes

An amorphous photoluminescent material based on a dithienylbenzothiadiazole structure has been used for the fabrication of organic red-light-emitting diodes. The synergistic effects of the electron-transport ability and exciton confinement of the emitting material allow for the fabrication of efficient pure-red-light-emitting devices without a hole blocker

The Y(4260) as an omega chi_{c1} molecular state

It is suggested that the newly observed Y(4260) by BARBAR collaboration is a molecular state composed of an omega and a chi_{c1}. Both the production and decay properties are discussed. A consequence for this molecular state, Y(4260), is that it decays into pi+pi-pi0 chi_{c1} with similar rate to pi+ pi- J/psi. It is also expected that Y(4260) -> pi0 pi0 J/psi is produced at half rate as Y(4260) ->pi+ pi- J/psi. These decay modes should be searched for in the B factories using initial state radiative return data and B decay data as well.Comment: 5 pages, 5 figure

Determining the upper limit of Gamma_{ee} for the Y(4260)

By fitting the R values between 3.7 and 5.0 GeV measured by the BES collaboration, the upper limit of the electron width of the newly discovered resonance Y(4260) is determined to be 580 eV at 90% C.L. Together with the BABAR measurement on the product of Gamma_{ee} and BR(Y(4260) --> pi+pi- J/psi), this implies a large decay width of Y(4260) --> pi+pi- J/psi final states.Comment: 8 pages, 4 figure

Possible tetraquark states in the π+χc1\pi^+ \chi_{c1} invariant mass distribution

In this article, we assume that there exist hidden charmed tetraquark states with the spin-parity $J^P=1^-$, and calculate their masses with the QCD sum rules. The numerical result indicates that the masses of the vector hidden charmed tetraquark states are about $M_{Z}=(5.12\pm0.15) \rm{GeV}$ or $M_{Z}=(5.16\pm0.16) \rm{GeV}$, which are inconsistent with the experimental data on the $\pi^+ \chi_{c1}$ invariant mass distribution. The hidden charmed mesons $Z_1$, $Z_2$ or $Z$ may be scalar hidden charmed tetraquark states, hadro-charmonium resonances or molecular states.Comment: 12 pages, 4 figure

Heavy quarkonium: progress, puzzles, and opportunities

A golden age for heavy quarkonium physics dawned a decade ago, initiated by the confluence of exciting advances in quantum chromodynamics (QCD) and an explosion of related experimental activity. The early years of this period were chronicled in the Quarkonium Working Group (QWG) CERN Yellow Report (YR) in 2004, which presented a comprehensive review of the status of the field at that time and provided specific recommendations for further progress. However, the broad spectrum of subsequent breakthroughs, surprises, and continuing puzzles could only be partially anticipated. Since the release of the YR, the BESII program concluded only to give birth to BESIII; the $B$-factories and CLEO-c flourished; quarkonium production and polarization measurements at HERA and the Tevatron matured; and heavy-ion collisions at RHIC have opened a window on the deconfinement regime. All these experiments leave legacies of quality, precision, and unsolved mysteries for quarkonium physics, and therefore beg for continuing investigations. The plethora of newly-found quarkonium-like states unleashed a flood of theoretical investigations into new forms of matter such as quark-gluon hybrids, mesonic molecules, and tetraquarks. Measurements of the spectroscopy, decays, production, and in-medium behavior of c\bar{c}, b\bar{b}, and b\bar{c} bound states have been shown to validate some theoretical approaches to QCD and highlight lack of quantitative success for others. The intriguing details of quarkonium suppression in heavy-ion collisions that have emerged from RHIC have elevated the importance of separating hot- and cold-nuclear-matter effects in quark-gluon plasma studies. This review systematically addresses all these matters and concludes by prioritizing directions for ongoing and future efforts.Comment: 182 pages, 112 figures. Editors: N. Brambilla, S. Eidelman, B. K. Heltsley, R. Vogt. Section Coordinators: G. T. Bodwin, E. Eichten, A. D. Frawley, A. B. Meyer, R. E. Mitchell, V. Papadimitriou, P. Petreczky, A. A. Petrov, P. Robbe, A. Vair

Uncoupling DNA damage from chromatin damage to detoxify doxorubicin

The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility. It is unclear whether these side effects are coupled to the chemotherapeutic efficacy. Doxo, Daun, Epi, and Ida execute two cellular activities: DNA damage, causing double-strand breaks (DSBs) following poisoning of topoisomerase II (Topo II), and chromatin damage, mediated through histone eviction at selected sites in the genome. Here we report that anthracycline-induced cardiotoxicity requires the combination of both cellular activities. Topo II poisons with either one of the activities fail to induce cardiotoxicity in mice and human cardiac microtissues, as observed for aclarubicin (Acla) and etoposide (Etop). Further, we show that Doxo can be detoxified by chemically separating these two activities. Anthracycline variants that induce chromatin damage without causing DSBs maintain similar anticancer potency in cell lines, mice, and human acute myeloid leukemia patients, implying that chromatin damage constitutes a major cytotoxic mechanismof anthracyclines. With these anthracyclines abstained from cardiotoxicity and therapy-related tumors, we thus uncoupled the side effects from anticancer efficacy. These results suggest that anthracycline variants acting primarily via chromatin damage may allow prolonged treatment of cancer patients and will improve the quality of life of cancer survivors.Therapeutic cell differentiatio

Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma

Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30-50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3-4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90-100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO's MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC.Immune checkpoint blockade has become standard care for patients with recurrent metastatic head and neck squamous cell carcinoma (HNSCC). Here the authors present the results of a non-randomized phase Ib/IIa trial, reporting safety and efficacy of neoadjuvant nivolumab monotherapy and nivolumab plus ipilimumab prior to standard-of-care surgery in patients with HNSCC. .Otorhinolaryngolog

Study of J/Psi decays into eta Kstar Kstar-bar

We report the first observation of \mPJpsi \to \mPeta\mPKst\mAPKst decay in a \mPJpsi sample of 58 million events collected with the BESII detector. The branching fraction is determined to be $(1.15 \pm 0.13 \pm 0.22)\times 10^{-3}$. The selected signal event sample is further used to search for the \mPY resonance through \mPJpsi \to \mPeta \mPY, \mPY\to\mPKst\mAPKst. No evidence of a signal is seen. An upper limit of \mathrm{Br}(\mPJpsi \to \mPeta \mPY)\cdot\mathrm{Br}(\mPY\to\mPKst\mAPKst) < 2.52\times 10^{-4} is set at the 90% confidence level.Comment: 11 pages, 4 figure