Abstract
The electronic instabilities in CsV
3
Sb
5
are believed to originate from the V 3
d
-electrons on the kagome plane, however the role of Sb 5
p
-electrons for 3-dimensional orders is largely ...unexplored. Here, using resonant tender X-ray scattering and high-pressure X-ray scattering, we report a rare realization of conjoined charge density waves (CDWs) in CsV
3
Sb
5
, where a 2 × 2 × 1 CDW in the kagome sublattice and a Sb 5
p
-electron assisted 2 × 2 × 2 CDW coexist. At ambient pressure, we discover a resonant enhancement on Sb
L
1
-edge (2
s
→5
p
) at the 2 × 2 × 2 CDW wavevectors. The resonance, however, is absent at the 2 × 2 × 1 CDW wavevectors. Applying hydrostatic pressure, CDW transition temperatures are separated, where the 2 × 2 × 2 CDW emerges 4 K above the 2 × 2 × 1 CDW at 1 GPa. These observations demonstrate that symmetry-breaking phases in CsV
3
Sb
5
go beyond the minimal framework of kagome electronic bands near van Hove filling.
The combination of nontrivial band topology and symmetry-breaking phases gives rise to novel quantum states and phenomena such as topological superconductivity, quantum anomalous Hall effect, and ...axion electrodynamics. Evidence of intertwined charge density wave (CDW) and superconducting order parameters has recently been observed in a novel kagome material AV_{3}Sb_{5} (A=K, Rb, Cs) that features a Z_{2} topological invariant in the electronic structure. However, the origin of the CDW and its intricate interplay with the topological state has yet to be determined. Here, using hard-x-ray scattering, we demonstrate a three-dimensional CDW with 2×2×2 superstructure in (Rb,Cs)V_{3}Sb_{5}. Unexpectedly, we find that the CDW fails to induce acoustic phonon anomalies at the CDW wave vector but yields a novel Raman mode that quickly damps into a broad continuum below the CDW transition temperature. Our observations exclude strong electron-phonon-coupling-driven CDW in AV_{3}Sb_{5} and support an unconventional CDW that was proposed in the kagome lattice at van Hove filling.
CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that ...CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.
Epithelial Ovarian Cancer (EOC) cells expression of a novel carbohydrate antigen was defined using a human VH4-34 encoded IgM monoclonal antibody (mAb216). MAb216 binds to a poly N-acetyllactosamine ...epitope expressed on B cells and kills normal and malignant B cells in vitro and in vivo. EOC patient ascites and EOC cell lines were used to study the anti tumor effect of mAb216. Various assays were used to characterize the epitope and demonstrate antibody-mediated binding and cytotoxicity in EOC. Drug and antibody combination effects were determined by calculating the combination index values using the Chou and Talalay method. MAb216 displays direct antibody mediated cytotoxicity on a population of human EOC tumor and ascites samples and EOC cell lines, which express high amounts of poly N-acetyllactosamine epitope, carried by CD147/CD98. Eighty four percent of patient samples, including platin resistant, had a tumor population that bound the monoclonal antibody. The binding pattern of mAb216 and mechanism of cytotoxicity was similar to that seen on normal and malignant B cells with unique general membrane disruption and "pore" formation. In vitro incubation with mAb216 and cisplatin enhanced killing of OVCAR3 cell line. In EOC cell lines percent cytotoxicity correlated with percent expression of epitope. Although in vitro data shows specific EOC cytotoxicity, for possible treatment of EOC MAb216 would need to be evaluated in a clinical trial with or without chemotherapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
High-grade epithelial ovarian carcinomas containing mutated
or
(
) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and PARP inhibitors (PARPi), while restoration of ...HR function due to secondary mutations in
has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pretreatment and postprogression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase II study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed ovarian carcinoma. In 6 of 12 pretreatment biopsies, a truncation mutation in
, or
was identified. In five of six paired postprogression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for
complementation assays and a patient-derived xenograft, as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations.
Analyses of primary and secondary mutations in
and
provide evidence for these primary mutations in conferring PARPi sensitivity and secondary mutations as a mechanism of acquired PARPi resistance. PARPi resistance due to secondary mutations underpins the need for early delivery of PARPi therapy and for combination strategies.
.
Multidrug resistance (MDR) is a major cause of chemotherapy failure in the clinic. Drugs that were once effective against naïve disease subsequently prove ineffective against recurrent disease, ...which often exhibits an MDR phenotype. MDR can be attributed to many factors; often dominating among these is the ability of a cell to suppress or block drug entry through upregulation of membrane-bound drug efflux pumps. Efflux pumps exhibit polyspecificity, recognizing and exporting many different types of drugs, especially those whose lipophilic nature contributes to residence in the membrane. We have developed a general strategy to overcome efflux-based resistance. This strategy involves conjugating a known drug that succumbs to efflux-mediated resistance to a cell-penetrating molecular transporter, specifically, the cell-penetrating peptide (CPP), d-octaarginine. The resultant conjugates are discrete single entities (not particle mixtures) and highly water-soluble. They rapidly enter cells, are not substrates for efflux pumps, and release the free drug only after cellular entry at a rate controlled by linker design and favored by target cell chemistry. This general strategy can be applied to many classes of drugs and allows for an exceptionally rapid advance to clinical testing, especially of drugs that succumb to resistance. The efficacy of this strategy has been successfully demonstrated with Taxol in cellular and animal models of resistant cancer and with ex vivo samples from patients with ovarian cancer. Next generation efforts in this area will involve the extension of this strategy to other chemotherapeutics and other MDR-susceptible diseases.
Riboswitches are structural RNA elements that are generally located in the 5' untranslated region of messenger RNA. During regulation of gene expression, ligand binding to the aptamer domain of a ...riboswitch triggers a signal to the downstream expression platform. A complete understanding of the structural basis of this mechanism requires the ability to study structural changes over time. Here we use femtosecond X-ray free electron laser (XFEL) pulses to obtain structural measurements from crystals so small that diffusion of a ligand can be timed to initiate a reaction before diffraction. We demonstrate this approach by determining four structures of the adenine riboswitch aptamer domain during the course of a reaction, involving two unbound apo structures, one ligand-bound intermediate, and the final ligand-bound conformation. These structures support a reaction mechanism model with at least four states and illustrate the structural basis of signal transmission. The three-way junction and the P1 switch helix of the two apo conformers are notably different from those in the ligand-bound conformation. Our time-resolved crystallographic measurements with a 10-second delay captured the structure of an intermediate with changes in the binding pocket that accommodate the ligand. With at least a 10-minute delay, the RNA molecules were fully converted to the ligand-bound state, in which the substantial conformational changes resulted in conversion of the space group. Such notable changes in crystallo highlight the important opportunities that micro- and nanocrystals may offer in these and similar time-resolved diffraction studies. Together, these results demonstrate the potential of 'mix-and-inject' time-resolved serial crystallography to study biochemically important interactions between biomacromolecules and ligands, including those that involve large conformational changes.
Aberrantly activated FOXM1 (forkhead box protein M1) leading to uncontrolled cell proliferation and dysregulation of FOXM1 transcription network occurs in 84% of ovarian cancer cases. It was ...demonstrated that thiostrepton, a thiazole antibiotic, decreases FOXM1 expression. We aimed to determine if targeting the FOXM1 pathway with thiostrepton could improve the efficacy of paclitaxel and cisplatin in human ovarian cancer ascites cells ex vivo.
Human ovarian cancer cell lines and patients' ascites cells were treated with paclitaxel, cisplatin, and thiostrepton or a combination for 48 hours, and cytotoxicity was assessed. Drug combination effects were determined by calculating the combination index values using the Chou and Talalay method. Quantitative reverse transcriptase-polymerase chain reaction was performed to determine changes in FOXM1 expression and its downstream targets.
Ovarian cancer cell lines and the patients' ascites cancer cells had an overexpression of FOXM1 expression levels. Targeting FOXM1 with thiostrepton decreased FOXM1 mRNA expression and its downstream targets such as CCNB1 and CDC25B, leading to cell death in both cell lines and patients' ascites cancer cells. Furthermore, addition of thiostrepton to paclitaxel and cisplatin showed synergistic effects in chemoresistant ovarian cancer patients' ascites cells ex vivo.
Targeting FOXM1 may lead to novel therapeutics for chemoresistant epithelial ovarian cancer.
This case series describes a constellation of novel adverse reactions in 3 of 9 patients with uveal melanoma receiving treatment targeting activity of the Brahma-associated factor chromatin ...remodeling complex.
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