Gallium Hydrides with a Radical-Anionic Ligand

The reaction of Cl₂GaH with a sodium salt of the dpp-Bian radical-anion (dpp-Bian^•–)Na (dpp-Bian = 1,2-bis­[(2,6-diisopropylphenyl)­imino]­acenaphthene) affords paramagnetic gallane (dpp-Bian^•–)­Ga­(Cl)­H (<b>1</b>). Oxidation of (dpp-Bian^2–)­Ga–Ga­(dpp-Bian^2–) (<b>2</b>) with N₂O results in the dimeric oxide (dpp-Bian^•–)­Ga­(μ²-O)₂Ga­(dpp-Bian^•–) (<b>3</b>). A treatment of the oxide <b>3</b> with phenylsilane affords paramagnetic gallium hydrides (dpp-Bian^•–)­GaH₂ (<b>4</b>) and (dpp-Bian^•–)­Ga­{OSi­(Ph)­H₂}H (<b>5</b>) depending on the reagent’s stoichiometry. The reaction of digallane <b>2</b> with benzaldehyde produces pinacolate (dpp-Bian^•–)­Ga­(O₂C₂H₂Ph₂) (<b>6</b>). In the presence of PhSiH₃, the reaction between digallane <b>2</b> and benzaldehyde (<b>2</b>: PhSiH₃: PhC­(H)­O = 1:4:4) affords compound <b>4</b>. The newly prepared complexes <b>1</b>, <b>3</b>–<b>6</b> consist of a spin-labeled diimine ligand–dpp-Bian radical-anion. The presence of the ligand-localized unpaired electron allows the use of the ESR spectroscopy for characterization of the gallium hydrides reported. The molecular structures of compounds <b>1</b>, <b>3</b>–<b>6</b> have been determined by the single-crystal X-ray analysis

Semiconductor disk laser pumped Cr2+:Znse lasers

A new flexible pump source, the optically-pumped semiconductor disk laser (SDL), for the Cr2+:ZnSe laser is reported. The SDL provides up to 6W output power at a free running central wavelength of 1.98μm. The Cr2+:ZnSe laser operated at an output power of 1.8W and a slope efficiency of ~50% with respect to absorbed pump power whilst maintaining a low output intensity noise figure of <0.14% RMS. The system required no optical isolation even under the situation of significant optical feedback

An Oncofetal Glycosaminoglycan Modification Provides Therapeutic Access to Cisplatin-resistant Bladder Cancer.

BACKGROUND Although cisplatin-based neoadjuvant chemotherapy (NAC) improves survival of unselected patients with muscle-invasive bladder cancer (MIBC), only a minority responds to therapy and chemoresistance remains a major challenge in this disease setting. OBJECTIVE To investigate the clinical significance of oncofetal chondroitin sulfate (ofCS) glycosaminoglycan chains in cisplatin-resistant MIBC and to evaluate these as targets for second-line therapy. DESIGN, SETTING, AND PARTICIPANTS An ofCS-binding recombinant VAR2CSA protein derived from the malaria parasite Plasmodium falciparum (rVAR2) was used as an in situ, in vitro, and in vivo ofCS-targeting reagent in cisplatin-resistant MIBC. The ofCS expression landscape was analyzed in two independent cohorts of matched pre- and post-NAC-treated MIBC patients. INTERVENTION An rVAR2 protein armed with cytotoxic hemiasterlin compounds (rVAR2 drug conjugate [VDC] 886) was evaluated as a novel therapeutic strategy in a xenograft model of cisplatin-resistant MIBC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Antineoplastic effects of targeting ofCS. RESULTS AND LIMITATIONS In situ, ofCS was significantly overexpressed in residual tumors after NAC in two independent patient cohorts (p<0.02). Global gene-expression profiling and biochemical analysis of primary tumors and cell lines revealed syndican-1 and chondroitin sulfate proteoglycan 4 as ofCS-modified proteoglycans in MIBC. In vitro, ofCS was expressed on all MIBC cell lines tested, and VDC886 eliminated these cells in the low-nanomolar IC50 concentration range. In vivo, VDC886 effectively retarded growth of chemoresistant orthotopic bladder cancer xenografts and prolonged survival (p=0.005). The use of cisplatin only for the generation of chemoresistant xenografts are limitations of our animal model design. CONCLUSIONS Targeting ofCS provides a promising second-line treatment strategy in cisplatin-resistant MIBC. PATIENT SUMMARY Cisplatin-resistant bladder cancer overexpresses particular sugar chains compared with chemotherapy-naïve bladder cancer. Using a recombinant protein from the malaria parasite Plasmodium falciparum, we can target these sugar chains, and our results showed a significant antitumor effect in cisplatin-resistant bladder cancer. This novel treatment paradigm provides therapeutic access to bladder cancers not responding to cisplatin

An oncofetal glycosaminoglycan modification provides therapeutic access to cisplatin-resistant bladder cancer

Background: although cisplatin-based neoadjuvant chemotherapy (NAC) improves survival of unselected patients with muscle-invasive bladder cancer (MIBC), only a minority responds to therapy and chemoresistance remains a major challenge in this disease setting.Objective: o investigate the clinical significance of oncofetal chondroitin sulfate (ofCS) glycosaminoglycan chains in cisplatin-resistant MIBC and to evaluate these as targets for second-line therapy.Design, setting, and participants: an ofCS-binding recombinant VAR2CSA protein derived from the malaria parasite Plasmodium falciparum (rVAR2) was used as an in situ, in vitro, and in vivo ofCS-targeting reagent in cisplatin-resistant MIBC. The ofCS expression landscape was analyzed in two independent cohorts of matched pre- and post-NAC–treated MIBC patients.Intervention: an rVAR2 protein armed with cytotoxic hemiasterlin compounds (rVAR2 drug conjugate [VDC] 886) was evaluated as a novel therapeutic strategy in a xenograft model of cisplatin-resistant MIBC.Outcome measurements and statistical analysis: antineoplastic effects of targeting ofCS.Results and limitations: in situ, ofCS was significantly overexpressed in residual tumors after NAC in two independent patient cohorts (p &lt; 0.02). Global gene-expression profiling and biochemical analysis of primary tumors and cell lines revealed syndican-1 and chondroitin sulfate proteoglycan 4 as ofCS-modified proteoglycans in MIBC. In vitro, ofCS was expressed on all MIBC cell lines tested, and VDC886 eliminated these cells in the low-nanomolar IC50 concentration range. In vivo, VDC886 effectively retarded growth of chemoresistant orthotopic bladder cancer xenografts and prolonged survival (p = 0.005). The use of cisplatin only for the generation of chemoresistant xenografts are limitations of our animal model design.Conclusions: targeting ofCS provides a promising second-line treatment strategy in cisplatin-resistant MIBC.Patient summary: cisplatin-resistant bladder cancer overexpresses particular sugar chains compared with chemotherapy-naïve bladder cancer. Using a recombinant protein from the malaria parasite Plasmodium falciparum, we can target these sugar chains, and our results showed a significant antitumor effect in cisplatin-resistant bladder cancer. This novel treatment paradigm provides therapeutic access to bladder cancers not responding to cisplatin.</p