Light Propagation in Linear Arrays of Spherical Particles

A propagation of dipolar radiation in a finite length linear chain of identical dielectric spheres is investigated using the multisphere Mie scattering formalism (MSMS). A frequency pass band is shown to be formed near every Mie resonances inherent in the spheres. The manifestation of the pass band depends on the polarization of the travelling radiation. To prove this effect, a point dipole placed by the end of the chain is used as an external source of radiation. It is found that, if this dipole is directed parallel to the to the chain axis, the frequency pass bands exist if the refractive index of dielectric spheres is sufficiently large. For the dipole normal to the chain axis, the pass band can always be formed if the chain is sufficiently long. Such a distinction is due to different behavior of the far-field dipolar interaction between the spheres induced by the external source. The edges of the pass bands are defined by the guiding wave criterion based on the light-cone constraint. The criterion of creation of the pass bands correlate with condition of formation of high quality factor modes in these systems found in our previous papers. A comparison with the results available for infinite chains is made. In particular, we clarify the nature of braking down the band structure for small enough wavevectors

Determinants of Apoptotic Sensitivity to HSP90 Inhibition In Acute Myeloid Leukemia

Abstract Abstract 2159 Background: Acute myeloid leukemia (AML) is a heterogeneous and intrinsically resistant disease group of malignant hematopoietic disorders that accounts for approximately 80% of all adult leukemias. Heat shock proteins (HSPs) are often overexpressed in AML are their expression is associated with poor-prognosis and resistance to chemotherapy. Among HSPs, HSP90 is the main chaperone required for the stabilization of multiple oncogenic kinases, which contribute to AML pathogenesis, providing a rationale for the use of HSP90 inhibitors in the treatment of AML. Hypothesis: To identify patients with AML who will benefit from HSP90 inhibitor therapy there is a need to discover molecules and pathways in AML cells that confer sensitivity and lead to significant apoptosis upon HSP90 inhibition. Study design and Results: To evaluate the spectrum of sensitivities of AML cells to HSP90 inhibitors, and to investigate a possible relationship between their genetic background and apoptotic sensitivity to HSP90 inhibition, we investigated the effects of HSP90 inhibitors in a set of genetically characterized human AML cells. Addition of several HSP90 inhibitors to each of these cell lines potently inhibited cell growth, with a potency reflective of their affinity for HSP90. Normal peripheral blood leukocytes were unaffected at similar concentrations. HSP90 inhibition was associated with destabilization and subsequent degradation of Akt and c-Raf in all tested cells, as well as of several cell-specific onco-proteins such as mutant Flt3 in MOLM-13, TEL-TRKC in M0-91, AML1-ETO and mutant cKit in Kasumi-1 and SKNO-1, and mutant Jak2 in HEL cells, respectively. Notably, the proclivity for these cells to undergo apoptosis upon HSP90 inhibition varied considerably. The most sensitive cell lines were MOLM-13, MV-4-11 and M0-91 cells, and for each these cell lines we observed near 100% killing of the initial cell population after 48–72 h of HSP90 inhibitor treatment. In contrast, only 20% death was seen in HEL and HL-60 cells under these conditions. We next made use of specific inhibitors of known oncogenic signaling pathways known to be dysregulated in AML to demonstrate that apoptotic sensitivity of AML cells to HSP90 inhibition correlated with PI3K-Akt and STAT5 activation, but not with activation of the Raf-MAPK pathway. Importantly, similar results were observed in cells lines, xenograft models and isogenic cell line systems. We also found that dual activation of these two pathways, especially in the context of Bcl-xL overexpression, lowers the apoptotic threshold of AML when HSP90 is inhibited. Conclusions: We found that activation of oncogenic signaling pathways and expression of leukemogenic anti-apoptotic molecules, most importantly p-Akt, predicts for AML sensitivity to HSP90 inhibitors. Importantly, 50– 70% of patients with AML display phosphorylation of both Thr308 and Ser4 Akt. This molecule contributes to proliferation, survival and drug resistance in AML, and is associated with adverse outcome. Taken together, our findings suggest that AML patients with activation of Akt and STAT5 signaling are most likely to benefit from HSP90 inhibitor therapy, and clinical trials should aim to enroll patients with specific activation of these important signaling pathways. Disclosures: No relevant conflicts of interest to declare

Clinical outcomes for previously treated patients with advanced biliary tract cancer - supplementary material

Supplemental Table 1: Search strategy for Embase (Embase 1974 to 2021 June 28)Supplemental Table 2: Search strategy for MEDLINE (Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to June 28, 2021)Supplemental Table 3: Search strategy for CENTRAL (EBM Reviews - Cochrane Central Register of Controlled Trials May 2021)Supplemental Table 4: Search strategy for American Society of Clinical Oncology conference abstracts (Northern Light Life Sciences Conference Abstracts 2010 to 2021 Week 24)Supplemental Table 5: Search strategy for European Society for Medical Oncology conference abstracts (Northern Light Life Sciences Conference Abstracts 2010 to 2021 Week 24)Supplemental Table 6: Search strategy for ClinicalTrials.govSupplemental Table 7: Detailed study characteristics for trials included in the systematic reviewSupplemental Table 8: Detailed treatment characteristics for trials included in the systematic reviewSupplemental Table 9: Detailed patient characteristics for trials included in the systematic reviewSupplemental Table 10: Response outcomes for trials included in the systematic reviewSupplemental Table 11: Survival outcomes for trials included in the systematic reviewSupplemental Table 12: Safety outcomes for trials included in the systematic reviewSupplemental Table 13: Patient-reported outcomes for trials included in the systematic reviewSupplemental Table 14: Quality assessment of included single-arm and non-randomized trialsSupplemental Table 15: Summary of pooled KM estimates of OS Supplemental Table 16: Summary of KM estimates of PFS Supplemental Figure 1: Risk of bias assessment of included RCTs </p

A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor-Specific Hsp90 Species

Acute myeloid leukemia (AML) is a heterogeneous and fatal disease with an urgent need for improved therapeutic regimens given that most patients die from relapsed disease. Irrespective of mutation status, the development of aggressive leukemias is enabled by increasing dependence on signaling networks. We demonstrate that a hyperactive signalosome drives addiction of AML cells to a tumor-specific Hsp90 species (teHsp90). Through genetic, environmental, and pharmacologic perturbations, we demonstrate a direct and quantitative link between hyperactivated signaling pathways and apoptotic sensitivity of AML to teHsp90 inhibition. Specifically, we find that hyperactive JAK-STAT and PI3K-AKT signaling networks are maintained by teHsp90 and, in fact, gradual activation of these networks drives tumors increasingly dependent on teHsp90. Thus, although clinically aggressive AML survives via signalosome activation, this addiction creates a vulnerability that can be exploited with Hsp90-directed therapy

Heat Shock Protein 70 Inhibitors. 1. 2,5′-Thiodipyrimidine and 5‑(Phenylthio)pyrimidine Acrylamides as Irreversible Binders to an Allosteric Site on Heat Shock Protein 70

Heat shock protein 70 (Hsp70) is an important emerging cancer target whose inhibition may affect multiple cancer-associated signaling pathways and, moreover, result in significant cancer cell apoptosis. Despite considerable interest from both academia and pharmaceutical companies in the discovery and development of druglike Hsp70 inhibitors, little success has been reported so far. Here we describe structure–activity relationship studies in the first rationally designed Hsp70 inhibitor class that binds to a novel allosteric pocket located in the N-terminal domain of the protein. These 2,5′-thiodipyrimidine and 5-(phenylthio)­pyrimidine acrylamides take advantage of an active cysteine embedded in the allosteric pocket to act as covalent protein modifiers upon binding. The study identifies derivatives <b>17a</b> and <b>20a</b>, which selectively bind to Hsp70 in cancer cells. Addition of high nanomolar to low micromolar concentrations of these inhibitors to cancer cells leads to a reduction in the steady-state levels of Hsp70-sheltered oncoproteins, an effect associated with inhibition of cancer cell growth and apoptosis. In summary, the described scaffolds represent a viable starting point for the development of druglike Hsp70 inhibitors as novel anticancer therapeutics

Conceptualising State Capacity: Comparing Kazakhstan and Kyrgyzstan

Strengthening the state is central to the post-communist reform agenda. Here, state capacity combines organisational, material and social resources and is conceptualised along four dimensions: ideational, political, technical and implementational. This conceptualisation is applied to a comparative, survey-based analysis in 2002 of 125 medium-ranking officials in two post- communist Central Asian countries, Kazakhstan and Kyrgyzstan. The findings reveal that although Kazakhstan's controlled economic reform programme and natural resources have placed it in a stronger position to develop its state capacity, important ideational, political and implementational problems pose long-term obstacles for reform. In turn, Kyrgyzstan's early liberalisation in the absence of economic and social resources may be serving to undermine its state capacity.</p

Affinity-purification probes of potential use to investigate the endogenous Hsp70 interactome in cancer

Heat shock protein 70 (Hsp70) is a family of proteins with key roles in regulating malignancy. Cancer cells rely on Hsp70 to inhibit apoptosis, regulate senescence and autophagy, and maintain the stability of numerous onco-proteins. Despite these important biological functions in cancer, robust chemical tools that enable the analysis of the Hsp70-regulated proteome in a tumor-by-tumor manner are yet unavailable. Here we take advantage of a recently reported Hsp70 ligand to design and develop an affinity purification chemical toolset for potential use in the investigation of the endogenous Hsp70-interacting proteome in cancer. We demonstrate that these tools lock Hsp70 in complex with onco-client proteins and effectively isolate Hsp70 complexes for identification through biochemical techniques. Using these tools we provide proof-of-concept analyses that glimpse into the complex roles played by Hsp70 in maintaining a multitude of cell-specific malignancy-driving proteins