High luminous efficiency and excellent thermal performance in rod-shaped YAG:Ce phosphor ceramics for laser lighting.

High power and high brightness laser lighting puts forward new requirements for phosphor converters such as high luminous efficiency, high thermal conductivity and high saturation threshold due to the severe thermal effect. The structure design of phosphor converters is proposed as what we believe to be a novel strategy for less heat production and more heat conduction. In this work, the rod-shaped YAG:Ce phosphor ceramics (PCs) and disc-shaped YAG:Ce PCs as control group were fabricated by the gel casting and vacuum sintering, to comparatively study the luminescence performance for LD lighting, on the premise that the total number of transverse Ce3+ ions and the volume of samples from two comparison groups were same. All rod YAG:Ce PCs with low Ce3+ concentration exhibited the high luminous efficiency and better thermal stability than YAG:Ce discs with high Ce3+ concentration. Under the laser power density of 47.8 W/mm2, the luminous saturation was never observed in all rod-shaped YAG:Ce PCs. The high luminous efficacy of 245∼274 lm/W, CRI of 56.3∼59.5 and CCT of 4509∼4478 K were achieved. More importantly, due to the extremely low Ce3+ doping concentration (0.01 at%), rod-shaped ceramics based LDs devices showed the excellent thermal performance and their surface temperatures were even below 30.5 °C surprisingly under the laser power density of 20.3 W·mm-2 (2 W). These results indicate that the rod shape of phosphor converter is a promising structure engineering for high power laser lighting.

High luminous efficiency and high saturation threshold in highly transparent LuAG:Ce phosphor ceramics for laser diodes lighting.

Lu3Al5O12:Ce (LuAG:Ce) phosphor ceramics (PCs) with the excellent thermal stability and high saturation threshold are considered as the best green-fluorescent converters for high-power laser diodes (LDs) lighting. In this study, the effects of sintering additives and sintering processes on the transmittance and microstructure of LuAG:Ce PCs were systematically studied, and the luminescence performance of ceramics with different transmittance was compared. LuAG:Ce PCs with the transmittance of 80% (@800 nm, 1.5 mm) were obtained by using 0.1 wt.% MgO and 0.5 wt.% TEOS as sintering additives, combined with optimized vacuum pre-sintering and hot isostatic pressing. Compared to the non-HIP samples, the transmittance had increased by 11%. The microstructure of ceramics indicated that high transparency was closely related to the decrease in intergranular pores. Notably, the luminous efficiency of 253 lm/W and its saturation thresholds of > 46 W/mm2 were obtained simultaneously in green-emitting LDs devices. Moreover, under 3W laser irradiation, highly transparent ceramics had the low surface temperature of 66.4 °C, indicating the good heat dissipation performance. The observed high luminous efficiency and high saturation threshold of LuAG:Ce PCs were attributed to fewer pores and oxygen vacancies. Therefore, this work proves that highly transparent LuAG:Ce PCs are promising green-fluorescent converters for high-power LDs lighting.

Passive microfluidic devices for cell separation.

The separation of specific cell populations is instrumental in gaining insights into cellular processes, elucidating disease mechanisms, and advancing applications in tissue engineering, regenerative medicine, diagnostics, and cell therapies. Microfluidic methods for cell separation have propelled the field forward, benefitting from miniaturization, advanced fabrication technologies, a profound understanding of fluid dynamics governing particle separation mechanisms, and a surge in interdisciplinary investigations focused on diverse applications. Cell separation methodologies can be categorized according to their underlying separation mechanisms. Passive microfluidic separation systems rely on channel structures and fluidic rheology, obviating the necessity for external force fields to facilitate label-free cell separation. These passive approaches offer a compelling combination of cost-effectiveness and scalability when compared to active methods that depend on external fields to manipulate cells. This review delves into the extensive utilization of passive microfluidic techniques for cell separation, encompassing various strategies such as filtration, sedimentation, adhesion-based techniques, pinched flow fractionation (PFF), deterministic lateral displacement (DLD), inertial microfluidics, hydrophoresis, viscoelastic microfluidics, and hybrid microfluidics. Besides, the review provides an in-depth discussion concerning cell types, separation markers, and the commercialization of these technologies. Subsequently, it outlines the current challenges faced in the field and presents a forward-looking perspective on potential future developments. This work hopes to aid in facilitating the dissemination of knowledge in cell separation, guiding future research, and informing practical applications across diverse scientific disciplines.

Immune profiling of patients with extranodal natural killer/T cell lymphoma treated with daratumumab.

Natural killer/T cell lymphoma (NKTCL) is a highly aggressive, heterogeneous non-Hodgkin lymphoma resulting from malignant proliferation of cytotoxic natural killer (NK) or T cells. Previous studies demonstrated variable expression of CD38 on NKTCL tumors. Daratumumab, a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, was hypothesized to be a novel therapeutic option for patients with relapsed or refractory (R/R) NKTCL. In the phase 2 NKT2001 study (ClinicalTrials.gov Identifier: NCT02927925) assessing the safety and efficacy of daratumumab, a suboptimal overall response rate was seen in R/R NKTCL patients. One patient, whose tumors did not express CD38, responded to treatment, suggesting that the immunomodulatory activities of daratumumab may be sufficient to confer clinical benefit. To understand the suboptimal response rate and short duration of response, we investigated the immune profile of NKTCL patients from NKT2001 in the context of daratumumab anti-tumor activity. Tumor tissue and whole blood were, respectively, analyzed for CD38 expression and patient immune landscapes, which were assessed via cytometry by time-of-flight (CyTOF), multiparameter flow cytometry (MPFC), clonal sequencing, and plasma Epstein-Barr virus (EBV)-DNA level measurements. Changes observed in the immune profiles of NKTCL patients from NKT2001, including differences in B and T cell populations between responders and nonresponders, suggest that modulation of the immune environment is crucial for daratumumab anti-tumor activities in NKTCL. In conclusion, these findings highlight that the clinical benefit of daratumumab in NKTCL may be enriched by B/T cell-related biomarkers.

Barcode-structured YAG:Ce/YAG:Ce,Mn ceramic phosphors for variable CCT and high CRI LED/LD lighting.

Ceramic phosphors are widely considered the next-generation phosphor material for white LED/LD lighting, and a wide spectrum is a key factor in improving the CRI of lighting sources. In this paper, a novel, to our knowledge, barcode-structured YAG:Ce/YAG:Ce,Mn ceramic phosphor was designed and fabricated. The lighting sources with the CRI value of 73.5 and 68.9 were obtained under the excitation of blue LEDs and blue LDs, respectively. Simultaneously, thanks to the effective supplementary emission from a red LD, the CRI of the ceramic-based lighting source reached 81.8 under blue LD excitation. Specifically, the microstructure and luminescent property of ceramic phosphors with different thicknesses and ion doping concentrations were systematically studied. Besides, by changing the blue power from 0.52 W to 2.60 W, the CCT of the laser lighting source with the encapsulation of optimized YAG:Ce/YAG:Ce,Mn ceramic phosphors ranged from 3928 K to 5895 K, while the CRI always maintained above 80. The above results indicate that barcode-structured Ce:YAG/Ce,MnYAG ceramic phosphor is a candidate to achieve a high CRI and ican be applied to various lighting occasions.

Bortezomib, Melphalan, and Prednisone With or Without Daratumumab in Transplant-ineligible Asian Patients With Newly Diagnosed Multiple Myeloma: The Phase 3 OCTANS Study.

INTRODUCTION: In the global phase 3 ALCYONE trial, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) improved outcomes versus VMP in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. Here, we report the primary analysis of the phase 3 OCTANS trial of D-VMP versus VMP in transplant-ineligible Asian NDMM patients. PATIENTS AND METHODS: In total, 220 patients were randomized (2:1) to receive 9 cycles of VMP (bortezomib 1.3 mg/m2 subcutaneously twice weekly in Cycle 1 and weekly in Cycles 2 to 9; melphalan 9 mg/m2 orally; and prednisone 60 mg/m2 orally on Days 1 to 4 of each cycle) ± daratumumab 16 mg/kg intravenously weekly in Cycle 1, every 3 weeks in Cycles 2 to 9, and every 4 weeks thereafter until disease progression. RESULTS: After a median follow-up of 12.3 months, very good partial response or better rates (primary endpoint) were 74.0% versus 43.2% with D-VMP versus VMP (odds ratio, 3.57; 95% confidence interval [CI], 1.99-6.43; P < .0001). Median progression-free survival (PFS) with D-VMP versus VMP was not reached versus 18.2 months (hazard ratio, .43; 95% CI, .24-.77; P = .0033); 12-month PFS rates were 84.2% versus 64.6%. The most frequent grade 3/4 treatment-emergent adverse events with D-VMP/VMP were thrombocytopenia (46.5%/45.1%), neutropenia (39.6%/50.7%), and leukopenia (31.3%/36.6%). CONCLUSION: D-VMP demonstrated a favorable benefit/risk profile in transplant-ineligible Asian NDMM patients. This trial was registered at www. CLINICALTRIALS: gov as #NCT03217812.

Optical properties and energy transfer performances in high quality Cr,Nd: YAG transparent laser ceramics for solar pumped lasers.

Realizing a high solar light conversion magnitude in Cr,Nd: YAG transparent ceramic is crucial to its applications in solar pumped solid state lasers. In this study, high quality Cr,Nd:YAG transparent laser ceramics with homogeneous microstructure and theoretical transmittance were fabricated, and an efficient laser oscillation of watt-level was realized by pumping ceramic at 808 nm. There were no any characteristic absorptions corresponding to Cr2+ or Cr4+ ions detected, even when the Cr3+ ion doping concentration reached 0.6 at.%. Increasing Cr3+ and Nd3+ doping concentrations significantly enhanced the emission intensity of ceramics at 1.06 µm, and energy transfer efficiency of the 0.3 at.% Cr,Nd: YAG ceramics was increased from 14.9% to 36.9% when increasing Nd3+ ion concentration from 0.3 at.% to 1.0 at.%, with an increasing magnitude of 247.6%. The results indicated that Cr,Nd: YAG transparent ceramic is a promising gain medium for solar pumped solid state lasers.

Discovery of Highly Potent and Selective IRAK1 Degraders to Probe Scaffolding Functions of IRAK1 in ABC DLBCL.

MyD88 gene mutation has been identified as one of the most prevalent driver mutations in the activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL). The published literature suggests that interleukin-1 receptor-associated kinase 1 (IRAK1) is an essential gene for ABC DLBCL harboring MyD88 mutation. Importantly, the scaffolding function of IRAK1, rather than its kinase activity, is required for tumor cell survival. Herein, we present our design, synthesis, and biological evaluation of a novel series of potent and selective IRAK1 degraders. One of the most potent compounds, Degrader-3 (JNJ-1013), effectively degraded cellular IRAK1 protein with a DC50 of 3 nM in HBL-1 cells. Furthermore, JNJ-1013 potently inhibited IRAK1 downstream signaling pathways and demonstrated strong anti-proliferative effects in ABC DLBCL cells with MyD88 mutation. This work suggests that IRAK1 degraders have the potential for treating cancers that are dependent on the IRAK1 scaffolding function.

Broadband emission Gd3Sc2Al3O12:Ce3+ transparent ceramics with a high color rendering index for high-power white LEDs/LDs.

The discovery of single structure Ce3+ doped garnet transparent ceramics (TCs) with a broad full width at half maximum (FWHM) is essential to realize a high CRI for high-power white light emitting diodes (LEDs) and laser diodes (LDs). In this work, by utilizing the ion substitution engineering strategy, pure phase Gd3Sc2Al3O12:Ce3+ (GSAG:Ce) TC with a broad FWHM of 132.4 nm and a high CRI value of 80.7 was fabricated through the vacuum sintering technique for the first time. The optimized in-line transmittance of TCs was 58.4% @ 800 nm. Notably, the GSAG:Ce TCs exhibited a remarkable red shift from 546 nm to 582 nm, with a high internal quantum efficiency (IQE) of 46.91%. The degraded thermal stability in Ce:GSAG TCs was observed compared with that of Ce:YAG TC, owing to the narrowed band gap of GSAG. Additionally, remote excitation white LEDs/LDs were constructed by combining GSAG:Ce TCs with blue LED chips or laser sources. A tunable color hue from yellow to shinning white was achieved in white LEDs, whereas the acquired CRI and CCT of the white LDs were 69.5 and 7766 K, respectively. This work provides a new perspective to develop TCs with high CRI for their real applications in high-power white LEDs/LDs.

Histone deacetylase SIR2 in Toxoplasma gondii modulates functions of murine macrophages in vitro and protects mice against acute toxoplasmosis in vivo.

Silent information regulator 2 (SIR2) in histone deacetylase (HDAC) is particularly conserved and widely expressed in all eukaryotic cells. HDAC is a crucial post-translational modification protein regulating gene expression. In the present study, a Toxoplasma gondii (T. gondii) silent information regulator 2 (TgSIR2) gene in HDAC was cloned and the modulation effects of recombinant TgSIR2 (rTgSIR2) on murine Ana-1 macrophages were characterized in vitro. The results indicated that rTgSIR2 had a good capacity to eliminate T. gondii by promoting proliferation, apoptosis, and phagocytosis, and modulating the secretion of nitric oxide (NO), pro-inflammatory cytokines, and anti-inflammatory cytokines. In in vivo experiments, animals were immunized with recombinant TgSIR2, followed by a lethal dose of T. gondii RH strain challenge 14 days after the second immunization. As compared to the blank and control group, the animals immunized with rTgSIR2 could generate specific humoral responses, as demonstrated by the significantly high titers of total IgG and subclasses IgG1 and IgG2a. Significant increases of IFN-γ, IL-4, and IL-10 were seen, while no significant changes were detected in IL-17. The percentage of CD4+ and CD8+ T lymphocytes in animals immunized with rTgSIR2 significantly increased. A significantly long survival time was also observed in animals vaccinated with rTgSIR2 14 days after the last immunization. All these results clearly indicate that rTgSIR2 played an essential role in modulating host macrophages and offered the potential to develop a therapeutic strategy against T. gondii.

Daratumumab monotherapy for patients with relapsed or refractory natural killer/T-cell lymphoma, nasal type: an open-label, single-arm, multicenter, phase 2 study.

BACKGROUND: Natural killer/T-cell lymphoma (NKTCL) is a disease with limited treatment options and poor outcomes. Daratumumab monotherapy demonstrated clinical activity in a single-patient case report. We present data from the primary analysis of a phase 2 study of daratumumab monotherapy in relapsed or refractory (R/R) NKTCL. METHODS: This phase 2 study with Simon's two-stage design evaluated daratumumab in patients with histologically confirmed extranodal NKTCL, nasal type, per WHO classification that was refractory to or relapsed after ≥ 1 line of chemotherapy, who were not candidates for other treatment modalities. All patients received daratumumab 16 mg/kg intravenously once weekly for Cycles 1 and 2, every other week for Cycles 3 through 6, and every 4 weeks thereafter until progression or unacceptable toxicity; all cycles were 28 days. The primary end point was objective response rate (ORR) based on blinded independent central review per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma (Lugano classification). RESULTS: In total, 32 Asian patients received daratumumab. The ORR was 25.0% (95% confidence interval [CI] 11.5-43.4); all 8 responders had a partial response; and the median duration of response was 55.0 days (95% CI 29-339). At 10.2 months of median follow-up, median progression-free survival (PFS) was 53.0 days (95% CI 43-106); the 4-month PFS rate was 13.0%. Median overall survival (OS) was 141.0 days (95% CI 94-438); the 6-month OS rate was 42.9%. Nineteen (59.4%) patients had grade 3/4 treatment-emergent adverse events (TEAEs); the most common was thrombocytopenia (25.0%; n = 8). TEAEs leading to death occurred in 4 patients (death, respiratory failure, septic shock, and pneumonia); all were unrelated to daratumumab. CONCLUSIONS: In patients with R/R NKTCL, daratumumab monotherapy was well tolerated with no new safety concerns and achieved an ORR of 25.0%. However, no patients achieved complete response, and duration of response was short. Trial registration ClinicalTrials.gov, NCT02927925. Registered 7 October 2016.

Selective antisense oligonucleotide inhibition of human IRF4 prevents malignant myeloma regeneration via cell cycle disruption.

In multiple myeloma, inflammatory and anti-viral pathways promote disease progression and cancer stem cell generation. Using diverse pre-clinical models, we investigated the role of interferon regulatory factor 4 (IRF4) in myeloma progenitor regeneration. In a patient-derived xenograft model that recapitulates IRF4 pathway activation in human myeloma, we test the effects of IRF4 antisense oligonucleotides (ASOs) and identify a lead agent for clinical development (ION251). IRF4 overexpression expands myeloma progenitors, while IRF4 ASOs impair myeloma cell survival and reduce IRF4 and c-MYC expression. IRF4 ASO monotherapy impedes tumor formation and myeloma dissemination in xenograft models, improving animal survival. Moreover, IRF4 ASOs eradicate myeloma progenitors and malignant plasma cells while sparing normal human hematopoietic stem cell development. Mechanistically, IRF4 inhibition disrupts cell cycle progression, downregulates stem cell and cell adhesion transcript expression, and promotes sensitivity to myeloma drugs. These findings will enable rapid clinical development of selective IRF4 inhibitors to prevent myeloma progenitor-driven relapse.

Modulation Effects of Toxoplasma gondii Histone H2A1 on Murine Macrophages and Encapsulation with Polymer as a Vaccine Candidate.

Toxoplasma gondii (T. gondii) is the most common zoonotic protozoa and has infected about one-third of the population worldwide. Recombinant epitopes encapsulated in nanospheres have advantages over traditional T. gondii vaccines. For an efficient delivery system, poly (DL-lactide-co-glycolide) (PLGA) and chitosan are the most frequently used biodegradable polymeric nanospheres with strong safety profiles. In the present study, we first expressed and purified histone H2A1 of T. gondii using the prokaryotic expression system. The effects of recombinant TgH2A1 on the functions of murine macrophages were then studied. Purified recombinant TgH2A1 was then encapsulated in nanospheres with PLGA and chitosan. After subcutaneous vaccination in mice, the immune response was evaluated by double antibody sandwich ELISA kits. The results from this study showed that PLGA and chitosan loaded with rTgH2A1 could trigger a stronger Th1 oriented immune response and prolong the survival time of mice effectively. In conclusion, PLGA and chitosan nanospheres loaded with histone H2A1 are an effective method for the development of vaccines against T. gondii. Further studies should focus on evaluating the regulatory mechanism of TgH2A1, vaccine potency, and cellular response in chronic T. gondii infections.

Assessing IRAK4 Functions in ABC DLBCL by IRAK4 Kinase Inhibition and Protein Degradation.

The interleukin-1 receptor-activated kinase 4 (IRAK4) belongs to the IRAK family of serine/threonine kinases and plays a central role in the innate immune response. However, the function of IRAK4 in tumor growth and progression remains elusive. Here we sought to determine the enzymatic and scaffolding functions of IRAK4 in activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). We chose a highly selective IRAK4 kinase inhibitor to probe the biological effects of kinase inhibition and developed a series of IRAK4 degraders to evaluate the effects of protein degradation in ABC DLBCL cells. Interestingly, the results demonstrated that neither IRAK4 kinase inhibition nor protein degradation led to cell death or growth inhibition, suggesting a redundant role for IRAK4 in ABC DLBCL cell survival. IRAK4 degraders characterized in this study provide useful tools for understanding IRAK4 protein scaffolding function, which was previously unachievable using pharmacological perturbation.

Interferon regulatory factor 4 as a therapeutic target in adult T-cell leukemia lymphoma.

BACKGROUND: Adult T-cell leukemia lymphoma (ATLL) is a chemotherapy-resistant malignancy with a median survival of less than one year that will afflict between one hundred thousand and one million individuals worldwide who are currently infected with human T-cell leukemia virus type 1. Recurrent somatic mutations in host genes have exposed the T-cell receptor pathway through nuclear factor κB to interferon regulatory factor 4 (IRF4) as an essential driver for this malignancy. We sought to determine if IRF4 represents a therapeutic target for ATLL and to identify downstream effectors and biomarkers of IRF4 signaling in vivo. RESULTS: ATLL cell lines, particularly Tax viral oncoprotein-negative cell lines, that most closely resemble ATLL in humans, were sensitive to dose- and time-dependent inhibition by a next-generation class of IRF4 antisense oligonucleotides (ASOs) that employ constrained ethyl residues that mediate RNase H-dependent RNA degradation. ATLL cell lines were also sensitive to lenalidomide, which repressed IRF4 expression. Both ASOs and lenalidomide inhibited ATLL proliferation in vitro and in vivo. To identify biomarkers of IRF4-mediated CD4 + T-cell expansion in vivo, transcriptomic analysis identified several genes that encode key regulators of ATLL, including interleukin 2 receptor subunits α and ß, KIT ligand, cytotoxic T-lymphocyte-associated protein 4, and thymocyte selection-associated high mobility group protein TOX 2. CONCLUSIONS: These data support the pursuit of IRF4 as a therapeutic target in ATLL with the use of either ASOs or lenalidomide.

Changes in Measles Seroprevalence in China After the Launch of Two Provincial Supplementary Immunization Activities During 2009 to 2013.

BACKGROUND: Supplementary immunization activities (SIAs) have been demonstrated being effective in reducing measles incidence within a short period of time in China, but the effects are short-lived if there is no follow-up SIA with high routine immunization coverage. OBJECTIVES: To assess the change in measles seroprevalence from 2009 to 2013 after the launch of 2 large-scale SIAs within the period. METHODS: Three population-based cross-sectional serologic surveys of measles antibodies were conducted in 2009, 2011 and 2013 in Zhejiang, a province in eastern China, with serologic samples collected from 1541, 896 and 1474 subjects, respectively. The serum levels of immunoglobulin G antibodies were measured by enzyme-linked immunosorbent assay. RESULTS: We found that the seropositivity rate among infants 0-7 months of age, a group having no vaccination benefit, was below 80% throughout the study period. In addition, the seropositivity rate among adults 30-49 years of age decreased significantly from 96.0% (95% confidence interval: 93.7%-98.3%) in 2011 to 88.5% (95% confidence interval: 84.3%-92.8%) in 2013. CONCLUSION: We showed that large-scale SIAs were effective, but their effects were not long lasting. Given the drop in seropositivity among adults, their susceptibility should be carefully monitored. While older individuals could benefit from the immunization activities, children who were too young to be vaccinated still have a weak seropositivity profile and the optimal age for the administration of the first dose of vaccine should be reconsidered.

Early Waning of Maternal Measles Antibodies in Infants in Zhejiang Province, China: A Comparison of Two Cross-Sectional Serosurveys.

In China, children aged <8 months, who were expected to be protected by maternal antibodies before receiving the first dose of measles vaccine, were the age group with the greatest risk of infection in recent years. In this study, we evaluated whether infants yet to be age-eligible for measles vaccine had a sufficient seropositive level of maternal measles antibodies in 2009 and 2013. Blood samples were collected from infants aged <8 months through population-based serological surveys conducted in Zhejiang, China. Serum levels of immunoglobulin G measles antibodies were quantified using enzyme-linked immunosorbent assay. In 2013, the mean geometric mean titres (GMTs) of infants aged 4 to 8 months were below the seropositivity threshold (<200 mIU/mL), decreasing from 118.6 mIU/mL (95% confidence interval [CI] 83.0, 169.3 mIU/mL) at 4 months to 28.6 mIU/mL (95% CI 15.6, 52.3 mIU/mL) at 7 months. Antibody levels were significantly lower in 2013 than in 2009 starting from 5 months of age. In conclusion, infants aged 4 to 8 months are susceptible to measles due to low levels of maternal measles antibodies. It is thus suggested to provide infants with a supplementary dose on top of the routine schedule, and/or launch catch-up vaccination campaigns among young women.

Enhanced Potency of GalNAc-Conjugated Antisense Oligonucleotides in Hepatocellular Cancer Models.

Antisense oligonucleotides (ASOs) are a novel therapeutic approach to target difficult-to-drug protein classes by targeting their corresponding mRNAs. Significantly enhanced ASO activity has been achieved by the targeted delivery of ASOs to selected tissues. One example is the targeted delivery of ASOs to hepatocytes, achieved with N-acetylgalactosamine (GalNAc) conjugation to ASO, which results in selective uptake by asialoglycoprotein receptor (ASGR). Here we have evaluated the potential of GalNAc-conjugated ASOs as a therapeutic approach to targeting difficult-to-drug pathways in hepatocellular carcinoma (HCC). The activity of GalNAc-conjugated ASOs was superior to that of the unconjugated parental ASO in ASGR (+) human HCC cells in vitro, but not in ASGR (-) cells. Both human- and mouse-derived HCC displayed reduced levels of ASGR, however, despite this, GalNAc-conjugated ASOs showed a 5- to 10-fold increase in potency in tumors. Systemically administered GalNAc-conjugated ASOs demonstrated both enhanced antisense activity and antitumor activity in the diethylnitrosamine-induced HCC tumor model. Finally, GalNAc conjugation enhanced ASO activity in human circulating tumor cells from HCC patients, demonstrating the potential of this approach in primary human HCC tumor cells. Taken together, these results provide a strong rationale for a potential therapeutic use of GalNAc-conjugated ASOs for the treatment of HCC.

An HK2 Antisense Oligonucleotide Induces Synthetic Lethality in HK1-HK2+ Multiple Myeloma.

Although the majority of adult tissues express only hexokinase 1 (HK1) for glycolysis, most cancers express hexokinase 2 (HK2) and many coexpress HK1 and HK2. In contrast to HK1+HK2+ cancers, HK1-HK2+ cancer subsets are sensitive to cytostasis induced by HK2shRNA knockdown and are also sensitive to synthetic lethality in response to the combination of HK2shRNA knockdown, an oxidative phosphorylation (OXPHOS) inhibitor diphenyleneiodonium (DPI), and a fatty acid oxidation (FAO) inhibitor perhexiline (PER). The majority of human multiple myeloma cell lines are HK1-HK2+. Here we describe an antisense oligonucleotide (ASO) directed against human HK2 (HK2-ASO1), which suppressed HK2 expression in human multiple myeloma cell cultures and human multiple myeloma mouse xenograft models. The HK2-ASO1/DPI/PER triple-combination achieved synthetic lethality in multiple myeloma cells in culture and prevented HK1-HK2+ multiple myeloma tumor xenograft progression. DPI was replaceable by the FDA-approved OXPHOS inhibitor metformin (MET), both for synthetic lethality in culture and for inhibition of tumor xenograft progression. In addition, we used an ASO targeting murine HK2 (mHK2-ASO1) to validate the safety of mHK2-ASO1/MET/PER combination therapy in mice bearing murine multiple myeloma tumors. HK2-ASO1 is the first agent that shows selective HK2 inhibition and therapeutic efficacy in cell culture and in animal models, supporting clinical development of this synthetically lethal combination as a therapy for HK1-HK2+ multiple myeloma. SIGNIFICANCE: A first-in-class HK2 antisense oligonucleotide suppresses HK2 expression in cell culture and in in vivo, presenting an effective, tolerated combination therapy for preventing progression of HK1-HK2+ multiple myeloma tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/10/2748/F1.large.jpg.

STAT3 antisense oligonucleotide AZD9150 in a subset of patients with heavily pretreated lymphoma: results of a phase 1b trial.

BACKGROUND: The Janus kinase (JAK) and signal transduction and activation of transcription (STAT) signaling pathway is an attractive target in multiple cancers. Activation of the JAK-STAT pathway is important in both tumorigenesis and activation of immune responses. In diffuse large B-cell lymphoma (DLBCL), the transcription factor STAT3 has been associated with aggressive disease phenotype and worse overall survival. While multiple therapies inhibit upstream signaling, there has been limited success in selectively targeting STAT3 in patients. Antisense oligonucleotides (ASOs) represent a compelling therapeutic approach to target difficult to drug proteins such as STAT3 through of mRNA targeting. We report the evaluation of a next generation STAT3 ASO (AZD9150) in a non-Hodgkin's lymphoma population, primarily consisting of patients with DLBCL. METHODS: Patients with relapsed or treatment refractory lymphoma were enrolled in this expansion cohort. AZD9150 was administered at 2 mg/kg and the 3 mg/kg (MTD determined by escalation cohort) dose levels with initial loading doses in the first week on days 1, 3, and 5 followed by weekly dosing. Patients were eligible to remain on therapy until unacceptable toxicity or progression. Blood was collected pre- and post-treatment for analysis of peripheral immune cells. RESULTS: Thirty patients were enrolled, 10 at 2 mg/kg and 20 at 3 mg/kg dose levels. Twenty-seven patients had DLBCL. AZD9150 was safe and well tolerated at both doses. Common drug-related adverse events included transaminitis, fatigue, and thrombocytopenia. The 3 mg/kg dose level is the recommended phase 2 dose. All responses were seen among DLBCL patients, including 2 complete responses with median duration of response 10.7 months and 2 partial responses. Peripheral blood cell analysis of three patients without a clinical response to therapy revealed a relative increase in proportion of macrophages, CD4+, and CD8+ T cells; this trend did not reach statistical significance. CONCLUSIONS: AZD9150 was well tolerated and demonstrated efficacy in a subset of heavily pretreated patients with DLBCL. Studies in combination with checkpoint immunotherapies are ongoing. TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT01563302 . First submitted 2/13/2012.