In a phenotypical screen of 56 acute myeloid leukemia (AML) patient samples and using a library of 10,000 compounds, we identified a hit with increased sensitivity toward SF3B1-mutated and adverse risk AMLs. Through structure-activity relationship studies, this hit was optimized into a potent, specific, and nongenotoxic molecule called UM4118. We demonstrated that UM4118 acts as a copper ionophore that initiates a mitochondrial-based noncanonical form of cell death known as cuproptosis. CRISPR-Cas9 loss-of-function screen further revealed that iron-sulfur cluster (ISC) deficiency enhances copper-mediated cell death. Specifically, we found that loss of the mitochondrial ISC transporter ABCB7 is synthetic lethal to UM4118. ABCB7 is misspliced and down-regulated in SF3B1-mutated leukemia, creating a vulnerability to copper ionophores. Accordingly, ABCB7 overexpression partially rescued SF3B1-mutated cells to copper overload. Together, our work provides mechanistic insights that link ISC deficiency to cuproptosis, as exemplified by the high sensitivity of SF3B1-mutated AMLs. We thus propose SF3B1 mutations as a biomarker for future copper ionophore-based therapies.

Supplementary Tables 1-6 from BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR

Legends for Supplementary Figures 1-2, Tables 1-6 from BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR

Supplementary Figure 1 from BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR

Cryogenic deuterium–tritium ice target implosions on OMEGA with new small-spot (SG5-650) distributed phase plates (DPPs) achieved an (11±4)% increase in energy coupling compared to implosions with larger-spot SG5-850 DPPs by decreasing the ratio of the laser spot diameter to the target diameter from 0.93 to 0.75. The SG5-650 DPPs provide a focus spot size of 674 μm, which is defined as the diameter that encircles 95% of the measured beam energy compared to 834 μm for the SG5-850, which are the standard DPPs in cryogenic target implosions on OMEGA. The hydrodynamic efficiency, defined as the ratio of the kinetic energy in the imploding shell to the laser energy, increased from 4.5% to 5.0% based on radiation-hydrodynamic calculations benchmarked to shell trajectory and bang-time measurements. The higher coupling came with a trade-off of an increased hot-electron production as well as increased hydrodynamic instabilities seeded by a larger mode-10 amplitude from the beam port geometry, both of which may have reduced the fusion neutron production and areal density.

Here, we present evidence, in the context of OMEGA cryogenic target implosions, that laser imprint, known to be capable of degrading laser-direct-drive target performance, plays a major role in generating fuel–ablator mix. OMEGA cryogenic target implosions show a performance boundary correlated with acceleration-phase shell stability; for sufficiently low adiabats (where the adiabat is the ratio of the pressure to the Fermi pressure) and high in-flight aspect ratios (IFAR's), the neutron-weighted shell areal density and neutron yield relative to the clean simulated values sharply decline. Direct evidence of Rayleigh–Taylor fuel–ablator mixing was previously obtained using a Si Heα backlighter driven by an ∼20-ps short pulse generated by OMEGA EP. The shadow cast by the shell shortly prior to stagnation, as diagnosed using backlit radiographs, shows a softening near the limb, which is evidence of an ablator–fuel mix region for a low-adiabat implosion (α ∼ 1.9, IFAR = 14) but not for a moderate adiabat implosion (α ∼ 2.5, IFAR = 10). We find good agreement between experimental and synthetic radiographs in simulations that model laser imprint and account for uncertainty in the initial ablator thickness. We further explore the role of other mechanisms such as classical instability growth at the fuel–ablator interface, species concentration diffusion, and long-wavelength drive and target asymmetries.

Background Hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) has been demonstrated as a negative intracellular immune checkpoint in mediating antitumor immunity in studies with HPK1 knockout and kinase dead mice. Pharmacological inhibition of HPK1 is desirable to investigate the role of HPK1 in human immune cells with therapeutic implications. However, a significant challenge remains to identify a small molecule inhibitor of HPK1 with sufficient potency, selectivity, and other drug-like properties suitable for proof-of-concept studies. In this report, we identified a novel, potent, and selective HPK1 small molecule kinase inhibitor, compound K (CompK). A series of studies were conducted to investigate the mechanism of action of CompK, aiming to understand its potential application in cancer immunotherapy. Methods Human primary T cells and dendritic cells (DCs) were investigated with CompK treatment under conditions relevant to tumor microenvironment (TME). Syngeneic tumor models were used to assess the in vivo pharmacology of CompK followed by human tumor interrogation ex vivo. Results CompK treatment demonstrated markedly enhanced human T-cell immune responses under immunosuppressive conditions relevant to the TME and an increased avidity of the T-cell receptor (TCR) to recognize viral and tumor-associated antigens (TAAs) in significant synergy with anti-PD1. Animal model studies, including 1956 sarcoma and MC38 syngeneic models, revealed improved immune responses and superb antitumor efficacy in combination of CompK with anti-PD-1. An elevated immune response induced by CompK was observed with fresh tumor samples from multiple patients with colorectal carcinoma, suggesting a mechanistic translation from mouse model to human disease. Conclusion CompK treatment significantly improved human T-cell functions, with enhanced TCR avidity to recognize TAAs and tumor cytolytic activity by CD8+ T cells. Additional benefits include DC maturation and priming facilitation in tumor draining lymph node. CompK represents a novel pharmacological agent to address cancer treatment resistance.

While the discovery of immune checkpoint inhibitors has led to robust, durable responses in a range of cancers, many patients do not respond to currently available therapeutics. Therefore, an urgent need exists to identify alternative mechanisms to augment the immune-mediated clearance of tumors. Hematopoetic progenitor kinase 1 (HPK1) is a serine-threonine kinase that acts as a negative regulator of T-cell receptor (TCR) signaling, to dampen the immune response. Herein we describe the structure-based discovery of isofuranones as inhibitors of HPK1. Optimization of the chemotype led to improvements in potency, selectivity, plasma protein binding, and metabolic stability, culminating in the identification of compound 24. Oral administration of 24, in combination with an anti-PD1 antibody, demonstrated robust enhancement of anti-PD1 efficacy in a syngeneic tumor model of colorectal cancer.

Purpose:Patients receiving adaptive magnetic resonance guided radiation therapy (MRgRT) undergo contour modification prior to treatment delivery, which takes 15 to over 60 minutes. We hypothesized that during the time required to create an adaptive MRgRT plan, organ movement will result in dosimetric changes to regional organs at risk (OARs). This study quantifies the dosimetric impact of OAR motion during the time required to perform adaptive MRgRT. Methods and Materials:Thirty-one patients with pancreatic adenocarcinoma, prostate adenocarcinoma, hepatocellular carcinoma, and oligo-metastases who received MRgRT using a 1.5 Tesla MR-Linac were prospectively enrolled in an open registry imaging trial (NCT03500081). Two magnetic resonance imaging (MRI) studies were acquired predelivery for each MRgRT treatment fraction: an initial "pretreatment" MRI (input to the adaptive evaluation with or without recontouring and replanning process), and a second "verification MRI" (acquired after the recontouring and adaption process and immediately before treatment delivery or "beam-on"). On the verification MRI, normal organs were recontoured offline. Recontoured normal organs included the colon, duodenum, small bowel, and stomach. Differences in OARs between organ positions represented the normal organ movement during the time required for plan adaption. Maximum dose (Dmax), volumetric (V) 0.5 cubic centimeter dose (D0.5cc), 3000 cGy (V30), and 2000 cGy (V20) were calculated from the recontoured verification MRI. Results:Differences in Dmax, per fraction, for the listed normal organs were as follows: colon/rectum 239.50 cGy (P = .09), duodenum 136.40 cGy (P = .05), small bowel 488.27 cGy (P < .01), and stomach 95.92 (P = .17). Small bowel demonstrated a significant difference in Dmax, D0.5cc, and V30. Conclusions:Statistically significant differences in small bowel doses are demonstrated as a result of motion during the timing required for adaptive MRgRT. These results reflect the importance of verifying MRI acquisition during adaptive MRgRT to confirm the location of OARs. They also identify the necessity of strategies to account for the dynamic nature of regional OARs.

Shadowgraphy and X-ray phase contrast (XPC) imaging are two techniques that are used for characterizing the deuterium-tritium ice layer in inertial confinement fusion targets. Each technique has limitations that affect how accurately they can characterize small crystalline defects and measure the ice thickness nonuniformities that may be only a few micrometers in height. The concern is that shadowgraphy may be overly sensitive to the shape and depth of defects in the ice surface and insufficiently sensitive to the shape of longer wavelength roughness, while XPC may be too insensitive to defects in the ice surface. Multiple ice layers with different thicknesses (40 to 63 mu m), thickness uniformities (peak-to-valley variations that range from < 2 to 12 mu m), and crystal defects were analyzed using shadowgraphy and XPC techniques. The results from each method agree when the ice layer is uniformly thick and the crystal lacks defects. That agreement worsens as the number of defects in the surface of the ice layer increases, and the roughness (that is determined from a shadowgram image of the target's limb) becomes greater than can be justified by the number of defects that are seen in the target's front and rear surfaces. The XPC technique is considerably less sensitive to surface defects, in part because of the poorer dynamic range and image resolution compared to shadowgraphy. Localized regions of the ice layer that are thicker or thinner than the average thickness of the layer are reported by shadowgraphy to be smaller in height and footprint (by up to 30%) than by XPC. As a result, the two techniques report different ice layer thicknesses that can vary by up to 10%. Shadowgraphy, which results from two caustics that trace different paths through the target, and in theory, image the same ice/vapor surface (but reflect from either the vapor or ice side of the interface), did not consistently characterize the size or shape of ice features to be the same magnitude. The XPC technique provides the best assessment of low-mode (l < 7) roughness in the ice layer. Shadowgraphy results using the strongest caustic is best for detecting the presence of grooves in the ice, although not for quantifying the size of them. If multiple grooves are present, it is best to discard and reform the ice layer.

Magnetic resonance imaging (MRI) has solidified its place in staging rectal cancer but its role in radiation therapy (RT) treatment planning is poorly defined. RT planning for rectal cancer has remained largely unchanged for decades with boost volumes, including those in historic dose escalation strategies, often based on bony anatomy using computed tomography (CT). This is despite routine utilization of MRI in defining RT treatment volumes for numerous other malignancies and its superior ability to define the extent of rectal tumors. We sought to investigate differences between historic CT-based boost volumes and MRI-based boost volumes in rectal adenocarcinoma. Rectal cancer patients treated in the department of radiation oncology from 2004 through 2017 were reviewed. Those with an initial staging pelvic MRI with available axial and sagittal T2-weighted sequences were uploaded into a commercially available deformable registration algorithm. These MRI's were used to contour a primary gross tumor volume (GTV) and nodal GTV for any lymph nodes greater than 5mm. A uniform expansion of 1 cm was added to each GTV to generate a planning target volume (PTV) in cm3 which served as the MRI-based gross tumor boost volume. This volume was compared to the delivered CT-based boost volume obtained from each individual patient's RT plan. Differences in these treatment volumes were examined using a paired t-test. A total of 77 patients met the inclusion criteria for our study. Fifty-three patients were male and 24 female with a median age of 56. The majority (79%) had clinical stage III disease followed by 9%, 9%, and 3% being classified as Stage IV, II, and I, respectively. Median RT dose was 50.4 Gy (range: 50.4 – 55.8). Concurrent chemotherapy consisted primarily of capecitabine (91%) followed by 6% of patients receiving 5-FU. The median CT and MRI-based boost volumes were 1,164 cc and 186 cc, respectively. The mean CT and MRI-based boost volumes were 1,275 cc (SD= 694) and 204 cc (SD = 93), respectively, resulting in a mean difference of 1,071 cc (SD= 673). After paired t-test analysis the null hypothesis of equal volume means was rejected, t(76) = 14.06, p < .001. Thus, the CT-based boost volume mean was statistically significantly greater than the MRI-based volume mean. Additionally, a paired t-test analysis was repeated after increasing the GTV to PTV expansion to 3 cm with results continuing to demonstrate rejection of the null hypothesis, t(76) = 5.73, p < .001. Boost treatment volumes based on MRI, including gross disease and radiologically suspicious nodes, are significantly smaller as compared to traditional boost volumes defined utilizing CT. Such differences in these volumes will likely enable safer dose escalation strategies. Future prospective investigations into dose escalated RT strategies for rectal cancer should consider the routine incorporation of MR based boosting strategies.

Changes in diffusion weighted image (DWI) parameters during chemotherapy (chemo) for pancreatic adenocarcinoma have been shown to correlate with clinical outcomes. It remains poorly understood if similar changes occur during a treatment course with radiation therapy (RT). The growing prevalence of integrated magnetic resonance imaging (MRI) and linear accelerators (MR-Linac) offers an opportunity to acquire advanced MRI sequences easily and routinely during a course of RT. We sought to determine the feasibility of acquisition and subsequent analysis of DWI using a 1.5 MR-Linac for patients undergoing RT for pancreatic cancer and investigate changes of mean tumor apparent diffusion coefficient (ADC) values during concurrent chemo-RT. Patients undergoing RT for pancreatic adenocarcinoma on conventional RT linear accelerators were enrolled in a prospective imaging trial and had fully quantitative MRI imaging with weekly DWI acquired using a 1.5 MR Linac. DWI was acquired using a free breathing single-shot spin echo EPI sequence (FOV: 380 mm2, matrix: 128x128, TE: 76 ms, TR: 3000 ms, ten b-values ranging from 0 to 800 s/mm). Fat suppression type, acceleration, and number of averages per b-value were optimized to maximize image quality and minimize geometric distortion. Tumors were contoured using imaging processing software and mean ADC values for each tumors were calculated. A total of 6 patients enrolled on this prospective imaging clinical trial (NCT03500081). The median patient age was 65 and the median tumor size was 37mm. Five of six patients were males and one was female. The resectability status included two resectable, one borderline resectable, one locally advanced type A, and two locally advanced type B patients. Each patient had a minimum of two MR scans acquired during their course of treatment, with a total of 20 MRI's with DWI images available. Multiple optimizations were made in the DWI scan parameters including SPAIR fat suppression, SENSE factor of 2.33, and b-value averages ranging between 2 and 7. These changes resulted in a mean DWI scan time of 312 seconds. The range of measured ADC values was 0.69 to 1.76. Measured changes in ADC values were variable; 3 patients demonstrated a measurable increase in mean ADC while 3 patients had stable ADC values with increasing radiation dose. We present the first series to demonstrate the feasibility of acquiring DWI MR images using a commercially available 1.5 MR Linac in patients with pancreatic adenocarcinoma. Our results reveal measurable changes in mean tumor ADC that occur in some patients during a course of RT for pancreatic adenocarcinoma. Such data presents a highly promising methodology for ADC-based biologically adaptive RT and future correlation with pathologic treatment response.

Improving the performance of direct-drive cryogenic targets at the Omega Laser Facility requires the development of a new cryogenic system to (1) field nonpermeable targets with a fill tube and (2) provide a clean environment around the target. This capability is to demonstrate that imploding a scaled-down version of the direct-drive ignition target for the National Ignition Facility (NIF) on the OMEGA laser will generate the hot-spot pressure that is needed for ignition; this will justify future cryogenic direct-drive experiments on the NIF cryogenic targets. The paper describes the target, the cryogenic equipment that is being constructed to achieve this goal, and the proposed target delivery process. Thermal calculations, fill tube-based target designs, and structural/vibrational analyses are provided to demonstrate the credibility of the design. This new design will include capabilities not available (or possible) with the existing OMEGA cryogenic system, with the emphasis being to preserve a pristinely clean environment around the target and to provide upgraded diagnostics to characterize both the ice layer and the target's surface. The conceptual design is complete and testing of prototypes and subcomponents is underway. The rationale and capabilities of the new design are discussed.

Direct-drive inertial fusion experiments conducted at the Laboratory for Laser Energetics implode 860-mu m-diameter, 8-mu m-thick glow-discharge polymer (GDP) capsules that have a solid, uniform, 60-to 80-mu m-thick layer of an equimolar mixture of deuterium and tritium (DT) on their interior. The DT is permeated through the capsule's wall up to pressures of 1000 atm in small pressure steps to prevent buckling; this occurs over many hours. The capsule is then cooled, the DTis solidified, and the uniform layer is formed using thermal gradients produced by heat deposited from beta decay of the tritium. Thermal contraction of the capsule from cooling is expected to be similar to 1% of the diameter. Capsules permeated with DT do not exhibit this contraction and retain their room-temperature diameter after cooling. Sources of error in the imaging system were explored, and a systematic 3 mu m over measurement of the diameter was revealed and corrected. However, both GDP capsules permeated with only deuteriumand polystyrene capsules permeated with DT do exhibit thermal contraction. The highly cross-linked GDP shell is under compressive stress after fabrication and experiences bond breakage when exposed to high-density DT during permeation. It is speculated that some of this compressive stress is relieved during bond cleavage and the capsule's wall swells, which counteracts contraction during cooling. In addition, mass spectrometry of the DT gas in the permeation system has revealed the presence of hydrocarbons and other carbon-containing species that increase with time, confirming the radio-degradation of the polymer.

Spherical polymer shells containing cryogenic DT ice layers have been imploded on the OMEGA Laser System and radiographed using Si backlighter targets (hv =1.865 keV) driven with 20-ps IR pulses from the OMEGA EP Laser System. We report on a series of implosions in which the deuterium tritium (DT) shell is imaged for a range of convergence ratios and in-flight aspect ratios. The shadows of the converging DT ice and polymer shells are recorded while the self-emission is minimized using a time-resolved (40-ps) monochromatic crystal imaging system. The images acquired have been analyzed for the level of ablator mixing into the DT fuel (even 0.1% of carbon mix can be reliably inferred). Simulations are compared with measured x-ray radiographs to provide insight into the early time and stagnation stages of an implosion, to guide the modeling efforts to improve the target designs, and to guide the development of this and other imagining techniques, such as Compton radiography. (C) 2017 Elsevier B.V. All rights reserved

Backlighting is a powerful technique to observe the flow of cold and dense material in high-energy-density–plasma experiments. High-performance, direct-drive cryogenic deuterium–tritium (DT) implosions are a challenging backlighting configuration because of the low opacity of the DT shell, the high shell velocity, the small size of the stagnating shell, and the very bright self-emission of the hot core. A crystal imaging system with a Si Heα backlighter at 1.865 keV driven by ∼20-ps short pulses from OMEGA EP was developed to radiograph the OMEGA cryogenic implosions. The high throughput of the crystal imaging system makes it possible to record high-quality images with good photon statistics and a spatial resolution of ∼15 μm at 10% to 90% modulation. This imager has been used to study the evolution of preimposed mass-density perturbations in the ablator, to quantify the perturbations caused by the stalk that is used to mount the target, and to study the mix caused by laser imprint or small-scale debris on the target surface. Because of the very low opacity of DT relative to carbon, even 0.1% of mix of carbon into the DT ice can be reliably inferred from the images. With the current implosion designs, mix is only observed for an adiabat below α = 4.

Sexual function is an important quality of life (QOL) determinant for patients with gynecologic cancers. Oncologic therapies commonly cause a decline in sexual QOL which is poorly characterized and multifactorial. In this cross sectional study, we examine the effect of radiation therapy (RT), including technique (external beam radiation therapy (EBRT) versus vaginal brachytherapy (VB)) and time course, on self-reported sexual function and QOL. We hypothesize that EBRT will result in more overall sexual dysfunction than VB, and that sexual function will decline initially after RT and then improve over time. All patients seen in a single gynecologic oncology clinic were enrolled May to June 2015. Participants completed validated questionnaires regarding QOL, including the Female Sexual Function Index (FSFI). FSFI surveys are scored from 2-36; scores < 26.5 indicate clinically significant dysfunction. Student t-test and ANOVA were performed to compare scores between different RT techniques and time ranges. Survey response rate was 88%, with 295 patients participating. Seventy-one underwent RT as part of their treatment course, of whom 35 completed every survey question. Diagnoses were primarily uterine (39), cervical (15), and ovarian (11) cancer. Mean age was 61.0 years. Most patients were ≥ 5 years postmenopausal (50). RT was delivered as EBRT alone (36), VB alone (6), or combined EBRT+VB (29). Mean FSFI for all patients was 16.78 ± 10.74, indicating significant sexual dysfunction in most patients. For EBRT alone, mean FSFI scores were 16.64 ± 7.44 for those on treatment, 16.70 ± 16.07 for patients < 6 months after completion of RT, and 16.39 ± 10.70 for those ≥ 6 months after completion (P = 0.96). For VB alone, the scores were 15.63 ± 1.72, 19.30 ± 23.05, and 18.33 ± 11.65 (P = 0.89) respectively. Mean FSFI for EBRT alone, VB alone, or EBRT+VB at all time points were 15.50 ± 10.24, 20.00 ± 15.61, and 17.59 ± 10.97, respectively (P = 0.75). Patient-reported sexual dysfunction is highly prevalent among women with gynecologic cancer treated with RT. In this cohort, we observed several trends: patients treated with VB alone had better sexual function than EBRT alone, combination RT with EBRT+VB scores fell between each modality alone, and VB patients had significant dysfunction during the treatment period, with later recovery. Additional patients and increased compliance with survey completion will strengthen our dataset, and may statistically validate these trends. Further investigation to identify RT factors that correlate with more severe or prolonged sexual dysfunction are warranted.

A record fuel hot-spot pressure P_{hs}=56±7  Gbar was inferred from x-ray and nuclear diagnostics for direct-drive inertial confinement fusion cryogenic, layered deuterium-tritium implosions on the 60-beam, 30-kJ, 351-nm OMEGA Laser System. When hydrodynamically scaled to the energy of the National Ignition Facility, these implosions achieved a Lawson parameter ∼60% of the value required for ignition [A. Bose et al., Phys. Rev. E 93, 011201(R) (2016)], similar to indirect-drive implosions [R. Betti et al., Phys. Rev. Lett. 114, 255003 (2015)], and nearly half of the direct-drive ignition-threshold pressure. Relative to symmetric, one-dimensional simulations, the inferred hot-spot pressure is approximately 40% lower. Three-dimensional simulations suggest that low-mode distortion of the hot spot seeded by laser-drive nonuniformity and target-positioning error reduces target performance.

The University of Rochester’s Laboratory for Laser Energetics has commissioned a hydrogen Isotope Separation System (ISS). The ISS uses two columns—palladium on kieselguhr and molecular sieve—that act in a complementary manner to separate the hydrogen species by mass. The 4-sL per day throughput system is compact and has no moving parts. The columns and the attendant gas storage and handling subsystems are housed in a 0.8-m3 glovebox. The glovebox uses a helium cover gas that is continuously processed to extract oxygen and water vapor that permeates through the glovebox gloves and any tritium that is released while attaching or detaching vessels to add feedstock to or drawing product from the system. The isotopic separation process is automated and does not require manual intervention. A total of 315TBq of tritium was extracted from 23.6sL of hydrogen with tritium purities reaching 99.5%. Deuterium was the sole residual component in the processed gas. Raffinate contained 0.2TBq of activity was captured for reprocessing. The total emission from the system to the environment was 0.4GBq over three weeks.