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Elemental tellurium is a strongly spin-orbit coupled Peierls-distorted semiconductor whose band structure features topologically protected Weyl nodes. Using time-dependent density functional theory calculations, we show that impulsive optical excitation can be used to transiently control the amplitude of the Peierls distortion, realizing a mechanism to switch tellurium between three states: Weyl semiconductor, Weyl metal and non-Weyl metal. Further, we present experimental evidence of this inverse-Peierls distortion using time-resolved optical second harmonic generation measurements. These results provide a pathway to multifunctional ultrafast Weyl devices and introduce Peierls systems as viable hosts of light-induced topological transitions., 7 pages main text, 4 figures, 11 pages supplementary information

Among the most actively studied issues in the cuprates are the natures of the pseudogap and strange metal states and their relationship to superconductivity1. There is general agreement that the low-energy physics of the Mott-insulating parent state is well captured by a two-dimensional spin S = 1/2 antiferromagnetic Heisenberg model2. However, recent observations of a large thermal Hall conductivity in several parent cuprates appear to defy this simple model and suggest proximity to a magneto-chiral state that breaks all mirror planes that are perpendicular to the CuO2 layers3–6. Here we use optical second harmonic generation to directly resolve the point group symmetries of the model parent cuprate Sr2CuO2Cl2. We report evidence of an order parameter that breaks all perpendicular mirror planes and is consistent with a magneto-chiral state in zero magnetic field. Although this order is clearly coupled to the antiferromagnetism, we are unable to realize its time-reversed partner by thermal cycling through the antiferromagnetic transition temperature or by sampling different spatial locations. This suggests that the order onsets above the Neel temperature and may be relevant to the mechanism of pseudogap formation. Several cuprate superconductors were recently shown to have chiral phonons. Here second harmonic generation measurements show that antiferromagnetism breaks all mirror symmetries in a related compound, consistent with a chiral state.

We review recent progress in the study of photogalvanic effects and optical second-harmonic generation in topological and noncentrosymmetric metals.

The fate of a Mott insulator under strong low frequency optical driving conditions is a fundamental problem in quantum many-body dynamics. Using ultrafast broadband optical spectroscopy, we measured the transient electronic structure and charge dynamics of an off-resonantly pumped Mott insulator Ca$_2$RuO$_4$. We observe coherent bandwidth renormalization and nonlinear doublon-holon pair production occurring in rapid succession within a sub-100 femtosecond pump pulse duration. By sweeping the electric field amplitude, we demonstrate continuous bandwidth tuning and a Keldysh cross-over from a multi-photon absorption to quantum tunneling dominated pair production regime. Our results provide a procedure to control coherent and nonlinear heating processes in Mott insulators, facilitating the discovery of novel out-of-equilibrium phenomena in strongly correlated systems., 6 pages main text, 4 figures, 16 pages supplementary information

Background: STING is an innate immune sensor critical for the development of immunity. Tumor cells can inactivate the STING pathway to avoid immune recognition, emphasizing its importance in generating tumor-specific immunity. Broad activation of STING in advanced cancers may be required to initiate CD8+ T cell priming against unique antigenic repertoires among distinct metastases and to reverse an immune-suppressive TME. Due its ubiquitous expression, systemic delivery of untargeted STING agonists may not achieve a therapeutic index. In contrast, expression of the cytosolic DNAse 3’ repair exonuclease (TREX1) is upregulated in tumor cells in response to genomic instability, inflammatory stimuli, and DNA replication, providing an opportunity for selective activation of the STING pathway. In addition to modulating cGAS/STING signaling, interaction with DNA replication enzymes that generate immunogenic DNA waste highlight a facet of TREX1 biology that may inform clinical development of targeted inhibitors. Methods: Using a structure-based drug design strategy, we designed and optimized small-molecule inhibitors of TREX1 with drug-like physicochemical properties that were profiled in biochemical and cell-based assays. X-ray crystallography studies, thermal shift, and biochemical assays were employed to determine mechanism of action. We evaluated the in vivo profile of select compounds. Results: Inhibitors of TREX1 with < 100 µM potency were optimized into a series with nanomolar potency against purified, recombinant murine and human TREX1 protein in biochemical assays. Inhibitors had similar IC50 values against TREX1 nuclease in an intact cell-based assay. Finally, TSA results demonstrated that compound interaction required magnesium. To our knowledge, we produced the first high-resolution co-crystal structures of inhibitor-bound human TREX1. We used this to dissect mouse- and human-specific interactions, confirming MOA predicted by earlier modeling efforts. Lead compounds demonstrated good bioavailability and achieved exposures necessary for target engagement in mouse models and resulted in tumor growth inhibition when combined with sub-therapeutic doses of doxorubicin. Conclusions: We present the identification and characterization of a potential first-in-class TREX1 inhibitor with nanomolar potency against human and mouse TREX1. Treatment with TREX1 inhibitors conferred profound anti-tumor activity when combined with DNA-damaging agents. Here we demonstrate that targeting TREX1 can specifically and locally engage the STING pathway in the tumor microenvironment, enhance tumor-specific immunity, and provide therapeutic benefit. Citation Format: Valerie Chen, Brian Francica, David Hsieh, Dave Freund, Anja Holtz, Saheli Samanta, Jamie Cope, Ryan Clark, Peppi Prasit, Anne Moon, Henry Johnson, Thomas Dubensky, Dara Burdette. Generation of novel potent human TREX1 inhibitors facilitated by crystallography [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1636.

600 Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is associated with a high mortality burden. Lenvatinib is an effective frontline tyrosine kinase inhibitor for HCC but is associated with primary and acquired resistance in most patients. Molecular mechanisms of resistance to lenvatinib remain unclear. Methods: We retrospectively analyzed 227 patients with HCC who underwent baseline ctDNA profiling as a component of routine clinical care, including 46 patients who had serial ctDNA analysis done at baseline and after progression to lenvatinib or ICI. Clinical data including demographics, treatment history, tumor responses, and survival outcomes were abstracted from the electronic medical record. Tumor response was categorized according to RECIST 1.1. A national registry of HCC that underwent ctDNA testing using Guardant360 was analyzed to determine the prevalence of EGFR/ERBB2 alterations in HCC. Results: Nearly a third of patients who progressed on lenvatinib demonstrated a gain in EGFR/ ERBB2 amplifications or activating mutations. No consistent trend in EGFR/ ERBB2 amplifications and alterations was found among ICI refractory HCC. Disease control rates (including complete response, partial response, and stable disease) were 20% in EGFR/ERBB2 altered HCC treated with lenvatinib, 62.5% in EGFR/ERBB2 wildtype HCC treated with lenvatinib (p = 0.05), and 58% in EGFR/ERBB2 altered HCC treated with ICIs (p = 0.09). PFS was also longer in EGFR/ERBB2 wildtype HCC treated with lenvatinib (5.9 months) and EGFR/ERBB2 altered HCC treated with ICIs (7.1 months) compared to EGFR/ERBB2 altered HCC treated with lenvatinib (2.2 months, p = 0.002). In a national cohort of 1739 patients with HCC, EGFR amplifications and activating mutations occurred in 6.5% and 1.5% of cases, respectively, and ERBB2 amplifications and activating mutations occurred in 1.9% and 0.7% of cases, respectively. Among EGFR/ERBB2 mutations, we identified recurrent gatekeeper mutations, including multiple A547T and T790M mutations, in 31% of patients. Conclusions: Our study substantiates EGFR/ERBB2 amplifications and mutations as putative drivers of lenvatinib resistance in patients with HCC and identifies the genetic mechanisms for EGFR pathway activation in refractory cancers. EGFR/ERBB2 alterations may thus represent predictive and pharmacodynamic markers of lenvatinib resistance. These findings lend support to the use of EGFR inhibitors combined with lenvatinib in previously untreated or lenvatinib refractory cancers.

584 Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is responsible for more than 500,000 deaths annually. Bavi, a monoclonal antibody designed to inhibit the immunosuppressive effects of phosphatidylserine through interaction with TIM and TAM receptor family members in the tumor microenvironment (TME), is being evaluated in combination with pembro, a monoclonal antibody designed to inhibit Programmed cell death protein 1 (PD-1), in patients with advanced HCC. Methods: This phase 2, open-label, multi-site trial included patients with histologically confirmed locally advanced or metastatic HCC who have not received prior systemic therapy. Patients were treated with pembro (200 mg Q3W) in combination with bavi (3 mg/kg QW) until disease progression. The primary endpoint of the trial is confirmed ORR by RECIST 1.1. A minimax two-stage method to analyze ORR after 15 patients and enroll an additional 13 patient if 3 or more responses observed in first 15 patients (NCT03519997). Results: Three out of 15 evaluable patients responded during Stage 1, allowing for enrollment to continue with a planned 13 additional patients in Stage 2. The study completed enrollment after a total of 28 patients were determined to be evaluable. The confirmed ORR based upon data from 28 patients evaluable for response was 32% (9 confirmed, partial responses). The disease control rate was 61% (9 partial responses, 8 stable disease). The safety profile of pembro plus bavi was consistent with the established profiles of individual drugs and updated adverse events will be reported at the time of presentation along with correlative studies. Conclusions: The combination of bavi and pembro appears to be well tolerated in this patient population and has a toxicity profile comparable to monotherapy immune checkpoint inhibitor. Preliminary analyses suggests that bavi and pembro may have promising anti-tumor activity in advanced HCC. Clinical trial information: NCT03519997 .

Protected by the interplay of on-site Coulomb interactions and spin-orbit coupling, Sr$_2$IrO$_4$ at high pressure is a rare example of a Mott insulator with a paramagnetic ground state. Here, using optical Raman scattering, we measure both the phonon and magnon evolution in Sr$_2$IrO$_4$ under pressure, and identify three different magnetically-ordered phases, culminating in a spin-disordered state beyond 18 GPa. A strong first-order structural phase transition drives the magnetic evolution at $\sim$10 GPa with reduced structural anisotropy in the IrO$_6$ cages, leading to increasingly isotropic exchange interactions between the Heisenberg spins and a spin-flip transition to $c$-axis-aligned antiferromagnetic order. In the disordered phase of Heisenberg $J_\mathrm{eff}=1/2$ pseudospins, the spin excitations are quasi-elastic and continuous to 10 meV, potentially hosting a gapless quantum spin liquid in Sr$_2$IrO$_4$.

${\mathrm{Sr}}_{2}{\mathrm{CuO}}_{2}{\mathrm{Cl}}_{2}$ (SCOC) is a model undoped cuprate with $I4/mmm$ crystallographic symmetry, and a simple magnetic space group ${C}_{A}mca$ with associated magnetic point group $mmm{1}^{\ensuremath{'}}$. However, recent second harmonic spectroscopy in the antiferromagnetic phase has challenged this picture, suggesting instead a magnetic point group $4/m{m}^{\ensuremath{'}}{m}^{\ensuremath{'}}$ that coexists with the antiferromagnetism and breaks the two orthogonal mirror planes containing the tetragonal $c$ axis. Here, we analyze the symmetry of SCOC in light of the second harmonic results, and discuss possible ground states that are consistent with the data.

In the presence of electron-phonon coupling, an excitonic insulator harbors two degenerate ground states described by an Ising-type order parameter. Starting from a microscopic Hamiltonian, we derive the equations of motion for the Ising order parameter in the phonon coupled excitonic insulator ${\mathrm{Ta}}_{2}{\mathrm{NiSe}}_{5}$ and show that it can be controllably reversed on ultrashort timescales using appropriate laser pulse sequences. Using a combination of theory and time-resolved optical reflectivity measurements, we report evidence of such order parameter reversal in ${\mathrm{Ta}}_{2}{\mathrm{NiSe}}_{5}$ based on the anomalous behavior of its coherently excited order-parameter-coupled phonons. Our Letter expands the field of ultrafast order parameter control beyond spin and charge ordered materials.

An anomalous optical second-harmonic generation (SHG) signal was previously reported in ${\mathrm{Sr}}_{2}\mathrm{Ir}{\mathrm{O}}_{4}$ and attributed to a hidden odd-parity bulk magnetic state. Here we investigate the origin of this SHG signal using a combination of bulk magnetic susceptibility, magnetic-field-dependent SHG rotational anisotropy, and overlapping wide-field SHG imaging and atomic force microscopy measurements. We find that the anomalous SHG signal exhibits a twofold rotational symmetry as a function of in-plane magnetic field orientation that is associated with a crystallographic distortion. We also show a change in SHG signal across step edges that tracks the bulk antiferromagnetic stacking pattern. While we do not rule out the existence of hidden order in ${\mathrm{Sr}}_{2}\mathrm{Ir}{\mathrm{O}}_{4}$, our results altogether show that the anomalous SHG signal in parent ${\mathrm{Sr}}_{2}\mathrm{Ir}{\mathrm{O}}_{4}$ originates instead from a surface-magnetization-induced electric-dipole process that is enhanced by strong spin-orbit coupling.

Voxilaprevir is a direct-acting antiviral agent (DAA) that targets the NS3/4A protease of hepatitis C virus (HCV). High sequence diversity of HCV and inadequate drug exposure during unsuccessful treatment may lead to the accumulation of variants with reduced susceptibility to DAAs, including NS3/4A protease inhibitors such as voxilaprevir. The voxilaprevir susceptibility of clinical and laboratory strains of HCV was assessed. The NS3 protease regions of viruses belonging to 6 genotypes and 29 subtypes from 345 DAA-naive or -experienced (including protease inhibitor) patients and 344 genotype 1 to 6 replicons bearing engineered NS3 resistance-associated substitutions (RASs) were tested in transient-transfection assays. The median voxilaprevir 50% effective concentration against NS3 from protease inhibitor-naive patient samples ranged from 0.38 nM for genotype 1 to 5.8 nM for genotype 3. Voxilaprevir susceptibilities of HCV replicons with NS3 RASs were dependent on subtype background and the type and number of substitutions introduced. The majority of RASs known to confer resistance to other protease inhibitors had little to no impact on voxilaprevir susceptibility, except A156L, T, or V in genotype 1 to 4 which conferred >100-fold reductions but exhibited low replication capacity in most genotypes. These data support the use of voxilaprevir in combination with other DAAs in DAA-naive and DAA-experienced patients infected with any subtype of HCV.

478 Background: Molecular profiling using circulating tumor DNA (ctDNA) is advantageous in cancers where tissue biopsies are not routinely obtained such as in hepatocellular carcinoma (HCC). We hypothesize that due to the expected evolution of cancer clones during treatment, serial analysis of ctDNA at the time of progression may identify additional actionable alterations. This study analyzed serial testing patterns and results for patients with HCC in a large laboratory database. Methods: Analysis of genomic results from blood samples prospectively collected between January 1, 2016-March 31, 2021 for clinical Guardant360 testing and a diagnosis of HCC as documented by ordering providers on the test requisition form (TRF) was performed. Serial tests were defined as having Guardant360 analysis performed on more than one sample collected at more than one timepoint. Chi-squared analysis was completed to assess associations between maximum variant allele fraction (maxVAF) changes and identification of new genes altered on subsequent tests. Results: 106 patients were tested serially with Guardant360 with a total of 272 tests. The median age of patients tested was 65 years (range: 16-91); 75% were male. Approximately 73% of patients had 2 serial tests, 95% had 2-4 serial tests; 5% had 5 or more. 105/106 (99%) of patients had serial tests with genomic alterations detected across multiple tests, of which 68 (64.8%) had new pathogenic alterations compared to their previous test(s) (Table). Increases in maxVAF at the time of re-testing were associated with findings of new molecular alterations (p=0.03). Potentially actionable molecular alterations accounted for 19% (13/68) of new alterations and included mutations in KIT and BRAF and amplifications in MET, BRAF, RAF1, PDGFRA, KIT, and FGFR2. Conclusions: Serial ctDNA testing in patients with HCC identified numerous potentially actionable alterations in nearly 1 in 5 patients for which a clinical trial or matched treatment option may be available. Non-invasive longitudinal genomic assessment via ctDNA provides an opportunity to examine these trends in a larger cohorts and assess impact on clinical outcomes for patients with HCC who undergo serial testing.[Table: see text]

386 Background: Although the incidence of cholangiocarcinoma is rising, little is known about the demographic and clinical characteristics of patients with young-onset cholangiocarcinoma (YOCC), diagnosed at age < 50 years. The objective of this study was to compare patients with YOCC, and patients with typical-onset cholangiocarcinoma (TOCC; diagnosed age >50 years), and to describe trends in treatment utilization and factors associated with survival in YOCC. Methods: We identified patients diagnosed with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and hilar cholangiocarcinoma from the National Cancer Database (NCDB) between 2004 and 2016. Patients were classified as either having YOCC or TOCC. Categorical variables were compared using the chi-square test with Bonferroni correction. Multivariate survival analyses were performed using the Cox-regression model after adjusting for age, gender, race/ethnicity, comorbidity index, insurance status, laterality, definitive surgery, radiotherapy, and chemotherapy. Results: We identified 26,346 patients, of which 2,520 had YOCC (9.6%, median age 44 years) and 23,826 had TOCC (90.4%, median age 68 years). Patients with YOCC were more likely to be non-White (YOCC 35.0% vs. TOCC 27.4%, p

477 Background: HCC is increasingly prevalent in older adults with rising incidence and an aging population worldwide. Retrospective studies show older patients with HCC may have an increased survival compared to younger patients. However, data is lacking regarding the genomic and biologic differences, that if identified, would potentially change how we treat this disease in younger vs. older patients. Hence, there is a need to better characterize the molecular landscape of the disease in an age-specific manner. We analyzed the association of age with genomic alterations and therapeutic response to sorafenib in a cohort of advanced HCC that had undergone comprehensive molecular profiling. Methods: 487 HCC samples (excluding variants) were analyzed using Next Generation Sequencing (592 gene panel, NextSeq), Whole Exome and Whole Transcriptome Sequencing (NovaSeq), and IHC at Caris Life Sciences (Phoenix, AZ). PD-L1 positivity was determined by IHC (SP-142 clone, cutoff ≥1, 1%). Tumor mutational burden (TMB) was a measure of total somatic mutations per Mb. Immune cell populations were determined by Microenvironment Cell Population (MCP) counter analysis of RNA expression data. Overall survival (OS) calculated from tissue collection to last contact and time on treatment (TOT) with sorafenib were extracted from insurance claims and calculated using Kaplan-Meier curves. Statistical analysis was done using Chi-square, Fisher Exact and Wilcoxon rank sum tests, with p values adjusted for multiple comparisons and q77: A3 (n=75)). With age, mutational frequencies in CTNNB1 (A1=13.04%, A2=33.43%, A3=38.24%) and TERT (A1=25%, A2=68.84%, A3=76.92%) increased, while ATM (A1=6.52%, A2=0.93%, A3=1.49%) decreased (p0.05). There were fold increases in median TMB (A2/A1=1.33, A3/A1=1.33, p65 (p=0.013). Conclusions: Increased alterations in oncogenic drivers and estimates of CD8+ T cells and B cells were observed in the elderly population with HCC. The enhanced presence of co-inhibitory molecules suggests potential immune evasion. While we observed reduced TOT with sorafenib, additional studies are needed to elucidate the impact of molecular alterations on outcomes with sorafenib and newer therapies (i.e. immunotherapy) in older adults.

The past decade has witnessed an explosion in the field of quantum materials, headlined by the predictions and discoveries of novel Landau-symmetry-broken phases in correlated electron systems, topological phases in systems with strong spin-orbit coupling, and ultra-manipulable materials platforms based on two-dimensional van der Waals crystals. Discovering pathways to experimentally realize quantum phases of matter and exert control over their properties is a central goal of modern condensed-matter physics, which holds promise for a new generation of electronic/photonic devices with currently inaccessible and likely unimaginable functionalities. In this Review, we describe emerging strategies for selectively perturbing microscopic interaction parameters, which can be used to transform materials into a desired quantum state. Particular emphasis will be placed on recent successes to tailor electronic interaction parameters through the application of intense fields, impulsive electromagnetic stimulation, and nanostructuring or interface engineering. Together these approaches outline a potential roadmap to an era of quantum phenomena on demand.

The transition metal thiophosphates $M$PS$_3$ ($M$ = Mn, Fe, Ni) are a class of van der Waals stacked insulating antiferromagnets that can be exfoliated down to the ultrathin limit. MnPS$_3$ is particularly interesting because its N$\acute{\textrm{e}}$el ordered state breaks both spatial-inversion and time-reversal symmetries, allowing for a linear magneto-electric phase that is rare among van der Waals materials. However, it is unknown whether this unique magnetic structure of bulk MnPS$_3$ remains stable in the ultrathin limit. Using optical second harmonic generation rotational anisotropy, we show that long-range linear magneto-electric type N$\acute{\textrm{e}}$el order in MnPS$_3$ persists down to at least 5.3 nm thickness. However an unusual mirror symmetry breaking develops in ultrathin samples on SiO$_2$ substrates that is absent in bulk materials, which is likely related to substrate induced strain., 6 pages, 4 figures

Metallic LiOsO$_3$ undergoes a continuous ferroelectric-like structural phase transition below $T_c$ = 140 K to realize a polar metal. To understand the microscopic interactions that drive this transition, we study its critical behavior above $T_c$ via electromechanical coupling - distortions of the lattice induced by short-range dipole-dipole correlations arising from Li off-center displacements. By mapping the full angular distribution of second harmonic electric-quadrupole radiation from LiOsO$_3$ and performing a simplified hyper-polarizable bond model analysis, we uncover subtle symmetry-preserving lattice distortions over a broad temperature range extending from $T_c$ up to around 230 K, characterized by non-uniform changes in the short and long Li-O bond lengths. Such an extended region of critical fluctuations may explain anomalous features reported in specific heat and Raman scattering data, and suggests the presence of competing interactions that are not accounted for in existing theoretical treatments. More broadly, our results showcase how electromechanical effects serve as a probe of critical behavior near inversion symmetry breaking transitions in metals., Comment: 6 pages main text, 4 figures, 10 pages supplementary information

Recent evidence from magnetic torque, electron spin resonance, and second harmonic generation indicate that the prototypical quantum spin liquid candidate, herbertsmithite, has a symmetry lower than its x-ray refined trigonal space group. Here, we consider known and possible distortions of this mineral class, along with related copper kagome oxides and fluorides, relate these to possible valence bond patterns, and comment on their relevance to the physics of these interesting materials.

Over 50 years ago, Anderson and Blount proposed that ferroelectric-like structural phase transitions may occur in metals, despite the expected screening of the Coulomb interactions that often drive polar transitions. Recently, theoretical treatments have suggested that such transitions require the itinerant electrons be decoupled from the soft transverse optical phonons responsible for polar order. However, this decoupled electron mechanism (DEM) has yet to be experimentally observed. Here we utilize ultrafast spectroscopy to uncover evidence of the DEM in LiOsO$_3$, the first known band metal to undergo a thermally driven polar phase transition ($T_c$ =140 K). We demonstrate that intra-band photo-carriers relax by selectively coupling to only a subset of the phonon spectrum, leaving as much as 60 % of the lattice heat capacity decoupled. This decoupled heat capacity is shown to be consistent with a previously undetected and partially displacive TO polar mode, indicating the DEM in LiOsO$_3$., Comment: 15 pages main text, 4 figures, 12 pages supplementary information

Magneto-elastic distortions are commonly detected across magnetic long-range ordering (LRO) transitions. In principle, they are also induced by the magnetic short-range ordering (SRO) that precedes a LRO transition, which contains information about short-range correlations and energetics that are essential for understanding how LRO is established. However these distortions are difficult to resolve because the associated atomic displacements are exceedingly small and do not break symmetry. Here we demonstrate high-multipole nonlinear optical polarimetry as a sensitive and mode selective probe of SRO induced distortions using CrSiTe$_3$ as a testbed. This compound is composed of weakly bonded sheets of nearly isotropic ferromagnetically interacting spins that, in the Heisenberg limit, would individually be impeded from LRO by the Mermin-Wagner theorem. Our results show that CrSiTe$_3$ evades this law via a two-step crossover from two- to three-dimensional magnetic SRO, manifested through two successive and previously undetected totally symmetric distortions above its Curie temperature., 17 pages main text, 4 figures, 12 pages supplementary information

Voxilaprevir is a direct-acting antiviral agent (DAA) that targets the NS3/4A protease of hepatitis C virus (HCV). High sequence diversity of HCV and inadequate drug exposure during unsuccessful treatment may lead to the accumulation of variants with reduced susceptibility to DAAs, including NS3/4A protease inhibitors such as voxilaprevir. The voxilaprevir susceptibility of clinical and laboratory strains of HCV was assessed. The NS3 protease regions of viruses belonging to 6 genotypes and 29 subtypes from 345 DAA-naive or -experienced (including protease inhibitor) patients and 344 genotype 1 to 6 replicons bearing engineered NS3 resistance-associated substitutions (RASs) were tested in transient-transfection assays. The median voxilaprevir 50% effective concentration against NS3 from protease inhibitor-naive patient samples ranged from 0.38 nM for genotype 1 to 5.8 nM for genotype 3. Voxilaprevir susceptibilities of HCV replicons with NS3 RASs were dependent on subtype background and the type and number of substitutions introduced. The majority of RASs known to confer resistance to other protease inhibitors had little to no impact on voxilaprevir susceptibility, except A156L, T, or V in genotype 1 to 4 which conferred >100-fold reductions but exhibited low replication capacity in most genotypes. These data support the use of voxilaprevir in combination with other DAAs in DAA-naive and DAA-experienced patients infected with any subtype of HCV.

Hepatitis B virus (HBV) capsids are assembled from HBV core protein and assembly is a critical step in the propagation of the virus. Due to its multiple functions in the viral life cycle, core is an attractive target for new antiviral therapies. For HBV capsid assembly modulators (CAMs), several resistance mutants have been identified, both from the clinic and in vitro. However, currently there is no convenient in vitro assay to monitor resistance to CAMs in the clinic. Here, we developed a facile, cassette-based phenotyping assay to assess the antiviral activity of CAMs on a panel of clinical isolates. Using this system, the core genes from 13 patients infected with HBV genotypes A–H were expressed as chimeric virus and tested for sensitivity to CAMs. No substantial differences in antiviral activity were observed across genotypes due to the conservation of the drug binding pocket. In addition, we tested a panel of constructs encoding 13 single amino acid polymorphs in the CAM binding site, including some polymorphs with previously-described resistance to CAMs. Overall, 11 of 13 constructs replicated in vitro, 6 constructs showed reduced susceptibility to CAMs. The 11 polymorphs which could replicate in vitro remained sensitive to the nucleotide analog tenofovir alafenamide (TAF), indicating that there is no cross-resistance.

e15516 Background: The biology of microsatellite instability-high (MSI-H) in elderly colorectal cancer (CRC) patients is attributed to hypermethylation of promoter region of genes coding for mismatch repair proteins. It is unknown if such patients are predisposed to other malignancies. It is also unknown if the presence or absence of multiple primary malignancies affects elderly MSI-H CRC patients' survival. We aimed to evaluate the clinicopathologic features and outcomes in elderly CRC patients with MSI-H and multiple primary malignancies. Methods: We analyzed the National Cancer Database and included elderly (≥ 65 years) patients with CRC diagnosed between 2010-2016. MSI status was determined using genetic and immunohistochemical testing and categorized as microsatellite stable (MSS) and MSI-H. We further categorized the population into single primary malignancy versus multiple primary malignancies. We compared the baseline characteristics using the Chi-square test. Kaplan-Meier and log-rank tests were performed to calculate the overall survival (OS). Results: Among 52,494 elderly CRC patients, 78.0% were MSS, and 22.0% were MSI-H. The probability of MSI-H disease increased with increasing age, female gender, and non-Hispanic White ethnicity (all p < .001). MSI-H patients were associated with elevated CEA, wild-type KRAS, multiple neoplasms, right-sided tumors, stage II disease, and grade III/IV histology. The proportion of patients with multiple primary malignancies was higher in the MSI-H population versus MSS (36% vs. 31%, p < 0.001). The rate of multiple primary malignancies increased with age in both groups. Among MSI-H CRC patients, the factors associated with multiple primary malignancies included female gender (61.6%), non-Hispanic White ethnicity (86.3%), comorbidity index ≥ 2 (14.8%), and right-sided tumors (77.2%). Multiple primary malignancies were more frequently associated with stage I-III CRC as compared to metastatic CRC. For stage III-IV elderly MSI-H patients, the utilization of chemotherapy was 57.8% overall, but it was not significantly different between single primary malignancy versus multiple primary malignancies groups. MSI-H patients with single primary malignancy had the highest OS, followed by MSS patients with single primary malignancy, MSI-H patients with multiple primary malignancies, and MSS patients with multiple primary malignancies (74.7, 66.7, 58.1, 54.8 mos, respectively) (log-rank p < 0.001). Conclusions: Elderly CRC patients with MSI-H had a higher rate of multiple primary malignancies than MSS. This was associated with female gender, non-Hispanic White ethnicity, and right-sided tumor. MSI-H patients with single primary malignancy had the highest survival while the presence of multiple primary malignancies adversely affected survival in both MSI-H and MSS populations.

The mammalian hairless (Hr) protein plays critical roles in skin and brain tissues, but how it interacts with DNA and partner protein is only now being defined. Our initial tests of four consensus response elements, revealed that rat Hr can specifically bind to a consensus p53 response element (p53RE), 5'-AGACATGCCTAGACATGCCT-3', but not to response elements for NF-κB, TCF4 or Sp1. We then employed ChIP assays which verified that human HR binds to a p53RE of the GADD45A gene in both HEK293 (embryonic kidney) and U87 (glioblastoma) cells. Further, HR was shown to interact directly with the p53 protein in a co-immunoprecipitation assay. Cotransfections with p53RE reporter gene constructs revealed that rat Hr can boost p53-mediated transactivation of a reporter gene linked to the GADD45A p53RE, but blunts p53-mediated transactivation when the reporter gene is linked to a p21 promoter fragment containing a p53RE, with implications for the regulation of these two cell cycle control genes. Finally, our investigations of HR phosphorylation revealed that rat Hr is a substrate for PKC, but not PKA, and that human HR is phosphorylated in intact U87 cells at Ser-416, located in a highly conserved region which partially fulfills the criteria of a PKC site. We propose that mammalian Hr is a phosphoprotein which can exert cross-talk with the p53 pathway with important implications for the regulation of cell proliferation and differentiation in tissues such as skin and brain where Hr is highly expressed. J. Cell. Biochem. 118: 341-350, 2017. © 2016 Wiley Periodicals, Inc.

TPS357 Background: Hepatocellular carcinoma (HCC) is the 4th leading cause of cancer related death worldwide. HCC typically develops in patients with cirrhosis and has a 5-year survival estimate of 20%. Only patients with early stage disease may be eligible for a curative approach using local treatment and/or transplant. The majority of patient present with advanced HCC and will require systemic treatment for disease control. Several systemic therapies are FDA-approved for the treatment of HCC; however, they are only approved for patients with Child-Pugh class A cirrhosis. There are limited data and no approved second-line therapy for HCC with more advanced cirrhosis, including Child-Pugh class B, which represents a significant proportion of patients. The aim of this trial is to determine the safety and efficacy of cabozantinib, a multi-kinase inhibitor, in patients with HCC with Child-Pugh class B cirrhosis. Methods: This investigator-initiated, phase I/II study is enrolling 32 patients with advanced HCC, Child-Pugh B7 or B8, who have previously received first-line systemic treatment. Patients receive cabozantinib at one of 3 dose levels (20 mg, 40 mg, and 60 mg) with a starting dose level of 40 mg to evaluate the safety profile and obtain the recommended phase 2 dose (RP2D). The primary endpoint is assessment of dose-limiting toxicity with a null hypothesis greater than 35%. Secondary endpoints include ORR per RECIST v1.1, PFS, OS, and PK profile. Exploratory endpoints include whole exome/RNAseq analysis (including MET, VEGF, AXL, and immune signature), spatial profiling of immune markers by multiplex immunofluorescence, and specimen banking (tissue, blood and imaging). The trial design is based on the Time-To-Event modification of the Continual Reassessment Method (TiTE-CRM), which allows for continued monitoring of toxicity as a function of a dose-over-time, and is flexible with regard to the number of patients treated at a certain dose. The trial is open at University of Michigan as lead and coordinating site, and due to open at 3 additional high-volume centers. Clinical trial information: 04497038.

40 Background: Colorectal cancer patients with brain metastases experience poor outcomes; however treatment strategies are understudied. In this study, we investigated the impact of different treatments for colorectal cancer patients with brain metastases. Methods: We identified stage 4 colorectal adenocarcinoma patients with brain metastasis using the National Cancer Database diagnosed between 2010 and 2015. Patients with unknown survival data, other histologies, and multiple primary sites were excluded. Patients with and without brain metastasis were compared using the Chi-square test. Kaplan-Meier method was performed to calculate univariable overall survival (OS). We used the Cox regression model for multivariable analysis after adjusting by age, race/ethnicity, comorbidity score, surgery, chemotherapy, and radiotherapy. Results: Among 75,901 patients with stage 4 colorectal adenocarcinoma, 1.6% had brain metastasis. Patients with brain metastasis were more likely to have bone (23% vs. 5%, p < 0.001) and lung metastasis (52% vs. 21%, p < 0.001), but less likely to have liver metastasis (56% vs. 72%, p < 0.001) compared to patients without brain metastasis. Patients with brain metastasis had higher KRAS mutation rate (54% vs. 43%, p < 0.001). Patients with brain metastasis were more likely to be age ≥ 50 years (85% vs. 83%, p = 0.01), white race (76% vs. 71%, p = 0.001), and receive radiotherapy (63% vs. 12%, p < 0.001). Total 26.4% of patients with brain metastasis underwent metastasectomy, and those patients had better OS compared to patients with non-metastasectomy (median OS 12 vs. 4 months, p < 0.001). Median OS in all patients with brain metastasis was 5.5 months. Patients with brain metastasis who received multiagent chemotherapy had improved OS compared with patients who received single-agent chemotherapy (mOS 13 vs. 6 months, p < 0.001). Patients with brain metastasis who received brain radiotherapy had better OS (mOS 6.3 vs. 3.7 months, p = 0.005) than those who did not. On multivariable analysis, metastasectomy (HR 0.65 95% CI [0.57-0.75]) and receipt of multiagent chemotherapy (HR 0.68 95% CI [0.54-0.86]) were associated with favorable prognosis, but brain radiotherapy was not (HR 1.04 95% CI [0.91-1.19]). Conclusions: Brain metastases are rare in colorectal cancer but portend poor survival. Lung and bone metastases are found more frequently in these patients. Treatment with metastasectomy or multiagent chemotherapy is associated with improved overall survival.

123 Background: The effect of hospital volume on the outcome of stage 4 pancreatic cancer is not well known. We evaluated the effect of hospital volume on time to treatment and survival in patients with stage 4 pancreatic adenocarcinoma (PDAC). Methods: We used the National Cancer Database, including 1,319 hospitals to identify the study population. Adult (≥ 18 years) patients with stage 4 PDAC were included. We excluded the patients who had other histologies, unknown follow-up, and survival of less than 30 days. We categorized the hospital volume as three groups: low- (75th centile). Time from diagnosis to chemotherapy initiation was classified as early (≤ 6 weeks) or late (> 6 weeks). Kaplan-Meier and Cox regression methods were used to evaluate the overall survival (OS) between HVH and low-volume hospital (LVH) groups. Results: Among 72,531 patients with stage 4 PDAC; 65% received chemotherapy. Patients treated at HVH had higher rates of chemotherapy ( 73% vs. 60%, p

3043 Background: Baseline circulating white blood cell differential counts have been proposed as possible markers of response to Immune therapy (ICI) and immune toxicity (irAE), but have not been validated for clinical practice. Methods: 214 patients with various cancers receiving ICI had clinical lab results and overall/organ specific irAE analyzed. Absolute lymphocyte (ALC), eosinophil (AEC) and neutrophil (ANC) counts

e16716 Background: Gallbladder cancer (GBC) is an uncommon but highly fatal malignancy. Surgery remains the only potentially curative treatment for GBC. The role of neoadjuvant chemotherapy in patients with locally advanced GBC undergoing surgery is unknown. We studied the association of neoadjuvant chemotherapy on survival in locally advanced GBC patients who underwent resection. Methods: We identified adult patients with locally advanced (stage III-IV) GBC who underwent definitive surgery between 2004 and 2016 using the National Cancer Database. Treatment was categorized as neoadjuvant chemotherapy plus surgery (NAT), surgery plus adjuvant therapy (AT), and surgery alone (SA). Categorical variables were compared using the chi-square test with Bonferroni correction. Kaplan-Meier and Cox regression were used for survival analyses. We used 1:3 nearest neighbor propensity score matching based on NAT for each group. Results: Out of a total of 5,962 patients, 122 (2.2%) received NAT, 2934 (53.6%) AT, and 2421 (44.2%) SA. NAT was associated with private insurance and treatment at an academic/research facility (all p < .001) while SA patients were older, Hispanic, had government insurance, and higher comorbidities (all p < .001). Although all groups had similar lymph node assessment (NAT: 45%, AT: 46%, SA: 37%, p < .001), NAT was associated with lymph node negative disease (NAT 23%, AT 13.2%, SA 13.2%, p < .001). Median overall survival was higher in NAT compared to AT or SA (21 vs. 14 vs. 6 months, p < .001) which persisted after propensity score matching (21 vs. 15 vs. 9 months, p < .001) and multivariable regression analysis (Table). In node positive GBC, NAT was associated with improved median overall survival (NAT 24, AT 18, SA 8 months, p < .001). Conclusions: NAT is infrequently used in patients with locally advanced GBC. NAT is associated with improved median overall survival compared to AT and SA, and appears to be most beneficial in node positive disease. Prospective studies are needed to evaluate the role of neoadjuvant chemotherapy in locally advanced GB. [Table: see text]

e15126 Background: The mechanisms by which immune checkpoint inhibitors (ICI) cause immune related adverse events (irAE) are not clear. No current blood tests predict which patients will suffer irAEs. Methods: 70 cancer patients had blood drawn prior to ICI and then 4-6 weeks later. 63 had lung cancer; median age was 69 yrs; 21 were female and median ICI treatment duration was 142 days. Patient blood samples were analyzed using flow cytometry for over 50 lymphoid and myeloid markers to determine levels of circulating white blood cells, as well as their changes over time. Medical records were reviewed for irAE’s grades in 8 groups: rash, colitis, hypothyroidism, hyperthyroidism, hypophysitis, hepatitis, adrenal insufficiency, and pneumonitis. To determine association between toxicity and cell counts we used logistic regression and random forest for the univariate and multivariate analysis. We included a random permutation of the baseline age (which is associated with higher toxicity rates) as the analytical control in the random forest model to help identify the threshold of association strength of a random noise and to identify only those cell subsets that were statistically significant (reported below). Results: Patients with elevated baseline levels of specific subsets of T-cells were more likely to develop irAE’s, and elderly patients were more likely to develop Grade 2 irAE’s. T-cell populations associated with any toxicity included CD3+CD8+PD1+; CD3+CD8+; CD25+CD127lowFoxP3+ and CD3+CD8+Ki-67+. Also, patients who developed any irAE’s demonstrated changes in the following cell types after 2 doses of immune therapy compared to their baseline readings. These included changes in the percentage of circulating cells that were CD3+CD8+PD1+; CD3+CD8+HLA-DR+; CD3+CD4+HLA-DR+; CD3+CD8+CCR7-; CD56+; CD3-CD19-; CD3+CD8+; CD16+CD56dim. Patients with grade ≥2 toxicities, or organ specific toxicities demonstrated statistically significant differing levels of T-cells subsets, though the number of patients in each group was limited. Patients with > median baseline expression of CD3+ CD8+ PD1+ cells had greater survival compared with those that had < median levels. Conclusions: Flow cytometry analysis of patients receiving immune therapy at baseline and 6 weeks after initiating therapy may predict which patients are at greater likelihood of any/organ specific irAEs, potentially leading to an improved understanding their mechanisms. Responding to leukocyte changes by substitution of drugs or shortening of treatment duration may reduce irAEs.

e16710 Background: Pancreatic neuroendocrine tumor (PNET) is a rare disease. There is a lack of data on the association of age and sociodemographic characteristics on survival in patients with NET. Our study aimed to evaluate clinical, molecular differences, and survival outcomes in young-onset PNET (YOPNET) and late-onset PNET (LOPNET). Methods: We used the National Cancer Database to identify patients with YOPNET ( < 50 years) and LOPNET (≥50 years) who underwent definitive surgery diagnosed between 2004 and 2015. We calculated the survival outcomes using Kaplan Meier and Cox regression methods before and after 1:1 nearest neighbor propensity score matching. We used the AACR Genie cohort to compare mutation frequency with the Benjamini-Hochberg method between YOPNET and LOPNET. Results: A total of 6,259 patients with PNET were selected, of which 27% were YOPNET. Patients with YOPNET were more likely to be female, black, and Hispanic, have private insurance versus LOPNET (all p < .001). Patients with YOPNET had less comorbidity score, but greater tumor size ( > 4 cm) and higher stage (all p < .001). Patients with LOPNET were more likely to be treated in an academic/research facility ( p < .001). Patients with YOPNET were more likely to be located in the head of the pancreas ( p = .004). Patients with YOPNET had better overall survival (OS) as compared to patients with LOPNET which persisted after propensity score matching ( p < .001). This difference continued after adjusting for clinically significant variables (unmatched p = .008; matched p = .01) (Table). For genomic analysis, we identified 177 patients; 27% was YOPNET, and patients with YOPNET had a significantly lower rate of MEN1 mutation than patients with LOPNET (26% vs. 56%, p < .001). Rate of other mutations was not different. Conclusions: Patients with YOPNET who underwent surgery had better OS than LOPNET and were more likely to have higher stage and greater tumor size. YOPNET represents a disease with distinct clinical and molecular features. [Table: see text]

4056 Background: Anal Squamous Cell Cancer (ASCC) is a highly curable cancer. Underserved and vulnerable populations are particularly at risk of developing this disease. We aimed to study racial disparities and overall survival (OS) in patients with ASCC who received radiation therapy (RT) or chemo-RT (CRT) using the National Cancer Database. Methods: We identified adult patients with early-stage (stage I-II) ASCC diagnosed between 2004-2016 who underwent RT or CRT. We compared the clinical and treatment characteristics of white and black patients. The chi-square test was used for categorical variables. Kaplan-Meier and Cox regression method performed for survival analyses. We used 1:1 nearest neighbor propensity score matching to eliminate selection bias. Results: A total of 10,014 patients; 90.2% were white and 9.8% were black. White patients were more likely to be female, older age, have higher rate high-school education, private insurance, higher income, and travel a longer distance (all p < .001). Black patients were more likely to be higher comorbidity score and be treated at an academic/research facility. White patients had a higher rate of CRT and significantly better overall survival (OS) as compared to black patients (5-year survival 76% vs. 70%, p < .001) which persisted after propensity score matching (5-year survival 76% vs. 70%, p = .002). This difference continued after adjusting for clinically important factors, including HPV status (unmatched p < .03, matched p = .008). In the patients who received CRT, white patients were associated with improved OS versus black patients (unmatched 77% vs. 71%, p < .001; matched 77% vs. 71%, p = .011), and even after multivariate Cox analysis (unmatched p < .001; matched .014) (Table). Conclusions: White patients had significantly better OS as compared to black patients with early-stage ASCC as well as in the patients who received CRT. White patients were associated with high education level, higher income, and private insurance. The rate of HPV positive was similar among groups. Further investigations are needed to enlighten these disparities and target the increase education of the population at risk. [Table: see text]

4103 Background: Prior studies have observed under-utilization of adjuvant chemotherapy (ACT) in stage III colon cancer. Our aims were to observe the rate of utilization of ACT in very healthy or “ideal candidates”, identify reasons for omission and socioeconomic factors associated with ACT use, and observe patient outcomes. Methods: We queried patients from the National Cancer Database (NCDB) with stage III colon cancer, age

Despite the remarkable success of immune checkpoint inhibitor (ICI) therapy, a significant number of patients develop severe and unpredictable immune-related adverse events (irAEs) affecting a wide variety of organs. Concerns over irAE have led to the exclusion of patients with autoimmune disease from ICI clinical trials. Role of host genetic and immune factors in mediating irAEs remain unclear and it is not clear if the manifestations of irAEs is associated with response to therapy. Here, we use multi-faceted approach to characterize changes in host immune system in 200 patients receiving ICI therapy at baseline and post immunotherapy. In addition, we assessed genetic predisposition to autoimmunity using the Illumina SNP array and via targeted resequencing of over 150 immunoregulatory loci including the HLA region. In this meeting, we will present our initial genetic data, serum cytokine and autoantibody profiles and RNA sequencing on peripheral blood mononuclear cells (PBMCs) at baseline and post immunotherapy in patients with and without irAEs. Our preliminary findings suggest that patients who developed irAEs have lower baseline levels and greater post-treatment increases in key interferon gamma inducible cytokine/chemokine levels. Our autoantibody profiling data reveals unique sets of autoantibodies associated with specific irAEs. We will present a comprehensive analysis of immune and genetic correlates of irAEs and response to therapy. We hope our study can help gain insight in to the mechanisms underlying irAE and to identify biomarker signatures predictive of irAEs and/or response. These findings may ultimately help identify high-risk patients, customize therapy, expand use of immunotherapy and prevent toxicities.

We present a scheme to control the spin-exchange interactions by manipulating the orbital degrees of freedom using a periodic drive. We discuss two different protocols for orbital Floquet engineering. In one case, a periodic drive modifies the properties of the ligand orbitals which mediate magnetic interactions between transition-metal ions. In the other case, we consider drive-induced mixing of $d$ orbitals on each magnetic ion. We first find that an AC Stark shift of orbitals induces a change comparable to that induced from photoinduced hopping schemes, but expands the applicable frequency ranges. Next, we find that radiatively induced coherent vibrations provide a realistic path for Floquet orbital engineering with short pulses of electric fields weaker than 0.5 V/\AA{} producing $5%--10%$ changes in the magnetic coupling of Mott insulators such as the rare-earth titanates.

Directly modifying spin exchange energies in a magnetic material with light can enable ultrafast control of its magnetic states. Current approaches rely on tuning charge hopping amplitudes that mediate exchange by optically exciting either virtual or real charge-transfer transitions (CT) between magnetic sites. Here we show that when exchange is mediated by a non-magnetic ligand, it can be substantially enhanced by optically exciting a real CT transition from the ligand to magnetic site, introducing lower order virtual hopping contributions. We demonstrate sub-picosecond enhancement in a superexchange dominated ferromagnet CrSiTe3 through this mechanism using phase-resolved coherent phonon spectroscopy. This technique can also be applied in the paramagnetic phase to disentangle light induced exchange modification from other ultrafast effects that alter the magnetization. This protocol can potentially be broadly applied to engineer thermally inaccessible spin Hamiltonians in superexchange dominated magnets., Comment: 13 pages main text, 4 figures, 14 pages supplementary information

Glioblastoma (GBM) is the most common malignant brain tumor and is associated with a poor prognosis, with most patients living less than a year after diagnosis. Given that GBM nearly always recurs after conventional treatments, there is an urgent need to identify novel molecular targets. Hairless (HR) is a nuclear factor enriched in the skin and has been previously implicated in hair cycling. HR is also highly expressed in the brain, but its significance is unknown. We found that human hairless gene (HR) expression is significantly decreased in all GBM subtypes compared with normal brain tissue and is predictive of prognosis, which suggests that loss of HR expression can contribute to GBM pathogenesis. HR was recently discovered to bind to and regulate p53 responsive elements, and thus we hypothesized that HR may have a tumor suppressive function in GBM by modulating p53 target gene expression. We found that HR indeed regulates p53 target genes, including those implicated in cell cycle progression and apoptosis in the GBM-derived U87 cell line, and restoring HR expression triggered G2/M arrest and apoptosis. An analysis of sequenced genomes from patients with GBM revealed 10 HR somatic mutations in patients with glioma, two of which are located in the histone demethylase domain of HR. These two mutations, P996S and K1004N, were reconstructed and found to have impaired p53 transactivating properties. Collectively, the results of our study suggest that HR has tumor suppressive functions in GBM, which may be clinically relevant and a potential avenue for therapeutic intervention.