Plasma versus tissue tumor mutational burden as biomarkers of durvalumab plus tremelimumab response in patients with metastatic colorectal cancer in the CO.26 trial.

PURPOSE: Tissue derived tumor mutation burden (TMB) of ≥10 mutations/Mb is a histology agnostic biomarker for the immune checkpoint inhibitor (ICI) pembrolizumab. However, the dataset on which this was validated lacked colorectal cancers (CRCs), and there is limited evidence for immunotherapy benefit in CRC using this threshold. PATIENTS AND METHODS: CO.26 was a randomized phase II study of 180 patients comparing durvalumab and tremelimumab (D+T, n=119 patients) versus best supportive care (BSC, n=61 patients). ctDNA sequencing was available for 168 patients (n=118 D+T, n=50), of which 165 had evaluable plasma TMB (pTMB). Tissue sequencing was available for 108 patients. Optimal thresholds for stratifying patients based on overall survival were determined using a minimal p-value approach. This report includes the final overall survival analysis. RESULTS: Tissue TMB ≥10 mutations/Mb was not predictive of benefit from D+T compared to BSC in microsatellite stable (MSS) metastatic CRC (HR 0.71 [95% CI:0.28-1.80], p=0.47). No tissue TMB threshold could identify a high TMB group that benefited from ICI. In contrast, plasma TMB (pTMB) ≥28 mutations/Mb was predictive of benefit from D+T (HR=0.34 [95%CI:0.13-0.85], p=0.022), as was clonal pTMB ≥10.6 mutations/Mb (HR=0.10 [95%CI:0.014-0.79], p=0.029) and subclonal pTMB ≥25.9/Mb (HR=0.20 [95% CI:0.061-0.69], p=0.010). Higher pTMB was associated with length of time on cytotoxic agents (p=0.021) and prior anti-EGFR exposure (p=2.44x10-06). CONCLUSION: pTMB derived from either clonal or subclonal mutations may identify a group more likely to benefit from immunotherapy, though validation is required. Tissue TMB provided no predictive utility for immunotherapy in this trial.

Influence of the Rare Earth Cation on the Magnetic Properties of Layered 12R-Ba4M4+Mn3O12 (M = Ce, Pr) Perovskites.

Material design is increasingly used to realize desired functional properties, and the perovskite structure family is one of the richest and most diverse: perovskites are employed in many applications due to their structural flexibility and compositional diversity. Hexagonal, layered perovskite structures with chains of face-sharing transition metal oxide octahedra have attracted great interest as quantum materials due to their magnetic and electronic properties. Ba4MMn3O12, a member of the "12R" class of hexagonal, layered perovskites, contains trimers of face-sharing MnO6 octahedra that are linked by a corner-sharing, bridging MO6 octahedron. Here, we investigate cluster magnetism in the Mn3O12 trimers and the role of this bridging octahedron on the magnetic properties of two isostructural 12R materials by systematically changing the M4+ cation from nonmagnetic Ce4+ (f0) to magnetic Pr4+ (f1). We synthesized 12R-Ba4MMn3O12 (M= Ce, Pr) with high phase purity and characterized their low-temperature crystal structures and magnetic properties. Using substantially higher purity samples than previously reported, we confirm the frustrated antiferromagnetic ground state of 12R-Ba4PrMn3O12 below TN ≈ 7.75 K and explore the cluster magnetism of its Mn3O12 trimers. Despite being atomically isostructural with 12R-Ba4CeMn3O12, the f1 electron associated with Pr4+ causes much more complex magnetic properties in 12R-Ba4PrMn3O12. In 12R-Ba4PrMn3O12, we observe a sharp, likely antiferromagnetic transition at T2 ≈ 12.15 K and an additional transition at T1 ≈ 200 K, likely in canted antiferromagnetic order. These results suggest that careful variation of composition within the family of hexagonal, layered perovskites can be used to tune material properties using the complex role of the Pr4+ ion in magnetism.

Early Immunomodulatory Program Triggered by Protolerogenic Bifidobacterium pseudolongum Drives Cardiac Transplant Outcomes.

BACKGROUND: Despite ongoing improvements to regimens preventing allograft rejection, most cardiac and other organ grafts eventually succumb to chronic vasculopathy, interstitial fibrosis, or endothelial changes, and eventually graft failure. The events leading to chronic rejection are still poorly understood and the gut microbiota is a known driving force in immune dysfunction. We previously showed that gut microbiota dysbiosis profoundly influences the outcome of vascularized cardiac allografts and subsequently identified biomarker species associated with these differential graft outcomes. METHODS: In this study, we further detailed the multifaceted immunomodulatory properties of protolerogenic and proinflammatory bacterial species over time, using our clinically relevant model of allogenic heart transplantation. RESULTS: In addition to tracing longitudinal changes in the recipient gut microbiome over time, we observed that Bifidobacterium pseudolongum induced an early anti-inflammatory phenotype within 7 d, whereas Desulfovibrio desulfuricans resulted in a proinflammatory phenotype, defined by alterations in leukocyte distribution and lymph node (LN) structure. Indeed, in vitro results showed that B pseudolongum and D desulfuricans acted directly on primary innate immune cells. However, by 40 d after treatment, these 2 bacterial strains were associated with mixed effects in their impact on LN architecture and immune cell composition and loss of colonization within gut microbiota, despite protection of allografts from inflammation with B pseudolongum treatment. CONCLUSIONS: These dynamic effects suggest a critical role for early microbiota-triggered immunologic events such as innate immune cell engagement, T-cell differentiation, and LN architectural changes in the subsequent modulation of protolerant versus proinflammatory immune responses in organ transplant recipients.

Halide Perovskites Breathe Too: The Iodide-Iodine Equilibrium and Self-Doping in Cs2SnI6.

The response of an oxide crystal to the atmosphere can be personified as breathing-a dynamic equilibrium between O2 gas and O2- anions in the solid. We characterize the analogous defect reaction in an iodide double-perovskite semiconductor, Cs2SnI6. Here, I2 gas is released from the crystal at room temperature, forming iodine vacancies. The iodine vacancy defect is a shallow electron donor and is therefore ionized at room temperature; thus, the loss of I2 is accompanied by spontaneous n-type self-doping. Conversely, at high I2 pressures, I2 gas is resorbed by the perovskite, consuming excess electrons as I2 is converted to 2I-. Halide mobility and irreversible halide loss or exchange reactions have been studied extensively in halide perovskites. However, the reversible exchange equilibrium between iodide and iodine [2I-(s) ↔ I2(g) + 2e-] described here has often been overlooked in prior studies, though it is likely general to halide perovskites and operative near room temperature, even in the dark. An analysis of the 2I-(s)/I2(g) equilibrium thermodynamics and related transport kinetics in single crystals of Cs2SnI6 therefore provides insight toward achieving stable composition and electronic properties in the large family of iodide perovskite semiconductors.

Electrostatic Gating of Spin Dynamics of a Quasi-2D Kagome Magnet.

Electrostatic gating has emerged as a powerful technique for tailoring the magnetic properties of two-dimensional (2D) magnets, offering exciting prospects including enhancement of magnetic anisotropy, boosting Curie temperature, and strengthening exchange coupling effects. Here, we focus on electrical control of the ferromagnetic resonance of the quasi-2D Kagome magnet Cu(1,3-bdc). By harnessing an electrostatic field through ionic liquid gating, significant shifts are observed in the ferromagnetic resonance field in both out-of-plane and in-plane measurements. Moreover, the effective magnetization and gyromagnetic ratios display voltage-dependent variations. A closer examination reveals that the voltage-induced changes can modulate magnetocrystalline anisotropy by several hundred gauss, while the impact on orbital magnetization remains relatively subtle. Density functional theory (DFT) calculations reveal varying d-orbital hybridizations at different voltages. This research unveils intricate physics within the Kagome lattice magnet and further underscores the potential of electrostatic manipulation in steering magnetism with promising implications for the development of spintronic devices.

Initial exploration of a novel fusion protein, IL-4/IL-34/IL-10, which promotes cardiac allograft survival mice through alloregulation.

Immune mediated graft loss still represents a major risk to transplant recipients. Creative approaches to immunosuppression that exploit the recipient's own alloregulatory mechanisms could reduce the need for pharmacologic immunosuppression and potentially induce immune tolerance. In the process of studying recipient derived myeloid derived suppressor cells (MDSCs), we identified key alloregulatory MDSC mechanisms, mediated by isolatable proteins IL-4, IL-34, and IL-10. We sought to purify these proteins and fuse them for subsequent infusion into transplant recipients as a means of inducing an alloregulatory response. In this introductory investigation, we leveraged molecular engineering technology to create a fusion protein (FP) of three cytokine coding sequences of IL-4, IL-34, and IL-10 and demonstrated their expressions by Western Blot analysis. Following purification, we tested whether FP IL-4/IL-34/IL-10 (FP1) can protect heart transplant allografts. Injection of FP1 significantly prolonged allogeneic cardiac graft survival in a dose-dependent fashion and the increase of graft survival time exceeded survival attributable to IL-34 alone. In vitro, MDSCs cells were expanded by FP1 treatment. However, FP1 did not directly inhibit T cell proliferation in vitro. In conclusion, newly developed FP1 improves the graft survival in cardiac transplantation mouse model. Significant additional work to optimize FP1 or include other novel proteins could supplement current treatment options for transplant patients.

Stabilizing Au2+ in a mixed-valence 3D halide perovskite.

Although Cu2+ is ubiquitous, the relativistic destabilization of the 5d orbitals makes the isoelectronic Au2+ exceedingly rare, typically stabilized only through Au-Au bonding or by using redox non-innocent ligands. Here we report the perovskite Cs4AuIIAuIII2Cl12, an extended solid with mononuclear Au2+ sites, which is stable to ambient conditions and characterized by single-crystal X-ray diffraction. The 2+ oxidation state of Au was assigned using 197Au Mössbauer spectroscopy, electron paramagnetic resonance, and magnetic susceptibility measurements, with comparison to paramagnetic and diamagnetic analogues with Cu2+ and Pd2+, respectively, as well as to density functional theory calculations. This gold perovskite offers an opportunity to study the optical and electronic transport of the uncommon Au2+/3+ mixed-valence state and the characteristics of the elusive Au2+ ion coordinated to simple ligands. Compared with the perovskite Cs2AuIAuIIICl6, which has been studied since the 1920s, Cs4AuIIAuIII2Cl12 exhibits a 0.7 eV reduction in optical absorption onset and a 103-fold increase in electronic conductivity.

FRC transplantation restores lymph node conduit defects in laminin α4-deficient mice.

Fibroblastic reticular cells (FRCs) play important roles in tolerance by producing laminin α4 (Lama4) and altering lymph node (LN) structure and function. The present study revealed the specific roles of extracellular matrix Lama4 in regulating LN conduits using FRC-specific KO mouse strains. FRC-derived Lama4 maintained conduit fiber integrity, as its depletion altered conduit morphology and structure and reduced homeostatic conduit flow. Lama4 regulated the lymphotoxin ß receptor (LTßR) pathway, which is critical for conduit and LN integrity. Depleting LTßR in FRCs further reduced conduits and impaired reticular fibers. Lama4 was indispensable for FRC generation and survival, as FRCs lacking Lama4 displayed reduced proliferation but upregulated senescence and apoptosis. During acute immunization, FRC Lama4 deficiency increased antigen flow through conduits. Importantly, adoptive transfer of WT FRCs to FRC Lama4-deficient mice rescued conduit structure, ameliorated Treg and chemokine distribution, and restored transplant allograft acceptance, which were all impaired by FRC Lama4 depletion. Single-cell RNA sequencing analysis of LN stromal cells indicated that the laminin and collagen signaling pathways linked crosstalk among FRC subsets and endothelial cells. This study demonstrated that FRC Lama4 is responsible for maintaining conduits by FRCs and can be harnessed to potentiate FRC-based immunomodulation.

Transport-Associated Vibrational Stress Triggers Drug-Reversible Apoptosis and Cardiac Allograft Failure in Mice.

Increasingly complex and long-range donor organ allocation routes coupled with implementation of unmanned aerial vehicles (UAVs) have prompted investigations of the conditions affecting organs once packaged for shipment. Our group has previously demonstrated that different modes of organ transport exert unique environmental stressors, in particular vibration. Using a mouse heart transplant model, we demonstrated that vibrational forces exert tangible, cellular effects in the form of cardiomyocyte apoptosis and cytoskeletal derangement. Functionally, these changes translated into accelerated allograft loss. Notably, administration of an apoptosis inhibitor, Z-VAD-FMK, helped to ameliorate the detrimental cellular and functional effects of mechanical vibration in a dose-dependent manner. These findings constitute one of the first reports of the negative impact of transit environment on transplant outcomes, a contributing mechanism underpinning this effect, and a potential agent to prophylax against this process. Given current limitations in measuring donor organ transit environments in situ, further study is required to better characterize the impact of transport environment and to potentially improve the care of donor organs during shipment. Clinical and Translational Impact Statement: We show that apoptosis inhibitor, Z-VAD-FMK, ameliorated transport-related vibrational stress in murine heart transplants, which presents a potential therapeutic or preservation solution additive for future use in transporting donor organs.

Circulating Tumor DNA Identifies Diverse Landscape of Acquired Resistance to Anti-Epidermal Growth Factor Receptor Therapy in Metastatic Colorectal Cancer.

PURPOSE: Anti-epidermal growth factor receptor (EGFR) antibodies are effective treatments for metastatic colorectal cancer. Improved understanding of acquired resistance mechanisms may facilitate circulating tumor DNA (ctDNA) monitoring, anti-EGFR rechallenge, and combinatorial strategies to delay resistance. METHODS: Patients with treatment-refractory metastatic colorectal cancer (n = 169) enrolled on the CO.26 trial had pre-anti-EGFR tissue whole-exome sequencing (WES) compared with baseline and week 8 ctDNA assessments with the GuardantOMNI assay. Acquired alterations were compared between patients with prior anti-EGFR therapy (n = 66) and those without. Anti-EGFR therapy occurred a median of 111 days before ctDNA assessment. RESULTS: ctDNA identified 12 genes with increased mutation frequency after anti-EGFR therapy, including EGFR (P = .0007), KRAS (P = .0017), LRP1B (P = .0046), ZNF217 (P = .0086), MAP2K1 (P = .018), PIK3CG (P = .018), BRAF (P = .048), and NRAS (P = .048). Acquired mutations appeared as multiple concurrent subclonal alterations, with most showing decay over time. Significant increases in copy-gain frequency were noted in 29 genes after anti-EGFR exposure, with notable alterations including EGFR (P < .0001), SMO (P < .0001), BRAF (P < .0001), MET (P = .0002), FLT3 (P = .0002), NOTCH4 (P = .0006), ERBB2 (P = .004), and FGFR1 (P = .006). Copy gains appeared stable without decay 8 weeks later. There were 13 gene fusions noted among 11 patients, all but one of which was associated with prior anti-EGFR therapy. Polyclonal resistance was common with acquisition of ≥ 10 resistance related alterations noted in 21% of patients with previous anti-EGFR therapy compared with 5% in those without (P = .010). Although tumor mutation burden (TMB) did not differ pretreatment (P = .63), anti-EGFR exposure increased TMB (P = .028), whereas lack of anti-EGFR exposure resulted in declining TMB (P = .014). CONCLUSION: Paired tissue and ctDNA sequencing identified multiple novel mutations, copy gains, and fusions associated with anti-EGFR therapy that frequently co-occur as subclonal alterations in the same patient.

Quasi-One-Dimensional Metallicity in Compressed CsSnI3.

Low-dimensional metal halides exhibit strong structural and electronic anisotropies, making them candidates for accessing unusual electronic properties. Here, we demonstrate pressure-induced quasi-one-dimensional (quasi-1D) metallicity in δ-CsSnI3. With the application of pressure up to 40 GPa, the initially insulating δ-CsSnI3 transforms to a metallic state. Synchrotron X-ray diffraction and Raman spectroscopy indicate that the starting 1D chain structure of edge-sharing Sn-I octahedra in δ-CsSnI3 is maintained in the high-pressure metallic phase while the SnI6 octahedral chains are distorted. Our experiments combined with first-principles density functional theory calculations reveal that pressure induces Sn-Sn hybridization and enhances Sn-I coupling within the chain, leading to band gap closure and formation of conductive SnI6 distorted octahedral chains. In contrast, the interchain I...I interactions remain minimal, resulting in a highly anisotropic electronic structure and quasi-1D metallicity. Our study offers a high-pressure approach for achieving diverse electronic platforms in the broad family of low-dimensional metal halides.

Cesium-mediated electron redistribution and electron-electron interaction in high-pressure metallic CsPbI3.

Electron-phonon coupling was believed to govern the carrier transport in halide perovskites and related phases. Here we demonstrate that electron-electron interaction enhanced by Cs-involved electron redistribution plays a direct and prominent role in the low-temperature electrical transport of compressed CsPbI3 and renders Fermi liquid (FL)-like behavior. By compressing δ-CsPbI3 to 80 GPa, an insulator-semimetal-metal transition occurs, concomitant with the completion of a slow structural transition from the one-dimensional Pnma (δ) phase to a three-dimensional Pmn21 (ε) phase. Deviation from FL behavior is observed upon CsPbI3 entering the metallic ε phase, which progressively evolves into a FL-like state at 186 GPa. First-principles density functional theory calculations reveal that the enhanced electron-electron coupling results from the sudden increase of the 5d state occupation in Cs and I atoms. Our study presents a promising strategy of cationic manipulation for tuning the electronic structure and carrier scattering of halide perovskites at high pressure.

Field-tuned ferroquadrupolar quantum phase transition in the insulator TmVO4.

We report results of low-temperature heat-capacity, magnetocaloric-effect, and neutron-diffraction measurements of TmVO4, an insulator that undergoes a continuous ferroquadrupolar phase transition associated with local partially filled 4f orbitals of the thulium (Tm[Formula: see text]) ions. The ferroquadrupolar transition, a realization of Ising nematicity, can be tuned to a quantum critical point by using a magnetic field oriented along the c axis of the tetragonal crystal lattice, which acts as an effective transverse field for the Ising-nematic order. In small magnetic fields, the thermal phase transition can be well described by using a semiclassical mean-field treatment of the transverse-field Ising model. However, in higher magnetic fields, closer to the field-tuned quantum phase transition, subtle deviations from this semiclassical behavior are observed, which are consistent with expectations of quantum fluctuations. Although the phase transition is driven by the local 4f degrees of freedom, the crystal lattice still plays a crucial role, both in terms of mediating the interactions between the local quadrupoles and in determining the critical scaling exponents, even though the phase transition itself can be described via mean field. In particular, bilinear coupling of the nematic order parameter to acoustic phonons changes the spatial and temporal fluctuations of the former in a fundamental way, resulting in different critical behavior of the nematic transverse-field Ising model, as compared to the usual case of the magnetic transverse-field Ising model. Our results establish TmVO4 as a model material and electronic nematicity as a paradigmatic example for quantum criticality in insulators.

Evidence of Magnon-Mediated Orbital Magnetism in a Quasi-2D Topological Magnon Insulator.

We explore spin dynamics in Cu(1,3-bdc), a quasi-2D topological magnon insulator. The results show that the thermal evolution of the Landé g factor (g) is anisotropic: gin-plane decreases while gout-of-plane increases with increasing temperature T. Moreover, the anisotropy of the g factor (Δg) and the anisotropy of saturation magnetization (ΔMs) are correlated below 4 K, but they diverge above 4 K. We show that the electronic orbital moment contributes to the g anisotropy at lower T, while the topological orbital moment induced by thermally excited spin chirality dictates the g anisotropy at higher T. Our work suggests an interplay among topology, spin chirality, and orbital magnetism in Cu(1,3-bdc).

Freezing of the Lattice in the Kagome Lattice Heisenberg Antiferromagnet Zn-Barlowite ZnCu_{3}(OD)_{6}FBr.

We use ^{79}Br nuclear quadrupole resonance (NQR) to demonstrate that ultraslow lattice dynamics set in below the temperature scale set by the Cu-Cu superexchange interaction J (≃160 K) in the kagome lattice Heisenberg antiferromagnet Zn-barlowite. The lattice completely freezes below 50 K, and ^{79}Br NQR line shapes become twice broader due to increased lattice distortions. Moreover, the frozen lattice exhibits an oscillatory component in the transverse spin echo decay, a typical signature of pairing of nuclear spins by indirect nuclear spin-spin interaction. This indicates that some Br sites form structural dimers via a pair of kagome Cu sites prior to the gradual emergence of spin singlets below ∼30 K. Our findings underscore the significant roles played by subtle structural distortions in determining the nature of the disordered magnetic ground state of the kagome lattice.

Treg tissue stability depends on lymphotoxin beta-receptor- and adenosine-receptor-driven lymphatic endothelial cell responses.

Regulatory T cell (Treg) lymphatic migration is required for resolving inflammation and prolonging allograft survival. Focusing on Treg interactions with lymphatic endothelial cells (LECs), we dissect mechanisms and functional consequences of Treg transendothelial migration (TEM). Using three genetic mouse models of pancreatic islet transplantation, we show that Treg lymphotoxin (LT) αß and LEC LTß receptor (LTßR) signaling are required for efficient Treg migration and suppressive function to prolong allograft survival. Inhibition of LT signaling increases Treg conversion to Foxp3loCD25lo exTregs. In a transwell-based model of TEM across polarized LECs, non-migrated Tregs become exTregs. Such conversion is regulated by LTßR nuclear factor κB (NF-κB) signaling in LECs, which increases interleukin-6 (IL-6) production and drives exTreg conversion. Migrating Tregs are ectonucleotidase CD39hi and resist exTreg conversion in an adenosine-receptor-2A-dependent fashion. Human Tregs migrating across human LECs behave similarly. These molecular interactions can be targeted for therapeutic manipulation of immunity and suppression.

Preclinical studies with ONC201/TIC10 and lurbinectedin as a novel combination therapy in small cell lung cancer (SCLC).

The American Cancer Society estimates that ~15% of all lung cancers are categorized as small cell lung cancer (SCLC) with an overall five-year survival rate of less than 7%. Due to disease aggressiveness, more other malignancies, the standard of care is based on clinical efficacy rather than helpful biomarkers. Lurbinectedin is a small molecule RNA polymerase II inhibitor that binds the minor groove of DNA to induce double-strand breaks. Lurbinectedin has efficacy towards SCLC cells at sub-nM concentration and received accelerated FDA approval in 2020 for metastatic SCLC that progressed on platinum-based therapy. ONC201/TIC10 is a TRAIL pathway-inducing compound that with demonstrated clinical efficacy in H3K27M-mutated diffuse midline glioma and neuroendocrine tumors, in early phase clinical trials. We hypothesized that combining ONC201 and lurbinectedin may yield synergistic and targeted killing of SCLC cells. SCLC cell lines H1048, H1105, H1882, and H1417 were treated with ONC201 and lurbinectedin and cell viability was determined using a CellTiter-Glo assay using varying drug concentrations. Synergistic growth inhibition of SCLC cells was noted with combination of ONC201 and lurbinectedin. Induction of the integrated stress response mediator ATF4 and CHOP was observed with ONC201 and lurbinectedin along with induction of PARP cleavage indicative of apoptosis in response to cellular stress. Additionally, SCLC lines treated with the combination therapy displayed increased DNA breakage-related proteins such as phosphorylated Chk-1, Wee1 and γ-H2AX. Combination index revealed the most potent synergy occurred at the concentrations of 0.16 µM ONC201 and 0.05 nM lurbinectedin in the H1048 cell line, demonstrating highly efficient and selective killing of these tumor cells in vitro. While these therapies showed potency against the cell lines derived from SCLC patients, it is noteworthy that the combination showed significantly less toxicity to healthy human lung epithelial cells. Future studies could explore the combination of ONC201 and lurbinectedin in SCLC cell lines, SCLC patient-derived organoids, other tumor types, including in vivo studies and clinical translation.

A Mobile Health Intervention to Support Parenting Self-Efficacy in the Neonatal Intensive Care Unit from Admission to Home.

OBJECTIVE: To test whether parents of premature infants less than 37 weeks of gestation provided with a unique smartphone app designed to support parents had greater parenting self-efficacy, a key element in parenting confidence, compared with controls. STUDY DESIGN: Using a quasiexperimental, time-lagged study design, parents were assigned to either usual care (control) or NICU2HOME app (intervention) groups. Both groups completed the validated Parenting Sense of Competence (PSOC) scale at 4 time points (approximately day of life 7, 1 day before discharge, and at 14 and 30 days after discharge) representing the neonatal intensive care unit, discharge, and home contexts. App use was described and categorized. Univariate group differences were assessed, and linear mixed effect regression models were used to assess treatment group effect on PSOC score across time, adjusted for covariates and controlling for overall family effect. RESULTS: We enrolled 298 parents (123 control, 175 intervention) with 256 completing 1 or more PSOC screenings. The intervention group had sustained higher PSOC scores than those of the control group (estimate, 4.3; P = .0042) from the first measurement onward with no significant change in PSOC score across time for either group. Average app use was 15 taps per average day; average and above-average users had significantly higher PSOC scores (estimate, 5.16; P = .0024; estimate, 5.16; P = .014) compared with controls or below-average users. CONCLUSIONS: Compared with controls, parents assigned to use the NICU2HOME app reported greater parenting self-efficacy while in the neonatal intensive care unit and this continued once discharged to home. Novel technologies such as point-of-care smartphone applications may hold promise for supporting parents in difficult and stressful situations. TRIAL REGISTRATION: ClincalTrials.gov: NCT03505424.

Combination of ONC201 and TLY012 induces selective, synergistic apoptosis in vitro and significantly delays PDAC xenograft growth in vivo.

The five-year survival rate for pancreatic ductal adenocarcinoma (PDAC) has remained a dismal 9% for approximately 40 years with an urgent need for novel therapeutic interventions. ONC201 is the founding member of the imipridone class, comprised of orally bioavailable small molecules that have shown efficacy in multiple tumor types both in animal models and in Phase I/II clinical trials. ONC201 is a potent inducer of the tumor necrosis factor related apoptosis inducing ligand (TRAIL) pathway. TRAIL is an innate immune mechanism which induces programmed cell death of cancer cells. We observed that PDAC cells upregulated ATF4, CHOP, and DR5 after treatment with ONC201. This occurred in cell lines that are susceptible to ONC201-induced apoptosis and in ones that are not. In response to ONC201, PDAC cells downregulated anti-apoptotic proteins including c-FLIP, BclXL, XIAP, cIAP1, and survivin. We hypothesized that TRAIL receptor agonists might induce selective, synergistic apoptosis in pancreatic cancer cell lines treated with ONC201. We screened 7 pancreatic cancer cell lines and found synergy with ONC201 and rhTRAIL or the novel TRAIL receptor agonist TLY012 in 6 of the 7 cell lines tested. In vivo experiments using BxPC3 and HPAFII xenograft models showed that the combination of ONC201 plus TLY012 significantly delays tumor growth as compared to controls. Immunohistochemical analysis of the tumors after three doses of the combination showed significantly increased cleavage of caspase 3 in vivo as compared to controls. Taken together, the preclinical efficacy of ONC201 and TLY012 represents a novel therapeutic option for further testing in pancreatic cancer patients. This combination showed marked efficacy in tumor cells that are both sensitive and resistant to the pro-apoptotic effects of ONC201, providing rationale to further investigate the combination of ONC201 plus TLY012 in patients with pancreatic cancer.

Maternal and Paternal Depression Symptoms During NICU Stay and Transition Home.

OBJECTIVE: To examine the trajectory and risk factors of depression symptoms among parents from NICU admission to 30 days postdischarge. We hypothesized depression symptom scores would decrease from admission and then increase from discharge to 30 days. METHODS: Prospective longitudinal cohort study of premature infants in NICU. Parents completed the validated Edinburgh Postnatal Depression Scale (EPDS) at 4 time points: NICU admission, discharge, and 14 days and 30 days postdischarge. EPDS score change across time and probability of a positive screen (EPDS ≥10) were by assessed using mixed effect regression models. RESULTS: Of 431 parents enrolled (mothers, n = 230 [53%]), 33% of mothers (n = 57) and 17% of fathers (n = 21) had a positive EPDS screening. Score change was 1.9 points different between mothers and fathers (confidence interval [CI]: 1.3-2.6; P < .0001), with mothers decreasing 2.9 points (CI: 2.1-3.7; P < .0001) and fathers decreasing 1.0 points (CI: 0.1-2.0; P = .04). Over time, mothers decreased 10.96 times (CI: 2.99-38.20; P = .0003); fathers decreased at a nonsignificant rate. Admission or discharge screening improved 30-day depressive symptom prediction (AUC 0.66 baseline demographics only versus 0.84+initial [P < .0001], and versus 0.80+discharge screening [P < .001]). CONCLUSIONS: Mothers and fathers experience different depressive symptom trajectories from NICU to home. Screening parents for postpartum depression during the NICU stay is likely to result in improved identification of parents at risk for postpartum depression after discharge. Focused attention on fathers appears warranted.