Niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer: final overall survival results from the PRIMA/ENGOT-OV26/GOG-3012 trial.

BACKGROUND: The phase III PRIMA/ENGOT-OV26/GOG-3012 trial met its primary endpoint. Niraparib first-line maintenance significantly prolonged progression-free survival (PFS) among patients with newly diagnosed advanced ovarian cancer that responded to first-line platinum-based chemotherapy, regardless of homologous recombination deficiency (HRD) status. Final overall survival (OS) results are reported. PATIENTS AND METHODS: Patients were randomized 2:1 to niraparib or placebo, stratified by response to first-line treatment, receipt of neoadjuvant chemotherapy, and tumor HRD status. After reaching 60% target maturity, OS was evaluated via a stratified log-rank test using randomization stratification factors and summarized using Kaplan-Meier methodology. OS testing was hierarchical [overall population first, then the homologous recombination-deficient (HRd) population]. Other secondary outcomes and long-term safety were assessed; an updated, ad hoc analysis of investigator-assessed PFS was also conducted (cut-off date, 8 April 2024). RESULTS: The median follow-up was 73.9 months. In the overall population, the OS hazard ratio was 1.01 [95% confidence interval (CI) 0.84-1.23; P = 0.8834] for niraparib (n = 487) versus placebo (n = 246). In the HRd (n = 373) and homologous recombination-proficient (n = 249) populations, the OS hazard ratios were 0.95 (95% CI 0.70-1.29) and 0.93 (95% CI 0.69-1.26), respectively. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 11.7% and 15.8% of niraparib patients and 37.8% and 48.4% of placebo patients in the overall and HRd populations, respectively. The 5-year PFS rate numerically favored niraparib in the overall (niraparib, 22%; placebo, 12%) and HRd populations (niraparib, 35%; placebo, 16%). Myelodysplastic syndromes/acute myeloid leukemia incidence was <2.5% (niraparib, 2.3%; placebo, 1.6%). No new safety signals were observed. CONCLUSIONS: In patients with newly diagnosed advanced ovarian cancer at high risk of recurrence, there was no difference in OS between treatment arms. In the HRd population, patients alive at 5 years were two times as likely to be progression free with niraparib treatment than placebo. Long-term safety remained consistent with the established niraparib safety profile.

Coexistence of Surface Ferromagnetism and a Gapless Topological State in MnBi_{2}Te_{4}.

Surface magnetism and its correlation with the electronic structure are critical to understanding the topological surface state in the intrinsic magnetic topological insulator MnBi_{2}Te_{4}. Here, using static and time resolved angle-resolved photoemission spectroscopy (ARPES), we find a significant ARPES intensity change together with a gap opening on a Rashba-like conduction band. Comparison with a model simulation strongly indicates that the surface magnetism on cleaved MnBi_{2}Te_{4} is the same as its bulk state. The inability of surface ferromagnetism to open a gap in the topological surface state uncovers the novel complexity of MnBi_{2}Te_{4} that may be responsible for the low quantum anomalous Hall temperature of exfoliated MnBi_{2}Te_{4}.

Interfacial mode coupling as the origin of the enhancement of T(c) in FeSe films on SrTiO3.

Films of iron selenide (FeSe) one unit cell thick grown on strontium titanate (SrTiO3 or STO) substrates have recently shown superconducting energy gaps opening at temperatures close to the boiling point of liquid nitrogen (77 kelvin), which is a record for the iron-based superconductors. The gap opening temperature usually sets the superconducting transition temperature Tc, as the gap signals the formation of Cooper pairs, the bound electron states responsible for superconductivity. To understand why Cooper pairs form at such high temperatures, we examine the role of the SrTiO3 substrate. Here we report high-resolution angle-resolved photoemission spectroscopy results that reveal an unexpected characteristic of the single-unit-cell FeSe/SrTiO3 system: shake-off bands suggesting the presence of bosonic modes, most probably oxygen optical phonons in SrTiO3 (refs 5, 6, 7), which couple to the FeSe electrons with only a small momentum transfer. Such interfacial coupling assists superconductivity in most channels, including those mediated by spin fluctuations. Our calculations suggest that this coupling is responsible for raising the superconducting gap opening temperature in single-unit-cell FeSe/SrTiO3.

Endometrial carcinoma recurrence according to race and ethnicity: An NRG Oncology/Gynecologic Oncology Group 210 Study.

Non-Hispanic black (NHB) women are more likely to experience an endometrial carcinoma (EC) recurrence compared to non-Hispanic white (NHW) women. The extent to which tumor characteristics, socioeconomic status (SES) and treatment contribute to this observation is not well defined. In the NRG Oncology/Gynecology Oncology Group (GOG) 210 Study we evaluated associations between race/ethnicity and EC recurrence according to tumor characteristics with adjustment for potential confounders. Our analysis included 3,199 NHW, 532 NHB and 232 Hispanic women with EC. Recurrence was documented during follow-up. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between race/ethnicity and EC recurrence in models stratified by histologic subtype (low-grade endometrioid, high-grade endometrioid, serous, mixed cell, carcinosarcoma, clear cell) or stage (I, II, III) and adjusted for age, SES, body mass index, smoking status and treatment. In histologic subtype-stratified models, higher EC recurrence was noted in NHB women with low-grade endometrioid (HR = 1.94, 95% CI = 1.21-3.10) or carcinosarcomas (HR = 1.66, 95% CI = 0.99-2.79) compared to NHWs. In stage-stratified models, higher EC recurrence was noted among NHB women with stage I (HR = 1.48, 95% CI = 1.06-2.05) and Hispanic women with stage III disease (HR = 1.81, 95% CI = 1.11-2.95). Our observations of higher EC recurrence risk among NHB and Hispanic women, as compared to NHW women, were not explained by tumor characteristics, SES, treatment or other confounders. Other factors, such as racial differences in tumor biology or other patient factors, should be explored as contributors to racial disparities in EC recurrence.

HE4 suppresses the expression of osteopontin in mononuclear cells and compromises their cytotoxicity against ovarian cancer cells.

Ovarian cancers are known to evade immunosurveillance and to orchestrate a suppressive immune microenvironment. Here we examine the role of human epididymis protein 4 (HE4), an ovarian cancer biomarker, in immune evasion. Through modified subtractive hybridization analyses we have characterized the gene targets of HE4 in human peripheral blood mononuclear cells (PBMCs), and established a preliminary mechanism for HE4-mediated immune failure in ovarian tumours. Upon exposure of purified PMBCs to HE4, osteopontin (OPN) and dual-specificity phosphatase 6 (DUSP6) emerged as the most suppressed and up-regulated genes, respectively. SKOV3 and OVCAR8, human ovarian carcinoma cell lines, exhibited enhanced proliferation in conditioned media from HE4-exposed PBMCs, an effect that was attenuated by the addition of recombinant OPN or OPN-inducible cytokines [interleukin (IL)-12 and interferon (IFN)-Ɣ]. Additionally, upon co-culture with PBMCs, HE4-silenced SKOV3 cells were found to be more susceptible to cytotoxic cell death. The relationship between HE4 and OPN was reinforced further through the analysis of serous ovarian cancer patient samples. In these biopsy specimens, the number of OPN+ T cells correlated positively with progression free survival (PFS) and inversely with serum HE4 level. Taken together, these findings show that HE4 enhances ovarian cancer tumorigenesis by compromising OPN-mediated T cell activation.

Coexistence of Replica Bands and Superconductivity in FeSe Monolayer Films.

To elucidate the mechanisms behind the enhanced T_{c} in monolayer (1 ML) FeSe on SrTiO_{3} (STO), we grew highly strained 1 ML FeSe on the rectangular (100) face of rutile TiO_{2}, and observed the coexistence of replica bands and superconductivity with a T_{c} of 63 K. From the similar T_{c} between this system and 1ML FeSe on STO (001), we conclude that strain and dielectric constant are likely unimportant to the enhanced T_{c} in these systems. A systematic comparison of 1 ML FeSe on TiO_{2} with other systems in the FeSe family shows that while charge transfer alone can enhance T_{c}, it is only with the addition of interfacial electron-phonon coupling that T_{c} can be increased to the level seen in 1 ML FeSe on STO.

Superconducting Gap Anisotropy in Monolayer FeSe Thin Film.

Superconductivity originates from pairing of electrons near the Fermi energy. The Fermi surface topology and pairing symmetry are thus two pivotal characteristics of a superconductor. Superconductivity in one monolayer (1 ML) FeSe thin film has attracted great interest recently due to its intriguing interfacial properties and possibly high superconducting transition temperature over 65 K. Here, we report high-resolution measurements of the Fermi surface and superconducting gaps in 1 ML FeSe using angle-resolved photoemission spectroscopy. Two ellipselike electron pockets are clearly resolved overlapping with each other at the Brillouin zone corner. The superconducting gap is nodeless but moderately anisotropic, which puts strong constraint on determining the pairing symmetry. The gap maxima locate on the d_{xy} bands along the major axis of the ellipse and four gap minima are observed at the intersections of electron pockets. The gap maximum location combined with the Fermi surface geometry deviate from a single d-wave, extended s-wave or s_{±} gap function, suggesting an important role of the multiorbital nature of Fermi surface and orbital-dependent pairing in 1 ML FeSe. The gap minima location may be explained by a sign change on the electron pockets, or a competition between intra- and interorbital pairing.

Interface ferroelectric transition near the gap-opening temperature in a single-unit-cell FeSe film grown on Nb-Doped SrTiO3 substrate.

We report findings of strong anomalies in both mutual inductance and inelastic Raman spectroscopy measurements of single-unit-cell FeSe film grown on Nb-doped SrTiO3, which occur near the temperature where the superconductinglike energy gap opens. Analysis suggests that the anomaly is associated with a broadened ferroelectric transition in a thin layer near the FeSe/SrTiO3 interface. The coincidence of the ferroelectric transition and gap-opening temperatures adds credence to the central role played by the film-substrate interaction on the strong Cooper pairing in this system. We discuss scenarios that could explain such a coincidence.

Phase competition in trisected superconducting dome.

A detailed phenomenology of low energy excitations is a crucial starting point for microscopic understanding of complex materials, such as the cuprate high-temperature superconductors. Because of its unique momentum-space discrimination, angle-resolved photoemission spectroscopy (ARPES) is ideally suited for this task in the cuprates, where emergent phases, particularly superconductivity and the pseudogap, have anisotropic gap structure in momentum space. We present a comprehensive doping- and temperature-dependence ARPES study of spectral gaps in Bi(2)Sr(2)CaCu(2)O(8+δ), covering much of the superconducting portion of the phase diagram. In the ground state, abrupt changes in near-nodal gap phenomenology give spectroscopic evidence for two potential quantum critical points, p = 0.19 for the pseudogap phase and p = 0.076 for another competing phase. Temperature dependence reveals that the pseudogap is not static below T(c) and exists p > 0.19 at higher temperatures. Our data imply a revised phase diagram that reconciles conflicting reports about the endpoint of the pseudogap in the literature, incorporates phase competition between the superconducting gap and pseudogap, and highlights distinct physics at the edge of the superconducting dome.

Speed limit of the insulator-metal transition in magnetite.

As the oldest known magnetic material, magnetite (Fe3O4) has fascinated mankind for millennia. As the first oxide in which a relationship between electrical conductivity and fluctuating/localized electronic order was shown, magnetite represents a model system for understanding correlated oxides in general. Nevertheless, the exact mechanism of the insulator-metal, or Verwey, transition has long remained inaccessible. Recently, three-Fe-site lattice distortions called trimerons were identified as the characteristic building blocks of the low-temperature insulating electronically ordered phase. Here we investigate the Verwey transition with pump-probe X-ray diffraction and optical reflectivity techniques, and show how trimerons become mobile across the insulator-metal transition. We find this to be a two-step process. After an initial 300 fs destruction of individual trimerons, phase separation occurs on a 1.5±0.2 ps timescale to yield residual insulating and metallic regions. This work establishes the speed limit for switching in future oxide electronics.

Direct optical coupling to an unoccupied dirac surface state in the topological insulator Bi2Se3.

We characterize the occupied and unoccupied electronic structure of the topological insulator Bi2Se3 by one-photon and two-photon angle-resolved photoemission spectroscopy and slab band structure calculations. We reveal a second, unoccupied Dirac surface state with similar electronic structure and physical origin to the well-known topological surface state. This state is energetically located 1.5 eV above the conduction band, which permits it to be directly excited by the output of a Ti:sapphire laser. This discovery demonstrates the feasibility of direct ultrafast optical coupling to a topologically protected, spin-textured surface state.

Measurement of coherent polarons in the strongly coupled antiferromagnetically ordered iron-chalcogenide Fe1.02Te using angle-resolved photoemission spectroscopy.

The nature of metallicity and the level of electronic correlations in the antiferromagnetically ordered parent compounds are two important open issues for the iron-based superconductivity. We perform a temperature-dependent angle-resolved photoemission spectroscopy study of Fe(1.02)Te, the parent compound for iron chalcogenide superconductors. Deep in the antiferromagnetic state, the spectra exhibit a "peak-dip-hump" line shape associated with two clearly separate branches of dispersion, characteristics of polarons seen in manganites and lightly doped cuprates. As temperature increases towards the Néel temperature (T(N)), we observe a decreasing renormalization of the peak dispersion and a counterintuitive sharpening of the hump linewidth, suggestive of an intimate connection between the weakening electron-phonon (e-ph) coupling and antiferromagnetism. Our finding points to the highly correlated nature of the Fe(1.02)Te ground state featured by strong interactions among the charge, spin, and lattice and a good metallicity plausibly contributed by the coherent polaron motion.

Real-time manifestation of strongly coupled spin and charge order parameters in stripe-ordered La(1.75)Sr(0.25)NiO(4) nickelate crystals using time-resolved resonant x-ray diffraction.

We investigate the order parameter dynamics of the stripe-ordered nickelate, La(1.75)Sr(0.25)NiO(4), using time-resolved resonant x-ray diffraction. In spite of distinct spin and charge energy scales, the two order parameters' amplitude dynamics are found to be linked together due to strong coupling. Additionally, the vector nature of the spin sector introduces a longer reorientation time scale which is absent in the charge sector. These findings demonstrate that the correlation linking the symmetry-broken states does not unbind during the nonequilibrium process, and the time scales are not necessarily associated with the characteristic energy scales of individual degrees of freedom.

Femtosecond dynamics of the collinear-to-spiral antiferromagnetic phase transition in CuO.

We report on the ultrafast dynamics of magnetic order in a single crystal of CuO at a temperature of 207 K in response to strong optical excitation using femtosecond resonant x-ray diffraction. In the experiment, a femtosecond laser pulse induces a sudden, nonequilibrium increase in magnetic disorder. After a short delay ranging from 400 fs to 2 ps, we observe changes in the relative intensity of the magnetic ordering diffraction peaks that indicate a shift from a collinear commensurate phase to a spiral incommensurate phase. These results indicate that the ultimate speed for this antiferromagnetic reorientation transition in CuO is limited by the long-wavelength magnetic excitation connecting the two phases.

Reaffirming the d(x2-y2) superconducting gap using the autocorrelation angle-resolved photoemission spectroscopy of Bi1.5Pb0.55Sr1.6La0.4CuO(6+δ).

Knowledge of the gap function is important to understand the pairing mechanism for high-temperature (T(c)) superconductivity. However, Fourier transform scanning tunneling spectroscopy (FT STS) and angle-resolved photoemission spectroscopy (ARPES) in the cuprates have reported contradictory gap functions, with FT-STS results deviating strongly from a canonical d(x2-y2) form. By applying an "octet model" analysis to autocorrelation ARPES, we reveal that a contradiction occurs because the octet model does not consider the effects of matrix elements and the pseudogap. This reaffirms the canonical d(x2-y2) superconducting gap around the node, which can be directly determined from ARPES. Further, our study suggests that the FT-STS reported fluctuating superconductivity around the node at far above T(c) is not necessary to explain the existence of the quasiparticle interference at low energy.

Single Dirac cone topological surface state and unusual thermoelectric property of compounds from a new topological insulator family.

Angle resolved photoemission spectroscopy study on TlBiTe2 and TlBiSe2 from a thallium-based ternary chalcogenides family revealed a single surface Dirac cone at the center of the Brillouin zone for both compounds. For TlBiSe2, the large bulk gap (∼200 meV) makes it a topological insulator with better mechanical properties than the previous binary 3D topological insualtor family. For TlBiTe2, the observed negative bulk gap indicates it as a semimetal, instead of a narrow-gap semiconductor as conventionally believed; this semimetality naturally explains its mysteriously small thermoelectric figure of merit comparing to other compounds in the family. Finally, the unique band structures of TlBiTe2 also suggest it as a candidate for topological superconductors.

Surface-stabilized nonferromagnetic ordering of a layered ferromagnetic manganite.

An outstanding question regarding the probing or possible device applications of correlated electronic materials (CEMs) with layered structure is the extent to which their bulk and surface properties differ or not. The broken translational symmetry at the surface can lead to distinct functionality due to the charge, lattice, orbital, and spin coupling. Here we report on the case of bilayered manganites with hole doping levels corresponding to bulk ferromagnetic order. We find that, although the hole doping level is measured to be the same as in the bulk, the surface layer is not ferromagnetic. Further, our low-energy electron diffraction and x-ray measurements show that there is a c-axis collapse in the outermost layer. Bulk theoretical calculations reveal that, even at fixed doping level, the relaxation of the Jahn-Teller distortion at the surface is consistent with the stabilization of an A-type antiferromagnetic state.

Femtosecond electron-phonon lock-in by photoemission and x-ray free-electron laser.

The interactions that lead to the emergence of superconductivity in iron-based materials remain a subject of debate. It has been suggested that electron-electron correlations enhance electron-phonon coupling in iron selenide (FeSe) and related pnictides, but direct experimental verification has been lacking. Here we show that the electron-phonon coupling strength in FeSe can be quantified by combining two time-domain experiments into a "coherent lock-in" measurement in the terahertz regime. X-ray diffraction tracks the light-induced femtosecond coherent lattice motion at a single phonon frequency, and photoemission monitors the subsequent coherent changes in the electronic band structure. Comparison with theory reveals a strong enhancement of the coupling strength in FeSe owing to correlation effects. Given that the electron-phonon coupling affects superconductivity exponentially, this enhancement highlights the importance of the cooperative interplay between electron-electron and electron-phonon interactions.

Persistent order due to transiently enhanced nesting in an electronically excited charge density wave.

Non-equilibrium conditions may lead to novel properties of materials with broken symmetry ground states not accessible in equilibrium as vividly demonstrated by non-linearly driven mid-infrared active phonon excitation. Potential energy surfaces of electronically excited states also allow to direct nuclear motion, but relaxation of the excess energy typically excites fluctuations leading to a reduced or even vanishing order parameter as characterized by an electronic energy gap. Here, using femtosecond time- and angle-resolved photoemission spectroscopy, we demonstrate a tendency towards transient stabilization of a charge density wave after near-infrared excitation, counteracting the suppression of order in the non-equilibrium state. Analysis of the dynamic electronic structure reveals a remaining energy gap in a highly excited transient state. Our observation can be explained by a competition between fluctuations in the electronically excited state, which tend to reduce order, and transiently enhanced Fermi surface nesting stabilizing the order.

HE4 promotes collateral resistance to cisplatin and paclitaxel in ovarian cancer cells.

BACKGROUND: Chemotherapy resistance presents a difficult challenge in treating epithelial ovarian cancer patients, particularly when tumors exhibit resistance to multiple chemotherapeutic agents. A few studies have shown that elevated serum levels of the ovarian cancer biomarker HE4 correlate with tumor chemoresistance, response to treatment, and survival. Here, we sought to confirm our previous results that HE4 contributes to collateral resistance to cisplatin and paclitaxel in vitro and uncover factors that may contribute to HE4-mediated chemoresistance. METHODS: MTS assays and western blots for cleaved PARP were used to assess resistance of HE4-overexpressing SKOV3 and OVCAR8 clones to cisplatin and paclitaxel. CRISPR/Cas technology was used to knockdown HE4 in HE4-overexpressing SKOV3 cells. A microarray was conducted to determine differential gene expression between SKOV3 null vector-transfected and HE4-overexpressing clones upon cisplatin exposure, and results were validated by quantitative RT-PCR. Regulation of mitogen activated protein kinases (MAPKs) and tubulins were assessed by western blot. RESULTS: HE4-overexpressing SKOV3 and OVCAR8 clones displayed increased resistance to cisplatin and paclitaxel. Knockdown of HE4 in HE4-overexpressing SKOV3 cells partially reversed chemoresistance. Microarray analysis revealed that HE4 overexpression resulted in suppression of cisplatin-mediated upregulation of EGR1, a MAPK-regulated gene involved in promoting apoptosis. Upregulation of p38, a MAPK activated in response to cisplatin, was suppressed in HE4-overexpressing clones. No differences in extracellular signal-regulated kinase (ERK) activation were noted in HE4-overexpressing clones treated with 25 µM cisplatin, but ERK activation was partially suppressed in HE4-overexpressing clones treated with 80 µM cisplatin. Furthermore, treatment of cells with recombinant HE4 dramatically affected ERK activation in SKOV3 and OVCAR8 wild type cells. Recombinant HE4 also upregulated α-tubulin and ß-tubulin levels in SKOV3 and OVCAR8 cells, and microtubule associated protein tau (MAPT) gene expression was increased in SKOV3 HE4-overexpressing clones. CONCLUSIONS: Overexpression of HE4 promotes collateral resistance to cisplatin and paclitaxel, and downregulation of HE4 partially reverses this chemoresistance. Multiple factors could be involved in HE4-mediated chemoresistance, including deregulation of MAPK signaling, as well as alterations in tubulin levels or stability.