julilili42/papers huggingface dataset:
A Nitrilium-Type N-Heterocyclic Aryne
2025-06-02

The first solution-phase synthesis and reactivity of a nitrilium-type <i>N</i>-hetaryne are described. The 1,2-azaborine-derived 1,6-BN-aryne <b>2</b> exhibits [4 + 2], [3 + 2], and [2 + 2] cycloadditions and electrophilic aromatic substitution (EAS) reactivity. The observed regio- and diastereoselectivities of the cycloaddition and EAS products are consistent with a polarized aryne/nitrilium species. The free 1,6-BN-aryne <b>2</b> was isolated and characterized under matrix isolation conditions. A Lewis structure description where the 1,6-BN-aryne <b>2</b> resonates between two limiting (ketenimine (dominant) vs nitrilium) forms is consistent with DFT calculations. New 1,2-azaborine structures that are functionalized at the C6- and N-positions, including highly strained derivatives that were previously not accessible, can now be accessed using 1,6-BN-aryne <b>2</b> as a versatile synthetic building block.
Quantum Synchronization of Twin Limit-Cycle Oscillators
2025-06-02

Quantum synchronization has been a subject of intensive research in the last decade. In this Letter, we propose a quantum Liénard system whose classical equivalent features two limit cycles to one of which the system will converge. In the quantum case, both limit cycles coexist in a single steady state. Each of these limit cycles localizes to a distinct phase if coupled to an external drive: one quantum state can thus be assigned two phases. Furthermore, coupling two such oscillators leads to the simultaneous appearance of synchronization and a synchronization blockade. To shed light on this apparent paradoxical result, we introduce finer measures of quantum synchronization.
Mass cytometric detection of homologous recombination proficiency in circulating tumor cells to predict chemoresistance of metastatic breast cancer patients
2025-06-02

Abstract Circulating tumor cells (CTCs) can serve as a liquid biopsy to gain insight into treatment responses and metastatic recurrence. Due to their rarity, the analysis of CTCs is challenging and commonly based on immunomagnetic technologies using antibodies against EpCAM. This study used mass cytometry (CyTOF®) for the identification and characterization of CTCs from longitudinally monitored metastatic breast cancer (mBC) patients. Functional analysis focused on DNA damage responses, particularly the DNA repair pathway of homologous recombination (HR) validated in BC cells from the pleura. Fifty‐two blood samples from 13 mBC patients were collected for the enumeration of CTCs using CellSearch® technology, isolation of CTCs together with peripheral blood mononuclear cells (PBMCs) and of plasma. Cell‐free DNA (cfDNA) from plasma was analyzed by shallow genome sequencing to determine tumor fraction (TF) and HR deficiency (HRD). CTC/PBMC mixtures were phenotyped by CyTOF® using a panel of 13 antibodies including anti‐γH2AX, 53BP1, and RAD51. CyTOF® identified CTCs correlating with CellSearch®‐ and cfDNA‐based quantifications, detected DNA damage in CTCs, and the dynamics of their HR status during genotoxic therapies. Our study shows that CyTOF®‐based phenotyping of CTCs from mBC patients shows promise as a method to monitor tumor progression and HR proficiency in real time for the identification of chemoresistance.
Colorectal Carcinoma in Childhood and Adolescence: Microsatellite Instability Correlates With a Favorable Prognosis
2025-06-02

ABSTRACT Background Colorectal cancer (CRC) accounts for 10% of cancer cases worldwide; however, pediatric CRC is extremely rare, with an annual incidence of one to two cases per million. Microsatellite instability (MSI) has been shown to play a relevant prognostic role in adult CRC. Corresponding data for pediatric CRC are lacking. This study examines MSI in pediatric CRC. Procedure Patient‐, tumor‐, and treatment‐related data of patients less than 18 years with CRC enrolled in the German Registry for Rare Pediatric Tumors (STEP) between 2005 and 2023 were analyzed and compared with data on patients less than 30 years with CRC and known MSI status from the Surveillance, Epidemiology, and End Results Program (SEER). Results Forty‐one patients with CRC were recorded in STEP. Cancer predisposition syndromes were identified in 52% of tested cases, especially in CRC with MSI (84.6%). The SEER cohort included 803 CRC patients under 30 years, 52 of whom were under 20 years. Most cases were at an advanced stage at diagnosis, with localized disease being rare (STEP: 4.9%, SEER: 16.4%). The 5‐year overall survival (OS) of STEP patients was 47.9% ± 9.7%. MSI was observed in 37.5% (STEP) and 32.7% (SEER &lt;20 years) of patients. CRCs with MSI had lower rates of distant metastases and were associated with a significantly better survival (STEP 5‐year OS: MSI 85.1% ± 9.7% vs. no‐MSI 28.3% ± 11.2%, p = 0.007). Conclusions While pediatric CRCs overall more often demonstrate advanced stages, unfavorable histology, and a poorer prognosis than adult CRC, MSI is more common in pediatric CRC and is associated with superior survival.
Immunohistochemical evaluation of a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease
2025-06-03

Clinical trials of anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer disease (AD) infer target engagement from Aβ positron emission tomography (PET) and/or fluid biomarkers such as cerebrospinal fluid (CSF) Aβ42/40. However, these biomarkers measure brain Aβ deposits indirectly and/or incompletely. In contrast, neuropathologic assessments allow direct investigation of treatment effects on brain Aβ deposits-and on potentially myriad 'downstream' pathologic features. From a clinical trial of anti-Aβ monoclonal antibodies in dominantly inherited AD (DIAD), in the largest study of its kind, we measured immunohistochemistry area fractions (AFs) for Aβ deposits (10D5), tauopathy (PHF1), microgliosis (IBA1), and astrocytosis (GFAP) in 10 brain regions from 10 trial cases-gantenerumab (n = 4), solanezumab (n = 4), placebo/no treatment (n = 2)-and 10 DIAD observational study cases. Strikingly, in proportion to total drug received, Aβ deposit AFs were significantly lower in the gantenerumab arm versus controls in almost all areas examined, including frontal, temporal, parietal, and occipital cortices, anterior cingulate, hippocampus, caudate, putamen, thalamus, and cerebellar gray matter; only posterior cingulate and cerebellar white matter comparisons were non-significant. In contrast, AFs of tauopathy, microgliosis, and astrocytosis showed no differences across groups. Our results demonstrate with direct histologic evidence that gantenerumab treatment in DIAD can reduce parenchymal Aβ deposits throughout the brain in a dose-dependent manner, suggesting that more complete removal may be possible with earlier and more aggressive treatment regimens. Although AFs of tauopathy, microgliosis, and astrocytosis showed no clear response to partial Aβ removal in this limited autopsy cohort, future examination of these cases with more sensitive techniques (e.g., mass spectrometry) may reveal more subtle 'downstream' effects.
Plant responses to light competition: Does evolutionary history matter?
2025-06-03

Abstract Plants can respond to light‐competition cues with sets of plastic responses that provide either shade avoidance or tolerance and are suggested to match these strategies to the competition scenarios they experience. However, little is known about the effect of plants' evolutionary history on their ability to shift between these strategies. To fill this knowledge gap, we performed a common‐garden experiment that examined shade avoidance and tolerance responses of the winter annual plant Hymenocarpos circinnatus to a variety of simulated light‐competition scenarios, including different heights and densities of a surrounding vegetation. These responses were compared across plants originating from six populations along a climatic gradient: from a semi‐arid region, where light competition is relatively weak and homogenous, to a mesic‐Mediterranean region, where light competition is stronger and more heterogenous. In most of the studied traits, including those related to shade avoidance such as vertical elongation, or to shade tolerance such as photosynthetic efficiency, we found no evidence for differences among H. circinnatus populations in the extent of their responses to light competition. Interestingly, however, regardless of their evolutionary history, H. circinnatus were more responsive to cues of neighbour density rather than height in both shade tolerance and avoidance traits. Moreover, we found differences among populations in mean values of some of the studied traits across treatments, particularly in the onset of flowering and internode length, which are related to adaptations to the shorter and unpredictable growth season in the more arid sites. The little divergence we found in light‐competition responses across populations along the climatic gradient might reflect low costs of plasticity in these traits in H. circinnatus . Moreover, our results indicate that procumbent plants such as H. circinnatus might respond more to lateral competition cues that indicate neighbour density than to vertical cues that indicate neighbour height, thus highlighting the need to incorporate the two types of cues when studying plastic responses of plants to competition. Read the free Plain Language Summary for this article on the Journal blog.
Nociceptor-specific signaling of the receptor guanylyl cyclase Npr2 contributes to acute and persistent pain
2025-06-03

Natriuretic peptide receptor 2 (Npr2; also termed guanylyl cyclase B) is a transmembrane guanylyl cyclase that is highly abundant in nociceptors. Here, we investigated the role of production of cyclic GMP (cGMP) by Npr2 in pain processing. Adult mice with a deletion of Npr2 specifically in nociceptive sensory neurons exhibited deficits in noxious heat sensing, which can activate the nonselective cation channels TRPV1 and TRPA1. In parallel, Npr2-deficient mice showed a reduction in TRPV1-mediated nocifensive behavior and Ca 2+ influx into sensory neurons. Furthermore, Npr2-deficient mice had considerably reduced hypersensitivity after hindpaw injection of TRPA1 and TRPV1 activators or after hindpaw injection of complete Freund adjuvant, a model of persistent inflammatory pain. These results indicate that Npr2 contributes to the pain sensitization that can lead to chronic pain. Patch-clamp recordings revealed that the endogenous Npr2 ligand, C-type natriuretic peptide (CNP), enhanced the excitability of nociceptive sensory neurons through Npr2. CNP/Npr2 signaling led to the phosphorylation of cysteine-rich LIM-only protein 4 (CRP4), a substrate of cGMP-dependent protein kinase I. Behavioral and electrophysiological analyses using CRP4-deficient mice revealed that CRP4 limited CNP/Npr2-mediated pain sensitization. Our findings reveal a role for CNP/Npr2 signaling in sensory neurons in acute nociceptive and chronic pain and suggest that CRP4 is a downstream target that attenuates pain sensitization.
Host Determinants for the Spread of Panton-Valentine Leukocidin–Positive Staphylococcus aureus in Sub-Saharan Africa
2025-06-03

Abstract The Panton-Valentine leukocidin (PVL) of Staphylococcus aureus can be associated with severe and recurrent skin and soft tissue infections. The prevalence of PVL is particularly high in sub-Saharan Africa. We assessed, in a multicenter cross-sectional study, whether host-related factors could explain this high PVL prevalence. We found higher serum anti–PVL-IgG levels in participants from Africa (Gabon, Nigeria, Congo) as compared with Europe (Germany). PVL-induced cytolysis of neutrophils was higher in Africans and linked to a polymorphism of the C5a receptor (rs11880097 T/G), the cellular target of the lukS subunit of PVL. The inflammasome response of monocytes to PVL is shifted toward IL-1β and IL-8 in Africans, while Europeans have a stronger IL-18 response. Thus, African neutrophils are more susceptible to PVL, and monocytes exert a stronger Th1 immune response, eventually increasing the risk of tissue damage (eg, due to a stronger recruitment of neutrophils via IL-1β and IL-8) in PVL-positive S aureus skin and soft tissue infections in Africans.
Heisenberg-limited Hamiltonian learning continuous variable systems via engineered dissipation
2025-06-03

Discrete and continuous variables oftentimes require different treatments in many learning tasks. Identifying the Hamiltonian governing the evolution of a quantum system is a fundamental task in quantum learning theory. While previous works mostly focused on quantum spin systems, where quantum states can be seen as superpositions of discrete bit-strings, relatively little is known about Hamiltonian learning for continuous-variable quantum systems. In this work we focus on learning the Hamiltonian of a bosonic quantum system, a common type of continuous-variable quantum system. This learning task involves an infinite-dimensional Hilbert space and unbounded operators, making mathematically rigorous treatments challenging. We introduce an analytic framework to study the effects of strong dissipation in such systems, enabling a rigorous analysis of cat qubit stabilization via engineered dissipation. This framework also supports the development of Heisenberg-limited algorithms for learning general bosonic Hamiltonians with higher-order terms of the creation and annihilation operators. Notably, our scheme requires a total Hamiltonian evolution time that scales only logarithmically with the number of modes and inversely with the precision of the reconstructed coefficients. On a theoretical level, we derive a new quantitative adiabatic approximation estimate for general Lindbladian evolutions with unbounded generators. Finally, we discuss possible experimental implementations.
TRUST: Trial of radical upfront surgical therapy in advanced ovarian cancer (ENGOT ov33/AGO‐OVAR OP7).
2025-06-04

LBA5500 Background: Optimal timing of cytoreduction in non-frail patients (pts) with seemingly resectable stage IIIB-IVB ovarian, tubal, and peritoneal carcinoma (OC) remains controversial. Methods: TRUST is an international randomized multicenter phase III trial in pts with stage IIIB-IVB OC and good performance status (ECOG 0/1) comparing primary cytoreductive surgery (PCS) followed by 6 cycles of intravenous (iv) chemotherapy to 3 cycles of neoadjuvant iv chemotherapy (NACT) followed by interval cytoreductive surgery (ICS) and 3 further iv cycles. Maintenance treatment with bevacizumab and/or PARP inhibitors was allowed if selection criteria was similar for both arms. Pts were eligible for the study if preoperative clinical and radiologic assessment identified them as potential candidates for PCS. To ensure surgical quality, participating centers complied with an onsite surgery quality assurance audit, had adequate infrastructure, surgical proficiency (complete resection rates ≥50% in PCS) and sufficient volume (≥36 PCS/year). The intent to treat analysis population included all eligible pts with confirmed stage IIIB-IVB disease. The primary endpoint was overall survival (OS). Superiority was tested using a two-sided stratified log-rank test with significance level 0.05. Secondary endpoints were progression-free survival (PFS) and surgical complications. Results: A total of 688 eligible pts (median age: 63y; range: 32-83) underwent randomization: 345 were assigned to PCS and 343 to NACT/ICS. 91% had high-grade serous histology. Complete resection was achieved in 61.7%/62.9% of all randomized/all operated pts in the PCS group and 72%/76.6% in the ICS group. Median PFS was 22.2 months in the PCS group, and 19.7 months in the ICS group (HR 0.80 95%CI: 0.66-0.96; p=0.02). Median OS was 54.3 months in the PCS group and 48.3 months in the ICS group (HR 0.89 95%CI: 0.74-1.08; p=0.24). Pts with complete cytoreduction after PCS had the most favorable outcome, with a median PFS and OS of 27.9 and 67.0 months, respectively. A long-term benefit from PCS was seen in all analyzed subgroups. The benefit of PCS was most prominent in stage III pts (n=468): median PFS for PCS vs ICS, 26.3 vs 21.4 mos; median OS for PCS vs ICS, 63.7 vs 53.2 months. Major postoperative complication rates were acceptable, with a 30-day postoperative mortality rate of &lt; 1% in both groups. Conclusions: In expert centers with proven surgical quality, PCS followed by iv chemotherapy resulted in a significantly longer median PFS and a numerically longer OS compared to NACT/ICS in non-frail OC pts. Although statistical significance in the primary endpoint was not reached, this is the first randomized trial to show a benefit of PCS over ICS. This benefit is likely to be associated with the high complete resection rate, reinforcing PCS as a standard of care in non-frail pts with seemingly resectable advanced OC. Clinical trial information: NCT02828618 .
Precision tools for the simulation of double-Higgs production via vector-boson fusion
2025-06-04

A bstract We present two precision tools for the simulation of Higgs-pair production via vector-boson fusion in the kappa framework for the parameterization of non-standard Higgs couplings. A new implementation of the process is developed in the framework of the POWHEG BOX program that can be used to provide predictions at the next-to-leading order (NLO) of QCD matched to parton showers (PS). In addition, the existing proVBFHH program for the computation of next-to-next-to-leading order (NNLO) QCD and next-to-next-to-next-to-leading order QCD corrections is extended to account for values of the Higgs couplings different from the expectation of the Standard Model. We systematically compare and analyse predictions obtained with the two programs and find that the NLO+PS predictions provide a good approximation of the NNLO results for observables of the tagging jets and Higgs bosons. The results turn out to be very sensitive to the values of the modified Higgs couplings. Finally we study the non-factorizable NNLO QCD corrections to the process in the presence of anomalous couplings. We find that the size of the non-factorizable corrections is very sensitive to the anomalous couplings.
Nivolumab plus relatlimab vs nivolumab alone for the adjuvant treatment of completely resected stage III–IV melanoma: Primary results from RELATIVITY-098.
2025-06-04

LBA9500 Background: NIVO + RELA fixed-dose combination (FDC), compared with NIVO alone, demonstrated a clinically meaningful benefit to progression-free survival (HR 0.79, 95% CI 0.66–0.95) and overall survival (OS; 0.80, 95% CI 0.66–0.99) after a 3-y follow-up, with a manageable safety profile in patients (pts) with untreated advanced melanoma (RELATIVITY-047). To address a current unmet need for more efficacious adjuvant regimens for completely resected melanoma, RELATIVITY-098 was designed to evaluate adjuvant NIVO + RELA FDC vs NIVO alone in pts after complete resection of stage III–IV melanoma (NCT05002569). Methods: In this phase 3, randomized, double-blind study, pts aged ≥ 12 years were stratified by AJCC v8 stage at screening (stage IIIA/IIIB vs IIIC vs IIID/IV) and geographic region (USA/Canada/Australia vs Europe vs rest of the world). Pts were randomized 1:1 to receive NIVO 480 mg + RELA 160 mg FDC or NIVO 480 mg every 4 weeks for a maximum of 1 year or until first recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was recurrence-free survival (RFS) by investigator; secondary endpoints included OS (key), distant metastasis-free survival (DMFS), and safety. Results: Pts randomized to NIVO + RELA (n = 547) vs NIVO alone (n = 546) had stage IIIA/B (38% vs 36%) or IIIC (49% vs 50%) disease; 80% vs 83% had cutaneous nonacral melanoma, 11% vs 10% had cutaneous acral, and 2% vs 1% had mucosal. Median duration of therapy was 11.0 mo for each arm. At a minimum follow-up of 23.4 mo, there was no statistical difference in RFS for NIVO + RELA vs NIVO (Table). The RFS outcome was generally consistent across stratification factors and prespecified subgroups. OS was not tested per the hierarchical testing strategy. There were 148 OS events (48% data maturity). DMFS was similar in both treatment groups (Table). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 19% of pts treated with NIVO + RELA vs 8% with NIVO alone (compared with 22% vs 12% in RELATIVITY-047); any-grade TRAEs led to discontinuation of therapy in 17% vs 9% of pts, respectively. There were 2 treatment-related deaths with NIVO + RELA and 1 with NIVO. Conclusions: NIVO + RELA did not result in significant RFS improvement vs NIVO alone as adjuvant treatment for pts after complete resection of stage III–IV melanoma. The safety profile of NIVO + RELA in this setting was generally consistent with results from RELATIVITY-047. A robust biomarker analysis for the study is currently underway. Clinical trial information: NCT05002569 . NIVO + RELA NIVO RFS 24-mo rate, %(95% CI) 62.0(57.7–66.0) 63.6 (59.4–67.6) Median, mo (95% CI)(events/pts) NR (30.8–NR)(214/547) 33.1 (31.0–NR)(213/546) HR 1.01 (95% CI, 0.83–1.22) DMFS 24-mo rate, %(95% CI) 73.1(68.8–76.9) 76.3(72.3–79.9) Median, mo (95% CI)(events/pts) NR (NR–NR)(133/499) 33.1 (31.5–NR)(129/494) HR 1.07 (95% CI 0.84–1.36) HR, hazard ratio; NR, not reached.
Impact of accretion assumptions on pulse profile modelling of superburst oscillations in 4U 1636−536
2025-06-04

ABSTRACT Modelling the coherent pulsations observed during thermonuclear bursts offers a valuable method to probe the poorly understood equation of state of dense and cold matter. Here we apply the pulse profile modelling technique to the pulsations observed with Rossi X-ray Timing Explorer during the 2001 superburst of 4U 1636−536. By employing a single, uniform-temperature hotspot model with varying size and temperature, along with various assumptions for background/accretion contribution, we find that each assumption leads to different inferred mass, radius, and compactness constraints. This highlights the critical need to better understand the mass accretion rate enhancement/reduction during thermonuclear bursts to accurately model burst oscillation sources using pulse profile modelling.