Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation.

BACKGROUND: Adagrasib, a KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib showed clinical activity and had an acceptable adverse-event profile in the phase 1-1b part of the KRYSTAL-1 phase 1-2 study. METHODS: In a registrational phase 2 cohort, we evaluated adagrasib (600 mg orally twice daily) in patients with KRASG12C -mutated non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy and anti-programmed death 1 or programmed death ligand 1 therapy. The primary end point was objective response assessed by blinded independent central review. Secondary end points included the duration of response, progression-free survival, overall survival, and safety. RESULTS: As of October 15, 2021, a total of 116 patients with KRASG12C -mutated NSCLC had been treated (median follow-up, 12.9 months); 98.3% had previously received both chemotherapy and immunotherapy. Of 112 patients with measurable disease at baseline, 48 (42.9%) had a confirmed objective response. The median duration of response was 8.5 months (95% confidence interval [CI], 6.2 to 13.8), and the median progression-free survival was 6.5 months (95% CI, 4.7 to 8.4). As of January 15, 2022 (median follow-up, 15.6 months), the median overall survival was 12.6 months (95% CI, 9.2 to 19.2). Among 33 patients with previously treated, stable central nervous system metastases, the intracranial confirmed objective response rate was 33.3% (95% CI, 18.0 to 51.8). Treatment-related adverse events occurred in 97.4% of the patients - grade 1 or 2 in 52.6% and grade 3 or higher in 44.8% (including two grade 5 events) - and resulted in drug discontinuation in 6.9% of patients. CONCLUSIONS: In patients with previously treated KRASG12C -mutated NSCLC, adagrasib showed clinical efficacy without new safety signals. (Funded by Mirati Therapeutics; ClinicalTrials.gov number, NCT03785249.).

Molecular diagnosis, clinical evaluation and phenotypic spectrum of Townes-Brocks syndrome: insights from a large Chinese hearing loss cohort.

BACKGROUND: Townes-Brocks syndrome (TBS) is a rare genetic disorder characterised by multiple malformations. Due to its phenotypic heterogeneity and rarity, diagnosis and recognition of TBS can be challenging and there has been a lack of investigation of patients with atypical TBS in large cohorts and delineation of their phenotypic characteristics. METHODS: We screened SALL1 and DACT1 variants using next-generation sequencing in the China Deafness Genetics Consortium (CDGC) cohort enrolling 20 666 unrelated hearing loss (HL) cases. Comprehensive clinical evaluations were conducted on seven members from a three-generation TBS family. Combining data from previously reported cases, we also provided a landscape of phenotypes and genotypes of patients with TBS. RESULTS: We identified five novel and two reported pathogenic/likely pathogenic (P/LP) SALL1 variants from seven families. Audiological features in patients differed in severity and binaural asymmetry. Moreover, previously undocumented malformations in the middle and inner ear were detected in one patient. By comprehensive clinical evaluations, we further provide evidence for the causal relationship between SALL1 variation and certain endocrine abnormalities. Penetrance analysis within familial contexts revealed incomplete penetrance among first-generation patients with TBS and a higher disease burden among their affected offspring. CONCLUSION: This study presents the first insight of genetic screening for patients with TBS in a large HL cohort. We broadened the phenotypic-genotypic spectrum of TBS and our results supported an underestimated prevalence of TBS. Due to the rarity and phenotypic heterogeneity of rare diseases, broader spectrum molecular tests, especially whole genome sequencing, can improve the situation of underdiagnosis and provide effective recommendations for clinical management.

Targeting multiple receptor tyrosine kinases with sitravatinib: A Phase 1b study in advanced renal cell carcinoma and castrate-resistant prostate cancer.

Sitravatinib (MGCD516) is an oral inhibitor of several closely related oncogenic tyrosine kinase receptors that include VEGFR-2 (vascular endothelial growth factor receptor-2), AXL, and MET (mesenchymal-epithelial transition). The safety and antitumor activity of sitravatinib are reported in patients from two histologic cohorts (anti-angiogenesis-refractory clear cell renal cell carcinoma [RCC] and castrate-resistant prostate cancer [CRPC] with bone metastases) who participated in a Phase 1/1b study. The patients were enrolled using a 3-stage design that was based on observed objective responses. Objective response rate (ORR) was the primary endpoint. Duration of response, progression-free survival (PFS), overall survival (OS), and safety were also assessed. Overall, 48 patients (RCC n = 38, CRPC n = 10) received ≥ 1 dose of sitravatinib. Both cohorts were heavily pretreated (median number of prior systemic therapies: RCC cohort 3, CRPC cohort 6). In the RCC cohort, ORR was 25.9%, P = 0.015 (null hypothesis [ORR ≤ 10%] was rejected). Responses were durable (median duration 13.2 months). Median PFS was 9.5 months and median OS was 30.0 months. No objective responses were seen in the CRPC cohort; median PFS and OS were 5.8 months and 10.1 months, respectively. Across both cohorts, diarrhea (72.9%), fatigue (54.2%), and hypertension (52.1%) were the most frequent all-cause treatment-emergent adverse events (TEAEs). Diarrhea and vomiting (both, 6.3%) were the most frequent serious TEAEs considered related to study treatment. Sitravatinib demonstrated an acceptable safety profile and promising clinical activity in patients with clear cell RCC refractory to prior angiogenesis inhibitor therapy. Strong indicators for clinical activity were not seen in patients with CRPC and bone metastases. Clinical trial registration:ClinicalTrials.gov NCT02219711.

Folding State within a Hysteresis Loop: Hidden Multistability in Nonlinear Physical Systems.

Identifying hidden states in nonlinear physical systems that evade direct experimental detection is important as disturbances and noises can place the system in a hidden state with detrimental consequences. We study a cavity magnonic system whose main physics is photon and magnon Kerr effects. Sweeping a bifurcation parameter in numerical experiments (as would be done in actual experiments) leads to a hysteresis loop with two distinct stable steady states, but analytic calculation gives a third folded steady state "hidden" in the loop, which gives rise to the phenomenon of hidden multistability. We propose an experimentally feasible control method to drive the system into the folded hidden state. We demonstrate, through a ternary cavity magnonic system and a gene regulatory network, that such hidden multistability is in fact quite common. Our findings shed light on hidden dynamical states in nonlinear physical systems which are not directly observable but can present challenges and opportunities in applications.

Spin-dependent Seebeck effect in zigzag-edge antimonene nanoribbons.

In spin caloritronics, the spin-dependent Seebeck effect provides a method for significantly reducing Joule heating and achieving ultra-high integration density. Here, we investigate the electronic transport and spin thermoelectric properties of zigzag-edge antimonene nanoribbons (ZANRs) with different widths using first-principles calculations. The results show that the ZANRs exhibit an excellent spin-dependent Seebeck effect. By modulating the ribbon width, thermal spin devices could generate large spin-dependent currents with small charge currents, making them ideal for spintronic applications with low power consumption and high efficiency. Interestingly, the spin current of ZANRs goes up oscillatingly as the ribbon width decreases, which is beneficial for device miniaturization. Our findings may offer insights into the development of spin caloritronic devices.

Two-dimensional graphene+ as an anode material for calcium-ion batteries with ultra-high capacity: a first-principles study.

Multivalent-ion batteries have garnered significant attention due to their high energy density, low cost, and superior safety. Calcium-ion batteries (CIBs) are regarded as the next-generation energy storage systems for their abundant natural resources and bivalent characteristics. However, the absence of high-performance anode materials poses a significant obstacle to the progress of battery technology. Two-dimensional (2D) Dirac materials have excellent conductivity and abundant active sites, rendering them promising candidates as anode materials. A novel 2D Dirac material known as "graphene+" has been theoretically reported, exhibiting prominent properties including good stability, exceptional ductility, and remarkable electronic conductivity. By using first-principles calculations, we systematically investigate the performance of graphene+ as an anode material for CIBs. Graphene+ exhibits an ultra-high theoretical capacity (1487.7 mA h g-1), a small diffusion barrier (0.21 eV), and a low average open-circuit voltage (0.51 V). Furthermore, we investigate the impact of the electrolyte solvation on the performance of Ca-ion adsorption and migration. Upon contact with electrolyte solvents, graphene+ exhibits strong adsorption strength and rapid migration of Ca-ions on its surface. These results demonstrate the promising potential of graphene+ as a high-performance anode material for CIBs.

Strain-induced ferroelectric polarization reversal without undergoing geometric inversion in blue SiSe monolayer.

Ferroelectricity in two-dimensional (2D) systems generally arises from phonons and has been widely investigated. On the contrary, electronic ferroelectricity in 2D systems has been rarely studied. Using first-principles calculations, the ferroelectric behavior of the buckled blue SiSe monolayer under strain are explored. It is found that the direction of the out-of-plane ferroelectric polarization can be reversed by applying an in-plane strain. And such polarization switching is realized without undergoing geometric inversion. Besides, the strain-triggered polarization reversal emerges in both biaxial and uniaxial strain cases, indicating it is an intrinsic feature of such a system. Further analysis shows that the polarization switching is the result of the reversal of the magnitudes of the positive and negative charge center vectors. And the variation of buckling is found to play an important role, which results in the switch. Moreover, a non-monotonic variation of band gap with strain is revealed. Our findings throws light on the investigation of novel electronic ferroelectric systems.

Flexible multicolor biaxial sensor for strain direction identification based on sandwich-structured mechanoluminescent materials.

Strain sensors capable of recognizing the direction of strain are crucial in applications such as robot attitude adjustment and detection of strain states in complex structures. In this study, a sandwich-structured flexible biaxial strain sensor was developed using polydimethylsiloxane as the substrate, mechanoluminescent materials as the luminescent elements, and rubber-ink as the light-blocking layer. By correlating the emitted light color with the stretching state, precise identification of the applied strain direction is achieved. Additionally, the mechanoluminescence of the sensor is collected by a photodiode, generating photocurrent that can be analyzed. This provides a solution for practical applications of sensor.

Staying up late increases cardiovascular disease risk in women with polycystic ovary syndrome.

STUDY QUESTION: What is the association between late bedtime, night sleep duration, and lifetime cardiovascular disease (CVD) risk in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Both late bedtime (≥1:00) and short sleep duration (<7 h/night) were independently associated with a high-lifetime CVD risk among women with PCOS. WHAT IS KNOWN ALREADY: Previous studies indicated that sleep disturbances, including altered sleep duration and staying up late (SUL), occurred more frequently among women with PCOS compared to women without PCOS. Studies have shown that both PCOS and sleep disturbances are associated with deterioration in cardiometabolic health in the longer term. However, there are limited data regarding the possible association between sleep disturbances and CVD risk among reproductive-aged women with PCOS. STUDY DESIGN, SIZE, DURATION: From the original 393 women identified at our center, a total of 213 women with PCOS aged 18-40 years were enrolled in a cross-sectional study between March 2020 and July 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Bedtime and night sleep duration were obtained from a standardized self-administered questionnaire. The prediction for atherosclerotic CVD risk in the China risk model was applied to estimate the lifetime CVD risk in the PCOS population. Restricted cubic spline regression was applied to explore the non-linear association between sleep duration and lifetime CVD risk in a series of models. Multivariable logistic regression analyses were performed to determine the association between bedtime, night sleep duration, and lifetime CVD risk. MAIN RESULTS AND THE ROLE OF CHANCE: In our study, we found that the proportion of SUL was 94.25% and the mean (±SD) of night sleep duration was 7.5 ± 1.1 h in women with PCOS. Restricted cubic spline regression analysis showed a U-shaped relation between sleep duration and lifetime CVD risk. After adjusting for occasional drinking, fasting insulin, triglyceride, low-density lipoprotein cholesterol, and testosterone in multivariable logistic analyses, compared with going to bed at 23-24 o'clock, those who went to bed after 1 o'clock were independently associated with high-lifetime CVD risk [odds ratio (OR) = 3.87, 95% CI: 1.56-9.62]; compared with optimal sleep duration (7-8 h/night), short sleep (<7 h/night) was also independently associated with high-lifetime CVD risk (OR = 2.46, 95% CI: 1.01-5.97). LIMITATIONS, REASONS FOR CAUTION: Inferring causality is limited owing to the cross-sectional design. All sleep variables data were obtained from a standardized self-administered questionnaire rather than measurements using objective approaches. Even after adjusting for potential confounders, we still cannot completely rule out the possibility of residual confounding from unmeasured factors such as socioeconomic status. Future studies with larger sample sizes are needed to further explore the relation between long sleep duration and lifetime CVD risk. Although these findings are not generalizable to non-SUL PCOS populations, they could be used for guiding multidimensional treatment. Lastly, there is no non-PCOS group in the current cross-sectional study, which limits the interpretation of the findings from the PCOS group. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to report that both late bedtime (≥1:00) and short sleep duration (<7 h/night) were independently associated with a high-lifetime CVD risk among reproductive-aged women with PCOS, in a sample of Chinese adults. Predicting cardiovascular risk and examining the association between sleep disturbances and predicted CVD risk among women with PCOS help to highlight the need for early interventions on sleep to improve their cardiovascular outcomes. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Natural Science Foundation of Fujian Province (No. 2020J011242), the Fujian provincial health technology project (No. 2022CXB016), the Joint Research Projects of Health and Education Commission of Fujian Province (No. 2019-WJ-39), and the Medical and Health project of Xiamen Science & Technology Bureau (No. 3502Z20214ZD1001). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Effect of external electric field on the electronic properties of the AlAs/SiC van der Waals heterostructure.

Type-II van der Waals (vdW) heterostructures are regarded as the optimum candidates for unipolar electronic device applications due to their capacity for spontaneous electron-hole separation. Here, we studied the electronic properties of the AlAs/SiC vdW heterostructure via density functional theory calculations. Results show that the conduction band minimum (CBM) and valence band maximum (VBM) of this heterostructure are mainly contributed by different materials, illustrating that the AlAs/SiC heterostructure has a type-II band alignment. Interestingly, this heterostructure possesses flat valence bands near the Fermi level. In addition, under the modulation of external electric field ranging between -1 V Å-1∼0.8 V Å-1, the band gap of the heterostructure can be tuned continuously, while the band structure maintains a stable type-II band alignment with flat top valence bands. When the electric field exceeds -1 or 0.8 V Å-1, the heterostructure transitions from semiconductor material to metal, indicating the tunability of electronic properties under external fields. These results indicate that the AlAs/SiC heterostructure shows great potential for application in high-performance optoelectronic devices and a strong correlation may exist in this system.