Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology.

Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. In a cohort of 647 SARS-CoV-2-infected subjects, we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics.

Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Spring Viremia of Carp Virus N Protein Negatively Regulates IFN Induction through Autophagy-Lysosome-Dependent Degradation of STING.

Fish possess a powerful IFN system to defend against aquatic virus infections. Nevertheless, spring viremia of carp virus (SVCV) causes large-scale mortality in common carp and significant economic losses to aquaculture. Therefore, it is necessary to investigate the strategies used by SVCV to escape the IFN response. In this study, we show that the SVCV nucleoprotein (N protein) negatively regulates cellular IFN production by degrading stimulator of IFN genes (STING) via the autophagy-lysosome-dependent pathway. First, overexpression of N protein inhibited the IFN promoter activation induced by polyinosinic-polycytidylic acid and STING. Second, the N protein associated with STING and experiments using a dominant-negative STING mutant demonstrated that the N-terminal transmembrane domains of STING were indispensable for this interaction. Then, the N protein degraded STING in a dose-dependent and autophagy-lysosome-dependent manner. Intriguingly, in the absence of STING, individual N proteins could not elicit host autophagic flow. Furthermore, the autophagy factor Beclin1 was found to interact with the N protein to attenuate N protein-mediated STING degradation after beclin1 knockdown. Finally, the N protein remarkably weakened STING-enhanced cellular antiviral responses. These findings reveal that SVCV uses the host autophagic process to achieve immune escape, thus broadening our understanding of aquatic virus pathogenesis.

Atomic-Site-Dependent Pairing Gap in Monolayer FeSe/SrTiO3(001)-(√13 × âˆš13).

The interfacial FeSe/TiO2-δ coupling induces high-temperature superconductivity in monolayer FeSe films. Using cryogenic atomically resolved scanning tunneling microscopy/spectroscopy, we obtained atomic-site dependent surface density of states, work function, and the pairing gap in the monolayer FeSe on the SrTiO3(001)-(√13 × âˆš13)-R33.7° surface. Our results disclosed the out-of-plane Se-Fe-Se triple layer gradient variation, switched DOS for Fe sites on and off TiO5□, and inequivalent Fe sublattices, which gives global spatial modulation of pairing gap contaminants with the (√13 × âˆš13) pattern. Moreover, the coherent lattice coupling induces strong inversion asymmetry and in-plane anisotropy in the monolayer FeSe, which is demonstrated to correlate with the particle-hole asymmetry in coherence peaks. These results disclose delicate atomic-scale correlations between pairing and lattice-electronic coupling in the Bardeen-Cooper-Schrieffer to Bose-Einstein condensation crossover regime, providing insights into understanding the pairing mechanism of multiorbital superconductivity.

Interlayer Fermi Polarons of Excited Exciton States in Quantizing Magnetic Fields.

The study of exciton polarons has offered profound insights into the many-body interactions between bosonic excitations and their immersed Fermi sea within layered heterostructures. However, little is known about the properties of exciton polarons with interlayer interactions. Here, through magneto-optical reflectance contrast measurements, we experimentally investigate interlayer Fermi polarons for 2s excitons in WSe2/graphene heterostructures, where the excited exciton states (2s) in the WSe2 layer are dressed by free charge carriers of the adjacent graphene layer in the Landau quantization regime. First, such a system enables an optical detection of integer and fractional quantum Hall states (e.g., ν = ±1/3, ±2/3) of monolayer graphene. Furthermore, we observe that the 2s state evolves into two distinct branches, denoted as attractive and repulsive polarons, when graphene is doped out of the incompressible quantum Hall gaps. Our work paves the way for the understanding of the excited composite quasiparticles and Bose-Fermi mixtures.

U2AF2-SNORA68 promotes triple-negative breast cancer stemness through the translocation of RPL23 from nucleoplasm to nucleolus and c-Myc expression.

BACKGROUND: Small nucleolar RNAs (snoRNAs) play key roles in ribosome biosynthesis. However, the mechanism by which snoRNAs regulate cancer stemness remains to be fully elucidated. METHODS: SNORA68 expression was evaluated in breast cancer tissues by in situ hybridization and qRT‒PCR. Proliferation, migration, apoptosis and stemness analyses were used to determine the role of SNORA68 in carcinogenesis and stemness maintenance. Mechanistically, RNA pull-down, RNA immunoprecipitation (RIP), cell fractionation and coimmunoprecipitation assays were conducted. RESULTS: SNORA68 exhibited high expression in triple-negative breast cancer (TNBC) and was significantly correlated with tumor size (P = 0.048), ki-67 level (P = 0.037), and TNM stage (P = 0.015). The plasma SNORA68 concentration was significantly lower in patients who achieved clinical benefit. The SNORA68-high patients had significantly shorter disease-free survival (DFS) (P = 0.036). Functionally, SNORA68 was found to promote the cell stemness and carcinogenesis of TNBC in vitro and in vivo. Furthermore, elevated SNORA68 expression led to increased nucleolar RPL23 expression and retained RPL23 in the nucleolus by binding U2AF2. RPL23 in the nucleolus subsequently upregulated c-Myc expression. This pathway was validated using a xenograft model. CONCLUSION: U2AF2-SNORA68 promotes TNBC stemness by retaining RPL23 in the nucleolus and increasing c-Myc expression, which provides new insight into the regulatory mechanism of stemness.

Effect of immune-modulating metronomic capecitabine as an adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma.

INTRODUCTION: Metronomic capecitabine used as an adjuvant therapy improves survival in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). This therapeutic approach may also contribute to improving immune function, consequently enhancing overall therapeutic efficacy. AIM: We aimed to evaluate the effect of metronomic capecitabine as adjuvant therapy on immune function and survival in cases of LA-NPC. SUBJECTS AND METHODS: 28 patients with LA-NPC were enrolled in the study and equally assigned to two groups of 14 each: experimental and control group. The experimental group received induction chemotherapy + concurrent chemotherapy + adjuvant chemotherapy as well as oral capecitabine at a dose of 650 mg/m² of body surface area twice daily for 1 year, with the option to discontinue in case of intolerance. The control group did not receive additional chemotherapy or targeted drugs after the induction chemotherapy + concurrent chemoradiotherapy; however, they were followed up regularly. Changes in immune function and survival were compared between the two groups. RESULTS: The median follow-up time was 43.5 months. One year after adjuvant chemotherapy, the experimental group showed higher levels of CD8 + cells, CD28 + CD8 + cells, and activated CD8 + cells compared to the control group (P < 0.05). The CD4/CD8 ratio and proportion of monocyte-derived dendritic cells were also higher in the experimental group than in the control group, but the difference was not statistically significant (P ≥ 0.05). Comparisons of 3-year overall survival, local-regional recurrence-free survival, progression-free survival, and distant metastasis-free survival between the two groups showed percentages of 92.9% vs. 78.6%, 92.9% vs. 92.9%, 78.6% vs. 71.4%, and 85.7% vs. 0.78 0.6% respectively, but these differences were not significant (P > 0 0.05 ). CONCLUSION: Metronomic capecitabine chemotherapy was observed to induce an immunomodulatory effect in LA-NPC. TRIAL REGISTRATION: NCT02958111, date of registration 04-11-2016.

Blocking of amino acid transporter OsAAP7 promoted tillering and yield by determining basic and neutral amino acids accumulation in rice.

BACKGROUND: Amino acids are not only the main form of N in rice, but also are vital for its growth and development. These processes are facilitated by amino acid transporters within the plant. Despite their significance, only a few AAP amino acid transporters have been reported. RESULTS: In this study, we observed that there were differences in the expression of amino acid transporter OsAAP7 among 521 wild cultivated rice varieties, and it directly negatively correlated with tillering and grain yield per plant. We revealed that OsAAP7 protein was localized to the endoplasmic reticulum and had absorption and transport affinity for amino acids such as phenylalanine (Phe), lysine (Lys), leucine (Leu), and arginine (Arg) using subcellular localization, yeast substrate testing, fluorescent amino acid uptake, and amino acid content determination. Further hydroponic studies showed that exogenous application of amino acids Phe, Lys and Arg inhibited the growth of axillary buds in the overexpression lines, and promoted the elongation of axillary buds in the mutant lines. Finally, RNA-seq analysis showed that the expression patterns of genes related to nitrogen, auxin and cytokinin pathways were changed in axillary buds of OsAAP7 transgenic plants. CONCLUSIONS: This study revealed the gene function of OsAAP7, and found that blocking of amino acid transporter OsAAP7 with CRISPR/Cas9 technology promoted tillering and yield by determining basic and neutral amino acids accumulation in rice.

The small nucleolar RNA SNORA51 enhances breast cancer stem cell-like properties via the RPL3/NPM1/c-MYC pathway.

Breast cancer stem cells (BCSCs) are key players in carcinogenesis and development. Small nucleolar RNAs (snoRNAs) seem to have a crucial influence on regulating stem cell-like properties in various cancers, but the underlying mechanism in breast cancer has not been determined. In this study, we first found that the expression of SNORA51 might be strongly and positively related to BCSCs-like properties. SNORA51 expression was assessed in breast cancer tissues (n = 158 patients) by in situ hybridization. Colony formation, cell counting kit-8, and sphere formation assays were used to detect cell proliferation and self-renewal, respectively. Wound healing and transwell assays were used to detect cell migration. Coimmunoprecipitation and molecular docking were used to determine the underlying mechanism through which SNORA51 regulates BCSCs-like properties. High SNORA51 expression was associated with a worse prognosis, overall survival, and disease-free survival, in 158 breast cancer patients and was also closely related to lymph node status, ER status, the Ki-67 index, histological grade, and TNM stage. Further analysis proved that SNORA51 could enhance and maintain stem cell-like properties, including cell proliferation, self-renewal, and migration, in breast cancer. Moreover, high SNORA51 expression could reduce nucleolar RPL3 expression, induce changes in the expression of NPM1 in the nucleolus and nucleoplasm, and ultimately increase c-MYC expression. Taken together, our findings demonstrated that SNORA51 could enhance BCSCs-like properties via the RPL3/NPM1/c-MYC pathway both in vitro and in vivo. Therefore, SNORA51 might be a significant biomarker and potential therapeutic target and might even provide a new viewpoint on the regulatory mechanism of snoRNAs in breast cancer or other malignant tumors.

Biodegradation of low-density polyethylene by mixed fungi composed of Alternaria sp. and Trametes sp. isolated from landfill sites.

With the development of industry and modern manufacturing, nondegradable low-density polyethylene (LDPE) has been widely used, posing a rising environmental hazard to natural ecosystems and public health. In this study, we isolated a series of LDPE-degrading fungi from landfill sites and carried out LDPE degradation experiments by combining highly efficient degrading fungi in pairs. The results showed that the mixed microorganisms composed of Alternaria sp. CPEF-1 and Trametes sp. PE2F-4 (H-3 group) had a greater degradation effect on heat-treated LDPE (T-LDPE). After 30 days of inoculation with combination strain H-3, the weight loss rate of the T-LDPE film was approximately 154% higher than that of the untreated LDPE (U-LDPE) film, and the weight loss rate reached 0.66 ± 0.06%. Environmental scanning electron microscopy (ESEM) and Fourier transform infrared spectroscopy (FTIR) were used to further investigate the biodegradation impacts of T-LDPE, including the changes on the surface and depolymerization of the LDPE films during the fungal degradation process. Our findings revealed that the combined fungal treatment is more effective at degrading T-LDPE than the single strain treatment, and it is expected that properly altering the composition of the microbial community can help lessen the detrimental impact of plastics on the environment.

Stepwise changes in flavonoids in spores/pollen contributed to terrestrial adaptation of plants.

Protecting haploid pollen and spores against UV-B light and high temperature, 2 major stresses inherent to the terrestrial environment, is critical for plant reproduction and dispersal. Here, we show flavonoids play an indispensable role in this process. First, we identified the flavanone naringenin, which serves to defend against UV-B damage, in the sporopollenin wall of all vascular plants tested. Second, we found that flavonols are present in the spore/pollen protoplasm of all euphyllophyte plants tested and that these flavonols scavenge reactive oxygen species to protect against environmental stresses, particularly heat. Genetic and biochemical analyses showed that these flavonoids are sequentially synthesized in both the tapetum and microspores during pollen ontogeny in Arabidopsis (Arabidopsis thaliana). We show that stepwise increases in the complexity of flavonoids in spores/pollen during plant evolution mirror their progressive adaptation to terrestrial environments. The close relationship between flavonoid complexity and phylogeny and its strong association with pollen survival phenotypes suggest that flavonoids played a central role in the progression of plants from aquatic environments into progressively dry land habitats.

Trembling Motion of Exciton Polaritons Close to the Rashba-Dresselhaus Regime.

We report the experimental observation of trembling quantum motion, or Zitterbewegung, of exciton polaritons in a perovskite microcavity at room temperature. By introducing liquid-crystal molecules into the microcavity, we achieve spinor states with synthetic Rashba-Dresselhaus spin-orbit coupling and tunable energy splitting. Under a resonant excitation, the polariton fluid exhibits clear trembling motion perpendicular to its flowing direction, accompanied by a unique spin pattern resembling interlocked fingers. Furthermore, leveraging the sizable tunability of energy gaps by external electrical voltages, we observe the continuous transition of polariton Zitterbewegung from relativistic (small gaps) to nonrelativistic (large gaps) regimes. Our findings pave the way for using exciton polaritons in the emulation of relativistic quantum physics.

π Phase Interlayer Shift and Stacking Fault in the Kagome Superconductor CsV_{3}Sb_{5}.

The stacking degree of freedom is a crucial factor in tuning material properties and has been extensively investigated in layered materials. The kagome superconductor CsV_{3}Sb_{5} was recently discovered to exhibit a three-dimensional CDW phase below T_{CDW}∼94 K. Despite the thorough investigation of in-plane modulation, the out-of-plane modulation has remained ambiguous. Here, our polarization- and temperature-dependent Raman measurements reveal the breaking of C_{6} rotational symmetry and the presence of three distinct domains oriented at approximately 120° to each other. The observations demonstrate that the CDW phase can be naturally explained as a 2c staggered order phase with adjacent layers exhibiting a relative π phase shift. Further, we discover a first-order structural phase transition at approximately 65 K and suggest that it is a stacking order-disorder phase transition due to stacking fault, supported by the thermal hysteresis behavior of a Cs-related phonon mode. Our findings highlight the significance of the stacking degree of freedom in CsV_{3}Sb_{5} and offer structural insights to comprehend the entanglement between superconductivity and CDW.

A pseudo-Double-Network Hydrogel Built upon Layered Double Hydroxides with Self-Strengthening Properties.

While great achievements have been made in the development of mechanically robust nanocomposite hydrogels, incorporating multiple interactions on the bases of two demensional inorganic cross-linkers to construct self-strengthening hydrogels has rarely been investigated. To this end, we propose here a new method for the coupling the dynamic covalent bonds and non-covalent interactions within a pseudo double-network system. The pseudo first network, formed through the Schiff Base reation between Tris-modified layered double hydroxides (Tris-LDHs) and oxidized dextran (ODex), is linked to the second network built upon non-covalent interactions between Tris-LDHs and poly(acrylamide-co-2-acrylamido-2-methyl-propanesulfonate) (p-(AM-co-AMPS). The swelling and mechanical properties of the resulting hydrogels have been investigated as a function of the ODex and AMPS contents. The as-prepared hydrogel can swell to 420 times of its original size and retain more than 99.9 wt.% of water. Mechanical tests show that the hydrogel can bear 90 % of compression and is able to be stretched to near 30 times of its original length. Cyclic tensile tests reveal that the hydrogels are capable of self-strengthening after mechanical training. The unique energy dissipation mechanism based on the dynamic covalent and non-covalent interactions is considered to be responsible for the outstanding swelling and mechanical performances.

Characterization of potassium-solubilizing fungi, Mortierella spp., isolated from a poplar plantation rhizosphere soil.

Potassium-solubilizing microorganisms are capable of secreting acidic chemicals that dissolve and release potassium from soil minerals, thus facilitating potassium uptake by plants. In this study, three potassium-dissolving filamentous fungi were isolated from the rhizosphere soil of a poplar plantation in Jiangsu Province, China. Phylogenetic analyses based on ITS, 18 S, and 28 S showed that these three isolates were most similar to Mortierella. These strains also possessed spherical or ellipsoidal spores, produced sporangia at the hyphal tip, and formed petal-like colonies on PDA media resembling those of Mortierella species. These findings, along with further phenotypic observations, suggest that these isolates were Mortierella species. In addition, the potassium-dissolution experiment showed that strain 2K4 had a relatively high potassium-solubilizing capacity among these isolated fungi. By investigating the influences of different nutrient conditions (carbon source, nitrogen source, and inorganic salt) and initial pH values on the potassium-dissolving ability, the optimal potassium-solubilization conditions of the isolate were determined. When potassium feldspar powder was used as an insoluble potassium source, isolate 2K4 exhibited a significantly better polysaccharide aggregation ability on the formed mycelium-potassium feldspar complex. The composition and content of organic acids secreted by strain 2K4 were further detected, and the potassium-dissolution mechanism of the Mortierella species and its growth promotion effect were discussed, using maize as an example.

Transcriptome-wide analysis of a superior xylan degrading isolate Penicillium oxalicum 5-18 revealed active lignocellulosic degrading genes.

Lignocellulose biomass raw materials have a high value in energy conversion. Recently, there has been growing interest in using microorganisms to secret a series of enzymes for converting low-cost biomass into high-value products such as biofuels. We previously isolated a strain of Penicillium oxalicun 5-18 with promising lignocellulose-degrading capability. However, the mechanisms of lignocellulosic degradation of this fungus on various substrates are still unclear. In this study, we performed transcriptome-wide profiling and comparative analysis of strain 5-18 cultivated in liquid media with glucose (Glu), xylan (Xyl) or wheat bran (WB) as sole carbon source. In comparison to Glu culture, the number of differentially expressed genes (DEGs) induced by WB and Xyl was 4134 and 1484, respectively, with 1176 and 868 genes upregulated. Identified DEGs were enriched in many of the same pathways in both comparison groups (WB vs. Glu and Xly vs. Glu). Specially, 118 and 82 CAZyme coding genes were highly upregulated in WB and Xyl cultures, respectively. Some specific pathways including (Hemi)cellulose metabolic processes were enriched in both comparison groups. The high upregulation of these genes also confirmed the ability of strain 5-18 to degrade lignocellulose. Co-expression and co-upregulated of genes encoding CE and AA CAZy families, as well as other (hemi)cellulase revealed a complex degradation strategy in this strain. Our findings provide new insights into critical genes, key pathways and enzyme arsenal involved in the biomass degradation of P. oxalicum 5-18.

Deep Eutectic Solvent-Assisted Corrosion Boosting Bulk FeCoNiCrMo High-Entropy Alloys as Highly Efficient Oxygen Evolution Reaction Catalyst.

The key to enhancing water electrolysis efficiency lies in selecting highly efficient catalysts. Currently, high-entropy alloys (HEAs) are utilized in electrocatalysis applications owing to their diverse elemental composition, disordered elemental distribution, and the high solubility of each element, endowing them with excellent catalytic performance. The experiments were conducted using isoatomic FeNiCrMo HEA as a precursor, with a high-activity three-dimensional nanoporous structure rapidly synthesized via electrochemical one-step dealloying in a choline chloride-thiourea (ChCl-TU) deep eutectic solvent (DES). The results indicate that the dealloyed Fe20Co20Ni20Cr20Mo20 HEA mainly consists of two phases: face-centered cubic and σ phases. The imbalance in the distribution of elements in these two phases leads to quite different corrosion speeds with the FCC phase being preferentially corroded. Furthermore, synergistic electron coupling between surface atoms in the three-dimensional nanoporous structure strengthens the behavior of the oxygen evolution reaction (OER). At a current density of 40 mA cm-2, the overpotential after dealloying decreased to 370 mV, demonstrating excellent stability. The technique demonstrated in this work provides a novel approach to improve the catalytic activity of OER.

Neoadjuvant savolitinib targeted therapy for stage IIIB-N3 lung adenocarcinoma harboring mesenchymal-epithelial transition exon 14 skipping mutation: a case report and literature review.

Savolitinib is a selective inhibitor that specifically targets the phosphorylation of mesenchymal-epithelial transition (MET) kinase. It has demonstrated significant inhibitory effects on the proliferation of tumor cells with METex14 skipping mutation, making it a promising treatment option. While it is the first approved small-molecule inhibitor specifically targeting MET kinase in China, there is limited information about its efficacy as neoadjuvant therapy for patients with supraclavicular lymph node metastasis (N3). In this case report, we presented the successful outcome of a 48-year-old male patient who was diagnosed with stage IIIB (T2bN3M0) lung adenocarcinoma originating from the left upper lobe. The patient exhibited the METex14 skipping alteration. Following two months of neoadjuvant savolitinib treatment, the patient achieved partial remission, with a significant reduction in the size of the primary tumor and metastatic lymph nodes. Postoperative pathological confirmation revealed a pathological complete response, and subsequent imaging examinations, including computed tomography scan and circulating tumor DNA-based molecular residual disease detection, showed no sign of recurrence at 7 months after surgery. Based on this case, neoadjuvant and adjuvant savolitinib therapy may be considered as a favorable alternative to chemotherapy for marginally resectable nonsmall cell lung cancer patients with METex14 skipping mutation.

Tailoring Escalation Adjuvant Therapy for Early-Stage Triple-Negative Breast Cancer in the CBCSG010 Clinical Trial Biomarker Analysis.

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease. The CBCSG010 trial is a prospective and multicenter phase III clinical trial confirming that adding adjuvant capecitabine significantly improved the 5-year disease-free survival (DFS) rate in patients with TNBC by 5.9%. In this study, we attempted to identify the specific population that benefited from adjuvant therapy. METHODS: In this retrospective exploratory analysis, we performed RNA sequencing of tumor tissues from patients with TNBC in the CBCSG010 clinical trial. A single-sample gene set enrichment analysis algorithm and survival analysis were performed to characterize the intrinsic molecular features of the TNBC microenvironment and assess the associations between immune-related gene expression levels or immune cell counts with capecitabine treatment efficacy. Additionally, we performed immunohistochemical staining of 2 markers, PD-L1 and CD8, and hematoxylin-eosin staining of stromal tumor-infiltrating lymphocytes (sTILs) on formalin-fixed, paraffin-embedded specimens to validate findings from bioinformatics analyses. RESULTS: We found that patients with TNBC with high immune-infiltration treated with capecitabine were more likely to have a better prognosis. We used a cutoff of ≥25 combined positive score (CPS) of PD-L1, ≥10% positive sTILs, and ≥10% positive cells of CD8 to define the "immune-hot" patients. Among immune-hot patients, Kaplan-Meier curves showed that 5-year DFS rates were 96.9% and 79.4% in the capecitabine and control groups, respectively (hazard ratio, 0.13; 95% CI, 0.03-0.52; P=.049 in favor of capecitabine). In the capecitabine group, the 5-year DFS rate was higher for immune-hot patients than for immune-cold patients (96.9% vs 76.4%; hazard ratio, 0.11; 95% CI, 0.04-0.29; P=.028). CONCLUSIONS: Our study suggested that immune-hot patients with TNBC are more likely to benefit from adjuvant capecitabine, and that combining immunotherapy with chemotherapy may be expected to be more effective in immune-hot patients.

[18F]FDG PET-CT radiomics signature to predict pathological complete response to neoadjuvant chemoimmunotherapy in non-small cell lung cancer: a multicenter study.

OBJECTIVES: This study aims to develop and validate a radiomics model based on 18F-fluorodeoxyglucose positron emission tomography-computed tomography ([18F]FDG PET-CT) images to predict pathological complete response (pCR) to neoadjuvant chemoimmunotherapy in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: One hundred eighty-five patients receiving neoadjuvant chemoimmunotherapy for NSCLC at 5 centers from January 2019 to December 2022 were included and divided into a training cohort and a validation cohort. Radiomics models were constructed via the least absolute shrinkage and selection operator (LASSO) method. The performances of models were evaluated by the area under the receiver operating characteristic curve (AUC). In addition, genetic analyses were conducted to reveal the underlying biological basis of the radiomics score. RESULTS: After the LASSO process, 9 PET-CT radiomics features were selected for pCR prediction. In the validation cohort, the ability of PET-CT radiomics model to predict pCR was shown to have an AUC of 0.818 (95% confidence interval [CI], 0.711, 0.925), which was better than the PET radiomics model (0.728 [95% CI, 0.610, 0.846]), CT radiomics model (0.732 [95% CI, 0.607, 0.857]), and maximum standard uptake value (0.603 [95% CI, 0.473, 0.733]) (p < 0.05). Moreover, a high radiomics score was related to the upregulation of pathways suppressing tumor proliferation and the infiltration of antitumor immune cell. CONCLUSION: The proposed PET-CT radiomics model was capable of predicting pCR to neoadjuvant chemoimmunotherapy in NSCLC patients. CLINICAL RELEVANCE STATEMENT: This study indicated that the generated 18F-fluorodeoxyglucose positron emission tomography-computed tomography radiomics model could predict pathological complete response to neoadjuvant chemoimmunotherapy, implying the potential of our radiomics model to personalize the neoadjuvant chemoimmunotherapy in lung cancer patients. KEY POINTS: • Recognizing patients potentially benefiting neoadjuvant chemoimmunotherapy is critical for individualized therapy of lung cancer. • [18F]FDG PET-CT radiomics could predict pathological complete response to neoadjuvant immunotherapy in non-small cell lung cancer. • [18F]FDG PET-CT radiomics model could personalize neoadjuvant chemoimmunotherapy in lung cancer patients.