Decision model for durable clinical benefit from front- or late-line immunotherapy alone or with chemotherapy in non-small cell lung cancer.

BACKGROUND: Predictive biomarkers and models of immune checkpoint inhibitors (ICIs) have been extensively studied in non-small cell lung cancer (NSCLC). However, evidence for many biomarkers remains inconclusive, and the opaqueness of machine learning models hinders practicality. We aimed to provide compelling evidence for biomarkers and develop a transparent decision tree model. METHODS: We consolidated data from 3,288 ICI-treated patients with NSCLC across real-world multicenter, public cohorts and the Choice-01 trial (ClinicalTrials.gov: NCT03856411). Over 50 features were examined for predicting durable clinical benefits (DCBs) from ICIs. Noteworthy biomarkers were identified to establish a decision tree model. Additionally, we explored the tumor microenvironment and peripheral CD8+ programmed death-1 (PD-1)+ T cell receptor (TCR) profiles. FINDINGS: Multivariate logistic regression analysis identified tumor histology, PD-ligand 1 (PD-L1) expression, tumor mutational burden, line, and regimen of ICI treatment as significant factors. Mutation subtypes of EGFR, KRAS, KEAP1, STK11, and disruptive TP53 mutations were associated with DCB. The decision tree (DT10) model, using the ten clinicopathological and genomic markers, showed superior performance in predicting DCB in the training set (area under the curve [AUC] = 0.82) and consistently outperformed other models in test sets. DT10-predicted-DCB patients manifested longer survival, an enriched inflamed tumor immune phenotype (67%), and higher peripheral TCR diversity, whereas the DT10-predicted-NDB (non-durable benefit) group showed an enriched desert immune phenotype (86%) and higher peripheral TCR clonality. CONCLUSIONS: The model effectively predicted DCB after front-/subsequent-line ICI treatment, with or without chemotherapy, for squamous and non-squamous lung cancer, offering clinicians valuable insights into efficacy prediction using cost-effective variables. FUNDING: This study was supported by the National Key R&D Program of China.

3D reconstruction of a gastrulating human embryo.

Progress in understanding early human development has been impeded by the scarcity of reference datasets from natural embryos, particularly those with spatial information during crucial stages like gastrulation. We conducted high-resolution spatial transcriptomics profiling on 38,562 spots from 62 transverse sections of an intact Carnegie stage (CS) 8 human embryo. From this spatial transcriptomic dataset, we constructed a 3D model of the CS8 embryo, in which a range of cell subtypes are identified, based on gene expression patterns and positional register, along the anterior-posterior, medial-lateral, and dorsal-ventral axis in the embryo. We further characterized the lineage trajectories of embryonic and extra-embryonic tissues and associated regulons and the regionalization of signaling centers and signaling activities that underpin lineage progression and tissue patterning during gastrulation. Collectively, the findings of this study provide insights into gastrulation and post-gastrulation development of the human embryo.

Novel PET Imaging Probe for Quantitative Detection of Senescence In Vivo.

Real-time detection of cellular senescence remains a clinical challenge. Here, we aimed to develop a positron emission tomography (PET) imaging probe targeting senescence-associated ß-galactosidase (SA-ß-Gal), the most widely used biomarker of cellular senescence, and investigate its performance for real-time in vivo quantitative detection of cellular senescence. A stable PET imaging agent [68Ga]Ga-BGal was obtained with a high labeling yield (90.0 ± 4.3%) and a radiochemical purity (>95%). [68Ga]Ga-BGal displayed high sensitivity and specificity for ß-Gal both in vitro and in vivo. The reaction and uptake of the probe correlated with the ß-Gal concentration and reaction time. In PET imaging, high ß-Gal-expressing CT26.CL25 tumors and doxorubicin-treated HeLa tumors showed high signals from [68Ga]Ga-BGal, while a low signal was observed in CT26.WT and untreated HeLa tumors. In summary, we showcased successful PET imaging of senescence in preclinical models using probe [68Ga]Ga-BGal. This finding holds the potential for translating senescence imaging into clinical applications.

Chemical toolbox to interrogate Heparanase-1 activity.

The development of a robust chemical toolbox to interrogate the activity of heparanase-1 (HPSE-1), an endo-ß-d-glucuronidase and the only known enzyme that cleaves heparan sulfate (HS), has become critically important. The primary function of HPSE-1, cleaving HS side chains from heparan sulfate proteoglycans (HSPGs), regulates the integrity of the extracellular matrix (ECM) and the bioavailability of active, heparan sulfate-binding partners such as enzymes, growth factors, chemokines, and cytokines. HPSE-1 enzymatic activity is strictly regulated and has been found to play fundamental roles in pathophysiological processes. HPSE-1 is significantly overexpressed under various conditions including cancer, metastasis, angiogenesis, and inflammation, making HPSE-1 a promising therapeutic and diagnostic target. Chemical tools that can detect and image HPSE-1 activity in vitro and/or in vivo can help drive the discovery of novel and efficacious anti-HPSE-1 drugs, investigate the basic biology of HPSE-1, and help serve as a diagnostic tool in clinical applications. Here, we will give an overview of the common chemical tools to detect HPSE-1 activity and highlight the novel heparanase probes recently developed in our lab.

A Fluorogenic Green Merocyanine-Based Probe to Detect Heparanase-1 Activity.

Heparanase-1 (HPSE-1), an endo-ß-D-glucuronidase, is an extracellular matrix (ECM) remodeling enzyme that degrades heparan sulfate (HS) chains of heparan sulfate proteoglycans (HSPGs). HPSE-1 functions to remodel the ECM and thereby disseminate cells, liberate HS-bound bioactive molecules, and release biologically active HS fragments. Being the only known enzyme for the cleavage of HS, HPSE-1 regulates a number of fundamental cellular processes including cell migration, cytokine regulation, angiogenesis, and wound healing. Overexpression of HPSE-1 has been discovered in most cancers, inflammatory diseases, viral infections, among others. As an emerging therapeutic target, the biological role of HPSE-1 remains to be explored but is hampered by a lack of research tools. To expand the chemical tool-kit of fluorogenic probes to interrogate HPSE-1 activity, we design and synthesized a fluorogenic green disaccharide-based HPSE-1 probe using our design strategy of tuning the electronic effect of the aryl aglycon. The novel probe exhibits a highly sensitive 278-fold fluorescence turn-on response in the presence of recombinant human HPSE-1, while emitting green light at 560 nm, enabling the fluorescence imaging of HPSE-1 activity in cells.

Hypercholesterolemia Is Associated With Dysregulation of Lipid Metabolism and Poor Prognosis in Primary Biliary Cholangitis.

BACKGROUND & AIMS: Hypercholesterolemia is frequently diagnosed in patients with primary biliary cholangitis (PBC). However, its association with the prognosis and lipid metabolism is unknown. In this study, we aimed to investigate the prognostic value of baseline total cholesterol (TC) levels in PBC and characterized the associated lipid metabolism. METHODS: Five hundred and thirty-one patients with PBC without prior cirrhosis-related complications were randomly divided into the derivation and validation cohorts at a ratio of 7:3. Complete clinical data were obtained and analyzed. The endpoints were defined as liver-related death, liver transplantation, and cirrhosis-related complications. Lipidomics was performed in 89 patients and 28 healthy controls. RESULTS: Baseline TC was independently associated with poor liver-related outcomes, and adjusted C-statistics were 0.80 (95% confidence interval [CI]: 0.74-0.85) and 0.88 (95% CI: 0.78-0.91) in the derivation and validation cohorts, respectively. The predictive ability of TC for disease outcomes was stable over time and comparable with the Globe score. The 200 mg/dL cut-off optimally divided patients into low- and high-TC groups. A combination of TC and Globe score provided a more accurate stratification of patients into risk subgroups. Lipidomics indicated an up-regulation of lipid families in high-TC patients. Pathway analysis of 66 up-regulated lipids revealed the dysregulation of glycerophospholipid and sphingolipid metabolism in high-TC patients, which were associated with poor liver-related outcomes. CONCLUSIONS: Our results indicate that patients with PBC having baseline TC levels above 200 mg/dL have unique lipidome characteristics and are at a higher risk of poor liver-related outcomes.

Morphological Profiling for Drug Discovery in the Era of Deep Learning.

Morphological profiling is a valuable tool in phenotypic drug discovery. The advent of high-throughput automated imaging has enabled the capturing of a wide range of morphological features of cells or organisms in response to perturbations at the single-cell resolution. Concurrently, significant advances in machine learning and deep learning, especially in computer vision, have led to substantial improvements in analyzing large-scale high-content images at high-throughput. These efforts have facilitated understanding of compound mechanism-of-action (MOA), drug repurposing, characterization of cell morphodynamics under perturbation, and ultimately contributing to the development of novel therapeutics. In this review, we provide a comprehensive overview of the recent advances in the field of morphological profiling. We summarize the image profiling analysis workflow, survey a broad spectrum of analysis strategies encompassing feature engineering- and deep learning-based approaches, and introduce publicly available benchmark datasets. We place a particular emphasis on the application of deep learning in this pipeline, covering cell segmentation, image representation learning, and multimodal learning. Additionally, we illuminate the application of morphological profiling in phenotypic drug discovery and highlight potential challenges and opportunities in this field.

Generation of DNAzyme in Bacterial Cells by a Bacterial Retron System.

DNAzymes are catalytically active single-stranded DNAs in which DNAzyme 10-23 (Dz 10-23) consists of a catalytic core and a substrate-binding arm that reduces gene expression through sequence-specific mRNA cleavage. However, the in vivo application of Dz 10-23 depends on exogenous delivery, which leads to its inability to be synthesized and stabilized in vivo, thus limiting its application. As a unique reverse transcription system, the bacterial retron system can synthesize single-stranded DNA in vivo using ncRNA msr/msd as a template. The objective of this work is to reduce target gene expression using Dz 10-23 generated in vivo by the retron system. In this regard, we successfully generated Dz 10-23 by cloning the Dz 10-23 coding sequence into the retron msd gene and tested its ability to reduce specific gene expression by examining the mRNA levels of cfp encoding cyan fluorescence protein and other functional genes such as mreB and ftsZ. We found that Dz had different repressive effects when targeting different mRNA regions, and in general, the repressive effect was stronger when targeting downstream of mRNAs. Our results also suggested that the reduction effect was due to cleavage of the substrate mRNA by Dz 10-23 rather than the antisense effect of the substrate-binding arm. Therefore, this study not only provided a retron-based method for the intracellular generation of Dz 10-23 but also demonstrated that Dz 10-23 could reduce gene expression by cleaving target mRNAs in cells. We believe that this new strategy would have great potential in the regulation of gene expression.

Global potential distribution of mangroves: Taking into account salt marsh interactions along latitudinal gradients.

Mangrove is one of the most productive and sensitive ecosystems in the world. Due to the complexity and specificity of mangrove habitat, the development of mangrove is regulated by several factors. Species distribution models (SDMs) are effective tools to identify the potential habitats for establishing and regenerating the ecosystem. Such models usually include exclusively environmental factors. Nevertheless, recent studies have challenged this notion and highlight the importance of including biotic interactions. Both factors are necessary for a mechanistic understanding of the mangrove distribution in order to promote the protection and restoration of mangroves. Thus, we present a novel approach of combining environmental factors and interactions with salt marsh for projecting mangrove distributions at the global level and within latitudinal zones. To test the salt marsh interaction, we fit the MaxEnt model with two predicting sets: (1) environments only and (2) environments + salt marsh interaction index (SII). We found that both sets of models had good predictive ability, although the SII improved model performance slightly. Potential distribution areas of mangrove decrease with latitudes, and are controlled by biotic and abiotic factors. Temperature, precipitation and wind speed are generally critical at both global scale and ecotones along latitudes. SII is important on global scale, with a contribution of 5.9%, ranking 6th, and is particularly critical in the 10-30°S and 20-30°N zone. Interactions with salt marsh, including facilitation and competition, are shown to affect the distribution of mangroves at the zone of coastal ecotone, especially in the latitudinal range from 10° - 30°. The contribution of SII to mangrove distribution increases with latitudes due to the difference in the adaptive capacity of salt marsh plants and mangroves to environments. Totally, this study identified and quantified the effects of salt marsh on mangrove distribution by establishing the SII. The results not only facilitate to establish a more accurate mangrove distribution map, but also improve the efficiency of mangrove restoration by considering the salt marsh interaction in the mangrove management projects. In addition, the method of incorporating biotic interaction into SDMs through establish the biotic interaction index has contributed to the development of SDMs.

Identifying optimal candidates for autologous peripheral blood stem cell therapy in patients with decompensated liver cirrhosis: a prognostic scoring system.

BACKGROUND: Stem cell transplantation shows great potential to improve the long-term survival of cirrhosis patients. However, therapeutic effects may not be homogeneous across the whole study population. This study constructed an easy-to-use nomogram to improve prognostic prediction and aid in treatment decision making for cirrhotic patients. METHODS: From August 2005 to April 2019, 315 patients with decompensated cirrhosis receiving autologous peripheral blood stem cell (PBSC) transplantation were enrolled in this study. They were randomly classified into training (2/3) and validation (1/3) groups. A predictive model was developed using Cox proportional hazard models and subsequently validated. The predictive performance of the model was evaluated and also compared with other prognostic models. RESULTS: Age, creatinine, neutrophil-to-lymphocyte ratio, and Child-Turcotte-Pugh class were included in the nomogram as prognostic variables. The nomogram showed high discrimination power concerning the area under receiver operating characteristic curves (3/5-year AUC: 0.742/0.698) and good consistency suggested by calibration plots. Patients could be accurately stratified into poor- and good-outcome groups regarding liver-transplantation free survival after receiving PBSC therapy (P < 0.001). Compared with poor-outcome group, the liver function of patients listed for liver transplantation in the good-outcome group was significantly improved (P < 0.001). Besides, our nomogram achieved a higher C-index (0.685, 95% CI 0.633-0.738) and better clinical utility compared with other conventional prognostic models. CONCLUSIONS: The proposed nomogram facilitated an accurate prognostic prediction for patients with decompensated cirrhosis receiving PBSC transplantation. Moreover, it also held the promise to stratify patients in clinical trials or practice to implement optimal treatment regimens for individuals.

Prognostic significance of liver stiffness in patients with primary biliary cholangitis: validation of Baveno VII criteria.

BACKGROUND: The role of liver stiffness measurements (LSM) in patients with primary biliary cholangitis (PBC) remains to be further elucidated. AIMS: To clarify the prognostic role of LSM and to validate the "novel concepts" proposed by the Baveno VII Working Group. METHODS: An analysis of the prognostic significance of LSM was performed involving 672 patients. RESULTS: LSM and ΔLSM/ΔT were independent risk factors for liver decompensation, liver transplantation, or liver-related death (primary outcomes, p < 0.001, both). A rule of 5 kPa for LSM (10-15-20 kPa) could be used to denote progressively higher relative risks of primary outcomes. Patients with LSM < 10 kPa have a negligible 3-year risk of primary outcomes (< 1%). Cut-off values of 10 and 15 kPa can be used to classify PBC patients into low-, medium-, and high-risk groups. A clinically significant decrease in LSM, evaluated at 6, 12, or 24 months elastography tests, was associated with a substantially reduced risk of primary outcomes (p < 0.05, all), which can be defined as a decrease in LSM of > - 20% associated with LSM < 20 kPa or any decrease to LSM < 10 kPa. A clinically significant increase in LSM, evaluated at 6, 12, or 24 months elastography tests, was associated with a substantially raised risk of primary outcomes (p < 0.05, all), which can be defined as an increase in LSM of ≥ + 20% or any increase to LSM ≥ 15 kPa. CONCLUSIONS: LSM can be used to monitor disease progression and predict long-term prognosis in patients with PBC.

Temperature-Controlled Switchable Photonic Nanojet Generated by Truncated Cylindrical Structure.

We propose a novel micro-nano structure that can realize a photonic nanojet (PNJ) switch by adjusting the temperature, which is composed of a truncated cylinder coated with a thin vanadium dioxide (VO2) film. The influence of temperature on the maximum strength, full width at half maximum (FWHM), working distance, and focal length of the PNJ were studied by finite-difference time-domain (FDTD) method. The results demonstrate that the structure can adjust the open and close state of the PNJ by changing the temperature. A PNJ with varying characteristics can be obtained at both high and low temperatures, and the maximum intensity ratio of the PNJ can reach up to 7.25. This discovery provides a new way of optical manipulation, sensing and detection, microscopy imaging, optoelectronic devices, and other fields.

Could the New pN Staging Classification Better Predict the Prognosis of Penile Cancer? A Population-Based Analysis.

BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) has made new revisions to the N staging of penile cancer (PeCa). This study aimed to evaluate the prognostic value of the new N staging classification. METHODS: This cohort was included from the Surveillance, Epidemiology, and End Results (SEER) database (1988-2016). Overall survival (OS) and cancer-specific survival (CSS) were evaluated using Kaplan-Meier survival curve. The Cox proportional hazards model was employed to calculate hazard ratio (HR) and 95% confidence intervals (CI). RESULTS: Among the included 583 patients, 270 patients had only one positive inguinal lymph node (ILNP), 115 had two ILNPs, and 198 had 3 or more ILNPs. Kaplan-Meier analysis indicated that The OS and CSS of patients with ILNP = 2 were not statistically different from those with ILNP = 1 (p = 0.394; p = 0.760), but had OS and CSS benefit over those with ILNP ≥3 (p = 0.017; p = 0.020). Cox proportional hazards regression analysis indicated that patients with ILNP = 2 and ILNP = 1 have similar OS and CSS (HR = 0.80, p = 0.153; HR = 0.74, p = 0.148), but patients with ILNP ≥3 had worse OS and CSS than patients with ILNP = 2 (HR = 1.56, p = 0.007; HR = 1.86, p = 0.003). CONCLUSIONS: PeCa patients with only one or two lymph node metastases had similar survival outcomes. AJCC 8th edition pN staging has a better discriminative ability to predict the prognosis and can accurately stratify mortality risk in PeCa.

Could the New pN Staging Classification Better Predict the Prognosis of Penile Cancer? A Population-Based Analysis

Background: The 8th edition of the American Joint Committee on Cancer (AJCC) has made new revisions to the N staging of penile cancer (PeCa). This study aimed to evaluate the prognostic value of the new N staging classification. Methods: This cohort was included from the Surveillance, Epidemiology, and End Results (SEER) database (1988–2016). Overall survival (OS) and cancer-specific survival (CSS) were evaluated using Kaplan–Meier survival curve. The Cox proportional hazards model was employed to calculate hazard ratio (HR) and 95% confidence intervals (CI). Results: Among the included 583 patients, 270 patients had only one positive inguinal lymph node (ILNP), 115 had two ILNPs, and 198 had 3 or more ILNPs. Kaplan–Meier analysis indicated that The OS and CSS of patients with ILNP = 2 were not statistically different from those with ILNP = 1 (p = 0.394; p = 0.760), but had OS and CSS benefit over those with ILNP ≥3 (p = 0.017; p = 0.020). Cox proportional hazards regression analysis indicated that patients with ILNP = 2 and ILNP = 1 have similar OS and CSS (HR = 0.80, p = 0.153; HR = 0.74, p = 0.148), but patients with ILNP ≥3 had worse OS and CSS than patients with ILNP = 2 (HR = 1.56, p = 0.007; HR = 1.86, p = 0.003). Conclusions: PeCa patients with only one or two lymph node metastases had similar survival outcomes. AJCC 8th edition pN staging has a better discriminative ability to predict the prognosis and can accurately stratify mortality risk in PeCa (AU)

Pancoronary plaque characteristics and clinical outcomes in acute coronary syndrome patients with cancer history.

BACKGROUND AND AIMS: The prevalence of acute coronary syndrome (ACS) patients with cancer history is increasing and it is associated with higher mortality. However, there is limited evidence on the characteristics of coronary plaque in ACS patients with cancer history. This study explored the pancoronary plaque characteristics in ACS patients with cancer history by optical coherence tomography (OCT). METHODS: A total of 306 ACS patients treated by 3-vessel OCT at the time of percutaneous coronary intervention (PCI) were included, retrospectively. Patients were divided into two groups according to the presence or absence of cancer history: one group with cancer history (n = 98) and a matched group without cancer history (n = 208). RESULTS: A total of 314 culprit lesions and 514 nonculprit lesions were identified by OCT in this study. In culprit lesions, ACS patients with cancer history had higher incidence of thin cap fibroatheroma (TCFA) (p = 0.016), cholesterol crystals (p = 0.028), calcification (p = 0.001) and thrombus (p = 0.001), and had thinner fibrous cap thickness (FCT) (p = 0.011), greater maximum lipid arc (p = 0.042) and lipid index (p < 0.001), compared to matched ACS patients without cancer history. In nonculprit lesions, ACS patients with cancer history had higher prevalence of high-risk plaque (14.7% vs. 7.7%, p = 0.017), nonculprit rupture (14.7% vs. 6.3%, p = 0.003), and TCFA (52.2% vs. 28.3%, p < 0.001), and had higher incidence of calcification (p = 0.003), thrombus (p = 0.029), cholesterol crystals (p = 0.002) and microchannels (p = 0.029). These non-culprit lesions had longer lesion length (p = 0.001), thinner FCT (p < 0.001), greater maximum lipid arc (p = 0.016) and lipid index (p < 0.001). CONCLUSIONS: ACS patients with cancer history showed more high-risk plaque features in culprit and nonculprit lesions, compared with ACS patients without cancer history. Therefore, ACS patients with cancer history may have greater pancoronary vulnerability. This may predict a poorer prognosis for ACS patients with cancer history.

The association between various dimensions of sleep parameters and mental health: A large cross-sectional study of 13554 Chinese students.

OBJECTIVES: We aimed to investigate the association between multiple sleep variables and mental health among Chinese students aged 9-22. METHOD: We stratified the included 13,554 students by educational levels. Sleep parameters contained sleep duration on school days and weekends, napping time, chronotype and social jetlag (SJL), which were calculated via questionnaires. Individual psychological well-being and distress were assessed by Warwick-Edinburgh mental Well-being scale and the Kessler Psychological Distress Scale 10 respectively. The multiple linear and binary logistic regression were applied to analyze the association of sleep with mental health. RESULTS: Short sleep on school days showed significantly positive association with psychological problems. While among senior high school students, we found reverse result that sleeping less might negatively associated with more severe distress (7-8 h: aOR = 0.67, 95% CI: 0.46, 0.97). The association of sleep duration with mental health was attenuated a lot on weekends. The chronotype was significantly related with mental health in primary and junior high school: intermediate chronotype (vs late chronotype) was associated with greater wellbeing (ß = 1.03, 95% CI: 0.09, 1.96; ß = 1.89, 95% CI: 0.81, 2.97) and less distress (aOR = 0.78, 95% CI: 0.60, 1.00; aOR = 0.73, 95% CI: 0.58, 0.91). The relationship between SJL, napping duration and psychological health problems were also observed in some educational levels. CONCLUSION: Sleep deprivation on school days, late chronotype and SJL were positively associated with worse mental health in our study, which differed among various educational stages.

Discovery and development of small-molecule heparanase inhibitors.

Heparanase-1 (HPSE) is a promising yet challenging therapeutic target. It is the only known enzyme that is responsible for cleavage of heparan sulfate (HS) side chains from heparan sulfate proteoglycans (HSPGs), and is the key enzyme involved in the remodeling and degradation of the extracellular matrix (ECM). Overexpression of HPSE is found in various types of diseases, including cancers, inflammations, diabetes, and viral infections. Inhibiting HPSE can restore ECM functions and integrity, making the development of HPSE inhibitors a highly sought-after topic. So far, all HPSE inhibitors that have entered clinical trials belong to the category of HS mimetics, and no small-molecule or drug-like HPSE inhibitors have made similar progress. None of the HS mimetics have been approved as drugs, with some clinical trials discontinued due to poor bioavailability, side effects, and unfavorable pharmacokinetics characteristics. Small-molecule HPSE inhibitors are, therefore, particularly appealing due to their drug-like characteristics. Advances in the chemical spaces and drug design technologies, including the increasing use of in vitro and in silico screening methods, have provided new opportunities in drug discovery. This article aims to review the discovery and development of small-molecule HPSE inhibitors via screening strategies to shed light on the future endeavors in the development of novel HPSE inhibitors.

FERONIA coordinates plant growth and salt tolerance via the phosphorylation of phyB.

Phosphorylation modification is required for the modulation of phytochrome B (phyB) thermal reversion, but the kinase(s) that phosphorylate(s) phyB and the biological significance of the phosphorylation are still unknown. Here we report that FERONIA (FER) phosphorylates phyB to regulate plant growth and salt tolerance, and the phosphorylation not only regulates dark-triggered photobody dissociation but also modulates phyB protein abundance in the nucleus. Further analysis indicates that phosphorylation of phyB by FER is sufficient to accelerate the conversion of phyB from the active form (Pfr) to the inactive form (Pr). Under salt stress, FER kinase activity is inhibited, leading to delayed photobody dissociation and increased phyB protein abundance in the nucleus. Our data also show that phyB mutation or overexpression of PIF5 attenuates growth inhibition and promotes plant survival under salt stress. Together, our study not only reveals a kinase that controls phyB turnover via a signature of phosphorylation, but also provides mechanistic insights into the role of the FER-phyB module in coordinating plant growth and stress tolerance.

Association between homologous recombination deficiency and outcomes with platinum and platinum-free chemotherapy in patients with triple-negative breast cancer.

OBJECTIVE: The choice of chemotherapeutic regimen for triple-negative breast cancer (TNBC) remains controversial. Homologous recombination deficiency (HRD) has attracted increasing attention in informing chemotherapy treatment. This study was aimed at investigating the feasibility of HRD as a clinically actionable biomarker for platinum-containing and platinum-free therapy. METHODS: Chinese patients with TNBC who received chemotherapy between May 1, 2008 and March 31, 2020 were retrospectively analyzed with a customized 3D-HRD panel. HRD positivity was defined by an HRD score ≥ 30 or deleterious BRCA1/2 mutation. A total of 386 chemotherapy-treated patients with TNBC were screened from a surgical cohort (NCT01150513) and a metastatic cohort, and 189 patients with available clinical and tumor sequencing data were included. RESULTS: In the entire cohort, 49.2% (93/189) of patients were identified as HRD positive (40 with deleterious BRCA1/2 mutations and 53 with BRCA1/2 intact with an HRD score of ≥ 30). In the first-line metastatic setting, platinum therapy was associated with longer median progression-free survival (mPFS) than platinum-free therapy [9.1 vs. 3.0 months; hazard ratio (HR), 0.43; 95% confidence interval 0.22-0.84; P = 0.01]. Among HRD-positive patients, the mPFS was significantly longer in those treated with platinum rather than platinum-free therapy (13.6 vs. 2.0 months; HR, 0.11; P = 0.001). Among patients administered a platinum-free regimen, HRD-negative patients showed a PFS significantly superior to that of HRD-positive patients (P = 0.02; treatment-biomarker P-interaction = 0.001). Similar results were observed in the BRCA1/2-intact subset. In the adjuvant setting, HRD-positive patients tended to benefit more from platinum chemotherapy than from platinum-free chemotherapy (P = 0.05, P-interaction = 0.02). CONCLUSIONS: HRD characterization may guide decision-making regarding the use of platinum treatment in patients with TNBC in both adjuvant and metastatic settings.

Tumor immune microenvironment changes are associated with response to neoadjuvant chemotherapy and long-term survival benefits in advanced epithelial ovarian cancer: A pilot study.

Little is known about the association between efficacy of neoadjuvant chemotherapy (NACT)/survival and the dynamic change of tumor immune environment (TIME) during treatment in epithelial ovarian cancer (EOC). This study investigated the TIME landscape of treatment-naive EOC tumors using multiplex immunofluorescence and associated the TIME before and after platinum-based NACT with treatment efficacy and prognosis in 33 patients with advanced EOC. NACT significantly increased the density of CD8+ T cells (P = 0.033), CD20+ B cells (P = 0.023), CD56 NK cells (P = 0.041), PD-1+ cells (P = 0.042), and PD-L1+CD68+ macrophages (P = 0.005) in the tissue specimens. Response to NACT was evaluated using CA125 response and chemotherapy response score (CRS). Compared with the non-responders, the responders displayed a larger proportion of tumors showing increase in the infiltration of CD20+ cells (P = 0.046) and in the M1/M2 ratio (P = 0.038) as well as fewer tumors showing increase in the infiltration of CD56bright cells (P = 0.041). No association was found between pre-NACT TIME and response to NACT. Density of pre-NACT CD8+ cells was positively associated with longer progression-free survival (PFS) (P = 0.011) and overall survival (OS) (P = 0.048). Post-NACT CD20+ and CD163+ macrophages (M2) infiltrates were associated with prolonged (P = 0.005) and shortened PFS (P = 0.021), respectively. Increase in the density of CD4+ T cells was predictive for longer PFS (P = 0.022) and OS (P = 0.023). In the multivariate analysis, high density of CD8+ cells pre-NACT (P = 0.042) were independently associated with improved OS.