Search

Li-Ping Ge,1,2,* Xi-Yu Liu,1,2,* Yi Xiao,1,2 Zong-Chao Gou,1,2 Shen Zhao,1,2 Yi-Zhou Jiang,1,2 Gen-Hong Di1,2 1Department of Breast Surgery, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: Occult breast cancer (OBC) is a rare type of breast cancer that has not been well studied. The clinicopathological characteristics and treatment recommendations for OBC are based on a limited number of retrospective studies and thus remain controversial.Patients and methods: We identified 479 OBC patients and 115,739 non-OBC patients from 2004 to 2014 in and the Surveillance, Epidemiology, and End Results (SEER) database. The clinicopathological characteristics and survival outcomes were compared between OBC and non-OBC patients. We used the propensity score 1:1 matching analysis to evaluate OBC vs non-OBC comparison using balanced groups with respect to the observed covariates. We further divided the OBC population into four groups based on different treatment strategies. Univariable and multivariable analyses were used to calculate and compare the four treatment outcomes within the OBC population.Results: OBC patients were older, exhibited a more advanced stage, a higher rate of negative estrogen receptor and progesterone receptor status, a higher rate of HER2-positive status, and a higher rate of ≥10 positive lymph nodes, and were less likely to undergo surgical treatment than non-OBC patients. After adjustments for clinicopathological factors, the OBC patients exhibited a significantly better survival than the non-OBC patients (P

Zong-Chao Gou,1,2,* Xi-Yu Liu,1,2,* Yi Xiao,1,2 Shen Zhao,1,2 Yi-Zhou Jiang,1,2 Zhi-Ming Shao1–3 1Department of Breast Surgery, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Institutes of Biomedical Sciences, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: Carcinoma of the axillary tail of Spence (CATS) is a poorly studied type of breast cancer. The clinicopathological characteristics and prognostic features of CATS are unclear. Methods: Using the Surveillance, Epidemiology, and End Results database, we identified 149,026 patients diagnosed with upper outer quadrant breast cancer (UOBC) (n=146,343) or CATS (n=2,683). The median follow-up was 88 months. The primary and secondary outcomes were breast cancer-specific survival (BCSS) and overall survival. The survival outcomes of UOBC and CATS were compared using competing risks analysis, log-rank test, Cox proportional hazards regression model, and propensity score matching method. Multivariate logistic regression was utilized to present the relationship between CATS and lymph node (LN) metastasis. Results: CATS presented a higher grade, higher negative hormone receptor rate, and more positive nodal metastasis. The 10-year BCSS rate was worse for CATS than for UOBC (85.1% vs 87.3%, P=0.001). The multivariate Cox analysis showed a higher hazard ratio (HR) for CATS over UOBC (BCSS: HR =1.20, P=0.001; overall survival: HR =1.11, P=0.019). The difference in the BCSS was also observed in a 1:1 matched cohort (BCSS P=0.019). A subgroup analysis revealed the inferior outcomes of CATS in the metastatic LN subgroup and the hormone receptor-negative subgroup. The multivariate logistic regression indicated that CATS is an independent contributing factor to LN metastasis. Conclusion: CATS had distinct clinicopathological characteristics and was more likely associated with LN metastasis. Compared to UOBC, CATS had adverse impacts on BCSS. Keywords: carcinoma of the axillary tail of Spence, upper outer quadrant breast cancer, breast cancer-specific survival, lymph node metastasis

HER2-positive breast cancer is an aggressive subtype that accounts for 15% to 20% of all breast cancers. Recent studies have suggested that HER2-positive breast cancer is a group of heterogeneous diseases with different sensitivities to standard treatment regimens. Revealing the molecular heterogeneity of HER2-positive breast cancer could potentially enable more precise treatment strategies. In this study, we performed multiomics profiling on a HER2-positive breast cancer cohort and identified four transcriptome-based subtypes. The classical HER2 (HER2-CLA) subtype comprised 28.3% of the samples and displayed high ERBB2 activation and significant benefit from anti-HER2 therapy. The immunomodulatory (HER2-IM) subtype (20%) featured an immune-activated microenvironment, potentially suitable for de-escalated treatment and immunotherapy. The luminal-like (HER2-LUM) subtype (30.6%) possessed similar molecular features of hormone receptor-positive HER2-negative breast cancer, suggesting endocrine therapy and CDK4/6 inhibitors as a potential therapeutic strategy. Lastly, the basal/mesenchymal-like (HER2-BM) subtype (21.1%) had a poor response to current dual HER2-targeted therapy and could potentially benefit from tyrosine kinase inhibitors. The molecular characteristics and clinical features of the subtypes were further explored across multiple cohorts, and the feasibility of the proposed treatment strategies was validated in patient-derived organoid and patient-derived tumor fragment models. This study elucidates the molecular heterogeneity of HER2-positive breast cancer and paves the way for a more tailored treatment. Significance: Illumination of the inherent heterogeneity within HER2-positive breast cancers through the delineation of distinct molecular subtypes lays the groundwork for developing more personalized treatment strategies based on specific patient characteristics., (©2024 American Association for Cancer Research.)

Elevated ribosome biogenesis correlates with the rapid growth and progression of cancer. Targeted blockade of ribosome biogenesis induces nucleolar stress, which preferentially leads to the elimination of malignant cells. In this study, it is reported that the nucleolar protein BRIX1 is a critical regulator for the homeostasis between ribosome biogenesis and p53 activation. BRIX1 facilitated the processing of pre-rRNA by supporting the formation of the PeBoW complex. In addition, BRIX1 prevented p53 activation in response to nucleolar stress by impairing the interactions between MDM2 and the ribosomal proteins, RPL5, and RPL11, thereby triggering the resistance of cancer cells to chemotherapy. Conversely, depletion of BRIX1 induced nucleolar stress, which in turn activated p53 through RPL5 and RPL11, consequently inhibiting the growth of tumors. Moreover, engineered exosomes are developed, which are surface-decorated with iRGD, a tumor-homing peptide, and loaded with siRNAs specific to BRIX1, for the treatment of cancer. iRGD-Exo-siBRIX1 significantly suppressed the growth of colorectal cancer and enhanced the efficacy of 5-FU chemotherapy in vivo. Overall, the study uncovers that BRIX1 functions as an oncoprotein to promote rRNA synthesis and dampen p53 activity, and also implies that targeted inhibition of BRIX1 via engineered exosomes can be a potent approach for cancer therapy., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Objective: To evaluate the feasibility of using a multigene signature to tailor individualised adjuvant therapy for patients with operable triple negative breast cancer., Design: Randomised, multicentre, open label, phase 3 trial., Setting: 7 cancer centres in China between 3 January 2016 and 17 July 2023., Participants: Female patients aged 18-70 years with early triple negative breast cancer after definitive surgery., Interventions: After risk stratification using the integrated signature, patients at high risk were randomised (1:1) to receive an intensive adjuvant treatment comprising four cycles of docetaxel, epirubicin, and cyclophosphamide followed by four cycles of gemcitabine and cisplatin (arm A; n=166) or a standard treatment of four cycles of epirubicin and cyclophosphamide followed by four cycles of docetaxel (arm B; n=170). Patients at low risk received the same adjuvant chemotherapy as arm B (arm C; n=168)., Main Outcome Measures: The primary endpoint was disease-free survival in the intention-to-treat analysis for arm A versus arm B. Secondary endpoints included disease-free survival for arm C versus arm B, recurrence-free survival, overall survival, and safety., Results: Among the 504 enrolled patients, 498 received study treatment. At a median follow-up of 45.1 months, the three year disease-free survival rate was 90.9% for patients in arm A and 80.6% for patients in arm B (hazard ratio 0.51, 95% confidence interval (CI) 0.28 to 0.95; P=0.03). The three year recurrence-free survival rate was 92.6% in arm A and 83.2% in arm B (hazard ratio 0.50, 95% CI 0.25 to 0.98; P=0.04). The three year overall survival rate was 98.2% in arm A and 91.3% in arm B (hazard ratio 0.58, 95% CI 0.22 to 1.54; P=0.27). The rates of disease-free survival (three year disease-free survival 90.1% v 80.6%; hazard ratio 0.57, 95% CI 0.33 to 0.98; P=0.04), recurrence-free survival (three year recurrence-free survival 94.5% v 83.2%; 0.42, 0.22 to 0.81; P=0.007), and overall survival (three year overall survival 100% v 91.3%; 0.14, 0.03 to 0.61; P=0.002) were significantly higher in patients in arm C than in those in arm B with the same chemotherapy regimen. The incidence of grade 3-4 treatment related adverse events were 64% (105/163), 51% (86/169), and 54% (90/166) for arms A, B, and C, respectively. No treatment related deaths occurred., Conclusions: The multigene signature showed potential for tailoring adjuvant chemotherapy for patients with operable triple negative breast cancer. Intensive regimens incorporating gemcitabine and cisplatin into anthracycline/taxane based therapy significantly improved disease-free survival with manageable toxicity., Trial Registration: ClinicalTrials.gov NCT02641847., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from the National Key Research and Development Project of China, National Natural Science Foundation of China, Science and Technology Commission of Shanghai Municipality, Shanghai Key Laboratory of Breast Cancer, SHDC Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals, and CSPC Pharmaceutical Co Ltd, Shijiazhuang, China, for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

High-precision phasemeters are a key technology in intersatellite laser interferometers used for detecting gravitational waves (GWs) in space. As the core of the readout system, the phasemeter must operate in the bandwidth of 5-25 MHz, and its resolution needs to reach the order of μrad/Hz at mHz. It presents significant challenges to electronic signal processing technology. To investigate the primary noise source in the low-frequency band, a mathematical model of thermal drift to phase noise was established, and a multi-point temperature sensing scheme for critical electronic components was proposed. In particular, we evaluated a phasemeter based on a commercial platform and assessed the thermal drift noise according to the proposed model. This study identifies and explains the effects of temperature linear drift and overcorrection in components, demonstrating that thermal drift noise is the main noise source for the phasemeter at frequencies from 0.1 to 1 mHz. In addition, the proposed scheme is universal in its applicability and may be implemented in any circuit for the evaluation of temperature effects on the components of interest., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Harnessing DNA double-strand breaks (DSBs) is a powerful approach for gene editing, but it may provoke loss of heterozygosity (LOH), which predisposes to tumorigenesis. To interrogate this risk, we developed a two- color flow cytometry-based system (Flo-LOH), detecting LOH in ∼5% of cells following a DSB. After this initial increase, cells with LOH decrease due to a competitive disadvantage with parental cells, but if isolated, they stably propagate. Segmental loss from terminal deletions with de novo telomere addition and nonreciprocal translocations is observed as well as whole chromosome loss, especially following a centromeric DSB. LOH spans megabases distal from the DSB, but also frequently tens of megabases centromere-proximal. Inhibition of microhomology-mediated end joining massively increases LOH, which is synergistically increased with concomitant inhibition of canonical nonhomologous end joining. The capacity for large-scale LOH must therefore be considered when using DSB-based gene editing, especially in conjunction with end joining inhibition.

Competing Interests: No potential conflicts of interest are disclosed.

Breast cancer is a common disease that causes great health concerns to women worldwide. During the diagnosis and treatment of breast cancer, medical imaging plays an essential role, but its interpretation relies on radiologists or clinical doctors. Radiomics can extract high-throughput quantitative imaging features from images of various modalities via traditional machine learning or deep learning methods following a series of standard processes. Hopefully, radiomic models may aid various processes in clinical practice. In this review, we summarize the current utilization of radiomics for predicting clinicopathological indices and clinical outcomes. We also focus on radio-multi-omics studies that bridge the gap between phenotypic and microscopic scale information. Acknowledging the deficiencies that currently hinder the clinical adoption of radiomic models, we discuss the underlying causes of this situation and propose future directions for advancing radiomics in breast cancer research., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The accumulation and systemic propagation of senescent cells contributes to physiological aging and age-related pathology. However, which cell types are most susceptible to the aged milieu and could be responsible for the propagation of senescence has remained unclear. Here we found that physiologically aged bone marrow monocytes/macrophages (BMMs) propagate senescence to multiple tissues, through extracellular vesicles (EVs), and drive age-associated dysfunction in mice. We identified peroxisome proliferator-activated receptor α (PPARα) as a target of microRNAs within aged BMM-EVs that regulates downstream effects on senescence and age-related dysfunction. Demonstrating therapeutic potential, we report that treatment with the PPARα agonist fenofibrate effectively restores tissue homeostasis in aged mice. Suggesting conservation to humans, in a cohort study of 7,986 participants, we found that fenofibrate use is associated with a reduced risk of age-related chronic disease and higher life expectancy. Together, our findings establish that BMMs can propagate senescence to distant tissues and cause age-related dysfunction, and they provide supportive evidence for fenofibrate to extend healthy lifespan., (© 2024. The Author(s).)

Background: The unpleasant taste of polyethylene glycol (PEG) has been a hindrance to patients undergoing colonoscopy., Aim: This study aims to determine whether the addition of a vitamin drink (Mizone) to the 4L split-dose PEG regimen would be effective in improving the solution's palatability, and reducing patient discomfort during bowel preparation., Methods: The present prospective, single endoscopist-blinded, randomized controlled study randomly assigned patients into two groups: PEG + Mizone group (3.6 L of PEG solution plus 0.4 L of Mizone) and PEG group (4 L of PEG solution). Palatability was assessed using a Likert scale of 1-5. The adverse events, amount of unconsumed solution, and willingness to repeat the same process were recorded through a questionnaire. The present study was registered in the Chinese Clinical Trial Registry (ChiCTR2000034484)., Results: A total of 132 patients were included. The demographic characteristics of these patients were comparable between the two groups. The palatability score (mean ± standard deviation [SD]) was higher in the PEG + Mizone group, when compared to the control group (4.00 ± 0.859 vs. 2.95 ± 0.999, p  < 0.001). Furthermore, the incidence of nausea was lower in the PEG + Mizone group (9.1 % vs. 28.8 %, p  = 0.004), while the other adverse events were similar between the two groups. The percentage of the completely consumed pre-prepared solution was significantly greater in the PEG + Mizone group (95.5 % vs. 78.8 %, p  = 0.004). Furthermore, the willingness to repeat the same process was higher in the PEG + Mizone group (83.3 % vs. 42.4 %, p  < 0.001). However, the consumption of either of these preparations did not significantly affect the electrolyte and blood glucose levels, and renal function., Conclusion: Compared to the conventional 4L PEG bowel preparation, the use of a vitamin drink (Mizone) as an adjuvant can improve the palatability, reduce adverse events, and increase the patient's willingness to undergo bowel preparation with the same regimen., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Radiomics offers a noninvasive avenue for predicting clinicopathological factors. However, thorough investigations into a robust breast cancer outcome-predicting model and its biological significance remain limited. This study develops a robust radiomic model for prognosis prediction, and further excavates its biological foundation and transferring prediction performance. We retrospectively collected preoperative dynamic contrast-enhanced MRI data from three distinct breast cancer patient cohorts. In FUSCC cohort (n = 466), Lasso was used to select features correlated with patient prognosis and multivariate Cox regression was utilized to integrate these features and build the radiomic risk model, while multiomic analysis was conducted to investigate the model's biological implications. DUKE cohort (n = 619) and I-SPY1 cohort (n = 128) were used to test the performance of the radiomic signature in outcome prediction. A thirteen-feature radiomic signature was identified in the FUSCC cohort training set and validated in the FUSCC cohort testing set, DUKE cohort and I-SPY1 cohort for predicting relapse-free survival (RFS) and overall survival (OS) (RFS: p = 0.013, p = 0.024 and p = 0.035; OS: p = 0.036, p = 0.005 and p = 0.027 in the three cohorts). Multiomic analysis uncovered metabolic dysregulation underlying the radiomic signature (ATP metabolic process: NES = 1.84, p-adjust = 0.02; cholesterol biosynthesis: NES = 1.79, p-adjust = 0.01). Regarding the therapeutic implications, the radiomic signature exhibited value when combining clinical factors for predicting the pathological complete response to neoadjuvant chemotherapy (DUKE cohort, AUC = 0.72; I-SPY1 cohort, AUC = 0.73). In conclusion, our study identified a breast cancer outcome-predicting radiomic signature in a multicenter radio-multiomic study, along with its correlations with multiomic features in prognostic risk assessment, laying the groundwork for future prospective clinical trials in personalized risk stratification and precision therapy., (© 2024. The Author(s).)

Tumors of the digestive system are one of the most important factors affecting people's quality of life and have become a serious public health problem globally.Early screening and intervention of tumor markers in high-risk groups for tumors is the key to tumor prevention. Follistatin-related proteins (FRP) are important members of the follistatin family and such proteins are involved in the pathological process of tumors of the reproductive system and respiratory system, among others. In recent years, FRP has attracted extensive attention in the study of digestive system tumors, suggesting that FRP may play a significant role in the development of digestive system tumors, and is a potential marker for clinical diagnosis and treatment. The article reviews the biological function, expression and potential mechanism of action of FRP associated with digestive system tumors, with a view to providing reference for the diagnosis and prevention of digestive system tumors, prognosis assessment and drug development.

Understanding and modeling perceived properties of sky-dome illumination is an important but challenging problem due to the interplay of several factors such as the materials and geometries of the objects present in the scene being observed. Existing models of sky-dome illumination focus on the physical properties of the sky. However, these parametric models often do not align well with the properties perceived by a human observer. In this work, drawing inspiration from the Hosek-Wilkie sky-dome model, we investigate the perceptual properties of outdoor illumination. For this purpose, we perform a large-scale user study via crowdsourcing to collect a dataset of perceived illumination properties (scattering, glare, and brightness) for different combinations of geometries and materials under a variety of outdoor illuminations, totaling 5,000 distinct images. We perform a thorough statistical analysis of the collected data which reveals several interesting effects. For instance, our analysis shows that when there are objects in the scene made of rough materials, the perceived scattering of the sky increases. Furthermore, we utilize our extensive collection of images and their corresponding perceptual attributes to train a predictor. This predictor, when provided with a single image as input, generates an estimation of perceived illumination properties that align with human perceptual judgments. Accurately estimating perceived illumination properties can greatly enhance the overall quality of integrating virtual objects into real scene photographs. Consequently, we showcase various applications of our predictor. For instance, we demonstrate its utility as a luminance editing tool for showcasing virtual objects in outdoor scenes.

Transposable elements (TEs), comprising nearly 50% of the human genome, have transitioned from being perceived as "genomic junk" to key players in cancer progression. Contemporary research links TE regulatory disruptions with cancer development, underscoring their therapeutic potential. Advances in long-read sequencing, computational analytics, single-cell sequencing, proteomics, and CRISPR-Cas9 technologies have enriched our understanding of TEs' clinical implications, notably their impact on genome architecture, gene regulation, and evolutionary processes. In cancer, TEs, including long interspersed element-1 (LINE-1), Alus, and long terminal repeat (LTR) elements, demonstrate altered patterns, influencing both tumorigenic and tumor-suppressive mechanisms. TE-derived nucleic acids and tumor antigens play critical roles in tumor immunity, bridging innate and adaptive responses. Given their central role in oncology, TE-targeted therapies, particularly through reverse transcriptase inhibitors and epigenetic modulators, represent a novel avenue in cancer treatment. Combining these TE-focused strategies with existing chemotherapy or immunotherapy regimens could enhance efficacy and offer a new dimension in cancer treatment. This review delves into recent TE detection advancements, explores their multifaceted roles in tumorigenesis and immune regulation, discusses emerging diagnostic and therapeutic approaches centered on TEs, and anticipates future directions in cancer research., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Liver transplantation (LT) has been proposed as a viable treatment option for selected methylmalonic acidemia (MMA) patients. However, there are still controversies regarding the therapeutic value of LT for MMA. The systematic assessment of health-related quality of life (HRQoL)-targeted MMA children before and after LT is also undetermined. This study aimed to comprehensively assess the long-term impact of LT on MMA, including multiorgan sequelae and HRQoL in children and families., Methods: We retrospectively evaluated 15 isolated MMA patients undergoing LT at our institution between June 2013 and March 2022. Pre- and post-transplant data were compared, including metabolic profiles, neurologic consequences, growth parameters, and HRQoL. To further assess the characteristics of the HRQoL outcomes in MMA, we compared the results with those of children with biliary atresia (BA)., Results: All patients had early onset MMA, and underwent LT at a mean age of 4.3 years. During 1.3-8.2 years of follow-up, the patient and graft survival rates were 100%. Metabolic stability was achieved in all patients with liberalized dietary protein intake. There was a significant overall improvement in height Z scores (P = 0.0047), and some preexisting neurological complications remained stable or even improved after LT. On the Pediatric Quality of Life Inventory (PedsQL™) generic core scales, the mean total, physical health, and psychosocial health scores improved significantly posttransplant (P < 0.05). In the family impact module, higher mean scores were noted for all subscales post-LT, especially family function and daily activities (P < 0.01). However, the total scores on the generic core scales and transplant module were significantly lower (Cohen's d = 0.57-1.17) when compared with BA recipients. In particular, social and school functioning (Cohen's d = 0.86-1.76), treatment anxiety, and communication (Cohen's d = 0.99-1.81) were far behind, with a large effect size., Conclusions: This large single-center study of the mainland of China showed an overall favorable impact of LT on isolated MMA in terms of long-term survival, metabolic control, and HRQoL in children and families. The potential for persistent neurocognitive impairment and inherent metabolic fragility requires long-term special care. Video Abstract (MP4 153780 KB)., (© 2023. The Author(s).)

Objective: To investigate the role of plasma circulating cell-free DNA (cf-DNA) in the screening and diagnosis of patients with newly diagnosed multiple myeloma (MM) and explore the changes of cf-DNA in terms of content and integrality in the assessment of disease in patients treated with chemotherapy., Methods: Peripheral blood specimens were collected from 35 newly diagnosed MM patients and 18 healthy volunteers, and 13 of the 35 patients who had finished 3 courses of standard induction chemotherapy were selected as follow-up group. The ALU247 and ALU115 fragments were used as the target genes, and the cf-DNA content in the plasma of patients and healthy controls was measured by quantitative polymerase chain reaction (qPCR). The integrality of cf-DNA was calculated by the ratio of ALU247 to ALU115., Results: Both the concentration of ALU247 and ALU115 fragments and the integrality of cf-DNA in patients were significantly higher than those in healthy controls (all P < 0.05). Patients who had underwent 3 courses of induction chemotherapy had significantly decreased concentration of ALU247 and ALU115 fragments and integrality of cf-DNA after treatment (all P < 0.05), and strong positive correlations were manifested between cf-DNA integrality and serum M protein content, as well as proportion of abnormal plasma cells in bone marrow before and after treatment ( r =0.703, 0.705)., Conclusions: Cf-DNA has certain positive significance for the screening and diagnosis of MM. Furthermore, cf-DNA may be a synergism or alternative to serum M-protein content and proportion of abnormal plasma cells in bone marrow in assessing the condition, curative effect and prognosis of patients.

Breast tumor-initiating cells (BTICs) of triple-negative breast cancer (TNBC) tissues actively repair DNA and are resistant to treatments including chemotherapy, radiotherapy, and targeted therapy. Herein, it is found that a previously reported secreted protein, sclerostin domain containing 1 (SOSTDC1), is abundantly expressed in BTICs of TNBC cells and positively correlated with a poor patient prognosis. SOSTDC1 knockdown impairs homologous recombination (HR) repair, BTIC maintenance, and sensitized bulk cells and BTICs to Olaparib. Mechanistically, following Olaparib treatment, SOSTDC1 translocates to the nucleus in an importin-α dependent manner. Nuclear SOSTDC1 interacts with the N-terminus of the nucleoprotein, chromatin helicase DNA-binding factor (CHD1), to promote HR repair and BTIC maintenance. Furthermore, nuclear SOSTDC1 bound to β-transducin repeat-containing protein (β-TrCP) binding motifs of CHD1 is found, thereby blocking the β-TrCP-CHD1 interaction and inhibiting β-TrCP-mediated CHD1 ubiquitination and degradation. Collectively, these findings identify a novel nuclear SOSTDC1 pathway in regulating HR repair and BTIC maintenance, providing insight into the TNBC therapeutic strategies., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Liver transplantation (LT) rejection remains the most pervasive problem associated with this procedure, while the mechanism involved is still complicated and undefined. One promising solution may involve the use of myeloid-derived suppressor cells (MDSC). However, the immunological mechanisms underlying the effects of MDSC after LT remain unclear. This study is meant to clarify the role MDSCs play after liver transplantation. In this study, we collected liver tissue and peripheral blood mononuclear cells (PBMC) from LT patients showing varying degrees of rejection, as well as liver and spleen tissue samples from mice LT models. These samples were then analyzed using flow cytometry, immunohistochemistry and multiple immunofluorescence. M-MDSCs and CD8 + T-cells extracted from C57/BL6 mice were enriched and cocultured for in vitro experiments. Results, as obtained in both LT patients and LT mice model, revealed that the proportion and frequency of M-MDSC and PD-1 + T-cells increased significantly under conditions associated with a high degree of LT rejection. Within the LT rejection group, our immunofluorescence results showed that a close spatial contiguity was present between PD-1 + T-cells and M-MDSCs in these liver tissue samples and the proportion of CD84/PD-L1 double-positive M-MDSC was greater than that of G-MDSC. There was a positive correlation between the activity of CD84 and immunosuppressive function of M-MDSCs including PD-L1 expression and reactive oxygen species (ROS) production, as demonstrated in our in vitro model. M-MDSCs treated with CD84 protein were able to induce co-cultured CD8 + T-cells to express high levels of exhaustion markers. We found that CD84 regulated M-MDSC function via expression of PD-L1 through activation of the Akt/Stat3 pathway. These results suggest that the capacity for CD84 to regulate M-MDSC induction of CD8 + T-cell exhaustion may play a key role in LT rejection. Such findings provide important, new insights into the mechanisms of tolerance induction in LT., (© 2024. The Author(s).)

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic options. IL1 receptor type 2 (IL1R2) promotes breast tumor-initiating cell (BTIC) self-renewal and tumor growth in TNBC, indicating that targeting it could improve patient treatment. In this study, we observed that IL1R2 blockade strongly attenuated macrophage recruitment and the polarization of tumor-associated macrophages (TAM) to inhibit BTIC self-renewal and CD8+ T-cell exhaustion, which resulted in reduced tumor burden and prolonged survival in TNBC mouse models. IL1R2 activation by TAM-derived IL1β increased PD-L1 expression by interacting with the transcription factor Yin Yang 1 (YY1) and inducing YY1 ubiquitination and proteasomal degradation in both TAMs and TNBC cells. Loss of YY1 alleviated the transcriptional repression of c-Fos, which is a transcriptional activator of PDL-1. Combined treatment with an IL1R2-neutralizing antibodies and anti-PD-1 led to enhanced antitumor efficacy and reduced TAMs, BTICs, and exhausted CD8+ T cells. These results suggest that IL1R2 blockade might be a strategy to potentiate immune checkpoint blockade efficacy in TNBC to improve patient outcomes. Significance: IL1R2 in both macrophages and breast cancer cells orchestrates an immunosuppressive tumor microenvironment by upregulating PD-L1 expression and can be targeted to enhance the efficacy of anti-PD-1 in triple-negative breast cancer., (©2024 American Association for Cancer Research.)

Histone deacetylase (HDAC) serves as a critical molecular regulator in the pathobiology of various malignancies and have garnered attention as a viable target for therapeutic intervention. A variety of HDAC inhibitors (HDACis) have been developed to target HDACs. Many preclinical studies have conclusively demonstrated the antitumor effects of HDACis, whether used as monotherapy or in combination treatments. On this basis, researchers have conducted various clinical studies to evaluate the potential of selective and pan-HDACis in clinical settings. In our work, we extensively summarized and organized current clinical trials, providing a comprehensive overview of the current clinical advancements in targeting HDAC therapy. Furthermore, we engaged in discussions about several clinical trials that did not yield positive outcomes, analyzing the factors that led to their lack of anticipated therapeutic effectiveness. Apart from the experimental design factors, issues such as toxicological side effects, tumor heterogeneity, and unexpected off-target effects also contributed to these less-than-expected results. These challenges have naturally become significant barriers to the application of HDACis. Despite these challenges, we believe that advancements in HDACi research and improvements in combination therapies will pave the way or lead to a broad and hopeful future in the treatment of solid tumors., (© 2024. The Author(s).)

Tumor-resident microbiota in breast cancer promotes cancer initiation and malignant progression. However, targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail. Here, we evaluated the microbiota composition of breast tumors and found that enterotoxigenic Bacteroides fragilis (ETBF) was highly enriched in the tumors of patients who did not respond to taxane-based neoadjuvant chemotherapy. ETBF, albeit at low biomass, secreted the toxic protein BFT-1 to promote breast cancer cell stemness and chemoresistance. Mechanistic studies showed that BFT-1 directly bound to NOD1 and stabilized NOD1 protein. NOD1 was highly expressed on ALDH+ breast cancer stem cells (BCSCs) and cooperated with GAK to phosphorylate NUMB and promote its lysosomal degradation, thereby activating the NOTCH1-HEY1 signaling pathway to increase BCSCs. NOD1 inhibition and ETBF clearance increase the chemosensitivity of breast cancer by impairing BCSCs., (© The Author(s) 2024. Published by Oxford University Press on behalf of Higher Education Press.)

Background: Thrombocytopenia 2, an autosomal dominant inherited disease characterized by moderate thrombocytopenia, predisposition to myeloid malignancies and normal platelet size and function, can be caused by 5'-untranslated region (UTR) point mutations in ankyrin repeat domain containing 26 (ANKRD26). Runt related transcription factor 1 (RUNX1) and friend leukemia integration 1 (FLI1) have been identified as negative regulators of ANKRD26 . However, the positive regulators of ANKRD26 are still unknown., Aim: To prove the positive regulatory effect of GATA binding protein 2 (GATA2) on ANKRD26 transcription., Methods: Human induced pluripotent stem cells derived from bone marrow (hiPSC-BM) and urothelium (hiPSC-U) were used to examine the ANKRD26 expression pattern in the early stage of differentiation. Then, transcriptome sequencing of these iPSCs and three public transcription factor (TF) databases (Cistrome DB, animal TFDB and ENCODE) were used to identify potential TF candidates for ANKRD26 . Furthermore, overexpression and dual-luciferase reporter experiments were used to verify the regulatory effect of the candidate TFs on ANKRD26 . Moreover, using the GENT2 platform, we analyzed the relationship between ANKRD26 expression and overall survival in cancer patients., Results: In hiPSC-BMs and hiPSC-Us, we found that the transcription levels of ANKRD26 varied in the absence of RUNX1 and FLI1. We sequenced hiPSC-BM and hiPSC-U and identified 68 candidate TFs for ANKRD26 . Together with three public TF databases, we found that GATA2 was the only candidate gene that could positively regulate ANKRD26 . Using dual-luciferase reporter experiments, we showed that GATA2 directly binds to the 5'-UTR of ANKRD26 and promotes its transcription. There are two identified binding sites of GATA2 that are located 2 kb upstream of the TSS of ANKRD26 . In addition, we discovered that high ANKRD26 expression is always related to a more favorable prognosis in breast and lung cancer patients., Conclusion: We first discovered that the transcription factor GATA2 plays a positive role in ANKRD26 transcription and identified its precise binding sites at the promoter region, and we revealed the importance of ANKRD26 in many tissue-derived cancers., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Silent information regulator type-1 (SIRT1), a nicotinamide adenine dinucleotide + -dependent deacetylase, is a member of the sirtuins family and has unique protein deacetylase activity. SIRT1 participates in physiological as well as pathophysiological processes by targeting a wide range of protein substrates and signalings. In this review, we described the latest progress of SIRT1 in pulmonary diseases. We have introduced the basic information and summarized the prominent role of SIRT1 in several lung diseases, such as acute lung injury, acute respiratory distress syndrome, chronic obstructive pulmonary disease, lung cancer, and aging-related diseases., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Immunotherapy has enhanced breast cancer outcomes, but optimizing combination therapies is crucial. Integrating additional treatment modalities, like physical therapies, holds promise for optimizing efficacy. Pan et al. recently reported that combining preoperative immunotherapy with microwave ablation is safe and feasible in early-stage breast cancer, effectively sensitizing peripheral CD8 + T cells. 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Extensive exploration of the molecular subtypes of triple-negative breast cancer (TNBC) is critical for advancing precision medicine. Notably, the luminal androgen receptor (LAR) subtype has attracted attention for targeted treatment combining androgen receptor antagonists and CDK4/6 inhibitors. Unfortunately, this strategy has proven to be of limited efficacy, highlighting the need for further optimization. Using our center's comprehensive multiomics dataset (n = 465), we identified novel therapeutic targets and evaluated their efficacy through multiple models, including in vitro LAR cell lines, in vivo cell-derived allograft models and ex vivo patient-derived organoids. Moreover, we conducted flow cytometry and RNA-seq analysis to unveil potential mechanisms underlying the regulation of tumor progression by these therapeutic strategies. LAR breast cancer cells exhibited sensitivity to chidamide and enzalutamide individually, with a drug combination assay revealing their synergistic effect. Crucially, this synergistic effect was verified through in vivo allograft models and patient-derived organoids. Furthermore, transcriptomic analysis demonstrated that the combination therapeutic strategy could inhibit tumor progression by regulating metabolism and autophagy. This study confirmed that the combination of histone deacetylase (HDAC) inhibitors and androgen receptor (AR) antagonists possessed greater therapeutic efficacy than monotherapy in LAR TNBC. This finding significantly bolsters the theoretical basis for the clinical translation of this combination therapy and provides an innovative strategy for the targeted treatment of LAR TNBC., (© 2024. The Author(s).)

Co-occurrence and mutual exclusivity of genomic alterations may reflect the existence of genetic interactions, potentially shaping distinct biological phenotypes and impacting therapeutic response in breast cancer. However, our understanding of them remains limited. Herein, we investigate a large-scale multi-omics cohort (n = 873) and a real-world clinical sequencing cohort (n = 4,405) including several clinical trials with detailed treatment outcomes and perform functional validation in patient-derived organoids, tumor fragments, and in vivo models. Through this comprehensive approach, we construct a network comprising co-alterations and mutually exclusive events and characterize their therapeutic potential and underlying biological basis. Notably, we identify associations between TP53 mut -AURKA amp and endocrine therapy resistance, germline BRCA1 mut -MYC amp and improved sensitivity to PARP inhibitors, and TP53 mut -MYB amp and immunotherapy resistance. Furthermore, we reveal that precision treatment strategies informed by co-alterations hold promise to improve patient outcomes. Our study highlights the significance of genetic interactions in guiding genome-informed treatment decisions beyond single driver alterations., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Molecular profiling guides precision treatment of breast cancer; however, Asian patients are underrepresented in publicly available large-scale studies. We established a comprehensive multiomics cohort of 773 Chinese patients with breast cancer and systematically analyzed their genomic, transcriptomic, proteomic, metabolomic, radiomic and digital pathology characteristics. Here we show that compared to breast cancers in white individuals, Asian individuals had more targetable AKT1 mutations. Integrated analysis revealed a higher proportion of HER2-enriched subtype and correspondingly more frequent ERBB2 amplification and higher HER2 protein abundance in the Chinese HR + HER2 + cohort, stressing anti-HER2 therapy for these individuals. Furthermore, comprehensive metabolomic and proteomic analyses revealed ferroptosis as a potential therapeutic target for basal-like tumors. The integration of clinical, transcriptomic, metabolomic, radiomic and pathological features allowed for efficient stratification of patients into groups with varying recurrence risks. Our study provides a public resource and new insights into the biology and ancestry specificity of breast cancer in the Asian population, offering potential for further precision treatment approaches., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Breast cancer is a highly heterogeneous disease with varied subtypes, prognoses and therapeutic responsiveness. Human leukocyte antigen class I (HLA-I) shapes the immunity and thereby influences the outcome of breast cancer. However, the implications of HLA-I variations in breast cancer remain poorly understood. In this study, we established a multiomics cohort of 1156 Chinese breast cancer patients for HLA-I investigation. We calculated four important HLA-I indicators in each individual, including HLA-I expression level, somatic HLA-I loss of heterozygosity (LOH), HLA-I evolutionary divergence (HED) and peptide-binding promiscuity (Pr). Then, we evaluated their distribution and prognostic significance in breast cancer subtypes. We found that the four breast cancer subtypes had distinct features of HLA-I indicators. Increased expression of HLA-I and LOH were enriched in triple-negative breast cancer (TNBC), while Pr was relatively higher in hot tumors within TNBCs. In particular, a higher Pr indicated a better prognosis in TNBCs by regulating the infiltration of immune cells and the expression of immune molecules. Using the matched genomic and transcriptomic data, we found that mismatch repair deficiency-related mutational signature and pathways were enriched in low-Pr TNBCs, suggesting that targeting mismatch repair deficiency for synthetic lethality might be promising therapy for these patients. In conclusion, we presented an overview of HLA-I indicators in breast cancer and provided hints for precision treatment for low-Pr TNBCs., (© The Author(s) 2024. Published by Oxford University Press.)

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited effective therapeutic options readily available. We have previously demonstrated that lovastatin, an FDA-approved lipid-lowering drug, selectively inhibits the stemness properties of TNBC. However, the intracellular targets of lovastatin in TNBC remain largely unknown. Here, we unexpectedly uncovered ribosome biogenesis as the predominant pathway targeted by lovastatin in TNBC. Lovastatin induced the translocation of ribosome biogenesis-related proteins including nucleophosmin (NPM), nucleolar and coiled-body phosphoprotein 1 (NOLC1), and the ribosomal protein RPL3. Lovastatin also suppressed the transcript levels of rRNAs and increased the nuclear protein level and transcriptional activity of p53, a master mediator of nucleolar stress. A prognostic model generated from 10 ribosome biogenesis-related genes showed outstanding performance in predicting the survival of TNBC patients. Mitochondrial ribosomal protein S27 (MRPS27), the top-ranked risky model gene, was highly expressed and correlated with tumor stage and lymph node involvement in TNBC. Mechanistically, MRPS27 knockdown inhibited the stemness properties and the malignant phenotypes of TNBC. Overexpression of MRPS27 attenuated the stemness-inhibitory effect of lovastatin in TNBC cells. Our findings reveal that dysregulated ribosome biogenesis is a targetable vulnerability and targeting MRPS27 could be a novel therapeutic strategy for TNBC patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Diet, serving as a vital source of nutrients, exerts a profound influence on human health and disease progression. Recently, dietary interventions have emerged as promising adjunctive treatment strategies not only for cancer but also for neurodegenerative diseases, autoimmune diseases, cardiovascular diseases, and metabolic disorders. These interventions have demonstrated substantial potential in modulating metabolism, disease trajectory, and therapeutic responses. Metabolic reprogramming is a hallmark of malignant progression, and a deeper understanding of this phenomenon in tumors and its effects on immune regulation is a significant challenge that impedes cancer eradication. Dietary intake, as a key environmental factor, can influence tumor metabolism. Emerging evidence indicates that dietary interventions might affect the nutrient availability in tumors, thereby increasing the efficacy of cancer treatments. However, the intricate interplay between dietary interventions and the pathogenesis of cancer and other diseases is complex. Despite encouraging results, the mechanisms underlying diet-based therapeutic strategies remain largely unexplored, often resulting in underutilization in disease management. In this review, we aim to illuminate the potential effects of various dietary interventions, including calorie restriction, fasting-mimicking diet, ketogenic diet, protein restriction diet, high-salt diet, high-fat diet, and high-fiber diet, on cancer and the aforementioned diseases. We explore the multifaceted impacts of these dietary interventions, encompassing their immunomodulatory effects, other biological impacts, and underlying molecular mechanisms. This review offers valuable insights into the potential application of these dietary interventions as adjunctive therapies in disease management., (© 2024. The Author(s).)

Background: Triple-negative breast cancers display heterogeneity in molecular drivers and immune traits. We previously classified triple-negative breast cancers into four subtypes: luminal androgen receptor (LAR), immunomodulatory, basal-like immune-suppressed (BLIS), and mesenchymal-like (MES). Here, we aimed to evaluate the efficacy and safety of subtyping-based therapy in the first-line treatment of triple-negative breast cancer., Methods: FUTURE-SUPER is an ongoing, open-label, randomised, controlled phase 2 trial being conducted at Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China. Eligible participants were females aged 18-70 years, with an Eastern Cooperative Oncology Group performance status of 0-1, and histologically confirmed, untreated metastatic or recurrent triple-negative breast cancer. After categorising participants into five cohorts according to molecular subtype and genomic biomarkers, participants were randomly assigned (1:1) with a block size of 4, stratified by subtype, to receive, in 28-day cycles, nab-paclitaxel (100 mg/m 2 , intravenously on days 1, 8, and 15) alone (control group) or with a subtyping-based regimen (subtyping-based group): pyrotinib (400 mg orally daily) for the LAR-HER2 mut subtype, everolimus (10 mg orally daily) for the LAR-PI3K/AKT mut and MES-PI3K/AKT mut subtypes, camrelizumab (200 mg intravenously on days 1 and 15) and famitinib (20 mg orally daily) for the immunomodulatory subtype, and bevacizumab (10 mg/kg intravenously on days 1 and 15) for the BLIS/MES-PI3K/AKT WT subtype. The primary endpoint was investigator-assessed progression-free survival for the pooled subtyping-based group versus the control group in the intention-to-treat population (all randomly assigned participants). Safety was analysed in all patients with safety records who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT04395989)., Findings: Between July 28, 2020, and Oct 16, 2022, 139 female participants were enrolled and randomly assigned to the subtyping-based group (n=69) or control group (n=70). At the data cutoff (May 31, 2023), the median follow-up was 22·5 months (IQR 15·2-29·0). Median progression-free survival was significantly longer in the pooled subtyping-based group (11·3 months [95% CI 8·6-15·2]) than in the control group (5·8 months [4·0-6·7]; hazard ratio 0·44 [95% CI 0·30-0·65]; p<0·0001). The most common grade 3-4 treatment-related adverse events were neutropenia (21 [30%] of 69 in the pooled subtyping-based group vs 16 [23%] of 70 in the control group), anaemia (five [7%] vs none), and increased alanine aminotransferase (four [6%] vs one [1%]). Treatment-related serious adverse events were reported for seven (10%) of 69 patients in the subtyping-based group and none in the control group. No treatment-related deaths were reported in either group., Interpretation: These findings highlight the potential clinical benefits of using molecular subtype-based treatment optimisation in patients with triple-negative breast cancer, suggesting a path for further clinical investigation. Phase 3 randomised clinical trials assessing the efficacy of subtyping-based regimens are now underway., Funding: National Natural Science Foundation of China, Natural Science Foundation of Shanghai, Shanghai Hospital Development Center, and Jiangsu Hengrui Pharmaceuticals., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests Y Xia and QL are employees of Jiangsu Hengrui Pharmaceuticals. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis. TNBCs with high homologous recombination deficiency (HRD) scores benefit from DNA-damaging agents, including platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, whereas those with low HRD scores still lack therapeutic options. Therefore, we sought to exploit metabolic alterations to induce HRD and sensitize DNA-damaging agents in TNBCs with low HRD scores. We systematically analyzed TNBC metabolomics and identified a metabolite, guanosine diphosphate (GDP)-mannose (GDP-M), that impeded homologous recombination repair (HRR). Mechanistically, the low expression of the upstream enzyme GDP-mannose-pyrophosphorylase-A (GMPPA) led to the endogenous up-regulation of GDP-M in TNBC. The accumulation of GDP-M in tumor cells further reduced the interaction between breast cancer susceptibility gene 2 (BRCA2) and ubiquitin-specific peptidase 21 (USP21), which promoted the ubiquitin-mediated degradation of BRCA2 to inhibit HRR. Therapeutically, we illustrated that the supplementation of GDP-M sensitized DNA-damaging agents to impair tumor growth in both in vitro (cancer cell line and patient-derived organoid) and in vivo (xenograft in immunodeficient mouse) models. Moreover, the combination of GDP-M with DNA-damaging agents activated STING-dependent antitumor immunity in immunocompetent syngeneic mouse models. Therefore, GDP-M supplementation combined with PARP inhibition augmented the efficacy of anti-PD-1 antibodies. Together, these findings suggest that GDP-M is a crucial HRD-related metabolite and propose a promising therapeutic strategy for TNBCs with low HRD scores using the combination of GDP-M, PARP inhibitors, and anti-PD-1 immunotherapy.

Biomarker discovery is essential for the understanding, diagnosis, targeted therapy and prognosis assessment of malignant diseases. However, it remains a huge challenge due to the lack of sensitive methods to identify disease-specific rare molecules. Here we present MORAC, molecular recognition based on affinity and catalysis, which enables the effective identification of candidate biomarkers with low abundance. MORAC relies on a class of DNAzymes, each cleaving a sole RNA linkage embedded in their DNA chain upon specifically sensing a complex system with no prior knowledge of the system's molecular content. We show that signal amplification from catalysis ensures the DNAzymes high sensitivity (for target probing); meanwhile, a simple RNA-to-DNA mutation can shut down their RNA cleavage ability and turn them into a pure affinity tool (for target pulldown). Using MORAC, we identify previously unknown, low-abundance candidate biomarkers with clear clinical value, including apolipoprotein L6 in breast cancer and seryl-tRNA synthetase 1 in polyps preceding colon cancer., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Triple-negative breast cancer (TNBC) is an aggressive disease characterized by remarkable intratumor heterogeneity (ITH), which poses therapeutic challenges. However, the clinical relevance and key determinant of ITH in TNBC are poorly understood. Here, we comprehensively characterized ITH levels using multi-omics data across our center's cohort (n = 260), The Cancer Genome Atlas cohort (n = 134), and four immunotherapy-treated cohorts (n = 109). Our results revealed that high ITH was associated with poor patient survival and immunotherapy resistance. Importantly, we identified zinc finger protein 689 (ZNF689) deficiency as a crucial determinant of ITH formation. Mechanistically, the ZNF689-TRIM28 complex was found to directly bind to the promoter of long interspersed element-1 (LINE-1), inducing H3K9me3-mediated transcriptional silencing. ZNF689 deficiency reactivated LINE-1 retrotransposition to exacerbate genomic instability, which fostered ITH. Single-cell RNA sequencing, spatially resolved transcriptomics and flow cytometry analysis confirmed that ZNF689 deficiency-induced ITH inhibited antigen presentation and T-cell activation, conferring immunotherapy resistance. Pharmacological inhibition of LINE-1 significantly reduced ITH, enhanced antitumor immunity, and eventually sensitized ZNF689-deficient tumors to immunotherapy in vivo. Consistently, ZNF689 expression positively correlated with favorable prognosis and immunotherapy response in clinical samples. Altogether, our study uncovers a previously unrecognized mechanism underlying ZNF689 deficiency-induced ITH and suggests LINE-1 inhibition combined with immunotherapy as a novel treatment strategy for TNBC., (© 2023. The Author(s) under exclusive licence to Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences.)

Germline-somatic mutation interactions are universal and associated with tumorigenesis, but their role in breast cancer, especially in non-Caucasians, remains poorly characterized. We performed large-scale prospective targeted sequencing of matched tumor-blood samples from 4079 Chinese females, coupled with detailed clinical annotation, to map interactions between germline and somatic alterations. We discovered 368 pathogenic germline variants and identified 5 breast cancer DNA repair-associated genes (BCDGs; BRCA1/BRCA2/CHEK2/PALB2/TP53). BCDG mutation carriers, especially those with two-hit inactivation, demonstrated younger onset, higher tumor mutation burden, and greater clinical benefits from platinum drugs, PARP inhibitors, and immune checkpoint inhibitors. Furthermore, we leveraged a multiomics cohort to reveal that clinical benefits derived from two-hit events are associated with increased genome instability and an immune-activated tumor microenvironment. We also established an ethnicity-specific tool to predict BCDG mutation and two-hit status for genetic evaluation and therapeutic decisions. Overall, this study leveraged the large sequencing cohort of Chinese breast cancers, optimizing genomics-guided selection of DNA damaging-targeted therapy and immunotherapy within a broader population., (© 2023. The Author(s).)

Background: Tumor-infiltrating lymphocytes (TILs) and programmed cell death 1 ligand 1 (PD-L1) remain imperfect in predicting clinical outcomes of triple-negative breast cancer because outcomes do not always correlate with the expression of these biomarkers. Genomic and transcriptomic alterations that may contribute to the expression of these biomarkers remain incompletely uncovered., Methods: We evaluated PD-L1 immunohistochemistry scores (SP142 and 28-8 assays) and TILs in our triple-negative breast cancer multiomics dataset and 2 immunotherapy clinical trial cohorts. Then, we analyzed genomic and transcriptomic alterations correlated with TILs, PD-L1 expression, and patient outcomes., Results: Despite TILs serving as a decent predictor for triple-negative breast cancer clinical outcomes, exceptions remained. Our study revealed that several genomic alterations were correlated with unexpected events. In particular, PD-L1 expression may cause a paradoxical relationship between TILs and prognosis in certain patients. Consequently, we classified triple-negative breast cancers into 4 groups based on PD-L1 and TIL levels. The TIL-negative PD-L1-positive and TIL-positive PD-L1-negative groups were not typical "hot" tumors; both were associated with worse prognoses and lower immunotherapy efficacy than TIL-positive PD-L1-positive tumors. Copy number variation of PD-L1 and oncogenic signaling activation were correlated with PD-L1 expression in the TIL-negative PD-L1-positive group, whereas GSK3B-induced degradation may cause undetectable PD-L1 expression in the TIL-positive PD-L1-negative group. These factors have the potential to affect the predictive function of both PD-L1 and TILs., Conclusions: Several genomic and transcriptomic alterations may cause paradoxical effects among TILs, PD-L1 expression, and prognosis in triple-negative breast cancer. Investigating and targeting these factors will advance precision immunotherapy for patients with this disease., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Fork reversal is a conserved mechanism to prevent stalled replication forks from collapsing. Formation and protection of reversed forks are two crucial steps in ensuring fork integrity and stability. Five RAD51 paralogs, namely, RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3, which share sequence and structural similarity to the recombinase RAD51, play poorly defined mechanistic roles in these processes. Here, using purified BCDX2 (RAD51BCD-XRCC2) and CX3 (RAD51C-XRCC3) complexes and in vitro reconstituted biochemical systems, we mechanistically dissect their functions in forming and protecting reversed forks. We show that both RAD51 paralog complexes lack fork reversal activities. Whereas CX3 exhibits modest fork protection activity, BCDX2 significantly synergizes with RAD51 to protect DNA against attack by the nucleases MRE11 and EXO1. DNA protection is contingent upon the ability of RAD51 to form a functional nucleoprotein filament on DNA. Collectively, our results provide evidence for a hitherto unknown function of RAD51 paralogs in synergizing with RAD51 nucleoprotein filament to prevent degradation of stressed replication forks., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)