Liaoning Cancer Hospital & Institute

BACKGROUND: Among breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these "HER2-low" cancers. METHODS: We conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor-positive cohort. The key secondary end points were progression-free survival among all patients and overall survival in the hormone receptor-positive cohort and among all patients. RESULTS: Of 557 patients who underwent randomization, 494 (88.7%) had hormone receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease. In the hormone receptor-positive cohort, the median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician's choice group (hazard ratio for disease progression or death, 0.51; P<0.001), and overall survival was 23.9 months and 17.5 months, respectively (hazard ratio for death, 0.64; P = 0.003). Among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician's choice group (hazard ratio for disease progression or death, 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P = 0.001). Adverse events of grade 3 or higher occurred in 52.6% of the patients who received trastuzumab deruxtecan and 67.4% of those who received the physician's choice of chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events. CONCLUSIONS: In this trial involving patients with HER2-low metastatic breast cancer, trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician's choice of chemotherapy. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast04 ClinicalTrials.gov number, NCT03734029.).

Reactive oxygen species (ROS) serve as cell signaling molecules generated in oxidative metabolism and are associated with a number of human diseases. The reprogramming of redox metabolism induces abnormal accumulation of ROS in cancer cells. It has been widely accepted that ROS play opposite roles in tumor growth, metastasis and apoptosis according to their different distributions, concentrations and durations in specific subcellular structures. These double-edged roles in cancer progression include the ROS-dependent malignant transformation and the oxidative stress-induced cell death. In this review, we summarize the notable literatures on ROS generation and scavenging, and discuss the related signal transduction networks and corresponding anticancer therapies. There is no doubt that an improved understanding of the sophisticated mechanism of redox biology is imperative to conquer cancer.

BACKGROUND: Cancer is the most prevalent cause of death globally, and radiotherapy is considered the standard of care for most solid tumors, including lung, breast, esophageal, and colorectal cancers and glioblastoma. Resistance to radiation can lead to local treatment failure and even cancer recurrence. MAIN BODY: In this review, we have extensively discussed several crucial aspects that cause resistance of cancer to radiation therapy, including radiation-induced DNA damage repair, cell cycle arrest, apoptosis escape, abundance of cancer stem cells, modification of cancer cells and their microenvironment, presence of exosomal and non-coding RNA, metabolic reprogramming, and ferroptosis. We aim to focus on the molecular mechanisms of cancer radiotherapy resistance in relation to these aspects and to discuss possible targets to improve treatment outcomes. CONCLUSIONS: Studying the molecular mechanisms responsible for radiotherapy resistance and its interactions with the tumor environment will help improve cancer responses to radiotherapy. Our review provides a foundation to identify and overcome the obstacles to effective radiotherapy.

Disulfide bonds have been widely used to develop reduction-responsive drug-delivery systems (DDS) for cancer therapy. We propose that disulfide bonds might be also used as an oxidation-responsive linkage just like thioether bonds, which can be oxidized to hydrophilic sulfoxide or sulphone in the presence of oxidation stimuli. To test our hypothesis, we design three novel paclitaxel-citronellol conjugates linked via different lengths of disulfide-bond-containing carbon chain. The prodrugs can self-assemble into uniform-size nanoparticles with impressively high drug loading (>55%). As expected, the disulfide-bond-bridged prodrug nanoparticles show redox dual-responsive drug release. More interestingly, the position of disulfide bonds in the carbon chain linkage has profound impacts on the redox dual responsiveness, thereby affecting the drug release, cytotoxicity, pharmacokinetics, biodistribution, and in vivo antitumor efficacy of prodrug nanoassemblies. The redox dual-responsive mechanism is elucidated, and how the position of disulfide bonds in the carbon chain affects the redox dual responsiveness and antitumor efficiency of prodrug nanoassemblies is also clarified. Our findings give new insight into the stimuli responsiveness of disulfide bonds and provide a good foundation for the development of novel redox dual-responsive DDS for cancer therapy.

AIMS: Baicalin (BAI), a flavonoid compound isolated from the root of Scutellaria baicalensis Georgi, has been established to have potent anti-inflammation and neuroprotective properties; however, its effects during Alzheimer's disease (AD) treatment have not been well studied. This study aimed to investigate the effects of BAI pretreatment on cognitive impairment and neuronal protection against microglia-induced neuroinflammation and to explore the mechanisms underlying its anti-inflammation effects. METHODS: To determine whether BAI plays a positive role in ameliorating the memory and cognition deficits in APP (amyloid beta precursor protein)/PS1 (presenilin-1) mice, behavioral experiments were conducted. We assessed the effects of BAI on microglial activation, the production of proinflammatory cytokines, and neuroinflammation-mediated neuron apoptosis in vivo and in vitro using Western blot, RT-PCR, ELISA, immunohistochemistry, and immunofluorescence. Finally, to elucidate the anti-inflammation mechanisms underlying the effects of BAI, the protein expression of NLRP3 inflammasomes and the expression of proteins involved in the TLR4/NF-κB signaling pathway were measured using Western blot and immunofluorescence. RESULTS: The results indicated that BAI treatment attenuated spatial memory dysfunction in APP/PS1 mice, as assessed by the passive avoidance test and the Morris water maze test. Additionally, BAI administration effectively decreased the number of activated microglia and proinflammatory cytokines, as well as neuroinflammation-mediated neuron apoptosis, in APP/PS1 mice and LPS (lipopolysaccharides)/Aβ-stimulated BV2 microglial cells. Lastly, the molecular mechanistic study revealed that BAI inhibited microglia-induced neuroinflammation via suppression of the activation of NLRP3 inflammasomes and the TLR4/NF-κB signaling pathway. CONCLUSION: Overall, the results of the present study indicated that BAI is a promising neuroprotective compound for use in the prevention and treatment of microglia-mediated neuroinflammation during AD progression.

Importance: Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective: To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions: Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. Main Outcomes and Measures: The primary end point was overall survival time from randomization. Results: Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Conclusions and Relevance: Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03745170.

BACKGROUND: For more than three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has provided a framework to quantify health loss due to diseases, injuries, and associated risk factors. This paper presents GBD 2023 findings on disease and injury burden and risk-attributable health loss, offering a global audit of the state of world health to inform public health priorities. This work captures the evolving landscape of health metrics across age groups, sexes, and locations, while reflecting on the remaining post-COVID-19 challenges to achieving our collective global health ambitions. METHODS: The GBD 2023 combined analysis estimated years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 375 diseases and injuries, and risk-attributable burden associated with 88 modifiable risk factors. Of the more than 310 000 total data sources used for all GBD 2023 (about 30% of which were new to this estimation round), more than 120 000 sources were used for estimation of disease and injury burden and 59 000 for risk factor estimation, and included vital registration systems, surveys, disease registries, and published scientific literature. Data were analysed using previously established modelling approaches, such as disease modelling meta-regression version 2.1 (DisMod-MR 2.1) and comparative risk assessment methods. Diseases and injuries were categorised into four levels on the basis of the established GBD cause hierarchy, as were risk factors using the GBD risk hierarchy. Estimates stratified by age, sex, location, and year from 1990 to 2023 were focused on disease-specific time trends over the 2010-23 period and presented as counts (to three significant figures) and age-standardised rates per 100 000 person-years (to one decimal place). For each measure, 95% uncertainty intervals [UIs] were calculated with the 2·5th and 97·5th percentile ordered values from a 250-draw distribution. FINDINGS: Total numbers of global DALYs grew 6·1% (95% UI 4·0-8·1), from 2·64 billion (2·46-2·86) in 2010 to 2·80 billion (2·57-3·08) in 2023, but age-standardised DALY rates, which account for population growth and ageing, decreased by 12·6% (11·0-14·1), revealing large long-term health improvements. Non-communicable diseases (NCDs) contributed 1·45 billion (1·31-1·61) global DALYs in 2010, increasing to 1·80 billion (1·63-2·03) in 2023, alongside a concurrent 4·1% (1·9-6·3) reduction in age-standardised rates. Based on DALY counts, the leading level 3 NCDs in 2023 were ischaemic heart disease (193 million [176-209] DALYs), stroke (157 million [141-172]), and diabetes (90·2 million [75·2-107]), with the largest increases in age-standardised rates since 2010 occurring for anxiety disorders (62·8% [34·0-107·5]), depressive disorders (26·3% [11·6-42·9]), and diabetes (14·9% [7·5-25·6]). Remarkable health gains were made for communicable, maternal, neonatal, and nutritional (CMNN) diseases, with DALYs falling from 874 million (837-917) in 2010 to 681 million (642-736) in 2023, and a 25·8% (22·6-28·7) reduction in age-standardised DALY rates. During the COVID-19 pandemic, DALYs due to CMNN diseases rose but returned to pre-pandemic levels by 2023. From 2010 to 2023, decreases in age-standardised rates for CMNN diseases were led by rate decreases of 49·1% (32·7-61·0) for diarrhoeal diseases, 42·9% (38·0-48·0) for HIV/AIDS, and 42·2% (23·6-56·6) for tuberculosis. Neonatal disorders and lower respiratory infections remained the leading level 3 CMNN causes globally in 2023, although both showed notable rate decreases from 2010, declining by 16·5% (10·6-22·0) and 24·8% (7·4-36·7), respectively. Injury-related age-standardised DALY rates decreased by 15·6% (10·7-19·8) over the same period. Differences in burden due to NCDs, CMNN diseases, and injuries persisted across age, sex, time, and location. Based on our risk analysis, nearly 50% (1·27 billion [1·18-1·38]) of the roughly 2·80 billion total global DALYs in 2023 were attributable to the 88 risk factors analysed in GBD. Globally, the five level 3 risk factors contributing the highest proportion of risk-attributable DALYs were high systolic blood pressure (SBP), particulate matter pollution, high fasting plasma glucose (FPG), smoking, and low birthweight and short gestation-with high SBP accounting for 8·4% (6·9-10·0) of total DALYs. Of the three overarching level 1 GBD risk factor categories-behavioural, metabolic, and environmental and occupational-risk-attributable DALYs rose between 2010 and 2023 only for metabolic risks, increasing by 30·7% (24·8-37·3); however, age-standardised DALY rates attributable to metabolic risks decreased by 6·7% (2·0-11·0) over the same period. For all but three of the 25 leading level 3 risk factors, age-standardised rates dropped between 2010 and 2023-eg, declining by 54·4% (38·7-65·3) for unsafe sanitation, 50·5% (33·3-63·1) for unsafe water source, and 45·2% (25·6-72·0) for no access to handwashing facility, and by 44·9% (37·3-53·5) for child growth failure. The three leading level 3 risk factors for which age-standardised attributable DALY rates rose were high BMI (10·5% [0·1 to 20·9]), drug use (8·4% [2·6 to 15·3]), and high FPG (6·2% [-2·7 to 15·6]; non-significant). INTERPRETATION: Our findings underscore the complex and dynamic nature of global health challenges. Since 2010, there have been large decreases in burden due to CMNN diseases and many environmental and behavioural risk factors, juxtaposed with sizeable increases in DALYs attributable to metabolic risk factors and NCDs in growing and ageing populations. This long-observed consequence of the global epidemiological transition was only temporarily interrupted by the COVID-19 pandemic. The substantially decreasing CMNN disease burden, despite the 2008 global financial crisis and pandemic-related disruptions, is one of the greatest collective public health successes known. However, these achievements are at risk of being reversed due to major cuts to development assistance for health globally, the effects of which will hit low-income countries with high burden the hardest. Without sustained investment in evidence-based interventions and policies, progress could stall or reverse, leading to widespread human costs and geopolitical instability. Moreover, the rising NCD burden necessitates intensified efforts to mitigate exposure to leading risk factors-eg, air pollution, smoking, and metabolic risks, such as high SBP, BMI, and FPG-including policies that promote food security, healthier diets, physical activity, and equitable and expanded access to potential treatments, such as GLP-1 receptor agonists. Decisive, coordinated action is needed to address long-standing yet growing health challenges, including depressive and anxiety disorders. Yet this can be only part of the solution. Our response to the NCD syndemic-the complex interaction of multiple health risks, social determinants, and systemic challenges-will define the future landscape of global health. To ensure human wellbeing, economic stability, and social equity, global action to sustain and advance health gains must prioritise reducing disparities by addressing socioeconomic and demographic determinants, ensuring equitable health-care access, tackling malnutrition, strengthening health systems, and improving vaccination coverage. We live in times of great opportunity. FUNDING: Gates Foundation and Bloomberg Philanthropies.

Abstract Purpose: The prognosis for patients with refractory soft-tissue sarcoma (STS) is dismal. Anlotinib has previously shown antitumor activity on STS in preclinical and phase I studies. Patients and Methods: Patients 18 years and older, progressing after anthracycline-based chemotherapy, naïve from angiogenesis inhibitors, with at least one measurable lesion according to RECIST 1.1, were enrolled. The main subtypes eligible were undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), leiomyosarcoma (LMS), synovial sarcoma (SS), fibrosarcoma (FS), alveolar soft-part sarcoma (ASPS), and clear cell sarcoma (CCS). Participants were treated with anlotinib. The primary endpoint was progression-free rate at 12 weeks (PFR12 weeks). Results: A total of 166 patients were included in the final analysis. Overall, the PFR12 weeks was 68%, and objective response rate was 13% (95% confidence interval, 7.6%–18%). The median progression-free survival (PFS) and overall survival (OS) were 5.6 and 12 months, respectively. The PFR12 weeks, median PFS and OS were: 58%, 4.1 and 11 months for UPS (n = 19); 63%, 5.6 and 13 months for LPS (n = 13); 75%, 11 and 15 months for LMS (n = 26); 75%, 7.7 and 12 months for SS (n = 47); 81%, 5.6 and 12 months for FS (n = 18); 77%, 21 and not reached for ASPS (n = 13); 54%, 11 and 16 months for CCS (n = 7); and 44%, 2.8 and 8.8 months for other sarcoma (n = 23), respectively. The most common clinically significant grade 3 or higher adverse events were hypertension (4.8%), triglyceride elevation (3.6%), and pneumothorax (2.4%). No treatment-related death occurred. Conclusions: Anlotinib showed antitumor activity in several STS entities. The toxicity was manageable. Clin Cancer Res; 24(21); 5233–8. ©2018 AACR.

N6-Methyladenosine (m6A) is the most common posttranscriptional modification of RNA and plays critical roles in cancer pathogenesis. However, the biological function of long noncoding RNA (lncRNA) methylation remains unclear. As a demethylase, ALKBH5 (alkylation repair homolog protein 5) is involved in mediating methylation reversal. The purpose of this study was to investigate lncRNA m6A modification and its role in gastric cancer (GC). Bioinformatics predicted interactions of ALKBH5 with lncRNAs. Five methods were employed to assess the function of nuclear paraspeckle assembly transcript 1 (NEAT1), including gene silencing, RT-PCR, separation of nuclear and cytoplasmic fractions, scrape motility assays, and transwell migration assays. Then, m6A RNA immunoprecipitation and immunofluorescence were used to detect methylated NEAT1 in GC cells. Rescue assays were performed to define the relationship between NEAT1 and ALKBH5. NEAT1 is a potential binding lncRNA of ALKBH5. NEAT1 was overexpressed in GC cells and tissue. Additional experiments confirmed that knockdown of NEAT1 significantly repressed invasion and metastasis of GC cells. ALKBH5 affected the m6A level of NEAT1. The binding of ALKBH5 and NEAT1 influences the expression of EZH2 (a subunit of the polycomb repressive complex) and thus affects GC invasion and metastasis. Our findings indicate a novel mechanism by which ALKBH5 promotes GC invasion and metastasis by demethylating the lncRNA NEAT1. They may be potential therapeutic targets for GC.

Tumor cells are characterized as redox-heterogeneous intracellular microenvironment due to the simultaneous overproduction of reactive oxygen species and glutathione. Rational design of redox-responsive drug delivery systems is a promising prospect for efficient cancer therapy. Herein, six paclitaxel-citronellol conjugates are synthesized using either thioether bond, disulfide bond, selenoether bond, diselenide bond, carbon bond or carbon-carbon bond as linkages. These prodrugs can self-assemble into uniform nanoparticles with ultrahigh drug-loading capacity. Interestingly, sulfur/selenium/carbon bonds significantly affect the efficiency of prodrug nanoassemblies. The bond angles/dihedral angles impact the self-assembly, stability and pharmacokinetics. The redox-responsivity of sulfur/selenium/carbon bonds has remarkable influence on drug release and cytotoxicity. Moreover, selenoether/diselenide bond possess unique ability to produce reactive oxygen species, which further improve the cytotoxicity of these prodrugs. Our findings give deep insight into the impact of chemical linkages on prodrug nanoassemblies and provide strategies to the rational design of redox-responsive drug delivery systems for cancer therapy.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) constitutes a public health emergency globally. The number of infected people and deaths are proliferating every day, which is putting tremendous pressure on our social and healthcare system. Rapid detection of COVID-19 cases is a significant step to fight against this virus as well as release pressure off the healthcare system. OBJECTIVE: One of the critical factors behind the rapid spread of COVID-19 pandemic is a lengthy clinical testing time. The imaging tool, such as Chest X-ray (CXR), can speed up the identification process. Therefore, our objective is to develop an automated CAD system for the detection of COVID-19 samples from healthy and pneumonia cases using CXR images. METHODS: Due to the scarcity of the COVID-19 benchmark dataset, we have employed deep transfer learning techniques, where we examined 15 different pre-trained CNN models to find the most suitable one for this task. RESULTS: A total of 860 images (260 COVID-19 cases, 300 healthy and 300 pneumonia cases) have been employed to investigate the performance of the proposed algorithm, where 70% images of each class are accepted for training, 15% is used for validation, and rest is for testing. It is observed that the VGG19 obtains the highest classification accuracy of 89.3% with an average precision, recall, and F1 score of 0.90, 0.89, 0.90, respectively. CONCLUSION: This study demonstrates the effectiveness of deep transfer learning techniques for the identification of COVID-19 cases using CXR images.

, cancer and bacterial infection) has recently attracted increased research attention, which is significantly important for the construction of molecular libraries for diagnostic and therapeutic integration. However, reviews focusing on integrated design strategies for rhodamine dye-based diagnosis and treatment and their wide application in disease treatment are extremely rare. In this review, first, a brief history of the development of rhodamine fluorescent dyes, the transformation of rhodamine fluorescent dyes from bioimaging to disease therapy, and the concept of optics-based diagnosis and treatment integration and its significance to human development are presented. Next, a systematic review of several excellent rhodamine-based derivatives for bioimaging, as well as for disease diagnosis and treatment, is presented. Finally, the challenges in practical integration of rhodamine-based diagnostic and treatment dyes and the future outlook of clinical translation are also discussed.

PURPOSE Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor approved in China. This double-blind phase III trial evaluated the efficacy and safety of aumolertinib compared with gefitinib as a first-line treatment for locally advanced or metastatic EGFR-mutated non–small-cell lung cancer (NSCLC; ClinicalTrials.gov identifier: NCT03849768 ). METHODS Patients at 53 sites in China were randomly assigned 1:1 to receive either aumolertinib (110 mg) or gefitinib (250 mg) once daily. The primary end point was progression-free survival (PFS) per investigator assessment. RESULTS A total of 429 patients who were naïve to treatment for locally advanced or metastatic NSCLC were enrolled. PFS was significantly longer with aumolertinib compared with gefitinib (hazard ratio, 0.46; 95% CI, 0.36 to 0.60; P &lt; .0001). The median PFS with aumolertinib was 19.3 months (95% CI, 17.8 to 20.8) versus 9.9 months with gefitinib (95% CI, 8.3 to 12.6). Objective response rate and disease control rate were similar in the aumolertinib and gefitinib groups (objective response rate, 73.8% and 72.1%, respectively; disease control rate, 93.0% and 96.7%, respectively). The median duration of response was 18.1 months (95% CI, 15.2 to not applicable) with aumolertinib versus 8.3 months (95% CI, 6.9 to 11.1) with gefitinib. Adverse events of grade ≥ 3 severity (any cause) were observed in 36.4% and 35.8% of patients in the aumolertinib and gefitinib groups, respectively. Rash and diarrhea (any grade) were observed in 23.4% and 16.4% of patients who received aumolertinib compared with 41.4% and 35.8% of those who received gefitinib, respectively. CONCLUSION Aumolertinib is a well-tolerated third-generation epidermal growth factor receptor tyrosine kinase inhibitor that could serve as a treatment option for EGFR-mutant NSCLC in the first-line setting.

PURPOSE: The epidermal growth factor receptor (EGFR) inhibitor gefitinib (Iressa) has shown antitumor activity in clinical trials against cancers, such as non-small cell lung cancer and head and neck squamous cell carcinoma (HNSCC). Research on non-small cell lung cancer has elucidated factors that may predict response to gefitinib. Less is known about molecular markers that may predict response to gefitinib in HNSCC patients. EXPERIMENTAL DESIGN: We analyzed possible associations of responsiveness to gefitinib with molecular markers of the EGFR/ErbB receptor family signaling pathway using 10 established HNSCC lines in vitro. IC50 of gefitinib sensitivity was determined using clonogenic survival assays. ErbB signaling was assessed by Western and real-time reverse transcription-PCR analyses of EGFR, ErbB2, ErbB3, and ErbB4 expression levels as well as by phosphorylation analysis of pEGFR, pErbB2, pErbB3, pAkt, and pErk. EGFR sequences encoding kinase domain and EGFR gene copy numbers were determined by cDNA sequencing and real-time PCR, respectively. Finally, responsiveness to gefitinib was compared with responsiveness to the anti-EGFR antibody cetuximab (Erbitux). RESULTS: Expression levels of pErbB2 (P = 0.02) and total ErbB3 protein (P = 0.02) associated with resistance to gefitinib. Combining gefitinib with pertuzumab (Omnitarg), an antibody targeting ErbB2 heterodimerization, provided additional growth-inhibitory effect over gefitinib alone on relatively gefitinib-resistant HNSCC cell lines. The same markers did not predict resistance to cetuximab. In contrast, a similar trend suggesting association between EGFR gene copy number and drug sensitivity was observed for both gefitinib (P = 0.0498) and cetuximab (P = 0.053). No activating EGFR mutations were identified. CONCLUSIONS: EGFR amplification may predict sensitivity to gefitinib in HNSCC. However, other EGFR/ErbB receptor family members than EGFR may contribute to resistance to gefitinib. ErbB2 and ErbB3 may have potential as predictive markers and as therapeutic targets for combination therapy in treatment of HNSCC with gefitinib.

PURPOSE: Mammographic breast density is an established risk marker for breast cancer and is visually assessed by radiologists in routine mammogram image reading, using four qualitative Breast Imaging and Reporting Data System (BI-RADS) breast density categories. It is particularly difficult for radiologists to consistently distinguish the two most common and most variably assigned BI-RADS categories, i.e., "scattered density" and "heterogeneously dense". The aim of this work was to investigate a deep learning-based breast density classifier to consistently distinguish these two categories, aiming at providing a potential computerized tool to assist radiologists in assigning a BI-RADS category in current clinical workflow. METHODS: In this study, we constructed a convolutional neural network (CNN)-based model coupled with a large (i.e., 22,000 images) digital mammogram imaging dataset to evaluate the classification performance between the two aforementioned breast density categories. All images were collected from a cohort of 1,427 women who underwent standard digital mammography screening from 2005 to 2016 at our institution. The truths of the density categories were based on standard clinical assessment made by board-certified breast imaging radiologists. Effects of direct training from scratch solely using digital mammogram images and transfer learning of a pretrained model on a large nonmedical imaging dataset were evaluated for the specific task of breast density classification. In order to measure the classification performance, the CNN classifier was also tested on a refined version of the mammogram image dataset by removing some potentially inaccurately labeled images. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used to measure the accuracy of the classifier. RESULTS: The AUC was 0.9421 when the CNN-model was trained from scratch on our own mammogram images, and the accuracy increased gradually along with an increased size of training samples. Using the pretrained model followed by a fine-tuning process with as few as 500 mammogram images led to an AUC of 0.9265. After removing the potentially inaccurately labeled images, AUC was increased to 0.9882 and 0.9857 for without and with the pretrained model, respectively, both significantly higher (P < 0.001) than when using the full imaging dataset. CONCLUSIONS: Our study demonstrated high classification accuracies between two difficult to distinguish breast density categories that are routinely assessed by radiologists. We anticipate that our approach will help enhance current clinical assessment of breast density and better support consistent density notification to patients in breast cancer screening.

Abstract Background Hypoxia-inducible factor 1α (HIF-1α) is essential in hepatocellular carcinoma (HCC) glycolysis and progression. Yes-associated protein (YAP) is a powerful regulator and is overexpressed in many cancers, including HCC. The regulatory mechanism of YAP and HIF-1α in HCC glycolysis is unknown. Methods We detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. The relationship between YAP mRNA expression and that of HIF-1α was analyzed using The Cancer Genome Atlas HCC tissue data. We cultured HepG2 and Huh7 HCC cells under normoxic (20% O 2 ) and hypoxic (1% O 2 ) conditions, and measured the lactate and glucose levels, migration and invasive capability, and the molecular mechanism of HCC cell glycolysis and progression. Results In this study, we detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. We observed that hypoxia-induced YAP activation is crucial for accelerating HCC cell glycolysis. Hypoxia inhibited the Hippo signaling pathway and promoted YAP nuclear localization, and decreased phosphorylated YAP expression in HCC cells. YAP knockdown inhibited HCC cell glycolysis under hypoxic. Mechanistically, hypoxic stress in the HCC cells promoted YAP binding to HIF-1α in the nucleus and sustained HIF-1α protein stability to bind to PKM2 gene and directly activates PKM2 transcription to accelerate glycolysis. Conclusions Our findings describe a new regulatory mechanism of hypoxia-mediated HCC metabolism, and YAP might be a promising therapeutic target in HCC.

The efficacy and safety of chidamide, a new subtype-selective histone deacetylase (HDAC) inhibitor, have been demonstrated in a pivotal phase II clinical trial, and chidamide has been approved by the China Food and Drug Administration (CFDA) as a treatment for relapsed or refractory peripheral T cell lymphoma (PTCL). This study sought to further evaluate the real-world utilization of chidamide in 383 relapsed or refractory PTCL patients from April 2015 to February 2016 in mainland China. For patients receiving chidamide monotherapy (n = 256), the overall response rate (ORR) and disease control rate (DCR) were 39.06 and 64.45%, respectively. The ORR and DCR were 51.18 and 74.02%, respectively, for patients receiving chidamide combined with chemotherapy (n = 127). For patients receiving chidamide monotherapy and chidamide combined with chemotherapy, the median progression-free survival (PFS) was 129 (95% CI 82 to 194) days for the monotherapy group and 152 (95% CI 93 to 201) days for the combined therapy group (P = 0.3266). Most adverse events (AEs) were of grade 1 to 2. AEs of grade 3 or higher that occurred in ≥5% of patients receiving chidamide monotherapy included thrombocytopenia (10.2%) and neutropenia (6.2%). For patients receiving chidamide combined with chemotherapy, grade 3 to 4 AEs that occurred in ≥5% of patients included thrombocytopenia (18.1%), neutropenia (12.6%), anemia (7.1%), and fatigue (5.5%). This large real-world study demonstrates that chidamide has a favorable efficacy and an acceptable safety profile for refractory and relapsed PTCL patients. Chidamide combined with chemotherapy may be a new treatment choice for refractory and relapsed PTCL patients but requires further investigation.

BACKGROUND: Accumulating evidences indicate that non-coding RNAs (ncRNAs) including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) acting as crucial regulators in osteosarcoma (OS). Previously, we reported that Rho associated coiled-coil containing protein kinase 1 (ROCK1), a metastatic-related gene was negatively regulated by microRNA-335-5p (miR-335-5p) and work as an oncogene in osteosarcoma. Whether any long non-coding RNAs participate in the upstream of miR-335-5p/ROCK1 axial remains unclear. METHODS: Expression of differentiation antagonizing non-protein coding RNA (DANCR) and miR-335-5p/miR-1972 in osteosarcoma tissues were determined by a qRT-PCR assay and an ISH assay. Osteosarcoma cells' proliferation and migration/invasion ability changes were measured by a CCK-8/EDU assay and a transwell assay respectively. ROCK1 expression changes were checked by a qRT-PCR assay and a western blot assay. Targeted binding effects between miR-335-5p/miR-1972 and ROCK1 or DANCR were verified by a dual luciferase reporter assay and a RIP assay. In vivo experiments including a nude formation assay as well as a CT scan were applied to detect tumor growth and metastasis changes in animal level. RESULTS: In the present study, an elevated DNACR was found in osteosarcoma tissue specimens and in osteosarcoma cell lines, and the elevated DNACR was closely correlated with poor prognosis in clinical patients. Functional experiments illustrated that a depression of DANCR suppressed ROCK1-mediated proliferation and metastasis in osteosarcoma cells. The results of western blot assays and qRT-PCR assays revealed that DANCR regulated ROCK1 via crosstalk with miR-335-5p and miR-1972. Further cellular behavioral experiments demonstrated that DNACR promoted ROCK1-meidated proliferation and metastasis through decoying both miR-335-5p and miR-1972. Finally, the outcomes of in vivo animal models showed that DANCR promoted tumor growth and lung metastasis of osteosarcoma. CONCLUSIONS: LncRNA DANCR work as an oncogene and promoted ROCK1-mediated proliferation and metastasis through acting as a competing endogenous RNA (ceRNA) in osteosarcoma.

The most common working mechanism of photodynamic therapy is based on high-toxicity singlet oxygen, which is called Type II photodynamic therapy. But it is highly dependent on oxygen consumption. Recently, Type I photodynamic therapy has been found to have better hypoxia tolerance to ease this restriction. However, few strategies are available on the design of Type I photosensitizers. We herein report an unexpected strategy to alleviate the limitation of traditional photodynamic therapy by biotinylation of three photosensitizers (two fluorescein-based photosensitizers and the commercially available Protoporphyrin). The three biotiylated photosensitizers named as compound 1, 2 and 3, exhibit impressive ability in generating both superoxide anion radicals and singlet oxygen. Moreover, compound 1 can be activated upon low-power white light irradiation with stronger ability of anion radicals generation than the other two. The excellent combinational Type I / Type II photodynamic therapy performance has been demonstrated with the photosensitizers 1. This work presents a universal protocol to provide tumor-targeting ability and enhance or trigger the generation of anion radicals by biotinylation of Type II photosensitizers against tumor hypoxia.

BACKGROUND: According to the very limited cancer registry, incidence and mortality rates for female breast cancer in China are regarded to be increasing especially in the metropolitan areas. Representative data on the breast cancer profile of Chinese women and its time trend over years are relatively rare. The aims of the current study are to illustrate the breast cancer profile of Chinese women in time span and to explore the current treatment approaches to female breast cancer. METHODS: This was a hospital-based nation-wide and multi-center retrospective study of female primary breast cancer cases. China was divided into 7 regions according to the geographic distribution; from each region, one tertiary hospital was selected. With the exception of January and February, one month was randomly selected to represent each year from year 1999 to 2008 at every hospital. All inpatient cases within the selected month were reviewed and related information was collected based on the designed case report form (CRF). The Cancer Hospital/Institute, Chinese Academy of Medical Sciences (CICAMS) was the leading hospital in this study. RESULTS: Four-thousand two-hundred and eleven cases were randomly selected from the total pool of 45,200 patients and were included in the analysis. The mean age at diagnosis was 48.7 years (s.d. = 10.5 yrs) and breast cancer peaked in age group 40-49 yrs (38.6%). The most common subtype was infiltrating ductal carcinoma (86.5%). Clinical stage I & II accounted for 60.6% of 4,211 patients. Three-thousand five-hundred and thirty-four cases had estrogen receptor (ER) and progestin receptor (PR) tests, among them, 47.9% were positive for both. Two-thousand eight-hundred and forty-nine cases had human epidermal growth factor receptor 2(HER-2) tests, 25.8% of them were HER-2 positive. Among all treatment options, surgery (96.9% (4,078/4,211)) was predominant, followed by chemotherapy (81.4% (3,428/4,211). Much less patients underwent radiotherapy (22.6% (952/4,211)) and endocrine therapy (38.0% (1,599/4,211)). CONCLUSIONS: The younger age of breast cancer onset among Chinese women and more advanced tumor stages pose a great challenge. Adjuvant therapy, especially radiotherapy and endocrine therapy are of great unmet needs.