The development of drugs with rapid distribution in the kidney and long-term retention in the renal tubule is a breakthrough for enhanced treatment of acute kidney injury (AKI). Here, l-serine–modified chitosan (SC) was synthesized as a potential AKI kidney–targeting agent due to the native cationic property of chitosan and specific interaction between kidney injury molecule–1 (Kim-1) and serine. Results indicated that SC was rapidly accumulated and long-term retained in ischemia-reperfusion–induced AKI kidneys, especially in renal tubules, which was possibly due to the specific interactions between SC and Kim-1. SC-TK-SS31 was then prepared by conjugating SS31, a mitochondria-targeted antioxidant, to SC via reactive oxygen species (ROS)–sensitive thioketal linker. Because of the effective renal distribution combined with ROS-responsive drug release behavior, the administration of SC-TK-SS31 led to an enhanced therapeutic effect of SS31 by protecting mitochondria from damage and reducing the oxidative stress, inflammation, and cell apoptosis.

Background Cancer immunotherapy with immune checkpoint blockade (CKB) is now standard of care for multiple cancers. The clinical response to CKB is associated with T cell immunity targeting cancer-induced mutations that generate novel HLA-binding epitopes (neoepitopes). Methods Here, we developed a rapid bioinformatics pipeline and filtering strategy, EpitopeHunter, to identify and prioritize clinically relevant neoepitopes from the landscape of somatic mutations. We used the pipeline to determine the frequency of neoepitopes from the TCGA dataset of invasive breast cancers. We predicted HLA class I-binding neoepitopes for 870 breast cancer samples and filtered the neoepitopes based on tumor transcript abundance. Results We found that the total mutational burden (TMB) was highest for triple-negative breast cancer, TNBC, (median = 63 mutations, range: 2–765); followed by HER-2(+) (median = 39 mutations, range: 1–1206); and lowest for ER/PR(+)HER-2(−) (median = 32 mutations, range: 1–2860). 40% of the nonsynonymous mutations led to the generation of predicted neoepitopes. The neoepitope load (NEL) is highly correlated with the mutational burden (R 2 = 0.86). Conclusions Only half (51%) of the predicted neoepitopes are expressed at the RNA level (FPKM≥2), indicating the importance of assessing whether neoepitopes are transcribed. However, of all patients, 93% have at least one expressed predicted neoepitope, indicating that most breast cancer patients have the potential for neo-epitope targeted immunotherapy. Electronic supplementary material The online version of this article (10.1186/s12885-019-5402-1) contains supplementary material, which is available to authorized users.

BackgroundElevated PD-L1 expression on tumor cells, a context associated with an adaptive immune response, has been linked to the total burden of copy number variants (CNVs) in aneuploid tumors, to microsatellite instability (MSI), and to specific genomic driver lesions, including loss of PTEN, MYC amplification, and activating mutations in driver oncogenes such as KRAS and PIK3CA. Triple-negative breast cancers (TNBCs) typically have high levels of CNVs and diverse driver lesions in their genomes. Thus, there is significant interest in exploiting genomic data to develop predictive immunotherapy biomarkers for patients with TNBC.MethodsWhole tissue samples from 55 resected TNBCs were screened by immunohistochemistry (IHC) for PD-1 and PD-L1 by using validated antibodies and established scoring methods for staining of tumor and non-tumor cells. In parallel, we interrogated biopsies from each resection with DNA content flow cytometry and sorted the nuclei of diploid, tetraploid, and aneuploid cell populations. CNVs were mapped with CNV oligonucleotide arrays by using purified (>95%) tumor populations. We generated whole exome data for 12 sorted tumor samples to increase the resolution within loci of interest and to incorporate somatic mutations into our genomic signatures.Results and ConclusionsPD-L1 staining was detected on tumor cells in 29 out of 54 (54%) evaluable cases and was associated with increased overall survival (P = 0.0024). High levels of PD-1 and PD-L1 (IHC ≥4) were present in 11 out of 54 (20%) and 20 out of 54 (37%) cases with staining of PD-L1 primarily on tumor cells for 17 out of 20 (85%) cases. The latter included tumors with both high (>50) and low (<20) numbers of CNVs. Notably, homozygous deletion of PTEN (n = 6) or activating mutation in PIK3CA (n = 1) was not associated with increased expression of either immune checkpoint activator in TNBC. In contrast, two treatment-naïve cases with EGFR driver amplicons had high PD-L1 tumor staining. High mutational load and predicted neoepitopes were observed in MSI+ and high CNV burden TNBCs but were not associated with high PD-L1 expression on tumor cells. Our results challenge current models of genomic-based immunotherapy signatures yet suggest that discrete genomic lesions may complement existing biomarkers to advance immune checkpoint therapies for patients with TNBC.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1004-0) contains supplementary material, which is available to authorized users.

Antimicrobial resistance is widely recognised as a global threat to human health. This paper explores the mobilisation of biomedical concepts and technologies within local semantic registers and addresses the implications of translation and knowledge complexity for attempts to mitigate the problem of antibiotic resistance. In China, antibiotics are frequently prescribed for common complaints and are widely available without prescription. Drawing on field research in three rural counties of one province, we show that current patterns of antibiotic use are the result of sociocultural, economic and systems drivers within a medical context that draws on precepts from both biomedicine and Chinese medical knowledge. Comparative analysis with European settings suggests that pathogenicity, the set of explanatory frameworks regarding the production of disease, varies socio-temporally in the causal mechanisms that are prioritised. Incorporated within diagnostic strategies that direct treatment towards the bodily response to infection rather than to the infecting pathogen, 'anti-inflammatory medicine' as the popular term for antibiotics in parts of Asia foregrounds physiological process over microbial invasion. We examine the articulation of biomedical knowledge paradigms within a non-Pasteurian milieu in relation to socio-historical process, including hybridisation between ontologically distinct medical traditions and the heterogeneity of scientific knowledge claims that underpin contemporary practices of antibiotic prescribing. We conclude that the concept of inflammation functions as a boundary object which effectively mediates the interfaces between popular knowledges, biomedical sciences and local medical practices. Our analysis may have wide relevance because popular and scientific understandings of inflammation alike draw on metaphors grounded in universal sensory experience that provides a common basis for culturally diverse conceptual elaboration. Situated understandings of inflammation and associated treatment preferences constitute a contextually coherent response to available medical technologies in community health care. Our analysis also calls into question simplistic interpretations of antibiotic use for non-bacterial conditions as deriving from lack of education or public awareness and suggests a need to reconsider current public health knowledge translation strategies.

IntroductionThis study aims to investigate patterns of antibiotic treatment-seeking, describe current levels of and drivers for antibiotic use for common infections (respiratory tract and urinary tract infections) and test the feasibility of determining the prevalence and epidemiology of antimicrobial resistance (AMR) in rural areas of Anhui province, in order to identify potential interventions to promote antibiotic stewardship and reduce the burden of AMR in China.Methods and analysisWe will conduct direct observations, structured and semistructured interviews in retail pharmacies, village clinics and township health centres to investigate treatment-seeking and antibiotic use. Clinical isolates from 1550 sputum, throat swab and urine samples taken from consenting patients at village and township health centres will be analysed to identify bacterial pathogens and ascertain antibiotic susceptibilities. Healthcare records will be surveyed for a subsample of those recruited to the study to assess their completeness and accuracy.Ethics and disseminationThe full research protocol has been reviewed and approved by the Biomedical Ethics Committee of Anhui Medical University (reference number: 20170271). Participation of patients and doctors is voluntary and written informed consent is sought from all participants. Findings from the study will be disseminated through academic routes including peer-reviewed publications and conference presentations, via tailored research summaries for health professionals, health service managers and policymakers and through an end of project impact workshop with local and regional stakeholders to identify key messages and priorities for action.

Primary care clinicians in rural China are required to balance their immediate duty of care to their patients with patient expectations for antibiotics, financial pressures, and their wider responsibilities to public health. The clinicians in our sample appear to make greater efforts in managing immediate clinical risks and personal reputation than in considering the long-term consequences of their actions as potentially contributing to antimicrobial resistance. This paper employs Bourdieu's theory of capital to examine the perspectives and practices of Chinese primary care clinicians prescribing antibiotics at low-level health facilities in rural Anhui province, China. We examine the institutional context and clinical realities of these rural health facilities and identify how these influence the way clinicians utilize antibiotics in the management of common upper respiratory tract infections. Confronted with various official regulations and institutional pressures to generate revenues, informants' desire to maintain good relations with patients coupled with their concerns for patient safety result in tensions between their professional knowledge of "rational" antibiotic use and their actual prescribing practices. Informants often deferred responsibility for antimicrobial stewardship to the government or upper echelons of the healthcare system and drew on the powerful public discourse of "suzhi" (human quality) to legitimize their liberal prescribing of antibiotics in an imagined socioeconomic hierarchy. The demands of both practitioners' and patients' social, cultural, and economic forms of capital help to explain patterns of antibiotic prescribing in rural Chinese health facilities.

These data suggest that the JAK2/STAT1 pathway in TNBC might regulate the dynamic expression of PD-L1 that is induced in the setting of an inflammatory response. Inhibition of JAK2 might provide a synergistic therapy when combined with other immunotherapies in the subset of TNBC with 9p24.1 amplification.

The amplification of chromosome 9p24.1 encoding PD-L1, PD-L2, and JAK2 has been reported in multiple types of cancer and is associated with poor outcome, upregulation of PD-L1, and activation of the JAK/STAT pathway. We have developed a novel fluorescence in situ hybridization assay which combines 3 probes mapping to 9p24.1 with a commercial chromosome 9 centromere (CEN9) probe for detection of the JAK2/9p24.1 amplification. JAK2 fluorescence in situ hybridization was compared with array-based comparative genomic hybridization in 34 samples of triple negative breast cancer tumor. By array-based comparative genomic hybridization, 15 had 9p24.1 copy-number gain (logratio>0.3) and 19 were classified as non-gain (logratio≤0.3). Copy-number gain was defined as JAK2/CEN9 ratio ≥1.1 or average JAK2 signals≥3.0. Twelve of 15 samples with copy-number gain by array-based comparative genomic hybridization were also detected by fluorescence in situ hybridization. Eighteen of 19 samples classified as copy-number non-gain by array-based comparative genomic hybridization were concordant by array-based comparative genomic hybridization. The sensitivity and specificity of the fluorescence in situ hybridization assay was 80% and 95%, respectively (P=0.02). The sample with the highest level of amplification by array-based comparative genomic hybridization (logratio=3.6) also scored highest by fluorescence in situ hybridization (ratio=8.2). There was a correlation between the expression of JAK2 and amplification status (Mean 633 vs 393, P=0.02), and there was a trend of association with PD-L1 RNA expression (Mean 46 vs 22, P=0.11). No significant association was observed between PD-L1 immunohistochemistry expression and copy-number gain status. In summary, the novel array-based comparative genomic hybridization assay for detection of chromosome 9p24.1 strongly correlates with the detection of copy-number gain by array-based comparative genomic hybridization. In triple negative breast cancer, this biomarker may identify a relevant subset of patients for targeted molecular therapies.