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Discrete Pt(II) metallacycles have attracted particular attention for the chemotherapeutic treatment of cancer. However, a single chemotherapy cannot simultaneously balance efficiency and safety be...

BACKGROUND Since several lines of evidence suggest that estrogens may be involved in lung carcinogenesis, it has been hypothesized that intake of phytoestrogens, similar in molecular structure to mammalian estrogens, may be associated with lung cancer development. OBJECTIVE To prospectively evaluate the association between phytoestrogen exposure and lung cancer risk in never-smoking females. DESIGN We conducted a nested case-control study within a population-based prospective cohort study of adult females. A total of 478 incident lung cancer cases and their individually matched controls were identified among never-smoking females after a mean follow-up of 15.6 years. Habitual intake of and internal exposure to phytoestrogens were assessed by repeated dietary surveys and urinary biomarkers, respectively. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer were estimated in conditional logistic regression models. RESULTS After adjustment for potential confounders, a moderate intake of dietary isoflavones was inversely associated with lung cancer risk in never-smoking females, with OR for the second quartile vs lowest quartile of intake being 0.52 (95% CI: 0.35, 0.76). Further increasing intake did not convey additional benefits, with ORs (95% CI) for the third and fourth quartiles being 0.53 (0.36, 0.78) and 0.47 (0.31, 0.72), respectively (P-overall < 0.001 and P-nonlinearity = 0.006). A similar association shape was seen when exposure to isoflavones was assessed by urinary biomarkers. ORs (95% CI) for the second, third and fourth quartiles vs lowest quartile of urinary isoflavone excretion were 0.57 (0.39, 0.83), 0.64 (0.44, 0.92) and 0.60 (0.41, 0.86), respectively. The inverse association plateaued beyond the second quartile, with P-overall = 0.04 and P-nonlinearity = 0.15. Urinary excretion of gut-microbiota-derived metabolites of lignans was not related to lung cancer risk. CONCLUSIONS The study suggests that moderately increasing intake of isoflavone-rich foods is associated with lower risk of lung cancer in never-smoking females.

Quantitative ultrasound (QUS), which is commonly used to extract quantitative features from the ultrasound radiofrequency (RF) data or the RF envelope signals for tissue characterization, is becoming a promising technique for noninvasive assessments of liver fibrosis. However, the number of feature variables examined and finally used in the existing QUS methods is typically small, to some extent limiting the diagnostic performance. Therefore, this paper devises a new multiparametric QUS (MP-QUS) method which enables the extraction of a large number of feature variables from US RF signals and allows for the use of feature-engineering and machinelearning based algorithms for liver fibrosis assessment. In the MP-QUS, eighty-four feature variables were extracted from multiple QUS parametric maps derived from the RF signals and the envelope data. Afterwards, feature reduction and selection were performed in turn to remove the feature redundancy and identify the best combination of features in the reduced feature set. Finally, a variety of machine-learning algorithms were tested for classifying liver fibrosis with the selected features, based on the results of which the optimal classifier was established and used for final classification. The performance of the proposed MPQUS method for staging liver fibrosis was evaluated on an animal model, with histologic examination as the reference standard. The mean accuracy, sensitivity, specificity and area under the receiver-operating-characteristic curve achieved by MP-QUS are respectively 83.38%, 86.04%, 80.82% and 0.891 for recognizing significant liver fibrosis, and 85.50%, 88.92%, 85.24% and 0.924 for diagnosing liver cirrhosis. The proposed MP-QUS method paves a way for its future extension to assess liver fibrosis in human subjects.

Lead (Pb) is a well-known neurotoxicant and environmental hazard. Recent experimental evidence has linked Pb exposure with neurological deterioration leading to neurodegenerative diseases, such as Alzheimer’s disease. To understand brain regional distribution of Pb and its interaction with other metal ions, we used synchrotron micro-x-ray fluorescence technique (μ-XRF) to map the metal distribution pattern and to quantify metal concentrations in mouse brains. Lead-exposed mice received oral gavage of Pb acetate once daily for 4 weeks; the control mice received sodium acetate. Brain tissues were cut into slices and subjected for analysis. Synchrotron μ-XRF scans were run on the PETRA III P06 beamline (DESY). Coarse scans of the entire brain were performed to locate the cortex and hippocampus, after which scans with higher resolution were run in these areas. The results showed that: a) the total Pb intensity in Pb-exposed brain slices was significantly higher than in control brain; b) Pb typically deposited in localized particles of

Introduction n-3 long-chain polyunsaturated fatty acids (LCPUFA) have anti-inflammatory effects and may reduce colorectal cancer risk. The purpose of this study was to evaluate the effects of n-3 LCPUFA supplementation on markers of rectal cell proliferation and apoptosis and examine how genetic variation in desaturase enzymes might modify this effect. Methods We conducted a randomized, double-blind, control six-month trial of 2.5 grams of n-3 LCPUFA per day compared to olive oil. Study participants had a history of colorectal adenomas. Randomization was stratified based on the gene variant rs174535 in the fatty acid desaturase 1 enzyme (FADS1). Our primary outcome was change in markers of rectal epithelial proliferation and apoptosis. Results A total of 141 subjects were randomized. We found no difference in apoptosis markers between participants randomized to n-3 LCPUFA compared to olive oil (P = 0.41). N-3 LCPUFA supplementation increased cell proliferation in the lower colonic crypt compared to olive oil (P = 0.03) however baseline indexes of proliferation were different between the groups at randomization. We found no evidence that genotype modified the effect. Conclusions Our study did not show evidence of a proliferative or pro-apoptotic effect on n-3 LCPUFA supplementation on rectal mucosa regardless of the FADS genotype.ClinicalTrials.gov Identifier: NCT01661764Supplemental data for this article is available online at https://dx.doi.org/10.1080/01635581.2021.1955286.

Colonization of specific bacteria in the human mouth were reported to be associated with gastric cancer risk. However, previous studies were limited by retrospective study designs and low taxonomic resolutions. We performed a prospective case-control study nested within three cohorts to investigate the relationship between oral microbiome and gastric cancer risk. Shotgun metagenomic sequencing was employed to characterize the microbiome in pre-diagnostic buccal samples from 165 cases and 323 matched controls. Associations of overall microbial richness and abundance of microbial taxa, gene families, and metabolic pathways with gastric cancer risk were evaluated via conditional logistic regression. Analyses were performed within each cohort and results were combined by meta-analyses. We found that overall microbial richness was associated with decreased gastric cancer risk, with an odds ratio (OR) per standard deviation (SD) increase in Simpson's reciprocal index of 0.77 (95% confidence interval [CI]=0.61-0.99). Nine taxa, 38 gene families, and six pathways also showed associations with gastric cancer risk at P

Age-related cerebral small-vessel disease (CSVD) is a major cause of stroke and dementia. Despite a widespread acceptance of small-vessel arteriopathy, lacunar infarction, diffuse white matter injury, and cognitive impairment as four cardinal features of CSVD, a unifying pathologic mechanism of CSVD remains elusive. Herein, we introduce partial endothelial nitric oxide synthase (eNOS)-deficient mice as a model of age-dependent, spontaneous CSVD. These mice developed cerebral hypoperfusion and blood-brain barrier leakage at a young age, which progressively worsened with advanced age. Their brains exhibited elevated oxidative stress, astrogliosis, cerebral amyloid angiopathy, microbleeds, microinfarction, and white matter pathology. Partial eNOS-deficient mice developed gait disturbances at middle age, and hippocampus-dependent memory deficits at older ages. These mice also showed enhanced expression of bone morphogenetic protein 4 (BMP4) in brain pericytes before myelin loss and white matter pathology. Because BMP4 signaling not only promotes astrogliogenesis but also blocks oligodendrocyte differentiation, we posit that paracrine actions of BMP4, localized within the neurovascular unit, promote white matter disorganization and neurodegeneration. These observations point to BMP4 signaling pathway in the aging brain vasculature as a potential therapeutic target. Finally, because studies in partial eNOS-deficient mice corroborated recent clinical evidence that blood-brain barrier disruption is a primary cause of white matter pathology, the mechanism of impaired nitric oxide signaling-mediated CSVD warrants further investigation.

La Crosse virus (LACV) is a mosquito-borne orthobunyavirus that causes approximately 60 to 80 hospitalized pediatric encephalitis cases in the United States yearly. The primary treatment for most viral encephalitis, including LACV, is palliative care, and specific antiviral therapeutics are needed. We screened the National Center for Advancing Translational Sciences library of 3,833 FDA-approved and bioactive small molecules for the ability to inhibit LACV-induced death in SH-SY5Y neuronal cells. The top three hits from the initial screen were validated by examining their ability to inhibit virus-induced cell death in multiple neuronal cell lines. Rottlerin consistently reduced LACV-induced death by 50% in multiple human and mouse neuronal cell lines with an effective concentration of 0.16–0.69 µg ml−1 depending on cell line. Rottlerin was effective up to 12 hours post-infection in vitro and inhibited virus particle trafficking from the Golgi apparatus to trans-Golgi vesicles. In human inducible pluripotent stem cell-derived cerebral organoids, rottlerin reduced virus production by one log and cell death by 35% compared with dimethyl sulfoxide-treated controls. Administration of rottlerin in mice by intraperitoneal or intracranial routes starting at 3 days post-infection decreased disease development by 30–50%. Furthermore, rottlerin also inhibited virus replication of other pathogenic California serogroup orthobunyaviruses (Jamestown Canyon and Tahyna virus) in neuronal cell lines. Viral encephalitis caused in mice by La Crosse arbovirus can be treated with rottlerin, which prevents viral trafficking from the Golgi and reduces virus titres and neuronal cell death in the central nervous system.

High nut consumption is associated with reduced total and certain cause-specific mortality in general populations. However, its association with cancer outcomes among long-term breast cancer survivors remains unknown. We examined the associations of nut consumption (including peanuts and tree nuts), assessed at 5-year postdiagnosis, with overall survival (OS) and disease-free survival (DFS) among 3449 long-term breast cancer survivors from the Shanghai Breast Cancer Survival Study, applying Cox regression analysis. During a median follow-up of 8.27 years post dietary assessment, there were 374 deaths, including 252 breast cancer deaths. Among 3274 survivors without previous recurrence at the dietary assessment, 209 developed breast cancer-specific events, that is, recurrence, metastasis or breast cancer mortality. At 5-year post dietary assessment (ie, 10-year postdiagnosis), regular nut consumers had higher OS (93.7% vs 89.0%) and DFS (94.1% vs 86.2%) rates. After multivariable adjustment, nut consumption was positively associated with OS (Ptrend = .022) and DFS (Ptrend = .003) following a dose-response pattern, with hazard ratios (95% confidence interval) of 0.72 (0.52-1.05) for OS and 0.48 (0.31-0.73) for DFS, for participants with greater than median nut intake compared with nonconsumers. The associations did not vary by nut type. Stratified analyses showed that the associations were more evident among participants with a higher total energy intake for OS (Pinteraction = .02) and among participants with early stage (I-II) breast cancers for DFS (Pinteraction = .04). The nut-DFS associations were not modified by estrogen receptor/progesterone receptor status or other known prognostic factors. In conclusion, nut consumption was associated with better survival, particularly DFS, among long-term breast cancer survivors.

BACKGROUND Myxoma is the most common tumor of the heart that can cause embolism, obstruction, and cardiac failure, but rarely causes chylothorax. We herein report a case of chylothorax caused by left atrial myxoma, which responded to diuretic therapy and was subsequently cured by resecting cardiac myxoma. CASE PRESENTATION This is a case of a 63-year-old male with symptoms of cardiac insufficiency who was diagnosed with a left atrial myxoma. The patient also had a massive pleural effusion on the right side, which was diagnosed as chylothorax by Sudan III staining and the content of triglyceride. The pleural effusion disappeared and the symptoms of heart failure were relieved after draining the effusion with a fine thoracic drainage tube, but pleural effusion and cardiac insufficiency symptoms relapsed soon. Although diuretic treatment can improve the symptoms and reduced the amount of chylous fluid preoperatively, the chylous pleural effusion was eventually cured by surgical removal of the tumor, and no recurrence of the tumor and chylothorax was found in the 6-month follow-up. CONCLUSIONS Chylothorax is rare comorbidity of cardiac myxoma. Large myxoma can cause congestive heart failure and lead to disfunction of chylous reflux, resulting in chylothorax, which can be cured by resection of the primary tumor.

BACKGROUND Diffuse large B-cell lymphoma (DLBCL) is a common non-Hodgkin's lymphoma. R-CHOP is a protocol for long-term chemotherapy for DLBCL patients. Long-term chemotherapy can lead to low immunity and increase the risk of opportunistic pathogen infections in immunocompromised patients. CASE SUMMARY We report a case of coinfection with Pneumocystis jirovecii (P. jirovecii) and Legionella pneumophila (L. pneumophila) in a patient with DLBCL. The patient was a 40-year-old female who was diagnosed with DLBCL and was admitted due to pulmonary infection. P. jirovecii and L. pneumophila were detected in her bronchoalveolar lavage fluid by hexamine silver staining, isothermal amplification and metagenomic sequencing. CONCLUSION To the best of our knowledge, this is the first case of P. jirovecii and L. pneumophila coinfection found in a DLBCL patient. Clinicians should be aware of the risk of complicated infection in patients undergoing long-term chemotherapy.

BackgroundRecurrent preimplantation embryo developmental arrest (RPEA) is the most common cause of assisted reproductive technology treatment failure associated with identified genetic abnormalities. Variants in known maternal genes can only account for 20%–30% of these cases. The underlying genetic causes for the other affected individuals remain unknown.MethodsWhole exome sequencing was performed for 100 independent infertile females that experienced RPEA. Functional characterisations of the identified candidate disease-causative variants were validated by Sanger sequencing, bioinformatics and in vitro functional analyses, and single-cell RNA sequencing of zygotes.ResultsBiallelic variants in ZFP36L2 were associated with RPEA and the recurrent variant (p.Ser308_Ser310del) prevented maternal mRNA decay in zygotes and HeLa cells.ConclusionThese findings emphasise the relevance of the relationship between maternal mRNA decay and human preimplantation embryo development and highlight a novel gene potentially responsible for RPEA, which may facilitate genetic diagnoses.

Resection of high-grade glioma with sodium fluorescein can improve the resection rate of the glioma and improve survival. However, it is unclear whether the yellow fluorescence boundary of the high-grade glioma is consistent with the actual boundary of the tumor. This study explores the yellow fluorescence boundary and the actual tumor boundary in high-grade glioma surgery.This is a retrospective analysis of 10 patients with high-grade gliomas who underwent tumor visualization with sodium fluorescein. After staining of the tumor, random selections of both developed and non-developed yellow fluorescent border tissue at the fluorescence chromogenic boundary were made, followed by pathological examination. Claudin-5, an important component of the tight connections between vascular endothelial cells, was assessed by immunohistochemistry and qRT-PCR in the tumor and surrounding tissues in order to determine the tumor cell content of the tissue, blood-brain barrier damage, and vascular proliferation. The yellow fluorescence boundary was compared with the actual tumor boundary and the results analyzed.Tumor cells were still detected outside the yellow fluorescence boundary during high-grade glioma surgery (There is a difference between the yellow fluorescence boundary and the actual boundary of the tumor in high-grade glioma, and there are glioma cell infiltrations in the brain tissue of the undeveloped yellow fluorescent border. To ensure patient recovery and function, it is recommended that tumor resection be expanded based on yellow fluorescence visualization. Claudin-5 is overall up-regulated in high-grade gliomas, but some Claudin-5 expression is disconnected. This Claudin-5 expression pattern may be related to the development of yellow fluorescence.

Background Inborn error of bile acid synthesis type 4 is a peroxisomal disease with impaired bile acid synthesis caused by a-methylacyl-CoA racemase (AMACR) gene mutation. The disease is usually found in children with mild to severe liver disease, cholestasis and poor fat-soluble vitamin absorption. At present, there is no report of inborn errors of bile acid synthesis type 4 in adults with liver disease and poor fat-soluble vitamin absorption. Case summary A 71-year-old man was hospitalized in our department for recurrent liver dysfunction. The clinical manifestations were chronic liver disease and yellow skin and sclera. Serum transaminase, bilirubin and bile acid were abnormally increased; and fat-soluble vitamins decreased. Liver cirrhosis and ascites were diagnosed by computed tomography. The patient had poor coagulation function and ascites and did not undergo liver puncture. Genetic testing showed AMACR gene missense mutation. The patient was diagnosed with inborn error of bile acid synthesis type 4. He was treated with ursodeoxycholic acid, liver protection and vitamin supplementation, and jaundice of the skin and sclera was reduced. The indicators of liver function and the quality of life were significantly improved. Conclusion When adults have recurrent liver function abnormalities, physicians should be alert to genetic diseases and provide timely treatment.

Background DNA methylation and gene expression are known to play important roles in the etiology of human diseases such as prostate cancer (PCa). However, it has not yet been possible to incorporate information of DNA methylation and gene expression into polygenic risk scores (PRSs). Here, we aimed to develop and validate an improved PRS for PCa risk by incorporating genetically predicted gene expression and DNA methylation, and other genomic information using an integrative method. Methods Using data from the PRACTICAL consortium, we derived multiple sets of genetic scores, including those based on available single‐nucleotide polymorphisms through widely used methods of pruning and thresholding, LDpred, LDpred‐funt, AnnoPred, and EBPRS, as well as PRS constructed using the genetically predicted gene expression and DNA methylation through a revised pruning and thresholding strategy. In the tuning step, using the UK Biobank data (1458 prevalent cases and 1467 controls), we selected PRSs with the best performance. Using an independent set of data from the UK Biobank, we developed an integrative PRS combining information from individual scores. Furthermore, in the testing step, we tested the performance of the integrative PRS in another independent set of UK Biobank data of incident cases and controls. Results Our constructed PRS had improved performance (C statistics: 76.1%) over PRSs constructed by individual benchmark methods (from 69.6% to 74.7%). Furthermore, our new PRS had much higher risk assessment power than family history. The overall net reclassification improvement was 69.0% by adding PRS to the baseline model compared with 12.5% by adding family history. Conclusions We developed and validated a new PRS which may improve the utility in predicting the risk of developing PCa. Our innovative method can also be applied to other human diseases to improve risk prediction across multiple outcomes., An integrative score incorporating genetically predicted gene expression and DNA methylation and other genomic and non‐genomic information advanced our understanding of using genomic information to stratify subjects for prostate cancer.

Background Accumulating evidence suggests that consuming coffee may lower the risk of death, but evidence regarding tea consumption in Asians is limited. We examined the association between coffee and tea consumption and mortality in Asian populations. Methods We used data from 12 prospective cohort studies including 248 050 men and 280 454 women from the Asia Cohort Consortium conducted in China, Japan, Korea and Singapore. We estimated the study-specific association of coffee, green tea and black tea consumption with mortality using Cox proportional-hazards regression models and the pooled study-specific hazard ratios (HRs) using a random-effects model. Results In total, 94 744 deaths were identified during the follow-up, which ranged from an average of 6.5 to 22.7 years. Compared with coffee non-drinkers, men and women who drank at least five cups of coffee per day had a 24% [95% confidence interval (CI) 17%, 29%] and a 28% (95% CI 19%, 37%) lower risk of all-cause mortality, respectively. Similarly, we found inverse associations for coffee consumption with cardiovascular disease (CVD)-specific and cancer-specific mortality among both men and women. Green tea consumption was associated with lower risk of mortality from all causes, CVD and other causes but not from cancer. The association of drinking green tea with CVD-specific mortality was particularly strong, with HRs (95% CIs) of 0.79 (0.68, 0.91) for men and 0.78 (0.68, 0.90) for women who drank at least five cups per day of green tea compared with non-drinkers. The association between black tea consumption and mortality was weak, with no clear trends noted across the categories of consumption. Conclusions In Asian populations, coffee consumption is associated with a lower risk of death overall and with lower risks of death from CVD and cancer. Green tea consumption is associated with lower risks of death from all causes and CVD.

PURPOSE: Oral microbiome plays an important role in oral health and systemic diseases, including cancer. We aimed to prospectively investigate the association of oral microbiome with lung cancer risk. METHODS: We analyzed 156 incident lung cancer cases (73 European Americans and 83 African Americans) and 156 individually matched controls nested within the Southern Community Cohort Study. Oral microbiota were assessed using 16S rRNA gene sequencing in pre-diagnostic mouth rinse samples. Paired t-test and the permutation multivariate analysis of variance test were used to evaluate lung cancer risk association with alpha diversity or beta diversity, respectively. Conditional logistic regression models were used to evaluate the association of individual bacterial abundance or prevalence with lung cancer risk. RESULTS: No significant differences were observed for alpha or beta diversity between lung cancer cases and controls. Abundance of families Lachnospiraceae_[XIV], Peptostreptococcaceae_[XI] and Erysipelotrichaceae, and species Parvimonas micra was associated with decreased lung cancer risk, with odds ratios (ORs) and 95% confidence intervals (CIs) of 0.76 (0.59–0.98), 0.80 (0.66–0.97), 0.81 (0.67–0.99), and 0.83 (0.71–0.98), respectively (all P

Glioblastoma (GBM) is the most common histological type of glioma, which has the most aggressive biological characters and the worst outcome. The targeted therapy of GBM requires more progression, and new biomarkers should be identified. In our study, we firstly retrieved the data of TCGA and compared the TPMs of all ANXAs in TCGA database. By quantitative PCR (qPCR), we detected the mRNA levels of ANXAs in 8 pairs of GBM tissues and their corresponding normal brain tissues. Moreover, we detected the expression of ANXAs in 118 cases of GBMs, and further evaluated their clinical significance by analyzing the correlation with clinicopathological factors, and estimated their prognostic significance with univariate and multivariate analyses. In the TCGA database, ANXA1, ANXA2, ANXA4, and ANXA5 had higher transcripts per million (TPMs) in GBM tissues compared with the normal brain tissues, while ANXA3 expression was downregulated in GBM tissues. With qPCR, ANXA1, ANXA2, and ANXA10 were verified to be the upregulated genes in GBM, but other ANXAs had no significant differences. ANXA2 and ANXA10, but not ANXA1, were correlated with poor prognosis of GBM and identified as independent prognostic biomarkers for poor outcome. ANXA1, ANXA2, and ANXA10 are the upregulated genes in GBM. ANXA2 and ANXA10, but not ANXA1, are independent prognostic biomarkers indicating unfavorable outcome. Our results suggest that expression profiles based on ANXA10 expression may be a new classification system to predict prognosis of GBM patients.

Background Hepatocellular carcinoma (HCC) is a highly vascularized tumor in which abnormal blood vessels contribute to poor treatment efficacy and prognosis. In this study, we assessed the efficacy, safety, and potential ability of bevacizumab to normalize tumor vascularity in patients with advanced HCC. Methods Patients with histologically or clinically confirmed advanced HCC that were refractory to conventional transarterial chemoembolization (c-TACE) received a transarterial infusion of bevacizumab (5 mg/kg), followed by c-TACE (named as BEVA-TACE). The primary endpoint was overall survival (OS), which was defined as the time from a patient identified as TACE refractory to the occurrence of death. The secondary endpoints included progression-free survival (PFS) and the disease control rate (DCR). Results From January 2014 to December 2017, 20 patients with Barcelona Clinic Liver Cancer (BCLC) staging scores C (80.0%) or D (20.0%) received BEVA-TACE. The median OS time was 9.2 months [95% confidence interval (CI): 2.1-22.6 months]. The median PFS time was 6.3 months (95% CI: 1.0-10.5 months). Despite the late stage, 1 patient (5.0%) had a complete response (CR), 6 patients (30.0%) had a partial response (PR), and 10 patients (50.0%) had stable disease (SD) [overall response rate (ORR) 30.0%; DCR 85.0%]. The most common adverse events (AEs) were postembolic syndrome (25%), hyperbilirubinemia (10.0%), and melena (10.0%). Severe III-IV oral mucositis and hypertension were observed in only 1 patient (5.0%) during the follow-up period. Conclusions BEVA-TACE showed clinical efficacy, and patients with TACE-refractory HCC had acceptable AE rates. A low dose of targeted localized vessel bevacizumab infusion may normalize the condition of tumor blood vessels in patients with advanced HCC.

Anaplasma phagocytophilum is an obligate intracellular bacterium and a common tick-borne infectious pathogen that can cause human granulocytic anaplasmosis (HGA). Effector proteins play an important role in the pathogenic mechanism of A. phagocytophilum, but the specifics of the disease mechanism are unclear. We studied the effector protein AptA (A. phagocytophilum toxin A) using yeast two hybrid assays to screen its interacting protein proteasome assembly chaperone 3 (PSMG3, PAC3), and identified new mechanisms for the pathogenicity of A. phagocytophilum in HEK293T cells. After AptA enters the host cell, it interacts with PSMG3 to enhance the activity of the proteasome, causing ubiquitination and autophagy in the host cell and thereby increasing cross-talk between the ubiquitination-proteasome system (UPS) and autophagy. AptA also reduces the apoptotic efficiency of the host cells. These results offer new clues as to the pathogenic mechanism of A. phagocytophilum and support the hypothesis that AptA interacts with host PSMG3.

PURPOSE: There is an urgent need to understand the biological factors contributing to the racial survival disparity among women with hormone receptor-positive (HR+), HER2− breast cancer. In this study, we examined the impact of PAM50 subtype on 10-year mortality rate in women with HR+, HER2− breast cancer by race. METHODS: Women with localized, HR+, HER2− breast cancer diagnosed between 2002 to 2012 from two population-based cohorts were evaluated. Archival tumors were obtained and classified by PAM50 into four molecular subtypes (i.e., luminal A, luminal B, HER2-enriched, and basal-like). The molecular subtypes within HR+, HER2− breast cancers and corresponding 10-year mortality rate were compared between Black and Non-Hispanic White (NHW) women using Cox proportional hazard ratios and survival analysis, adjusting for covariates. RESULTS: In this study, 318 women with localized, HR+, HER2− breast cancer were included—227 Black (71%) and 91 NHW (29%). Young Black women (age≤50) had the highest proportion of HR+,non-luminal A tumors (47%), compared to young NHW (10%), older Black women (31%), and older NHW (30%). Overall, women with HR+,non-luminal A subtypes had a higher 10-year mortality rate compared to HR+, luminal A subtypes after adjustment for age, stage and income (HR 4.21 for Blacks, 95% CI=1.74–10.18 and HR 3.44 for NHW, 95% CI=1.31–9.03). Among HR+, non-luminal A subtypes there was however no significant racial difference in 10-yr mortality observed (Black vs. NHW: HR 1.23, 95% CI=0.58–2.58). CONCLUSION: Molecular subtype classification highlights racial disparities in PAM50 subtype distribution among women with HR+, HER2− breast cancer. Among women with HR+, HER2− breast cancer, racial survival disparities are ameliorated after adjusting for molecular subtype.

In this work, we develop a deep learning-guided fiberoptic Raman diagnostic platform to assess its ability of real-time in vivo nasopharyngeal carcinoma (NPC) diagnosis and post-treatment follow-up of NPC patients. The robust Raman diagnostic platform is established using innovative multi-layer Raman-specified convolutional neural networks (RS-CNN) together with simultaneous fingerprint and high-wavenumber spectra acquired within sub-seconds using a fiberoptic Raman endoscopy system. We have acquired a total of 15,354 FP/HW in vivo Raman spectra (control: 1761; NPC: 4147; and post-treatment (PT): 9446) from 888 tissue sites of 418 subjects (healthy control: 85; NPC: 82; and PT: 251) during endoscopic examination. The optimized RS-CNN model provides an overall diagnostic accuracy of 82.09% (sensitivity of 92.18% and specificity of 73.99%) for identifying NPC from control and post-treatment patients, which is superior to the best diagnosis performance (accuracy of 73.57%; sensitivity of 89.74%; and specificity of 58.10%) using partial-least-squares linear-discriminate-analysis, proving the robustness and high spectral information sensitiveness of the RS-CNN model developed. We further investigate the saliency map of the best RS-CNN models using the correctly predicted Raman spectra. The specific Raman signatures that are related to the cancer-associated biomolecular variations (e.g., collagens, lipids, and nucleic acids) are uncovered in the map, validating the diagnostic capability of RS-CNN models to correlate with biomolecular signatures. Deep learning-based Raman spectroscopy is a powerful diagnostic tool for rapid screening and surveillance of NPC patients and can also be deployed for longitudinal follow-up monitoring of post-treatment NPC patients to detect early cancer recurrences in the head and neck.

Background Pregnant women with a history of gestational diabetes mellitus (GDM) are at high risk of GDM. It is unclear whether this population has pregnancy characteristics different from the general population. Whether these features affect the perinatal outcome has not yet been elucidated. Methods A retrospective study was conducted, including baseline characteristics, laboratory data, gestational weight gain (GWG), and pregnancy outcomes of 441 pregnant women with prior GDM. Besides, 1637 women without a history of GDM treated in the same period were randomly selected as the control group. The above indicators of the two groups were compared. Multivariable logistic regression analysis was performed to investigate how GWG was associated with perinatal outcomes for previous GDM women. Results Among women with GDM history, triglycerides (TG) and fasting plasma glucose (FPG) in the 1st trimester were higher than those without GDM history. GWG was lower in women with prior GDM relative to the control group at various pregnancy stages. However, women with GDM history had a higher risk of developing GDM (OR 3.25, 95% CI 2.26–4.68) and pregnancy-induced hypertension (OR 1.50, 95% CI 1.05–2.45). In women with previous GDM, excessive GWG before OGTT exhibited a positive correlation with pregnancy-induced hypertension (OR 1.47, 95% CI 1.05–3.32), while inadequate GWG was not a protective factor for GDM and pregnancy-induced hypertension. Conclusion Women with prior GDM have glucose and lipid metabolism disorders in the 1st trimester. Limited reduction of GWG before oral glucose tolerance test (OGTT) was insufficient to offset the adverse effects of glucose and lipid metabolism disorders in women with previous GDM. Relevant interventions may be required at early stage or even before pregnancy.

Nontuberculous mycobacteria infections present mostly pulmonary characteristics. However, the incidence of skin and soft tissue infections caused by nontuberculous mycobacteria has increased in part due to the increased popularity of cosmetic and plastic surgery. Here, we report a case of Mycobacterium agri infection. The patient underwent a one-year course of anti-infection therapy. To the best of our knowledge, this is the first report of a previously healthy patient presenting a skin and soft tissue infection caused by Mycobacterium agri. Clinical personnel should be aware of possible causes of persistent skin and soft tissue infection after cosmetic and plastic surgery.

Objectives To evaluate the safety and feasibility of microwave ablation for treating venous malformations (VMs) with severe localized intravascular coagulopathy (LIC). Patients and methods Data for patients with the diagnosis of VMs coupled with severe LIC who underwent color Doppler-guided microwave dynamic ablation between January 2017 and June 2019 were retrospectively reviewed and analyzed. All patients had previously received sclerotherapy or other treatments with poor outcomes and gradual aggravation of coagulation abnormalities. Microwave treatment with “dynamic ablation” was performed with real-time color Doppler monitoring and was repeated if necessary after 3 months. Low-molecular-weight heparin (LMWH) was used to control consumptive coagulopathy. The therapeutic efficacy including coagulation function and lesion size was evaluated using the four-level scale developed by Achauer. Results Among 15 patients with extensive diffuse or multiple VMs, 10 patients presented with lesions in a single lower extremity, one in both lower extremities and the perineum, one in both upper extremities and the trunk, and three with multiple lesions. The patients underwent a total of 74 microwave ablation sessions, with an average of 4.9 sessions per person. Coagulation abnormalities were temporarily aggravated in 59 sessions within the first seven days post-ablation but improved to grade II (fair) a week later. From six months to three years after the ablation, the lesions improved to grade IV (excellent) in one patient, grade III (good) in six patients, and grade II (fair) in eight patients. Moreover, the coagulation function improved to grade IV in four patients, grade III in eight patients, and grade II in three patients, resulting in an efficiency rate of 80% (12/15). Post-ablation complications included fever, hemoglobinuria, and elevations in aspartate aminotransferase, lactate dehydrogenase, and alanine aminotransferase. The patients with fever and hemoglobinuria recovered after specific therapeutic measures, but elevations in aspartate aminotransferase, lactate dehydrogenase, and alanine aminotransferase recovered spontaneously without further interventions. Conclusions Ablation coupled with anticoagulation can effectively treat VMs in patients with severe LIC and improve the long-term coagulation function.

MicroRNAs (miRNA) have been shown to be associated with tumor diagnosis, prognosis, and therapeutic response. MiR-328-3p plays a significant role in breast cancer growth; however, its actual function and how it modulates specific biological functions is poorly understood. Here, miR-328-3p was significantly downregulated in breast cancer, especially in patients with metastasis. Mitochondrial carnitine palmitoyl transferase 1a (CPT1A) is a downstream target gene in the miR-328-3p-regulated pathway. Furthermore, the miR-328-3p/CPT1A/fatty acid β-oxidation/stemness axis was shown responsible for breast cancer metastasis. Collectively, this study revealed that miR-328-3p is a potential therapeutic target for the treatment of breast cancer patients with metastasis, and also a model for the miRNA-fatty acid β-oxidation-stemness axis, which may assist inunderstanding the cancer stem cell signaling functions of miRNA.

BACKGROUND Primary bone lymphoma (PBL) is an uncommon extranodal disease that represents approximately 1%-3% of lymphomas. Anaplastic lymphoma kinase (ALK) positive anaplastic large-cell lymphoma (ALCL) is an extremely rare type of PBL. The aim of this report is describe the symptoms, diagnosis, and treatment of primary bone ALK-positive ALCL. CASE SUMMARY A 66-year-old man presented to our hospital with neck and shoulder pain and intermittent fever that lasted for 1 mo. After extensive evaluation, positron emission tomography-computed tomography (CT) examination showed multiple osteolytic bone lesions without other sites lesions. CT-guided biopsy of the T10 vertebral body was performed, and the pathology results showed that neoplastic cells were positive for ALK-1, CD30, and CD3. A diagnosis of primary bone ALK positive ALCL was ultimately made. The patient was in partial response after four cycle soft cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, and we planned to repeat the biopsy and radiological examination after completion of the fifth cycle of therapy. CONCLUSION Primary bone ALK positive ALCL is a rare disease and physicians should keep in mind that ALCL can present with isolated osseous involvement without nodal involvement, and lymphoma should be considered in the differential diagnosis of primary bone lesions.

PURPOSE: TUBB8 is a gene that is frequently analysed in the genetic diagnosis of female infertility; 102 variants of this gene have been identified. However, the evaluation of its pathogenicity and the resulting phenotypes vary. Here, we aimed to identify novel TUBB8 variants as well as to summarize the reported variants and phenotypes in order for them to be included in genetic counselling analyses. METHODS: We performed whole exome sequencing to screen for candidate variants in 100 infertile female subjects and 100 controls who were able to conceive naturally. All variants were confirmed by Sanger sequencing. The effects of the variants in oocytes/arrested embryos were assessed by morphological observations, polar body biopsies, and chromosome analysis. A molecular modelling analysis was used to evaluate the possible effects of variants on protein secondary structure. RESULTS: We identified 29 TUBB8 variants, of which 20 were novel and five were maternally inherited. We identified three of a total of six recurrent variants that were specific for complete cleavage failure. Moreover, we obtained evidence that TUBB8 variants with large polar bodies had chromosome segregation errors. CONCLUSIONS: Our study expands the spectrum of TUBB8 variants, particularly for embryonic arrest. Together with the extant knowledge of TUBB8 variants, this study provides a foundation for the genetic counselling of female infertility. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-021-02219-9.

Background Little is known about the time course of mortality reduction following smoking cessation in Asians who have smoking behaviours distinct from their Western counterparts. We evaluated the level of reduction in all-cause, cardiovascular disease (CVD) and lung cancer mortality by years since quitting smoking, in Asia. Methods Using Cox regression, we analysed individual participant data (n = 709 151) from 16 prospective cohorts conducted in China, Japan, Korea/Singapore, and India/Bangladesh, separately by cohorts. Cohort-specific hazard ratios (HRs) were combined using a random-effects meta-analysis. Results During a mean follow-up of 12.0 years, 108 287 deaths were ascertained—35 658 from CVD and 7546 from lung cancer. Among Asian men, a dose-response relationship of risk reduction in deaths from all causes, CVD and lung cancer was observed with an increase in years after smoking cessation. Compared with never smokers, however, all-cause and CVD mortality among former smokers remained elevated 10–14 years after quitting [multivariable-adjusted HR (95% confidence interval (CI) = 1.25 (1.13–1.37) and 1.20 (1.02–1.41), respectively]. Lung cancer mortality stayed almost 2-fold higher than among never smokers 15–19 years after smoking cessation [1.97 (1.41–2.73)], particularly among former heavy smokers [2.62 (1.71–4.00)]. Women who quitted for ≥5 years retained a significantly elevated mortality from all causes, CVD and lung cancer. Overall patterns of the cessation-mortality associations were similar across countries. Conclusions Our findings suggest that adverse effects of tobacco smoking persist for an extended time period, even for more than two decades, which is beyond the time windows defined in current clinical guidelines for risk assessment of lung cancer and CVD.

Background Blood type has been associated with the risk of gastric cancer, but few studies have examined the association with esophageal squamous cell carcinoma (ESCC). Methods We conducted a case-control study using genotyping data of Chinese individuals, including cases of 2022 ESCC, 1189 gastric cardia adenocarcinoma, 1161 gastric noncardia adenocarcinoma, and 2696 controls. Genetic blood type was imputed using three single nucleotide polymorphisms. We used logistic regression to examine the association between blood type and the risk of each cancer. Results Compared to blood type O, the risk of ESCC was significantly elevated for blood type B and AB, with the highest risk for type AB (OR, 95%CI: 1.34, 1.07–1.67). Analysis of genotype suggested that the association of ESCC was from carrying the B allele. Similarly, blood type was significantly associated with gastric noncardia adenocarcinoma (P P = 0.13). Conclusions This study provides novel insights into the association between blood type and the risk of ESCC and restricted previously observed association to only gastric noncardia cancer, providing important evidence to clarify the pattern of association and suggesting mechanisms of action.

Background: Metabolomics is widely used to identify potential novel biomarkers for cancer risk. No investigation, however, has been conducted to prospectively evaluate the role of perturbation of metabolome in gastric cancer development. Methods: 250 incident cases diagnosed with primary gastric cancer were selected from the Shanghai Women’s Health and the Shanghai Men’s Health Study, and each was individually matched to one control by incidence density sampling. An untargeted global profiling platform was used to measure approximately 1,000 metabolites in prediagnostic plasma. Conditional logistic regression was utilized to generate ORs and P values. Results: Eighteen metabolites were associated with gastric cancer risk at P < 0.01. Among them, 11 metabolites were lysophospholipids or lipids of other classes; for example, 1-(1-enyl-palmitoyl)-GPE (P-16:0) (OR = 1.56; P = 1.89 × 10–4). Levels of methylmalonate, a suggested biomarker of vitamin B12 deficiency, was correlated with increased gastric cancer risk (OR = 1.42; P = 0.004). Inverse associations were found for three biomarkers for coffee/tea consumption (3-hydroxypyridine sulfate, quinate and N-(2-furoyl) glycine), although the associations were only significant when comparing cases that were diagnosed within 5 years after the blood collection to matched controls. Most of the identified associations were more profound in women and never smokers than their male or ever smoking counterparts and some with notable significant interactions. Conclusions: Our study identified multiple potential risk biomarkers for gastric cancer independent of Helicobacter pylori infection and other major risk factors. Impact: New risk-assessment tools to identify high-risk population could be developed to improve prevention of gastric cancer. See related commentary by Drew et al., p. 1601

Background Non-small cell lung carcinoma (NSCLC) is one of the most common human cancers, comprising approximately 80–85% of all lung carcinomas. An estimated incidence of NSCLC is approximately 2 million new cases per year worldwide. Results In recent decade, the treatment of NSCLC has made breakthrough progress owing to a large number of targeted therapies which were approved for clinical use. Epidemiology, genetic susceptibility, and molecular profiles in patients are likely to play an important factor in response rates and survival benefits to these targeted treatments and thus warrant further investigation on ethnic differences in NSCLC. In this study, a total number of 1500 Chinese patient samples,1000 formalin fixed paraffin-embedded (FFPE) and 500 blood samples, from patients with NSCLC were analyzed by targeted sequencing to explore mutational landscape in ethnic groups associated with China. Conclusions Overall, the data presented here provide a comprehensive analysis of NSCLC mutational landscape in Chinese patients and findings are discussed in the context of similar studies on different ethnic groups.

The JAK2/STAT pathway is hyperactivated in many cancers, and such hyperactivation is associated with a poor clinical prognosis and drug resistance. The mechanism regulating JAK2 activity is complex. Although translocation of JAK2 between nucleus and cytoplasm is an important regulatory mechanism, how JAK2 translocation is regulated and what is the physiological function of this translocation remain largely unknown. Here, we found that protease SENP1 directly interacts with and deSUMOylates JAK2, and the deSUMOylation of JAK2 leads to its accumulation at cytoplasm, where JAK2 is activated. Significantly, this novel SENP1/JAK2 axis is activated in platinum-resistant ovarian cancer in a manner dependent on a transcription factor RUNX2 and activated RUNX2/SENP1/JAK2 is critical for platinum-resistance in ovarian cancer. To explore the application of anti-SENP1/JAK2 for treatment of platinum-resistant ovarian cancer, we found SENP1 deficiency or treatment by SENP1 inhibitor Momordin Ic significantly overcomes platinum-resistance of ovarian cancer. Thus, this study not only identifies a novel mechanism regulating JAK2 activity, but also provides with a potential approach to treat platinum-resistant ovarian cancer by targeting SENP1/JAK2 pathway.

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer–specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5–25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06–1.34)]; current versus never smoking [1.37 (1.27–1.47)], high versus low physical activity [0.43 (0.21–0.86)], age ≥30 years versus 0– Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

Immunotherapy has provided a promising strategy for the treatment of cancers. However, even in tumors with high antigen burdens, the systemic inhibition of the antigen presentation still greatly restricts the application of immunotherapy. Here, we construct a tumor protein-engineering system based on the functional tripeptide, Asp-Phe-Tyr (DFY), which can automatically collect and deliver immunogenetic tumor proteins from targeted cells to immune cells. Through a tyrosinase-catalyzed polymerization, the DFY tripeptide selectively accumulates in tyrosinase high-expressed melanoma cells. Then quinone-rich intermediates are covalently linked with tumor-specific proteins by Michael addition and form tumor protein-carried microfibers that could be engulfed by antigen-presenting cells and exhibited tumor antigenic properties for boosting immune effect. In melanoma cells with deficient antigen presentation, this system can successfully enrich and transport tumor antigen-containing proteins to immune cells. Furthermore, in the in vivo study on murine melanoma, the transdermal delivery of the DFY tripeptide suppressed the tumor growth and the postsurgery recurrence. Our findings provide an avenue for the regulation of the immune system on an organism by taking advantage of certain polymerization reactions by virtue of chemical biology.

Objective To establish trimester-specific reference intervals (TSRIs) for blood lipid profiles in Chinese women and explore their associations with pregnancy outcomes. Methods Participants were women with singleton pregnancies aged 18-45 years without pre-existing chronic diseases who delivered from January 2018 to December 2018 from an ongoing cohort in Beijing, China. Baseline information and pregnancy outcomes were from the medical records. Blood lipid levels were measured at 7-13, 24-28, and 32-34 weeks of pregnancy. We estimated TSRIs for lipid profiles using an indirect Hoffmann method and evaluated their associations with pregnancy outcomes, including gestational diabetes, pregnancy-induced hypertension, macrosomia, low birth weight, large or small for gestational age, and preterm delivery. Results The established TSRIs were 3.21-5.38, 4.64-7.56, and 4.86-8.20 mmol/L for total cholesterol; 0.37-1.81, 1.14-3.49, and 1.61-4.63 mmol/L for triglycerides; 1.12-2.19, 1.33-2.49, and 1.24 2.31 mmol/L for high-density lipoprotein cholesterol; 1.33-2.98,1.97-4.36, and 2.02-4.92 mmol/L for low-density lipoprotein cholesterol from first trimeseter to third trimester, respectively. Both higher and lower levels of lipid profiles than TSRIs were associated with adverse pregnancy outcomes. Conclusion We suggested TSRIs for blood lipid levels in a Chinese population. Inappropriate lipid levels were associated with adverse pregnancy outcomes.

Extensive clinical studies have indicated that the epidermal growth factor receptor (EGFR)- tyrosine kinase inhibitors (TKIs) can significantly improve the survival rate of patients with EGFRmutation-positive malignancies. However, acquired resistance to the third-generation EGFR-TKI osimertinib is an intractable obstacle for many clinical oncologists. The resistance mechanism of osimertinib is very complicated, and the individual treatment varies greatly. We present the case of a 76-year-old woman with advanced non-small cell lung cancer (NSCLC) with EGFR L858R mutation, as well as multiple lung metastases and multiple liver metastases. The patient's lung lesions progressed after almost 2 years of treatment with Osimertinib. Due to poor physical condition, she could not tolerate chemotherapy or invasive examination. A next-generation sequencing (NGS) panel of a plasma sample showed missense mutations of KRAS (G12S), MET (D1028Y), AR (S697P), LRP1B (S2662C) with allelic frequencies of 0.6%, 0.5%, 0.2%, 0.2%, respectively), 2 nonsense mutations [ZNF521 (E307*), MET (Q42*), with allelic frequencies of 0.5%, 0.3%, respectively], and a splicing mutation in FAT1 (c.3266-1G>C) with an allelic frequency of 0.5%. After treatment with camrelizumab (200 mg fortnightly) combined with small dose of apatinib (125 mg qd), the patient's lung lesions were successfully overcome with significant reduction and necrosis formation. And the patient's symptoms were significantly relieved and was well tolerated. To our knowledge, this is the first report on the successful treatment of such patients. It indicated a promising treatment option in the clinic to the NSCLC with osimertinib resistance.

The US Preventive Services Task Force (USPSTF) recently proposed to widen the current lung cancer screening guideline to include less-heavy smokers. We sought to incorporate both genetic and tobacco smoking data to evaluate the proposed new guideline in white smokers. We constructed a polygenic risk score (PRS) using lung cancer risk variants. Using data from 308 490 participants of European descent in the UK Biobank, a population-based cohort study, we estimated hazard ratios of lung cancer associated with both tobacco smoking and PRS to identify individuals at a similar or higher risk than the group of heavy smokers who are recommended for screening under the USPSTF-2014 guideline (≥30 pack-years, either current or former smokers who quit within 15 years). During a median follow-up of 5.8 years, 1449 incident cases of lung cancer were identified. We found a similar lung cancer risk for current smokers with 20–29 pack-years [hazard ratio = 20.7, 95% confidence interval: 16.3–26.4] and the ‘heavy smoker group’ defined above (hazard ratio = 19.9, 95% confidence interval: 16.8–23.6) compared with never smokers. Current smokers with 20–29 pack-years did not reach a 6-year absolute risk of 0.0151, a suggested risk threshold for using low-dose computed tomography screening, until the age of 55 years. However, these smokers at high genetic risk (PRS ≥ 80%) reached this risk level at the age of 50. Our findings support the USPSTF proposal to lower the smoking pack-year eligibility to 20 pack-years for current smokers and suggest that PRS for lung cancer could be considered to identify high-risk smokers for screening.

Background:Factors contributing to breast cancer survival disparities in underrepresented racial and ethnic groups and low-income populations are poorly understood as few clinical trials and population based studies have included these underserved populations. The Southern Community Cohort Study (SCCS), a prospective cohort of underserved, low-income adults with high representation of Black participants, provides a unique opportunity to evaluate such disparities in cancer outcomes. A previous study utilizing SCCS data found no evidence of increased breast cancer risk among women with diabetes in this population. The purpose of this study was to evaluate the association of diabetes with overall survival in women with breast cancer in the SCCS. Methods:The SCCS enrolled approximately 86,000 participants aged 40-79 from 12 southeastern states between 2002-2009, 86% of whom were enrolled at Community Health Centers. This analysis includes women diagnosed with incident localized breast cancers identified through annual cohort linkage with 12 state cancer registries. Demographic data including participant age at breast cancer diagnosis, self-reported history of diabetes (patient answered yes to “has a doctor ever told you that you have diabetes”), body mass index (BMI), race, household income, and insurance coverage were obtained from baseline surveys, cancer type and stage data from state cancer registries, and survival data from death registries. Survival time was defined as the number of months between initial breast cancer diagnosis and death from any cause. Descriptive characteristics including mean (standard deviation) or number (%) were used to summarize demographics. We used Pearson Chi-squared analysis to examine the association between diabetes and overall survival. Multivariable Cox proportional hazards regression was used to evaluate overall survival and diabetes, adjusting for covariates including age (continuous), race, BMI (categorical by WHO classifications), household income (binary – annual income =$25,000), insurance coverage, cancer subtype, and cancer stage). Results:We identified a total of 1,347 women diagnosed with breast cancer. Of these, 1,016 were diagnosed with localized disease (stage 1-3) and comprised our analytic sample. Difference in denominators reflects missing data. The women were predominantly Black (667/1,016, 65.6%), low income (719/1,016 annual income less than $25,000, 70.8%), and insured (Private insurance 220/763, 28.8%; Medicare 331/763, 43.4%; Medicaid 178/763, 23.3%). Average age at diagnosis was 60.7 years (SD 9.1, IQR 41-88). Approximately one quarter of the patients (258/994, 26.0%) self-reported diabetes and 59.6% (605/1,016) were obese (BMI >=30). The breast cancer immunohistochemistry subtypes in this cohort of women included HR+HER2- (392/564, 69.5%), HR+,HER2+ (55/564, 9.8%), HR-,HER2+ (31/564, 5.5%), and HR-HER2- (86/564, 15.3%). Women with diabetes had lower overall survival (174/258, 67.4%) than women without diabetes (587/746, 79.8%) (p Conclusion: In a low-income, predominantly Black population with incident localized breast cancer, decreased overall survival was observed among women diabetes compared to those without diabetes. Future studies should explore additional biological, societal, and socio-economic factors affecting survival among women with breast cancer in medically underserved minority populations. Citation Format: Lucy B. Spalluto, Sonya Reid, Diane Haddad, Tuya Pal, Ingrid A. Mayer, Xiao-ou Shu, Maureen Sanderson, Wei Zheng, William J. Blot, Loren Lipworth. Diabetes decreases overall survival in women with breast cancer in the southern community cohort study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD11-05.

Prior studies suggest a strong genetic influence on breast cancer prognosis. Six genome-wide association studies (GWAS) on breast cancer prognosis have been published to date. However, none of the reported loci was replicated across studies and only two passed genome-wide significance (P < 5 x 10-8). In the Pathways Study, a prospective cohort of breast cancer survivors begun in Kaiser Permanente Northern California (KPNC) in 2006, we carried out a GWAS of overall survival (OS) in 3,973 patients. Trans-ethnic meta-GWAS identified an association with OS of a locus on chromosome 15 that almost reached genome-wide significance (P = 9.42 x 10-8). This locus spanned the UACA gene, a key regulator of tumor suppressor Par-4. We found that receipt of chemotherapy modified the effect of the UACA locus on OS (Pinteraction = 2.4 x 10-4). This observation led us to hypothesize that the UACA locus effect on OS may be specific to Par-4 dependent chemotherapies, which include anti-HER2 therapy and doxorubicin. We stratified patients into two groups, those who received Par-4 dependent chemotherapy agents versus other patients. In separate trans-ethnic meta-GWAS, the UACA locus was significantly associated with OS in patients taking Par-4 dependent chemotherapies (P = 1.27 x 10-9), while no association was observed in the other patients (P = 0.21). To evaluate whether the UACA gene may be responsible for this association, we performed a transcriptome-wide association study (TWAS) of OS in White patients taking Par-4 dependent chemotherapies. Higher UACA gene expression was significantly associated with OS (P = 4.68 x 10-7), the only gene reaching transcriptome-wide significance (P < 4.34 x 10-6). These results suggest that higher UACA expression may inhibit Par-4 induced apoptosis and lead to stronger chemoresistance and worse survival. We attempted to validate our findings in the independent KPNC Genetic Epidemiology Research on Aging (GERA) cohort. The GERA cohort included only 168 White patients with incident breast cancer after DNA collection who received Par-4 dependent chemotherapies. We found a non-significant association (hazard ratio (HR) = 1.46, P = 0.66) consistent with Pathways Study findings. However, the GERA cohort also included 1,983 prevalent breast cancer patients with biospecimen collection after diagnosis. In this group, the risk allele frequency in breast cancer survivors receiving Par-4 dependent chemotherapies was significantly lower than that in the White population (P = 5.50 x 10-3) while the risk allele frequency in the those not receiving these chemotherapies was similar to the population (P = 0.07). This is consistent with Pathways Study observations that the UACA locus risk allele significantly increased risk of mortality in patients taking Par-4 dependent chemotherapies. A higher mortality in breast cancer survivors carrying the risk allele would result in decreased risk allele frequency. We further validated our findings in Shanghai Breast Cancer Survival Study (SBCSS)and Shanghai Breast Cancer Study, which were conducted from 1996 to 2006 in urban Shanghai and recruited 5,575 breast cancer patients. In this independent Asian breast cancer population, the UACA locus was modestly associated with OS in the overall population (HR = 1.18, P = 0.012), and more significantly in 1,289 SBCSS patients who received anthracyclines (HR = 1.66, P = 1.55 x 10-4). This is the first human study suggesting the Par-4 pathway affects breast cancer patient survival with UACA a key modulator of treatment outcomes by anti-Her2 therapy and doxorubicin. Our findings suggest a path toward new predictive pharmacogenetic markers for personalized medicine targeting the Par-4 pathway for breast cancer treatment. Citation Format: Lawrence H Kushi, Qianqian Zhu, Emily Schultz, Jirong Long, Janise M Roh, Emily Valice, Cecile A Laurent, Li Yan, Isaac J Ergas, Warren Davis, Dilrini K Ranatunga, Marilyn L Kwan, Ping-Ping Bao, Wei Zheng, Xiao-Ou Shu, Christine B Ambrosone, Song Yao. Genome-wide association study identifies UACA as a modulator of breast cancer chemoresistance and survival [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS2-05.

Background:Breast cancer outcomes in minority and low socioeconomic status populations are not clearly defined due to underrepresentation of these underserved populations in breast cancer clinical trials and population-based studies. The Southern Community Cohort Study (SCCS), a prospective cohort of underserved, predominantly Black participants, provides a unique opportunity to evaluate disparities in breast cancer outcomes. We sought to examine the association between race and socioeconomic status (SES) and overall survival (OS) in women with localized breast cancer in the SCCS. Methods:The SCCS enrolled approximately 86,000 participants aged 40-79 from 12 Southeastern states between 2002-2009, 86% of whom were enrolled at Community Health Centers. This analysis includes women diagnosed with incident localized breast cancer (stage I-III) identified through annual cohort linkage with 12 state cancer registries through December 20, 2017. Demographic data including participant age, self-reported history of diagnosed diabetes, body mass index (BMI), race, annual household income, and insurance coverage were obtained from baseline surveys. Tumor grade and stage were obtained from state cancer registries, and survival data were obtained from death registry records. Immunohistochemical (IHC) subtype was determined from tumor estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status obtained from cancer registry records and pathology reports. Survival time was defined as the number of months between initial breast cancer diagnosis and death from any cause. Descriptive analyses including mean (standard deviation) and number (%) were used to summarize clinical and sociodemographic characteristics by race. Multivariable Cox survival analysis was used to evaluate OS by race and annual household income, adjusting for age, insurance, stage, IHC subtype, diabetes, and BMI. Results:Of the 1347 women diagnosed with incident breast cancer, 1016 had localized disease (stage I-III) and comprised our analytic sample. Compared to White women, Black women were more likely to have lower income, higher prevalence of triple negative breast cancer (TNBC), grade III tumors and stage III breast cancer (Table 1). After adjusting for clinical and sociodemographic factors, Black women had similar OS compared to White women (HR 0.67; 95% CI 0.42-1.07). However, after adjusting for race, women with a household income ≥ $25,000 had an improved OS compared to those with annual household income < $25,000 (HR 0.53; 95% CI 0.30-0.93). Conclusion: In a low-income, medically underserved population, Black women with localized breast cancer had similar OS compared to White women. However, socioeconomic disparities were observed, with worse OS for women with low annual household income. Future studies focused on minority, underserved groups are imperative to better understand the non-biological and biological factors contributing to disparities in survival among women with breast cancer. Table 1. Patient characteristics overall and by racePatient CharacteristicsTotal(N=1016)Black(N=667)White(N=349)P-value*Age at diagnosis, years (Mean, SD)61 (9)60 (9)63 (9)Income, annual household (N, %) < $25,000 ≥ $25,000719 (71)297 (29)503 (75)164 (25)216(62)133 (38) Citation Format: Sonya Reid, Lucy B Spalluto, Diane Haddad, Tuya Pal, Ingrid Mayer, Xiao-ou Shu, Wei Zheng, Maureen Sanderson, William Blot, Loren Lipworth. The association of race and socioeconomic status with overall survival in women with breast cancer in the southern community cohort study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-34.

It is unclear whether racial/ethnic disparities in triple-negative breast cancer (TNBC) mortality remain after accounting for clinical characteristics, treatment, and access-to-care–related factors. In this study, women with a primary diagnosis of TNBC during 2010–2014 were identified from the National Cancer Database. Hazard ratios (HR) and 95% confidence intervals (CI) for 3- and 5-year all-cause mortality associated with race/ethnicity were estimated using Cox proportional hazards models with stepwise adjustments for age, clinical characteristics, treatment, and access-to-care–related factors. Of 78,708 patients, non-Hispanic (NH) black women had the lowest 3-year overall survival rates (79.4%), followed by NH-whites (83.1%), Hispanics (86.0%), and Asians (87.1%). After adjustment for clinical characteristics, NH-blacks had a 12% higher risk of dying 3 years post-diagnosis (HR, 1.12; 95% CI, 1.07–1.17), whereas Hispanics and Asians had a 24% (HR, 0.76; 95% CI, 0.70–0.83) and 17% (HR, 0.83; 95% CI, 0.73–0.94) lower risk than their NH-white counterparts. The black–white disparity became non-significant after combined adjustment for treatment and access-to-care–related factors (HR, 1.04; 95% CI, 0.99–1.09), whereas the white-Hispanic and white-Asian differences remained. Stratified analyses revealed that among women aged less than or equal to 50 with stage III cancer, the elevated risk among NH-blacks persisted (HR, 1.20; 95% CI, 1.04–1.39) after full adjustments. Similar results were seen for 5-year mortality. Overall, clinical characteristics, treatment, and access-to-care–related factors accounted for most of the white–black differences in all-cause mortality of TNBC but explained little about Hispanic- and Asian-white differences. Significance: These findings highlight the need for equal healthcare to mitigate the black–white disparity and for investigations of contributors beyond healthcare for lower mortality among Asians and Hispanics.

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10–8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82–0.93; former smokers 1.00, 95% CI, 0.91–1.07; current smokers 1.25, 95% CI 1.12–1.40, Pinteraction = 3.08 × 10–9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. Significance: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.

Background Coenzyme Q10 (CoQ10) is a ubiquitous molecule in living organisms serving as a cofactor in energy production. Epidemiological studies have reported low CoQ10 levels being associated with an increased risk of various cancers. We conducted the first study to evaluate the association of CoQ10 concentrations with lung cancer risk. Methods A nested case‐control study including 201 lung cancer cases and 395 matched controls from the Southern Community Cohort Study was conducted. Plasma CoQ10 levels were measured using high‐performance liquid chromatography with photo‐diode array detection. Conditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between plasma CoQ10 levels and lung cancer risk. Results Plasma CoQ10 concentration was inversely associated with the risk of lung cancer. After adjusting for age, sex, race, and socioeconomic status, the OR (95% CI) comparing the third to first tertile was 0.57 (0.36–0.91, P for trend = 0.02). Further adjustments for smoking, alcohol, chronic obstructive pulmonary disease, and body mass index attenuated the point estimate slightly (OR = 0.60, 95% CI = 0.34–1.08, P for trend = 0.11), comparing third to first tertiles. Stratified analyses identified a significant inverse association between plasma CoQ10 levels and lung cancer risk in current smokers, but not in former/never smokers. The association was more evident in cases who were diagnosed within 1 year of blood draw than in cases diagnosed after 1 year. Conclusions Low plasma CoQ10 was significantly associated with increased lung cancer risk, particularly among current smokers. The stronger association seen shortly following the blood draw suggests that CoQ10 may be related to disease progression., We conducted a nested case‐control study to determine the association between plasma coenzyme Q10 and lung cancer risk. Low coenzyme Q10 was associated with a greater risk of lung cancer among current smokers and participants diagnosed within 1 year following blood draw.

Objective Most women with epithelial ovarian cancer (EOC) are diagnosed after the disease has metastasized and survival in this group remains poor. Circulating proteins associated with the risk of developing EOC have the potential to serve as biomarkers for early detection and diagnosis. We integrated large-scale genomic and proteomic data to identify novel plasma proteins associated with EOC risk. Methods We used the germline genetic variants most strongly associated (P

Background The relationship between eosinophilic esophagitis (EoE) and achalasia is not completely understood. There have been reports of eosinophilic infiltration of all esophageal layers in patients with achalasia. However, a routine endoscopic biopsy of the muscular layer is usually not feasible. We evaluate the safety and efficacy of muscle layer biopsy during per-oral endoscopic myotomy (POEM) as well as the prevalence of eosinophilic infiltration of the esophageal mucosa and muscular layer in patients with achalasia. Patients and Methods All enrolled patients had diagnosed achalasia and had simultaneous biopsies of the muscular layer at the middle esophagus and distal esophageal sphincter as well as the mucosal layer of the proximal and distal esophagus during POEM. All POEM procedures took place from August 2018 to December 2018 or September 2019 to November 2019. Various demographic, disease-related, and procedure-related data were collected from chart review. Eosinophilic infiltration in the biopsy specimen was examined. Key Results Twenty consecutive patients (65% female, age range: 21–84) with a pre-procedure Eckardt score of >6 were enrolled during the study period, with the duration of their achalasia ranging from 1 to 32 years. Eighteen patients had clinical symptomatic improvement after POEM, as defined by an Eckardt score

Most genetic variants for colorectal cancer (CRC) identified in genome-wide association studies (GWAS) are located in intergenic regions, implying pathogenic dysregulations of gene expression. However, comprehensive assessments of target genes in CRC remain to be explored. We conducted a multi-omics analysis using transcriptome and/or DNA methylation data from the Genotype-Tissue Expression, The Cancer Genome Atlas and the Colonomics projects. We identified 116 putative target genes for 45 GWAS-identified variants. Using summary-data-based Mendelian randomization approach (SMR), we demonstrated that the CRC susceptibility for 29 out of the 45 CRC variants may be mediated by cis-effects on gene regulation. At a cutoff of the Bonferroni-corrected PSMR

Recurrent nasopharyngeal carcinoma (NPC) is the main cause of poor prognosis for NPC patients after chemo- and radiotherapies. Subsequent long-term follow-ups of post-treatment patients are crucial for the early discovery of tumor recurrence with timely intervention. Current clinical imaging methods based on tissue morphology encounter difficulties in differentiating recurrent tumors from post-treatment inflammation and fibrosis. In this work, we apply a unique fiberoptic Raman endoscopy technique to address the challenges for label-free follow-up surveying of post-treatment NPC patients and accurate detection of tumor recurrence. Significant Raman spectral differences can be observed among normal, NPC, and nonrecurring post-treatment patients. Raman endoscopy provides diagnostic accuracy of 100% for detecting recurrent NPC from early post-treatment inflammation and diagnostic accuracy of 98.21% for separating recurrent NPC from long-term post-treatment fibrosis. Further quantitative Raman modeling on in vivo nasopharyngeal tissue Raman data acquired unveils the changes of major tissue biochemicals (e.g., triolein, elastin, keratin, fibrillar collagen, and type IV collagen) associated with primary NPC and post-treatment recurrent NPC tissue compared to normal nasopharyngeal tissue. This work demonstrates that fiberoptic Raman endoscopy can be a clinically powerful diagnostic tool for rapid, label-free post-treatment surveying and recurrent tumor detection in NPC patients at the molecular level.

Recently, the effects of ketamine on the circadian rhythm have suggested that ketamine’s rapid antidepressant effects are associated with and without sleep disturbance improvement. Here, we evaluated the antidepressant efficacy of repeated ketamine infusions in patients with sleep disturbances. This study included 127 patients with major depressive disorder or bipolar disorder who received ketamine treatments during a 12-day period. Sleep quality was assessed by the 17-item Hamilton Depression Rating Scale sleep disturbance factor (SDF) (items 4, 5 and 6). Serum brain-derived neurotrophic factor (BDNF) was measured at baseline, day 13 and day 26. This study was a post-hoc analysis. Significant differences were found in the HAMD-17 score at 13 post-infusion time points compared to baseline, as well as the scores in SDF score at each of the 7 post-infusion (4 h after each infusion excluded) time points among all patients. Logistic regression and linear correlation analyses revealed that a greater reduction in the SDF after 24 h of the first ketamine infusion resulted in a better antidepressant effect in the last two follow-up visits. Moreover, BDNF levels were significantly higher in sleep responders than in non-responders. In the 127 patients, six ketamine infusions induced better therapeutic effects in sleep responders than in sleep non-responders and patients without sleep disturbances. The sleep response after repeated ketamine infusions was positively associated with high serum BDNF levels. Early sleep disturbance improvement (as early as 24 h after the first ketamine injection) may predict the antidepressant effect of repeated-dose ketamine.