tbuckley/cabot-search huggingface dataset:
Spatial Metabolomics Identifies Distinct Tumor-Specific Subtypes in Gastric Cancer Patients
Authors: Jun Wang, Thomas Kunzke, Verena M. Prade, Jian Shen, Achim Buck, Annette Feuchtinger, Ivonne Haffner, Birgit Luber, Drolaiz H.W. Liu, Rupert Langer, Florian Lordick, Na Sun, Axel Walch
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Current systems of gastric cancer molecular classification include genomic, molecular, and morphological features. Gastric cancer classification based on tissue metabolomics remains lacking. This study aimed to define metabolically distinct gastric cancer subtypes and identify their clinicopathological and molecular characteristics. Experimental Design: Spatial metabolomics by high mass resolution imaging mass spectrometry was performed in 362 patients with gastric cancer. K−means clustering was used to define tumor and stroma-related subtypes based on tissue metabolites. The identified subtypes were linked with clinicopathological characteristics, molecular features, and metabolic signatures. Responses to trastuzumab treatment were investigated across the subtypes by introducing an independent patient cohort with HER2-positive gastric cancer from a multicenter observational study. Results: Three tumor- and three stroma-specific subtypes with distinct tissue metabolite patterns were identified. Tumor-specific subtype T1(HER2+MIB+CD3+) positively correlated with HER2, MIB1, DEFA-1, CD3, CD8, FOXP3, but negatively correlated with MMR. Tumor-specific subtype T2(HER2−MIB−CD3−) negatively correlated with HER2, MIB1, CD3, FOXP3, but positively correlated with MMR. Tumor-specific subtype T3(pEGFR+) positively correlated with pEGFR. Patients with tumor subtype T1(HER2+MIB+CD3+) had elevated nucleotide levels, enhanced DNA metabolism, and a better prognosis than T2(HER2−MIB−CD3−) and T3(pEGFR+). An independent validation cohort confirmed that the T1 subtype benefited from trastuzumab therapy. Stroma-specific subtypes had no association with clinicopathological characteristics, however, linked to distinct metabolic pathways and molecular features. Conclusions: Patient subtypes derived by tissue-based spatial metabolomics are a valuable addition to existing gastric cancer molecular classification systems. Metabolic differences between the subtypes and their associations with molecular features could provide a valuable tool to aid in selecting specific treatment approaches.
Long-term trends in urban NO2 concentrations and associated paediatric asthma incidence: estimates from global datasets
Authors: Susan C Anenberg, Arash Mohegh, Daniel L Goldberg, Gaige H Kerr, Michael Brauer, Katrin Burkart, Perry Hystad, Andrew Larkin, Sarah Wozniak, Lok Lamsal
Journal: The Lancet Planetary Health (2022)

BackgroundCombustion-related nitrogen dioxide (NO2) air pollution is associated with paediatric asthma incidence. We aimed to estimate global surface NO2 concentrations consistent with the Global Burden of Disease study for 1990–2019 at a 1 km resolution, and the concentrations and attributable paediatric asthma incidence trends in 13 189 cities from 2000 to 2019.MethodsWe scaled an existing annual average NO2 concentration dataset for 2010–12 from a land use regression model (based on 5220 NO2 monitors in 58 countries and land use variables) to other years using NO2 column densities from satellite and reanalysis datasets. We applied these concentrations in an epidemiologically derived concentration–response function with population and baseline asthma rates to estimate NO2-attributable paediatric asthma incidence.FindingsWe estimated that 1·85 million (95% uncertainty interval [UI] 0·93–2·80 million) new paediatric asthma cases were attributable to NO2 globally in 2019, two thirds of which occurred in urban areas (1·22 million cases; 95% UI 0·60–1·8 million). The proportion of paediatric asthma incidence that is attributable to NO2 in urban areas declined from 19·8% (1·22 million attributable cases of 6·14 million total cases) in 2000 to 16·0% (1·24 million attributable cases of 7·73 million total cases) in 2019. Urban attributable fractions dropped in high-income countries (–41%), Latin America and the Caribbean (–16%), central Europe, eastern Europe, and central Asia (–13%), and southeast Asia, east Asia, and Oceania (–6%), and rose in south Asia (+23%), sub-Saharan Africa (+11%), and north Africa and the Middle East (+5%). The contribution of NO2 concentrations, paediatric population size, and asthma incidence rates to the change in NO2-attributable paediatric asthma incidence differed regionally.InterpretationDespite improvements in some regions, combustion-related NO2 pollution continues to be an important contributor to paediatric asthma incidence globally, particularly in cities. Mitigating air pollution should be a crucial element of public health strategies for children.FundingHealth Effects Institute, NASA.
Does hormonal therapy improve sperm retrieval rates in men with non-obstructive azoospermia: a systematic review and meta-analysis
Authors: Tharu Tharakan, Giovanni Corona, Daniel Foran, Andrea Salonia, Nikolaos Sofikitis, Aleksander Giwercman, Csilla Krausz, Tet Yap, Channa N Jayasena, Suks Minhas
Journal: Human Reproduction Update (2022)

The beneficial effects of hormonal therapy in stimulating spermatogenesis in patients with non-obstructive azoospermia (NOA) and either normal gonadotrophins or hypergonadotropic hypogonadism prior to surgical sperm retrieval (SSR) is controversial. Although the European Association of Urology guidelines state that hormone stimulation is not recommended in routine clinical practice, a significant number of patients undergo empiric therapy prior to SSR. The success rate for SSR from microdissection testicular sperm extraction is only 40-60%, thus hormonal therapy could prove to be an effective adjunctive therapy to increase SSR rates.The primary aim of this systematic review and meta-analysis was to compare the SSR rates in men with NOA (excluding those with hypogonadotropic hypogonadism) receiving hormone therapy compared to placebo or no treatment. The secondary objective was to compare the effects of hormonal therapy in normogonadotropic and hypergonadotropic NOA men.A literature search was performed using the Medline, Embase, Web of Science and Clinicaltrials.gov databases from 01 January 1946 to 17 September 2020. We included all studies where hormone status was confirmed. We excluded non-English language and animal studies. Heterogeneity was calculated using I2 statistics and risk of bias was assessed using Cochrane tools. We performed a meta-analysis on all the eligible controlled trials to determine whether hormone stimulation (irrespective of class) improved SSR rates and also whether this was affected by baseline hormone status (hypergonadotropic versus normogonadotropic NOA men). Sensitivity analyses were performed when indicated.A total of 3846 studies were screened and 22 studies were included with 1706 participants. A higher SSR rate in subjects pre-treated with hormonal therapy was observed (odds ratio (OR) 1.96, 95% CI: 1.08-3.56, P = 0.03) and this trend persisted when excluding a study containing only men with Klinefelter syndrome (OR 1.90, 95% CI: 1.03-3.51, P = 0.04). However, the subgroup analysis of baseline hormone status demonstrated a significant improvement only in normogonadotropic men (OR 2.13, 95% CI: 1.10-4.14, P = 0.02) and not in hypergonadotropic patients (OR 1.73, 95% CI: 0.44-6.77, P = 0.43). The literature was at moderate or severe risk of bias.This meta-analysis demonstrates that hormone therapy is not associated with improved SSR rates in hypergonadotropic hypogonadism. While hormone therapy improved SSR rates in eugonadal men with NOA, the quality of evidence was low with a moderate to high risk of bias. Therefore, hormone therapy should not be routinely used in men with NOA prior to SSR and large scale, prospective randomized controlled trials are needed to validate the meta-analysis findings.
Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor–Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002)
Authors: Xin Hua, Xi-Wen Bi, Jian-Li Zhao, Yan-Xia Shi, Ying Lin, Zhi-Yong Wu, Yuan-Qi Zhang, Le-Hong Zhang, An-Qing Zhang, Heng Huang, Xin-Mei Liu, Fei Xu, Ying Guo, Wen Xia, Ruo-Xi Hong, Kui-Kui Jiang, Cong Xue, Xin An, Yong-Yi Zhong, Shu-Sen Wang, Jia-Jia Huang, Zhong-Yu Yuan
Journal: Clinical Cancer Research (2021)

There is no research evidence demonstrate which is the better partner strategy, endocrine therapy or chemotherapy, to combine with anti-HER2 therapy as the first-line management of hormone receptor (HR)-positive (HR+) and HER2-positive (HER2+) metastatic breast cancer (MBC). We wished to ascertain if trastuzumab plus endocrine therapy is noninferior to trastuzumab plus chemotherapy.
Cancer incidence, patterns, and genotype–phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study
Authors: Kelvin César de Andrade, Payal P Khincha, Jessica N Hatton, Megan N Frone, Talia Wegman-Ostrosky, Phuong L Mai, Ana F Best, Sharon A Savage
Journal: The Lancet Oncology (2021)
Outcome of Patients With an Ultralow-Risk 70-Gene Signature in the MINDACT Trial
Authors: Josephine M.N. Lopes Cardozo, Caroline A. Drukker, Emiel J.T. Rutgers, Marjanka K. Schmidt, Annuska M. Glas, Anke Witteveen, Fatima Cardoso, Martine Piccart, Laura J. Esserman, Coralie Poncet, Laura J. van 't Veer
Journal: Journal of Clinical Oncology (2022)

Patients with 70-gene signature ultralow-risk breast cancers have shown excellent survival in historic cohorts, including randomized trials. The ultralow-risk subgroup was characterized to help avoid overtreatment. We evaluated outcomes of ultralow-risk patients in the largest cohort to date.Of the 6,693 patients enrolled in the EORTC-10041/BIG-3-04 randomized phase III MINDACT trial, profiling revealed an ultralow-risk 70-gene signature in 1,000 patients (15%). Distant metastasis-free interval (DMFI) and breast cancer-specific survival (BCSS) were assessed in patients stratified by 70-gene signature result (high, low, and ultralow) by Kaplan-Meier analysis and hazard ratios with 95% CI from Cox regression.Median follow-up was 8.7 years. Of the ultralow-risk patients (n = 1,000), 67% were > 50 years, 81% had tumors ≤ 2 cm, 80% were lymph node-negative, 96% had grade 1 or 2 tumors, and 99% were estrogen receptor (ER)-positive. Systemic therapy was received by 84% of patients (69% endocrine therapy, 14% endocrine therapy plus chemotherapy, 1% other) and 16% received no adjuvant systemic treatment. The 8-year DMFI for ultralow-risk patients was 97.0% (95% CI, 95.8 to 98.1), which was 2.5% higher than for patients with low-risk tumors (n = 3,295, 94.5% [95% CI, 93.6 to 95.3]). The hazard ratio for DMFI was 0.65 (95% CI, 0.45 to 0.94) for ultralow versus low risk, after adjusting for clinical-pathologic and treatment characteristics. The 8-year BCSS for ultralow-risk patients was 99.6% (95% CI, 99.1 to 100).Patients with an ultralow-risk 70-gene signature have the best prognosis, distinctive from low risk, with 8-year BCSS above 99%, and very few patients developed distant metastases with an 8-year DMFI rate of 97%. These patients could be candidates for further de-escalation of treatment, to avoid overtreatment and the risk of side effects.
Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype
Authors: Younglang Lee, Alex W. Wessel, Jiazhi Xu, Julia G. Reinke, Eries Lee, Somin M. Kim, Amy P. Hsu, Jevgenia Zilberman-Rudenko, Sha Cao, Clinton Enos, Stephen R. Brooks, Zuoming Deng, Bin Lin, Adriana A. de Jesus, Daniel N. Hupalo, Daniela G.P. Piotto, Maria T. Terreri, Victoria R. Dimitriades, Clifton L. Dalgard, Steven M. Holland, Raphaela Goldbach-Mansky, Richard M. Siegel, Eric P. Hanson
Journal: Journal of Clinical Investigation (2022)

Host defense and inflammation are regulated by the NF-κB essential modulator (NEMO), a scaffolding protein with a broad immune cell and tissue expression profile. Hypomorphic mutations in inhibitor of NF-κB kinase regulatory subunit gamma (IKBKG) encoding NEMO typically present with immunodeficiency. Here, we characterized a pediatric autoinflammatory syndrome in 3 unrelated male patients with distinct X-linked IKBKG germline mutations that led to overexpression of a NEMO protein isoform lacking the domain encoded by exon 5 (NEMO-Δex5). This isoform failed to associate with TANK binding kinase 1 (TBK1), and dermal fibroblasts from affected patients activated NF-κB in response to TNF but not TLR3 or RIG-I-like receptor (RLR) stimulation when isoform levels were high. By contrast, T cells, monocytes, and macrophages that expressed NEMO-Δex5 exhibited increased NF-κB activation and IFN production, and blood cells from these patients expressed a strong IFN and NF-κB transcriptional signature. Immune cells and TNF-stimulated dermal fibroblasts upregulated the inducible IKK protein (IKKi) that was stabilized by NEMO-Δex5, promoting type I IFN induction and antiviral responses. These data revealed how IKBKG mutations that lead to alternative splicing of skipping exon 5 cause a clinical phenotype we have named NEMO deleted exon 5 autoinflammatory syndrome (NDAS), distinct from the immune deficiency syndrome resulting from loss-of-function IKBKG mutations.
Immune Profiling of Combined Hepatocellular- Cholangiocarcinoma Reveals Distinct Subtypes and Activation of Gene Signatures Predictive of Response to Immunotherapy
Authors: Cong Trung Nguyen, Stefano Caruso, Pascale Maille, Aurélie Beaufrère, Jérémy Augustin, Loetitia Favre, Anaïs Pujals, Camille Boulagnon-Rombi, Rami Rhaiem, Giuliana Amaddeo, Luca di Tommaso, Alain Luciani, Hélène Regnault, Raffaele Brustia, Olivier Scatton, Frédéric Charlotte, Isabelle Brochériou, Daniele Sommacale, Patrick Soussan, Vincent Leroy, Alexis Laurent, Van Ky Le, Van To Ta, Hong Son Trinh, Thi Lan Tran, David Gentien, Audrey Rapinat, Jean Charles Nault, Manon Allaire, Sebastien Mulé, Jessica Zucman-Rossi, Jean-Michel Pawlotsky, Christophe Tournigand, Fouad Lafdil, Valérie Paradis, Julien Calderaro
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare malignancy associated with an overall poor prognosis. We aimed to investigate the immune profile of cHCC-CCA and determine its impact on disease outcome. Experimental Design: We performed a multicenter study of 96 patients with cHCC-CCA. Gene expression profile was analyzed using nCounter PanCancer IO 360 Panel. Densities of main immune cells subsets were quantified from digital slides of IHC stainings. Genetic alterations were investigated using targeted next-generation sequencing. Results: Two main immune subtypes of cHCC-CCA were identified by clustering analysis: an “immune-high” (IH) subtype (57% of the cases) and an “immune-low” (IL) subtype (43% of the cases). Tumors classified as IH showed overexpression of genes related to immune cells recruitment, adaptive and innate immunity, antigen presentation, cytotoxicity, immune suppression, and inflammation (P &amp;lt; 0.0001). IH cHCC-CCAs also displayed activation of gene signatures recently shown to be associated with response to immunotherapy in patients with HCC. Quantification of immunostainings confirmed that IH tumors were also characterized by higher densities of immune cells. Immune subtypes were not associated with any genetic alterations. Finally, multivariate analysis showed that the IH subtype was an independent predictor of improved overall survival. Conclusions: We have identified a subgroup of cHCC-CCA that displays features of an ongoing intratumor immune response, along with an activation of gene signatures predictive of response to immunotherapy in HCC. This tumor subclass is associated with an improved clinical outcome. These findings suggest that a subset of patients with cHCC-CCA may benefit from immunomodulating therapeutic approaches.
Genomic Analysis of Cutaneous CD30-Positive Lymphoproliferative Disorders
Authors: Farah R Abdulla, Weiwei Zhang, Xiwei Wu, Kord Honda, Hanjun Qin, Hyejin Cho, Christiane Querfeld, Jasmine Zain, Steven T. Rosen, Wing C. Chan, Vishwas Parekh, Joo Y. Song
Journal: Blood (2021)
FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes
Authors: Nina Kim, Kelly J. Norsworthy, Sriram Subramaniam, Haiyan Chen, Michael L. Manning, Eliford Kitabi, Justin Earp, Lori A. Ehrlich, Olanrewaju O. Okusanya, Jonathon Vallejo, Brenda J. Gehrke, R. Angelo de Claro, Richard Pazdur
Journal: Clinical Cancer Research (2022)

Abstract On July 7, 2020, the Food and Drug Administration approved Inqovi (Otsuka Pharmaceutical Co.), an oral fixed-dose combination tablet comprising 35 mg decitabine, a hypomethylating agent, and 100 mg cedazuridine, a cytidine deaminase inhibitor (abbreviated DEC-C) for treatment of adult patients with myelodysplastic syndromes (MDS). Evidence of effectiveness of DEC-C was established in phase III ASTX727-02 (N = 133) in adults with MDS. The study involved a two-sequence crossover comparing DEC-C and intravenous (IV) decitabine 20 mg/m2 once daily for the first 5 days of each 28-day cycle in the first 2 cycles. From cycle 3 onward, patients received DEC-C. Five-day cumulative area under the curve (5-d AUC) of decitabine for DEC-C was similar to that of IV decitabine, with geometric mean ratio 0.99 (90% confidence interval: 0.93–1.06). Clinical benefit was supported by study ASTX727-02 and the similarly designed phase II study ASTX727-01-B (n = 80), with complete remission (CR) of 21% and 18% and median duration of CR 7.5 and 8.7 months, respectively. Adverse reactions were consistent with IV decitabine. Postmarketing assessments were issued to address the effect of cedazuridine on QT prolongation, food effect, moderate and severe hepatic impairment, and severe renal impairment on the pharmacokinetics and safety of DEC-C.
scINSIGHT for interpreting single-cell gene expression from biologically heterogeneous data
Authors: Kun Qian, Shiwei Fu, Hongwei Li, Wei Vivian Li
Journal: Genome biology (2022)

The increasing number of scRNA-seq data emphasizes the need for integrative analysis to interpret similarities and differences between single-cell samples. Although different batch effect removal methods have been developed, none are suitable for heterogeneous single-cell samples coming from multiple biological conditions. We propose a method, scINSIGHT, to learn coordinated gene expression patterns that are common among, or specific to, different biological conditions, and identify cellular identities and processes across single-cell samples. We compare scINSIGHT with state-of-the-art methods using simulated and real data, which demonstrate its improved performance. Our results show the applicability of scINSIGHT in diverse biomedical and clinical problems.
Primary Intraosseous Squamous Cell Carcinoma of the Mandible Mimicking Inflammation on FDG PET/CT
Authors: Qiuping Fan, Rang Wang, Rong Tian, Minggang Su
Journal: Clinical Nuclear Medicine (2021)

Primary intraosseous squamous cell carcinoma (SCC) is an uncommon malignant cancer involving the jaw bones. We herein reported the imaging findings of a primary intraosseous SCC of the mandible in a 47-year-old man. He was diagnosed as cancer of unknown primary in the cervical node. FDG PET/CT revealed a focal hypermetabolic lesion around the tooth root of the right lower molar. MRI showed the lesion had hyperintensity on T2-weighted imaging and significant enhancement on T1-weighted imaging fat saturate images. The final diagnosis of primary intraosseous SCC of mandible was confirmed pathologically.
A Validated Risk Prediction Model for Breast Cancer in US Black Women
Authors: Julie R. Palmer, Gary Zirpoli, Kimberly A. Bertrand, Tracy Battaglia, Leslie Bernstein, Christine B. Ambrosone, Elisa V. Bandera, Melissa A. Troester, Lynn Rosenberg, Ruth M. Pfeiffer, Ludovic Trinquart
Journal: Journal of Clinical Oncology (2021)

PURPOSE Breast cancer risk prediction models are used to identify high-risk women for early detection, targeted interventions, and enrollment into prevention trials. We sought to develop and evaluate a risk prediction model for breast cancer in US Black women, suitable for use in primary care settings. METHODS Breast cancer relative risks and attributable risks were estimated using data from Black women in three US population-based case-control studies (3,468 breast cancer cases; 3,578 controls age 30-69 years) and combined with SEER age- and race-specific incidence rates, with incorporation of competing mortality, to develop an absolute risk model. The model was validated in prospective data among 51,798 participants of the Black Women's Health Study, including 1,515 who developed invasive breast cancer. A second risk prediction model was developed on the basis of estrogen receptor (ER)–specific relative risks and attributable risks. Model performance was assessed by calibration (expected/observed cases) and discriminatory accuracy (C-statistic). RESULTS The expected/observed ratio was 1.01 (95% CI, 0.95 to 1.07). Age-adjusted C-statistics were 0.58 (95% CI, 0.56 to 0.59) overall and 0.63 (95% CI, 0.58 to 0.68) among women younger than 40 years. These measures were almost identical in the model based on estrogen receptor–specific relative risks and attributable risks. CONCLUSION Discriminatory accuracy of the new model was similar to that of the most frequently used questionnaire-based breast cancer risk prediction models in White women, suggesting that effective risk stratification for Black women is now possible. This model may be especially valuable for risk stratification of young Black women, who are below the ages at which breast cancer screening is typically begun.
LncRNA HIF1A-AS1 Promotes Gemcitabine Resistance of Pancreatic Cancer by Enhancing Glycolysis through Modulating the AKT/YB1/HIF1α Pathway
Authors: Fengyu Xu, Mengqi Huang, Qingyong Chen, Yi Niu, Yuhang Hu, Ping Hu, Ding Chen, Chi He, Kang Huang, Zhu Zeng, Jiang Tang, Fan Wang, Yong Zhao, Chunyou Wang, Gang Zhao
Journal: Cancer Research (2021)

Gemcitabine (GEM) resistance is a major challenge for chemotherapy of pancreatic cancer. Previous studies have reported on the role of long noncoding RNA (lncRNA) in tumorigenesis of pancreatic cancer, however, the involvement of lncRNA in the development of GEM resistance of pancreatic cancer remains unclear. In the present study, we demonstrated that the antisense RNA1 of HIF1α (HIF1A-AS1) was significantly elevated in the GEM-resistant pancreatic cancer cells. Gain- and lost-of-function experiments validated that HIF1A-AS1 promoted GEM resistance of pancreatic cancer cells both in vitro and vivo. We further revealed that HIF1A-AS1 upregulated HIF1α expression and thus promoted glycolysis to enhance GEM resistance of pancreatic cancer cells. Mechanistically, HIF1A-AS1 facilitated the interaction between serine/threonine kinase AKT and Y-box-binding protein 1 (YB1), which promoted phosphorylation of YB1 (pYB1). Meanwhile, HIF1A-AS1 recruited pYB1 to HIF1α mRNA that consequently promoted translation of HIF1α. Furthermore, HIF1α promoted HIF1A-AS1 transcription by directly binding to the HIF1α response element in the promoter area of HIF1A-AS1 to form a positive feedback. Consistently, both HIF1A-AS1 and HIF1α were upregulated in pancreatic cancer tissues and associated with poor overall survival. Together, our results underline a reciprocal loop of HIF1A-AS1 and HIF1α that contributes to GEM resistance of pancreatic cancer and indicate that HIF1A-AS1 might serve as a novel therapeutic target for GEM resistance of pancreatic cancer. SIGNIFICANCE: These findings show that a reciprocal feedback of HIF1A-AS1 and HIF1α promotes gemcitabine resistance of pancreatic cancer, which provides an applicable therapeutic target.