tbuckley/cabot-search huggingface dataset:
Is adjuvant chemotherapy after secondary debulking surgery for recurrent ovarian cancer necessary?
Authors: Munetaka Takekuma, Keita Mori, Satomi Komeda, Shiho Kuji, Aki Tanaka, Nobutaka Takahashi, Masakazu Abe, Yasuyuki Hirashima
Journal: Journal of Clinical Oncology (2013)

e16507 Background: Secondary debulking surgery (SDS) for recurrent ovarian cancer is recognized as a valuable options. However, to our knowledge, the value of chemotherapy after SDS has not been reported. Methods: Between November 2003 and November 2011, 30 patients with recurrent ovarian cancer underwent SDS at our hospital. We statistically analyzed which variables influenced survival. Results: After SDS, the median follow-up was 22.9 months, and the median survival was 26.7 months (range, 0.1-61 months). Twenty-five patients (83.3%) had no residual tumor after SDS. With Fisher's exact method, the patients who had serum CA125 levels ≥ 40 U/ml tended to show disease progression after SDS (p = 0.13). Adjuvant chemotherapy after SDS had no significant clinical benefit with regard to disease progression (p = 0.25). Moreover, log-rank test showed median progression free survival to be 31.8 months for patients who had serum CA125 levels &lt; 40 U/ml as compared with 8.9 months for patients who had serum CA125 levels ≥ 40 U/ml (p = 0.0351). For patients who received adjuvant chemotherapy after SDS, the median progression free survival was 13.0 months, versus 8.0 months for patients not given adjuvant chemotherapy after SDS (p = 0.5871). Conclusions: We suggest that a serum CA125 level &lt; 40 U/ml should be used as a selection criterion for offering SDS. Adjuvant chemotherapy after SDS does not appear to prolong survival. We advocate that a randomized trial to verify the necessity of chemotherapy after SDS be initiated to confirm this finding.
Indicators of impending pig kidney and heart xenograft failure: Relevance to clinical organ xenotransplantation - Review article
Authors: Hayato Iwase, Abhijit Jagdale, Takayuki Yamamoto, Guoqiang Zhang, Qi Li, Jeremy Foote, David Ayares, Burcin Ekser, Hidetaka Hara, David K C Cooper
Journal: International Journal of Surgery (2019)
Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice
Authors: Jasper M. A. de Jong, Wenfei Sun, Nuno D. Pires, Andrea Frontini, Miroslav Balaz, Naja Z. Jespersen, Amir Feizi, Katarina Petrovic, Alexander W. Fischer, Muhammad Hamza Bokhari, Tarja Niemi, Pirjo Nuutila, Saverio Cinti, Søren Nielsen, Camilla Scheele, Kirsi Virtanen, Barbara Cannon, Jan Nedergaard, Christian Wolfrum, Natasa Petrovic
Journal: Nature Metabolism (2019)
A distinct subset of FcγRI-expressing Th1 cells exert antibody-mediated cytotoxic activity
Authors: Diana Rasoulouniriana, Nadine Santana-Magal, Amit Gutwillig, Leen Farhat-Younis, Yariv Wine, Corey Saperia, Lior Tal, Haim Gutman, Alexander Tsivian, Ronen Brenner, Eiman Abu Bandora, Nathan E. Reticker-Flynn, Peleg Rider, Yaron Carmi
Journal: Journal of Clinical Investigation (2019)

While a high frequency of Th1 cells in tumors is associated with improved cancer prognosis, this benefit has been attributed mainly to support of cytotoxic activity of CD8+ T cells. By attempting to potentiate antibody-driven immunity, we found a remarkable synergy between CD4+ T cells and tumor-binding antibodies. This surprising synergy was mediated by a small subset of tumor-infiltrating CD4+ T cells that express the high-affinity Fcγ receptor for IgG (FcγRI) in both mouse and human patients. These cells efficiently lyse tumor cells coated with antibodies through concomitant crosslinking of their T cell receptor (TCR) and FcγRI. By expressing FcγRI and its signaling chain in conventional CD4+ T cells, we successfully employed this mechanism to treat established solid cancers. Overall, this discovery sheds new light on the biology of this T cell subset, their function during tumor immunity, and the means to utilize their unique killing signals in immunotherapy.
SAT0190 Hfe genotype in patients with rheumatic diseases
Authors: MM Etemad, UH Hanusch-Enserer, KC Cauza, AD Dunky, EC Cauza
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Hereditary haemochromatosis is a very common autosomal recessive disorder of iron metabolism. Among Northern Europeans the carrier frequency is estimated 1 in 10, while up to 1 in 200 are affected by the disease. Arthropathy is one early clinical manifestation of this disease (the spectrum ranged from arthralgia to classic polyarthrits), but the articular features are often misdiagnosed. We tested the usefulness of measuring the HLA-linked haemochromatosis gene (HFE) in rheumatology clinic population. <h3>Objectives</h3> <h3>Methods</h3> Over a period of 12 month 203 consecutive patients, mean age 62.0 years (33 male/170 female) attending our rheumatologic clinic were screened for HFE mutations (C282Y and H63D). Mutations were evaluated by separation on PAGE of digest (by SnapI and Bcl-I, for C282Y and H63D, respectively) of PCR-amplificates of DNA obtained from PBMC's. <h3>Results</h3> The C282Y and H63D allele frequencies were 6.9 and 18.2 in patients with rheumatic diseases. Five patients were homozygote for H63D(2.5%),1 for C282Y(0.5%). Three patients were compound heterozygotes (1.4%). Diagnosis of patients are summarised in Table 1. The observed C282Y allele frequency in rheumatic patients with undifferentiated arthritis exceeded that of healthy subjects or patients with chronic hepatitis C in Austria.<sup>1</sup> <h3>Conclusion</h3> Determination of HFE genotype is clinically useful in the group of patients with undifferentiated peripheral arthropathy and may lead to identification of otherwise unsuspected C282Y homozygotes. <h3>Reference</h3> Kazemi, <i>et al</i>. Gastroenterology 1999;116(1):12–34
Comparing Transbronchial Cryobiopsy and Surgical Biopsy in Idiopathic Pulmonary Fibrosis
Authors: Silvia Quadrelli, Juan Ignacio Enghelmayer, Maria Otaola, Edgardo Sobrino
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

presumably with access to clinical information as well as both TBLC and SLB specimens) and the final diagnosis made at the second multidisciplinary assessment (MDA2) occurred in 17 of 21 cases.This is better than the concordance observed between both blinded SLB and MDA2 (13/21 cases) and TBLC and MDA2 (10/21 cases).Although the additional tissue that local pathologists would have had may be responsible for this difference, we wondered if access to clinical information may have been the major driver.Finally, if an MDA meeting is taken as the gold standard for ILD diagnosis, both blinded SLB and TBLC performed poorly, and the difference in concordance between pathology specimens and MDA2 (13/21 cases for SLB vs. 10/21 cases for TBLC) did not appear dramatic.Given the potential morbidity associated with either biopsy approach, many questioned whether lung biopsy of any kind truly leads to meaningful improvements in clinical outcomes in ILD (6, 7).In conclusion, we commend the authors for their well-done study, and acknowledge our ongoing confusion about the utility of lung histology for ILD diagnosis.Despite the poor concordance between TBLC and SLB, we hope cryobiopsy remains an area of study, as this paper has not completely "cooled off" our interest in this new and less invasive diagnostic technique.
Small molecule immunomodulation: the tumor microenvironment and overcoming immune escape
Authors: Arsen Osipov, May Tun Saung, Lei Zheng, Adrian G. Murphy
Journal: Journal for ImmunoTherapy of Cancer (2019)

Immunotherapy has led to a paradigm shift in the treatment of many advanced malignancies. Despite the success in treatment of tumors like non-small cell lung cancer (NSCLC) and melanoma, checkpoint inhibition-based immunotherapy has limitations. Many tumors, such as pancreatic cancer, are less responsive to checkpoint inhibitors, where patients tend to have a limited duration of benefit and where clinical responses are more robust in patients who are positive for predictive biomarkers. One of the critical factors that influence the efficacy of immunotherapy is the tumor microenvironment (TME), which contains a heterogeneous composition of immunosuppressive cells. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) alter the immune landscape of the TME and serve as facilitators of tumor proliferation, metastatic growth and immunotherapy resistance. Small molecule inhibitors that target these components of the TME have been developed. This special issue review focuses on two promising classes of immunomodulatory small molecule inhibitors: colony stimulating factor-1 receptor (CSF-1R) and focal adhesion kinase (FAK). Small molecule inhibitors of CSF-1R reprogram the TME and TAMs, and lead to enhanced T-cell-mediated tumor eradication. FAK small molecule inhibitors decrease the infiltration MDSCs, TAMs and regulatory T-cells. Additionally, FAK inhibitors are implicated as modulators of stromal density and cancer stem cells, leading to a TME more conducive to an anti-tumor immune response. Immunomodulatory small molecule inhibitors present a unique opportunity to attenuate immune escape of tumors and potentiate the effectiveness of immunotherapy and traditional cytotoxic therapy.
Surgery plus ELFE (epirubicin, leucovorin, 5-fluorouracil and etoposide) vs surgery alone in radically resected gastric cancer (GC): Final results of a randomised phase III trial by the Gruppo Oncologico dell’ Italia Meridionale (GOIM)
Authors: F. De Vita, F. Giuliani, V. Gebbia, G. Galizia, M. Orditura, E. Maiello, S. Romito, G. Cartenì, L. Manzione, G. Catalano, G. Colucci
Journal: Journal of Clinical Oncology (2006)

4014 Background: In a previous phase II study the ELFE regimen resulted to be active and well tolerated for the treatment of advanced GC (Am J Clin Oncol 22:262;1999). Based on this background the G.O.I.M. conducted a randomised phase III study (trial 9602) to evaluate efficacy and toxicity of ELFE regimen as adjuvant therapy for radically resected GC patients (pts). Methods: All enrolled pts underwent total or subtotal gastrectomy with at least a D1 lymphoadenectomy. After stratification for nodal involvement (N+ vs N-) pts were randomised to follow-up alone (116 pts) or 6 cycles of ELFE regimen ( EPI 60mg/m 2 d1, LV100 mg/m 2 d 1–5, 5FU 375 mg/m 2 d 1–5, VP-16 100 mg/m 2 d1–3, every 3 weeks). Results: From June 1997 to June 2001, 228 pts with stage IB-IIIB GC were enrolled. Pts characteristics were: median age 63 yrs (29–70); total gastrectomy 148 pts; N+ 163 pts; PS 0–1 according ECOG scale 210. A total number of 638 cycles were delivered with a median number of 5/pt. During chemotherapy, the most frequent G3–4 side-effects graded according to NCI-CTC included alopecia (32%), neutropenia (26%), diarrhea (26%), nausea/emesis (17%), thrombocytopenia (12%) and stomatitis (11%). With a median follow-up of 60 months, the 5-years overall survival was 48% in the treatment arm and 43.5% in the control arm ( p=0.610); the 5-years disease-free survival was 44% in the treatment arm and 39% in the control arm ( p=0.305). Between patients with positive nodes the 5-years overall survival was 41% in the treatment arm and 34% in the control arm( p=0.068), while the 5-years disease-free survival was 39% in the treatment arm and 31% in the control arm (p=0.052). Multivariate analysis showed TNM stage as the only covariate that was independently associated with overall and disease-free survival. Conclusions: In radically resected GC adjuvantELFE chemotherapy produces an absolute difference in overall survival and disease-free survival at 5 years respectively of 4.5% and 5%, but this advantage was not statistically significant. No significant financial relationships to disclose.
Complement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammation
Authors: Britta Höchsmann, Yoshiko Murakami, Makiko Osato, Alexej Knaus, Michi Kawamoto, Norimitsu Inoue, Tetsuya Hirata, Shogo Murata, Markus Anliker, Thomas Eggermann, Marten Jäger, Ricarda Floettmann, Alexander Höllein, Sho Murase, Yasutaka Ueda, Jun-ichi Nishimura, Yuzuru Kanakura, Nobuo Kohara, Hubert Schrezenmeier, Peter M. Krawitz, Taroh Kinoshita
Journal: Journal of Clinical Investigation (2019)

Patients with paroxysmal nocturnal hemoglobinuria (PNH) have a clonal population of blood cells deficient in glycosylphosphatidylinositol-anchored (GPI-anchored) proteins, resulting from a mutation in the X-linked gene PIGA. Here we report on a set of patients in whom PNH results instead from biallelic mutation of PIGT on chromosome 20. These PIGT-PNH patients have clinically typical PNH, but they have in addition prominent autoinflammatory features, including recurrent attacks of aseptic meningitis. In all these patients we find a germ-line point mutation in one PIGT allele, whereas the other PIGT allele is removed by somatic deletion of a 20q region comprising maternally imprinted genes implicated in myeloproliferative syndromes. Unlike in PIGA-PNH cells, GPI is synthesized in PIGT-PNH cells and, since its attachment to proteins is blocked, free GPI is expressed on the cell surface. From studies of patients’ leukocytes and of PIGT-KO THP-1 cells we show that, through increased IL-1β secretion, activation of the lectin pathway of complement and generation of C5b-9 complexes, free GPI is the agent of autoinflammation. Eculizumab treatment abrogates not only intravascular hemolysis, but also autoinflammation. Thus, PIGT-PNH differs from PIGA-PNH both in the mechanism of clonal expansion and in clinical manifestations.
WTAP facilitates progression of hepatocellular carcinoma via m6A-HuR-dependent epigenetic silencing of ETS1
Authors: Yunhao Chen, Chuanhui Peng, Junru Chen, Diyu Chen, Beng Yang, Bin He, Wendi Hu, Yanpeng Zhang, Hua Liu, Longfei Dai, Haiyang Xie, Lin Zhou, Jian Wu, Shusen Zheng
Journal: Molecular Cancer (2019)

N6-methyladenosine (m6A) methylation, a well-known modification with new epigenetic functions, has been reported to participate in the tumorigenesis of hepatocellular carcinoma (HCC), providing novel insights into the molecular pathogenesis of this disease. However, as the key component of m6A methylation, Wilms tumor 1-associated protein (WTAP) has not been well studied in HCC. Here we investigated the biological role and underlying mechanism of WTAP in liver cancer. We determined the expression of WTAP and its correlation with clinicopathological features using tissue microarrays and the Cancer Genome Atlas (TCGA) dataset. And we clarified the effects of WTAP on HCC cells using cell proliferation assay, colony formation, Edu assay and subcutaneous xenograft experiments. We then applied RNA sequencing combined with gene expression omnibus (GEO) data to screen candidate targets of WTAP. Finally, we investigated the regulatory mechanism of WTAP in HCC by m6A dot blot assay, methylated RNA immunoprecipitation (MeRIP) assay, dual luciferase reporter assay, RNA immunoprecipitation (RIP) assay and Chromatin immunoprecipitation (ChIP) assay. We demonstrated that WTAP was highly expressed in HCC which indicated the poor prognosis, and that WTAP expression served as an independent predictor of HCC survival. Functionally, WTAP promoted the proliferation capability and tumor growth of HCC cells in vitro and in vivo. Furthermore, ETS proto-oncogene 1 (ETS1) was identified as the downstream effector of WTAP. The m6A modification regulated by WTAP led to post-transcriptional suppression of ETS1, with the implication of Hu-Antigen R (HuR) as an RNA stabilizer. Then ETS1 was found to inhibit the progression of HCC and could rescue the phenotype induced by WTAP deficiency. Moreover, WTAP modulated the G2/M phase of HCC cells through a p21/p27-dependent pattern mediated by ETS1. We have identified that WTAP is significantly up-regulated in HCC and promotes liver cancer development. WTAP-guided m6A modification contributes to the progression of HCC via the HuR-ETS1-p21/p27 axis. Our study is the first to report that WTAP-mediated m6A methylation has a crucial role in HCC oncogenesis, and highlights WTAP as a potential therapeutic target of HCC treatment.
Wnt Signaling in Cancer: Not a Binary ON:OFF Switch
Authors: Dustin J. Flanagan, Elizabeth Vincan, Toby J. Phesse
Journal: Cancer Research (2019)

Abstract In the March 1 issue of Cancer Research, we identified the Wnt receptor Fzd7 as an attractive therapeutic target for the treatment of gastric cancer. In summary, we showed that pharmacological inhibition of Wnt receptors, or genetic deletion of Fzd7, blocks the initiation and growth of gastric tumors. Inhibiting Fzd receptors, specifically Fzd7, inhibits the growth of gastric cancer cells even in the presence of adenomatous polyposis coli (Apc) mutation. Apc is located in the cytoplasm downstream of Fzd7 in the Wnt signaling cascade and APC mutations activate Wnt/β-catenin signaling, therefore, this result seems counterintuitive. Here, we analyze this result in greater detail in the context of current knowledge of Wnt signaling and discuss the wider implications of this aspect of Wnt signaling in other cancers.
A phase I trial of the mTOR inhibitor temsirolimus (TEM) in combination with capecitabine (CAP) in patients with advanced malignancies.
Authors: Michael J. Pishvaian, Hongkun Wang, Rosemarie A. Hardesty, John F. Deeken, Aiwu Ruth He, Deepa Suresh Subramaniam, Tingting Zhuang, Damian L. McCarthy, Heather Melville, Christopher Albanese, John Marshall, Jimmy J. Hwang
Journal: Journal of Clinical Oncology (2012)

3095 Background: The mammalian target of rapamycin (mTOR) signaling pathway is critical for cell growth and proliferation. mTOR antagonists, such as TEM, have proven anti-cancer efficacy. Pre-clinical models and early phase clinical trials have demonstrated increased efficacy when an mTOR antagonist is combined with cytotoxic chemotherapy. Methods: Patients (pts) with advanced malignancies and adequate hepatic and renal function were eligible for enrollment. An alternating dose escalation of TEM and CAP was employed in separate q2week and q3week arms. Planned dose levels were: TEM 15 and 25mg IV weekly; and CAP 500, 750, 1000, and 1250 mg/m 2 orally twice daily (BID). Restaging occurred every 4 cycles for the q2week arm, and every 3 cycles for the q3week arm. PK samples assessed serum levels of sirolimus at Day 0, 8, and 15 of the q2week arm. Archived tumor specimens were assayed by immunohistochemistry (IHC) for expression of phospho-AKT, phospo-4EBP1, phoshpo-p70S6, and PTEN. Results: Thirty-two pts were enrolled, 30 of whom were evaluable for toxicity, of which 18 were male, age range 30-72 years, 25 with colorectal cancer. Pts had received an average of 4 prior lines of therapy. The most common adverse events (AEs) were mucositis and fatigue. The most common grade 3/4 AEs were fatigue (n=4), diarrhea (n=2), and hypophosphatemia (n=2). In 16/30 pts, the dose of CAP was reduced. There were two DLTs, both hypophosphatemia in the q3week arm (TEM=25mg and CAP=1000mg/m 2 ). For the q2week arm, the recommended phase II dose (RP2D) was TEM 25 mg + CAP 1000mg/m 2 . For the q3week arm, the RP2D was TEM 25mg + CAP 750mg/m 2 . Twenty-five pts were evaluable for response (18 for OS). There were no PRs or CRs, but 14/25 pts (56%) had SD, with 4/24 (16%) having prolonged SD of &gt;6 months. Median TTP and OS were 3 and 7 months, respectively. Five pts are still on study. PK assessment of serum sirolimus levels, and the results of the IHC on archived tumor samples will be presented. Conclusions: The combination of TEM and CAP is safe on both a q2week and a q3week schedule. The combination demonstrated promising evidence of disease control in this highly refractory population and should be tested in disease-specific phase II trials.
Extreme Hemolysis and Red-Cell Distortion in Erythrocyte Pyruvate Kinase Deficiency
Authors: David G. Nathan, Frank A. Oski, Victor W. Sidel, Louis K. Diamond
Journal: New England Journal of Medicine (1965)

Original Article from The New England Journal of Medicine — Extreme Hemolysis and Red-Cell Distortion in Erythrocyte Pyruvate Kinase Deficiency — Measurements of Erythrocyte Glucose Consumption, Potassium Flux and Adenosine Triphosphate Stability
Myositis Autoantibodies: A Comparison of Results From the Oklahoma Medical Research Foundation Myositis Panel to the Euroimmun Research Line Blot
Authors: Christopher A. Mecoli, Jemima Albayda, Eleni Tiniakou, Julie J. Paik, Umar Zahid, Sonye K. Danoff, Livia Casciola‐Rosen, Maria Casal‐Dominguez, Katherine Pak, Iago Pinal‐Fernandez, Andrew L. Mammen, Lisa Christopher‐Stine
Journal: Arthritis & Rheumatology (2019)
Regulation of rumen development in neonatal ruminants through microbial metagenomes and host transcriptomes
Authors: Nilusha Malmuthuge, Guanxiang Liang, Le Luo Guan
Journal: Genome biology (2019)

In ruminants, early rumen development is vital for efficient fermentation that converts plant materials to human edible food such as milk and meat. Here, we investigate the extent and functional basis of host-microbial interactions regulating rumen development during the first 6 weeks of life. The use of microbial metagenomics, together with quantification of volatile fatty acids (VFAs) and qPCR, reveals the colonization of an active bacterial community in the rumen at birth. Colonization of active complex carbohydrate fermenters and archaea with methyl-coenzyme M reductase activity was also observed from the first week of life in the absence of a solid diet. Integrating microbial metagenomics and host transcriptomics reveals only 26.3% of mRNA transcripts, and 46.4% of miRNAs were responsive to VFAs, while others were ontogenic. Among these, one host gene module was positively associated with VFAs, while two other host gene modules and one miRNA module were negatively associated with VFAs. Eight host genes and five miRNAs involved in zinc ion binding-related transcriptional regulation were associated with a rumen bacterial cluster consisting of Prevotella, Bacteroides, and Ruminococcus. This three-way interaction suggests a potential role of bacteria-driven transcriptional regulation in early rumen development via miRNAs. Our results reveal a highly active early microbiome that regulates rumen development of neonatal calves at the cellular level, and miRNAs may coordinate these host-microbial interactions.
Addressing Limitations in Case-Control Study of Patients Undergoing Resuscitative Endovascular Balloon Occlusion of the Aorta
Authors: William Yuan, Charles H. Cook, Gabriel A. Brat
Journal: JAMA Surgery (2019)

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Correlation of Serum Ferritin Levels with Liver Iron Concentration By MRI Measurement in Sickle Cell Patients with Transfusional Iron Overload
Authors: Germame Ajebo, Abhishek A. Mangaonkar, Imran Ahmad, Nadine Barrett, Leigh Wells, Niren Patel, Hongyan Xu, Abdullah Kutlar
Journal: Blood (2018)