tbuckley/cabot-search huggingface dataset:
The next big LEAP2 understanding ghrelin function
Authors: Zane B. Andrews
Journal: Journal of Clinical Investigation (2019)

Ghrelin is a key signal driving energy seeking and storage in order to reverse energy deficit. In line with this view, the metabolic status of an organism predicts sensitivity to ghrelin, with fasting increasing and obesity decreasing ghrelin sensitivity. However, the mechanism responsible for controlling this sensitivity is unknown. In this issue of the JCI, Mani and colleagues show that plasma levels of plasma liver-enriched antimicrobial peptide-2 (LEAP2), a recently identified hormone that antagonizes the ghrelin receptor, are inversely correlated with those of plasma acyl-ghrelin under conditions of both energy deficit and energy surplus in mice and humans. Their results show that a fall in plasma LEAP2 during energy deficit facilitates the actions of acyl-ghrelin, whereas increased LEAP2 in obesity suppresses the actions of acyl-ghrelin. This important discovery helps reshape our understanding of ghrelin function and may provide a new approach to aiding weight maintenance after diet-induced weight loss.
RRM2 increases MMP9 mRNA expresssion, decreases TSP1 mRNA expression in human oropharyngeal carcinoma KB cells
Authors: Keqiang Zhang, Shuya Hu, Linling Chen, Xiyong Liu, Bingshen Zhou, Yun Yen
Journal: Cancer Research (2008)

1135  Ribonucleotide Reductase (RR) is an enzyme that catalyzes de novo conversion of ribonucleotide 59-diphosphates to their 29-deoxynucleotide forms. It is a rate-limiting step in the production of 29-deoxyribonucleoside 59-triphosphates required for DNA synthesis. RR consists of two subunits, RRM1 and RRM2. RRM2 subunit has been known to function as the catalytic domain of RR. Futher studies also have shown that RRM2 plays important roles in cell proliferation, invasiveness, metastasis and drug resistance. To explore the causative role of RRM2 in invasion and metastasis, we examined the RRM2 overexpression transfectant in human oropharyngeal carcinoma KB cells. Using the quantitative RT-PCR, we demonstrated that overexpression of RRM2 results in increase of MMP2, MMP9 and TIMP2 mRNA expression, while it decreases TSP1 mRNA expression. Gelatin Zymography assay showed that the activities of MMP2 and MMP9 are also induced by RRM2 overexpression. This study may shed light on the mechanism of RRM2 in the regulation of tumor invasion and metastasis.
Exonic mutations associated with atopic dermatitis disrupt lympho‐epithelial Kazal‐type related inhibitor action and enhance its degradation
Authors: Karthik Ramesh, Sri Anusha Matta, Fook Tim Chew, Yu Keung Mok
Journal: Allergy (2019)

Abstract Background Skin desquamation is facilitated by serine proteases KLK5 and KLK7, which are tightly regulated by lympho‐epithelial Kazal‐type related inhibitor (LEKTI). LEKTI itself is controlled through degraded by mesotrypsin. Here, we sought to determine whether LEKTI exonic mutations associated with atopic dermatitis (AD) affect the protease inhibitory activity of LEKTI or its susceptibility to mesotrypsin degradation. Methods The inhibitory activities of the LEKTI domain 4 (D4) and D6 WT and AD‐associated mutants on the enzyme activities of KLK5 and KLK7 were compared using fluorogenic substrates. A keratinocyte cell culture system using HaCat cells was established to assess the role of D6 WT and D386N on triggering inflammation via the induction of thymic stromal lymphopoietin (TSLP). A degradation assay was used to assess the susceptibility of D4 and D6 mutants to mesotrypsin degradation. Results Enzymatic assays revealed that the D6 D386N mutation affected the inhibitory activity of LEKTI on KLK5 but not KLK7. Other exonic mutations on D6 (N368S, V395M, and E420K) and D4 (R267Q) did not alter LEKTI inhibition. The D386N mutation disrupted the role of D6 in suppressing TSLP induction by KLK5 in HaCat cells. Although WT D4 is more susceptible to mesotrypsin degradation than WT D6, the D4 R267Q mutant was more resistant to mesotrypsin degradation, whereas the D6 E420K mutant showed enhanced mesotrypsin‐mediated degradation. Conclusion Exonic mutations in D6, which previously have been associated with AD, may cause a disruption of inhibitory activity on KLK5 or enhance the degradation by mesotrypsin.
Relationships of peripheral blood lymphocyte counts (PBLC) with antitumor activity of NGR-hTNF given in combination with chemotherapy (CT).
Authors: Alessandra Bulotta, Vanesa Gregorc, Gilda Rossoni, Gabriele Todisco, Maria Grazia Viganò, Cristina Ammannati, Giulia Mazzola, Antonio Lambiase, Claudio Bordignon
Journal: Journal of Clinical Oncology (2013)

3038 Background: Antitumor effects of NGR-hTNF (N), a tumor-targeted antivascular agent, are driven at low dose by an early vessel stabilization that greatly enhances both intratumoral CT uptake and T-cell infiltration. Synergism with CT was shown in immunocompetent mice, but not in nude mice lacking functional T cells. Methods: By an individual patient pooled analysis of 396 patients (pts) from 7 ph II trials in 6 tumor types, we estimated the effects of baseline PBLC on the antitumor activity of N (with or without CT) and CT alone. Low dose N (0.8 μg/m 2 ) was given in combination with CT in 171 pts. Control groups of 140 and 85 pts receiving N and CT alone, respectively, were also analyzed. CT was doxorubicin or a platinum-based regimen. In all trials, response to therapy was assessed every 6 weeks by RECIST. Endpoints of interest were response rate (RR, complete plus partial response), disease control rate (DCR, RR plus stable disease), duration of response (DOR) and progression-free survival (PFS). In logistic and Cox regression analyses, PBLC data were dichotomized in high or low levels by the median cutpoint (1.5/mL; 95% CI, 1.4-1.6). Multivariate models included age, sex, PS and tumor type as covariates. Results: In both N-alone and CT-alone groups, there was no statistically significant difference in treatment effect according to baseline PBLC. Conversely, high PBLC were related to better treatment outcome in the N plus CT group, compared to low PBLC. In this N plus CT group, high PBLC (vs low) were associated with higher RR (OR=2.8; 95% CI, 1.2-6.3; p=.01) and DCR (OR=2.6; 1.3-4.9; p=.004), and with longer DOR (HR=0.39; 0.16-0.96; p=.04) and PFS (HR=0.60; 0.43-0.85; p=.004). For high vs low PBLC, RR was 29% vs 14%, DCR 76% vs 57%, median DOR 8.2 vs 6.3 months, and median PFS 5.0 vs 3.0 months, respectively. On multivariate analyses, high PBLC remained an independent predictor of increased RR (OR=2.7; p=.01) and DCR (OR=2.6; p=.005), and improved DOR (HR=0.36; p=.04) and PFS (HR=0.60; p=.005). Conclusions: Consistently with preclinical data, these results highlight the potential value of PBLC in predicting tumor response to NGR-hTNF in combination with CT, which merits further clinical validation Clinical trial information: NCT00994097-NCT00484432-NCT00484276-NCT00484211-NCT00483509-NCT00483080-NCT01358071.
Abstract #3043: Adaptive immunity and childhood acute lymphoblastic leukemia
Authors: Jeffrey Chang, Joseph Wiemels, Anand Chokkalingam, Catherine Metayer, John Wiencke, Patricia Buffler
Journal: Cancer Research (2009)

Childhood acute lymphoblastic leukemia (ALL) has been hypothesized to have an infectious etiology. Although the existence of specific leukemia-causing agents is controversial, it is generally agreed that the lack of immune priming in a child\#8217;s early development may result in abnormal immune responses to microbial challenges later in life and increase the risk of childhood ALL. The current analyses examined the association between childhood ALL and 29 adaptive immune function genes involved in the development and the function of Th1, Th2, T regulatory, and Th17 cells among 377 cases and 448 controls from the Northern California Childhood Leukemia study. The analyses were stratified by Hispanic status when evidence of heterogeneity was observed; otherwise, subjects of all ethnicities were combined for analysis. Single SNP analyses were performed assuming a log-additive model using unconditional logistic regression adjusted for sex, age, Hispanic status, and race. Haplotype analyses were performed using the sliding window approach with haplotypes consisted of 2 to 6 SNPs. Of the 208 SNPs analyzed, 19 SNPs belonging to 10 genes (IL12A, STAT4, IL12B, GATA3, PHF11, STAT6, IL10, CTLA4, IL2RA, and MME) showed a significant (p  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3043.
Malignancy testing by AmpliSeq cancer panel sequencing-based assessment in NSCLC.
Authors: Rensheng Lai, Xiaobin Wu, Yi Sun, Jie Chen, Ling Xie, Bo Yu, Lele Sun
Journal: Journal of Clinical Oncology (2013)

e22026 Background: Bringing PGM sequencing into clinical laboratories needs the same confidence and consistency with Sanger sequencing. We have developed a approach to assess the known EGFR mutation of NSCLC using AmpliSeq Cancer Panel and demonstrated high specificity and sensitivity. Methods: Fifteen standard cell line samples with known EGFR mutation frequency (1%, 5%, 20%, 50%) were issued by CPC of National Health Ministry. These were first examined by sanger sequencing, then by AmpliSeq cancer panel on PGM. Results were compared each other. Next, we applied the AmpliSeq cancer panel sequencing to test the mutation status of 8 clinical malignancy FFPE samples including 4 NSCLC, 1 Esophagus Cancer, 1 Breast Cancer, 1 Gastric Cancer and 1 stroma tumor. gDNA was extracted from FFPE section then subject to library construction. Emulsion PCR was performed and beads were enriched, Sequencing was performed with 200 bp readlength by pooling 2-4 samples on one 314 chip. Data yield ranges from 13,311 to 203,061 eligible reads (2 Mb to 44M) per sample. Results: Validation of AmpliSeq Cancer Panel Sequencing: Among all 15 samples, 14 cases (14/15, 93%) were confirmed by Sanger sequencing. AmpliSeq FFPE malignancy: For all 8 FFPE samples, the sequencing depth of EGFR site ranges from 20x to 2000x with 100% on-target coverage. Each patient can be identified with more than 3 target drugs based on mutant frequency (&gt;5%) with 99% confidence (CI 0.99-0.995). All patients were shown with the presence of rare subpopulations of interrogating 739 mutations in 46 genes (0.1% to 94% allele frequency). Conclusions: AmpliSeq cancer panel sequencing shows equal or higher sensitivity to sanger sequencing . Call analysis shows that a minimum of 100x coverage is required to detect mutations ≥ 5%. [Table: see text]
Order of genetic events during colorectal carcinogenesis revealed by analysis of cell subpopulations
Authors: Teodora Goranova, Masayuki Ohue, Kikuya Kato
Journal: Cancer Research (2008)

4581  Multi-stage carcinogenesis is an important concept in cancer biology. The model of Vogelstein and colleagues on temporal sequence of genetic events in colorectal cancer (APC → K-ras → p53) is known as a typical example. However, it is based on adenoma-carcinoma sequence and data from cohorts of patients, and lacks direct evidence in individual tumor tissues.  Biological and genetic heterogeneity within a single cancer tissue is a biological feature of human cancer. We hypothesize that the heterogeneity would be derived from the co-existence of precursors of the final form, i.e., the major population, and that the identification of the precursors enables us to trace the order of genetic events.  Seventy-nine bulk colorectal cancer tissue samples were examined for mutations in genes APC, K-ras and p53. In eleven tissues, all three genes had mutations, and these samples were used in the experiments. In order to analyze intratumor heterogeneity of mutations, 50 regions (100x100x40µm) consisting of only tumor cells were microdissected from each sample. Mutational status was determined by SNaPshot assay, a primer extension assay.  In eight out of ten tumor tissues analyzed, we identified cancer cell subpopulations corresponding to putative precursors: those with mutations in one or two of the three genes. The results are summarized in the table. The deduced temporal sequences of the mutations are various. The results with two tissues accompanying adenoma histology did not contradict the core of the Vogelstein model, i.e., APC is the first.  Our approach is promising to uncover the process of carcinogenesis directly from the patient’s tumor tissue. Because intratumor heterogeneity is a common characteristic of human cancer, the approach should work with other cancers.
Concerns About Potential Bias in a Randomized Clinical Trial of Integrated Prolonged Exposure Therapy vs Seeking Safety Integrated Coping Skills Therapy
Authors: Lisa M. Najavits
Journal: JAMA Psychiatry (2019)

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Edith Irby Jones: broke through racial barriers to ensure poor patients got the best possible care
Authors: Rebecca Wallersteiner
Journal: BMJ (2019)

Fig 1 
Edith Irby Jones graduated from University of Arkansas for Medical Sciences in 1952



Edith Irby Jones, who devoted her life to treating poor patients and is widely believed to have been the first black student enrolled in any all white medical school in the American South, has died at the age of 91.

Edith Mae Irby was born in Mayflower, Arkansas, to Mattie, a domestic worker, and Robert, a sharecropper. The family lived on a farm. When Edith was around 3 years old, her father was fatally injured after his horse was stung by a bee and kicked him in the chest. The fatherless family were evicted from their home by the owner, owing to a small debt. Further tragedy followed four years later, in the early 1930s, when Edith’s older siblings contracted typhoid fever. Her brother Robert recovered, but her sister, Juanita, died. Seven year old Edith was haunted by the thought that Juanita had received inadequate care because they were poor. She recalled that a doctor had visited Juanita just once while she was sick, lavishing more time on his affluent patients. It was then that Edith determined to become a doctor who would care for neglected poor people. “I was going to particularly see those who did not have money and those who were less fortunate, who would get the kind of care that …
Identification and characterization of a new tumor antigen: SPCT-1
Authors: Raphael B. Parmigiani, Marilene H. Lopes, Isabela W. Cunha, Fernando A. Soares, Sandro J. De Souza, Anamaria A. Camargo
Journal: Cancer Research (2005)

5141  Based on a transcriptome database generated through the alignment of expressed sequences tags (ESTs) to the human genome sequence, we developed a transcript finishing strategy for the characterization of new human genes1. Using this strategy we identified a transcript cluster composed of ESTs derived from normal testis and tumor tissues. This suited the expression pattern observed for a category of tumor antigens: the cancer-testis (CT) antigens. These antigens are considered promising candidates for cancer immunotherapy and the identification of new CT antigens is essential for the development of polyvalent vaccines designed to overcome tumor heterogeneity and antigen loss. The restricted expression pattern of the new transcript was confirmed by RT-PCR using cDNA panels derived from 21 normal tissues and 21 tumor cell lines as well as from tumor samples derived from 15 different types of tumors. Among the 177 tumor samples analyzed, 41% expressed our transcript. The complete sequence of this new transcript, now named SPCT-1, was generated and mapped to chromosome 21. The transcript has 3916bp, distributed over 15 exons and presents several alternative splicing isoforms. The presence of anti-SPCT1 antibodies was examined by Western blot in sera derived from cancer patients and normal individuals. Anti-SPCT1 antibodies were exclusively detected in sera derived from cancer patients (20% of the 148 sera analysed so far). Immunohistochemical analysis for SPCT-1 using a specific polyclonal antibody revealed a strong staining in spermatogonias and in tumor cells. Taken together, these results show that SPCT-1 is a new member of the CT-antigen family with tumor-testis specific expression and high immunogenicity in cancer patients. 1-Ludwig-FAPESP Transcript Finishing Initiative. Genome Res. 2004 Jul;14(7):1413-23
The Pros and Cons of Incorporating Transcriptomics in the Age of Precision Oncology
Authors: Victor T G Lin, Eddy S Yang
Journal: JNCI Journal of the National Cancer Institute (2019)

The treatment of cancer continues to evolve toward personalized therapies based on individual patient and tumor characteristics. Our successes and failures in adopting a precision-oncology approach have demonstrated the utmost importance in identifying the proper predictive biomarkers of response. Until recently, most biomarkers were identified using immunohistochemistry for protein expression or single-gene analysis to identify targetable alterations. With the rapid propagation of next-generation sequencing to evaluate tumor tissue and "liquid biopsies," identification of genomic biomarkers is now standard, particularly in non-small cell lung cancer, for which there is now an extensive catalog of biomarker-directed therapies with more anticipated to come. Despite these great strides, it has also become apparent that using genomic biomarkers alone will be insufficient, as it has been consistently shown that at least one-half of patients who undergo tumor genomic profiling have no actionable alteration. This is perhaps to be expected given the remarkable breadth of nongenetic factors that contribute to tumor initiation and progression. Some have proposed that the next logical step is to use transcriptome profiling to define new biomarkers of response to targeted agents. Recently, results from the WINTHER trial were published, specifically investigating the use of transcriptomics to improve match rates over genomic next-generation sequencing alone. In this review, we discuss the complexities of precision-oncology efforts and appraise the available evidence supporting the incorporation of transcriptomic data into the precision-oncology framework in the historical context of the development of biomarkers for directing cancer therapy.
H7K(R2)2-modified pH-sensitive self-assembled nanoparticles delivering small interfering RNA targeting hepatoma-derived growth factor for malignant glioma treatment
Authors: Meiling Zhou, Nan Jiang, Junting Fan, Song Fu, Honghua Luo, Ping Su, Mingwan Zhang, Huihui Shi, Jiaqi Zeng, Yuan Huang, Yang Li, Hong Shen, Aixia Zhang, Rui Li
Journal: Journal of Controlled Release (2019)
Effect of interleukin-2 (IL-2) and 13-cis retinoic acid (RA) on vascular endothelial growth factor (VEGF) and durable response in patients with advanced solid tumors showing a partial response (PR) or stable disease (SD) to chemotherapy
Authors: F. Recchia, G. Saggio, A. Di Blasio, G. Amiconi, A. Cesta, G. Candeloro, E. Alesse, S. Rea
Journal: Journal of Clinical Oncology (2006)

2521 Background: A large proportion of patients with advanced solid tumors (AST), showing response to chemotherapy, experiences relapse from resistant stem cells that form minimal residual disease (MRD). High serum levels of VEGF have been shown to be associated with MRD and with a short relapse-free survival (RFS). We have shown, that low-dose IL-2 and RA, decreased VEGF and enhanced the immune function of patients with AST responding to chemotherapy (Clin Cancer Res 2001, Anticancer Res 2005). Primary endpoint of this study was to evaluate if IL-2/RA decreased VEGF and restored the immune function in patients with AST that had a PR or SD to chemotherapy. Secondary endpoint was the evaluation of the efficacy of IL2/RA in RFS and overall survival (OS). Methods: 100 consecutive AST patients (66% PR, 34% SD), with a mean VEGF of 520 pg/mm 3 , were entered into the study from 01/97 to 05/04. Median age was 66 years with 57% males. Diagnosis: Lung 28, head &amp; neck 15, kidney 13, gastric 11, ovary 10, breast 10, miscellanea 13. Therapy consisted of self-administered subcutaneous IL-2, 1.8 X 10 6 IU and oral RA, 0.5 mg/Kg for 5 days/week for 2 cycles of 3 weeks, with a 1-week rest, for 1 year. Therapy was continued, with intermittent schedules until progression. Immune function and tumor markers were assessed every 2 months, response every 4 months. Results: After a median follow-up time of 42 months (16–106) and 900 courses of therapy, a statistically significant decrease of VEGF (148 pg/mm 3 , p&lt;0.002) and improvement of lymphocytes, NK and CD4 + /CD8 + ratio, with respect to baseline values, was observed. 5-year RFS and OS were 30% and 38%, respectively. 28% of patients were converted to a complete response: Their 5-year RFS and OS were 73% and 94%, respectively. No WHO grade 3 or 4 toxicity was observed, while grade 2 cutaneous toxicity and fever occurred in 20% and 13% of patients, respectively. Conclusions: The administration of IL-2/RA determines, with a low toxicity profile, a statistically significant decrease of VEGF, an improvement of all immunological parameters known to be prognostically relevant and a durable clinical response in 28% of patients. No significant financial relationships to disclose.