tbuckley/cabot-search huggingface dataset:
Second primary thyroid cancer after a first childhood malignancy: A report from the Childhood Cancer Survivor Study.
Authors: Cécile M. Ronckers, Alice J. Sigurdson, Ann C. Mertens, Charles A. Sklar, Marilyn Stovall, Susan A. Smith, Yan Liu, Sue Hammond, Roger Berkow, Joseph P. Neglia, Anna T. Meadows, Leslie L. Robison, Peter D. Inskip
Journal: Cancer Research (2004)

3113  Survivors of a childhood malignancy have a greater than 10-fold increased risk of developing a second primary thyroid cancer. While radiation treatment is the single most dominant risk factor, the magnitude of risk over the range of therapeutic doses has not been well established. Studies with wide dose ranges and large sample sizes are required to describe the shape of the dose-response curve, specifically for risks above 10 Gy, where the effect of cell killing may become important. We conducted the largest study of second thyroid cancer to date using the Childhood Cancer Survivor Study (CCSS). The CCSS cohort is comprised of over 14,000 five-year survivors of a childhood leukemia, lymphoma, central nervous system tumor, soft tissue and bone sarcoma, neuroblastoma, and kidney cancer diagnosed between January 1, 1970 and December 31, 1986. A nested case-control study was conducted that included 69 cases with a pathologically confirmed subsequent thyroid cancer and 277 controls without thyroid cancer. Controls were matched to cases on age at diagnosis, gender and follow-up time. For each patient, cumulative radiation doses to the right and left lobes of the thyroid gland were calculated based on individual treatment records. Conditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI). The ORs peaked at 11-fold (95% CI, 3.1-38.0) for radiation doses between 20-29 Gy. At thyroid gland radiation doses above 30 Gy, a downturn in the dose-response relation, consistent with a cell-killing effect, was present. Chemotherapy for the first cancer was not associated with risk of subsequent thyroid cancer, nor did chemotherapy modify the effect of radiation treatment on thyroid cancer risk. No effect of radiation dose to the pituitary gland on the risk of thyroid cancer was observed. Among cases, 42% had a first diagnosis of Hodgkin lymphoma (HL) compared to 19% of controls. After adjusting for radiation dose and radiation sensitivity by age at diagnosis, the risk by type of first cancer remained elevated for HL and thyroid cancer (OR = 3.4; 95% CI, 0.9-12.4). Possibly due to close surveillance of HL patients, the proportion of second thyroid cancers that were less than 1 cm among HL survivors was 42%, compared to 17% among persons who had other types of childhood cancer (p
Abstract 1289: Conjugation of indomethacin with novel oleanolic acid oximes increases its Nrf2 and NF-κB signaling pathways modulating effect in pancreatic cancer cells
Authors: Wanda Baer-Dubowska, Maria Narozna, Violetta Krajka-Kuźniak, Barbara Bednarczyk-Cwynar
Journal: Cancer Research (2021)

Abstract Chronic inflammation is a key factor in the etiology of neoplastic diseases, including pancreatic cancer. Nonsteroidal anti-inflammatory drugs (NSAIDs) were approved for the chemoprevention of colon tumors and suggested for pancreas cancers prophylaxis. Anti-inflammatory and anti-tumorigenic activities are also exerted by naturally occurring and synthetic triterpenoids. Coupling of triterpenoid analogues with NSAIDs may enhance this effect and prevent the unfavorable side effects related to NSAIDs long-term use. In this study novel oleanolic acid oxime (OAO) derivatives conjugated with indomethacin (IND) differing in substitution group at position C-17 were evaluated in the context of their possible modulating effect of Nrf2-ARE and NF-κB signaling pathways in pancreatic cancer cells.PSN-1 cells were incubated for 24h with IND and OAO-IND derivatives at the concentrations of 10µM and 20µM selected based on the results of the MTT assay. The activation of Nrf2 and NF-κB was assessed by the evaluation of its translocation into the nucleus and binding to specific DNA sequences by the ELISA assay. Expression of Nrf2, SOD-1, NF-κBp50, NF-κBp65 and COX-2 was evaluated by RT-PCR and Western blot methods.Cell viability was affected mostly by 3-indomethacinoxyiminoolean-12-en-28-oic acid morpholide and 3-indomethacinoxyiminoolean-en-28-oic acid benzyl ester. The level of Nrf2 in the nucleus and binding to ARE sequence was decreased in PSN-1 cells, similarly as was NF-κBp50 and NF-κBp65 binding and nuclear accumulation. As result of diminished activation of these transcription factors decreased expression of SOD-1 and COX-2 i.e. mRNA and protein levels were found. These results indicate that the OAO-IND derivatives, particularly morpholide and benzyl ester conjugates, are more potent suppressors of NF-κB signaling pathway than IND alone. Moreover, conjugation of IND with novel OAO may protect cancer cells against chemoresistance through inhibition of the Nrf2-ARE pathway. Those novel compounds might be considered the potential modulators of hepatocellular carcinoma therapy and chemopreventive agents. Funding: This work was supported by Polish National Science Centre, grant 2016/21/B/NZ7/01758. Citation Format: Wanda Baer-Dubowska, Maria Narozna, Violetta Krajka-Kuźniak, Barbara Bednarczyk-Cwynar. Conjugation of indomethacin with novel oleanolic acid oximes increases its Nrf2 and NF-κB signaling pathways modulating effect in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1289.
Abstract 463: Features consistent with a small-cell neuroendocrine like (SC/NE-L) transformation can be readily detected and quantified in circulating tumor cells (CTCs)
Authors: Howard I. Scher, Adam Jendrisak, Cole Gilbertson, Audrey Gill, Ethan Barnett, Anuradha Gopalan, Niamh Keegan, Samir Zaidi, Hannah Benoliel, Carbone Emily, Eva Wang, James Lu, Alisa Tubbs, Amanda Anderson, Joshua Jones, Joseph D. Schonhoft, Rick Wenstrup
Journal: Cancer Research (2021)

Abstract Background: The increasing availability and earlier use of life prolonging drugs targeting the androgen receptor signaling axis (ARSI) has resulted in an increase in the frequency of late state tumors with “small cell/neuroendocrine like (SC/NE-L) phenotypes” similar to small-cell lung cancer (SCLC). These tumors are typically heterogenous wherein the small-cell component represents only a portion of CTC's present. Definitive pathologic criteria to diagnose small-cell neuroendocrine transformation are lacking, and the eligibility criteria across trials in this space inconsistent, limiting the ability to relate outcomes between studies. We hypothesize that an analytically validated assay for a rigorously defined “small-cell CTC” phenotype would clarify the identification and diagnosis of SC/NE-L tumors. Methods: Using the WHO guidelines for small-cell diagnosis in tissue as reference, we defined an equivalent set of single-cell criteria for defining a CTC with small cell or neuroendocrine like (SC/NE) histology that include: a circulating CD45- cell with a high nuclear to cytoplasm area ratio, small size, high circularity, lack of detectable nucleoli, salt and pepper chromatin, SC/NE or tumor-related protein expression (DLL3, CD56, CK etc.), and other features associated with lineage plasticity (i.e., CK speckling). Clinical feasibility of feature extraction was explored on CTCs detected using the Epic Sciences platform in the blood of patients with small-cell lung and late state prostate cancers. Results: Using the Epic Sciences platform, morphologic features associated with small-cell or neuroendocrine transformation can be readily identified and quantified automatically in CTCs in a liquid biopsy from patients with small-cell lung and prostate cancers. Conclusions: Identifying small-cell to neuroendocrine like (SC/NE-L) CTC subtypes may aid in establishing that lineage transformation to a SC/NE-L phenotype has occurred where invasive single site tissue biopsies may not be informative or feasible. Citation Format: Howard I. Scher, Adam Jendrisak, Cole Gilbertson, Audrey Gill, Ethan Barnett, Anuradha Gopalan, Niamh Keegan, Samir Zaidi, Hannah Benoliel, Carbone Emily, Eva Wang, James Lu, Alisa Tubbs, Amanda Anderson, Joshua Jones, Joseph D. Schonhoft, Rick Wenstrup. Features consistent with a small-cell neuroendocrine like (SC/NE-L) transformation can be readily detected and quantified in circulating tumor cells (CTCs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 463.
Genetic models of latent tuberculosis in mice reveal differential influence of adaptive immunity
Authors: Hongwei Su, Kan Lin, Divya Tiwari, Claire Healy, Carolina Trujillo, Yao Liu, Thomas R. Ioerger, Dirk Schnappinger, Sabine Ehrt
Journal: The Journal of Experimental Medicine (2021)

Studying latent Mycobacterium tuberculosis (Mtb) infection has been limited by the lack of a suitable mouse model. We discovered that transient depletion of biotin protein ligase (BPL) and thioredoxin reductase (TrxB2) results in latent infections during which Mtb cannot be detected but that relapse in a subset of mice. The immune requirements for Mtb control during latency, and the frequency of relapse, were strikingly different depending on how latency was established. TrxB2 depletion resulted in a latent infection that required adaptive immunity for control and reactivated with high frequency, whereas latent infection after BPL depletion was independent of adaptive immunity and rarely reactivated. We identified immune signatures of T cells indicative of relapse and demonstrated that BCG vaccination failed to protect mice from TB relapse. These reproducible genetic latency models allow investigation of the host immunological determinants that control the latent state and offer opportunities to evaluate therapeutic strategies in settings that mimic aspects of latency and TB relapse in humans.
Haplotype-resolved germline and somatic alterations in renal medullary carcinomas
Authors: Kar-Tong Tan, Hyunji Kim, Jian Carrot-Zhang, Yuxiang Zhang, Won Jun Kim, Guillaume Kugener, Jeremiah A. Wala, Thomas P. Howard, Yueh-Yun Chi, Rameen Beroukhim, Heng Li, Gavin Ha, Seth L. Alper, Elizabeth J. Perlman, Elizabeth A. Mullen, William C. Hahn, Matthew Meyerson, Andrew L. Hong
Journal: Genome Medicine (2021)

Abstract Background Renal medullary carcinomas (RMCs) are rare kidney cancers that occur in adolescents and young adults of African ancestry. Although RMC is associated with the sickle cell trait and somatic loss of the tumor suppressor, SMARCB1 , the ancestral origins of RMC remain unknown. Further, characterization of structural variants (SVs) involving SMARCB1 in RMC remains limited. Methods We used linked-read genome sequencing to reconstruct germline and somatic haplotypes in 15 unrelated patients with RMC registered on the Children’s Oncology Group (COG) AREN03B2 study between 2006 and 2017 or from our prior study. We performed fine-mapping of the HBB locus and assessed the germline for cancer predisposition genes. Subsequently, we assessed the tumor samples for mutations outside of SMARCB1 and integrated RNA sequencing to interrogate the structural variants at the SMARCB1 locus. Results We find that the haplotype of the sickle cell mutation in patients with RMC originated from three geographical regions in Africa. In addition, fine-mapping of the HBB locus identified the sickle cell mutation as the sole candidate variant. We further identify that the SMARCB1 structural variants are characterized by blunt or 1-bp homology events. Conclusions Our findings suggest that RMC does not arise from a single founder population and that the HbS allele is a strong candidate germline allele which confers risk for RMC. Furthermore, we find that the SVs that disrupt SMARCB1 function are likely repaired by non-homologous end-joining. These findings highlight how haplotype-based analyses using linked-read genome sequencing can be applied to identify potential risk variants in small and rare disease cohorts and provide nucleotide resolution to structural variants.
Adenovirus vector vaccination reprograms pulmonary fibroblastic niches to support protective inflating memory CD8+ T cells
Authors: Jovana Cupovic, Sandra S. Ring, Lucas Onder, Julia M. Colston, Mechthild Lütge, Hung-Wei Cheng, Angelina De Martin, Nicholas M. Provine, Lukas Flatz, Annette Oxenius, Elke Scandella, Philippe Krebs, Daniel Engeler, Paul Klenerman, Burkhard Ludewig
Journal: Nature Immunology (2021)
Surgical treatment in ischaemic and non-ischaemic priapism: A systematic review
Authors: U. Milenkovic, A. Cocci, R. Veeratterapillay, K. Dimitropoulos, L. Boeri, P. Capogrosso, N.C. Cilesiz, M. Gul, G. Hatzichristodoulou, V. Modgil, G.I. Russo, T. Tharakan, M.I. Omar, C. Bettocchi, J. Carvalho, Y. Yuhong, G. Corona, H. Jones, A. Kadioglu, J.I. Martinez-Salamanca, P. Verze, E.C. Serefoglu, S. Minhas, A. Salonia
Journal: European Urology (2021)
血小板活性化因子のKupffer細胞放出は核酸ナノキャリアの用量制限毒性を駆動する【JST・京大機械翻訳】
Authors: A Jackson Meredith, S Patel Shrusti, Yu Fang, A Cottam Matthew, B Glass Evan, N Hoogenboezem Ella, Fletcher R. Brock, R Dollinger Bryan, Patil Prarthana, D Liu Danielle, B Kelly Isom, K Bedingfield Sean, R King Allyson, E Miles Rachel, M Hasty Alyssa, D Giorgio Todd, L Duvall Craig
Journal: Biomaterials (2021)
Metastatic prostate cancer patients’ Attitudes towards Treatment of the local Tumour and metastasis Evaluative Research (IP5-MATTER): A multicentre, discrete choice experiment trial-in-progress
Authors: M.J. Connor, M.G. Genie, M. Gonzalez, F. Hosking-Jervis, K. Thippu Jayaprakash, N. Sarwar, G. Horan, N. Klimowska-Nassar, J. Sukumar, T. Pokrovska, D. Basak, B. Rai, A. Robinson, M. Beresford, S. Mangar, A. Falconer, T. Dudderidge, V. Khoo, M. Winkler, V. Watson, H.U. Ahmed
Journal: European Urology (2021)
Abstract 1335: Dual MCT1/4 inhibition promotes anti-tumor immunity in triple-negative breast cancer
Authors: Gregory James Goreczny, Jaime Escobedo, Vincent Sandanayaka
Journal: Cancer Research (2021)

Abstract Despite the recent FDA approval of Abraxane (nab-paclitaxel) and Atezolizumab (anti-PD-L1) for a subset of Triple-Negative Breast Cancer (TNBC) patients, there remains an unmet need to develop novel therapeutic strategies to effectively combat this disease. Nirogy Therapeutics has developed a first-in-class, orally bioavailable small molecule inhibitor targeting MonoCarboxylate Transporters (MCTs), specifically MCT1 and MCT4, which transport lactate into and out of the cell. MCT1/4 expression are upregulated in TNBC patients, and high MCT4 expression correlates with worse outcome. Although a MCT1-specific inhibitor is currently under investigation in clinical trials for some cancers that express only MCT1, primary resistance to these inhibitors occur via the upregulation of MCT4. Most cancers overexpress both MCT1 and MCT4. Thus, the need for dual MCT1/4 inhibitors (dMCTi) that block both MCT1 and MCT4 is crucial to effectively treat these patients. We have shown that our dMCTi compound, NGY-B, exhibits direct cytotoxicity against a panel of TNBC cell lines with various MCT1/4 expression patterns, and it inhibits lactate import through MCT1 and export through MCT4. Furthermore, NGY-B exhibited a significant tumor growth reduction in an MDA-MB-231 CDX mouse model of TNBC compared to the current standard-of-care chemotherapy. Using the syngeneic 4T1 mouse model of TNBC, we have shown that NGY-B also exhibited a significant reduction of tumor growth, indicating potential impact on anti-tumor immunity as well. Further analysis of the 4T1 model showed that NGY-B significantly enriched the CD8+ tumor infiltrating lymphocyte (TIL) population while exhibiting a concurrent reduction in the macrophage M2/M1 ratio, indicating preferred polarization to M1-phenotype. Also, we observed a significant reduction in granulocytic suppressor cells, gMDSCs in the tumor microenvironment (TME). Further work has demonstrated that NGY-B synergizes with immune checkpoint blockade to promote an anti-tumor immune response. By blocking lactate accumulation in the TME, our compound activates local immunity by overcoming lactate mediated immunosuppression in cytotoxic T-cells while suppressing inhibitory immune populations. Therefore, such a broader effect on multiple immune cells by NGY-B leads to overall immune activation in the TME. Our pre-clinical work shows that NGY-B intervenes two key hallmarks of caner; metabolism and immunity, providing us a novel therapeutic modality to combat TNBC. Citation Format: Gregory James Goreczny, Jaime Escobedo, Vincent Sandanayaka. Dual MCT1/4 inhibition promotes anti-tumor immunity in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1335.
Drug companies are fined more than £260m for overcharging NHS for hydrocortisone pills
Authors: Abi Rimmer
Journal: BMJ (2021)

The Competition and Markets Authority has fined drug companies over £260m (€305m; $360m) for inflating the price of hydrocortisone tablets by more than 10 000%.

The rising costs meant that the amount the NHS paid for a single pack of 10 mg hydrocortisone tablets rose from 70 p in April 2008 to £88 by March 2016, the CMA said.1 For the 20 mg version the price rose from £1.07 to £102.74 a pack over the same period.

Before April 2008 the NHS was spending around £500 000 a year on hydrocortisone tablets, the CMA said. This had risen to …
Neuroprosthesis for Decoding Speech in a Paralyzed Person with Anarthria
Authors: David A. Moses, Sean L. Metzger, Jessie R. Liu, Gopala K. Anumanchipalli, Joseph G. Makin, Pengfei F. Sun, Josh Chartier, Maximilian E. Dougherty, Patricia M. Liu, Gary M. Abrams, Adelyn Tu-Chan, Karunesh Ganguly, Edward F. Chang
Journal: New England Journal of Medicine (2021)

Technology to restore the ability to communicate in paralyzed persons who cannot speak has the potential to improve autonomy and quality of life. An approach that decodes words and sentences directly from the cerebral cortical activity of such patients may represent an advancement over existing methods for assisted communication.We implanted a subdural, high-density, multielectrode array over the area of the sensorimotor cortex that controls speech in a person with anarthria (the loss of the ability to articulate speech) and spastic quadriparesis caused by a brain-stem stroke. Over the course of 48 sessions, we recorded 22 hours of cortical activity while the participant attempted to say individual words from a vocabulary set of 50 words. We used deep-learning algorithms to create computational models for the detection and classification of words from patterns in the recorded cortical activity. We applied these computational models, as well as a natural-language model that yielded next-word probabilities given the preceding words in a sequence, to decode full sentences as the participant attempted to say them.We decoded sentences from the participant's cortical activity in real time at a median rate of 15.2 words per minute, with a median word error rate of 25.6%. In post hoc analyses, we detected 98% of the attempts by the participant to produce individual words, and we classified words with 47.1% accuracy using cortical signals that were stable throughout the 81-week study period.In a person with anarthria and spastic quadriparesis caused by a brain-stem stroke, words and sentences were decoded directly from cortical activity during attempted speech with the use of deep-learning models and a natural-language model. (Funded by Facebook and others; ClinicalTrials.gov number, NCT03698149.).
A recurrent rash on the penis
Authors: Alexander Kreuter, Bijan Koushk-Jalali
Journal: BMJ (2021)

<h3>Abstract</h3> Dynamic functional connectivity within brain circuits requires coordination of intercellular signaling and intracellular signal transduction. Critical roles for cAMP-dependent protein kinase A (PKA) signaling are well established in the <i>Drosophila</i> mushroom body (MB) learning and memory circuitry, but local PKA activity within this well-mapped neuronal network is uncharacterized. Here, we use an <i>in vivo</i> PKA activity sensor (PKA-SPARK) to test spatiotemporal regulatory requirements in the MB axon lobes. We find immature animals have little detectable PKA activity, whereas postcritical period adults show high field-selective activation primarily in just 3/16 defined output regions. In addition to the age-dependent PKA activity in distinct α’/β’ lobe nodes, females show sex-dependent elevation compared with males in these same restricted regions. Loss of neural cell body Fragile X mental retardation protein (FMRP) and Rugose [human Neurobeachin (NBEA)] suppresses localized PKA activity, whereas overexpression (OE) of MB lobe PKA-synergist Meng-Po (human SBK1) promotes PKA activity. Elevated Meng-Po subverts the PKA age-dependence, with elevated activity in immature animals, and spatial-restriction, with striking γ lobe activity. Testing circuit signaling requirements with temperature-sensitive <i>shibire</i> (human Dynamin) blockade, we find broadly expanded PKA activity within the MB lobes. Using transgenic tetanus toxin to block MB synaptic output, we find greatly heightened PKA activity in virtually all MB lobe fields, although the age-dependence is maintained. We conclude spatiotemporally restricted PKA activity signaling within this well-mapped learning/memory circuit is age-dependent and sex-dependent, driven by FMRP-Rugose pathway activation, temporally promoted by Meng-Po kinase function, and restricted by output neurotransmission providing network feedback.
Abstract 2673: The cytoplasmic adaptor FRS2beta fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis
Authors: Noriko Gotoh, Yasuto Takeuchi, Natsuko Kimura, Takehiko Murayama, Yukino Machida, Daisuke Iejima, Tatsunori Nishimura, Mizuki Yamamoto, Jun-ichito Inoue, Kouichi Akashi, Hideyuki Saya, Masahiko Kuroda, Issay Kitabayashi, Arinobu Tojo
Journal: Cancer Research (2021)

Abstract It is widely held that pro-inflammatory changes often precede the onset of breast cancer. However, the underlying molecular mechanisms are largely unknown. Here, we demonstrate that FRS2β, a membrane-linked adaptor protein expressed in a small subset of luminal epithelial cells, triggers the inflammatory changes in precancerous mammary tissues and is responsible for the onset of the disease. FRS2β-deficiency in a mouse mammary tumor virus (MMTV)-ErbB2 genetic background markedly attenuated mammary tumorigenesis. Importantly, tumor cells derived from MMTV-ErbB2 mice failed to generate tumors when grafted in the FRS2β-deficient precancerous mammary tissue niche. we observed that the co-localization of FRS2β and the NEMO subunit of the IκB kinase (IKK) complex on early endosomes led to activation of nuclear factor-κB (NFκB). Moreover, the expression of numerous cytokines, including CXC chemokine ligand (CXCL)12, was elevated owing to the activation of NFκB. CXCL12 may in turn activate NFκB in an autocrine and paracrine loop, leading to the inflammatory changes that promote tumorigenesis. The elucidation of the FRS2β-dependent NFκB-activation pathway uncovers a hitherto unknown molecular link between the tissue inflammation and the onset of breast cancer. Citation Format: Noriko Gotoh, Yasuto Takeuchi, Natsuko Kimura, Takehiko Murayama, Yukino Machida, Daisuke Iejima, Tatsunori Nishimura, Mizuki Yamamoto, Jun-ichito Inoue, Kouichi Akashi, Hideyuki Saya, Masahiko Kuroda, Issay Kitabayashi, Arinobu Tojo. The cytoplasmic adaptor FRS2beta fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2673.