tbuckley/cabot-search huggingface dataset:
H Jack Geiger: a doctor takes on poverty, racism, and nuclear war
Authors: Joanne Silberner
Journal: BMJ (2021)

Photo shows H Jack Geiger and John Hatch during the construction of the Tufts-Delta Health Center 

In the 1960s, H Jack Geiger, working at a clinic in the impoverished “Deep South” of the US, began writing prescriptions for food that were paid for through the clinic’s government funded pharmacy budget. Called to task by a federal official for misusing funds, Geiger had a ready answer. “The last time I checked my medical textbooks,” he replied, “the specific therapy for malnutrition was, in fact, food.”

Jack Geiger forged the field of social medicine with his strong belief that health involves more than just treating the illnesses that brought patients to his clinic. He co-founded the first community health centre in the US and inspired many more. He was a co-founder and president of two physicians’ activist groups that went on to win Nobel peace prizes.

“He was a spectacularly important leader, a pioneer in public health,” says Irwin Redlener, a public health activist and professor of health policy and of paediatrics at Columbia University, and one of Geiger’s many mentees. He was also a crackerjack physician, a “doctor’s doctor,” says Redlener.

Being a physician wasn’t how Geiger initially saw himself. Born in New York City to a doctor father and—rare for that time—a mother who was a microbiologist, Geiger graduated from high school at the age of 14, too young to be accepted at a university. That same year he ran …
Detection of SARS-CoV-2 lineage P.1 in patients from a region with exponentially increasing hospitalisation rate, February 2021, Rio Grande do Sul, Southern Brazil
Authors: Andreza Francisco Martins, Alexandre Prehn Zavascki, Priscila Lamb Wink, Fabiana Caroline Zempulski Volpato, Francielle Liz Monteiro, Clévia Rosset, Fernanda De-Paris, Álvaro Krüger Ramos, Afonso Luís Barth
Journal: Eurosurveillance (2021)

The emergence of SARS-CoV-2 P.1 lineage coincided with a surge in hospitalisations in the North region of Brazil. In the South region's Rio Grande do Sul state, severe COVID-19 case numbers rose 3.8 fold in February 2021. During that month, at a COVID-19 referral hospital in this state, whole-genome sequencing of a subset of cases' specimens (n = 27) revealed P.1 lineage SARS-CoV-2 in most (n = 24). Findings raise concerns regarding a possible association between lineage P.1 and rapid case and hospitalisation increases.
Single-cell transcriptome dissection of the toxic impact of Di (2-ethylhexyl) phthalate on primordial follicle assembly
Authors: Jun-Jie Wang, Yu Tian, Ming-Hao Li, Yan-Qin Feng, Li Kong, Fa-Li Zhang, Wei Shen
Journal: Theranostics (2021)

Rationale: Accumulated evidence indicates that environmental plasticizers are a threat to human and animal fertility. Di (2-ethylhexyl) phthalate (DEHP), a plasticizer to which humans are exposed daily, can trigger reproductive toxicity by acting as an endocrine-disrupting chemical. In mammals, the female primordial follicle pool forms the lifetime available ovarian reserve, which does not undergo regeneration once it is established during the fetal and neonatal period. It is therefore critical to examine the toxicity of DEHP regarding the establishment of the ovarian reserve as it has not been well investigated. Methods: The ovarian cells of postnatal pups, following maternal DEHP exposure, were prepared for single cell-RNA sequencing, and the effects of DEHP on primordial follicle formation were revealed using gene differential expression analysis and single-cell developmental trajectory. In addition, further biochemical experiments, including immunohistochemical staining, apoptosis detection, and Western blotting, were performed to verify the dataset results. Results: Using single-cell RNA sequencing, we revealed the gene expression dynamics of female germ cells and granulosa cells following exposure to DEHP in mice. Regarding germ cells: DEHP impeded the progression of follicle assembly and interfered with their developmental status, while key genes such as Lhx8, Figla, and others, strongly evidenced the reduction. As for granulosa cells: DEHP likely inhibited their proliferative activity, and activated the regulation of cell death. Furthermore, the interaction between ovarian cells mediated by transforming growth factor-beta signaling, was disrupted by DEHP exposure, since the expression of GDF9, BMPR1A, and SMAD3 was affected. In addition, DNA damage and apoptosis were elevated in germ cells and/or somatic cells. Conclusion: These findings offer substantial novel insights into the reproductive toxicity of DEHP exposure during murine germ cell cyst breakdown and primordial follicle formation. These results may enhance the understanding of DEHP exposure on reproductive health.
Type I T cells sensitize treatment refractory tumors to chemotherapy through inhibition of oncogenic signaling pathways
Authors: Denise Cecil, Kyong Hwa Park, Benjamin Curtis, Lauren Corulli, Mary (Nora) Disis
Journal: Journal for ImmunoTherapy of Cancer (2021)

The most common clinical outcome observed after treatment with immune checkpoint inhibitor antibodies is disease stabilization. Using vaccines to generate high levels of tumor antigen-specific T-helper 1 (Th1), we show that tumors not eradicated by vaccination demonstrate prolonged disease stabilization. We evaluated the mechanism by which type I T cells inhibit disease progression and potentially influence the subsequent clinical response to standard therapy in treatment refractory cancers. We employed a meta-analysis of studies with tumor growth from four different vaccines in two different mammary cancer models. The T-cell subtype and cytokine essential for vaccine-induced tumor inhibition was determined by in vivo neutralization studies and immunohistochemistry. The role of interferon gamma (IFN-γ) in receptor tyrosine kinase and downstream signaling was determined by immunoblotting. The role of suppressor of cytokine signaling 1 (SOCS1) on IFN-γ signaling was evaluated on SOCS1-silenced cells with immunoblotting and immunoprecipitation. The effect of vaccination on growth factor receptor signaling pathways, performed in both luminal (TgMMTVneu) and basal (C3(1)-Tag) mammary cancer models treated with paclitaxel or an anti-HER2-neu monoclonal antibody were assessed via immunoblotting. Immunization with an epitope-based vaccine targeting a representative tumor antigen resulted in elevated tumor trafficking Tbet+CD4 T cells, decreased tumor proliferation and increased apoptosis compared with control vaccinated mice. The resulting disease stabilization was dependent on IFN-γ-secreting CD4+ T cells. In the presence of excess IFN-γ, SOCS1 became upregulated in tumor cells, bound insulin receptor, insulin like growth factor receptor 1 and epidermal growth factor receptor resulting in profound oncogenic signaling inhibition. Silencing SOCS1 restored growth factor receptor signaling and proliferation and prevented cell death. Similar signaling perturbations were detected in vaccinated mice developing antigen-specific Th1 cells. Vaccination synergized with standard therapies and restored disease sensitivity to treatment with both a neu-specific antibody and paclitaxel in TgMMTVneu and to paclitaxel in C3(1)-Tag. Combination of vaccination and chemotherapy or biological therapy was more effective than monotherapy alone in either model and resulted in complete resolution of disease in some individuals. These data suggest the clinical activity of type I T cells extends beyond direct tumor killing and immune therapies designed to increase type I T cells and could be integrated into standard chemotherapy regimens to enhance therapeutic efficacy.
Biomarker Technologies to Support Early Clinical Immuno-oncology Development: Advances and Interpretation
Authors: Michael A. Cannarile, Bruno Gomes, Marta Canamero, Bernhard Reis, Allyson Byrd, Jehad Charo, Mahesh Yadav, Vaios Karanikas
Journal: Clinical Cancer Research (2021)

Abstract Today, there is a huge effort to develop cancer immunotherapeutics capable of combating cancer cells as well as the biological environment in which they can grow, adapt, and survive. For such treatments to benefit more patients, there is a great need to dissect the complex interplays between tumor cells and the host's immune system. Monitoring mechanisms of resistance to immunotherapeutics can delineate the evolution of key players capable of driving an efficacious antitumor immune response. In doing so, simultaneous and systematic interrogation of multiple biomarkers beyond single biomarker approaches needs to be undertaken. Zooming into cell-to-cell interactions using technological advancements with unprecedented cellular resolution such as single-cell spatial transcriptomics, advanced tissue histology approaches, and new molecular immune profiling tools promises to provide a unique level of molecular granularity of the tumor environment and may support better decision-making during drug development. This review will focus on how such technological tools are applied in clinical settings, to inform the underlying tumor–immune biology of patients and offer a deeper understanding of cancer immune responsiveness to immuno-oncology treatments.
Oral ixazomib, lenalidomide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma
Authors: Thierry Facon, Christopher P. Venner, Nizar J. Bahlis, Fritz Offner, Darrell J. White, Lionel Karlin, Lotfi Benboubker, Sophie Rigaudeau, Philippe Rodon, Eric Voog, Sung-Soo Yoon, Kenshi Suzuki, Hirohiko Shibayama, Xiaoquan Zhang, Philip Twumasi-Ankrah, Godwin Yung, Robert M. Rifkin, Philippe Moreau, Sagar Lonial, Shaji K. Kumar, Paul G. Richardson, S. Vincent Rajkumar
Journal: Blood (2021)
P35.08 RNA-Based Gene Alteration and Expression Analysis in Sq-NSCLC with known FGFR1 Amplification and Protein Expression Status
Authors: J. Moes-Sosnowska, A. Rozy, M. Skupinska, U. Lechowicz, E. Szczepulska-Wojcik, R. Langfort, P. Rudzinski, T. Orlowski, D. Popiel, M. Wieczorek, A. Stańczak, J. Chorostowska-Wynimko
Journal: Journal of Thoracic Oncology (2021)
Eosinophil ETosis–Mediated Release of Galectin‐10 in Eosinophilic Granulomatosis With Polyangiitis
Authors: Mineyo Fukuchi, Yosuke Kamide, Shigeharu Ueki, Yui Miyabe, Yasunori Konno, Nobuyuki Oka, Hiroki Takeuchi, Souichi Koyota, Makoto Hirokawa, Takechiyo Yamada, Rossana C. N. Melo, Peter F. Weller, Masami Taniguchi
Journal: Arthritis & Rheumatology (2021)

Objective Eosinophils are tissue‐dwelling immune cells. Accumulating evidence indicates that a type of cell death termed ETosis is an important cell fate involved in the pathophysiology of inflammatory diseases. Although the critical role of eosinophils in eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg‐Strauss syndrome) is well established, the presence of eosinophil ETosis (EETosis) is poorly understood. We undertook this study to better understand the characteristics of EETosis. Methods In vitro studies using blood‐derived eosinophils were conducted to characterize EETosis. The occurrence of EETosis in tissues from patients with EGPA was studied by immunostaining and electron microscopy. Serum concentrations of eosinophil‐derived proteins in healthy controls, patients with asthma, and EGPA patients with active disease or with disease in remission (n = 15 per group) were examined. Results EETosis was reliant on reactive oxygen species and peptidylarginine deiminase type 4–dependent histone citrullination, resulting in the cytolytic release of net‐like eosinophil extracellular traps, free galectin‐10, and membrane‐bound intact granules. The signature of EETosis, including loss of cytoplasmic galectin‐10 and deposition of granules, was observed in eosinophils infiltrating various tissues from EGPA patients. Serum eosinophil granule proteins and galectin‐10 levels were increased in EGPA and positively correlated with disease activity as assessed by the Birmingham Vasculitis Activity Score (r = 0.8531, P &lt; 0.0001 for galectin‐10). When normalized to blood eosinophil counts, this correlation remained for galectin‐10 (r = 0.7168, P &lt; 0.0001) but not for granule proteins. Galectin‐10 levels in active EGPA positively correlated with serum interleukin‐5 levels. Conclusion Eosinophils infiltrating diseased tissues in EGPA undergo EETosis. Considering the exclusive expression and large pool of cytoplasmic galectin‐10 in eosinophils, elevated serum galectin‐10 levels in patients with EGPA might reflect the systemic occurrence of cytolytic EETosis.
N6-methyladenosine-induced circ1662 promotes metastasis of colorectal cancer by accelerating YAP1 nuclear localization
Authors: Chen Chen, Weitang Yuan, Quanbo Zhou, Bo Shao, Yuying Guo, Weiwei Wang, Shuaixi Yang, Yaxin Guo, Luyang Zhao, Qin Dang, Xiuxiu Yang, Guixian Wang, Qiaozhen Kang, Zhenyu Ji, Jinbo Liu, Zhenqiang Sun
Journal: Theranostics (2021)

Tumor metastasis is the leading cause of death in patients with colorectal cancer (CRC). Circular RNAs (circRNAs) have been shown to be involved in cancer progression. However, the regulatory mechanisms of circRNAs involved in CRC tumor metastasis are currently unknown. Methods: High-throughput sequencing was performed on 6 pairs of CRC and adjacent normal tissues to identify the expression profiles of mRNA and circRNA. circ1662 was assessed by RNA-ISH and IHC of a tissue chip. The function of circ1662 in CRC was evaluated by knocking down or overexpressing circ1662. MeRIP-qPCR, RIP-qPCR, and RNA pull-down were performed to determine the relationship between METTL3, circ1662, and YAP1. Results: A novel circRNA, circ1662, exhibited significantly higher expression in CRC tissues than paired normal tissues. High circ1662 expression was correlated with poor prognosis and tumor depth in patients with CRC. Functionally, circ1662 promoted CRC cell invasion and migration by controlling EMT in vitro and in vivo. Mechanistically, circ1662 directly bound to YAP1 and accelerated its nuclear accumulation to regulate the SMAD3 pathway. Additionally, circ1662 enhanced CRC invasion and migration depending on YAP1 and SMAD3. Interestingly, METTL3 induced circ1662 expression by binding its flanking sequences and installing m6A modifications. Clinically, circ1662 expression strongly correlated with METTL3 and YAP1 protein expression. Moreover, YAP1 expression was negatively correlated with SMAD3 expression. Conclusions: METTL3-induced circ1662 promoted CRC cell invasion and migration by accelerating YAP1 nuclear transport. This result implies that circ1662 is a new prognostic and therapeutic marker for CRC metastasis.
Exploiting albumin as a mucosal vaccine chaperone for robust generation of lung-resident memory T cells
Authors: Kavya Rakhra, Wuhbet Abraham, Chensu Wang, Kelly D. Moynihan, Na Li, Nathan Donahue, Alexis D. Baldeon, Darrell J. Irvine
Journal: Science Immunology (2021)

Tissue-resident memory T cells (TRMs) can profoundly enhance mucosal immunity, but parameters governing TRM induction by vaccination remain poorly understood. Here, we describe an approach exploiting natural albumin transport across the airway epithelium to enhance mucosal TRM generation by vaccination. Pulmonary immunization with albumin-binding amphiphile conjugates of peptide antigens and CpG adjuvant (amph-vaccines) increased vaccine accumulation in the lung and mediastinal lymph nodes (MLNs). Amph-vaccines prolonged antigen presentation in MLNs over 2 weeks, leading to 25-fold increased lung-resident T cell responses over traditional immunization and enhanced protection from viral or tumor challenge. Mimicking such prolonged exposure through repeated administration of soluble vaccine revealed that persistence of both antigen and adjuvant was critical for optimal TRM induction, mediated through T cell priming in MLNs after prime, and directly in the lung tissue after boost. Thus, vaccine persistence strongly promotes TRM induction, and amph-conjugates may provide a practical approach to achieve such kinetics in mucosal vaccines.
Deciphering the autophagy regulatory network via single-cell transcriptome analysis reveals a requirement for autophagy homeostasis in spermatogenesis
Authors: Mei Wang, Yanwen Xu, Yuncong Zhang, Yuhan Chen, Gang Chang, Geng An, Xinyan Yang, Caihong Zheng, Jiexiang Zhao, Zhaoting Liu, Dazhuang Wang, Kai Miao, Shuan Rao, Meng Dai, Dong Wang, Xiao-Yang Zhao
Journal: Theranostics (2021)

Background: Autophagy has been implicated as a crucial component in spermatogenesis, and autophagy dysfunction can lead to reproductive disorders in animal models, including yeast, C. elegans and mice. However, the sophisticated transcriptional networks of autophagic genes throughout human spermatogenesis and their biological significance remain largely uncharacterized. Methods: We profiled the transcriptional signatures of autophagy-related genes during human spermatogenesis by assessing specimens from nine fertile controls (including two normal persons and seven obstructive azoospermia (OA) patients) and one nonobstructive azoospermia (NOA) patient using single-cell RNA sequencing (scRNA-seq) analysis. Dysregulation of autophagy was confirmed in two additional NOA patients by immunofluorescence staining. Gene knockdown was used to identify the role of Cst3 in autophagy during spermatogenesis. Results: Our data uncovered a unique, global stage-specific enrichment of autophagy-related genes. Human-mouse comparison analysis revealed that the stage-specific expression pattern of autophagy-related genes was highly conserved in mammals. More importantly, dysregulation of some clusters of autophagy-related genes was observed in NOA patients, suggesting the association of autophagy with male infertility. Cst3, a human-mouse conserved and autophagy-related gene that is actively expressed in spermatogonia and early spermatocytes, was found to regulate spermatogonial stem cell (SSC) maintenance and subsequent male germ cell development. Knockdown of Cst3 increased autophagic activity in mouse SSCs and subsequently suppressed the transcription of SSC core factors such as Oct4, Id1, and Nanos3, which could be efficiently rescued by manipulating autophagic activity. Conclusions: Our study provides comprehensive insights into the global transcriptional signatures of autophagy-related genes and confirms the importance of autophagy homeostasis in SSC maintenance and normal spermatogenesis, opening new avenues for further dissecting the significance of the autophagy regulatory network in spermatogenesis as well as male infertility.
Complete mesogastric excision for locally advanced gastric cancer: short-term outcomes of a randomized clinical trial
Authors: Daxing Xie, Jie Shen, Liang Liu, Beibei Cao, Yatao Wang, Jichao Qin, Jianhong Wu, Qun Yan, Yuanlong Hu, Chuanyong Yang, Zhixin Cao, Junbo Hu, Ping Yin, Jianping Gong
Journal: Cell Reports Medicine (2021)

Implementation of complete mesogastric excision in gastric cancer surgery, named D2 lymphadenectomy plus complete mesogastric excision (D2+CME), has recently been proposed as an optimal procedure. However, the safety and efficacy of D2+CME remain uncertain. In this randomized controlled trial, patients receiving D2+CME exhibit less intraoperative blood loss, more lymph node harvesting, and earlier postoperative flatus than patients receiving conventional D2 radical surgery. Univariate Cox regression analysis reveals that the risk ratio for postoperative flatus in D2+CME group is 1.247 (p = 0.044). Overall postoperative complications are comparable between the two groups, but complications are significantly less severe in the D2+CME group than the D2 group (Clavien-Dindo classification grade ≥ IIIa: 4 D2+CME patients [11.8%] versus 9 D2 patients [33.3%]; p = 0.041). In conclusion, our work shows that D2+CME is associated with better short-term outcomes and surgical safety than conventional D2 dissection for patients with advanced gastric cancer.
Distinct placental molecular processes associated with early-onset and late-onset preeclampsia
Authors: Zhonglu Ren, Yunfei Gao, Yue Gao, Guanmei Liang, Qian Chen, Sijia Jiang, Xiaoxue Yang, Cuixia Fan, Haizhen Wang, Jing Wang, Yi-Wu Shi, Chaoqun Xiao, Mei Zhong, Xinping Yang
Journal: Theranostics (2021)

Background: Patients with preeclampsia display a spectrum of onset time and severity of clinical presentation, yet the underlying molecular bases for the early-onset and late-onset clinical subtypes are not known. Although several transcriptome studies have been done on placentae from PE patients, only a small number of differentially expressed genes have been identified due to very small sample sizes and no distinguishing of clinical subtypes. Methods: We carried out RNA-seq on 65 high-quality placenta samples, including 33 from 30 patients and 32 from 30 control subjects, to search for dysregulated genes and the molecular network and pathways they are involved in. Results: We identified two functionally distinct sets of dysregulated genes in the two major subtypes: 2,977 differentially expressed genes in early-onset severe preeclampsia, which are enriched with metabolism-related pathways, notably transporter functions; and 375 differentially expressed genes in late-onset severe preeclampsia, which are enriched with immune-related pathways. We also identified some key transcription factors, which may drive the widespread gene dysregulation in both early-onset and late-onset patients. Conclusion: These results suggest that early-onset and late-onset severe preeclampsia have different molecular mechanisms, whereas the late-onset mild preeclampsia may have no placenta-specific causal factors. A few regulators may be the key drivers of the dysregulated molecular pathways.
P37.17 Prevalence of Epidermal Growth Factor Receptor (EGFR) Mutations in Non-small Cell Lung Cancer (NSCLC): A Global Meta-analysis
Authors: B. Melosky, E. Laack, K. Kambartel, M. Häntschel, M. Bennetts, D. Nickens, J. Brinkmann, A. Kayser, M. Moran, F. Cappuzzo
Journal: Journal of Thoracic Oncology (2021)
Abstract 3669: Relationship Between Coronary Collateral Circulation and Ischemic Preconditioning During Percutaneous Coronary Intervention
Authors: Takashi Yamano, Satoshi Ueno, Takashi Kubo, Shigeho Takarada, Takashi Masho, Yoshiaki Tomobuchi, Takashi Akasaka
Journal: Circulation (2006)

Background: Ischemic preconditioning (IP) is related to various factors, and the mechanism remains uncertain. We examined the hypothesis that repeated ischemia increases collateral flow and is rela...