tbuckley/cabot-search huggingface dataset:
Unescheduled visits in cancer patients treated in a clinical trials unit (CTU).
Authors: Lydia Gaba, Iván Victoria, Óscar Reig, Sandra Lopez, Pedro Gascon, Laura Vidal
Journal: Journal of Clinical Oncology (2013)

e17580 Background: A number of unscheduled visits may occur in addition to the predefined protocol-specific visit calendars in a CTU. The aim of this prospective study was to characterize and assesss the frequency, causes and the probable relationship of the emergencies with the investigational products (IPs). Methods: A consecutive sample of patients treated in a CTU who presented an urgent medical consultation from July 2012 to January 2013 was registered. Epidemiological data, characteristics of emergency visits and relationship with IPs were revised. Results: 141 patients were registered; 75 men (53.2%) and 66 women (46.8%) with a median age of 61.4 years. Most of them had metastatic cancer and 63 patients (44.7%) had been included in phase III clinical trials. Tumors which produced a higher number of events were melanoma (n=53, 37.6%), colorectal (n=24, 17%) and breast cancer (n=21, 14.9%). Those treatments associated with more unscheduled consultations were chemotherapy agents, Braf inhibitors and antiEGFR antibodies. Of those, 45.4% were in-person consultations, whereas the 54.6% were performed by phone. The main causes were pain (18.4%), diarrhea (12.1%), fever (12.1%) and skin symptoms (10.6%). 48.9% were related to an adverse event of the IPs. 78.7% of the consultations were oriented and specifically treated at the moment of the appointment, whereas the 21.3% had to be referred to another service. 36.2% of the unscheduled visits were directly related with the IPs. Of those, 30% were 3-4 graded. Conclusions: Patients treated on a clinical trial generated an elevated number of unescheduled visits and a significant percentage of them are related to the IPs. Most of them should be managed by staff with the appropriate knowledge and training.
Long Noncoding RNA-Maternally Expressed Gene 3 Contributes to Hypoxic Pulmonary Hypertension
Authors: Yan Xing, Xiaodong Zheng, Yao Fu, Jing Qi, Minghui Li, Mingfei Ma, Shuang Wang, Shuzhen Li, Daling Zhu
Journal: Molecular Therapy (2019)

The expression and function of long noncoding RNAs (lncRNAs) in the development of hypoxic pulmonary hypertension (HPH), especially in the proliferation of pulmonary artery smooth muscle cells (PASMCs), are largely unknown. Herein, we examined the expression and role of lncRNA-maternally expressed gene 3 (lncRNA-MEG3) in HPH. lncRNA-MEG3 was significantly increased and primarily localized in the cytoplasm of hypoxic PASMCs. lncRNA-MEG3 knockdown by lung-specific delivery of small interfering RNAs (siRNAs) significantly inhibited the development of HPH in vivo. Silencing of lncRNA-MEG3 by siRNAs and gapmers attenuated proliferation and cell-cycle progression in both PASMCs from idiopathic pulmonary arterial hypertension (iPAH) patients (iPAH-PASMCs) and hypoxia-exposed PASMCs in vitro. Mechanistically, we found that lncRNA-MEG3 interacts with and leads to the degradation of microRNA-328-3p (miR-328-3p), leading to upregulation of insulin-like growth factor 1 receptor (IGF1R). Additionally, higher expression of lncRNA-MEG3 and IGF1R and lower expression of miR-328-3p were observed in iPAH-PASMCs and relevant HPH models. These data provide insights into the contribution of lncRNA-MEG3 to HPH. Upregulation of lncRNA-MEG3 sequesters cytoplasmic miR-328-3p, eventually leading to expression of IGF1R, revealing a regulatory mechanism by lncRNAs in hypoxia-induced PASMC proliferation. The expression and function of long noncoding RNAs (lncRNAs) in the development of hypoxic pulmonary hypertension (HPH), especially in the proliferation of pulmonary artery smooth muscle cells (PASMCs), are largely unknown. Herein, we examined the expression and role of lncRNA-maternally expressed gene 3 (lncRNA-MEG3) in HPH. lncRNA-MEG3 was significantly increased and primarily localized in the cytoplasm of hypoxic PASMCs. lncRNA-MEG3 knockdown by lung-specific delivery of small interfering RNAs (siRNAs) significantly inhibited the development of HPH in vivo. Silencing of lncRNA-MEG3 by siRNAs and gapmers attenuated proliferation and cell-cycle progression in both PASMCs from idiopathic pulmonary arterial hypertension (iPAH) patients (iPAH-PASMCs) and hypoxia-exposed PASMCs in vitro. Mechanistically, we found that lncRNA-MEG3 interacts with and leads to the degradation of microRNA-328-3p (miR-328-3p), leading to upregulation of insulin-like growth factor 1 receptor (IGF1R). Additionally, higher expression of lncRNA-MEG3 and IGF1R and lower expression of miR-328-3p were observed in iPAH-PASMCs and relevant HPH models. These data provide insights into the contribution of lncRNA-MEG3 to HPH. Upregulation of lncRNA-MEG3 sequesters cytoplasmic miR-328-3p, eventually leading to expression of IGF1R, revealing a regulatory mechanism by lncRNAs in hypoxia-induced PASMC proliferation.
Another Option for Hypoactive Sexual Desire
Authors: Feyza Sancar
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
A phase II single-arm study of nivolumab and ipilimumab (Nivo/Ipi) in previously treated Classic Kaposi sarcoma (CKS).
Authors: Alona Zer, Oded Icht, Lilach Joseph, Dana Avram, Oded Jacobi, Eyal Fenig, Sivan Shamai, Ronnie Shapira Frommer, Hanna Bernstine, Rony Weitzen, Gil Bar-Sela, Salomon M. Stemmer, Michal Lotem
Journal: Journal of Clinical Oncology (2019)

11064 Background: CKS is an angioproliferative mesenchymal neoplasm causatively associated with human herpes virus 8 infection. Though recombinant IFNa is approved for treatment of AIDS-related KS, data is limited regarding the role of immune modulation in CKS therapy. Based on favorable responses in viral-induced cancers, we hypothesized that CTLA-4 and PD-1 blockade can induce tumor regression in CKS. We present pre-planned interim analysis of a phase II study of Nivo/Ipi in previously treated progressive CKS (NCT03219671). Methods: CKS pts with progressive disease after ≥ 1 line of systemic therapy and measurable disease by PET/CT and/or physical exam received nivolumab 240mg d1,15,28 and ipilimumab 1mg/kg d1 q42 days until progression or toxicity. The primary endpoint was overall response rate (ORR), secondary endpoints include 6-months progression free survival rate (PFS) and safety. Correlative studies in tumor and serum samples are ongoing using an NGS panel for DNA and RNA and proteomic staining (Tempus Labs Inc). A pre-planned interim analysis was conducted after the first ten enrolled patients for efficacy and toxicity evaluation. Results: Ten patients were enrolled and evaluable between April2018 and February2019. Median age 72 (61-79), all male. At a median FU of 3.1 months (1.5-8.1) ORR was 50% (4 patients PR, 1 patient CR, 5 patients SD). Median PFS was not reached however no progression of disease was documented so far. The safety profile was as expected with all patients experiencing G1 toxicity and four patients with G2 toxicity (1 ALT/AST increase, 2 asymptomatic lipase increase). One SAE was reported (TIA considered not related to therapy) and treatment was discontinued in one patient (G2 LFT increase. maintaining CR 4 months after treatment discontinuation). Correlative results are pending. Conclusions: The interim analysis in this prospectively designed phase II study of nivolumab and low-dose ipilimumab demonstrate promising activity in progressive CKS, with 50% ORR and no events of progression thus far. We expect to report the updated efficacy and correlative data. Clinical trial information: NCT03219671.
IL-2 production by self-reactive CD4 thymocytes scales regulatory T cell generation in the thymus
Authors: Saskia Hemmers, Michail Schizas, Elham Azizi, Stanislav Dikiy, Yi Zhong, Yongqiang Feng, Grégoire Altan-Bonnet, Alexander Y. Rudensky
Journal: The Journal of Experimental Medicine (2019)

Regulatory T (T reg) cells, a specialized subset of CD4+ T cells, are essential to prevent fatal autoimmunity. Expression of the T reg lineage-defining transcription factor Foxp3, and therefore their differentiation in the thymus, is dependent upon T cell receptor (TCR) and interleukin-2 (IL-2) signaling. Here, we report that the majority of IL-2–producing cells in the thymus are mature CD4 single-positive (CD4SP) thymocytes and that continuous IL-2 production sustained thymic T reg cell generation and control of systemic immune activation. Furthermore, single-cell RNA sequencing analysis of CD4 thymocyte subsets revealed that IL-2 was expressed in self-reactive CD4SP thymocytes, which also contain T reg precursor cells. Thus, our results suggest that the thymic T reg cell pool size is scaled by a key niche factor, IL-2, produced by self-reactive CD4SP thymocytes. This IL-2–dependent scaling of thymic T reg cell generation by overall self-reactivity of a mature post-selection thymic precursor pool may likely ensure adequate control of autoimmunity.
Former patients of Derbyshire psychiatric unit will be compensated for experimental treatment
Authors: Clare Dyer
Journal: BMJ (2019)

Dozens of former patients at a psychiatric hospital who claim that they were experimented on by being held down and given sodium amytal as children in the 1960s and ’70s will receive compensation in a settlement scheme agreed with the NHS.

Claimants say that they suffered physical, sexual, and emotional abuse at the hands of Kenneth Milner, head physician at Aston Hall psychiatric hospital in Derbyshire, which closed in 2004. Milner died in 1975, but Derbyshire Police said last year that he would have been questioned under caution had he …
Targeting Mechanistic Target of Rapamycin Complex 1 Restricts Proinflammatory T Cell Differentiation and Ameliorates Takayasu Arteritis
Authors: Jifeng Zhang, Lei Zhao, Jing Wang, Zhihua Cheng, Mengyao Sun, Jiayi Zhao, Bin Liu, Xiyu Liu, Zhenke Wen, Zhibo Li
Journal: Arthritis & Rheumatology (2019)

Objective Takayasu arteritis ( TAK ) is a progressive autoimmune large vessel vasculitis with infiltration of proinflammatory T cells, with a largely unknown etiology. This study was undertaken to explore the involvement of mechanistic target of rapamycin ( mTOR ) in proinflammatory T cell differentiation and disease progression in TAK . Methods Ninety‐five patients with TAK , 26 patients with small vessel vasculitis, and 40 healthy donors were enrolled. Naive and memory CD 4+ T cells were activated with anti‐ CD 3/ CD 28 beads and analyzed for lineage differentiation. The mTORC 1 activity was determined by quantifying intracellular phospho–S6 kinase 1 and phospho–S6 ribosomal protein. Rapamycin and lentiviral regulatory‐associated protein of mTOR short hairpin RNA were used to block mTORC 1 activity. Human artery– NSG mouse chimeras representing human TAK were established for targeting mTORC 1 in disease treatment. Results TAK CD 4+ T cells were selectively prepositioned with hyperactivity of mTORC 1 ( P &lt; 0.001), resulting in spontaneous maldifferentiation of Th1 and Th17 cells ( P &lt; 0.001). Activity of mTORC 1 high in circulating CD 4+ T cells predicted elevated frequencies of proinflammatory T cells and active disease in TAK patients ( P &lt; 0.001). Blockade of mTORC 1 with rapamycin efficiently abrogated the maldifferentiation of Th1 and Th17 cells ( P &lt; 0.01) and ameliorated vasculitis in humanized TAK chimeras ( P &lt; 0.001). Inhibition of mTORC 1 using RNA interference technology is sufficient to reduce proinflammatory T cell frequencies ( P &lt; 0.01) and restrict TAK disease progression in vivo ( P &lt; 0.01). Conclusion Our findings indicate that hyperactivity of mTORC 1 is a critical cell‐intrinsic mechanism underlying spontaneous maldifferentiation of proinflammatory T cells in TAK patients. Targeting mTORC 1 is a promising therapeutic strategy against TAK.
AB0206 Investigation of the inducibility of retroviruses from rheumatoid arthritis synovial fibroblasts (ra-sf) and ra-synovial fluid cells (ra-sfc)
Authors: CA Seemayer, SA Kolb, J Böni, M Neidhart, B Simmen, RE Gay, BA Michel, J Schüpbach, S Gay
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> In many investigations virus like particles (VLP) and especially type-C retroviruses could be activated from tumour cells in culture after stimulation with DNA damaging agents. Co-culture with H9 cells, a lymphatic cell line, has been successfully used to isolate exogenous human retroviruses such as HTLV and HRV-5. The aim of this study was to induce potentially hidden retroviruses from cell cultures from RA patients and to analyse for VLP and reverse transcriptase (RT)-activity. <h3>Methods</h3> Rheumatoid arthritis synovial fibroblasts (RA-SF) were derived from synovial biopsies and synovial fluid cells from RA synovial fluids. Normal skin fibroblasts served as controls for the RA-SF and SFC from arthritis urica as well as unclassified oligoarthritis for the RA-SFC. As positive control we used baby hamster kidney cells, murine mast cells and pig fibroblasts, which produce endogenous retroviruses. Subconfluent RA-SF and controls were incubated with azacytidin (AzaC: 2 μg/ml for 24 h), bromodeoxyuridine (BUDR: 25 μg/ml for 24 h) or irradiated with 2 or 8 Gy X-rays, respectively. Supernatants of cell cultures were taken after 24 h or 48 h and analysed for RT-activity by the product enhanced reverse transcriptase (PERT)-assay. The cells were harvested on days 2–6 without trypsinization, fixed in glutaraldehyde and prepared for electron microscopy. Furthermore, RA-SF and RA-SFC were co-cultured with H9 cells for more than 3 weeks, and the supernatant was collected every 3–4 days and analysed by the PERT-assay. <h3>Results</h3> In the virus induction and co-culture experiments, no evidence for RT-activity could be detected. In contrast, the positive controls including supernatants of cell cultures from baby hamster kidney cells, murine mast cells and pig fibroblasts revealed a strong positive RT-activity. The electron microscopical investigation of the AzaC, BUDR treated or irradiated cells did not reveal VLP. <h3>Conclusion</h3> The current investigation does not support the involvement of infectious retroviruses in RA, but cannot exclude a role of exogenous and/or endogenous retroviruses, or the involvement of endogenous retroviral elements in the pathogenesis of RA. C. A. Seemayer supported by the DAAD and by the Theodor und Ida Herzog-Egli Stiftung, all others by their institutions.
Radiochemotherapy for lung cancer with cisplatin and vinorelbine orally and shrinking field radiotherapy: Effectivity and feasibility in a nonselected patient collective.
Authors: Miriam Zagel, Anja Tobermann, Ludwig Fischer von Weikersthal, Antje Fahrig
Journal: Journal of Clinical Oncology (2012)

e17516 Background: To explore the side effects and effectivity of simultaneous radiochemotherapy (sim RCT) with cisplatin (Cis-DDP) and vinorelbine orally (VRBo) in pts. with NSCLC. Methods: From 2009 and 2011, a total of 20 pts. (5 female, 15 male) aged between 46 and 82 yrs. with NSCLC stage IIIA/B were irradiated with a median dose of 66.6 Gy to the primary and 45 Gy to the involved nodes as neoadjuvant or palliative treatment. Treatment volumes were adapted to tumor shrinkage after 19.8, 30.6, 45 and 59.4 Gy. Cis-DDP (20 mg/qm d1-4, d29-32) and VRBo (50 mg/qm d1,8,15,22,36,43) were administered simultaneously. Comorbidity was scored by the Charlson Index and nutritional status was monitored. Results: Toxicity rates: thrombopenia 3° 10%, 4° 0%, leucopenia 3° 15%, 4° 20%, haemoglobin 0% 3°/4°, esophagitis 3° 5%, 4° 0%, pneumonitis 3° 0%, 4° 5%. No reduction of planned RT-dose. Chx reduction was done due to hematologic toxicity in 35%. Response rates: CR 10%, PR 75%, SD 10%, PD 5%. 11pts. (55%) are alive after a median FU of 19 months. Conclusions: Sim RCT with Cis-DDP and VRBo results in good tumor response rates and is feasible with acceptable side effects. Shrinking treatment volumes allow adequate dose escalation without the risk for early locoregional recurrence.
Investigating causal pathways in severe falciparum malaria: A pooled retrospective analysis of clinical studies
Authors: Stije J. Leopold, James A. Watson, Atthanee Jeeyapant, Julie A. Simpson, Nguyen H. Phu, Tran T. Hien, Nicholas P. J. Day, Arjen M. Dondorp, Nicholas J. White
Journal: PLoS Medicine (2019)

Severe falciparum malaria is a medical emergency characterised by potentially lethal vital organ dysfunction. Patient fatality rates even with parenteral artesunate treatment remain high. Despite considerable research into adjuvant therapies targeting organ and tissue dysfunction, none have shown efficacy apart from renal replacement therapy. Understanding the causal contributions of clinical and laboratory abnormalities to mortality is essential for the design and evaluation of novel therapeutic interventions.We used a structural model causal inference approach to investigate causal relationships between epidemiological, laboratory, and clinical variables in patients with severe falciparum malaria enrolled in clinical trials and their in-hospital mortality. Under this causal model, we analysed records from 9,040 hospitalised children (0-12 years, n = 5,635) and adults (n = 3,405, 12-87 years) with severe falciparum malaria from 15 countries in Africa and Asia who were studied prospectively over the past 35 years. On admission, patient covariates associated with increased in-hospital mortality were severity of acidosis (odds ratio [OR] 2.10 for a 7-mEq/L increase in base deficit [95% CI 1.93-2.28]), renal impairment (OR 1.71 for a 2-fold increase in blood urea nitrogen [95% CI 1.58, 1.86]), coma (OR 3.59 [95% CI 3.07-4.21]), seizures (OR 1.40 [95% CI 1.16-1.68]), shock (OR 1.51 [95% CI 1.14-1.99]), and presumed pulmonary oedema (OR 1.58 [95% CI 1.04-2.39]). Lower in-hospital mortality was associated with moderate anaemia (OR 0.87 for a decrease of 10 percentage points in haematocrit [95% CI 0.80-0.95]). Circulating parasite density was not associated with mortality (OR 1.02 for a 6-fold increase [95% CI 0.94-1.11]), so the pathological effects of parasitaemia appear to be mediated entirely by the downstream effects of sequestration. Treatment with an artemisinin derivative decreased mortality compared with quinine (OR 0.64 [95% CI 0.56-0.74]). These estimates were consistent across children and adults (mainly representing African and Asian patients, respectively). Using inverse probability weighting, transfusion was not estimated to be beneficial in children with admission haematocrit values between 15% and 25% (OR 0.99 [95% CI 0.97-1.02]). Except for the effects of artemisinin treatment and transfusion, causal interpretations of these estimates could be biased by unmeasured confounding from severe bacterial sepsis, immunity, and duration of illness.These data suggest that moderate anaemia is associated with a reduced risk of death in severe falciparum malaria. This is possibly a direct causal association. The severe anaemia threshold criteria for a definition of severe falciparum malaria should be reconsidered.
Immunophenotypic Evidence for Reactive Polyclonal Marrow Plasmacytosis in Multiple Myeloma Patients Receiving Long-Term Lenalidomide Therapy
Authors: Hani Hassoun, Mikhail Roshal, Joshua Sabari, Brittany Cooper, James Nguyen, Rosalyn Ruiz, Qi Gao, Heather Landau, Nikoletta Lendvai, David J. Chung, Alexander M. Lesokhin, Neha S Korde, Sham Mailankody, Sergio A. Giralt, Ola Landgren
Journal: Blood (2016)
Recommended Change in the N Descriptor Proposed by the International Association for the Study of Lung Cancer: A Validation Study
Authors: Byung Jo Park, Tae Ho Kim, Sumin Shin, Hong Kwan Kim, Yong Soo Choi, Jhingook Kim, Jae Ill Zo, Young Mog Shim, Jong Ho Cho
Journal: Journal of Thoracic Oncology (2019)
Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity
Authors: Shengnan Yu, Ming Yi, Shuang Qin, Kongming Wu
Journal: Molecular Cancer (2019)

Chimeric antigen receptor T (CAR-T) cell therapy is an emerging and effective cancer immunotherapy. Especially in hematological malignancies, CAR-T cells have achieved exciting results. Two Anti-CD19 CAR-T therapies have been approved for the treatment of CD19-positive leukemia or lymphoma. However, the application of CAR-T cells is obviously hampered by the adverse effects, such as cytokines release syndrome and on-target off-tumor toxicity. In some clinical trials, patients quitted the treatment of CAR-T cells due to life-threatening toxicity. Seeking to alleviate these toxicities or prevent the occurrence, researchers have developed a number of safety strategies of CAR-T cells, including suicide genes, synthetic Notch receptor, on-switch CAR, combinatorial target-antigen recognition, bispecific T cell engager and inhibitory CAR. This review summarized the preclinical studies and clinical trials of the safety strategies of CAR-T cells and their respective strengths and weaknesses.