tbuckley/cabot-search huggingface dataset:
Bullous pemphigoid and pemphigus vulgaris
Authors: Mahaz Kayani, Arif M Aslam
Journal: BMJ (2017)

#### What you need to know

Autoimmune bullous diseases are characterised by blistering of the skin or mucous membranes.1 Blisters form due to the antibodies against structural skin components. The two most common bullous diseases are bullous pemphigoid and pemphigus vulgaris. Most of our epidemiological data comes from European studies. Estimates of the incidence of bullous pemphigoid range from 2.8 per 100 000 person years in the US2 to 4.28 per 100 000 person years in the UK3 most commonly presenting in people over 80 years old. Pemphigus vulgaris is rarer and its geographic distribution more variable: whereas in Israel the incidence has been estimated at 5.3 per 100 000 person years, in the UK it was only 0.7.4

To the generalist these may seem to be niche diseases and are often overlooked or misdiagnosed, leading to poor patient outcomes. Because of their chronic nature, high morbidity and mortality, and the systemic effects from treatment, affected people require intensive management. In the past few decades great strides have been made in understanding these diseases but and the development of novel treatments, however these treatments themselves are associated with substantial disease burden. This article highlights the pathophysiology, investigations, and management of bullous pemphigoid and pemphigus vulgaris.

The aetiology of bullous pemphigoid and pemphigus vulgaris is poorly understood. Possible triggers for bullous pemphigoid include trauma as …
Control of tumor outgrowth by regional immunization with peptide-pulsed dendritic cells depends on epitope density
Authors: David W. Mullins, Victor H. Engelhard
Journal: Cancer Research (2004)

4843   Immunization route with activated, peptide-pulsed dendritic cells (DC) determines the location of antigen-specific CD8 memory populations and determines the efficacy of tumor control in different organ compartments. Thus, DC can be targeted to specific lymphoid organs to generate functionally divergent immune responses. However, no study has evaluated whether epitope density on immunizing DC differentially controls the induction of antigen-specific primary immune responses in different lymphoid compartments. Using a preclinical HLA-A2-transgenic mouse model and an endogenously-expressed antigen from tyrosinase (Tyr 369-377 ), we evaluated the immunogenicity and anti-tumor efficacy of regionally delivered DC pulsed with a range of peptide concentrations. Following intravenous injection, DC infiltrated spleen but not lymph nodes; Tyr 369-377 -specific primary and memory T cells were likewise confined to spleen. Increasing the density of Tyr 369-377  epitope on immunizing DC progressively increased the magnitude of Ag-specific CD8 +  T cell response in spleen, and also enhanced the control of HLA-A2-expressing melanoma growing in the lungs. In contrast, subcutaneous delivery of peptide-pulsed DC targeted both draining peripheral lymph nodes and spleen, and antigen-specific CD8 +  cells were present in both compartments. Interestingly, the optimal epitope density for the induction of primary antigen-specific CD8 +  T cell responses in lymph node and control of a subcutaneously-growing HLA-A2-expressing melanoma was 3 logs lower than previously determined for spleen. Furthermore, the requirement for increased epitope density to mediate responses in spleen was independent of DC injection route. The disparity in optimal epitope density between lymphoid compartments reflects a differential kinetic of migration DC to, or retention of DC in, the lymph node and spleen. In both lymph nodes and spleen, supra-optimal epitope densities ablated Ag-specific CD8 +  T cells, underscoring the need to optimize antigen density prior to clinical therapeutic application. Collectively, these data demonstrate a fundamental difference in lymph node and spleen as site for activation of anti-tumor immune responses. Supported by the American Cancer Society (DWM) and USPHS R01CA78400 (VHE).
SL-401, a Novel IL-3Rα/CD123-Directed Agent Targets Stem-like Cells in Multiple Myeloma
Authors: Arghya Ray, Yan Song, Deepika Sharma Das, Vincent Macri, Janice Chen, Claudia Paba-Praba, Paul G. Richardson, Christopher L. Brooks, Dharminder Chauhan, Kenneth C. Anderson
Journal: Blood (2016)
Effect of denosumab on bone mineral density (T-score classification of −1.0 to −2.5) in postmenopausal Japanese women receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer.
Authors: Katsuhiko Nakatsukasa, Takayuki Matsuda, Tetsuya Taguchi
Journal: Journal of Clinical Oncology (2017)

552 Background: Adjuvant aromatase inhibitor (AI) therapy is well established in postmenopausal women with hormone receptor-positive breast cancer, but such therapy is associated with bone loss and increased fracture risk. Denosumab, a fully human monoclonal antibody against receptor of nuclear-κB ligand, was previously proven to protect against AI-induced bone loss. In Japan, however, the efficacy of denosumab in the treatment of AI-associated bone loss has not been proven in a prospective study. Methods: This non-randomized prospective study was conducted at four institutions in Japan. we prospectively evaluated the bone mineral density (BMD) of the lumbar spine and bilateral femoral neck in hormone-receptor positive clinical stageⅠ–ⅢA, postoperative postmenopausal breast cancer patients who were scheduled for treatment with AI as adjuvant endocrine therapy or during AI adjuvant therapy. They received supplemental calcium, vitamin D and subcutaneous denosumab 60mg (n=103) every six months. At enrollment, all patients were required to have evidence of low bone mass, excluding osteoporosis. The primary endpoint was percentage change in lumbar spine BMD from baseline to month 12. The secondary endpoint was percentage change in bilateral femoral neck BMD from baseline to month 12. This is the first trial where the right and left femoral neck BMD are measured separately. Results: We enrolled 103 patients between November, 2014 to October, 2016. At 12 months, lumber spine BMD increased by 4.7 %. The patients who were administered prior AI therapy (n=60) had a 4.8 % increase, and the patients without prior AI therapy (n=40) had a 4.6 % increase. At 12 months, the right and left femoral neck BMD increased by 2.9 % and 2.0 %, respectively. Hypocalcemia ≥ grade2, osteonecrosis of the jaw (ONJ) and non-traumatic clinical fracture were absent in this study. Conclusions: Twice-yearly treatment with denosumab was associated with consistently greater gains in BMD among Japanese women receiving adjuvant AI therapy, regardless of whether prior AI therapy was administered. Clinical trial information: UMIN000013863.
Non-Driver Mutations Profile Identified By a 206-Gene NGS Panel in Patients with Primary Myelofibrosis and Post-Polycythaemic/Essential Thromocythaemia Myelofibrosis in a Single Center from China
Authors: Bing Li, Lei Zhang, Jie Bai, Zefeng Xu, Tiejun Qin, Yue Zhang, Jinqin Liu, Gang Huang, Zhijian Xiao
Journal: Blood (2016)
Tumor pharmacokinetics (PK) and pharmacodynamics (PD) of SAR245409 (XL765) and SAR245408 (XL147) administered as single agents to patients with recurrent glioblastoma (GBM): An Ivy Foundation early-phase clinical trials consortium study.
Authors: Timothy Francis Cloughesy, Paul S. Mischel, Antonio Marcilio Padula Omuro, Michael Prados, Patrick Y. Wen, Bin Wu, Kevin Rockich, Yi Xu, Joanne J. Lager, Ingo K. Mellinghoff
Journal: Journal of Clinical Oncology (2013)

2012 Background: XL765 is a potent pan PI3K inhibitor with activity against mTOR and XL147 is a potent pan-PI3K inhibitor. Inhibition of the PI3K/mTOR pathway may be beneficial in the treatment of GBM. Methods: Patients with GBM who were candidates for a surgical resection were eligible for this exploratory study. Cohorts of 6-10 patients were treated with one of three regimens: Cohort 1: XL765 50mg twice daily (BID), Cohort 2: XL147 200mg once daily (QD), Cohort 3: XL765 90mg QD for &gt;10 days prior to undergoing tumor resection. Tumor tissue was obtained at ~12, 24 and 3 hours after the last dose, respectively. Frozen tumor tissue and blood were analyzed for drug concentration (PK) and pathway modulation was analyzed in post-dose frozen tumor tissue and compared to reference tumor samples from GBM patients not treated with XL765 or XL147. Pharmacodynamic impact (PD) on the pathway, apoptosis and proliferation was examined by immunohistochemistry (IHC) in an FFPE tumor sample from each patient and compared to an archived tumor sample from an earlier surgery. Results: Enrollment is complete with 21 patients enrolled; 6, 6 and 7 were evaluable for the PK/PD analysis in cohorts 1, 2 and 3, respectively. The toxicity profiles for both drugs were consistent with previous studies. PK analyses revealed a mean tumor to plasma ratio of 0.38 and 0.40 in cohorts 1 and 3 and 0.27 in cohort 2. PD analysis by IHC revealed reduction compared to archived tumor in pS6K1 in 4/6 and 7/7 patients in cohorts 1 and 3 and 6/6 patients in cohort 2. Reduction in Ki67 was observed in 6/6 and 5/7 patients in cohorts 1 and 3 and 4/6 patients in cohort 2. Conclusions: XL765 when given on a QD or BID schedule to patients with glioma yields moderately higher distribution of XL765 into CNS tumor compared to XL147 based on tumor to plasma ratios. Decreases in pS6K1, consistent with pathway inhibition, and decreases in Ki67, consistent with inhibition of proliferation, were observed following treatment with both XL147 and XL765. Clinical trial information: NCT01240460.
Abstract 156: The Nitroxyl Donor Angeli's Salt Elicits Concomitant Concentration-Dependent Coronary Vasodilatory and Inotropic Actions in the Intact Rat Heart
Authors: Rebecca H Ritchie, Kai Yee Chin, Chengxue Qin, Nga Cao, Barbara K Kemp-Harper, Owen L Woodman
Journal: Circulation Research (2012)

Nitroxyl (HNO) is a novel redox sibling of NO• that elicits vasodilator, antihypertrophic and superoxide-suppressing actions. HNO is however resistant to scavenging by superoxide, and has high reactivity with thiols (enabling potent enhancement of LV function). In the present study, hearts from adult male Sprague-Dawley rats were Langendorff-perfused at constant pressure. Dose-response curves to the HNO donor Angeli’s salt were performed following preconstriction with U46619 to ∼50% of baseline coronary flow (CF). Angeli’s salt (10pmol-10µmol, n=6) elicited significant dose-dependent increases in left ventricular systolic pressure (LVSP), LV developed pressure (LVDP), LV end-diastolic pressure (LVEDP), LV±dP/dt, and CF. The effects of the highest dose of Angeli's salt studied on LV function are shown in the Table; these were significantly inhibited by co-administration of the HNO scavenger L-cysteine (4mM, n=6) or the soluble guanylyl cyclase inhibitor ODQ (10µM, n=5). The EC 50 for Angeli's salt-induced vasodilatation was increased from -8.6±0.3mol to -7.5±0.2mol (p&lt;0.01) and -7.6±0.3mol (p&lt;0.05) by L-cysteine and ODQ, respectively. Although CGRP is a putative mediator of HNO actions, both the inotropic and vasodilator actions of Angeli's salt were insensitive to the CGRP antagonist CGRP 8-37 (0.1µM, n=5). The vehicle for Angeli’s salt, 0.01M NaOH, had no effect on any of these parameters (n=3, results not shown). Our results demonstrate that the cardiac effects of Angeli’s salt are thiol-sensitive, and mediated by HNO and cGMP, but not CGRP. HNO donors represent potential therapy for the failing heart, alone or in addition to standard care.
High Lymphoid Enhancer-Binding Factor-1 (LEF1) Expression Is Associated with ZAP70 Positivity, Requirement of Treatment, and Fibromodulin (FMOD) Expression In Chronic Lymphocytic Leukemia (CLL)
Authors: Felix Erdfelder, Simon Jonas Poll-Wolbeck, Iris Gehrke, Michael Hallek, Karl-Anton Kreuzer
Journal: Blood (2010)
Safety and tolerability of the dual PI3K/mTOR inhibitor LY3023414 in combination with fulvestrant in treatment refractory advanced breast cancer patients.
Authors: Anna M. Varghese, Kathleen N. Moore, Erika Paige Hamilton, David Michael Hyman, Komal L. Jhaveri, Xuejing Aimee Wang, Sophie Callies, Aaron Alan Fink, Volker Wacheck, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2017)

1064 Background: Thephosphatidylinositol 3-kinase (PI3K) /mammalian target of rapamycin (mTOR) pathway is frequently activated in breast cancer. LY3023414 (LY) is an oral ATP- competitive inhibitor that selectively and potently inhibits class I PI3K isoforms, mTOR, and DNA-PK. The recommended phase 2 dose (RP2D) of LY monotherapy was previously established to be 200 mg twice daily (BID). Here we present the safety and preliminary activity data of LY in combination with fulvestrant (F) for breast cancer patients (pts) as part of a multi-cohort Phase 1 study. Methods: Pts with advanced HR+, HER2- breast cancer refractory to standard treatment received 200 mg LY BID + 500 mg F (day 1 and 15, then once monthly). Eligible pts had measurable disease and baseline tumor tissue available. Primary objective was to determine a RP2D. Other objectives included assessment of pharmacokinetics (PK), antitumor activity, and biomarker analysis. Results: 9 pts received LY + F in the breast cancer expansion cohort. All pts had multiple lines of prior systemic therapy (range 3-12), including chemotherapy. Dose limiting toxicity was observed in one pt in the form of grade (Gr) 3 oral mucositis. Common possibly related adverse events included nausea (5 pts), vomiting (4 pts), oral mucositis (4 pts), decreased appetite (3 pts), fatigue (3 pts), mucosal inflammation (2 pts), and paresthesia (2 pts). No obvious impact of LY on F PK or of F on LY PK was observed. Median duration of treatment was 15 weeks (range 3-63). In the 6 pts evaluable for tumor response, there was 1 durable partial response according to RECIST (still on treatment for ≥11 months) and 4 further pts had a decrease in their target lesions for a disease control rate of 56%. The median progression-free survival for this cohort is 4.2 months (90% CI 1.8, NA). Of note, the partial response was observed in a pt harboring an activating PIK3CA mutation (H1047R). Further biomarker analysis is ongoing. Conclusions: The RP2D of LY in combination with F is 200mg BID and may cause tumor regression or stabilization in breast cancer pts. Clinical trial information: NCT01655225.
The Crux of Molecular Prognostications in NSCLC : An Optimized Biomarker Panel Fails to Outperform Clinical Parameters
Authors: Dijana Djureinovic, Marianna Grinberg, Johanna Sofia Margareta Mattsson, Karolina Edlund, Joerg Rahnenfuehrer, Jan Hengstler, Linnea La Fleur, Simon Ekman, Hans Brunnström, Hirsh Koyi, Eva Branden, Mats Lambe, Karin Jirström, Fredrik Pontén, Johan Botling, Patrick Micke
Journal: Journal of Thoracic Oncology (2015)
Detection of the t(4;14)(p!6.3;q32) chromosomal translocation in multiple myeloma by rt-pcr analysis of 1gh-mmset fusion transcripts
Authors: Antonino Neri, Ursula Malgeri, Vittorio Perfetti, Sonia Fabrisgualtiero Colombo, Valentina Lotti, Daniela Intini, Luigia Lombardi Sivana Compasso, Anna Teresa Maiolo, Luca Baldini
Journal: Blood (2000)
Suppression Of β-catenin Nuclear Translocation By CGP57380 Decelerates Poor Progression And Potentiates Radiation-Induced Apoptosis in Nasopharyngeal Carcinoma
Authors: Weiyuan Wang, Qiuyuan Wen, Jiadi Luo, Shuzhou Chu, Lingjiao Chen, Lina Xu, Hongjing Zang, Mohannad Ma Alnemah, Jinghe Li, Jianhua Zhou, Songqing Fan
Journal: Theranostics (2017)

Nuclear localization of β-catenin is essential for the progression of various human cancers via transcriptional upregulation of downstream genes. The MAP kinase interacting serine/threonine kinase (MNK)-eukaryotic translation initiation factor 4E (eIF4E) axis has been reported to activate Wnt/β-catenin signaling, and CGP57380, an inhibitor of MNK kinases, inhibits the proliferation of multiple cancers. In this study, we showed that β-catenin signaling (including β-catenin, cyclin D1, c-Myc, and MMP-7) and p-eIF4E expression were elevated in nasopharyngeal carcinoma (NPC) compared with non-cancerous nasopharyngeal epithelial tissues, and was associated with clinical characteristics of NPC patients. Lymph node metastasis, gender, aberrant β-catenin expression, and elevated levels of MMP-7 and cyclin D1 were independent prognostic factors. Significantly, expression of p-eIF4E was positively correlated with β-catenin, and targeting the MNK-eIF4E axis with CGP57380 downregulated β-catenin in the nucleus, which in turn decreased proliferation, cell cycle progression, migration, invasion, and metastasis of NPC in vitro and in vivo. CGP57380 also potentiated radiation-induced apoptosis in NPC. Moreover, CGP57380 upregulated β-catenin in the cytoplasm thus blocking epithelial-mesenchymal transition (EMT), a key mechanism in cancer cell invasiveness and metastasis. Mechanistically, inhibition of β-catenin nuclear translocation by CGP57380 was dependent on AKT activation. Notably, identification of the MNK/eIF4E/β-catenin axis might provide a potential target for overcoming the poor prognosis mediated by β-catenin in NPC.
Multiple gene movements into and out of haploid sex chromosomes
Authors: Agnieszka P. Lipinska, Nicholas R. T. Toda, Svenja Heesch, Akira F. Peters, J. Mark Cock, Susana M. Coelho
Journal: Genome biology (2017)

Long-term evolution of sex chromosomes is a dynamic process shaped by gene gain and gene loss. Sex chromosome gene traffic has been studied in XY and ZW systems but no detailed analyses have been carried out for haploid phase UV sex chromosomes. Here, we explore sex-specific sequences of seven brown algal species to understand the dynamics of the sex-determining region (SDR) gene content across 100 million years of evolution. A core set of sex-linked genes is conserved across all the species investigated, but we also identify modifications of both the U and the V SDRs that occurred in a lineage-specific fashion. These modifications involve gene loss, gene gain and relocation of genes from the SDR to autosomes. Evolutionary analyses suggest that the SDR genes are evolving rapidly and that this is due to relaxed purifying selection. Expression analysis indicates that genes that were acquired from the autosomes have been retained in the SDR because they confer a sex-specific role in reproduction. By examining retroposed genes in Saccharina japonica, we demonstrate that UV sex chromosomes have generated a disproportionate number of functional orphan retrogenes compared with autosomes. Movement of genes out of the UV sex chromosome could be a means to compensate for gene loss from the non-recombining region, as has been suggested for Y-derived retrogenes in XY sexual systems. This study provides the first analysis of gene traffic in a haploid UV system and identifies several features of general relevance to the evolution of sex chromosomes.
Complications précoces et résultats à long terme de la sphinctérotomie endoscopique dans une population pédiatrique: une expérience monocentrique
Journal: Endoscopy (2017)

La Sphinctérotomie Endoscopique (SE) est largement utilisée en population adulte avec un risque de complications immédiates et tardives non-nulles. Le but de cette étude était d’évaluer les résultats précoces et tardifs de la SE dans une population pédiatrique.
Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion
Authors: Franco Locatelli, Pietro Merli, Daria Pagliara, Giuseppina Li Pira, Michela Falco, Daniela Pende, Roberto Rondelli, Barbarella Lucarelli, Letizia Pomponia Brescia, Riccardo Masetti, Giuseppe Maria Milano, Valentina Bertaina, Mattia Algeri, Rita Maria Pinto, Luisa Strocchio, Raffaella Meazza, Lavinia Grapulin, Rupert Handgretinger, Alessandro Moretta, Alice Bertaina, Lorenzo Moretta
Journal: Blood (2017)
Safety and efficacy of the BCL2 inhibitor venetoclax in estrogen receptor (ER) and BCL2-positive metastatic breast cancer: The mBEP study.
Authors: Geoffrey John Lindeman, Sheau Wen Lok, Alice Ruth Bergin, James Richard Whittle, Kylie Shackleton, Peter Sherman, Sarah-Jane Dawson, Jayesh Desai, Danny Liew, Bruce Mann, Anand Murugasu, Andrew Warwick Roberts, Mark Rosenthal, Jane Visvader
Journal: Journal of Clinical Oncology (2017)

1044 Background: The anti-apoptotic protein BCL2 is overexpressed in ~85% of ER + breast cancer (BC). Venetoclax (ABT-199), a BCL2 inhibitor approved for CLL (400 mg/day), synergizes with tamoxifen in preclinical patient derived xenograft models by increasing apoptosis. In the first study to evaluate venetoclax in solid tumors, we tested the safety and efficacy of this combination in ER + BCL2 + metastatic BC. Methods: A ‘3+3 design’ dose escalation phase 1b study enrolled women with ER + ( &gt; 1%), BCL2 + ( &gt; 10%, mod-high) and HER2 non-amplified metastatic BC. Patients received escalating doses of venetoclax 200, 400, 600 or 800 mg/day with tamoxifen 20 mg/day. The primary objective was to determine dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) over 4 weeks. There was no limit to the number of prior lines of therapy. Results: Fifteen patients were enrolled (mean age 62 years, range 44-78; previous tamoxifen, 10 pts). Mean lines of prior therapy for metastatic BC was 2.5 (median 2, range 0-6) and included tamoxifen (6 pts). ESR1 mutations were present in ctDNA of 4 patients. Treatment was well tolerated, with no DLT observed. MTD was not reached; 6 patients received the maximal planned dose (800 mg). The most common adverse event (AE) was lymphopenia (67% Grade 1-2; 13% Grade 3; No Grade 4), followed by nausea (46%, Grade 1-2), which was readily managed. Of 13 women with measurable disease (RECIST v1.1), 4 (31%) had a partial response and 5 (38%) had stable disease (clinical benefit rate, 69%). For patients with a partial response, tumor regression was rapid (evident at first restaging) and occurred in the 400-800 mg dose levels. Two patients with non-measurable bone-only disease had clinically stable disease (1 ongoing &gt; 64 weeks). The median duration of response has not yet been reached (range, 12 to &gt; 64 weeks). Conclusions: We demonstrated the safety of tamoxifen and venetoclax in ER + BCL2 + metastatic BC, with preliminary evidence of clinically relevant activity. A dose expansion study including serial biopsy, ctDNA and PET scans is ongoing at the 800 mg/day recommended phase 2 dose. Sponsor: Royal Melbourne Hospital Clinical trial information: ISRCTN98335443 , ACTRN12615000702516.