tbuckley/cabot-search huggingface dataset:
Using Population Genetics to Interrogate the Monogenic Nephrotic Syndrome Diagnosis in a Case Cohort
Authors: Matthew G. Sampson, Christopher E. Gillies, Catherine C. Robertson, Brendan Crawford, Virginia Vega-Warner, Edgar A. Otto, Matthias Kretzler, Hyun Min Kang
Journal: Journal of the American Society of Nephrology (2015)

To maximize clinical benefits of genetic screening of patients with nephrotic syndrome (NS) to diagnose monogenic causes, reliably distinguishing NS-causing variants from the background of rare, noncausal variants prevalent in all genomes is vital. To determine the prevalence of monogenic NS in a North American case cohort while accounting for background prevalence of genetic variation, we sequenced 21 implicated monogenic NS genes in 312 participants from the Nephrotic Syndrome Study Network and 61 putative controls from the 1000 Genomes Project (1000G). These analyses were extended to available sequence data from approximately 2500 subjects from the 1000G. A typical pathogenicity filter identified causal variants for NS in 4.2% of patients and 5.8% of subjects from the 1000G. We devised a more stringent pathogenicity filtering strategy, reducing background prevalence of causal variants to 1.5%. When applying this stringent filter to patients, prevalence of monogenic NS was 2.9%; of these patients, 67% were pediatric, and 44% had FSGS on biopsy. The rate of complete remission did not associate with monogenic classification. Thus, we identified factors contributing to inaccurate monogenic classification of NS and developed a more accurate variant filtering strategy. The prevalence and clinical correlates of monogenic NS in this sporadically affected cohort differ substantially from those reported for patients referred for genetic analysis. Particularly in unselected, population-based cases, considering putative causal variants in known NS genes from a probabilistic rather than a deterministic perspective may be more precise. We also introduce GeneVetter, a web tool for monogenic assessment of rare disease.
Results of a multicenter prospective phase II trial investigating the safety and efficacy of lenalidomide in patients with myelodysplastic syndromes with isolated del(5q) (LE-MON 5)
Authors: E Schuler, A Giagounidis, D Haase, K Shirneshan, G Büsche, U Platzbecker, F Nolte, K Götze, R F Schlenk, A Ganser, A Letsch, F Braulke, M Lübbert, G Bug, P Schafhausen, U Bacher, N Gattermann, M Wulfert, R Haas, U Germing
Journal: Leukemia (2015)
A phase I dose-escalation study of the safety and pharmacokinetics (PK) of XL184, a VEGFR and MET kinase inhibitor, administered orally to patients (pts) with advanced malignancies
Authors: R. Salgia, D. S. Hong, L. H. Camacho, C. S. Ng, L. Janisch, M. J. Ratain, R. Kurzrock
Journal: Journal of Clinical Oncology (2007)

14031 Background: XL184 is a potent orally available small molecule inhibitor of MET and VEGFR2/KDR, and also inhibits KIT, RET, FLT3, and Tie-2. Methods: This is a ph 1 cohort dose escalation study. Pts with advanced malignancies are treated with 2 cycles of XL184 orally daily for 5 consecutive days every 2 weeks. Response is assessed every 8 wks by RECIST criteria and pts with SD or better receive maintenance therapy. Plasma markers of angiogenesis VEGF-A, sVEGFR2 and Ang2 are being analyzed. Results: A total of 25 pts with advanced malignancies have been treated across 7 dose levels: 0.08 to 5.12 mg/kg. A total of 10 pts have had SD lasting &gt; 3 months. Three pts with medullary thyroid carcinoma (one of whom had a documented RET mutation) had substantial reductions in plasma calcitonin. Three pts have had stable disease for over 6 months, including 1 pt with carcinoid (20% decrease in liver metastases) and 1 pt with T- cell lymphoma (on treatment for &gt;12 mos). One pt with papillary renal cell cancer, a disease that sometimes bears activating MET mutations, demonstrated 9% tumor reduction at first restaging. There have been no DLTs to date. Preliminary PK analysis (0.08–1.28 mg/kg) suggests linear PK with average Cmax values 34.2, 70, 198, 322 and 603 ng/mL following the fifth dose at 0.08, 0.16, 0.32, 0.64 and 1.28 mg/kg, respectively. The terminal half-life is 80–90 hrs, resulting in concentrations exceeding 200 ng/mL for 96 hours following the fifth dose at 1.28 mg/kg. Conclusions: XL184 appears generally well tolerated at doses tested to date. XL184 has a long terminal half-life. Early signs of antitumor activity have been observed, at doses not associated with toxicity, in patients with various cancers, including but not limited to those that may have RET (medullary thyroid) or MET (papillary renal) mutations. No significant financial relationships to disclose.
Bispecific antibody releasing-mesenchymal stromal cell machinery for retargeting T cells towards acute myeloid leukemia blasts
Authors: R Aliperta, M Cartellieri, A Feldmann, C Arndt, S Koristka, I Michalk, M von Bonin, A Ehninger, J Bachmann, G Ehninger, M Bornhäuser, M P Bachmann
Journal: Blood Cancer Journal (2015)

Abstract Bispecific antibodies (bsAbs) engaging T cells are emerging as a promising immunotherapeutic tool for the treatment of hematologic malignancies. Because their low molecular mass, bsAbs have short half-lives. To achieve clinical responses, they have to be infused into patients continously, for a long period of time. As a valid alternative we examined the use of mesenchymal stromal cells (MSCs) as autonomous cellular machines for the constant production of a recently described, fully humanized anti-CD33-anti-CD3 bsAb, which is capable of redirecting human T cells against CD33-expressing leukemic cells. The immortalized human MSC line SCP-1 was genetically modified into expressing bsAb at sufficient amounts to redirect T cells efficiently against CD33 presenting target cells, both in vitro and in an immunodeficient mouse model. Moreover, T cells of patients suffering from acute myeloid leukemia (AML) in blast crisis eliminated autologous leukemic cells in the presence of the bsAb secreting MSCs over time. The immune response against AML cells could be enhanced further by providing T cells an additional co-stimulus via the CD137-CD137 ligand axis through CD137L expression on MSCs. This study demonstrates that MSCs have the potential to be used as cellular production machines for bsAb-based tumor immunotherapy in the future.
Poly TLR agonist polyantigenic vaccine (Mycobacterium w) in palliative therapy of head and neck cancer
Authors: R. I. Dave, U. Tripathi, S. Shah, K. M. Patel
Journal: Journal of Clinical Oncology (2006)

12512 Background: Poly TLR poly-antigenic vaccine containing Mycobacterium w (Mw) is found useful in the management of lung cancer and bladder cancer when used along with standard therapy 1,2 but not in Head and Neck cancer 3–4 . This study was carried out to evaluate its efficacy as a single agent in advanced head &amp; neck cancer. Methods: In a prospective study consecutive 75 symptomatic patients with advanced head &amp; neck cancer (squamous cell) attending hospital for palliative care following failure of standard therapy were administered Mw once a week for 8 weeks. Results: Of 75 patients 43 were male &amp; 32 females with 76% between the ages of 31 to 60). 18 had buccal mucosa tumor, 12 alveolar and 11 at base of the tongue. Partial response was seen in 27. It was associated with Pain relief (27/27), Healing of ulcer/fistula (4/5), improvement in dysphagia (7/15), improvement in voice(5/19). All 27 showed improvement in constitutional symptoms also. No systemic side effects were seen. Conclusions: Mw vaccine is useful in palliative care of head &amp; neck cancer. Reference 1 Sur PK, Dastidar AG. Role of mycobacterium w as adjuvant treatment of lung cancer. J Indian Med Assoc. 2003;101:118, 120. 2 Chaudhuri P, Mukhopadhyay S. Bladder preserving approach for muscle invasive bladder cancer–role of mycobacterium w. J Indian Med Assoc. 2003;101:559–60 3 M. C. Pant, R. Hadi, R. Prasad, D. Dalela, et al. Role of immuno-therapy as a adjuvant treatment in advance head &amp; neck cancer, patient receiving chemo radiotherapy. Journal of Clinical Oncology 2005; 23, (16S Part 1): 190S 4 S. K. Sarkar, C. Dasgupta. Role of Mycobacterium W as an adjuvant treatment of Head &amp; Neck Cancer_A Randomised trial. Journal of Clinical Oncology 2005; 23, (16S Part 1): 521 s. No significant financial relationships to disclose.
SWOG 99–16: Randomized phase III trial of docetaxel (D)/estramustine (E) versus mitoxantrone(M)/prednisone(p) in men with androgen-independent prostate cancer (AIPCA)
Authors: D. P. Petrylak, C. Tangen, M. Hussain, P. N. Lara, J. Jones, M. E. Talpin, P. Burch, G. Greene, E. Small, E. D. Crawford
Journal: Journal of Clinical Oncology (2004)

3 Background: The median survival of AIPCA patients (pts) treated with M+P is 10–12 months. Phase I/II trials of AIPCA pts treated with D+E reported survivals of 20–23 months. SWOG 99–16 was designed to compare the survival D+E to M+P. Methods: 770 men with progressive AIPCA were randomized to either Arm 1) Dexamethasone 60 mg premedication; D=60 mg/m2 day(D) 2, E= 280 mg PO D1–5 Q 21 D or Arm 2) M 12 mg/m2 + P 5 mg PO BID q 21 D. Pts were dose escalated to 70 mg/m2 in Arm 1 and 14 mg/m2in Arm 2 if no Grade(G) 3 or 4 toxicities were observed in cycle 1. Assuming 310 eligible pts in each arm, the study had 0.80 power to detect a 33% difference in survival. All p-values reported are two-sided. Results: Pt Characteristics: Eligible pts Arm 1:334; Arm 2 :332. Pretreatment characteristics were equally balanced for age, race, performance status, PSA and symptoms. Response and Survival: The median survival of men treated on Arm 1 was 18 months and Arm 2 was 15 months (logrank p=.008). The hazard ratio was 0.77 (95% confidence interval 0.64, 0.94). Arm 1 also demonstrated a superior median time to progression (6 months) compared to Arm 2 (3 months) logrank p<0.0001. The measurable disease response rates in Arm 1 and 2 were 17% and 10% (p=.30), respectively. Toxicity: G 3 or 4 toxicity was reported in 175 pts (54%) on Arm 1 and 109 pts (34%) on Arm 2, due to higher rates of gastrointestinal (63pts vs. 21pts) and cardiovascular (44pts vs 20pts) events on Arm 1. There was no significant difference in toxic deaths observed Arm 1 (n=7, 2%) vs. Arm 2 (n=4, 1%). Conclusions: The 23% improvement in survival in men treated with D+E supports its use as first line therapy for AIPCA. This is the first large randomized trial demonstrating a survival advantage in AIPCA. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis
Northern Ireland assembly must decide whether to issue new abortion law
Authors: Clare Dyer
Journal: BMJ (2015)

Northern Ireland’s abortion laws breach the European Convention on Human Rights, but any change must await legislation by the province’s assembly, a High Court judge has ruled.

Mr Justice Horner declared last month that the near blanket ban on abortion in Northern Ireland violated the convention in denying terminations to women or girls whose fetuses had fatal abnormalities or were conceived as a result of rape or incest. …
Time-Lapse Cinematographic Observations of Normal Human Cervical Epithelium, Dysplasia, and Carcinoma In Situ2
Authors: Ralph M. Richart, Virginia Lerch
Journal: JNCI Journal of the National Cancer Institute (1966)

Journal Article Time-Lapse Cinematographic Observations of Normal Human Cervical Epithelium, Dysplasia, and Carcinoma In Situ Get access Ralph M. Richart, Ralph M. Richart Search for other works by this author on: Oxford Academic PubMed Google Scholar Virginia Lerch Virginia Lerch Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 37, Issue 3, September 1966, Pages 317–329, https://doi.org/10.1093/jnci/37.3.317 Published: 01 September 1966 Article history Received: 07 January 1966 Published: 01 September 1966
Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy
Authors: Christopher A. Klebanoff, Christopher D. Scott, Anthony J. Leonardi, Tori N. Yamamoto, Anthony C. Cruz, Claudia Ouyang, Madhu Ramaswamy, Rahul Roychoudhuri, Yun Ji, Robert L. Eil, Madhusudhanan Sukumar, Joseph G. Crompton, Douglas C. Palmer, Zachary A. Borman, David Clever, Stacy K. Thomas, Shashankkumar Patel, Zhiya Yu, Pawel Muranski, Hui Liu, Ena Wang, Francesco M. Marincola, Alena Gros, Luca Gattinoni, Steven A. Rosenberg, Richard M. Siegel, Nicholas P. Restifo
Journal: Journal of Clinical Investigation (2015)

Adoptive cell transfer (ACT) of purified naive, stem cell memory, and central memory T cell subsets results in superior persistence and antitumor immunity compared with ACT of populations containing more-differentiated effector memory and effector T cells. Despite a clear advantage of the less-differentiated populations, the majority of ACT trials utilize unfractionated T cell subsets. Here, we have challenged the notion that the mere presence of less-differentiated T cells in starting populations used to generate therapeutic T cells is sufficient to convey their desirable attributes. Using both mouse and human cells, we identified a T cell-T cell interaction whereby antigen-experienced subsets directly promote the phenotypic, functional, and metabolic differentiation of naive T cells. This process led to the loss of less-differentiated T cell subsets and resulted in impaired cellular persistence and tumor regression in mouse models following ACT. The T memory-induced conversion of naive T cells was mediated by a nonapoptotic Fas signal, resulting in Akt-driven cellular differentiation. Thus, induction of Fas signaling enhanced T cell differentiation and impaired antitumor immunity, while Fas signaling blockade preserved the antitumor efficacy of naive cells within mixed populations. These findings reveal that T cell subsets can synchronize their differentiation state in a process similar to quorum sensing in unicellular organisms and suggest that disruption of this quorum-like behavior among T cells has potential to enhance T cell-based immunotherapies.
The Pathology of Paraneoplastic Encephalomyelopathies
Authors: D. Moffie, S. Z. Stefanko
Journal: Neuro-Oncology (1980)

Paraneoplastic disorders may be defined as diseases which are due to tumours elsewhere in the body but not caused by a local metastasis or tumour infiltrations. Other terms used in literature are paracarcinomatous syndrome and meta-carcinomatous syndrome.
Abstract 19212: The Zinc-finger Protein 148(zfp148) Attenuates Aortic Aneurysm Formation and is a Novel Smooth Muscle Cell Regulator
Authors: Morgan Salmon, Nicolas H Pope, William F Johnston, John P Davis, Gary K Owens, Juanita L Merchant, Gilbert R Upchurch, Gorav Ailawadi
Journal: Circulation (2014)

Objective: Previously, we found that the zinc-finger protein 148(ZFP148) binds to smooth muscle(SMC) genes following ligation injury; however, it has no known role in aortic aneurysm formation. The study objective was to determine whether ZFP148 is important in AA formation. Methods: ZFP148 was examined via qPCR in human aortic aneurysms(n=12/group). 8-12 week male C57/B6 mice (n=6/group) underwent elastase perfusion and were harvested at 3, 7, and 14 days for qPCR for ZFP148. Separately, 8-12 week male (n=10/group) ZFP flx/flx Myh11 Cre+(SMC tamoxifen ZFP148 KO), Myh11 ZFP148 flx/wt Cre+ and Myh11 ZFP wt/wt Cre+ underwent elastase perfusion. At 14 days, maximal aortic dilation was measured with video micrometry. ZFP148 flx/flx ERT Cre+ (n=10/group) and ZFP148 flx/flx ERT Cre-(WT) mice also underwent elastase perfusion. A separate set of mice were bred to an ApoE-/- background and administered Angiotensin II via osmotic pump. Aortic samples were evaluated with histology for α-actin, macrophages, neutrophils, T lymphocytes, caspase3, Ki67, and elastin. In vitro ZFP148 was knocked down using siRNA in smooth muscle cells and stimulated with elastase, or IL-1β. Results: ZFP148 expression was elevated in human and murine AA. Maximal aortic dilation was significantly reduced in SMC ZFP148 KO mice compared with controls (55.7 ± 6.32% versus 106.4 ± 8.43%, p&lt;0.05). Maximal aortic dilation of ERT Cre+ ZFP148 mice was significantly decreased versus WT controls (50.4± 8.65% versus 101.3± 9.43%, p&lt;0.05). Knock-out of ZFP148 in both elastase models demonstrated reduced macrophage, T-cell, Ki-67, Caspase3 and neutrophil staining. Kaplan-Meier curves demonstrated increased survival in SM-MHC ZFP148 flx/flx (Chi2=4.357, p=0.0421) and flx/wt mice (Chi2=4.169, p=0.0476) compared to their WT controls following Angiotensin II infusion. Knock-down of ZFP148 followed by treatment with elastase or IL-1β in SMCs attenuated the down-regulation of SM22α, SM-MHC, and SMαA. ZFP148 bound via ChIP analysis to SMC marker genes in vitro and in vivo and was found to bind within the proximal promoter region of SmαA and SM22α. Conclusions: ZFP148 KO attenuates AA formation and binds to smooth muscle marker genes. ZFP148 could represent a novel regulator of vascular disease.
Opioids should be last resort to treat chronic pain, says draft CDC guideline
Authors: Michael McCarthy
Journal: BMJ (2015)

Doctors should consider prescribing opioids for chronic pain only “if [the] expected benefits for both pain and function are anticipated to outweigh risks to the patient,” the US Centers for Disease Control and Prevention (CDC) has said in a draft guideline released on 14 December.1 

The preferred treatment for patients with chronic pain is non-opioid drugs and physical, psychological, and other non-pharmacologic therapy, the CDC said, given the lack of evidence that long term treatment with opioids is effective for chronic pain and given the known risks of abuse, dependence, overdose, and death associated with long term use. 

Over the past decade and a half the number of deaths related to overdose of opioid analgesics in the United States has soared, with more than 16 000 such deaths reported in 2013 alone. The epidemic has been blamed largely on the increased use of prescribed opioids.2 …
Pancreatic cancer survivorship: Intrathecal drug delivery system for pain management
Authors: L. J. Stearns, W. H. Poling, J. Kiser, J. Nasternak, E. Berryman
Journal: Journal of Clinical Oncology (2006)

14100 Background: Pancreatic cancer is predominantly unresectable at diagnosis and is most frequently fatal. Nationally the average survivorship is 10 months. Among pancreatic cancer patients, pain is associated with decreased survival rates. Quality of life and survivorship are the principal outcome measures for these patients. Successful pain management may be a significant predictor of prolonged survivorship. No study has demonstrated an impact on survivorship secondary to the treatment of pancreatic cancer pain and the use of Intrathecal Drug Delivery Systems (IDDS). Methods: A retrospective chart review identified all pancreatic cancer patients treated at a cancer pain treatment center between January 2002 and June 2005. 43 patients had known dates of diagnosis and known dates of death. The Arizona Department of Health Services Cancer Registry provided similar information for pancreatic cancer patients residing in Maricopa County for that time period. 713 Maricopa county residents had known dates of diagnosis and known dates of death. Results: Among the Maricopa County pancreatic cancer patients, the mean survivorship was 5 months. Among the treatement center patients who did not receive the IDDS for pain, 10 (23.3%), the mean survivorship was 10.8 months. Among the pancreatic cancer patients receiving IDDS for pain management, 33 (76.7%), the mean survivorship was 14.2 months. Mean survivorship among the treatment center patients receiving IDDS for pain management is nearly 3 times greater than the general survivorship of pancreatic cancer patients in Maricopa County. Among the treatement center patients the mean survivorship is nearly 50% greater for patients receiving IDDS versus those that did not. Conclusions: The implantable IDDS for pain management among pancreatic cancer patients may be a significant predictor of increased survivorship. A larger sample size may be needed to detect significant differences in survivorship. Controlled studies examining survivorship as the primary outcome for patients with unresectable pancreatic cancer by evaluating the implantable IDDS as compared to usual care modalities such as comprehensive medical management (CMM) or neurolytic celiac plexus block (NCPB) for pain management are warranted. No significant financial relationships to disclose.
Long-Term Anticoagulation for Unprovoked Pulmonary Embolism, Monitoring Sleep with an App, and Interventional Bronchoscopy for Airway Obstruction
Authors: Jared M. Radbel, Aesha M. Jobanputra, Jasvinder Singh, Sugeet Jagpal, Sabiha Hussain
Journal: American Journal of Respiratory and Critical Care Medicine (2015)
O057 : Long-term follow-up of treatment-emergent resistance-associated variants in NS3, NS5A and NS5B with paritaprevir/r-, ombitasvir- and dasabuvir-based regimens
Authors: P. Krishnan, R. Tripathi, G. Schnell, T. Reisch, J. Beyer, T. Dekhtyar, M. Irvin, W. Xie, L. Larsen, T. Podsadecki, T. Pilot-Matias, C. Collins
Journal: Journal of Hepatology (2015)
Abstract 2293: Deletion of Tid1 in hepatocyte promotes steatosis, fibrosis, and tumorigenesis
Authors: Yu-Syuan Chen, Jeng-Fan Lo
Journal: Cancer Research (2015)

Abstract Background: Tid1, DnaJ cochaperone protein, is a mammalian homolog of the Drosophila tumor suppressor Tid56 whose anti-tumor function is through its capacity to regulate cell differentiation in imaginal discs. In our previous studies, we found Tid1 regulates early mouse embryogenesis and T cell development. In addition, it has been identified that Tid1 can act as a tumor suppressor in breast, colon, lung and head and neck cancer. Tid1 protein is highly expressed in mouse and human hepatocyte. However, the physiological role of Tid1 in hepatocyte development and hepatic tumorigenesis remains elusive. Methods: Mice with loss of Tid1 lead to embryonic lethality as early as E4.5. Therefore; we generated a hepatocyte specific Tid1 knockout mice by crossing the Tid1flx/flx mice generated in our lab with transgenic mice expressing Cre recombinase activity driven by albumin promoter. Both spontaneous or carcinogen (diethylnitrosamine; DEN) mediated hepatocellular carcinoma (HCC) in Tid1 deficiency mice will be monitored. In addition, the physiological function of hepatocytes including albumin, plasma alanine aminotransferase (ALT), triglyceride (TG) and cholesterol collected from the control and mutant mice will be examined. Results: We have successfully established mice with hepatocyte specific ablation of Tid1 mice. Immunohistochemistry staining and western blot showed that conditional knockout mice were deficient on Tid1 expression in hepatocyte. Deletion of Tid1 in hepatocyte caused the hepatic steatosis and fibrosis. Consequently, spontaneous HCC tumor was found in thirteen-month-old Tid1 knockout mice. In DEN-treated mice model, deletion of Tid1 also enhanced the induction of HCC accompanying with elevatiof of plasma ALT and cholesterol. Conclusion: The progression of steatosis, fibrosis to HCC was observed in Tid1 deficient mice, which similarly reflects to those observed in tumorigenesis of human HCC. Therefore, we could further characterize the molecular mechanisms to understand how human HCC is developed through our Tid1-deficent HCC mice model. Ultimately, therapeutic regime for HCC could be developed from the Tid1-deficent mice for improving future HCC therapy. Citation Format: Yu-Syuan Chen, Jeng-Fan Lo. Deletion of Tid1 in hepatocyte promotes steatosis, fibrosis, and tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2293. doi:10.1158/1538-7445.AM2015-2293