tbuckley/cabot-search huggingface dataset:
Pifithrin-α, an experimental inhibitor of cancer therapy toxicity, is a potent aryl hydrocarbon receptor agonist.
Authors: Martin S. Hoagland, Erica M. Hoagland, Georgia M. Ziegler, Hollie I. Swanson
Journal: Cancer Research (2004)

2029   Pifithrin-α (PFTa) is a chemical compound that inhibits p53-dependent apoptosis through an undetermined mechanism. Since the toxicities of most chemotherapeutic agents are most frequently associated with p53 activation and apoptosis in healthy cells, PFTa is currently being evaluated in pre-clinical trials for its ability to alleviate these side effects. Given the structural similarities between PFTa and AhR (aryl hydrocarbon receptor) agonists, we hypothesized that PFTa may act as an AhR ligand. Activation of AhR results in translocation to the nucleus, dimerization to its DNA-binding partner (ARNT), and regulation of gene transcription through binding of DNA at dioxin-response elements (DREs). A well-characterized effect of AhR ligands β-naphthoflavone (BNF) and 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) is the up-regulation of xenobiotic-metabolizing enzymes including CYP1A1, CYP1A2, and CYP1B1. In this study, we have characterized PFTa as a potent AhR agonist by demonstrating that PFTa is able to 1) activate gene expression through the CYP1A1 gene promoter as well as DREs, 2) induce expression of CYP1A1, 3) induce DNA binding by AhR/ARNT, as well as 4) competitively displace [ 3 H]TCDD from AhR. These studies imply that the ability of PFTa to inhibit p53-mediated apoptosis may require its activation of the AhR signaling pathway.
Clinical correlates of the lithium pump
Authors: D L Dunner, H L Meltzer, R R Fieve
Journal: American Journal of Psychiatry (1978)

The active efflux of lithium from erythrocytes, expressed as the rate constant ko, was studied in patients with primary affective disorder and in controls. The authors' data suggest that ko is stable within individuals over time, is inhibited during treatment with lithium carbonate, and may be a good index of lithium toxicity. ko correlates significantly with the lithium erythrocyte/plasma ratio but is seemingly not related to age, sex, or affective disease subtype. Preliminary data suggest that ko may be determined, at least in part, by a genetic factor.
Dermatologic Clues in Surgical Diagnosis
Authors: Walter B. Shelley
Journal: New England Journal of Medicine (1950)

THE significance of dermatologic findings in the diagnostic study of a surgical patient has not been sufficiently felt. Textbooks of surgery and dermatology, alike, grant the subject only a few occult sentences. The literature reveals isolated bursts of attention, the most notable being Wiener's1 excellent monograph on the general problem of skin manifestations of internal disease. It was with the hope of further stimulating interest in the subject that this review was prepared.The purpose of this presentation is to review certain dermatologic clues that are of aid in surgical diagnosis. No mention is made of the many dermatoses that . . .
Novel Kras-directed therapy in combination with chemotherapy for locally advanced pancreatic adenocarcinoma.
Authors: Talia Golan, Ayala Hubert, Amotz Shemi, Amiel Segal, Elina Zorde Khvalevsky, Avi Domb, Eliel Ben-David, Stephen Raskin, Yuri Goldes, Maor Lahav, Alan Dancour, Eithan Galun
Journal: Journal of Clinical Oncology (2014)

270 Background: K-Ras mutation G12D is most prevalent in pancreatic adenocarcinoma (PDAC). siRNA against the K-Ras G12D (siG12D) mutant had showed significant preclinical anti-tumor effects. siG12D LODER - is a miniature biodegradable polymeric matrix that encompasses anti K-RasG12D siRNA drug, designed to release the drug regionally along 4 months. The siG12D LODER is placed with Endoscopic US biopsy. Methods: Open label phase I study of patients with locally advanced non-operable PDAC in the first-line setting. Patients were assigned to receive siG12D LODERs in a dose escalation, dose cohorts were: 0.025mg, 0.75mg and 3.0mg. Gemcitabine 1000 mg/m 2 IV was given on a weekly basis, following the siG12D LODER insertion, until disease progression. The RP2D (recommended phase II dose) was further examined in highest dose cohort in combination with modified Folfirinox (Oxaliplatin 85mg/m2, Irinotecan 150mg/m2 followed by a Fluorouracil continuous IV infusion 2,400mg/m2 46 hours every 2 weeks). Follow up period was 8 weeks and survival follow up until death. Primary study objectives were to determine the dose-limiting toxicities (DLT) and maximum tolerated doses (MTD). Results: 15 patients with locally advanced PDAC have been enrolled. Two patients were omitted from study but followed for safety due to metastatic disease detected on day 1 post siG12D LODER implant imaging. Median age = 70 (range 52-85); male:female =8:7. Among 13 treated patients, the most frequent adverse events observed in the study were typically grade 1- 2 in severity; 4 patients experienced serious adverse events (SAE). No DLTs were observed. CT performed 8-12 weeks following the procedure showed tumor regression in 66% (8 of the first 12 patients, 7/8 from 2nd and 3rd cohorts).Reduction in tumor marker CA 19-9 was observed in 64% (7/11) of patients. Median overall survival was 16.26 months, 14.01 months and 15.11 months in the 0.025 mg, 0.75 mg and the 3 mg treatment groups respectively. Conclusions: The combination of siG12D LODER and chemotherapy is well tolerated. The combination has demonstrated promising efficacy in locally advanced pancreatic cancer with durable responses. NCT01188785. Clinical trial information: NCT01188785.
Lymphocyte Stimulation in Hepatitis B Infections
Authors: Myron J. Tong, Alana M. Wallace, Robert L. Peters, Telfer B. Reynolds
Journal: New England Journal of Medicine (1975)

Cell-mediated responses in patients with acute and chronic forms of Type B hepatitis were tested by lymphocyte transformation to purified hepatitis surface antigen (HBS Ag) and to phytohemagglutinin, by dinitrochlorobenzene sensitization and by response to skin-test antigens. Although absent during acute Type B hepatitis, lymphocyte transformation by HBS Ag appeared during early convalescence and remained detectable for six years after recovery. Patients with Type B chronic active hepatitis with increased serum transaminase levels showed a partial lymphocyte transformation with HBS Ag, whereas those with normal transaminase values demonstrated no transformation. Patients with Type B chronic persistent hepatitis and carriers of HBS Ag did not have lymphocyte transformation. Normal responses to dinitrochlorobenzene, intradermal skin tests and phytohemagglutinin were found in all patients with acute, chronic active or chronic persistent hepatitis and carriers. These results indicate that recovery from Type B hepatitis is associated with the ability to elicit a specific lymphocyte response to HBS Ag. (N Engl J Med 283:318–322, 1975)
Endovascular treatment for stroke
Authors: José G Merino
Journal: BMJ (2016)

Shortly after a clot occludes a cerebral artery, cells in the infarct core—the most severely ischaemic area—start dying. The tissue surrounding the ischaemic core, the penumbra, is hypoperfused and at risk of progressing to infarction over minutes to hours, depending on the degree of ischaemia. The goal of treatment for acute stroke is to restore blood flow to these potentially salvageable areas as soon as possible. Thrombolysis is traditionally used, but in this issue Rodrigues and colleagues (doi:10.1136/bmj.i1754) summarise the evidence supporting mechanical thrombectomy.1

For more than 20 years the only treatment proven effective for patients with acute stroke was intravenous recombinant tissue plasminogen activator (rt-PA).2 3 When administered within 4.5 hours from symptom onset, rt-PA increases the odds of survival without clinically significant disability at three to six months.4 The treatment effect is time dependent: the odds ratio for a good outcome is 1.75 when rt-PA is given within three hours of the onset of symptoms, 1.26 when started between three and 4.5 hours, and a non-statistically significant 1.15 if administered beyond 4.5 hours.4 But this treatment has limitations. …
Ly6E/K Signaling to TGFβ Promotes Breast Cancer Progression, Immune Escape, and Drug Resistance
Authors: Midrar AlHossiny, Linlin Luo, William R. Frazier, Noriko Steiner, Yuriy Gusev, Bhaskar Kallakury, Eric Glasgow, Karen Creswell, Subha Madhavan, Rakesh Kumar, Geeta Upadhyay
Journal: Cancer Research (2016)

Stem cell antigen Sca-1 is implicated in murine cancer stem cell biology and breast cancer models, but the role of its human homologs Ly6K and Ly6E in breast cancer are not established. Here we report increased expression of Ly6K/E in human breast cancer specimens correlates with poor overall survival, with an additional specific role for Ly6E in poor therapeutic outcomes. Increased expression of Ly6K/E also correlated with increased expression of the immune checkpoint molecules PDL1 and CTLA4, increased tumor-infiltrating T regulatory cells, and decreased natural killer (NK) cell activation. Mechanistically, Ly6K/E was required for TGFβ signaling and proliferation in breast cancer cells, where they contributed to phosphorylation of Smad1/5 and Smad2/3. Furthermore, Ly6K/E promoted cytokine-induced PDL1 expression and activation and binding of NK cells to cancer cells. Finally, we found that Ly6K/E promoted drug resistance and facilitated immune escape in this setting. Overall, our results establish a pivotal role for a Ly6K/E signaling axis involving TGFβ in breast cancer pathophysiology and drug response, and highlight this signaling axis as a compelling realm for therapeutic invention. Cancer Res; 76(11); 3376-86. ©2016 AACR.
Phase II study of first line combination therapy with pegylated liposomal doxorubicin (PLD) and carboplatin in patients (pts) with extensive disease small cell lung cancer(ED SCLC)
Authors: D. A. Vorobiof, B. L. Rapoport, H. S. Hlophe, C. F. Slabber, A. S. Alberts
Journal: Journal of Clinical Oncology (2008)

19089 Background: To assess the anti-tumour effect and safety of a first line combination chemotherapy of carboplatin and PLD in pts with ED SCLC. Methods: The objective of this phase II study is to determine efficacy and toxicity of PLD at a dose of 50mg/m2 in combination with carboplatin (AUC = 5), in pts with ED SCLC. Cycles were repeated every 28 days. 31 pts were enrolled. The median age was 63 years (range 40–73), 6 pts has an ECOG PS of 2, 23 had a PS of 1 and 2 had PS of 0. A total of 136 cycles have been administered, with a median of 4 cycles (range 1–6). Results: Response: A total of 12 pts responded to treatment (38.8%) (95% confidence interval 21.8% - 57.8%).There were 4 CR and 8 PR. The median time to treatment failure was 168 days (7–1068 days). The median survival was 244 days (range 10–2089) with 1 pt still alive at 2089 days. Toxicity: No toxic related deaths were documented. Grade 3 and 4 haematological toxicity includes anaemia (grade 3: 8 pts), neutropenia (grade 3: 4 pts; grade 4: 2 pts) and thrombocytopenia (grade 3: 5 pts; grade 4: 2 pts). Febrile neutropenia: 2 pts. No active clinical bleeding was documented. Other relevant toxicities included PPE (grade 1: 13 pts; grade 2: 2 pts). Stomatitis (grade 1: 8 pts; grade 2: 7 pts; grade 3: 2 pts; grade 4: 1 pt) and aesthenia (grade 1–3: 17 pts). No renal toxicity or cardiac events were observed. Conclusion: The combination of PLD at 50mg/m2 with carboplatin (AUC = 5) q 28days is a safe and active chemotherapy regime for pts with ED SCLC. No significant financial relationships to disclose.
Diagnosis and Treatment of Skin Manifestations of Capillary Fragility
Authors: Samuel M. Peck, Alfred L. Copley
Journal: New England Journal of Medicine (1946)

THIS subject is discussed under the following headings: vascular anatomy of the skin, with special reference to the site of capillary reactions; the methods of testing capillary fragility; the mechanisms of capillary fragility; the clinical manifestations of capillary fragility as part of general diseases and as purely dermatologie conditions; the relation of capillary-fragility tests to clinical diagnosis; and treatment.Vascular Anatomy of the Skin, with Special Reference to the Site of Capillary ReactionsThe skin is supplied from the underlying tissues through small arteries. In the deepest portion of the cutis the arteries form a rich anastomosing plexus from which . . .
Sex-specific effects of TLR9 promoter variants on spontaneous clearance of HCV infection
Authors: Janett Fischer, Alexander N R Weber, Stephan Böhm, Sabine Dickhöfer, Souhayla El Maadidi, Danilo Deichsel, Viola Knop, Hartwig Klinker, Bernd Möller, Jens Rasenack, Lisa Wang, Manu Sharma, Holger Hinrichsen, Ulrich Spengler, Peter Buggisch, Christoph Sarrazin, Michael Pawlita, Tim Waterboer, Manfred Wiese, Elsbeth Probst-Müller, Raffaele Malinverni, Pierre-Yves Bochud, Clair Gardiner, Cliona O'Farrelly, Thomas Berg
Journal: Gut (2016)

<h3>Objective</h3> As pathogen sensors, Toll-like receptors (TLR) play a role in the first defence line during HCV infection. However, the impact of the DNA sensor TLR9 on the natural course of HCV infection is unknown. To address this, <i>TLR9</i> promoter polymorphisms (single nucleotide polymorphisms (SNPs)) rs187084 and rs5743836 were investigated for their effect on disease progression. <h3>Design</h3> Therefore, the <i>TLR9</i> SNPs and the <i>interferon lambda 4</i> (<i>IFNL4</i>) rs12979860 were genotyped in chronically HCV type 1 infected (n=333), in patients who spontaneously cleared the infection (n=161), in the Swiss HCV cohort (n=1057) and the well-characterised German (n=305) and Irish (n=198) 'anti-D' cohorts. Functional analyses were done with promoter reporter constructs of human <i>TLR9</i> in B cells and assessing <i>TLR9</i> mRNA levels in whole blood of healthy volunteers. <h3>Results</h3> The <i>TLR9</i> rs187084 C allele was associated with spontaneous virus clearance in women of the study cohort (OR=2.15 (95% CI 1.18 to 3.90) p=0.012), of the Swiss HCV cohort (OR=2.06 (95% CI 1.02 to 4.18) p=0.044) and in both 'anti-D' cohorts (German: OR=2.01 (95% CI 1.14 to 3.55) p=0.016; Irish: OR=1.93 (95% CI 1.10 to 3.68) p=0.047). Multivariate analysis in the combined study and Swiss HCV cohorts supported the results (OR=1.99 (95% CI 1.30 to 3.05) p=0.002). Functional analyses revealed higher transcriptional activities for both <i>TLR9</i> variants and an association of the C allele of rs5743836 with allele-specific <i>TLR9</i> mRNA regulation by oestrogens in women. <h3>Conclusions</h3> <i>TLR9</i> promoter SNPs are associated with the natural course of HCV infection and show higher transcriptional activities. Our results imply the DNA sensor TLR9 in natural immunity against the RNA virus, HCV.
P81 Feasibility of measuring lung clearance index (LCI) in a clinic setting in preschool children with a range of airway diseases
Authors: B Downing, S Irving, Y Bingham, L Fleming, A Bush, S Saglani
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> LCI is a measurement of lung function (in particular distal airway disease) derived from the multiple breath washout (MBW) test (<i>Eur Resp J </i>2013; 41:507–22). Although practical in a research setting, feasibility in a clinic setting (with limited time and without using sedation) in young children is not known. We looked at success rates of LCI, and LCI0.5 (a shortened washout which can be accomplished more quickly) in preschool children (aged 2–6 years) with recurrent wheeze (<i>Eur Resp J </i>2008; 32:1096–110), cystic fibrosis (CF), recurrent cough/infections, and healthy controls. Our hypothesis (based on other research performed in this field (<i>Thorax</i> 2012; 68:586–587) was that shortened LCI0.5 would be more feasible than full LCI, and that the test would be more feasible in older preschool children than younger. <h3>Methods</h3> 62 preschool children median age 3.9 (2.07–5.95) years, 34 male, (n = 21 with wheeze, n = 11 CF, n = 2 PCD, n = 22 other, n = 5 healthy controls) performed MBW test during a routine outpatient visit. Wheeze was doctor diagnosed or parent reported via wheeze questionnaire. <h3>Results</h3> 66% of children successfully completed either the LCI or LCI0.5. Completion according to age group is shown in Figure 1. LCI success rate in wheezers was 67%, healthy controls 100%, CF 82%, PCD 100% and recurrent cough/infections 50%. Success rate was identical between males and females (61%), and was similar comparing LCI0.5 (42/62) to full LCI (38/62). Three of the four that only completed LCI0.5 were less than 3.5 years old. <h3>Conclusions</h3> LCI is a feasible test in the clinic setting for preschool children; however success rates under 3 years of age in all disease groups are very low. Use of the shortened washout (LCI0.5) marginally improves success rates, but may improve test completion in the youngest children.
Chronic Primary Adrenal Insufficiency without Hyperpigmentation
Authors: Robert E. Fellows, J. Robert Buchanan, Ralph E. Peterson, Peter E. Stokes
Journal: New England Journal of Medicine (1962)

SINCE chronic primary adrenal insufficiency was first described by Addison1 in 1855 hyperpigmentation of mucous membranes and skin, particularly of pressure points, areolas, genitalia and scars, has been considered a cardinal manifestation of the disease.2 3 4 For this reason physicians are wary of diagnosing primary adrenal insufficiency in the absence of hyperpigmentation. In the cases in which adrenal insufficiency has been established in the absence of hyperpigmentation it has been considered an acute event or secondary to insufficiency of one or more pituitary trophic hormones. Chronic adrenal insufficiency without hyperpigmentation has rarely been confirmed by appropriate determinations of adrenal steroids.5 , 6 With . . .
The Relation of Product Formulation to Absorption of Oral Theophylline
Authors: Miles Weinberger, Leslie Hendeles, Lyle Bighley, Julia Speer Munson
Journal: New England Journal of Medicine (1978)

To assess the potential for therapeutic problems related to the bioavailability of oral theophylline preparations, we examined the rate and extent of absorption for various formulations in adult volunteers. Absorption of theophylline from a solution or from uncoated tablets was rapid and complete. Three of six sustained-release formulations were more slowly, but still completely and consistently, absorbed. Absorption of the other three sustained-release formulations appeared to be more erratic and less complete. Serum concentration-time curves during multiple eight-hour dosing were simulated for the bioavailable preparations. With three sustained-release formulations it was predicted that fluctuations in serum theophylline concentrations between doses would decrease, as compared with uncoated tablets, to a clinically important extent, particularly in children, in whom elimination of theophylline is generally rapid. (N Engl J Med 299:852–857, 1978)
Collateral Sensitivity Between Methylene Dimethane Sulfonate and Halogenated Methotrexate Derivatives in the Yoshida Sarcoma In Vivo and In Vitro23
Authors: Brian W. Fox
Journal: JNCI Journal of the National Cancer Institute (1977)

A Yoshida lymphosarcoma line (YMDR8) resistant to methylene dimethane sulfonate (MDMS) showed collateral sensitivity against three halogenated methotrexates: 3'-bromomethotrexate (NSC-98580), 3'-bromo-5'-chloromethotrexate (NSC-98579), and 3',5'-dichloromethotrexate (NSC-29630); however, it was cross-resistant to methotrexate itself. Two other independently derived MDMS-resistant cell lines, YMDR7 and YMDR9, also demonstrated collateral sensitivity against 3'-bromomethotrexate, but with the latter, the origin of the "induced" sensitivity probably was not due to interference with antigenic or oncogenic properties of the cell line. When these agents were used in vivo (in Wistar rats) and in vitro, subpopulation changes within the tumor lines could be observed. The possible importance of this parameter in the development of such sensitivity is discussed.
Circulating levels of the breast cancer growth factor GP88 in the serum of breast cancer (BC) patients
Authors: G. Serrero, K. Tkaczuk, N. Tait, O. Golubeva, H. Dai, F. S. Feldman, L. Jones
Journal: Journal of Clinical Oncology (2006)

20050 Background: The 88 kDa autocrine growth factor PC-Cell Derived Growth Factor (GP88) plays a critical role in breast tumorigenesis. GP88 expression was low in estrogen receptor positive cells, whereas in ER negative cells, it was constitutively overexpressed. Increased GP88 expression was associated with anti-estrogen therapy resistance in ER + cells and Herceptin resistance in Her-2 overexpressing breast tumors. Antisense inhibition of GP88 expression in human breast adenocarcinoma lead to inhibition of tumor growth in vivo. Immunohistochemical studies have shown that GP88 was expressed in 80% of invasive ductal carcinomas in correlation with expression of poor prognosis markers whereas normal tissues and benign breast lesions were negative. Since GP88 is secreted by breast cancer cells, we examined whether GP88 was found in the circulation at an elevated level in the sera of breast cancer patients when compared to healthy individuals. Methods: A blood sampling study was conducted to determine the serum level of GP88 in healthy volunteers (HV) and breast cancer patients (BC pts). Ten ml of blood was drawn every three months to obtain serum. GP88 serum concentration was determined in triplicate by quantitative enzyme immunoassay using human GP88 as standard. 126 BC pts were accrued. . In addition, sera from 53 healthy volunteers were obtained to establish a GP88 baseline in HV. BC pts characteristics: race: Caucasian- 61, African American-60, Asian-5; median age: 52.5 (range 26–84), stage I-32, II-34, III-18, IV-42. Results: Circulating GP88 was measurable in the serum. Median level of GP88 was 32.8 ng/ml (range 15.3–42.8) in HV and 43.8 ng/ml (range 15.4–158.4) in BC pts, (p-value = 0.0007). Conclusions: GP88 is measurable in the sera of HV and BC pts. Comparison between the two groups indicates that GP88 level is significantly higher in the sera of BC pts. These studies are important since it identifies GP88 as a measurable biomarker that is also a therapeutic target of malignant transformation or malignant progression of breast carcinoma (BC). Future studies will examine the correlation of GP88 level with BC prognostic factors. Correlation between the serum level of GP88 and therapeutic response to systemic therapy in breast cancer patients will also be assessed. [Table: see text]
The Use of the Term “Psychoneurosis”
Authors: Jackson M. Thomas
Journal: New England Journal of Medicine (1945)

MANY men and women discharged from the Army for medical reasons have been classified as neuropsychiatric cases. This fact and the trend of statistics in medical journals, newspapers and magazines pertaining to war neuroses suggest that it would be unfashionable today not to show alarm at the rate soldiers are developing nervous disorders. History discloses, however, that there is a similarity between the widespread concern over the conditions generally described as psychoneuroses and the ill-founded apprehension voiced by Beard1 in 1881, when he declared:All this is modern and originally American; and no age, no country and no form of . . .