tbuckley/cabot-search huggingface dataset:
PTPS-30COMPARISON OF MAPK PATHWAY TARGETS AS POTENTIAL THERAPIES FOR MAPK-ACTIVATED GLIOMAS
Authors: Jie Zhang, Tsun-Wen Yao, Albert Truong, Theodore Nicolaides
Journal: Neuro-Oncology (2015)

The RAS/RAF/MEK/MAPK signaling pathway plays a key role in regulating cell proliferation, survival and differentiation. As hyperactivation of MAPK signaling is a common driver in a subgroup of adult and pediatric gliomas, MAPK pathway blockade has been an attractive target for anti-glioma therapy. We have previously shown that pharmacological inhibition of BRAF and MEK significantly reduces glioma growth in intracranial xenograft models. Here, we compare the efficacy of inhibiting three MAPK pathway targets: BRAF (PLX4720 and PLX4032), MEK (PD901 and GDC0973) and ERK (SCH772984), in reducing glioma growth. In all of the three glioma cell lines examined, AM38 (BRAFV600E-mutant), DBTRG-05MG (BRAFV600E-mutant) and LN229 (NF-1 deficient), ERK and MEK inhibition efficiently suppressed the activation of downstream effectors of MAPK pathway, including p90RSK and cyclin D1, at less than 1uM. In contrast, BRAFV600E inhibitor PLX4720 and PLX4032 inhibits MEK and ERK phosphorylation at 0.1 uM, but yield insignificant effects on downstream components of MAPK (p90RSK and cyclin D1) even at high concentration (10 uM). Concordant with the extent of MAPK pathway blockade, MEK and ERK inhibition is more efficient in suppressing glioma cell growth compared to BRAF inhibition. Future work is required to understand the mechanisms underlying the variations in potency amongst inhibiting various MAPK pathway targets.
Mortality risk in European children with end-stage renal disease on dialysis
Authors: Nicholas C. Chesnaye, Franz Schaefer, Jaap W. Groothoff, Marjolein Bonthuis, György Reusz, James G. Heaf, Malcolm Lewis, Elisabeth Maurer, Dušan Paripović, Ilona Zagozdzon, Karlijn J. van Stralen, Kitty J. Jager
Journal: Kidney International (2016)
Loss of MiR-143 and MiR-145 Inhibits Hematopoietic Stem Cell Self-Renewal through Dysregulated TGFβ Signaling
Authors: Jeffrey C Lam, Joanna Wegrzyn-Woltosz, Rawa Ibrahim, Kate Slowski, Patricia Umlandt, Megan Fuller, Aly Karsan
Journal: Blood (2014)
Bilateral Diaphragmatic Contraction Synchronous with Cardiac Systole
Authors: Robert L. Frye, Eugene Braunwald
Journal: New England Journal of Medicine (1960)

ABNORMAL, involuntary contractions of the diaphragm are generally quite rapid and unrelated in rate or time of occurrence to the cardiac cycle. Rarely, however, the left leaf of the diaphragm has been reported to contract synchronously with the heart beat.1 2 3 4 Recently, we had the opportunity to study a patient who exhibited bilateral diaphragmatic contractions synchronous with cardiac systole, and since this condition has apparently not been reported previously, the case is described in detail in this report.Case ReportW.N. (N.H.I. 02–51–66), a 29-year-old man, was admitted to the National Heart Institute for evaluation of a heart murmur and abnormal . . .
Reversal of Tumor-Induced Biochemical Abnormalities by Insulin Treatment in Rats&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN2"&gt;3&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;4&lt;/xref&gt;
Authors: W T Chance, M Muggia-Sullam, M H Chen, R F Murphy, J E Fischer
Journal: JNCI Journal of the National Cancer Institute (1986)

In F344 rats bearing transplantable 3-methylcholanthrene (CAS: 56-49-5)-induced sarcomas, plasma concentrations of immunoreactive insulin were decreased following the development of mild or severe anorexia. Plasma levels of immunoreactive glucagon and lactate were elevated in severely anorectic tumor-bearing (TB) rats, while plasma glucose concentrations remained normal. Both groups of TB rats exhibited decreased plasma levels of serine, glutamine, citrulline, and tryptophan and increased concentrations of alanine. Plasma levels of proline and phenylalanine were also elevated in the severely anorectic TB rats. In a second experiment, 7 daily treatments with insulin corrected the anorexia for 6 days and increased body weights of TB rats. Plasma concentrations of lactate and immunoreactive glucagon were decreased, and the abnormal plasma concentrations of glutamine, proline, analine, and phenylalanine were altered toward normal following the insulin treatments. Therefore, these data are consistent with insulin treatments benefiting the TB host by increasing feeding, increasing body weight, reducing tumor glycolysis and metabolism, reducing gluconeogenesis, and reducing host catabolism, while not stimulating tumor growth. Thus insulin therapy may have potential benefits in cancer treatment by shifting glucose metabolism toward the host and away from the tumor.
Glucose Counterregulation, Hypoglycemia, and Intensive Insulin Therapy in Diabetes Mellitus
Authors: Franklin H. Epstein, Philip E. Cryer, John E. Gerich
Journal: New England Journal of Medicine (1985)

The prevention or correction of hypoglycemia is the result of both dissipation of insulin and activation of counterregulatory systems. In the models studied to date, glucagon and epinephrine have been shown to be the key counterregulatory factors; the potential roles of other hormones, neural factors, or substrate mechanisms in other models and during more gradual recovery from hypoglycemia remain to be defined. Deficient glucagon responses to decrements in plasma glucose, which are common in patients with IDDM and occur in some patients with NIDDM, result in altered counterregulation. But counterregulation is generally adequate, because epinephrine compensates for it. Defective glucose counterregulation due to combined deficiencies of glucagon and epinephrine secretory responses occurs in many patients, typically those with longstanding diabetes, and must be added to the list of factors known to increase the risk of hypoglycemia, at least during intensive therapy. From the material reviewed, it should be apparent that much has been learned about glucose counterregulation. It should be equally clear that much remains to be learned. Among the many possibilities, we consider four worthy of emphasis. First of all, we need to examine the physiology and pathophysiology of glucose counterregulation in additional models (e.g., during exercise) and over longer periods. Secondly, we need to determine whether central nervous system adaptation to antecedent glycemia occurs and, if so, identify its mechanisms. Thirdly, we need to develop better methods of insulin delivery or learn to correct or compensate for defective counterregulatory systems, if we are to achieve euglycemia safely in diabetic patients with defective glucose counterregulation. Finally, we need to know whether effective control of diabetes mellitus prevents development of defective glucose counterregulation.
P211 Impact of door-to-radiograph time on pneumonia management
Authors: JM Dudziak, KL Scott, A Ashton, R Varia
Journal: Thorax (2015)

<h3>Introduction</h3> Pneumonia continues to be associated with significant mortality.<sup>1</sup> The diagnostic gold standard remains the Chest X-Ray (CXR). Quality indicators such as door-to-antibiotic or door-to-radiograph time are monitored as surrogate outcome measures. <h3>Objective</h3> To assess the impact of CXR availability at first clinician contact in cases where initial antibiotics were delayed. <h3>Methods</h3> We interrogated the time of initial consultation, radiographs and diagnosis for 57 CAP patients between March 2013 and February 2014 whose initial antibiotics were delayed beyond 4 h. <h3>Results</h3> The median age was 77 (interquartile range 67–85), 32 (53%) were female. Presentation was to the ED in 45 (79%) and to the GP assessment unit (GPAU) in 12 (21%) cases. 37 (65%) cases had SIRS, 45% had a CURB-65 score of 3 or above. CXR reports were compatible with pneumonia in 44 (77%) cases, but only 11 (19%) had a CXR at time of first doctor contact. Interestingly, a reported consolidation was not associated with an initial diagnosis of pneumonia (p = 1.0000, Fisher’s exact test, two-tailed p). Median time to first clinician contact was 2:14 h (ED 2:03 h, GPAU 4:33 h). Overall, 20 patients (35%) had a diagnosis of pneumonia after the initial consultation, 7 (58%) in GPAU and 13 (29%) in the ED. CXRs were obtained within 4 h in 49 (86%) cases. Median time to diagnosis was 7:06 h (ED 8:35 h, GPAU 5:54 h). CXR availability at first clinician contact differed significantly – GPAU 50%/6 vs ED 11%/5 (p = 0.0068, Fisher’s exact test, two tailed p). <h3>Discussion</h3> There were significant delays to diagnosis, despite most CXR reports indicative of pneumonia. The absence of a CXR on initial clinician contact may contribute to the poor diagnostic accuracy seen in this case series. Notably the 4 h door-to-radiograph target set by BTS was largely met. We will deploy the GPAU pneumonia care bundle in the ED, which was shown to improve door-to-radiograph time (CURECAP, reported previously<sup>2</sup>). The efficacy of this intervention will be the subject of further studies. <h3>References</h3> 1 Gibson GJ, <i>et al</i>.<i> Eur Respir J</i>. 2013;<b>42</b>:559–563 2 Cunningham P, <i>et al</i>. <i>Thorax</i> 2013;<b>68</b>(Suppl 3):A186
Review of Fifteen Years' Experience with Gastrectomy in a Community Hospital
Authors: Paul R. Hinchey
Journal: New England Journal of Medicine (1955)

THIS report is based on a study of the total experience with gastrectomy at the Salem Hospital during a fifteen-year period, 1939–1953. Three hundred and eight gastrectomies were performed by 26 surgeons. Indications for gastrectomy are listed in Table 1.The contrast between increasing frequency of gastrectomy for ulcer disease and the fairly constant number for gastric carcinoma is striking (Fig. 1). A study of a fifteen-year period was made to minimize the error potential of an inadequate number of cases. It is appreciated that certain statistics such as the mortality rate must necessarily suffer by comparison with rates cited in . . .
A Tumor-Related Vitamin B<sub>12</sub>Binding Protein in Adolescent Hepatoma
Authors: Samuel Waxman, Harriet S. Gilbert
Journal: New England Journal of Medicine (1973)

Extraordinary elevations of serum vitamin B12 content and serum levels of vitamin B12 binding protein were found in three young patients with hepatoma. All had normal white-cell counts and no evidence of megaloblastosis. Despite a superficial resemblance to the alterations of vitamin B12 and vitamin B12 binders observed in chronic myeloid leukemia, the vitamin B12 binding protein in hepatoma serum exhibited distinct and unique properties that suggest a novel, tumor-related protein. (N Engl J Med 289:1053–1056, 1973)
Authors’ reply to Mendelsohn
Authors: Jamie Hartmann-Boyce, Paul Aveyard
Journal: BMJ (2016)

Mendelsohn highlights an important point.1 2 There are valid reasons to think that patches may be more useful prequit than other forms of nicotine replacement therapy (NRT). Research has shown that concurrent use of cigarettes and patches increases blood nicotine concentrations (by 54%), whereas with simultaneous use of cigarettes and shorter acting forms of NRT they remain unchanged.3 It …
Association of single nucleotide polymorphisms (SNP) in the ABCB1 gene with neutropenia and diarrhea protection in capecitabine and 5-fluorouracil-treated colorectal cancer patients respectively.
Authors: P. Garcia Alfonso, S. Alvarez, A. Muñoz, M. Riesco, E. Gonzalez-Haba, C. López-Lillo, N. Barrueco, M. Sanjurjo, M. Martin, L. Lopez-Fernandez
Journal: Journal of Clinical Oncology (2010)

e14080 Background: ABCB1 polymorphisms have been identified as predictors for response of 5-fluorouracil (5- FU) in colorectal cancer (CRC) although there is limited data regarding toxicity. Our purpose was to assess the association between the ABCB1 C3435C>T, G2677G>T/A, and C1236C>T SNPs with adverse effects in CRC patients treated with 5-FU or capecitabine-based regimens. Methods: The study was carried out at Gregorio Marañon Hospital in 120 CRC patients. 56 patients were receiving 5-FU alone or in combination and 64 capecitabine alone or combined. Patients were genotyped for C1236 (rs1128503), G2677 (rs2032582) and C3435 (rs1045642) SNPs in ABCB1 gene. Toxicity was assessed according to CTCAE. Results: Neutropenia and diarrhea were the most common adverse reactions related to capecitabine and 5-FU. Moderate-severe neutropenia was observed in 42.85% and 12.5% of patients treated with 5-FU or capecitabine-based regimens respectively. Moderate-severe diarrhea was reported in 31.48% and 26.56% of 5-FU or capecitabine-treated patients respectively. A significant association was found between rs1128503 and moderate-severe neutropenia in patients receiving any capecitabine-based regimen (p = 0.026). Mild-severe neutropenia was reported in 31.2% of wild-type homozygous (C/C) and 9.4% of heterozygous (C/T) for rs1128503. Patients with homozygous mutant (T/T) genotype for rs1128503 did not develop moderate-severe neutropenia. Diarrhea was associated with rs1045642 in patients with any 5-FU-based regimen (p = 0.031). Mild-severe diarrhea was more frequent in patients homozygous for the mutant allele of rs1045642 (46.2%) than in heterozygous (37%) or homozygous wild type carriers (6.2%). There were no differences on these frequencies when irinotecan-treated patients were excluded. Conclusions: Homozygous TT genotype for ABCB1 C1236T SNP could be consider a prognostic biomarker of CRC patient's resistance to develop neutropenia associated to capecitabine-based regimen, whereas homozygous CC genotype for ABCB1 C3435T SNP may be a prognostic marker of resistance for diarrhea in 5-FU-treated patients. No significant financial relationships to disclose.
A rugby player’s finger injury
Authors: Thomas F M Yeoman, Philippa A Rust
Journal: BMJ (2016)

A 16 year old right hand dominant schoolboy presented to the emergency department with a painful, swollen right ring finger. Three days earlier he had injured his finger playing rugby and he thought the injury occurred while he was tackling an opponent. Although he was able to finish the game he has had discomfort and reduced movement in the finger since.

Ecchymosis and tenderness were noted over the distal phalanx on the palmar aspect of his hand, as well as some swelling and tenderness at the base of the ring finger (fig 1⇓). The finger had no neurovascular deficit and examination of the rest of the right hand was normal. No fracture was seen on a plain radiograph of the ring finger.



Fig 1  The patient’s right hand in a relaxed posture showing loss of normal cascade of the ring finger



1.  What key aspect of the clinical examination would confirm the diagnosis?

2.  What is the name of this injury (the name provides a clue to its mechanism)?

3.  Which finger is most commonly affected?

4.  How are these injuries classified?

5.  How are these injuries managed?

### 1. What key aspect of the clinical examination would confirm the diagnosis?

#### Short answer

Inability to actively flex the distal interphalangeal joint (DIPJ) is pathognomonic of rupture of the flexor digitorum profundus (FDP) tendon. To test the FDP tendon function, isolate the DIPJ by holding the proximal interphalangeal joint (PIPJ) in extension, thereby preventing the action of the flexor digitorum superficialis (FDS).

#### Discussion

FDP tendon avulsion is diagnosed on physical examination—patients have a lack of isolated DIPJ flexion. To test for this, the DIPJ is isolated by holding the PIPJ in extension (fig 2⇓). The finger will probably be painful and swollen. Ecchymosis may be present on the volar side of the finger. The affected finger is often in an extended position relative to the other fingers, with loss of …
Screening should be organised by GPs
Authors: A Rauf, R P L Wormald, B. Aylward
Journal: BMJ (1995)

skills are maximised through experience and that cost efficiency is increased.The cost of identifying each true case of retinopathy needing treatment has been shown to fall as throughput increases.3Patients are recalled to the screening clinics through use of a computerised appointment system and a centralised register.Diabetes care requires several health care processes, as well as screening of the eyes, to be performed regularly in a large number of people.The Clinical Standards Advisory Group has recommended that, for this to be organised efficiently and completely, health districts should develop and maintain registers of all people with diabetes in the locality to span the boundaries of the provision of primary and secondary care.4
Abstract A36: Validation of candidate cancer genes using the CRISPR system
Authors: Natalie Wolf, Branden Smeester, Madison Weg, David A. Largaespada, Branden Scott Moriarity
Journal: Cancer Research (2016)

Abstract We have used Sleeping Beauty (SB) transposon mutagenesis to study the development of several types of sarcomas including osteosarcoma (OS) and malignant peripheral nerve sheath tumors (MPNST). This work has revealed the power of SB mutagenesis to identify critical genes and genetic pathways that, when altered, can cooperate to cause these tumors. We have discovered specific novel oncogenes, such as FOXR2 in MPNST and SEMA4D in OS, recurrent alterations in certain pathways, such as the Wnt/β−catenin pathway in MPNST, and information about what genetic alterations can cooperate in sarcomagenesis, such as loss of NF1 and PTEN in MPNST. We have functionally validated these genetic alterations in several ways, including the use of genetically engineered mouse (GEM) models and TAL effector nucleases (TALEN) or CRISPR RNA-guided Cas9 nuclease modified human cell lines. However, these studies typically analyzed only single candidates of great interest due to the alteration observed in comparative genomics analyses or novelty in the cancer field. In an attempt to further study our candidate cancer genes (CCGs) we have implemented the CRISPR nuclease system to perform a medium throughput screen of all candidate tumor suppressor genes (TSGs). To this end, we are generating and validating CRISPR gRNAs to target all TSGs identified in our MPNST and OS SB screens (~300 genes). Using immortalized human cell lines we have targeted these candidate TSGs and screened for their ability to increase colony formation in soft agar, migration, and xenograft tumor formation. We have identified numerous genes that when mutated by CRISPR resulted in increased tumorigenic properties. These genes are currently being tested for their ability to induce xenograft formation in immunocompromised mice. This CRISPR screen for MPNST and OS CCGs is ongoing and new results will be reported. Citation Format: Natalie Wolf, Branden Smeester, Madison Weg, David A. Largaespada, Branden Scott Moriarity. Validation of candidate cancer genes using the CRISPR system. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A36.
Stability and distinctness of borderline personality disorder
Authors: A Barasch, A Frances, S Hurt, J Clarkin, S Cohen
Journal: American Journal of Psychiatry (1985)

In a 3-year follow-up study the authors examined the diagnostic stability of borderline personality disorder over time, its relation to affective disorder, and the severity of functional impairment. The data support the usefulness of borderline personality disorder as a diagnostic construct.
MPTH-24COMBINATION GENETIC SIGNATURE STRATIFIES PROGNOSIS IN LOWER-GRADE GLIOMAS BUT IDH STATUS ALONE DOES NOT SUPERSEDE HISTOLOGIC GRADES
Authors: Aden Ka-Yin Chan, Yu Yao, Zhen-Yu Zhang, Zhifeng Shi, Liang Chen, Nellie Yuk-Fei Chung, Kay Ka-Wai Li, Danny Tat-Ming Chan, Wai Sang Poon, Liangfu Zhou, Ho-Keung Ng
Journal: Neuro-Oncology (2015)

We studied if combination genetic signature potentially stratifies lower-grade gliomas better than histology by investigating 214 lower-grade gliomas for IDH1/2 and TERTp mutations, 1p/19q codeletion and EGFR amplification as to their impact on prognostication. Prognostic association of grading was independent of other prognostic variables including age, histological type, IDH1/2, 1p/19q and TERTp status. No single marker, including IDH1/2, superseded grading in prognostication, indicating grading was still a very important tool. Prognosis was most favorable in 31.7% of patients with IDH1/2 mutation and either 1p/19q codeletion or TERTp mutation (IDHmut-OT), intermediate in 45.8% of patients with IDH1/2 mutation only (IDHmut) and 16.9% of patients without any of the alterations (IDHwt), and poorest in 5.6% of patients with wild-type IDH1/2 and either TERTp mutation or EGFR amplification (IDHwt-ET). Our results suggested not all IDH1/2 wild-type lower-grade gliomas are aggressive and additional biomarkers are required to identify glioblastoma-equivalent tumors. Multivariate analysis revealed independent prognostic values of grading and genetic signature. Grade II IDHwt-ET gliomas exhibited shorter survival than IDH1/2 mutated grade III gliomas, suggesting combination genetic signature potentially superseded grading in prognostication. In summary, biomarker-based stratification is useful in the diagnosis and prognostication of lower-grade gliomas, and should be used together with grading.
Two New Variants of Infection with Coxsackie Virus Group B, Type 5, in Young Children
Authors: W. Siegel, F. J. Spencer, D. J. Smith, J. M. Toman, W. F. Skinner, M. B. Marx
Journal: New England Journal of Medicine (1963)

BETWEEN March and August, 1961, an outbreak of illness was seen at the Naval Weapons Laboratory, Dahlgren, Virginia, characterized by epidemic pleurodynia in adults and older children, with viral pneumonia, and a syndrome of painful hepatomegaly or splenomegaly (or both), fever, anorexia, nausea, vomiting, conjunctivitis and cervical or axillary adenopathy in younger children. When we found the two syndromes were caused by a common agent a clinical and epidemiologic survey was performed.Clinical EvaluationMethodThe cases were divided into two groups at first but the pneumonias were added when a relation was noted. Unfortunately, viral studies were performed in . . .
Termination of Ventricular Fibrillation in Man by Externally Applied Electric Countershock
Authors: Paul M. Zoll, Arthur J. Linenthal, William Gibson, Milton H. Paul, Leona R. Norman
Journal: New England Journal of Medicine (1956)

VENTRICULAR fibrillation is usually a rapidly fatal arrhythmia that may occur in cardiac patients, in any patient under anesthesia and in drowning and electrocution. In cardiac patients it is a frequent cause of sudden death in the course of coronary-artery disease, a well recognized mechanism of Stokes–Adams attacks, an uncommon toxic reaction to digitalis, quinidine and procaine amide, an occasional terminating event in ventricular tachycardia and a rare, but dreaded, complication of cardiac catheterization. In the operating room ventricular standstill is the usual initial mechanism of cardiac arrest, but ventricular fibrillation occasionally occurs,1 particularly during hypothermia or during anesthesia with . . .
Neurocirculatory Asthenia, Anxiety and Neurosis
Authors: Henry H. W. Miles, Stanley Cobb
Journal: New England Journal of Medicine (1951)

Neurocirculatory Asthenia versus Anxiety NeurosisTHE constellation of symptoms called neurocirculatory asthenia (NCA) is frequently encountered in medical practice, but despite its prevalence it is still a source of much argument and confusion. Extensive clinical and laboratory investigations have resulted in data that are inconsistent and controversial. Some recent reports1 2 3 4 have stressed the opinion that NCA is identical with "anxiety neurosis."§ We believe this to be an unsound postulate and will attempt in the present paper to clarify our views. The patients classified by Wheeler and his co-workers3 as having "neurocirculatory asthenia (effort syndrome, anxiety neurosis)" are grouped together merely . . .