tbuckley/cabot-search huggingface dataset:
CCR5 thwarts West Nile virus
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2006)

A genetic mutation that protects against HIV infection increases the risk of developing clinical West Nile virus (WNV) infection, according to Glass and colleagues on page 35.






Figure 1

Individuals homozygous for the CCR5Δ32 allele are more likely to suffer from fatal West Nile Virus infection.




The mutation in question is a 32-bp deletion in a gene that encodes the chemokine receptor CCR5, which was identified in 1996 as a cellular coreceptor for HIV. Individuals homozygous for this mutation (CCR5Δ32) are highly resistant to HIV infection, even when repeatedly exposed to the virus. This resistance was the theoretical basis for the development of therapeutic CCR5 inhibitors, several of which are now in clinical trials. CCR5 seemed like an ideal drug target, as people missing the receptor were healthy and no diseases or infections were known to be more frequent or severe in individuals homozygous for CCR5Δ32. Mice appeared to be equally unfazed by the lack of CCR5.

But new evidence suggests that the lack of CCR5 is not completely innocuous. This group recently showed that infection with WNV—a mosquito-borne virus that has spread rapidly across the United States since 1999, often causing fatal encephalitis—was uniformly fatal in mice lacking CCR5. This finding prompted the group to look for the CCR5Δ32 allele in two cohorts of patients in the United States who had symptomatic WNV infections. They now report that 4–5% of the infected individuals were homozygous for the CCR5Δ32 allele, compared with less than 1% of the general population, suggesting that the lack of CCR5 puts people at risk for developing clinical WNV infections. The magnitude of this risk is comparable to the magnitude of protection against HIV that is conferred by this genotype. It remains to be tested whether CCR5-deficient humans, like mice, develop more severe disease because fewer protective immune cells gain access to the brain.

This study identifies not only the first genetic susceptibility factor for WNV infection but also the first association of the CCR5Δ32 allele with susceptibility to an infectious disease. These data might also raise a red flag for the use of CCR5 inhibitors in HIV-infected patients—at least in areas endemic for WNV—as such inhibitors might increase the recipients' vulnerability to severe WNV infection.
Use of percutaneous needle biopsy in the investigation of solitary pulmonary nodules.
Authors: A R Penketh, A A Robinson, V Barker, C D Flower
Journal: Thorax (1987)

Percutaneous needle biopsies were performed on 683 patients with solitary pulmonary nodules during 1976-84. A cytological diagnosis of malignancy was made from the first biopsy in 473 patients (69%). A second biopsy was performed in 43 patients, a diagnosis of malignancy being made in a further 16 cases (37%). Histological material was available for comparison with cytological findings in 203 patients. Cytological examination was reliable in the diagnosis of malignancy with a high yield (75%) and low false positive rate (1.5%). Specific benign lesions were correctly diagnosed in 10 patients (1.5%). There was a false negative rate for the diagnosis of malignancy of 18% for the patients with a subsequent histological diagnosis. This compares with a false negative rate of 9% overall; the true rate probably lies between these figures. These results imply that a cytology report indicating no evidence of malignancy, but not diagnostic of a specific benign condition, does not reliably exclude a malignant lesion. In this series cytological typing was not accurate at predicting the cell type determined by histological examination (61% agreement) and was not able to discriminate between small cell and non-small cell lung cancer.
Evidence against roles for phorbol binding protein Munc13-1, ADAM adaptor Eve-1, or vesicle trafficking phosphoproteins Munc18 or NSF as phospho-state-sensitive modulators of phorbol/PKC-activated Alzheimer APP ectodomain shedding
Authors: Annat F Ikin, Mirsada Causevic, Steve Pedrini, Lyndsey S Benson, Joseph D Buxbaum, Toshiharu Suzuki, Simon Lovestone, Shigeki Higashiyama, Tomas Mustelin, Robert D Burgoyne, Sam Gandy
Journal: Molecular Neurodegeneration (2007)

Shedding of the Alzheimer amyloid precursor protein (APP) ectodomain can be accelerated by phorbol esters, compounds that act via protein kinase C (PKC) or through unconventional phorbol-binding proteins such as Munc13-1. We have previously demonstrated that application of phorbol esters or purified PKC potentiates budding of APP-bearing secretory vesicles at the trans-Golgi network (TGN) and toward the plasma membrane where APP becomes a substrate for enzymes responsible for shedding, known collectively as alpha-secretase(s). However, molecular identification of the presumptive "phospho-state-sensitive modulators of ectodomain shedding" (PMES) responsible for regulated shedding has been challenging. Here, we examined the effects on APP ectodomain shedding of four phorbol-sensitive proteins involved in regulation of vesicular membrane trafficking of APP: Munc13-1, Munc18, NSF, and Eve-1.Overexpression of either phorbol-sensitive wildtype Munc13-1 or phorbol-insensitive Munc13-1 H567K resulted in increased basal APP ectodomain shedding. However, in contrast to the report of Rossner et al (2004), phorbol ester-dependent APP ectodomain shedding from cells overexpressing APP and Munc13-1 wildtype was indistinguishable from that observed following application of phorbol to cells overexpressing APP and Munc13-1 H567K mutant. This pattern of similar effects on basal and stimulated APP shedding was also observed for Munc18 and NSF. Eve-1, an ADAM adaptor protein reported to be essential for PKC-regulated shedding of pro-EGF, was found to play no obvious role in regulated shedding of sAPPalpha.Our results indicate that, in the HEK293 system, Munc13-1, Munc18, NSF, and EVE-1 fail to meet essential criteria for identity as PMES for APP.
Left sided inferior vena cava duplication and venous thromboembolism: case report and review of literature
Authors: Cannon Milani, Maria Constantinou, David Berz, James N Butera, Gerald A Colvin
Journal: Journal of Hematology & Oncology (2008)

The etiology of venous thromboembolism in young patients is frequently associated with hereditary coagulation abnormalities, immunologic diseases, and neoplasia. The advent of radiological advances, namely Computed Tomography (CT) scans and venography has identified vena cava malformations as a new etiologic factor worthy of consideration. In this case report, we describe the unusual occurrence of venous thromboembolism in association with a duplicated inferior vena cava. Duplications of the inferior vena cava (IVC) are seen with an incidence of 0.2% to 3.0% in the general population. Embryogenesis of the IVC is a complex process involving the intricate formation and regression of numerous anastomoses, potentially leading to various anomalies. We present a 23-year-old Caucasian woman with IVC duplication who developed a deep venous thrombosis and multiple pulmonary emboli. Anomaly of the IVC is a rare example of a congenital condition that predisposes to thromboembolism, presumably by favoring venous stasis. This diagnosis should be considered in patients under the age of 30 with spontaneous occurrence of blood clots.
Family Consent to Orders Not to Resuscitate
Authors: J C Hackler, F C Hiller
Journal: JAMA (1990)

Hospital policies typically require that cardiopulmonary resuscitation be attempted unless a do-not-resuscitate order has been written, and they further require that family permission for the order be obtained. This sometimes forces physicians to perform procedures that are useless or that add to the patient's suffering without corresponding benefit. Policies should be changed to allow physicians to write a do-not-resuscitate order over family objections when (1) the patient lacks decision-making capacity, (2) the burdens of treatment clearly outweigh the benefits, (3) the surrogate does not give an appropriate reason in terms of patient values, preferences, or best interests, and (4) the physician has made serious efforts to communicate with the family and to mediate the disagreement. Furthermore, when resuscitation would clearly provide no medical benefit to the patient, policy should not require that it be discussed with either the patient or the family. (<i>JAMA</i>. 1990;264:1281-1283)
Effectiveness: The Next Question for Breast Cancer Screening
Authors: Russell Harris
Journal: JNCI Journal of the National Cancer Institute (2005)

The discussion about breast cancer screening has changed. Yesterday’s question was about effi cacy — whether screening, under ideal circumstances, can reduce breast cancer mortality. Today’s discussion is about a different question, effectiveness. To what extent is current screening, under usual conditions within the community, reducing mortality from breast cancer? The second question may prove to be as complex as the fi rst. The effi cacy discussion largely concerned the internal validity of the eight randomized controlled trials (RCTs) of screening that were conducted between the mid-1960s and the mid-1980s. For the most part (there are still a few lingering issues), the question of effi cacy is resolved. Careful observers, while acknowledging the presence of some bias in the RCTs, have concluded that the magnitude of these biases is not suffi cient to invalidate the primary results of these trials, that periodic mammography, with or without clinical breast examination, reduces breast cancer mortality for women between 50 and 74 years of age. For women between the ages of 40 and 49 years, the absolute reduction in breast cancer mortality due to screening gradually increases over this decade of life, only appearing several years longer after the initiation of screening than for older women. Decision-makers must weigh these benefi ts against the harms of false-positive tests, overdiagnosis, and overtreatment. A meta-analysis of the RCTs for the U.S. Preventive Services Task Force found a 15% reduction in the risk of dying of breast cancer in the screened group (summary relative risk [RR] = 0.85, 95% credible interval [CrI] = 0.73 to 0.99) for women aged 40 – 49 years after an average of 14 years of observation. For women aged 50 – 74 years, the reduction was 22% (summary RR = 0.78, 95% CrI = 0.70 to 0.87) over the same period of observation ( 1 ) . Now that widespread screening has been under way for more than 15 years, the discussion has turned to the issue of effectiveness. This issue requires us to consider whether the RCTs have external validity for the general population, and to develop new evidence about the effects of current screening practices within the community. To what extent is widespread screening in the United States in 2005 contributing to reducing breast cancer mortality?
IOC consensus paper on the use of platelet-rich plasma in sports medicine
Authors: Lars Engebretsen, Kathrin Steffen, Joseph Alsousou, Eduardo Anitua, Norbert Bachl, Roger Devilee, Peter Everts, Bruce Hamilton, Johnny Huard, Peter Jenoure, Francois Kelberine, Elizaveta Kon, Nicola Maffulli, Gordon Matheson, Omer Mei-Dan, Jacques Menetrey, Marc Philippon, Pietro Randelli, Patrick Schamasch, Martin Schwellnus, Alan Vernec, Geoffrey Verrall
Journal: British Journal of Sports Medicine (2010)

or fi brin glue) was introduced; a biomaterial with
Fungal contamination of bedding
Authors: A. A. Woodcock, N. Steel, C. B. Moore, S. J. Howard, A. Custovic, D. W. Denning
Journal: Allergy (2005)

It is currently believed that most fungal exposure occurs external to the home.To enumerate the fungal flora of used synthetic and feather pillows and the dust vacuumed from them, in the UK.10 pillows aged between 1.5 and >20 years in regular use were collected and quantitatively cultured for fungi. Swatches were taken from nine sections of the pillow and dust was also collected by vacuum from five pillows. Pillow vacuuming was carried out prior to pillow culture. All were cultured at room temperature, 30 and 37 degrees C for 7 days in broth before plating, and a subset were also cultured for 24 h in broth and then plated. Fungi were identified by standard morphological methods.The commonest three species isolated were Aspergillus fumigatus (n = 10), Aureobasidium pullulans (n = 6) and Rhodotorula mucilaginosa (n = 6). Another 47 species were isolated from pillows and vacuum dust. The number of species isolated per pillow varied from 4 to 16, with a higher number from synthetic pillows. Compared with the nonallergenic A. pullulans, more A. fumigatus was found in synthetic than feather pillows.We have examined pillows for fungal contamination, and show that the typical used pillow contains a substantial load of many species of fungi, particularly A. fumigatus. Given the time spent sleeping, and the proximity of the pillow to the airway, synthetic and feather pillows could be the primary source of fungi and fungal products. This has important implications for patients with respiratory disease, and especially asthma and sinusitis.
Methylation status of the p15INK4B gene in hematopoietic progenitors and peripheral blood cells in myelodysplastic syndromes
Authors: E Aoki, T Uchida, H Ohashi, H Nagai, T Murase, A Ichikawa, K Yamao, T Hotta, T Kinoshita, H Saito, T Murate
Journal: Leukemia (2000)
Immune function in female elite rowers and non-athletes
Authors: David C Nieman, Sandra L Nehlsen-Cannarella, Omar R Fagoaga, Dru A Henson, Michael Shannon, Jannica M E Hjertman, Robert L Schmitt, Marc R Bolton, Melanie D Austin, Brian K Schilling, Richard Thorpe
Journal: British Journal of Sports Medicine (2000)

Objective —To compare immune function in female rowers and controls in the resting state, and then correlate the results with a two month history of upper respiratory tract infection (URTI). Methods —Subjects included 20 elite female rowers located at the ARCO Olympic Training Centre in Chula Vista, California, and 19 non-athletic female controls. These two groups were compared cross sectionally for immune function and infection rates. Results —Granulocyte/monocyte phagocytosis, oxidative burst activity, and plasma cytokine concentrations (interleukin-6, tumour necrosis factor-α, and interleukin-1 receptor antagonist) did not differ significantly between groups. Phytohaemagglutinin induced lymphocyte proliferative response (adjusted whole blood method) was significantly higher (31% and 36% for optimal and suboptimal concentrations respectively) in rowers than in controls. Natural killer cell activity was substantially higher (1.6-fold for total lytic units) in the female rowers than in controls. Two month health logs disclosed 5.2 (1.2) and 3.3 (1.1) days with URTI symptoms for the rowers and controls respectively (p = 0.268). For all 39 subjects combined, and for the 20 rowers separately, none of the immune parameters correlated significantly with number of days with URTI symptoms. Conclusions —In this cross sectional comparison of elite female rowers and non-athletes, a group difference was found for natural killer cell activity and phytohaemagglutinin induced proliferative response (whole blood technique), but not other measures of immune function. The number of days with URTI symptoms during the spring season did not differ between groups, and variations in blood measures of immunity were unrelated to URTI.
Epithelial-to-Mesenchymal Transition and Ovarian Tumor Progression Induced by Tissue Transglutaminase
Authors: Minghai Shao, Liyun Cao, Changyu Shen, Minati Satpathy, Bhadrani Chelladurai, Robert M. Bigsby, Harikrishna Nakshatri, Daniela Matei
Journal: Cancer Research (2009)

Abstract Tissue transglutaminase (TG2), an enzyme that catalyzes Ca2+-dependent aggregation and polymerization of proteins, is overexpressed in ovarian cancer cells and tumors. We previously reported that TG2 facilitates tumor dissemination using an i.p. xenograft model. Here we show that TG2 modulates epithelial-to-mesenchymal transition (EMT), contributing to increased ovarian cancer cell invasiveness and tumor metastasis. By using stable knockdown and overexpression in epithelial ovarian cancer cells, we show that TG2 induces a mesenchymal phenotype, characterized by cadherin switch and invasive behavior in a Matrigel matrix. This is mediated at the transcriptional level by altering the expression levels and function of several transcriptional repressors, including Zeb1. One mechanism through which TG2 induces Zeb1 is by activating the nuclear factor-κB complex. The effects of TG2 on ovarian cancer cell phenotype and invasiveness translate into increased tumor formation and metastasis in vivo, as assessed by an orthotopic ovarian xenograft model. Highly expressed in ovarian tumors, TG2 promotes EMT and enhances ovarian tumor metastasis by activating oncogenic signaling. [Cancer Res 2009;69(24):9192–201]
Mutation of the <i>PIK3CA</i> Gene in Anaplastic Thyroid Cancer
Authors: Ginesa García-Rostán, Angela M. Costa, Isabel Pereira-Castro, Giuliana Salvatore, Radhames Hernandez, Mario J.A. Hermsem, Agustin Herrero, Alfredo Fusco, Jose Cameselle-Teijeiro, Massimo Santoro
Journal: Cancer Research (2005)

Abstract The phosphatidylinositol 3′-kinase (PI3K) pathway is frequently activated in thyroid carcinomas through the constitutive activation of stimulatory molecules (e.g., Ras) and/or the loss of expression and/or function of the inhibitory PTEN protein that results in Akt activation. Recently, it has been reported that somatic mutations within the PI3K catalytic subunit, PIK3CA, are common (25-40%) among colorectal, gastric, breast, ovarian cancers, and high-grade brain tumors. Moreover, PIK3CA mutations have a tendency to cluster within the helical (exon 9) and the kinase (exon 20) domains. In this study, 13 thyroid cancer cell lines, 80 well-differentiated thyroid carcinomas of follicular (WDFC) and papillary (WDPC) type, and 70 anaplastic thyroid carcinomas (ATC) were investigated, by PCR-direct sequencing, for activating PIK3CA mutations at exons 9 and 20. Nonsynonymous somatic mutations were found in 16 ATC (23%), two WDFC (8%), and one WDPC (2%). In 18 of the 20 ATC cases showing coexisting differentiated carcinoma, mutations, when present, were restricted to the ATC component and located primarily within the kinase domain. Three cell lines of papillary and follicular lineage (K1, K2, and K5) were also found mutated. In addition, activation of Akt was observed in most of the ATC harboring PIK3CA mutations. These findings indicate that mutant PIK3CA is likely to function as an oncogene among ATC and less frequently well-differentiated thyroid carcinomas. The data also argue for a role of PIK3CA targeting in the treatment of ATC patients.
A BIOCHEMICAL STUDY OF THE PHENOMENA KNOWN AS COMPLEMENT-SPLITTING
Authors: Jacob Bronfenbrenner, Hideyo Noguchi
Journal: The Journal of Experimental Medicine (1912)

It is generally accepted that complement may be split into a mid-piece and an end-piece. The mid-piece is thought to be in the globulin fraction, and the end-piece in the albumin fraction. The restoration of complement activity by putting together the albumin and globulin fractions does not prove, however, that each fraction contained a part of the complement, for the albumin fraction can be reactivated in the absence of the globulin fraction. Complement-splitting as brought about by hydrochloric acid, carbon dioxid, and dialysis, is really an inactivation of the whole complement by certain acids or alkalis, either added in the free state to the serum, or liberated as a result of the dissociation of certain electrolytes. That the whole complement, and not a part only, is present in the albumin fraction of the serum can be demonstrated by the removal of the inhibitory action of the acid or alkali. This can be effected by the addition, not only of alkali or acid, but also of any amphoteric substance. When hydrochloric acid, carbon dioxid, or dialysis are employed to produce the phenomenon known as complement-splitting, the complement is merely inactivated, not split.
Optimizing the treatment of BRAF mutant melanoma
Authors: Jeff Settleman
Journal: Genome Medicine (2014)

Selective inhibitors of the kinases BRAF and MEK for the treatment of patients with otherwise refractory BRAF mutant melanoma have demonstrated impressive efficacy, and combination treatment with these agents may prove to be even more effective. However, these drugs are not curative, mainly because of the relatively rapid development of drug resistance. Furthermore, they can produce undesired, and even unanticipated, side effects, including the emergence of neoplastic lesions harboring activating RAS mutations. Two recent reports reveal new considerations for the optimal approach to targeting this key oncogenic pathway in melanoma, highlighting the importance of combination treatment and therapeutic scheduling.
Managing passengers with stable respiratory disease planning air travel: British Thoracic Society recommendations
Authors: D. Shrikrishna, R. K. Coker
Journal: Thorax (2011)

This article summarises the key points from the 2011 British Thoracic Society (BTS) recommendations on managing passengers with respiratory disease planning air travel. The guidance aims to provide practical advice for respiratory specialists in secondary care and serves as a valuable reference for other healthcare professionals managing these patients. A greater awareness of the challenges posed by air travel will allow improved clinical assessment and practical advice to encourage patients to fly safely wherever possible.
Neuroimmune mechanisms in postoperative ileus
Authors: G E Boeckxstaens, W J de Jonge
Journal: Gut (2009)

Postoperative ileus (POI) is a common clinical condition arising after almost every abdominal surgical procedure, leading to increased patient morbidity and prolonged hospitalisation. Recent advances in insight into the underlying pathophysiology have identified intestinal inflammation triggered by handling of the intestine as the main mechanism. Not only does the local inflammatory process compromise the contractile activity of the handled intestine, but it also activates inhibitory neural pathways and possibly triggers inflammation at distant untouched areas, leading to a generalised impairment of gastrointestinal motility. Macrophages residing in the muscularis externa and mast cells are the key players in this inflammatory cascade. Pharmacological interventions preventing the activation of these immune cells reduce the influx of leucocytes into the intestine, an effect associated with a reduction of the duration of POI. New potential therapeutic strategies to shorten POI based on these new insights will undoubtedly enter the clinical arena soon.