tbuckley/cabot-search huggingface dataset:
Pyroptosis triggers pore-induced intracellular traps (PITs) that capture bacteria and lead to their clearance by efferocytosis
Authors: Ine Jorgensen, Yue Zhang, Bryan A. Krantz, Edward A. Miao
Journal: The Journal of Experimental Medicine (2016)

Inflammasomes activate caspase-1 in response to cytosolic contamination or perturbation. This inflammatory caspase triggers the opening of the GSDMD pore in the plasma membrane, resulting in lytic cell death called pyroptosis. We had previously assumed that pyroptosis releases intracellular bacteria to the extracellular space. Here, we find that viable bacteria instead remain trapped within the cellular debris of pyroptotic macrophages. This trapping appears to be an inevitable consequence of how osmotic lysis ruptures the plasma membrane, and may also apply to necroptosis and some forms of nonprogrammed necrosis. Although membrane tears release soluble cytosolic contents, they are small enough to retain organelles and bacteria. We call this structure the pore-induced intracellular trap (PIT), which is conceptually parallel to the neutrophil extracellular trap (NET). The PIT coordinates innate immune responses via complement and scavenger receptors to drive recruitment of and efferocytosis by neutrophils. Ultimately, this secondary phagocyte kills the bacteria. Hence, caspase-1-driven pore-induced cell death triggers a multifaceted defense against intracellular bacteria facilitated by trapping the pathogen within the cellular debris. Bona fide intracellular bacterial pathogens, such as Salmonella, must prevent or delay pyroptosis to avoid being trapped in the PIT and subsequently killed by neutrophils.
Encouraging activity of bicalutamide and everolimus in castration-resistant prostate cancer (CRPC): Early results from a phase I/II clinical trial.
Authors: C. Pan, P. Ghosh, J. M. Suga, P. Pasquinelli, L. Beckett, R. deere White, P. Lara
Journal: Journal of Clinical Oncology (2010)

e15131 Background: Multiple signaling pathways are involved in the development of CRPC. We previously showed that the mTOR pathway is activated in CRPC cell lines while inhibition of this pathway results in upregulation of androgen receptor (AR) signaling (Wang et al, Oncogene. 2008). Simultaneous blockade of the mTOR and AR pathways synergize in inducing PCa cell death and delaying tumor formation in mouse models. We hypothesize that simultaneous blockade of the AR and mTOR pathways in CRPC patients with bicalutamide and everolimus will result in improved efficacy compared to bicalutamide alone. Methods: A phase II clinical trial with a lead-in safety phase was designed to determine the efficacy and tolerability of the bicalutamide and everolimus combination in CRPC patients (pts) compared with bicalutamide alone. Pts must have histologically confirmed disease and disease progression (PSA or radiographically) while on androgen deprivation therapy. At the lead-in phase (n = 8), all pts receive both agents. At the phase II stage (n = 80), pts are randomized to bicalutamide ± everolimus. The primary endpoint is PSA response. The second endpoints include progression-free survival, time-to-treatment failure, overall survival and toxicity. Here, we report the results of the lead-in phase. Results: To date, 13 pts have been screened and 8 pts enrolled with a mean age of 68 and performance status of ECOG 0. In the lead-in phase, bicalutamide + everolimus has been well tolerated with no unexpected toxicities. One pt developed grade 3 pneumonitis (attributed to everolimus) that improved with dose reduction and steroid treatment. Of these 8 patients in the lead-in phase, there are 6 responses (at least 30% decline in PSA) and 2 stable diseases. Two patients who had measureable diseases had radiological response. Tumor and blood specimens are being collected for molecular correlative studies of mTOR pathway markers. Conclusions: The rational combination of bicalutamide and everolimus appears to have promising antitumor activity and an acceptable toxicity profile. The randomized phase of the clinical trial is currently ongoing and will be reported. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis
Radiation alone (RT) versus RT with concomitant chemotherapy (CT) in stages III and IV oropharynx carcinoma: Ten-year results of the 94-01 GORTEC randomized study.
Authors: G. Calais, S. Chapet, Y. Pointreau, E. Bardet, C. Sire, T. Germain
Journal: Journal of Clinical Oncology (2010)

5516 Background: The purpose of this study is to report long-term results of a randomized study designed to test whether the addition of three cycles of chemotherapy during standard radiation therapy would improve disease-free survival in patients with stages III and IV oropharynx carcinoma. Methods: Between July 1994 and September 1997, 226 patients with locally advanced oropharynx stage III and IV tumors have been entered in a phase III multicentric randomized trial comparing RT alone (arm A, 115 patients) to RT with concomitant CT (arm B, 111 patients). RT was identical in the two arms, delivering 70 Gy in 35 fractions. In arm B patients received simultaneously on d1, d22 and d43, 3 cycles of a 4 day regimen containing carboplatin (70 mg/m2/d) and 5FU (600 mg/m2/d) continuous infusion. 34% were stage III and 66% were stage IV. The 2 arms were equally balanced regarding to age, gender, stage, performance status, histology, tumor biology, and primary tumor site. Results: Results have been published in 1999 (G. Calais et al. J Natl Cancer Inst 91, 2081-2086, 1999) and updated in 2004 (F. Denis et al. J Clin Oncol 22,69-76, 2004). RT compliance was similar in the 2 arms regarding to total dose, treatment duration and treatment interruption. Relative dose intensity in arm B was 78% and 76% for carboplatin and 5FU. Grade 3 and 4 mucositis rate was significantly higher in arm B (67% vs. 36%). Skin toxicity was not different. Haematologic toxicity was higher in arm B on neutrophil count and hemoglobin level. With a median follow-up of 11 years, 78 patients have died in arm A versus 58 in arm B. Ten-year overall actuarial survival and disease- free survival rates were respectively 32% versus 18% and 30% versus 15% for patients treated with combined modality versus radiation alone (p = 0.03 and 0.04). Local and regional control rate has been improved in arm B. Actuarial grade 3 and 4 late toxicity rate was 30% in the RT-alone arm and 51% in the combined treatment arm. Quality of life and functional results of long-term survivors will be presented. Conclusions: The long-term results of this study support the use of concomitant CT combined with RT in the management of oropharynx carcinoma. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Serono
The future of surgical training in the context of the ‘Shape of Training’ Review: Consensus recommendations by the Association of Surgeons in Training
Authors: Rhiannon L. Harries, Adam P. Williams, Henry J.M. Ferguson, Helen M. Mohan, Andrew J. Beamish, Vimal J. Gokani
Journal: International Journal of Surgery (2016)

ASiT has long maintained that in order to provide the best quality care to patients in the UK and Republic of Ireland, it is critical that surgeons are trained to the highest standards. In addition, it is imperative that surgery remains an attractive career choice, with opportunities for career progression and job satisfaction to attract and retain the best candidates. In 2013, the Shape of Training review report set out recommendations for the structure and delivery of postgraduate training in light of an ever increasingly poly-morbid and ageing population. This consensus statement outlines ASIT's position regarding recommendations for improving surgical training and aims to help guide discussions with regard to future proposed changes to surgical training.
Current perspective on actinic keratosis: a review
Authors: J.A. Siegel, K. Korgavkar, M.A. Weinstock
Journal: British Journal of Dermatology (2016)

Actinic keratoses (AKs) are common, with prevalence in the U.S.A. estimated at almost 40 million in 2004 and annual costs of > $1 billion (U.S.D.). However, there is no universally accepted definition of AK and thus it is difficult to identify reliably. AKs are lesions of epidermal keratinocytic dysplasia that result from chronic sun exposure and have the ability to progress to invasive squamous cell carcinoma (SCC), but clinicians disagree about whether AKs are premalignant lesions, superficial SCCin situ or epiphenomena of chronically sun‐damaged skin. Yearly AK to SCC progression rates of 0·6% were reported in an elderly population with multiple prior keratinocyte carcinomas (KCs); and rates of spontaneous AK regression have been reported to be > 50%, but regressed lesions often reappear. As AKs have both cosmetic consequences and potential for malignant transformation, there are multiple reasons for treatment. There is no current agreement on the most efficacious treatment, but 5‐fluorouracil has been shown to both prevent and treat AKs, and imiquimod and photodynamic therapy may have the best cosmetic outcomes. AKs may be treated to improve appearance and relieve symptoms, but the keratinocytic dysplasia that gives rise to malignancy, and sometimes appears as an AK, may be what actually threatens patient health. Thus, treatments should aim to decrease the risk of KC or facilitate KC diagnosis by reducing the potential for misidentification created when a KC appears in a field of AKs. Improved agreement among clinicians on AK definition may improve management.
Abstract 36: Administration of 17β-Estradiol in C57Bl/6N Female Mice Leads to Cardiac Atrophy and Dysfunction via a β-Catenin Mechanism
Authors: Georgios Kararigas, Laura C Zelarayan, Karl Toischer, Gerd Hasenfuss, Hubertus Jarry, Vera Regitz-Zagrosek
Journal: Circulation Research (2015)

The steroid hormone 17β-estradiol (E2) regulates several biological processes. In contrast to its anti-hypertrophic effects under pressure overload, we recently found that E2 induced physiological hypertrophic growth in healthy C57Bl/6J mice but not C57Bl/6N mice. Here, we aimed at the characterization of the effects of E2 in C57Bl/6N mice and tested the hypothesis that β-catenin mediates these E2 effects. Following ovariectomy, 2-month-old C57Bl/6N wild-type and cardiac-specific β-catenin-deleted (β-cat Δex2-6 ) mice were randomized to an E2-containing or soy-free (control, CON) diet ( n = 7-13/group). Cardiac function was examined by echocardiography following established procedures. The 3-month physiological dose of E2 led to a higher relative uterus weight compared with CON ( P &lt; 0.001) in both WT and β-cat Δex2-6 mice. The relative heart weight was significantly reduced by E2 compared with CON in WT mice ( P &lt; 0.001), while there was no significant effect in β-cat Δex2-6 mice. Cardiomyocyte cross-sectional area was also significantly decreased by E2 ( n = 5-7/group; P &lt; 0.001) compared with CON in WT mice, while there was no significant effect in β-cat Δex2-6 mice. Echocardiography revealed a significant decrease in septum width ( P &lt; 0.001) and posterior wall thickness ( P &lt; 0.01) in E2 treated WT mice compared with CON, while there was no significant effect in β-cat Δex2-6 mice ( n = 8/group). These E2-induced structural changes in WT mice were accompanied by a significant decrease in cardiac function, namely a 23% decrease in fractional shortening compared with CON ( P &lt; 0.05), while there was no significant effect in β-cat Δex2-6 mice. Immunoblotting revealed a significant increase in the levels of the ubiquitin ligase and key regulator of proteasome-dependent protein degradation muscle-specific RING finger protein 1 (MuRF1) by E2 compared with CON in WT mice ( P &lt; 0.05), while there was no significant effect in β-cat Δex2-6 mice. Although we hypothesized increased autophagic activity, we found no effect on the autophagy-related protein LC3 in WT or β-cat Δex2-6 mice. In conclusion, our surprising findings show that E2 leads to cardiac atrophy and dysfunction in C57Bl/6N mice via a β-catenin mechanism seemingly in an autophagy-independent manner.
AIDS and the Nervous System
Authors: M Dalakas, A Wichman, J Sever
Journal: JAMA (1989)

<h3>A SELECTED CASE</h3> A 32-YEAR-OLD, healthy homosexual man was found to be seropositive for human immunodeficiency virus (HIV) on routine testing. He was in good general health. His peripheral blood lymphocyte subsets were normal. Eight months later, he noted a gradual onset of weakness and paresthesias in both legs. Weakness progressed, and within a 2-month period he became wheelchair bound. On examination, he had severe, primarily distal muscle weakness with bilateral footdrop and areflexia. Pinprick sensation was diminished below the knees and vibratory and position sensation was absent in his feet. The cerebrospinal fluid (CSF) protein level was increased to 2.12 g/L with pleocytosis. Nerve conduction velocity was slow (averaging 22 m/s), with conduction block consistent with demyelinating polyneuropathy. A sural nerve biopsy specimen showed features of segmental demyelination with perivascular inflammation. Normal results were obtained from blood chemistries, a serum immunoglobulin profile, thyroid studies, and a complete blood cell
Genome-Wide DNA Methylation Analysis Reveals Biological and Clinical Insights In Relapsed Childhood Acute Lymphoblastic Leukemia: A Report From The COG ALL Target Project
Authors: Huimin Geng, Mignon L. Loh, Richard C. Harvey, I-Ming Chen, Meenakshi Devidas, Tanja M. Davidsen, Jaime M. Guidry Auvil, Daniela S. Gerhard, Malcolm A. Smith, Andrew J. Carroll, Nyla A. Heerema, Julie M. Gastier-Foster, Cheryl L. Willman, Charles G. Mullighan, Stephen P. Hunger, Ari Melnick
Journal: Blood (2013)
Outbreak of Plague in a High Malaria Endemic Region — Nyimba District, Zambia, March–May 2015
Authors: Nyambe Sinyange, Ramya Kumar, Akatama Inambao, Loveness Moonde, Jonathan Chama, Mapopa Banda, Elliot Tembo, Beron Nsonga, John Mwaba, Sombo Fwoloshi, Kebby Musokotwane, Elizabeth Chizema, Muzala Kapin'a, Benard Mudenda Hang’ombe, Henry C. Baggett, Lottie Hachaambwa
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Outbreaks of plague have been recognized in Zambia since 1917 (1). On April 10, 2015, Zambia's Ministry of Health was notified by the Eastern Provincial Medical Office of possible bubonic plague cases in Nyimba District. Eleven patients with acute fever and cervical lymphadenopathy had been evaluated at two rural health centers during March 28-April 9, 2015; three patients died. To confirm the outbreak and develop control measures, the Zambia Ministry of Health's Field Epidemiology Training Program (ZFETP) conducted epidemiologic and laboratory investigations in partnership with the University of Zambia's schools of Medicine and Veterinary Medicine and the provincial and district medical offices. Twenty-one patients with clinically compatible plague were identified, with symptom onset during March 26-May 5, 2015. The median age was 8 years, and all patients were from the same village. Blood specimens or lymph node aspirates from six (29%) patients tested positive for Yersinia pestis by polymerase chain reaction (PCR). There is an urgent need to improve early identification and treatment of plague cases. PCR is a potential complementary tool for identifying plague, especially in areas with limited microbiologic capacity. Twelve (57%) patients, including all six with PCR-positive plague and all three who died, also tested positive for malaria by rapid diagnostic test (RDT). Plague patients coinfected with malaria might be misdiagnosed as solely having malaria, and appropriate antibacterial treatment to combat plague might not be given, increasing risk for mortality. Because patients with malaria might be coinfected with other pathogens, broad spectrum antibiotic treatment to cover other pathogens is recommended for all children with severe malaria, until a bacterial infection is excluded.
Functional recovery after surgery in patients with breast cancer
Authors: B. Springer, J. Danoff, E. Levy, N. Stout, L. Pfalzer, C. McGarvey, L. Gerber, P. Soballe
Journal: Journal of Clinical Oncology (2009)

e20539 Background: Upper extremity dysfunction and decreased quality of life are frequently reported sequelae of the treatment for early stage breast cancer (BC). Surgical trauma and/or radiation therapy may lead to upper extremity (UE) impairments, functional limitations and disabilities including pain, stiffness, lymphedema, decreased strength and range of motion (ROM) and decreased activity tolerance. In this study we examined specific functional characteristics of shoulder impairments and associated limitations. Methods: Women (n=88, mean age = 53y [SD=11.81]) newly diagnosed with unilateral, Stage I to III BC were screened pre-operatively for this prospective trial. Patient data and physical therapy based assessments were recorded at the pre-operative visit (baseline) and at 1, 3, and 12+ months (BA, M1, M3, M12) after surgical treatment including pain (VAS on 10 point scale), bilateral shoulder ROM and strength (MMT). Volumes for upper extremities were taken using an optoelectric device (Perometer®). During post BC treatment visits, appropriate physical therapy was provided, and if there was a diagnosis of lymphedema, a light-grade compression garment was fitted. ROMs (shoulder Abd, ER, Flex, IR), a composite MMT value, and volume were analyzed with one-way repeated ANOVA including Greenhouse-Geisser correction for non-normal data where necessary. Post hoc testing was done using Within-Subjects Contrasts. Limited range of values for pain resulted in a highly skewed distribution, inappropriate for statistical testing. Results: For the variables Abd, ER, Flex, and sumMMT there was a decrease in function from BA to M1, improvement from M1 to M3, and further improvement from M3 to M12 (all p &lt; 0.0001). For IR there was a decrease from BA to M1, no difference between M1 and M3, and an improvement from M1 and M3 to M12 (p &lt; 0.3). Pain remained relatively low with 60–80% of the women reporting ≤2/10. Conclusions: After surgery for breast cancer, a decrement in shoulder function may be expected around 1 month after the procedure. Most subjects demonstrated significant improvement in function by 3 months after the procedure, and by 12 months, subjects achieved near complete recovery of shoulder impairment. No significant financial relationships to disclose.
Balance between transmitted HLA preadapted and nonassociated polymorphisms is a major determinant of HIV-1 disease progression
Authors: Daniela C. Mónaco, Dario A. Dilernia, Andrew Fiore-Gartland, Tianwei Yu, Jessica L. Prince, Kristine K. Dennis, Kai Qin, Malinda Schaefer, Daniel T. Claiborne, William Kilembe, Jianming Tang, Matt A. Price, Paul Farmer, Jill Gilmour, Anju Bansal, Susan Allen, Paul Goepfert, Eric Hunter
Journal: The Journal of Experimental Medicine (2016)

HIV-1 adapts to a new host through mutations that facilitate immune escape. Here, we evaluate the impact on viral control and disease progression of transmitted polymorphisms that were either preadapted to or nonassociated with the new host’s HLA. In a cohort of 169 Zambian heterosexual transmission pairs, we found that almost one-third of possible HLA-linked target sites in the transmitted virus Gag protein are already adapted, and that this transmitted preadaptation significantly reduced early immune recognition of epitopes. Transmitted preadapted and nonassociated polymorphisms showed opposing effects on set-point VL and the balance between the two was significantly associated with higher set-point VLs in a multivariable model including other risk factors. Transmitted preadaptation was also significantly associated with faster CD4 decline (&amp;lt;350 cells/µl) and this association was stronger after accounting for nonassociated polymorphisms, which were linked with slower CD4 decline. Overall, the relative ratio of the two classes of polymorphisms was found to be the major determinant of CD4 decline in a multivariable model including other risk factors. This study reveals that, even before an immune response is mounted in the new host, the balance of these opposing factors can significantly influence the outcome of HIV-1 infection.
Preparation and characterisation of solid dispersions of tanshinone IIA, cryptotanshinone and total tanshinones
Authors: Xifeng Zhai, Chunguang Li, George Binh Lenon, Charlie C.L. Xue, Weize Li
Journal: Asian Journal of Pharmaceutical Sciences (2016)

Total tanshinones are lipophilic active constituents extracted from Salvia miltiorrhiza Bge. Tanshinone IIA and cryptotanshinone are the major components in total tanshinones. However, the bioavailability of both compounds is low due to poor water solubility. To enhance the solubility and dissolution rate of tanshinone IIA, cryptotanshinone and total tanshinones, three common used hydrophilic carriers including PEG 6000, poloxamer 188 and PVP K30 were used to prepare the solid dispersions at different ratios, respectively. The solid dispersions were characterised by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR). The results of powder X-ray diffraction confirmed the microcrystal state of total tanshinones in solid dispersions and no chemical interaction between total tanshinones and carriers was observed in FTIR spectra. The solubility and dissolution rate of tanshinone IIA and cryptotanshinone were significantly increased in all solid dispersions. Regarding tanshinone IIA, the solubility and dissolution rate of in solid dispersions prepared with poloxamer 188 were significantly higher than that with PEG 6000 and PVP K30. The higher solubility and dissolution rate of cryptotanshinone were obtained in solid dispersion of PVP K30 than that of PEG 6000 solid dispersions but no significant difference from poloxamer 188 solid dispersions. The results indicate that the superior carrier for preparation of tanshinone IIA and total tanshinones solid dispersions is poloxamer 188, and that for cryptotanshinone is PVP K30.
Targeted case finding improves treatment of patients at high risk for CVD, study finds
Authors: Susan Mayor
Journal: BMJ (2016)

Targeted case finding based on estimating patients’ cardiovascular risk and then inviting those likely to be at high risk for a full assessment increases the number of patients started on antihypertensive and statin treatment for primary prevention of cardiovascular disease (CVD), a general practice study has found.1

Preventive treatment with statins and antihypertensive drugs is effective and is recommended for primary prevention of CVD in high risk patients, but many remain untreated. Those at risk can be identified …