Miracle-dz/UniFAR-FTUs huggingface dataset:
CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials

Background Central nervous system (CNS) metastases are common in patients with non-small-cell lung cancer (NSCLC). Osimertinib has shown systemic efficacy in patients with CNS metastases, and early clinical evidence shows efficacy in the CNS. To evaluate osimertinib activity further, we present a pre-specified subgroup analysis of CNS response using pooled data from two phase II studies: AURA extension (NCT01802632) and AURA2 (NCT02094261). Patients and methods Patients with T790M-positive advanced NSCLC, who had progressed following prior epidermal growth factor receptor-tyrosine kinase inhibitor treatment, received osimertinib 80 mg od (n = 411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment; prior CNS treatment was allowed. Patients with ≥1 measurable CNS lesion (per RECIST 1.1) on baseline brain scan by blinded independent central neuroradiology review (BICR) were included in the evaluable for CNS response set (cEFR). The primary outcome for this CNS analysis was CNS objective response rate (ORR) by BICR; secondary outcomes included CNS duration of response, disease control rate (DCR) and progression-free survival (PFS). Results Of 128 patients with CNS metastases on baseline brain scans, 50 were included in the cEFR. Confirmed CNS ORR and DCR were 54% [27/50; 95% confidence interval (CI) 39-68] and 92% (46/50; 95% CI 81-98), respectively. CNS response was observed regardless of prior radiotherapy to the brain. Median CNS duration of response (22% maturity) was not reached (range, 1-15 months); at 9 months, 75% (95% CI 53-88) of patients were estimated to remain in response. Median follow-up for CNS PFS was 11 months; median CNS PFS was not reached (95% CI, 7, not calculable). The safety profile observed in the cEFR was consistent with the overall patient population. Conclusions Osimertinib demonstrated clinically meaningful efficacy against CNS metastases, with a high DCR, encouraging ORR, and safety profile consistent with that reported previously. ClinicalTrials.gov number NCT01802632; NCT02094261.
Pharmaceutical Marketing: Medical and Industry Biases

Pharmaceutical sales representatives provide useful information about products, but they have incentives to be overly positive. The literature written by physicians about pharmaceutical marketing and promotion generally focuses on the harmful aspects of promotion, and misses the benefits. This suspected harm occurs because physicians who have contact with pharmaceutical sales representatives sometimes change their prescribing behavior. However, this result has few implications about the benefits of this change in behavior. The response might be because of the information provided, or because of the excessive optimism of sales representatives. Physicians might be self selected to interact with representatives promoting drugs that the physicians are already interested in. Some physicians might spend more time learning about drugs by reading the professional literature than do others, who would learn from salespeople. Pharmaceutical representatives are interested in selling drugs, not directly in providing information. Thus, in some instances promotion will be harmful; in some, beneficial; and in some, ambiguous. The existing research has not tried to distinguish among these possibilities. Pharmaceutical companies are in the best position to provide information to physicians about drugs. What appear to be bribes may merely be methods of seeking attention or compensating physicians for their time. This article sets forth some additional hypotheses that could be tested regarding the positive and negative effects of promotion.
Regulation of tissue‐ and stimulus‐specific cell fate decisions by p53 in vivo

The tumour suppressor p53 pathway is often inactivated by multiple mechanisms in the genesis of human cancers. Aberrant cellular proliferation, DNA damage, hypoxia, and ribosomal stress cause activation of the p53 tumour suppressor with multiple possible consequences to the cell: cell death, cell cycle arrest, or senescence. These mechanisms ultimately ensure that the cell does not replicate, and are thus potent tumour suppressor mechanisms. An important question that has eluded the field is how p53 makes these cell fate decisions. This review summarizes the current status of knowledge regarding p53‐mediated stress and tissue‐dependent cell fate decisions in mouse models and human tumours. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Warfarin-related intracerebral hemorrhage: How to proceed

Warfarin-related intracerebral hemorrhage (WICH) is a devastating stroke subtype and represents a medical and neurosurgical emergency with a 1-month mortality of approximately 50%. Warfarin is commonly prescribed to prevent ischemic stroke in patients with atrial fibrillation and to prevent pulmonary embolism (PE) in patients with deep vein thrombosis (DVT). Owing to the aging population and the increased incidence of atrial fibrillation with age and subsequent warfarin use, the incidence of WICH is expected to rise in the future. When WICH occurs, immediate discontinuation of warfarin and simultaneous rapid warfarin-reversal remain the first-line interventions, sometimes with neurosurgical intervention. The optimal agent for the most rapid warfarin anticoagulation reversal remains to be defined owing to the lack of prospective randomized trials. We review current literature about WICH pathogenesis, risk factors, acute management strategies and prospects for future research for this devastating neurologic.
Inzidenz, Rezidiv, Pflegebedürftigkeit und Mortalität von Schlaganfall

We present the results of a secondary analysis of claims data for 2004 and 2005 of a nationwide statutory health insurance in Germany. This insurance covers 1 700 000 members, corresponding to 2.4 % of the statutory insured population in Germany. All members with a first-ever hospitalised stroke were followed for 12 months after hospitalisation. Inclusion took place on the basis of the hospital-based main diagnoses ICD I60-64. For the following 12 months hospitalisation due to relapse, statutory nursing care dependency and mortality were recorded. The gender-adjusted incidence was 126 / 100 000 in 2005 and 123 / 100 000 in 2006. The percentage of persons with relapse was 11.2 %, among them 2.4 % with 2 and more relapses. The percentage of patients becoming dependent on statutory nursing care after the event was 14.3 %. Regression analysis revealed associations between nursing care dependency and age, gender and type of stroke. The risk for nursing care dependency was 41 % higher in women compared to men. This risk grew by 13 % for every year of life from age 40 years on. Patients with haemorrhagic stroke had a 74 % higher risk of nursing care dependency than those with infarction. Mortality was 7.1 % during hospitalisation and further 10.3 % within the first 12 months of the observation period. Regression analysis showed an increase in mortality risk of 7 % for every year of life and an increase by 29 % for women in comparison to men. Haemorrhagic strokes had a 3.5-higher mortality risk than stroke due to infarction. The results of this study suggest a growing prevention and / or treatment success for stroke in recent years in Germany.
Protrusions of Disks and Nerve Compression in the Lumbar Region

Two years ago the author of the present paper published a report on the results of an anatomic study of protrusions of disks through the intervertebral foramina of the lumbar vertebrae. The following pararaph summarizes the conclusions reached. Dorsolateral protrusions of disks at the intervertebral foramina are often observed in anatomic specimens, and these are largely combined with compression of the nerves and ganglia on a line with the outer part of the foramina at the point where the nerve pierces the disk. At a lecture read before a meeting of the Swedish Societies for Internal Medicine and Medical Radiology, in December 1941, the writer expressed the opinion that these nerve compressions are so common that no further explanation need be sought to account for the symptoms occurring in the large majority of sciatica cases; in other words, »Sciatica means the rupture of a disk». This thesis aroused opposition, however, and severe criticism was directed from many quarters against the interpretation placed on the anatomic findings and the absence of clinical information with regard to sciatic pain in most of the cases reported. The writer has therefore extended his studies, and the present communication offers an account of both the earlier results and those obtained from the later investigation. The previous literature on the subject is almost exclusively concerned with protrusions and ruptures of disks into the vertebral canal, whereas herniated disks with a more lateral location, causing compression of the nerves, such as those described by the writer, have not earlier received attention or been attributed much clinical significance. The AngloAmerican literature of the past two years has not been available for study, however. Of the publications from other countries, mention may be made
Rpl27a mutation in the sooty foot ataxia mouse phenocopies high p53 mouse models

Ribosomal stress is an important, yet poorly understood, mechanism that results in activation of the p53 tumour suppressor. We present a mutation in the ribosomal protein Rpl27a gene (sooty foot ataxia mice), isolated through a sensitized N‐ethyl‐N‐nitrosourea (ENU) mutagenesis screen for p53 pathway defects, that shares striking phenotypic similarities with high p53 mouse models, including cerebellar ataxia, pancytopenia and epidermal hyperpigmentation. This phenocopy is rescued in a haploinsufficient p53 background. A detailed examination of the bone marrow in these mice identified reduced numbers of haematopoietic stem cells and a p53‐dependent c‐Kit down‐regulation. These studies suggest that reduced Rpl27a increases p53 activity in vivo, further evident with a delay in tumorigenesis in mutant mice. Taken together, these data demonstrate that Rpl27a plays a crucial role in multiple tissues and that disruption of this ribosomal protein affects both development and transformation. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Patient and Family Experiences of Psychiatric Services and African Indigenous Healers

The experiences and satisfaction of African psychiatric patients and their families with services rendered by indigenous healers and psychiatric facilities were explored in Cape Town, South Africa. Illness conceptualization and its impact on satisfaction were also investigated. Sixty-two African patients and their families were interviewed using an adapted version of Weiss’s Explanatory Model Interview Catalogue (EMIC). While respondents were satisfied with herbalists and faith healers, they reported negative experiences with diviners. Respondents expressed less dissatisfaction with psychiatric services than was expected. The study provides further evidence that indigenous names are used as explanatory categories which include the consideration of psychosocial and other explanations, and that the use of indigenous names does not preclude satisfaction with conventional psychiatric services.
PARP inhibition induces BAX/BAK‐independent synthetic lethality of BRCA1‐deficient non‐small cell lung cancer

Evasion of apoptosis contributes to both tumourigenesis and drug resistance in non‐small cell lung carcinoma (NSCLC). The pro‐apoptotic BCL‐2 family proteins BAX and BAK are critical regulators of mitochondrial apoptosis. New strategies for targeting NSCLC in a mitochondria‐independent manner should bypass this common mechanism of apoptosis block. BRCA1 mutation frequency in lung cancer is low; however, decreased BRCA1 mRNA and protein expression levels have been reported in a significant proportion of lung adenocarcinomas. BRCA1 mutation/deficiency confers a defect in homologous recombination DNA repair that has been exploited by synthetic lethality through inhibition of PARP (PARPi) in breast and ovarian cells; however, it is not known whether this same synthetic lethal mechanism exists in NSCLC cells. Additionally, it is unknown whether the mitochondrial apoptotic pathway is required for BRCA1/PARPi‐mediated synthetic lethality. Here we demonstrate that silencing of BRCA1 expression by RNA interference sensitizes NSCLC cells to PARP inhibition. Importantly, this sensitivity was not attenuated in cells harbouring mitochondrial apoptosis block induced by co‐depletion of BAX and BAK. Furthermore, we demonstrate that BRCA1 inhibition cannot override platinum resistance, which is often mediated by loss of mitochondrial apoptosis signalling, but can still sensitize to PARP inhibition. Finally we demonstrate the existence of a BRCA1‐deficient subgroup (11–19%) of NSCLC patients by analysing BRCA1 protein levels using immunohistochemistry in two independent primary NSCLC cohorts. Taken together, the existence of BRCA1‐immunodeficient NSCLC suggests that this molecular subgroup could be effectively targeted by PARP inhibitors in the clinic and that PARP inhibitors could be used for the treatment of BRCA1‐immunodeficient, platinum‐resistant tumours. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Balance and Spasticity: What We Know and What We Believe

In September 1992, the Executive Committee of the Consortium of Multiple Sclerosis Centers selected members for the physical therapy specialty panel. The group's responsibility was to review current literature and clinical practice on spasticity and balance in multiple sclerosis care. This task was achieved through individual work and conference calls and the results were reported at the multidisciplinary "What Do We Know About MS? " conference in June 1993. With input from forty other health care professionals experienced with MS care, two research questions were generated by the physical therapy panel. The question for balance was "Which of the three clinical measurement tools—Tinetti, Berg, or Functional Reach—is the best predictor of falls in the MS client, and how do they correlate with an experienced clinician's subjective evaluation? " The question for spasticity was "Will a daily stretching program result in decreased spasticity severity and improved functional mobility in ambulatory MS clients? " The findings from the spasticity question will provide a scientific basis for a common clinical practice in MS. The findings from the balance question will validate reliable clinical tools that may assess risk for falling in MS clients. The experience and findings were shared at the annual Consortium meeting in Victoria in September 1993.
Severity of doxorubicin‐induced small intestinal mucositis is regulated by the TLR‐2 and TLR‐9 pathways

Intestinal mucositis is a serious complication of cancer chemotherapy and radiotherapy; it frequently compromises treatment and dramatically reduces the quality of life of patients. Different approaches to limit the damage to the intestine during anti‐cancer therapy have been largely ineffective due to insufficient knowledge of the mechanism of mucositis development. This study aimed to define the role of TLR‐2 and TLR‐9 in the modulation of small intestinal damage in a model of doxorubicin‐induced mucositis. Doxorubicin‐induced intestinal damage was verified by a histological score (HS), analysis of leukocyte influx into the lamina propria, and determination of the number of apoptotic cells. Additionally, the activation status of glycogen synthase kinase 3β (GSK‐3β) was assessed. Wild‐type (WT) mice injected with doxorubicin demonstrated severe intestinal damage (HS 8.0 ± 0.81), reduction of villus length to 43.9% ± 13.7% of original length, and increased influx of leukocytes as compared to vehicle‐injected mice (HS 1.33 ± 1.15). The protective effect of TLR‐2 or TLR‐9 deficiency was associated with a significant decrease of the HS as compared to WT mice. In the ileum, a minor reduction of villus length and a decreased number of infiltrating leukocytes and TUNEL‐positive cells was observed. We demonstrate that the TLR‐9 antagonist ODN2088 reduces doxorubicin‐induced intestinal damage. Furthermore, we show that GSK‐3β activity is inhibited in the absence of TLR‐2. The protective capacity of GSK‐3β suppression was observed in WT mice by inhibiting it with the specific inhibitor SB216763. Overall, our findings demonstrate that the TLR‐2/GSK‐3β and TLR‐9 signalling pathways play a central role in the development of intestinal mucositis and we suggest a new therapeutic strategy for limiting doxorubicin‐induced intestinal inflammation. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Free energy contributions to the hcp-bcc transformation in transition metals.

The electronic and vibrational free energies of some hcp and bcc transition metals are computed {ital ab} {ital initio}. The vibrational part is obtained from a total-energy calculation over lattices with atoms randomly displaced according to a Gaussian distribution. The relative importance of electronic and vibrational excitations in the stabilization of the high-temperature bcc structure is clarified. {copyright} {ital 1996 The American Physical Society. }
Online support in study skills for international students at UCLAN

This article highlights the issue of study skills support for international students within the context of an MSc course at the University of Central Lancashire, Preston, UK (UCLAN). It provides an overview of key aspects of international students’ study experiences, and analyses UCLAN’s, and other Universities’ attempts to accommodate the needs of students in this respect. It is a reflective piece of work which reports on the authors’ involvement in an internationally oriented study skills programme, and aims to present an empathic approach to students’ experiences of study in a new country. A course-specific online study skills package is posited as a useful way of enhancing the academic success of international students prior to commencement of study in the UK. The article describes a piece of ‘action oriented research’ (Small 1995) which will assess the efficacy of such a package with respect to the MSc Applied Public Health at UCLAN.
CDC4/FBXW7 and the ‘just enough’ model of tumourigenesis

There is good evidence to show that cancer‐causing mutations are not always simple gain‐ and loss‐of‐function changes. One example is the APC gene, where the combination of mutations produces a ‘just‐right’ level of Wnt signalling. A recent article by Berger and colleagues posited a ‘continuum model’ in which increasing or decreasing gene expression of function was linearly associated with tumourigenesis. Berger also proposed an ‘obligate haploinsufficiency’ or ‘fail‐safe’ model, whereby heterozygous mutations produce sufficient derangement for tumourigenesis, yet homozygous mutations are cell‐lethal or senescence‐causing. One gene highlighted by Berger and colleagues as an example of a gene following a ‘continuum’ or ‘fail‐safe’ model was FBXW7/CDC4, a gene mutated in several different types of malignancy. We have analysed the COSMIC FBXW7 data. FBXW7 does not obviously follow a ‘continuum’ or ‘fail‐safe’ model and the most common mutant genotypes are mono‐allelic missense changes that affect critical arginine residues involved in interactions with substrates. There is no strong selection for complete loss of FBXW7 protein function, but bi‐allelic inactivating mutations do occur. For FBXW7, we suggest a variant of ‘just right’ which we call ‘just enough’. For FBXW7 mutations that occur away from the propellor tips, the heterozygote may have some effect on tumourigenesis, but there is selective pressure for a ‘second hit’. For propellor tip mutations, by contrast, there is weak pressure for a ‘second hit’ because they usually provide sufficient functional derangement on their own. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Frequent activating GNAS mutations in villous adenoma of the colorectum

To elucidate the role of GNAS mutations in colorectal tumourigenesis, we performed a mutation analysis in a total of 234 colorectal tumours, including adenomas, serrated lesions and adenocarcinomas. Activating GNAS mutations were found in 20 of the 24 villous adenomas (83%) but were absent in all the other tumours, except for one tubulovillous adenoma (3%) and two adenocarcinomas (3%). KRAS and BRAF mutations were always mutually exclusive. KRAS mutations were frequent in villous (67%) and tubulovillous (60%) adenomas but were rare or absent in tubular adenomas (6%) and serrated lesions, including hyperplastic polyps, sessile serrated polyps/sessile serrated lesions and traditional serrated adenomas (0‐9%). BRAF mutations were found in four villous adenomas (17%) and in the large majority of serrated lesions (81‐92%), but were absent in tubular and tubulovillous adenomas. Seventeen villous adenomas (71%) harboured GNAS mutations concomitantly with KRAS or BRAF mutations. Immunohistochemically, all the villous adenomas retained mismatch repair protein expression, suggesting that they are microsatellite‐stable. The current study showed that the presence of activating GNAS mutations, in association with KRAS or BRAF mutations, is a characteristic genetic feature of colorectal villous adenoma. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The pathological roles of BART miRNAs in nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer prevalent in south‐east Asia and southern China, where it constitutes a significant health burden. Although the close association of NPC with Epstein–Barr virus (EBV) infection has been known for more than four decades, the exact role that EBV plays in the pathogenesis of this malignancy is still unclear. While NPC tumours are known to express a number of EBV‐encoded proteins, they also express a large number of virus‐encoded microRNAs (miRNAs), the most abundant of which are those encoded from the BamHI‐A region of the viral genome: the so‐called BART miRNAs. miRNAs are small non‐coding mRNAs that negatively regulate the expression of various genes at the post‐transcriptional level. Accumulating evidence suggests that miRNAs play important roles in tumourigenesis. Here, we review the role of EBV‐encoded BART miRNAs in modulating apoptosis and host innate defence mechanisms and their contribution to NPC pathogenesis. The rationale and strategies for therapeutic targeting of BART miRNAs in EBV‐infected NPC are also discussed. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Aldosterone and the Kidney

Abstract The mineralocorticoid aldosterone is a key regulator of blood pressure, fluid and electrolyte homeostasis, and acts via the mineralocorticoid receptor (MR). In recent years, an increasing number of studies revealed deleterious effects of aldosterone via its receptor. Especially in patients with primary hyperaldosteronism (PHA) a significant higher risk of developing cardiovascular comorbidities and comortalities was reported. Also renal insufficiency is clearly increased in patients with PHA indicating a role of aldosterone and the MR in the pathogenesis of renal injury. It has been shown that aldosterone in combination with an elevated salt intake, leads to renal inflammation, fibrosis, podocyte injury, and mesangial cell proliferation. This review focuses on the current knowledge of aldosterone effects in the kidney and highlights this topic from 2 perspectives: from clinical medicine and from experimental studies.