Miracle-dz/UniFAR-FTUs huggingface dataset:
EGFR and KRAS status of primary sarcomatoid carcinomas of the lung: Implications for anti‐EGFR treatment of a rare lung malignancy

Sarcomatoid carcinomas (SC) of the lung are uncommon malignant tumors composed of carcinomatous and sarcomatous cell components and characterized by a more aggressive outcome than other histological subtypes of nonsmall cell lung cancer (NSCLC). Although epidermal growth factor receptor (EGFR)‐targeted therapies have emerged as a promising therapeutic approach in patients with advanced typical NSCLC such as adenocarcinoma, the potential clinical activity of these drugs in lung SC is still unknown. To investigate this point, we have analyzed the status of 4 EGFR pathways biomarkers in a series of lung SC. EGFR protein expression, EGFR gene copy number, EGFR mutational status and KRAS mutational status were assessed in a series of 22 consecutive cases of primary lung SC. EGFR protein overexpression was observed in all the cases. High level of polysomy (≥4 copies of the gene in >40% of cells) was detected in 5 cases (23%). No EGFR mutation was detected. KRAS mutations were found in 8 patients (38%; Gly12Cys in 6 cases and Gly12Val in 2 cases). The consistent EGFR protein overexpression and the high rate of KRAS mutation may contribute to the poorer outcome of lung SC in comparison with typical NSCLC. The rare incidence of increased EGFR gene copy number, the lack of EGFR mutation and the high rate of KRAS mutation observed in our series also suggest that most patients with lung SC are not likely to benefit from anti‐EGFR therapies. © 2009 UICC
Effects of oral creatine supplementation on performance and muscle metabolism during maximal exercise

The purpose of this study was to determine the effects of oral creatine supplementation on performance and muscle metabolism during maximal exercise. Nine subjects (5 female, 4 male) performed two 30 s maximal exercise bouts on a cycle ergometer separated by a period of two weeks to allow for adequate washout. Each exercise bout was preceded by 4 days of supplementation with a placebo (PL) or creatine (CR). The subjects consumed 5g of PL or CR four times a day prior to the trial. Treatments were administered in a double-blind, cross over design. Power output was measured in watts every second for 30 s. There were no significant differences in average power output, peak power, or percent decline from peak power. There were no significant differences in muscle or plasma lactate concentrations. Total muscle Cr concentration was significantly higher in CR (20.0 + 0.9 vs . 15.8 + 2.0 mmol/kg; p<0.05) prior to exercise and immediately following exercise (20.7 + 0.9 vs. 14.8 + 1.7 mmol/kg; p<0.05). There was no significant difference in muscle creatine phosphate concentration; however, the change in muscle PCr concentration tended to be greater during CR (6.4 + 1.3 vs. 2.5 + 1.6 mmol/kg; p = 0.07). The results indicate that four days of oral creatine supplementation does not improve power output on a single maximal cycle ergome ter exercise, but may affect energy use in muscle metabolism.
Synergistic effect of HLA class II loci and cytokine gene polymorphisms on the risk of gastric cancer in Japanese patients with Helicobacter pylori infection

It has been reported that polymorphisms of human leukocyte antigen (HLA) genes and several cytokine genes are associated with an increased risk of developing gastric cancer (GC). However, the results of studies from different geographic regions, ethnic groups and study groups are inconsistent. The aim of this study was to evaluate the influence of H. pylori infection and host genetic factors on GC susceptibility in Japanese patients with GC. We analyzed genotypes for HLA class I and II, tumor necrosis factor α, interleukin (IL)‐1β, IL‐1 receptor, IL‐4, IL‐4Rα and IL‐10 in 330 H. pylori‐infected noncardia patients with GC and 190 H. pylori‐infected nonulcer dyspeptic controls. Haplotype analyses indicated that the frequencies of the HLA DRB1*0405 and DQB1*0401 alleles were increased in the patients with intestinal‐type GC when compared with controls (both DRB1*0405 and DQB1*0401: p = 0.015, OR = 1.57, 95% CI = 1.09–2.26), but the changes were not statistically significant after correction for multiple comparisons. None of the cytokine gene polymorphisms were associated with GC susceptibility, whether patients with GC were analyzed as a group according to the histological subtype. Of interest was the comparison of controls and patients with intestinal‐type GC. The frequency of an IL‐10‐592AA homozygote showing concomitant carriage of the HLA DRB1*0405‐DQB1*0401 haplotype was significantly higher in patients with intestinal‐type GC (χ2 = 6.369, p = 0.0116, pc = 0.0464, OR = 2.43, 95% CI = 1.21–4.48). Our results suggest that the HLA class II and IL‐10‐592A/C polymorphisms synergistically affect the susceptibility to GC development of H. pylori‐infected individuals in the Japanese population. © 2009 UICC
The validity degree vectors of formulae in two-valued predicate logic

AbstractBy means of infinite product of uniformly distributed probability spaces of cardinal n, the concept of n-validity degrees and validity degree vectors of formulae in two-valued predicate logic are introduced. It is proved that the validity degree vectors of formulae can preserve the logical relation between formulae. Moreover, a consistency theorem is obtained which says that the n-validity degree τn(A) of the quantifierfree first-order formula A without any repeated predicate symbols or terms is independent of the natural number n, and is a constant equal to the validity degree τ (A0) of the corresponding proposition A0 in classical propositional logic.
Improving interactive facility with vision training

The measurement of accommodative facility has gained acceptance in optometric examinations because it can provide valuable information on the dynamics of accommodation. Accommodative infacility is usually treated by prescribing various orthoptic exercises. This study arose from a need to investigate the effects of specific vision training procedures on binocular accommodative facility (interactive facility). The results indicate that even relatively short periods of accommodative rock training can improve the level of interactive facility.
The Janus‐faced role of ezrin in “linking” cells to either normal or metastatic phenotype

In the majority of eukaryotic cells, the ezrin, radixin and moesin (ERM) proteins are involved in many physiologic functions including regulation of actin cytoskeleton, control of cell shape, adhesion, motility and modulation of signal transduction pathways. In a previous study, we used a dominant negative ezrin‐mutant to address ezrin involvement in remodeling of actin cytoskeleton and subsequently we depicted ezrin key role in melanoma cell migration and progression. Herein, we highlight recent advances on ezrin involvement in the metastatic phenomenon, including also some more neglected ezrin‐related functions. Novel molecular processes driven by ezrin activation include: phagocytosis, acquisition of resistance to chemotherapeutics and triggering of programmed cell death signals. Recent data support an integrated role of ezrin also in development of tumor malignancy. On one hand, ezrin may be responsible of deranged execution of specific known functions such as adhesion and motility and on the other, it may also participate to unique metastatic determinants, through the establishment of aberrant linkages with tumor‐related proteins. For instance, ezrin misslocalization, absence or deranged activity has started to be correlated with tumor progression in many tumors of different species, including humans. Concomitantly, ezrin may act simultaneously as a regulatory or deregulatory chaperon in both normal and tumor cells. It is still to be established whether this Janus‐faced feature of ezrin is due to some unknown transforming Zelig‐like property or to the fact that a tumor‐associated molecule preferentially links to ezrin thus distracting it from its normal connections. However, the contribution of ezrin functional deregulation to the acquisition of the metastatic phenotype appears clear and ezrin or ezrin aberrant associations may represent good candidates for future anti‐tumor therapies. © 2009 UICC
Epidemiologic and virologic assessment of the 2009 influenza A (H1N1) pandemic on selected temperate countries in the Southern Hemisphere: Argentina, Australia, Chile, New Zealand and South Africa

Please cite this paper as: Van Kerkhove et al. (2011) Epidemiologic and virologic assessment of the 2009 influenza A (H1N1) pandemic on selected temperate countries in the Southern Hemisphere: Argentina, Australia, Chile, New Zealand and South Africa. Influenza and Other Respiratory Viruses 5(6), e487–e498.
Nationwide Survey of School-Based Physical Therapy Practice

Purpose: The Individuals with Disabilities Education Improvement Act and related literature have implications for school-based physical therapy. This study examined therapists' reports of their actual practice, compared with literature-based recommendations for “ideal” practice, and explored their conceptions of ideal practice. Methods: Participation in an online survey was requested of school-based physical therapists. Analysis of the results compared the therapists' reports of their actual practice with their views about ideal practice. Results: Among the 561 respondents, there was general agreement that actual practice was always or usually consistent with the literature. However, poor agreement was found between their reported actual practice and their opinions of ideal practice. The majority of service delivery was direct intervention. Ninety percent believed they were “adequately” meeting their students' needs. Conclusions: Actual reported practice generally met literature descriptions of ideal practice but not to the extent the respondents thought ideal.
The effects of gefitinib in tamoxifen‐resistant and hormone‐insensitive breast cancer: A phase II study

Estrogen receptor (ER)‐positive acquired tamoxifen‐resistant (TAM‐R) MCF‐7 breast cancer cell lines exhibit epidermal growth factor receptor (EGFR) expression/signaling and are growth‐inhibited by gefitinib (IRESSA). We examined the effect of gefitinib on ER‐positive TAM‐R and ER‐negative hormone‐insensitive breast cancer in a Phase II study. Fifty‐four patients with breast cancer [ER‐positive/acquired TAM‐R (n = 28); ER‐negative (n = 26)] received oral gefitinib 500 mg/day. Tumor biopsies were taken pre‐ (n = 28) and 8 weeks post‐treatment (n = 14 matched samples). Gefitinib was well tolerated and the clinical benefit rate (objective response or stable disease >24 weeks) was 33.3% overall (n = 18/54), and 53.6 and 11.5% in ER‐positive/TAM‐R and ER‐negative patients, respectively. Pretreatment ER and progesterone receptor‐positivity were associated with response (p < 0.001 and 0.016, respectively) and longer progression‐free survival (PFS; p= 0.001 and 0.013, respectively). All patients expressed EGFR, but high pretreatment levels predicted poorer outcome (p = 0.005) and shorter PFS (p = 0.012) with gefitinib. In patients with clinical benefit, reduced Ki67 staining during treatment (p = 0.024) was commonly observed, and those with >10% decline in EGFR phosphorylation demonstrated parallel decreases in ERK1/2 MAPK phosphorylation. Acquired tamoxifen resistance appears in part mediated through EGFR signaling and can be blocked with gefitinib.
Cerebellar Cortical Demyelination in the Murine Cuprizone Model

In multiple sclerosis, demyelination occurs beside the white‐matter structures and in the cerebral and cerebellar cortex. We have previously shown that, in the cuprizone model, demyelination is present not only in the corpus callosum but also in the cerebral cortex. Here, we have performed a detailed analysis of the dynamics of de‐ and remyelination in the cerebellar cortex and white matter at nine timepoints in two cerebellar regions. To induce demyelination, C57BL/6 mice were fed with 0.2% cuprizone for 12 weeks followed by a recovery of 8 weeks. Both cortex and white‐matter structures were significantly demyelinated after 12 weeks of cuprizone feeding. Remyelination occurred after withdrawal of cuprizone but was less prominent in the more caudal cerebellar region. Microglia infiltration was prominent in all analyzed cerebellar areas, preceding demyelination by approximately 2–4 weeks, and was delayed in the more caudal cerebellar region. Astrogliosis was also seen but did not reach the extent observed in the cerebrum. In summary, cuprizone feeding provides an excellent model for the investigation of de‐ and remyelination processes in the cerebellar cortex and white matter. Furthermore, demyelination, microglia and astrocyte changes were different in the cerebellum as compared with the cerebrum, indicating region‐dependent pathomechanisms.
The end of a monolith: Deconstructing the Cnn-Polo interaction

ABSTRACT In Drosophila melanogaster a functional pericentriolar matrix (PCM) at mitotic centrosomes requires Centrosomin-Long Form (Cnn-LF) proteins. Moreover, tissue culture cells have shown that the centrosomal localization of both Cnn-LF and Polo kinase are co-dependent, suggesting a direct interaction. Our recent study found Cnn potentially binds to and is phosphorylated by Polo kinase at 2 residues encoded by Exon1A, the initiating exon of a subset of Cnn isoforms. These interactions are required for the centrosomal localization of Cnn-LF in syncytial embryos and a mutation of either phosphorylation site is sufficient to block localization of both mutant and wild-type Cnn when they are co-expressed. Immunoprecipitation experiments show that Cnn-LF interacts directly with mitotically activated Polo kinase and requires the 2 phosphorylation sites in Exon1A. These IP experiments also show that Cnn-LF proteins form multimers. Depending on the stoichiometry between functional and mutant peptides, heteromultimers exhibit dominant negative or positive trans-complementation (rescue) effects on mitosis. Additionally, following the completion of meiosis, Cnn-Short Form (Cnn-SF) proteins are required for polar body formation in embryos, a process previously shown to require Polo kinase. These findings, when combined with previous work, clearly demonstrate the complexity of cnn and show that a view of cnn as encoding a single peptide is too simplistic.
Type‐specific roles of histone deacetylase (HDAC) overexpression in ovarian carcinoma: HDAC1 enhances cell proliferation and HDAC3 stimulates cell migration with downregulation of E‐cadherin

Histone acetylation/deacetylation controls chromatin activity and subsequent gene transcription. Recent studies demonstrated the activation of histone deacetylases (HDACs) in various human malignancies; however, the expression and function of HDACs in ovarian tumors are not fully understood. In this study, we examined the immunohistochemical expression of HDAC1, HDAC2 and HDAC3 using tissues obtained from 115 cases of ovarian tumors and compared it with that of Ki‐67 (a growth marker), p21, and E‐cadherin and clinicopathological parameters. In addition, we analyzed the effect of specific siRNA for HDAC1, HDAC2 and HDAC3 on the expression of cell cycle‐related molecules and E‐cadherin to clarify the functional difference among the 3 HDACs. The results indicated that the immunohistochemical expression of nuclear HDAC1, HDAC2 and HDAC3 proteins increased stepwise in benign, borderline and malignant tumors. The expression of HDAC1 and HDAC2 was correlated with Ki‐67 expression and that of HDAC3 was inversely correlated with E‐cadherin expression. Among the HDACs examined, only HDAC1 was associated with a poor outcome, when overexpressed. Treatment with HDAC inhibitors suppressed the proliferation of ovarian cancer cells in association with apoptosis. A specific siRNA for HDAC1 significantly reduced the proliferation of ovarian carcinoma cells via downregulation of cyclin A expression, but siRNA for HDAC3 reduced the cell migration with elevated E‐cadherin expression. Our results suggested that HDAC1 plays an important role in the proliferation of ovarian cancer cells, whereas HDAC3 functions in cell adhesion and migration. Therefore, specific therapeutic approaches should be considered according to the HDAC subtypes.
Tumors exposed to acute cyclic hypoxic stress show enhanced angiogenesis, perfusion and metastatic dissemination

Clinical studies have shown that patients with highly hypoxic primary tumors may have poor disease‐free and overall survival rates. Studies of experimental tumors have revealed that acutely hypoxic cells may be more metastatic than normoxic or chronically hypoxic cells. In the present work, causal relations between acute cyclic hypoxia and metastasis were studied by periodically exposing BALB/c nu/nu mice bearing A‐07 human melanoma xenografts to a low oxygen atmosphere. The hypoxia treatment consisted of 12 cycles of 10 min of 8% O2 in N2 followed by 10 min of air for a total of 4 hr, began on the first day after tumor cell inoculation and was given daily until the tumors reached a volume of 100 mm3. Twenty‐four hours after the last hypoxia exposure, the primary tumors were subjected to dynamic contrast‐enhanced magnetic resonance imaging for assessment of blood perfusion before being resected and processed for immunohistochemical examinations of microvascular density and expression of proangiogenic factors. Mice exposed to acute cyclic hypoxia showed increased incidence of pulmonary metastases, and the primary tumors of these mice showed increased blood perfusion, microvascular density and vascular endothelial growth factor‐A (VEGF‐A) expression; whereas, the expression of interleukin‐8, platelet‐derived endothelial cell growth factor and basic fibroblast growth factor was unchanged. The increased pulmonary metastasis was most likely a consequence of hypoxia‐induced VEGF‐A upregulation, which resulted in increased angiogenic activity and blood perfusion in the primary tumor and thus facilitated tumor cell intravasation and hematogenous transport into the general circulation.
Modulation of nociceptive ion channels and receptors via protein-protein interactions: implications for pain relief

In the last 2 decades biomedical research has provided great insights into the molecular signatures underlying painful conditions. However, chronic pain still imposes substantial challenges to researchers, clinicians and patients alike. Under pathological conditions, pain therapeutics often lack efficacy and exhibit only minimal safety profiles, which can be largely attributed to the targeting of molecules with key physiological functions throughout the body. In light of these difficulties, the identification of molecules and associated protein complexes specifically involved in chronic pain states is of paramount importance for designing selective interventions. Ion channels and receptors represent primary targets, as they critically shape nociceptive signaling from the periphery to the brain. Moreover, their function requires tight control, which is usually implemented by protein-protein interactions (PPIs). Indeed, manipulation of such PPIs entails the modulation of ion channel activity with widespread implications for influencing nociceptive signaling in a more specific way. In this review, we highlight recent advances in modulating ion channels and receptors via their PPI networks in the pursuit of relieving chronic pain. Moreover, we critically discuss the potential of targeting PPIs for developing novel pain therapies exhibiting higher efficacy and improved safety profiles.
Development of a Challenge Assessment Tool for High-Functioning Children With an Acquired Brain Injury

Purpose: To develop a performance-based challenge assessment to evaluate gross motor abilities of high-functioning youth with an acquired brain injury (ABI). Methods: Potential items were identified from the literature. A panel of 4 expert physical therapists selected items on the basis of 3 criteria: safety to test, feasibility to administer, and importance to perform. Item reduction was completed using ratings from a physical therapist web survey. The Acquired Brain Injury-Challenge Assessment (ABI-CA) was created and pilot tested with youth with an ABI. Results: Seventy-eight items were identified and reduced to 47 items following expert panel discussion. Web-survey item reduction by 75 pediatric physical therapists yielded a 24-item ABI-CA that was administered to 6 youth with an ABI, aged 8 to 17 years. The ABI-CA mean score was 50.7/81.0 (SD = 17.4). Conclusion: The ABI-CA was feasible to administer and demonstrated gross motor activity challenges beyond the Gross Motor Function Measure. Response option refinement and measure validation are required prior to clinical/research use.
Interactions between N and C termini of α1C subunit regulate inactivation of CaV1.2 L-type Ca2+ channel

The modulation and regulation of voltage-gated Ca2+ channels is affected by the pore-forming segments, the cytosolic parts of the channel, and interacting intracellular proteins. In this study we demonstrate a direct physical interaction between the N terminus (NT) and C terminus (CT) of the main subunit of the L-type Ca2+ channel CaV1.2, α1C, and explore the importance of this interaction for the regulation of the channel. We used biochemistry to measure the strength of the interaction and to map the location of the interaction sites, and electrophysiology to investigate the functional impact of the interaction. We show that the full-length NT (amino acids 1-154) and the proximal (close to the plasma membrane) part of the CT, pCT (amino acids 1508-1669) interact with sub-micromolar to low-micromolar affinity. Calmodulin (CaM) is not essential for the binding. The results further suggest that the NT-CT interaction regulates the channel's inactivation, and that Ca2+, presumably through binding to calmodulin (CaM), reduces the strength of NT-CT interaction. We propose a molecular mechanism in which NT and CT of the channel serve as levers whose movements regulate inactivation by promoting changes in the transmembrane core of the channel via S1 (NT) or S6 (pCT) segments of domains I and IV, accordingly, and not as a kind of pore blocker. We hypothesize that Ca2+-CaM-induced changes in NT-CT interaction may, in part, underlie the acceleration of CaV1.2 inactivation induced by Ca2+ entry into the cell.
CACNA1H missense mutations associated with amyotrophic lateral sclerosis alter Cav3.2 T-type calcium channel activity and reticular thalamic neuron firing

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. In a recent study by Steinberg and colleagues, 2 recessive missense mutations were identified in the Cav3.2 T-type calcium channel gene (CACNA1H), in a family with an affected proband (early onset, long duration ALS) and 2 unaffected parents. We have introduced and functionally characterized these mutations using transiently expressed human Cav3.2 channels in tsA-201 cells. Both of these mutations produced mild but significant changes on T-type channel activity that are consistent with a loss of channel function. Computer modeling in thalamic reticular neurons suggested that these mutations result in decreased neuronal excitability of thalamic structures. Taken together, these findings implicate CACNA1H as a susceptibility gene in amyotrophic lateral sclerosis.