gebhart/patrepeval huggingface dataset:
Truncated forms of PspA that are secreted from Streptococcus pneumoniae and their use in functional studies and cloning of the pspA gene (1992)

Insertion-duplication mutagenesis was used to generate mutants of Streptococcus pneumoniae that produced truncated forms of PspA (pneumococcal surface protein A). The truncated products, representing from 20 to 80% of the complete PspA molecule, were all secreted from the cell and could be detected in unconcentrated culture medium. Analysis of the truncated molecules showed that the antigenic variability known to be associated with PspA is located in the alpha-helical N-terminal half of the molecule. This region was also found to contain immunogenic and protection-eliciting epitopes and to define the maximum region of the molecule that is likely to be surface exposed. The apparent molecular weight variability seen for PspA molecules of different S. pneumoniae strains was localized to both the N- and C-terminal halves of the protein. Attachment of PspA to S. pneumoniae was found to require regions located carboxy to the fifth repeat unit in the C-terminal end of the molecule. From the insertion-duplication mutants, the complete pspA gene was cloned and expressed in Escherichia coli. Differences in apparent molecular weight were observed when the same cloned product was expressed in E. coli and S. pneumoniae, suggesting that PspA is modified differently in the two hosts.
Disulphide bridge formation in the periplasm of Escherichia coli: β‐lactamase::human lgG3 hinge fusions as a model system (1992)

Summary We report the construction and the expression in Escherichia coli of three different fusion genes encoding the extended human lgG3 hinge region (Hi) fused in‐phase to the C ‐terminal end of bacterial TEM1 β‐lactamase (Bla). In the first fusion gene blahi , the hinge sequence was directly coupled to the 3′ end of the β‐lactamase gene, whereas in the two other constructs, blal1hi and blal2hi , a linker encoding 14 and 10 amino acids, respectively, was inserted between the two subunits. After expression (24 h, 20° C) under control of the constitutive kanamycin phosphoribosyl transferase promoter, the fusion proteins, BlaHi, BlaL 1Hi and BlaL2Hi, respectively, were almost exclusively detected in the periplasmic fraction, and they conferred carbenicillin‐resistance to the cells. These results indicate that β‐lactamase can efficiently direct the export of proteins fused to its C‐ terminus, and moreover, at least some of the exported fusion proteins must carry the β‐lactamase moiety in a properly folded form. Analysis of their assembly, however, revealed that only a minor fraction was recovered as the expected F(ab′) 2 ‐nke dimer. The presence in the periplasm of oxidized’monomers (with intrachain disulphide bonds) as well as of several high‐molecular‐mass proteins, probably resulting from the association between monomers and other cysteine‐rich proteins, strongly suggests that the conditions in the bacterial periplasm are insufficient to allow proper assembly of multimeric proteins with several interchain disulphide bonds.
Enhanced Therapeutic Potential of Adoptive Immunotherapy by In Vitro CD28/4-1BB Costimulation of Tumor-Reactive T Cells Against a Poorly Immunogenic, Major Histocompatibility Complex Class I-Negative A9P Melanoma (2000)

Costimulation plays a critical role in T-cell activation and amplification of anti-tumor immunity. Although CD28 engagement triggers an early activation signal, activation-induced 4-1BB molecule on T cells transmits a crucial signal for further expansion and maturation of effector cells. In this report, the authors show that costimulation through CD28 and 4-1BB pathways synergistically enhances the therapeutic efficacy of T cells from tumor-draining lymph nodes. Intravenous adoptive transfer of costimulated T cells into mice bearing disseminated micrometastasis of a poorly immunogenic, major histocompatibility complex class I-negative A9P melanoma results in a 60% cure rate. Autopsy of mice that died after unsuccessful treatment revealed tumor growth in the liver, spleen, and skin with minimal or no evidence of pulmonary disease. In contrast, mice that received no treatment or noncostimulated T cells had massive pulmonary tumors, suggesting that adoptively transferred T cells are less effective against growth of extrapulmonary tumors. These results show that costimulation of tumor-draining lymph node T cells through CD28 and 4-1BB increases their potential for cancer immunotherapy and suggests that improper trafficking of tumor-reactive T cells to extrapulmonary sites must be improved to enhance clinical efficacy.
Method to Our Madness or Madness in Our Methods? Pitfalls in Trial Methodology (2012)

In the article that accompanies this editorial, the results of three clinical trials in patients with non–small-cell lung cancer (NSCLC) are reported. An important aim of an editorial can be to evaluate whether the design of the trial and the methods used to analyze the results permit readers to draw definitive conclusions that inform clinical practice or guide the development of future clinical trials. Each of these articles raises important issues about trial methodology that the reader may not have had the time to think about and that could influence the interpretation of the results. Ipilimumab is an exciting new targeted agent which specifically blocks the binding of cytotoxic T-lymphocyte antigen-4 (CTLA-4) to its ligands. This blockade augments T-cell activation leading to tumor regression. Ipilimumab was recently shown to improve survival in patients with advanced melanoma. 1,2 Lynch et al 3 conducted a randomized phase II trial in patients with NSCLC to estimate the additional activity of ipilimumab over chemotherapy alone using immune-related progression-free survival (irPFS) as an outcome measure. The use of a placebo for ipilimumab and the double-blind design strengthened the comparison of carboplatin and paclitaxel plus the immune-targeted agent with chemotherapy alone. Another important objective of the trial was to address the scheduling of ipilimumab and chemotherapy. Two schedules were tested: (1) ipilimumab administered concurrently with chemotherapy (concurrent), and (2) two cycles of chemotherapy followed by four cycles of chemotherapy and ipilimumab together (phased). The authors reported that the phased regimen improved irPFS significantly compared with the control regimen (hazard ratio [HR] 0.72; 95% CI, 0.50 to1.06; P .05), but the concurrent regimen did not (HR 0.81; CI, 0.55 to 1.17,P .13). It is the choice of the optimal regimen that we want to comment on. Not only is the phased regimen active but so is the concurrent one. Note that both HRs are less than 1 and in the Kaplan-Meier plots, the curves for both the phased and concurrent regimens are above that of the chemotherapy control (Fig 2 in publication). A larger sample size could well have resulted in the concurrent approach being significant too. It did not appear that the rules for selecting the optimum schedule were specified a priori. Nonetheless, the conclusion to support further investigation of phased-ipilimumab plus paclitaxel/carboplatin over the concurrent-ipilimumab chemotherapy regimen seems sensible given that the “phased” arm is consistently the best for all the outcome measures, and clearly superior for the progression (PFS) outcomes.
How should imipenem‐cilastatin be Used in the treatment of fever and infection in neutropenic cancer patients? (1998)

BACKGROUND Imipenem-cilastatin (referred to hereafter as imipenem) is administered at different doses as monotherapy or with other agents. Limited comparisons of the alternatives exist. The authors compared the efficacy and safety of several imipenem-containing regimens (ICRs) to determine the appropriate dose and the need for combination therapy. METHODS Between 1985 and 1994, febrile neutropenic patients were given ICRs according to the same methodology on prospective trials at a referral cancer center. The ICRs were high dose imipenem (HIP), high dose imipenem and amikacin (HIPA), high dose imipenem and vancomycin (HIPV), and low dose imipenem and vancomycin (LIPV). RESULTS The overall response rates were comparable (70-77%). There was a univariate trend toward better response among patients with pneumonia and documented infections with unidentified organisms who received HIPV versus LIPV (P = 0.06), as well as a significantly better response among patients with gram positive infections who received HIPV versus HIP (P = 0.02) and HIPA (P = 0.002). HIPV was a more effective treatment for documented infections with identified organisms (P = 0.05) and bloodstream infections (P = 0.04) than HIP; there was a univariate trend toward better response among patients infected with gram negative organisms who received HIPA versus HIP (P = 0.12). Multivariate adjustment for baseline and prognostic factors did not reveal a relative advantage for any regimen. No differences in overall toxicities were observed between HIPV and LIPV. CONCLUSIONS Imipenem monotherapy is adequate treatment for most febrile neutropenic cancer patients. Low dose imipenem could be effective and safe in uncomplicated cases without pneumonia. Further studies are needed to establish the usefulness of low dose imipenem in this context. Cancer 1998;82:2449-2458. © 1998 American Cancer Society.
Simultaneous generation of multi‐gene knockouts in human cells (2016)

Genome-editing techniques enable the generation of gene knockouts in various mammalian cell lines. However, it remains technically challenging to completely disrupt a targeted gene using a canonical method in a timely manner. To improve the efficiency of producing reliable genomic modifications, we designed a method using a linear donor fragment containing a reporter system. Combined with a homologous recombination-independent knock-in strategy, we successfully enriched those cell clones that specifically carry the target gene mutations. We observed a much improved success rate when generating single- and multiple-gene knockouts in a one-step procedure using this special protocol coupled with the CRISPR/Cas9 system. This new approach further empowers the molecular biological study of genes and their functions.
T Cells from Human Allergen-Induced Late Asthmatic Responses Express IL-12 Receptor β2 Subunit mRNA and Respond to IL-12 In Vitro (2000)

IL-12 suppresses proallergic Th2-type cytokine production and induces Th1-type cytokine production by peripheral blood T cells from subjects with allergic disease. The objective of the present study was to examine the relevance of these findings to target organ T cell responses in human asthma. Bronchoalveolar lavage (BAL) and PBMC were collected from atopic asthmatics 24 h after fiberoptic allergen challenge of a segmental bronchus. BAL T cells and PBMC were cultured with allergen in the presence of recombinant IL-12 or IFN-gamma, and cytokines were measured in culture supernatants after 6 days. IL-5 production by BAL T cells and PBMC was inhibited by IL-12 and, to a lesser extent, by IFN-gamma. IL-12 also induced IFN-gamma production by BAL T cells and PBMC. The effects of IL-12 nor IFN-gamma on IL-5 production could not be reversed by neutralizing anti-IFN-gamma or anti-IL-12 mAbs, respectively. Thus, the effect of neither IL-12 nor IFN-gamma appeared to be mediated through induction of the other cytokine. In situ hybridization revealed that approximately one-third of BAL T cells expressed mRNA transcripts encoding the IL-12R beta 2 subunit following allergen challenge. Thus, human T cells obtained from BAL during asthmatic late responses, like T cells in the peripheral circulation, remain susceptible to immunomodulation by IL-12. These findings raise the possibility that IL-12 may hold therapeutic potential in allergic diseases such as asthma.
Hyperhomocyst(e)inemia and Thrombophilia (2002)

Consensus was reached on 9 recommendations concerning the criteria for diagnosis, the method of testing, and the approach for clinical management. A major point of consensus was that no causal role of hyperhomocyst(e)inemia in venous or arterial thrombosis is yet established. Testing methods used to measure homocysteine directly are sensitive and reliable, and provide more information than does genotyping for markers linked to abnormal plasma homocysteine.
Targeting lipid metabolism for the treatment of anaplastic thyroid carcinoma (2015)

This section is used to summarize the current research efforts underway in defining the role of lipid metabolism specifically in thyroid carcinoma. Included is a brief summary of lipid metabolism factors for which inhibitors have been generated and are under current investigation as anti-cancer agents. Finally, research limitations regarding the use of these inhibitors against components of this pathway are discussed.
Tumor necrosis factor α promotes the expression of stem cell factor in synovial fibroblasts and their capacity to induce mast cell chemotaxis (2000)

Our results show that SFB (in RA and OA) express SCF and induce MC chemotaxis. Furthermore, TNFalpha was found to augment SCF expression in SFB. It is hypothesized that these cellular interactions play an important role in MC accumulation and related events in RA.
Myeloid Biomarkers Associated with Glioblastoma Response to Anti-VEGF Therapy with Aflibercept (2011)

These data suggest that decreases in VEGF posttreatment are associated with radiographic response to aflibercept. Elevated baseline chemokines of monocyte lineage in responding patients supports a role for myeloid cells and chemokines as potential biomarkers and regulators of glioma angiogenesis.
Combination suicide and cytokine gene therapy for hepatic metastases of colon carcinoma: sustained antitumor immunity prolongs animal survival. (1996)

The effectiveness of combination therapy using a suicide gene and cytokine genes for the treatment of metastatic colon carcinoma in the mouse liver was investigated. Pre-established hepatic tumors treated with a recombinant adenoviral vector containing the herpes simplex virus thymidine kinase gene(tk) exhibited substantial regression, although all treated animals suffered from subsequent relapses. Although cotreatment with a mouse interleukin 2 (mIL-2)-containing adenoviral vector induced an effective antitumor immune response, the immunity waned with time, and the treated animals eventually succumbed to hepatic tumor relapse or distant metastases. In this study, mouse granulocyte macrophage colony-stimulating factor (mGM-CSF) gene was tested for its ability to further enhance and prolong the antitumoral cellular immunity. A fraction of the animals treated with tk + mIL-2 + mGM-CSF developed long-term antitumor immunity and survived for more than 4 months without recurrence. This long-term antitumor immunity could be enhanced further by subsequent "vaccination" with mIL-2-expressing parental tumor cells. The results indicate that local expression of GM-CSF in the hepatic tumors and prolonged mIL-2 expression are necessary to generate persistent antitumor immunity that is essential for the prevention of tumor recurrence and long-term animal survival.
Identification of Brucella by Ribosomal-Spacer-Region PCR and Differentiation of Brucella canis from Other Brucella spp. Pathogenic for Humans by Carbohydrate Profiles (1998)

Molecular and chemical characteristics often provide complementary information in the differentiation of closely related organisms. The genus Brucella consists of a highly conserved group of organisms. Identification of the four species pathogenic in humans (Brucella melitensis, Brucella abortus, Brucella suis, and Brucella canis) is problematic for many clinical laboratories that depend primarily on serology and phenotypic characteristics to differentiate species. PCR amplification of the 16S-23S ribosomal DNA interspace region was evaluated for species-specific polymorphism. B. abortus, B. melitensis, B. suis, and B. canis produced identical PCR interspace profiles. However, these PCR products were unique to brucellae, allowing them to be readily distinguished from other gram-negative bacteria (including Bartonella spp. and Agrobacterium spp.). Carbohydrate profiles differentiated B. canis from the other three Brucella species due to the absence of the rare amino sugar quinovosamine in the three other species. PCR of the rRNA interspace region is useful in identification of the genus Brucella, while carbohydrate profiling is capable of differentiating B. canis from the other Brucella species.
Isotropic 3D Nanoscopy based on single emitter switching (2008)

We propose and analyze a method for isotropic resolution in far-field fluorescence nanoscopy based on switching and mathematically localizing individual emitters. Under typical imaging conditions, the coherent detection of fluorescence light through two opposing high angle lenses strongly improves the 3D-resolution down to 5-10nm in all directions. Furthermore, we give a detailed analysis of the resolution of this and other single molecule switching based approaches using the Fisher information matrix.We verify the results by Monte-Carlo simulations of the imaging process and by applying a simple maximum-likelihood estimator for position determination.
High‐resolution T1 mapping of the brain at 3T with driven equilibrium single pulse observation of T1 with high‐speed incorporation of RF field inhomogeneities (DESPOT1‐HIFI) (2007)

The described approach, dubbed DESPOT1-HIFI, permits whole-brain T1 mapping at 3T, with 1 mm(3) isotropic voxels, in a clinically feasible time (approximately 10 minutes) with T1 accuracy greater than 5% and with high precision.
Robust segmentation algorithm using LOG edge detector for effective border detection of noisy skin lesions (2011)

Melanoma can be cured if it is detected early, so early diagnosis is very important in dermatological practice today. Early and non-invasive diagnosis of melanomas can be done by accurate image segmentation of skin lesions. The medical images, while acquisition are generally bound to contain noise. This paper proposes a robust and efficient image segmentation algorithm using LOG edge detector to extract the true border of noisy clinical skin images containing lesions, that reveals the global structure irregularity, which may suggest excessive cell growth or regression of a melanoma. The proposed segmentation algorithm is applied to a RGB image containing the lesion, where the RGB image is converted to grayscale intensity image and adds salt and pepper noise to the image and uses background noise reduction techniques to filter noise. The algorithm converts an image to a binary image, based on threshold, and finds the xor image and then finds the edges in this image using log edge detector. The black and white image is used to find the row co-ordinate of the pixel on the border of the object to be traced and the edge detected image is used to find the column co-ordinate of the pixel on the border of the object to be traced and using this pixel found on the border of the object as the starting pixel, the border of the lesion is traced using the proposed robust segmentation algorithm successfully. In this paper, we have developed a robust segmentation method using LOG detector for border detection of real skin lesions for noisy skin lesion images and compared with variational formulation for geometric active contours for detecting, the desired image features, such as object boundaries by Chunming Li et al. The algorithm was applied on many noisy clinical skin images containing lesions. The proposed segmentation algorithm successfully detects the border of noisy clinical skin images.
Role of Chemical Drive in Recruiting Upper Airway and Inspiratory Intercostal Muscles in Patients with Obstructive Sleep Apnea (1993)

Upper airway dilating muscle activity increases during apneic episodes in patients with obstructive sleep apnea (OSA). To elucidate the relative contribution of chemical and nonchemical stimuli to augmentation of the upper airway dilating muscle, we measured the response of genioglossus muscle (GG) and inspiratory intercostal muscle (IIM) activities to obstructive apnea during non-REM sleep and compared them with the response to progressive hypoxia and hypercapnia during awake periods in seven male patients with OSA. GG EMG was measured with a wire electrode inserted percutaneously, and IIM EMG was measured with surface electrodes placed in the second intercostal space parasternally. Responses to hypoxia and to hypercapnia were assessed by rebreathing methods in the supine position while awake. Following these measurements, a sleep study was conducted with the EMG electrodes placed in the same locations. The relationship between GG and IIM activities during the cycle of apnea and postapneic ventilation in non-REM sleep was quasi-linear, and the slope of the regression line was significantly greater than those during progressive hypoxia and progressive hypercapnia. The amplitude of GG activity at 70% of maximum IIM activities in the hypoxic test was 140 +/- 20% (mean +/- SEM) during non-REM sleep, which was also significantly greater than that during hypoxia (51 +/- 10%) and that during hypercapnia (59 +/- 15%). These results suggest that nonchemical factors contribute considerably to augmentation of GG activity during obstructive apneic episodes. The nonchemical stimuli may arise from mechanoreceptors activated by upper airway obstruction and behavioral factors associated with change in sleep states.
Membrane glycoprotein IV (CD36) is physically associated with the Fyn, Lyn, and Yes protein-tyrosine kinases in human platelets. (1991)

Activation of platelets with thrombin and other agonists causes a rapid increase in the phosphorylation of multiple proteins on tyrosine. To identify candidate protein-tyrosine kinases (PTKs; EC 2.7.1.112) that may be responsible for these phosphorylation events, we analyzed the expression of seven Src-family PTKs and examined the association of these kinases with known platelet membrane glycoproteins. Five Src-related PTKs were detected in platelets: pp60SRC, pp60FYN, pp62YES, pp61HCK, and two LYN products of Mr 54,000 and 58,000. The Fgr and Lck PTKs were not detected. Although strict comparative quantification of protein levels was not possible, pp60SRC was detected at higher levels than any of the other kinases. In addition, glycoprotein IV (GPIV, CD36), one of the major platelet membrane glycoproteins, was associated in a complex with the Fyn, Yes, and Lyn proteins in platelet lysates. Similar complexes were also found in two GPIV-expressing cell lines, C32 melanoma cells and HEL cells. Since PTKs appear to be involved in stimulus-response coupling at the plasma membrane, these results suggest that ligand interaction with GPIV may activate signaling pathways that are triggered by tyrosine phosphorylation.
Star Polymers and Nanospheres from Cross-Linkable Diblock Copolymers (1996)

Polystyrene-block-poly(2-cinnamoylethyl methacrylate) (PS-b-PCEMA) formed micelles in THF/cyclohexane or chloroform/cyclohexane mixtures with the PCEMA block as the core. Depending on the relative length of the PS and PCEMA block, star and crewcut micelles were prepared. Upon UV irradiation, the PCEMA block selectively cross-linked to form star polymers and nanospheres from the corresponding star and crewcut micelles. The cross-linked micelles were characterized by solution and solid-state NMR, FTIR, GPC, TEM, and dynamic and static light scattering.