Animals bearing malignant grafts reject normal grafts that express through gene transfer the same antigen.

Breaking the state of immunological unresponsiveness of tumor-bearing individuals to cancer is a prerequisite for active or passive tumor-specific immunotherapy. To study this problem the immunogenic MHC class I antigen, K216 was transfected into a progressor tumor. The transfected tumors were regularly rejected by normal mice but grew progressively in mice bearing nontransfected tumors. In addition, transgenic mice were derived to obtain normal cells and tissues expressing the same K216 gene product. Normal mice rejected K216-positive normal or malignant tissue grafts and generated K216-specific CTL in vitro and in vivo in response to these challenges. In contrast, mice bearing nontransfected tumors, though rejecting K216-positive nonmalignant tissue grafts, did not reject K216-positive tumors nor generate K216-specific CTL in response to K216-positive tumor cells. Mice bearing K216-positive tumors also rejected the nonmalignant K216-positive tissue grafts, but this in vivo response failed to lead to rejection of the simultaneously present tumor graft expressing the same antigen; in fact, immunity had no measurable effect whatsoever on tumor size or incidence and caused no selection for antigen loss variants. Taken together, the present findings suggest that transfer of expression of a target antigen into nonmalignant cells provides a way for obtaining effective stimulation of antigen-specific CTL in tumor-bearing mice, but that additional manipulations will be required to cause immunological rejection of established tumors

Development of a yeast model to study the contribution of vacuolar polyphosphate metabolism to lysine polyphosphorylation

A recently discovered protein post-translational modification, lysine polyphosphorylation (K-PPn), consists of the covalent attachment of inorganic polyphosphate (polyP) to lysine residues. The non-enzymatic nature of K-PPn means that the degree of this modification depends on both polyP abundance and the amino acids surrounding the modified lysine. K-PPn was originally discovered in budding yeast (Saccharomyces cerevisiae), in which polyP anabolism and catabolism are well characterized. However, yeast vacuoles accumulate large amounts of polyP, and upon cell lysis, the release of the vacuolar polyP could non-physiologically cause K-PPn of nuclear and cytosolic targets. Moreover, yeast vacuoles possess two very active endopolyphosphatases, Ppn1 and Ppn2, that could have opposing effects on the extent of K-PPn. Here, we characterized the contribution of vacuolar polyP metabolism to K-PPn of two yeast proteins, Top1 (DNA topoisomerase 1) and Nsr1 (nuclear signal recognition 1). We discovered that whereas Top1-targeting K-PPn is only marginally affected by vacuolar polyP metabolism, Nsr1-targeting K-PPn is highly sensitive to the release of polyP and of endopolyphosphatases from the vacuole. Therefore, to better study K-PPn of cytosolic and nuclear targets, we constructed a yeast strain devoid of vacuolar polyP by targeting the exopolyphosphatase Ppx1 to the vacuole and concomitantly depleting the two endopolyphosphatases (ppn1Δppn2Δ, vt-Ppx1). This strain enabled us to study K-PPn of cytosolic and nuclear targets without the interfering effects of cell lysis on vacuole polyP and of endopolyphosphatases. Furthermore, we also define the fundamental nature of the acidic amino acid residues to the K-PPn target domain

Four Phosphates at One Blow: Access to Pentaphosphorylated Magic Spot Nucleotides and Their Analysis by Capillary Electrophoresis

The complex phosphorylation pattern of natural and modified pentaphosphorylated magic spot nucleotides is generated in a highly efficient way. A cyclic pyrophosphoryl phosphoramidite (cPyPA) reagent is used to introduce four phosphates on nucleosides regioselectively in a one-flask key transformation. The obtained magic spot nucleotides are used to develop a capillary electrophoresis UV detection method, enabling nucleotide assignment in complex bacterial extracts

Uncommon cause for anterior knee pain - Aggressive aneurysmal bone cyst of the patella

A 56-year-old man presented with a two month history of increasing anterior knee pain without previous trauma. As usual we recommended physiotherapy with stretching exercises of the quadriceps muscle. Since symptoms did not improve after 6 weeks MRI was performed. Surprisingly a hyperintense lobulated mass of the patella with small fluid-filled cavities at the inferior pole was revealed. We performed an open biopsy to exclude any malignancy and diagnosed an aneurysmal bone cyst. Further examination with CT scans showed an aggressive behaviour with cortical breakthrough

Non-small cell lung cancer presenting with choroidal metastasis as first sign and showing good response to chemotherapy alone: a case report

<p>Abstract</p> <p>Introduction</p> <p>Metastatic tumors are the most common intra-ocular malignancies and choroid is by far the most common site for intra-ocular malignancies. Multiple foci are usually involved, and bilateral involvement is frequently seen. The primary sites for choroidal metastasis in decreasing order and by gender are: breast, lung, unknown primary, gastrointestinal and pancreas, skin melanoma and other rare sources in females, and lung, unknown primary, gastrointestinal and pancreas, prostate, kidney, skin melanoma and other rare sources in males. Available treatment options are external beam radiotherapy and plaque radiotherapy, while new methods like surgical resection, transpupillary thermotherapy and intravitreal chemotherapy offer promises for the future. The use of chemotherapy alone for choroidal metastases is not widely reported.</p> <p>Case presentation</p> <p>We report the case of a 50-year-old Indian man who had a unilateral solitary lesion in his right eye. He was found to have an adenocarcinoma of the lung with choroidal metastasis as the first presenting sign. There were no findings of metastasis involving his contralateral eye. He was administered chemotherapy based on gemcitabine and carboplatin. He had significant progressive subjective and objective improvement since his first chemotherapy. His current best corrected visual acuity is 20/60 after three cycles of chemotherapy.</p> <p>Conclusions</p> <p>Chemotherapy alone can be used as an effective mode of treatment in patients who have primary tumors that respond to chemotherapy.</p

Association between major surgical admissions and the cognitive trajectory: 19 year follow-up of Whitehall II cohort study

Objective: To quantify the association between major surgery and the age related cognitive trajectory. / Design: Prospective longitudinal cohort study. / Setting: United Kingdom. / Participants: 7532 adults with as many as five cognitive assessments between 1997 and 2016 in the Whitehall II study, with linkage to hospital episode statistics. Exposures of interest included any major hospital admission, defined as requiring more than one overnight stay during follow-up. / Main outcomes measures: The primary outcome was the global cognitive score established from a battery of cognitive tests encompassing reasoning, memory, and phonemic and semantic fluency. Bayesian linear mixed effects models were used to calculate the change in the age related cognitive trajectory after hospital admission. The odds of substantial cognitive decline induced by surgery defined as more than 1.96 standard deviations from a predicted trajectory (based on the first three cognitive waves of data) was also calculated. / Results: After accounting for the age related cognitive trajectory, major surgery was associated with a small additional cognitive decline, equivalent on average to less than five months of aging (95% credible interval 0.01 to 0.73 years). In comparison, admissions for medical conditions and stroke were associated with 1.4 (1.0 to 1.8) and 13 (9.6 to 16) years of aging, respectively. Substantial cognitive decline occurred in 2.5% of participants with no admissions, 5.5% of surgical admissions, and 12.7% of medical admissions. Compared with participants with no major hospital admissions, those with surgical or medical events were more likely to have substantial decline from their predicted trajectory (surgical admissions odds ratio 2.3, 95% credible interval 1.4 to 3.9; medical admissions 6.2, 3.4 to 11.0). / Conclusions: Major surgery is associated with a small, long term change in the average cognitive trajectory that is less profound than for major medical admissions. The odds of substantial cognitive decline after surgery was about doubled, though lower than for medical admissions. During informed consent, this information should be weighed against the potential health benefits of surgery

Association between major surgical admissions and the cognitive trajectory: 19 year follow-up of Whitehall II cohort study

OBJECTIVE: To quantify the association between major surgery and the age related cognitive trajectory. // DESIGN: Prospective longitudinal cohort study. // SETTING: United Kingdom. // PARTICIPANTS: 7532 adults with as many as five cognitive assessments between 1997 and 2016 in the Whitehall II study, with linkage to hospital episode statistics. Exposures of interest included any major hospital admission, defined as requiring more than one overnight stay during follow-up. // MAIN OUTCOMES MEASURES: The primary outcome was the global cognitive score established from a battery of cognitive tests encompassing reasoning, memory, and phonemic and semantic fluency. Bayesian linear mixed effects models were used to calculate the change in the age related cognitive trajectory after hospital admission. The odds of substantial cognitive decline induced by surgery defined as more than 1.96 standard deviations from a predicted trajectory (based on the first three cognitive waves of data) was also calculated. // RESULTS: After accounting for the age related cognitive trajectory, major surgery was associated with a small additional cognitive decline, equivalent on average to less than five months of aging (95% credible interval 0.01 to 0.73 years). In comparison, admissions for medical conditions and stroke were associated with 1.4 (1.0 to 1.8) and 13 (9.6 to 16) years of aging, respectively. Substantial cognitive decline occurred in 2.5% of participants with no admissions, 5.5% of surgical admissions, and 12.7% of medical admissions. Compared with participants with no major hospital admissions, those with surgical or medical events were more likely to have substantial decline from their predicted trajectory (surgical admissions odds ratio 2.3, 95% credible interval 1.4 to 3.9; medical admissions 6.2, 3.4 to 11.0). // CONCLUSIONS: Major surgery is associated with a small, long term change in the average cognitive trajectory that is less profound than for major medical admissions. The odds of substantial cognitive decline after surgery was about doubled, though lower than for medical admissions. During informed consent, this information should be weighed against the potential health benefits of surgery

Factors Associated with Participation in a Multidomain Web-Based Dementia Prevention Trial: Evidence from Maintain Your Brain (MYB)

Background: The Maintain Your Brain (MYB) trial aims to prevent cognitive decline and dementia through multidomain, web-based risk-reduction. To facilitate translation, it is important to understand drivers of participation. Objective: To describe characteristics associated with participation in MYB. Methods: This was an observational ancillary study of MYB, a randomized controlled trial nested within the 45 and Up Study in New South Wales, Australia. We linked 45 and Up Study survey and MYB participation data. The study cohort comprised 45 and Up Study participants, aged 55-77 years at 1 January 2018, who were invited to participate in MYB. 45 and Up Study participant characteristics and subsequent MYB consent and participation were examined. Results: Of 98,836 invited, 13,882 (14%) consented to participate and 6,190 participated (6%). Adjusting for age and sex, a wide range of factors were related to participation. Higher educational attainment had the strongest relationship with increased MYB participation (university versus school non-completion; AdjOR = 5.15; 95% CI:4.70-5.64) and lower self-rated quality of life with reduced participation (Poor versus Excellent: AdjOR = 0.19; 95% CI:0.11-0.32). A family history of Alzheimer's disease was related to increased participation but most other dementia risk factors such as diabetes, obesity, stroke, high blood pressure, and current smoking were associated with reduced participation. Conclusion: Higher socio-economic status, particularly educational attainment, is strongly associated with engagement in online dementia prevention research. Increasing population awareness of dementia risk factors, and better understanding the participation barriers in at-risk groups, is necessary to ensure online interventions are optimally designed to promote maximum participation

Nonlinear damping in mechanical resonators based on graphene and carbon nanotubes

Carbon nanotubes and graphene allow fabricating outstanding nanomechanical resonators. They hold promise for various scientific and technological applications, including sensing of mass, force, and charge, as well as the study of quantum phenomena at the mesoscopic scale. Here, we have discovered that the dynamics of nanotube and graphene resonators is in fact highly exotic. We propose an unprecedented scenario where mechanical dissipation is entirely determined by nonlinear damping. As a striking consequence, the quality factor Q strongly depends on the amplitude of the motion. This scenario is radically different from that of other resonators, whose dissipation is dominated by a linear damping term. We believe that the difference stems from the reduced dimensionality of carbon nanotubes and graphene. Besides, we exploit the nonlinear nature of the damping to improve the figure of merit of nanotube/graphene resonators.Comment: main text with 4 figures, supplementary informatio

The secreted triose phosphate isomerase of Brugia malayi is required to sustain microfilaria production in vivo

Human lymphatic filariasis is a major tropical disease transmitted through mosquito vectors which take up microfilarial larvae from the blood of infected subjects. Microfilariae are produced by long-lived adult parasites, which also release a suite of excretory-secretory products that have recently been subject to in-depth proteomic analysis. Surprisingly, the most abundant secreted protein of adult Brugia malayi is triose phosphate isomerase (TPI), a glycolytic enzyme usually associated with the cytosol. We now show that while TPI is a prominent target of the antibody response to infection, there is little antibody-mediated inhibition of catalytic activity by polyclonal sera. We generated a panel of twenty-three anti-TPI monoclonal antibodies and found only two were able to block TPI enzymatic activity. Immunisation of jirds with B. malayi TPI, or mice with the homologous protein from the rodent filaria Litomosoides sigmodontis, failed to induce neutralising antibodies or protective immunity. In contrast, passive transfer of neutralising monoclonal antibody to mice prior to implantation with adult B. malayi resulted in 60–70% reductions in microfilarial levels in vivo and both oocyte and microfilarial production by individual adult females. The loss of fecundity was accompanied by reduced IFNγ expression by CD4+ T cells and a higher proportion of macrophages at the site of infection. Thus, enzymatically active TPI plays an important role in the transmission cycle of B. malayi filarial parasites and is identified as a potential target for immunological and pharmacological intervention against filarial infections