Toxicity to immune checkpoint inhibitors presenting as pulmonary arterial vasculopathy and rapidly progressing right ventricular dysfunction

Introduction: Immune Checkpoint Inhibitors (ICIs) are antitumor drugs associated with a number of serious immune-related adverse events (IRAEs). ICIs enhance anti-tumor immunity, thereby  energized  patient's immune system to fight cancer. IRAEs may affect functions of various organs, including heart, and may lead to morbidity and, to some  extent  mortality. Left ventricle (LV) myocarditis with dysfunction is a known side effect of this class of drugs. However, right ventricle (RV) myocarditis and pulmonary vasculitis are an unknown entity and has not been previously reported.  Here, we present the first case of  IRAEs causing selective RV involvement with dysfunctions, attributed to immune checkpoint inhibitors described till date in medical literature.Presentation of Case: A 58-year male presented  with history of low-grade fever and  weight loss. On palpation, he had diffuse cervical lymphadenopathy. Histopathology evaluation of  lymph node revealed  metastatic lesions of Renal Cell Carcinoma (RCC).Conclusion: Fatal cardiovascular adverse events can occur as a side effect of ICI. The combination of RV myocarditis with progressive pulmonary hypertension is fatal. Treatment with high dose corticosteroids and immunomodulators may help in patient survival. Physicians treating patients with ICIs should be aware of their lethal cardiotoxic side effects  to reduce adverse cardiac outcomes. Because the number of patients exposed to this new immune therapy is expected to increase remarkably in the near future, our study encourages further work to define guidelines for cardiovascular monitoring and management

Inert gas clearance from tissue by co-currently and counter-currently arranged microvessels

To elucidate the clearance of dissolved inert gas from tissues, we have developed numerical models of gas transport in a cylindrical block of tissue supplied by one or two capillaries. With two capillaries, attention is given to the effects of co-current and counter-current flow on tissue gas clearance. Clearance by counter-current flow is compared with clearance by a single capillary or by two co-currently arranged capillaries. Effects of the blood velocity, solubility, and diffusivity of the gas in the tissue are investigated using parameters with physiological values. It is found that under the conditions investigated, almost identical clearances are achieved by a single capillary as by a co-current pair when the total flow per tissue volume in each unit is the same (i.e., flow velocity in the single capillary is twice that in each co-current vessel). For both co-current and counter-current arrangements, approximate linear relations exist between the tissue gas clearance rate and tissue blood perfusion rate. However, the counter-current arrangement of capillaries results in less-efficient clearance of the inert gas from tissues. Furthermore, this difference in efficiency increases at higher blood flow rates. At a given blood flow, the simple conduction-capacitance model, which has been used to estimate tissue blood perfusion rate from inert gas clearance, underestimates gas clearance rates predicted by the numerical models for single vessel or for two vessels with co-current flow. This difference is accounted for in discussion, which also considers the choice of parameters and possible effects of microvascular architecture on the interpretation of tissue inert gas clearance

Simultaneous TE Analysis of 19 Heliconiine Butterflies Yields Novel Insights into Rapid TE-Based Genome Diversification and Multiple SINE Births and Deaths

Transposable elements (TEs) play major roles in the evolution of genome structure and function. However, because of their repetitive nature, they are difficult to annotate and discovering the specific roles they may play in a lineage can be a daunting task. Heliconiine butterflies are models for the study of multiple evolutionary processes including phenotype evolution and hybridization. We attempted to determine how TEs may play a role in the diversification of genomes within this clade by performing a detailed examination of TE content and accumulation in 19 species whose genomes were recently sequenced. We found that TE content has diverged substantially and rapidly in the time since several subclades shared a common ancestor with each lineage harboring a unique TE repertoire. Several novel SINE lineages have been established that are restricted to a subset of species. Furthermore, the previously described SINE, Metulj, appears to have gone extinct in two subclades while expanding to significant numbers in others. This diversity in TE content and activity has the potential to impact how heliconiine butterflies continue to evolve and diverge

Spontaneous bacterial peritonitis from Salmonella: an unusual bacterium with unusual presentation

Spontaneous bacterial peritonitis (SBP) is a common cause of morbidity and mortality in patients with advanced cirrhosis and portal hypertension. While gram-negative rods and Enterococcus species are the common offending organisms, Salmonella has also been recognized as a rare and atypical offending organism. Atypical features of Salmonella SBP include both its occurrence in cirrhotic patients with immunosuppressive state and its lack of typical neutroascitic response. Diagnosis is often delayed as it requires confirmation from ascitic fluid culture. We report a case of Salmonella SBP occurring in a patient with decompensated cryptogenic cirrhosis with concurrent low-grade non-Hodgkin lymphoma and prior treatment with rituximab. Physicians should be aware of the atypical presentation, especially in cirrhotic patients who are immunosuppressed

Polycation-π Interactions Are a Driving Force for Molecular Recognition by an Intrinsically Disordered Oncoprotein Family

Molecular recognition by intrinsically disordered proteins (IDPs) commonly involves specific localized contacts and target-induced disorder to order transitions. However, some IDPs remain disordered in the bound state, a phenomenon coined "fuzziness", often characterized by IDP polyvalency, sequence-insensitivity and a dynamic ensemble of disordered bound-state conformations. Besides the above general features, specific biophysical models for fuzzy interactions are mostly lacking. The transcriptional activation domain of the Ewing's Sarcoma oncoprotein family (EAD) is an IDP that exhibits many features of fuzziness, with multiple EAD aromatic side chains driving molecular recognition. Considering the prevalent role of cation-π interactions at various protein-protein interfaces, we hypothesized that EAD-target binding involves polycation- π contacts between a disordered EAD and basic residues on the target. Herein we evaluated the polycation-π hypothesis via functional and theoretical interrogation of EAD variants. The experimental effects of a range of EAD sequence variations, including aromatic number, aromatic density and charge perturbations, all support the cation-π model. Moreover, the activity trends observed are well captured by a coarse-grained EAD chain model and a corresponding analytical model based on interaction between EAD aromatics and surface cations of a generic globular target. EAD-target binding, in the context of pathological Ewing's Sarcoma oncoproteins, is thus seen to be driven by a balance between EAD conformational entropy and favorable EAD-target cation-π contacts. Such a highly versatile mode of molecular recognition offers a general conceptual framework for promiscuous target recognition by polyvalent IDPs. © 2013 Song et al

Effects of Chloride ions on Carbonation Rate of Hardened Cement Paste by X-ray CT Techniques

Corrosion of steel bars in concrete structures is initiated as a result of concrete carbonation and/or chloride intrusion, and influenced by their interaction. This paper presents an experimental investigation into the effect of chloride ions on carbonation of cement paste by means of X-ray CT techniques and mercury intrusion porosimetry(MIP), which is benchmarked by the conventional phenolphthalein method. A group of the cement paste cylinders with different amounts of chlorides ions were manufactured and cured before they were subjected to an accelerated carbonation process in a conditional cabinet regime for different ages. The carbonation front of the cement paste was first evaluated using phenolphthalein method. This was followed by an investigation of microstructure evolution of the cement paste using XCT and MIP techniques. The experimental results show that the carbonation of a cement paste increases with its water to cement ratio and with carbonation ages, but decrease with its amount of chloride ions. In particular, it has been found that increases of chloride ion of a cement paste refine its porous structures, decrease its porosity and eventually mitigate its carbonation rate. The relevant results can be referred to for durability design and prediction of reinforced concrete structures

Dominant features in three-dimensional turbulence structure: comparison of non-uniform accelerating and decelerating flows

The results are presented from an experimental study to investigate three-dimensional turbulence structure profiles, including turbulence intensity and Reynolds stress, of different non-uniform open channel flows over smooth bed in subcritical flow regime. In the analysis, the uniform flow profiles have been used to compare with those of the non-uniform flows to investigate their time-averaged spatial flow turbulence structure characteristics. The measured non-uniform velocity profiles are used to verify the von Karman constant κ and to estimate sets of log-law integration constant B r and wake parameter П, where their findings are also compared with values from previous studies. From κ, B r and П findings, it has been found that the log-wake law can sufficiently represent the non-uniform flow in its non-modified form, and all κ, B r and П follow universal rules for different bed roughness conditions. The non-uniform flow experiments also show that both the turbulence intensity and Reynolds stress are governed well by exponential pressure gradient parameter β equations. Their exponential constants are described by quadratic functions in the investigated β range. Through this experimental study, it has been observed that the decelerating flow shows higher empirical constants, in both the turbulence intensity and Reynolds stress compared to the accelerating flow. The decelerating flow also has stronger dominance to determine the flow non-uniformity, because it presents higher Reynolds stress profile than uniform flow, whereas the accelerating flow does not

The impact of point mutations in the human androgen receptor : classification of mutations on the basis of transcriptional activity

Peer reviewedPublisher PD