A Current Review of Targeted Therapeutics for Ovarian Cancer

Difficult to detect, ovarian cancer typically presents at an advanced stage. Significant progress has been achieved in the treatment of ovarian cancer with therapeutics focused on DNA replication or cell division. However, despite sensitivity to induction chemotherapy the majority of patients will develop recurrent disease. Conventional agents for recurrent disease offer little in terms of long-term responses. Various targeted therapeutics have been explored in the management of ovarian cancer. These include monoclonal antibodies to epidermal growth factor receptors, small molecule tyrosine kinase inhibitors, monoclonal antibodies directed at the vascular endothelial growth factor (bevacizumab), and the small tyrosine kinase inhibitors that target the vascular endothelial growth factor receptor. Recently, several other agents have come forth as potential therapeutic agents in the management of ovarian cancer. These include monoclonal antibodies to the folate receptor, triple angiokinase inhibitors, PARP inhibitors, aurora kinase inhibitors, inhibitors of the Hedgehog pathway, folate receptor antagonists, and MTOR inhibitors

A retrospective cohort study of factors associated with severity of falls in hospital patients

Severity of falls in hospital patients are threat to patient safety which can result in a financial burden on the patient’s family and health care services. Both patient specific and environmental and organisational factors are associated with severity of falls in hospital. It is important to continuously analyse the factors associated with severity of fall which can inform the implementation of any fall preventive strategies. This study aims to identify factors associated with the severity of falls in hospitalised adult patients in Western Australia. This study involved a retrospective cohort analysis of inpatient falls records extracted from the hospital’s Clinical Incident Database from May 2014 to April 2019. Severity of falls were classified as three Severity Assessment Code (SAC): SAC 1 was “high” causing serious harm or death; SAC 2 was “medium” causing moderate or minor harm; and SAC 3 was “low” indicating no harm. Univariable and multivariable generalised ordinal logistic regression models were used to quantify the magnitude of effects of the potential risk factors on severity of falls at 5 % level of significance and reported the crude odds and adjusted odds ratio of falling at a higher severity level. There were 3705 complete reported cases of falls with the average age of the patients was 68.5 ± 17.0 years, with 40.2 % identified as female. The risk of falling at a higher level of severity increased by patient age over 50 years. Females were 15.1 % more likely to fall at higher severity level compared to females. Fall incidents occurred during toileting and showering activities and incidents in a communal area were 14.5 % and 26 % more likely to occur at a higher severity respectively. Similarly, depression (167 %), influence of alcohol or illicit drugs (more than 300 %), use of medications (86 %) and fragile skin (75 %) significantly increased the odds of falling at higher level of severity. Identification of underlying risk factors associated with fall severity provides information which can guide nurses and clinicians to design and implement effective interventional strategies that mitigate the risk of serious fall injuries. The results suggest that fall prevention strategies should target patients with these risk factors to avoid severity of falls

Charting the evolutionary path of the SUMO modification system in plants reveals molecular hardwiring of development to stress adaptation

SUMO modification is part of the spectrum of Ubiquitin-like (UBL) systems that give rise to proteoform complexity through post-translational modifications (PTMs). Proteoforms are essential modifiers of cell signaling for plant adaptation to changing environments. Exploration of the evolutionary emergence of Ubiquitin-like (UBL) systems unveils their origin from prokaryotes where it is linked to the mechanisms that enable sulfur uptake into biomolecules. We explore the emergence of the SUMO machinery across the plant lineage from single-cell to land plants. We reveal the evolutionary point at which plants acquired the ability to form SUMO chains through the emergence of SUMO E4 ligases hinting at its role in facilitating multicellularity. Additionally, we explore the possible mechanism for the neofunctionalization of SUMO proteases through the fusion of conserved catalytic domains with divergent sequences. We highlight the pivotal role of SUMO proteases in plant development and adaptation, offering new insights into target specificity mechanisms of SUMO modification during plant evolution. Correlating the emergence of adaptive traits in the plant lineage with established experimental evidence for SUMO in developmental processes we propose that SUMO modification has evolved to link developmental processes to adaptive functions in land plants

Deletion of the autoregulatory insert modulates intraprotein electron transfer in rat neuronal nitric oxide synthase

AbstractComparative CO photolysis kinetics studies on wild-type and autoregulatory (AR) insert-deletion mutant of rat nNOS holoenzyme were conducted to directly investigate the role of the unique AR insert in the catalytically significant FMN–heme intraprotein electron transfer (IET). Although the amplitude of the IET kinetic traces was decreased two- to three-fold, the AR deletion did not change the rate constant for the calmodulin-controlled IET. This suggests that the rate-limiting conversion of the electron-accepting state to a new electron-donating (output) state does not involve interactions with the AR insert, but that AR may stabilize the output state once it is formed

Sub-picosecond injection of electrons from excited [Ru(2,2′-bipy-4,4′-dicarboxy)₂(SCN)₂] into TiO₂ using transient mid-infrared spectroscopy

We have used femtosecond pump-probe spectroscopy to time resolve the injection of electrons into nanocrystalline TiO2 film electodes under ambient conditions following photoexcitation of the adsorbed dye, [Ru(4,4’-dicarboxy-2,2’-bipyridine)2(NCS)2] (N3). Pumping at one of the metal-to-ligand charge transfer adsorption peaks and probing the absorption of electrons injected into the TiO2 conduction band at 1.52 µm and in the range of 4.1 to 7.0 µm, we have directly observed the arrival of the injected electrons. Our measurements indicate an instrument-limited ~50-fs upper limit on the electron injection time under ambient conditions in air. We have compared the infrared transient absorption for noninjecting (blank) systems consisting of N3 in ethanol and N3 adsorbed to films of nanocrystalline Al2O3 and ZrO2, and found no indication of electron injection at probe wavelengths in the mid-IR (4.1 to 7.0 µm). At 1.52 µm interferences exist in the observed transient adsorption signal for the blanks

Elevated serum homocysteine levels have differential gender-specific associations with motor and cognitive states in Parkinson’s disease

Background: Studies attempting to elucidate an association between homocysteine and symptom progression in Parkinson’s disease (PD) have had largely discrepant findings. This study aimed to investigate elevated serum homocysteine levels and symptom progression in a cohort of PD patients. Methods: Serum homocysteine, folate, and vitamin B12 levels were measured in 205 people with PD and 78 age-matched healthy controls. People with Parkinson’s disease underwent a battery of clinical assessments to evaluate symptom severity, including motor (MDS-UPDRS) and cognitive (ACE-R) assessments. Multivariate generalized linear models were created, controlling for confounding variables, and were used to determine whether serum markers are associated with various symptom outcome measures. Results; People with Parkinson’s disease displayed significantly elevated homocysteine levels (p\u3c0.001), but not folate or vitamin B12 levels, when compared to healthy controls. A significant positive correlation between homocysteine and MDS-UPDRS III score was identified in males with Parkinson’s disease (rs=0.319, p\u3c0.001), but not in females, whereas a significant negative correlation between homocysteine levels and total ACE-R score was observed in females with Parkinson’s disease (rs=−0.449, p\u3c0.001), but not in males. Multivariate general linear models confirmed that homocysteine was significantly predictive of MDS-UPDRSIII score in male patients (p = 0.004) and predictive of total ACE-R score in female patients (p = 0.021). Conclusion: Elevated serum homocysteine levels are associated with a greater motor impairment in males with Parkinson’s disease and poorer cognitive performance in females with Parkinson’s disease. Our gender specific findings may help to explain previous discrepancies in the literature surrounding the utility of homocysteine as a biomarker in PD

Uveitis-mediated immune cell invasion through the extracellular matrix of the lens capsule

While the eye is considered an immune privileged site, its privilege is abrogated when immune cells are recruited from the surrounding vasculature in response to trauma, infection, aging, and autoimmune diseases like uveitis. Here, we investigate whether in uveitis immune cells become associated with the lens capsule and compromise its privilege in studies of C57BL/6J mice with experimental autoimmune uveitis. These studies show that at D14, the peak of uveitis in these mice, T cells, macrophages, and Ly6G/Ly6C+ immune cells associate with the lens basement membrane capsule, burrow into the capsule matrix, and remain integrated with the capsule as immune resolution is occurring at D26. 3D surface rendering image analytics of confocal z-stacks and scanning electron microscopy imaging of the lens surface show the degradation of the lens capsule as these lens-associated immune cells integrate with and invade the lens capsule, with a subset infiltrating both epithelial and fiber cell regions of lens tissue, abrogating its immune privilege. Those immune cells that remain on the surface often become entwined with a fibrillar net-like structure. Immune cell invasion of the lens capsule in uveitis has not been described previously and may play a role in induction of lens and other eye pathologies associated with autoimmunity

Uveitis-mediated immune cell invasion through the extracellular matrix of the lens capsule.

While the eye is considered an immune privileged site, its privilege is abrogated when immune cells are recruited from the surrounding vasculature in response to trauma, infection, aging, and autoimmune diseases like uveitis. Here, we investigate whether in uveitis immune cells become associated with the lens capsule and compromise its privilege in studies of C57BL/6J mice with experimental autoimmune uveitis. These studies show that at D14, the peak of uveitis in these mice, T cells, macrophages, and Ly6G/Ly6C+ immune cells associate with the lens basement membrane capsule, burrow into the capsule matrix, and remain integrated with the capsule as immune resolution is occurring at D26. 3D surface rendering image analytics of confocal z-stacks and scanning electron microscopy imaging of the lens surface show the degradation of the lens capsule as these lens-associated immune cells integrate with and invade the lens capsule, with a subset infiltrating both epithelial and fiber cell regions of lens tissue, abrogating its immune privilege. Those immune cells that remain on the surface often become entwined with a fibrillar net-like structure. Immune cell invasion of the lens capsule in uveitis has not been described previously and may play a role in induction of lens and other eye pathologies associated with autoimmunity