Theranostic applications of peptide-based nanoformulations for growth factor defective cancers.

Growth factors play a pivotal role in orchestrating cellular growth and division by binding to specific cell surface receptors. Dysregulation of growth factor production or activity can contribute to the uncontrolled cell proliferation observed in cancer. Peptide-based nanoformulations (PNFs) have emerged as promising therapeutic strategies for growth factor-deficient cancers. PNFs offer multifaceted capabilities including targeted delivery, imaging modalities, combination therapies, resistance modulation, and personalized medicine approaches. Nevertheless, several challenges remain, including limited specificity, stability, pharmacokinetics, tissue penetration, toxicity, and immunogenicity. To address these challenges and optimize PNFs for clinical translation, in-depth investigations are warranted. Future research should focus on elucidating the intricate interplay between peptides and nanoparticles, developing robust spectroscopic and computational methodologies, and establishing a comprehensive understanding of the structure-activity relationship governing peptide-nanoparticle interactions. Bridging these knowledge gaps will propel the translation of peptide-nanoparticle therapies from bench to bedside. While a few peptide-nanoparticle drugs have obtained FDA approval for cancer treatment, the integration of nanostructured platforms with peptide-based medications holds tremendous potential to expedite the implementation of innovative anticancer interventions. Therefore, growth factor-deficient cancers present both challenges and opportunities for targeted therapeutic interventions, with peptide-based nanoformulations positioned as a promising avenue. Nonetheless, concerted research and development endeavors are essential to optimize the specificity, stability, and safety profiles of PNFs, thereby advancing the field of peptide-based nanotherapeutics in the realm of oncology research.

Association of Systemic Lupus International Collaborating Clinics Frailty Index With Damage in Systemic Lupus Erythematosus Patients: Results From a Multiethnic, Multicenter US Cohort of Patients With Lupus.

OBJECTIVE: To evaluate the association between the Systemic Lupus International Collaborating Clinics frailty index (SLICC-FI) and damage accrual in systemic lupus erythematosus (SLE) patients. METHODS: Patients from the multiethnic, multicenter LUpus in MInorities, NAture versus nurture (LUMINA) cohort were included. Damage was ascertained with the SLICC/American College of Rheumatology Damage Index (SDI) at last visit (range 0-51). The first visit in which the SLICC-FI score could be derived was considered as the baseline (range 0-1). Univariable and multivariable negative binomial regression models were performed to determine the association between the baseline SLICC-FI score (per 0.05 increase) and the change in the SDI score (difference between last and baseline SDI score), adjusted for sex, age at diagnosis, ethnicity, insurance, prednisone daily dose, and antimalarial and immunosuppressive drug use at baseline. Age and sex were included a priori in the multivariable model; the other variables were included if they reached P < 0.10 in the univariable models. RESULTS: Of the 503 patients included, 454 (90.3%) were female, with a mean ± SD age of 37.1 ± 12.5 years at diagnosis. The mean ± SD baseline SLICC-FI score was 0.26 ± 0.06. The mean ± SD baseline SDI score was 0.6 ± 1.0, and the mean ± SD change in the SDI score was 1.9 ± 2.2. Higher SLICC-FI scores at baseline (per 0.05 increase) were associated with greater damage accrual in the multivariable model after adjustment for possible confounders (incidence rate ratio 1.20 [95% confidence interval 1.08-1.33], P = 0.0015). CONCLUSION: The SLICC-FI is associated with damage accrual in SLE patients from a multiethnic cohort, supporting the importance of this index in the evaluation of SLE patients, combining several aspects of their disease.

A Simple Microfluidic Chip for Long-Term Growth and Imaging of Caenorhabditis elegans.

Caenorhabditis elegans (C. elegans) have proved to be a valuable model system for studying developmental and cell biological processes. Understanding these biological processes often requires long-term and repeated imaging of the same animal. Long recovery times associated with conventional immobilization methods done on agar pads have detrimental effects on animal health making it inappropriate to repeatedly image the same animal over long periods of time. This paper describes a microfluidic chip design, fabrication method, on-chip C. elegans culturing protocol, and three examples of long-term imaging to study developmental processes in individual animals. The chip, fabricated with polydimethylsiloxane and bonded on a cover glass, immobilizes animals on a glass substrate using an elastomeric membrane that is deflected using nitrogen gas. Complete immobilization of C. elegans enables robust time-lapse imaging of cellular and sub-cellular events in an anesthetic-free manner. A channel geometry with a large cross-section allows the animal to move freely within two partially sealed isolation membranes permitting growth in the channel with a continuous food supply. Using this simple chip, imaging of developmental phenomena such as neuronal process growth, vulval development, and dendritic arborization in the PVD sensory neurons, as the animal grows inside the channel, can be performed. The long-term growth and imaging chip operates with a single pressure line, no external valves, inexpensive fluidic consumables, and utilizes standard worm handling protocols that can easily be adapted by other laboratories using C. elegans.

Tracking Mitochondrial Density and Positioning along a Growing Neuronal Process in Individual C. elegans Neuron Using a Long-Term Growth and Imaging Microfluidic Device.

The long cellular architecture of neurons requires regulation in part through transport and anchoring events to distribute intracellular organelles. During development, cellular and subcellular events such as organelle additions and their recruitment at specific sites on the growing axons occur over different time scales and often show interanimal variability thus making it difficult to identify specific phenomena in population averages. To measure the variability in subcellular events such as organelle positions, we developed a microfluidic device to feed and immobilize Caenorhabditis elegans for high-resolution imaging over several days. The microfluidic device enabled long-term imaging of individual animals and allowed us to investigate organelle density using mitochondria as a testbed in a growing neuronal process in vivo Subcellular imaging of an individual neuron in multiple animals, over 36 h in our microfluidic device, shows the addition of new mitochondria along the neuronal process and an increase in the accumulation of synaptic vesicles (SVs) at synapses. Long-term imaging of individual C. elegans touch receptor neurons (TRNs) shows that the addition of new mitochondria takes place along the entire neuronal process length at a rate of ∼0.6 mitochondria/h. The threshold for the addition of a new mitochondrion occurs when the average separation between the two preexisting mitochondria exceeds 24 µm. Our assay provides a new opportunity to move beyond simple observations obtained from in vitro assays to allow the discovery of genes that regulate positioning of mitochondria in neurons.

Application of systane complete for the treatment of contact lens discomfort.

PURPOSE: To understand the safety of treating contact lens (CL) discomfort with a new artificial tear when it is directly applied to a CL-wearing eye. METHODS: This was a two-week, two-visit, double-masked study that randomized participants with CL discomfort to use Systane Complete (artificial tear), Sensitive Eyes (rewetting drop), or no treatment. Drops were applied before, twice during, and after CL use each day. Corneal staining served as the primary safety metric. Conjunctival staining, tear break-up time, Schirmer's test, CL comfort (Contact Lens Dry Eye Questionnaire-8 [CLDEQ-8]), and dry eye symptoms (Standardized Patient Evaluation of Eye Dryness [SPEED]) were also evaluated. RESULTS: This study recruited 73 participants with a mean age of 30.3 ± 11.5 years; 18 % of the participants were male. There were no significant changes in ocular surface signs from baseline or between the artificial tear and rewetting drop groups after two weeks (p ≥ 0.05). Participants in the artificial tear and rewetting drop groups had significant improvements in CLDEQ-8 scores after two weeks of treatment compared with baseline (p < 0.0001), though scores for this test were not significantly different between these groups after two weeks (p = 0.94). CLDEQ-8 scores were significantly better in the artificial tear and rewetting drop groups compared with no treatment after two weeks (p < 0.0001). CONCLUSIONS: Both drops were found to be safe for use with CLs while also significantly improving ocular symptoms compared to no treatment after two weeks of use.

Tropical Milky White Mushroom, Calocybe indica (Agaricomycetes): An Effective Antimicrobial Agent Working in Synergism with Standard Antibiotics.

Synergistic effect of mushroom extracts with standard antibiotics against pathogenic bacteria is beneficial for treating infectious diseases. The present investigation tested the antibacterial activity and synergistic effect from an edible mushroom, Calocybe indica, with standard antibiotics. The minimum inhibitory concentration (MIC) of different extracts from C. indica was checked against pathogenic and opportunistic pathogenic bacteria such as Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus, S. epidermidis, and Bacillus subtilis using the broth dilution and agar well diffusion method. The agar disc diffusion method, checkerboard study, and growth curve analysis were used to test synergism. The preliminary mechanism of action regarding cellular morphology, membrane permeability, and damage to protein and DNA were evaluated. Maximum antimicrobial activity was found in the methanolic crude extract (MCE) from C. indica, with a MIC value ranging from 5 to 10 mg/mL. It showed a significant increase in the efficiency of ciprofloxacin (CIP) acting synergistically. The fractional inhibitory concentration index (FICI) of MCE was significant for E. coli and S. aureus with values of 0.46 and 0.45 respectively. Results showed an increase in the loss of cell viability, damage to cell membrane permeability, and damage to bacterial protein and DNA as the probable synergistic mechanism of action for the MCE and the antibiotic. HR-LCMS analysis of the MCE showed the presence of phenolic acid, terpenoids, fatty acid ester, and carboxylic acid, which, in combination, increased the bacterial susceptibility. The present study is significant because it considered the methanolic crude extract from C. indica as complementary medicine for infectious diseases.

Corrigendum: Neurodegeneration and microtubule dynamics: death by a thousand cuts.

[This corrects the article on p. 343 in vol. 9, PMID: 26441521.].

RAB-6.1 and RAB-6.2 Promote Retrograde Transport in C. elegans.

Retrograde transport is a critical mechanism for recycling certain membrane cargo. Following endocytosis from the plasma membrane, retrograde cargo is moved from early endosomes to Golgi followed by transport (recycling) back to the plasma membrane. The complete molecular and cellular mechanisms of retrograde transport remain unclear. The small GTPase RAB-6.2 mediates the retrograde recycling of the AMPA-type glutamate receptor (AMPAR) subunit GLR-1 in C. elegans neurons. Here we show that RAB-6.2 and a close paralog, RAB-6.1, together regulate retrograde transport in both neurons and non-neuronal tissue. Mutants for rab-6.1 or rab-6.2 fail to recycle GLR-1 receptors, resulting in GLR-1 turnover and behavioral defects indicative of diminished GLR-1 function. Loss of both rab-6.1 and rab-6.2 results in an additive effect on GLR-1 retrograde recycling, indicating that these two C. elegans Rab6 isoforms have overlapping functions. MIG-14 (Wntless) protein, which undergoes retrograde recycling, undergoes a similar degradation in intestinal epithelia in both rab-6.1 and rab-6.2 mutants, suggesting a broader role for these proteins in retrograde transport. Surprisingly, MIG-14 is localized to separate, spatially segregated endosomal compartments in rab-6.1 mutants compared to rab-6.2 mutants. Our results indicate that RAB-6.1 and RAB-6.2 have partially redundant functions in overall retrograde transport, but also have their own unique cellular- and subcellular functions.

Neurodegeneration and microtubule dynamics: death by a thousand cuts.

Microtubules form important cytoskeletal structures that play a role in establishing and maintaining neuronal polarity, regulating neuronal morphology, transporting cargo, and scaffolding signaling molecules to form signaling hubs. Within a neuronal cell, microtubules are found to have variable lengths and can be both stable and dynamic. Microtubule associated proteins, post-translational modifications of tubulin subunits, microtubule severing enzymes, and signaling molecules are all known to influence both stable and dynamic pools of microtubules. Microtubule dynamics, the process of interconversion between stable and dynamic pools, and the proportions of these two pools have the potential to influence a wide variety of cellular processes. Reduced microtubule stability has been observed in several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and tauopathies like Progressive Supranuclear Palsy. Hyperstable microtubules, as seen in Hereditary Spastic Paraplegia (HSP), also lead to neurodegeneration. Therefore, the ratio of stable and dynamic microtubules is likely to be important for neuronal function and perturbation in microtubule dynamics might contribute to disease progression.

Developmental exposure to As, Cd, and Pb mixture diminishes skeletal growth and causes osteopenia at maturity via osteoblast and chondrocyte malfunctioning in female rats.

We studied the effect of metal mixture (MM), comprising As, Cd, and Pb, in developing female rat skeleton from gestation day 5 until postnatal day 60 (P-60). MM resulted in synergistic inhibition in viability and differentiation of osteoblasts in vitro, likely induced by reactive oxygen species. MM, administered at their most frequently occurring concentrations present in the groundwater of India, i.e., As: 0.38 ppm, Pb: 0.22 ppm, and Cd: 0.098 ppm or 10× of the ratio to developing rats, exhibited a synergistic decrease in ex vivo mineralization of bone marrow stromal (osteoprogenitor) cells. MM group showed a dose-dependent attenuation in weight and axial lengths and shortening of tibias at P-60. Furthermore, the growth plate was shortened, which was associated with shorter proliferative and hypertrophic zones, decreased parathyroid hormone-related protein and Indian hedgehog expression in the chondrocytes, reduced primary and secondary spongiosa, and hypomineralized osteoids-a major characteristic of osteomalacia. In addition, compared with the control, MM-treated rats were clearly osteopenic based on bone mineral density, microarchitecture, biomechanical strength, and particularly the biochemical profile, that suggested high turnover bone loss. Finally, in comparison to the control, the fracture-healing ability of MM group was delayed and accompanied by inferior quality of the healed bone. Together, these data demonstrated that the mixture of As, Cd, and Pb induced synergistic toxicity to developing skeleton, thereby diminishing modeling-directed bone accrual, inducing osteopenia and dampening fracture healing.