ProNAi Therapeutics (United States)

Abstract Objective: Preterm birth (PTB) is a leading cause of neonatal morbidity and mortality worldwide with India alone contributing nearly 27% of the global PTB burden. Although alterations in the vaginal microbiome have been implicated in PTB its association in the Indian context is underemployed. This study aimed to investigate the association of vaginal microbiome and PTB in Indian women at the time of delivery. Study design: The vaginal swabs were collected at the time of delivery from 72 women (31 term 41 preterm) admitted to a tertiary care hospital in Western India. Microbial DNA was extracted and the V3 V4 region of the 16S rRNA gene was sequenced. Community composition alpha and beta diversity and differential taxonomic abundance were assessed using bioinformatics pipelines. Results: At the time of delivery there were no significant differences in alpha or beta diversity between term and preterm groups. Principal coordinate and unsupervised clustering analyses showed no group wise segregation. The relative abundance of individual Lactobacillus species including L. iners and L. helveticus did not differ significantly between the two groups. However a modest difference in the relative abundance of Streptococcus was observed between the two groups after adjustment. Conclusion: This study found no major microbial shifts in the vaginal microbiome associated with preterm birth in this cross sectional cohort of Indian women suggesting that vaginal dysbiosis at the time of delivery may not be a principal driver of PTB in this population. These findings underscore the need for larger longitudinal and ethnically diverse studies using standardized methodologies better to understand the microbiomes role in PTB risk. Key Words: Prematurity Lactobacillus Streptococcus bacteria association

BackgroundLipid biology is profoundly disrupted in AD, as evidenced by abundant genetic studies highlighting the roles of lipid metabolism, endosomal/lysosomal trafficking, bioenergetics, and other cellular and molecular alterations. Despite these observations, there is currently no unified hypothesis to explain the etiology of AD that reconciles lipid disruption with neuronal loss.MethodUsing baseline measurements from ADNI plasma lipidomics and CSF proteomics, extensive reconciliation of the literature, and methods related to systems engineering and QSP, we built a model of brain homeostasis centered around feedback loops and mass balance. We then apply our model to several large multiomic datasets, including those in ADNI and GNPC for validation.ResultWe identified multiomic/proteomic evidence of two convergent feedback loops driving AD pathophysiology: 1) Saturated Microglial Flux Capacity: Microglia become overwhelmed by neuronal and myelin debris, leading to impaired processing. 2) Impaired ANLS Signaling: Elevated astrocyte membrane cholesterol disrupts ANLS, compromising neuronal metabolic support.ConclusionNeurodegeneration in AD is driven by the brain's failure to process excess cholesterol from neuronal debris, resulting in widespread lipidomic, metabolic, and proteomic disruptions. Disruptions in lipid homeostasis occur upstream of both amyloid and tau pathology, as excess cholesterol accumulation enhances APP translocation to γ‐secretase, accelerating amyloid production, while also impairing astrocytic metabolic support, leading to ATP deficits, elevated intracellular Ca²⁺, and aberrant tau phosphorylation. This breakdown in cholesterol homeostasis offers a comprehensive explanation for the observed multi‐omic alterations in AD, positioning lipid dysregulation as a primary driver of disease progression. Our unified hypothesis enables us to leverage large omics data to learn new biology, and identify and evaluate novel therapeutic targets for both the prevention and treatment of AD.

Noncoding variants increase neuropsychiatric disease risk, but our understanding of their cell-type-specific role remains incomplete. We conducted large-scale chromatin accessibility profiling of neurons and non-neurons from 2 neocortical regions in 1,393 libraries. We observed substantial differences in neuronal chromatin accessibility between schizophrenia (SCZ) cases and controls, with upregulated open chromatin regions (OCRs) in neurons associated with SCZ risk loci. A comparison of SCZ-associated OCRs with fetal brain-specific OCRs revealed a strong correlation between upregulated changes in SCZ chromatin and openness in fetal cortical brains, linking disease-related chromatin alterations to neurodevelopment. Here we show that a prominent neuronal trans-regulatory domain containing upregulated OCRs consolidates key neurodevelopmental chromatin signatures and is enriched for immature glutamatergic neurons. These findings link altered adult cortical chromatin states to early developmental mechanisms in SCZ. This study provides a comprehensive cell-type-resolved chromatin accessibility resource for the human cortex and offers insights into the regulatory architecture underlying SCZ risk.

Bipolar disorder is a complex psychiatric condition characterized by recurrent mood episodes and fluctuating symptom severity. Our study investigates post-diagnosis complexities using 17-year longitudinal data from the Prechter Bipolar Research Program. We analyzed mood trajectories of 525 bipolar I disorder (BP1) and 150 bipolar II disorder (BP2) patients, using the Linear Analysis Mixed Model Phenotyper (LAMP) to identify subgroups. This approach revealed shared and distinct patterns across individual trajectories, classifying these subgroups into meaningful longitudinal phenotypes. Regression modeling was then applied to identify associations between these phenotypes and relevant factors. We found that medication use and alcohol use disorder significantly impacted long-term mood trajectories. Polypharmacy was associated with resistant/worsening trajectories in both BP1 (PHQ-9: OR: 1.09, CI: 1.02-1.17) and BP2 (GAD-7: OR: 1.21, CI: 1.05-1.43), with each additional medication increasing the risk of a worse trajectory by 9% and 21%, respectively. In BP1, antidepressant use improved trajectories (PHQ-9: OR: 0.40, CI: 0.19-0.83), but when combined with antipsychotics, increasing use frequency from 0% to 20% raised the risk of resistant/worsening trajectories (OR: 2.09, CI: 1.33- 3.28). In BP2, antipsychotic use was associated with improved trajectories (PHQ-9: OR: 0.04, CI: 0.00-0.56). Alcohol use disorder in BP1 increased resistant/worsening risk by 83% (PHQ-9: OR: 1.83, CI: 1.15-2.93). Our results indicate that polypharmacy and alcohol use disorder contribute to resistant or worsening mood trajectories. In BP1, while antidepressants are beneficial, their combination with antipsychotics substantially increases risk, highlighting the need for individualized, diagnosis-specific treatment approaches. LAMP analysis pipeline aided in improving treatment approaches in bipolar disorder.17 years of PrBP data provided comprehensive analysis of long-term mood trajectories.Polypharmacy and alcohol use disorder worsened mood trajectory.The combination of antidepressants and antipsychotics worsened mood trajectory.

SPECIALTY GRAND CHALLENGE article Front. Syst. Biol., 06 March 2024Sec. Systems Concepts, Theory and Policy in Biology and Medicine Volume 4 - 2024 | https://doi.org/10.3389/fsysb.2024.1385458

203 Background: Cetuximab (CTX) and Panitumumab (PMB) therapies directed at EGFR have been restricted to left-sided CRC harboring wild-type KRAS ( KRASWT), limiting their utility. Approximately 50% of mCRC fail to respond to EGFRi, thus identification of predictive biomarkers is an unmet need. Here we evaluate a CTX sensitivity score (CTX-S) that we previously reported (Yang M. et al., 2019), in a large, real-world population of RAS/BRAF mutant vs wild-type and in right- vs left-sided tumors. Methods: CTX/PMB-treated CRC specimens (n=1124) with clinical outcomes, NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) were tested at Caris Life Sciences (Phoenix, AZ). 1097 specimens were MSS as determined by IHC of MMR proteins and/or NGS. Association of CTX-S with RAS/BRAF mutation and tumor sidedness was performed in MSS tumors. Tumors with likely pathogenic mutations in KRAS, NRAS or BRAF were considered as RASMUT /BRAFMUT, or RASWT /BRAFWT if no mutation was detected for each gene. Samples were stratified based on CTX-S quintiles. Survival on EGFRi was calculated from the initiation of EGFRi to last contact using Kaplan-Meir method. Results: Higher CTX-S quintiles were significantly associated with longer survival on EGFRi in RAS/BRAF wild-type as well as -mutant subpopulations. Similar results were seen in left- vs. right-sided tumors (Table). Higher CTX-S quintiles were associated with a survival benefit in all CMS classes but CMS2; however, the vast majority of CMS2 tumors (460/467) were among the top 3 CTX-S quintiles. As the median survival among the top 3 quintiles was ~2-fold higher than the bottom 2 quintiles, we used stratification by the 40th percentile for the genomic analysis. CTX-S >40th percentile was associated with an increased prevalence in APC (91 vs 47%) and TP53 (93 vs 76%) mutations and decreased prevalence in BRAF (6 vs 32%), SMAD4 (8 vs 19%), RNF43 (1 vs 12%) and ATM (2 vs 5%) mutations (all q<0.05). Conclusions: Our data suggest that CTX-S may predict longer survival on EGFRi, surprisingly independent of RAS/BRAF mutation status as well as tumor sidedness. Patients with high CTX-S had increased prevalence of CMS2 and harbored more APC and TP53 mutations. A strong EGFRi biomarker would likely expand the utility of EGFRi to right-sided tumors and possibly to RASMUT tumors. Further validation of these biomarkers in a prospective clinical trial is warranted and could change our current standard of care for CRC.[Table: see text]

Fibromyalgia (FM) is a highly prevalent chronic disease. About 4.7% of the world's population suffers from generalized pain and hypersensitivity, in addition to a wide range of physical and psychological symptoms. The etiopathogenesis of this disease is multifactorial, which makes its diagnosis and treatment challenging. Recently, the increase in the number of studies on microbiota has provided new data that can help to understand the onset and development of FM. An updated systematic review of the causes of FM has been carried out in this work. Particularly in the last decade, research has focused on the gut-brain axis, which has emerged as a crucial mechanism for microbiota-host crosstalk. In FM patients, quantitative imbalances of the intestinal microbiota (dysbiosis) and bacterial metabolites with differential relative abundance have been found, especially short-chain fatty acids and lipopolysaccharides. Furthermore, the microbiota has been found to indirectly influence host neurotransmitter mechanisms, mainly through the serotonin precursor, glutamate, and gamma-aminobutyric acid. Thus, all these mechanisms and their influence on the etiopathogenesis of FM are discussed in this review.

<b/> It has generally been assumed that MEK mutants function similarly to one another and respond in the same manner to targeted drugs. Gao and colleagues challenge this assumption and report that MEK1 mutants fall into three unique phenotypic classes with respect to RAF dependency. A new class of MEK1 mutants is shown here to be RAF-independent, resistant to allosteric MEK inhibitors, and yet sensitive to treatment with a new ATP-competitive MEK inhibitor. Cancer Discov; 8(5); 534-6. ©2018 AACRSee related article by Gao et al., p. 648.

PurposeIn order to attenuate the drug release rate, a single freeze-thaw step was previously shown to convert encapsulated drug into a single nanocrystal within each liposome vesicle. The goal of this study was to alter the nanocrystalline character, and thus the drug encapsulation state and release profile, by addition of surfactant prior to freeze-thaw.MethodsA liposomal ciprofloxacin (CFI) formulation was modified by the addition of surfactant and frozen. After thawing, these formulations were characterized in terms of drug encapsulation by centrifugation-filtration, liposome structure by cryo-TEM imaging, vesicle size by dynamic light scattering, and in vitro release (IVR) performance.ResultsThe addition of increasing levels of polysorbate 20 (0.05 to 0.4%) or Brij 30 (0.05 to 0.3%) to the CFI preparations followed by subsequent freeze-thaw, resulted in a greater proportion of vesicles without drug nanocrystals and reduced the extent of growth of the nanocrystals thus leading to modified release rates including an increase in the ratio of non-encapsulated to sustained release of drug.ConclusionsThis study provides another lever to achieve the desired release rate profile from a liposomal formulation by addition of surfactant and subsequent freeze-thaw, and thus may provide a personalized approach to treating patients.