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BioRxiv : the Preprint Server For... Jun 2024Precision genetic medicine enlists antisense oligonucleotides (ASOs) to bind to nucleic acid targets important for human disease. Peptide nucleic acids (PNAs) have many...
Precision genetic medicine enlists antisense oligonucleotides (ASOs) to bind to nucleic acid targets important for human disease. Peptide nucleic acids (PNAs) have many desirable attributes as ASOs but lack cellular permeability. Here, we use an assay based on the corrective splicing of an mRNA to assess the ability of synthetic peptides to deliver a functional PNA into a human cell. We find that the endosomolytic peptides L17E and L17ER are highly efficacious delivery vehicles. Co-treatment of a PNA with low micromolar L17E or L17ER enables robust corrective splicing in nearly all treated cells. Peptide-PNA conjugates are even more effective. These results enhance the utility of PNAs as research tools and potential therapeutic agents.
PubMed: 38948866
DOI: 10.1101/2024.06.18.599558 -
BioRxiv : the Preprint Server For... Jun 2024About one-third of all human cancers encode abnormal RAS proteins locked in a constitutively activated state to drive malignant transformation and uncontrolled tumor...
About one-third of all human cancers encode abnormal RAS proteins locked in a constitutively activated state to drive malignant transformation and uncontrolled tumor growth. Despite progress in development of small molecules for treatment of mutant KRAS cancers, there is a need for a pan-RAS inhibitor that is effective against all RAS isoforms and variants and that avoids drug resistance. We have previously shown that the naturally occurring bacterial enzyme RAS/RAP1-specific endopeptidase (RRSP) is a potent RAS degrader that can be re-engineered as a biologic therapy to induce regression of colorectal, breast, and pancreatic tumors. Here, we have developed a strategy for in vivo expression of this RAS degrader via mRNA delivery using a synthetic nonviral gene delivery platform composed of the poly(ethylene glycol)--poly(propylene sulfide) (PEG--PPS) block copolymer conjugated to a dendritic cationic peptide (PPDP2). Using this strategy, PPDP2 is shown to deliver mRNA to both human and mouse pancreatic cells resulting in RRSP gene expression, activity, and loss of cell proliferation. Further, pancreatic tumors are reduced with residual tumors lacking detectable RAS and phosphorylated ERK. These data support that mRNA-loaded synthetic nanocarrier delivery of a RAS degrader can interrupt the RAS signaling system within pancreatic cancer cells while avoiding side effects during therapy.
PubMed: 38948803
DOI: 10.1101/2024.06.11.598439 -
BioRxiv : the Preprint Server For... Jun 2024Early diagnosis and biomarker discovery to bolster the therapeutic pipeline for Parkinson's disease (PD) are urgently needed. In this study, we leverage the large-scale...
UNLABELLED
Early diagnosis and biomarker discovery to bolster the therapeutic pipeline for Parkinson's disease (PD) are urgently needed. In this study, we leverage the large-scale whole-blood total RNA-seq dataset from the Accelerating Medicine Partnership in Parkinson's Disease (AMP PD) program to identify PD-associated RNAs, including both known genes and novel circular RNAs (circRNA) and enhancer RNAs (eRNAs). There were 1,111 significant marker RNAs, including 491 genes, 599 eRNAs, and 21 circRNAs, that were first discovered in the PPMI cohort (FDR < 0.05) and confirmed in the PDBP/BioFIND cohorts (nominal < 0.05). Functional enrichment analysis showed that the PD-associated genes are involved in neutrophil activation and degranulation, as well as the TNF-alpha signaling pathway. We further compare the PD-associated genes in blood with those in post-mortem brain dopamine neurons in our BRAINcode cohort. 44 genes show significant changes with the same direction in both PD brain neurons and PD blood, including neuroinflammation-associated genes , , and . Finally, we built a novel multi-omics machine learning model to predict PD diagnosis with high performance (AUC = 0.89), which was superior to previous studies and might aid the decision-making for PD diagnosis in clinical practice. In summary, this study delineates a wide spectrum of the known and novel RNAs linked to PD and are detectable in circulating blood cells in a harmonized, large-scale dataset. It provides a generally useful computational framework for further biomarker development and early disease prediction.
SIGNIFICANCE STATEMENT
Early and accurate diagnosis of Parkinson's disease (PD) is urgently needed. However, biomarkers for early detection of PD are still lacking. Also, the limit of sample size remains one of the main pitfalls of current PD biomarker studies. We employed an analysis of large-scale whole-blood RNA-seq data. By identifying 1,111 significant marker RNAs, we establish a robust foundation for early PD detection, which implicated in neutrophil activation, degranulation, and TNF-alpha signaling, offer unprecedented insights into PD pathogenesis. Our multi-omics machine learning model, boasting an AUC of 0.89, outperforms previous studies, promising a transformative tool for precise PD diagnosis in clinical settings. This study marks a pivotal step toward enhanced biomarker development and early disease prediction.
PubMed: 38948706
DOI: 10.1101/2024.06.18.599639 -
EJC Paediatric Oncology Dec 2024An integral part of understanding and then designing programs to reduce childhood cancer inequities includes adequate representation of people with cancer in research,...
An integral part of understanding and then designing programs to reduce childhood cancer inequities includes adequate representation of people with cancer in research, including children. A scoping review was carried out to understand how cancer research is oriented toward inequities and to identify who has participated in childhood qualitative cancer research. A systematic search identified 119 qualitative studies that met inclusion criteria, with most studies taking place in high-income countries (n=84). Overall, data were lacking on social determinants of health at multiple levels-structural, household, child, and guardian. Only 29 studies reported on race and/or ethnicity, with the majority of those including predominantly or all white children. Six articles included socioeconomic information, and across most articles, attention was absent to the financial ramifications of cancer care. Limited reporting of sociodemographics highlights a broader issue of neglecting key demographics and social factors that contribute to inequities.
PubMed: 38948690
DOI: 10.1016/j.ejcped.2024.100171 -
Postepy Psychiatrii Neurologii Mar 2024Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy, with paresthesias and pain in the hand and wrist. CTS is also associated with insomnia and...
Validation of the Polish version of the Boston Carpal Tunnel Questionnaire, and the influence of treatment for disordered sleep and daytime sleepiness in carpal tunnel syndrome.
PURPOSE
Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy, with paresthesias and pain in the hand and wrist. CTS is also associated with insomnia and excessive daytime sleepiness (EDS) resulting from the nocturnal exacerbation of symptoms. The Boston Carpal Tunnel Questionnaire (BCTQ) was developed for the assessment of therapeutic outcomes. It consists of two subscales: the Symptom Severity Scale (SSS) and the Functional Status Scale (FSS). The aim of this study was to perform an adaptation and validation of the Polish language version of BCTQ (pBCTQ). A second aim was to investigate the influence of treatment of CTS on insomnia and EDS.
METHODS
The validation of the pBCTQ followed the widely accepted recommendations. In our consecutive sampling survey 130 patients with CTS filled out the pBCTQ, EQ-5D-5L quality of life questionnaire, the Athens Insomnia Scale (AIS) and the Epworth Sleepiness Scale (ESS). 26 of them filled out pBCTQ once again, two weeks later, and 35 filled out the pBCTQ and other items after therapy.
RESULTS
The pBCTQ showed good internal consistency: 0.91 for SSS and 0.93 for FSS (Cronbach's α). The test-retest reliability showed an intraclass coefficient of 0.69 for SSS and 0.55 for FSS. Both subscales correlated also with nerve conduction studies (NCS) as well as with the EQ-5D-5L, AIS, and ESS. After therapy, both subscales and AIS significantly decreased. Improvement was also seen in the NCS and EQ-5D-5L, but not in the ESS.
CONCLUSIONS
The pBCTQ is a reliable, valid, and responsive tool for measuring the outcome of CTS. Therapy for CTS leads to the improvement of concurrent insomnia but may not change daytime sleepiness.
PubMed: 38948689
DOI: 10.5114/ppn.2024.136429 -
Postepy Psychiatrii Neurologii Mar 2024Tolosa-Hunt syndrome (THS) is a rare cause of painful ophtalmoplegia with different clinical manifestations. It is described as a unilateral periorbital headache with...
PURPOSE
Tolosa-Hunt syndrome (THS) is a rare cause of painful ophtalmoplegia with different clinical manifestations. It is described as a unilateral periorbital headache with concomitant dysfunction of at least one out of the IIIrd, IVth and VIth cranial nerves due to the granulomatous inflammation of periorbital structures, but no underlying cause has been established.
CASE DESCRIPTION
We present six patients referred to the Neurology Department due to a unilateral headache with ipsilateral paresis of at least one cranial nerve responsible for eye movements. The THS diagnostic criteria of the International Headache Disorders Classification (ICHD-3) were applied and analysed. Few patients had atypical clinical manifestations according to these criteria.
COMMENT
Diagnosing THS may prove very challenging. There is a lack of specific markers for the disorder, whereas diagnostic criteria leave a wide area for misdiagnosis. The diagnostic approach should be focused on the exclusion of other pathologies because typical steroid therapy may prove fatal in otherwise benign cases.
PubMed: 38948688
DOI: 10.5114/ppn.2023.135176 -
Frontiers in Veterinary Science 2024This study investigated the description and feasibility of a surgical procedure for enucleation-exenteration of the equine eye via the supraorbital fossa. A preliminary...
This study investigated the description and feasibility of a surgical procedure for enucleation-exenteration of the equine eye via the supraorbital fossa. A preliminary study was performed on both eyes of four cadaveric heads of native breed donkeys () to describe the surgical anatomy and demonstrate a new supraorbital enucleation surgical approach. For the clinical study, eight donkeys were admitted for unilateral enucleation. All procedures were performed in a lateral recumbent position under the influence of inhalation anesthesia in combination with a retrobulbar nerve block. A semi-circular incision was made in the skin and fascia of the supraorbital fossa to gain access into the orbital cavity, after which the periorbital fat was dissected and removed. Bleeding was controlled by electrocautery and large blood vessels were ligated, then the eyeball was dissected sharply and freed from its bony attachment. The procedure was successfully accomplished in all clinical cases, and no significant complications occurred during or throughout the postoperative follow-up period. The initial results suggest the feasibility and safety of the supraorbital enucleation technique described in this study for equine eye enucleation. This new technique seems promising due to its feasibility, safety, and positive outcomes observed in both cadaveric and clinical studies.
PubMed: 38948677
DOI: 10.3389/fvets.2024.1379151 -
Frontiers in Veterinary Science 2024(), also known as group B (GBS), is a highly infectious pathogen. Prolonged antibiotic usage leads to significant issues of antibiotic residue and resistance....
(), also known as group B (GBS), is a highly infectious pathogen. Prolonged antibiotic usage leads to significant issues of antibiotic residue and resistance. Chelerythrine (CHE) is a naturally occurring benzophenidine alkaloid and chelerythrine chloride (CHEC) is its hydrochloride form with diverse biological and pharmacological activities. However, the antibacterial mechanism of CHEC against GBS remains unclear. Thus, this study aims to investigate the antibacterial activity of CHEC on GBS and elucidate its underlying mechanism. The antibacterial effect of CHEC on GBS was assessed using inhibitory zone, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC) assays, as well as by constructing a time-kill curve. The antibacterial mechanism of CHEC was investigated through techniques such as scanning electron microscopy (SEM) and transmission electron microscopy (TEM), measurement of alkaline phosphatase (AKP) activity, determination of Na K, Ca Mg-adenosine triphosphate (ATP) activity, observation of membrane permeability, and analysis of intracellular reactive oxygen species (ROS) and mRNA expression levels of key virulence genes. The results demonstrated that the inhibition zone diameters of CHEC against GBS were 14.32 mm, 12.67 mm, and 10.76 mm at concentrations of 2 mg/mL, 1 mg/mL, and 0.5 mg/mL, respectively. The MIC and MBC values were determined as 256 μg/mL and 512 μg/mL correspondingly. In the time-kill curve, 8 × MIC, 4 × MIC and 2 × MIC CHEC could completely kill GBS within 24 h. SEM and TEM analyses revealed significant morphological alterations in GBS cells treated with CHEC including shrinkage, collapse, and leakage of cellular fluids. Furthermore, the antibacterial mechanism underlying CHEC's efficacy against GBS was attributed to its disruption of cell wall integrity as well as membrane permeability resulting in extracellular release of intracellular ATP, AKP, Na K, Ca Mg. Additionally CHEC could increase the ROS production leading to oxidative damage and downregulating mRNA expression levels of key virulence genes in GBS cells. In conclusion, CHEC holds potential as an antimicrobial agent against GBS and further investigations are necessary to elucidate additional molecular mechanisms.
PubMed: 38948675
DOI: 10.3389/fvets.2024.1408376 -
Frontiers in Veterinary Science 2024
PubMed: 38948673
DOI: 10.3389/fvets.2024.1440527 -
Frontiers in Veterinary Science 2024Feline chronic gingivostomatitis (FCGS) is an ulcerative and/or proliferative disease that typically affects the palatoglossal folds. Because of its unknown pathogenesis...
Feline chronic gingivostomatitis (FCGS) is an ulcerative and/or proliferative disease that typically affects the palatoglossal folds. Because of its unknown pathogenesis and long disease course, it is difficult to treat and has a high recurrence rate. Most of the bacteria in the oral microbiota exist in the mouth symbiotically and maintain a dynamic balance, and when the balance is disrupted, they may cause disease. Disturbance of the oral microbiota may play an important role in the development of FCGS. In this study, the medical records of 3109 cats in three general pet hospitals in Xi 'an were collected. Sixty-one cats with FCGS were investigated via questionnaires, routine oral examinations and laboratory examinations. Oral microbiota samples were collected from 16 FCGS-affected cats, and microbial species were identified by 16S rDNA sequencing. The results showed that the incidence of FCGS had no significant correlation with age, sex or breed. However, the incidence of FCGS was associated with immunization, a history of homelessness and multicat rearing environments. The number of neutrophils and the serum amyloid A concentration were increased, and the percentage of cells positive for calicivirus antigen was high in all cases. All the cats had different degrees of dental calculus, and there were problems such as loss of alveolar bone or tooth resorption. Compared with those in healthy cats, the bacterial diversity and the abundance of anaerobic bacteria were significantly increased in cats with FCGS. , and were abundant in the mouths of the affected cats and may be potential pathogens of FCGS. After tooth extraction, a shift could be seen in the composition of the oral microbiota in cats with FCGS. An isolated bacteria obtained from the mouths of the affected cats was homologous to . Both the identified oral microbiota and the isolated strain of the cats with FCGS had high sensitivity to enrofloxacin and low sensitivity to metronidazole. This study provides support to current clinical criteria in diagnosing FCGS and proposes a more suitable antibiotic therapy.
PubMed: 38948672
DOI: 10.3389/fvets.2024.1418101